A Multicenter, Prospective, Open-label, Clinical Study to Assess the Effect of Using a New Risk Score Approach to Select the Most Appropriate Prophylaxis Regimen for Reaching a Favorable Outcome, When Hemophilia A Patients Switch From Standard Half-life Products to Damoctocog Alfa Pegol (Jivi)
Phase: PHASE4
Conditions: Hemophilia A, Prophylaxis of Bleeding
Sponsor: Bayer

CONFIDENTIAL 
Clinical Study Protocol Amendment 3 (Global) 
No. BAY 94-9027 / 21924 
02 OCT 2023 
Page:  1 of 119 
Title Page 
Protocol Title: 
A multicenter, prospective, open-label, clinical study to assess the effect of using a new risk 
score approach to select the most appropriate prophylaxis regimen for reaching a favorable 
outcome, when hemophilia A patients switch from standard half-life products to damoctocog 
alfa pegol (Jivi) 
Protocol Number: 
 
21924 
Amendment Number: 
3 
Version: 
4.0 
Compound Number: 
BAY 94-9027/ Damoctocog alfa pegol; Human Pegylated 
rFVIII; Jivi 
Brief Title:  
Jivi interventional study to assess a new risk score approach 
Study Phase: 
Phase 4 
Acronym:  
PREDICT (PRediction factors for optimal Efficacy and Dosing 
regimen when swItChing from SHL To EHL) 
Sponsor Name: 
Bayer HealthCare Pharmaceuticals Inc. 
Legal Registered Address: Bayer HealthCare Pharmaceuticals Inc. 
100 Bayer Boulevard, P.O. Box 915 
Whippany NJ 07981-0915, USA 
Regulatory Agency Identifier Number(s): TBD 
NCT: NCT05036278 

CONFIDENTIAL 
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Document History Table 
DOCUMENT HISTORY 
Document 
Version  Date 
Comments (if applicable) 
Amendment 3 
4.0 
02 OCT 2023 
 
Amendment 2 
3.0 
19 AUG 2022 
 
Amendment 1 
2.0 
17 SEP 2021 
 
Clinical Study 
Protocol 
1.0 
28 JUN 2021 
Original version (internal use only) 
Amendment 3 (02 OCT 2023) 
Overall Rationale for the Amendment: 
It was planned to enroll a maximum of 70 participants such that approximately 60 evaluable 
participants would complete the study. Due to the observed rate of recruitment, it will not be 
feasible to enroll 70 participants within the planned recruitment period. Given the actual 
recruitment (as of August 2023), it is assumed that only 20-25 participants will be enrolled by 
the end of 2023. The protocol was updated to describe the anticipated reduced sample size 
and the impact on the precision of estimates. 
Furthermore, the inclusion criteria were adjusted to reduce restrictions to enrollment. 
Although the change in inclusion criteria has the potential to introduce bias in comparisons to 
patients enrolled prior to the amendment, the risk is thought to be minimal given the 2 
possible extreme scenarios below:  
o 
1 – interruptions in treatment (eg, insurance, migration): a maximum period of 
6 months (assuming untreated during that time) is not expected to dramatically change 
patients’ disease phenotype such that it would reflect during Jivi prophylaxis while on 
study 
o 
2 – patients treated with an extended half-life (EHL) prior to study entry: the 
reason for switching to an EHL following stable SHL prophylaxis could be due to 
external conditions unrelated to patients’ bleeding phenotype (eg, formulary changes, 
insurance requirements, patient preference, etc.). Nevertheless, if the change to an 
EHL treatment was due to a patient’s bleeding phenotype and/or any structural 
differences compared to any patients enrolled before amendment 3, the risk of bias is 
thought to be low, since any data from the time of EHL treatment are excluded from 
the risk score calculation for those patients remaining to be enrolled. 
Due to the decision to no longer pursue enrolling participants from Colombia, the protocol is 
amended back to a single country United States study. 
The changes incorporated in this amendment are described in the table below. Edits to update 
amendment number and dates in the current version, and minor editorial changes for style 
have been made, but are not documented in the table. 
Section #  
and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis, Overall Design 
1.1 Synopsis, Number of 
Participants 
Changed number of participants 
approximately assigned to study 
intervention from 70 to 20-25 
Due to feasibility reasons, 
specifically the observed rate of 
recruitment 
Added definition for determination of 
pre-study annualized bleed (ABR), 
treatment frequency, and stable 
standard half-life (SHL) prophylaxis. 
Clarification of terms used in 
protocol, and removal of 
reference to multi-country study 
design 

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Removed “multi-country” 
Section 1.2 Figure 1-1: Dosing 
Regimen Schema 
Updated N and clarified trough level 
timepoint at Month 3 
Updated due to reduction of 
study sample size and for 
clarification 
Section 1.3 Schedule of Activities 
(SoA) 
Human coagulation factor VIII (FVIII) 
levels line item: added note 
describing required washout period 
for patients whose previous product 
was an SHL or extended 
half-life (EHL). Added a conditional 
measurement timepoint in Visit 5 
and Visit 6 columns and new 
footnote g in Visit 2, Visit 5, and Visit 
6 columns 
Clarification of washout period 
and addition of a conditional 
measurement timepoint 
Web-Accessible Population 
Pharmacokinetic Service-Hemophilia 
(WAPPS-Hemo) analysis line item: 
added note describing use of FVIII 
levels from Visit 2 and Visit 5, and a 
reference to footnote h 
Clarification of which FVIII levels 
to use in WAPPS-Hemo 
FVIII trough levels line item: added a 
note clarifying that Visit 5 level will 
be first of 2 trough levels for those 
on a 2x/week regimen 
Clarification; text moved from 
footnote to table 
Created new footnote g; subsequent 
footnotes renumbered 
Creation of footnote describing 
conditional timepoint for 
repeating FVIII levels 
Updated footnote h to clarify 
timepoints for WAPPS-Hemo data 
entry 
Clarification 
Clarified footnote j regarding timing 
of trough level measurements 
Clarification 
Section 2.1 Study Rationale; 
Section 4.1 Overall Design;  
Added definition for determination of 
pre--study ABR, treatment 
frequency, and stable SHL 
prophylaxis 
Clarification of terms used 
throughout protocol 
 
The rationale to continue with 
the current baseline definition is 
that a comparison between SHL 
and score-based Jivi 
prophylaxis is intended, and 
inclusion of another period 
(untreated or different 
treatment) would bias this 
comparison. 
Section 4.1 Overall Design; 
Section 9.4.1 General 
Considerations; Section 9.4.5.1 
Disposition of Participants 
Removed text identifying the study 
as a multi-country design, text 
stating that primary endpoint tables 
will be stratified by country to 
consider a potential country effect, 
and text stating that disposition will 
be presented by country 
Due to decision to no longer 
pursue enrolling participants 
from Colombia 
Section 4.1 Overall Design 
Added Screening schematic to 
clarify screening process 
(Figure 4-1); updated subsequent 
figure numbering 
Clarification 
Text describing possible interim 
analysis removed due to reduction in 
study sample size 
Due to reduction in sample size 
Text describing rationale for the 
baseline definition, and statement 
regarding feasibility of drawing 
conclusions with reduced sample 
size added 
Clarification 
Cross-reference to Section 9.4.2 
Clarification and improvement of 

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added for full definition of pre-study 
ABR, treatment frequency, and 
stable SHL prophylaxis 
document navigation 
Section 4.1, Table 4-1: Parameters 
for determining participant risk 
scores 
Participant Variables were clarified. 
New footnotes a and b were added 
and subsequent footnotes 
renumbered accordingly 
Clarification 
Section 4.1.1 Screening 
Text clarified to read that during the 
screening period, participants will 
continue treatment with their current 
FVIII treatment 
Clarification 
Section 5 Study Population 
Text added to allow that 
adolescent/adult participants must 
be previously treated, and on 
continuous prophylaxis with an SHL 
FVIII product for at least 6 
consecutive months within the 
previous 12 months prior to the 
screening visit 
Adjustment of requirements for 
participants 
Section 5.1 Inclusion Criteria; 
Inclusion Criterion #3 
Text added to modify requirements 
and window for prophylaxis with SHL 
FVIII with a stable frequency prior to 
start of study intervention, to define 
stable frequency, and to permit 
non-Jivi EHL between the 6-month 
stable SHL prophylaxis period and 
start of study treatment 
Adjustment to reduce 
restrictions to enrollment 
Section 5.1 Inclusion Criteria; 
Inclusion Criterion #4 
Text added to clarify requirements 
and to clarify that window for 
evaluating documented bleeding rate 
(ABR) occurs prior to screening 
Clarification 
Section 5.1 Inclusion Criteria; 
Inclusion Criterion #5 
Text added to modify conditions 
under which a participant can be 
enrolled if they had past evidence of 
a positive inhibitor titer 
To relax restrictions to 
enrollment due to lack of 
evidence of past FVIII inhibitors 
presenting an issue in patients 
with subsequent negative titers 
for inhibitors 
Section 5.2 Exclusion Criteria; 
Exclusion Criterion #3 
Reduced evidence of inhibitor to 
FVIII from 3 years to 1 year 
Alignment with Inclusion 
Criterion #5 
Section 5.2 Exclusion Criteria; 
Exclusion Criterion #6 
Added cross-reference to Inclusion 
Criterion #4 and Section 9.4.2 
Clarification and cross-reference 
to full definition for improved 
document navigation 
Section 6.3 Measures to Minimize 
Bias: Randomization and Blinding 
Text added to describe potential for 
introduction of bias due to pre-study 
window of bleed frequency data 
collection 
Transparency about possible 
introduction of bias due to 
change in data collection time 
period 
Section 8.1.1 Demographics 
Removed country from demographic 
characteristics to be recorded at 
screening 
Due to decision to no longer 
pursue enrolling participants 
from Colombia 
Section 8.1.3 Disease History 
Clarification of information on history 
of hemophilia to be recorded at 
screening 
Clarification 
Section 8.2 Effectiveness 
Assessment 
Note added with cross-references to 
the sections of the protocol with full 
definitions of pre-study ABR, 
treatment frequency, and stable SHL 
prophylaxis 
Clarification and improvement of 
document navigation 
Section 8.2.1 Treatment 
Logs/Bleeding Verification 
Corrected that participants and their 
parent or legal guardian will be 
trained on the use of eDiary at the 
Baseline Visit rather than the 
screening visit 
Corrected to align with SoA 
Section 8.2.3 Joint status 
assessment 
Corrected that joint status 
assessment will occur at baseline 
Correction 

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rather than at screening 
Section 8.4.1 Time Period and 
Frequency for Collecting AE and 
SAE Information 
Text added to clarify that bleeds that 
occur during the screening period 
should be recorded in the 
participant’s medical record 
Clarification 
Section 9.2 Sample Size 
Determination 
Anticipated sample size changed 
from 70 to 20-25. Precision of 
estimates for the primary outcome 
updated accordingly. Statement 
regarding low expected precision 
added 
Table 9-1 replaced with table 
presenting updated estimates 
appropriate for reduction in sample 
size 
Statement regarding feasibility of 
drawing conclusions with reduced 
sample size added 
Due to feasibility reasons. To be 
transparent about estimate 
precision for reduced study size 
Section 9.4.2 Primary Endpoints 
Text added to comprehensively 
define the basis for establishing 
pre-study ABR and treatment 
frequency, and stable SHL 
prophylaxis 
Clarification 
Removed text stating that outcome 
on risk score-selected prophylaxis 
regimen will be presented by country 
Due to decision to no longer 
pursue enrolling participants 
from Colombia 
Section 9.4.3 Secondary Endpoints 
Added cross-reference to 
Section 9.4.2 for definition of 
pre-study values 
Clarification of terms and 
improvement of document 
navigation 
Section 9.5 Interim Analysis 
Text was changed to Not applicable, 
as due to reduction in sample size 
for the study, no interim analysis will 
be performed 
Due to change in study sample 
size 
Appendix 7 Section 11.7.4 Visit 5 – 
(Month 3) and Section 11.7.5 Visit 
6 – (Month 6, End of Study/Early 
Withdrawal) 
Text added regarding a conditional 
measurement timepoint, to align with 
new footnote g in Visit 5 and Visit 6 
columns of the SoA 
Consistency and addition of a 
conditional measurement 
timepoint 
Appendix 10, Section 11.10 
Definitions (Common Terms) 
Added definitions for Pre-study ABR, 
Pre-study Treatment Frequency, and 
Stable SHL prophylaxis 
Clarification of common terms 
used throughout the protocol 
Section 11.3 Appendix 3, Clinical 
Laboratory Tests 
Referenced table number corrected 
from 10-1 to 11-1 
Correction 
Section 11.7.1 Visit 1-Sceening 
(Up to 30 Days Prior to Baseline) 
Corrected table number referenced 
for blood sample information from 
10-1 to 11-1 
Correction 

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Protocol Date:  
02 OCT 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 Trial Master File 
(TMF) and available on request. 
 
Medical Monitor (Study Medical Expert) name and contact information can be found in the 
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. 
 
PPD
PPD
PPD

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Table of Contents 
Title Page ............................................................................................................................. 1 
Document History Table .................................................................................................... 2 
Table of Tables .................................................................................................................. 10 
Table of Figures................................................................................................................. 10 
1.
Protocol Summary ..................................................................................................... 11 
1.1 
Synopsis .................................................................................................................... 11 
1.2 
Schema for Dosing Regimen Assignment ................................................................ 15 
1.3 
Schedule of Activities (SoA) .................................................................................... 16 
2.
Introduction ................................................................................................................ 19 
2.1 
Study Rationale ........................................................................................................ 19 
2.2 
Background ............................................................................................................... 21 
2.3 
Benefit/Risk Assessment .......................................................................................... 22 
2.3.1 
Overall Benefit/Risk Conclusion .......................................................................... 23 
3.
Objectives and Endpoints ......................................................................................... 23 
4.
Study Design ............................................................................................................... 24 
4.1 
Overall Design .......................................................................................................... 24 
4.1.1 
Screening ............................................................................................................... 29 
4.1.2 
Treatment .............................................................................................................. 30 
4.2 
Scientific Rationale for Study Design ...................................................................... 31 
4.3 
Justification for Dose ................................................................................................ 33 
4.4 
End of Study Definition ............................................................................................ 33 
5.
Study Population ........................................................................................................ 33 
5.1 
Inclusion Criteria ...................................................................................................... 33 
5.2 
Exclusion Criteria ..................................................................................................... 35 
5.3 
Lifestyle Considerations ........................................................................................... 36 
5.4 
Screen Failures ......................................................................................................... 36 
5.5 
Criteria for Temporarily Delaying Study Intervention Administration ................... 37 
6.
Study Intervention and Concomitant Therapy ....................................................... 37 
6.1 
Study Intervention Administered ............................................................................. 37 
6.1.1 
Medical Devices .................................................................................................... 39 
6.2 
Preparation/Handling/Storage/Accountability ......................................................... 39 
6.3 
Measures to Minimize Bias: Randomization and Blinding ...................................... 40 
6.4 
Study Intervention Compliance ................................................................................ 40 
6.5 
Dose Modification .................................................................................................... 41 
6.6 
Continued Access to Study Intervention After the End of the Study ....................... 41 
6.7 
Treatment of Overdose ............................................................................................. 41 
6.8 
Concomitant Therapy ............................................................................................... 42 
7.
Discontinuation of Study Intervention and Participant
Discontinuation/Withdrawal ..................................................................................... 43 
7.1 
Discontinuation of Study Intervention ..................................................................... 43 
7.1.1 
Inhibitor Development .......................................................................................... 43 
7.1.2 
Planned Major Surgery During the Study ............................................................. 43 
7.1.3 
Temporary Discontinuation from Study Intervention ........................................... 43 

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7.2 
Participant Discontinuation/Withdrawal from the Study ......................................... 44 
7.3 
Lost to Follow-Up .................................................................................................... 44 
8. 
Study Assessments and Procedures .......................................................................... 45 
8.1 
Population Characteristics ........................................................................................ 46 
8.1.1 
Demographics ....................................................................................................... 46 
8.1.2 
Medical and Surgical History ................................................................................ 46 
8.1.3 
Disease History ..................................................................................................... 46 
8.1.4 
Other ...................................................................................................................... 46 
8.2 
Effectiveness Assessments ....................................................................................... 46 
8.2.1 
Treatment Logs/Bleeding Verification ................................................................. 47 
8.2.2 
Patient Reported Outcomes ................................................................................... 48 
8.2.3 
Joint Status Assessment ........................................................................................ 49 
8.3 
Safety Assessments .................................................................................................. 50 
8.3.1 
Measurements of Immunogenicity ........................................................................ 50 
8.3.2 
Physical Examinations .......................................................................................... 50 
8.3.3 
Clinical Safety Laboratory Assessments ............................................................... 50 
8.3.4 
von Willebrand Factor (vWF) Antigen ................................................................. 50 
8.3.5 
Pregnancy Testing ................................................................................................. 51 
8.4 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Safety Reporting
 .................................................................................................................................. 51 
8.4.1 
Time Period and Frequency for Collecting AE and SAE Information ................. 51 
8.4.2 
Method of Detecting AEs and SAEs ..................................................................... 52 
8.4.3 
Follow-up of AEs and SAEs ................................................................................. 52 
8.4.4 
Regulatory Reporting Requirements for SAEs ..................................................... 52 
8.4.5 
Pregnancy .............................................................................................................. 52 
8.4.6 
Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs ................................................................................................................. 53 
8.4.7 
Events of Special Interest ...................................................................................... 53 
8.4.8 
Medical Device Deficiencies ................................................................................ 54 
8.5 
Pharmacokinetics ...................................................................................................... 54 
8.5.1 
Incremental Recovery and Trough Levels of Jivi ................................................. 54 
8.5.2 
Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-
Hemo) Analysis ..................................................................................................... 55 
8.6 
Pharmacodynamics ................................................................................................... 56 
8.7 
Genetics .................................................................................................................... 56 
8.8 
Biomarkers ............................................................................................................... 56 
8.9 
Other Investigations .................................................................................................. 56 
8.10 Medical Resource Utilization and Health Economics .............................................. 56 
9. 
Statistical Considerations .......................................................................................... 56 
9.1 
Statistical Hypotheses ............................................................................................... 56 
9.2 
Sample Size Determination ...................................................................................... 56 
9.3 
Analysis Set .............................................................................................................. 57 
9.4 
Statistical Analyses ................................................................................................... 58 
9.4.1 
General Considerations ......................................................................................... 58 
9.4.2 
Primary Endpoint .................................................................................................. 58 
9.4.3 
Secondary Endpoints ............................................................................................. 59 
9.4.4 
Safety Analyses ..................................................................................................... 60 
9.4.4.1 
Immunogenicity ................................................................................................. 60 

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9.4.4.2 
Pharmacokinetics ............................................................................................... 60 
9.4.5 
Other Analyses ...................................................................................................... 60 
9.4.5.1 
Disposition of participants ................................................................................. 60 
9.4.5.2 
Demographics and other baseline characteristics .............................................. 60 
9.5 
Interim Analysis ....................................................................................................... 60 
10. Tokenization (United States Participants Only) ..................................................... 60 
11. Supporting Documentation and Operational Considerations ............................... 63 
11.1 Appendix 1: Regulatory, Ethical, and Study Oversight Considerations .................. 63 
11.1.1 Regulatory and Ethical Considerations ................................................................. 63 
11.1.2 Financial Disclosure .............................................................................................. 63 
11.1.3 Informed Consent and Pediatric Participant Assent Process ................................ 63 
11.1.4 Data Protection ...................................................................................................... 64 
11.1.5 Committees Structure ............................................................................................ 64 
11.1.6 Dissemination of Clinical Study Data ................................................................... 64 
11.1.7 Data Quality Assurance ......................................................................................... 65 
11.1.8 Source Documents ................................................................................................ 66 
11.1.9 Study and Site Start and Closure ........................................................................... 66 
11.1.10 Publication Policy ................................................................................................. 66 
11.2 Appendix 2: Patient Reported Outcomes ................................................................. 67 
11.2.1 Haemophilia specific quality of life questionnaires (Haem-A-QoL and Haemo-
QoL) ...................................................................................................................... 68 
11.2.2 Patient’s Global Impression of Change (PGI-C) .................................................. 79 
11.2.3 Five-Level European Quality of Life Five Dimension (EQ-5D-5L) .................... 82 
11.2.4 Treatment Satisfaction Questionnaire for Medication (TSQM) ........................... 86 
11.2.5 Work Productivity and Activity Impairment (WPAI) Questionnaire ................... 90 
11.3 Appendix 3: Clinical Laboratory Tests .................................................................... 93 
11.4 Appendix 4: AEs and SAEs: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ......................................................................................... 94 
11.4.1 Definition of AE .................................................................................................... 94 
11.4.2 Definition of SAE ................................................................................................. 95 
11.4.3 Recording and Follow-Up of AE and/or SAE ...................................................... 96 
11.4.4 Reporting of SAEs ................................................................................................ 97 
11.5 Appendix 5: Medical Device AEs, SAEs, and Device Deficiencies: Definitions and 
Procedures for Recording, Evaluating, Follow-up, and Reporting .......................... 99 
11.5.1 Definition of Medical Device AE ....................................................................... 100 
11.5.2 Definition of Medical Device SAE ..................................................................... 100 
11.5.3 Definition of Device Deficiency ......................................................................... 100 
11.5.4 Recording and Follow-up of Medical Device AEs/SAEs/Device Deficiencies . 100 
11.5.5 Reporting of AEs/SAEs Related to the Device ................................................... 101 
11.6 Appendix 6: Contraceptive Guidance and Collection of Pregnancy Information .. 103 
11.7 Appendix 7: Visit Description ................................................................................ 105 
11.7.1 Visit 1 – Screening (Up to 30 Days Prior to Baseline) ....................................... 105 
11.7.2 Visit 2 – Baseline (Day 1) ................................................................................... 106 
11.7.3 Visit 3, 4 – (Months 1, 2) .................................................................................... 107 
11.7.4 Visit 5 – (Month 3) .............................................................................................. 107 
11.7.5 Visit 6 – (Month 6, End of Study/Early Withdrawal) ......................................... 107 
11.7.6 Visit 7 – (Safety Follow-up; 7 to 14 days after last dose of study intervention) 108 
11.8 Appendix 8: Tokenization ...................................................................................... 109 

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11.9 Appendix 9: Protocol Amendment History ............................................................ 113 
11.10 Appendix 10: Abbreviations ................................................................................... 116 
12. References ................................................................................................................. 118 
Table of Tables 
Table 4–1: Parameters for Determining Participant Risk Scores ............................................ 26 
Table 4–2: Risk Score Treatment Assignment ........................................................................ 29 
Table 4–3: Dosing Regimens ................................................................................................... 31 
Table 6–1: Study Intervention ................................................................................................. 38 
Table 9–1: Expected Precision of Estimates by Sample Size and Assumed Proportion of 
Participants with Favorable Outcome ................................................................... 57 
Table 9–2: Analysis Sets .......................................................................................................... 57 
Table 11–1: Protocol-required Laboratory Tests ..................................................................... 93 
Table of Figures 
Figure 1–1: Dosing Regimen Schema ..................................................................................... 15 
Figure 4–1: Pre-study Timeline ............................................................................................... 25 
Figure 4–2: National Hemophilia Foundation Activity Rankings ........................................... 27 

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1. 
Protocol Summary 
1.1 
Synopsis 
Protocol Title:  
A multicenter, prospective, open-label clinical study to assess the 
effect of using a new risk score approach to select the most appropriate 
prophylaxis regimen for reaching a favorable outcome, when 
hemophilia A patients switch from standard half-life products to 
damoctocog alfa pegol (Jivi) 
Brief Title:  
Jivi interventional study to assess a new risk score approach 
Rationale: 
This study aims to assess a new risk score approach utilizing the best 
known phenotypic and biologic variables to select the most appropriate 
prophylaxis regimen for reaching a favorable outcome when switching 
from standard half-life (SHL) human coagulation factor VIII (FVIII) 
treatment to Jivi. 
 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
To assess the effect of using a baseline risk 
score, based on a participant’s phenotypic 
and biologic variables, to select the most 
appropriate prophylaxis regimen for 
reaching a favorable outcome, when 
switching from a SHL product to Jivi  
Occurrence of favorable outcome on the 
score selected dosing regimen 
Secondary 
 
To assess the effectiveness of Jivi 
compared to a previous SHL treatment 
ABR (total, joint, spontaneous) and change 
in total ABR from pre-study 
To assess the frequency of Jivi 
administration 
Change in the frequency of pre-study SHL 
treatment to the frequency of Jivi 
administration (infusions/month) 
To assess the proportion of participants 
with 0 and ≤ 1 spontaneous bleeds 
Occurrence of participants with 0 and ≤ 1 
spontaneous bleeds 
To assess participant quality of life (QoL) 
and physical activity, as measured by 
Patient Reported Outcomes (PROs)  
Change in Haemophilia Quality of Life 
Questionnaire (Haem-A-QoL or 
Haemo-QoL); Patient’s Global Impression 
of Change (PGI-C); EuroQoL 5 Dimensions 
(EQ-5D-5L) questionnaire; Treatment 
Satisfaction Questionnaire for Medication 
(TSQM); Work Productivity and Activity 
Impairment (WPAI) questionnaire scores 
To assess target joint status, per 
International Society on Thrombosis and 
Haemostasis (ISTH) guidelines 
Number of target joints and change in target 
joint status from baseline 

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Other, Pre-specified 
 
To assess whether blood type and body 
mass index (BMI) would have led to a 
different score allocation  
Participant score considering ABO type and 
BMI 
 
To describe pharmacokinetic (PK) 
parameters derived from Web-Accessible 
Population Pharmacokinetic 
Service-Hemophilia (WAPPS-Hemo) and 
assess an association with clinical risk score 
PK parameters derived from WAPPS-Hemo 
 
To determine participant Jivi trough levels 
while on a specific regimen  
Trough measurement of Jivi levels  
 
To determine the percentage of participants 
who can maintain > 1%, > 3 %, and > 5% 
FVIII trough levels while on a specific 
prophylaxis regimen 
Occurrence of trough levels above 1%, 3% 
and 5%, stratified by prophylaxis regimen 
 
Abbreviations: ABR = annualized bleeding rate; EQ-5D-5L = EuroQoL 5 dimensions; FVIII = human 
coagulation factor VIII; SHL = standard half-life 
Overall Design: 
This is a multicenter, open-label, single arm, prospective study of previously-treated 
adolescent/adult (≥12 years) patients (PTPs) with congenital hemophilia A treated with a 
SHL FVIII product for regular prophylaxis who are willing to switch to the extended half-life 
(EHL) product, Jivi (throughout this document, the symbol ® indicating a proprietary name 
is not displayed for Jivi. However, the omission of the symbol does not imply that this name 
is not protected). The study will be conducted to assess the effect of using a new risk score 
approach to select the most appropriate prophylaxis regimen for reaching a favorable 
outcome. Favorable outcome is defined for this study as: no dosing regimen change from the 
risk score-assigned regimen during the study period along with an improved annualized 
bleeding rate (ABR) from pre-study ABR and decreased or similar dosing frequency 
compared to the previous treatment, or no dosing regimen change compared to risk score-
assigned regimen with a similar ABR and a decreased dosing frequency compared to the 
previous treatment. All participants will have received prophylaxis with any licensed SHL 
FVIII product with a stable dosing regimen. Pre-study ABR and treatment frequency is based 
on data from a minimum of 6 continuous months (up to a maximum of 12 months) of stable 
SHL prophylaxis at any given time within the 12 months prior to the screening visit. Stable 
SHL prophylaxis is defined as a minimum of 18 weeks of treatment in a 6 (consecutive) 
calendar month period in the 12 months prior to the screening visit. 
At baseline, participants’ total risk scores will be determined based on 5 individually 
weighted variables: pre-study bleeding phenotype, number of active target joints, von 
Willebrand factor (vWF) antigen levels, previous treatment frequency, and physical activity. 
All parameters are determined at screening. If the physical activity variable is missing, then 
zero will be assigned. When other variables are missing, the participant score cannot be 
determined and participant data cannot be analyzed. The total risk score is used to assign 
participants to 1 of 3 prophylaxis regimens according to their score. The effect of 
participants’ risk scores on determining the most appropriate prophylaxis regimen will be 
evaluated by the proportion of participants with a favorable outcome. 

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Along with regimen details and ABR, data collected will include PRO measurements 
(Haemophilia Quality of Life Questionnaire [Haem-A-QoL or Haemo-QoL], Patient’s Global 
Impression of Change [PGI-C], EuroQoL 5 Dimensions [EQ-5D-5L], Treatment Satisfaction 
Questionnaire for Medication [TSQM], and Work Productivity and Activity Impairment 
[WPAI] questionnaires), joint status outcomes, human recombinant factor VIII (rFVIII) 
incremental recovery and trough levels, and safety including treatment-emergent adverse 
events (AEs). Additional data will include documentation of blood type and BMI, and a 
Web-Accessible Population Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) 
pharmacokinetic (PK) analysis to determine whether these would have contributed to another 
risk score assignment for the prophylaxis regimen. 
Intervention Model: Single group 
Primary Purpose: 
Assess the effect of using a new risk score approach to select the most 
appropriate prophylaxis regimen  
Number of Arms: 
One treatment arm with 3 different regimens 
Masking: 
 
No masking 
Brief Summary: 
The purpose of this study is to assess the effect of a new risk score approach based on 
participant’s phenotypic and biologic variables to determine the most appropriate prophylaxis 
regimen for adolescent/adult (≥ 12 years) PTPs with congenital hemophilia A who switch 
from a SHL FVIII prophylaxis to an EHL product (Jivi). 
Study Duration: Approximately 7.5 months 
Treatment Duration: 6 months  
Number of Participants: Approximately 20 – 25 participants will be assigned to study 
intervention. 
Intervention Groups and Duration: 
All eligible participants will be assigned a risk score at baseline and will start treatment 
2x/week (40 IU/kg/dose) with Jivi for 4 weeks. Treatment will then continue based on their 
assignment to 1 of the 3 following prophylaxis regimens: 
• Participants with a high risk score (> 4) continue on prophylaxis 2x/week 
(40 IU/kg/dose) 
• Participants with a medium risk score (2 to 4) will switch after 4 weeks to prophylaxis 
Q5D (50 IU/kg/dose) 
• Participants with a low risk score (< 2) will switch after 4 weeks to prophylaxis Q5D 
(50 IU/kg/dose) and then after 4 weeks to a less frequent (e.g. Q7D) regimen 
(60 IU/kg/dose) 
Prophylaxis regimens will not be altered during the study period unless a participant 
experiences ≥ 2 muscle or joint bleeds (without evident trauma) during any given 8-week 
period during the 6-month study. These participants will be assigned to the next highest 
dosing frequency. In line with the Jivi prescribing information, the treating investigator 
reserves the right to change a participant’s regimen at any time if the investigator determines 
the score-determined regimen is not well-suited for the participant. 

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The participants’ planned study duration, including a screening (up to 30 days), treatment 
(6 months), and safety follow-up period (14 days after last dose), will be approximately 
7.5 months. 
The details regarding duration and risk score assigned prophylaxis regimen are as follows: 
Dosing Regimen: 
Procedure 
Duration 
Dose regimen 
Screening 
Up to 30 days 
prior to Baseline 
Continuation of previous treatment 
Treatment Phase 
Weeks 1-4 
Starting dose 40 IU/kg/dose 2x/week 
Weeks 5-8 
Low 
Risk 
Switch to 50 IU/kg/dose Q5D until Week 8 
Medium 
Risk 
Switch to 50 IU/kg/dose Q5D until end of study 
  
High 
Risk 
Continue 40 IU/kg/dose 2x/week until end of 
study 
Week 9 
Low 
Risk 
Switch to less frequent dosing 60 IU/kg/dose 
(e.g. Q7D)a until end of study 
Abbreviations: Q5D = every 5 days; Q7D = every 7 days. 
a As determined by the investigator.  
Note: If ≥ 2 muscle or joint bleeds (without evident trauma) occur within any given 8 week period 
during the 6 month study, then participant will be assigned to next highest frequency regimen. 
Per protocol, the treating investigator reserves the right to change a participant’s regimen at any 
time if the treating investigator determines the score-determined regimen is not well-suited for 
the participant. 
Data Monitoring/Other Committee: No 

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1.2 
Schema for Dosing Regimen Assignment 
Figure 1–1: Dosing Regimen Schema 
 
Abbreviations: PK = pharmacokinetics; Q5D = every 5 days; Q7D = every 7 days; SHL = standard half-life; vWF = von 
Willebrand factor. 
a Score exception: if ≥2 muscle or joint bleeds (without evident trauma) occur within any given 8-week period during the 
6-month study, then the protocol recommends assigning the participant to the next highest frequency regimen. Per protocol, 
the treating investigator reserves the right to change a participant’s regimen at any time if they perceive the risk score-
determined regimen is not well-suited for the participant. 
 

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1.3 
Schedule of Activities (SoA) 
Procedure 
 
Intervention Period Months 
 
Notes 
 
Visit 1 
(Screening) 
Visit 2a 
(Baseline) 
Visit 3 
Visit 4 
Visit 5a 
Visit 6a 
(EOS/Early 
Withdrawal)b 
Visit 7 
(Safety 
Follow-up) 
Up to 30 
days before 
Day 1 
Day 1 
Month 1 
(±7 days) 
Month 2 
(±7 days) 
Month 3  
(±7 days) 
Month 6  
(+14 days) 
7 to 14 days 
after last dose 
Contact 
Visit  
Visit 
Phone 
Phone 
Visit 
Visit 
Phone 
 
Informed consent/assent 
X 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
Recheck clinical status before 
first dose of study medication. 
Demography 
X 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
X 
 
 
 
Physical examination including height, weight 
 
X 
 
 
 
X 
 
 
Joint status (defined by ISTH) 
 
X 
 
 
 
X 
 
 
Highly sensitive serum pregnancy test 
(WOCBP only) 
X 
Xc 
 
 
X 
X 
 
 
Physical activity level (contact/no 
contact/sedentary) 
 
Xd 
 
 
X 
X 
 
 
History of hemophilia 
X 
 
 
 
 
 
 
 
Previous hemophilia treatment 
X 
 
 
 
 
 
 
 
Other past and current medical conditions and 
surgical history (includes substance usage) 
X 
 
 
 
 
 
 
Substances: drugs 
Total risk score calculation 
 
X 
 
 
 
 
 
 
PROse 
 
X 
 
 
Xf 
X 
 
 
FVIII levels: pre-dose, 15-30 minutes 
post-infusion, and at a minimum of 4 hours 
post-infusion 
 
Xg 
 
 
Xg 
Xg 
 
A 3- or 5-day wash-out period 
is required for those patients 
whose previous product was 
an SHL or EHL, respectively 
WAPPS-Hemo analysis 
 
 
 
 
Xh 
Xg, h 
 
FVIII levels to be used from 
Visit 2 (if felt to be accurate 
levels) and Visit 5 (72-hour 
post-infusion level). See 
footnote h 

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Abbreviations: AE = adverse event; CBC = complete blood count; EHL = extended half-life; EOS = End of Study visit; EQ-5D-5L = EuroQoL 5 Dimensions questionnaire; FVIII = human 
coagulation factor VIII; Haem-A-QoL = Haemophilia Quality of Life Questionnaire; ISTH = International Society on Thrombosis and Haemostasis; PGI-C = Patient’s Global Impression of 
Change questionnaire; PRO = Patient Reported Outcome; SAE = serious adverse event; SHL = standard half-life; TSQM = Treatment Satisfaction Questionnaire for Medication; WOCBP = 
women of childbearing potential; WPAI = Work Productivity and Activity Impairment questionnaire. 
a Visit 2 (Baseline) should occur 72 hours after the prior prophylaxis infusion. Visit 5 should occur 72 hours after the last Jivi infusion. Visit 6 should occur on the following days of the 
assigned prophylaxis regimen (i.e. as close as possible to the next infusion): on Day 4 for those on the 2x/week regimen, on Day 5 for those on the Q5D regimen, and on Day 7 for those 
Procedure 
 
Intervention Period Months 
 
Notes 
 
Visit 1 
(Screening) 
Visit 2a 
(Baseline) 
Visit 3 
Visit 4 
Visit 5a 
Visit 6a 
(EOS/Early 
Withdrawal)b 
Visit 7 
(Safety 
Follow-up) 
Up to 30 
days before 
Day 1 
Day 1 
Month 1 
(±7 days) 
Month 2 
(±7 days) 
Month 3  
(±7 days) 
Month 6  
(+14 days) 
7 to 14 days 
after last dose 
Laboratory assessments (hematology: CBC) 
X 
 
 
 
 
 
 
 
Immunogenicity (FVIII inhibitor) 
X 
 
 
 
 
 
 
If suspect inhibitor to follow 
local clinical guidance for 
inhibitor testing 
History of previous FVIII inhibitor  
X 
 
 
 
 
 
 
Please refer to eligibility 
criteria (Section 5.1 and 5.2) 
for participants with a history 
of inhibitors. Recovery and 
half-life data for the SHL 
product should be extracted 
from medical records when 
available. 
von Willebrand factor antigen (if not available 
in medical records) 
Xi 
 
 
 
 
 
 
Please review Section 8.3.4 
when drawing blood for von 
Willebrand factor antigen. 
FVIII trough levels with study intervention 
 
 
 
 
Xj 
X 
 
Visit 5 72-hour level will also 
serve as the first of 2 trough 
levels for those on a 2x/week 
regimen 
AE/SAE review 
Xk 
==================================== 
X 
 
Concomitant medication review 
==================================================== 
X 
 
Dispense study intervention 
 
X 
 
 
X 
 
 
 
Administration of study interventionl,m 
 
==================================== 
 
 
Return used vials 
 
 
 
 
X 
X 
 
 
Training on use of eDiary 
 
X 
 
 
 
 
 
 
eDiary (bleed and study intervention) review  
 
==================================== 
 
 

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on less frequent dosing regimens. 
b In case of withdrawal of consent, these activities will occur at the time of the return of the unused vials. 
c If > 14 days since last menstrual period or from screening (Visit 1). 
d Refers to the participant’s usual physical activity level, based on the last 12 months. Level of activity will be defined as Sedentary, Low, or Medium/High. If a significant change in activity 
level is expected in the next 6 months, the criteria for the physical activity variable should be based on that anticipated level. 
e Haem-A-QoL or Haemo-QoL, EQ-5D-5L, WPAI, TSQM. At Visit 6 (Month 6), PGI-C will also be collected. 
f EQ-5D-5L only. 
g If the investigator feels the baseline peak FVIII level at 15-30 minutes or 4-8 hours post-infusion at Visit 2 does not seem to be appropriate for the dose infused, then, if possible, the levels 
should be repeated at Visit 5 and the results also uploaded to WAPPS-Hemo. For those patients who do not have appropriate FVIII levels at either Visit 2 or Visit 5, the levels should be 
repeated at Visit 6. 
h WAPPS-Hemo data entry should include FVIII levels measured pre-dose, post-infusion, hour 4-8 at Baseline (Day 1) and Month 3 (Visit 5; 72 hours after the last Jivi infusion). 
i von Willebrand factor levels should be recorded within 12 months of screening. Please refer to Section 8.3.4 for timing of von Willebrand factor blood draw. 
j At Month 3 (72 hours after the previous infusion for all subjects). Post-infusion FVIII levels will be measured for all participants and included in the WAPPS-Hemo analysis. 
k Only (S)AEs which are related to protocol-required study procedures will be recorded from the signing of the consent form until the start of study intervention. 
l The first Jivi dose will be administered at the clinic at Baseline (Day 1) and may be administered at the clinic at Month 3 (Visit 5) and Month 6 (EOS/Early withdrawal; as long as the 
infusion does not occur before blood sampling). All other doses will be self-administered at home. 
m In case of any infusion-related AE at a site visit, vital signs will be collected. 

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2. 
Introduction 
2.1 
Study Rationale 
Hemophilia A is an X-linked, inherited, genetic bleeding disorder characterized by deficiency 
of human coagulation factor VIII (FVIII) (Srivastava et al., 2013; NHF, 2021). Hemophilia A 
patients are treated by intravenous (IV) administration of FVIII on-demand or as a 
prophylactic therapy administered 2 to 4 times a week with FVIII products. The need for 
frequent IV infusion creates barriers to patient compliance and makes adherence to 
prophylaxis difficult. According to the World Federation of Hemophilia (WFH), it is 
estimated that only between 25% and 30% of hemophilia patients globally are adequately 
diagnosed and managed (WFH, 2021). 
Prophylactic regimens lead to favorable outcomes by reducing the amount of spontaneous 
bleeds. The hemophilia A treatment landscape is evolving from using standard half-life 
(SHL) recombinant coagulation FVIII (rFVIII) products for routine prophylaxis to extended 
half-life (EHL) products. Switching patients from a SHL to an EHL factor product allows for 
the maintenance of efficacy with less frequent dosing, leading to significant benefit in long-
term outcomes and quality of life (QoL) improvement for patients with hemophilia.  
The EHL products, which provide treatment options with dosing intervals of 3 to 5 days for 
prophylactic treatment (such as Esperoct®, Eloctate®, Adynovate®, Jivi), have been 
approved recently in several countries worldwide. Any other FVIII products are considered 
SHL. Jivi was developed as an EHL FVIII for prophylaxis, peri-operative management, and 
treatment of acute bleeding events. Site-specific PEGylation was used to increase the FVIII 
half-life, resulting in a longer duration of the effect by raising plasma levels for a longer 
duration, thereby allowing for less frequent dosing when used in a prophylaxis setting. 
Efficacy and safety of Jivi were demonstrated in the pivotal trials (Reding et al., 2017; 
Coyle et al., 2014).  
There is still no agreement on what constitutes an optimal prophylactic treatment regimen in 
adults with hemophilia. Consequently, the dose and frequency of infusions are often 
determined according to local established practice and left to clinicians’ judgment. In general, 
the current strategies used for prophylaxis can be divided into those that aim to maintain 
FVIII activity > 1 IU/dL and those that are guided by the clinical bleeding patterns of 
individual patients. Currently, if Health Care Professionals (HCPs) do not rely on traditional 
pharmacokinetic (PK) or population PK analysis of rFVIII decay curves to determine an 
optimal treatment regimen when patients are switching to EHL products, the most common 
approach is to rely on assumptions that are informed by patients' characteristics and clinical 
history. This “trial and error” approach could lead to suboptimal protection of the patient and 
cause harmful, potentially avoidable bleeds or, on the other hand, an excessive use of rFVIII 
products that will have an economic impact and might not ease the burden of frequent 
infusions (Yu et al., 2019). The difficulty in determining the most optimal prophylaxis 
regimen for a patient lies with the disease variability among patients; it is comprised of a 
series of phenotypic and biologic parameters that render every patient unique in his/her 
treatment needs and begs for an individualized tailored approach. 
The challenge, then, is to optimize hemophilia therapy by individualizing prophylactic 
regimens to the needs of each patient, while reducing the burdens associated with IV 
infusion. Thus, the clinical community has several unanswered questions regarding the most 
appropriate treatment regimen for a patient switching products and the best approach to 

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achieve an optimal therapeutic and economic regimen with the first attempt. Clinicians rely 
on their own clinical judgment, using criteria that potentially have an impact on predicting 
the right dosing regimen. However, these criteria have neither been studied prospectively to 
select the optimal treatment regimen nor were they studied for their combinatorial usefulness. 
In this proposed clinical study, the effect of using a new risk score approach, based on the 
best known predictive phenotypic and biologic variables, to select the most appropriate 
prophylaxis regimen for reaching a favorable outcome will be assessed for participants 
switching from SHL to Jivi. The scoring approach in this study has not yet been validated and 
is different from classical risk-based models in that the score allocation and the dosing 
regimen itself has an influence on the outcome of interest. Due to the nature of the study, the 
inclusion of sub-populations such as mild/moderate hemophilia patients, women, and patients 
with past FVIII inhibitors should not prevent them from participating. 
The scoring approach will be composed of 5 individually weighted variables: pre-study 
bleeding phenotype, previous treatment frequency, number of active target joints, von 
Willebrand factor (vWF) antigen levels, and physical activity. These variables were selected 
on the basis of the existing data regarding their established or potential role in determining 
the most appropriate EHL regimen. 
The relevance of pre-study bleeding patterns and prior treatment frequency in tailoring an 
appropriate prophylaxis regimen is supported by the results of the Jivi PROTECT VIII study. 
In the main study, significant improvements in ABR were demonstrated for patients in 
3 prophylaxis regimens selected on the basis of prior bleeding pattern (Reding et al., 2017). 
Importantly, ABR and total bleeds were further reduced after on-study dosing adjustments 
(e.g. changes from Q7D to Q5D dosing) were made based on treatment response and 
individual patient preference (Lalezari et al., 2019). Clinical outcomes have also been 
correlated with baseline disease burden as measured by the presence or absence of target 
joints. Substantially lower health-related QoL scores were observed in hemophilia patients 
with 2 or more target joints affected, and score decreases were likewise recorded in patients 
with only one active joint (Carroll et al., 2019). Variability at the cellular level should also be 
accounted for when assessing the value of different prophylaxis regimens. The 
pharmacokinetics of FVIII is regulated by the clearance of vWF from plasma 
(Swystun et al., 2019). Therefore, individual differences in vWF levels and the genetic 
determinants that impact FVIII-vWF binding will influence the response to EHL FVIII 
prophylaxis regimens. The final variable in the scoring approach weighs the link between 
physical activity and bleed risk. Data regarding the bleeding risk associated with various 
levels of physical activity is inconclusive due to variations in frequency, intensity, and the 
age of the patient. However, risk has been associated with high levels of physical activity 
and, in one study, this risk was mitigated by typical prophylactic regimens 
(Broderick et al., 2012). Dose and frequency modifications in alignment with the activity 
level of the patient may improve clinical response. 
Each of the variables will have an assigned maximum and minimum value for a given 
participant that are summed into a personalized risk score for each participant. With defined 
value thresholds, this total risk score is expected to predict the most appropriate Jivi regimen 
(2x/week, Q5D, or less frequent dosing [e.g. Q7D]) leading to a favorable outcome for at 
least 70% of the participants enrolled in this study. 
A favorable outcome is defined as: 
• no change of the risk score-assigned dosing regimen during the study, with one of the 
following: 

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o improved ABR versus pre-study ABR and decreased frequency of administration 
versus pre-study frequency. 
o improved ABR versus pre-study ABR with similar frequency of administration 
vs. pre-study frequency. 
o decreased frequency of administration versus pre-study frequency and similar 
ABR versus pre-study ABR. 
Pre-study ABR and treatment frequency is based on data from a minimum of 6 continuous 
months (up to a maximum of 12 months) of stable SHL prophylaxis at any given time within 
the 12 months prior to the screening visit. Stable SHL prophylaxis is defined as a minimum 
of 18 weeks of treatment in a 6 (consecutive) calendar month period in the 12 months prior to 
the screening visit. Pre-study ABR will be determined by treatment infusion history or by a 
participant’s bleed diary, if one is available. This cannot be controlled or mitigated in the 
study design (refer to Section 6.3 for additional details). 
2.2 
Background 
Hemophilia A comprises approximately 80% of all hemophilia cases, with an annual 
incidence of approximately 1 in 5,000 live male births (NHF, 2021). All races and economic 
groups are affected equally. Prevalence estimates vary by country, ranging between 5 and 
21 cases per 100,000 male inhabitants. Individuals with severe hemophilia A experience 
frequent and recurrent bleeding into the soft tissue and joints, resulting in joint damage and 
debility, as well as significant negative effects on their QoL, psychosocial well-being, 
education, and financial condition. Factor replacement therapy is used to treat bleeding events 
when they occur; however, such “on-demand” therapy is insufficient for the prevention of 
arthropathy (Petrini et al., 1991; Aledort et al., 1994). International treatment guidelines 
recommend that all individuals with severe hemophilia should be treated with some form of 
prophylactic therapy. The current accepted standard regimen for prophylaxis consists of 
regularly scheduled infusion of FVIII as often as every other day. The efficacy of standard 
regimens has been confirmed in multiple observational and interventional studies 
(Löfqvist et al., 1997; Ljung, 1998; Nilsson et al., 1992) and the value of prophylaxis starting 
early in childhood was recently confirmed to prevent joint damage (Manco-Johnson et al., 
2017). 
Jivi is a recombinant B-domain deleted human coagulation FVIII variant site specifically 
conjugated with a 60 kDa, branched (30 kDa each) polyethylene glycol (PEG). Jivi was 
developed as an EHL rFVIII product through PEGylation resulting in a reduced clearance 
from plasma while retaining the normal activity of the FVIII molecule. Pharmacokinetic 
studies with Jivi demonstrated a prolonged half-life and improved area under the curve 
(AUC) compared to Kogenate® (antihemophilic factor [recombinant]) (Coyle et al., 2014). 
Clinical efficacy and safety for treatment of bleeds and prophylaxis with 2x/week, Q5D, and 
Q7D have been evaluated in the clinical development program including 232 patients 
between the ages of 2 and 65 years. Jivi has received market authorization approval for 
treatment and prophylaxis of bleeding in previously-treated patients (PTPs) ≥ 12 years of age 
with hemophilia A (congenital FVIII deficiency). For prophylaxis, the recommended initial 
dosing regimen is 30 to 40 IU/kg/dose twice weekly, which may be adjusted to 45 to 
60 IU/kg/dose every 5 days based on a patient’s bleeding episodes. Further adjustments can 
be made for less or more frequent dosing, and the total recommended maximum dose per 
infusion is 6000 IU. 

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2.3 
Benefit/Risk Assessment 
Jivi has received marketing authorization by the Food and Drug Administration (FDA), 
European Medicines Agency (EMA), Pharmaceutical and Medical Devices Agency (PMDA), 
Health Canada and other regions of the world for the treatment and prevention of bleeds in 
patients ≥12 years of age. 
Jivi has demonstrated the potential for dosing Q5D or Q7D in a majority of participants in 
clinical studies, offering the option of a prophylaxis treatment with less frequent dosing for 
hemophilia A patients ≥ 12 years of age. For patients with increased bleeding tendency, 
2x/week treatment with Jivi provided an efficacious treatment option. 
The potential benefits to participants are less frequent dosing and less reliance on central 
venous catheters, which may reduce physical and emotional burden for the participant, 
leading to better adherence. This, in turn, may translate into improved FVIII activity, good 
activity coverage, and good prophylactic coverage from bleeds. 
As with all FVIII replacement therapies, the most serious expected adverse event (AE) is the 
development of inhibitory antibodies against FVIII rendering FVIII treatments ineffective. 
No new or confirmed inhibitors have been observed during the clinical studies. Other known 
risks for the class of FVIII replacement products are allergic type of hypersensitivity 
reactions which may progress to anaphylaxis (including shock), cardiovascular events, and 
possible catheter-related complications. Data from more than 200 patients aged 2 to 62 years 
demonstrated that these risks are not different for Jivi administered to PTPs. No cases of 
anaphylaxis were reported, and no serious cardiovascular event was observed. 
A clinical immune response associated with anti-PEG antibodies, manifested as symptoms of 
acute hypersensitivity and/or loss of drug effect has been observed within the first 4 exposure 
days (EDs) primarily in children < 6 years of age (Study 15912 – PROTECT VIII Kids). Low 
post-infusion FVIII levels in the absence of detectable FVIII inhibitors indicate that loss of 
drug effect is likely due to anti-PEG IgM antibodies; in such cases Jivi should be 
discontinued and patients switched to a previously effective FVIII product. 
More detailed information about the known risks and reasonably expected AEs of Jivi may be 
found in the approved prescribing information. 
There is a risk of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection 
for study participants as long as the coronavirus disease 2019 (COVID-19) pandemic 
situation is ongoing. To minimize their infection risk during study participation, the 
investigators/sites will follow all recommendations issued by local authorities and guidelines 
aiming to reduce the risk of disease spreading. Details on the measures are specified by the 
site and agreed with the sponsor. 
As part of the study procedures, participants will be closely monitored (including for signs of 
COVID-19) during the entire study duration. A pre-visit call before each in-person study visit 
is recommended to confirm the study participant does not have any symptoms suspicious for 
a SARS-CoV-2 infection. 
Measures which prioritize participant safety and data validity are implemented. In case these 
2 objectives conflict, participant safety always prevails. 
During a pandemic situation, further measures according to recommendations and 
requirements from local health authorities may become necessary. These will be followed 
within the context of this study as far as applicable. 

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2.3.1 
Overall Benefit/Risk Conclusion 
Taking into account the measures taken to minimize risk to participants in this study, the 
potential risks identified in association with Jivi are justified by the anticipated benefits that 
may be afforded to participants with hemophilia A. 
3. 
Objectives and Endpoints  
Objectives 
Endpoints 
Primary 
 
To assess the effect of using a baseline risk 
score, based on a participant’s phenotypic 
and biologic variables, to select the most 
appropriate prophylaxis regimen for 
reaching a favorable outcome, when 
switching from a SHL product to Jivi  
Occurrence of favorable outcome on the 
score selected dosing regimen 
Secondary 
 
To assess the effectiveness of Jivi 
compared to a previous SHL treatment 
ABR (total, joint, spontaneous) and change 
in total ABR from pre-study 
To assess the frequency of Jivi 
administration 
Change in the frequency of pre-study SHL 
treatment to the frequency of Jivi 
administration (infusions/month) 
To assess the proportion of participants 
with 0 and ≤ 1 spontaneous bleeds 
Occurrence of participants with 0 and ≤ 1 
spontaneous bleeds 
To assess participant QoL and physical 
activity, as measured by Patient Reported 
Outcomes (PROs)  
Change in Haemophilia Quality of Life 
Questionnaire (Haem-A-QoL or 
Haemo-QoL); Patient’s Global Impression 
of Change (PGI-C); EuroQoL 5 Dimensions 
(EQ-5D-5L) questionnaire; Treatment 
Satisfaction Questionnaire for Medication 
(TSQM); Work Productivity and Activity 
Impairment (WPAI) questionnaire scores 
To assess target joint status, per 
International Society on Thrombosis and 
Haemostasis (ISTH) guidelines 
Number of target joints and change in target 
joint status from baseline 

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Other, Pre-specified 
 
To assess whether blood type and body 
mass index (BMI) would have led to a 
different score allocation  
Participant score considering ABO type and 
BMI 
 
To describe pharmacokinetic (PK) 
parameters derived from Web-Accessible 
Population Pharmacokinetic 
Service-Hemophilia (WAPPS-Hemo) and 
assess an association with clinical risk score 
PK parameters derived from WAPPS-Hemo 
 
To determine participant Jivi trough levels 
while on a specific regimen  
Trough measurement of Jivi levels  
 
To determine the percentage of participants 
who can maintain > 1%, > 3 %, and > 5% 
FVIII trough levels while on a specific 
prophylaxis regimen 
Occurrence of trough levels above 1%, 3% 
and 5%, stratified by prophylaxis regimen 
 
Abbreviations: ABR = annualized bleeding rate; EQ-5D-5L = EuroQoL 5 dimensions; FVIII = human 
coagulation factor VIII; SHL = standard half-life 
4. 
Study Design 
4.1 
Overall Design 
This is a multicenter, open-label, single arm, prospective study to assess the effect of using a 
new risk score approach to select the most appropriate prophylaxis regimen for reaching 
favorable outcomes when PTPs with congenital hemophilia A switch from a SHL FVIII 
product for regular prophylaxis to the EHL FVIII product, Jivi. Participants will be ≥ 12 
years of age with congenital hemophilia A who have a documented history of at least 150 
EDs with any FVIII product. All participants will have received prophylaxis with any 
licensed SHL FVIII product with a stable dosing regimen for at least 6 consecutive months 
within the previous 12 months prior to the screening visit.  
At baseline, participants’ total risk scores will be determined based on 5 individually 
weighted variables: pre-study bleeding phenotype, previous treatment frequency, number of 
active target joints, vWF levels, and physical activity (Table 4–1). If the physical activity 
variable is missing, then 0 will be assigned. When other variables are missing, the participant 
total risk score cannot be determined and participant data cannot be analyzed. The rationale 
for the baseline definition is that a comparison between SHL and score-based Jivi 
prophylaxis is intended and inclusion of another period (untreated or different treatment) 
would bias this comparison. 
While it may not be possible to draw any conclusions based on the reduced sample size, the 
study may provide first hints whether the score could be useful in clinical practice. 

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Figure 4–1: Pre-study Timeline 
Abbreviations: ABR = annualized bleed rate; SHL = standard half-life; vWF = von Willebrand factor. 

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Table 4–1: Parameters for Determining Participant Risk Scores 
Participant Variables 
Score Assignment 
Bleed phenotype (total bleeds, occurring during the 
stable SHL perioda) 
ABR ≤ 1 
-2
1 < ABR ≤ 4 
+2
ABR > 4 
+3
Treatment frequency derived from the stable SHL 
perioda 
< 3x/week 
-1
3x/week 
0
> 3x/week
+1
Number of active target jointsb 
0 
-1
1 
0
2 
+1
> 2
+2
vWF antigen levels (within previous 12 months) 
vWF ≥ 150% 
-1
100% ≤ vWF < 150% 
0
vWF < 100% 
+2
Physical activityc 
Lowd (non-contact sports) 
-1
Sedentarye 
0
Medium/highf (contact sports) 
+1
Abbreviations: ABR = annualized bleeding rate; SHL = standard half-life; vWF = von Willebrand 
Factor. 
a Stable SHL period: Stable SHL prophylaxis for at least 6 months within the 12 months prior to the 
screening visit. 
b Derived at baseline from the patients most current status. 
c Refers to a participant’s usual physical activity level, based on the last 12 months. If a significant 
change in activity level is expected in the next 6 months, the criteria for the physical activity 
variable should be based on that anticipated level. 
d Low intensity activities are those that involve gentle and fluid motions, and may include non-
contact sports such as swimming, elliptical training, or archery (please refer to Figure 4–2 
[scores <1.5]). 
e Sedentary behavior refers to time spent sitting or lying down (except when sleeping), with very 
little energy expenditure (please refer to Figure 4–2). 
f Medium/High activities are those that require some effort or lead to harder breathing, or puffing 
and panting (depending on your fitness) including contact sports (please refer to Figure 4–2 
[scores ≥1.5]). 

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Figure 4–2: National Hemophilia Foundation Activity Rankings 
 
 

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Source: https://stepsforliving.hemophilia.org/resources/physical-activity/playing-it-
safe-activity-ratings-chart?page=1 

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Participants will be scored on a range of -6 (low risk) to +9 (high risk), and will be allocated 
to the prophylaxis regimens presented in Table 4–2. 
Table 4–2: Risk Score Treatment Assignment 
Total Risk Score 
(Baseline) 
Assignment 
Dosing Regimen 
High (> 4) 
2x/week 
2x/week infusions at 40 IU/kg/dose for 6 
months 
Medium (2-4) 
Q5D 
2x/week at 40 IU/kg/dose for 1 month + 
Q5D infusions at 50 IU/kg/dose for 5 
months 
Low (< 2) 
Less frequent 
dosing (e.g. Q7D) 
2x/week at 40 IU/kg/dose for 1 month + 
Q5D infusions at 50 IU/kg/dose for 1 
month + less frequent infusions (e.g. 
Q7D)a at 60 IU/kg/dose for 4 months. 
Abbreviations: Q5D = every 5 days; Q7D = every 7 days. 
a As determined by the investigator. 
The effect of using participant’s baseline risk score to determine the most appropriate 
prophylaxis regimen will be evaluated by the proportion of participants with a favorable 
outcome defined as: 
• no change of the risk score-assigned dosing regimen during the study, with one of the 
following: 
o improved ABR versus pre-study ABR and decreased frequency of administration 
versus pre-study frequency. 
o improved ABR versus pre-study ABR with similar frequency of administration 
versus pre-study frequency. 
o decreased frequency of administration versus pre-study frequency and similar 
ABR versus pre-study ABR. 
See Section 9.4.2 for complete definitions of pre-study ABR, treatment frequency, and stable 
SHL prophylaxis. 
Along with regimen details and ABR, prospective data will include PRO measurements 
(Haemophilia Quality of Life [Haem-A-QoL or Haemo-QoL], Patient’s Global Impression of 
Change [PGI-C], EuroQoL 5 Dimensions [EQ-5D-5L], Treatment Satisfaction Questionnaire 
for Medication [TSQM], and Work Productivity and Activity Impairment [WPAI] 
questionnaires), joint status outcomes, and safety. Additional data will include Jivi trough 
level measurements and documentation of blood type, BMI, and Web-accessible Population 
Pharmacokinetic Service-Hemophilia (WAPPS-Hemo) PK measurements to determine 
whether these would have contributed to another risk score assignment for the prophylaxis 
regimen. 
The participants’ planned study duration, including a screening (up to 30 days), treatment 
(6 months), and safety follow-up period (7 to 14 days after the last dose), will be 
approximately 7.5 months. 
4.1.1 
Screening 
Screening examinations will only be performed after the participant (and parent[s] or legal 
guardian) has signed the informed consent form (ICF) and assent form (if necessary). 

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Participants will be screened for eligibility for up to 30 days prior to the treatment period. 
During this period, the inclusion and exclusion criteria will be evaluated and all screening 
procedures will be performed, including the risk score calculation based on the variables 
presented in Table 4–1. Participants will be assigned a patient identification (PID) code via 
the Interactive Voice/Web Response System (IxRS) at the screening visit for use by the site 
only. All screening evaluations must be completed and reviewed prior to treatment allocation. 
Results of all screening evaluations must be reviewed by the investigator or his/her designee 
prior to enrollment of each participant into the study to ensure that all inclusion and exclusion 
criteria are met. During the screening period, participants will continue treatment with their 
current FVIII treatment. 
4.1.2 
Treatment 
All participants will receive treatment for a total of 6 months, dispensed using the study 
IxRS. The total duration of the study will be approximately 7.5 months (including screening, 
treatment, and safety follow-up period). During the study, all participants will receive 
treatment with Jivi as prophylaxis and for treatment of bleeds, if they occur. All participants 
will start with a Jivi dosing regimen of 2x/week (40 IU/kg/dose) for 1 month. Participants 
will then continue in 1 of 3 treatment regimens assigned according to pre-calculated baseline 
risk score. 
The details about duration and recommended dose regimen of study participation are 
presented in Table 4-3. 

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Table 4–3: Dosing Regimens 
Procedure 
Duration 
Dose regimen 
Screening 
Up to 30 days 
prior to Baseline 
Continuation of previous treatment 
Treatment Phase 
Week 1-4 
Starting dose 40 IU/kg/dose 2x/week 
Week 5-8 
Low Risk 
Switch to 50 IU/kg/dose Q5D until Week 8 
Medium 
Risk 
Switch to 50 IU/kg/dose Q5D until end of 
study 
High Risk 
Continue 40 IU/kg/dose 2x/week until end of 
study 
Week 9 
Low Risk 
Switch to less frequent dosing 60 IU/kg/dose 
(e.g. Q7D)a until end of study 
Abbreviations: CRF = case report form; Q5D = every 5 days; Q7D = every 7 days. 
a As determined by the investigator. 
Note: For twice weekly dosing regimens, dosing must be administered at 3- and 4-day intervals. If a 
dose is missed, it will be documented in the CRF and the next dose will be administered as 
soon as possible before resuming the regular schedule. 
Note: If ≥ 2 muscle or joint bleeds (without evident trauma) occur within any given 8week- period 
during the 6-month study, then the participant will be assigned to next highest frequency 
regimen. Per protocol, the treating investigator reserves the right to change a participant’s 
regimen at any time if the treating investigator determines the score-determined regimen is not 
well-suited for the participant. 
Participants are allowed to change the dose frequency at any time during the study in case of 
increase in bleeding frequency as per investigator judgment. The recommended maximum 
total dose per infusion should not be higher than 6000 IU. 
Participants who have an unplanned major surgery will be treated at the discretion of the 
investigator per their standard of care. Treatment with other FVIII products after unplanned 
major surgery is also acceptable according to local practice at the discretion of investigators. 
Participants will resume their prophylaxis regimen with Jivi as per protocol after recovery. 
4.2 
Scientific Rationale for Study Design 
This is a Phase 4, open-label, prospective study aiming to assess the effect of using a new 
scoring approach based on known phenotypic variables to select the most appropriate 
prophylaxis regimen for a favorable outcome in adolescent/adult (≥ 12 years) PTPs with 
congenital hemophilia A switching from SHL products to Jivi. Participants will receive 
prophylaxis with Jivi at authorized doses in regimens of 2x/week, Q5D, and less frequently 
(e.g. Q7D, as determined by the investigator). Observations with the currently available FVIII 
products suggest that prevention of bleeds with extended interval treatment regimens is 
possible in many patients treated with individualized approaches who are selected on the 
basis of bleeding frequency and disease severity. 
Prophylaxis regimens will be determined according to bleeding risk scores calculated at 
baseline using the variables in Table 4–1. Participants with high risk for bleeding will be 
treated with a twice weekly regimen throughout the study. Participants with a medium or low 

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risk for bleeding are assigned to an extended interval after a treatment period of 4 weeks with 
the twice weekly dosing. As no formal statistical comparisons between treatment regimens 
are planned, balanced treatment allocation to each of the 3 groups is not required as part of 
the study design (Section 9.1). 
The new scoring approach uses the best known predictive phenotypic and biologic variables 
to provide a more comprehensive measurement of the clinical severity of the disease and 
individual requirements and to determine a tailored dosing regimen. The following variables 
have been documented in the literature as having high predictive potential that may aid in 
determining the most appropriate prophylaxis regimen for a patient which results in the most 
favorable treatment outcome. 
• Bleeding frequency (ABR): This is the most logical identifier for the clinical 
identification of phenotype. One study in patients receiving prophylactic Jivi dosing 
regimens (including dosing intervals of up to every 7 days) showed that those 
randomized based on baseline bleeding phenotype achieved bleeding control that was 
better than or comparable to their pre-study levels, highlighting the value of 
individualized phenotype-based dosing with Jivi (Reding et al., 2017 
[PROTECT VIII]). In the run-in period of this study, the vast majority of patients 
were identified as having low bleeding risk (≤1 bleed). Most of these patients were 
randomized to receive higher prophylaxis dosing regimens (e.g. Q5D or Q7D) and 
achieved good bleed control in the remaining study period (Lalezari et al., 2019). The 
substantial benefit in ABR experienced by this more common low-risk patient 
population supports a non-linear score characterization for this variable in the baseline 
risk calculation, with considerably more risk assigned to patients with a pre-study 
ABR > 4. 
• Treatment frequency: Variations in treatment requirements may reflect variations in 
the underlying bleeding tendency. In a retrospective analysis of patients with 
hemophilia A, median infusion intervals of 2.6 days and 11.1 days were recorded in 
those receiving prophylaxis and on-demand therapy, respectively, while patients who 
switched from on-demand to prophylaxis regimens had a 3.8 day infusion interval 
(Ay et al., 2020). As expected, ABR was lowest in the prophylaxis group, with 
substantial differences appearing within 1 week of observation. Notable decreases in 
ABR were also observed in patients who switched from on-demand to prophylaxis 
regimens, and this variability should be accounted for in any phenotype-guided dosing 
scheme. 
• Joint status: A strong correlation has been shown between the presence of 2 or more 
target joints and decreases in health-related QoL measures for patients with 
hemophilia A (Carroll et al., 2019). In a recent assessment of bleeding patterns and 
treatment frequency, a 5-fold decrease of ABR at target joints was observed in 
patients on prophylaxis compared to those receiving on-demand therapy 
(Ay et al., 2020). Moreover, in patients who switched from on-demand to 
prophylactic FVIII regimens, decreases were observed in both the number of target 
joints and ABR at active joints. Individual variations in the number and location of 
active target joints with frequent bleeding are an important factor in the determination 
of prophylaxis dosing frequency. 
• Endogenous vWF levels: This is another important parameter when considering 
individualized dosing due to correlation with the PK of rFVIII. A previous study has 
shown that higher vWF levels are associated with decreased rFVIII clearance, 

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increased rFVIII AUC, and longer half-lives resulting in a significant correlation with 
ABR (Lalezari et al., 2014). A recent integrated regression analysis of 6 clinical 
studies showed a consistent vWF and PK relationship amongst 5 modified and 
unmodified FVIII products (including Jivi), further supporting the usefulness of vWF 
antigen levels in dose regimen selection (Iorio et al., 2019). 
• Physical activity: Physical activity involved with various contact sports is associated 
with increased risk of bleeding; however, moderate physical activity may also 
decrease the risk of bleeding episodes. In children and adolescents, the bleeding risk 
associated with vigorous physical activity was moderate and could be mitigated by 
typical prophylactic regimens (Broderick et al., 2012). Determining the degree of 
bleeding risk connected to variations in types of physical activity and the age of the 
patient is important in determining the most appropriate prophylaxis regimen. 
The study will be open-label. A controlled comparator arm is not necessary for this study. 
4.3 
Justification for Dose 
The dose is based on the approved United States label (United States Prescribing 
Information). 
Prophylactic treatment regimens should be guided by clinical judgment based on individual 
patient characteristics and treatment response. 
4.4 
End of Study Definition 
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last visit or the last scheduled procedure shown in the SoA. The end 
of study (EOS) is defined as the date of the clean database. 
Primary completion 
The primary completion is defined as the date when all participants have completed the last 
visit for the primary endpoint (i.e. measurement of favorable outcomes based on changes in 
ABR and frequency of administration). 
5. 
Study Population 
Previously-treated adolescent/adult (≥ 12 years) patients with congenital hemophilia A on 
continuous prophylaxis with an SHL FVIII product for at least 6 consecutive months within 
the previous 12 months prior to the screening visit will be included. Medical records or a 
detailed participant documentation (i.e. diary, etc.) covering the last year is required to 
confirm the participant’s prophylaxis treatment modality. 
5.1 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1. Participants must be ≥ 12 years of age inclusive, at the time of signing the informed 
consent/assent. 
Types of Participants and Disease Characteristics 
2. Previously-treated patients (≥ 150 EDs) with congenital hemophilia A. 

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3. Prophylaxis with any SHL FVIII product with a stable frequency for at least 6 
consecutive months within the last 12 months prior to screening, before entering the 
study and documented in medical records. 
• Stable frequency is defined as a minimum of 18 weeks of treatment in a 6 
(consecutive) calendar month period in the 12 months prior to screening. 
• Patients can be on any non-Jivi EHL between the 6 -month stable SHL 
prophylaxis period and start of study treatment.  
4. Documented bleeding rate (ABR) while on stable frequency prophylaxis for at least 
6 consecutive months within the last 12 months prior to screening.  
5. No current evidence (≥ 0.6 BU/mL) of FVIII inhibitors. 
• If a participant has had a positive inhibitor titer in the past (≥ 0.6 BU/mL on 
2 occasions) but has been tolerized for at least 1 year since the last positive 
titer with at least 1 negative inhibitor assay test during that period, they can 
be enrolled. 
• If a participant has had a positive inhibitor titer in the past (≥ 0.6 BU/mL) 
but did not require tolerization and has had at least 1 negative inhibitor assay 
test during a minimum period of at least 1 year since the last positive titer, 
they can be enrolled. 
6. If they are human immunodeficiency virus (HIV) positive, cluster of differentiation 
4 (CD4)+ lymphocyte count should be > 200/mm3 within 1 year before entering the 
study and documented in medical records. 
7. Participants who are willing to complete an electronic diary (eDiary). 
Sex and Contraceptive/Barrier Requirements 
8. Male or female participants 
Contraceptive use should be consistent with local regulations regarding the methods of 
contraception for those participating in clinical studies. 
• Male participants: It has been shown that there is no target-related specific transport 
mechanism for Jivi into semen or from semen into the conceptus. Following 
administration to a male participant, Jivi would not be bioavailable via seminal 
delivery to the developing conceptus of an untreated partner. Therefore, no method of 
contraception for male participants is needed. 
• Female participants of childbearing potential (see Section 11.6) can only be included 
in the study if a pregnancy test is negative at the screening visit and if they agree to 
use adequate contraception during the study and until 8 weeks (inclusive) after last 
dose of study intervention. Adequate contraception is defined as any combination of 
at least 2 effective methods of birth control, of which at least 1 is a physical barrier 
(e.g. condoms with hormonal contraception or implants or combined oral 
contraceptives, certain intrauterine devices). 
o For adolescent (nulliparous) participants, long-acting reversible contraception 
(LARC) methods are considered first-line options. 
• Postmenopausal females (no menses for 12 months without an alternative medical 
cause; see Section 11.6) are not required to use contraception. A high follicle-

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stimulating hormone (FSH) level in the postmenopausal range may be used to confirm 
a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
confirmation with more than 1 FSH measurement is required. 
• Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
• Females of non-childbearing potential (premenarchal, documented hysterectomy, 
documented bilateral salpingectomy, documented bilateral oophorectomy) are not 
required to use contraception. 
o If the childbearing potential changes after start of the study (e.g. a premenarchal 
female participant experiences menarche) or the risk of pregnancy changes (e.g. a 
female participant who is not heterosexually active becomes active), the 
participant must discuss this with the investigator, who should determine if a 
female participant must begin a highly effective method of contraception (e.g. 
LARC) or a male participant must use a condom. If reproductive status is 
questionable, additional evaluation should be considered. 
• For females with permanent infertility due to an alternate medical cause other than the 
above, (e.g. mullerian agenesis or androgen insensitivity), investigator discretion 
should be applied to determining study entry. 
Informed Consent 
9. Participant and/or parent(s)/legal guardian is capable of giving signed informed 
consent (and informed assent, as required) as described in Section 11.1.3 of the 
protocol which includes compliance with the requirements and restrictions listed in 
the ICF and in the protocol. 
Other 
10. For adolescent participants (≥ 12 to < 18 years), a legal guardian must be available to 
help the study site personnel ensure follow-up; accompany the participant to the 
study site on each assessment day according to the SoA (e.g. able to comply with 
scheduled visits, treatment plan, laboratory tests and other study procedures); 
consistently and consecutively be available to provide information on the participant 
using the PROs during the scheduled study visits; accurately and reliably dispense 
study intervention as directed. 
11. For adolescent participants, a legal guardian must be able to accurately maintain the 
child’s take-home record, including items of general health. 
5.2 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Any other inherited or acquired bleeding disorder in addition to hemophilia A. Note: 
von Willebrand disease should be diagnosed per local clinical practice. Participants 
with a diagnosis of von Willebrand disease in medical records or diagnosed at the 
time of screening will be excluded. 

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2. Platelet count < 100,000/mm3. 
3. Evidence of inhibitor to FVIII (≥ 0.6 BU/mL) within the last 1 year (refer to 
Inclusion Criterion #5). 
Prior/Concurrent Clinical Study Experience 
4. The participant is currently participating in another investigational drug study or has 
participated in a clinical study involving an investigational drug or device within 30 
days of signing informed consent. 
Other Exclusions 
5. The participant has a planned major surgery. 
Note: Major surgery is defined as any surgical or invasive procedure (elective or 
emergent) in which the overall bleeding risk may be excessive, would require a 
general anesthetic in an individual without a bleeding disorder, penetrates or 
exposes a major body cavity, could result in substantial impairment of physical or 
physiological functions, or requires special anatomic knowledge or manipulative 
skill (e.g. tonsillectomy, laparotomy, thoracotomy, joint replacement). 
6. Documentation for any of the following risk score parameters is missing/unknown: 
ABR, pre-study treatment frequency (refer to Inclusion Criterion #4 and Section 
9.4.2), number of target joints affected, and vWF levels. 
7. Known hypersensitivity to the drug substance, excipients, or mouse or hamster 
protein. 
8. Any other significant medical condition that the investigator feels would be a risk to 
the participant or would impede the study. 
9. Close affiliation with the investigational site (e.g. a close relative of the investigator) 
or dependent person (e.g. employee or student of the investigational site). 
10. Otherwise vulnerable participants (e.g. participants who are in custody by order of 
an authority). 
11. Judgment by the investigator that the participant should not participate in the study 
if the participant is unlikely to comply with study procedures (i.e. eDiary 
completion), restrictions, and requirements. 
5.3 
Lifestyle Considerations 
No specific restrictions from the participants are required in the study. 
5.4 
Screen Failures 
Screen failures are defined as participants who consent (or assent) to participate in the clinical 
study but are not subsequently entered in the treatment phase of the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE). 

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Individuals who do not meet the criteria for participation in this study (screen failure) may 
not be rescreened. 
5.5 
Criteria for Temporarily Delaying Study Intervention Administration 
The following conditions may allow a participant to be started on study intervention once the 
conditions have resolved and the participant is otherwise eligible: 
• Unexpected or life-threatening SAE 
• Current febrile illness (temperature of 38.0°C [100.4°F]) or other acute illness, 
including reaction after COVID-19 vaccination, within 48 hours before the first study 
intervention administration at baseline. If such an intercurrent acute event occurs, the 
screening period can be prolonged without a need to repeat the screening assessment. 
6. 
Study Intervention and Concomitant Therapy 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol. 
6.1 
Study Intervention Administered 
Treatment decisions for identifying appropriate prophylaxis regimens should be guided by 
treatment regimens as defined by the protocol, clinical judgment, and individual participant 
characteristics (Table 6-1). Refer to Section 9.4.2 for details regarding statistical analysis of 
participants who switch from the protocol-assigned regimen. 

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Table 6–1: Study Intervention 
Treatment 
2x/week 
Every 5 days 
Less Frequent (e.g. 
every 7 days) 
Intervention Name 
Jivi  
Type 
Biologic 
Dose formulation 
Ampule 
Duration of 
intervention 
6 months using study IxRS  
Unit dose strengths 
500 or 2000 IU/vial  
Dosage Levels 
40 IU/kg/dose 
Two times per week 
50 IU/kg/dose 
Every 5 days 
The total recommended 
maximum dose/infusion 
is 6000 IU. 
60 IU/kg/dose 
Less frequent dosing 
(e.g. every 7 days)a 
The total 
recommended 
maximum dose/infusion 
is 6000 IU. 
Route of 
Administration 
IV infusion 
IMP 
IMP (Jivi) 
Sourcing 
Provided by the sponsor  
Packaging and 
Labeling 
Jivi will be provided in glass vials with a prefilled syringe. Each glass vial will 
be labeled per local requirements. 
Current Name / 
Former Name 
Commercial name: Jivi / BAY 94-9027 
Abbreviations: IMP = Investigational medicinal product; IV = intravenous; IxRS = Interactive 
Voice/Web Response System. 
a As determined by the investigator. 
Treatment of bleeds 
All bleeding events that occur in participants receiving prophylactic infusion after the start of 
treatment (Visit 2) will be treated with Jivi as outlined in the approved prescribing 
information. If a bleed occurs on a day of the planned infusion, the participant should treat 
the bleed instead of receiving the scheduled prophylactic infusion. 
All bleeding events that occur after the start of treatment will be treated with Jivi in 
accordance with the bleeding location and severity of the bleed, and treatment will be 
repeated as needed. The dose to be used for treating the bleed will depend on the severity of 
the bleed, the participant’s prior experience with treatment of bleeding events, and the 
treating physician’s recommendations. The recommended maximum dose is 60 IU/kg (with 
maximum 6000 IU). Additional follow-up treatments can be administered as needed, and the 
dose may be tailored to a participant’s individual response. 
The appropriate treatment of bleeding events is left to the discretion of the treating physician, 
local clinical practice, and may be extrapolated from published guidelines (e.g. WHO/ 
WFH/ISTH/EMA). 
If the bleed occurs on a non-scheduled prophylactic infusion day, then the prophylactic 
schedule with Jivi is not affected by the additional treatment of bleeds (e.g. if a participant 
treats a bleed on Sunday and is due to infuse his/her prophylactic dose on Monday, he/she 
will still receive the scheduled infusion). If a repeated treatment for the bleed is required and 
falls on a day of a scheduled prophylactic infusion, the dose administered on the scheduled 
infusion day may be modified to ensure the participant receives appropriate treatment. 

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6.1.1 
Medical Devices 
The Jivi vials will be supplied with the necessary medical devices to facilitate the preparation 
and infusion of the study intervention. The medical devices that are used in this study are the 
same as those marketed with Jivi (approved for use in PTPs ≥ 12 years), as well as Kovaltry, 
a rFVIII product manufactured by the sponsor and indicated for use in patients with 
congenital hemophilia A, including patients < 12 years. 
The medical devices provided by the sponsor for use in the study are: 
• Vial adapter 
• Prefilled syringe contain sterile water for injection 
• Administration set 
If device deficiencies occur (including malfunction, use error, and inadequate labeling), they 
shall be documented and reported by the investigator to the sponsor throughout the clinical 
investigation (see Section 8.4.8) and appropriately managed by the sponsor. 
6.2 
Preparation/Handling/Storage/Accountability 
The current approved prescribing information for use of Jivi are relevant for this study and 
will be provided to the participants and caregivers. 
Jivi is supplied as a lyophilized powder in glass vials. Study vials may contain 500 IU or 
2000 IU. The vials of Jivi will be packaged together with a needle-less reconstitution system, 
which contains the following: a vial adapter with built-in 15-micrometer filter and a 2.5-mL 
diluent in a 5-mL syringe 25-gauge butterfly needle. 
Instructions for the preparation of study interventions can be found in the leaflet for using 
Jivi. Jivi must be stored under refrigeration (2°C to 8°C) for up to 24 months from the date of 
manufacture. Within this period, the unopened product carton may be stored for up to 
6 months at room temperature, but should not be returned to the refrigerator. The 
reconstituted product should be used within 3 hours of reconstitution at room temperature. 
All study intervention will 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 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. 
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention. 
2. Only eligible participants enrolled in the study (and parent[s] or legal guardian) will 
receive study intervention and only authorized site staff will supply study 
intervention. The responsible site personnel will instruct participants (or parent[s] 
and legal guardian) on requirements for proper home transport/storage of study 
drug. Study intervention will be administered by participants (or parent[s] or legal 
guardian). All study intervention must be stored in a secure, environmentally 
controlled, and monitored (manual or automated) area in accordance with the 

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labeled storage conditions with access limited to the investigator and authorized site 
staff. 
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 intervention accountability, 
reconciliation, and record maintenance. Receipt, distribution, return, and destruction 
(if any) of the study intervention must be properly documented using the study 
IxRS, according to the sponsor’s agreed and specified procedures. 
The investigator maintains responsibility and control for dispensing via IxRS. Participants 
can obtain study intervention at the site. At selected sites, site-to-patient distribution of study 
intervention can occur and the sponsor may contract a distribution provider to facilitate 
distribution including the delegation of storage and handling as needed until handover to the 
participant. 
6.3 
Measures to Minimize Bias: Randomization and Blinding 
This is an open-label, single treatment arm study, and no randomization or masking will be 
performed. All participants will receive study intervention and will be allocated to a 
prophylaxis regimen based on the total risk score determined at baseline. The retrospective 
data collection on bleed frequency before trial for comparison may be biased towards lower 
bleed rates due to incomplete documentation and collection from any given 6-month period 
within 12 months of study screening, as it is assumed that the time a subject is not on stable 
prophylaxis (up to 6 months prior to enrollment) does not have an influence on the 
occurrence of bleeds during the study period. This would affect the outcome negatively, 
because the data collection during the study is prospective. Nevertheless, the pre-study bleed 
rate has been documented in all clinical studies based on participant diaries as per local 
standard of care and has been seen to provide a good estimate of the participant’s bleed rate. 
Participants will be identified by a unique participant number with 9 digits once the ICFs 
(and assent forms) are signed. The first 5 digits will identify the country and study site; the 
last 4 digits are assigned to the participant of the specific site in increasing order.  
6.4 
Study Intervention Compliance 
Study intervention will be self-administered by the participant or by a parent or legal 
guardian. Study personnel should review dose administration requirements with the 
participant, as appropriate, and with the delegated legal guardian(s) or parent(s) before 
administration and throughout the study as necessary. 
Participant compliance with study intervention will be assessed at each visit. 
Used vials of study medication will be returned to the site at every visit for accounting. Any 
discrepancies between actual and expected amount of returned vials must be discussed with 
the participant (and his/her parent[s] or legal guardian) at the time of the visit, and any 
explanation must be documented in the source records. 
The participant eDiary will be used to assess the participant’s compliance with the treatment 
schedule/dose, and to reconcile study medication inventory. The eDiary 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.  

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The eDiary will be reviewed at visits and at regular contacts with the participant during the 
study. 
6.5 
Dose Modification 
If a participant treated with an extended interval regimen experiences ≥ 2 muscle or joint 
bleeds (without evident trauma) within any given 8-week period during the study, then he/she 
will be assigned to next highest frequency regimen. In line with the Jivi prescribing 
information, the treating investigator reserves the right to change a participant’s regimen at 
any time if he/she determines the score-determined regimen is not well-suited for the 
participant. 
Further dose adaptations according to participant needs and at the investigator’s discretion are 
allowed within the approved dose range and rounding up to full vials which may result in 
slightly higher dosages. 
6.6 
Continued Access to Study Intervention After the End of the Study 
After completion of the study, treatment with study intervention will end. Subsequent 
treatment will be mutually agreed upon by the participants and the investigator. 
6.7 
Treatment of Overdose 
The recommended maximum dose as per the approved prescribing information is 
approximately 6000 IU (rounded to vial size). The sponsor does not recommend specific 
treatment for an overdose. Any intervention is left to the discretion of the treating physician, 
local clinical practice, and may be extrapolated from published guidelines (e.g. 
WHO/WFH/ISTH/EMA). No symptoms of overdose have been reported during the pivotal 
clinical trials. The next dose after the discovery of a dose above the maximum recommended 
one should be corrected and not delayed. 

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In the event of an overdose, the investigator/treating physician should: 
• 
Contact the Medical Monitor immediately. 
• 
Evaluate the participant to determine, in consultation with the Medical Monitor, 
whether study intervention should be interrupted or whether the dose should be 
reduced. 
• 
Closely monitor the participant for any AE/SAE and laboratory abnormalities. 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
6.8 
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 along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency. 
The Medical Monitor (Study Medical Expert) should be contacted if there are any questions 
regarding concomitant or prior therapy. 
Bleeds which 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 ICF (and assent 
form) is signed, including FVIII products other than study intervention, will be listed in the 
appropriate case report form (CRF). All concurrent prescription and nonprescription 
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 prior to screening will be recorded in the CRF and 
throughout the treatment and safety follow-up periods. 
All planned vaccinations should be completed at least 2 weeks prior to start of study 
intervention. If a vaccination (including the COVID-19 vaccine) is to occur during the study, 
the vaccination should occur no more than 2 days after a Jivi infusion to prevent any potential 
bleeding at the injection site. 
The participant should not be taking any other investigational drug while receiving treatment 
with Jivi, and all SHL prophylactics will have been stopped at least 3 days prior to the start of 
Jivi administration. All bleeding events that occur in participants receiving prophylactic 
infusion after the start of treatment (Visit 2) will be treated with Jivi as outlined in the 
approved prescribing information. After treatment of bleeding, the prophylactic Jivi regimen 
will be resumed according to assigned dosing schedule. 
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 inhibitors, or brief courses of corticosteroids to 
treat pain or acute synovitis is at the discretion of the treating physician.  

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Inhaled or topical steroid medications (as required 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. 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
All participants who enter the study should complete all applicable study periods. Participants 
can be withdrawn from any study period at any time. Withdrawal from the treatment period 
alone does not constitute withdrawal from the study. 
Participants who withdraw from the treatment period for any reason are to be encouraged to 
remain on the study for follow-up of primary, secondary and other objectives. Participants are 
expected to participate in follow-up unless they explicitly object. Withdrawal of consent to 
the treatment period should be documented in the participant’s medical record. If 
the participant does not wish to be followed up further, this additional consent withdrawal for 
follow-up must also be documented. 
7.1 
Discontinuation of Study Intervention  
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. If study intervention is permanently discontinued, the participant will not 
remain in the study and an EOS visit will be performed.  
See the SoA (Section 1.3) for data to be collected at the time of discontinuation of study 
intervention and follow-up and for any further evaluations that need to be completed. 
7.1.1 
Inhibitor Development 
Any inhibitor development (≥ 0.6 BU/mL, confirmed; see Section 9.4.4.1) is considered a 
SAE. Discontinuation of study intervention due to a high titer inhibitor development 
(titer > 5 BU/mL) should be considered if the investigator believes that it is in the best 
interest of the participant and/or if bypassing agents are needed to treat bleeds. Participants 
who discontinue study intervention due to inhibitor development cannot continue in the study 
and will be withdrawn. 
7.1.2 
Planned Major Surgery During the Study 
Planned major surgeries are exclusionary for this study (see Section 5.2, Exclusion 
Criterion #5). 
If the participant has an unplanned emergency surgery during the study, the investigator and 
sponsor will determine if the participant can continue in the study and if any change in 
participant management is needed. 
7.1.3 
Temporary Discontinuation from Study Intervention 
Participants who have an elective unplanned major surgery during the study will be treated 
outside of the clinical study. The participant may be treated according to local practice at the 
discretion of investigators. Participants will resume their treatment assignment of Jivi as per 
this protocol after surgical recovery. 

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Participants with a concurrent illness requiring study intervention interruption may be 
discontinued, at the discretion of the investigator, as explained in Section 7.2. In the event of 
a trial-continuity issue (e.g. caused by a pandemic), the sponsor may provide additional 
guidance in study-specific communication. 
7.2 
Participant Discontinuation/Withdrawal from the Study 
• A participant (and his/her parent[s] or legal guardian) has the right to withdraw 
permission at any time during the study. If the study staff identify any reluctance in 
the legal guardian or pediatric participant (e.g. signs of verbal or physical dissent) 
about continued participation in the study, the pediatric participant’s continuation in 
the study should be reevaluated. The same principles that govern 
permission/assent/consent also govern his/her withdrawal. 
• The participant may be withdrawn at any time at the discretion of the investigator for 
safety, behavioral, or compliance reasons. 
• At the time of discontinuing from the study, if possible, an early withdrawal visit 
should be conducted, as shown in the SoA. See SoA (Section 1.3) for data to be 
collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
• The participant will be permanently discontinued both from the study intervention and 
from the study at that time. 
• If the participant withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of 
consent. 
• A participant must be withdrawn from the study if the development of an inhibitory 
antibody to Jivi (i.e. FVIII antibody or antibody to PEG) that neutralizes activity 
sufficiently to interfere with effective treatment or requires use of a bypassing agent 
to treat bleeds occurs. 
• A participant must be withdrawn from the study if he/she fails to comply with 
scheduled appointments for the study-related evaluations and with eDiary data entry 
to an extent that compromises collection of critical data. 
• A participant must be withdrawn from the study if significant concurrent illness or 
deterioration occurs in the participant’s condition, including laboratory values that the 
investigator deems to be incompatible with the participant’s continued safe 
participation in the study. 
7.3 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant (and his/her parent[s] or legal 
guardian[s]) and reschedule the missed visit as soon as possible and counsel the 
participant on the importance of maintaining the assigned visit schedule and ascertain 
if the participant wishes to and/or should continue in the study. 

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• Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (and his/her parent[s] or legal 
guardian[s]) where possible (3 telephone calls and, if necessary, a certified letter to 
the participant’s last known mailing address or local equivalent methods). These 
contact attempts should be documented in the participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered lost to 
follow-up. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1. 
8. 
Study Assessments and Procedures 
• Study procedures and their timing are summarized in the SoA (Section 1.3) and visit 
description in Appendix 7. Protocol waivers or exemptions are not allowed. 
• Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log 
to record details of all participants screened and to confirm eligibility or record 
reasons for screening failure, as applicable.  
• Procedures conducted as part of the participant’s routine clinical management (e.g. 
blood count) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and 
were performed within the time frame defined in the SoA. 
• If deemed necessary for an individual participant, the investigator or designee, at 
his/her discretion, may arrange visits in addition to the scheduled study visits. 
Unscheduled visits will be documented in the electronic CRF. 
• In the event of a significant trial-continuity issue (e.g. caused by a pandemic), 
alternate strategies for participant visits, assessments, medication distribution and 
monitoring may be implemented by the sponsor or the investigator, as per local health 
authority/ethics requirements. 
The study consists of a screening period of up to 30 days prior to Day 1, a 6-month treatment 
period, and a Safety Follow-up Visit 7 to 14 days after the last dose of study intervention. 
After laboratory visits at screening and Baseline (Day 1), 5 visits are scheduled, including 
telephone-only visits at Months 1 and 2 and Safety Follow-up, and site visits at Months 3 and 
6 (EOS/Early withdrawal). The telephone visits between the participant and personnel at the 
study site are required to check documentation compliance, adherence and response to 
treatment, AEs, concomitant medications, and other medical problems that may occur 
between study visits. Contacts should be documented in the medical record. 
The maximum time interval between screening and Baseline (Day 1) visits is up to 30 days. 
There is no minimal interval between screening and Baseline visits, except for the amount of 
time required to confirm eligibility criteria. 

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8.1 
Population Characteristics 
8.1.1 
Demographics 
Demographic characteristics to be recorded at screening will include age, sex, race and 
ethnicity, and blood type. Employment will also be recorded at Baseline (Day 1). 
8.1.2 
Medical and Surgical History 
Medical history findings (i.e. previous diagnoses, diseases, surgeries, and substance usage) 
meeting all criteria listed below will be collected at screening: 
• Not pertaining to study indication 
• Start before signing of informed consent 
• Considered relevant to the study 
• Include any information on cardiovascular risk, hepatic disease, renal impairment, 
prior use of PEGylated medications (e.g. PEG- interferon, PEG-anti-TNF), and 
concomitant medications 
8.1.3 
Disease History 
Specific information on history of hemophilia to be recorded at screening will include date of 
diagnosis, start of therapy, start of prophylaxis, for all prior and current FVIII products within 
12 months, estimated number of EDs, type of FVIII gene mutation (from history, if 
available), family history, FVIII level and type of assay, family and personal history of past 
inhibitor formation (including date of inhibitor testing, whether immune tolerance induction 
was performed, and recovery and half-life data, if available; Section 1.3), previous or current 
SHL treatment product and regimen, used for score calculation, within 12 months of Baseline 
Visit, and number and type of bleeds derived from the before-mentioned SHL time period of 
a minimum of 6 months within the last 12 months of study screening . If available, data on 
prior PK with the participants’ previous SHL FVIII product (used for score calculation) will 
be collected (concentration timepoints, and half-life). 
Blood samples will be collected at screening to determine the participant’s vWF antigen 
levels, if not already available in the medical records. If available in the medical records, 
vWF antigen testing should have been performed within 12 months prior to enrollment. 
8.1.4 
Other 
At screening, blood type will be recorded and BMI will be calculated. 
Physical activity levels (medium/high [contact sports]; low [non-contact sports]; and 
sedentary) will be recorded at Baseline (Day 1). 
8.2 
Effectiveness Assessments 
This is an exploratory study of the effect of using a risk score approach to select the most 
appropriate prophylaxis regimen for favorable clinical outcomes and reduced treatment 
burden. Planned time points for all effectiveness assessments are provided in the SoA 
(Section 1.3). Effectiveness variables to be evaluated are listed below (further details will be 
provided in the Statistical Analysis Plan [SAP]). 
• ABR (total, joint, spontaneous) 
• Jivi treatment frequency, expressed as total number of infusions per month 

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• Occurrence of participants with 0 and ≤ 1 spontaneous bleeds 
• Quality of life, as measured by Haem-A-QoL or Haemo-QoL, PGI-C, EQ-5D-5L, 
TSQM, and WPAI 
• Number and location of affected target joints, defined per ISTH 
The primary effectiveness variables used in the determination of favorable outcome will be 
change in total ABR and FVIII treatment frequency (infusions/month). The primary endpoint 
is the occurrence of favorable outcome (see Section 9.4.2 for additional details), defined as: 
• no change of the risk score-assigned dosing regimen during the study, with one of the 
following: 
o improved ABR versus pre-study ABR and decreased frequency of 
administration versus pre-study frequency. 
o improved ABR versus pre-study ABR with similar frequency of 
administration versus pre-study frequency. 
o decreased frequency of administration versus pre-study frequency and similar 
ABR versus pre-study ABR. 
NOTE: The full definitions of pre-study ABR, treatment frequency, and stable SHL 
prophylaxis are provided in Section 9.4.2 and Section 11.10. 
8.2.1 
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 effectiveness. Study-specific treatment logs will be provided in the national 
language. The system for this study will be an eDiary since this allows for an interactive, 
record-stamp date and time of fulfillment and facilitates the clarification of data with the site 
as well as the data cleaning process. Participants will be provided access to the eDiary for the 
entire study. At the Baseline Visit, participants (and their parent[s] or legal guardian) will be 
trained in the use of the eDiary. These logs will be used to document 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 eDiary will be considered the source for these data. In the event a 
participant does not have internet access, alternative means of diary completion will be 
provided. 
For each infusion of Jivi, information must be recorded in the diary as follows: 
Each infusion of Jivi:  
a. Date and time 
b. Infusion record  
c. Individual vial/batch number (bar code scan from vial label or manual entry) and units 
administered 
d. Reason for treatment 
• Prophylaxis 
• Spontaneous bleed first treatment 

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• Trauma bleed first treatment 
• Follow-up treatment 
• Unscheduled Prophylaxis due to surgery 
• Unscheduled Prophylaxis due to injury 
• Unscheduled Prophylaxis due to activity 
• Other (as specified by participant or legally authorized representative) 
Infusions of Jivi as part of protocol-mandated visits and procedures will be recorded on the 
respective CRF pages. 
All bleeding episodes (regardless if treated or not, or treated at home or under medical 
supervision) as well as any potential treatment with other hemophilia drugs will be recorded 
in the diary: 
Bleeding episode (onset) 
a. Date and time of onset 
b. Type of bleed (spontaneous, trauma; joint, muscle, skin/mucosal, internal, other)  
c. Location 
d. Intensity (mild, moderate, severe) 
e. Treated [YES/NO]; If YES, the following is to be recorded: 
• Date and time  
• Number of infusions 
• Dose/infusion 
8.2.2 
Patient Reported Outcomes 
The PRO data on QoL and health status, work and school productivity, pain, and treatment 
satisfaction will be collected. The objective of PRO data is to collect the participant’s 
perspectives and opinions on the impact and effectiveness of Jivi in the treatment of 
hemophilia. Questionnaires will be filled out by the participant in the treatment center at 
Baseline (Day 1; Haem-A-QoL or Haemo-QoL, PGI-C, EQ-5D-5L, TSQM, and WPAI), 
Month 3 (EQ-5D-5L only), and Month 6 (EOS; Haem-A-QoL or Haemo-QoL, PGI-C, 
EQ-5D-5L, TSQM, and WPAI). Appendix 2 provides representative examples of the PROs 
to be used in the study. 
The following PROs assessments will be obtained: 
• Haemophilia specific quality of life (Haem-A-QoL and Haemo-QoL) 
questionnaires: 
The questionnaire will be used to capture the full impact of Jivi and the treatment 
modalities on the participants’ hemophilia-specific QoL during the previous 4 weeks. 
The Haem-A-QoL is a hemophilia-specific QoL questionnaire for adults aged 18 
years and above. The questionnaire has 41-items covering 6 domains: Physical 
Functioning, Role Functioning, Worry, Consequences of Bleeding, Emotional Impact, 
and Treatment Concerns. For participants 17 years and younger, the Haemo-QoL 
Short Form Questionnaire for children and adolescents will be used. The Haemo-QoL 

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Short Form contains 35 questions covering 9 domains: Physical Health, View of 
Yourself, Family, Friends, Others, Sports, Dealing, and Treatment. 
The respondent burden for both questionnaires is approximately 15 minutes. 
• Patient’s Global Impression of Change (PGI-C) 
The self-report measure PGI-C reflects a participant’s belief about the efficacy of 
treatment. The PGI-C consists of a 7-point scale depicting a participant’s rating of 
overall improvement. Participants rate their change as “very much improved,” “much 
improved,” “minimally improved,” “no change,” “minimally worse,” “much worse,” 
or “very much worse.” 
The respondent burden for the questionnaire is approximately 5 minutes. 
• Five-Level European Quality of Life Five Dimension (EQ-5D-5L) 
The EQ-5D-5L is a standardized health-related QoL questionnaire that provides a 
simple, generic measure of health for clinical and economic appraisal. The EQ-5D-5L 
descriptive system comprises 5 dimensions: mobility, self-care, usual activities, pain 
and discomfort, and anxiety and depression. Each dimension has 3 levels: no 
problems, some problems, or severe problems. The respondent is asked to indicate 
his/her health state by ticking (or placing a cross) in the box against the most 
appropriate statement in each of the 5 dimensions. 
The respondent burden for the questionnaire is approximately 5 minutes. 
• Treatment Satisfaction Questionnaire for Medication (TSQM) 
The TSQM comprises 9 items across 3 domains focusing on effectiveness (3 items), 
convenience (3 items), and global satisfaction (3 items) of the medication over the 
previous 2 to 3 weeks, or since last use. All items have 5 or 7 responses, scored from 
one (least satisfied) to 5 or 7 (most satisfied). Item scores are summed to give 
3 domain scores, which are in turn transformed to a scale of 0-100. 
The respondent burden for the questionnaire is approximately 5 minutes. 
• Work Productivity and Activity Impairment (WPAI) questionnaire: 
The WPAI is a validated instrument to assess the effect of hemophilia on ability to 
work, attend classes, and perform regular daily activities in ages 12 and above. The 
WPAI will also contain classroom impairment questions. The questionnaire is 
self-administered and comprises 9 questions that elicit information on work, 
classroom, and daily activity impairment during the previous 7 days. Scores are 
expressed as percentages of impairment/productivity loss, with higher scores 
indicating greater impairment.  
The respondent burden for this questionnaire is approximately 10 minutes. 
8.2.3 
Joint Status Assessment 
A joint status assessment (including target joints) will be recorded at baseline and EOS using 
the ISTH criteria. A target joint is defined as one having 3 or more spontaneous bleeds into a 
single joint within a consecutive 6-month period. Where there have been ≤ 2 bleeds into the 
joint within a consecutive 12-month period the joint is no longer considered a target joint 
(Blanchette et al., 2014). 

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8.3 
Safety Assessments 
Safety will be assessed by monitoring and recording all AEs, AEs of special interest (AESIs), 
and SAEs, and any abnormal findings observed during the performance of physical 
examinations. 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.3.1 
Measurements of Immunogenicity 
All participants will be tested for inhibitors to FVIII according to the Bethesda assay as per 
local clinical practice. A positive inhibitor test is defined with a threshold of ≥ 0.6 BU/mL. 
Repeat testing should be obtained within 1 to 2 weeks of initial identification of a positive 
result. Only after confirmation of a second positive result does the inhibitor have to be 
reported as a SAE. 
A low post-infusion FVIII level in the absence of detectable FVIII inhibitors indicates that 
loss of drug effect is likely due to anti-PEG antibodies. Jivi should be discontinued and 
participants switched to a previously effective FVIII product (refer to Section 8.4.7 as this 
qualifies for an AESI-Loss of Efficacy [LoE]). 
8.3.2 
Physical Examinations 
• Physical examinations will be performed at Baseline (Day 1) and EOS/Early 
Withdrawal Visit. 
• A physical examination will include, at a minimum, assessments of the general health 
status, and review of systems. Height and weight will also be measured using a 
calibrated stadiometer (appropriate for the participant’s age) and recorded. 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. Any abnormal finding should be documented. 
8.3.3 
Clinical Safety Laboratory Assessments 
• See Section 11.3 for the list of clinical laboratory tests to be performed and the SoA 
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 are those which are not associated 
with the underlying disease, unless judged by the investigator to be more severe than 
expected for the participant's condition. 
8.3.4 
von Willebrand Factor (vWF) Antigen 
The investigator must ensure absence of the following conditions or other factors which may 
influence the levels of vWF before drawing blood for the vWF test. 
A number of transient clinical conditions can raise the vWF levels of individuals with 
congenital deficiency into the normal range. The vWF is an acute phase reactant and levels 
can increase due to stress, inflammation, acute infection, physical exercise, and following 
surgery. Levels can also increase with estrogen administration for contraception or hormone 
replacement (Adcock et al., 2006). Furthermore, two- to three-fold increases in the second 
and third trimesters of pregnancy have been observed (Brandt, 2002; Rick, 2002). In addition, 

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vWF levels may increase during menstruation and should not be measured during active 
menstruation (Brown et al., 2019). 
Note: Individuals with blood type O tend to have approximately 30% lower vWF levels than 
those with other blood types. 
8.3.5 
Pregnancy Testing 
A negative serum pregnancy test during screening and at Visit 5 (Month 3) and Visit 6 
(Month 6) is required for women of childbearing potential (WOCBP) (see Section 1.3). If 
Visit 2 (baseline) occurs > 14 days after a female participant’s last menstrual period, an 
additional pregnancy test is required. Premenarchal women, postmenopausal women with no 
menses for at least 1 year, or surgically sterilized women will not be required to undergo a 
pregnancy test. Confirmation of childbearing status should be documented in the medical 
history page of the CRF. 
8.4 
Adverse Events (AEs), Serious Adverse Events (SAEs), and Other 
Safety Reporting 
The definitions of an AE or SAE can be found in Section 11.4. 
The AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally authorized representative or HCP 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, AESI, or SAE. They remain responsible 
for following up on SAEs or AEs considered related to the study intervention or study 
procedures, or those events 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, AESIs, and SAEs will be collected from Baseline until the end of the Safety 
Follow-up Visit at the time points specified in the SoA (Section 1.3).  
(S)AEs which are related to protocol-required study procedures (e.g. [S]AEs related to 
invasive study procedures) will be recorded as (S)AEs from the signing of the ICF until the 
start of study intervention. Medical occurrences that begin before the start of study 
intervention but after obtaining informed consent (and assent) but are diagnosed at screening 
or during the screening period (e.g. abnormal lab values) will be recorded on the Medical 
History/Current Medical Conditions section of the electronic CRF not the AE section, with 
the exception of bleeds occurring during the screening period which should be recorded in the 
patient’s medical record. 
All SAEs and AESIs will be recorded and reported to the sponsor or designee immediately; 
under no circumstances should this exceed 24 hours, as indicated in Section 11.4. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of the data 
being available. 
Investigators are not obligated to actively seek information regarding AEs or SAEs after the 
conclusion of study participation. However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she considers 

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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 AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Section 11.4. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences.  
Clinical Presentation of Adverse Events in Pediatric Population 
Study site staff should instruct the legal guardian(s) on how to report signs and symptoms 
(e.g. pain) in the individual pediatric participant. The legal guardian(s) will be instructed to 
report both specific and non-specific symptoms (including vomiting, diarrhea, sleepiness, 
etc.). These non-specific symptoms may be the only manifestations of some adverse reaction 
observed. Care should be taken that the clinical presentation of adverse reactions is not 
misinterpreted as the manifestation of a pre-existing or unrelated condition. 
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 SAEs and AESIs (as defined in Section 8.4.7) 
will be followed until resolution, stabilization, the event is otherwise explained, or the 
participant is lost to follow-up (as defined in Section 7.3). Further information on follow-up 
procedures is given in Section 11.4.3. 
8.4.4 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the investigator to the sponsor of an SAE or AESI is essential 
so that legal obligations and ethical responsibilities towards the safety of participants 
and the safety of a study intervention under clinical investigation are met.  
• The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Board 
(IRB), and investigators. 
• Investigator safety reports must be prepared 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, 
if appropriate according to local requirements. 
8.4.5 
Pregnancy 
• Details of all pregnancies in female participants will be collected after the start of 
study intervention and until 8 weeks after last dose of study intervention. 

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• If a pregnancy is reported, the investigator will record pregnancy information on the 
appropriate form and submit it to the sponsor within 24 hours of learning of the 
female participant pregnancy. 
• While the pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be 
reported as an AE or SAE. 
• Abnormal pregnancy outcomes (e.g. spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs, and will be reported 
as such. 
• The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and 
the information will be forwarded to the sponsor. 
• Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 8.4.4. While the investigator is not obligated to actively seek this information 
in former study participants, he/she may learn of an SAE through spontaneous 
reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention and be withdrawn from the study after completing the 
early withdrawal visit. 
8.4.6 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs 
The following disease-related event is common in participants with hemophilia A and can be 
serious/life-threatening: 
• Bleeding event 
Any bleeding event, regardless if treated or not, occurring during the study will not be 
documented as an AE, because this is captured in the assessment of effectiveness. 
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 participant diary. 
NOTE: However, if the bleed fulfills the criterion for an SAE (e.g. results in hospitalization), 
then the event should be recorded and reported as an SAE (see Section 11.4.2). 
8.4.7 
Events of Special Interest 
Hypersensitivity reactions, including severe allergic reactions (which can progress to 
anaphylaxis), chest or throat tightness, dizziness, mild hypotension, and nausea, are known 
and listed adverse drug reactions for FVIII products and have been reported with use of Jivi. 
Loss of efficacy of the drug product has also been reported in children < 6 years of age and 
may be associated with the development of antibodies to PEG. Loss of efficacy can present as 
bleeding and must be confirmed by low recovery or post-infusion FVIII level, and a negative 
FVIII inhibitor test. A low recovery or no detectable FVIII post-infusion in a participant with 
a hypersensitivity reaction in the presence of PEG IgM antibodies is considered LoE even in 
the absence of a bleeding event. All such reported events (hypersensitivity and LoE) occurred 
early in treatment (within the first 4 EDs). 

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Hypersensitivity reactions and LoE are defined in this study as AESIs and must be reported 
within 24 hours of the investigator’s awareness. The LoE must be confirmed by an abnormal 
low recovery after the infusion of Jivi. 
In the event of reported LoE of the study intervention, the following is to be done:  
1. Schedule a visit within 4 days of the reported event. 
2. Obtain 2 pre-infusion blood/plasma samples for FVIII levels and FVIII inhibitor (for 
local laboratory). 
3. Administer BAY 94-9027 (use current prophylaxis dose [IU/kg]). 
4. Obtain one post-infusion blood/plasma samples (for local laboratory) for FVIII levels 
(15-30 minutes post-infusion). 
Non-serious hypersensitivity events should not automatically be upgraded by the reporting 
investigator to serious. 
If hypersensitivity reactions occur, immediately discontinue study intervention administration 
and initiate appropriate treatment. Please refer to the approved prescribing information. 
8.4.8 
Medical Device Deficiencies 
Medical devices approved for use with Jivi are being provided for use in this study to 
facilitate the preparation and infusion of the study intervention. To fulfill regulatory reporting 
obligations worldwide, the investigator is responsible for the detection and documentation of 
events meeting the definitions of device deficiency that occur during the study with such 
devices. 
The definition of a medical device deficiency can be found in Section 11.5.3. 
Device deficiencies only should be reported to the sponsor, by completing the Product 
Technical Complaint form and submitting it to the sponsor via the email address 
(ptc-imp@bayer.com) given to the site.  
NOTE: Deficiencies fulfilling the definition of an AE/SAE will follow the processes outlined 
in Section 11.5.5 of the protocol.  
8.5 
Pharmacokinetics 
8.5.1 
Incremental Recovery and Trough Levels of Jivi 
Blood samples for Jivi incremental recovery, FVIII levels, and FVIII trough levels will be 
collected in all participants. Incremental recovery will be determined at Baseline (Day 1) by 
collecting a sample for FVIII level before the scheduled infusion and a second sample 
collected 15 to 30 minutes after end of the infusion. A third sample collected at a minimum of 
4 hours after the end of the infusion to assess FVIII levels. The measurements should only be 
performed when the participant is not actively bleeding. If a participant is actively bleeding, 
the samples for incremental recovery will be postponed until the sample can be done after a 
prophylactic dose. 
The exact sampling times before and after infusion and the dose administered will be 
documented in the CRF. Incremental recovery of Jivi is determined by measuring FVIII 
activity with a validated assay for FVIII.  

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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.  
All samples will be processed in the investigator’s local laboratory. Plasma concentrations of 
FVIII will be measured using a validated FVIII activity assay. 
Recoveries should be performed using the participants assigned treatment dose, rounded to 
full vial size. 
At Month 3 (72 hours after the previous infusion), FVIII levels will be measured for all 
participants for the WAPPS-Hemo PK analysis. For participants on the twice weekly 
regimen, this will also serve as 1 of 2 trough level measurements (i.e. Day 3 of 2x/week 
regimen). At Month 6 [EOS]), samples for trough levels will be collected just prior to the 
scheduled infusion for all participants in alignment with the prophylaxis regimen (i.e. at 
Day 4 for 2x/week regimen, at Day 5 for Q5D regimen, and at Day 7 for less frequent 
regimens). 
8.5.2 
Web-Accessible Population Pharmacokinetic Service-Hemophilia 
(WAPPS-Hemo) Analysis  
The WAPPS-Hemo database will be used to assess sources of variability between 
participants’ PK data and clinical risk scores. WAPPS-Hemo is a centralized, dedicated, 
actively moderated database run by the Health Information Research Unit at McMaster 
University that allows participating hemophilia treatment sites to input FVIII data from 
sparse samples and receive individual PK estimates. These estimates are generated by an 
automated proprietary population PK engine and are then manually validated.  
The WAPPS-Hemo analysis will be performed at the end of Visit 5 (Month 3). Each study 
site investigator will register in WAPPS-Hemo database 
(https://www.wapps-hemo.org/UserRegistration.aspx), if not already registered. Once a site is 
registered, the investigator will enter the required participant details (gender, date of birth, 
baseline factor level, blood group, and positive history of inhibitors). The investigator will 
then enter infusion data at least 3 time points post-infusion (with or without pre-infusion 
levels), as specified in the SoA (Section 1.3). The investigator will be required to input the 
following data for each infusion: weight, height, dose and type of factor administered (as total 
and IU/kg), and infusion duration. If available, hematocrit, hemoglobin, serum creatinine, 
vWF measurements, and laboratory methods used to measure FVIII will also be entered. 
Data entered will be cleaned by WAPPS-Hemo PK experts. Duplicate submissions will be 
removed, and all original data that was duplicated from merged infusions will be deleted. 
Any data not valid for modelling, such as user input errors, insufficient data, or conditions 
that exclude use of participant data will be removed and excluded from analysis. The dataset 
will be analyzed to search for outliers. Input errors missed at the source will be corrected 
where the incorrect measurement has been used (i.e. weight, height). 
The investigator will then request extraction of the following from the database: predicted 
post-infusion measurement of plasma factor activity level on Day 0 (Day of Infusion) up to 
Day 8, estimated terminal half-life, and time to 0.01, 0.02, 0.05, 0.1, and 0.2 IU/mL (with 
their credibility intervals), FVIII trough level (2 measures for participants with 2x/week 
regimen), AUC, clearance, and predicted peak factor value. Once extracted, the data will be 
stored in the participant’s medical record and entered into the electronic CRF. 

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8.6 
Pharmacodynamics 
Pharmacodynamics parameters are not evaluated in this study. 
8.7 
Genetics 
Genetics parameters are not evaluated in this study. 
8.8 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.9 
Other Investigations 
Investigations related to the mode of action or the safety of Jivi and similar drugs may be 
performed. The same applies to further investigations deemed relevant to hematologic 
diseases and associated health problems. Examples of these investigations include diagnostic, 
safety, pharmacodynamics, monitoring, or potentially predictive biomarkers. 
Results from any additional investigations may be reported separately. 
8.10 
Medical Resource Utilization and Health Economics  
Medical Resource Utilization and Health Economics data, associated with medical 
encounters, will be collected by the investigator and study site personnel for all participants 
throughout the study. Protocol-mandated procedures, tests, and encounters are excluded.  
The data collected may be used to conduct exploratory economic analyses and will include: 
• Number and duration of medical care encounters, including surgeries, and other 
selected procedures (inpatient and outpatient) 
• Duration of hospitalization (total days or length of stay, including duration by wards 
[e.g. intensive care unit]) 
• Number and type of diagnostic and therapeutic tests and procedures 
• Outpatient medical encounters and interventions (including physician or emergency 
room visits, tests and procedures, and medications). 
9. 
Statistical Considerations  
9.1 
Statistical Hypotheses 
The study is not designed to test any predefined hypothesis. All analyses will be descriptive 
or exploratory. 
9.2 
Sample Size Determination  
The primary endpoint is the occurrence of favorable outcome on the score selected dosing 
regimen, which will be described via the proportion of participants with a favorable outcome. 
The target sample size for this study is based on feasibility. It is expected that a minimum of 
20-25 participants will be enrolled. The precisions, in terms of the width of the 95% 
confidence intervals (CIs), for different sample sizes and proportions of participants with a 
favorable outcome are shown in Table 9-1. 

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Table 9–1: Expected Precision of Estimates by Sample Size and Assumed Proportion of 
Participants with Favorable Outcome 
N 
Assumed true 
proportion of 
participants with 
favorable outcome 
Expected observed 
proportion of 
participants with 
favorable outcome 
95% CI, % 
Width of CI, 
% 
15 
65% 
  9/15 = 60% 
[32.3; 83.7] 
51.4 
70% 
10/15 = 67% 
[38.4; 88.2] 
49.8 
75% 
11/15 = 73% 
[44.9; 92.2] 
47.3 
80% 
12/15 = 80% 
[51.9; 95.7] 
43.8 
85% 
12/15 = 80% 
[51.9; 95.7] 
43.8 
90% 
13/15 = 87% 
[59.5; 98.3] 
38.8 
20 
65% 
13/20 = 65% 
[40.8; 84.6] 
43.8 
70% 
14/20 = 70% 
[45.7; 88.1] 
42.4 
75% 
15/20 = 75% 
[50.9; 91.3] 
40.4 
80% 
16/20 = 80% 
[56.3; 94.3] 
37.9 
85% 
17/20 =85% 
[62.1; 96.8] 
34.7 
90% 
18/20 = 90% 
[68.3; 98.8] 
30.5 
25 
65% 
16/25 = 64% 
[42.5; 82.0] 
39.5 
70% 
17/25 = 68% 
[46.5; 85.1] 
38.6 
75% 
18/25 = 72% 
[50.6; 87.9] 
37.3 
80% 
20/25 = 80% 
[59.3; 93.2] 
33.9 
85% 
21/25 = 84% 
[63.9; 95.5] 
31.5 
90% 
22/25 = 88% 
[68.8; 97.5] 
28.7 
30 
65% 
19/30 = 63% 
[43.9; 80.1] 
36.2 
70% 
21/30 = 70% 
[50.6; 85.3] 
34.7 
75% 
22/30 = 73% 
[54.1; 87.7] 
33.6 
80% 
24/30 = 80% 
[61.4; 92.3] 
30.9 
85% 
25/30 = 83% 
[65.3; 94.4] 
29.1 
90% 
27/30 = 90% 
[73.5; 97.9] 
24.4 
Abbreviation: CI = confidence interval. 
Exact Clopper-Pearson 95% CIs were calculated. 
When 70% of participants with favorable outcome are observed, a sample size of 
20 participants will produce a two-sided 95% CI with a width of 42.4% (95% CI = 45.7% to 
88.1%). It is acknowledged that the precision of estimates will be low for the anticipated 
sample size range. This will be considered in the interpretation of results. While it may not be 
possible to draw any conclusions based on the reduced sample size, the study may provide 
first hints whether the score could be useful in clinical practice. 
9.3 
Analysis Set 
For the purposes of analysis, the following analysis sets are defined in Table 9–2: 
Table 9–2: Analysis Sets 
Participant Analysis Set 
Description 
Enrolled 
All participants who signed the ICF 
Modified intention-to-treat (mITT) 
set 
All enrolled participants who had received at least 1 dose of 
study intervention, who have infusions/bleeding data from the 
diary and CRF available, and who have been followed for a 
minimum of 4 months 
Safety analysis set 
All participants who had received at least 1 dose of study 
intervention 
Abbreviations: CRF = case report form; ICF = informed consent form. 

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9.4 
Statistical Analyses 
The SAP will be finalized prior to before first participant first visit (FPFV) and will include a 
more technical and detailed description of the statistical analyses described in this section. 
This section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints. 
9.4.1 
General Considerations 
Statistical analyses will be performed using SAS release 9.2 or higher (SAS Institute Inc., 
Cary, North Carolina, United States [US]). The version used will be specified in the SAP.  
All variables will be analyzed descriptively with appropriate statistical methods: categorical 
variables by frequency tables (absolute and relative frequencies) and continuous variables by 
sample statistics (i.e. mean, standard deviation [SD], minimum, median, quartiles, and 
maximum). Continuous variables will be described by absolute value and as change from 
baseline per analysis time point, if applicable.  
All endpoints will be analyzed according to the modified intention-to-treat (mITT). The 
entire study period will be analyzed regardless of the regimen. 
Some tables will be stratified by the risk score-selected dosing regimen. Additionally, some 
selected tables (including the primary endpoint, safety events, study intervention 
administration, prophylaxis regimen, and PK parameters) will be presented in total and by 
subgroup of history of FVIII inhibitors for sensitivity purposes. 
In general, missing clinical outcomes collected in this study will not be imputed. Missing 
exposure and AE/concomitant medication start/end date will be imputed based on a 
worst-case scenario. 
Baseline is defined as time point of enrollment into study. The participant total risk score will 
be calculated at baseline and the resulting prophylaxis regimen will be assigned as describe in 
Section 4.1. 
9.4.2 
Primary Endpoint 
The analysis of the primary endpoint will be performed on the mITT population. The entire 
study treatment period will be analyzed regardless of the dosing regimen. 
The proportion and 95% CI of participants with favorable outcome on the risk score-selected 
prophylaxis regimen will be described. The proportion will be provided overall, as well as by 
assigned prophylaxis regimen.  
Favorable outcome is defined as no change of the score-assigned dosing regimen with one of 
the following intra-individual measures: 
o improved ABR and decreased frequency of administration. 
o improved ABR with similar frequency of administration. 
o decreased frequency of administration and similar ABR. 
Definitions 
• No regimen change during study: participant is treated according to the score-
assigned regimen and does not deviate or switch frequency. 
• Improved ABR: Reduction from pre-study ABR is ≥ 1. 
• Similar ABR: Absolute change from pre-study ABR is < 1. 

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• Worse ABR: Increase from pre-study ABR is ≥ 1. 
• Decreased frequency of administration: Reduction from pre-study in number of 
infusions per month is ≥ 2. 
• Similar frequency of administration: Absolute change from pre-study in number of 
infusions per month < 2. 
• Worse frequency of administration: Increase from pre-study in number of infusions 
per month is ≥ 2. 
Pre-study ABR and treatment frequency is based on data from a minimum of 6 continuous 
months (up to a maximum of 12 months) of stable SHL prophylaxis at any given time within 
the 12 months prior to screening. Stable SHL prophylaxis is defined as a minimum of 18 
weeks of treatment in a 6 (consecutive) calendar month period in the 12 months prior to the 
screening visit. 
A switch to a higher frequency regimen due to a bleed during study is considered as non-
favorable outcome, whereas participants who switch due to other reasons (e.g. personal 
decision, study compliance issues, or changes in physical activity level) will be censored at 
time of switch.  
The number (frequency) of participants switching the risk score-selected dosing regimen will 
be summarized. 
As sensitivity analyses, the proportion of participants with favorable outcome on the risk 
score-selected prophylaxis regimen will be presented by inhibitor history. 
9.4.3 
Secondary Endpoints 
The components of the primary endpoint, ABR (total, joint, spontaneous) and frequency of 
administration (infusions/month), will be presented via summary statistics and will be 
presented overall only. Values for the study period and intra-individual change from 
pre-study value will be presented for total ABR and frequency of administration (see 
Section 9.4.2 for full definition). In addition, the proportion and 95% CIs of participants with 
improved/similar/worse value of total ABR and frequency of administration will be provided. 
The other secondary objectives will be demonstrated by the following endpoints: 
• Proportion of participants with 0 and ≤ 1 spontaneous bleeds 
o Frequency tables will be provided for the proportion and 95% CIs of participants 
with 0, ≤ 1, and > 1 spontaneous bleeds. 
• PROs 
o PRO data will be summarized by presenting descriptive statistics during the study 
and as change from baseline to EOS. The questionnaires are summarized in 
Section 8.2.2. 
• Joint status assessment 
o The number and location of affected target joints (per ISTH; see Section 8.1.3) at 
baseline and at EOS will be summarized descriptively. The change from baseline 
in the number of affected joints will be evaluated at EOS. 
Other pre-specified exploratory endpoints will be described in the SAP finalized 
before FPFV.  

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9.4.4 
Safety Analyses 
All safety analyses will be performed on the Safety Population and will be presented overall 
and stratified by FVIII inhibitor history. 
Adverse events will be reported using the latest version of the Medical Dictionary for 
Regulatory Affairs (MedDRA). 
Individual listings of AEs will be provided which will include any information on history of 
FVIII inhibitors. 
9.4.4.1 
Immunogenicity 
Inhibitor development will be summarized by time point and presented in participant listings. 
The purpose of the listing is to delineate the clinical factors which may be positively 
associated with development of the inhibitor. Confirmation of positive inhibitor titers 
(Bethesda assay, as per local clinical practice, ≥ 0.6 BU/mL) will require repeat 
measurement. If the repeated inhibitor result is < 0.6 BU 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. 
9.4.4.2 
Pharmacokinetics 
PK parameters will be analyzed via descriptive statistics (e.g. mean, standard deviation, 
minimum, median, and maximum) and will be presented overall as well as by FVIII inhibitor 
history. Details will be provided within the SAP. 
9.4.5 
Other Analyses 
9.4.5.1 
Disposition of participants 
The number and percentage of participants screened, assigned to treatment, and treated will 
be presented by score-assigned prophylaxis regimen and overall. The reasons for participants 
discontinuing from treatment will be summarized by score-assigned prophylaxis regimen. In 
addition, the number of participants screened and included in each analysis population will be 
displayed overall and by investigator. 
9.4.5.2 
Demographics and other baseline characteristics 
Summary statistics (arithmetic mean, SD, median, minimum, and maximum) will be 
presented for quantitative variables by score-assigned prophylaxis regimen. Frequency tables 
for qualitative data will be provided. The summaries will be provided for both mITT and 
Safety analysis set. 
Medical history findings will be summarized using the latest version of MedDRA terms by 
prophylaxis dosing regimen for the mITT analysis set. 
9.5 
Interim Analysis 
Not applicable. 
10. 
Tokenization (United States Participants Only) 
Participation in tokenization is optional and those who decline to participate in tokenization 
will still be able to join the clinical study. 

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Data linkage with real-world data 
Data linkage using de-identified data provides the opportunity to connect clinical trial data to 
real-world data (e.g. claims, electronic health records, laboratory results, pharmacy, etc.) at 
the participant level without compromising the privacy of trial participants. Dedicated 
software will be used to encrypt the original participant identification information into a new 
de-identified key (i.e. a “token”) that is unique to each participant (Appendix 8, Figure A). 
Third -party entities will create the encrypted tokens and verify privacy compliance.  
No additional compensation will be provided to participants for participating in tokenization 
and linking of their data. Participants would still receive compensation for their participation 
in the clinical study. 
Benefits 
Participants’ de-identified data could be linked to and/or combined with real-world datasets 
for research purposes within the scope of this clinical study or subsequent future medical 
research uses (e.g. retrospective analyses, long-term follow-up, or healthcare resource 
utilization studies) (Appendix 8, Figures B and C). 
This may decrease the need for follow-up studies and also expedite future results. Ultimately, 
the accelerated time will benefit patients awaiting the development of treatments and ensure 
sponsors can more readily investigate benefits and risks.  
Additionally, by linking tokenized clinical trial data with real-world data, a more 
comprehensive picture of a participant’s medical history will be available to researchers, 
further improving future patient experience. 
Risks 
The encryption process for tokenization will be performed by sites and will occur without the 
sponsor’s involvement. Furthermore, the sponsor has no access to participant identifiable 
information. A third-party will verify that de-identified data cannot be traced back to the 
original participant identifiable information. Therefore, the tokenization process will not 
increase loss of confidentiality risk. The sponsor will handle de-identified participant 
protected health information in a confidential manner with reasonable security measures, as 
required by key data protection regulation and in accordance with national/local data 
protection laws. However, as with any de-identified study, there exists a minimal potential 
loss of confidentiality risk.  
Informed consent process 
At the time a participant is screened for enrollment into the clinical study, he or she can opt-
in via the additional consent language for tokenization for the linking of their clinical trial 
data. No additional study procedures beyond what is outlined in the clinical study protocol 
would be completed as result of his or her participation in the trial. Participation in 
tokenization is optional and participants who decline to participate in tokenization will still be 
able to join the clinical study. Non-participation in tokenization will not affect the study or 
the clinical care of the participants (Appendix 8, Figure D). A participant’s tokenized data 
will be available for linking to other future data indefinitely or until they withdraw their 
consent for future data linking. If a participant chooses to withdraw their tokenized data from 
future data linking, he or she can access the trial tokenization portal or contact the study site 
at the phone number (provided in the ICF). A participant can locate his or her PID 
information (found on the cover page of the ICF), and state that they would like to withdraw 

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their consent for future use of their clinical trial data (i.e. future linking). Note that any of the 
participant’s data that has been linked prior to the withdrawal of their consent for re-use will 
remain linked. Once the participant withdraws consent for the re-use of their data, no further 
data links will be created. 
 
 

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11. 
Supporting Documentation and Operational Considerations 
11.1 
Appendix 1: Regulatory, Ethical, and Study Oversight Considerations 
11.1.1 
Regulatory and Ethical Considerations 
• The protocol, protocol amendments, ICF, informed assent form, approved prescribing 
information, and other relevant documents (e.g. advertisements) must be submitted to 
an IRB by the investigator and reviewed and approved by the IRB before the study is 
initiated.  
• Any amendments to the protocol will require IRB 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 annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB 
• 
Notifying the IRB of SAEs or other significant safety findings as required by 
IRB procedures 
• 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR) 50, International 
Council for Harmonisation (ICH) guidelines, the IRB, and all other applicable 
local regulations 
• 
Reporting cases of suspected child abuse and/or neglect according to local 
regulations including local medical association (e.g. American Academy of 
Pediatrics, European Union [EU] Academy of Pediatrics), or Health Department 
guidelines. 
11.1.2 
Financial Disclosure 
Investigators and sub-investigators directly involved in the treatment or evaluation of study 
participants will provide the sponsor with sufficient, accurate financial information as 
requested to allow the sponsor to submit complete and accurate financial certification or 
disclosure statements to the appropriate regulatory authorities. Investigators are responsible 
for providing information on financial interests during the course of the study and for 1 year 
after completion of the study. 
11.1.3 
Informed Consent and Pediatric Participant Assent Process 
• The investigator or his/her representative will explain the nature of the study to the 
participants (and parent[s] or legal guardian) and answer all questions regarding the 
study, based on the patient informed consent. The patient informed consent and assent 
forms will contain all relevant information on the study.  
• The investigator, or a person designated by the investigator, will provide the 
participant and/or legal guardian (refer to Appendix 9: Abbreviations and Definitions) 
with the written ICF and the pediatric participant with the assent if applicable. They 
must be informed that participation is voluntary. The participant and/or legal guardian 
will be required to sign written consent, and the participant if applicable will be 
required to sign written assent, that meets the requirements of 21 CFR 50, local 
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(HIPAA) requirements, where applicable, and the IRB or study center after the nature 
of the study has been fully explained and before performance of any study-related 
activity. 
• Assent requirements for pediatric participants may vary across regions; local 
regulations should be followed as appropriate. 
• The medical record must include a statement that written informed consent (and 
written informed assent for pediatric participants) was obtained before the participant 
was enrolled in the study and the date the written consent (and assent) was obtained. 
The authorized person obtaining the informed consent (and assent) must also sign the 
ICF. 
• Participants (and parent[s] or legal guardian) must be reconsented to the most current 
version of the ICF(s) during their participation in the study.  
• Minor participants who assent to a study and later withdraw that assent should not be 
maintained in the study against their will, even if their legal guardian still wants them 
to participate. 
• Minor participants must be reconsented if they reach the age of majority during the 
course of the study to continue participating. 
• As appropriate, pediatric participants may be given the opportunity to meet privately 
with a member of the site staff to ask confidential questions and to decline assent for 
confidential reasons, which, at their request, would not be shared with their legal 
guardian, unless required by local law. 
• A copy of the consent forms and assent forms must be provided to the participant (and 
parent[s] or legal guardian).  
11.1.4 
Data Protection 
• Participants will be assigned a unique identifier by the sponsor. Any participant 
records or datasets that are transferred to the sponsor will contain the identifier only; 
participant names or any information which would make the participant identifiable 
will not be transferred.  
• The participant must be informed that his/her personal study-related data will be used 
by the sponsor in accordance with local data protection law. The level of disclosure 
must also be explained to the participant.  
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB members, and by inspectors from regulatory authorities.  
11.1.5 
Committees Structure 
A Data Monitoring Committee will not be used. 
11.1.6 
Dissemination of Clinical Study Data 
Result Summaries of Bayer's sponsored clinical studies in drug development Phases 2, 3, and 
4 and Phase 1 studies in patients are provided in the Bayer Trial Finder application after 
marketing authorization approval in line with the position of the global pharmaceutical 
industry associations laid down in the "Joint Position on the Disclosure of Clinical Trial 
Information via Clinical Trial Registries and Databases". In addition, results of clinical drug 

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studies will be provided on the publicly funded website www.ClinicalTrials.gov in line with 
the applicable regulations. 
Bayer commits to sharing, upon request from qualified scientific and medical researchers, 
patient-level clinical study data, study-level clinical study data, and protocols from clinical 
studies in patients for medicines and indications approved in the US and EU on or after 
January 01, 2014 as necessary for conducting legitimate research.  
All Bayer-sponsored clinical studies are considered for publication in the scientific literature 
irrespective of whether the results of the clinical studies are positive or negative. 
11.1.7 
Data Quality Assurance 
• All participant data relating to the study will be recorded on electronic CRFs unless 
transmitted to the sponsor or designee electronically (e.g. laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.  
• 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 review, and 
regulatory agency inspections and provide direct access to source data documents.  
• Monitoring details describing strategy (e.g. risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical 
Risk -Based Monitoring), methods, responsibilities and requirements, including 
handling of noncompliance issues and monitoring techniques (central, remote, or 
on-site monitoring) are provided in the Monitoring Plan. 
• The sponsor or designee is responsible for the data management of this study 
including quality checking of the data.  
• The sponsor assumes accountability for actions delegated to other individuals (e.g. 
Contract Research Organizations). 
• Study monitors will perform ongoing source data verification to confirm that data 
entered into the CRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.  
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may 
be destroyed during the retention period without the written approval of the sponsor. 
No records may be transferred to another location or party without written notification 
to the sponsor.  

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11.1.8 
Source Documents 
• Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected. Source documents are filed at the 
investigator’s site. 
• Data reported in the eCRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, 
depending on the study. Also, current medical records must be available. 
• Definition of what constitutes source data can be found in a source document 
checklist. 
11.1.9 
Study and Site Start and Closure 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed. 
The investigator may initiate study site closure at any time, provided there is reasonable 
cause and sufficient notice is given in advance of the intended termination. 
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 or local health authorities, the sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the investigator 
11.1.10 
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. 
 
 

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11.2 
Appendix 2: Patient Reported Outcomes 

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11.2.1 
Haemophilia specific quality of life questionnaires (Haem-A-QoL and 
Haemo-QoL) 
 
 

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11.2.2 
Patient’s Global Impression of Change (PGI-C)

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11.2.3 
Five-Level European Quality of Life Five Dimension (EQ-5D-5L) 
 
 

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Health Questionnaire 
 
 
English version for the USA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Under each heading, please check the ONE box that best describes your health 
TODAY. 
  
 
MOBILITY 
 
I have no problems walking 
 
I have slight problems walking 
 
I have moderate problems walking 
 
I have severe problems walking 
 
I am unable to walk 
 
SELF-CARE 
 
I have no problems washing or dressing myself 
 
I have slight problems washing or dressing myself 
 
I have moderate problems washing or dressing myself 
 
I have severe problems washing or dressing myself 
 
I am unable to wash or dress myself 
 
USUAL ACTIVITIES (e.g. work, study, housework, family or leisure 
activities) 
 
I have no problems doing my usual activities 
 
I have slight problems doing my usual activities 
 
I have moderate problems doing my usual activities 
 
I have severe problems doing my usual activities 
 
I am unable to do my usual activities 
 
PAIN / DISCOMFORT 
 
I have no pain or discomfort 
 
I have slight pain or discomfort 
 
I have moderate pain or discomfort 
 
I have severe pain or discomfort 
 
I have extreme pain or discomfort 
 
ANXIETY / DEPRESSION 
 
I am not anxious or depressed 
 
I am slightly anxious or depressed 
 
I am moderately anxious or depressed 
 
I am severely anxious or depressed 
 
I am extremely anxious or depressed 
 

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The worst health 
you can imagine 
 
 
 
 
 
 
 
 
 
 
 
 
• We would like to know how good or bad your health is 
TODAY. 
• This scale is numbered from 0 to 100. 
• 100 means the best health you can imagine. 
0 means the worst health you can imagine. 
• Mark an X on the scale to indicate how your health is 
TODAY. 
• Now, please write the number you marked on the 
scale in the box below. 
The best health 
you can imagine 
YOUR HEALTH TODAY = 
10
0 
20
30
40
50
60
80
70
90
100 
5 
15
25
35
45
55
75
65
85
95

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11.2.4 
Treatment Satisfaction Questionnaire for Medication (TSQM) 

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11.2.5 
Work Productivity and Activity Impairment (WPAI) Questionnaire 

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11.3 
Appendix 3: Clinical Laboratory Tests 
•
The tests detailed in Table 11-1 will be performed by the local laboratory.
•
All laboratory analyses will be performed at local laboratories according to local
standards.
•
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 locally or centrally as
needed.
Table 11–1: Protocol-required Laboratory Tests 
Laboratory 
Assessments 
Parameters 
Hematology 
von Willebrand Factor antigen 
Complete blood count (platelets) 
Other 
Laboratory 
Tests 
Pregnancy: Highly sensitive serum pregnancy test (as needed for WOCBP) 
Serology: HIV antibody for screening purpose only, if not available in 
medical records 
CD4+ lymphocyte count: For HIV positive participants only, if not available 
in medical records 
FVIII inhibitor by Bethesda assay as per local clinical practice 
FVIII level by validated one-stage or chromogenic assay 
Abbreviations: CD4+ = cluster of differentiation 4; FVIII = human coagulation factor VIII; 
HIV = human immunodeficiency virus; WOCBP = women of childbearing potential 
Note: All routine study-required laboratory assessments will be performed by the local 
laboratory. 
Investigators must document their review of each laboratory safety report. 

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11.4 
Appendix 4: AEs and SAEs: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting 
11.4.1 
Definition of AE 
Adverse Event (AE) Definition 
• An AE is any untoward medical occurrence in a clinical study participant, 
associated with the use of study intervention, whether or not considered related to 
the study intervention. 
• 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) or other safety assessments 
(e.g. 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/serious AE (SAE) unless it is an intentional overdose taken 
with possible suicidal/self-harming intent. Such overdoses should be reported 
regardless of sequelae. 
• The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE. 
“Lack of efficacy” or “failure of expected pharmacological action” also 
constitutes an AE or SAE. 
 
Events NOT Meeting the AE Definition  
• 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. 

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• 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 effectiveness. However, if the bleed 
fulfills the criterion for an SAE (e.g. results in hospitalization), then the event 
should be recorded and reported as an SAE. 
11.4.2 
Definition of SAE 
An SAE is defined as any AE 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 admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any 
other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the AE should be considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d. 
Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g. sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
• Medical or scientific judgment should be exercised by the investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant 
medical events that may jeopardize the participant or may require medical or 
surgical intervention to prevent 1 of the other outcomes listed in the above 
definition. These events should usually be considered serious. 

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• Examples of such events include invasive or malignant cancers, intensive 
treatment for allergic bronchospasm, blood dyscrasias, convulsions, or 
development of intervention dependency or intervention abuse. 
11.4.3 
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. 
• It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Study Monitor/Medical Monitor (Study Medical Expert) in lieu 
of completion of the AE/SAE CRF/required form. 
• There may be instances when copies of medical records for certain cases are 
requested by the sponsor. In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the 
medical records before submission to the sponsor. 
• The investigator will attempt to establish a diagnosis of the event based on 
signs, symptoms, and/or other clinical information. Whenever possible, the 
diagnosis (not the individual signs/symptoms) will be documented as the 
AE/SAE. 
Assessment of Intensity 
• The investigator will make an assessment of intensity for each AE and SAE 
reported during the study and assign it to 1 of the following categories:  
• Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort to interfere 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; 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. 

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Assessment of Causality 
• The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE/SAE. 
• A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• The investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The investigator will also consult the Investigator’s Brochure and/or Product 
Information, for marketed products, in his/her assessment. 
• For each AE/SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor. However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the sponsor. 
• The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment. 
• The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
Follow-up of AEs and SAEs 
• The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other HCPs. 
• New or updated information will be recorded in the originally submitted 
documents. 
• The investigator will submit any updated SAE data to the sponsor within 24 hours 
of receipt of the information. 
11.4.4 
Reporting of SAEs 
SAE Reporting to the Sponsor via an Electronic Data Collection Tool 
• The primary mechanism for reporting an SAE to the sponsor will be the electronic 
data collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data 
transmission (see next section) to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes 
available. 

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• After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives 
updated data on a previously reported SAE after the electronic data collection tool 
has been taken off-line, then the site can report this information on a paper SAE 
form (see next section) or to the sponsor’s Medical Monitor (Study Medical 
Expert) by telephone. 
• Contacts for SAE reporting can be found in the Investigator Site File. 
 
SAE Reporting to the Sponsor via Paper Data Collection Tool 
• Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the sponsor’s Medical Monitor (Study Medical Expert). 
• In rare circumstances and if email transmission is not feasible, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service. 
• Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE data collection tool within the designated reporting 
time frames. 
• Contacts for SAE reporting can be found in the Investigator Site File. 
 
 

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11.5 
Appendix 5: Medical Device AEs, SAEs, and Device Deficiencies: 
Definitions and Procedures for Recording, Evaluating, Follow-up, and 
Reporting 
• Both the investigator and the sponsor will comply with all local reporting 
requirements for medical devices. 
• The detection and documentation procedures described in this protocol apply to all 
sponsor medical devices provided for use in the study. See Section 6.1.1 for the list of 
sponsor medical devices. 

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11.5.1 
Definition of Medical Device AE 
Medical Device AE  
• An AE is any untoward medical occurrence in a clinical study participant, users, or 
other persons, temporally associated with the use of study intervention, whether or 
not considered related to the medical device provided by the study sponsor. An AE 
can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of the medical device. This definition includes events 
related to the investigational medical device and events related to the procedures 
involved. 
11.5.2 
Definition of Medical Device SAE 
A medical device SAE is any SAE that: 
a. Led to death  
b. Led to serious deterioration in the health of the participant, that either resulted in: 
• A life-threatening illness or injury. The term ‘life-threatening’ in the definition 
of ‘serious’ refers to an event in which the participant was at risk of death at 
the time of the event. It does not refer to an event, which hypothetically might 
have caused death, if it were more severe. 
• A permanent impairment of a body structure or a body function. 
• Inpatient or prolonged hospitalization, planned hospitalization for a pre-
existing condition, or a procedure required by the protocol, without serious 
deterioration in health, is not considered an SAE. 
• Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function. 
• Chronic disease (EU Medical Device Regulation 2017/745). 
c. Led to fetal distress, fetal death or a congenital abnormality or birth defect  
11.5.3 
Definition of Device Deficiency 
Device Deficiency Definition 
• A device deficiency is an inadequacy of a medical device with respect to its 
identity, quality, durability, reliability, safety, or performance. Device 
deficiencies include malfunctions, use errors, and inadequacy of the 
information supplied by the manufacturer. 
11.5.4 
Recording and Follow-up of Medical Device AEs/SAEs/Device 
Deficiencies 
Assessment of Intensity 

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The investigator will make an assessment of intensity for each AE/SAE/device 
deficiency reported during the study and assign it to one of the following categories:  
• Mild: Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
• Moderate: Minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental Activities of Daily Living (ADL). Instrumental 
ADL refers to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc. 
• Severe: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling, limiting 
self-care ADL. Self-care ADL refers to bathing, dressing and undressing, feeding 
self, using the toilet, taking medications, and not bedridden. 
Assessment of Causality 
The investigator will provide a preliminary assessment of the relationship between the 
event and the medical devices listed in Section 6.1.1. 
Follow-up of AE/SAE/Device Deficiency 
• The investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations as medically indicated or as 
requested by the sponsor to elucidate the nature and/or causality of the 
AE/SAE/device deficiency as fully as possible. This may include additional 
laboratory tests or investigations, histopathological examinations, or consultation 
with other HCPs. 
• If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide the sponsor with a copy of any 
postmortem findings including histopathology. 
• New or updated information will be recorded in the originally completed form. 
The investigator will submit any updated SAE data to the sponsor within 24 hours of 
receipt of the information. 
 
11.5.5 
Reporting of AEs/SAEs Related to the Device 
• For any SAE that was assessed as device-related: the investigator should 
manually complete the Medical Device Incident form and electronically complete 
the complementary SAE page in RAVE. The Medical Device Incident form will 
be sent to the sponsor via email at PV.caseprocessing@bayer.com within 24 
hours. 
• For any AE that was assessed as device-related: the investigator should manually 
complete the Medical Device Incident form and electronically complete the 
complementary AE page in RAVE. The Medical Device Incident form will be 
sent to the sponsor via email at PV.caseprocessing@bayer.com within 24 hours. 

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• If the device deficiencies could potentially lead to the death or serious 
deterioration of health (serious injury) of the study pa or others (e.g. staff), 
manually complete the Medical Device Incident form only and send it to the 
sponsor via email at PV.caseprocessing@bayer.com within 24 hours. 
For any AE or SAE that occurred in a person other than the study participant, the 
investigator should manually complete the Medical Device Incident form only 
and send it to the sponsor via email at PV.caseprocessing@bayer.com within 
24 hours. 
 
 

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11.6 
Appendix 6: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below). 
If fertility is unclear (e.g. amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before first dose of study intervention, additional evaluation should be 
considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the 
above, (e.g. mullerian agenesis, androgen insensitivity), investigator discretion should be 
applied to determine study entry. 
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
o A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with more 
than one FSH measurement is required.  
• Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
Contraception Guidance: 
WOCBP can only be included in the study if a pregnancy test is negative at the screening 
visit and if they agree to use adequate contraception during the study period until 8 weeks 
after last study intervention. Adequate contraception is defined as any combination of at least 
2 effective methods of birth control, of which at least 1 is a physical barrier (e.g. condoms 
with hormonal contraception or implants or combined oral contraceptives, certain intrauterine 
devices).  
For nulliparous adolescent participants, LARC methods are considered first-line options. 

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Collection of pregnancy information for female participants who become pregnant: 
• The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the sponsor within 24 hours of 
learning of a participant's pregnancy.  
• The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and 
the information will be forwarded to the sponsor. Generally, follow-up will not be 
required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or serious AE (SAE), any 
pregnancy complication or elective termination of a pregnancy for medical reasons 
will be reported as an AE or SAE.  
• A spontaneous abortion (occurring at < 22 weeks’ gestational age) or still birth 
(occurring at > 22 weeks’ gestational age) is always considered to be an SAE and will 
be reported as such. 
• Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 8.4.4. While the investigator is not obligated to actively seek this information 
in former study participants, he or she may learn of an SAE through spontaneous 
reporting.  
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention and be withdrawn from the study after completing 
early withdrawal visit. 
 
 

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11.7 
Appendix 7: Visit Description 
11.7.1 
Visit 1 – Screening (Up to 30 Days Prior to Baseline) 
Screening may take place over multiple site visits. At the screening visit, the following 
procedures and assessments will be performed: 
• Obtain signed informed consent (and assent) from participant and parent(s) or legal 
guardian(s), as necessary. 
Note: No screening procedures should be performed unless written informed consent 
(and assent) has been obtained. 
• Allocation of a unique participant number. 
• Review of eligibility requirements; no participant should receive study intervention 
unless all inclusion and no exclusion criteria are met as listed in Section 5.1 and 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 (age, sex, race, ethnicity) as well as blood type and weight. 
• Collect information on previous hemophilia treatment. 
• Obtain a complete medical and surgical history (general, disease, family history of 
hemophilia, and history of inhibitor development). 
o 
Specific information on history of hemophilia (date of diagnosis, start of 
prophylaxis, prior and current FVIII products, estimated number of ED, type of 
human coagulation FVIII gene mutation (from history), family history, FVIII 
level and type of assay, family and personal history of past inhibitor formation 
(including date of inhibitor testing, whether immune tolerance induction was 
performed, and recovery and half-life data, if available; Section 1.3), current 
treatment product and regimen, number and type of bleeds in the last 12 months, 
and presence and location of target joints). If available, data on prior 
pharmacokinetics with the participants’ previous FVIII product will be collected 
(e.g. concentration timepoints and half-life). 
• Collect information on previous medication (medication history, including substance 
usage). 
• Concomitant medication review. 
• AE/SAE review 
Note: Only events which are related to protocol-required study procedures will be 
recorded from the signing of the ICF. 
• Blood samples for the following (see details in Table 11-1): 
o 
Pregnancy test (female participants) 
o 
Laboratory evaluation (platelets and von Willebrand factor (vWF): antigen). 
Note: If available in the medical records, vWF antigen testing should have been 
performed within 12 months prior to enrollment 
o 
HIV screening, if not available in medical records 

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o 
CD 4+ cell count (only if participant is HIV positive and if not available in 
medical records) 
o 
Immunogenicity testing (human recombinant factor VIII [rFVIII] inhibitor) 
• Training on use of eDiary and confirm participant access to eDiary 
11.7.2 
Visit 2 – Baseline (Day 1) 
This visit will serve as the Baseline Visit; it will include the first administration of study 
intervention. The Baseline Visit should take place within 30 days after the screening visit. 
This visit should start with the following assessments: 
• Confirmation of eligibility including check of laboratory test results 
Note: Participants must have negative results from the local laboratory for inhibitory 
antibodies against FVIII (< 0.6 BU/mL determined with the Bethesda assay as per 
local clinical practice) 
Thereafter, the following procedures and assessments will be performed and data recorded: 
• Physical examination including height and weight 
• Collect information on physical activity level (medium/high [contact sports]; low 
[non-contact sports]; sedentary). Please see Table 4–1 and Figure 4–1. 
• Assessment of joint status 
• Concomitant medication review 
• AE/SAE/AESI review 
• Administration and completion of PRO questionnaires (Haemophilia Quality of Life 
[Haem-A-QoL or Haemo-QoL], EuroQoL 5 Dimensions [EQ-5D-5L], Treatment 
Satisfaction Questionnaire for Medication [TSQM], and Work Productivity and 
Activity Impairment [WPAI] questionnaires) 
• Blood sample collection before administration of study intervention for incremental 
recovery of Jivi (FVIII levels) 
• Infusion of Jivi at study site 
• Procedures and sample collection after administration of study intervention for 
incremental recovery of Jivi (15 to 30 minutes after end of infusion and at a minimum 
of 4 hours after end of infusion to assess FVIII levels; see Section 8.5.1) 
o In case of any infusion-related AE, vital signs will be collected.  
• Pregnancy test for female participants if visit occurs >14 days after last menstrual 
period 
• Bleeding risk score calculation and prophylaxis regimen selection 
• Dispense study intervention for home infusions 
• Instruction on the treatment regimen to be administered to the participant 
• Check of eDiary entries and bleeding history 

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Begin regular monthly contact between participant and the site to check eDiary 
documentation and review AEs and concomitant medication use until the EOS/Early 
Withdrawal. 
11.7.3 
Visit 3, 4 – (Months 1, 2) 
This visit should take place via telephone. 
• Dose regimen adjustment according to score. At Visit 3 for medium risk participants 
and Visits 3 and 4 for low risk participants 
• At home infusion of Jivi  
• Concomitant medication review 
• AE/SAE/AESI review 
• Check of eDiary entries and bleeding history 
11.7.4 
Visit 5 – (Month 3) 
This in-person visit should take place 72 hours after the last infusion of Jivi. 
• Collect information on physical activity level (medium/high [contact sports]; low 
[non-contact sports]; sedentary) 
• Measurement of weight 
• Blood sample collection 3 days after previous dose for all participants: FVIII (Jivi) 
levels for all participants for Web-accessible Population Pharmacokinetic 
Service-Hemophilia (WAPPS-Hemo) PK analysis. For participants on the 2x/week 
regimen, collected samples will also serve as a trough level measurement. 
• If the PI feels the baseline peak FVIII level at 15-30 minutes or 4-8 hours 
post-infusion at Visit 2 does not seem to be appropriate for the dose infused, then the 
levels should be repeated at Visit 5 and the results also uploaded to WAPPS-Hemo. 
For those patients who do not have appropriate FVIII levels at either Visit 2 or 
Visit 5, the levels should be repeated at Visit 6. 
• Pregnancy test (female participants) 
• Infusion of Jivi at study site (not mandatory)  
• Concomitant medication review 
• AE/SAE review 
• Administration and completion of PRO questionnaire (EQ-5D-5L only) 
• Return used vials, and dispense remainder of study intervention 
• Check of eDiary entries and bleeding history 
11.7.5 
Visit 6 – (Month 6, End of Study/Early Withdrawal) 
This in-person visit should take place in alignment with the weekly prophylaxis regimen (i.e. 
as close as possible to the participant’s next infusion) as follows: on Day 4 for participants on 
the 2x/week regimen, on Day 5 for participants on the Q5D regimen, and on Day 7 for 
participants on less frequent regimens (e.g. Q7D). 

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The following procedures and assessments will be performed in participants at the EOS visit 
or at the time of premature termination: 
• Concomitant medication review 
• AE/SAE/AESI review 
• Physical examination including height and weight 
• Assessment of joint status 
• Collect information on physical activity level (medium/high [contact sports]; low 
[non-contact sports]; sedentary) 
• Blood sample collection before administration of study intervention: FVIII (Jivi) 
trough levels 
o Sample collection on Day 4 for participants on the 2x/week regimen, on Day 5 
for participants on the Q5D regimen, and on Day 7 for participants on less 
frequent regimens (e.g. Q7D) 
• Pregnancy test (female participants) 
• In-hospital infusion of Jivi 
• If the PI feels the baseline peak FVIII level at 15-30 minutes or 4-8 hours 
post-infusion at Visit 2 does not seem to be appropriate for the dose infused, then the 
levels should be repeated at Visit 5 and the results also uploaded to WAPPS-Hemo. 
For those patients who do not have appropriate FVIII levels at either Visit 2 or 
Visit 5, the levels should be repeated at Visit 6. 
• Administration and completion of PROs (Haem-A-QoL or Haemo-QoL, EQ-5D-5L, 
TSQM, WPAI, and Patient’s Global Impression of Change [PGI-C]) 
• Return used and unused vials 
• Check of eDiary entries and bleeding history 
11.7.6 
Visit 7 – (Safety Follow-up; 7 to 14 days after last dose of study 
intervention) 
This visit should take place 7 to 14 days after the last dose of study intervention visit via 
telephone. 
The following procedures and assessments will be performed: 
• Concomitant medication review 
• AE/SAE/AESI review 
 
 

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11.8 
Appendix 8: Tokenization 
Figure A: What is Tokenization 
 
Figure B: Use of De-identified Data in Retrospective and Future Outcomes Analyses
 
PPD

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Figure C: Linking of De-identified Clinical Trial Data 
 
 
 
 
Figure D: Methodology for Initiating Tokenization 
 
The flow chart below presents the steps a participant will undertake after deciding whether to 
consent to tokenization. 
 
 
 
 

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Tokenization Frequently Asked Questions 
For conversations between health care providers and potential study participants 
1) What is Tokenization? 
Tokenization is the process of transforming sensitive personal data, such as 
participant identifiable information, into non-sensitive data (tokens) whereby 
information cannot be connected back to the participant. Each participant record is 
converted into a token, which is like a secret code that retains these records (e.g., 
gender, birth year, disease state, etc.) without revealing any information about the 
participant’s identity. 
2) What is the purpose of Tokenization? 
Every time a participant is in contact with a healthcare entity, some information on 
that participant is retained by healthcare systems. Each healthcare entity (including 
insurance companies) is using different ways of storing this data. Tokenization will 
help to bundle all the different pieces of information, without identifying the 
participant. 
As a result, researchers who use datasets from different sources have no common way 
to connect participant level data from these sources together to understand the full 
participant healthcare journey. Tokenization will allow us to connect the fragmented 
data without identifying the participant. 
3) What are the benefits of Tokenization? 
Tokenization allows investigators to connect participant data from the multiple studies 
in which they may have participated. This means that the information is not just 
reflecting a snapshot in time but rather over time. 
4) How is participant privacy maintained? 
Each token or participant code is encrypted (coded to prevent hacking) which helps 
retain essential information (e.g. gender, birth year, disease state, etc.) but does not 
contain traceable information about the participant. This allows for participant 
information to be connected from different sources while maintaining the participant’s 
privacy. 
5) How does HIPAA impact Tokenization? 
In the US, the HIPAA Privacy Rule establishes national standards to protect 
individuals' medical records and other individually identifiable health information 
(collectively defined as “protected health information”) This is covered under federal 
regulation known as Code of Federal Regulations (CFR). Tokenization is also under 
the same CFR and as such all information used in tokenization is protected. If there is 
no way health information can identify an individual participant, then the Privacy 
Rule does not restrict the use or disclosure of the de-identified health information by 
covered health entities 
6) In which Countries is Tokenization used? 
Currently, tokenization is only used in the US, and conducted by select health 
information technology companies (vendors) such as Datavant, HealthVerity, and 
Synoma. 

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7) How is a Token created? 
The few authorized vendors use a special software which is installed, at the study site. 
The participant information is then transformed into tokens/codes that are unique to 
each participant but common across different health entities with information about 
the same participant. A third-party technology company not associated with Bayer or 
other healthcare providers, verifies, and ensures that these tokens cannot be reversed 
to reveal the identity of the participant. 
8) Will I be declined to participate in this study if I do not consent to this? 
A patient’s participation in a study is not dependent on their consent to tokenization. 
A participant who declines to take part in the tokenization but who is otherwise 
qualified for the study, is still allowed to take part in the study. Therefore, the format 
of this consent is specifically an opt-in consent that is included in the main ICF. This 
is similar to a consent you might receive from a biobank to store tissue (e.g., tumor 
tissue) for potential future research use. 
9) Do I get paid to participate in Tokenization? 
You will not be paid to participate in tokenization. 
10) If I participate in multiple studies will my data be tracked? 
Every time you participate in a new study, a new tokenization consent form will be 
used. Data across studies cannot lead back to you as a person. 
11) Will my health data be supplied to insurance companies or Federal agencies? 
Data privacy is maintained at all times. Your data does not lead back to you as a 
person. However, combined de-identified data can be part of submission packages to 
regulatory (Federal) agencies. 
12) Can I be denied insurance or claims if I participate in Tokenization? 
Tokenization contains de-identified participant-specific data, which cannot be 
connected to the participant and therefore, there is no ability for an insurance 
company to deny a claim based on tokenized data. 
13) What happens if I withdraw consent? 
Participants are allowed to withdraw their consent for tokenization at any point in the 
study. When withdrawal happens, this will prevent further connecting of their 
information to the study but maintains previously collected data. 
Also, withdrawing consent for tokenization does not prevent you from continuing in 
the PREDICT study. 
14) Will my data still be used if I withdraw consent half-way through the study? 
The participants’ data tracking will be stopped. The data entered up until the date of 
your withdrawal will remain in the system. 
15) What are some of the data you are able to link? 
This is a new concept which is being used for the first time by Bayer. Tokenization 
might allow researchers to access data across various sources such as clinical studies, 
insurance claims (open and closed), electronic health records, Specialty Pharmacy 
aggregators, labs, participant-reported outcomes, etc. in the US. 

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11.9 
Appendix 9: Protocol Amendment History 
Amendment 1 (17 SEP 2021) 
Overall Rationale for the Amendment: 
This amendment was prepared prior to the initial IRB submission to clarify the protocol 
language. Additional updates were made to reflect the latest sponsor standards related to 
safety reporting/assessments. 
Amendment 2 (19 AUG 2022) 
Overall Rationale for the Amendment: 
The primary purpose of this amendment was to accommodate the inclusion of additional 
countries in the study. This and other changes incorporated in this amendment are described 
in the following table. In addition, minor text clarifications, administrative changes, and 
changes for consistency across the clinical program have been made; as these changes were 
minor, they are not listed in detail in the table. 
Section #  
and Name 
Description of Change 
Brief Rationale 
Title Page 
Added National Clinical Trial 
number. 
To align with regulatory 
requirements. 
Section 1.1 Synopsis, Section 4.1 
Overall Design 
Added modification that this is a 
multi-country study, and removed 
statement that the study will be 
conducted in the United States 
(US) only. 
To accommodate the inclusion of 
additional countries. 
Section 1.1 Synopsis, Section 1.2 
Schema for Dosing (Figure 1-1, 
Footnote “a”), Section 2.3 
Benefit/Risk Assessment, Section 
4.1.2 Treatment, Section 6.1 Study 
Intervention Administered, Section 
6.2 Preparation/Handling/ 
Storage/Accountability, Section 6.7 
Treatment of Overdose, Section 6.8 
Concomitant Therapy, Section 8.4.7 
Events of Special Interest, Appendix 
1 Regulatory, Ethical, and Study 
Oversight Considerations 
Removed reference to US 
prescribing information (USPI) 
and, as applicable, referenced 
the protocol instructions or 
approved prescribing information. 
To accommodate the inclusion of 
additional countries. 
Section 1.2 Schema for Dosing 
Regimen Assignment, Section 9.4.1 
General Considerations 
Removed text referring to “run-in“ 
period. 
To align with currently preferred 
study terminology. 
Section 1.3 Schedule of Activities 
Revised note for inhibitor testing 
to follow local clinical guidance if 
human coagulation factor VIII 
(FVIII) inhibition is suspected 
upon screening, and added 
row/note regarding collection of 
data for patients with a history of 
inhibitors. 
To accommodate inclusion of 
additional countries and align 
with modified eligibility criteria 
regarding participants with a 
history of FVIII inhibitors. 
Section 2.1 Study Rationale 
Added statement regarding 
inclusion of sub-populations. 
For alignment with revised 
eligibility criteria. 
Section 4.3 Justification for Dose 
Added modification that dosing 
has been chosen based on the 
USPI. 
To avoid ambiguity. 
Section 5.1 Inclusion Criteria 
Removed eligibility requirement 
that participants have no history 
of FVIII inhibitors and added 
To clarify participant eligibility 
criteria related to FVIII inhibitor 
medical history. 

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specifications for participants with 
past positive inhibitor titers. 
Section 5.2 Exclusion Criteria 
Added clarification in Exclusion 
Criterion #1 that participants with 
a diagnosis of von Willebrand 
disease are not eligible to 
participate in the study. 
To align with standard clinical 
practice and clarify that local 
diagnosis guidelines should be 
followed. 
Section 5.2 Exclusion Criteria 
Added criterion regarding 
participants with evidence of FVIII 
inhibitors within the last 3 years 
and referenced revised Inclusion 
Criterion #5. 
To clarify participant eligibility 
criteria related to current and 
historical used of FVIII inhibitors. 
Section 6.1 Study Intervention 
Administered 
Modified statement detailing how 
investigators should identify 
appropriate prophylaxis regimen. 
To highlight for investigators that, 
while choice of prophylaxis 
regimen should ultimately be 
guided by protocol, clinical and 
individual participant factors 
should be considered in the 
decision-making process. 
Added reference to statistical 
analysis section for details 
regarding participants who switch 
from the protocol-assigned 
regimen. 
To avoid ambiguity. 
Section 6.2 Preparation/Handling/ 
Storage/Accountability 
Modified statement regarding 
dispensation of study intervention 
to allow participants to obtain 
study intervention on site. 
To allow flexibility for study 
participants and sites. 
Section 8.1.1 Demographics 
Added country to list of 
demographic characteristics to be 
recorded at screening. 
To align with expansion of study. 
Section 8.1.3 Disease History, 
Appendix 7 Visit Description 
Included additional details to be 
collected with regard to past FVIII 
inhibitor formation. 
For alignment with new eligibility 
criteria regarding participants 
with previous FVIII inhibitor use. 
Added statement that von 
Willebrand factor (vWF) antigen 
levels extracted from the Medical 
Record should have been 
performed within 12 months prior 
to screening. 
For alignment with current best 
safety practices. 
Section 8.3.1 Measurements of 
Immunogenicity, Section 9.4.4.1 
Immunogenicity, Appendix 3 Clinical 
Laboratory Tests, Appendix 7 Visit 
Description 
Deleted reference to Nijmegen 
modified Bethesda assay and 
revised to include Bethesda 
assay per local clinical practice. 
To allow flexibility in assay used 
based on local clinical practice. 
Section 8.4.5 Pregnancy, Appendix 6 
Contraceptive Guidance and 
Collection of Pregnancy Information 
Removed section regarding 
collection of pregnancy 
information for female partners of 
male participants. 
For alignment with current Jivi 
safety information. 
Section 9.4.1 General considerations 
Added statement that primary 
endpoint table and table for 
number of participants enrolled 
will be presented in total and by 
country. 
To align with expansion of study. 
Added statement that select 
statistical tables will be presented 
by subgroup of participants with 
FVIII inhibitor history. 
To assess the impact of previous 
FVIII inhibitor use on frequency 
of prophylaxis administration and 
other factors. 
Section 9.4.2 Primary Endpoint 
Added statement that data for 
participants with favorable 
outcome will be presented by 
FVIII inhibitor history and by 
country. 
To assess the impact of previous 
FVIII inhibitor use and 
country-specific differences in 
those participants with favorable 
outcomes. 
Section 9.4.4 Safety Analyses 
Added clarification that safety 
To assess the impact of previous 

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analyses will be stratified by FVIII 
inhibitor history and AE listings 
will include data related to 
previous FVIII inhibitors. 
FVIII inhibitor use on safety. 
Section 9.4.4.2 Pharmacokinetics 
Added clarification that 
pharmacokinetic (PK) parameters 
will be presented overall and by 
FVIII inhibitor history. 
To assess the impact of FVIII 
inhibitor use on PK parameters. 
Section 9.4.5.1 Disposition of 
participants 
Revised analyses of participant 
disposition to include by country 
assessments. 
To align with expansion of study. 
Section 10 Tokenization 
Added clarification that 
tokenization is an option for US 
participants only. 
To avoid ambiguity. 
Appendix 8 Tokenization 
Added Frequently Asked 
Questions related to tokenization. 
To support the 
physician/investigator and 
participant interaction. 
Administrative change: Sponsor’s 
medically responsible person 
Sponsor’s medical expert role 
was changed from Clinical 
Development Leader to Medical 
Director. 
Clarification of sponsor 
personnel. 
 
 
 

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11.10 
Appendix 10: Abbreviations  
ABR 
Annualized bleed rate 
ADL 
Activities of Daily Living 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AUC 
Area under the curve 
BMI 
Body mass index 
CD4 
Cluster of differentiation 4 (CD4 receptor) 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
COVID-19 
Coronavirus disease 2019 
CRF 
Case report form (either paper or electronic) 
EHL 
Extended half-life 
EMA 
European Medicines Agency 
EU 
European Union 
FDA 
US Food and Drug Administration 
FPFV 
First participant first visit 
FSH 
Follicle-stimulating hormone 
FVIII 
Human coagulation factor VIII 
GCP 
Good Clinical Practice  
HCP 
Health Care Professional 
HIV 
Human immunodeficiency virus 
HRT 
Hormonal-replacement therapy 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
ISTH 
International Society on Thrombosis and Haemostasis 
IU 
International units 
IV 
Intravenous 
IxRS 
Interactive Voice/Web Response System 
kg 
Kilogram 
LARC 
Long-acting reversible contraception 
LoE 
Loss of efficacy 
MedDRA 
Medical Dictionary for Regulatory Affairs 
mITT 
Modified intention-to-treat 
PEG 
Polyethylene glycol 
PGI-C 
Patient’s Global Impression of Change 
PID 
Patient Identification Code 
PK 
Pharmacokinetic(s) 
PMDA 
Pharmaceuticals and Medical Devices Agency 
PRO 
Patient Reported Outcome 
PTP 
Previously-treated patients 
QoL 
Quality of Life 
rFVIII 
Human recombinant factor VIII 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SARS-CoV-2 
Severe acute respiratory syndrome Coronavirus 2 
SD 
Standard deviation 

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SHL 
Standard half-life 
SoA 
Schedule of activities 
SUSAR 
Suspected unexpected serious adverse reaction 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
US 
United States 
vWF 
von Willebrand factor 
WAPPS-Hemo 
Web-Accessible Population Pharmacokinetic 
Service-Hemophilia 
WFH 
World Federation of Hemophilia 
WHO 
World Health Organization 
WOCBP 
Woman of childbearing potential 
WPAI 
Work Productivity and Activity Impairment 
 
DEFINITIONS (Common Terms) 
Term 
Definition 
Legal guardian 
parent(s) (preferably both if available or as per local 
requirements), legally appointed guardian(s), or 
legally acceptable representative(s), as defined by 
national and local laws and regulations, who 
consent(s) on behalf of the minor. For the purposes of 
this study, all references to informed consent and 
assent refer to the pediatric participant (child) and his 
or her legal guardian who have provided consent (and 
assent as applicable) according to the Informed 
Consent Process and Assent Form described in 
Section 11.1.3. 
Pre-study ABR 
Pre-study ABR is based on data from a minimum of 
6 continuous months (up to a maximum of 12 
months) of stable SHL prophylaxis at any given time 
within the 12 months prior to the screening visit 
(refer to Section 9.4.2). 
Pre-study treatment frequency 
Pre-study treatment frequency is based on data from 
a minimum of 6 continuous months (up to a 
maximum of 12 months) of stable SHL prophylaxis 
at any given time within the 12 months prior to the 
screening visit (refer to Section 9.4.2). 
Stable SHL prophylaxis 
Stable SHL prophylaxis is defined as a minimum of 
18 weeks of treatment in a 6 (consecutive) calendar 
month period in the 12 months prior to the screening 
visit (refer to Section 9.4.2). 
 
 

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12. 
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