A Post Approval Commitment Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of KOVALTRY in Chinese Children, Adolescents /Adults With Severe Hemophilia A
Phase: PHASE4
Conditions: Hemophilia A
Sponsor: Bayer

 
Document Type: 
Study Protocol 
Official Title: 
A Post Approval Commitment study to evaluate the efficacy, 
safety, and pharmacokinetics of KOVALTRY in Chinese children, 
adolescents /adults with severe hemophilia A 
NCT Number: 
NCT04565236 
Document Date: 
12-MAY-2023 
 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  1 of 105 
 
Title Page 
Protocol Title: 
A Post Approval Commitment study to evaluate the efficacy, safety, 
and pharmacokinetics of KOVALTRY in Chinese children, 
adolescents/adults with severe hemophilia A. 
Protocol Number: 
 
19855 
Amendment Number: 
Amendment 2 
Protocol Version:  
 
4.0 
Compound Number: 
KOVALTRY (No. BAY 81-8973) 
Study Phase:  
 
Phase IV 
Short Title: KOVALTRY Efficacy, Safety, and PK Study in Chinese hemophilia A patients. 
Sponsor Name: 
 
Bayer Healthcare Company Limited 
Legal Registered Address: No.7 Rong Jing East Street BDA, Beijing, China 
Regulatory Agency Identifier Number(s):  
 
CHINA IDL (Imported Drug License) Number: 
 
(corresponding strength for 250IU, 500IU & 1000 IU) 
Protocol Amendment Date:  12 MAY 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. 
Study Medical Expert name and contact information can be found in the Trial Master File 
(TMF). 
 
 
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. 
 
 
CCI
PPD
PPD
PPD

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page: 2 of 105 
 
Document History Table 
DOCUMENT HISTORY 
Document 
Version 
Date 
Comments (if applicable) 
Amendment 2 (Global) 
4.0 
12 MAY 2023 
Version 3.0 (dated 12 OCT 
2022) was obsoleted. 
Amendment 1 (Global) 
2.0 
22 OCT 2020 
 
Original Protocol 
1.0 
29 JAN 2020 
 
Amendment 2 (12 MAY 2023) 
Overall Rationale for the Amendment: 
Protocol Amendment Summary of Changes Table 
Section Number and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
Section 1.3.2 Part B (PUPs/MTPs) 
SoA 
Section 4.1 Overall Design 
Section 5.1.2 Part B (PUPs/MTPs) 
Inclusion Criteria 
Section 6.8.3 Participant 
Discontinuation/Withdrawal from 
the Study 
Section 7.2.2 Visit 2/Baseline (No 
Later Than 4 Weeks From Visit 1) 
Section 7.3.2 Incremental Recovery 
of KOVALTRY 
Section 8 Safety Assessments 
Section 8.10.2 Part B (PUPs/MTPs) 
Immunogenicity Assessments 
Section 10.2 Appendix 2: Clinical 
Laboratory Tests 
Section 10.5.2 Optional ITI 
Treatment - Schedule of Activities 
Change all the assays planned in 
central lab to local lab for Part B. 
According to the approved 
KOVALTRY label, FVIII levels 
can be measured in plasma with 
a one stage coagulation assay as 
well as with a chromogenic 
assay using the routine methods 
of the local laboratory. In 
addition, it will shorten the 
turnover time of lab report. 
Section 1.1 Synopsis 
Section 1.3.2 Part B (PUPs/MTPs) 
SoA 
Section 4.1.2 Part B (PUPs/MTPs) 
Section 7.2 Study Visits - Part B 
(PUPs/MTPs) 
Section 7.2.2 Visit 2/Baseline (No 
Later Than 4 Weeks From Visit 1) 
Romove the Combined Screening 
and Baseline (PUPs only) in Part 
B. 
Combined Visit in Part B was 
designed for PUPs to avoid 
unnecessarily prolonged 
screening period due to 5-7 days 
turnover from central lab. Since 
local lab will be adopted, PUPs 
can be randomized shortly after 
Visit 1. 
Section 1.3.2 Part B (PUPs/MTPs) 
SoA 
Section 7.2.2 Visit 2/Baseline (No 
Later Than 4 Weeks From Visit 1) 
Remove FVIII trough level 
assessment from Visit 2 in Part B. 
For PUPs, retesting of FVIII 
trough level in Visit 2 is not 
necessary becasuse it will be 
evaluated and documented in 
Visit 1 which is just shortly 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page: 3 of 105 
 
before Visit 2. For MTPs with 
longer screening period, the 
FVIII trough level has already 
been included in recovery 
evaluation after randomization. 
Section 7.3.2 Incremental Recovery 
of KOVALTRY 
 
The chromogenic assay was 
changed to one-stage clotting 
assay in all plasma concentrations 
of FVIII measurement for Part B. 
The chromogenic assay is not 
available in local lab and the 
FVIII:C of KOVALTRY can be 
measured in plasma with a 
one-stage coagulation assay as 
well as with a chromogenic 
assay using the routine methods 
of the laboratory. 
Section 10.2 Appendix 2: Clinical 
Laboratory Tests 
 
To indicate that a separate page 
for local laboratory results will be 
provided in eCRF for Part B. 
A separate page for local 
laboratory results capturing for 
Part B should be provided in 
eCRF since all the assays 
planned in central lab will be 
changed to local lab. 
Section 1.2 Schema 
Change captions for Figure 1.2-1 
and Figure 1.2-2 to Figure 1-1 
and Figure 1-2. 
Technical update. 
In addition, editorial and administrative changes have been made throughout the document. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page: 4 of 105 
 
Table of Contents 
Title Page ............................................................................................................................... 1 
Document History Table ...................................................................................................... 2 
Table of Tables ..................................................................................................................... 7 
Table of Figures .................................................................................................................... 7 
1. 
Protocol Summary ........................................................................................................ 8 
1.1 
Synopsis ....................................................................................................................... 8 
1.2 
Schema ....................................................................................................................... 12 
1.3 
Schedule of Activities (SoA) ..................................................................................... 15 
1.3.1 
Part A (PTPs) SoA .................................................................................................. 15 
1.3.2 
Part B (PUPs/MTPs) SoA ...................................................................................... 17 
2. 
Introduction ................................................................................................................. 19 
2.1 
Study Rationale .......................................................................................................... 19 
2.2 
Background ................................................................................................................ 20 
2.3 
Benefit/Risk Assessment ........................................................................................... 20 
2.3.1 
Risk Assessment ..................................................................................................... 21 
2.3.2 
Benefit Assessment ................................................................................................ 22 
2.3.3 
Overall Benefit: Risk Conclusion ........................................................................... 22 
3. 
Objectives and Endpoints ........................................................................................... 23 
3.1 
Objectives and Endpoints - Part A (PTPs) ................................................................. 23 
3.2 
Objectives and Endpoints - Part B (PUPs/MTPs) ..................................................... 24 
4. 
Study Design ................................................................................................................ 25 
4.1 
Overall Design ........................................................................................................... 25 
4.1.1 
Part A (PTPs) .......................................................................................................... 25 
4.1.2 
Part B (PUPs/MTPs) ............................................................................................... 25 
4.2 
Scientific Rationale for Study Design ....................................................................... 26 
4.2.1 
Participant Input into Design .................................................................................. 26 
4.3 
Justification for Dose ................................................................................................. 26 
4.3.1 
Routine Prophylaxis ............................................................................................... 26 
4.3.1.1 
Prophylaxis Treatment for Adolescent and Adult Patients ................................. 26 
4.3.1.2 
Pediatric Patients ................................................................................................. 27 
4.3.2 
Treatment of Bleeding Episodes............................................................................. 27 
4.4 
End of Study Definition ............................................................................................. 27 
5. 
Study Population ......................................................................................................... 28 
5.1 
Inclusion Criteria ....................................................................................................... 28 
5.1.1 
Part A (PTPs) Inclusion Criteria ............................................................................. 28 
5.1.2 
Part B (PUPs/MTPs) Inclusion Criteria ................................................................. 29 
5.2 
Exclusion Criteria ...................................................................................................... 30 
5.2.1 
Part A (PTPs) Exclusion Criteria............................................................................ 30 
5.2.2 
Part B (PUPs/MTPs) Exclusion Criteria ................................................................ 31 
5.3 
Lifestyle Considerations ............................................................................................ 32 
5.3.1 
Meals and Dietary Restrictions .............................................................................. 32 
5.3.2 
Caffeine, Alcohol, and Tobacco ............................................................................. 32 
5.3.3 
Concomitant Medications ....................................................................................... 32 
5.4 
Screen Failures ........................................................................................................... 32 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page: 5 of 105 
 
6. 
Study Intervention ...................................................................................................... 33 
6.1 
Study Intervention Administered ............................................................................... 33 
6.2 
Preparation/Handling/Storage/Accountability ........................................................... 34 
6.3 
Measures to Minimize Bias: Randomization and Blinding ....................................... 35 
6.4 
Study Intervention Compliance ................................................................................. 35 
6.5 
Concomitant Therapy ................................................................................................ 36 
6.5.1 
Rescue Medicine..................................................................................................... 37 
6.6 
Dose Modification ..................................................................................................... 37 
6.6.1 
Dose Modification in Part A (PTPs) ...................................................................... 37 
6.6.2 
Dose Modification in Part B (PUPs/MTPs) ........................................................... 37 
6.6.3 
Breakthrough Bleeds and Minor Surgery ............................................................... 38 
6.7 
Intervention After the End of the Study ..................................................................... 38 
6.8 
Discontinuation of Study Intervention and Participant Discontinuation/Withdrawal
 ................................................................................................................................... 38 
6.8.1 
Discontinuation of Study Intervention ................................................................... 38 
6.8.2 
Temporary Discontinuation of Study Intervention ................................................. 38 
6.8.3 
Participant Discontinuation/Withdrawal from the Study ....................................... 39 
6.9 
Lost to Follow-Up ...................................................................................................... 40 
7. 
Study Assessments and Procedures ........................................................................... 41 
7.1 
Study Visits - Part A (PTPs) ...................................................................................... 41 
7.1.1 
Screening/Visit 1 (Up to 6 Weeks Prior to Baseline) ............................................. 41 
7.1.2 
Baseline/Visit 2 (No Later Than 6 Weeks From Visit 1) ....................................... 42 
7.1.3 
Visit 3/Month 1 (±7 Days)...................................................................................... 43 
7.1.4 
Visit 4/Month 2 (±7 Days)...................................................................................... 44 
7.1.5 
Visit 5/Month 6 (±7 Days)/Final Visit/Early Termination ..................................... 44 
7.1.6 
Follow-Up Call (+2 Weeks ±7 Days After the Final Visit) ................................... 45 
7.2 
Study Visits - Part B (PUPs/MTPs) ........................................................................... 45 
7.2.1 
Visit 1/Screening .................................................................................................... 45 
7.2.2 
Visit 2/Baseline (No Later Than 4 Weeks From Visit 1) ....................................... 46 
7.2.3 
Visit 3/ED ~5 (4 ED ±1) ......................................................................................... 47 
7.2.4 
Visit 4/ED ~10 (9 ED ±1) ....................................................................................... 48 
7.2.5 
Visit 5/ED ~15 (14 ED ±1) ..................................................................................... 48 
7.2.6 
Visit 6/ED 20 (20 ED ±1) ....................................................................................... 48 
7.2.7 
Visit 7/Interim Visit/30 to 40 ED ........................................................................... 49 
7.2.8 
Final Visit/50 ED (+7 Days)/Early Termination .................................................... 49 
7.2.9 
Follow-Up Call (2 Weeks ±7 Days After the Final Visit) ...................................... 50 
7.3 
Efficacy Assessments ................................................................................................ 50 
7.3.1 
Treatment Logs/Bleeding Verification ................................................................... 51 
7.3.2 
Incremental Recovery of KOVALTRY ................................................................. 53 
8. 
Safety Assessments ...................................................................................................... 53 
8.1 
Physical Examination ................................................................................................ 53 
8.2 
Vital Signs .................................................................................................................. 54 
8.3 
Clinical Safety Laboratory Assessments ................................................................... 54 
8.4 
Adverse Events and Serious Adverse Events ............................................................ 54 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information................... 55 
8.4.2 
Method of Detecting AEs and SAEs ...................................................................... 55 
8.4.3 
Follow-up of AEs and SAEs .................................................................................. 55 
8.4.4 
Regulatory Reporting Requirements for SAEs ...................................................... 55 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page: 6 of 105 
 
8.4.5 
Pregnancy ............................................................................................................... 56 
8.4.6 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs ................................................................................................................... 56 
8.4.7 
Adverse Events of Special Interest (AESI) ............................................................ 57 
8.5 
Treatment of Overdose .............................................................................................. 57 
8.6 
Pharmacokinetics ....................................................................................................... 57 
8.7 
Pharmacodynamics .................................................................................................... 58 
8.8 
Genetics ..................................................................................................................... 58 
8.9 
Biomarkers ................................................................................................................. 58 
8.10 Immunogenicity Assessments .................................................................................... 58 
8.10.1 Part A (PTPs) Immunogenicity Assessments ......................................................... 58 
8.10.2 Part B (PUPs/MTPs) Immunogenicity Assessments .............................................. 58 
8.11 Health Economics ...................................................................................................... 58 
9. 
Statistical Considerations ........................................................................................... 59 
9.1 
Statistical Hypotheses ................................................................................................ 59 
9.2 
Sample Size Determination ....................................................................................... 59 
9.2.1 
Sample Size Determination in Part A (PTPs) ......................................................... 59 
9.2.2 
Sample Size Determination in Part B (PUPs/MTPs) ............................................. 59 
9.3 
Populations for Analyses ........................................................................................... 60 
9.4 
Statistical Analyses .................................................................................................... 60 
9.4.1 
General Considerations........................................................................................... 60 
9.4.2 
Primary Endpoint(s) ............................................................................................... 61 
9.4.3 
Secondary Endpoint(s) ........................................................................................... 62 
9.4.4 
Safety Analyse(s) .................................................................................................... 62 
9.4.5 
Pharmacokinetic Analyses ...................................................................................... 63 
9.5 
Interim Analyses ........................................................................................................ 63 
9.6 
Data Monitoring Committee (DMC) ......................................................................... 63 
10. Supporting Documentation and Operational Considerations ................................ 64 
10.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations .................... 64 
10.1.1 Regulatory and Ethical Considerations .................................................................. 64 
10.1.2 Informed Consent Process ...................................................................................... 64 
10.1.3 Data Protection ....................................................................................................... 65 
10.1.4 Committees Structure ............................................................................................. 65 
10.1.5 Dissemination of Clinical Study Data .................................................................... 65 
10.1.6 Data Quality Assurance .......................................................................................... 66 
10.1.7 Source Documents .................................................................................................. 66 
10.1.8 Study and Site Start and Closure ............................................................................ 67 
10.1.9 Financial Disclosure ............................................................................................... 67 
10.1.10 Publication Policy ................................................................................................... 67 
10.2 Appendix 2: Clinical Laboratory Tests ...................................................................... 68 
10.3 Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting .......................................................................................... 70 
10.3.1 Definition of AE ..................................................................................................... 70 
10.3.2 Definition of SAE ................................................................................................... 71 
10.3.3 Recording and Follow-Up of AE and/or SAE ........................................................ 72 
10.3.4 Reporting of SAEs .................................................................................................. 74 
10.4 Appendix 4: A Guide for Dosing for Bleeding and Surgery ..................................... 76 
10.5 Appendix 5: Optional Immune Tolerance Induction Treatment................................ 78 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page: 7 of 105 
 
10.5.1 Optional ITI Treatment for Participants who Develop High-Titer Inhibitors During 
the Study ................................................................................................................. 78 
10.5.2 Optional ITI Treatment - Schedule of Activities .................................................... 79 
10.5.3 Chinese Hemophilia Society Guideline for ITI ...................................................... 80 
10.6 Appendix 6: Abbreviations ........................................................................................ 81 
10.7 Appendix 7: Protocol Amendment History ............................................................... 82 
10.7.1 Amendment 2 ......................................................................................................... 82 
10.7.2 Amendment 1 ......................................................................................................... 82 
11. References .................................................................................................................... 84 
12. Attachments – Package Insert for China .................................................................. 86 
 
 
Table of Tables 
Table 6–1: Study Intervention by Arm and Dose .................................................................... 33 
Table 9–1: Analysis Populations .............................................................................................. 60 
Table 10–1: Recommended Blood Draw Volume ................................................................... 68 
Table 10–2: Protocol-Required Safety Laboratory Assessments ............................................. 69 
Table 10–3: Dosing for Control of Bleeding Episodes ............................................................ 76 
Table 10–4: Dosing for Perioperative Management ................................................................ 76 
Table 10–5: Definition of Adequacy of Hemostasis for Surgical Procedures ......................... 77 
 
 
Table of Figures 
Figure 1–1: Part A (PTPs) Study Schema ................................................................................ 13 
Figure 1–2: Part B (PUPs/MTPs) Study Schema ..................................................................... 14 
 
 
 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page: 8 of 105 
 
1. 
Protocol Summary 
1.1 
Synopsis 
Protocol Title: 
A Post-Approval Commitment (PAC) study to evaluate the efficacy, 
safety, and pharmacokinetics of KOVALTRY in Chinese children, 
adolescents/adults with severe hemophilia A. 
Short Title: 
KOVALTRY Efficacy, Safety, and PK Study in Chinese hemophilia A 
patients. 
Rationale: 
This study is being done to fulfill a post-approval commitment for 
KOVALTRY received from the China Center for Drug Evaluation 
(CDE) and China National Medical Products Administration (NMPA). 
The marketing authorization of KOVALTRY in China is based on 
demonstrated safety and efficacy of KOVALTRY in completed studies 
in previously treated severe hemophilia A patients (PTPs), which 
included 29 adult Chinese PTPs. China CDE and NMPA requested 
additional efficacy, safety, and PK data for KOVALTRY in previously 
treated Chinese hemophilia A patients as well as previously untreated 
patients (PUPs). The design, objectives, and endpoints for this study 
were developed in consultation with China CDE. As agreed with CDE, 
Part A of this planned study will obtain additional efficacy, safety, and 
pharmacokinetic data for KOVALTRY in Chinese PTPs (children 
(<12 years of age) and also adult/adolescents (≥12 years of age)) with 
severe hemophilia A. Additionally, as per consultation with CDE, 
Part B of the study will obtain efficacy and safety data in previously 
untreated/minimally treated Chinese children (<6 years of age) with 
severe hemophilia A. The results (at least interim) from this Phase IV 
study will be submitted with the KOVALTRY licensure renewal 
application in China. 
Objectives and Endpoints: 
Part A: Efficacy, Safety, and Pharmacokinetics of KOVALTRY in PTPs  
(Children <12 Years of Age and Adolescents/Adults ≥12 Years of Age) 
Objectives 
Endpoints 
Primary 
 
Efficacy 
 
• 
Evaluate the efficacy of prophylaxis 
treatment with KOVALTRY in Chinese 
children (<12 years) and 
adolescents/adults (≥12 years) with severe 
hemophilia A 
• 
Annualized bleeding rate (ABR) 
Secondary 
 
Efficacy 
 
• 
Evaluate efficacy of KOVALTRY for 
treatment of bleeding episodes 
 
• 
Assess efficacy within 48 hours of 
previous prophylaxis infusion 
• 
Evaluate the in vivo recovery of 
KOVALTRY 
• 
Number of infusions needed to 
achieve hemostasis and response to 
treatment of bleeds 
• 
ABR within 48h of previous 
prophylaxis infusion 
• 
In vivo recovery of KOVALTRY at 
baseline, 2 months after start of 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page: 9 of 105 
 
 
• 
Hemostatic control for minor surgeries 
study treatment, and study end 
• 
Physician assessment of adequacy 
of hemostasis in minor surgery 
Safety 
 
• 
Assess the safety of KOVALTRY for 
prophylaxis and treatment of bleeding 
episodes in Chinese children (<12 years) 
and adolescents/adults (≥12 years) with 
severe hemophilia A 
• 
FVIII inhibitor development by the 
Nijmegen Bethesda assay 
• 
Treatment-emergent adverse events 
(TEAEs) 
Pharmacokinetics 
 
• 
Evaluate pharmacokinetics (PK) of 
KOVALTRY in Chinese children 
(<12 years) and adolescents/adults 
(≥12 years to 65 years) severe hemophilia 
A patients 
• 
PK parameters include Cmax, AUC, 
and t½ 
Part B: Efficacy and Safety of KOVALTRY in PUPs/MTPs (Children <6 Years of Age) 
Objectives 
Endpoints 
Primary 
 
Efficacy 
 
• 
Assess the efficacy of KOVALTRY within 
48 hours of previous prophylaxis infusion 
in previously untreated/minimally treated 
Chinese children (<6 years of age) with 
severe hemophilia A 
• 
ABR within 48 hours of previous 
prophylaxis infusion 
Secondary 
 
Efficacy 
 
• 
Evaluate the efficacy of prophylaxis 
treatment with KOVALTRY 
• 
Assess the efficacy of KOVALTRY for 
treatment of bleeding episodes 
 
• 
Evaluate the in vivo recovery of 
KOVALTRY 
• 
Hemostatic control for minor surgeries 
• 
ABR during the prophylaxis period 
 
• 
Number of infusions required to treat 
a bleed and response to treatment of 
bleeds 
• 
In vivo recovery of KOVALTRY at 
baseline and study end 
• 
Physician assessment of adequacy 
of hemostasis in minor surgery 
Safety 
 
• 
Assess the safety of KOVALTRY for 
prophylaxis and treatment of bleeding 
episodes in previously untreated/minimally 
treated Chinese children (<6 years of age) 
with severe hemophilia A 
• 
FVIII inhibitor development by the 
Nijmegen Bethesda assay 
• 
Treatment-emergent adverse events 
(TEAEs) 
The Sponsor expects the study to provide additional efficacy and safety results to support the 
results obtained from the completed clinical studies with KOVALTRY (LEOPOLD I, 
LEOPOLD II, and LEOPOLD Kids Part A) in previously treated severe hemophilia A 
patients. 
Additionally, the Sponsor expects efficacy and safety results in PUPs/MTPs to be in line with 
that known for the class of FVIII products in this patient population. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page: 10 of 105 
 
Overall Design: 
This is a multicenter, uncontrolled, open-label, single arm treatment, 2-part study. 
• Part A will assess efficacy, safety, and PK of KOVALTRY in previously treated 
Chinese children and adolescents/adults with severe hemophilia A (defined as 
FVIII:C <1% with one-stage clotting assay). 
• 6 months of prophylaxis treatment with KOVALTRY 
• PK assessments are planned in a subset of 12 children, <12 years and 
12 adolescents/adults, ≥12 years 
• Part B will assess efficacy and safety of KOVALTRY in previously 
untreated/minimally treated Chinese children with severe hemophilia A (defined as 
FVIII:C <1% with one-stage clotting assay). Participants will receive treatment 
with KOVALTRY until at least 50 exposure days (ED) is achieved. 
Disclosure Statement: This is an open-label treatment study in previously treated, minimally 
treated, and previously untreated Chinese children and adolescents/adults with severe 
hemophilia A. 
Intervention Model: Participants are in a single treatment arm for the duration of the study. 
Primary Purpose: Treatment 
Number of Treatment Groups: 
• Part A (PTPs): 1 treatment group with two arms based on age 
• Part B (PUPs/MTPs): 1 treatment group 
Blinding: No blinding. 
Number of Participants: 
• Part A of this study plans to enroll a total of 42 previously treated Chinese patients 
with severe hemophilia A (see Section 5), defined as FVIII:C <1% with one-stage 
clotting assay. 
• Children: 30 males with severe hemophilia A, <12 years with 
≥ 50 exposure days (ED) to any FVIII medication (excluding 
cryoprecipitate and fresh frozen plasma (FFP)), no history of inhibitors, and 
no other bleeding disorders 
• Adolescents and Adults: 12 males ages ≥12 to 65 years with ≥150 ED to 
any FVIII medication (excluding cryoprecipitate and FFP), no history of 
inhibitors, and no other bleeding disorders 
• Part B of this study plans to enroll approximately 6 Chinese PUPs/MTPs with 
severe hemophilia A, <6 years of age, with no prior exposure to FVIII product 
(PUPs) or no more than 1 ED with any purified FVIII concentrate or 3 exposures 
with FFP or cryoprecipitate (MTPs), no history of inhibitors (MTPs), and no other 
bleeding disorders. 
After signing Informed Consent and/or Assent (or informed consent signed by the 
participant’s parent or legal representative), the participants will be screened to ensure they 
meet all inclusion and none of the exclusion requirements. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page: 11 of 105 
 
Approximately 50 participants will be screened in order to achieve 42 evaluable participants 
in Part A. About 10 participants will be screened in order to achieve approximately 
6 evaluable participants in Part B. 
Intervention Groups and Duration: 
The study intervention will be used both for treatment and prevention of bleeding events and 
with surgical procedures. Individual participant dose decisions are at the discretion of the 
investigator. 
Part A: All participants in Part A are expected to be treated for 6 months. 
According to the Prescribing Information for KOVALTRY, dose regimens for prophylaxis 
are: 
• Study participants ≤12 years: 25 to 50 IU of KOVALTRY per kg body weight 
(given IV) twice weekly, three times weekly, or every other day according to 
individual requirements for 6 months 
• Study participants >12 to 65 years: 20 to 40 IU of KOVALTRY per kg of body 
weight (given IV) two or three times per week for 6 months 
Part B: All participants in Part B are expected to be treated for 50 ED. Treatment in Part B 
may begin with start of prophylaxis with 15 to 50 IU/kg (minimum dose: 250 IU) at least 
1 day a week; alternatively, prophylaxis can be started directly with a once-a-week schedule 
minimum dose of 250 IU for PUPs/MTPs of any weight. The starting dose may be tailored to 
the participant’s weight or demonstrated bleeding tendency. 
Study participants who develop high-titer inhibitor (>5 BU/mL, confirmed by local 
laboratory) related to study drug, that interferes with effective treatment with FVIII, may opt 
to enter optional ITI treatment with study drug (Section 10.5.1) or leave the study and be 
treated with other therapies outside of the study at the discretion of the investigator. The 
optional ITI treatment with the study drug within the study requires a separate signed 
informed consent. Refer to Section 10.5 for additional details. 
Study Visits: 
Part A: Part A will include the following study visits: 
• Visit 1: Screening (up to 6 weeks prior to Baseline), 
• Visit 2: Baseline (first study drug administration, no more than 6 weeks after 
completion of the screening assessments), 
• Visit 3: (1 month after baseline), 
• Visit 4: (2 months after baseline), 
• Visit 5: Final visit (6 months after baseline)/Early Termination. 
Part B: Part B will include the following study visits: 
• Visit 1: Screening, 
• Visit 2: Baseline (first study drug administration for MTPs only), 
• Visit 3: ~5 ED, 
• Visit 4: ~10 ED, 
• Visit 5: ~15 ED, 
• Visit 6: ~20 ED, 
• Visit 7/Interim visit: 30 to 40 ED, 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page: 12 of 105 
 
• Visit 8/Final visit (50 ED)/Early Termination. 
All participants or parents/caregivers in Part A and Part B will receive a safety follow-up call 
approximately 2 weeks after the Final visit. 
Data Monitoring Committee: 
No 
 
1.2 
Schema 
The schema of study visits for Part A is shown in Figure 1–1, and details of the study 
activities in Part A are displayed in Section 1.3.1. 
The schema of study visits for Part B is shown in Figure 1–2, and details of the study 
activities in Part B are displayed in Section 1.3.2. 
 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  13 of 105 
 
Figure 1–1: Part A (PTPs) Study Schema 
 
Visit 1 
Screening 
 
Visit 2   
Baseline  
 
Visit 3  
 
Visit 4  
 
 
Visit 5  
Final visit/ 
Early 
Termination 
 
 
 
Follow-up 
call 
 
Up to 6 weeks 
prior to 
Baseline 
 
(no later than  
6 weeks 
from Visit 1) 
 
Month 1 
±7 days 
 
Month 2 
±7 days 
 
Month 6 
±7days 
 
2 weeks  
(± 7 days) 
after the 
final visit 
 
Notes: 
 
Between the scheduled study visits, drug dispensing visits approximately every 28 days (± 7 days) may require participants and/or their caregivers to return to the 
study center to obtain additional study drug. 
 
 
Between scheduled visits, participants and/or their caregivers will receive a phone call approximately every 2 weeks between Baseline and Visit 5 (Month 6) from 
the study center to verify proper completion of the participant diary, to review any new AEs and changes in concomitant medication since the last study visit, to 
update the status of the participant, respond to any questions, and to confirm the next dispensing and study visits. 
 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  14 of 105 
 
Figure 1–2: Part B (PUPs/MTPs) Study Schema 
 
 
 
Notes: 
 
Drug dispensing visits will be done in accordance with the individual drug dispensing schedule. Additional drug dispensing visits could be performed between 
Visit 6 and the Final visit in order to ensure study participants have sufficient study drug to cover the period between the scheduled study visits. 
 
 
Study center staff will call the participant or parent/caregiver approximately every 2 weeks between Baseline and Visit 8 (Final visit) and approximately 2 weeks 
after the last visit to verify proper completion of the electronic patient diary, review any new adverse events and changes in concomitant medication since the last 
study visit, update the status of the participant, respond to any questions, and confirm the next dispensing and study visits. 
 
 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  15 of 105 
 
1.3 
Schedule of Activities (SoA) 
1.3.1 
Part A (PTPs) SoA 
Assessment 
Visit 1a 
Screening 
Visit 2a 
Baseline 
(no later than  
6 weeks  
from Visit 1) 
Visit 3a 
Month 1 
±7 days 
Visit 4a 
Month 2 
±7 days 
Visit 5a 
Final Visit/ 
Early Termination 
Month 6 
±7days 
Follow-Up Call 
+2 weeks  
(±7 days) after 
the Final Visit 
Screening and enrollment 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
Inclusion / exclusion criteria  
X 
X 
 
 
 
 
Demographic data  
X 
 
 
 
 
 
Height and weightb 
X 
X 
X 
X 
X 
 
Medical, surgical history 
X 
 
 
 
 
 
Prior medication (medication history)c 
X 
 
 
 
 
 
Physical examination 
X 
X 
 
 
X 
 
FVIII trough level (at least 72 hours after last pre-study FVIII 
infusion) – one stage assay 
X 
 
 
 
 
 
Study drug administration (as per prescribed regimen)
d 
 
Given continuously in accordance with assigned prophylaxis regimen 
 
Study drug dispensationd 
 
X 
X 
X 
 
 
Study drug accountability 
 
 
X 
X 
X 
 
Efficacy 
 
 
 
 
 
 
Electronic patient diary (EPD) training and dispensinge 
X 
 
 
 
 
 
eDiary documentation and review (continuously)e 
 
X 
X 
X 
X 
 
Recovery (FVIII level)f 
 
X 
 
X 
X 
 
PK in children <12 years (in a subset of participants)g 
 
X 
 
 
 
 
PK in adolescents/adults ≥12 yearsh 
 
X 
 
 
X 
 
Safety 
 
 
 
 
 
 
Adverse events  
 
X 
X 
X 
X 
X 
Concomitant medication 
 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
 
Serology screening (HBV, HCV, HIV) and CD4 count 
X 
 
 
 
 
 
Laboratory examinationi 
X 
X 
 
X 
X 
 
Blood sample for inhibitor testj 
X 
X 
X 
X 
X 
 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  16 of 105 
 
Assessment 
Visit 1a 
Screening 
Visit 2a 
Baseline 
(no later than  
6 weeks  
from Visit 1) 
Visit 3a 
Month 1 
±7 days 
Visit 4a 
Month 2 
±7 days 
Visit 5a 
Final Visit/ 
Early Termination 
Month 6 
±7days 
Follow-Up Call 
+2 weeks  
(±7 days) after 
the Final Visit 
Phone callsk 
 
 
 
 
 
X 
Abbreviations: AE = adverse event; CD4 = cluster of differentiation 4; CRF = case report form; EPD = electronic patient diary; FVIII = factor VIII; HBV = hepatitis B virus; 
HCV = hepatitis C virus; HIV = human immunodeficiency virus; PK = pharmacokinetics; PTP = previously treated patient; RAVE = data base for electronic case report 
a. 
The scheduled study visits are shown in the table. Unscheduled visits are permitted at any time at the discretion of the investigator. In addition, participants may visit 
the study center approximately every 28 days (± 7 days) for medication supplies and receive phone calls, as outlined below in notes e and k. 
b. 
Height and weight will be obtained for all participants at screening. At all subsequent visits, height and weight will be obtained for children and adolescents. For adults, 
only weight will be collected after screening. 
c. 
Prior medication will be recorded at screening as part of medical history. Concomitant medication will be recorded at subsequent visits. 
d. 
Study drug will be injected throughout the study in accordance with assigned prophylaxis regimen. Drug dispensing will be done in accordance with the individual drug 
dispensing schedule every 28 days (± 7 days). 
e. 
The EPD may be given to the participants to take home at any time between Screening and Baseline, but no entries are to be made before the first infusion of study 
drug at Baseline. 
f. 
Blood samples for FVIII level are to be taken pre-infusion and 15 to 30 minutes after end of infusion to calculate recovery at Visits 2, 4, and 5. Infusion doses for 
recovery measurements must be given in hospital and directly reported in RAVE. The bioanalysis will be done at a central laboratory. 
g. 
PK evaluation is required only once in a subset of pediatric participants (12 children). Blood samples to be taken at the following time points subsequent to a washout 
of at least 48 h after last dose of KOVALTRY: pre-infusion, 15 to 30 min, 4 h, and 24 h post-infusion. Exact times need to be entered into CRF. PK evaluation should 
be done at Visit 2. Infusion doses for PK measurements must be given in hospital and directly reported in CRF. A standard dose of 50 IU/Kg should be given prior to 
PK evaluation. 
h. 
PK evaluation is required at start and end of treatment in all adolescent/adult participants only (12 adolescent/adults) . Blood samples to be taken at the following time 
points subsequent to a washout of at least 48 h after last dose of KOVALTRY: pre-infusion, 10 to 15 min, 30 min, 1 h, 4 h, 6 to 8 h, 24 h, and 30 to 48 h post-infusion. 
Exact times need to be entered into CRF. PK evaluation should be done at Visit 2 and Visit 5. Infusion doses for PK measurements must be given in hospital and 
directly reported in RAVE. A standard dose of 50 IU/kg should be given prior to PK evaluation. 
i. 
Standard laboratory assessments include hematology and clinical chemistry. 
j. 
The first positive inhibitor test after start of treatment with study intervention must be confirmed by analysis of a second sample and by analysis of FVIII level recovery 
within 2 weeks of the investigator’s notification. 
k. 
Study center staff will call the participant or parent/caregiver approximately every 2 weeks between Baseline and Visit 5 (Month 6) and approximately 2 weeks after the 
last visit (Visit 5) to verify proper completion of the participant diary and to review any new AEs and changes in concomitant medication since the last study visit. 
 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  17 of 105 
 
1.3.2 
Part B (PUPs/MTPs) SoA 
Assessments 
Visit 1a 
Screeningb 
Visit 2a 
Baseline 
(no later than  
4 weeks  
from Visit 1) 
Visit 3a 
ED ~5 
Visit 4a 
ED ~10 
Visit 5a 
ED ~15 
Visit 6a 
ED ~20 
Visit 7a/ Interim 
Visitc 
30 to 40 ED 
Visit 8a/Final Visit 
50 EDd/ 
Early Termination 
+2 weeks 
Follow-Up Calle 
2 weeks  
±7 days after the 
Final Visit 
Screening and enrollment 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion / exclusion criteria  
X 
X 
 
 
 
 
 
 
 
Demographic data  
X 
 
 
 
 
 
 
 
 
Height/length and weightf 
X 
X 
X 
X 
X 
X 
X 
X 
 
Medical and surgical history 
X 
 
 
 
 
 
 
 
 
Prior medications (medication 
history)g 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
X 
 
FVIII trough level (at least 
72 hours after last pre-study 
FVIII infusion) - one-stage 
assay 
Xh 
 
 
 
 
 
 
 
 
FVIII inhibitor (at least 
72 hours after last pre-study 
FVIII infusion) - one-stage 
assay 
Xh 
Xi 
 
 
 
 
 
 
 
Study drug administration (as 
per prescribed regimen)j 
 
Given continuously in accordance with assigned prophylaxis regimen 
 
Study drug dispensationj 
 
X 
X 
X 
X 
X 
X 
 
 
Study drug accountability 
 
 
X 
X 
X 
X 
X 
X 
 
Efficacy 
 
 
 
 
 
 
 
 
 
EPD training and dispensingk 
X 
X 
 
 
 
 
 
 
 
EPD documentation and 
review (continuously) 
 
X 
X 
X 
X 
X 
X 
X 
 
Recovery (FVIII level)l 
 
Xm 
 
 
 
X 
 
X 
 
Safety 
 
 
 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse events  
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
(continuously)g 
 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory examinationn 
X 
 
 
 
 
 
 
 
 
FVIII inhibitoro 
 
 
X 
X 
X 
X 
X 
X 
 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  18 of 105 
 
Assessments 
Visit 1a 
Screeningb 
Visit 2a 
Baseline 
(no later than  
4 weeks  
from Visit 1) 
Visit 3a 
ED ~5 
Visit 4a 
ED ~10 
Visit 5a 
ED ~15 
Visit 6a 
ED ~20 
Visit 7a/ Interim 
Visitc 
30 to 40 ED 
Visit 8a/Final Visit 
50 EDd/ 
Early Termination 
+2 weeks 
Follow-Up Calle 
2 weeks  
±7 days after the 
Final Visit 
FVIII trough levelo 
 
 
X 
X 
X 
 
X 
 
 
Phone calls (biweekly)p 
 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: ED = exposure days; EPD = electronic patient diary; FVIII = factor VIII; ITI = immune tolerance induction; MTP = minimally treated patients; PUP = previously 
untreated patients; RAVE = data base for electronic case report 
a 
The scheduled study visits are shown in the table. Unscheduled visits are permitted at any time at the discretion of the investigator. 
b 
For MTPs, the Screening visit should only take place after a washout period of at least 72 hours following any previous treatment with any FVIII replacement product. 
c 
This visit is required only for PUPs and MTPs who have less than 40 ED, 6 months after the Baseline visit. The intent is to have at least one scheduled visit between 
completion of 20 ED and the expected date of accumulating 50 ED. The primary purpose of the visit is to assess the well-being of the participant, ensure continued 
compliance with the treatment, and make any needed adjustments in dosage or infusion frequency based upon weight or bleeding events. 
d 
For participants who do not develop high-titer FVIII inhibitor, the Final visit can be performed as soon as a minimum of 50 ED is achieved, but no later than 2 weeks 
after achieving 50 ED. 
e 
This follow-up is not required for study participants who develop high-titer inhibitor and continue in the study in the Optional ITI Treatment (Section 10.5.1). 
f 
Height/length and weight will be obtained for all participants at screening and at all subsequent visits. 
g 
Prior medications will be recorded at screening as part of medical history. Concomitant medications will be recorded at subsequent visits. 
h 
Inhibitor is to be evaluated at screening and in repeat sampling at least 1 week but not more than 2 weeks after screening (local laboratory testing) in MTPs only (i.e., 
unnecessary to be evaluated in PUPs). For MTPs, FVIII level and presence of FVIII inhibitor should be measured at least 72 hours after the last dose of FVIII. For 
MTPs, study drug administration should start upon availability of result from local laboratory testing documenting negative inhibitor titer.  
i 
Baseline inhibitor testing will be done in MTPs only. 
j 
Study intervention will be administered throughout the study in accordance with the assigned prophylaxis regimen. Drug dispensing will be done in accordance with the 
individual drug dispensing schedule. Additional drug dispensing visits could be performed between Visit 6 and the Final visit in order to ensure study participants have 
sufficient study drug to cover the period between the scheduled study visits. 
k 
The EPD may be given to the parent/caregiver to take home at any time between the Screening and Baseline visits, but no entries should be made before the first 
infusion of study drug at the Baseline Visit. 
l 
Blood samples for FVIII level will be taken pre-infusion and at 15 to 30 minutes after end of infusion to calculate recovery at the Baseline visit and Visits 6 and 8 (Final 
visit). Infusion doses for recovery measurements must be given in hospital and directly reported in RAVE. The bioanalysis will be done at a local laboratory. 
m 
For PUPs who do not start treatment with study drug at the Baseline, recovery evaluation should be done at the study visit when prophylaxis is started. 
n 
Standard laboratory assessments include hematology and clinical chemistry. Guidance for blood draws in participants ≤10 kg is provided in Section 10.2. 
o 
Inhibitor will be evaluated at every visit after the start of treatment with study drug for MTPs as well as for PUPs. FVIII level and presence of FVIII inhibitor should be 
measured at least 48 hours after the last dose of study drug. The first positive inhibitor test after start of treatment with study drug must be confirmed by analysis of a 
second sample and by analysis of FVIII level recovery within 2 weeks of the investigator’s notification. 
p 
Study center staff will call the parents/caregivers of participants approximately every 2 weeks between Baseline and Visit 8 (Final visit) and approximately 2 weeks 
after the last visit to verify proper completion of the participant diary and to review any new AEs and changes in concomitant medication since the last study visit. 
 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  19 of 105 
 
2. 
Introduction 
KOVALTRY (BAY 81-8973), antihemophilic factor (recombinant), is a recombinant, human 
DNA sequence derived, full length Factor VIII concentrate indicated for use in adults and 
children with hemophilia A (congenital Factor VIII deficiency). As described in the 
KOVALTRY Prescribing Information in China (provided as an attachment in Section 12),1 
KOVALTRY temporarily replaces the missing clotting factor VIII needed for effective 
hemostasis in patients with hemophilia A. Upon activation of the clotting cascade, FVIII is 
converted to activated FVIII and acts as a cofactor for activated factor IX, accelerating the 
conversion of factor X to activated factor X on phospholipid surfaces, which ultimately 
converts prothrombin to thrombin and leads to the formation of a fibrin clot.1 
The multinational clinical development program for KOVALTRY (LEOPOLD) included 
3 clinical studies (LEOPOLD I, LEOPOLD II, and LEOPOLD Kids) that have demonstrated 
efficacy and safety for preventing and treating bleeding episodes in approximately 
240 children, adolescents, and adults with severe hemophilia A across different populations 
and different regions of the world, including 6 Chinese participants in the LEOPOLD I study 
(PK evaluation part) and 23 adult/adolescent Chinese patients in the LEOPOLD II study. 
KOVALTRY is currently authorized to be marketed in 
 countries including China under 
the proprietary name KOVALTRY. 
2.1 
Study Rationale 
Based on efficacy and safety data from completed multinational studies with KOVALTRY 
and the consistent results for both PK and clinical efficacy/safety in 29 adult/adolescent 
patients with severe hemophilia A from China, KOVALTRY was conditionally approved for 
use in adults and children in China in July 2018 for: 
• Routine prophylaxis to reduce the frequency of bleeding episodes 
• On-demand treatment and control of bleeding episodes 
• Perioperative management of bleeding 
Approved dosing recommendations for routine prophylaxis (as prescribing information, 
Section 12): 
• Adolescents and adults: 20 to 40 IU of KOVALTRY per kg of body weight two or 
three times per week 
• Children ≤12 years old: 25 to 50 IU of KOVALTRY per kg body weight twice 
weekly, three times weekly, or every other day according to individual requirements 
Efficacy and safety of KOVALTRY for prophylaxis, treatment of bleeding episodes, and 
perioperative management of hemophilia A patients were demonstrated in the completed 
LEOPOLD clinical trials in previously treated severe hemophilia A patients and supported 
approval for use of KOVALTRY in the management of hemophilia A patients in 
49 countries, including China. LEOPOLD I and LEOPOLD II studies included 6 and 
23 previously treated Chinese severe hemophilia A patients, respectively. There were no 
Chinese hemophilia A patients enrolled into LEOPOLD Kids study. 
As part of the China NDA post-approval commitment, the China CDE and NMPA requested 
additional efficacy and safety data in previously treated and previously untreated Chinese 
hemophilia A patients. As agreed with China CDE, Part A of this study will obtain additional 
efficacy, safety, and PK data for KOVALTRY in Chinese PTPs (children <12 years of age 
CC
I

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  20 of 105 
 
and adolescents/adults ≥12 years of age). Additionally, as per consultation with CDE, Part B 
of the study will obtain efficacy and safety data in Chinese PUPs/minimally treated patients 
(MTPs [children <6 years of age]). 
In the event that the study is not be finalized in time for a report to be delivered for license 
renewal, an interim analysis will be performed with all available data. 
2.2 
Background 
Hemophilia A is a congenital disorder in which mutations in the FVIII gene lead to a 
qualitative or quantitative deﬁciency of FVIII protein and activity resulting in prolonged 
bleeding after trauma and recurrent spontaneous bleeding episodes.2 The World Federation of 
Hemophilia’s global survey 2016 (the most recent year for which statistics are available) 
reported 14,390 cases of hemophilia in China. Of these, 12,533 cases were hemophilia A.3 
Individuals with severe hemophilia A experience frequent, recurrent bleeding into the soft 
tissue and joints, resulting in joint damage and debility, and significant negative effects on 
their Quality of Life (QoL), psychosocial well-being, education, and financial condition.2, 4, 5 
Standard treatment for hemophilia A patients is the replacement of the missing protein by 
infusion of exogenous FVIII concentrates, either as plasma-derived FVIII (pdFVIII) or 
recombinant rFVIII concentrates.2 FVIII is an important component of normal coagulation, 
and the biologic behavior is similar across all populations.6 Treatment is specifically directed 
to achieve desired plasma FVIII levels. There is a direct correlation between plasma FVIII 
levels, coagulant activity, and clinical manifestations. 
Treatment regimens are typically either on-demand therapy (given when a bleeding occurs) or 
prophylaxis (which consists of regular infusion of FVIII given at scheduled intervals (e.g., 
2x per week, 3x per week) to prevent bleeding). 
Standard prophylaxis using regularly scheduled infusions at doses and dose intervals 
sufficient to prevent bleeding events have been demonstrated to result in not only preservation 
of joint function and reducing the incidence of early disability and death, but also reduced 
frequency of intracranial hemorrhage, fewer hospital admissions, less joint surgery, and fewer 
missed days at work.2, 6 These benefits are the direct result of continuously improving 
standard of care, earlier diagnosis, and start of prophylactic treatment, and was made possible 
by the greater availability of a safe and consistently available source of factor concentrates. 
However, due to the diverse access to hemophilia treatment centers in different cities in 
China, the treatment approach mostly used for hemophilia A patients is on-demand treatment, 
especially for adult patients. Historically, lack of access to routine prophylaxis treatment in 
some Chinese regions increased the likelihood of joint damage and compromised  
health-related quality of life. Low dose secondary prophylaxis (10 IU/kg, 2 times per week, 
10-30 IU/kg weekly) has been explored as a cost saving approach for the treatment of Chinese 
patients with hemophilia.7, 8 Although the results of this approach have been encouraging, 
there remains the goal of establishing effective individualized prophylaxis and standardized 
care for Chinese hemophilia patients. In recent years, the proportion of prophylaxis use in 
pediatric patients is increasing.3 
2.3 
Benefit/Risk Assessment 
The benefit/risk assessment of KOVALTRY has been demonstrated as favorable in the 
LEOPOLD program for children, adolescents, and adults. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  21 of 105 
 
In general, in clinical trials of both children and adolescents/adults, KOVALTRY has been 
shown to be well tolerated. 
The most significant risk with KOVALTRY, like any FVIII replacement product, is the 
development of FVIII inhibitors. Detailed information about the known and expected benefits 
and risks and expected adverse events of KOVALTRY may be found in the Chinese Package 
Insert (see Section 12). 
2.3.1 
Risk Assessment 
Potential Risk of Clinical 
Significance 
Summary of Data/ 
Rationale for Risk 
Mitigation Strategy 
Important identified risks: 
• 
Development of 
factor VIII inhibitors 
• 
Hypersensitivity and 
allergic reactions 
Development of factor VIII inhibitors: 
The formation of neutralizing 
antibodies (inhibitors) to FVIII is a 
known complication in the 
management of individuals with 
hemophilia A and a class effect for all 
FVIII products. For previously 
untreated patients (PUPs), the risk to 
develop inhibitors is considered very 
common (approximately 30% to 50%), 
whereas the risk for PTPs is 
considered uncommon (<1%). 
 
Hypersensitivity and allergic reactions: 
Hypersensitivity reactions, including 
anaphylaxis, are possible with 
KOVALTRY. No anaphylactic reactions 
have been reported with KOVALTRY. 
Allergic type hypersensitivity reactions 
are possible with KOVALTRY. The 
product may contain traces of hamster 
or mouse proteins, which in some 
patients may cause allergic reactions. 
The informed consent will 
outline the important 
identified and potential 
risks. 
 
Inhibitor titer is assessed 
at scheduled study visits. 
 
Planned time points for 
all safety assessments 
are provided in the 
Schedule of Activities 
[Section 1.3]. 
Study Intervention - KOVALTRY 
Drug infusion: This 
procedure can cause pain or 
bruising at the site of the 
infusion. 
The study treatment is administered as 
intravenous infusion [see Section 6.1]. 
Study participants will be 
informed of these 
potential risks in the 
informed consent. 
Study Procedures 
Blood draw: This procedure 
can cause discomfort from 
the needle, pain, and 
bruising at the site of the 
draw.  
There is rarely any infection. 
Drug infusion: This 
procedure can cause pain or 
bruising at the site of the 
infusion. 
Blood samples will be obtained at 
baseline to confirm study eligibility. 
As outlined in Section 7.1 and 
Section 7.2, there will be additional 
blood draws at scheduled study visits 
for FVIII recovery, FVIII inhibitor 
assessment, and for a subset of 
participants in Part A, additional PK 
analysis sampling.  
Study participants will be 
informed of these 
potential risks in the 
informed consent. 
 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  22 of 105 
 
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. KOVALTRY is a full-length rFVIII product approved for the prevention 
and treatment of bleeding episodes in patients with hemophilia A.1 The LEOPOLD clinical 
trial program conclusively demonstrated that KOVALTRY is efficacious in preventing and 
treating bleeding episodes as well as maintaining hemostasis during surgery in children, 
adolescents, and adults with severe hemophilia A.9, 10, 11 
Prophylaxis with KOVALTRY decreases bleeding frequency compared with on-demand 
treatment. KOVALTRY prophylaxis is efficacious when administered either twice weekly or 
three times weekly, and in addition in pediatric patients also every other day.9, 10, 11 
LEOPOLD study data support the use of individualized prophylaxis dosing of KOVALTRY 
based on a patient’s clinical history. In the LEOPOLD clinical studies, a low pre-study 
bleeding rate was a good predictor of a low annualized bleeding rate with KOVALTRY 
prophylaxis.9 KOVALTRY also effectively maintains hemostasis in patients with hemophilia 
A undergoing major or minor surgical procedures.9, 10, 11 
The risk associated with infusion of study treatment is not more than what would be expected 
for hemophilia A patients receiving KOVALTRY as standard of care. 
Blood samples will be collected at screening to confirm study eligibility, during scheduled 
study visits as part of safety assessment for the study, and for the PK sub-study (optional for 
children <12 years of age) in Part A. 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 KOVALTRY 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. Additionally, the 
protocol includes a guideline providing the recommended blood volume to be drawn from 
children 1-10 kg for study related tests. Therefore, it is expected that the risk associated with 
blood draws is not more than would be expected with standard of care. 
2.3.3 
Overall Benefit: Risk Conclusion 
Considering the measures taken to minimize risk to participants in this study, the potential 
risks identified in association with KOVALTRY are justified by the anticipated benefits of 
prophylaxis treatment with KOVALTRY for study participants. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  23 of 105 
 
3. 
Objectives and Endpoints 
3.1 
Objectives and Endpoints - Part A (PTPs) 
Objectives 
Endpoints 
Primary 
 
Efficacy 
 
• 
Evaluate the efficacy of prophylaxis 
treatment with KOVALTRY in Chinese 
children (<12 years) and adolescents/adults 
(≥12 years) with severe hemophilia A 
• 
Annualized bleeding rate (ABR) 
Secondary 
 
Efficacy 
 
• 
Evaluate efficacy of KOVALTRY for 
treatment of bleeding episodes 
 
• 
Assess efficacy within 48 hours of previous 
prophylaxis infusion 
• 
Evaluate the in vivo recovery of 
KOVALTRY 
 
• 
Hemostatic control for minor surgeries 
• 
Number of infusions needed to 
achieve hemostasis and response 
to treatment of bleeds 
• 
ABR within 48h of previous 
prophylaxis infusion 
• 
In vivo recovery of KOVALTRY at 
baseline, 2 months after start of 
study treatment, and study end 
• 
Physician assessment of adequacy 
of hemostasis in minor surgery 
Safety 
 
• 
Assess the safety of KOVALTRY for 
prophylaxis and treatment of bleeding 
episodes in Chinese children (<12 years) 
and adolescents/adults (≥12 years) with 
severe hemophilia A 
• 
FVIII inhibitor development by the 
Nijmegen Bethesda assay 
• 
Treatment-emergent adverse 
events (TEAEs) 
Pharmacokinetics 
 
• 
Evaluate pharmacokinetics (PK) of 
KOVALTRY in Chinese children (<12 years) 
and adolescents/adults (≥12 years to 
65 years) severe hemophilia A patients 
• 
PK parameters include Cmax, AUC, 
and t½ 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  24 of 105 
 
3.2 
Objectives and Endpoints - Part B (PUPs/MTPs) 
Objectives 
Endpoints 
Primary 
 
Efficacy 
 
• 
Assess the efficacy of KOVALTRY within 
48 hours of previous prophylaxis infusion 
in previously untreated/minimally treated 
Chinese children (<6 years of age) with 
severe hemophilia A 
• 
ABR within 48 hours of previous 
prophylaxis infusion 
Secondary 
 
Efficacy 
 
• 
Evaluate the efficacy of prophylaxis 
treatment with KOVALTRY 
• 
Assess the efficacy of KOVALTRY for 
treatment of bleeding episodes 
 
• 
Evaluate the in vivo recovery of 
KOVALTRY 
• 
Hemostatic control for minor surgeries 
• 
ABR during the prophylaxis period 
 
• 
Number of infusions required to treat 
a bleed and response to treatment of 
bleeds 
• 
In vivo recovery of KOVALTRY at 
baseline and study end 
• 
Physician assessment of adequacy 
of hemostasis in minor surgery 
Safety 
 
• 
Assess the safety of KOVALTRY for 
prophylaxis and treatment of bleeding 
episodes in previously untreated/minimally 
treated Chinese children (<6 years of age) 
with severe hemophilia A 
• 
FVIII inhibitor development by the 
Nijmegen Bethesda assay 
• 
Treatment-emergent adverse events 
(TEAEs) 
 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  25 of 105 
 
4. 
Study Design 
4.1 
Overall Design 
This is a multicenter, uncontrolled, open-label, single arm treatment, 2-part study in 
previously treated, previously untreated, and minimally treated Chinese children and 
adolescents/adults with severe hemophilia A. 
Study participants who develop high-titer inhibitor (>5 BU/mL, confirmed by central lab for 
Part A or local laboratory for part B) related to study drug, that interferes with effective 
treatment with FVIII, may opt to enter optional ITI treatment with study drug (Section 10.5.1) 
or leave the study and be treated with other therapies outside of the study at the discretion of 
the investigator. The optional ITI treatment with the study drug within the study requires a 
separate signed informed consent. Refer to Section 10.5 for additional details. 
4.1.1 
Part A (PTPs) 
Part A will assess the efficacy, safety, and PK of KOVALTRY in previously treated Chinese 
children and adolescents/adults with severe hemophilia A. Part A is planned to investigate a 
total of 42 PTPs. Efficacy and safety assessments are outlined in the Schedule of Activities 
(SoA) in Section 1.3.1. 
PK will be assessed in a subset of 12 children (<12 years) and 12 adolescents/adults 
(≥12 years). Details of the PK parameters to be assessed are provided in Section 8.6. 
Efficacy and safety data for use of KOVALTRY for treatment of bleeding episodes will also 
be collected. 
• Study participants will be treated for 6 months at the following doses according to 
the prescribing information for KOVALTRY: 
• Study participants ≤12 years of age: 25 to 50 IU of KOVALTRY per kg 
body weight twice weekly, three times weekly, or every other day 
according to individual requirements for 6 months 
• Study participants >12 years: 20 to 40 IU of KOVALTRY per kg of body 
weight two or three times per week according to individual requirements 
for 6 months 
• Part A will include 5 study visits (Screening, Baseline, Visit 3/Month 1, 
Visit 4/Month 2, Visit 5/Final visit/Early Termination). All participants will also 
receive a safety follow-up call approximately 2 weeks after the final study visit. 
4.1.2 
Part B (PUPs/MTPs) 
Part B will assess the efficacy and safety of KOVALTRY in previously untreated/minimally 
treated Chinese children with severe hemophilia A. Part B will investigate approximately 
6 PUPs/MTPs. Efficacy and safety assessments are outlined in the SoA in Section 1.3.2. 
Efficacy and safety data for the use of KOVALTRY for treatment of bleeding episodes will 
also be collected. 
• Study participants will be treated until at least 50 ED is achieved.  
• Treatment may begin with start of prophylaxis with 15 to 50 IU/kg 
(minimum dose: 250 IU) at least 1 day a week; alternatively, prophylaxis 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  26 of 105 
 
can be started directly with a once-a-week schedule minimum dose of 
250 IU for PUPs/MTPs of any weight. 
• The starting dose may be tailored to the participant’s weight or 
demonstrated bleeding tendency. 
• Individual participant dose decisions are at the discretion of the 
investigator. 
• Part B will include 8 study visits (Screening, Baseline, Visit 3 [approximately 5 
ED], Visit 4 [approximately 10 ED], Visit 5 [approximately 15 ED], Visit 6 
[approximately 20 ED], Visit 7/Interim visit [approximately 30 to 40 ED], and 
Visit 8/Final visit [50 ED]/Early Termination). All parents/caregivers of 
participants in Part B will receive a safety follow-up call approximately 2 weeks 
after the end of treatment. 
4.2 
Scientific Rationale for Study Design 
Part A of this study will collect clinical data in 42 previously treated Chinese participants with 
severe hemophilia A (30 children and 12 adolescents/adults) to provide additional efficacy 
and safety data for the use of KOVALTRY for prophylaxis and treatment of bleeding 
episodes in this patient population. Pharmacokinetic data will also be collected from 
24 participants (see Section 8.6 for details). 
Part B of this study will collect clinical data in approximately 6 previously 
untreated/minimally treated Chinese participants with severe hemophilia A (6 children) to 
provide additional efficacy and safety data for the use of KOVALTRY for prophylaxis and 
treatment of bleeding episodes in this patient population. 
4.2.1 
Participant Input into Design 
Not applicable. 
4.3 
Justification for Dose 
The routine prophylaxis doses used in this study are the approved doses in the Chinese 
prescribing information for KOVALTRY (Section 12). 
4.3.1 
Routine Prophylaxis 
• Adults and adolescents: 20 to 40 IU of KOVALTRY per kg of body weight two or 
three times per week 
• Children ≤12 years old: 25 to 50 IU of KOVALTRY per kg body weight twice 
weekly, three times weekly, or every other day according to individual requirements 
Prophylactic treatment regimens should be guided by clinical judgement based on individual 
patient characteristics and treatment response. 
4.3.1.1 
Prophylaxis Treatment for Adolescent and Adult Patients 
For long-term prophylaxis against bleeding in patients with severe hemophilia A, the 
recommended doses are 20 to 40 IU of factor VIII per kg body weight two or three times per 
week. In some cases, especially in younger patients, shorter dosage intervals or higher doses 
may be used. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  27 of 105 
 
4.3.1.2 
Pediatric Patients 
KOVALTRY is approved for use in pediatric patients. Safety and efficacy studies have been 
performed in children 0-12 years. The recommended prophylaxis doses are 25-50 IU/kg twice 
weekly, three times weekly, or every other day according to individual requirements. For 
pediatric patients above the age of 12, the dose recommendations are the same as for adults. 
For PUPs/MTPs, prophylaxis with study intervention may be initiated at 15 to 50 IU/kg 
(minimum dose: 250 IU) at least 1 day per week. 
Frequent infusions may be difficult for small children and their caregivers. Consequently, the 
benefit for each individual child must be evaluated against this burden, particularly in very 
young children for whom venous access may be difficult. 
4.3.2 
Treatment of Bleeding Episodes 
The required dose is determined using the following formula: 
Required units = body weight (kg) x desired factor VIII rise (% or IU/dL) x reciprocal 
of observed recovery 
The usual single dose for bleeding episodes of mild to moderate severity is 10-30 IU/kg body 
weight. Higher dosages are recommended for life threatening or major hemorrhages. 
For participants with a recovery below 2 (which may occur, e.g., in small children), higher 
dosages may be needed. Further guidance is included in Section 12. 
4.4 
End of Study Definition 
A participant is considered to have completed the study if he has completed the last study 
visit, as shown in the Schedule of Activities for Part A (Section 1.3.1) or Part B 
(Section 1.3.2), or optional ITI treatment (Section 10.5.2). 
Completion of Part A is when the last participant in Part A completes the final visit or early 
termination as shown in the Schedule of Activities for Part A (Section 1.3.1). 
Completion of Part B is when the last participant in Part B completes the final visit or early 
termination as shown in the Schedule of Activities for Part B (Section 1.3.2). 
Study participants who develop high-titer FVIII inhibitor and decide to enter optional ITI 
treatment with study intervention will discontinue participation in either Part A or Part B and 
complete the Early Termination visit. The end of study for these participants is defined as 
completion of the Optional ITI Treatment (Section 10.5.1). 
Study participants who develop high titer FVIII inhibitor and decide to receive ITI with 
another product outside of the study will complete the Early Termination visit and leave the 
study. 
The study itself will be considered complete after the last visit of the last participant for all 
centers has occurred. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  28 of 105 
 
5. 
Study Population 
Part A of the study plans to enroll 42 previously treated severe hemophilia A, defined as less 
than 1% of factor VIII in the blood (based on one-stage assay), patients (PTPs) in China. 
Approximately 30 children aged <12 years and 12 adolescents/adults ≥12 years up to 65 years 
with documented severe hemophilia A will be enrolled in two age groups. 
Part B of the study plans to enroll approximately 6 Chinese PUPs/MTPs (children <6 years) 
with documented severe hemophilia A, defined as less than 1% of factor VIII in the blood 
(based on one-stage assay). 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion Criteria 
5.1.1 
Part A (PTPs) Inclusion Criteria 
Participants are eligible to be included in Part A of the study only if all of the following 
criteria apply: 
Age 
1. Participants enrolled as children must be <12 years at the time of their parent or legal 
representative’s signature of informed consent on the participant’s behalf, or if 
enrolled as adolescents/adults, must be ≥ age 12 to 65 years at the time of signed 
informed consent. 
Type of Participant and Disease Characteristics 
2. Chinese participants with severe hemophilia A (defined as FVIII:C <1% with  
one-stage clotting assay documented at the time of screening). If screening results 
show FVIII:C as equal to or higher than 1%, then severe hemophilia A may be 
confirmed by documented historical evidence from a (certified) clinical laboratory 
demonstrating <1% FVIII:C as determined by a one-stage clotting assay. 
3. Currently receiving on-demand or any type of prophylaxis treatment regimen with 
any FVIII product (excluding treatment with fresh-frozen plasma and  
cryo-precipitate). 
4. For participants <12 years of age, ≥50 exposure days (ED); for participants ≥12 to 
65 years of age, ≥150 ED with any Factor VIII product (excluding treatment with 
fresh-frozen plasma and cryo-precipitate). 
5. No current evidence of inhibitor antibody as measured by the Nijmegen-modified 
Bethesda assay [<0.6 Bethesda units (BU)/mL] in 2 consecutive samples and absence 
of clinical signs or symptoms of decreased response to FVIII administration. (First 
negative sample can be historical if obtained within 3 months prior to screening with 
a result of <0.6 BU/mL by classical Bethesda assay. The testing for a second 
negative, confirmatory sample must, in all cases, be performed by a central laboratory 
using the Nijmegen-modified Bethesda test. If a first recent sample is not available, 
then testing for 2 negative samples must be performed by the central laboratory at 
least 1 week apart). Participants may not receive FVIII within 72 hours prior to the 
collection of samples for inhibitor testing. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  29 of 105 
 
6. No history of FVIII inhibitor formation. Documentation of negative result in medical 
records is required (Nijmegen-modified Bethesda assay or classical Bethesda assay); 
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 successive negative results 
(<0.6 BU/mL) thereafter are eligible. 
Sex 
7. Male participants only. 
Informed Consent 
8. Each adult participant must be capable of giving signed informed consent/assent as 
described in Section 10.1.2, which includes compliance with the requirements and 
restrictions listed in the informed consent form (ICF) and in this protocol. For 
children and adolescents under the age of consent/assent in China, parents or a legal 
representative must be able to provide a signed informed consent/assent on behalf of 
the minor child/adolescent. 
Other 
9. Willingness and ability of participants, parents, or caregiver to comply with 
prophylaxis schedule and complete training on the use of the study electronic patient 
diary (EPD) and to use the diary to document bleeding and infusion information 
during the study. 
5.1.2 
Part B (PUPs/MTPs) Inclusion Criteria 
Participants are eligible to be included in Part B of the study only if all of the following 
criteria apply: 
Age 
1. Participants must be <6 years of age at the time of their parent or legal 
representative’s signature of informed consent on the participant’s behalf. 
Type of Participant and Disease Characteristics 
2. Chinese participants with severe hemophilia A (defined as FVIII:C <1% with 
one-stage clotting assay documented at the time of screening). If screening results 
show FVIII:C as equal to or higher than 1%, then severe hemophilia A may be 
confirmed by documented historical evidence from a (certified) clinical laboratory 
demonstrating FVIII:C <1% as determined by a one-stage clotting assay. 
3. PUPs must have no previous exposure to any FVIII product. 
MTPs must have no more than 1 ED with any purified FVIII concentrate or 
3 exposures with FFP or cryoprecipitate. 
4. MTPs have no current evidence of inhibitor antibody as measured by the 
Nijmegen-modified Bethesda assay (<0.6 BU/mL) in 2 consecutive samples and must 
have absence of clinical signs or symptoms of decreased response to FVIII 
administration. Testing for the 2 negative samples must be performed by the local 
laboratory at least 1 week but not more than 2 weeks apart. Participants may not 
receive FVIII product within 72 hours prior to the collection of samples for inhibitor 
testing. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  30 of 105 
 
5. PUPs and MTPs must observe a 6-month washout period if they have received 
subcutaneous factor substitution therapy (emicizumab). 
6. PUPs may be included if they will receive their first FVIII dose with KOVALTRY 
for treatment of first bleeds and agree to start prophylaxis as part of their care. 
MTPs may be included if they agree to start prophylaxis as part of their care. 
Sex 
7. Male participants only 
Informed Consent 
8. The parents or a legal representative of the participant must be able to provide a 
signed informed consent on behalf of the participant. 
Other 
9. The participant’s parent/caregiver must be willing and able to comply with the 
prophylaxis schedule and to complete training on the use of the study EPD and use 
the EPD to document bleeding and treatment information during the study. 
5.2 
Exclusion Criteria 
5.2.1 
Part A (PTPs) Exclusion Criteria 
Participants are excluded from Part A of the study if any of the following criteria apply: 
Medical Conditions 
1. Any other bleeding disease that is different from hemophilia A (e.g., von Willebrand 
disease, hemophilia B). 
2. Platelet count <100 000/mm3 based on screening laboratory assessments. 
3. Impaired renal function (serum creatinine >2.0 mg/dL) or active liver disease (alanine 
aminotransferase/aspartate aminotransferase [ALT/AST] >5x ULN) based on 
screening laboratory. 
4. Human immunodeficiency virus (HIV) positive with an absolute CD4 lymphocyte cell 
count <250 cells/µL. 
5. Known hypersensitivity to the active substance, mouse or hamster protein. 
Prior/Concomitant Therapy 
6. Receiving chemotherapy or immune modulatory drugs (e.g., intravenous [IV] 
immunoglobulin, cyclosporine) other than anti-retroviral chemotherapy or chronic use 
of oral or intravenous (IV) corticosteroids (>14 days) within the last 3 months. Brief 
courses of prednisone/methyprednisolone (<14 days) for treatment of disorders such 
as synovitis, asthma, etc. are allowed at the discretion of the treating physician 
7. Requiring any pre-medication to tolerate FVIII infusions (e.g., antihistamines). 
Prior/Concurrent Clinical Study Experience 
8. Currently participating in another investigational drug study, or having previously 
participated in a clinical study involving an investigational drug within 30 days of 
signing informed consent or participated in completed interventional clinical studies 
with BAY 81-8973 (KOVALTRY). 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  31 of 105 
 
Other Exclusions 
9. Unwilling to comply with study visits or other protocol requirements or is not suitable 
for participation in this study for any reason, according to the Investigator. 
10. Planned major surgery, defined as surgery with respiratory assistance and/or general 
anesthesia. 
11. Close affiliation with the investigational site; e.g., a close relative of the investigator, 
dependent person (e.g., employee or student of the investigational site). 
5.2.2 
Part B (PUPs/MTPs) Exclusion Criteria 
Participants are excluded from Part B of the study if any of the following criteria apply: 
Medical Conditions 
1. Any other bleeding disorder that is different from hemophilia A (e.g., von Willebrand 
disease, hemophilia B). 
2. Platelet count <100 000/mm3 based on screening laboratory assessments. 
3. Impaired renal function (serum creatinine >2× upper limit of normal [ULN]) or active 
liver disease (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] 
>5× ULN) based on screening laboratory assessments. 
4. MTPs with history of FVIII inhibitor formation. 
5. Known hypersensitivity to the active substance, mouse or hamster protein. 
6. First treatment with KOVALTRY for high-risk bleeding situations (e.g., surgery, 
intracranial bleed) or requiring intensive or prolonged treatment. 
7. Planned major surgery, defined as surgery with respiratory assistance and/or general 
anesthesia. 
Prior/Concomitant Therapy 
8. Receiving chemotherapy or immune modulatory drugs (e.g., IV immunoglobulin, 
cyclosporine) other than anti-retroviral chemotherapy or chronic use (>14 days) of 
oral or IV corticosteroids within the last 3 months. Brief courses (<14 days) of 
prednisone/methyprednisolone for treatment of disorders such as synovitis, asthma, 
etc. are allowed at the discretion of the treating physician. 
9. Requiring any pre-medication to tolerate FVIII infusions (e.g., antihistamines). 
Prior/Concurrent Clinical Study Experience 
10. Currently participating, or have participated within 30 days of signing informed 
consent, in another clinical study involving an investigational drug. 
Other Exclusions 
11. Unwilling to comply with study visits or other protocol requirements or is not suitable 
for participation in this study for any reason, according to the investigator’s judgment. 
12. Close affiliation with the investigational site (e.g., a close relative of the investigator, 
dependent person [e.g., employee or student of the investigational site]). 
13. Unable to tolerate volume of blood draws required for study participation (see 
Section 10.2). 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  32 of 105 
 
5.3 
Lifestyle Considerations 
No restrictions are required. 
5.3.1 
Meals and Dietary Restrictions 
No restrictions are required. 
5.3.2 
Caffeine, Alcohol, and Tobacco 
No restrictions are required. 
5.3.3 
Concomitant Medications 
Medications that cause a bleeding diathesis (for example, Aspirin® or any acetylsalicylic 
acid) should be avoided in individuals with hemophilia, except as specifically prescribed by a 
treating physician. Low dose aspirin should not be discontinued in participants who have been 
identified to be at risk for cardiovascular events. Further details are provided in Section 6.5. 
5.4 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently receiving study intervention. A minimal set of screen failure information 
is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse events (AEs). 
Individuals who do not meet the criteria for participation in this study (screen failure) cannot 
be rescreened. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  33 of 105 
 
6. 
Study Intervention 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol. 
6.1 
Study Intervention Administered 
All treatment decisions for identifying appropriate prophylactic treatment regimen should be 
guided by clinical judgment based on the approved prescribing information (PI) and the 
individual participant characteristics and treatment response. 
Table 6–1: Study Intervention by Arm and Dose 
 
Part A 
Part B 
Arm Name 
Child 
(Age <12 years) 
Adolescent/Adult 
(Ages ≥12 to 65 years) 
Child  
(Age <6 years) 
Intervention 
Name 
KOVALTRY 
KOVALTRY 
KOVALTRY 
Type  
Full-length human 
recombinant Factor VIII 
(rFVIII) protein 
Full-length human 
recombinant Factor VIII 
(rFVIII) protein 
Full-length human 
recombinant Factor VIII 
(rFVIII) protein 
Dose 
Formulation 
Powder for solution for 
infusion or infusion 
Powder for solution for 
infusion or infusion 
Powder for solution for 
infusion or infusion 
Unit Dose 
Strengths 
250 IU, 500 IU, 1000 IU 
250 IU, 500 IU, 1000 IU 
250 IU, 500 IU, 1000 IU 
Dosage (for 
prophylaxis) 
25 to 50 IU of 
KOVALTRY per kg body 
weight (rounded to the 
nearest vial size) twice 
weekly, three times 
weekly, or every other 
day according to 
individual requirements 
for 6 months 
12 year-old: 25 to 50 IU 
of KOVALTRY per kg 
body weight (rounded to 
the nearest vial size) 
twice weekly, three times 
weekly, or every other 
day for 6 months 
 
>12 year-old: 20 to 40 IU 
of KOVALTRY per kg of 
body weight (rounded to 
the nearest vial size) 
two or three times per 
week for 6 months 
15 to 50 IU (minimum 
250 IU) of KOVALTRY 
per kg body weight 
[rounded to the nearest 
vial size]) at least 1 day 
per week.  
 
Alternatively, prophylaxis 
can be started directly 
with a once-a-week 
schedule minimum dose 
of 250 IU for 
PUPs/MTPs of any 
weight. 
 
The starting dose may 
be tailored to the 
participant’s weight or 
demonstrated bleeding 
tendency.  
 
Treatment is continued 
until 50 ED is achieved.  
Route of 
Administration 
IV infusion 
IV infusion 
IV infusion 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  34 of 105 
 
 
Part A 
Part B 
Arm Name 
Child 
(Age <12 years) 
Adolescent/Adult 
(Ages ≥12 to 65 years) 
Child  
(Age <6 years) 
Packaging and 
Labeling 
(identical for 
all arms) 
Study intervention will be 
provided in vials 
packaged together with 
a container of the 
appropriate amount of 
sterile water for infusion 
for reconstitution. For 
KOVALTRY, the volume 
of diluent is 2.5 mL for 
all vial sizes. The vials 
will also be supplied with 
an infusion set 
composed of 1 syringe 
containing the diluent 
and 1 butterfly needle to 
facilitate infusion. 
Instructions for 
reconstitution are 
supplied in each kit. The 
kits will be labeled as 
required by the Chinese 
Regulatory Authority. 
Instructions on storage 
and transport of the 
drugs provided for home 
administration will be 
provided in training 
given at the Baseline 
visit. 
Study intervention will be 
provided in vials 
packaged together with a 
container of the 
appropriate amount of 
sterile water for infusion 
for reconstitution. For 
KOVALTRY, the volume 
of diluent is 2.5 mL for all 
vial sizes. The vials will 
also be supplied with an 
infusion set composed of 
1 syringe containing the 
diluent and 1 butterfly 
needle to facilitate 
infusion. Instructions for 
reconstitution are 
supplied in each kit. The 
kits will be labeled as 
required by the Chinese 
Regulatory Authority. 
Instructions on storage 
and transport of the 
drugs provided for home 
administration will be 
provided in training given 
at the Baseline visit. 
Study intervention will be 
provided in vials 
packaged together with 
a container of the 
appropriate amount of 
sterile water for infusion 
for reconstitution. For 
KOVALTRY, the volume 
of diluent is 2.5 mL for all 
vial sizes. The vials will 
also be supplied with an 
infusion set composed of 
1 syringe containing the 
diluent and 1 butterfly 
needle to facilitate 
infusion. Instructions for 
reconstitution are 
supplied in each kit. The 
kits will be labeled as 
required by the Chinese 
Regulatory Authority. 
Instructions on storage 
and transport of the 
drugs provided for home 
administration will be 
provided in training given 
at the Baseline visit. 
Current/Former 
Name(s) or 
Alias(es) 
Commercial name: 
KOVALTRY  
(BAY 81-8973) 
Commercial name: 
KOVALTRY  
(BAY 81-8973) 
Commercial name: 
KOVALTRY  
(BAY 81-8973) 
KOVALTRY will also be used for treatment of bleeding events and with surgical procedures 
(see Section 10.4) and optional ITI (see Section 10.5). 
For optional ITI treatment with Kovaltry, ITI will be provided at a dose of up to 200 IU/kg 
daily for up to a maximum of 18 months or until failure (see Section 10.5 for additional 
information). 
6.2 
Preparation/Handling/Storage/Accountability 
The instructions for reconstitution using a vial adaptor will be provided to the participant 
and/or his parent/caregiver at the start of the study, and study site staff will instruct all 
participants and/or their caregivers on how to reconstitute and administer KOVALTRY. 
The participants and/or their caregivers will be instructed to administer reconstituted 
KOVALTRY as soon as possible, and no longer than 3 hours after reconstitution, according to 
the individual participant’s dosing schedule. 
KOVALTRY must be stored under refrigeration (2°C to 8°C, do not freeze). Participants and 
parents/caregivers will be provided with detailed instructions for proper storage of the study 
intervention. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  35 of 105 
 
KOVALTRY must be stored at the investigational site in accordance with Good Clinical 
Practice (GCP) and Good Manufacturing Practice (GMP) requirements and the instructions 
given by the clinical supplies department of the Sponsor or its affiliates. 
Special study site storage conditions and a complete record of batch numbers and expiry dates 
can be found in the Sponsor’s study file; the site-relevant elements of this information will be 
available in the investigator site file. On the day of receipt, the responsible site personnel will 
confirm receipt of study intervention via IxRS. 
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received, and any 
discrepancies are reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study will 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. Participants and/or their 
parents/caregivers will be instructed on proper storage at home. 
3. The personnel will use the study intervention only within the framework of this 
clinical study and in accordance with this protocol. 
4. The authorized site staff is responsible for study accountability, reconciliation, and 
record maintenance. Receipt, distribution, return and destruction (if any) of the study 
intervention must be properly documented according to the Sponsor’s agreed and 
specified procedures. 
5. Further guidance and information for the final disposition of unused study 
interventions are provided separately. 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
Not applicable. The study arms are based only on age and/or treatment status (PTPs and 
PUPs/MTPs). This is an open label study, and no blinding or randomization will be used. 
6.4 
Study Intervention Compliance 
Participant compliance with study intervention/treatment will be assessed at each visit. 
Used and unused vials of study medication will be returned to the clinic at every site visit for 
accounting. Any discrepancies between actual and expected number of returned vials must be 
discussed with the participant at the time of the visit, and any explanation must be 
documented in the source records. 
When participants are dosed at the site (at Baseline and the indicated study visits in 
Section 1.3.1 [Part A] or Section 1.3.2 [Part B] as per their individual participant’s regimen), 
they will receive study medication according to the standard of the institution. The date and 
time of each dose administered in the clinic will be recorded in the source documents and 
recorded in the case report form (CRF). 
The majority of dosing will be done at home, by the participant or his parent/caregiver, in 
accordance with the written instructions and demonstration provided by study center staff at 
the Baseline visit. Instruction on reconstituting KOVALTRY and other aspects of IV 
administration will be provided in detail. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  36 of 105 
 
In Part A, KOVALTRY will be dispensed on a monthly basis (in accordance with the 
individual drug dispensing schedule every 28 [±7] days) at the study center and will not be 
linked to the scheduled study visit schedule (see Section 1.3.1). In Part B, drug dispensing 
will be done in accordance with the individual drug dispensing schedule; additional drug 
dispensing visits might be performed between Visit 6 and the Final visit in order to ensure 
study participants have sufficient study drug to cover the period between the scheduled study 
visits (see Section 1.3.2). 
The electronic patient diary (EPD) will be the source document that will be used to assess the 
participant’s compliance with the treatment schedule/dose and to reconcile study medication 
inventory. The EPD will be used to record date and time of self-administration of study 
intervention for prophylaxis, as well as every bleeding episode with details of the bleeding 
and administered intervention. Data on the EPD will be transmitted on a regular basis. 
The EPD will be reviewed at visits and at regular contacts with the participant and/or his 
parent/caregiver during the study. 
6.5 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or 
receives during the study must be recorded in the CRF along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
The Study Medical Expert should be contacted if there are any questions regarding 
concomitant or prior therapy. 
Bleeding episodes that occur during the screening period (Screening visit until Visit 2) will be 
treated with the participant’s previous FVIII product. 
All medications and blood products required by the participant after the informed consent is 
signed, including FVIII products other than study intervention, will be listed in the 
appropriate eCRF page. All concurrent prescription and non-prescription medications 
including over-the-counter and alternative preparations (including herbal remedies, vitamins, 
and health food supplements), antibiotics, and pain medications being administered starting at 
least 3 months, and FVIII and bispecific activated FVIII mimetic products at least 12 months 
prior to study enrollment, will be recorded in the CRF at screening and throughout the 
treatment period and follow-up call. 
The participant should not be taking any other investigational drug or any other FVIII 
treatment (except in emergencies) while receiving treatment with KOVALTRY. 
Pre-medications to tolerate treatment with KOVALTRY are not allowed. Use of topical 
anesthetics prior to venipuncture is permitted. 
Medications which cause a bleeding diathesis (for example, Aspirin® or any acetylsalicylic 
acid) should be avoided in individuals with hemophilia, except as specifically prescribed by a 
treating physician. Low dose aspirin should not be discontinued in participants who have been 
identified to be at risk for cardiovascular events. The decision to prescribe non-steroidal  
anti-inflammatory drugs, cyclooxygenase-2 (COX-2) inhibitors, or brief courses of 
corticosteroids to treat pain or acute synovitis is at the discretion of the treating physician. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  37 of 105 
 
Inhaled or topical steroid medications (as for the treatment of asthma or eczema) are allowed. 
Brief courses of prednisone/methylprednisolone (<14 days) for treatment of disorders such as 
synovitis, asthma, etc. are at the discretion of the treating physician. For any participant 
requiring longer courses of corticosteroids or use of other immunomodulatory treatment, the 
investigator should notify the Sponsor. 
6.5.1 Rescue Medicine 
Not applicable. 
6.6 
Dose Modification 
6.6.1 
Dose Modification in Part A (PTPs) 
Dosing recommendations for prophylaxis in adults/adolescents and children are provided as 
per the approved label. Dose modifications should be individualized based on clinical 
response at the investigator discretion. 
Study participants receiving prophylaxis treatment 2x per week (i.e., on a 2x/week 
prophylaxis regimen) should increase prophylaxis dosing frequency to three times per week if 
they experience 2 or more spontaneous joint and/or muscle bleeding episodes within a 6-week 
period. 
Study participants receiving prophylaxis treatment 3x per week (i.e., on a 3x/week 
prophylaxis regimen) should increase prophylaxis dosing frequency to every other day if they 
experience 2 or more spontaneous joint and/or muscle bleeding episodes within a 6-week 
period. 
6.6.2 
Dose Modification in Part B (PUPs/MTPs) 
Individual participant dose decisions are at the discretion of the investigator. 
Recent studies have demonstrated that the timing of the first exposures to FVIII may be 
critical for the tolerance of the drug. The CANAL study showed that early intensive 
treatment, such as those required for surgery or severe bleeds, increased the risk for inhibitor 
development, whereas regular prophylaxis was associated with a lower risk.12 This 
observation was subsequently supported by studies demonstrating lower inhibitor rates in 
boys treated with low dose early prophylaxis in treatment centers in Germany.13  
Taking these observations into account, the following are treatment recommendations for 
PUPs/MTPs participating in Part B: 
1. Prophylaxis can be started directly with 15 to 50 IU/kg (minimum dose: 250 IU) 
once per week; the starting dose may be tailored to the participant’s weight or 
demonstrated bleeding tendency. 
2. Alternatively, treatment can be initiated with an on-demand regimen. Prophylaxis 
should begin after a minimal number of on-demand FVIII exposures with 
KOVALTRY (no more than 2 to 3 bleeding events) or when the child is large 
enough to tolerate weekly infusion. 
3. Avoid starting prophylaxis during a febrile illness or other identified inflammatory 
events.  
4. Avoid surgery or need for high dose intensive treatment lasting more than 4 days 
during the first 20 ED. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  38 of 105 
 
5. KOVALTRY must not be given as prophylaxis for vaccinations. 
After treatment with KOVALTRY begins, inhibitor testing every 3 to 5 ED is required until 
20 ED are accumulated or in case of non-response to treatment. 
6.6.3 
Breakthrough Bleeds and Minor Surgery 
KOVALTRY will also be used for the treatment of bleeding episodes in this study. The dose 
should be individualized according to severity of the specific bleeding episode. 
KOVALTRY will also be used for perioperative management of minor surgery that may 
occur during the course of the study. 
The dosages used for treatment of breakthrough bleeds or minor surgery will be at the 
discretion of the investigator.  
A guide for dosing for bleeding episodes and surgery, as well as a guide for the assessment of 
adequacy of hemostasis during surgery, are provided in Section 10.4. 
Definitions of response to treatment of breakthrough bleeds (i.e., excellent, good, moderate, 
or poor [or none]) is provided in Section 7.3.1. 
6.7 
Intervention After the End of the Study 
No intervention or extended treatment will be provided after the end of the study. 
6.8 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
6.8.1 
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, but will be evaluated for safety at his last study visit. Unscheduled visits are 
permitted at any time at the discretion of the investigator. 
See the SoAs (Section 1.3.1 for Part A and Section 1.3.2 for Part B) for data to be collected at 
the time of intervention discontinuation and for any further evaluations that need to be 
completed. For cases of early termination in Part A, all investigations for Visit 5 should be 
performed. For cases of early termination in Part B, all investigations for Visit 8/Final visit 
should be performed. 
6.8.2 
Temporary Discontinuation of Study Intervention 
Participants who have an emergency major surgery during the study may be treated with 
KOVALTRY or other FVIII, according to local practice at the discretion of investigators. 
Participants will resume their treatment assignment of KOVALTRY as per this protocol after 
surgical recovery. Duration of interruption of study intervention (i.e., prophylaxis treatment 
with KOVALTRY) should not be more than 2 weeks. 
During the trial, it is expected that all reasonable attempts will be made to ensure that study 
participants will comply with and adhere to their prophylaxis infusion schedule with few 
interruptions. In rare instances, it may be necessary for a study participant to temporarily 
discontinue study intervention (e.g., difficulty with IV access in children, travel to locations 
where appropriate support for infusions is not available). Study participants/caregivers should 
inform the investigator of all such situations, and the reasons must be documented in the 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  39 of 105 
 
medical record. Prolonged periods (>2 weeks) or repeated breaks in the prophylaxis schedule 
should be avoided and could result in the study participant being removed from the study. 
6.8.3 
Participant Discontinuation/Withdrawal from the Study 
A participant who withdraws is one who discontinues from a clinical study for any reason. 
The participant will not suffer any disadvantage as a result. 
A participant may be withdrawn from the study at any time: 
• At their own request or at the request of their parent/legal representative. Without 
giving reasons, a participant may decline to participate further. 
• At the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons. 
A participant must be withdrawn from the study: 
• In case of positive inhibitor result at Screening or in case of high titer inhibitor result 
at the Baseline visit. 
• In case of development of a high-titer inhibitor related to the study drug (>5 BU/mL, 
confirmed on a second measurement done in central laboratory [Part A] or in local 
laboratory [Part B] within 2 weeks of notification of initial detection of high-titer 
inhibitor) that interferes with effective treatment with FVIII and the investigator 
believes that it is in the best interest of the participant to receive treatment for 
management with ITI outside of the study. There is the option to receive ITI with 
study drug. In this case, the participant discontinues participation in Part A or Part B 
and continues in the Optional ITI Treatment. ITI with study drug will be provided at a 
dose of up to 200 IU/kg daily for up to a maximum of 18 months (see Section 10.5.1 
for additional information). While awaiting confirmatory testing for the initial result, 
treatment will be at the investigator’s discretion according to local standard of care. 
• If he fails to comply with scheduled appointments for the study-related evaluations 
and with EPD data entry to an extent that compromises collection of critical data. 
If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
At the time of discontinuing from the study, any attempts should be taken to conduct an early 
discontinuation visit (Visit 5 for Part A or Visit 8/Final visit for Part B). See the SoAs 
(Section 1.3.1 for Part A and Section 1.3.2 for Part B) 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 reason for each withdrawal must be recorded in the CRF and in participant´s medical 
record. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  40 of 105 
 
6.9 
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: 
• The site must attempt to contact the participant and reschedule the missed visit as soon 
as possible and counsel the participant on the importance of maintaining the assigned 
visit schedule and ascertain whether or not the participant wishes to and/or should 
continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing address 
or local equivalent methods). These contact attempts should be documented in the 
participant’s medical record. 
• Should the participant continue to be unreachable, he will be considered lost to  
follow-up. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  41 of 105 
 
7. 
Study Assessments and Procedures 
The list of study assessments and timing of these assessments and procedures are displayed in 
the SoAs (Section 1.3.1 for Part A and Section 1.3.2 for Part B) and are described in detail 
here. 
General Study Procedure Notes: 
• Protocol waivers or exemptions are not allowed. 
• Immediate safety concerns should be discussed with the Sponsor as soon as possible 
after the investigator becomes aware of an occurrence to determine if the participant 
should continue or discontinue study intervention. 
• Adherence to the study design requirements, including those specified in the SoAs 
(Section 1.3.1 for Part A and Section 1.3.2 for Part B), is essential and required for 
study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable. 
• Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and obtained before signing of the ICF may be utilized for 
screening or baseline purposes provided the procedures met the protocol-specified 
criteria and were performed within the time frame defined in the SoA. 
If deemed necessary for an individual participant, the investigator or designee, at his/her 
discretion, may arrange visits in addition to the scheduled study visits. Unscheduled visits will 
be documented in the eCRF. 
Visits during Optional ITI Treatment are described in Section 10.5.2. 
Blood Draw Volume 
Every effort has been made to minimize the volumes of blood required for participation in the 
study. 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 (see 
Section 10.2). For participants <10 kg, the maximum amount of blood collected from each 
participant over the duration of the study, including any extra assessments that may be 
required, should follow recommendations for blood draws in participants <10 kg. Repeat or 
unscheduled samples may be taken for safety reasons or for technical issues with the samples. 
7.1 
Study Visits - Part A (PTPs) 
7.1.1 
Screening/Visit 1 (Up to 6 Weeks Prior to Baseline) 
After obtaining signed Informed Consent from the prospective participant or his parent or 
legal representative, as required, the following screening assessments will be obtained 
(screening assessments may require multiple site visits prior to baseline): 
• Inclusion/exclusion criteria verification 
• Allocation of a unique participant number 
• Review of eligibility requirements; no participant should receive study 
intervention unless all inclusion and exclusion criteria are met as listed in 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  42 of 105 
 
Section 5.1 and Section 5.2. Confirmation of selection criteria may be based on 
medical records for some conditions, but laboratory test results must be available 
for the listed items to confirm eligibility. 
• Collect demographic data (e.g., age, sex [male only], race, etc.) 
• Height and body weight (kg) 
• Obtain a complete medical and surgical history (e.g., general, hemophilia, family 
history of hemophilia, and history of inhibitor development) 
• Specific information on history of hemophilia (date of diagnosis, start of 
therapy, prior and current factor VIII products, number of ED, family 
history, FVIII level at diagnosis, family and personal history of past 
inhibitor formation, current treatment product and regimen, number and 
type of bleeding episodes in the last 12 months, and presence and location 
of target joints [defined as at least 3 spontaneous bleeding episodes into a 
single joint within a consecutive 6-month period]) 
• Prior medication (medication history), see Section 6.5 
• Concomitant medication, see Section 6.5 
• Physical examination, see Section 8.1 
• Vital signs (including systolic and diastolic blood pressure, heart rate, and body 
temperature), see Section 8.2 for details 
• Procedures and sample collection (see Section 8.3 and Section 10.2) 
• Blood samples for: 
• Serology screening (HBV, HCV, HIV, and only if participant is 
HIV positive, CD4 count) 
• FVIII trough level (at least 72 hours after last pre-study FVIII infusion) 
• Factor VIII inhibitor (Section 8.10) 
• Laboratory evaluation (hematology and clinical chemistry) 
• Training on and dispense of EPD device 
Electronic patient diary (EPD) training and dispensing will also be done at the Screening visit 
after enrollment is completed and a study participant number is assigned. The EPD will be 
given to the participants or his caregivers to take home at any time between Screening and 
Baseline; however, participants/caregivers will be informed that no entries are to be made 
before the first infusion at Baseline. 
In addition to the patient diary training at clinic visits, participants/caregivers will be told that 
study center staff will call each participant or parent/caregiver approximately every 2 weeks 
between Baseline and Visit 5 (Month 6) to verify proper completion of the participant diary 
and to review any new AEs and changes in concomitant medication since the last study visit 
and AEs. 
7.1.2 
Baseline/Visit 2 (No Later Than 6 Weeks From Visit 1) 
The Baseline visit will include the following assessments and procedures: 
• Inclusion/exclusion criteria verification, i.e., confirmation of eligibility including 
check of laboratory test results 
Note: Participants must have negative results from the central laboratory for 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  43 of 105 
 
inhibitory antibodies against FVIII (<0.6 BU/mL determined with the 
Nijmegen-modified Bethesda assay) 
• Height and weight for children/adolescents. Weight for adults. 
• Physical examination 
• Vital signs 
• Concomitant medication review 
• Blood sampling before administration of study drug intervention 
• FVIII inhibitor assessment (Section 8.10) 
• FVIII pre-infusion recovery (Section 7.3.2) 
• Laboratory evaluation (hematology, clinical chemistry) 
• In-hospital administration of KOVALTRY 
• Blood sampling after administration of study intervention (Section 7.3.2): 
• Incremental recovery (15 to 30 minutes post infusion) 
• PK subset: Blood samples for PK assessments as outlined in Section 8.6 
• Adverse events review 
• Study drug dispensation for home infusions in accordance with IxRS drug 
dispensing schedule 
• Diary training review. Participants or their caregivers will be instructed to 
complete the EPD as required (see Section 7.3.1) beginning at Baseline and 
through the end of the study (Visit 6). 
• Begin regular bi-weekly contact between participant and the site to check EPD 
documentation and AE review until the End of Study/Early Termination 
Although the first dose of study medication will be administered in the study center, 
additional study intervention supplies will be dispensed to participants or his caregivers for 
home infusions in accordance with IxRS drug dispensing schedule. Details of the study 
intervention provided are described in Section 6. 
7.1.3 
Visit 3/Month 1 (±7 Days) 
At Visit 3, the following assessments and procedures will be performed as displayed in 
Section 1.3.1: 
• Height and weight for children/adolescents 
• Weight for adults 
• Vital signs 
• Concomitant medication review 
• Review of EPD entries and bleeding history 
• Blood sampling for Factor VIII inhibitor (Section 8.10) 
• AE review 
• Study drug dispensation for home infusions in accordance with IxRS drug 
dispensing schedule 
• Return used and unused study intervention, drug accountability 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  44 of 105 
 
• Continue regular bi-weekly contact between participant and the site to check EPD 
documentation and AE review until the End of Study/Early Termination 
7.1.4 
Visit 4/Month 2 (±7 Days) 
At Visit 4 (Month 2), the following assessments and procedures will be performed as 
displayed in Section 1.3.1: 
• Height and weight for children/adolescents 
• Weight for adults 
• Vital signs 
• Concomitant medication review 
• Review of EPD entries and bleeding history 
• Blood sampling before administration of study drug intervention 
• FVIII inhibitor assessment (Section 8.10) 
• FVIII pre-infusion recovery (Section 7.3.2) 
• Laboratory evaluation (hematology, clinical chemistry) 
• In-hospital administration of KOVALTRY 
• Blood sampling after administration of study intervention (Section 7.3.2): 
• Incremental recovery (15 to 30 minutes post infusion) 
• AE review 
• Study drug dispensation for home infusions in accordance with IxRS drug 
dispensing schedule 
• Return used and unused study intervention, drug accountability 
• Continue regular bi-weekly contact between participant and the site to check EPD 
documentation and AE review until the End of Study/Early Termination 
7.1.5 
Visit 5/Month 6 (±7 Days)/Final Visit/Early Termination 
At Visit 5 (Month 6 [±7 days]), the following assessments and procedures will be performed 
as described in Section 1.3.1: 
• Height and weight (children and adolescents; weight only is obtained for adults) 
• Physical examination 
• Vital signs 
• Concomitant medication review 
• Blood sampling before administration of study drug intervention 
• FVIII inhibitor assessment (Section 8.10) 
• FVIII pre-infusion recovery (Section 7.3.2) 
• Laboratory evaluation (hematology, clinical chemistry) 
• In-hospital administration of KOVALTRY 
• Blood sampling after administration of study intervention (Section 7.3.2): 
• Incremental recovery (15 to 30 minutes post infusion) 
• PK subset of adolescents/adults participants ≥12 years: Blood samples for PK 
assessments as outlined in Section 8.6 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  45 of 105 
 
• Adverse events review 
• Review of EPD entries and bleeding history (see Section 7.3.1) and return EPD 
• Return used and unused study intervention, drug accountability 
7.1.6 
Follow-Up Call (+2 Weeks ±7 Days After the Final Visit) 
For this telephone contact, each participant or caregiver will be asked about adverse events 
occurring since Visit 5 (6 months) and any concomitant medications including FVIII product 
used. 
7.2 
Study Visits - Part B (PUPs/MTPs) 
Part B consists of a screening period followed by at least 50 ED per participant. 
For MTPs, the Screening visit should only take place after a washout period of at least 
72 hours following previous treatment with any FVIII replacement product. 
The treatment period will last until 50 ED have been accumulated. The duration will vary and 
is dependent upon the frequency of prophylactic infusion and the number of bleeding events. 
7.2.1 
Visit 1/Screening 
After obtaining signed Informed Consent from the prospective participant’s parent or legal 
representative, as required, the following screening assessments will be performed: 
• Inclusion/exclusion criteria verification 
• Allocation of a unique participant number 
• Review of eligibility requirements; no participant should receive study 
intervention unless all inclusion and exclusion criteria are met as listed in 
Section 5.1 and Section 5.2, respectively. Confirmation of selection criteria may be 
based on medical records for some conditions, but laboratory test results must be 
available for the listed items to confirm eligibility. 
• Collect demographic data (e.g., age, sex [male only], race, etc.) 
• Height/length and body weight (kg) 
• Obtain a complete medical and surgical history (e.g., general, hemophilia, family 
history of hemophilia) 
• PUPs: Specific information on history of hemophilia (date of diagnosis, 
family history, FVIII level at diagnosis, treatment received for hemophilia, 
family history of past inhibitor formation, number and type of bleeding 
episodes in the last 12 months, and presence and location of target joints) 
• MTPs: Specific information on history of hemophilia (date of diagnosis, 
start of therapy, current FVIII product, number of ED, family history, FVIII 
level at diagnosis, history of inhibitor development, family history of past 
inhibitor formation, current treatment product and regimen, number and 
type of bleeding episodes in the last 12 months, and presence and location 
of target joints [defined as at least 3 spontaneous bleeding episodes into a 
single joint within a consecutive 6-month period]) 
• Prior medication (medication history), see Section 6.5 
• Physical examination, see Section 8.1 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  46 of 105 
 
• Vital signs (including systolic and diastolic blood pressure, heart rate, and body 
temperature); blood pressure may be deferred if the appropriate cuff size or 
equipment is not available (see Section 8.2 for details) 
• Procedures and sample collection (see Section 8.3 and Section 10.2) 
• Blood samples for the following: 
• Baseline FVIII level (≥72 hours after the last pre-study FVIII infusion 
for MTPs) 
• FVIII inhibitor assessment (Section 8.10; not required for PUPs but 
required for MTPs) 
• Laboratory evaluation (hematology and clinical chemistry) 
• Training on and dispensation of EPD device 
EPD training and dispensation will also be done at the Screening visit after enrollment is 
completed and a study participant number is assigned. The EPD will be given to the 
parent/caregiver to take home at any time between Screening and Baseline; however, 
parents/caregivers will be informed that no entries are to be made before the first infusion at 
Baseline. 
In addition to the EPD training at clinic visits, parents/caregivers will be told that study center 
staff will call each participant’s parent/caregiver every 2 weeks between Baseline and the 
Final visit to verify proper completion of the participant diary and to review any new AEs and 
changes in concomitant medication since the last study visit. 
7.2.2 
Visit 2/Baseline (No Later Than 4 Weeks From Visit 1) 
For MTPs, this visit will include the first administration of study drug. 
For PUPs, the first dose of KOVALTRY may be for treatment of a bleed. First treatment 
should not occur during high risk situations, surgery, or bleeds requiring prolonged or 
intensive treatment (see Section 6.6.2). 
The following activities will be performed: 
• Inclusion/exclusion criteria verification, i.e., confirmation of eligibility including 
check of laboratory test results. 
Note: MTPs must be inhibitor negative as evaluated via local laboratory testing at 
the Screening visit. A confirmatory inhibitor test must be taken at least 1 week but 
not more than 2 weeks after the Screening visit. Results from local laboratory 
testing must be negative (<0.6 BU/mL) prior to administration of study 
intervention. 
• Height/length and weight 
• Vital signs (including systolic and diastolic blood pressure, heart rate, and body 
temperature); blood pressure may be deferred if the appropriate cuff size or 
equipment is not available (see Section 8.2 for details) 
• Concomitant medication review 
• Blood sampling before administration of study drug intervention 
• FVIII inhibitor assessment (Section 8.10; not required for PUPs but 
required for MTPs) 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  47 of 105 
 
• In-hospital administration of the first dose of study drug (for MTPs and PUPs who 
are starting treatment at baseline). 
Note: First exposure to study drug may be either for treatment of an uncomplicated 
bleed or for start of prophylaxis. Inhibitor testing is mandatory every 3 to 5 ED 
until 20 ED are accumulated (see Section 6.6.2). 
• Blood sampling after administration of study intervention (Section 7.3.2): 
• Incremental recovery (15 to 30 minutes post infusion) only for participants 
who start prophylaxis at Baseline; for PUPs who do not start prophylaxis at 
baseline, recovery should be done when prophylaxis is started 
• AE review 
• Study drug dispensation for home infusions in accordance with the IxRS drug 
dispensing schedule 
• Diary training review; participants/caregivers will be instructed to complete the 
EPD as required (see Section 7.3.1) beginning at Baseline through the end of the 
study (see Section 4.4) 
• Instruction on the prophylaxis regimen to be administered to the participant 
• Begin regular biweekly contact between the participant’s parent/caregiver and the 
site to check EPD documentation and AE review until the End of Study/Early 
Termination 
It is recommended for PUPs to have the first dose of study intervention administered in the 
study center. Details of the study intervention provided are described in Section 6. 
7.2.3 
Visit 3/ED ~5 (4 ED ±1) 
At Visit 3, the following assessments and procedures will be performed as displayed in 
Section 1.3.2. 
• Height/length and weight 
• Vital signs (see Section 8.2 for details) 
• Concomitant medication review 
• Review of EPD entries and bleeding history 
• Blood sampling for laboratory tests 
• FVIII inhibitor assessment (Section 8.10) 
• FVIII:C trough level (≥48 hours after the last FVIII treatment) 
• AE review 
• Study drug dispensation for home infusions in accordance with the IxRS drug 
dispensing schedule 
• Return used and unused study intervention (study drug accountability) 
• Continue regular biweekly contact between the participant’s parent/caregiver and 
the site to check EPD documentation and AE review until the End of Study/Early 
Termination 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  48 of 105 
 
7.2.4 
Visit 4/ED ~10 (9 ED ±1) 
At Visit 4, the following assessments and procedures will be performed as displayed in 
Section 1.3.2. 
• Height/length and weight 
• Vital signs (see Section 8.2 for details) 
• Concomitant medication review 
• Review of EPD entries and bleeding history 
• Blood sampling for laboratory tests 
• FVIII inhibitor assessment (Section 8.10) 
• FVIII:C trough level (≥48 hours after the last FVIII treatment) 
• AE review 
• Study drug dispensation for home infusions in accordance with the IxRS drug 
dispensing schedule 
• Return used and unused study intervention (study drug accountability) 
• Continue regular biweekly contact between the participant’s parent/caregiver and 
the site to check EPD documentation and AE review until the End of Study/Early 
Termination 
7.2.5 
Visit 5/ED ~15 (14 ED ±1) 
At Visit 5, the following assessments and procedures will be performed as displayed in 
Section 1.3.2. 
• Height/length and weight 
• Vital signs (see Section 8.2 for details) 
• Concomitant medication review 
• Review of EPD entries and bleeding history 
• Blood sampling for laboratory tests 
• FVIII inhibitor assessment (Section 8.10) 
• FVIII:C trough level (≥48 hours after the last FVIII treatment) 
• AE review 
• Study drug dispensation for home infusions in accordance with the IxRS drug 
dispensing schedule 
• Return used and unused study intervention (study drug accountability) 
• Continue regular biweekly contact between the participant’s parent/caregiver and 
the site to check EPD documentation and AE review until the End of Study/Early 
Termination 
7.2.6 
Visit 6/ED 20 (20 ED ±1) 
At Visit 6, the following assessments and procedures will be performed as displayed in 
Section 1.3.2. 
• Height/length and weight 
• Vital signs (see Section 8.2 for details) 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  49 of 105 
 
• Concomitant medication review 
• Review of EPD entries and bleeding history 
• Blood sampling for laboratory tests 
• FVIII inhibitor assessment (Section 8.10) 
• FVIII:C trough level (≥48 hours after the last FVIII treatment) 
• In-hospital administration of study intervention 
• Blood sampling after administration of study intervention (Section 7.3.2): 
• Incremental recovery (15 to 30 minutes post infusion) 
• AE review 
• Study drug dispensation for home infusions in accordance with the IxRS drug 
dispensing schedule 
• Return used and unused study intervention (study drug accountability) 
• Continue regular biweekly contact between the participant’s parent/caregiver and 
the site to check EPD documentation and AE review until the End of Study/Early 
Termination 
7.2.7 
Visit 7/Interim Visit/30 to 40 ED 
This visit is required only for PUPs and MTPs who have less than 40 ED 6 months after the 
Baseline visit. The intent is to have at least one scheduled visit between completion of 20 ED 
and the expected date of accumulating 50 ED. The primary purpose of the visit is to assess the 
well-being of the participant, ensure continued compliance with the treatment, and make any 
needed adjustments in dosage or infusion frequency based upon weight or bleeding events. 
The following procedures and assessments will be performed: 
• Height/length and weight 
• Vital signs (see Section 8.2 for details) 
• Concomitant medication review 
• Review of EPD entries and bleeding history 
• Blood sampling for laboratory tests 
• FVIII inhibitor assessment (Section 8.10) 
• FVIII:C trough level (≥48 hours after the last FVIII treatment) 
• AE review 
• Study drug dispensation for home infusions in accordance with the IxRS drug 
dispensing schedule 
• Return used and unused study intervention (study drug accountability) 
• Continue regular biweekly contact between the participant’s parent/caregiver and 
the site to check EPD documentation and AE review until the End of Study/Early 
Termination 
7.2.8 
Final Visit/50 ED (+7 Days)/Early Termination 
This visit will take place after 50 ED with study intervention are accumulated in participants 
who do not develop high titer FVIII inhibitor, or in the case of early termination. It is 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  50 of 105 
 
expected that 50 ED will be achieved for most participants between 6 and 12 months after the 
start of prophylactic treatment. 
The following procedures and assessments will be performed: 
• Height/length and weight 
• Physical examination 
• Vital signs (see Section 8.2 for details) 
• Concomitant medication review 
• Review of EPD entries and bleeding history 
• Blood sampling for laboratory tests 
• FVIII inhibitor assessment (Section 8.10) 
• FVIII:C trough level (≥48 hours after the last FVIII treatment) 
• In-hospital administration of study intervention 
• Blood sampling after administration of study intervention (Section 7.3.2): 
• Incremental recovery (15 to 30 minutes post infusion) 
• AE review 
• Return of EPD 
• Return of used and unused study intervention for final study drug accountability 
7.2.9 
Follow-Up Call (2 Weeks ±7 Days After the Final Visit) 
In this telephone contact, each participant’s parent/caregiver will be asked about any new AEs 
and changes in concomitant medication, including FVIII products, since the last study visit. 
7.3 
Efficacy Assessments 
The primary efficacy variable in Part A is the ABR of all bleeding episodes during 
prophylaxis. The ABR of all bleeding episodes within 48 hours of a previous prophylaxis 
infusion is the primary efficacy variable in Part B. The ABR of all bleeding episodes during 
prophylaxis in Part B and the ABR of all bleeding episodes within 48 hours of a previous 
prophylaxis infusion in Part A will be assessed as secondary efficacy parameters. 
Additionally, the ABR for the following efficacy variables will be summarized for both 
Part A and Part B: 
• Treated bleeding episodes 
• Joint bleeding episodes 
• Joint bleeding episodes within 48h of previous prophylaxis infusion 
• Target joint bleeding episodes 
• Spontaneous bleeding episodes 
• Spontaneous bleeding episodes within 48h of previous prophylaxis infusion 
• Spontaneous joint bleeding episodes 
• Trauma bleeding episodes 
• Trauma bleeding episodes within 48h of previous prophylaxis infusion 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  51 of 105 
 
Other efficacy variables include: 
• Minor surgery bleeding control 
• Participants’/parents’/physician’s (in case of surgery) assessment of the response 
to treatment of bleeding episodes (excellent, good, moderate, or poor) 
• The number of infusions required to treat a bleeding episode 
• Factor VIII usage (expressed as number of infusions and IU/kg per year, as well as 
IU/kg per event) 
• Extent of exposure in terms of exposure days (EDs) 
• Type, location, and severity of bleeding episodes 
• Reason for each infusion 
• Incremental recovery 
7.3.1 
Treatment Logs/Bleeding Verification 
Treatment logs are commonly used for hemophilia participants for documentation of their 
home treatment. Home treatment and bleeding information are the key variables for 
evaluation of efficacy. Study specific treatment logs will be provided in national language. 
The preferred system for this study will be EPD devices since they are interactive, allow for 
real time data transmission, record-stamp date and time of fulfillment, and facilitate the 
clarification of data with the site and the data cleaning process. Participants will be provided 
with EPDs for the entire study. At the Screening visit, participants/caregivers will be trained 
in the use of the device. These logs will be used to collect the treatment data and bleeding 
episodes by the participants, and the data will be verified for accuracy and completion by the 
investigator or delegate during regularly scheduled interactions with the participant. Thus, the 
EPD will be considered the source for these data. 
Infusion of KOVALTRY 
For each self-administered infusion of KOVALTRY, information must be recorded on the 
EPD as follows: 
a. Date and time 
b. Individual vial number (bar code scan from vial label or manual entry) and units 
administered 
c. Reason for treatment: 
- 
Prophylaxis 
- 
Unscheduled prophylaxis (e.g., for physical activities, suspected or non-evident 
bleeding following identified trauma) 
- 
Spontaneous bleeding first treatment 
- 
Trauma bleeding first treatment 
- 
Follow-up treatment 
- 
Surgery 
- 
ITI (only applicable to participants who develop high-titer inhibitor and received 
ITI) 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  52 of 105 
 
Infusions of KOVALTRY as part of protocol mandated visits and procedures (e.g., for 
recovery and PK) will be recorded on the respective CRF pages. 
Bleeding Episode 
All bleeding episodes (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: 
a. Date and time of onset 
b. Type of bleeding (spontaneous, trauma, joint, muscle, skin/mucosal, internal, other) 
c. Location 
d. Intensity (mild, moderate, severe) 
e. Treated [yes/no]: 
If “yes”: 
Date and time 
Product used: KOVALTRY or other 
Doses 
If KOVALTRY is used for the treatment of a bleeding episode, the response to treatment 
(excellent, good, moderate, poor, too early to tell) must to be recorded. If “too early to tell” is 
entered, the participant will be queried for a response the next time the device is used. 
For guidance to the participant or their caregiver, the following definitions for response to 
treatment are suggested. Individual participant responses may vary. 
• Excellent: Abrupt pain relief and/or improvement in signs of bleeding with no 
additional infusion administered 
• Good: Definite pain relief and/or improvement in signs of bleeding, but possibly 
requiring more than one infusion for complete resolution 
• Moderate: Probable or slight improvement, with at least one additional infusion 
for complete resolution 
• Poor (or None): No improvement or condition worsens 
The following additional guidance should be used for clarification of whether information 
should be recorded in the EPDs or in the CRFs: 
• Information on study treatment administration must be captured in either the CRFs 
or in the EPDs, but not both. Information should not be duplicated. 
• All use of study treatment outside the hospital/clinic should be recorded in the 
EPD. 
• Use of study treatment in the hospital/clinic as defined in the protocol (e.g., at 
protocol-defined visits, for PK or recovery) should be recorded in the CRFs. 
• In the extremely unlikely event that an infusion at a protocol-defined visit 
is given for a bleeding, the information should be recorded in the EPD 
rather than the CRFs, since additional information needs to be collected for 
bleeding that is not collected in CRFs but only in the EPD. 
• 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 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  53 of 105 
 
(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). 
7.3.2 
Incremental Recovery of KOVALTRY 
Incremental recovery will be determined by collecting a sample for KOVALTRY level before 
the scheduled infusion, and a second sample collected 15 to 30 min after end of the infusion. 
Blood samples for KOVALTRY trough (predose) and recovery levels (15 to 30 min post 
infusion) will be collected in all participants at Visits 2, 4, and 5 in Part A; at Visits 2, 6, and 
8 in Part B; and at additional time points based on the investigator’s discretion. Infusions must 
be given in hospital and use the participants assigned treatment dose, rounded to full vial size. 
The exact times for infusion and blood sampling before and after infusion and the dose 
administered will be documented in the CRF. 
Infusions given at study visits will be recorded in the site participant records, which will be 
the source documents and will be used to enter this information in the CRF. 
The samples will be collected as described in detail in the laboratory manual. All samples will 
be processed in the central laboratory (Part A) or local laboratory (Part B). Plasma 
concentrations of FVIII will be measured using a validated FVIII activity assay 
(“chromogenic assay” for Part A, “one-stage clotting assay” for Part B). 
Samples for incremental recovery should be collected on days when the next prophylactic 
infusion is scheduled and at least 48 h after the last infusion prior to this. The measurements 
should only be performed when the participant is not actively bleeding and when FVIII:C 
levels are close to trough. 
8. 
Safety Assessments 
Planned time points for all safety assessments are provided in the SoAs (Section 1.3.1 for 
Part A and Section 1.3.2 for Part B). 
The safety endpoints for the study include: 
• 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 confirmed by testing a second (separately drawn) sample in a central 
laboratory (Part A) or local laboratory (Part B). 
• TEAEs 
• Laboratory values and vital signs 
The safety assessments for optional ITI treatment will be analyzed separately (see Section 9). 
8.1 
Physical Examination 
• Physical examinations will be performed at Screening, Baseline, and at the Final 
visit/Early Termination visit. 
• A complete physical examination will include, at a minimum, assessments 
of the general appearance, dermatologic, head, eyes, ears, nose, 
mouth/throat/neck, thyroid, lymph nodes, cardiovascular, respiratory, 
gastrointestinal, extremities, neurological, and musculoskeletal, and review 
of systems. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  54 of 105 
 
• Investigators should pay special attention to clinical signs related to 
previous serious illnesses. Any abnormal finding should be documented. 
• Height and weight will also be measured and recorded at the time points described 
in the SoAs (Section 1.3.1 for Part A and Section 1.3.2 for Part B). Body length 
will be measured instead of height, as age appropriate. 
8.2 
Vital Signs 
• Vital signs will be measured at all visits. In case of any in-hospital infusion related 
AE, vital signs will be measured post-infusion for participants. 
• Heart rate, body temperature, respiratory rate, and systolic and diastolic blood 
pressures will be assessed. Blood pressure may be deferred in infants if the 
appropriate size cuff or equipment is not available. 
• Blood pressure and heart rate measurements should be preceded by at least 
5 minutes of rest for the participant in a supine or seated position without 
distractions (e.g., television, cell phones). 
8.3 
Clinical Safety Laboratory Assessments 
See Section 10.2 for the list of clinical laboratory tests to be performed and the SoAs 
(Section 1.3.1 for Part A and Section 1.3.2 for Part B) for the timing and frequency. 
• The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE section 
of the CRF. The laboratory reports must be filed with the source documents. 
Clinically significant abnormal laboratory findings (based on the normal reference 
ranges supplied in investigator training) are those that are not associated with the 
underlying disease, unless judged by the investigator to be more severe than 
expected for the participant’s condition. 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or 
baseline or are no longer considered clinically significant by the investigator. 
• If such values do not return to normal/baseline within a period of time 
judged reasonable by the investigator, the etiology should be identified and 
the Sponsor notified. 
• All protocol-required laboratory assessments, as defined in Section 1.3.1 
and Section 1.3.2, must be conducted in accordance with the laboratory 
manual and the SoAs. 
• If laboratory values from non-protocol specified laboratory assessments 
performed at the institution’s local laboratory require a change in 
participant management or are considered clinically significant by the 
investigator (e.g., SAE or AE or dose modification), then the results must 
be recorded in the CRF. 
8.4 
Adverse Events and Serious Adverse Events 
As described in Section 10.3, an AE is any untoward medical occurrence in a patient or 
clinical study participant, associated with the use of study intervention, whether or not 
considered related to the study intervention. Detailed definitions and procedures for recording, 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  55 of 105 
 
evaluating, follow-up, and reporting of all types of adverse events including SAEs can be 
found in Section 10.3. Events identified as adverse events of special interest (AESIs) for this 
study are specified in Section 8.4.7. 
Any AE may be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant’s legally authorized representative or health care professional not involved 
in the study). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE. They remain responsible for 
following up SAEs, AEs considered related to the study intervention or study procedures, or 
those that caused the participant to discontinue the study. Events of Special Interest have to be 
followed up regardless of causality or relationship to study intervention (see Section 8.4.7). 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information 
All AEs and SAEs will be collected from the signing of the informed consent form (ICF) until 
the Follow-up call after the Final visit at the time points specified in the SoAs (Section 1.3.1 
for Part A and Section 1.3.2 for Part B). 
Medical occurrences that begin before the start of study intervention but after obtaining 
informed consent will be recorded on the AE Report Form of the case report form (CRF). 
Adverse events that in the opinion of the investigator occurred as a result of a study screening 
procedure will be considered non-treatment emergent adverse events and will be recorded as 
AEs in the eCRF. 
All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstances should this exceed 24 hours, as indicated in Section 10.3. The investigator will 
submit any updated SAE data to the Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE after conclusion of the study 
participation. However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and the investigator considers the event 
to be reasonably related to the study intervention or study participation, the investigator must 
promptly notify the Sponsor. 
8.4.2 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Section 10.3. 
Care will be taken to not introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.4.3 
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 AEs/SAEs/AESIs will be followed until 
resolution, stabilization, the event is otherwise explained, or the participant is lost to  
follow-up (as defined in Section 6.9). Further information on follow-up procedures is 
provided in Section 10.3. 
8.4.4 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the investigator to the Sponsor of an SAE within 24 hours 
is essential so that legal obligations and ethical responsibilities towards the safety 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  56 of 105 
 
of participants and the safety of a study intervention under clinical investigation 
are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a study intervention under 
clinical investigation. The Sponsor will comply with country-specific regulatory 
requirements relating to safety reporting to the regulatory authority, Institutional 
Review Boards (IRBs)/Independent Ethics Committees (IECs), and investigators. 
• Safety reports must be prepared by Sponsor for suspected unexpected serious 
adverse reactions (SUSAR) according to local regulatory requirements and 
Sponsor policy and forwarded to investigators as necessary. 
• An investigator who receives an investigator safety report describing an SAE or 
other specific safety information (e.g., summary or listing of SAEs) from the 
Sponsor will review and then file it along with the Investigator’s Brochure and will 
notify the IRB/IEC, if appropriate according to local requirements. 
8.4.5 
Pregnancy 
Only male participants will be enrolled in this study ages <12 years and ≥12 to 65 years in 
Part A and <6 years in Part B. There is no target-related specific transport mechanism for 
KOVALTRY into semen or from semen into the conceptus. Following administration to a 
male participant, KOVALTRY would not be bioavailable via seminal delivery to the 
developing conceptus of an untreated partner. Therefore, no method of contraception is 
needed. 
Bayer usually does not gather pregnancy information of drug exposure via father; however, if 
those cases are reported, details of all pregnancies in female partners of male participants will 
be collected after the start of study intervention and until the one-week period that is at least 
5 terminal half-lives after the last dose. If a pregnancy is reported, the investigator should 
inform the Sponsor of learning of the pregnancy. 
8.4.6 
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: 
• 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 8.4.4). 
NOTE: If either of the following conditions applies, then the event must be recorded and 
reported as an SAE (instead of a DRE): 
• The event is, in the investigator’s opinion, of greater intensity, frequency, or 
duration than expected for the individual participant. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  57 of 105 
 
OR 
• The investigator considers that there is a reasonable possibility that the event was 
related to study intervention. 
8.4.7 
Adverse Events of Special Interest (AESI) 
The adverse events of special interest in this study are: 
• Development of factor VIII inhibitors: It is mandatory that inhibitor development is 
assessed as “serious” and reported to the study Sponsor within 24 hours of awareness 
as a medical important event, following standards for SAE reporting. 
• Hypersensitivity and allergic reactions including skin related and systemic reactions, 
such as anaphylactic reactions (seriousness should be a case by case decision). 
8.5 
Treatment of Overdose 
Not applicable. No symptoms of overdose have been reported according to the Prescribing 
Information (see Section 12). 
8.6 
Pharmacokinetics 
PK assessments will be performed in Part A only. 
The PK assessments are planned in a subset of 12 children <12 years and in 
12 adolescents/adults ≥12 years. For participants <12 years old, the study would strive for 
balance between the two subgroups (<6y and 6 to <12y). 
Based on the observed PK of KOVALTRY in prior studies, it is expected that a reduced 
sampling strategy will be sufficient to calculate relevant PK parameters in children below 
12 years reliably. 
For the PK of KOVALTRY assessment, participants will be administered a dose of 50 IU/kg. 
The participant must have no signs or symptoms of an acute bleeding episode. Measurement 
of FVIII activity of KOVALTRY will be done pre-infusion, 15 to 30 min, 4h, and 24 h  
post-infusion in children below 12 years and pre-infusion, 10 to 15min, 30min, 1h, 4h, 6 to 
8h, 24h, and 30 to 48h in adolescent/adult participants. Samples should be collected as close 
as possible to the designated sampling times and at least 48 hours after previous treatment to 
ensure that pre-infusion KOVALTRY levels are measured at trough. If there is a delay in 
collecting a sample, it should still be collected. In all cases, the exact time of start and end of 
infusion and the time of actual sample collection should be noted in the CRF. Infusion doses 
for PK measurements and recovery should be given at the study center and directly reported 
in CRF. 
The actual sampling times will be used for PK evaluation. Deviations from planned PK blood 
sampling times are not considered protocol deviations. 
All samples will be processed in the central laboratory. 
For children below 12 years, the evaluation of PK of KOVALTRY is only required once and 
should be performed at Visit 2. 
For adolescents/adult participants 12 years or older, two PK profiles for the evaluation of PK 
of KOVALTRY are required. The first PK profile should be performed with start of treatment 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  58 of 105 
 
with KOVALTRY at Visit 2. The second PK profile should be performed after approximately 
6 months of treatment at Visit 5. 
Based on the plasma concentration time data, the following PK parameters will be derived: 
Cmax, AUC, AUCnorm, AUC (0-t last), AUC (0-t last) norm, Cmax norm, clearance, MRT, Vss, and t½. 
Details about the collection, processing, storage, and shipment of samples will be provided 
separately (e.g., sample handling sheets or laboratory manual). 
8.7 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.8 
Genetics 
Genetics are not evaluated in this study. 
8.9 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.10 
Immunogenicity Assessments 
8.10.1 
Part A (PTPs) Immunogenicity Assessments 
All participants in Part A will be tested for Factor VIII inhibitor development at Screening, 
Baseline (Day 1), Visit 3, Visit 4, and Visit 5 (Month 6, End of Study/Early Termination), or 
in case of suspicion of Loss of Efficacy (LoE). 
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 at the central laboratory. If an 
inhibitor to the study drug (KOVALTRY) is detected after the participant has started 
treatment with study drug, 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. 
8.10.2 
Part B (PUPs/MTPs) Immunogenicity Assessments 
In Part B, the requirement for FVIII inhibitor testing before start of study treatment at 
Screening and Baseline will only be done in MTPs; this assessment is not applicable for 
PUPs. The absence of inhibitors will be assessed by local laboratory testing at Screening 
(<0.6 BU/mL) of 2 consecutive samples at least 1 week but not more than 2 weeks apart. 
After study treatment is started, PUPs/MTPs must be tested for development of inhibitor to 
study drug (KOVALTRY) at Visit 3 [approximately 5 ED], Visit 4 [approximately 10 ED], 
Visit 5 [approximately 15 ED], Visit 6 [approximately 20 ED], Visit 7/Interim visit 
[approximately 30 to 40 ED], and Visit 8/Final visit [50 ED]/Early Termination). The first 
positive inhibitor test must be confirmed by analysis of a second sample and by analysis of 
FVIII level recovery within 2 weeks of notification. After confirmation of the positive result, 
the inhibitor development will be reported as SAE. 
8.11 
Health Economics 
Health Economics parameters are not evaluated in this study. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  59 of 105 
 
9. 
Statistical Considerations 
In order to reduce the risk generally associated with open-label trials, the final SAP will be 
available before the first participant first visit. 
9.1 
Statistical Hypotheses 
The study is not designed to test any predefined hypothesis. The statistical analysis planned 
for the study is aimed to follow the analyses of the completed LEOPOLD studies and will be 
descriptive. The Statistical Analysis Plan (SAP) will provide the details of all planned 
analyses. 
9.2 
Sample Size Determination 
9.2.1 
Sample Size Determination in Part A (PTPs) 
The primary variable “annualized bleeding rate (ABR)” is used for the evaluation of the 
efficacy. The mean ABR for total bleeding episodes for previously treated severe 
hemophilia A study participants <12 years of age receiving prophylaxis with KOVALTRY in 
completed LEOPOLD Kids Part A study was 3.75 ± 4.98 (median (Q1; Q3): 1.90 (0.00; 
6.02)).11 Assuming that the average ABR for this patient population is 4 bleeding episodes 
and the standard deviation is 5 bleeding episodes per year, a sample size of 30 participants 
will allow estimating ABR by means of a 95% confidence interval with a half-width of 1.8 
(the confidence interval is 2.2-5.8) which will consider to provide reasonable precision on the 
estimations. 
For the previously treated adult/adolescent treatment arm, the proposed sample size of 
12 participants is adequate for collection of PK data and will also allow for collection of 
supplemental efficacy and safety data in this population. 
The sample size (30 children + 12 adolescents and adults) has been confirmed in consultation 
with China CDE as adequate to provide additional clinical data for comprehensive evaluation 
of efficacy, safety, and PK of KOVALTRY in Chinese hemophilia A patients. 
9.2.2 
Sample Size Determination in Part B (PUPs/MTPs) 
To fulfill the post-approval commitment enforced for KOVALTRY, the Sponsor is committed 
to collecting additional efficacy and safety data in previously untreated Chinese severe 
hemophilia A patients, in line with the CDE Technical Guideline on the Clinical Investigation 
of Recombinant Human Coagulation Factor VIII. 
It is considered feasible to enroll approximately 6 PUPs/MTPs in Part B of this study. 
Part B of this study is designed in accordance with the multinational clinical trial of 
KOVALTRY in previously untreated/minimally treated patients, LEOPOLD Kids Part B, 
where the annualized number of bleeds that occur within 48 hours after a prophylaxis infusion 
was the primary efficacy endpoint. 
A mean of 1.9 (standard deviation 3.3) was observed for this ABR in LEOPOLD Kids Part B. 
Assuming the same distribution, the point estimate for the ABR within 48 hours after a 
prophylaxis infusion of 6 patients will be smaller than 2.9 with a probability of more than 
80% (based on simulations of data for 6 patients from a negative binomial distribution). 
In addition, in the SIPPET study14 (a multinational, prospective, randomized trial that 
assessed the incidence of FVIII inhibitors among PUPs treated with plasma-derived FVIII 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  60 of 105 
 
containing von Willebrand factor or rFVIII products), the incidence of inhibitor development 
for the class of rFVIII products was 44.5% (95% CI: 34.7% to 54.3%). 
Therefore, the true inhibitor rate for PUPs/MTPs is assumed to be within the range of 35% to 
54%. With a sample size of 6 PUPs/MTPs, there is at least 92% power to observe at least 
1 participant developing an inhibitor if the rate is between 35% and 54%. In case an event of 
inhibitor development is not observed, this sample size would provide more than 
90% reassurance that the inhibitor rate should be no more than 35%. 
9.3 
Populations for Analyses 
For purposes of analysis, the following populations are defined in Table 9–1. 
Table 9–1: Analysis Populations 
Population 
Description 
Enrolled 
All participants who signed the ICF or had an ICF signed on their behalf 
by a parent or legal representative. 
Safety 
Participants enrolled into the study and received at least 1 dose of study 
drug. The safety population will be used for the safety analysis. 
Modified Intent-to-Treat 
(mITT)* 
All study participants who have infusion/bleeding data from the EPD 
and/or CRF. The mITT population will be used for the efficacy analysis. 
Per Protocol (PP)** 
All mITT participants who completed study treatment and have at least 
50 exposure days on study, without major protocol deviations. 
PK analysis population 
All participants with evaluable PK data will be included in the analysis of 
pharmacokinetic data. 
ITI treatment analysis 
population 
All participants who enter ITI treatment with study intervention will be 
included in the analysis for ITI treatment. 
* 
The ITT is inclusive of all enrolled and eligible patients. Modified ITT was introduced for this study 
as there is an additional condition that is to be met for participants included in ITT. This condition 
is that study participants need to have infusion/bleeding data from the EPD and /or CRF. 
Therefore, ITT analysis population is renamed “modified ITT” for this study. 
** Only to be used if at least 5% of mITT participants (<12 or ≥12 years of age) are excluded from 
the PP population. The PP population is only in Part A; Part B will not have a PP population. 
 
9.4 
Statistical Analyses 
The statistical analysis plan (SAP) will be developed and finalized before the first participant 
first visit (FPFV) and will describe the participant populations to be included in the analyses 
and procedures for accounting for missing, unused, and spurious data. This section is a 
summary of the planned statistical analyses of the primary endpoints in Part A and Part B of 
the study. 
9.4.1 
General Considerations 
There is no confirmatory comparison planned for this study; study results will be numerically 
evaluated and compared with the data in the completed LEOPOLD Clinical Trials. 
Efficacy analyses outlined in this section only include the data from Part A or Part B (i.e., 
data from the Optional ITI Treatment are excluded). 
For the efficacy endpoints, bleeding events will be presented as summary statistics by age 
groups. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  61 of 105 
 
The annualized bleeding rates for each participant are estimated via 
Annualized bleeding rate [per year] =  
365.25 [days per year] x (# of bleeding episodes in treatment period) /  
duration of treatment period [in days] 
The treatment period is defined as from the date and time of first study treatment until the date 
and time of last infusion of study medication, or last visit, whichever is later (not including 
the Optional ITI Treatment). Before this period is the screening period, after this period is the 
follow-up period. 
Further, for the derivation of analysis variables for bleeding episodes, the following rules will 
apply: 
• “24-hour rule”:  
No more than 1 bleeding episode in a calendar day is counted. If there is more than 
1 bleeding episode in a calendar day, to determine which bleeding episodes are 
counted, priority is given to treated bleeding episodes, spontaneous or trauma 
bleeding episodes, then joint bleeding episodes. Otherwise, the first bleeding 
episode in the day is counted. Severity and treatment response will be the worst 
value of the bleeding episodes of the day. The bleeding site will be aggregated 
over all bleeding events from that day. 
• “72-hour rule”:  
A spontaneous joint or spontaneous muscle bleeding episode will not be counted if 
it occurs within 72 hours of a prior bleeding episode (or infusion for that bleeding 
episode) at the same site. For a bleeding episode to be affected by this rule, all sites 
listed for the bleeding episode must be the same sites specified in the previous 
bleeding episode. If the current and previous bleeds are both skin/mucosa bleeds, 
this rule does not apply. Infusions for such bleeding episodes will be considered to 
be follow-up infusions. 
Missing information on date and time of bleeding episodes will be substituted by the date and 
time of first treatment, if available. 
Further handling of missing data will be described in the SAP. 
9.4.2 
Primary Endpoint(s) 
All efficacy analyses will be performed on the mITT population. In case of PP population 
(Part A only), more than 5% of participants in one arm (children or adolescents/adults) are 
excluded from the mITT population, and analyses for primary and secondary endpoints will 
be repeated in the PP population. As the non-adherence to the EPD documentation is 
considered independent from the treatment efficacy, the exclusion of participants without 
bleeding/infusion data from the EPD does not interfere with the intention-to-treat principle. 
These participants are excluded in order not to dilute the treatment effect. 
The primary endpoint in Part A is the ABR of all bleeding episodes during prophylaxis 
treatment, and it will be summarized by age group (<12 y, ≥12 y) separately. 
The primary endpoint in Part B is the ABR of all bleeding episodes within 48 hours of a 
previous prophylaxis infusion. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  62 of 105 
 
9.4.3 
Secondary Endpoint(s) 
Spontaneous bleeding episodes, trauma bleeding episodes, joint bleeding episodes, and other 
bleeding episodes types will be summarized separately. 
Other efficacy variables are: 
• ABR of treated bleeding episodes 
• ABR of target joint bleeding episodes 
• ABR of bleeding episodes within 48h of previous prophylaxis infusion (total, joint, 
spontaneous, trauma) [for Part A] 
• ABR of all bleeding episodes during prophylaxis treatment [for Part B] 
• Study participant’s/caregiver’s assessment of response to treatment of bleeding 
episodes (excellent, moderate, good, or poor) 
• Physician’s assessment of the response to treatment of bleeding episodes in minor 
surgery (excellent, moderate, good, or poor) 
• Evaluate proportion of patients without bleeding episodes 
• The number of infusions per bleeding episode 
• Factor VIII usage (expressed as number of infusions and IU/kg per year, as well as 
IU/kg per event) 
• Incremental recovery 
All details of the analysis will be provided in the SAP. 
9.4.4 
Safety Analyse(s) 
Safety analysis will be performed separately for Part A, Part B, and Optional ITI Treatment. 
Safety data will be summarized for all participants in the safety population for overall and by 
age groups respectively for Part A and summarized for Part B. Laboratory findings, AEs, 
concomitant medications, vital signs, and medical history data will be provided in participant 
listings. Laboratory values and vital signs will be summarized. 
Individual listings of AEs (including age, AEs as reported, start, duration, severity, relation to 
study drug) will be provided. An AE is defined as treatment-emergent if it started or 
deteriorated after the first infusion and not later than three days after the last infusion in 
Part A or Part B. The incidence of treatment-emergent AEs will be summarized using the 
Medical Dictionary for Regulatory Affairs (MedDRA). 
Inhibitor development as measured by Nijmegen-modified Bethesda assay will be 
summarized by time point and presented in participant listings. The purpose of the listing is to 
delineate the clinical factors that may be positively associated with development of the 
inhibitor. Confirmation of the first positive inhibitor titer (Bethesda ≥0.6 BU/mL) will require 
repeat measurement of a second different sample. 
If the repeated inhibitor result is <0.6 BU/mL without intervention, the inhibitor is not 
confirmed and should not be reported as an SAE. Inhibitors will be classified as being either 
low titer (≥0.6 BU/mL and ≤5 BU/mL) or high titer based upon persistence of an inhibitor 
>5 BU/mL. Proportions of participants with inhibitor will be presented in an overview table. 
Exact Clopper Pearson CI for the proportion will be given if any inhibitor exists. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  63 of 105 
 
The rate of inhibitor development will be summarized and described for both the pediatric and 
the adolescent/adult populations, and for the overall study population combined. 
Safety analysis for optional ITI treatment is based on the ITI treatment set. Laboratory 
findings (inhibitor titer and recovery), AEs, concomitant medications, and EDs will be 
provided in participant listings. More details will be provided in the SAP. 
9.4.5 
Pharmacokinetic Analyses 
Pharmacokinetic analyses will be described in the statistical analysis plan finalized before 
FPFV. 
In addition, the pharmacokinetic data collected during this study might be analyzed by means 
of a population PK approach. The results of this evaluation may be reported in a separate 
Modeling and Simulation report. The actual sampling times will be used for PK evaluation. 
9.5 
Interim Analyses 
In case the study will not be completed at the time of next KOVALTRY license renewal 
application in China, the most current results will be delivered for license renewal, and an 
interim analysis will be performed with all available data. This approach has been agreed with 
CDE. 
9.6 
Data Monitoring Committee (DMC) 
Not applicable to this study. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  64 of 105 
 
10. 
Supporting Documentation and Operational Considerations 
10.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
10.1.1 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines. 
• Applicable ICH Good Clinical Practice (GCP) Guidelines. 
• Regulations on Management of Human Genetic Resources of the People's 
Republic of China. 
• The protocol, protocol amendments, ICF, Prescribing Information, Investigator 
Brochure, and other relevant documents (e.g., advertisements) must be submitted 
to an IRB/IEC by the investigator and reviewed and approved by the IRB/IEC 
before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary 
to eliminate an immediate hazard to study participants. 
The investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 
536/2014 for clinical studies (if applicable), and all other applicable local 
regulations 
10.1.2 
Informed Consent Process 
• The investigator or his/her representative will explain the nature of the study to the 
participant or his parent, guardian, or legally authorized representative and answer 
all questions regarding the study. 
• For minors, consent shall be given by the parents/legal representative. The assent 
of a minor shall also be requested where such a person is able to express his own 
will. His refusal or the withdrawal of his consent may not be disregarded. 
• The informed consent form and any other written information provided to 
participants/legal representatives will be revised whenever important new 
information becomes available that may be relevant to the participants’/parents’ 
consent, or there is an amendment to the protocol that necessitates a change to the 
content of the participant information and/or the written informed consent form. 
The investigator will inform the participant/legal representative of changes in a 
timely manner and will ask the participant to confirm his participation in the study 
by signing the revised informed consent form. Any revised written informed 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  65 of 105 
 
consent form and written information must receive the IEC/IRB’s approval / 
favorable opinion in advance of use. 
• Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 
• The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during 
their participation in the study. 
• A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 
10.1.3 
Data Protection 
• Participants will be assigned a unique identifier by the Sponsor. Any participant 
records or datasets that are transferred to the Sponsor will contain the identifier 
only; participant names or any information which would make the participant 
identifiable will not be transferred. 
• The participant must be informed that his personal study-related data will be used 
by the Sponsor in accordance with local data protection law. The level of 
disclosure must also be explained to the participant who will be required to give 
consent for their data to be used as described in the informed consent. 
• The participant must be informed that his 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. 
10.1.4 
Committees Structure 
Not applicable to this study. 
10.1.5 
Dissemination of Clinical Study Data 
The Clinical Study Report (CSR) will be written within 1 year of the end of study and sent to 
the involved ECs and Regulatory Authorities. It will be reviewed and approved by the 
Coordinating Investigator as required by local authorities. 
The Sponsor will ensure required disclosure of CSRs, periodic safety reports, and clinical 
study summary reports after review by regulatory authorities, including CSRs from studies 
with negative outcomes and from terminated development programs and posting of  
company-sponsored study information and tabular study results on the US National Institutes 
of Health’s website www.ClinicalTrials.gov and other publicly-accessible sites. 
Publication planning and other activities related to non-promotional, peer-reviewed 
publications to ensure the scientific integrity and credibility of publication activities may be 
performed by the Sponsor. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  66 of 105 
 
The Sponsor may also grant access to analyzable datasets from clinical studies through a 
secure system, following an independent assessment of the scientific merit of a rigorously 
defined research question from a third party. 
10.1.6 
Data Quality Assurance 
• All participant data relating to the study will be recorded on printed or electronic 
CRF unless transmitted to the Sponsor or designee electronically (e.g., laboratory 
data). The investigator is responsible for verifying that data entries are accurate 
and correct by physically or electronically signing the CRF. 
• The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. 
• The investigator must permit study-related monitoring, audits, IRB/IEC review, 
and regulatory agency inspections and provide direct access to source data 
documents. 
• Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical  
Risk-Based Monitoring), methods, responsibilities and requirements, including 
handling of noncompliance issues and monitoring techniques (central, remote, or 
on-site monitoring) are provided in the Monitoring Plan. 
• The Sponsor or designee is responsible for the data management of this study 
including quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals 
(e.g. Contract Research Organizations). 
• Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are 
being protected; and that the study is being conducted in accordance with the 
currently approved protocol and any other study agreements, ICH GCP, and all 
applicable regulatory requirements. 
• Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for 15 years after study completion 
unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written 
approval of the Sponsor. No records may be transferred to another location or 
party without written notification to the Sponsor. 
10.1.7 
Source Documents 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
Data reported in the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. Definition of what constitutes source data can be found in 
the Study/Site source data identification checklist. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  67 of 105 
 
10.1.8 
Study and Site Start and Closure 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The Sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the investigator 
• Discontinuation of further study intervention development 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The Investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up. 
10.1.9 
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 
or within 1 year post clinical study close/end of study participation. 
10.1.10 
Publication Policy 
• The results of this study may be published or presented at scientific meetings. If 
this is foreseen, the investigator agrees to submit all manuscripts or abstracts to the 
Sponsor before submission. This allows the Sponsor to protect proprietary 
information and to provide comments. 
• The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter studies only in their entirety and not as 
individual site data. In this case, a coordinating investigator will be designated by 
mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  68 of 105 
 
10.2 
Appendix 2: Clinical Laboratory Tests 
Table 10–1 shows the estimated total blood volume for children 1-10 kg and the 
recommended amount of blood for study purposes. These volumes should be considered a 
guideline, and may be exceeded if determined to be safe by the investigator. 
Table 10–1: Recommended Blood Draw Volume 
Body 
Wt.  
(kg) 
Body 
Wt. 
(lbs) 
Total blood 
volume  
(mL) 
Allowable volume (mL) in 
one blood draw 
(1% of total blood volume) 
Total volume (mL) drawn in a 
30-day period  
(3% of total blood volume) 
1 
2.2 
100 
1 
3 
2 
4.4 
200 
2 
6 
3 
6.3 
240 
2.4 
7.2 
4 
8.8 
320 
3.2 
9.6 
5 
11 
400 
4 
12 
6 
13.2 
480 
4.8 
14.4 
7 
15.4 
560 
5 
16.8 
8 
17.6 
640 
6.4 
19.2 
9 
19.8 
720 
7.2 
21.6 
10 
22 
800 
8 
24 
Abbreviations: Wt.: Body weight 
Source: (15) 
 
For infants of at least 7 kg at study enrollment, the volumes listed for each individual visit 
should be well tolerated. 
The tests described in Section 8.3 and listed in Table 10–2 will be performed by the central 
laboratory (Part A, investigators will be provided with a laboratory manual for instructions on 
how to collect and process samples) or local laboratory (Part B). For part A if a local sample 
analysis is required, it is important that the sample for central analysis is obtained at the same 
time. Additionally, if the local laboratory results are used to make either a study intervention 
decision or response evaluation, the results must be entered into the CRF. For part B, a 
separated page for local laboratory results will be available in eCRF. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
Additional tests may be performed at any time during the study as determined necessary by 
the investigator or required by local regulations. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  69 of 105 
 
Table 10–2: Protocol-Required Safety Laboratory Assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet count 
White blood cell (WBC) count with differential (neutrophils, 
lymphocytes, monocytes, eosinophils, basophils) 
Erythrocyte 
count 
Hemoglobin 
Hematocrit 
Clinical 
chemistry 
Blood urea 
nitrogen (BUN) 
Potassium 
Aspartate 
aminotransferase (AST) 
Total bilirubin 
Creatinine 
Sodium 
Alanine 
aminotransferase (ALT) 
Total protein 
Albumin 
Chloride 
(Cl) 
Bicarbonate (CO3) 
Lactate dehydrogenase 
(LDH) 
Other tests 
• 
HCV, HBV, and HIV antibody (for screening only); CD4 count for patients 
who are HIV positive 
• 
Factor VIII inhibitor 
• 
Factor VIII level 
Notes: 
• 
All routine study-required laboratory assessments will be performed by a 
central lab for Part A, the exception of some samples sent by central lab 
to an independent specialty lab for required tests of FVIII level and FVIII 
inhibitors. All routine study-required laboratory assessments will be 
performed by local lab for Part B. 
• 
The results of each test will be transferred into the clinical database. 
Investigators must document their review of each laboratory safety report. 
 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  70 of 105 
 
10.3 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
10.3.1 
Definition of AE 
AE Definition 
• An AE is any untoward medical occurrence in a patient or clinical study 
participant, associated with the use of study intervention, whether or not considered 
related to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) associated 
with the use of study intervention. 
Events Meeting the AE Definition  
• Any abnormal laboratory test results (hematology, clinical chemistry, or 
urinalysis) or other safety assessments (e.g., ECG, radiological scans, vital 
signs measurements), including those that worsen from baseline, considered 
clinically significant in the medical and scientific judgment of the investigator 
(i.e., not related to progression of underlying disease). 
• Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration 
even though it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
study intervention or a concomitant medication. Overdose per se will not be 
reported as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent. Such overdoses should be reported regardless of 
sequelae. 
• “Lack of efficacy” or “failure of expected pharmacological action” per se will 
not be reported as an AE or SAE. Such instances will be captured in the 
efficacy assessments. However, the signs, symptoms, and/or clinical sequelae 
resulting from lack of efficacy will be reported as AE or SAE if they fulfills the 
definition of an AE or SAE. 
Events NOT Meeting the AE Definition  
• Any clinically significant abnormal laboratory findings or other abnormal 
safety assessments which are associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s 
condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
participant’s condition. 
• Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition 
that leads to the procedure is the AE. If a procedure is performed prior to study 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  71 of 105 
 
start, then associated AEs are not reported as AEs, unless the associated 
condition has deteriorated since study initiation. 
• Situations in which an untoward medical occurrence did not occur (social 
and/or convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen. 
• Any bleeding event occurring during the study will not be documented as an 
AE, because this is captured in the assessment of efficacy. However, 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. 
10.3.2 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a. 
Results in death 
b. 
Is life-threatening 
• The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the participant was at risk of death at the time of the event. It does not 
refer to an event, which hypothetically might have caused death, if it were more 
severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the participant has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward 
for observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills 
any other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered 
serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d. 
Results in persistent disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. 
• This definition is not intended to include experiences of relatively minor 
medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g., sprained ankle) which may 
interfere with or prevent everyday life functions but do not constitute a 
substantial disruption. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  72 of 105 
 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations/medical important event: 
• Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events 
should usually be considered serious. 
• Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug 
dependency or drug abuse. 
Action taken with study treatment: 
• Action taken with study treatment 
• Any action on study treatment to resolve the AE is to be documented using the 
categories listed below. 
o Drug withdrawn 
o Drug interrupted 
o Dose reduced 
o Dose not changed 
o Dose increased 
o Not applicable 
o Unknown 
The outcome of the AE is to be documented as follows: 
• Recovered/resolved 
• Recovering/resolving 
• Recovered/resolved with sequelae 
• Not recovered/not resolved 
• Fatal 
• Unknown 
10.3.3 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
• The investigator will then record all relevant AE/SAE information in the CRF. 
• It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Sponsor in lieu of completion of the AE/SAE CRF page. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  73 of 105 
 
• There may be instances when copies of medical records for certain cases are 
requested by 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 Sponsor. 
• The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
the individual signs/symptoms) will be documented as the AE/SAE. 
• Each event should be described in detail along with start and stop dates, severity, 
relationship to investigational product, action taken, and outcome 
Assessment of Intensity 
• The investigator will make an assessment of intensity for each AE and SAE 
reported during the study and assign it to 1 of the following categories: 
• Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with an SAE. Severe is a category utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe. 
• An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe. 
Assessment of Causality 
An Adverse Reaction (AR) is defined as a response to a medicinal product which is 
noxious and unintended. An AR is any AE judged as having a reasonable suspected causal 
relationship to the medicinal product 
Causal relationship: The assessment of the causal relationship between an AE and the 
administration of treatment is a clinical decision based on all available information at the 
time of the completion of the CRF. The assessment is based on the question whether there 
was a "reasonable causal relationship" to the study treatment in question. Possible answers 
are "yes" or "no": 
• The investigator is obligated to assess the relationship between study 
intervention and each occurrence of each AE/SAE. 
• A “reasonable possibility” of a relationship conveys that there are facts, 
evidence, and/or arguments to suggest a causal relationship, rather than a 
relationship cannot be ruled out. 
• The investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and 
other risk factors, as well as the temporal relationship of the event to study 
intervention administration will be considered and investigated. 
• The investigator will also consult the Investigator’s Brochure (IB) and/or 
Product Information, for marketed products, in his/her assessment. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  74 of 105 
 
• For each AE/SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the Sponsor. However, it 
is very important that the investigator always make an assessment of 
causality for every event before the initial transmission of the SAE data to 
the Sponsor 
• The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• The causality assessment is one of the criteria used when determining 
regulatory reporting requirements. 
Follow-up of AEs and SAEs 
• The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations as medically indicated, or as 
requested by the Sponsor to elucidate the nature and/or causality of the AE or 
SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other 
health care professionals. 
• If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide to the Sponsor with a copy of 
any post-mortem findings including histopathology. 
• New or updated information will be recorded in the originally completed CRF. 
• The investigator will submit any updated SAE data to the Sponsor within 
24 hours of receipt of the information. 
10.3.4 
Reporting of SAEs 
Starting with the signature of the informed consent, all non-serious adverse events (AE) must 
be documented on the AE Report Form or in the CRF / electronic data capture (EDC) system 
and forwarded to the MAH within 7 calendar days (for EU countries or if required by local 
regulations of participating country) / 60 days (for countries outside the EU) of awareness. All 
serious AEs (SAE) must be documented and forwarded immediately (within 24 hours of 
awareness). For each AE, the physician must assess and document the seriousness, duration, 
relationship to product, action taken and outcome of the event. 
SAE Reporting to Sponsor via an Electronic Data Collection Tool 
• The primary mechanism for reporting an SAE to Sponsor will be the electronic 
data collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it 
becomes available. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  75 of 105 
 
• After the study is completed at a given site, the electronic data collection tool 
will be taken off-line to prevent the entry of new data or changes to existing 
data. 
• If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic data collection 
tool has been taken off-line, then the site can report this information on a paper 
SAE form (see next section) or to the Sponsor´s Medical Expert by telephone. 
• Contacts for SAE reporting can be found in Investigators’ Site File. 
SAE Reporting to the Sponsor via Paper CRF 
• Facsimile transmission of the SAE paper CRF is the preferred method to 
transmit this information to the Sponsor´s Medical Expert. 
• In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service. 
• Initial notification via telephone does not replace the need for the investigator 
to complete and sign the SAE CRF pages within the designated reporting time 
frames. 
• Contacts for SAE reporting can be found in Investigators’ Site File 
 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  76 of 105 
 
10.4 
Appendix 4: A Guide for Dosing for Bleeding and Surgery 
Table 10–3: Dosing for Control of Bleeding Episodes 
Degree of Bleeding 
Factor VIII Level 
Required 
(IU/dL or % of Normal) 
Frequency of Doses  
(hours) 
Duration of Therapy  
(days) 
Minor (early hemarthrosis, minor muscle, oral 
bleeding) 
20–40 
Repeat every 12–24 hours 
At least 1 day, until bleeding episode as 
indicated by pain is resolved or healing is 
achieved 
Moderate (more extensive hemarthrosis, muscle 
bleeding, or hematoma) 
30–60 
Repeat every 12–24 hours 3 to 4 days or more until pain and acute disability 
are resolved 
Major (intracranial, intra-abdominal or intrathoracic 
hemorrhages, gastrointestinal bleeding, central 
nervous system bleeding, bleeding in the 
retropharyngeal or retroperitoneal spaces, or 
iliopsoas sheath, life or limb threatening hemorrhage) 
60–100 
Repeat every 8–24 hours 
Until bleeding is resolved 
 
Table 10–4: Dosing for Perioperative Management 
Type of Surgery 
Factor VIII Level Required 
(IU/dL or % of Normal) 
Frequency of Doses 
(hours) 
Duration of Therapy  
(days) 
Minor (such as tooth extraction) 
30–60 (pre- and post-operative) 
Repeat every 24 hours 
At least 1 day until healing is achieved 
Major (such as intracranial,  
intra-abdominal, intrathoracic, or 
joint replacement surgery) 
80–100 (pre- and post-operative) 
Repeat every 8–24 hours 
Until adequate wound healing is complete, then 
continue therapy for at least another 7 days to 
maintain Factor VIII activity of 30%–60% (IU/dL) 
 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  77 of 105 
 
Table 10–5: Definition of Adequacy of Hemostasis for Surgical Procedures 
Excellent 
Intraoperative and postoperative blood loss similar (within 10%) to that in the non-hemophilic patient. 
• 
No extra (unplanned) doses of FVIII/bypassing agent needed and 
• 
Blood component transfusions required are similar to those in a non-hemophilic patient 
Good 
Intraoperative and/or postoperative blood loss slightly increased over expectation for the non-hemophilic patient (between 10% and 
25% of expected), but the difference is judged by the involved surgeon/anesthetist to be clinically insignificant. 
• 
No extra (unplanned) doses of FVIII /bypassing agents needed and 
• 
Blood component transfusions required are similar to those in the non-hemophilic patient 
Moderate (Fair) 
Intraoperative and/or postoperative blood loss increased over expectation (25% to 50%) for the non-hemophilic patient, and additional 
treatment is needed. 
• 
Extra (unplanned) dose of FVIII /bypassing agents needed or 
• 
Increased blood component (within 2-fold) of the anticipated transfusion requirement 
Poor 
Significant intraoperative and/or postoperative blood loss that is substantially increased over expectation (>50%) for the non-hemophilic 
patient, requires intervention, and is not explained by a surgical/medical issue other than hemophilia. 
• 
Unexpected hypotension or unexpected transfer to intensive care unit (ICU) due to bleeding or 
• 
Substantially increased blood component (>2-fold) of the anticipated transfusion requirement 
Abbreviation: FVIII = factor VIII 
Source: (16) 
Notes: 
1. If required for minor surgery or emergency major surgery, Kovaltry infusions will be recorded in the case report form (CRF). The doses infused and 
the frequency of repeat treatment will be collected. The surgeon or interventionalist will be asked to compare estimated blood loss from experience 
with non-hemophilic patients undergoing comparable procedures, and assess intraoperative efficacy at the end of the procedure. Post-surgical 
efficacy will be assessed at least 24 h after the first dose of Kovaltry has been given by surgical staff at drain removal, if required, and by the 
hematologist at discharge. 
2. Data on blood loss will be collected, as estimated at the time of surgery, change or drop in hemoglobin/hematocrit, the need for additional or other 
hemostatic medications, and the type and number of blood products transfused. Hemostatic-related surgical complications will also be obtained 
including data on specific diagnostic evaluations needed (e.g., imaging to follow the size of a hematoma). 
 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  78 of 105 
 
10.5 
Appendix 5: Optional Immune Tolerance Induction Treatment 
10.5.1 
Optional ITI Treatment for Participants who Develop High-Titer 
Inhibitors During the Study 
If the option to receive ITI with the study intervention is made, the participant will 
discontinue participation in either Part A or Part B and continue in the Optional ITI 
Treatment, during which ITI will be provided at a dose of up to 200 IU/kg daily for up to a 
maximum of 18 months or until failure. A separate signed informed consent is required. 
Initiation of ITI therapy (ITI Visit 1) should occur no later than 4 weeks from the date of 
notification by the investigator of the high-titer inhibitor development. In patients with a peak 
inhibitor titer >10 BU/mL, it is recommended to postpone initiation of ITI until the inhibitor 
titer drops to ≤10 BU/mL. It is recommended to monitor the inhibitor titer monthly. In 
patients with a peak inhibitor titer >10 BU/mL who experience serious or life-threatening 
bleeding or have frequent mild to moderate bleeding and are being considered for bypassing 
agent prophylaxis, an earlier start to ITI may be considered to avoid the morbidity associated 
with ongoing bleeding. 
Response to ITI therapy may be observed earlier than 18 months and is defined as having no 
detectable inhibitor based on Nijmegen assay (<0.6 BU/mL) and FVIII recovery of >66% of 
predicted value. Failure is defined as no response (<20% decrease in the inhibitor level) 
within a 6-month period after the initial 3 months of ITI and in the absence of any infection. 
In case of failure, ITI should be discontinued, and the Early ITI Termination visit will occur. 
During the Optional ITI Treatment, failure to adhere to follow-up visits as per protocol (see 
Section 10.5.2) will lead to discontinuation of ITI support. 
At the investigator’s discretion, the participant may stop ITI with study drug. The Early ITI 
Termination visit should be done if the decision is made by the investigator/participant to stop 
ITI prior to documented negative inhibitor titer. 
For analysis of Optional ITI Treatment data, see Section 9.3, Section 9.4.1, and Section 9.4.4. 
Efficacy (ABR) will not be analyzed for ITI patients. Safety will be analyzed separately for 
the ITI treatment set. 
 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  79 of 105 
 
10.5.2 
Optional ITI Treatment - Schedule of Activities 
Assessments 
ITI Visit 1a 
ITI Visit 2a 
Month 2 
ITI Visit 3a 
Month 4 
ITI Visit 4a 
Month 6 
ITI Visit Xa 
Month X 
Confirmatory 
Visitb 
Final ITI Visitc/  
Early ITI 
Termination 
Visitd 
Informed consent 
X 
 
 
 
 
 
 
Study drug dispensatione 
X 
X 
X 
X 
X 
X 
 
ITI treatment accountability 
 
X 
X 
X 
X 
X 
X 
EPD documentation and review (continuously)f 
X 
X 
X 
X 
X 
X 
X 
FVIII inhibitor testingd 
X 
X 
X 
X 
X 
Xc 
 
Recovery (FVIII level)d, g 
 
 
 
 
 
Xc 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications (continuously)h 
X 
X 
X 
X 
X 
X 
X 
Phone callsi 
 
X 
X 
X 
X 
X 
 
Abbreviations: CRF = case report form; EPD = electronic patient diary; FVIII = factor VIII; ITI = immune tolerance induction; RAVE = data base for electronic case report 
a 
ITI visits should be performed every 2 months until the first negative inhibitor titer of <0.6 BU/mL. 
b 
A confirmatory inhibitor testing and recovery evaluation should be performed within 1 month after the first negative testing. After the first negative testing, ITI treatment 
will continue until result of the second (confirmatory) inhibitor testing is obtained. At the discretion of the investigator, participants may stop ITI treatment without a 
second (confirmatory) inhibitory testing. 
c 
The Final ITI visit will occur 2 weeks (±7 days) after the notification of the second (confirmatory) negative inhibitor testing and recovery. 
d 
Participants who undergo the Early ITI Termination visit are recommended to have FVIII inhibitor testing and recovery evaluation. 
e 
Drug dispensing will be done in accordance with the individual drug dispensing schedule every 28 days (±7 days). 
f 
ITI treatment and bleeding episodes will be entered into the EPD. 
g 
Blood samples for FVIII level will be taken pre-infusion and at 15 to 30 minutes after end of infusion to calculate recovery. Infusion doses for recovery measurements 
must be given in hospital and directly reported in RAVE. The bioanalysis will be done at a central laboratory (Part A) or local laboratory (Part B). 
h 
Bypassing agents will be entered into the concomitant medications page of the CRF. 
i 
Study center staff will call the participant or parent/caregiver approximately every 4 weeks between ITI visits to review any new adverse events and changes in 
concomitant medication since the last ITI visit. 
 
 
 
 
 
 
 
 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  80 of 105 
 
10.5.3 
Chinese Hemophilia Society Guideline for ITI 
Please refer to (17). 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  81 of 105 
 
10.6 
Appendix 6: Abbreviations 
ABR 
Annualized bleeding rate 
ALT 
Alanine Aminotransferase 
AE 
adverse event 
AESI 
adverse event of special interest 
AST 
Aspartate Aminotransferase 
AUC 
area under the plasma concentration vs time curve from zero to infinity after single (first) 
dose 
AUCnorm 
area under the plasma concentration by the standard normative distribution 
AUC(0-t last) 
AUC from time 0 to the last data point 
AUC(0-t last) norm 
Up to the last measurable concentration (otherwise called AUClast by the standard normative 
distribution) 
BU 
Bethesda Unit 
BHK 
Baby Hamster Kidney 
CD4 
cluster of differentiation 4 
CDE 
Center for Drug Evaluation 
CFR 
Code of Federal Regulations Title 21 
Cmax 
maximum concentration of FVIII in plasma 
CRF 
case report form (either paper or electronic) 
CSR 
Clinical study report 
CVAD 
central venous access devices 
ECG 
electrocardiography 
eCRF 
electronic case report form 
ED 
exposure days 
e.g. 
exempli gratia, for example 
EPD 
Electronic patient diary 
EU 
European Union 
FPFV 
First Patient First Visit 
FVIII 
human coagulation factor VIII 
FVIII:C 
factor VIII concentration 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HSP 
human heat shock protein 
ICF 
informed consent form 
ICH 
International Conference on Harmonization 
ICU 
intensive care unit 
i.e. 
id est, that is 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ITI 
immune tolerance induction 
ITT 
intent to treat 
IU 
international units 
IV 
Intravenous 
IxRS 
Interactive voice/web Response System 
kg 
kilogram 
LD 
Lactate Dehydrogenase  
MedDRA 
Medical Dictionary for Regulatory Activities  
mITT 
Modified Intent-to-Treat 
MRT 
mean resistance time 
MTPs 
minimally treated patients 
NMPA  
National Medical Products Administration 
PI 
Principle Investigator or Package Insert 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  82 of 105 
 
PK 
pharmacokinetics 
PTPs 
previously treated patients 
PUPs 
previously untreated patients 
RAVE 
data base for electronic case report 
rFVIII 
recombinant coagulation factor VIII 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SUSAR 
suspected unexpected serious adverse reactions 
TMF 
Trial Master File 
TEAEs 
treatment-emergent adverse event 
t1/2 
half-life 
ULN 
upper limit of normal 
US 
United States 
Vss 
apparent volume of distribution at steady state 
WBC 
white blood cell 
 
10.7 
Appendix 7: Protocol Amendment History 
10.7.1 
Amendment 2 
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
10.7.2 
Amendment 1 
Amendment 1 (22 OCT 2020) 
Overall Rationale for the Amendment: 
Section Number and Name 
Description of Change 
Brief Rationale 
Section 1, Protocol Summary 
Section 2.1, Study Rationale 
Section 3, Objectives and Endpoints 
Section 4.1, Overall Design 
Section 4.3, Justification for Dose 
Section 5.1, Inclusion Criteria 
Section 5.2, Exclusion Criteria 
Section 6.1, Study Intervention 
Administered 
Addition of previously untreated 
patients (PUPs) and minimally 
treated patients (MTPs) to the 
study such that the study has 
2 parts (Part A for previously 
treated patients and Part B for 
PUPs/MTPs) 
Fulfillment of post approval 
commitment received from the 
China Center for Drug 
Evaluation (CDE) and China 
National Medical Products 
Administration (NMPA) to 
obtain additional efficacy and 
safety data for KOVALTRY in 
previously untreated/minimally 
treated Chinese hemophilia A 
patients 
Section 1, Protocol Summary 
Section 4.4, End of Study 
Definition 
Section 6.1, Study Intervention 
Administered 
Section 6.8.3, Participant 
Discontinuation/Withdrawal from 
the Study 
Section 7.3.1, Treatment 
Logs/Bleeding Verification 
Addition of a new section to 
describe optional immune 
tolerance induction therapy for 
participants who develop 
high-titer FVIII inhibitor 
To provide management options 
to participants who develop high 
titer FVIII inhibitor 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  83 of 105 
 
Section 10.5, Appendix 5: Optional 
Immune Tolerance Induction 
Treatment 
Section 8.4.1, Time Period and 
Frequency for Collecting AE and 
SAE Information 
Change in the CRF location of 
documentation of AEs from 
Medical History section to AE 
Report Form 
Correction regarding reporting 
process for adverse events 
In addition, editorial and administrative changes have been made throughout the document. 
 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  84 of 105 
 
11. 
References 
1. KOVALTRY® [Prescribing Information]. Shanghai, China: Bayer China Ltd. 2018. 
2. Srivastava A, Brewer AK, Mauser‐Bunschoten EP, Key NS, Kitchen S, Llinas A, et 
al. Guidelines for the management of hemophilia. Haemophilia. 2013 Jan;19(1):e1-47. 
3. World Federation of Hemophilia. World Federation of Hemophilia Report on the 
Annual Global Survey 2016. Quebec: World Federation of Hemophilia; 2017. 80 p. 
4. O’Hara J, Walsh S, Camp C, Mazza G, Carroll L, Hoxer C, et al. The impact of severe 
haemophilia and the presence of target joints on health-related quality-of-life. Health 
Qual Life Outcomes. 2018 May;16(1):84. 
5. Chen SL. Economic costs of hemophilia and the impact of prophylactic treatment on 
patient management. Am J Manag Care. 2016 Apr 1;22(5 Suppl):s126-33. 
6. Collins PW, Fischer K, Morfini M, Blanchette VS, Björkman S, International 
Prophylaxis Study Group Pharmacokinetics Expert Working Group. Implications of 
coagulation factor VIII and IX pharmacokinetics in the prophylactic treatment of 
haemophilia. Haemophilia. 2011 Jan;17(1):2-10. 
7. Tang L, Wu R, Sun J, Zhang X, Feng X, Zhang X, et al. Short-term low-dose 
secondary prophylaxis for severe/moderate haemophilia A children is beneficial to 
reduce bleed and improve daily activity, but there are obstacle in its execution: a 
multi-centre pilot study in China. Haemophilia. 2013;19(1):27-34. 
8. Yang R, Sun J, Zhao Y, Wang X, Wu D, Tseneklidou-Stoeter D, et al. Efficacy and 
safety of prophylaxis with BAY 81-8973 in Chinese patients with severe haemophilia 
A enrolled in the LEOPOLD II trial. Haemophilia. 2019;25(3):e153–e158. 
doi:10.1111/hae.13751. 
9. Saxena K, Lalezari S, Oldenburg J, Tseneklidou-Stoeter D, Beckmann H, Yoon M, et 
al. Efficacy and safety of BAY 81-8973, a full-length recombinant factor VIII: results 
from the LEOPOLD I trial. Haemophilia. 2016 Sep;22(5):706-12. 
10. Kavakli K, Yang R, Rusen L, Beckmann H, Tseneklidou‐Stoeter D, Maas Enriquez 
M, et al. Prophylaxis vs. on-demand treatment with BAY 81‐8973, a full-length 
plasma protein-free recombinant factor VIII product: results from a randomized trial 
(LEOPOLD II). J Throm Haemost. 2015 Mar;13(3):360-9. 
11. Ljung R, Kenet G, Mancuso ME, Kaleva V, Rusen L, Tseneklidou-Stoeter D, et al. 
BAY 81-8973 safety and efficacy for prophylaxis and treatment of bleeds in 
previously treated children with severe haemophilia A: Results of the LEOPOLD Kids 
Trial. Haemophilia. 2016;22(3):354–60. 
12. Gouw SC, van der Bom JG, Marijke van den Berg H. Treatment-related risk factors of 
inhibitor development in previously untreated patients with hemophilia A: the 
CANAL cohort study. Blood. 2007;109(11):4648-54. 
13. Kurnik K, Bidlingmaier C, Engl W, Chehadeh H, Reipert B, Auerswald G. New early 
prophylaxis regimen that avoids immunological danger signals can reduce FVIII 
inhibitor development. Haemophilia. 2010;16(2):256-62. 
14. Peyvandi F, Mannucci PM, Garagiola I, El-Beshlawy A, Elalfy M, Ramanan V, et al. 
A randomized trial of factor VIII and neutralizing antibodies in hemophilia A. N Engl 
J Med 2016;374:2054-64. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  85 of 105 
 
15. Ernst DJ. Applied Phlebotomy. Baltimore, MD: Lippincott Williams & Wilkins. 2005. 
16. Srivastava A, Santagostino E, Dougall A, Kitchen S, Sutherland M, Pipe SW, et al. 
WFH Guidelines for the Management of Hemophilia, 3rd edition. Haemophilia. 2020 
Aug 3. doi: 10.1111/hae.14046. Online ahead of print. 
17. Thrombosis and Hemostasis Group, Chinese Society of Hematology; Chinese Medical 
Association/Hemophilia Treatment Center Collaborative Network of China. [Chinese 
guidelines on the treatment of hemophilia (version 2020)]. Zhonghua Xue Ye Xue Za 
Zhi. 2020 Apr 14;41(4):265-271. Chinese. doi: 10.3760/cma.j.issn.0253-
2727.2020.04.001. PMID: 32295333; PMCID: PMC7364913. 
 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  86 of 105 
 
12. 
Attachments – Package Insert for China 
Approval date: 18 July 2018 
Revision date: 
 
Recombinant Coagulation Factor VIII for Injection 
Please carefully read the Instructions and use under the supervision of a physician 
 
[Drug Names] 
Chinese INN: Recombinant Coagulation Factor VIII for Injection 
Trade name: Kovaltry® (Ke Yue Qi®) 
English name: Recombinant Coagulation Factor VIII for Injection 
Chinese Pinyin: Zhusheyong Chongzu Ren Ningxue Yinzi VIII 
 
[Composition] 
KOVALTRY is a sterile, stable, purified, non-pyrogenic dried concentrate produced by a 
genetically engineered Baby Hamster Kidney (BHK) cell line into which the human Factor 
VIII gene was introduced together with the human heat shock protein 70 (HSP 70) gene. 
Active ingredient: Recombinant coagulation factor VIII. 
Excipients: glycine, sucrose, sodium chloride, calcium chloride, histidine and polysorbate80. 
 
[Description] 
White to slightly yellow powder. Colorless and clear liquid after reconstitution by adding sterile water 
for injection according to the labeled amount. 
 
[Indications] 
KOVALTRY, indicated for use in adults and children with hemophilia A (congenital Factor VIII 
deficiency) for: 
- 
Routine prophylaxis to reduce the frequency of bleeding episodes 
- 
On-demand treatment and control of bleeding episodes 
- 
Perioperative management of bleeding 
KOVALTRY is not indicated for the treatment of von Willebrand disease. 
 
[Strength] 
250 IU/vial, 500 IU/vial, 1000 IU/vial 
 
[Dosage and Administration] 
For intravenous use after reconstitution only.  

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  87 of 105 
 
The dosage of children < 12 years of age is determined according to global pivotal study. The clinical 
data of Chinese children < 12 years of age have not been collected. 
 
Dose 
• 
Dosage and duration of treatment depend on the severity of the Factor VIII deficiency, the 
location and extent of bleeding, and the patient’s clinical condition. Careful control of 
replacement therapy is especially important in cases of major surgery or life-threatening bleeding 
episodes. 
• 
Each vial label of KOVALTRY states the Factor VIII potency in international units (IU). One IU 
is defined by the current WHO (World Health Organization) international standard (IS) for Factor 
VIII concentrate. 
• 
Potency assignment for KOVALTRY is determined using a chromogenic substrate assay. A field 
study involving 41 clinical laboratories from around the world measured recoveries of 
KOVALTRY spiked into hemophilic plasma. The results of the field study indicated that the 
Factor VIII activity of KOVALTRY can be accurately measured in plasma using either a one-
stage clotting or chromogenic substrate assay according to routine methods of the testing 
laboratory. 
• 
The required dose for a desired Factor VIII level expressed as IU/dL (or % of normal) can be 
estimated using the following formula: 
Required dose (IU)  
= body weight (kg) x desired Factor VIII rise (% of normal or IU/dL) 
x reciprocal of expected/observed recovery (e.g., 0.5 for a recovery of 2 IU/dL per IU/kg) 
• 
The expected in vivo peak increase of Factor VIII level expressed as IU/dL (or % of normal) can 
be estimated using the following formula: 
Estimated increment of Factor VIII (IU/dL or % of normal)  
= [Total dose (IU)/body weight (kg)] x 2 (IU/dL per IU/kg) 
 
Examples (assuming patient’s baseline Factor VIII is <1%): 
(1). A peak of 50% is required in a 20 kg child. In this situation, the required dose of KOVALTRY 
would be 20 kg x 50 IU/dL x 0.5 (for recovery of 2 IU/dL per IU/kg) = 500 IU 
(2). A dose of 2000 IU of KOVALTRY administered to a 50 kg patient should be expected to result in 
post-infusion Factor VIII increase of 2000 IU / 50 kg (body weight) x 2 IU/dL per IU/kg = 80 IU/dL 
(80% of normal) 
 
• 
Adjust dose to the patient’s clinical response. Patients may vary in their pharmacokinetic (e.g., 
half-life, incremental recovery) and clinical responses to KOVALTRY. 
 
 
 
❖ On-demand Treatment and Control of Bleeding Episodes 
A guide for dosing KOVALTRY for the on-demand treatment and control of bleeding episodes is 
provided in Table 1. The goal of treatment is to maintain a plasma Factor VIII activity level at or 
above the plasma levels (in % of normal or in IU/dL) outlined in Table 1. 
 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  88 of 105 
 
Table 1: Dosing for Control of Bleeding Episodes 
 
Degree of Bleeding 
Factor VIII 
Level 
Required (IU/dL 
or % of normal) 
Frequency of 
Doses 
(hours) 
Duration of 
Therapy (days) 
Minor (Early hemarthrosis, 
minor 
muscle, oral bleeds) 
20–40 
Repeat every 
12–24 hours 
At least 1 day, until 
bleeding episode as 
indicated by pain is 
resolved or healing is 
achieved 
Moderate (More extensive 
hemarthrosis, 
muscle bleeding, or hematoma) 
30–60 
 
 
Repeat every 
12–24 hours 
3 to 4 days or more 
until pain and acute 
disability are 
resolved 
Major (intracranial, intra-
abdominal or 
intrathoracic hemorrhages, 
gastrointestinal 
bleeding, central nervous 
system bleeding, bleeding in the 
retropharyngeal or 
retroperitoneal spaces, or 
iliopsoas sheath, life or limb 
threatening hemorrhage) 
60–100 
Repeat every 
8–24 hours 
Until bleeding is 
resolved 
 
 
❖ Perioperative Management of Bleeding 
A guide for dosing KOVALTRY during surgery (perioperative management) is provided in Table 2. 
The goal of treatment is to maintain a plasma Factor VIII activity level at or above the plasma level (in 
% of normal or in IU/dL) outlined in Table 2. During major surgery, monitoring with appropriate 
laboratory tests, including serial Factor VIII activity assays, is highly recommended (See 
[Precautions]) 
Table 2: Dosing for Perioperative Management 
Type of Surgery 
Factor VIII Level 
Required (IU/dL or 
% of normal) 
Frequency of 
Doses (hours) 
Duration of 
Therapy (days) 
Minor (Such as tooth 
extraction) 
30–60 (pre- and 
postoperative) 
Repeat every 
24 hours 
At least 1 day until 
healing is achieved 
Major (Such as 
intracranial, 
intraabdominal, 
intrathoracic, or joint 
replacement surgery) 
80–100 
(pre- and 
postoperative) 
Repeat every 
8–24 hours 
Until adequate 
wound healing is 
complete, then 
continue therapy 
for at least another 7 
days to maintain 
Factor VIII activity 
of 30–60% (IU/dL) 
 
❖ Routine Prophylaxis 
• 
Individualize the patient’s dose based on clinical response. 
• 
Adults and adolescents: 20 to 40 IU of KOVALTRY per kg of body weight two or three times per 
week. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  89 of 105 
 
• 
Children ≤12 years old: 25 to 50 IU of KOVALTRY per kg body weight twice weekly, three 
times weekly, or every other day according to individual requirements. (See [Pediatric Use]) 
 
1. Preparation and Reconstitution before Administration (refer to the Appendix in the end of the 
PI) 
 
 
2. Administration 
For intravenous use only. 
• 
Inspect reconstituted KOVALTRY visually for particulate matter and discoloration prior to 
administration. Do not use if you notice any particulate matter or discoloration and immediately 
contact Bayer Medical Communications at Bayer Hotline (400-810-0360). 
• 
Administer reconstituted KOVALTRY as soon as possible. If not, store at room temperature for 
no longer than 3 hours. 
• 
Infuse KOVALTRY intravenously over a period of 1 to 15 minutes. Adapt the rate of 
administration to the response of each individual patient. 
 
[Adverse Reactions] 
The most frequently reported adverse reactions in clinical trials (≥3%) were headache, pyrexia, and 
pruritus (see Table 3). 
 
1. Clinical Trials Experience 
The safety profile of KOVALTRY was evaluated in 193 previously treated patients (PTPs) (inclusive 
of 51 pediatric patients <12 years of age) with at least three months of exposure to KOVALTRY. The 
safety analysis was done using a pooled database from three multi-center, prospective, open-label 
clinical studies. The median time on study for patients ≥12 years of age was 372 days with a median of 
159 exposure days (EDs). The median time on study for patients <12 years of age was 182 days with a 
median of 73 EDs. Subjects who received KOVALTRY for perioperative management (n=5) with 
treatment period of 2 to 3 weeks and those who received single doses of KOVALTRY for PK studies 
(n=6) were excluded from safety analysis. Table 3 lists the adverse reactions reported during clinical 
studies. The frequency, type, and severity of adverse reactions in children are similar to those in 
adults. 
Table 3: Adverse Reactions in Previously Treated Patients (PTPs) (N=193) 
MedDRA Primary System Organ Class 
Preferred term 
Frequency 
N (%) 
Blood and the Lymphatic System Disorders 
Lymphadenopathy 
 
2 (1.0%) 
Cardiac Disorders 
Palpitation 
Sinus tachycardia 
 
2 (1.0%) 
2 (1.0%) 
Gastrointestinal Disorders 
Abdominal pain 
Abdominal discomfort 
Dyspepsia 
 
4 (2.1%) 
3 (1.6%) 
4 (2.1%) 
General Disorders and Administration Site Conditions 
Pyrexia 
Chest discomfort 
Injection site reactionsa 
 
8 (4.1%) 
2 (1.0%) 
5 (2.6%) 
Immune System Disorders 
Hypersensitivity 
 
1 (0.5%) 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  90 of 105 
 
Nervous System Disorders 
Dizziness 
Dysgeusia 
Headache 
 
2 (1.0%) 
1 (0.5%) 
14 (7.3%) 
Psychiatric Disorders 
Insomnia 
 
5 (2.6%) 
Skin and Subcutaneous Tissue Disorders 
Dermatitis allergic 
Pruritus 
Rashb 
Urticaria 
 
2 (1.0%) 
6 (3.1%) 
5 (2.6%) 
1 (0.5%) 
Vascular disorders 
Flushing 
 
1 (0.5%) 
aIncludes injection site extravasation and hematoma, infusion site pain, pruritus, and swelling 
bIncludes rash, rash erythematous, and rash pruritic 
 
Immunogenicity 
All clinical trial subjects were monitored for neutralizing antibodies (inhibitors) to Factor VIII by the 
modified Bethesda assay using blood samples obtained prior to the first infusion of KOVALTRY, at 
defined intervals during the studies and at the completion visit. 
Clinical trials (Phases 1 through 3) with KOVALTRY evaluated a total of 204 pediatric and adult 
patients diagnosed with severe hemophilia A (Factor VIII <1%) with previous exposure to Factor VIII 
concentrates ≥50 EDs, and no history of inhibitors. 
In the completed studies, no PTP developed neutralizing antibodies to Factor VIII. In an ongoing 
extension study, a 13 year old PTP had a titer of 0.6 BU after 550 EDs concurrent with an acute 
infection and positive IgG anticardiolipin antibodies. The Factor VIII recovery was 2.2 IU/dL per 
IU/kg, annualized bleeding rate (ABR) was zero, and no change in therapy was required. 
In an actively enrolling clinical trial in PUPs, 6 of 14 treated subjects (42.9% with a 95% Confidence 
Interval of 17.7-71.1%) developed an inhibitor. Of these, 3 subjects (21.4%) had high titer inhibitors, 
and 3 subjects (21.4%) had transient low titer inhibitors for which no change in therapy was required. 
The detection of antibody formation is dependent on the sensitivity and specificity of the assay. 
Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an 
assay may be influenced by several factors including assay methodology, sample handling, timing of 
sample collection, concomitant medications, and underlying disease. For these reasons, it may be 
misleading to compare the incidence of antibodies to KOVALTRY with the incidence of antibodies to 
other products. 
 
[Contraindications] 
KOVALTRY is contraindicated in patients who have a history of hypersensitivity reactions to the 
active substance, to any of the excipients, or to mouse or hamster proteins. (See [Composition]) 
 
[Precautions] 
1 Hypersensitivity Reactions 
Hypersensitivity reactions, including anaphylaxis, are possible with KOVALTRY. Early signs of 
hypersensitivity reactions, which can progress to anaphylaxis, may include chest or throat tightness, 
dizziness, mild hypotension and nausea. Discontinue KOVALTRY if symptoms (instances of severe 
anaphylaxis) occur and seek immediate emergency treatment. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  91 of 105 
 
KOVALTRY may contain trace amounts of mouse and hamster proteins (See [Composition]). 
Patients treated with this product may develop hypersensitivity to these non-human mammalian 
proteins. 
 
2 Neutralizing Antibodies 
Neutralizing antibody (inhibitor) formation can occur following administration of KOVALTRY. 
Previously untreated patients (PUPs) are at greatest risk for inhibitor development with all Factor VIII 
products  (see [Adverse Reactions]). 
Carefully monitor patients for the development of Factor VIII inhibitors, using appropriate clinical 
observations and laboratory tests. If expected plasma Factor VIII activity levels are not attained or if 
bleeding is not controlled as expected with administered dose, suspect the presence of an inhibitor 
(neutralizing antibody) . 
 
3 Cardiovascular Risk Factors 
Hemophilic patients with cardiovascular risk factors or diseases may be at the same risk to develop 
cardiovascular events as non-hemophilic patients when clotting has been normalized by treatment with 
Factor VIII. 
 
4 Catheter-related Infections 
Catheter-related infections may be observed when KOVALTRY is administered via central venous 
access devices (CVADs). These infections have not been associated with the product itself. 
 
5 Monitoring Laboratory Tests 
• 
Monitor plasma Factor VIII activity levels using a validated test to confirm that adequate Factor 
VIII levels have been achieved and maintained (see [Dosage and Administration]). 
• 
Monitor for development of Factor VIII inhibitors. Perform a Bethesda inhibitor assay if expected 
Factor VIII plasma levels are not attained or if bleeding is not controlled with the expected dose 
of KOVALTRY. Use Bethesda Units (BU) to report inhibitor titers. 
 
[Use in Pregnancy and Lactation] 
1. Pregnancy 
Risk Summary 
There are no data with KOVALTRY use in pregnant women to inform on drug-associated risk. 
Animal reproduction studies have not been conducted using KOVALTRY. It is not known whether 
KOVALTRY can cause fetal harm when administered to a pregnant woman or can affect reproduction 
capacity. KOVALTRY should be given to a pregnant woman only if clearly needed. The rates for 
birth defects and miscarriage based on available general population worldwide are 2.6-6.9% and 10-
21%, respectively.   
 
2. Lactation 
Risk Summary 
There is no information regarding the presence of KOVALTRY in human milk, the effects on the 
breastfed infant, or the effects on milk production. The developmental and health benefits of 
breastfeeding should be considered along with the mother’s clinical need for KOVALTRY and any 
potential adverse effects on the breastfed infant from KOVALTRY or from the underlying maternal 
condition. 
 
 
 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  92 of 105 
 
[Pediatric Use] 
The dosage of children < 12 years of age is determined according to global pivotal study. The clinical 
data of Chinese children < 12 years of age have not been collected. 
Safety and efficacy studies with KOVALTRY have been performed in pediatric PTPs. Body weight 
adjusted clearance of Factor VIII in children ≤12 years of age is higher than in adults and adolescents. 
Consider higher or more frequent dosing in children to account for this difference in clearance (see 
[Pharmacology and toxicology]). 
 
[Geriatric Use] 
Clinical studies with KOVALTRY did not include patients aged 65 and over to determine whether or 
not they respond differently from younger patients. However, clinical experience with other Factor 
VIII products has not identified differences between the elderly and younger patients. As with any 
patient receiving recombinant Factor VIII, dose selection for an elderly patient should be 
individualized. 
 
[Drug interactions] 
No interactions of human coagulation factor VIII products with other medicinal products have been 
reported. 
 
[Overdose] 
No symptoms of overdose have been reported. 
 
[Clinical Studies] 
The safety and efficacy of KOVALTRY for on-demand treatment and control of bleeding episodes, 
perioperative management of bleeding, and routine prophylaxis in subjects with severe hemophilia A 
(<1% Factor VIII) was evaluated in three international (including China.) clinical studies. 
Immunocompetent subjects with severe hemophilia A (Factor VIII activity ≤1%) and no history of 
Factor VIII inhibitors were eligible for the trials. 
Study 1: a multi-center, open-label, cross-over, uncontrolled, study in adolescent and adult (age ≥12 
years to <65 years) PTPs (≥150 EDs) evaluated the pharmacokinetics, efficacy and safety of routine 
prophylaxis, and perioperative management of bleeding of KOVALTRY (see Table 4). The primary 
efficacy variable was ABR. The prophylactic regimen was 20 to 50 IU/kg two or three times per week 
in which the dosing frequency was assigned by the investigator based on the subject’s individual 
requirements. 
Study 2: a multi-center, open-label, cross-over, uncontrolled, randomized study in adolescent and adult 
(age ≥12 years to <65 years) PTPs (≥150 EDs) evaluated the superiority of prophylaxis over on-
demand treatment with KOVALTRY over a 12 one-year treatment period (see Table 4). The primary 
efficacy variable was ABR. The prophylactic regimen was 20 to 30 IU/kg two times per week or 30 to 
40 IU/kg three times per week and the treatment group was assigned by randomization. 
Study 3: a multi-center, open-label, uncontrolled study in pediatric (age ≤12 years) PTPs (≥50 EDs) 
evaluated the pharmacokinetics, efficacy and safety of routine prophylaxis, and perioperative 
management of bleeding of KOVALTRY (see Table 5). The primary efficacy variable was annualized 
number of total bleeds during routine prophylaxis that occurred within 48 hours following previous 
prophylaxis infusion. ABR during prophylaxis, independent of time of infusion, was also analyzed. 
The prophylactic regimen was 25 to 50 IU/kg at frequencies of either 2 times per week, 3 times per 
week or every other day and could be adapted to individual subject’s need by the investigator. 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  93 of 105 
 
In all studies, treatments of breakthrough bleeds and perioperative management were at the 
investigator’s discretion based on standard of care. 
A total of 204 subjects were enrolled in the completed clinical trials, 153 subjects ≥12 years of age and 
51 subjects <12 years of age. One hundred-forty (140) subjects were treated for at least 12 months, 
and 43 of these subjects were treated for 24 months. 
 
Table 4: Overview of Study 1 (Prophylaxis Treatment Phase) and Study 2 
 
Study 1(N=62) 
Study 2(N=80) 
Age: mean ±SD 
31.5±12.7 years 
29.6 ±11.0 years 
Previous treatment: % 
Prophylaxis: 80.6% 
On-demand: 100% 
Number of Target joints at 
baseline: mean ±SD 
1.4 ±1.3 
3.0 ±2.1 
Joint hemorrhage history 
(during 12 months prior to 
study): mean ±SD of joint 
bleeds 
8.0 ±11.9 
32.1 ± 23.8 
 
Table 5: Overview of Study 3 
 
Study 3 
Previously Treated Patients 
(PTPs) 0 to <6 yrs (N=25) 
Previously Treated Patients 
(PTPs) 6 to 12 yrs (N=26) 
Age: mean ±SD (range) 
3.8 ±1.3 years (1-5) 
8.8 ±1.8 years (6-11) 
Previous treatment: % 
Prophylaxis: 92.0% 
Prophylaxis: 65.4% 
Number of Target joints at 
baseline: mean ± SD 
0.2 ±0.4 
0.7 ±1.1 
 
 
 
❖  On-demand Treatment and Control of Bleeding Episodes 
Adolescents and Adults 
A total of 1892 bleeding episodes in 110 subjects were treated with KOVALTRY in Study 1 and 
Study 2 (see Table 6). The majority of the bleeding episodes were spontaneous, localized in joints, and 
mild to moderate in severity. 
In Study 1 and Study 2, the treatment responses in a total of 1859 treated bleeds were assessed by the 
subjects compared to their previous treatment experience. 
 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  94 of 105 
 
Table 6: On-demand Treatment and Control of Bleeding Episodes in Adolescents and Adults 
Treated with KOVALTRY 
 
aTotal number excluding uncharacterized bleeds 
bThe % is calculated from number of treated bleeds assessed for response 
 
Children 12 Years of Age and Younger 
A total of 97 bleeding episodes in 28 pediatric subjects were treated with KOVALTRY. Majority 
(96.9%) of the bleeds were mild to moderate in severity. Fifty-nine (72.8%) bleeds were trauma 
related. During the 6 month treatment period, the median dose of KOVALTRY for the treatment of 
breakthrough bleeds was 36.94 IU/kg per infusion (range 20.8– 71.6 IU/kg). 
Assessment of response to treatment of bleeds was as follows: 
Excellent: Abrupt pain relief and/or improvement in signs of bleeding with no additional infusion 
administered; Good: Definite pain relief and/or improvement in signs of bleeding but possibly 
requiring more than one infusion for complete resolution; Moderate: Probable or slight improvement 
in signs of bleeding with at least one additional infusion for complete resolution; Poor: No 
improvement at all between infusions or condition worsens. 
The hemostatic efficacy in on-demand treatment of bleeds was assessed as either “good” or 
“excellent” in 90.1% of cases (97.8% in the younger age group and 81.0% in the older age group). 
Majority of bleeds (89.7%) were successfully treated with ≤2 infusions. Response to treatment was 
similar for children aged 0 to <6 compared to 6 to 12 years of age (see Table 7). 
 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  95 of 105 
 
Table 7: On-demand Treatment and Control of Bleeding Episodes in Children Treated with 
KOVALTRY 
 
aTotal number of treated bleeds 
bThe % is calculated from number of treated bleeds assessed for response 
 
❖ Perioperative Management 
A total of 14 major and 46 minor surgeries were performed in 44 previously treated subjects (43 adults 
and adolescents and 1 child under 12 years of age) with severe hemophilia A. Seven of the 14 major 
surgeries were orthopedic procedures, including joint replacement. Approximately 51% of the minor 
surgeries were dental extractions. All subjects received KOVALTRY as bolus infusions. In the 
adolescent and adult subjects, the initial KOVALTRY doses administered ranged between 3000–5000 
IU. The median total dose on the day of surgery was 107.5 IU/kg (range 60–207 IU/kg). In a single 
subject younger than 12 years of age who underwent a major surgery, the total initial KOVALTRY 
dose administered was 2500 IU (108.7 IU/kg). 
The blood loss, during and after surgery, was within expected ranges. Hemostatic control was assessed 
by surgeons as “good” (perioperative bleeding slightly but not clinically significantly increased over 
expectations for the non-hemophilic patient; treatment similar to non-hemophilic patient) or 
“excellent” (perioperative blood loss similar to the non-hemophilic patient). 
 
❖ Routine Prophylaxis 
Adolescents and Adults 
A total of 140 subjects were treated with KOVALTRY for at least 12 months with median (range) 157 
EDs (25-178) in Study 1, [305 EDs (25-355) inclusive of extension phase], and 153 EDs (103-187) in 
Study 2 (see Table 8). In both studies, subjects in the Intent-to-Treat (ITT) population received 95% to 
100% of the prescribed number of prophylaxis infusions. 
 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  96 of 105 
 
Table 8: Prophylaxis Treatment with KOVALTRY in Adolescents and Adults – Treatment 
Exposure 
 
Study 1 (N=62)a 
Study 2 (N=59) 
Median nominal b 
prophylaxis dose/ infusion 
(range) 
All 
Prophylaxis 2 times per week 
Prophylaxis 3 times per week 
 
 
31.2 IU/kg (21-43 IU/kg) 
35.0 IU/kg (21-42 IU/kg) 
31.1 IU/kg (24-43 IU/kg) 
 
 
31.7 IU/kg (21-42 IU/kg) 
30.4 IU/kg (21-34 IU/kg) 
37.4 IU/kg (30-42 IU/kg) 
Treatment duration 
1 year main study 
1 year 
Study 1: 2 times per week (n=18); 3 times per week (n=44) 
Study 2: 2 times per week (n=28); 3 times per week (n=31) 
aStudy 1 included PK, safety and efficacy of prophylaxis and hemostasis during surgeries. Prophylaxis 
phase data are presented. 
b nominal dose is based on the labelled potency 
 
The mean and median ABR for the ITT population in Study 1 was 3.8 ± 5.2 and 1 bleed/year, 
respectively. In Study 2, comparison of the bleeding rates between subjects receiving on-demand 
therapy versus prophylaxis in an ANOVA demonstrated a statistically significant difference 
(p<0.0001) in the median ABR in subjects receiving on-demand therapy (60 bleeds per year) as 
compared to subjects receiving prophylaxis (2 bleeds per year). In Study 2, mean ABR in subjects 
receiving on-demand therapy was 57.7 ± 24.6 versus 4.9 ± 6.8 in the subjects receiving prophylaxis. 
Table 9: ABR in Adolescent and Adult Subjects 
 
aIQR = Interquartile Range 
bMonth 1-6 refers to the first six months of the treatment period and Month 7-12 refer to the second six 
months of the treatment period 
cObservation of one-year treatment period 
dn=total number of subjects with zero bleeds 
en=total number of subjects randomized to treatment arms 
 
The ABR for subjects (n=21) receiving on-demand therapy in Study 2 [median (IQR Q1; Q3)] for all 
bleeds: 60 (41.7; 76.3); spontaneous bleeds: 42.1 (24.3; 61.3); joint bleeds: 38.8 (24.3; 60.0). 
 
 
Children 12 Years of Age and Younger 
A total of 51 PTPs were treated with KOVALTRY for at least 6 months with median (range) 73 EDs 
(37-103) (see Table 10). Subjects received >95% of the prescribed number of prophylaxis infusions. 
 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  97 of 105 
 
Table 10: Prophylaxis Treatment with KOVALTRY in Children 12 Years of Age or Younger – 
Treatment Exposure 
 
aTreatment regimen at the start of the study. Study duration was six months. 
 
In children 12 years of age and younger (n=51), the median (IQR Q1; Q3) ABR within 48 hours after 
prophylactic infusion was 0 (0; 4) for all bleeds, and 0 (0; 0) for spontaneous and joint bleeds. The 
median (IQR Q1; Q3) ABR during prophylactic treatment independent of time of infusion was 1.9 (0; 
6) for all bleeds, 0 (0; 0) for spontaneous bleeds and 0 (0; 2) for joint bleeds. The mean ABR within 48 
hours after prophylactic infusion was 2.04 ± 2.91. The mean ABR at any time during the prophylaxis 
regimen was 3.75 ± 4.98. 
In both age groups (0 to <6 years and 6 to 12 years), the ABR for spontaneous bleeds and joint bleeds 
within 48 hours after prophylactic treatment [ABR median (IQR Q1; Q3)] was 0 (0; 0). The median 
(IQR Q1; Q3) annualized number of spontaneous bleeds during prophylactic treatment independent of 
time of infusion was 0 (0; 0). The median (IQR Q1; Q3) annualized number of joint bleeds during 
prophylactic treatment independent of time of infusion was 0 (0; 1.9) in 0 to <6 years age group and 0 
(0; 2.1) in 6 to 12 years age group (see Table 11). 
The majority (32/53) of bleeds that occurred within 48 hours after a previous prophylaxis infusion 
were trauma related. Twenty-three (45.1%) subjects reported no bleeds during the six-month 
prophylaxis period. 
 
 
Table 11: ABR in Children 12 Years of Age or Younger 
 
aIQR = Interquartile Range 
bIndependent of time of infusion 
 
 
<Chinese patients clinical study summary> 
 
There were twenty-three subjects in China entering study 2, which was randomized and received at 
least 1 injection of BAY 81-8973. No relevant differences between the on-demand and prophylaxis 
groups were seen for demographic and disease characteristics at baseline. 
 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  98 of 105 
 
Table 12: Chinese subgroup overview 
 
China subgroup 
（N = 23） 
Age: mean±SD 
28.6 ± 8.8years* 
Previous treatment: % 
On-demand：100％ 
Number of Target joints at baseline: 
mean±SD 
2.5 ± 1.8 
Joint hemorrhage history 
(during 12 months prior to study): 
mean±SD of joint bleeds 
38.1 ± 26.5 
*The only adolescent subject in the Chinese subset was randomized to high-dose prophylaxis. 
 
❖ On-demand Treatment and Control of Bleeding Episodes 
A total of 499 bleeds were reported in the 23 Chinese subjects during this study. Most of these bleeds were of 
mild or moderate intensity and were spontaneous bleeds into joints. 
 
Table 13：On-demand Treatment and Control of Bleeding Episodes 
in China Subgroup Patients Treated with KOVALTRY 
 
China subgroup 
Characteristics of Bleeding 
Episodes 
prophylaxis 
N = 17 
On-demand 
N = 6 
Total number of bleeds 
67 
432 
Spontaneous: n/total (%) 
46/62a（74.2％） 
299/430a（69.5％） 
Trauma: n/total (%) 
16/62a 
（25.8％） 
131/430a（30.5％） 
Joint bleeds: n/total (%) 
56/67（83.6％） 
314/432（72.7％） 
Mild/moderate: n/total (%) 
62/67（92.5％） 
420/432（97.2％） 
% of bleeds treated with 
≤2 infusions 
97.0％ 
97.7％ 
Response to treatment of 
bleeds assessed as “Excellent” 
or “Good”: n/total (%) 
39/62b（62.9％） 
237/432（54.9％） 
Median dose per infusion 
(range) 
27.33 IU/kg  
（23.5-41.6 IU/kg） 
21.39 IU/kg 
（15-23.5 IU/kg） 
a Total number excluding uncharacterized bleeds. 
b: 5 missing data of response to treatment of bleeds in prophylaxis group.  
 
❖ Perioperative Management 
A total of 1 major and 7 minor surgeries were performed in 4 previously treated subjects with severe hemophilia 
A. 1 major surgery was elective hemorrhoidectomy with local anesthesia. 6 of 7 minor surgeries were dental 
extractions. The remaining surgery was an oral pseudotumor resection. All subjects received KOVALTRY as 
bolus infusions. The initial KOVALTRY doses administered of the major surgery was 3252 IU (pre-surgery) and 
3252 IU in the same day (post-surgery). The pre-surgery doses for 7 minor surgeries ranged from 1500 to 2033 
IU. 
The blood loss, during and after surgery, was within expected ranges. Hemostatic control was assessed by 
surgeons as ”good” (perioperative bleeding slightly but not clinically significantly increased over expectations 
for the non-hemophilic patient; treatment similar to non-hemophilic patient) or “excellent” (perioperative blood 
loss similar to the non-hemophilic patient). 
 
 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  99 of 105 
 
❖ Routine Prophylaxis 
A total of 17 subjects were treated with KOVALTRY for at least 12 months with median (range) 153 EDs (106-
182).  
 
Table 14: Prophylaxis Treatment with KOVALTRY in Adolescents and Adults – Treatment Exposure 
 
China subgroup  
（N = 17a） 
Median nominal prophylaxis dose/ 
infusion (range) 
 
All 
31.69 IU/kg（21.5-41.9 IU/kg） 
Prophylaxis, 2 times per week, low dose 
30.42 IU/kg（21.6-32.0 IU/kg） 
Prophylaxis, 3 times per week, high dose 
40.41 IU/kg（30.7-41.9 IU/kg） 
Treatment duration 
1 year 
a: 2 times per week (n=7); 3 times per week (n=10) 
 
Comparison of the bleeding rates between subjects receiving on-demand therapy versus prophylaxis in an 
ANOVA demonstrated a statistically significant difference (p<0.0001) in the median ABR in subjects receiving 
on-demand therapy (63.54 bleeds per year) as compared to subjects receiving prophylaxis (1.98 bleeds per year). 
Mean ABR in subjects receiving on-demand therapy was 71.93 ± 22.96 versus 3.91 ± 4.79 in the subjects 
receiving prophylaxis. 
 
Table 15：ABR in Adolescent and Adult Subjects 
 
China subgroup 
prophylaxis（N = 17） 
 
2 times per week（n=7） 
3 times per week 
（n=10） 
ABR Median (IQRa Q1; Q3) 
 
 
All Bleeds 
 
 
5.04（1.95；11.04） 
1-6 months b：4.02； 
7-12months b：3.64 
 
 
1.98（0.0；2.0） 
1-6 months b：1.93； 
7-12 months b：1.95 
Spontaneous Bleeds 
2.01（0.0；9.0） 
0.0（0.0；0.0） 
Joint Bleeds 
4.03（2.0；7.9） 
0.0（0.0；2.0） 
Subjects with Zero Bleeding 
Episodesc % (n) 
14.3% (1/7 d) 
30.0% (3/10d) 
aIQR = Interquartile Range 
bMonth 1-6 refers to the first six months of the treatment period and Month 7-12 refer to the second six months of the 
treatment period 
cObservation of one-year treatment period 
dn=total number of subjects randomized to treatment arms 
 
[Pharmacology and toxicology]  
Pharmacology 
KOVALTRY temporarily replaces the missing clotting Factor VIII. 
Plasma clotting time as measured by the activated partial thromboplastin time (aPTT) is prolonged in 
patients with hemophilia A. Treatment with KOVALTRY normalizes the aPTT. 
 
Toxicology 
KOVALTRY was negative in the modified in-vitro (Mammalian Mutation and Chromosome 
Aberration Assay with Mouse Lymphoma Cells) genotoxicity test. 
Studies in animals to evaluate carcinogenic potential of KOVALTRY have not been performed. 
 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  100 of 105 
 
[Pharmacokinetics] 
The pharmacokinetics (PK) of KOVALTRY were investigated in PTPs (0 to 61 years of age) with 
severe Hemophilia A following administration of 50 IU/kg of KOVALTRY. The PK parameters of 
KOVALTRY are presented in Table 16 (one-stage clotting assay) and Table 17 (chromogenic 
substrate assay). The PK of KOVALTRY were similar between single and repeat dosing (in 19 
subjects following 6 to 12 months of prophylaxis). 
Table 16: Pharmacokinetic Parameters [Arithmetic Mean ±SD] for KOVALTRY (50 IU/kg 
dose), One-Stage Clotting Assay 
 
AUC: area under the curve 
Cmax: maximum drug concentration in plasma after single dose 
t½ : terminal half-life 
MRTIV: mean residence time after an IV administration 
Vss: apparent volume distribution at steady-state 
CL: clearance 
 
The PK parameters of KOVALTRY for 8 subjects in age group 0 to <6 years and 10 subjects in age 
group 6 to <12 years are shown in Table 17. In general, children <12 years of age demonstrated lower 
plasma concentrations when compared to PTP children ≥12 years of age. 
 
Table 17: Pharmacokinetic Parameters [Arithmetic Mean ±SD] for KOVALTRY (50 IU/kg 
dose), Chromogenic Substrate Assay 
 
an=7 
bOne subject considered PK outlier was excluded 
  

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  101 of 105 
 
Incremental Recovery: 
Recovery values according to the chromogenic assay were similar to measurements with the one-stage 
assay (see Table 18). Incremental Recovery analysis after 6 months of prophylactic treatment yielded 
comparable results with incremental recovery after the first dose (see Table 19). 
 
Table 18. Incremental Recovery in PTPs ≥ 12 Years of Age  
 
Table 19: Incremental Recovery in PTPs 0-12 Years of Age 
Study participants 
Study 3 
PTPs 0 to <6 yrs 
PTPs 6 to 12 yrs 
N=24 
N=25 
Start of study: 
Chromogenic assay results 
Median (Q1; Q3) 
(IU/dL per IU/kg) 
1.6 (1.3; 1.9) 
1.7 (1.4; 2.0) 
 
N=23 
N=25 
After 6 months:  
Chromogenic assay results 
Median (Q1; Q3) 
(IU/dL per IU/kg) 
1.8 (1.4; 2.0) 
1.8 (1.1; 2.1) 
 
[Storage] 
KOVALTRY should be stored and transported at 2-8℃. Do not freeze. 
Administer reconstituted KOVALTRY as soon as possible. If not, store at room temperature for no 
longer than 3 hours. 
 
[Package] 
• 
Packaging materials in direct contact with drug product: Type I glass vial , bromobutyl grey 
stopper  
• 
A vial of recombinant coagulation factor VIII for injection 
• 
A prefilled diluent syringe containing 2.5 ml of sterile water for injection 
• 
A sterile vial adapter 
• 
A single use administration set with filter 
 
[Shelf life] 
30 months 
 
Study 1 
Study 2 
Pooled Analysis 
Study participants 
N=59 
N=56 
N=115 
Chromogenic assay results 
Median (Q1; Q3) 
(IU/dL per IU/kg) 
2.5 (2.1; 2.8) 
2.1 (1.7; 2.4) 
2.3 (1.8; 2.6) 
One-stage assay results 
Median (Q1; Q3) 
(IU/dL per IU/kg) 
2.2 (1.9; 2.5) 
2.1 (1.7; 2.3) 
2.2 (1.8; 2.4) 

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  102 of 105 
 
 
[Executive Specification] 
Registration specification for imported drug JS20160071 
 
[Import Drug License No.] 
250 IU/vial：
 
500 IU/vial：
 
1000 IU/vial：
 
 
[Manufacturer] 
Name: Bayer Health Care LLC  
Address: 800 Dwight Way, Berkeley, CA 94710, US 
 
[Domestic Contact division] 
Company name: Bayer Healthcare Co.,Ltd., Beijing, China 
Address: No.7 Rongjing East Street, Beijing Economic and Technology Development Area 
Post Code: 100176 
Tel.: 010 59218282 
Fax: 010 59218181 
 
[Hotline] 400-810-0360 
 
 
CCI
CCI
CCI

CONFIDENTIAL
Clinical Study Protocol Amendment 2 (Global)
BAY 81-8973 (KOVALTRY) / 19855
12 MAY 2023
Page:  103 of 105
<Appendix: Preparation and Reconstitution>
•
Reconstitute and administer KOVALTRY with the components provided with each package. If 
any component of the package is opened or damaged, do not use this component.
•
For any questions about the handling, reconstitution and administration of KOVALTRY, contact 
Bayer Medical Communications at Bayer Hotline (400-810-0360).
The procedures below are provided as general guidelines for the reconstitution of KOVALTRY using 
the sterile vial adapter with a 15 micrometer filter and a prefilled diluent syringe, which together serve 
as an alternative needleless reconstitution system.
Usability Testing of Vial Adapter
Usability testing was conducted with 60 users, including 15 pediatric hemophilia A patients (between 
10-17 years of age), 15 adult hemophilia A patients (≥18 years of age), 15 caregivers, and 15 
healthcare providers. To mimic real life, the pediatric and adult patients and the caregivers were given 
minimal training, which included participants performing a supervised reconstitution and later 
performing a single unaided reconstitution. Healthcare providers were untrained in this study and 
could learn the procedure from the provided Instructions for Use. All participants were able to 
successfully and safely use the vial adapter device for reconstitution.
Reconstitution
•
Work on a clean surface and wash hands thoroughly using soap and warm water before 
performing the procedures.
•
Reconstitute KOVALTRY with the components provided with each package. If any component 
of the package is opened or damaged, do not use this component.
•
Filter the reconstituted product to remove potential particulate matter in the solution. Filtering is 
achieved by using the vial adapter.
1.Warm both unopened KOVALTRY vial and prefilled diluent syringe
in your hands to a comfortable temperature (do not exceed 37°C or 99°F).
2. Remove the protective cap from the vial (A). Aseptically cleanse the
rubber stopper with a sterile alcohol swab, being careful not to handle 
the rubber stopper.
3. Place the product vial on a firm, non-skid surface. Peel off the paper 
cover on the vial adapter plastic housing. Do not remove the adapter 
from the plastic housing. Holding the adapter housing, place over the 
product vial and firmly press down (B). The adapter will snap over the 
vial cap. Do not remove the adapter housing at this step.
4. Holding the syringe by the barrel, snap the syringe cap off the tip 
(C). Do not touch the syringe tip with your hand or any surface. Set the 
syringe aside for further use.

CONFIDENTIAL
Clinical Study Protocol Amendment 2 (Global)
BAY 81-8973 (KOVALTRY) / 19855
12 MAY 2023
Page:  104 of 105
5. Now remove and discard the adapter plastic housing (D).
6. Attach the prefilled syringe to the vial adapter thread by turning 
clockwise (E).
7. Remove the clear plastic plunger rod from the carton. Grasp the 
plunger rod by the top plate. Avoid touching the sides and threads of 
the plunger rod. Attach the plunger rod by turning it clockwise into the 
threaded rubber stopper of the prefilled syringe (F).
8. Inject the diluent slowly by pushing down on the plunger rod (G).
9. Swirl vial gently until all powder on all sides of the vial is dissolved 
(H). Do not shake vial. Be sure that all powder is completely 
dissolved. Do not use if solution contains visible particles or is cloudy.
10. Push down on the plunger to push all air back into the vial. Then 
while holding the plunger down, turn the vial with syringe upside-
down (invert) so the vial is now above the syringe (I).
11. Withdraw all the solution into the syringe by pulling the plunger 
rod back slowly and smoothly (J). Tilt the vial to the side and back to 
make sure all the solution has been drawn toward the large opening in 
the rubber stopper and into the syringe. Remove as much air as
possible before removing the syringe from the vial by slowly and 
carefully pushing the air back into the vial.

CONFIDENTIAL 
Clinical Study Protocol Amendment 2 (Global) 
BAY 81-8973 (KOVALTRY) / 19855 
12 MAY 2023 
Page:  105 of 105 
 
12. Detach the syringe with plunger rod from the vial adapter by 
turning counter-clockwise. Attach the syringe to the administration set 
provided and inject intravenously (K). 
 
Note: follow instructions for infusion set provided. 
 
 
 
Pooling 
If the dose requires more than one vial, reconstitute each vial as described above with the diluent 
syringe provided. Use a larger plastic syringe (not provided) to combine the content of the vials into 
the syringe.