A Phase 3 Open-Label, Multicenter Study of the Safety, Efficacy, and Pharmacokinetics of Intravenous Recombinant Coagulation Factor VIII Fc-von Willebrand Factor-XTEN Fusion Protein (rFVIIIFc-VWF-XTEN; BIVV001) in Previously Treated Patients ≥12 Years of Age With Severe Hemophilia A
Phase: PHASE3
Conditions: Factor VIII Deficiency
Sponsor: Bioverativ, a Sanofi company

 
 
 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive property of Sanofi (or any of its 
affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: RDSD-002540 VERSION N° 3.0 (19-FEB-2019) based on TransCelerate CPT version 5 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 05  
Protocol title: 
A Phase 3 Open-Label, Multicenter Study of the Safety, Efficacy, 
and Pharmacokinetics of Intravenous Recombinant Coagulation 
Factor VIII Fc-von Willebrand Factor-XTEN Fusion Protein 
(rFVIIIFc-VWF-XTEN; BIVV001) in Previously Treated Patients 
≥12 Years of Age With Severe Hemophilia A 
Protocol number: 
EFC16293 
Amendment number: 
5 
Compound number 
(INN/Trademark): 
BIVV001 (efanesoctocog alfa) 
 
Study phase: 
Phase 3 
Short title: 
XTEND-1 
Sponsor name: 
Bioverativ Therapeutics Inc. (a Sanofi Company) 
Legal registered 
address: 
225 Second Avenue 
Waltham, MA 02451 
United States 
Monitoring Team’s 
Representative Name 
and Contact Information 
 
 
Regulatory agency identifier number(s): 
IND: 
17464 
EudraCT: 
2019-002023-15 
NCT: 
NCT04161495 
WHO: 
U1111-1223-4867 
Other: 
Not Applicable 
 
Approval Date: 
20-Aug-2021 
Total number of pages: 202 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293  - efanesoctocog alfa 
20-Aug-2021 
 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY  
 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 05 
All 
20 Aug 2021, version 1 (electronic 7.0) 
Amended Clinical Trial Protocol 04 
All 
13 May 2020, version 1 (electronic 5.0) 
Amended Clinical Trial Protocol 03 
Italy only 
06 April 2020, version 1 (electronic 4.0) 
Amended Clinical Trial Protocol 02 
France only 
06 Feb 2020, version 1 (electronic 2.0)  
Amended Clinical Trial Protocol 01  
All 
28 August 2019, version 1 (electronic 1.0) 
Original Protocol 
All 
17 June 2019, version 1 (electronic 1.0) 
Amended protocol 05 (20 August 2021) 
This amended protocol (amendment 05) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT  
The protocol is amended with the following main changes: 
• Addition of statistical testing for some secondary efficacy endpoints 
• Addition of an exit interview for participants from selected countries 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Cover page and 
Section 2 
Introduction 
The international nonproprietary name (INN), efanesoctocog alfa, 
was added.  
To introduce the INN 
Section 1.1 
Synopsis, Section 3 
Objectives and 
endpoints, Section 9 
Statistical 
Considerations 
The secondary efficacy endpoint analysis was revised to allow 
formal statistical testing and update the multiplicity adjustment for 
the Haem-A-QoL (≥17 years old) Physical Health score, PROMIS 
Pain Intensity 3a and Hemophilia Joint Health Score (HJHS) total 
score measures.  
To include analysis of Patient 
Reported Outcomes within the 
overall statistical testing 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293  - efanesoctocog alfa 
20-Aug-2021 
 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 3 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.1 
Synopsis and 
Section 9.1 
Statistical 
Hypotheses and 9.2 
Sample Size 
Determination 
The selection of participants to be included in the analysis for the 
key secondary efficacy endpoint (ie, an intra-patient comparison of 
ABR during the BIVV001 weekly prophylaxis treatment period versus 
the historical prophylaxis ABR) was updated to clarify that 
participants in Arm A must have at least 6 months of study duration 
in both this study and in observational study 242HA201/OBS16221. 
Update to align with the 
statistical analytical plan (SAP) 
Section 1.3 
Schedule of 
Activities (SoA), 
Section 3 Objectives 
and endpoints, 
Section 8.1.2 Patient 
reported outcomes, 
Appendix 10.14.11 
Treatment 
Satisfaction 
Questionnaire for 
Medication 
It was clarified that the 9-item version of the Treatment Satisfaction 
Questionnaire for Medication (TSQM-9) is being used, and the 
appendix was updated to include a copy of the full questionnaire 
For clarification 
Section 1.3 
Schedule of 
Activities (SoA), 
Section 3 Objectives 
and endpoints, 
Section 8.1.3 Exit 
interviews, Appendix 
10.14.16 
An exit interview and footnote “kk” related to the exit interview were 
added in Section 1.3 Table 1. A related endpoint was added to the 
exploratory objective for patient reported outcome measures in 
Table 5. A description of the assessment is provided in Section 8.1.3 
(new section) and a copy of the instrument to be administered to 
participants was added to the appendix. 
To evaluate participants’ 
expectations of treatment and 
perception of treatment impact 
Section 1.3 
Schedule of 
Activities (SoA) and 
Section 8.3.8 
Disease-related 
events and/or 
disease-related 
outcomes not 
qualifying as AEs or 
SAEs 
In Table 1, footnote “II” was added to clarify that only training on the 
electronic patient diary (ePD) is performed at the Screening visit. 
ePD devices are given to the patients at the baseline visit. 
In Section 8.3.8, the following text was added: (if a bleed occurs 
during the Screening period, before the baseline visit, it will be 
recorded in the eCRF). 
To provide clarification that 
bleeds occurring during the 
Screening period should be 
recorded in the eCRF and not 
in the ePD.  
Section 1.3 
Schedule of 
Activities (SoA) 
In Table 4, the following text was added to footnote “h”: In the case 
of minor dental surgery, blood samples can be drawn within 3 days 
prior to the day of surgery. In addition, footnote “h” was added to the 
blood draw for FVIII activity (1-stage clotting aPTT and 2-stage 
chromogenic assays) to be performed on the day of surgery. 
To give greater flexibility to 
participants who undergo minor 
dental surgery outside of the 
hospital 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293  - efanesoctocog alfa 
20-Aug-2021 
 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 4 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 6.1.1.4 
Surgical dosing and 
Section 8.1.1.6 
Surgery 
In Table 8, the text was updated as follows: Major surgery, only 
allowed after 6 EDs.  In Section 8.1.1.6, the following text: 
“Participants must have 6 EDs to BIVV001 and a negative inhibitor 
test within 4 weeks prior to surgery to be eligible for the surgery 
subgroup” was revised to “Participants should have at least 6 EDs to 
BIVV001 to be eligible for major surgery. In addition, a negative 
inhibitor test within 4 weeks prior to surgery is required”. 
For clarification 
Section 6.5 
Concomitant 
Therapy 
The list of Prohibited concomitant therapy was updated to allow the 
one-off use of another FVIII product in exceptional circumstances 
(described in Section 7.1.1) and to specify that the Investigator must 
discuss the use of anticoagulant agents with the Medical Monitor. 
For clarification and to allow the 
one-off use of another FVIII 
product in exceptional 
circumstances 
Section 7.1.1 
Definitive 
discontinuation 
The following was added as an event requiring permanent treatment 
discontinuation : Use of FVIII products other than BIVV001, unless it 
occurs in 1 life-threatening emergency or as a result of 1 accidental 
use and the Sponsor agrees to retain the participant in the study. 
Use must be recorded in the eCRF and the Investigator should 
contact the Medical Monitor. 
For clarification  
Section 8.1.2 Patient 
reported outcomes 
The text was revised to state that the PROMIS-SF Physical Function 
- SF 6b instrument does not use a 7-day recall period 
For clarification 
Section 9 Statistical 
considerations 
In addition to changes described above related to formal statistical 
testing of secondary efficacy endpoints, changes were made 
throughout this section to reflect updates to the SAP. The following 
sections were added: 
9.4.1.5 Multiplicity issue 
9.4.4 Immunogenicity analysis 
To be consistent with the SAP 
Appendix 10.14.13 
Patient Global 
Impression of 
Severity (PGIS) 
A copy of the instrument for assessing “Patient Global Impression of 
Severity – Physical activity” was added 
For completeness 
Throughout the 
document 
Editorial corrections were made 
For consistency and clarity  
 
 
 
 
 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293  - efanesoctocog alfa 
20-Aug-2021 
 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 5 
TABLE OF CONTENTS  
AMENDED CLINICAL TRIAL PROTOCOL 05 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
DOCUMENT HISTORY ................................................................................................................................... 2 
OVERALL RATIONALE FOR THE AMENDMENT ........................................................................................ 2 
TABLE OF CONTENTS .................................................................................................................................. 5 
LIST OF TABLES ......................................................................................................................................... 10 
LIST OF FIGURES ........................................................................................................................................ 10 
1 
PROTOCOL SUMMARY ............................................................................................................... 11 
1.1 
SYNOPSIS ..................................................................................................................................... 11 
1.2 
SCHEMA ........................................................................................................................................ 16 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 17 
2 
INTRODUCTION ............................................................................................................................ 26 
2.1 
STUDY RATIONALE ...................................................................................................................... 26 
2.2 
BACKGROUND ............................................................................................................................. 28 
2.2.1 
BIVV001 ......................................................................................................................................... 28 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 31 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 33 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 35 
4 
STUDY DESIGN ............................................................................................................................ 36 
4.1 
OVERALL DESIGN ........................................................................................................................ 36 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 38 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 39 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 41 
4.5 
STUDY STOPPING RULES .......................................................................................................... 42 
4.5.1 
Criteria for dose and/or enrollment suspension ............................................................................. 42 
5 
STUDY POPULATION .................................................................................................................. 43 
5.1 
INCLUSION CRITERIA .................................................................................................................. 43 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293  - efanesoctocog alfa 
20-Aug-2021 
 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 6 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 45 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 47 
5.4 
SCREEN FAILURES ...................................................................................................................... 47 
6 
STUDY INTERVENTION ............................................................................................................... 48 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 48 
6.1.1 
Investigational medicinal product(s) ............................................................................................... 48 
6.1.1.1 
Study treatment schedule and administration ................................................................................ 49 
6.1.1.2 
Treatment of bleeding episodes during Prophylactic Treatment Regimen .................................... 49 
6.1.1.3 
Treatment of bleeding episodes during the On-Demand Treatment Regimen .............................. 50 
6.1.1.4 
Surgical dosing ............................................................................................................................... 50 
6.1.1.5 
Bleeding episodes that occur prior to the baseline and during PK sampling period ..................... 51 
6.1.2 
BIVV001 dosing calculations ......................................................................................................... 52 
6.1.2.1 
Definitions of Nominal Strength versus Actual Potency ................................................................. 52 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY ....................................................... 52 
6.2.1 
Study drug packaging and labelling ............................................................................................... 53 
6.2.2 
Study drug storage ......................................................................................................................... 53 
6.2.3 
Study drug preparation................................................................................................................... 53 
6.2.4 
Study drug administration .............................................................................................................. 53 
6.2.5 
Study drug accountability ............................................................................................................... 53 
6.2.6 
Study drug handling and disposal .................................................................................................. 54 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 54 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 54 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 55 
6.6 
DOSE MODIFICATION .................................................................................................................. 56 
6.7 
INTERVENTION AFTER THE END OF THE STUDY ................................................................... 56 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 57 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  ..................................................................... 57 
7.1.1 
Definitive discontinuation ............................................................................................................... 57 
7.1.2 
Temporary discontinuation ............................................................................................................. 58 
7.1.2.1 
Rechallenge ................................................................................................................................... 58 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 58 
7.3 
LOST TO FOLLOW UP.................................................................................................................. 59 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293  - efanesoctocog alfa 
20-Aug-2021 
 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 7 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 60 
8.1 
EFFICACY ASSESSMENTS  ........................................................................................................ 60 
8.1.1 
Efficacy assessments ..................................................................................................................... 60 
8.1.1.1 
Bleeding episode data.................................................................................................................... 60 
8.1.1.2 
Assessment of clinical response to BIVV001 treatment for bleeding episodes ............................. 62 
8.1.1.3 
Physician’s Global Assessment (PGA) .......................................................................................... 62 
8.1.1.4 
Hemophilia Joint Health Score (HJHS) .......................................................................................... 63 
8.1.1.5 
Target joint resolution ..................................................................................................................... 63 
8.1.1.6 
Surgery ........................................................................................................................................... 63 
8.1.2 
Patient reported outcomes ............................................................................................................. 65 
8.1.3 
Exit interviews ................................................................................................................................ 68 
8.1.4 
Physical activity monitoring ............................................................................................................ 68 
8.1.5 
Ultrasound measures (if applicable) .............................................................................................. 68 
8.1.6 
Future scientific research ............................................................................................................... 69 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 69 
8.2.1 
Physical examination ..................................................................................................................... 69 
8.2.2 
Vital signs ....................................................................................................................................... 69 
8.2.3 
Clinical safety laboratory assessments .......................................................................................... 70 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................... 70 
8.3.1 
Adverse event of special interest ................................................................................................... 71 
8.3.1.1 
Other compound specific AESI(s) .................................................................................................. 71 
8.3.2 
Time period and frequency for collecting AE and SAE information ............................................... 72 
8.3.3 
Method of detecting AEs and SAEs ............................................................................................... 72 
8.3.4 
Follow-up of AEs and SAEs ........................................................................................................... 72 
8.3.5 
Regulatory reporting requirements for SAEs ................................................................................. 72 
8.3.6 
Pregnancy ...................................................................................................................................... 73 
8.3.7 
Deaths ............................................................................................................................................ 73 
8.3.8 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 73 
8.3.9 
Guidelines for reporting product complaints .................................................................................. 74 
8.4 
TREATMENT OF OVERDOSE ...................................................................................................... 74 
8.5 
PHARMACOKINETICS .................................................................................................................. 74 
8.6 
PHARMACODYNAMICS ............................................................................................................... 77 
8.7 
GENETICS ..................................................................................................................................... 77 
8.8 
BIOMARKERS ............................................................................................................................... 77 
8.8.1 
Immunogenicity assessments ........................................................................................................ 77 
8.8.1.1 
Inhibitor development ..................................................................................................................... 77 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293  - efanesoctocog alfa 
20-Aug-2021 
 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 8 
8.8.1.2 
Anti-drug antibodies ....................................................................................................................... 78 
8.9 
HEALTHCARE RESOURCE UTILIZATION .................................................................................. 78 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 79 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 79 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 79 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 81 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 81 
9.4.1 
Efficacy analyses ........................................................................................................................... 82 
9.4.1.1 
Primary efficacy endpoint ............................................................................................................... 82 
9.4.1.2 
Key secondary efficacy endpoints ................................................................................................. 83 
9.4.1.3 
Other secondary efficacy endpoints ............................................................................................... 83 
9.4.1.4 
Exploratory efficacy endpoints ....................................................................................................... 84 
9.4.1.5 
Multiplicity Issue ............................................................................................................................. 84 
9.4.2 
Safety analyses .............................................................................................................................. 85 
9.4.3 
Pharmacokinetics ........................................................................................................................... 86 
9.4.4 
Immunogenicity analysis ................................................................................................................ 87 
9.4.4.1 
Anti-drug antibody .......................................................................................................................... 87 
9.5 
INTERIM ANALYSES  ................................................................................................................... 87 
9.5.1 
Data Monitoring Committee (DMC) ................................................................................................ 87 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 88 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 88 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 88 
10.1.2 
Financial disclosure ........................................................................................................................ 88 
10.1.3 
Informed consent process .............................................................................................................. 89 
10.1.4 
Data protection ............................................................................................................................... 89 
10.1.5 
Dissemination of clinical study data ............................................................................................... 90 
10.1.6 
Data quality assurance................................................................................................................... 90 
10.1.7 
Source documents ......................................................................................................................... 91 
10.1.8 
Study and site closure .................................................................................................................... 91 
10.1.9 
Publication policy ........................................................................................................................... 92 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 92 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING................................................. 94 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION .............................................................................................................................. 99 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293  - efanesoctocog alfa 
20-Aug-2021 
 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 9 
10.5 
APPENDIX 5: OVERDOSE ......................................................................................................... 102 
10.6 
APPENDIX 6: GENETICS............................................................................................................ 102 
10.7 
APPENDIX 7: DEFINITIONS OF MINOR AND MAJOR SURGERY ........................................... 102 
10.8 
APPENDIX 8: ASSESSMENTS ................................................................................................... 103 
10.9 
APPENDIX 9:  WASHOUT AND BLOOD SAMPLING SUMMARY ............................................. 103 
10.10 
APPENDIX 10: DEFINITIONS OF MINOR, MODERATE, AND MAJOR BLEEDING 
EPISODES ................................................................................................................................... 106 
10.11 
APPENDIX 11: COUNTRY-SPECIFIC REQUIREMENTS .......................................................... 106 
10.11.1 France .......................................................................................................................................... 106 
10.11.2 Italy ............................................................................................................................................... 108 
10.12 
APPENDIX 12: ABBREVIATIONS ............................................................................................... 109 
10.13 
APPENDIX 13 HEMOPHILIA JOINT HEALTH SCORE (HJHS) ................................................. 110 
10.14 
APPENDIX 14: PATIENT REPORTED OUTCOMES .................................................................. 111 
10.14.1 PROMIS-SF v 1.0 Pain Intensity 3a ............................................................................................. 111 
10.14.2 PROMIS-SF v1.0 – Pain Interference 6a ..................................................................................... 112 
10.14.3 PROMIS Pediatric SF v2.0 – Pain Interference 8a ...................................................................... 113 
10.14.4 PROMIS-SF v2.0 Physical Function 6b ....................................................................................... 114 
10.14.5 PROMIS Pediatric-SF v1.0 – Physical Activity 8a ....................................................................... 115 
10.14.6 Haem-A-QoL ................................................................................................................................ 116 
10.14.7 Haemo-QoL 8-12 ......................................................................................................................... 123 
10.14.8 Haemo-QoL 13-16 ....................................................................................................................... 131 
10.14.9 Hemophilia Activities List (HAL) ................................................................................................... 141 
10.14.10 Pediatric Hemophilia Activities List (pedHAL) .............................................................................. 152 
10.14.11 Treatment Satisfaction Questionnaire for Medication (TSQM-9) ................................................. 161 
10.14.12 EuroQoL 5-dimension 5-level (EQ-5D-5L) ................................................................................... 164 
10.14.13 Patient Global Impression of Severity (PGIS) .............................................................................. 167 
10.14.14 Patient Global Impression of Change (PGIC) .............................................................................. 169 
10.14.15 Treatment Preference Survey ...................................................................................................... 170 
10.14.16 Exit Interview ................................................................................................................................ 171 
10.14.17 Health Resource Utilization (HRU) .............................................................................................. 185 
10.15 
APPENDIX 15: PROTOCOL AMENDMENT HISTORY .............................................................. 186 
11 
REFERENCES ............................................................................................................................. 197 
 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293  - efanesoctocog alfa 
20-Aug-2021 
 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 10 
LIST OF TABLES  
Table 1 - Overall schedule of activities from screening to safety follow-up call or visit................................. 17 
Table 2 - Abbreviated PK sampling schedule of activities ............................................................................ 22 
Table 3 - PK sampling schedule of activities first dose (Week 1) and Week 26 for sequential PK subgroup
 ....................................................................................................................................................................... 22 
Table 4 - Surgical schedule of activities ........................................................................................................ 23 
Table 5 - Objectives and endpoints ............................................................................................................... 33 
Table 6 - Overview of study interventions administered ............................................................................... 48 
Table 7 - Home Injection:  BIVV001 weight-based vial injection rate recommendations .............................. 49 
Table 8 - Intravenous BIVV001 treatment ..................................................................................................... 51 
Table 9 - ISTH assessment of treatment of acute bleeds ............................................................................. 62 
Table 10 - Physician’s Global Assessment ................................................................................................... 62 
Table 11 - ISTH hemostatic response for surgical procedures scale ........................................................... 65 
Table 12 - Patient reported outcome concepts and questionnaires .............................................................. 65 
Table 13 - Populations for analyses .............................................................................................................. 81 
Table 14 - Protocol-required laboratory assessments .................................................................................. 93 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 16 
Figure 2 - Overall design and components of BIVV001 ................................................................................ 26 
 
 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293  - efanesoctocog alfa 
20-Aug-2021 
 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 13 
Overall design: 
This is a multinational, multicenter, open-label Phase 3 study of the safety, efficacy, and PK of IV 
BIVV001 in previously treated patients (PTPs) ≥12 years of age with severe hemophilia A 
(defined as <1 IU/dL [<1%] endogenous FVIII). The study is comprised of 2 Arms: Arm A and 
Arm B.  Participants currently on a prophylaxis treatment regimen with FVIII will enter Arm A 
and receive BIVV001 at a dose of 50 IU/kg IV QW. Participants currently on an on-demand 
treatment regimen will enter Arm B for 26 weeks of on-demand treatment of bleeding episodes 
with BIVV001 at a dose of 50 IU/kg IV on demand, then switch to receive BIVV001 at a dose of 
50 IU/kg IV QW on a prophylaxis treatment regimen for 26 weeks. 
Following a washout period (at least 4 to 5 days, depending on current therapy), all participants 
(except those in the sequential PK subgroup of Arm A) will undergo abbreviated PK sampling 
after the first dose of BIVV001 (Baseline). The washout period before the Baseline Visit for 
subjects in abbreviated PK sampling may be modified at the discretion of the Investigator based 
on individual PK data and clinical phenotype in consultation with medical monitor.  Sixteen 
participants at selected sites will participate in the sequential PK subgroup of Arm A and will 
undergo more extensive PK sampling at Baseline and again at Week 26.  
Participants from any arm who undergo major surgery during the study will be included in the 
surgery subset. A minimum of 10 major surgeries in at least 5 patients will be targeted to assess 
control and prevention of bleeding in the surgical setting. The definition of major surgery is 
included in Section 10.7. 
Disclosure Statement: This is a Parallel Treatment study with 2 arms that is open label for PTPs 
12 years of age or older with severe hemophilia A. 
Number of participants: 
Approximately 150 participants will be enrolled to collect sufficient data to assess the safety, 
efficacy, and PK of IV BIVV001 in this population. Approximately 124 participants will be in 
Arm A, of which at least 75 participants will have had at least 6 months of participation in 
Study 242HA201/OBS16221 prior to baseline. Sixteen participants from Part A will be included 
in the sequential PK subgroup. Approximately 26 participants will be in Arm B. For the surgery 
subset, a minimum of 10 major surgeries in at least 5 participants will be targeted to assess control 
and prevention of bleeding in the surgical setting. 
Intervention groups and duration: 
Participants in Arm A will receive a QW prophylactic dose of BIVV001 for 52 weeks. 
Participants in Arm B will receive BIVV001 on demand for 26 weeks followed by a switch to 
QW prophylaxis for another 26 weeks. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293  - efanesoctocog alfa 
20-Aug-2021 
 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 14 
Study intervention(s) 
Investigational medicinal product(s) 
• Formulation: Recombinant coagulation factor VIII Fc-von Willebrand Factor XTEN 
Fusion Protein. 
• Route(s) of administration: Intravenous 
• Dose regimen:  The dose regimen of Arm A consists of a prophylactic dose regimen of 
50 IU/kg IV QW for 52 weeks. The dose regimen of Arm B is comprised of 2 parts: an 
on-demand dose regimen of 50 IU/kg IV for 26 weeks, and a prophylactic regimen of 
50 IU/kg IV QW for 26 weeks.  
Statistical considerations: 
Sample size calculations: The sample size was estimated to rule out a greater-than-acceptable risk 
of immunogenicity. Assuming a drop-out rate of approximately 15%, a sample size of 
124 participants in the prophylaxis arm is expected to provide 104 evaluable participants with at 
least 50 exposure days (ED).  If ≤2 participants out of 104 evaluable participants develop an 
inhibitor, then the upper bound of an exact 95% confidence interval would exclude 6.8%, a 
threshold determined at the FDA Factor VIII FDA Inhibitor Workshop that was held in 2003. 
The primary efficacy objective of this study is to evaluate the efficacy of BIVV001 weekly 
prophylaxis as estimated by the mean ABR and one-sided 97.5% CI in Arm A.  Based on 
currently marketed FVIII products, mean ABR during clinical trials typically ranges from 2 to 
5  bleeds per year but can be as high as 6 bleeding episodes per year (1, 2, 3, 4, 5, 6, 7). This 
indicates that while the ABR is typically low with adequate treatment, there is variability in 
clinical bleeding phenotype with some severe hemophilia A participants having higher bleeding 
rates than others.  In order to show adequate control of bleeding consistent with currently 
marketed FVIII products, and to account for this variability, a clinically meaningful treatment 
effect may be claimed if the upper bound of the confidence interval of the estimated ABR is less 
than or equal to 6.  In a Phase 3 study of rFVIIIFc, the mean ABR for an individualized 
prophylaxis arm was 2.9 (6) and the dispersion factor was estimated at 2.3 (REF: data on file).  
Based on 2000 simulations of a negative binomial regression model with mean ABR of 2.9 and 
dispersion factor of 2.3, a sample size of 124 participants will provide at least 90% power for the 
upper bound of the one-sided 97.5% confidence interval to exclude an ABR greater than 6, 
assuming a 15% drop out rate.  
For the key secondary efficacy endpoint, an intra-patient comparison of ABR during the 
BIVV001 weekly prophylaxis treatment period versus the historical prophylaxis ABR will be 
performed using non-inferiority testing for participants in Arm A who have at least 6 months of 
participation in this study and at least 6 months of historical data on prophylaxis treatment from 
observational Study 242HA201/OBS16221. The non-inferiority margin was estimated based on 
the known treatment effect between on-demand and prophylaxis treatment. A meta-analysis of 
Phase 3 registrational studies for recombinant FVIII products that include both on-demand and 
prophylaxis treatment arms estimated an average reduction of 31 bleeds per year between 
on-demand and prophylaxis treatment regimens (5, 6, 7, 8, 9, 10, 11). The lower bound of this 
treatment effect was 27 bleeds per year. Using a fixed margin approach to maintain a substantial 
amount (85%) of the treatment effect results in a non-inferiority margin of 4. Further details of the 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293  - efanesoctocog alfa 
20-Aug-2021 
 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 15 
meta-analysis and derivation of the non-inferiority margin will be specified in the Statistical 
Analysis Plan. For a non-inferiority test of the null hypothesis (median difference in ABR exceeds 
or is equal to non-inferiority margin) versus the alternative hypothesis (median difference in ABR 
is less than non-inferiority margin), a sample size of 63 achieves 90% power to detect non-
inferiority using a one-sided paired Wilcoxon Signed Rank test at a 0.025 significance level when 
the actual mean of paired differences is 0 and the non-inferiority margin is 4. Without prior 
knowledge of the standard deviation of the paired differences, a conservative estimate of 10 was 
assumed. In order to account for drop-out and the use of the Per Protocol Set, at least 
75 participants who have completed at least 6 months of participation in observational 
Study 242HA201/OBS16221 will be enrolled in Arm A. 
Primary efficacy analysis: The primary analysis of the primary endpoint will estimate the mean   
ABR and one-sided 97.5% confidence interval using a Negative-Binomial regression model for 
weekly prophylaxis treatment arm (Arm A). If the upper limit of the confidence interval is less 
than or equal to 6, the weekly prophylaxis treatment regimen will be considered to provide 
adequate bleeding control. 
Key secondary efficacy analysis: The analysis of the key secondary efficacy endpoint will 
estimate that the  paired differences in ABR between BIVV001 weekly prophylaxis treatment and 
historical prophylaxis for participants in Arm A who have at least 6 months of participation in the 
study and at least 6 months of historical data on prophylaxis treatment from observational 
Study 242HA201/OBS16221 is less than the non-inferiority margin of 4 bleeds per year using the 
Negative-Binomial regression model. If non-inferiority is achieved, superiority will be evaluated 
sequentially using the Full Analysis Set. 
Secondary efficacy analyses for Haem-A-QoL (≥17 years old) Physical Health score, PROMIS 
Pain Intensity 3a and HJHS total score: The mixed-effects model repeated measures (MMRM) 
analysis will be conducted on the 3 endpoints in Arm A. The adjusted mean change in each of the 
3 endpoints from baseline to Week 52, along with its 95% CI, will be estimated by the MMRM 
model. 
Analysis of other secondary efficacy endpoints: All secondary efficacy endpoints will be 
summarized descriptively by treatment arm, as applicable. Continuous endpoints will be 
summarized using the number of non-missing values (n), mean, standard deviation (SD), median, 
minimum, and maximum.  Categorical endpoints will be summarized by counts and percentages. 
The multiplicity will be adjusted through a hierarchical testing framework. 
Analysis of safety endpoints: The incidence and severity of AEs will be assessed by study arm, 
treatment regimen, and overall.  Clinically significant changes from baseline in laboratory 
parameters, vital signs, and physical examination findings will be summarized using descriptive 
statistics.  In addition, incidence of inhibitor development will be assessed using an exact 95% 
confidence interval based on the binomial distribution. The occurrence of embolic and thrombotic 
events will be described. 
Analysis of PK endpoints: PK parameters will be summarized descriptively for both the one-stage 
aPTT clotting assay and two-stage chromogenic assay. 
Data Monitoring Committee: No
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa 
20-Aug-2021 
Version number: 1  
 
Property of the Sanofi group - strictly confidential 
Page 16 
1.2 
SCHEMA  
Figure 1 - Graphical study design  
 
 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa 
20-Aug-2021 
Version number: 1  
 
Property of the Sanofi group - strictly confidential 
Page 17 
1.3 
SCHEDULE OF ACTIVITIES (SOA)  
Table 1 - Overall schedule of activities from screening to safety follow-up call or visit  
Tests and assessments 
Screeninga 
(Week -8 to 
Day 1) 
Baselineb 
BIVV001 
Day 1 
Week 4c  
±7 days 
Week 13c 
±7 days 
Week 
26c,d  
±7 days 
Week 39c  
±7 days 
Week 52/ 
EOS/ETc  
±7 days 
Unscheduled 
visite 
Safety 
follow-up 
call or visitf 
Informed consentg 
X 
 
 
 
 
 
 
 
 
Assessment of eligibility 
X 
X 
 
 
 
 
 
 
 
Demographicsh 
X 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
 
 
Heightjj 
X 
 
 
 
 
 
 
 
 
Medical, surgical, and hemophilia 
historyi 
X 
 
 
 
 
 
 
 
 
FVIII activity (1-stage aPTT assay)k  
X 
 
 
 
 
 
 
 
 
Genotypej 
 
X 
 
 
 
 
 
 
 
In-clinic BIVV001 dosingl 
 
 
X 
(applicable to 
both Arm A 
and Arm B) 
X (applicable 
to Arm A 
only) 
X  
(applicable to 
Arm A only) 
X 
X 
X 
 
 
Safety 
Physical examjj 
X 
X 
X 
 
X 
 
X 
X 
 
Vital signsm 
X 
X 
X 
 
X 
 
X 
X 
 
Pregnancy testingn 
X 
X 
 
X 
X 
X 
X 
 
 
HIV, HBV, and HCV statuso 
X 
 
 
 
 
 
 
 
 
CD4 count, viral loadp 
X 
 
 
 
 
 
 
 
 
Hematologyq 
X 
X 
X 
X 
X 
X 
X 
 
 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa 
20-Aug-2021 
Version number: 1  
 
Property of the Sanofi group - strictly confidential 
Page 18 
Tests and assessments 
Screeninga 
(Week -8 to 
Day 1) 
Baselineb 
BIVV001 
Day 1 
Week 4c  
±7 days 
Week 13c 
±7 days 
Week 
26c,d  
±7 days 
Week 39c  
±7 days 
Week 52/ 
EOS/ETc  
±7 days 
Unscheduled 
visite 
Safety 
follow-up 
call or visitf 
Coagulation parameters ii 
 
X 
 
 
X 
 
X 
 
 
Clinical chemistryr 
X 
X 
X 
X 
X 
X 
X 
 
 
von Willebrand Comprehensive Panels 
X 
X 
X 
X 
X 
X 
X 
 
 
Nijmegen-modified Bethesda assay 
(inhibitor assay) k 
X 
X 
X 
X 
X 
X 
X 
 
 
Anti-rFVIIIFc-VWF-XTEN Antibody 
(ADA) k 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse event/serious adverse event 
recordingt 
<<ongoing; monitor and record at all visits>> 
Prior and concomitant medications and 
concomitant therapies and proceduresu 
<<ongoing; monitor and record at all visits>> 
Monthly telephone call v 
<<ongoing; once per month starting at Week 4>> 
Efficacy 
HJHS joint assessmentsw 
 
X 
 
 
X 
 
X 
 
 
Investigator’s target joint assessment 
 
X 
 
 
 
 
  
 
 
Physician’s global assessment of 
response to treatment (PGA) 
 
 
X 
X 
X 
X 
X 
 
 
Investigator’s assessment of 
participant’s response to treatment of 
bleeding episodes treated at the study 
sitex  
 
<<ongoing >> 
 
Ultrasound joint assessmentsy 
 
X 
 
 
 
 
X 
 
 
Serum and plasma samplesz (optional) 
X 
X 
X 
X 
X 
X 
X 
 
 
Electronic patient diary (ePD) training / 
administration/ review 
Xll 
X 
<<ongoing >> 
 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa 
20-Aug-2021 
Version number: 1  
 
Property of the Sanofi group - strictly confidential 
Page 19 
Tests and assessments 
Screeninga 
(Week -8 to 
Day 1) 
Baselineb 
BIVV001 
Day 1 
Week 4c  
±7 days 
Week 13c 
±7 days 
Week 
26c,d  
±7 days 
Week 39c  
±7 days 
Week 52/ 
EOS/ETc  
±7 days 
Unscheduled 
visite 
Safety 
follow-up 
call or visitf 
Participant’s completion of ePD 
including at-home dosing, bleeding 
episodes, and assessment of response 
to treatment of bleeding episodesaa 
 
<<ongoing >> 
 
Pharmacokinetics 
Abbreviated pharmacokinetic 
Samplingbb 
 
X 
 
 
 
 
 
 
 
Sequential pharmacokinetic samplingcc 
 
X 
 
  
X  
 
 
 
 
FVIII peak and trough samplingdd 
 
 
X 
Arm A only 
X 
Arm A only 
X 
X 
X 
 
 
Participant-Reported Outcomes 
PROMIS Assessmentsee 
 
X 
 
  
X 
  
X 
 
 
Haem-A-QoL (≥17 years old) or Haemo 
QoL (<17 years old) 
 
X 
 
  
X 
  
X 
 
 
HAL (≥18 years old) or 
pedHAL (<18 years old) 
 
X 
 
 
X 
 
X 
 
 
TSQM-9 
 
X 
 
 
X 
 
X 
 
 
Patient Global Impression of Severity 
(activity and joint)ff 
 
X 
 
 
X 
 
X 
 
 
Patient Global Impression of Change  
 
 
 
 
X 
 
X 
 
 
EQ-5D-5L 
 
X 
 
  
X 
  
X 
 
 
Treatment Preference Surveygg 
 
 
 
 
 
 
X 
 
 
Physical Activity Monitor 
(ActiGraph Activity Monitor)hh  
 
X 
X 
X 
X 
X 
X 
X 
 
 
Exit interviewkk 
 
 
 
 
 
 
X 
 
 
Healthcare Resource Utilization 
 
X 
 
 
X 
 
X 
 
 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa 
20-Aug-2021 
Version number: 1  
 
Property of the Sanofi group - strictly confidential 
Page 20 
BIVV001 = rFVIIIFc-VWF-XTEN (recombinant coagulation factor VIII Fc - von Willebrand factor - XTEN fusion protein), BU = Bethesda units, FVIII = Factor VIII, HBV = hepatitis B virus, HCV = hepatitis C virus, HIV = 
human immunodeficiency virus, HJHS=Hemophilia Joint Health Score HAL=Hemophilia Activities List, pedHAL=Pediatric Hemophilia Activities List, TSQM=Treatment Satisfaction Questionnaire for Medications, 
PGIC=Patient Global Impression of Change, PGIS=Patient Global Impression of Severity 
a 
Screening may be accomplished over the course of more than 1 study visit if needed. The Screening Period is up to 8 weeks before Baseline. Washout prior to the Screening inhibitor test is at least 48 hours to 
obtain interpretable test results. 
b 
Washout prior to BIVV001 Day 1 dose administration is at least 96 hours (4 days) if the participant is receiving a conventional FVIII product and at least 120 hours (5 days) if current treatment is with an EHL FVIII 
product. The washout period before the Baseline Visit for subjects in abbreviated PK sampling may be modified at the discretion of the Investigator based on individual PK data and clinical phenotype in 
consultation with medical monitor.   
c 
Participants  should schedule their study visits to be 7 ±1 day after the previous prophylactic dose of BIVV001.  
d 
At this visit, participants in Arm B (on-demand treatment) switch to prophylaxis. Participants in the Sequential PK arm should schedule their Week 26 study visit to be 7 (+2) days after the previous prophylactic 
dose of BIVV001. 
e 
Unscheduled visits may be necessary during the study to repeat any blood sampling if required, or at the discretion of the Investigator. If a participant has an unscheduled visit, the Investigator will record data as 
appropriate based on the purpose of the visit. 
f 
This call or visit will occur 14 (+7) days after the last dose of BIVV001, unless the participant enrolls in the open-label extension study. For France specific pregnancy testing at the safety follow-up visit refer to 
Section 10.11.1. 
g 
Informed consent from the participant or the participant’s legal guardian MUST be obtained prior to any study-related procedures, including washout of current FVIII therapy specifically for entry into the study, or 
the country’s local regulations. Participant assent must also be obtained where applicable (according to the study site’s geographic region). 
h 
Demographics include sex, race, ethnicity, and date of birth (year of birth only), as permitted by local regulations. Race and ethnicity will be collected for reasons described in Section 10.1.4. 
i 
Includes hemophilia history assessment of disease severity, blood type, and Rh factor if not previously documented. For Repeat Screening Visit, update with any changes since original Screening Visit.  
j 
Collection of samples for genotype analysis (as permitted by local regulations and ethics committees) will be governed by a separate informed consent. HLA genotype will not be needed if previously 
documented.  
k 
Washout prior to the Screening inhibitor test is at least 48 hours to obtain interpretable test results. Washout prior to BIVV001 Day 1 dose administration is at least 96 hours (4 days) if the participant is receiving a 
conventional FVIII product and at least 120 hours (5 days) if current treatment is with an EHL FVIII product.  The washout period prior to BIVV001 Day 1 dose administration for subjects in abbreviated PK 
sampling may be modified at the discretion of the Investigator based on individual PK data and clinical phenotype in consultation with medical monitor. Washout prior to all other scheduled inhibitor tests must be 
at least 7±1 days. Inhibitor and ADA samples will be collected prior to BIVV001 dosing. Separate samples for anti-rFVIIIFc-VWF-XTEN antibody (ADA) testing will be collected at the same timepoint when any 
samples are collected for inhibitor testing (including samples for suspected inhibitor and confirmatory inhibitor tests). All inhibitor assays, including the assay for the Screening Visit and any confirmatory assays, 
will be performed by the central laboratory using the Nijmegen-modified Bethesda assay. If a Nijmegen-modified Bethesda assay result returns as ≥0.6 BU/mL, a separate sample must be collected and tested 
for confirmation of inhibitor development within 2 to 4 weeks of the original sample. Testing for potential ADA formation will be performed at a central laboratory using a validated rFVIIIFc-VWF-XTEN-specific 
ADA assay. Confirmed positive samples will be further characterized for antibodies specific to FVIII, Fc, D′D3, or XTEN. 
l 
Participants in Arm A will have BIVV001 doses given at each applicable scheduled visit. Participants in Arm B will have BIVV001 doses at visits Day 1, Weeks 26, 39, and 52. During the Scheduled study visits, 
BIVV001 will be delivered via a slow push IV injection of 8 ±2 minutes, at a rate of administration determined by the participant’s comfort level. For all BIVV001 injections performed at home BIVV001 will be 
delivered via a slow push IV injection at a rate of administration determined by the participant’s comfort level according to the vial and injection rate recommendations (Table 7). Injection start and stop time will be 
recorded in the eCRF. Other doses may be self/caregiver administered at home (or in clinic) (Table 3) 
m 
Vital signs include blood pressure, pulse rate, respiratory rate, and temperature (°C). Vital signs should be taken after the participant has been resting supine for 5 minutes. Vital signs will be measured pre-
injection and 30 (±15 minutes) from the start of injection at clinic visits. Vital signs should also be taken at any unscheduled visit. 
n 
Applicable to female participants only. A serum pregnancy test should be performed at screening. For all other time points, the choice of the pregnancy test (urine or serum) is at the discretion of the Investigator. 
If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from further participation if the serum pregnancy 
result is positive.  
o 
For participants who have been historically negative, viral testing will be performed at a central laboratory. Human immunodeficiency virus (HIV) tests will include HIV-1 antibodies, HIV-2 antibodies and HIV-1 
p24 antigen. Hepatitis B virus (HBV) tests will include HBV surface antigen, anti-HBV surface antibody and anti-HBV core antibody. Hepatitis C virus (HCV) tests will include anti-HCV antibodies. 
p 
For participants known to be HIV antibody positive, CD4 count and viral load tests must be performed at the central laboratory if results are not available from within 26 weeks prior to screening. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa 
20-Aug-2021 
Version number: 1  
 
Property of the Sanofi group - strictly confidential 
Page 21 
q 
Hematology parameters include red blood cell (RBC) count, white blood cell (WBC) count and differential, platelet count, hemoglobin (Hgb), and hematocrit (Hct). Blood samples for hematology analysis will be 
collected prior to BIVV001 dosing. 
r 
Clinical chemistry parameters include alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), bilirubin, blood urea nitrogen (BUN), 
creatinine, glucose, total protein, sodium, potassium, and chloride. Blood samples for clinical chemistry analysis will be collected prior to BIVV001 dosing. 
s 
The Von Willebrand comprehensive panel (includes assessments of von Willebrand Factor [VWF] ristocetin cofactor activity and VWF antigen).  Blood samples for analysis of Von Willebrand comprehensive 
panel will be collected prior to any BIVV001 dosing.  
t 
Adverse events (AEs) and serious adverse events (SAEs) occurring after signing of the informed consent form (ICF) through the Safety Follow-Up Call or Visit will be recorded on the case report form (CRF).  
u 
Prior and concomitant medications from up to 30 days prior to Screening and concomitant therapies and procedures from signing of ICF through the Safety Follow-Up Call or Visit will be recorded on the CRF. 
Pain medication related to Hemophilia and administered within 2 weeks prior to the visit will be recorded on the CRF. 
v 
In addition to scheduled clinic visits, telephone calls are planned approximately once a month for the site staff to check on each participant’s status.  During the monthly telephone call, the participant’s 
parent/caregiver will also be reminded about the requirement for timely ePD data entry, and assessments of “spontaneous” and “traumatic” bleeding episodes will be noted. 
w 
Investigator will examine each participant’s joints per the Haemophilia Joint Health Score (HJHS). At baseline, the Investigator will assess the presence of any target joints according to ISTH criteria. 
x 
For bleeding episodes treated at the study sites, the Investigator will contact the participant approximately 72 hours from the time the BIVV001 injection was administered to treat the bleeding episode and record 
the participant’s assessment of response to BIVV001 treatment on the eCRF using a 4-point bleeding response scale.  For bleeding episodes that are treated at home, participants will record response to 
bleeding episodes in the ePD.   
y 
Anatomical structural joint-health assessment via ultrasound imaging per Joint Tissue Activity and Damage Examination (JADE) protocol and/or Hemophilia Early Arthropathy Detection with Ultrasound (HEAD-
US) in a subpopulation of participants from Arm A at selected sites. The Ultrasound can be performed at the Baseline visit or up to 2 weeks after the Baseline Visit. 
z 
Samples will be collected prior to any BIVV001 dosing and will be archived by the central laboratory (if required) for future research, eg., immunology assays, further coagulation assays, or clarification of any 
clinical or laboratory AE, etc. This is optional and participants will sign an additional consent for this research.  
aa 
Participants will record all bleeding episodes in the ePD beginning at Baseline.  Assessment of response to bleeding episodes using a 4-point bleeding response scale.  The participant should record response 
approximately 72 hours from the time the first BIVV001 injection was administered to treat the bleeding episode, unless treatment of the bleed was administered in the clinic. In that case, the investigator will 
report the participant’s response to treatment via the eCRF.   
bb 
All participants (except those in the sequential PK subgroup of Arm A) will undergo abbreviated PK sampling after the first dose of BIVV001 (Baseline). See abbreviated PK sampling details in Table 2. 
cc 
Participants in the sequential PK subgroup (n=16) will undergo more extensive PK sampling at Baseline and again at Week 26. See sequential PK sampling details as described in Table 3. 
dd 
Peak and trough sample only (collected within 30 min prior to rFVIIIFc-VWF-XTEN dosing and 15 min ± 3 min post injection. This trough sample should be collected at the same time point as the trough inhibitor 
and anti-drug antibody (ADA) samples taken predose (Table 2). 
ee 
PROMIS Assessments to include Pain Intensity, Pain Interference (PROMIS-SF Pain Interference ≥18 years old or PROMIS Pediatric-SF Pain Interference <18 years old), and Physical Function (PROMIS-SF 
Physical Function ≥18 years old or PROMIS Pediatric-SF Physical Activity <18 years old). See Section 8.1.2. 
ff 
Patient Global Impression of Severity (PGIS) assessment will include a single question on patient perception of activity and a single question on patient perception of joint health. See Section 8.1.2. 
gg 
Treatment preference survey will consist of 2 questions on patient preference and a single question on Patient Global Impression of Change (PGIC). See Section 8.1.2. 
hh 
Where available, assessments of physical activity (PA) will be done by using a triaxial medical grade accelerometer (ActiGraph Activity Monitor) worn on the nondominant wrist. Device will be worn daily for 8 
consecutive days after the scheduled visits at Screening, Baseline, Weeks 4, 13, 26, 39, and for 8 consecutive days before the Week 52 visit. Refer to Section 8.1.4  
ii 
Coagulation parameters include activated partial thromboplastin time (aPTT) 
jj 
Please refer to Section 10.11.2 for Italy specific requirement 
kk 
 Interviews will be conducted with a subset of participants and may be done up to 6 months after the Week 52/EOS Visit, but before the EOS is declared. 
ll 
ePD training only. ePD devices are given to the patients at the baseline visit 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa 
20-Aug-2021 
Version number: 1  
 
Property of the Sanofi group - strictly confidential 
Page 22 
Table 2 - Abbreviated PK sampling schedule of activities  
Assessmentsa 
Pre-Doseb 
Post-Dosec 
Day 1 Week 
1 
Day 1 Week 1 
Day 2 
Day 4 
Day 8d (study drug can be 
taken after assessments on 
Day 8) 
15 m 
(±3 m) 
3 h 
(±15 m) 
24 h 
(±2 h) 
72 h 
(±5 h) 
168 h 
(±5 h) 
FVIII activity (measured 
by one-stage clotting 
aPTT and two-stage 
chromogenic assays)e 
X 
X 
X 
X 
X 
X 
NOTE: Initial dosing of BIVV001 is in the clinic on Day 1 Week 1. 
 
a 
All participants (except those in the sequential PK subgroup in Arm A) regardless of treatment arm. 
b 
Washout of at least 96 hours (for participants who were on conventional FVIII product) and at least 120 hours (for participants who were on EHL product) prior to sample collection is required. The washout period 
may be modified at the discretion of the Investigator based on individual PK data and clinical phenotype in consultation with medical monitor. 
c 
All sampling times are relative to the start of injection  
d 
Before injection 
e 
Details regarding sample handling and volume are provided in the Central Laboratory Manual  
Table 3 - PK sampling schedule of activities first dose (Week 1) and Week 26 for sequential PK subgroup  
Assessmenta 
Pre-Doseb  
Post-Dosec  
Day 1/ Week 1 
and Week 26d 
Day 1 
Day 2 
Day 4 
Day 8 
Day 11 
Day 15e 
15 m 
(±3 m) 
3 h 
(±15 m) 
24 h 
(±2 h) 
72 h 
(±5 h) 
168 h 
(±5 h) 
240 h 
(±5 h) 
336 h 
(±5 h) 
FVIII activity 
(measured by 1-stage 
clotting and 2-stage 
chromogenic assays)f 
X 
X 
X 
X 
X 
X 
X 
X 
Note: Participants in the sequential PK subgroup will not receive BIVV001 at Week 2 and Week 27 (or 1 week after the repeat PK).  
 
a 
For a subset of participants who are in the sequential PK subgroup (n=16 from Arm A). 
b 
For Day 1, a washout of at least 96 hours (for participants who were on conventional FVIII product) and at least 120 hours (for participants who were on EHL product) prior to sample collection is required.  For 
Week 26, a washout of 7 (+ 2) days is required. 
c 
All sampling times are relative to the start of injection 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa 
20-Aug-2021 
Version number: 1  
 
Property of the Sanofi group - strictly confidential 
Page 23 
d 
At Week 26, repeat the Day 1 sampling from Pre-Dose through Day 15 hour 336. If repeat PK assessments cannot be done at Week 26, an additional visit should be done as soon as possible and prior to Week 
39. In this instance, peak and trough measurements will need to be done at Week 26 and an additional visit scheduled to conduct the repeat PK profile. These assessments must be done before Week 39. Home 
nursing may be used. 
e 
Study drug will be withheld on Week 2 and Week 27 to allow for continued PK sampling on Day 8 Day 11, and Day 15. Study drug should then be taken after blood draw on Day 15.  
f 
Details regarding sample handling and volume are provided in the Central Laboratory Manual 
Table 4 - Surgical schedule of activities  
Tests and Assessments 
Pre-operative Assessment 
4 Weeks Prior to Surgerya 
(±7 days) 
Day of Surgery  
Post-operative Follow-up  
24 hours 
(±6 hours)b  
End of Perioperative 
Period Follow-up Phone 
Callc 
Minor surgery: at least 1 
week post-surgery 
Major surgery: at least 2 
weeks post-surgery 
Physical exam 
Xd 
 
 
 
Weight 
X 
X 
 
 
Vital signse 
Xd 
X 
 
 
Laboratory safety panelsf 
Xd 
Xh 
 
 
FVIII activity (1-stage clotting aPTT 
and 2-stage chromogenic assays)g  
Xd 
Xh,i  
X 
 
Nijmegen-modified Bethesda Assay 
(inhibitor assay) 
Xd 
Xh 
 
 
Anti-rFVIIIFc-VWF-XTEN Antibody 
(ADA) 
Xd 
Xh 
 
 
BIVV001 surgical administration 
 
Xi  
Xj 
 
BIVV001 between-clinic visit 
administration(s) 
<continued> 
 
 
 
ePD training review 
Xd 
 
 
 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa 
20-Aug-2021 
Version number: 1  
 
Property of the Sanofi group - strictly confidential 
Page 24 
Tests and Assessments 
Pre-operative Assessment 
4 Weeks Prior to Surgerya 
(±7 days) 
Day of Surgery  
Post-operative Follow-up  
24 hours 
(±6 hours)b  
End of Perioperative 
Period Follow-up Phone 
Callc 
Minor surgery: at least 1 
week post-surgery 
Major surgery: at least 2 
weeks post-surgery 
Participant’s assessment of 
response to treatment of bleeding 
episode in the ePDk 
<<ongoing as applicable>> 
 
Surgeon’s/Investigator’s 
assessment of response to surgeryl 
 
 
X 
 
Investigator’s assessment of 
response to a bleeding episode 
treated at the study sitem 
<<ongoing as applicable>> 
Adverse events/ 
serious adverse event recording 
<<continuous>> 
Concomitant medications, 
therapies, and procedures 
<<continuous>> 
BIVV001 = rFVIIIFc-VWF-XTEN (recombinant coagulation factor VIII Fc - von Willebrand factor - XTEN fusion protein), BU = Bethesda units, FVIII = Factor VIII. 
NOTE: 
In addition to scheduled clinic visits, telephone calls are planned approximately every 2 weeks for study site staff to check on each participant’s status.  Unscheduled visits may be necessary during the 
study to repeat safety assessments or to repeat blood sampling if required. 
 
a In the case of emergent surgery, Pre-operative Assessments 4 weeks prior to surgery are not required.  Day of Surgery Assessments must be completed. 
b Following a 24-hour post-operative study assessment, participants will follow the recommended postoperative treatment regimen as per Investigator’s advice.  
c Day 1/Week 1 PK profile with BIVV001 must be available to determine the doses and intervals to provide hemostasis during the surgical treatment period. The perioperative period may be extended at the 
discretion of the Investigator. Reasons include extended hospital stay or other clinical reasons that prohibit resumption of normal prophylactic regimen/on-demand treatment.  At the end of the perioperative period, 
participants will be instructed to resume their pre-surgery treatment regimen and register their treatment accordingly in the ePD. For participants who undergo major surgery at the end of the study, the EOS 
assessments will be scheduled at least 14 days post surgery, if applicable. 
d Assessments do not need to be repeated as part of the Preoperative Assessment if done within 4 weeks prior to surgery at a scheduled study visit.  If surgery is delayed ≥4 weeks, preoperative study assessments 
must be repeated. 
e Vital signs include blood pressure, pulse, respiratory rate, and temperature (°C), and should be taken after the participant has been resting supine for 5 minutes. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa 
20-Aug-2021 
Version number: 1  
 
Property of the Sanofi group - strictly confidential 
Page 25 
f 
Hematology parameters include red blood cell (RBC) count, white blood cell (WBC) count and differential, platelet count, hemoglobin (Hgb), and hematocrit (Hct). Clinical chemistry parameters include alanine 
aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), bilirubin, blood urea nitrogen (BUN), creatinine, glucose, total protein, sodium, 
potassium, and chloride. The Von Willebrand comprehensive panel (includes assessments of von Willebrand Factor [VWF] ristocetin cofactor activity and VWF antigen).  All blood samples will be collected prior to 
dosing. 
g FVIII activity samples should be taken according to local procedure and as required to monitor the participant’s FVIII levels during surgery and post-surgery until discharge from the hospital.  It is requested that a 
portion of the plasma from any FVIII activity samples also be sent to the central laboratory.  As a minimum requirement, at least 1 FVIII activity sample should be taken each day the participant is hospitalized.  If 
FVIII activity is not sampled daily per local requirements, sampling must occur specifically for study central laboratory analysis. The FVIII activity at the 24h follow up will be done only for patient with major surgery 
(for minor surgery it will be done only if clinically warranted).  
h It is not necessary to wait for central laboratory result before proceeding with surgery. In the case of minor dental surgery, blood samples can be drawn within 3 days prior to the day of surgery. 
i 
FVIII levels, tested during surgery, via local laboratory for immediate reference.  A portion of any FVIII activity sample to be sent to the central laboratory for reporting purposes. 
j 
Guidelines for perioperative management are provided in Section 8.1.1.6. The 24h post-operative BIVV001 dosing will be performed only if clinically needed (based on FVIII activity level). 
k Assessment of response to bleeding episodes using a 4-point bleeding response scale. The participant should record assessment of response to treatment of bleeding episode in the ePD, approximately 72 hours 
from the time the BIVV001 injection was administered to treat the bleeding episode.   
l 
Investigators’ or Surgeons’ assessment of participant’s hemostatic response to BIVV001 treatment on the ISTH 4 point response for surgical procedures scale when the participant has completed the surgical 
period, which includes the 24-hour postoperative period. 
m For bleeding episodes treated in-clinic/hospital, the investigator will contact the participant approximately 72 hours from the time the BIVV001 injection was administered to treat the bleeding episode and record the 
participant's assessment of response to BIVV001 treatment on the eCRF using a 4-point bleeding response scale 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 26 
2 
INTRODUCTION  
Recombinant coagulation factor VIII Fc – von Willebrand factor – XTEN fusion protein 
(rFVIIIFc-VWF-XTEN, efanesoctocog alfa) (BIVV001; BIIB073) is designed to be a next-
generation extended half-life (EHL) blood clotting factor VIII (FVIII) product. As with existing 
FVIII products, BIVV001 temporarily replaces the missing FVIII needed for effective hemostasis 
in hemophilia A patients. 
BIVV001 is a novel fusion protein consisting of single-chain B-domain deleted (BDD) human 
FVIII, the Fc domain of human immunoglobulin G1 (IgG1), the FVIII-binding D’D3 domain of 
human von Willebrand factor (VWF), and 2 XTEN polypeptide linkers. The Fc, VWF, and XTEN 
linker portions of the molecule are each designed to extend the half-life of the FVIII molecule in 
plasma. 
Figure 2 - Overall design and components of BIVV001  
 
 
2.1 
STUDY RATIONALE  
BIVV001 is designed to be a next-generation extended half-life (EHL) blood clotting factor VIII. 
Preclinical and clinical experience indicate that BIVV001 has an extended half-life, which can 
potentially achieve and maintain substantially higher factor activity levels than currently available 
treatments, with less frequent administration. This study is being conducted to determine the 
safety, efficacy, and PK of BIVV001 administered intravenously (IV) every week (QW) as 
prophylaxis or on-demand treatment. 
Hemophilia A is an X chromosome-linked bleeding disorder that occurs predominantly in males, 
and is characterized by deficiency of functional FVIII. It is caused by any of a variety of 
mutations of the coagulation FVIII gene, including missense or nonsense mutations, gene 
deletions, inversions, and splice junction mutations (12, 13). The worldwide prevalence of 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 27 
hemophilia A is estimated to be 1 in 10,000 and worldwide incidence is approximately 1 in 
5000 male births (14). Hemophilia A appears to be equally distributed across the world (15, 16). 
The severity of disease is characterized by the endogenous level of FVIII measured in the plasma. 
Severe hemophilia A (<1% endogenous FVIII activity level [ie, <1 IU/dL]) accounts for 
approximately 30% to 50% of all cases of hemophilia A (17, 18, 19). 
Individuals with severe hemophilia experience frequent bleeding episodes into major joints, soft 
tissue, and muscle, either spontaneously or following minor trauma. The disease can be acutely 
life-threatening. Repeated bleeding can lead to debilitating long-term complications, including 
hemophilic arthropathy from bleeding into the joints (20). Another severe complication is the 
development of target joints from inflammation due to prior bleeding. Intracranial hemorrhage 
can result in disability and death and is the leading cause of hemorrhagic death in individuals with 
hemophilia (21). Significant effects on physical and psychosocial well-being and quality of life 
and substantial financial burden have been reported in patients with severe hemophilia (22).  
Current therapies for Hemophilia A 
The use of cryoprecipitate in the 1960s and the large-scale production of commercial freeze-dried 
FVIII concentrates from plasma in the 1970s allowed for outpatient treatment of hemorrhages and 
reduced the risk during surgeries in patients (23, 24). In the 1970s and 1980s, techniques were 
developed to eliminate infectious agents, including treatment with heat and detergent, as well as 
immunoaffinity chromatography (25). 
Observations of a milder bleeding phenotype and superior joint health in patients with moderate 
hemophilia (FVIII activity 1% to 5%) compared to severe hemophilia prompted physicians to 
investigate the effect of regular injections of FVIII concentrate (26). Significant decreases in the 
frequency of bleeding and progression of arthropathy, as compared to historical data, were 
observed. These findings were confirmed by subsequent large cohort studies (27) and randomized 
clinical trials (28, 29, 30) comparing prophylactic treatment regimens with episodic (on-demand) 
treatment. Patients with hemophilia A treated episodically have been estimated to have from 20 to 
more than 40 bleeding episodes per year) (31, 32). With prophylactic treatment, annual median 
bleeding rates of less than 10 to as low as 1 bleeding episode per year have been reported (31). As 
a result, prophylaxis treatment regimens are being adopted as the standard of care in many 
countries, with episodic treatment an alternative option. 
However, it is well recognized that there are still many hemophilia patients throughout the world 
that continue with on-demand treatment regimens for a multitude of reasons, including high 
treatment burden of current prophylactic FVIII replacement therapies (33). This also includes 
newer generation extended half-life FVIII therapies that still require 2 to 3 injections per week to 
maintain activity levels ≥1% (34). The administration of FVIII is challenging, particularly in 
children, due to the requirement for venous access, dosing compliance due to time commitment, 
and the cost associated with frequent administration Intravenous (IV) access may be impaired in 
children and central venous access comes with its own set of complications including infection, 
sepsis, and catheter-related thrombosis. While overall prophylactic treatment continues to become 
more prevalent many hemophilia patients continue with on-demand treatment as their standard-of-
care, even with the current extended half-life FVIII products as the burden of current regimens 
remains an obstacle to adoption of and adherence to prophylaxis (35).  
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 28 
Next-generation extended half-life FVIII products that prevent and control bleeding episodes for 
longer periods of time potentially reduce the burden of frequent IV administration, and in turn 
may improve the quality of life for hemophilia patients. Products with a longer t½ would also offer 
the opportunity for reduced time below the threshold of FVIII activity levels at which there may 
be an increased risk of bleeding events (36). Indeed, it is well established that the accepted 
minimum targets of FVIII activity trough level (1 to 3 %) of current prophylactic treatment 
regimens is not adequate to protect patients from all bleeds and the resulting morbidity associated 
with such bleeding episodes. Joint bleeds still occur at these levels, leaving patients susceptible to 
long-term morbidity, especially joint damage (37, 38, 39). The ability to increase patient 
protection by achieving higher sustained levels of factor activity remains a critical need for 
patients (40) and follows recommendations from World Federation of Hemophilia (15). 
2.2 
BACKGROUND  
2.2.1 BIVV001  
BIVV001 is a recombinant fusion protein consisting of single-chain FVIII, the Fc domain of 
human immunoglobulin G1 (IgG1), the FVIII-binding D′D3 domain of von Willebrand factor 
(VWF), and 2 XTEN linkers. It is believed that the plasma t½ of FVIII is prolonged by its 
interaction with VWF. All current EHL rFVIII products interact with VWF and have comparable 
circulating half-lives, consistent with upper limits on the half-life of rFVIII variants, owing to the 
approximate 15-hour t½ of endogenous VWF (41). BIVV001 is the first rFVIII engineered to be 
independent of VWF, theoretically extending its t½. Nonclinical studies of BIVV001 have 
demonstrated that its t½ is significantly prolonged compared with current FVIII products. 
BIVV001 was engineered to include an rFVIIIFc containing a B-domain deleted human FVIII 
covalently linked to the Fc domain of human IgG1 that is currently approved for individuals with 
hemophilia A (42). The rFVIIIFc binds to the neonatal Fc receptor, utilizing a naturally occurring 
pathway by which the receptor binds the Fc region of IgG1 and protects immunoglobulins from 
lysosomal degradation. The rFVIIIFc fusion thereby allows for longer plasma t½ than endogenous 
FVIII. The fusion of Fc to human FVIII utilized a proven approach for increasing the t½ of 
therapeutic proteins, including several approved drugs (43, 44). Additionally, the rFVIIIFc in 
BIVV001 has been appended to the D′D3 domain of VWF, which not only provides protection 
and stability to FVIII but also prevents FVIII interaction with endogenous VWF, thus overcoming 
the limitation on FVIII t½ imposed by VWF (45, 46). The D′D3 domain has not been reported to 
interact with other targets. Additionally, in silico tools were utilized in the design and preparation 
of BIVV001 to assess and reduce the immunogenic potential of this fusion protein. Finally, the 
XTEN linkers (unstructured polypeptides composed exclusively of natural amino acids) extend 
the half-life of the fusion protein by altering the hydrodynamic radius of the molecule, which in 
turn reduces its clearance (47). 
Brief summary of clinical data of BIVV001 
The BIVV001 clinical development program includes a completed Phase 1/2a study (242HA101) 
and a clinically completed Phase 1 study (242HA102) evaluating the safety, tolerability, and PK 
of BIVV001 administered as single and repeat IV doses, respectively. In Study 242HA101, 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 29 
15 participants received a single dose of BIVV001. In Study 242HA102, 24 participants had 
received at least 1 dose of BIVV001. 
Study 242HA101 
Study 242HA101 was a FIH, Phase 1/2a open-label, dose-escalation, multicenter study to assess 
the safety, tolerability and PK of a single IV dose of BIVV001 in adult male previously treated 
patients (PTPs) with severe hemophilia A and completed on 12 November 2018 (last patient last 
visit).  Participants received a single IV dose of 25 IU/kg or 65 IU/kg rFVIII comparator (Advate) 
in the low and high dose cohorts, respectively, followed by a washout period and a single IV dose 
of 25 IU/kg or 65 IU/kg of BIVV001 in the low and high dose cohorts, respectively.  Of the  
16 participants enrolled in the study, all received a single dose of Advate ([25 IU/kg, n=7],  
[65 IU/kg, n=9]) and 15 received a single dose of BIVV001 ([25 IU/kg, n=6], [65 IU/kg, n=9]). 
Safety results 
Of the 16 participants enrolled, all 16 received a single dose of Advate and were included in the 
safety analysis.  During the Advate treatment period, 8 treatment emergent adverse events 
(TEAEs) were reported in 3 participants.  This included 4 treatment emergent serious adverse 
events (TESAEs) that occurred in 1 participant in the setting of a motor vehicle accident after 
which the participant was withdrawn from the study.  The most common TEAE during the Advate 
treatment period was Thrombin-antithrombin III complex increased (2 participants, 1 from each 
cohort).  
Of the 16 participants enrolled, 15 received a single dose of BIVV001 and were included in the 
safety analysis.  During the BIVV001 treatment period, 18 TEAEs were reported in 9 participants.  
This included 1 TESAE of a small intestinal obstruction; the Investigator attributed the event to 
complications from a prior appendectomy.  The most common TEAEs during both the BIVV001 
treatment period were Thrombin-antithrombin III complex increased and headache (2 participants 
each, 1 from each cohort). No inhibitor development to FVIII was detected and there were no 
reports of serious hypersensitivity or anaphylaxis.  Overall, single dose BIVV001 was well 
tolerated and no safety concerns were identified. 
Pharmacokinetic results 
In the low-dose (25 IU/kg) cohort, 6 participants had evaluable PK data for BIVV001 treatment. 
The average FVIII activity level as measured by the one-stage aPTT assay in the low-dose  
(25 IU/kg) cohort was 26.2% after 72 hours for BIVV001 as compared to 0.7% for Advate.  The 
extended PK profile for BIVV001 showed average FVIII activity levels of 12.2% at 5 days, 
5.3% at 7 days, and 1.3% at 10 days, based on the one-stage aPTT assay. The geometric mean of 
half-life was 37.6 hours for BIVV001 compared with 9.1 hours for Advate based on FVIII activity 
measured by the one-stage aPTT clotting assay [GMR=4.1 (95% CI: 2.9, 5.8); p<0.001] in the 
low-dose (25 IU/kg) cohort. 
In the high-dose (65 IU/kg) cohort, 8 participants had evaluable PK data for BIVV001 treatment. 
The average FVIII activity level as measured by the one-stage aPTT assay in the high-dose 
(65 IU/kg) cohort, was 78.2% after 72 hours for BIVV001 as compared to 2.3% for Advate.  The 
extended PK profile for BIVV001 showed average FVIII activity levels of 37.8% at 5 days, 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 30 
17.0% at 7 days and 1.1% at 14 days, based on the one-stage aPTT assay. The geometric mean of 
half-life was 42.5 hours for BIVV001 compared with 13.2 hours for Advate based on FVIII 
activity measured by the one-stage aPTT clotting assay [geometric means ration (GMR)=3.2 
(95% CI: 2.8, 3.8); p<0.001] in the high-dose (65 IU/kg) cohort. 
Study 242HA102 
Study 242HA102 was a Phase 1, open-label, single-site study to assess the safety, tolerability, and 
PK of repeat-dose BIVV001 in adult male PTPs with severe hemophilia A that was clinically 
completed on 12 April 2019 (last patient last visit). Participants enrolled into either Cohort 1 or 
Cohort 2 to receive a total of 4 once-weekly doses (Days 1, 8, 15, and 22) of BIVV001 at 
50 IU/kg and 65 IU/kg, respectively. A predose PK sample was taken on Day 1. In addition, there 
were multiple PK samples taken after dosing on Days 1 and 22, and a trough (168h) sample taken 
prior to dosing on Days 8, 15, and 22. A total of 10 participants enrolled in the 50 IU/kg dosing 
cohort and 14 participants enrolled in the 65 IU/kg dosing cohort. All 10 participants in the 
50 IU/kg dosing cohort received 4 doses of BIVV001 and all 14 participants enrolled in the 
65 IU/kg dosing cohort received 4 doses of BIVV001. 
Safety results 
All 24 participants enrolled received at least 1 dose of BIVV001 and were included in the safety 
analysis. Overall, 25 TEAEs were reported in 12 participants. There were no serious or related 
TEAEs reported and no participant discontinued the study due to a TEAE. The most common 
TEAEs were rhinitis (4 participants), arthralgia, upper respiratory tract infection, headache 
(2 participants, each). No inhibitor development to FVIII was detected and there were no reports 
of serious hypersensitivity or anaphylaxis. 
Pharmacokinetic results 
The PK analysis set (PKAS) included 9 participants from the 50 IU/kg dosing cohort and 
14 participants from the 50 IU/kg dosing cohort who had adequate blood sample collections 
following BIVV001 administration.  
Following BIVV001 dosing of 50 IU/kg on Day 1, mean FVIII activities based on one-stage and 
chromogenic assays were 45.53% and 29.37% at 72 hours, 21.56% and 13.49% at 120 hours, and 
7.91% and 5.97% at 168 hours, respectively. On Day 22 with QW dosing, mean FVIII activities 
based on one-stage and chromogenic assays were 46.28% and 30.46% at 72 hours, 22.30% and 
14.48% at 120 hours, and 9.83% and 6.74% at 168 hours, respectively. 
Following BIVV001 50 IU/kg QW dosing, the geometric mean elimination half-life (t1/2) of FVIII 
activities with one-stage and chromogenic assays were 41.25 and 43.87 hours, respectively. 
Following Day 1 dosing at 50 IU/kg, the geometric mean maximum FVIII activities (Cmax) with 
one-stage and chromogenic assays were 113 and 108 IU/dL, respectively, and those following 
Day 22 dosing were 131 and 115 IU/dL, respectively.  
Following Day 1 dosing at 50 IU/kg, the geometric mean cumulative FVIII activities (AUC0-tau) 
with one-stage and chromogenic assays were 7650 and 5630 hr*IU/dL, respectively, and those 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 31 
following Day 22 dosing were 8290 and 5860 hr*IU/dL, respectively, indicating minimal 
accumulation after the weekly dosing regimen. 
Following BIVV001 dosing of 65 IU/kg on Day 1, mean FVIII activities based on one-stage and 
chromogenic assays were 65.65% and 35.09% at 72 hours, 26.88% and 14.32% at 120 hours, and 
10.54% and 6.49% at 168 hours, respectively. On Day 22 with QW dosing, mean FVIII activities 
based on one-stage and chromogenic assays were 69.31% and 37.63% at 72 hours, 27.21% and 
16.51% at 120 hours, and 11.81% and 7.64% at 168 hours, respectively.  
Following BIVV001 65 IU/kg QW dosing, the geometric mean t1/2 of FVIII activities with 
one-stage and chromogenic assays were 37.31 and 42.51 hours, respectively. Following Day 1 
dosing at 65 IU/kg, the geometric mean Cmax with one-stage and chromogenic assays were 
158 and 155 IU/dL, respectively, and those following Day 22 dosing were 171 and 172 IU/dL, 
respectively. Following Day 1 dosing at 65 IU/kg, the geometric mean AUC0-tau with one-stage 
and chromogenic assays were 10500 and 7100 hr*IU/dL, respectively, and those following 
Day 22 dosing were 11200 and 7870 hr*IU/dL, respectively, indicating minimal accumulation 
after the weekly dosing regimen. 
A more detailed description of the chemistry, pharmacology, and safety of BIVV001 is provided 
in the BIVV001 Investigator’s Brochure. 
2.3 
BENEFIT/RISK ASSESSMENT  
Benefits 
BIVV001 is designed to be a new class of blood clotting FVIII engineered to be independent of 
VWF. A new class of FVIII products that prevents and controls bleeding episodes for longer 
periods of time potentially reduces the burden of frequent IV administration and in turn, may 
improve adherence and outcomes, including quality of life for individuals with hemophilia A. In 
addition to the patient burden that results from frequent administration (33) it is well established 
that the currently accepted FVIII activity trough level (1 to 3 %) is not adequate to protect patients 
from all bleeds and the resulting morbidity associated with such bleeding episodes. Joint bleeds 
still occur at these levels, leaving patients susceptible to long-term morbidity (39, 37, 38). The 
ability to increase patient protection by achieving higher sustained levels of factor activity 
remains a critical need for patients (40) and follows recommendations from the World Federation 
of Hemophilia (15). BIVV001 has the potential to achieve and maintain higher factor activity 
levels than currently available therapies, with less frequent administration, which would represent 
a major advance in hemophilia management.  
Risks 
There is a long history of therapeutic use of rFVIII products in the treatment of hemophilia A, 
with a well characterized safety profile. Patients treated with other rFVIII products have reported 
adverse reactions that include hypersensitivity, anaphylaxis, and development of inhibitors to 
FVIII.  Based on the currently available non-clinical and clinical data it is expected that BIVV001 
will have a safety profile similar to other rFVIII products.  
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 32 
The safety and tolerability of BIVV001 in previously treated adults with severe hemophilia A was 
evaluated in a single dose Phase 1/2a study (Study 242HA101) and in a repeat dose Phase 1 study 
(Study 242HA102).  Based on final data from these completed studies, single and repeat doses of 
BIVV001 were well tolerated and no safety concerns were identified. 
Conclusion 
Overall, the clinical development program for BIVV001 is supported by the available nonclinical 
and clinical data as well as the potential benefits associated with development of a rFVIII product 
with an extended half-life that offers increased protection in the treatment of individuals with 
hemophilia A.  
More detailed information may be found in the Investigator’s Brochure. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 33 
3 
OBJECTIVES AND ENDPOINTS  
Table 5 - Objectives and endpoints  
Objectives 
Endpoint 
Primary Efficacy Objective 
Primary Efficacy Endpoint 
• 
To evaluate the efficacy of BIVV001 as a 
prophylaxis treatment 
• 
Annualized bleeding rate (ABR) in Arm A 
Secondary Efficacy Objectives 
Secondary Efficacy Endpoints 
• 
To evaluate the efficacy of BIVV001 as a 
prophylaxis treatment   
• 
Intra-patient comparison of ABR during the BIVV001 
weekly prophylaxis treatment period versus the historical 
prophylaxis ABR for participants in Arm A who 
participated in Study 242HA201/OBS16221, an 
observational study (key secondary endpoint)  
• 
ABR by type and location for prophylaxis treatment per 
study arm   
• 
ABR for all bleeding episodes (including untreated 
bleeding episodes) for prophylaxis treatment per study 
arm   
• 
Intra-patient comparison of ABR during the QW 
prophylaxis treatment period versus the ABR during the 
on-demand treatment period in Arm B   
• 
Percentage of participants who maintain FVIII activity 
levels over 1%, 5%, 10%, 15%, and 20% in Arm A   
 
• 
To evaluate the efficacy of BIVV001 in the 
treatment of bleeding episodes     
• 
Number of injections and dose of BIVV001 to treat a 
bleeding episode per study arm and treatment regimen   
• 
Percentage of bleeding episodes treated with a single 
injection of BIVV001 per study arm and treatment 
regimen 
• 
Assessment of response to BIVV001 treatment of 
individual bleeding episodes based on the International 
Society on Thrombosis and Haemostasis (ISTH) 4-point 
response scale per study arm and treatment regimen 
• 
Physician’s global assessment (PGA) of participant’s 
response to BIVV001 treatment based on a 4-point 
response scale per study arm and treatment regimen 
• 
To evaluate BIVV001 consumption for the 
prevention and treatment of bleeding episodes  
• 
Total annualized BIVV001 consumption per participant 
per study arm and treatment regimen 
• 
To evaluate the effect of BIVV001 prophylaxis on 
joint health outcomes  
• 
 Change from Baseline to Week 52 in total score and 
domain scores (eg, swelling and strength) assessed by 
the Hemophilia Joint Health Score (HJHS) in Arm A 
• 
 Annualized Joint Bleeding Rate (AJBR) per study arm 
and treatment regimen 
• 
Target joint resolution at Week 52, based on ISTH criteria 
in Arm A 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 34 
Objectives 
Endpoint 
• 
 To evaluate the effect of BIVV001 prophylaxis on 
Quality of Life (QoL) outcomes 
• 
Changes in Haem-A-QoL (≥ 17 years old) total score and 
physical health score measures from Baseline to Week 
52 in Arm A 
• 
Changes in PROMIS Pain Intensity 3a from Baseline to 
Week 52 in Arm A 
• 
Changes in PROMIS SF Physical Function (≥18 years 
old) measures from Baseline to Week 52 in Arm A 
• 
To evaluate the efficacy of BIVV001 for 
perioperative management   
• 
Investigators’ or Surgeons’ assessment of participant’s 
hemostatic response to BIVV001 treatment on the ISTH 
4-point response for surgical procedures scale   
• 
Number of injections and dose to maintain hemostasis 
during perioperative period for major surgery   
• 
Total BIVV001 consumption during perioperative period 
for major surgery   
• 
Number and type of blood component transfusions used 
during perioperative period for major surgery   
• 
Estimated blood loss during perioperative period for major 
surgery   
 
Safety Objective 
• 
To evaluate the safety and tolerability of BIVV001 
treatment   
Safety Endpoints 
• 
The occurrence of adverse events (AEs) and serious 
adverse events (SAEs)   
• 
The occurrence of clinically significant changes from 
baseline in physical examination, vital signs, and 
laboratory tests   
• 
Development of inhibitors (neutralizing antibodies directed 
against factor VIII [FVIII]) as determined via the Nijmegen 
modified Bethesda assay   
• 
The occurrence of embolic and thrombotic events   
Pharmacokinetic Objective 
• 
To assess the PK of BIVV001 based on the one-
stage activated partial thromboplastin time (aPTT) 
and two-stage chromogenic FVIII activity assays   
Pharmacokinetic Endpoint 
• 
PK parameters including, but not limited to, maximum 
activity (Cmax), elimination half-life (t1/2), total clearance 
(CL), total clearance at steady state (CLss), accumulation 
index (AI), area under the activity time curve (AUC), 
volume of distribution at steady state (Vss), mean 
residence time (MRT), incremental recovery (IR), trough 
activity (Ctrough), time above predefined FVIII activity levels 
Exploratory Objectives 
Exploratory Endpoints 
• 
To evaluate joint-health structural outcomes via 
ultrasound using the Joint Activity and Damage 
Exam (JADE) protocol and/or Hemophilia Early 
Arthropathy Detection with Ultrasound (HEAD-US) 
• 
Changes in anatomical structural joint health outcomes 
via the JADE and/or HEAD-US protocol for ultrasound 
imaging from Baseline to Week 52 in a subpopulation at 
selected sites in Arm A 
• 
To assess the impact of BIVV001 treatment on  
patient reported outcome (PRO) measurements 
and physical activity (measures per study arm and 
treatment regimen) 
• 
Changes in PRO measures and physical activity per 
study arm and treatment regimen  
- 
PROMIS-SF Physical Function (≥18 years old) or 
PROMIS Pediatric-SF Physical Activity (<18 years 
old) 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 35 
Objectives 
Endpoint 
- 
Haem-A-QoL (≥17 years old) or Haemo-QoL  
(<17 years old) total score and subscale scores 
- 
PROMIS-SF Pain Interference ( ≥18 years old) or 
PROMIS Pediatric-SF Pain Interference (<18 years 
old)  
- 
EQ-5D-5L 
- 
Treatment Satisfaction Questionnaire for 
Medications (TSQM-9) 
- 
Patient Global Impression of Severity (PGIS) 
(activity component) 
- 
PGIS (joint component) 
- 
Change in physical activity measures (ActiGraph 
Activity Monitor) 
- 
Hemophilia Activities List (HAL) (≥18 years old) or 
pedHAL (<18 years old)  
• 
Change in HJHS total score and domain score (eg, 
swelling and strength) in Arm B by treatment regimen 
• 
Patient Global Impression of Change (PGIC) at Week 26 
and Week 52 per study arm and treatment regimen 
• 
Patient Preference at Week 52 per study arm and 
treatment regimen 
• 
Exit interview at Week 52 (or at subsequent follow-up 
visit) 
3.1 
APPROPRIATENESS OF MEASUREMENTS  
Each of the safety and efficacy assessments chosen for use in this study are considered well 
established and relevant in hemophilia. In addition, suitable steps have been built into each of 
these assessments to ensure their reliability and accuracy to minimize any risks to participant 
safety. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 36 
4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This is a Phase 3, open-label, multinational, multicenter study of the safety, efficacy and PK of IV 
BIVV001 in approximately 150 previously treated patients PTPs ≥12 years of age with severe 
hemophilia A (defined as <1 IU/dL [<1%] endogenous FVIII). Approximately 124 participants 
currently on a prophylaxis treatment regimen with FVIII will enter Arm A and receive BIVV001 
at a dose of 50 IU/kg IV once-weekly (QW) on a prophylaxis treatment regimen for 52 weeks. At 
least 75 participants of Arm A will have at least 6 months of participation in 
Study 242HA201/OBS16221 prior to baseline. Approximately 26 participants currently on an 
on-demand treatment regimen will enter Arm B and receive BIVV001 at a dose of 50 IU/kg IV on 
an on-demand basis for 26 weeks, then receive BIVV001 at a dose of 50 IU/kg IV QW on a 
prophylaxis treatment regimen for 26 weeks. 
All participants (except those in the sequential PK subgroup of Arm A) will undergo abbreviated 
PK sampling after the first dose of BIVV001 (Baseline). Participants in the Sequential PK 
Subgroup of Arm A will undergo more extensive PK sampling at Baseline and again at Week 26. 
In addition, participants from any arm who undergo major surgery during the study will be 
included in the surgery subset to assess control and prevention of bleeding during use of 
BIVV001 in the surgical setting. The definition of major surgery is included in Section 10.5. 
Screening 
Participants will come to the clinic for determination of eligibility. All screening evaluations must 
be completed within 8 weeks 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 rescreened, to confirm eligibility or record reasons for screening failure, 
as applicable. If a participant is considered a screen failure, the reasons for exclusion must be 
documented in his/her source documents and on the Screening log. 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 publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demographics, screen failure details, 
eligibility criteria, and any AEs. Participants who rescreen will sign the ICF again and repeat all 
assessments.  
Participants will undergo a washout period of at least 48 hours prior to the Screening inhibitor test 
to obtain interpretable test results. 
Washout prior to BIVV001 Day 1 dose administration (Baseline Visit) is at least 96 hours 
(4 days) if the participant is receiving a conventional FVIII product and at least 120 hours (5 days) 
if current treatment is with an EHL FVIII product. The washout period prior to the Baseline Visit 
for subjects in abbreviated PK sampling may be modified at the discretion of the Investigator 
based on individual PK data and clinical phenotype in consultation with medical monitor. 
Participants will be registered as screened in the Interactive Response Technology (IRT) system 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 37 
and will be assigned a unique identification number that will be used on study-related documents 
pertaining to the participant.  
Enrollment and baseline (Day 1) 
Participants will be enrolled via IRT, after all screening assessments have been successfully 
completed and after the Investigator has verified that the participant is eligible to participate in the 
study per criteria detailed in Section 5.1 and Section 5.2. Approximately 124 participants will be 
enrolled into Arm A: Prophylaxis Treatment regimen and 26 participants will be enrolled in Arm 
B: On-Demand Switch to Prophylaxis Treatment regimen; 16 participants will be enrolled in the 
sequential PK subgroup of Arm A. 
Participants who enter Arm A will receive BIVV001 as weekly prophylaxis for 52 weeks.  
Additional doses will be given as necessary to treat breakthrough bleeding episodes according to 
Section 6.1.1.2. Doses will be given in clinic according to the Schedule of Activities (Table 1).  
Other doses will be administered by the participant or caregiver at home, or in clinic. 
Participants who enter Arm B will receive BIVV001 to treat bleeds during the 26-week 
on-demand period. See Section 6.1.1.3 on doses for treatment of bleeds. At Week 26, participants 
in Arm B will switch to prophylaxis dosing, and dose BIVV001 at 50 IU/kg once weekly, until 
Week 52.  Additional doses will be given as necessary to treat breakthrough bleeding episodes 
during the 26-week prophylaxis period, according to Section 6.1.1.2. Doses will be given in clinic 
according to the Schedule of Activities (Table 1).  Other doses will be administered by participant 
or caregiver at home, or in clinic. 
Participants will be supplied with an electronic patient diary (ePD) at the Baseline visit to record 
all bleeding episodes and doses of BIVV001 administered after the Baseline visit. Entries are to 
be made in a timely manner and it is preferred that details of doses are entered immediately upon 
administration or within 7 days. Participants will be prompted to enter bleeding location, type 
(spontaneous or traumatic), and reasons for dosing (prophylaxis or treatment of a bleeding 
episode). An ePD training will be completed at the study site at the Baseline visit. Training of 
participants and/or caregivers should be documented in the appropriate source record. The ePD 
refresher training should also be provided at any point during the study.  
Participants with pre-planned surgery participating in the sequential PK subgroup should not enter 
the surgery subgroup until repeat PK sampling has been completed 26 weeks following the 
BIVV001 Day 1 PK profiling. 
Participants from any arm who undergo major surgery during the study will be included in the 
surgery subgroup.  A minimum of 10 major surgeries in at least 5 participants will be targeted to 
assess control and prevention of bleeding in the surgical setting.  
All participants will have an initial dose of BIVV001 on Day 1 and have subsequent PK 
assessments.  
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 38 
Study clinic visits 
All enrolled participants will come in to scheduled visits at the following time points: Baseline 
(Day 1), Week 4, Week 13, Week 26, Week 39, and Week 52.  Details of each visit are provided 
in Table 1. 
For participants in Arm A: each scheduled study visit subsequent to BIVV001 Day 1 is to be 
arranged 7 days (±1 day) after the preceding prophylaxis dose. The participant should withhold 
the weekly prophylaxis dose on the day of the study visit, so that it can be administered at the 
study visit.  
A subgroup of participants in Arm A (Sequential PK subgroup) will undergo Baseline BIVV001 
PK sampling and repeat BIVV001 PK sampling at the Week 26 Visit (to occur 7 (+2) days after 
preceding prophylaxis dose). 
For participants in Arm B: each scheduled study visit subsequent to Week 26 is to be arranged 
when a scheduled dose is due 7 days (±1 day) after the preceding prophylaxis dose. The 
participant should withhold the weekly prophylaxis dose, so that it can be administered at the 
study visit. 
Participants will undergo efficacy and safety assessments throughout their participation in the 
study. Safety assessments will include testing for inhibitor development to FVIII.  A Follow-up 
Safety Visit or Telephone Call  will occur 2 to 3 weeks after the last dose of BIVV001, unless the 
participant enrolls in the open-label extension study. Participants will complete their End of Study 
(EOS) Visit 52 weeks (±7 days) post-Baseline, or earlier if EOS has been declared.  
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
This multicenter, open-label, Phase 3 clinical study is being conducted to determine the safety, 
efficacy, and PK of BIVV001, administered as QW prophylaxis or on-demand at a dose of 
50 IU/kg IV. The study will enroll previously treated patients (PTPs) with severe hemophilia A 
aged 12 years or older. The study design takes into consideration the published guidelines for the 
clinical investigation of recombinant and human plasma-derived factor VIII products per the 
EMA guidelines (48). Based on current treatment patterns for hemophilia A, the current study 
design allows for inclusion of hemophilia patients treated with either prophylactic therapy (Arm 
A) or on-demand therapy (Arm B). 
Arm A will enroll participants currently treated with prophylactic therapy to receive prophylactic 
BIVV001 at QW dosing interval for 52 weeks.  Arm B will enroll participants currently treated 
with on-demand therapy. Participants in Arm B will enter to receive BIVV001 at a dose of 
50 IU/kg IV on an on-demand basis for 26 weeks, then switch to receive BIVV001 at a dose of 
50 IU/kg IV QW on a prophylaxis treatment regimen for 26 weeks.   
The primary efficacy endpoint will be ABR for prophylaxis treatment.  ABR has traditionally 
been used to assess efficacy of FVIII products in the clinical trial setting and is considered an 
objective and measurable endpoint consistent with current EMA guidance and established 
regulatory precedents.  Efficacy assessments in clinical studies of novel hemophilia therapies have 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 39 
typically compared prophylaxis to on-demand treatment regimens.  However, it is now well 
recognized that prophylaxis is considered standard-of-care therapy for hemophilia A and reflected 
in current hemophilia treatment guidelines (49). Therefore, to more appropriately reflect the 
current practice patterns and treatment guidelines of hemophilia, the primary efficacy will be 
assessed for prophylaxis treatment in Arm A. Given the robust information available from 
previously marketed FVIII products and the well-characterized efficacy of prophylaxis treatment, 
an estimation approach will be used for the primary efficacy analysis.  The mean annualized 
bleeding rate and one-sided 97.5% confidence interval will be estimated for prophylaxis treatment 
in Arm A using a Negative-Binomial regression model with a pre-defined success threshold based 
on published historical data from other marketed FVIII products.  Notably, recently approved 
hemophilia therapies have also utilized the estimation approach for key efficacy endpoint analysis 
(50, 51).   
In addition, a key secondary efficacy endpoint will compare ABR between BIVV001 weekly 
prophylaxis treatment and historical prophylaxis treatment using an intra-patient comparison for 
participants in Arm A who participated in observational Study 242HA201/OBS16221. A 
non-inferiority test using a margin that preserves a substantial amount of the treatment effect will 
provide meaningful data in the context of current standard of care therapy. The observational 
study allows prospective data collection on bleeding episodes and treatment administration for 
participants on marketed FVIII products. Utilization of an ePD for data collection in a similar 
manner to the data collection in this Phase 3 study facilitates a robust comparison to support the 
primary endpoint results. 
While prophylactic therapy continues to evolve as the standard of care, it is well recognized that 
there are still many hemophilia patients around the world who continue with on-demand treatment 
regimens for a multitude of reasons, including high treatment burden of current prophylactic 
FVIII replacement therapies (33). This also includes newer generation extended half-life FVIII 
therapies that still require 2 to 3 injections per week to maintain activity levels ≥1% (34). On-
demand treatment regimens continue to persist throughout the world, where it is estimated that 
one-third to one-half of patients are not on routine prophylactic therapy (52, 53). Thus, many 
hemophilia patients continue with on-demand treatment as overall prophylactic treatment as 
standard-of-care continues to become more prevalent (35). Including an on-demand arm for 
BIVV001 Phase 3 study is also consistent with clinical studies of recently approved hemophilia A 
therapies (11, 54, 51). Given that the superiority of prophylaxis treatment compared to on-demand 
treatment has already been established, and prophylaxis treatment is continuing to evolve as 
standard-of-care therapy, the traditional comparison of ABR between on-demand and prophylaxis 
treatment regimens will be performed as a secondary efficacy analysis.  The switch design of Arm 
B enables an intra-subject comparison of on-demand treatment vs prophylactic treatment.  Finally, 
Arm B will also support evaluation of efficacy of BIVV001 for on-demand treatment of bleeding 
episodes and surgical management. 
4.3 
JUSTIFICATION FOR DOSE  
The dose of 50 IU/kg IV QW was selected as the prophylactic and on-demand dose in adults and 
adolescents ≥12 years. The once-weekly dosing schedule was chosen to optimize participant 
protection and to reduce the treatment burden on participants and their families. The dose was 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 40 
selected and confirmed based on data from Study 242HA101, which assessed the PK of 2 single 
dose levels of BIVV001 (25 IU/kg and 65 IU/kg) and Study 242HA102, which assessed the PK of 
2 QW dose levels of BIVV001 (50 IU/kg and 65 IU/kg). A population PK model was built with 
data from the single dose Study 242HA101 and multiple dose Study 242HA102, and simulations 
were performed to understand steady state kinetics of BIVV001.  
At a dose of 50 IU/kg IV QW, the model predicted a population mean time for which there is 
normal or near normal FVIII activity levels of greater than 40% for 3.3 days with the one-stage 
aPTT assay and 2.3 days with the chromogenic assay, providing a sustained level of protection. 
The model predicted for this dose, a population mean Cmax of less than or approximately 
150 IU/dL (120 and 159 IU/dL for the chromogenic and 1 stage aPTT assay respectively) which is 
the upper limit of the physiological range of FVIII activity. At the dose of 50 IU/kg, the 
population mean Ctrough was 10 and 7 IU/dL, and Cavg was 51 and 37 IU/dL based on one-stage 
aPTT and chromogenic assays, respectively. Recent literature suggests that maintenance of Cavg 
>20% may significantly reduce joint bleeds in the hemophilia population (38, 55).  
The Sponsor’s proposed dosing regimen was selected taking into consideration the potential 
increased protection conferred by sustained FVIII activity levels in the normal to mild range along 
with the decreased treatment burden of once weekly dosing. This combined level of FVIII activity 
protection and dosing interval is not possible with current intravenous FVIII replacement 
therapies (34). BIVV001 is the first FVIII replacement therapy to overcome the half-life 
limitations of VWF (41) and could thus allow for higher sustained levels of protection. In 
addition, BIVV001 is the first FVIII replacement therapy that allows prospective testing of the 
hypothesis that higher sustained factor levels will further reduce or eliminate joint bleeds and 
potentially provide other clinical benefits.  
Development of an extended half-life FVIII replacement therapy whose half-life extension is 
independent of VWF and can be administered less frequently while achieving higher factor levels 
would represent a major advance in hemophilia management. Historically, prophylactic therapy 
for patients with hemophilia A targeted FVIII activity levels of ≥1% (29). However, it has become 
clear that the currently defined FVIII activity threshold of 1%-3% trough for prophylactic therapy 
is insufficient to prevent all bleeding and does not eliminate the considerable long-term joint 
damage associated with severe hemophilia A, albeit it does delay its onset (39, 56). Manco-
Johnson and colleagues recently evaluated prophylaxis use in the United States in relation to 
bleeding rates and joint health outcomes (37). Despite increasing rates of prophylaxis usage in this 
population, patients on prophylaxis continued to suffer from joint bleeds and experience target 
joints. This trend is also noted in the pediatric population where despite prophylactic treatment 
regimens, pediatric patients also develop joint damage as evidenced on MRI at an early age (28) 
when the burden and incidence would likely increase over time. The development of joint damage 
is also impacted by the time at which prophylaxis therapy is initiated (57). Further evidence in 
severe hemophilia A patients demonstrates improved bleeding rates in patients targeting high 
troughs (8%-12%) vs the low troughs (1%-3%), with a similar safety profile (58). Thus, the 
continued development of joint damage despite prophylactic treatment suggests that current 
treatment regimens targeting FVIII activity trough levels of ≥1% are inadequate (40). 
Recommendations from World Federation of Hemophilia have supported the maintenance of 
higher FVIII activity levels (15). 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 41 
It is recognized that chronic elevations in FVIII above the physiological upper range of 150 IU/dL 
in patients without hemophilia or deficits in coagulation increases thrombotic risk in a 
dose-dependent manner (59). Data from the 65 IU/kg cohort in Study 242HA101 demonstrate that 
mean Cmax levels were maintained in the physiological upper range of FVIII activity and similar to 
the mean Cmax levels for a recently approved EHL FVIII replacement therapy with a dose of 
60 IU/kg (60). Additionally, following 4 weekly doses of BIVV001 with 50 IU/kg dose, the mean 
FVIII activity level did not reach 150 IU/dL. A population PK model using data from 
Studies 242HA101 and 242HA102 with a BIVV001 dose of 50 IU/kg at steady state predicted a 
median time above 150% activity level of 0.77 hours and 0 hours for the one-stage aPTT and 
two-stage chromogenic assays, respectively. Therefore, the Sponsor believes the proposed dose of 
50 IU/kg will yield potential benefit by sustaining FVIII activity levels without an unacceptable 
thrombotic risk to participants in the Phase 3 studies.  
The dose of BIVV001 recommended for treating bleeding episodes and surgical management 
follows published treatment guidelines to achieve minimum FVIII activity levels (16). 
Simulations were conducted using the population PK model mentioned above and scenario testing 
indicated that these dosing paradigms would achieve the minimum FVIII activity levels for 
surgery as defined by WFH guidelines (16).  
A dose 50 IU/kg of BIVV001 is recommended for treating bleeding episodes. This dose maintains 
the mean FVIII activity levels in the normal to low normal range (more than 40%) for up to 2 to 
3 days postdose. Using the same dose for treatment of bleeding episodes as for the prophylactic 
treatment regimen is recommended to avoid complexity and dosing mistakes. Most bleeding 
episodes will require treatment with 1 dose of BIVV001. On clinical indication, additional doses 
of 30 or 50 IU/kg can be considered every 2 to 3 days. For minor/moderate bleeding episodes that 
occur within 2 to 3 days after a prophylaxis dose and require treatment, the investigator has the 
option to choose a lower initial dose of 30 IU/kg. The Sponsor has defined minor/moderate/major 
bleeding episodes in Section 10.10 of the protocol. 
A loading dose of 50 IU/kg of BIVV001 is recommended for perioperative management. 
Simulations were conducted using the population PK model mentioned above and scenario testing 
indicated that for minor surgery, mean factor levels in the range suggested by WFH are obtained 
with a single dose. Alternatively, the procedure may be planned around a standing prophylactic 
dose without the need for additional dosing. For major surgeries that require target FVIII activity 
levels in the normal range that decrease over time from surgery, repeated doses of 30 or 50 IU/kg 
is recommended. 
4.4 
END OF STUDY DEFINITION  
End of Study will occur when all of the following criteria have been met:  
• 104 participants have reached 50 exposure days (EDs) and have completed a valid 
inhibitor test after the 50th ED.   
• At least 63 participants in Arm A have at least 6 months of participation in this study and 
have at least 6 months of participation in Study 242HA201/OBS16221 prior to baseline. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 42 
• Thirteen participants in the PK subgroup have completed the BIVV001 Day 1 PK profile, 
and a repeat 14-day BIVV001 PK profile 26 weeks later with adequate estimate of 
terminal half-life. 
If there are participants still ongoing in the study when EOS is declared, they will return to the 
study for an EOS visit to complete their participation. 
For France specific clarification on end of study requirements refer to Section 10.11.1. 
4.5 
STUDY STOPPING RULES  
The Sponsor may terminate the study at any time, after informing Investigators, Institutional 
Review Boards/Ethics Committees, and applicable regulatory agencies.  Investigators will be 
notified by the Sponsor (or designee) if enrollment and dosing are suspended, completed, or 
closed.  
For France specific clarification on end of study requirements refer to Section 10.11.1  
4.5.1 Criteria for dose and/or enrollment suspension  
The occurrence of specific study events will require that further enrollment in the study and 
further dosing be suspended.  In this situation, the event(s) will be investigated prior to enrollment 
and dosing of any additional participants.   
In this study, events requiring dose and/or enrollment suspension are as follows: 
• Inhibitor development in 3 or more participants following administration of BIVV001 
(See Section 8.3.1.1 for definition of inhibitor development). 
• The Investigator and Sponsor (or Sponsor alone) determine that an event or current data 
warrant further evaluation. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 43 
5 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted. 
5.1 
INCLUSION CRITERIA  
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
I 01. Participant must be equal to or greater than 12 years of age inclusive, at the time of signing 
the informed consent.  
Type of participant and disease characteristics 
I 02. Severe hemophilia A, defined as <1 IU/dL (<1%) endogenous FVIII activity as 
documented either by central laboratory testing at Screening or in historical medical 
records from a clinical laboratory demonstrating <1% FVIII coagulant activity (FVIII:C) 
or a documented genotype known to produce severe hemophilia A 
I 03. Previous treatment for hemophilia A (prophylaxis or on demand) with any recombinant 
and/or plasma-derived FVIII, or cryoprecipitate for at least 150 EDs. 
I 04. Current regimen includes one of the following: 
• Prophylactic treatment regimen with a FVIII product or prophylactic emicizumab therapy 
for at least 6 months during the previous 12 months. Appropriate washout time needs to be 
taken into account. 
• On-demand regimen with a  FVIII product with a history of at least 12 bleeding episodes 
in the previous 12 months or at least 6 bleeding episodes in the previous 6 months prior to 
study enrollment.  
- 
On-demand participant is accepting to move to a prophylaxis treatment regimen after 
26-week on-demand period. 
I 05. Platelet count ≥100,000 cells/μL at Screening. 
I 06. A participant known to be human immunodeficiency virus (HIV) antibody positive, either 
previously documented or identified from screening assessments, must have the following 
results prior to enrollment. 
a. CD4 lymphocyte count >200 cells/mm³ 
b. Viral load of <400 copies/mL 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 44 
Documented results of CD4 lymphocyte count and viral load will be accepted if samples 
were collected within 26 weeks prior to Screening or if samples were collected during 
Screening and evaluated by the central laboratory. 
Participants who have previously tested negative for HIV must have a repeat test by the 
central laboratory during Screening 
I 07. Willingness and ability of the participant or surrogate (a caregiver or a family member  
≥18 years of age) to complete training in the use of the study electronic Patient Diary 
(ePD) and to use the ePD throughout the study.  
Sex 
I 08. Male or Female 
Contraceptive use by men or women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
a) Male participants 
- 
No contraceptive measures required for this study. 
b) Female participants 
- 
A female participant is eligible to participate if she is not pregnant or 
breastfeeding, and at least one of the following conditions applies: 
- 
Is not a woman of childbearing potential (WOCBP), as defined in Section 10.4 
or 
- 
Is a WOCBP and using an acceptable contraceptive method as described  
Section 10.4 during the intervention period (at a minimum until Safety Follow-up 
Call or Visit). The investigator should evaluate the effectiveness of the 
contraceptive method in relationship to the first dose of study intervention. 
and 
- 
A WOCBP must have a negative highly sensitive pregnancy test before the first 
dose of study intervention as described in Section 10.2. A serum pregnancy test 
should be performed at screening. For all other time points, the choice of the 
pregnancy test (urine or serum) is at the discretion of the Investigator. 
Additional requirements for pregnancy testing during and after study intervention are located in 
Section 10.2. 
The investigator is responsible for review of medical history, menstrual history, and recent sexual 
activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 45 
Informed Consent 
I 09. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1) 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. [In countries where legal age of majority is above 
18 years, a specific ICF must also be signed by the participant’s legally authorized 
representative]. 
I 10. Ability of the participant or his or her legally authorized representative (eg., parent or legal 
guardian) to understand the purpose and risks of the study and provide signed and dated 
informed consent or assent (as applicable) and authorization to use protected health 
information in accordance with national and local participant privacy regulations. 
5.2 
EXCLUSION CRITERIA   
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. Any concurrent clinically significant liver disease that, in the opinion of the Investigator, 
would make the participant unsuitable for enrollment. This may include, but is not limited 
to cirrhosis, portal hypertension, and acute hepatitis. 
E 02. Serious active bacterial or viral infection (other than chronic hepatitis or HIV) present 
within 30 days of Screening. 
E 03. Other known coagulation disorder(s) in addition to hemophilia A. 
E 04. History of hypersensitivity or anaphylaxis associated with any FVIII product 
E 05. History of a positive inhibitor test defined as ≥0.6 BU/mL, or any value greater than or 
equal to the lower sensitivity cut-off for laboratories with cut-offs for inhibitor detection 
between 0.7 and 1.0 BU/mL, or clinical signs or symptoms of decreased response to FVIII 
administrations. Family history of inhibitors will not exclude the participant. 
E 06. Positive inhibitor result, defined as ≥0.6 BU/mL at Screening. 
E 07. Abnormal renal function, defined as serum creatinine >2.0 mg/dL taken at Screening. For 
Italy-specific E07 requirements refer to Section 10.11.2. 
E 08. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5 x upper 
limit of normal (ULN) taken at Screening. 
E 09. Serum total bilirubin >3 x ULN, taken at Screening. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 46 
Prior/concomitant therapy 
E 10. Vaccination within 30 days of Screening. 
E 11. Treatment with acetylsalicylic acid (ASA) or non-NSAID anti-platelet therapies within  
2 weeks prior to screening. 
E 12. Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) above the maximum dose 
specified in the regional prescribing information within 2 weeks prior to Screening. 
E 13. Systemic treatment within 12 weeks prior to Screening with chemotherapy and/or other 
immunosuppressive drugs (except for the treatment of hepatitis C virus [HCV] or HIV). 
Use of corticosteroids is allowed, except for systemic corticosteroid treatment given daily 
or on alternate days for >14 days. Local, topical, and/or inhaled steroid use is permitted. 
Prior/concurrent clinical study experience 
E 14. Emicizumab use within the 20 weeks prior to Screening. 
E 15. Previous enrolment in this study; participants who fail Screening may re-screen. 
E 16. Treatment with an investigational product within 30 days or 5.5 half-lives prior to 
Screening, whichever is longer. For investigational products with a pharmacodynamic 
effect that persists longer than the half-life, the maximal pharmacodynamic effect must 
return to baseline prior to Screening. 
 Other exclusions 
E 17. Major surgery within 8 weeks prior to Screening. Major surgery is defined as any surgical 
procedure (elective or emergent) that usually, but not always, involves general anesthesia 
and/or respiratory assistance, in which a major body cavity is penetrated and exposed, or a 
substantial impairment of physical or physiological functions is produced (eg, laparotomy, 
thoracotomy, craniotomy, joint replacement, or limb amputation). 
E 18. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized.  
E 19. Any country-related specific regulation that would prevent the participant from entering 
the study – see Appendix 10 (Section 10.11) (country specific requirements). 
E 20. Participant not suitable for participation, whatever the reason, as judged by the 
Investigator, including medical or clinical conditions, or participants potentially at risk of 
noncompliance to study procedures. 
E 21. Participants are dependent on the Sponsor or Investigator (in conjunction with Section 1.61 
of the ICH-GCP Ordinance E6). 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 47 
E 22. Participants are employees of the clinical study site or other individuals directly involved 
in the conduct of the study, or immediate family members of such individuals. 
E 23. Sensitivity to any of the study interventions, or components thereof, or drug or other 
allergy that, in the opinion of the Investigator, contraindicates participation in the study. 
For additional France-specific exclusion criteria refer to Section 10.11.1. 
5.3 
LIFESTYLE CONSIDERATIONS  
Participants who routinely administer an additional dose of FVIII prior to a sports activity or 
increased physical activity will not be allowed to do so in this study. However, the day of dosing 
BIVV001 in Arms A and B (prophylaxis period) could be chosen prior to a weekly recurring 
physical activity   
5.4 
SCREEN FAILURES  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in 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 screen failure reasons, and any serious adverse event 
(SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened twice (maximum). Rescreened participants should be assigned the same participant 
number as for the initial screening. If a participant is considered a screen failure, the reasons for 
exclusion must be documented in his/her source documents and on the Screening log. Reasons for 
screen failure will be captured in the IXRS.  
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 48 
6 
STUDY INTERVENTION  
Study intervention is defined as any investigational intervention intended to be administered to a 
study participant according to the study protocol. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
Table 6 - Overview of study interventions administered  
ARM name 
Prophylaxis 
On-demand 
Intervention name 
rFVIIIFc-VWF-XTEN (BIVV001) 
rFVIIIFc-VWF-XTEN (BIVV001) 
Type 
Drug 
Drug 
Dose formulation 
Lyophilized powder in a sterile vial 
that requires 
reconstitution with Sterile Water for 
Injection (diluent) 
Lyophilized powder in a sterile vial 
that requires reconstitution  with 
Sterile Water for Injection (diluent) 
Unit dose strength(s) 
250, 500, 1000, 2000, 3000 
and 4000 IU per vial 
250, 500, 1000, 2000, 3000 and  
4000 IU per vial 
Dosage level(s) 
50 IU/Kg every week 
50 IU/Kg 
Route of administration 
Intravenous 
Intravenous 
IMP and NIMP 
IMP 
IMP 
Packaging and labeling 
Study intervention will be provided in 
vials. Each vial will be labeled as 
required per country requirement 
Study Intervention will be provided in 
vials. Each vial will be labeled as 
required per country requirement. 
[Current/Former name(s) or 
alias(es)] 
--- 
--- 
6.1.1 Investigational medicinal product(s)  
BIVV001 drug product will be supplied as a lyophilized powder in a sterile vial that requires 
reconstitution with Sterile Water for Injection (diluent), which will also be supplied by Sanofi. For 
this study, each vial of drug product includes either of 250, 500, 1000, 2000, 3000 or 4000 IU of 
BIVV001 in the formulation buffer (10 mM L-histidine, 250 mM Arginine-HCl, 5mM CaCl2, 5% 
(w/v) sucrose, 0.05% (w/v) polysorbate 80, pH 7.0). Please refer to the BIVV001 Directions for 
Handling and Administration (DHA), which is part of the Pharmacy Manual, or the BIVV001 IB 
for additional details. 
BIVV001 must be dispensed only by the Pharmacist or appropriately qualified staff. BIVV001 is 
to be dispensed only to participants or to caretakers and legal guardians of participants enrolled in 
this study. Once BIVV001 is prepared for a participant, it can be administered only to that 
participant. The first dose of BIVV001 must be administered at the Baseline visit by the 
Investigator or qualified delegate at each study site, where medication and resuscitation 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 49 
equipment for the emergent management of an allergic reaction are readily available. BIVV001 
preparations are for one-time study use only; the study site staff should not use any leftover 
BIVV001 remaining in the vial for another participant. 
6.1.1.1 Study treatment schedule and administration  
Instructions for the preparation and administration of BIVV001 are provided in the Directions for 
Handling and Administration (DHA) and the Information for Patients.  
The prophylactic treatment regimen is once weekly (every 7 days) dosing with 50 IU/kg 
BIVV001. The dose was determined based on a population PK simulation with PK parameters 
derived from Study 242HA101.  The aim of the 50 IU/kg IV QW treatment regimen is to provide 
sustained FVIII activity levels in the normal to mild hemophilia range (maintaining FVIII trough 
level between about 10% and 20% at Day 7) and to decrease treatment burden with once weekly 
dosing. (For full details see Section 4.3) 
During Scheduled study visit BIVV001 will be delivered via a slow push IV injection of 8 ±2 
minutes, at a rate of administration determined by the participant’s comfort level. For all 
BIVV001 injections performed at home BIVV001 will be delivered via a slow push IV injection 
at a rate of administration determined by the participant’s comfort level according to the vial 
injection rate recommendations (Table 7).  
Table 7 - Home Injection:  BIVV001 weight-based vial injection rate recommendations  
Participant Weight 
Minimum Injection Duration Per Vial 
<=55 kg 
2 minutes per vial 
>55 kg 
1 minute per vial 
Any missed doses should be taken as soon as possible or according to the instructions of the 
Investigator, taking into account that 2 consecutive prophylactic doses of 50 IU/kg should be 
separated by a period of at least 72 hours.   
During the clinic visits and monthly telephone calls, the study site staff will verify whether or not 
a bleeding episode has occurred, and it was “spontaneous” or “traumatic”. During the monthly 
telephone call, the participant or participant’s parent/caregiver will also be reminded about the 
requirement that ePD data be entered as soon as possible, (within a maximum of 7 days) 
following an injection, as well as verify treatment regimen compliance. 
6.1.1.2 Treatment of bleeding episodes during Prophylactic Treatment Regimen  
The patient will be instructed by the clinic on how to treat a bleeding episode at home and record 
this in the ePD (Section 8.1.1.1). 
Bleeding episodes requiring treatment during prophylaxis with BIVV001 will be treated with a 
single dose of 50 IU/kg, as described in Table 8. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 50 
Major bleeding episodes will be treated in the hospital/clinic or at home, as applicable.  The 
participant will be instructed to consult the investigational site prior to dosing a follow-up 
injection. Administration of a second dose of BIVV001 as follow-up treatment will be determined 
by the Investigator and participant based on the participant’s clinical condition. If a bleed does not 
improve, additional doses of 30 or 50 IU/kg every 2 to 3 days may be considered. For 
mild/moderate bleeds within 2-3 days of a recent prophylactic dose, a 30 IU/kg dose may also be 
used. Treatment of any bleeding reported within 72 hours of a previous episode at the same 
location should be considered a follow-up injection and the event should not be recorded as a new 
bleeding episode. If a bleeding episode occurs at the time when a regular prophylaxis dose of 
BIVV001 is due, the participant will inject with a dose of 50 IU/kg.  
Resumption of prophylaxis dosing following treatment for bleeding episodes is outlined below: 
If the bleeding episode is stopped with a single dose of 50 IU/kg BIVV001, the participant will 
continue with the schedule of weekly prophylaxis dosing he/she was on prior to the bleeding 
episode, unless the next scheduled prophylaxis dose is within 72 hours of the treatment of the 
bleeding episode.  In this case, the prophylaxis dose should be delayed until 72 hours after last 
50 IU/kg dose for treatment of the bleeding episode. Thereafter, the participant should return to 
the schedule of weekly prophylaxis dosing that he/she was on prior to the bleeding episode. If the 
participant was treated with an initial dose of 30 IU/kg or needs additional doses of 30 IU/kg after 
the first 50 IU/kg dose to treat a bleeding episode, these additional doses will not require any 
further delay of the next prophylaxis dose.  
6.1.1.3 Treatment of bleeding episodes during the On-Demand Treatment Regimen  
Bleeding episodes during the on-demand treatment regimen with BIVV001 (first 26 weeks of 
Arm B) will be treated with a single dose of 50 IU/kg BIVV001. Bleeding episodes will be treated 
in the hospital/clinic or at home, as applicable.  The participant will be instructed to consult the 
investigational site prior to dosing a follow-up injection. Administration of a second dose of 
BIVV001 as follow-up treatment will be determined by the Investigator based on the participant’s 
clinical condition. If a bleeding episode does not improve, additional doses of 30 or 50 IU/kg 
every 2 to 3 days may be considered. Treatment of any bleeding reported within 72 hours of a 
previous episode at the same location should be considered a follow-up injection and the event 
should not be recorded as a new bleeding episode.  
6.1.1.4 Surgical dosing  
Minor surgeries can be performed while participating in this trial by administering a dose of 
50 IU/kg BIVV001 (Table 8). 
Participants from any arm who undergo major surgery during the study will be included in the 
surgery subset. Definitions for major and minor surgery are listed in Section 10.7. 
Prior to surgery, the Investigator will plan the perioperative treatment regimen of FVIII 
replacement therapy generally required for the type of planned surgery in accordance with the 
dosing guidance in Table 8. Recommendation for the appropriate dosing of BIVV001 in the 
surgical treatment period, including any rehabilitation time, will be discussed among the 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 51 
Investigator, Surgeon, and Sanofi BIVV001 Medical Monitor. Continuous infusion will not be 
allowed in this study. 
For all participants in the surgery subgroup, the surgical period will begin with their first dose of 
BIVV001 given for the surgery (ie, the pre-operative loading dose) of 50 IU/kg IV. All patients 
will receive a pre-operative loading dose prior to the surgical procedure. If needed, the dose level 
of BIVV001 should be adjusted to aim for a FVIII activity level of at least 100% and maintained 
during the surgery according to WFH Guidelines.  
Post-operatively, FVIII activity levels should be monitored by daily measurements of FVIII 
activity locally as long as the patient is hospitalized; a portion of the samples should also be sent 
to the central laboratory for analysis. FVIII levels should be maintained at recommended levels 
and duration according to WFH Guideline. Depending on the targeted FVIII activity level this 
likely means a need to administer a second dose approximately 48-72 hours after the pre-operative 
loading dose. Additional doses of 30 or 50 IU/kg every 2 to 3 days may be administered 
depending on the desired FVIII activity levels and the severity of the procedure. Due to the long 
half-life of BIVV001, the frequency of dosing in the post-surgical period may be extended after 
the first week post-surgery. 
Table 8 - Intravenous BIVV001 treatment  
Indication 
Dosage 
Frequency 
Prophylaxis 
50 IU/kg 
Once weekly 
Bleeding episodea 
50 IU/kg 
Single dose for all bleeding episodes. Additional and adjusted doses only after 
consultation with the Investigator:  
If a bleeding episode does not improve, additional doses of 30 or 50 IU/kg every 2 to 3 
days may be considered. For minor/moderate bleeding episodes occurring within 2 to 
3 days after a recent prophylactic dose, an initial 30 IU/kg dose may also be used. 
Minor surgery 
50 IU/kg 
Single dose prior to surgery 
Major surgery, 
allowed after 6 EDs 
50 IU/kg 
Additional doses of 30 or 50 IU/kg every 2 to 3 days may be administered. 
a Refer to Section 10.10 for definitions of minor, moderate, and major bleeding episodes. 
6.1.1.5 Bleeding episodes that occur prior to the baseline and during PK sampling period  
If a participant experiences a bleeding episode during the washout period before PK sampling in 
conjunction with their first dose of BIVV001, the participant should treat the bleeding episode 
with their pre-study FVIII product. A participant who experiences a bleeding episode in the 
dosing interval prior to a scheduled visit to monitor trough PK levels should be treated with 
BIVV001 using the treatment guidelines described Table 8.  
Section 10.9 provides detailed guidelines for washout and sampling details. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 52 
6.1.2 BIVV001 dosing calculations  
6.1.2.1 Definitions of Nominal Strength versus Actual Potency  
This section explains when the actual potency or nominal strength is to be used for dose 
calculations. The definitions of these terms and the types of dose calculations in this study are 
described below.  
Definitions 
The nominal strength is the target potency of the vial (that is, 250 IU, 500 IU, 1000 IU, 2000 IU, 
3000 IU, or 4000 IU per vial). 
The actual potency is the true potency of the vial as measured by a validated potency assay. 
(Actual potency may vary between 80 to 125% of nominal strength.)  
Calculation and Recording of Actual versus Nominal Dosing 
Actual potency must be used for dose calculations for the following: 
Baseline PK, Sequential PK (Baseline and Week 26), and all Peak and Trough: Dose for PK 
is 50 IU/kg. The actual potency shown on the vial must be used to calculate the volume of 
BIVV001, using partial vial(s). The instructions provided in the DHA manual must be used to 
calculate the volume for administration based on actual potency.  
Nominal strength can be used for dose calculations for the following: 
Dosing for prophylactic treatment or treatment of bleeds. The nominal strength should be used 
for calculations and rounded up to the nearest whole vial.  Note: The instructions provided in the 
DHA manual must be used to calculate the number of vials for administration based on nominal 
strength (unless an equivalent alternative site-specific template is approved by the CRA prior to 
use).  
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
The Investigator or designee must maintain accurate records of receipt and the condition of the 
study drug supplied for this study including dates of receipt. They must confirm appropriate 
temperature conditions have been maintained during transit for all study drug received and any 
discrepancies are reported and resolved before use of the study drug. 
Only participants enrolled in the study may receive study drug and only authorized site staff may 
supply or administer study drug. Accurate records must be kept of when and how much study 
drug is dispensed and administered to each participant in the study. Any reasons for departure 
from the protocol dispensing treatment regimen must also be recorded. BIVV001 may be supplied 
at the site or from the site to the participant via a Sponsor-approved courier company, where 
allowed by local regulations and approved by the participant. 
All drug must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited to the 
Investigator and authorized site staff. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 53 
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study drug accountability, reconciliation, and record maintenance (ie, receipt, 
reconciliation, and final disposition records). 
Further guidance and information about drug accountability and the final disposition of unused 
study drugs are provided in the Directions for Handling and Administration (DHA). 
Any quality issue noticed with the receipt or use of an IMP/NIMP/device (deficiency in condition, 
appearance, pertaining documentation, labeling, expiration date, etc) must be promptly notified to 
the Sponsor. Some deficiencies may be recorded through a complaint procedure (see 
Section 8.3.8). 
A potential defect in the quality of IMP/NIMP/device may be participant to initiation of a recall 
procedure by the Sponsor. In this case, the Investigator will be responsible for promptly 
addressing any request made by the Sponsor, in order to recall the IMP/NIMP/device and 
eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP/NIMP/device to a third party (except for 
DTP shipment, for which a courier company has been approved by the Sponsor), allow the 
IMP/NIMP/device to be used other than as directed by this clinical trial protocol, or dispose of 
IMP/NIMP/device in any other manner. 
6.2.1 Study drug packaging and labelling  
BIVV001 will be manufactured, handled, and stored in accordance with applicable Good 
Manufacturing Practice (GMP). BIVV001 vials will be labeled according to the requirements of 
local law and legislation. Label text will be approved according to Bioverativ procedures, and 
copies of the labels will be made available to the study site upon request. 
6.2.2 Study drug storage  
The study site staff should follow the BIVV001 DHA for specific instructions on its storage. 
6.2.3 Study drug preparation  
The study site staff should follow the BIVV001 DHA for specific instructions on its preparation. 
6.2.4 Study drug administration  
The study site staff should follow the BIVV001 DHA for specific instructions on its 
administration. During study visits, for reliable PK assessment, PK sampling should not be done 
via the same intravenous access route as used for the BIVV001 administration. 
6.2.5 Study drug accountability  
Accountability for BIVV001 is the responsibility of the Investigator. The study site must maintain 
accurate records demonstrating dates and amount of BIVV001 received, to whom dispensed 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 54 
(participant-by-participant accounting), and accounts of any BIVV001 accidentally or deliberately 
destroyed or lost. The study site staff should follow the BIVV001 DHA for specific instructions 
on its accountability.  
6.2.6 Study drug handling and disposal  
Unless otherwise notified, all BIVV001 vials (used and unused) must be saved for BIVV001 
accountability. Participants should bring in all used and unused vials to the clinic during their 
scheduled visits. Reconciliation must be made between the amount of BIVV001 supplied, 
dispensed, and subsequently destroyed, lost, or returned to the Sponsor. A written explanation 
must be provided for any discrepancies. The study site staff should follow the BIVV001 DHA for 
specific instructions on its disposal. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
This is an open-label study and will not utilize randomization or blinding. The primary efficacy 
analysis will be based on the Full Analysis Set. The key secondary efficacy analysis will include 
participants in Arm A who have at least 6 months of historical data on prophylaxis treatment from 
observational Study 242HA201/OBS16221. Because poor quality or adherence to the protocol can 
introduce bias towards the alternative hypothesis in a non-inferiority analysis, the key secondary 
efficacy analysis will be based on the Per Protocol Set. In order to minimize potential selection 
bias for the key secondary efficacy analysis, sites who participate in observational 
Study 242HA201/OBS16221 are expected to enroll qualified participants into this Phase 3 study 
with prior participation in the observational study. In addition, at least 75 participants with at least 
6 months of participation from the observational study will be targeted to enroll in Arm A before 
additional participants from the observational study are enrolled in Arm A. Additional sites that 
are not participating in the observational study may enroll participants directly into this Phase 3 
study. 
6.4 
STUDY INTERVENTION COMPLIANCE  
The Investigator or pharmacist will keep accurate records of the quantities of the IMP dispensed, 
used, and unused. The product accountability and inventory form is to be updated each time 
investigational product is dispensed. The study monitor will periodically check the supplies of the 
IMP held by the Investigator or pharmacist to verify accountability. 
Treatment kit number has to be recorded on the appropriate page of the electronic Case Report 
Form (eCRF) and also on the product accountability and inventory form.  
All used, partially used, or unused treatments will be destroyed according to the standard practice 
at the site or per local regulations. A detailed treatment log of the IMP will be established with the 
Investigator or other personnel designated by the Investigator, and countersigned by the 
Investigator and the Monitoring Team. Confirmation of destruction will be provided to the 
Sponsor. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 55 
6.5 
CONCOMITANT THERAPY  
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
• 
Reason for use. 
• 
Dates of administration including start and end dates. 
• 
Dosage information including dose and frequency. 
Participants must abstain from taking prescription or nonprescription drugs (including vitamins 
and dietary or herbal supplements) within 7 days (or 14 days if the drug is a potential enzyme 
inducer) or 5 half-lives (whichever is longer) before the start of study intervention until 
completion of the Follow-up Visit, unless, in the opinion of the Investigator and Sponsor, the 
medication will not interfere with the study. 
Permitted concomitant therapy 
Participants taking medication routinely for a pre-existing condition should be on a treatment 
regimen that has been stable for at least 3 weeks prior to enrollment, and dosage changes should 
not be anticipated during the observation period for this study. Pre-study stable NSAID doses 
below the maximum dose specified in the local prescribing information at the time of enrollment 
are permitted. All concurrent prescription and nonprescription medications including over-the-
counter and alternative preparations (including herbal remedies, vitamins, and health food 
supplements) should be recorded at Screening and throughout the treatment and follow-up 
periods. 
Prohibited concomitant therapy 
No premedication for pain or pyrexia relief is to be given for administration of BIVV001. Should 
pre-medications be contemplated, this will be discussed on a case-by-case basis with the Sanofi 
Study Medical Monitor or designee and before administration. 
Medications prohibited during the study include: 
1. Acetylsalicylic acid (ASA) or non-NSAID anti-platelet therapies. 
2. NSAIDs at doses above the maximum dose specified in local prescribing information. 
3. Systemic treatment with chemotherapy and/or other immunosuppressive drugs (except for 
the treatment of hepatitis C virus [HCV] or HIV). The use of systemic steroids for the 
treatment of acute respiratory illness (eg, asthma), acute allergic episodes, or otherwise life 
threatening episodes is allowed. Treatment in these circumstances should not exceed a 
14 day duration. Local, topical, and/or inhaled steroid use is permitted. 
4. Any other FVIII product (with exceptions listed in Section 7.1.1). 
5. Emicizumab. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 56 
6. Anticoagulant agents, excluding the use of heparin for intermittent flushing for 
maintenance of patency of intravenous catheters, and short-term thromboembolic 
prophylaxis during immobilization and/or perioperatively. The Investigator must discuss 
the use of anticoagulant agents with the medical monitor. 
As stated in Section 5.3, participants who routinely administer an additional dose of FVIII prior to 
a sports activity or increased physical activity will not be allowed to do so in this study. However, 
the day of dosing BIVV001 in Arms A and B (prophylaxis period) could be chosen prior to a 
weekly recurring physical activity. 
6.6 
DOSE MODIFICATION  
Not applicable 
6.7 
INTERVENTION AFTER THE END OF THE STUDY  
The Sponsor plans to perform a long-term safety trial. Enrollment in this open-label extension 
study will be offered to participants after completion of this study based on eligibility criteria. No 
other post study treatment access will be offered.  
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 57 
7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
Participants or their parent are free to discontinue treatment or withdraw from the study at any 
time and for any reason, without penalty to their continuing medical care. Any discontinuation of 
treatment or withdrawal from the study must be fully documented in the eCRF and should be 
followed up by the Investigator. The Investigator or sponsor may withdraw a participant at any 
time if it is considered to be in the participant’s best interest. 
Discontinuation of study drug and withdrawal from the study are described in Section 7.1 and 
Section 7.2, respectively. 
7.1 
DISCONTINUATION OF STUDY INTERVENTION   
7.1.1 Definitive discontinuation  
Participants who discontinue study drug for any reason should have every effort made to conduct 
assessments at EOS/ET visit. See the Schedule of Assessments (SoA) (Table 1).  
The Investigator, Sponsor, or designee may discontinue dosing in a participant if the participant: 
• Is in significant violation of the protocol. 
• Is non-adherent to treatment regimen. 
• Experiences a serious or intolerable AE. 
• Requires a prohibited medication. 
A participant must permanently discontinue study treatment if any of the following occur: 
• Participant develops an inhibitor (See Section 8.3.1.1 for definition of inhibitor 
development). 
• Participant experiences a Grade 3 or greater allergic reaction per Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 or an anaphylactic reaction in 
association with BIVV001 administration. 
• Use of FVIII products other than BIVV001, unless it occurs in 1 life-threatening emergency or 
as a result of 1 accidental use and the Sponsor agrees to retain the participant in the study. Use 
must be recorded in the eCRF and the Investigator should contact the Medical Monitor.  
• A female becomes pregnant while participating in the study. 
• The participant withdraws consent. 
The Investigator may confer with the Sponsor or Study Medical Manager before discontinuing 
dosing in the participant. 
Participants (or their parent) may decide to discontinue IMP. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 58 
If a participant discontinues dosing due to an AE or SAE, the event should be followed as 
described in Section 8.3.4. When a participant discontinues IMP dosing, the primary reason must 
be recorded in the appropriate section of the eCRF.  
See the SoA (Table 1) for data to be collected at the time of study drug discontinuation and 
follow-up, and for any further evaluations that need to be completed. 
      
Handling of participants after definitive intervention discontinuation 
Participants will be followed-up according to the study procedures specified in this protocol up to 
the scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. 
If possible, and after the definitive discontinuation of study drug, the participants will be assessed 
using the procedures in the EOT/EOS visits. All participants should also complete the Safety 
Follow-up Call or Visit, refer to Section 1.3. 
All cases of definitive study drug discontinuation must be recorded by the Investigator in the 
appropriate pages of the e-CRF when considered as confirmed. 
7.1.2 Temporary discontinuation  
Temporary study drug discontinuation may be considered by the Investigator because of a 
suspected adverse reaction. For all temporary study drug discontinuations, duration should be 
recorded by the Investigator in the appropriate pages of the eCRF and AEs should be reported 
according to Section 8.3. 
7.1.2.1 Rechallenge  
Re-initiation of intervention with the IMP will be done under close and appropriate clinical/and or 
laboratory monitoring once the Investigator will have considered according to his/her best medical 
judgment that the responsibility of the IMP(s) in the occurrence of the concerned event was 
unlikely and if the selection criteria for the study are still met (refer to Section 5). 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
• A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator or Sponsor for safety, 
behavioral, compliance, or administrative reasons. This is expected to be uncommon. 
• 
At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the SoA (Table 1). See SoA 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. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 59 
• 
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. 
• 
If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
Participants who withdraw from the study intervention should be explicitly asked about the 
contribution of possible AEs to their decision, and any AE information elicited must be 
documented. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
e-CRF and in the participant’s medical records. In the medical record, at least the date of the 
withdrawal and the reason should be documented. 
In addition, a participant may withdraw his/her consent to stop participating in the study. 
Withdrawal of consent for intervention should be distinguished from withdrawal of consent for 
follow-up visits and from withdrawal of consent for non-participant contact follow-up, 
eg, medical record checks. The site should document any case of withdrawal of consent. 
Participants who have withdrawn from the study cannot be re-treated in the study. Their inclusion 
and intervention numbers must not be reused. 
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 reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• Before a participant is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1).  
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 60 
8 
STUDY ASSESSMENTS AND PROCEDURES  
Study procedures and their timing are summarized in the SoA (Table 1). 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 
IMP. 
• 
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 (eg, 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 (Table 1). 
8.1 
EFFICACY ASSESSMENTS   
8.1.1 Efficacy assessments  
Planned time points for all efficacy assessments are provided in the SoA (Table 1). 
8.1.1.1 Bleeding episode data  
In this study, a standardized definition of a bleeding episode based on International Society on 
Thrombosis and Haemostasis (ISTH) criteria will be used (61). A bleeding episode is defined as 
an episode that starts from the first sign of bleeding and ends no more than 72 hours after the last 
injection to treat the bleeding episode. Any subsequent bleeding at the same location and 
injections administered ≤72 hours from the previous injection will be considered as the same 
bleeding episode. Multiple bleeding locations treated with a single injection will also be 
considered a single bleeding episode. Any injection to treat the bleeding episode that is 
administered >72 hours after the preceding one will be considered the first injection to treat a new 
bleeding episode in the same location. Any injection used to treat subsequent bleeding at a 
different location will be considered a separate bleeding episode, regardless of the time from the 
last injection to treat a bleeding episode.  
If a bleeding episode occurs on the same day as a regularly scheduled prophylaxis dose, 
participants are instructed to record in their diary: 
• Treatment for bleeding episode: if the bleeding episode required BIVV001 treatment on 
the regular prophylaxis day. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 61 
• Follow up injection: if an additional injection to is required to treat the bleed on the regular 
prophylaxis day.  
OR 
• Prophylaxis dose: if the bleeding episode did not require BIVV001 treatment on the 
regular prophylaxis day. In this case, the bleeding episode should be recorded and 
considered as an untreated bleeding episode.  
Bleeding episodes or hemorrhages will be classified as either spontaneous or traumatic. The 
participant’s ePD will serve as the primary source document for bleeding episodes while the 
participant is enrolled in the study. Spontaneous and traumatic bleeding episodes are further 
defined as follows: 
• Spontaneous bleeding episodes: Bleeding episodes are classified as spontaneous if a 
participant or caregiver records a bleeding episode when there is no known contributing 
factor, such as a definite trauma or antecedent “strenuous” activity. The determination of 
“strenuous” is at the discretion of the Investigator, and the parent/caregiver/participant 
needs to be instructed by the Investigator on the proper categorization. 
• Traumatic bleeding episodes: Bleeding episodes are classified as traumatic if the 
participant or caregiver records a bleeding episode when there is a known or believed 
reason for the bleed. For example, if a participant exercised strenuously and then had a 
bleeding episode in the absence of any obvious injury, the bleeding episode is still 
recorded as traumatic. Target joint bleeding episodes can be traumatic if a known action 
led to bleeding into the joint. 
During the clinic visits and telephone calls with the participant, the Investigator will review the 
bleeding episode data in the ePD. If the Investigator judges that the classification by the 
participant/caregiver was incorrect, the Investigator will document it in the participant's medical 
records with the rationale for the new classification, and in the eCRF, documenting the new 
classification of the bleeding episode according to the Investigator and whether or not the 
participant/caregiver agreed with this new classification. 
Bleeding episodes will be reported for each participant during the treatment period, either in the 
ePD or the eCRF, as follows: 
• Bleeding episodes and doses to treat bleeding episodes outside the clinic: Participant 
completion and Investigator review of the participant’s ePD are captured by the participant 
using the ePD. The date and details of injection and bleeding episodes will be recorded by 
the participant in the ePD. 
• Bleeding episodes in-clinic and doses to treat bleeds given at the clinic are captured by the 
Investigator in the eCRF. 
• ePD Review and Training: Investigator or designee to review ongoing ePD data and 
perform participant retraining as necessary.  
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 62 
• Assessment of response to treatment of a bleeding episode, using 4-point bleeding 
response scale based on ISTH definitions: 
- 
Bleeding episodes that occur outside the clinic: assessment of response will be 
recorded in ePD for each bleeding episode. 
- 
Bleeding episodes treated in the clinic/hospital: assessment of response will be 
obtained from the participant by the Investigator and recorded in the eCRF. 
8.1.1.2 Assessment of clinical response to BIVV001 treatment for bleeding episodes  
The ISTH 4-point assessment scale of treatment of acute bleeds will be used throughout the study 
for the assessment of response to treatment with BIVV001 for bleeding episodes (61, Table 9). 
The assessment should be performed approximately 72 hours after the initial treatment for the 
bleeding episode. 
Table 9 - ISTH assessment of treatment of acute bleeds  
Excellent 
Complete pain relief within 8 h and/or complete resolution of signs of bleeding after the initial injection and not 
requiring any further replacement therapy for relief of persistent symptoms and signs in the same joint within 
72 h 
Good 
Significant pain relief and/or improvement in signs of bleeding within approximately 8 h after a single injection, 
but requiring more than one dose of replacement therapy within 72 h for complete resolution 
Moderate 
Modest pain relief and/or improvement in signs of bleeding within approximately 8 h after the initial injection 
and requiring more than one injection within 72 h but without complete resolution 
None 
No or minimal improvement, or condition worsens, within approximately 8 h after the initial injection 
 
8.1.1.3 Physician’s Global Assessment (PGA)  
The PGA is an assessment of the physician’s assessment of the participant’s response to treatment 
using a 4-point response scale (Table 10). 
Table 10 - Physician’s Global Assessment  
Excellent 
• 
Bleeding episodes responded to fewer than or the usual number of injections or less than or 
the usual dose of FVIII , OR 
• 
The rate of breakthrough bleeding during prophylaxis was less than or equal to that usually 
observed. 
Effective 
• 
Most bleeding episodes responded to the same number of injections and dose, but some 
required more injections or higher doses, OR 
• 
There was a minor increase in the rate of breakthrough bleeding. 
Partially Effective 
• 
Bleeding episodes most often required more injections and/or higher doses than expected, 
OR 
• 
Adequate breakthrough bleeding prevention during prophylaxis required more frequent 
injections and/or higher doses. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 63 
Excellent 
• 
Bleeding episodes responded to fewer than or the usual number of injections or less than or 
the usual dose of FVIII , OR 
• 
The rate of breakthrough bleeding during prophylaxis was less than or equal to that usually 
observed. 
Ineffective 
• 
Routine failure to control hemostasis or hemostatic control required additional agents. 
8.1.1.4 Hemophilia Joint Health Score (HJHS)  
Joint function assessed by physical joint examination performed by an experienced health care 
professional is often used as the primary outcome for haemophilic arthropathy. The Hemophilia 
Joint Health Score (HJHS) is a functional measure of joint health assessing ankles, knees and 
elbows (flexion, extension, range of movement, muscle strength, swelling, duration of swelling, 
crepitus, pain, and muscle atrophy) and general gait. The assessment is administered by a 
healthcare professional trained in the use of anthropometric measures. Ideally, HJHS should be 
performed and assessed by the same Investigator or designee at each time point. The HJHS will 
be assessed at Baseline, Weeks 26 and 52 (Section 10.13).  
8.1.1.5 Target joint resolution  
The Investigator will assess target joints at Baseline according to the International Society on 
Thrombosis and Haemostasis (ISTH) criteria. A target joint is defined as a major joint (eg, hip, 
elbow, wrist, shoulder, knee or ankle) into which ≥3 spontaneous bleeding episodes occurred in a 
consecutive 6-month period. Target joint resolution is defined as ≤2 bleeding episodes in the 
target joint over 12 months of continuous exposure.  
8.1.1.6 Surgery  
The Investigators/Surgeons who complete the surgical procedures will assess the participant’s 
response to surgery with BIVV001 treatment using a 4-point scale as described below. This 
includes observations during surgery and the 24-hour post-operative time period. This assessment 
will be performed 24 hours after the surgery. 
Participants should have at least 6 EDs to BIVV001 to be eligible for major surgery. In addition, a 
negative inhibitor test within 4 weeks prior to surgery is required. Prior to surgery, the 
Investigator will plan the perioperative treatment regimen of FVIII replacement therapy generally 
required for the type of surgery in accordance with the dosing guidance in Table 8. 
Recommendation for the appropriate dosing of BIVV001 in the surgical treatment period, 
including any rehabilitation time, will be discussed among the Investigator, Surgeon, and Sanofi 
BIVV001 Medical Monitor. Continuous infusions will not be allowed for this study.  
Guidelines on surgical dosing are found in Section 6.1.1.4. Pharmacokinetic samples taken during 
surgical procedures will be analyzed locally, but the site is requested to split the plasma and send 
an aliquot to the central laboratory for analysis. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 64 
Following a 24-hour post-operative study assessment, participants will follow the recommended 
postoperative treatment regimen as per Investigator’s advice.  
Data collected during the surgical/rehabilitation period for major and minor surgeries will be 
excluded from the analysis, including all bleeding episodes as well as the follow-up time during 
this period. The surgical/rehabilitation period will typically begin with the first dose of BIVV001 
given for the surgery (ie, the pre-operative loading dose). The end of the surgical/rehabilitation 
period will occur with the latest of one of the following dates: 1) the date of discharge from the 
hospital; 2) the date of the perioperative period follow-up phone call; or 3) the end of a two-week 
period (one-week for minor surgeries) after the resumption of the participant’s pre-surgery 
treatment regimen. 
The perioperative period may be extended at the discretion of the Investigator. Reasons include 
extended hospital stay or other clinical reasons that prohibit resumption of normal prophylactic 
regimen/on-demand treatment. At the end of the perioperative period, participants will be 
instructed to resume their pre-surgery treatment regimen and register their treatment accordingly 
in the ePD. For participants who undergo major surgery at the end of the study, the EOS 
assessments will be scheduled at least 14 days post surgery, if applicable. 
In the case of minor surgery (eg, simple tooth extractions, incision and drainage of abscess, or 
simple excisions), participants will remain in their assigned arms and be treated with BIVV001 
during the minor intervention according to the guidelines on surgical dosing found in 
Section 6.1.1.4. A post-operative follow-up call should occur 24 hours following minor surgery 
for the surgeon/investigator’s assessment of response to surgery. If clinically warranted and at the 
discretion of the surgeon/investigator, the participant will be brought back into the clinic 24 hours 
post-minor surgery for BIVV001 activity sampling (pre-dose if an administration of BIVV001 is 
planned) and for the surgeon/investigator’s assessment of response. 
All doses administered in the hospital will be captured in the electronic case report form (eCRF). 
Any doses administered outside of the clinic prior to returning to the pre-surgical treatment 
regimen will be captured in the ePD. At the final post-operative visit, participants will be 
instructed to return to their pre-surgical treatment regimen.  
Participants will remain on the dose and schedule prescribed for the post-operative surgical 
prophylaxis until the Investigator deems that it is appropriate for the participant to return to his 
previous treated arm (Arm A or B). Participants who undergo major surgery within 2 weeks 
before the end of study should have their end of study visit performed no earlier than 14 days 
post-surgery. 
The Investigator/Surgeon who completed the surgical procedures will assess the participant’s 
response to surgery with BIVV001 treatment using a 4-point clinical scale: Excellent, Good, Fair, 
and Poor. 
This includes observations during surgery and the 24-hour post-operative time period so this 
assessment will be done 24 hours after the surgery. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 65 
Table 11 - ISTH hemostatic response for surgical procedures scale  
Excellent 
Intraoperative and postoperative blood loss similar (within 10%) to the non‐hemophilic patient with no 
extra (unplanned) doses of FVIII/FIX/‘bypassing agents’ needed and blood component transfusions are 
similar to the non‐hemophilic patient 
Good 
Intraoperative and/or postoperative blood loss slightly increased over expectation for the non‐
hemophilic patient (between 10 and 25% of expected), but the difference is judged by the involved 
surgeon/anesthetist/relevant healthcare professional to be clinically insignificant as evidenced by no 
extra (unplanned) doses of FVIII/FIX/‘bypassing agents’ needed and blood component transfusions are 
similar to the non‐hemophilic patient 
Fair 
Intraoperative and/or postoperative blood loss increased over expectation (25–50%) for the non‐
hemophilic patient and additional treatment is needed such as extra (unplanned) doses of 
FVIII/FIX/‘bypassing agents’ or increased blood component use (within two‐fold) of the anticipated 
transfusion requirement 
Poor 
Significant intraoperative and/or postoperative blood loss that is substantially increased over 
expectation (>50%) for the non‐hemophilic patient, requires intervention, and is not explained by a 
surgical/medical issue other than hemophilia, unexpected hypotension or unexpected transfer to an 
Intensive Care Unit due to bleeding or substantially increased blood component use (>2 fold) of the 
anticipated transfusion requirement 
8.1.2 Patient reported outcomes  
Table 12 shows the concepts of measurement and their related patient reported outcomes (PRO) 
questionnaires to be used in the trial. The Sponsor or designee will provide the translations for all 
PRO instruments, where translations are available. Where available, the PROs (excluding the 
HRU assessment) will be distributed to adult and pediatric patients as specified in the SoA 
(Table 1). All PROs, excluding the HRU, are collected via an electronic tablet and transmitted to a 
third party vendor data server over public networks using encrypted data. 
Table 12 - Patient reported outcome concepts and questionnaires  
Concept 
PRO questionnaire 
Assessment schedule 
Pain and Physical Function (PROMIS 
Instruments) 
1. PROMIS Pain Intensity 
2. PROMIS-SF Pain Interference (≥18 years 
old) or PROMIS Pediatric-SF Pain Interference 
(<18 years old) 
3. PROMIS-SF Physical Function (≥18 years 
old) or PROMIS Pediatric-SF Physical Activity 
(<18 years old) 
Baseline, Weeks 26,52 
Hemophilia specific  
Haem-A-QoL (≥17 years old) or Haemo QoL 
(<17 years old) 
Baseline, Weeks 26,52 
 
Activities list 
HAL (≥18 years old) or pedHAL (<18 years old) 
Baseline, Weeks 26, 52 
Treatment satisfaction 
TSQM-9 
Baseline, Weeks 26, 52 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 66 
Concept 
PRO questionnaire 
Assessment schedule 
Health status 
EQ-5D-5L 
Baseline, Weeks 26 ,52 
Global impression of change 
PGIC 
Weeks 26, 52 
Global impression of severity 
1. PGIS - activity component 
2. PGIS - joint component 
Baseline, Weeks 26, 52 
 
Patient preference survey 
 
Preference questionnaire 
 
Week 52 
 
Healthcare resource utilization 
 
HRU questionnaire 
 
Baseline, Week 26, Week 52 
PROMIS Instruments 
PROMIS (Patient-Reported Outcomes Measurement Information System) is a system of reliable 
and precise measures of participant-reported heath status (62). The PROMIS initiative is part of 
the National Institute of Health (NIH) goal to develop systems to support NIH-funded research 
across all its institutes and centers. PROMIS measures cover physical, mental and social health 
and can be used for many chronic conditions. These questionnaires use a 5-point Likert response 
scale and, with the exception of the PROMIS-SF Physical Function - SF 6b instrument, have a 
recall period of the past 7 days. The PROMIS instruments will be administered at Baseline and 
Weeks 26 and 52. 
PROMIS-SF v 1.0 Pain Intensity 3a 
The PROMIS Pain Intensity instrument assesses pain intensity on a 5-point Likert scale (all 
participants). The estimated completion time is <1 minute (Section 10.14.1).  
PROMIS-SF v1.0 – Pain Interference 6a 
The PROMIS-SF v1.0 – Pain Interference 6a is a participant-assessed instrument and is used in 
adults to measure pain interference. The estimated time of completion is 1-2 minutes 
(Section 10.14.2). 
PROMIS Pediatric SF v2.0 – Pain Interference 8a 
The PROMIS Pediatric-SF v2.0 – Pain Interference 8a is for participants <18 years of age and is 
used to measure pain interference. The estimated time of completion is 1 minute 
(Section 10.14.3). 
PROMIS-SF v2.0 Physical Function 6b 
The PROMIS-SF v2.0 Physical Function 6b is used to access physical functioning in adults. The 
estimated completion time is 1 minute (Section 10.14.4). 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 67 
PROMIS Pediatric-SF v1.0 – Physical Activity 8a 
The PROMIS Pediatric-SF v1.0 – Physical Activity 8a is used to assess physical activity in 
participants <18 years of age. The estimated completion time is 1-2 minutes (Section 10.14.5). 
Haem-A-QoL 
The Haem-A-Qol questionnaire for participants with hemophilia who are ≥17 years of age 
consists of 46 items pertaining to 10 dimensions including physical health (5 items), feeling  
(4 items), view of self (5 items), sports and leisure (5 items), work and school (4 items), dealing 
with hemophilia (3 items), treatment (8 items), future (5 items), family planning (4 items), and 
partnership and sexuality (3 items). Estimated completion time is approximately 14 minutes (63). 
The Haem-A-QOL instruments will be administered at Baseline and Weeks 26 and 52 
(Section 10.14.6). 
Haemo-QoL 
The Haemo-QoL questionnaire for children with hemophilia is available for participants  
<17 years of age. Estimated completion time is approximately 14 minutes (64).The instrument 
(children’s long version for age group II/III [8-16 years of age]) will be administered to 
adolescents at Baseline and Weeks 26 and 52 (Section 10.14.7). 
HAL/pedHAL 
The Hemophilia Activities List (HAL) and pediatric HAL (pedHAL) questionnaires will assess 
the participant’s functional ability to perform activities of daily living (65). The HAL will be 
assessed in patients ≥18 years of age, and the pedHAL will be assessed in patients <18 years of 
age. The HAL/pedHAL will be administered at Baseline, Weeks 26 and 52 (Section 10.14.9 and 
Section 10.14.10). 
TSQM-9 
The 9-Item Treatment Satisfaction Questionnaire for Medication (TSQM-9) will assess patient 
satisfaction with treatment. The TSQM-9 is a validated psychometric tool that provides a general 
measure of patient satisfaction with medication (66). The TSQM-9 will be administered at 
Baseline, Weeks 26 and 52 (Section 10.14.11). 
Patient global impression of severity 
Patient global impression of severity (PGIS) is a single item scale in which patients indicate an 
overall assessment of their symptoms. Two components of the PGIS will be utilized for joint 
symptoms and physical activity. The PGIS will be administered at Baseline, Weeks 26 and 52 
(Section 10.14.13).  
Patient global impression of change 
The Patient Global Impression of Change (PGIC) consists of one item adapted to the patient that 
evaluates all aspects of patients' health and assesses if there has been an improvement or decline 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 68 
in clinical status since they started taking the study medication. The PGIC will be administered at 
Weeks 26 and 52 (Section 10.14.14).  
Health status 
The EuroQoL 5-dimension 5-level (EQ-5D-5L) is used widely in clinical trials to assess 
5 dimensions of health outcome (mobility, self-care, usual activities, pain/discomfort, 
anxiety/depression) from a wide variety of interventions on a common scale, for purposes of 
converting into a single summary score of health state. The EQ-5D-5L will be administered at 
Baseline, Weeks 26 and 52 (Section 10.14.12). 
Patient preference survey 
The patient preference survey is a 2-item questionnaire developed to evaluate the perceived 
impact of treatment at the end of the study. The questionnaire will be administered at the end of 
the study at Week 52 (Section 10.14.15).  
8.1.3 Exit interviews  
Qualitative semi-structured interviews will be conducted in a subset of adult participants from 
selected countries within 6 months of exiting the study but before the EOS is declared. 
Participants must be willing and able to participate in a 60-minute telephone interview. The 
interviews will evaluate participants’ expectations from treatment, and perception of treatment 
impact. The interviews will be conducted by trained interviewers from RTI Health Solutions or 
their qualitative research partner following a semi-structured interview guide  
(Appendix 10.14.16). 
8.1.4 Physical activity monitoring  
Where available, assessments of physical activity (PA) will be done by using a triaxial medical 
grade accelerometer (ActiGraph Activity Monitor). Patients will be issued the wrist-worn device 
for continuous monitoring during pre-specified intervals as outlined in the SoA. The monitoring 
intervals will be 8 consecutive days after the scheduled visits at Screening, Baseline, Weeks 4, 13, 
26, 39, and for 8 consecutive days before the Week 52 visit (in order to collect data for a full week 
7 + 1 additional day). The device will be worn on the non-dominant wrist throughout the 
monitoring periods. Physical activity measures will include raw acceleration, activity counts, steps 
taken, physical activity intensity, activity bouts, sedentary bouts and body position among other 
biometric measures. The calculation of PA measures during the assessment period requires less 
than 50% of missing data.  
8.1.5 Ultrasound measures (if applicable)  
A subset of study sites will be selected to perform evaluation of treatment efficacy using the US 
joint images from the Joint Tissue Activity and Damage Examination (JADE) Protocol in 
Musculoskeletal Ultrasound (MSKUS) and/or Hemophilia Early Arthropathy Detection with 
Ultrasound (HEAD-US). Participants at designated and MSKUS-experienced sites who are in 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 69 
Arm A (prophylactic treatment), meet enrollment criteria and are >17 years of age at enrollment 
will have the option to participate in the US sub-study, performed according to the Schedule of 
Assessments (Table 1). Assessments will include the following indicators of joint health: 
• Changes in synovial hypertrophy 
• Changes in cartilage thickness 
• Changes in synovial hyperaemia, as observed by power Doppler (JADE) 
The US joint images will be scanned and sent to the third-party imaging CRO for evaluation of 
the indicators listed above, using two blinded readers with separate adjudication for 
disagreements. 
8.1.6 Future scientific research  
Serum and plasma samples, as well as unused backup samples, will be archived for testing by the 
central laboratory for future scientific research (eg, immunology assays, further coagulation 
assays, clarification of any clinical or laboratory AE, viral analysis). This is optional, and only 
participants who have consented for sample collection and use of unused samples are to be used 
for future research and will have the samples archived. 
8.2 
SAFETY ASSESSMENTS  
Planned time points for all safety assessments are provided in the SoA (Table 1). 
8.2.1 Physical examination  
A complete physical examination will include, at a minimum, assessments of the [Cardiovascular, 
Respiratory, Gastrointestinal, Neurological, Dermatological and Musculoskeletal] systems. Height 
and weight will also be measured and recorded. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
For participants with a central or peripheral indwelling venous access, the physical examination 
should include an assessment of the device. 
Any new finding or worsening of a previous finding should be reported as a new AE. 
8.2.2 Vital signs  
Oral, tympanic, axillary, or temporal temperature, pulse rate, respiratory rate, and blood pressure 
will be assessed. 
Blood pressure and pulse measurements will be assessed in the supine position with a completely 
automated device. Manual techniques will be used only if an automated device is not available. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 70 
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the 
participant in a quiet setting without distractions (eg, television, cell phones). 
Vital signs will consist of 1 pulse and 3 blood pressure measurements (3 consecutive blood 
pressure readings will be recorded at intervals of at least 1 minute). The average of the 3 blood 
pressure readings will be recorded on the CRF. 
Vital signs will be measured pre-injection (before blood collection for laboratory tests) and  
30 (±15 minutes) from the start of injection at clinic visits. Vital signs should also be taken at any 
unscheduled visits.  
8.2.3 Clinical safety laboratory assessments  
See Section 10.2 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 significant 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. 
All laboratory tests with values considered abnormal and clinically significant during participation 
in the study or within 3 weeks after the last dose of study intervention should be repeated until the 
values return to normal or baseline or are no longer considered clinically significant by the 
Investigator and/or medical monitor. 
If such values do not return to normal/baseline within a period of time judged reasonable by the 
Investigator, the etiology should be identified and the Sponsor notified. 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the laboratory manual and the SoA.  
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the Investigator (eg, SAE or AE or dose modification), then the results 
must be recorded in the CRF.  
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3). 
Adverse events and SAEs will be reported by the participant (or, when appropriate, by a 
caregiver, surrogate, or the participant's legally authorized representative).  
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 71 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention (see Section 7). 
8.3.1 Adverse event of special interest  
An adverse event of special interest (AESI) is an AE (serious or nonserious) of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
immediate notification by the Investigator to the Sponsor is required. Such events may require 
further investigation in order to characterize and understand them. Adverse events of special 
interest may be added, modified or removed during a study by protocol amendment. 
• Pregnancy of a female participant entered in a study as well as pregnancy occurring in a 
female partner of a male participant entered in a study with IMP/NIMP; 
- 
Pregnancy will be qualified as an SAE only if it fulfills one of the seriousness criteria 
(see Appendix 3 [Section 10.3]). 
- 
In the event of pregnancy in a female participant, IMP should be discontinued.  
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined  
(See Appendix 4 [Section 10.4]) 
• Symptomatic overdose (serious or nonserious) with IMP/non-investigational medicinal 
product (NIMP) 
- 
An overdose (accidental or intentional) with the IMP/NIMP is an event suspected by 
the Investigator or spontaneously notified by the participant and defined as follows: 
any dose of study treatment administered to a participant or taken by a participant that 
exceeds the dose assigned to the participant according to the protocol. 
8.3.1.1 Other compound specific AESI(s)  
Compound specific AESIs include the following: 
• A participant develops an inhibitor (defined as an inhibitor result of >0.6 BU/mL that is 
confirmed by a second test result of >0.6 BU/mL from a separate sample, drawn 2 to 
4 weeks following the date when the original sample was drawn. Both tests must be 
performed by the central laboratory using the Nijmegen-modified Bethesda assay) 
• A participant develops a Grade 3 or higher allergic reaction per Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 or an anaphylactic reaction in 
association with BIVV001 administration. 
- 
Grade 3 allergic reaction: bronchospasm or hospitalization indicated for clinical 
sequelae or intravenous intervention indicated. 
- 
Grade 4 allergic reaction: Life-threatening consequences or urgent intervention 
indicated. 
- 
Grade 5 allergic reaction: Death. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 72 
• A participant develops an embolic or thrombotic event, except for injection site 
thrombophlebitis. 
8.3.2 Time period and frequency for collecting AE and SAE information  
All AEs and SAEs will be collected from the signing of the informed consent form (ICF) until the 
safety follow-up call or visit at the time points specified in the SoA (Section 1.3). 
All SAEs and AESIs will be recorded and reported to the Sponsor or designee immediately and 
under no circumstance should this exceed 24 hours, as indicated in Appendix 3 (Section 10.3). 
The Investigator will submit any updated SAE and AESI data to the Sponsor within 24 hours of it 
being available. 
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation. However, if the Investigator learns of any SAE, including a death, at any time after 
a participant has been discharged from the study, and he/she considers the event to be related to 
the study intervention or study participation, the Investigator must promptly notify the Sponsor. 
8.3.3 Method of detecting AEs and SAEs  
The method of recording, evaluating, and assessing causality of AEs, SAEs, and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
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. 
8.3.4 Follow-up of AEs and SAEs  
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. At the pre-specified study end-date, all SAEs and AESIs 
(as defined in Section 8.3), will be followed until resolution, stabilization, or the participant is lost 
to follow-up (as defined in Section 7.3). Further information on follow-up procedures is given in 
Appendix 3 (Section 10.3). 
8.3.5 Regulatory reporting requirements for SAEs  
Prompt notification by the Investigator to the Sponsor of an SAE 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 Boards (IRB)/Independent Ethics Committees 
(IEC), and Investigators. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 73 
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. 
Adverse events that are considered expected will be specified in the reference safety information. 
An Investigator who receives an Investigator safety report describing a SAE or other specific 
safety information (eg, summary or listing of SAEs) from the Sponsor will review and then file it 
along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to 
local requirements 
8.3.6  Pregnancy  
Details of all pregnancies in female participants and female partners of male participants will be 
collected after the start of study intervention, and until the final safety Follow-up Visit or phone 
call. 
If a pregnancy is reported, the Investigator should inform the Sponsor (or representative) within 
24 hours of learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 10.4). 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.3.7 Deaths  
Death is an outcome of an event. The event that resulted in death should be recorded and reported 
on the appropriate eCRF. All causes of death must be reported as SAEs within 24 hours of the site 
becoming aware of the event. The Investigator should make every effort to obtain and send death 
certificates and autopsy reports. The term death should be reported as an SAE only if the cause of 
death is not known and cannot be determined.  
8.3.8 Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs  
The following disease related events (DREs) are common in participants with hemophilia A and 
can be serious/life threatening: 
• Bleeding 
Bleeding episodes in this patient population are not considered AEs. Bleeding episodes that meet 
a serious criterion (see Section 10.3, Adverse Events Definitions for Recording, Evaluating, and 
Reporting) should be reported as an SAE. All bleeding episodes after signature of the ICF will be 
captured in the ePD that the participant and/or the participant’s parents/caregivers will be 
maintaining throughout the study period (if a bleed occurs during the screening period, before the 
baseline visit, it will be recorded in the eCRF).  
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 74 
8.3.9 Guidelines for reporting product complaints  
Any defect in the IMP/device must be reported as soon as possible by the Investigator to the 
monitoring team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
8.4 
TREATMENT OF OVERDOSE  
Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the Investigator/treating physician should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for any AE/SAE and laboratory abnormalities as 
applicable.  
3. Obtain a plasma sample for PK analysis within 1 day from the date of the last dose of 
study intervention if requested by the Medical Monitor (determined on a case-by-case 
basis). 
4. Document appropriately in the CRF. 
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. 
8.5 
PHARMACOKINETICS  
Pharmacokinetic sampling in Arm A and Arm B will be conducted as outlined in the sections that 
follow. Detailed guidelines of washout and PK sampling requirements for baseline and bleeding 
scenarios are provided in Section 10.9. Washout prior to the BIVV001 Day 1 dose administration 
is at least 96 hours (4 days) if the participant is receiving a conventional FVIII product and at least 
120 hours (5 days) if current treatment is with an EHL FVIII product. The washout period for 
subjects in abbreviated PK sampling may be modified at the discretion of the Investigator based 
on individual PK data and clinical phenotype in consultation with medical monitor  
During study visits, for reliable PK assessment, PK sampling should not be done via the same 
intravenous access route as used for the BIVV001 administration. 
If a participant has a bleed during the PK time period above, the participant should enter the bleed 
into the ePD, contact the Investigator as soon as possible and follow the criteria given in  
Section 10.9. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 75 
Arm A: Prophylaxis Treatment regimen 
Participants will undergo PK sampling (up to 168 hours) for BIVV001 activity as follows: 
• Dosing at Day 1: single dose of BIVV001 50 IU/kg administered under medical 
supervision (using a partial vial and actual potency dosing, see Section 6.1.2.1). 
See Table 2 for all participants except participants in the sequential PK subgroup. 
If a participant has a bleed during the PK time period above, the participant should enter the bleed 
into the ePD and contact the Investigator as soon as possible.  
Sequential PK Subgroup (Subgroup of Arm A Participants Only) 
A minimum of 16 participants from Arm A will enroll in the Sequential PK Subgroup to ensure 
that a minimum of 13 participants complete the PK sampling as required for the estimation of the 
terminal half-life, as follows:  
• Dosing at Day 1: A single dose of 50 IU/kg of BIVV001 under medical supervision (using 
a partial vial and actual potency dosing (see Section 6.1.2.1). 
• Sampling for PK profiling beginning at Day 1: 
Pre-injection and 15 (±3) minutes, 3 hours (±15 minutes), 24 (±2) hours, 72 (±5) hours 
[Day 4], 168 (±5) hours [Day 8], 240 (±5) hours [Day 11], and 336 (±5) hours [Day 15] 
from the start of the injection. 
Participants with pre-planned surgery participating in the PK subgroup should not enter the 
surgery subgroup until repeat PK sampling has been completed 26 weeks following the BIVV001 
Day 1 PK profiling. If the surgery was performed before repeat PK sampling has been completed, 
then the participant will continue the study and replaced in PK subgroup. 
Repeat PK profiling will be conducted at 26 weeks. Participants should attend the visit at trough. 
If the participant is unable to conduct repeat PK at Week 26, he/she should return to clinic for PK 
as soon as possible before Week 39.  
• Dosing for repeat BIVV001 profiling: single dose of 50 IU/kg of BIVV001 (using a partial 
vial and actual potency dosing, see Section 6.1.2.1). 
• Sampling for repeat BIVV001 profiling: 
Pre-injection and 15 (±3) minutes, 3 hours (±15 minutes), 24 (±2) hours, 72 (±5) hours 
[Day 4], 168 (±5) hours [Day 8], 240 (±5) hours [Day 11], and 336 (±5) hours [Day 15] 
from the start of the injection. 
Participants in the Sequential PK subgroup may need to miss their regular BIVV001 dose due to 
the repeat 240 and 336 hour PK sampling; the dose immediately missed should be administered 
just after the 336 hour PK sample has been drawn. Participants in the sequential PK subgroup will 
not receive BIVV001 at Week 2 and Week 27 (or 1 week after the repeat PK). The participant 
will then revert to his previous dosing schedule. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 76 
If a participant has a bleed during the PK time period above, the participant should enter the bleed 
into the ePD and contact the Investigator as soon as possible. Instructions for repeat washout and 
PK sampling are provided in Section 10.9. 
Arm B –On-demand switch to prophylaxis treatment regimen 
Participants in Arm B will receive a Day 1 dose of BIVV001, and have abbreviated BIVV001 PK 
profiling as follows (see Table 2): 
• Dosing at BIVV001 Day 1: single dose of BIVV001 50 IU/kg administered under medical 
supervision, (using a partial vial and actual potency dosing, see Section 6.1.2.1). 
Abbreviated sampling beginning at BIVV001 Day 1:  
• Pre-injection and 15 (±3) minutes, 3 hours (±15 minutes), 24 hours (±2) hours [Day 2], 
72 (±5) hours [Day 4], and 168 (±5) hours [Day 8] from the start of the injection. 
For all participants, PK assessments will be based on FVIII activity levels determined by one-
stage clotting assay and two-stage chromogenic assay performed at all scheduled visits.  
Pharmacokinetic assessments will be conducted on varying schedules, according to participants’ 
group assignments. All participants will undergo PK sampling at Day 1. Participants in Arms A 
and B will have trough and peak sampling at all scheduled visits subsequent to Day 1. A subgroup 
of participants in Arm A (n=16) will undergo extensive PK sampling and a repeat PK sampling at 
Week 26.  
Participants in the PK subgroup will be replaced if they do not complete PK sampling for the 
Day 1 and the repeat PK profiling. Refer to Section 10.8 for PK sampling completion criteria.  
The following summarizes the PK assessments: 
• Abbreviated pharmacokinetic sampling or sequential pharmacokinetic sampling, will be 
used to estimate PK parameters, including but not limited to the following :  
- 
Maximum activity (Cmax), Elimination half-life (t1/2), total clearance (CL), total 
clearance at steady state (CLss), Accumulation index (AI), Area under the activity-
time curve (AUC), Volume of distribution at steady state (Vss), Mean residence time 
(MRT), Incremental recovery (IR), Trough activity (Ctrough) and time above 1% FVIII 
activity. 
• Trough and peak measurements (1-stage aPTT and chromogenic assays) for Arm A, and 
Arm B (post week 26): 
- 
Trough measurement: pre-injection. 
- 
Dosing: single dose of 50 IU/kg BIVV001 administered (using a partial vial and actual 
potency dosing, see Section 6.1.2.1). 
Peak measurement: 15 (±3) minutes from the start of the injection. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 77 
8.6 
PHARMACODYNAMICS  
Pharmacodynamic parameters are not evaluated in this study. 
8.7 
GENETICS  
There is 1 target gene for hemophilia A. The name of the target gene is F8. Genotyping may 
provide information regarding the predisposition of genotypic subpopulations to experience 
different bleeding frequencies. The development of an inhibitor to treatment with factor 
concentrates is the single most serious complication of factor replacement. One of the decisive 
risk factors for the development of inhibitors is the type of mutation (eg, full or missense) that 
codes for a protein that may be absent, truncated, or present but not functional. There is a 
correlation between the resultant protein and the likelihood of developing inhibitors to factor 
replacement (67). 
Where local regulations and EC allow approval, for participants whose factor VIII genotype is not 
known, an optional sample will be collected at Baseline for genotype analysis, including FVIII 
and human leukocyte antigen (HLA) genotype. The sample will not be needed if previously 
documented. Genotype will not be a criterion for inclusion or exclusion. The results will be shared 
with the Investigator.  
The DNA samples will be coded with the participant’s identification number and stored for 
15 years or a duration dictated by local, national, or regional laws or regulations. Participants may 
withdraw consent and request to have their sample destroyed at any time and no further genetic 
data will be generated; any data already generated will not be destroyed.  
8.8 
BIOMARKERS  
There are no planned analyses of biomarkers or pharmacogenetics. 
8.8.1 Immunogenicity assessments  
8.8.1.1  Inhibitor development  
Blood samples will be collected per the schedule in Table 1 for the detection of inhibitors. 
Samples may also be collected at the time of any clinical event deemed relevant to inhibitor 
testing. Inhibitor development will be assessed at a central laboratory by the Nijmegen-modified 
Bethesda assay and is defined as an initial test result of ≥0.6 BU/mL confirmed by a second test 
result from an independent blood sample collected within 2 to 4 weeks of the first positive 
sample. 
• 
Low titer inhibitor development is defined as inhibitor test results of >0.6 and 
<5.00 BU/mL. 
• 
High titer inhibitor development is defined as inhibitor test results of ≥5.00 BU/mL. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 78 
Participants with discrepant inhibitor test results (initial low titer result followed by high titer 
result or initial high titer result followed by low titer result) should have repeat inhibitor testing 
performed by the central laboratory from a separate blood sample collected 2 to 4 weeks 
following the previous sample. 
• 
If 2 of 3 test results are <5.00 BU/mL, the inhibitor is considered low titer. 
• 
If 2 of 3 test results are ≥5.00 BU/mL, the inhibitor is considered high titer. 
8.8.1.2 Anti-drug antibodies  
Blood samples will be collected per the schedule in Table 1 for the detection and analysis of anti-
BIVV001 antibodies. Samples may also be collected at the time of any clinical event deemed 
relevant to anti-BIVV001 antibody testing. Testing for potential antibody formation will be 
performed at a central laboratory using a validated BIVV001-specific ADA assay. Confirmed 
positive samples will be further characterized for antibodies specific to FVIII, Fc, XTEN, or 
D’D3.  
8.9 
Healthcare resource utilization  
Healthcare resource utilization (HRU) associated with medical encounters and attributable to 
Hemophilia A will be collected in the CRF by the Investigator and study-site personnel for all 
participants at Baseline and Weeks 26 and 52.  
The data collected may be used to conduct exploratory economic analyses and will include: 
• Number of non-study medical care encounters (outpatient, urgent-care, emergency room). 
• Duration of hospitalization (total days or length of stay, including duration by wards (eg, 
intensive care unit). 
• The full HRU questionnaire is provided in Section 10.14.17. Medical resource utilization 
data associated with medical encounters will be collected in the CRF by the Investigator 
and study-site personnel for all participants throughout the study. Protocol-mandated 
procedures, tests, and encounters are excluded. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 79 
9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES  
The primary endpoint of ABR will be analyzed using an estimation approach. The mean ABR and 
one-sided 97.5% confidence interval will be estimated using a Negative-Binomial regression 
model for the weekly prophylaxis treatment arm (Arm A). If the upper limit of the confidence 
interval is less than or equal to 6, the weekly prophylaxis treatment regimen will be considered to 
provide adequate bleeding control. 
As a key secondary endpoint, an intra-patient comparison of ABR between BIVV001 weekly 
prophylaxis treatment and historical prophylaxis treatment for participants in Arm A who have at 
least 6 months of participation in this study and at least 6 months of historical data on prophylaxis 
treatment from observational Study 242HA201/OBS16221 will be performed using a Negative-
Binomial regression model under the following statistical hypotheses: 
H0 (null): Paired ABR difference (BIVV001 prophylaxis – historical prophylaxis)  ≥ M versus H1 
(alternative): Paired ABR difference (BIVV001 prophylaxis – historical prophylaxis)  < M 
where M is the non-inferiority margin. The null hypothesis will be declared if the upper bound of 
the one-sided 97.5% CI is less than 4. If non-inferiority is achieved, then superiority will be 
evaluated sequentially using a Negative-Binomial regression model as specified above. The paired 
ABR ratio and 95% CI will be estimated using the FAS. The null hypothesis that the paired ABR 
ratio (BIVV001 prophylaxis: historical prophylaxis) is ≥1 will be tested against the alternative 
hypothesis that the ABR ratio is <1.  Superiority will be declared if the upper bound of the one-
sided 97.5% confidence interval is less than 1. 
In addition, the 3 secondary endpoints – change from baseline to Week 52 in Haem-A-QoL 
physical health score, PROMIS Pain Intensity 3a, and HJHS total score – will be analyzed via 
mixed-effects model repeated measures (MMRM).  
9.2 
SAMPLE SIZE DETERMINATION  
The sample size was estimated to rule out a greater-than-acceptable risk of immunogenicity. 
Assuming a drop-out rate of approximately 15%, a sample size of 124 participants in the 
prophylaxis arm is expected to provide 104 evaluable participants with at least 50 EDs. An ED is 
defined as a 24-hour period in which one or more BIVV001 injections are given. If ≤2 participants 
out of 104 evaluable participants develop an inhibitor, then the upper bound of an exact 95% 
confidence interval would exclude 6.8%, a threshold determined at the FDA Factor VIII Inhibitor 
Workshop that was held in 2003. Approximately 124 participants who are currently on a 
prophylaxis treatment regimen will enroll in Arm A, a 52-week prophylaxis arm, of which 
approximately 16 participants will be enrolled in the sequential PK subgroup. In addition, 
approximately 26 participants who are currently on an on-demand treatment regimen will enroll in 
Arm B and will receive BIVV001 on-demand for 26 weeks followed by weekly prophylaxis for 
26 weeks. Thus, the overall sample size is approximately 150 subjects (ie, 124 in Arm A and 26 in 
Arm B). 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 80 
The primary efficacy objective of this study is to evaluate the efficacy of BIVV001 weekly 
prophylaxis as estimated by the mean ABR and one-sided 97.5% CI in Arm A. Based on currently 
marketed FVIII products, mean ABR during clinical trials typically ranges from 2 to 5 bleeds per 
year but can be as high as 6 bleeding episodes per year (1, 2, 3, 4, 5, 6, 7). This indicates that 
while the ABR is typically low with adequate treatment, there is variability in clinical bleeding 
phenotype with some severe hemophilia A participants having higher bleeding rates than others. 
In order to show adequate control of bleeding consistent with currently marketed FVIII products, 
and to account for this variability, a clinically meaningful treatment effect may be claimed if the 
upper bound of the confidence interval of the estimated ABR is less than or equal to 6. In a  
Phase 3 study of rFVIIIFc, the mean ABR for an individualized prophylaxis arm was 2.9 and the 
dispersion factor was estimated at 2.3 (REF: data on file). Based on 2000 simulations of a 
negative binomial regression model with mean ABR of 2.9 and dispersion factor of 2.3, a sample 
size of 124 participants will provide at least 90% power for the upper bound of the one-sided 
97.5% confidence interval to exclude an ABR greater than 6, assuming a 15% drop out rate. 
For the key secondary efficacy endpoint, an intra-patient comparison of ABR during the 
BIVV001 weekly prophylaxis treatment period versus the historical prophylaxis ABR will be 
performed using non-inferiority testing for participants in Arm A who have at least 6 months of 
participation in this study and at least 6 months of historical data on prophylaxis treatment from 
observational Study 242HA201/OBS16221. The non-inferiority margin was estimated based on 
the known treatment effect between on-demand and prophylaxis treatment. A meta-analysis of 
Phase 3 registrational studies for recombinant FVIII products that include both on-demand and 
prophylaxis treatment arms estimated an average reduction of 31 bleeds per year between on-
demand and prophylaxis treatment regimens (5, 7, 8, 9, 6, 10, 11). The lower bound of this 
treatment effect was 27 bleeds per year. Using a fixed margin approach to maintain a substantial 
amount (85%) of the treatment effect results in a non-inferiority margin of 4. Further details on 
the meta-analysis and derivation of the non-inferiority margin will be specified in the statistical 
analysis plan. For a non-inferiority test of the null hypothesis (median difference in ABR exceeds 
or is equal to non-inferiority margin) versus the alternative hypothesis (median difference in ABR 
is less than non-inferiority margin), a sample size of 63 achieves 90% power to detect non-
inferiority using a one-sided paired Wilcoxon Signed Rank test at a 0.025 significance level when 
the actual mean of paired differences is 0 and the non-inferiority margin is 4. Without prior 
knowledge of the standard deviation of the paired differences, a conservative estimate of 10 was 
assumed. In order to account for drop-out and the use of the Per Protocol Set, at least 
75 participants who have completed at least 6 months of participation in observational 
Study 242HA201/OBS16221 will be enrolled in Arm A. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 81 
9.3 
POPULATIONS FOR ANALYSES  
For purposes of analysis, the following populations are defined (Table 13): 
Table 13 - Populations for analyses  
Population 
Description 
All-Enrolled Analysis Set 
All participants who were enrolled in the study, regardless of whether they were 
dosed with study drug or not.   
Participants will be considered enrolled when the Investigator has verified that they 
are eligible according to the criteria in Section 5 of the protocol. Participant 
disposition and enrollment summaries will be based on the All-Enrolled Analysis 
Set. 
Full Analysis Set 
All participants who receive at least one dose of study drug. 
Per Protocol Set 
A subset of the Full Analysis Set including participants who do not have important 
protocol deviations potentially impacting efficacy. 
Safety Analysis Set 
The safety analysis set is the same as the full analysis set and will include all 
participants who receive at least one dose of study drug. 
PK Analysis Set 
All participants who have completed adequate blood sample collection to assess 
key PK parameters, as determined by the PK scientist. 
Sequential Pharmacokinetic Subgroup 
All participants who have evaluable PK profiles for both the Baseline and Repeat 
PK profiles, as determined by the PK scientist. 
Surgery Subgroup 
All participants who have undergone major surgery after the first dose of study drug.  
 
9.4 
STATISTICAL ANALYSES  
The statistical analysis plan will be developed and finalized before database lock and will describe 
the participant populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. This section is a summary of the planned statistical analyses 
of the primary and secondary endpoints. 
Data for bleeding episodes will be collected by each participant via an electronic diary or, in the 
case of bleeding episodes occurring and/or treated at the study site, on the electronic case report 
form and will include type of bleed, location of bleed, and treatment dates, if applicable. This 
information will be used to derive the primary and related secondary efficacy endpoints. 
All analyses of bleeding endpoints will be based on treated bleeding episodes, except for the 
summary of ABR for all bleeding episodes which will include both treated and untreated bleeding 
episodes 
All primary analyses of bleeding endpoints will be based on treated bleeding episodes consistent 
with ISTH criteria (61) using a standardized definition, as follows. A bleeding episode starts from 
the first sign of bleeding and ends no more than 72 hours after the last injection to treat the 
bleeding episode. Any subsequent bleeding at the same location and injections administered less 
than or equal to 72 hours from the previous injection will be considered the same bleeding 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 82 
episode. Multiple bleeding locations treated with a single injection will also be considered a single 
bleeding episode. Any injection to treat the bleeding episode that is administered more than  
72 hours after the preceding one will be considered the first injection to treat a new bleeding 
episode in the same location. Any injection used to treat subsequent bleeding at a different 
location will be considered a separate bleeding episode, regardless of the time from the last 
injection to treat a bleeding episode. If a bleeding episode occurs on the same day as a regularly 
scheduled prophylaxis dose, participants are instructed to record in their diary treated and 
untreated bleeds and the timing of prophylactic and bleed treatments (see Section 8.1.1.1). 
In addition, an analysis of all bleeding episodes (including untreated bleeds) will be performed. 
The definition of all bleeds will follow the ISTH criteria, except that untreated bleeds will be 
counted based on the date and time of the bleed itself, as described in the SAP. 
9.4.1 Efficacy analyses  
The primary analysis of all primary, secondary, and exploratory efficacy endpoints will be based 
on the Full Analysis Set. The primary analysis of the key secondary endpoint will be based on the 
Per Protocol Set, consistent with guidelines for non-inferiority testing. In general, continuous 
variables will be summarized by descriptive statistics, including mean, median, SD, minimum, 
and maximum. Categorical variables will be presented with the number and percentage in each 
category. 
All analyses and summaries relating to bleeding and consumption will be based on the efficacy 
period (specified in SAP); data collected during the PK and surgical/rehabilitation periods (major 
and minor) will not be included.  
All other efficacy analyses will be based on the treatment regimen period (specified in SAP), 
excluding data that occurs during any major surgical/rehabilitation period to avoid confounding 
the treatment effect.  
9.4.1.1 Primary efficacy endpoint  
The primary analysis of the primary endpoint will estimate the mean ABR and one sided 97.5% 
CI using a Negative Binomial regression model for the weekly prophylaxis arm (Arm A). If the 
upper limit of the CI is less than or equal to 6, the weekly prophylaxis treatment regimen will be 
considered to provide adequate control. A bleeding episode is counted in the primary analysis if it 
was treated. All types of bleeding episodes (spontaneous, traumatic, and unknown) will be 
included in determining the annualized number. The observed ABR for each individual 
participant will be calculated as the total number of bleeding episodes experienced by a 
participant divided by the total number of days in the respective efficacy period for each treatment 
regimen, multiplied by 365.25. 
Sensitivity and subgroup analyses of the primary endpoint will be described in the Statistical 
Analysis Plan. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 83 
9.4.1.2 Key secondary efficacy endpoints  
The key secondary efficacy endpoint will be analyzed for participants in Arm A who have at least 
6 months of participation in this study and at least 6 months of participation in 
Study 242HA201/OBS16221 prior to baseline using the Per Protocol Set. The paired differences 
in ABR between BIVV001 weekly prophylaxis treatment and historical prophylaxis will be 
analyzed by using a Negative-Binomial regression model. Non-inferiority will be established if 
the upper bound of the one-sided 97.5% CI is less than 4. If non-inferiority is achieved, 
superiority will be evaluated sequentially using the Full Analysis Set. As a supportive analysis, 
the non-inferiority analysis will also be performed using the Wilcoxon signed rank test. 
Specifically, the median of the paired differences in ABR between BIVV001 weekly prophylaxis 
and historical prophylaxis will be tested using a Wilcoxon Signed Rank test, using the Per 
Protocol Set.  The null hypothesis that the median difference is ≥4 will be tested against the 
alternative hypothesis that the median difference is <4. The null hypothesis will be rejected if 
p<0.025, establishing non-inferiority of BIVV001 weekly prophylaxis treatment to historical 
prophylaxis.   
In addition, the MMRM will be conducted on each of the 3 endpoints (ie, Haem-A-QoL physical 
health score, PROMIS Pain Intensity 3a, and HJHS Total Score) in Arm A, excluding visits that 
are coincidental with a major surgical/rehabilitation period. The MMRM model will include the 
baseline value of Haem-A-QoL physical health score, PROMIS Pain Intensity 3a, HJHS total 
score as a covariate and visit as a fixed effect, respectively. An unstructured variance-covariance 
matrix within a subject will be used. The adjusted mean change in Haem-A-QoL physical health 
score, PROMIS Pain Intensity 3a, HJHS total score from baseline to Week 52, along with its 95% 
CI, will be estimated by the MMRM model, respectively. A sensitivity analysis will be performed 
on the participants who roll over from lead-in observational study using the same MMRM model 
for the 3 endpoints as described above. 
9.4.1.3 Other secondary efficacy endpoints  
Annualized bleeding rate will be summarized descriptively by type of bleed (spontaneous, 
traumatic, or unknown) and location of bleed (joint, muscle, internal, or skin/mucosa) by study 
arm and treatment regimen. The summary of ABR by type and the summary of ABR by location 
will also be presented by age group (12-17 years, ≥18 years) for the weekly prophylaxis arm (Arm 
A) based on the FAS. ABR will also be summarized descriptively for all bleeding episodes, 
including untreated bleeding episodes, by study arm and treatment regimen. 
The consumption of BIVV001 will be annualized and summarized by study arm and treatment 
regimen.  
The number of injections and total dose of BIVV001 (IU/kg) to treat a bleeding episode will be 
summarized by study arm and treatment regimen on both a per-bleeding-episode and a per-
participant basis, where the per-participant basis will be determined as the average over all 
bleeding episodes for a given participant. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 84 
The participant’s response to treatment of individual bleeding episodes will be summarized by 
study arm and treatment regimen as the number and percentage of bleeding episodes with each 
response (excellent, good, moderate, or no response). 
The physician’s global assessment of the participant’s overall response to BIVV001 treatment will 
be summarized by study arm and treatment regimen for each study visit and across all visits as the 
number and percentage classified as excellent, effective, partially effective, and ineffective.  
The number and percentage of participants achieving trough FVIII activity levels above 1%, 5%, 
10%, 15%, and 20% will be summarized for Arm A. In these summaries, FVIII activity level will 
be based on the average trough samples (ie, nominal 168 hour time point) from each scheduled 
visit (Week 4, Week 13, Week 26, Week 39, Week 52) using the one-stage aPTT assay. 
Participants with trough samples that are outside 168 ±5 hours from the previous dose will be 
excluded from this analysis. 
The percentage of participants with resolution of at least 1 target joint and the percentage of total 
target joints that are resolved at 52 weeks will be summarized for Arm A. A target joint is defined 
as a major joint (eg, hip, elbow, wrist, shoulder, knee or ankle) into which ≥3 spontaneous 
bleeding episodes occurred in a consecutive 6-month period and resolution is achieved when 
≤2 bleeding episodes occur into that joint during 12 months of continuous exposure .  
Changes in HJHS domain scores such as swelling and strength from Baseline to Week 52 will be 
summarized descriptively by visit and by study arm. 
For PROMIS endpoints, norm-based T-scores will be calculated for each domain such that a score 
of 50 (SD=10) represents the mean of the general population. T-scores will be summarized 
descriptively by visit and by study arm. For Haem-A-QoL, total score and subscale scores will be 
summarized descriptively by visit and by study arm. 
Surgical endpoints will be summarized descriptively for the surgical subgroup. Continuous 
endpoints will be summarized using the number of non-missing values (n), mean, standard 
deviation (SD), median, minimum, and maximum. Categorical endpoints will be summarized by 
counts and percentages. 
9.4.1.4 Exploratory efficacy endpoints  
Analyses of exploratory efficacy endpoints will be described in the Statistical Analysis Plan 
finalized before database lock. 
9.4.1.5 Multiplicity Issue  
Type I error for secondary endpoints is controlled through a hierarchical testing framework. The α 
level is 0.05. Following the estimation approach described for the primary efficacy endpoint 
(ABR in Arm A), the key and selected secondary endpoints are included in the hierarchy in the 
following order:   
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 85 
1. Arm A intra-patient comparison non-inferiority (NI): ABR of BIVV001 weekly 
prophylaxis treatment vs. historical prophylaxis treatment (Section 9.1). 
2. Arm A intra-patient comparison superiority: ABR of BIVV001 weekly prophylaxis 
treatment vs. historical prophylaxis treatment (Section 9.1). 
3. Arm A change from Baseline to Week 52: Haem-A-QoL physical health score  
(Section 9.1). 
4. Arm A change from Baseline to Week 52: PROMIS pain intensity 3a (Section 9.1). 
5. Arm A change from Baseline to Week 52: HJHS total score (Section 9.1). 
No multiplicity adjustment will be made on any secondary efficacy variable other than those 
mentioned above. 
9.4.2 Safety analyses  
All safety analyses will be performed on the Safety Analysis Set. 
All safety analyses will be based on the safety period (specified in SAP). Unless otherwise 
specified, adverse events and laboratory evaluations occurred during major surgical/rehabilitation 
periods will not be included in the safety summaries. 
Safety will be assessed through descriptive summaries of AEs, laboratory test results, physical 
examination, and vital signs. 
In addition, incidence of inhibitor development will be assessed using an exact 95% confidence 
interval based on the binomial distribution. For the assessment of inhibitors, any participant who 
develops an inhibitor following the initial BIVV001 administration will be included in the 
numerator, regardless of the number of EDs to BIVV001; the denominator will include 
participants who have an inhibitor as well as participants with a valid inhibitor test following at 
least 50 EDs of BIVV001. The calculation will also be performed including all participants with a 
valid inhibitor test following at least 25 EDs and including all participants with a valid inhibitor 
test, regardless of how many days they were exposed to BIVV001.  
The occurrence of embolic and thrombotic events will be described. The analysis will consist of a 
search of TEAE data using the Embolic and Thrombotic Events Standard MedDRA Query 
(SMQ). Medical adjudication of the search results will also be performed according to the below 
definition. 
Safety endpoint definitions 
Inhibitor development 
Defined as an inhibitor result of >0.6 BU/mL that is confirmed by a second test result of 
>0.6 BU/mL from a separate sample, drawn 2 to 4 weeks following the date when the original 
sample was drawn. Both tests must be performed by the central laboratory using the 
Nijmegen-modified Bethesda assay. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 86 
Embolic and thrombotic events 
The following definition will be used for purposes of medical adjudication of the TEAE data 
resulting from a search conducted using the Embolic and Thrombotic Events SMQ. 
Embolic and thrombotic events are defined as arterial or venous thrombosis, confirmed by 
imaging. 
Coronary artery thrombosis/occlusion must be confirmed by coronary angiography to be included 
as part of medical adjudication. 
Thrombosis involving the cerebral vasculature must be confirmed by imaging such as magnetic 
resonance imaging venogram (MRV), computed tomography venogram (CTV), magnetic 
resonance angiography (MRA), or computed tomography angiography (CTA) to be included as 
part of medical adjudication. 
An indwelling central venous access device is a well-established risk factor for thrombosis (68) 
and thrombotic events associated with such devices will not be included as part of medical 
adjudication. Occlusion or malfunction of a central venous access device also will not be included 
as part of medical adjudication. 
Infusion thrombophlebitis is a recognized complication of peripheral vein infusion (69) and will 
not be included as part of medical adjudication. 
9.4.3 Pharmacokinetics  
FVIII activity measured by one-stage clotting and chromogenic coagulation assay will be used to 
estimate PK parameters using noncompartmental analysis. Primary PK parameters of FVIII 
activity (Cmax, t1/2, CL, CLss, AI, AUC, Vss, MRT, IR, Ctrough) using the one-stage clotting assay 
will be estimated. These analyses will be repeated for PK parameters of FVIII activity using the 
chromogenic coagulation assay. Summary descriptive statistics and individual participant listings 
will be presented for FVIII activity (using both the one-stage clotting assay and two-stage 
chromogenic assay) by time point. Mean FVIII activity versus time profiles will be plotted for 
BIVV001 at both Day 1 and the repeat PK profile. For the abbreviated PK group, baseline PK 
parameters will be estimated. For the Sequential PK subgroup, geometric means for the intra-
subject ratios of baseline BIVV001 to repeat BIVV001 will be provided with 95% confidence 
intervals for selected PK parameters. Individual PK parameter estimates will be listed for each 
participant and summarized descriptively by visit (Day 1 and the repeat PK profile). 
The population PK analysis will be presented separately from the main clinical study report 
(CSR). Population PK analysis will be described fully in the population PK analysis plan and will 
be finalized before database lock. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 87 
9.4.4 Immunogenicity analysis  
9.4.4.1 Anti-drug antibody  
Participant’s ADA status (ie, Pre-existing ADA, Treatment-boosted ADA, Unclassified ADA, 
Treatment-induced ADA, Treatment-emergent ADA [see SAP for definitions]) will be 
summarized on the safety analysis set. Descriptive statistics (median, 25th/75th quantiles, minimal 
and maximal) will be used for the analysis ADA titer of different ADA status. The number and 
percentage of participants with different ADA kinetic status (ie, persistent ADA response, 
transient ADA responses, and indeterminate ADA response [see SAP for definitions]) will be 
summarized for the safety analysis set. 
9.5 
INTERIM ANALYSES   
No formal interim analyses are planned. 
9.5.1 Data Monitoring Committee (DMC)  
There is no DMC in this open-label study, but the study suspension rules (see Section 4.5) will be 
strictly adhered to throughout the study. 
 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 88 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS  
10.1.1 Regulatory and ethical considerations  
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and the applicable amendments and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines 
• Applicable ICH Good Clinical Practice (GCP) Guidelines 
• Applicable laws and regulations 
• The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
• The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations 
10.1.2 Financial disclosure  
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. The Investigator should address any potential conflicts of 
interest (eg, financial interest in Bioverativ) with the participant before the participant makes a 
decision to participate in the study. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 89 
10.1.3 Informed consent process  
• The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study. 
• Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center. 
• No study procedures other than the informed consent can be performed before the 
informed consent is signed by the patient and authorized representative. 
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
• A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 
Participants who are rescreened are required to sign a new ICF. 
The ICF will contain a separate section that addresses the use of remaining mandatory samples for 
optional exploratory research. The Investigator or authorized designee will explain to each 
participant the objectives of the exploratory research. Participants will be told that they are free to 
refuse to participate and may withdraw their consent at any time and for any reason during the 
storage period. A separate signature will be required to document a participant's agreement to 
allow any remaining specimens to be used for exploratory research. Participants who decline to 
participate in this optional research will not provide this separate signature. The ICF will also 
contain a separate section for the joint ultrasound sub-study (only at participating sites). The 
participants will have to check-off agreement to participate/not participate in the sub-study and 
provide a separate signature. 
10.1.4 Data protection  
All personal data collected related to participants, Investigators, or any person involved in the 
study, which may be included in the Sponsor’s databases, shall be treated in compliance with all 
applicable laws and regulations including the GDPR (Global Data Protection Regulation). 
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
• 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 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 90 
names or any information which would make the participant identifiable will not be 
transferred. 
• The race and ethnicity of participants will be collected in this study. These data may be 
used in the analysis of the safety and/or PK profile of the study treatment. In previous 
cross-sectional analyses of different ethnic groups, differences in the occurrence of FVIII 
inhibitors have been observed (70, 71). Additionally, differential responses to FVIII 
products may occur in different haplotypes of FVIII that also differ across racial and 
ethnic groups (72). 
• 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/IEC members, and by inspectors from regulatory authorities. 
• When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor shall take all appropriate measures to safeguard and prevent 
access to this data by any unauthorized third party. 
10.1.5 Dissemination of clinical study data  
Sanofi shares information about clinical trials and results on publicly accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations. These 
websites include clinicaltrials.gov, EU clinical trial register (eu.ctr), and sanofi.com, as well as 
some national registries. 
In addition, results from clinical trials in patients are required to be submitted to peer-reviewed 
journals following internal company review for accuracy, fair balance and intellectual property. 
For those journals that request sharing of the analyzable data sets that are reported in the 
publication, interested researchers are directed to submit their request to 
clinicalstudydatarequest.com. 
Individual participant data and supporting clinical documents are available for request at 
clinicalstudydatarequest.com. While making information available we continue to protect the 
privacy of participants in our clinical trials. Details on data sharing criteria and process for 
requesting access can be found at this web address: clinicalstudydatarequest.com. 
10.1.6 Data quality assurance  
• All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 91 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing strategy (eg, 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 separate study documents. 
• 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 
(eg, 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 25 years after the signature of the final study 
report unless local regulations or institutional policies require a longer retention period. No 
records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor. 
10.1.7 Source documents  
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
10.1.8 Study and site 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. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 92 
Reasons for study termination by the Sponsor, as well as reasons for the early closure of a study 
site by the Sponsor or Investigator may include but are not limited to: 
• For study termination: 
- 
Information on the product leads to doubt as to the benefit/risk ratio 
- 
Discontinuation of further study intervention development 
• For site termination: 
- 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines 
- 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator 
- 
Total number of participants included earlier than expected 
10.1.9 Publication policy  
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments. 
• The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating Investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS  
The tests detailed in Table 14 will be performed by the central laboratory.  
Local laboratory results are only required in the event that the central laboratory results are not 
available in time for either study intervention administration and/or response evaluation. If a local 
sample is required, it is important that the sample for central analysis is obtained at the same 
time. Additionally, if the local laboratory results are used to make either a study intervention 
decision or response evaluation, the results must be entered into the CRF. Unless stated in the 
protocol, local laboratory results are not permitted for the assessment of inhibitor development as 
part of this study. 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in  
Section 4.5 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.      
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 93 
Table 14 - Protocol-required laboratory assessments  
Laboratory assessments 
Parameters 
Hematology 
 
 
• 
Platelet count 
 
• 
Red blood cell (RBC) count 
• 
White blood cell (WBC) count and differential 
 
• 
Hemoglobin (Hgb) 
• 
Hematocrit (HCT) 
Clinical chemistrya 
• 
Alanine amino transferase (ALT) 
 
• 
Aspartate amino transferase (AST) 
• 
Alkaline phosphatase (ALP) 
• 
Gamma glutamyl transferase (GGT) 
• 
Bilirubin 
• 
Blood Urea Nitrogen (BUN) 
 
• 
Creatinine 
 
• 
Glucose [non-fasting] 
• 
Total protein 
 
• 
Potassium 
 
• 
Sodium 
• 
Chloride 
Von Willebrand comprehensive 
panel 
• 
VWF ristocetin cofactor activity 
• 
VWF antigen 
Immunogenicity 
• 
Nijmegen modified Bethesda inhibitor assay 
• 
ADA 
• 
ADA subtype 
Coagulation parameters 
• 
Activated partial thromboplastin time (aPTT) 
Other tests and assessments 
• 
Ultrasound assessment using the JADE and/or HEAD US protocol (select sites 
only) 
• 
Highly sensitive [Serum or urine] human chorionic gonadotropin (hCG) pregnancy 
test (as needed for women of childbearing potential)b 
• 
HIV (HIV-1 antibodies, HIV-2 antibodies, and HIV-1 p24 antigen), HBV (HBV 
surface antigen [HBsAg], anti-HBV surface antibody and anti-HBV core antibody) 
and HCV (anti-HCV antibodies) for patients who have been historically negative 
Follicle stimulating hormone and estradiol (as needed in women of non-child 
bearing potential only) 
• 
CD4 count and viral load (for patients known to be HIV positive) 
NOTES : 
a All events which may indicate severe liver injury (possible Hy’s Law) must be reported as an SAE (excluding studies of hepatic impairment 
or cirrhosis).  
b Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC. 
Investigators must document their review of each laboratory safety report. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 94 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING  
DEFINITION OF AE 
AE definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally 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) temporally 
associated with the use of study intervention. 
Events meeting the AE definition 
• Abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, ECG, radiological scans, vital signs measurements), that worsen 
from baseline, and are considered clinically significant in the medical and scientific 
judgment of the Investigator (ie, not related to progression of underlying disease), eg: 
• Symptomatic and/or 
• Requiring either corrective treatment or consultation, and/or  
• Leading to IMP discontinuation or modification of dosing, and/or  
• Fulfilling a seriousness criterion, and/or  
• Defined as an AESI 
• 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. 
• "Lack of efficacy" or "failure of expected pharmacological action" per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE. 
Events NOT meeting the AE definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 95 
• 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 (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur. 
• 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. 
DEFINITION OF SAE 
 A SAE is defined as any untoward medical occurrence that, at any dose: 
a) Results in death 
b) Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
c) Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
d) Results in persistent disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct normal 
life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and 
accidental trauma (eg, 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 in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events should usually be considered serious. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 96 
- 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
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 (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The Investigator will then record all relevant AE/SAE information in the CRF. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor (or representative) in lieu of completion of the AE/SAE CRF page. 
• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor (or representative). 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 (or representative). 
• 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 and interferes with normal everyday 
activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with a SAE. Severe is a category utilized for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe. 
Assessment of causality 
The following definitions should be considered when evaluating the relationship of AEs and 
SAEs to the study treatment: 
Not related: An adverse event will be considered “not related” to the use of the investigational 
drug if there is not a reasonable possibility that the event has been caused by the product under 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 97 
investigation. Factors pointing toward this assessment include, but are not limited to: the lack of 
reasonable temporal relationship between administration of the drug and the event, the presence of 
a biologically implausible relationship between the product and the adverse event (eg., the event 
occurred before administration of drug), or the presence of a more likely alternative explanation 
for the adverse event. 
Related: An adverse event will be considered “related” to the use of the investigational drug if 
there is a possibility that the event may have been caused by the product under investigation. 
Factors that point toward this assessment include, but are not limited to: a positive rechallenge, a 
reasonable temporal sequence between administration of the drug and the event, a known 
response pattern of the suspected drug, improvement following discontinuation or dose reduction, 
a biologically plausible relationship between the drug and the adverse event, or a lack of an 
alternative explanation for the adverse event. 
• The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• The Investigator will use clinical judgment to determine the relationship. 
• The Investigator will also consult the Investigator’s Brochure (IB) 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 (or representative). 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 (or 
representative). The Investigator may change his/her opinion of causality in light of 
follow-up information and send a 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 (or 
representative) to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor (or representative) with a copy of any 
post-mortem findings including histopathology. 
• New or updated information will be recorded in the originally completed CRF. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 98 
• The Investigator will submit any updated SAE data to the Sponsor (or representative) 
within 24 hours of receipt of the information. 
REPORTING OF SAEs 
SAE reporting to the Sponsor (or representative) via an electronic data collection tool 
• The primary mechanism for reporting an SAE to the Sponsor (or representative) will be 
the electronic data collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) in order to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes available. 
• 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 (or representative)by facsimile transmission or email. 
• Contacts for SAE reporting can be found in the Study Manual. 
SAE reporting to the Sponsor (or representative) via paper CRF 
• Facsimile transmission or email of the SAE paper CRF is the preferred method to transmit 
this information to the Sponsor (or representative) if the electronic data collection tools is 
not available. 
• In rare circumstances, notification by telephone is acceptable with a copy of the SAE data 
collection tool sent by overnight mail or courier service. 
• Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames. 
• Contacts for SAE reporting can be found in the Study Manual. 
 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 99 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION  
DEFINITIONS: 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, 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, (eg, mullerian agenesis, androgen insensitivity), Investigator discretion 
should be applied to determining 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. 
• A high follicle 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 one FSH measurement (>40 IU/L or mIU/mL) 
is required. 
• Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-estrogen hormonal 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. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 100 
CONTRACEPTION GUIDANCE: 
 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methodsb That Have Low User Dependency Failure rate of <1% per year when 
used consistently and correctly. 
• Implantable progestogen-only hormone contraception associated with inhibition of 
ovulationb 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) b 
• Bilateral tubal occlusion 
• Vasectomized partner 
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the 
sole sexual partner of the woman of childbearing potential and the absence of sperm has been 
confirmed. If not, an additional highly effective method of contraception should be used. 
Spermatogenesis cycle is approximately 90 days.) 
Highly Effective Methodsb That Are User Dependent Failure rate of <1% per year when used 
consistently and correctly. 
Combined (estrogen- and progestogen-containing ) hormonal contraception associated with inhibition 
of ovulationc 
• oral 
• intravaginal 
• transdermal 
• injectable 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
− oral 
− injectable 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study intervention. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the 
preferred and usual lifestyle of the participant.) 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 101 
ACCEPTABLE METHODSd 
• Progestogen-only oral hormonal contraception where inhibition of ovulation is not the 
primary mode of action 
• Male or female condom with or without spermicidee 
• Cervical cap, diaphragm, or sponge with spermicide 
• A combination of male condom with either cervical cap, diaphragm, or sponge with 
spermicide (double-barrier methods)c 
a) Contraceptive use by men or women should be consistent with local regulations regarding the use of 
contraceptive methods for those participating in clinical studies. 
b) Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those 
when used consistently and correctly. 
c.) [Male condoms must be used in addition to hormonal contraception]. If locally required, in accordance with 
Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive methods are limited to those 
which inhibit ovulation as the primary mode of action. 
d) Considered effective, but not highly effective - failure rate of ≥1% per year. Periodic abstinence (calendar, 
symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational 
amenorrhoea method (LAM) are not acceptable methods of contraception.  
e) Male condom and female condom should not be used together (due to risk of failure with friction). 
 
COLLECTION OF PREGNANCY INFORMATION: 
Male participants with partners who become pregnant 
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive BIVV001. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
Female participants who become pregnant 
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. 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 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 102 
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. 
• Any pregnancy complication or elective termination of a pregnancy will be reported as an 
AE or SAE. A spontaneous abortion 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 8.3.6. 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 or be withdrawn from the study 
10.5 
 APPENDIX 5: OVERDOSE  
An overdose (accidental or intentional) with the IMP/NIMP is an event suspected by the 
Investigator or spontaneously notified by the participant and defined as any dose of study 
treatment administered to a participant or taken by a participant that exceeds the dose assigned to 
the participant according to the protocol. 
 
All overdoses (symptomatic and asymptomatic) must be recorded on the overdose form of the 
CRF within 24 hours of the site becoming aware of the overdose. All study drug-related dosing 
information must be recorded on the dosing CRF. 
 
The signs and symptoms associated with a symptomatic overdose (serious and/or non-serious) 
with IMP/NIMP must also be recorded as an AESI on the CRF (see Section 8.3.1). Treatment of 
overdoses are described in Section 8.4. 
 
Asymptomatic overdoses are not considered AEs and should not be recorded as an AE on the 
CRF. 
10.6 
APPENDIX 6: GENETICS  
Not applicable. 
10.7 
APPENDIX 7: DEFINITIONS OF MINOR AND MAJOR SURGERY  
Minor surgery is defined as any invasive operative procedure in which only skin, mucous 
membranes, or superficial connective tissue is manipulated and does not meet the criteria for 
major surgery (eg, dental extraction of <3 nonmolar teeth). Minor surgical procedures may be 
performed at a local health care provider institution. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 103 
Major surgery is defined as any invasive operative procedure that requires any of the following: 
• Opening into a major body cavity (eg, abdomen, thorax, skull) 
• Operation on a joint 
• Removal of an organ 
• Dental extraction of any molar teeth or ≥3 nonmolar teeth 
• Operative alteration of normal anatomy 
• Crossing of a mesenchymal barrier (eg, pleura, peritoneum, dura) 
It is recommended that any elective non-dental major surgery be performed at a study site, when 
possible. 
10.8 
APPENDIX 8: ASSESSMENTS  
Response to treatment: Defined as the number of injections and dose of BIVV001 to treat a 
bleeding episode, percentage of bleeding episodes treated with a single injection, participant’s 
assessment of response to BIVV001 treatment of individual bleeding episodes using a 4-point 
response scale, investigator’s global assessment of participant’s response to BIVV001 treatment 
using a 4 point response scale. 
Investigator’s Assessment of Response: Uses a 4 point response scale 
Response to Surgery: Investigator’s/Surgeon’s assessment of participant’s response to surgery 
with BIVV001 using a bleeding response scale when participant has completed the surgical period 
including a 24 hour post-operative time period. 
10.9 
APPENDIX 9:  WASHOUT AND BLOOD SAMPLING SUMMARY  
The following tables summarize the requirements for washout and blood sampling necessary to 
successfully complete both the washout and PK sampling. If a participant experiences a bleeding 
episode after receiving the dose of BIVV001 but prior to completing the PK sampling, PK 
sampling will be stopped at the time of the bleed. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 106 
10.10 APPENDIX 10: DEFINITIONS OF MINOR, MODERATE, AND MAJOR BLEEDING 
EPISODES  
Minor 
• Mild Epistaxis  
• Early signs of joint bleeding 
• Mild soft tissue bleed 
Moderate  
• Epistaxis with heavy blood flow 
• Muscle bleeding 
• Gastrointestinal/oral mucosal bleeds  
• Gum bleeding after dental extraction 
• Hematuria 
• Hemarthrosis 
Major to life-threatening 
• Epistaxis with very heavy blood flow 
• Retropharyngeal and pharyngeal bleeding 
• Abdominal and retroperitoneal bleeding  
• Post-surgical bleeding 
• CNS bleeding 
10.11 APPENDIX 11: COUNTRY-SPECIFIC REQUIREMENTS  
10.11.1 France  
Change to the protocol for France only: new text addition is presented as bold text and deleted 
text is presented in crossed text: 
 
Section 1.3 Schedule of Activities (Section 1.3, Table 1) 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 107 
Overall schedule of activities from screening to safety follow-up call or visit  
Tests and 
assessments 
Screeni
nga, b 
(Week -
8 to 
Day 1) 
Baseli
neb 
BIVV0
01 
Day 1 
Week 
4c 
±7 
days 
Week 
13c 
±7 days 
Week 
26c, d  
±7 
days 
Week 
39c 
±7day
s 
Week 
52/ 
EOS/E
Tc 
±7 
days 
Unschedu
led visite 
Safety 
follow-
up call 
or visitf 
Pregnancyn 
X 
X 
 
X 
X 
X 
X 
 
Xii 
f This call or visit will occur 14 (+7) days after the last dose of BIVV001, unless the participant 
enrolls in the open-label extension study. For female participants in France, a visit must be 
conducted for purposes of pregnancy testing. 
ii The pregnancy test at the Safety Follow up visit is to be performed in France only. 
 
Section 4.4 End of study definition (Section 4.4) 
End of Study will occur when all of the following criteria have been met:  
• 104 participants have reached 50 exposure days (EDs) and have completed a valid 
inhibitor test after the 50th ED.   
• At least 63 participants in Arm A have at least 6 months of participation in this study and 
have at least 6 months of participation in Study 242HA201/OBS16221 prior to baseline. 
• Thirteen participants in the PK subgroup have completed the BIVV001 Day 1 PK profile, 
and a repeat 14-day BIVV001 PK profile 26 weeks later with adequate estimate of 
terminal half-life. 
If there are participants still ongoing in the study when EOS is declared, they will return to the 
study for an EOS visit to complete their participation. 
At the end of the study eligible patients will have the option to participate in a long-term 
extension study. 
 
 Section 4.5 Study stopping rules (Section 4.5) 
The Sponsor may terminate the study at any time, after informing Investigators, Institutional 
Review Boards/Ethics Committees, and applicable regulatory agencies.  Investigators will be 
notified by the Sponsor (or designee) if enrollment and dosing are suspended, completed, or 
closed. 
At the end of the study eligible patients will have the option to participate in a long-term 
extension study. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 108 
 Section 5.2 Exclusion Criteria (Section 5.2) 
The following exclusion criterion has been deleted:  
 E 23. Any specific situation during study implementation/course that may raise ethical 
considerations 
The following exclusion criterion has been added:  
E25: History of an unprovoked venous thromboembolism, myocardial infarction within  
12 months prior to screening, or occlusive cerebral vascular accident within 12 months prior 
to screening. Patients who have experienced thrombosis associated with indwelling venous 
access may be enrolled. 
10.11.2  Italy   
Change to the protocol for Italy only: new text addition is presented as bold text and deleted text 
is presented in crossed text: 
Section 5.2 Exclusion Criteria (Section 5.2) 
The following exclusion criterion has been replaced:  
E07 Abnormal renal function, defined as serum creatinine >2.0 mg/dL taken at Screening   
by:  
E07 Impaired renal function, defined as creatinine clearance by Cockcroft-Gault formula 
<60 mL/min (for ≥18 years) or glomerular filtration rate by Bedside Schwartz formula  
<60 mL/min/1.73m2 (for <18 years) 
 
Section 1.3 Schedule of Activities (Section 1.3, Table 1) 
Overall schedule of activities from screening to safety follow-up call or visit  
Tests and 
assessments 
Screeni
nga, b 
(Week -
8 to 
Day 1) 
Baseli
neb 
BIVV0
01 
Day 1 
Week 
4c 
±7 
days 
Week 
13c 
±7 days 
Week 
26c, d  
±7 
days 
Week 
39c 
±7day
s 
Week 
52/ 
EOS/E
Tc 
±7 
days 
Unschedu
led visite 
Safety 
follow-
up call 
or visitf 
Height 
X 
Xii 
 
 
Xii 
 
Xii 
 
 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
 
ii Only applicable in participants 12-17 years of age 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 109 
10.12 APPENDIX 12: ABBREVIATIONS  
 
ABR: 
Annualized Bleeding Rate 
AESI: 
adverse event of special interest 
AIFA: 
Agenzia Italiana del Farmaco 
AJBR: 
annualized joint bleeding rate 
ANSM: 
Agence Nationale de Sécurité du Médicament et des Produits de Santé 
AUC: 
area under the activity time curve 
CL: 
total clearance 
CLss: 
total clearance at steady state 
Cmax: 
maximum activity 
Ctrough: 
trough activity 
eCRF: 
electronic Case Report Form 
ED: 
exposure days 
EHL: 
extended half-life 
ePD: 
electronic patient diary 
FVIII: 
factor VIII 
HEAD-US: 
Hemophilia Early Arthropathy Detection with Ultrasound 
HJHS: 
Hemophilia Joint Health Score 
ISTH: 
International Society on Thrombosis and Haemostasis 
JADE: 
Joint Tissue Activity and Damage Examination 
MRT: 
mean residence time 
NIMP: 
non-investigational medicinal product 
PGA: 
Physician's Global Assessment 
PGIC: 
patient global impression of change 
PGIS: 
patient global impression of severity 
PK: 
pharmacokinetics 
PTP: 
previously treated patient 
QW: 
every week 
SAE: 
serious adverse event 
SD: 
standard deviation 
t1/2: 
elimination half-life 
TESAE: 
treatment emergent serious adverse events 
Vss: 
volume of distribution at steady state 
 
  
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 142 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 161 
 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 181 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 184 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 186 
10.15 APPENDIX 15: PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment 5 is located 
directly before the Table of Contents (TOC). 
 
Amended protocol 04 (13 May 2020) 
This amended protocol 04 is considered to be non-substantial based on the criteria set forth in 
Article 10 (a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union, because it does not significantly impact the safety or physical/mental integrity of 
participants, nor the scientific value of the study. 
OVERALL RATIONALE FOR THE AMENDMENT  
The main reasons for this amendment are the following: 
• to modify the requirements for the washout of FVIII products before screening and allow 
inclusion of patients based on historical FVIII results or documented genotype known to 
produce severe hemophilia A 
• to allow for flexibility in the washout of FVIII products before the Baseline visit in 
patients participating in the abbreviated PK group  
• to allow for faster infusion rate for the BIVV001 injection performed at home 
• to clarify that in case of minor surgery the FVIII activity and the BIVV001 dosing at the 
24h follow up will be performed only if clinically warranted 
• to clarify the reporting of overdoses 
• to clarify that during study visits, for reliable PK assessment, PK sampling should not be 
done via the same intravenous access route as used for the BIVV001 administration 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Title Page 
Updated Sponsor name to - Bioverativ Therapeutics Inc. (a Sanofi Company) 
Added NCT number - NCT04161495 
Administrative change 
Section 1.1 
Synopsis 
Overall Design 
Added following sentence: 
The washout period before the Baseline Visit for subjects in abbreviated PK 
sampling may be modified at the discretion of the Investigator based on 
individual PK data and clinical phenotype in consultation with medical 
monitor.  
Allow for flexibility in 
the washout before 
the Baseline visit 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 187 
Section # and 
Name 
Description of Change 
Brief Rationale 
Table 1,  
Table 2,  
Section 4.1 Overall 
design - Screening 
Section 8.5 
Pharmacokinetics 
Washout prior to the Screening inhibitor test is updated to at least 48 hours 
(time period to obtain interpretable test results)  
The washout period before the baseline visit or prior to BIVV001 Day 1 dose 
administration for subjects in abbreviated PK sampling sub-group is updated 
to be modifiable at the discretion of the Investigator based on individual PK 
data and clinical phenotype in consultation with medical monitor. 
Modification of the 
washout period before 
the screening visit 
Allow for flexibility in 
the washout before 
the Baseline visit 
Table 1 - Overall 
schedule of 
activities from 
screening to safety 
follow-up call or visit 
Deleted chromogenic assays from FVIII activity assessments at screening 
visit 
 
Removal of the FVIII 
chromogenic assay at 
the screening visit 
Coagulation parameters (aPTT) assessment is added on Baseline, Week 26, 
and Week 52. 
Addition of 
coagulation 
parameters at the 
Baseline visit 
Footnote “c” is updated as described below: 
Participants should schedule their study visits to be 7 ±1 day after the 
previous prophylactic dose of BIVV001.  
To clarify this is 
applicable to all 
patients (not only to 
the sequential PK arm 
For home BIVV001 injections rate of administration is updated as per Table 7, 
section 6.1.1.1 Study treatment schedule and administration 
To allow for faster 
injection duration 
Footnote “n” is updated to clarify that for required pregnancy tests after 
screening, the choice of the pregnancy test (urine or serum) is at the 
discretion of the Investigator. 
Clarification 
Human immunodeficiency virus (HIV) tests will include HIV-1 antibodies, HIV-
2 antibodies and HIV-1 p24 antigen. Hepatitis B virus (HBV) tests will include 
HBV surface antigen, anti-HBV surface antibody and anti-HBV core antibody. 
Hepatitis C virus (HCV) tests will include anti-HCV antibodies. 
Clarification on the 
type of testing 
performed 
In prior and concomitant medications, pain medication related to Hemophilia 
and administered within 2 weeks prior to any visit is to be recorded in CRF. 
Clarification  
Ultrasound assessment is updated with flexibility of performance at Baseline 
visit or up to 2 weeks after the Baseline Visit. 
To allow flexibility  
ActiGraph Activity Monitor wearing by patient is updated to 8 consecutive 
days after the scheduled visits at Screening, Baseline, Weeks 4, 13, 26, 39, 
and for 8 consecutive days before the Week 52 visit 
Clarification 
Table 4 - Surgical 
schedule of 
activities   
Added below text in footnote “g” and “j”, respectively 
The FVIII activity at the 24h follow up will be done only for patient with major 
surgery (for minor surgery it will be done only if clinically warranted).  
The 24h post-operative BIVV001 dosing will be performed only if clinically 
needed (based on FVIII activity level). 
To clarify the 
requirement at the 24h 
follow up in case of 
minor surgery 
Section 2.3 
Benefit/Risk 
assessment  
The paragraphs pertaining to “Benefits” and “Risks” is updated for 
clarification. 
Clarification 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 188 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 5.1 
Inclusion criteria 
Inclusion criteria I02 is updated as below: 
I 02. 
Severe hemophilia A, defined as <1 IU/dL (<1%) endogenous FVIII 
activity as documented either by central laboratory testing at 
Screening or in historical medical records from a clinical laboratory 
demonstrating <1% FVIII coagulant activity (FVIII:C) or a 
documented genotype known to produce severe hemophilia A 
To allow for inclusion 
based on historical 
FVIII level or genetic 
testing 
 
Section 5.1 
Inclusion criteria 
Inclusion criteria I04 is updated as below: 
I 04. 
Current regimen includes one of the following: 
• 
Prophylactic treatment regimen with a FVIII product or prophylactic 
emicizumab therapy for at least 6 months during the previous  
12 months. Appropriate washout time needs to be taken into 
account. 
• 
On-demand regimen with a FVIII product with a history of at least 
12 bleeding episodes in the previous 12 months or at least 6 
bleeding episodes in the previous 6 months prior to study 
enrollment.  
- 
On-demand participant is accepting to move to a prophylaxis 
treatment regimen after 26-week on-demand period. 
Removal of the word 
“marketed” for 
clarification 
Section 5.1 
Inclusion criteria 
The contraceptive use condition by female participants in Inclusion criteria I08 
is updated as below: 
- 
A WOCBP must have a negative highly sensitive pregnancy test before 
the first dose of study intervention as described in Section 10.2. A serum 
pregnancy test should be performed at screening. For all other time 
points, the choice of the pregnancy test (urine or serum) is at the 
discretion of the Investigator. 
To clarify that for 
required pregnancy 
tests after screening, 
the choice of the 
pregnancy test (urine 
or serum) is at the 
discretion of the 
Investigator 
Section 5.3 
Exclusion criteria 
Exclusion criteria E11 is updated as below: 
Treatment with acetylsalicylic acid (ASA) or non-NSAID anti-platelet therapies 
within 2 weeks prior to screening 
Exclusion criteria E23 is removed. 
To add non NSAIDs 
antiplatelet agent to 
the exclusion criteria 
Section 6.1.1.1 
Study treatment 
schedule and 
administration 
Following paragraph is added: 
During Scheduled study visit BIVV001 will be delivered via a slow push IV 
injection of 8 ±2 minutes, at a rate of administration determined by the 
participant’s comfort level. For all BIVV001 injections performed at home 
BIVV001 will be delivered via a slow push IV injection at a rate of 
administration determined by the participant’s comfort level according to the 
vial injection rate recommendations (Table 7). 
Following table is added: 
To allow shorter 
duration of the BIV001 
infusion administered 
at home 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 189 
Section # and 
Name 
Description of Change 
Brief Rationale 
Table 7 – Home Injection:  BIVV001 weight-based vial injection rate 
recommendations 
Participant Weight 
Minimum Injection Duration Per Vial 
<=55 kg 
2 minutes per vial 
>55 kg 
1 minute per vial 
Following sentence is deleted: 
BIVV001 will be delivered via a slow push IV injection of 8 ±2 minutes at a 
rate of administration determined by the participant’s comfort level. 
Section 6.1.1.4 
Surgical dosing 
Added text for sending a portion of the samples to the central laboratory for 
analysis. 
Clarification 
Section 6.2 
Preparation/ 
Handling/ Storage/ 
Accountability 
Added option for drug delivery from clinical sites directly to patient’s home, in 
exceptional circumstances. 
For crisis 
management 
Section 6.2.4 Study 
drug administration 
The following sentence is added: 
During study visits, for reliable PK assessment, PK sampling should not be 
done via the same intravenous access route as used for the BIVV001 
administration. 
To clarify PK sampling 
procedures during 
study visits 
Section 6.5 
Concomitant 
Therapy 
Non-NSAID anti-platelet therapies is added in prohibited concomitant therapy 
during the study 
Addition of non-NSAID 
anti-platelet therapy to 
prohibited medication 
Section 6.7 
Intervention after the 
end of the Study 
Paragraph regarding long-term trial participation is updated as below: 
The Sponsor plans to perform a long-term safety trial.  Enrollment in this 
open-label extension study will be offered to participants after completion of 
this study based on eligibility criteria. No other post study treatment access 
will be offered.  
Clarification 
Section 8.1.1.6 
Surgery 
Sentence describing end of surgical/rehabilitation period is updated. 
Paragraph describing requirement for minor surgeries is updated. 
To clarify the 
requirement at the 24h 
follow up in case of 
minor surgery 
Section: 8.1.3 
Physical activity 
monitoring 
The paragraph regarding physical activity is updated. 
 
To clarify the period 
when the device is 
worn by the patient 
Section 8.1.4 
Ultrasound 
measures (if 
applicable) 
The section regarding ultrasound measures is updated for clarification 
 
Clarification 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 190 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 8.3.1.1 
Other compound 
specific AESI(s) 
Definitions of Grade 3, 4 and 5 allergic reactions are added 
Clarification 
Section 8.3.2 Time 
period and 
frequency for 
collecting AE and 
SAE information 
The sentence regarding SAE causality is updated as below: 
However, if the Investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers 
the event to be related to the study intervention or study participation, the 
Investigator must promptly notify the Sponsor. 
Clarification 
Section 8.3.4 
Follow-up of AEs 
and SAEs 
The sentence for SAE and AESI follow ups is updated as below: 
At the pre-specified study end-date, all SAEs, and AESIs [and non-serious 
AEs of special interest (as defined in Section 8.3), will be followed until 
resolution, stabilization, or the participant is lost to follow-up (as defined in 
Section 7.3). 
Clarification 
Section 9.4.3 
Pharmacokinetics 
Deleted below text: 
Non-compartmental PK analyses will be described fully in the statistical 
analysis plan finalized before database lock. 
Clarification 
Section 10.2 
Appendix 2: Clinical 
Laboratory Tests 
Table 14 - Protocol-required laboratory assessments updated for consistency 
along with Table 1 
 
For consistency with 
table 1 
Section 10.5 
 
Appendix 5: 
Overdose 
Added new appendix for information on reporting of Overdoses 
To add information on 
reporting of overdoses 
Section 10.9 
Appendix 9:  
Washout and Blood 
Sampling Summary 
Appendix 9 is updated for consistency along with Table 1 and PK chart 
 
For consistency 
 
Amended protocol 03 (06 Apr 2020) 
This amended protocol 03 is considered to be non-substantial based on the criteria set forth in 
Article 10 (a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 191 
OVERALL RATIONALE FOR THE AMENDMENT  
Based on the request from Italy Competent Authority (AIFA) the protocol is amended to update 
an exclusion criterion related to renal function, as well as to add additional assessments for height 
and physical examination. 
Protocol amendment summary of changes 
Section # and Name 
Description of Change 
Brief Rationale 
Section 5.2 Exclusion 
Criteria  
Added note on E07 with reference to Appendix 10.10.2 
Italy 
Appendix for Italy-specific 
requirements added as per 
AIFA request 
Section 1.3 Schedule of 
Activities (SOA) 
Added footnote with reference to Appendix 10.10.2 
Italy 
Appendix for Italy-specific 
requirements added as per 
AIFA request 
Appendix 10.10 
Country-specific 
requirement:  
Appendix 10.10.2 
Italy 
Added this appendix for country-specific requirement for Italy 
with changes as below: 
 
Modified Exclusion criterion E07 from: 
Abnormal renal function, defined as serum creatinine 
>2.0 mg/dL taken at Screening   
to: 
E07 Impaired renal function, defined as creatinine clearance by 
Cockcroft-Gault formula <60 mL/min (for ≥18 years) or 
glomerular filtration rate by Bedside Schwartz formula <60 
mL/min/1.73m2 (for <18 years) 
 
And 
Addition of height measurement at Day 1, Week 26, and Week 
52 visits for participants 12-17 years of age 
 
And 
Addition of physical exam at Week 13 and Week 39. 
Added as per AIFA request 
Amended protocol 02 (06 Feb 2020) 
This amended protocol 02 is considered to be nonsubstantial based on the criteria set forth in 
Article 10 (a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union [because it does not significantly impact the scientific value of the study]. 
OVERALL RATIONALE FOR THE AMENDMENT  
Based on the scientific advice from French Health Authority (ANSM), the protocol is amended to 
add a new exclusion criterion, add a pregnancy testing control at the safety follow-up visit, and 
provide clarity that the patient has the option at the end of the study to join a planned long-term 
study. Based on comments from the French Ethics Committee exclusion criterion E23 has been 
removed. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 192 
Protocol amendment summary of changes 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 Schedule of 
Activities (Table 1) 
 
The following sentence was added in footnote “f”:  For 
France-specific pregnancy testing at the safety follow-
up visit refer to Section 10.10.1. 
 
Added per French Health Authority 
request 
Section 4.4 
End of Study Definition 
Section 4.5 Study  
Stopping Rules 
 
The following sentence was added: “For France-
specific clarification on end of study refer to Section 
10.10.1. 
Added per French Health Authority 
request 
Section 5.2 Exclusion Criteria 
The following sentence added to exclusion criterion 
E23: For France-specific E23 requirements refer to 
Section 10.10.1. 
 
The following sentence was added: For additional 
France-specific exclusion criteria refer to Section 
10.10.1. 
 
Based on comments from the 
French Ethics Committee exclusion 
criterion E23 has been removed 
 
 
Added per French Health Authority 
request 
Appendix 10.10 
Country-specific requirement:  
Appendix 10.10.1 
France 
 
The following France-specific protocol revisions are 
provided in this appendix 
• 
A pregnancy assessment was added to the 
schedule of activities at the safety follow-up 
visit  
• 
Footnote “f” in the schedule of activities was 
revised to specify that for female participants 
in France, a visit must be conducted for 
purposes of pregnancy testing 
• 
Footnote “ii” was added to the schedule of 
activities to specify that pregnancy testing at 
the safety follow-up visit will be for France 
only  
• 
A statement was added in Section 4.4 (End 
of Study Definition)  and Section 4.5 (Study 
Stopping Rules) to clarify that at the end of 
study eligible patients will have the option to 
participate in a planned long-term extension 
study 
• 
The exclusion criterion E23 “Any specific 
situation during study implementation/course 
that may raise ethical considerations” was 
removed from Section 5.2. 
• 
A new exclusion criterion E25 was added in 
Section 5.2 as follows: History of an 
unprovoked venous thromboembolism, 
myocardial infarction within 12 months prior 
to screening, or occlusive cerebral vascular 
Added per French Health Authority 
request or based on comments 
from the French Ethics Committee 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 193 
Section # and Name 
Description of Change 
Brief Rationale 
accident within 12 months prior to screening. 
Patients who have experienced thrombosis 
associated with indwelling venous access 
may be enrolled. 
Amended protocol 01 (28 August 2019)  
This amended protocol (amendment 01) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union [because it significantly impacts the scientific value of the study]. 
OVERALL RATIONALE FOR THE AMENDMENT  
Based on the final results of the repeat dose study and in alignment with scientific advice from 
Health Authorities, the protocol is amended to modify the dose regimen, efficacy endpoint 
analysis pertaining to an intra-patient comparison, and the safety endpoint of “the occurrence of 
vascular thrombotic events”. 
• The prophylactic dosing regimen was amended from 65 IU/kg to 50 IU/kg once weekly 
(QW). For consistency and in accordance with the weekly prophylaxis dose, the treatment 
of a bleeding episode and the pre-operative loading dose has also been adapted to 
50 IU/kg. The treatment of a bleeding episode will also consist of a single injection of 
50 IU/kg. If a bleeding episode does not improve, additional doses of 30 or 50 IU/kg every 
2 to 3 days may be considered. The surgical treatment regimen will consist of a 
pre-operative loading dose of 50 IU/kg, with additional doses of 30 or 50 IU/kg every 2 to 
3 days depending on the desired FVIII activity levels and the severity of the procedure.  
• A key secondary efficacy endpoint analysis has been added to the study protocol. For 
participants in Arm A who previously participated in the observational 
Study 242HA201/OBS16221 and had at least 6 months of data collection on prophylaxis 
treatment, an intra-patient comparison of ABR during BIVV001 weekly prophylaxis and 
historical prophylaxis will be performed in a non-inferiority analysis. If non-inferiority is 
achieved, superiority will be evaluated. 
• The scope of the safety endpoint of “the occurrence of vascular thrombotic events,” has 
been revised to “the occurrence of embolic and thrombotic events.” Clarifying text has 
also been added to confirm that the Standard MedDRA Query of Embolic and Thrombotic 
events will be included as part of the endpoint analysis. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
All sections of the protocol 
describing the dose regimen 
Dose regimen is changed from 65 IU/kg to 50 IU/kg 
Based on the final results of the 
repeat dose study and in 
alignment with scientific advice 
from Health Authorities. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 194 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
Section 3 - Table 5 
objectives and endpoints  
The secondary efficacy endpoint related to intra-patient 
comparison of ABR during the BIVV001 weekly 
prophylaxis treatment period versus the historical 
prophylaxis ABR for participants in Arm A has been 
designated as “key secondary efficacy endpoint”. 
Updated one of the safety endpoints from “vascular 
thrombotic events” to “embolic and thrombotic events”. 
In alignment with scientific advice 
from Health Authorities. 
Section 1.1 Synopsis 
Section 3 - Table 5 
objectives and endpoints 
Clarified the ISTH 4-point response scale related endpoint. 
Added for clarity and in alignment 
with scientific advice from Health 
Authorities. 
Section 1.1 Synopsis 
(number of participants) 
Section 4.1 Overall Study 
Design 
Added that at least 75 participants of Arm A will have at 
least 6 months of participation in 
Study 242HA201/OBS16221 prior to baseline. 
To support non-inferiority analysis 
in alignment with scientific advice 
from Health Authorities. 
Section 1.1 Synopsis 
(Statistical Consideration) 
Section 9.2 Sample Size 
Determination 
Added sample size justification to enroll 75 participants of 
Arm A who will have at least 6 months of participation in 
Study 242HA201/OBS16221 prior to baseline for the 
assessment of key secondary efficacy endpoint.  
To support non-inferiority analysis 
in alignment with scientific advice 
from Health Authorities. 
Section 1.1 Synopsis 
(Statistical Consideration) 
Section 9.4 Statistical 
Analyses 
Added statistical analysis methods for the key secondary 
efficacy endpoint. 
Clarified safety analysis and the definition of embolic and 
thrombotic events.  
In alignment with scientific advice 
from Health Authorities and to 
support the analysis of the safety 
endpoints. 
Section 1.3 - Table 1 Overall 
schedule of activities from 
screening to safety follow-up 
call or visit 
Clarified that monthly telephone call will start from Week 4. 
Clarified that Investigator will assess participant’s 
response to treatment of bleeding episodes treated at the 
study site. 
Clarified that the participants will complete ePD including 
at-home dosing, bleeding episodes, and assessment of 
response to treatment of bleeding episodes. 
In footnote “f”, call or visit occurrence changed from 2 to 3 
weeks to 14 (+7) days after the last dose of BIVV001. 
In footnote “h”, cross reference to Section 4.5 has been 
updated to Section 10.1.4. 
In footnote “j”, it was clarified that genotype analysis (as 
permitted by local regulations and ethics committees) will 
be governed by a separate informed consent. 
Clarification. 
Table 4 Surgical schedule of 
activities 
Clarified that the participants will assess response to 
treatment of bleeding episodes. 
Clarified that investigators will assess response to a 
bleeding episode treated at the study site. 
In footnote “k”, it was clarified that the participant should 
record the assessment of response to treatment of 
bleeding episode in the ePD. 
In footnote “l”, it was clarified that Investigators or 
Surgeons will assess participant’s hemostatic response to 
BIVV001 treatment on the ISTH 4 point response for 
surgical procedures scale”. 
Clarification. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 195 
Section # and Name 
Description of Change 
Brief Rationale 
Section 2.2 Background 
Section updated to include the data of completed 
Study 242HA101. 
To provide updated information 
based on final results of the 
repeat dose study. 
Section 2.3 Benefit/Risk 
Assessment 
Modified from “BIVV001 has the potential to achieve and 
maintain substantially higher factor activity levels than 
currently available therapies…” to “BIVV001 has the 
potential to achieve and maintain higher factor activity 
levels than currently available therapies…” 
Clarification. 
Section 4.1 Overall Study 
Design 
Clarified that the refresher ePD training should be 
provided at any point during the study. 
Clarification. 
Section 4.2 Scientific 
Rationale for Study Design 
Added a rationale for the key secondary efficacy endpoint.  
In alignment with scientific advice 
from Health Authorities. 
Section 4.3 Justification for 
Dose 
Modified the section to provide justification for choosing 
dose of 50 IU/kg.  
Based on the final results of the 
repeat dose study. 
Section 4.4 End of Study 
Definition 
The criterion specifying that at least 63 participants in 
Arm A should have at least 6 months of participation in this 
study and at least 6 months of participation in Study 
242HA201/OBS16221 prior to baseline was added to 
define the End of Study. 
To ensure sufficient sample size 
for adequate statistical powering 
for the analysis of the key 
secondary endpoint. 
Section 5.2 Exclusion 
Criteria 
Removed criteria related to previous exposure to 
BIVV001. 
Previous exposure to BIVV001 
was not considered to be an 
exclusion criterion. 
Clarification. 
Section 5.2 Exclusion 
Criteria 
Clarified the criteria related to re-screen. 
Clarification based on the change 
in washout requirements in 
Section 10.8 Appendix 8. 
Section 6.1.1.1 Study 
treatment schedule and 
administration 
Clarified that BIVV001 will be delivered via a slow push IV 
injection of 8 ±2 minutes at a rate of administration 
determined by the participant’s comfort level. 
Clarification. 
Section 6.1.1.2 Treatment of 
bleeding episodes during 
Prophylactic Treatment 
Regimen 
Clarified that if the participant was treated with an initial 
dose of 30 IU/kg or needs additional doses of 30 IU/kg 
after the first 50 IU/kg dose to treat a bleeding episode, 
these additional doses will not require any further delay of 
the next prophylaxis dose. 
Clarification. 
Section 6.1.1.4 Surgical 
dosing 
Clarified that continuous infusion will not be allowed in this 
study. 
Added that due to the long half-life of BIVV001, the 
frequency of dosing in the post-surgical period may be 
extended after the first week post-surgery. 
In Table 7, for bleeding episodes, it was clarified that for 
minor/moderate bleeding episodes occurring within 2 to 3 
days after a recent prophylactic dose, an initial 30 IU/kg 
dose may also be used. 
Clarification. 
Section 6.3 Measures to 
minimize bias: 
Randomization and blinding 
Description of measures to prevent bias has been added 
as well as clarification on the analysis for primary and 
secondary efficacy endpoints. 
Clarification. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 196 
Section # and Name 
Description of Change 
Brief Rationale 
Section 7.2 Participation 
Discontinuation/Withdrawal 
from the study 
Clarified that participant withdrawal either by Investigator 
or Sponsor at any time during the study. 
Clarification. 
Section 8.1.1.5 Target joint 
resolution 
Clarified that the investigator will assess target joints at 
Baseline. 
Clarification. 
Section 8.1.1.6 Surgery 
Clarified that continuous infusion will not be allowed in this 
study. 
Clarified that any doses administered outside of the clinic 
prior to returning to the pre-surgical treatment regimen will 
be captured in the ePD. 
Clarification. 
Section 8.1.4 Ultrasound 
measures (if applicable) 
Clarified that participants at designated and 
MSKUS-experienced sites who are in Arm A (prophylactic 
treatment), meet enrollment criteria and are >17 years of 
age at enrollment will have the option to participate in the 
JADE and/or HEAD-US protocol. 
Clarification. 
Section 8.3.1.1 Other 
compound specific AESI(s) 
Modified “vascular thrombotic event” to “embolic or 
thrombotic event”. 
In alignment with scientific advice 
from Health Authorities. 
Section 9.1 Statistical 
Hypotheses 
Modified the statistical hypotheses inline with the modified 
key secondary efficacy endpoint. 
In alignment with scientific advice 
from Health Authorities. 
Section 9.2 Sample Size 
Determination 
Added a definition for exposure days.  
Clarification. 
Section 10.1.4 Data 
protection 
Added that the race and ethnicity of participants will be 
collected in this study and these data may be used in the 
analysis of the safety and/or PK profile of the study 
treatment. Added justification for the same. 
Clarification. 
Section 10.2 - 
Table 13 Protocol-required 
laboratory assessments 
Updated the footnote “a” related to clinical chemistry.  
Clarification. 
Section 10.8 Appendix 8 
Washout and Blood 
sampling summary 
Updated the criteria to consider additional attempts after 
consultation with medical monitor, if the second attempt at 
washout fails. 
Clarification for the washout 
requirements. 
Section 10.13.9 Hemophilia 
Activities List 
Updated the questionnaire 
To provide the most current 
questionnaire version. 
Throughout the protocol 
Minor editorial changes 
Update in reference numbers due to addition of new 
references and deletion of duplicate references. 
Clarification.  
 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 197 
11 
REFERENCES  
 
1. Xyntha [package insert]. Philadelphia, PA:  Wyeth Pharmaceuticals Inc; 2015. 
2. Kogenate [package insert]. Whippany, NJ: Bayer HealthCare LLC; 2016 
3. Nuwiq [package insert]. SE-112 75, Sweden: Octapharma; 2017 
4. Kavakli K, Yang R, Rusen L, Beckmann H, Tseneklidou‐Stoeter D, Maas Enriquez M. 
Prophylaxis vs. on-demand treatment with BAY 81-8973, a full-length plasma protein-free 
recombinant factor VIII product: results from a randomized trial (LEOPOLD II). J Thromb 
Haemost. 2015 Mar;13(3):360-9. 
5. Konkle B, Stasyshyn O, Chowdary P, Bevan DH, Mant T, Shima M, et al. Pegylated, full-
length, recombinant factor VIII for prophylactic and on-demand treatment of severe 
hemophilia A. Blood. 2015 Aug;126(9):1078-85. 
6. Mahlangu J, Powell JS, Ragni MV, Chowdary P, Josephson NC, Pabinger I, et al. Phase 3 
study of recombinant factor VIII Fc fusion protein in severe hemophilia A. Blood. 2014 
Jan;123(3):317-25. 
7. Mahlangu J, Kuliczkowski K, Karim FA, Stasyshyn O, Kosinova MV, Lepatan LM, et al. 
Efficacy and safety of rVIII-SingleChain: results of a phase 1/3 multicenter clinical trial in 
severe hemophilia A. Blood. 2016.  2016 Aug;128(5):630-7. 
8. Giangrande P, Andreeva T, Chowdary P, Ehrenforth S, Hanabusa H, Leebeek FW, et al. 
Clinical evaluation of glycoPEGylated recombinant FVIII: Efficacy and safety in severe 
haemophilia A. Thromb Haemost. 2017 Jan 26;117(2):252-261. 
9. Kavakli K, Yang R, Rusen L, Beckmann H, Tseneklidou-Stoeter D, Maas Enriquez M. 
Prophylaxis vs. on-demand treatment with BAY 81-8973, a full-length plasma protein-free 
recombinant factor VIII product: results from a randomized trial (LEOPOLD II). J Thromb 
Haemost. 2015 Mar;13(3):360-9. 
10. Manco-Johnson MJ, Kempton CL, Reding MT, Lissitchkov T, Goranov S, Gercheva L, et al. 
Randomized, controlled, parallel-group trial of routine prophylaxis vs. on-demand treatment 
with sucrose-formulated recombinant factor VIII in adults with severe hemophilia A 
(SPINART). J Thromb Haemost. 2013 Jun;11(6):1119-27. 
11. Reding MT, Ng HJ, Poulsen LH, Eyster ME, Pabinger I, Shin HJ, et al. Safety and efficacy of 
BAY 94-9027, a prolonged-half-life factor VIII. J Thromb Haemost. 2017 Mar;15(3):411-419. 
12. Furie B, Furie BC. Molecular basis of hemophilia. Semin Hematol. 1990; 27(3)270-85. 
13. Graw J, Brackmann HH, Oldenburg J, Schneppenheim R, Spannagl M, Schwaab R. 
Haemophilia A: from mutation analysis to new therapies. Nat Rev Genetic. 2005 Jun; 6(6): 
448. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 198 
14. Amy L and Dunn MD. Hemophilia A, in Transfusion Medicine and Hemostasis (2nd 
Ed.)2013. Clinical and Laboratory Aspects, Chapter 106, pp 699-704. 
15. Skinner MW. WFH: Closing the global gap—achieving optimal care. Haemophilia. 
2012;18(Suppl 4):1−12 
16. World Federation of Hemophilia. World Federation of Hemophilia Report on the Annual 
Global Survey 2017. Montreal, Quebeck: World Federation of Hemophilia; Oct 2018. 
Available at: http://www1.wfh/org/publications/files/pdf-1714.pdf. 
17. Aznar JA, Lucia F, Abad-Franch L, Jimenez-Yuste V, Perez R, Batlle J, et al. Haemophilia in 
Spain. Haemophilia. 2009 May; 15(3)665-75. 
18. Centers for Disease Control and Prevention (CDC). Summary Report of UDC Activity 
National, Patient Demographics (Hemophilia) 2017. Available at: 
https://www2a.cdc.gov/ncbddd/htcweb/UDC_Report/UDC_Report.asp.  
19. United Kingdom Haemophilia Centre Doctors' Organization (UCDO UKHCDO Bleeding 
Disorder Statistics for 2017 to 2018: a report from the National Haemophila Database. Oct 
2018. Available at: http://www.ukhcdo.org/wp-
content/uploads/2019/04/2018_UKHCDO_Annual_Report_2017_18_Data.pdf. 
20. Roosendall G, Lafeber FP. Blood-induced joint damage in hemophilia. Semin Thromb 
Hemost. 2003; 29(1): 37-42. 
21. Witmer C, Presley R, Kulkarni R, Soucie J, Manno CS, Raffini L. Associations between 
intracranial haemorrhage and prescribed prophylaxis in a large cohort of haemophilia patients 
in the United States. Br J Haematol. 2011. Jan; 152(2):211-6. 
22. Lee SO, Yu SY. Utilization Patterns of Coagulation Factor Consumption for Patients with 
Hemophila. J Korean Med Sci. 2016. Jan 1; 31(1):33-8. 
23. Lusher JM. Hemophilia: From plasma to recombinant factors. 2008. In: 50 Years in 
Hematology Research That Revolutionized Patient Care. Washington, DC: American Society 
of Hematology; p. 25-27. Available from: http://www.hematology.org/Publications/50 Years 
in Hematology/4323.aspx. 
24. Pool JG, Gershgold EJ, Pappenhagen AR. High potency antihaemophilic factor concentrate 
prepared from cryoglobulin precipitate. Nature. 1964;203:312. 
25. Kingdon HS, Lundblad RL. An adventure in biotechnology: the development of haemophilia 
A therapeutics from whole blood transfusion to recombinant DNA to gene therapy. Biotechnol 
Appl Biochem. 2002;35(Pt 2):141-8. 
26. Ramgren O. A clinical and medico-social study of haemophilia in Sweden. Acta Med Scand 
Suppl. 1962;379:111-90. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 199 
27. Steen Carlsson K, Höjgård S, Glomstein A, et al. On-demand vs. prophylactic treatment for 
severe haemophilia in Norway and Sweden: differences in treatment characteristics and 
outcome. Haemophilia. 2003;9(5):555-66 
28. Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, et al. 
Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. 
N Engl J Med. 2007;357:535-544. 
29. Nilsson IM, Berntorp E, Lofqvist T, Pettersson H. Twenty-five years experience of 
prophylactic treatment in severe hemophilia A and B. J Intern Med. 1992;232:25-32. 
30. Gringeri A, Lundin B, von Mackensen S, et al. A randomized clinical trial of prophylaxis in 
children with hemophilia A (the ESPRIT Study). J Thromb Haemost. 2011;9(4):700-10 
31. Blanchette VS, Shapiro AD, Liesner RJ, Navarro FH, Warrier I, Schroth PC, et al. Plasma and 
albumin-free recombinant factor VIII: pharmacokinetics, efficacy, and safety in previously 
treated pediatric patients. J Thromb Haemost. 2008;6:1319-1326. 
32. Valentino LA, Mamonov V, Hellmann A, et al. A randomized comparison of two prophylaxis 
regimens and a paired comparison of on-demand and prophylaxis treatments in hemophilia A 
management. J Thromb Haemost. 2012;10(3):359-67 
33. Mair FS, May CR. Thinking about the burden of treatment. BMJ. 2014; 349. 
34. Lambert T,  Benson G, Dolan G, Hermans C, Jimenez-Yuste V, Ljung R, Santagostino E.  
Practical aspects of extended half-life products for the treatment of haemophilia. Therapeutic 
Advances in Hematology. 2018; 295-308. 
35. Mazepa MA, Monahan PE, Baker JR, Riske BK, Soucie JM. Men with severe hemophilia in 
the United States: birth cohort analysis of a large national database. Blood. 2016;127:3073-
3081. 
36. Collins PW, Blanchette VS, Fischer K, Björkman S, Oh M, Fritsch S, et al. Break‐through 
bleeding in relation to predicted factor VIII levels in patients receiving prophylactic treatment 
for severe hemophilia A. J Thromb Haemost. 2009 Mar;7(3):413-20. 
37. Manco-Johnson MJ, SoucieJ M, Gill JC. Prophylaxis usage, bleeding rates, and joint 
outcomes of hemophilia, 1999 to 2010: a surveillance project. Blood. 2017; 2368-2374. 
38. Soucie JM, Monahan PE, Kulkarni BA, Konkle MA, Mazepa MA and US Hemophilia 
Treatment Center Network. The frequency of joint hemorrhages and procedures in nonsevere 
hemophilia A vs B. Blood Adv. 2018;2:2136-2144. 
39. Oldenburg J. Optimal treatment strategies for hemophilia: achievements and limitations of 
current prophylactic regimens. Blood. 2015;125:2038-2044. 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 200 
40. Jimenez-Yuste V, Auerswald G, Benson G, et al. Achieving and maintaining an optimal 
trough level for prophylaxis in haemophilia: the past, the present and the future. Blood 
Transfus. 2014; 12:314-319. 
41. Pipe SW, Montgomery RR, Pratt KP, Lenting PJ, and Lillicrap D. Life in the shadow of a 
dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A. 
Blood. 2016;128: 2007-16. 
42. Eloctate [package insert]. Waltham, MA: Bioverativ Therapeutics Inc.;2017 
43. Jazayeri JA, Carroll G. Half-life extension by Fusion to the Fc region. Theraputic Proteins: 
Strategies to Modulate Their Plasma Half-lives. 2012 Mar 14; 48.  
44. Benjamin WU, Sun YN. Pharmacokinetics of peptide-Fc fusion proteins. J Pharm Sci. 2014 
Jan 1; 103(1): 53-64.  
45. Yee A, Gildersleeve RD, Gu S, Kretz CA, McGee BM, Carr KM, et al. A von Willebrand 
factor fragment containing the D'D3 domains is sufficient to stabilize coagulation factor VIII 
in mice. Blood. 2014 Jul 17; 124(3):445-52. 
46. Lenting PJ, Muczynski V, Ayme G, Denis CV, Christophe OD. Von Willebrand Factor 
Interaction with FVIII: Development of Long Acting FVIII Therapies. Blood 2016; 128: SCI-
8. 
47. Schellenberger V, Wang CW, Geething NC, Spink BJ, Campbell A, To W, et al. A 
recombinant polypeptide extends the in vivo half-life of peptides and proteins in a tunable 
manner. Nat Biotechnology. 2009 Nov 15; 27(12):1186. 
48. European Medicines Agency (EMA) Guideline on the clinical investigation of recombinant 
and human plasma-derived factor VIII products.  26 July 2018. 
49. WFH. 2012. World Federation of Hemophilia. Guidelines for the management of hemophilia, 
2nd edition. 
50. Collins PW, Young G, Knobe K, Abdul Karim F, Angchaisuksiri P, et al. Recombinant long-
acting glycoPEGylated factor IX in hemophilia B: a multinational randomized phase 3 trial. 
Blood. 2014; 124(26): 3880-3886. 
51. Mahlangu J, Oldenburg J, Paz-Priel I, Negrier C, Niggli M, Mancuso M, et al. Emicizumab 
Prophylaxis in Patients Who Have Hemophilia A without Inhibitors. The New England 
Journal of Medicine. 2018; 811-822. 
52. Thornburg CD, & Duncan NA. Treatment adherence in hemophilia. Patient Preference and 
Adherence. 2017;11:1677-1686. 
53. Oldenburg J, Brackmann HH. Prophylaxis in adult patients with severe haemophilia A. 
Thrombosis Research. 2018;s33-s37 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 201 
54. Lentz SR, Misgav M, Ozelo M, Salek SZ, Veljkovic D, Recht M, et al. Results from a large 
multinational clinical trial (guardian 1) using prophylactic treatment with turocotocog alfa in 
adolescent and adult patients with severe haemophilia A: safety and efficacy. Haeomophilia. 
2013; 691-697. 
55. den Uijl IE, Mauser Bunschoten EP, Roosendaal G, Schutgens RE, Biesma DH, Grobbee DE, 
et al. Clinical severity of hemophilia A: does the classification of the 1950s still stand? 
Hemophilia. 17:849-853. 
56. Oldenburg J, Kulkarni R, Srivastava A, Mahlangu JN, Blanchette VS, Tsao E. Improved joint 
health in subjects with severe hemophilia A treated prophylactically with recombinant factor 
VIII Fc fusion protein. Hemophilia. 2018;24:77-84. 
57. Oldenburg J, Zimmerman R, Katsarou O, Theodossiades G, Zanon E, Niemann B, Kellermann 
E, Ludin B. Controlled, cross-sectional MRI evaluation of joint status in severe haemophilia A 
patients treated with prophylaxis vs on demand. Haemophilia. 2015; 21:171-179. 
58. Klamroth R, Windyga J, et al. Results from a phase 3, randomize, multicenter study of 
rurioctocog alfa pegol PK-guided prophylaxis targeting 2 FVIII trough levels in patients with 
severe hemophilia A (propel study). Poster P255 presented at: European Association for 
Haemophilia and Allied Disorders (EAHAD). 2019;Feb 6 - 9; Prague, Czech Republic. 
59. Jenkins PV, Rawley O, Smith OP, O’Donnell JS. Elevated factor VIII levels and risk of 
venous thrombosis.  Brit J Haematology. 2012. 157:653-663.  
60. Jivi [package insert]. Whippany, NJ: Bayer HealthCare LLC; 2018. 
61. Blanchette VS, Key NS, Ljung LR, Manco-Johnson MJ, Van den berg HM, Srivastava A. For 
the Subcommittee on Factor VIII, Factor IX, and Rare Coagulation Disorders. Definitions in 
hemophilia: communication from the SSC of the ISTH. J Thromb Haemost. 
2014;12(11):1935-9. 
62. Cella D, Yount S, Rothrock N, Gershon R, Cook K, Reeve, B, et al. The Patient-Reported 
Outcomes Measurement Information System (PROMIS): Progress of an NIH Roadmap 
Cooperative Group During Its First Two Years. Medical Care, 45(5 Suppl 1). 2007; S3-S11 
63. von Mackensen S, Gringeri A & the Haem-A-QoL study Group. Health-related Quality of 
Life in Adult Patients with Haemophilia – Assessment with a New Disease-specific 
Questionnaire (Haem-A-QoL). Journal Of Thrombosis and Haemostasis. 
2005;3(Sup1):P0813. 
64. Bullinger M, von Mackensen S, Fischer K, Khair K, Petersen C, Ravens-Sieberer U, et al. 
Pilot testing of the 'Haemo-QoL' quality of life questionnaire for haemophiliac children in six 
European countries. Haemophilia. 2002; Mar;8 Suppl 2:47-54 
65. Van Genderen FR, Westers P, Heijnen L, De KP, van den Berg HM, Helders PJ, et al. 
Measuring patients' perceptions on their functional abilities: validation of the Haemophilia 
Activities List. Haemophilia 2006 Jan; 12(1):36-46 
VV-CLIN-0548164 7.0

Amended clinical Trial Protocol 05 
EFC16293 - efanesoctocog alfa       
20-Aug-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 202 
66. Bharmal M, Payne K, Atkinson MJ, Desrosiers MP, Morisky DE, Gemmen E. Validation of 
an abbreviated Treatment Satisfaction Questionnaire for Medication (TSQM-9) among 
patients on antihypertensive medications. Health Qual Life Outcomes. 2009;7:36 
67. Oldenburg J.and Pavlova A. Genetic risk factors for inhibitors to factors VIII and IX. 
Haemophilia.2006;12(6):15-22. 
68. Baskin JL, Pui CH, Reiss U, Wilimas JA, Metzger ML, Ribeiro RC, Howard SC. 
Management of occlusion and thrombosis associated with longterm indwelling central venous 
catheters. Lancet. 2009. 374(9684): 159-69. 
69. Tagalakis V, Kahn SR, Libman M, Blostein M. The epidemiology of peripheral vein infusion 
thrombophlebitis: A critical review. Am J Med. 2002. 113(2):146-51.  
70. Astermark J, Oldenburg J, Escobar M, White GC 2nd, Berntorp E, Malmo International 
Brother Study study group. The Malmo International Brother Study (MIBS). Genetic defects 
and inhibitor development in siblings with severe Hemophilia A. Haematologica. 
2005;90(7):924-31. 
71. Carpenter SL, Michael Soucie J, Sterner S, Presley R, Hemophilia Treatment Center Network 
I. Increased prevalence of inhibitors in Hispanic patients with severe haemophilia A enrolled 
in the Universal Data Collection database. Haemophilia.2012;18(3):e260-5. 
72. Viel KR, Ameri A, Abshire TC, Iyer RV, Watts RG, Lutcher C, et al. Inhibitors of factor VIII 
in black patients with hemophilia. N Engl J Med. 2009;360(16):1618-27 
 
 
 
VV-CLIN-0548164 7.0

Signature Page for VV-CLIN-0548164 v7.0
efc16293-16-1-1-amended-protocol05
Approve & eSign
Approve & eSign
VV-CLIN-0548164 7.0