Clinical trial NCT04759131
Conditions: Hemophilia A
Sponsor: Bioverativ, a Sanofi company
Start date: 2021-02-19; Completion date: 2023-01-18
Enrollment: 74 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary Objective:

\- To evaluate the safety of BIVV001 in previously treated pediatric participants with hemophilia A.

Secondary Objectives:

* To evaluate the efficacy of BIVV001 as a prophylaxis treatment.
* To evaluate the efficacy of BIVV001 in the treatment of bleeding episodes.
* To evaluate BIVV001 consumption for prevention and treatment of bleeding episodes.
* To evaluate the effect of BIVV001 prophylaxis on joint health outcomes.
* To evaluate the effect of BIVV001 prophylaxis on Quality of Life (QoL) outcomes.
* To evaluate the efficacy of BIVV001 for perioperative management.
* To evaluate the safety and tolerability of BIVV001 treatment.
* To assess the pharmacokinetics (PK) of BIVV001.

Detailed description:
Study duration per participants was approximately 60 weeks (maximum 8 weeks for screening and 52 weeks of treatment).

All participants completing or remaining at the end of study were offered participation in the planned extension trial.

Arms: arm 1: Participants aged less than (\<) 6 years received BIVV001 at a dose of 50 international units per kilogram (IU/kg) intravenous (IV) injection once-weekly (QW) prophylaxis for 52 weeks. arm 2: Participants aged 6 to \<12 years received BIVV001 at a dose of 50 IU/kg IV injection QW prophylaxis for 52 weeks.
Interventions: intervention 1: efanesoctocog alfa (BIVV001)
Intervention descriptions: intervention 1: Pharmaceutical form: solution for injection Route of administration: IV

Protocol documents:
Prot_000.pdf: 
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 
Based on Template: Sanofi OneDocument Version 2.0, dated 14-OCT-2019 
Page 1 
CLINICAL TRIAL PROTOCOL 
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 pediatric patients <12 years of age 
with severe hemophilia A 
Protocol number: 
EFC16295 
Amendment number: Not applicable 
Compound number 
(INN/Trademark): 
BIVV001 
Study phase: 
Phase 3 
Short title: 
Safety, efficacy and PK of BIVV001 in pediatric patients 
with hemophilia A (XTEND-Kids)  
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: 
EudraCT: 
NCT: 
WHO: 
EUDAMED 
Other: 
017464 
2020-000769-18 
NCT04759131 
U1111-1244-0558 
Not applicable 
Not applicable 
Date: 
15-May-2020
Total number of pages: 128 
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TABLE OF CONTENTS  
CLINICAL TRIAL PROTOCOL ....................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF TABLES ........................................................................................................................................... 7 
LIST OF FIGURES .......................................................................................................................................... 7 
1 
PROTOCOL SUMMARY ................................................................................................................. 8 
1.1 
SYNOPSIS ....................................................................................................................................... 8 
1.2 
SCHEMA ........................................................................................................................................ 14 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 15 
2 
INTRODUCTION ............................................................................................................................ 23 
2.1 
STUDY RATIONALE...................................................................................................................... 23 
2.2 
BACKGROUND ............................................................................................................................. 24 
2.2.1 
Current therapies for Hemophilia A ................................................................................................ 24 
2.2.2 
BIVV001 ......................................................................................................................................... 25 
2.2.3 
Brief summary of clinical data of BIVV001 ..................................................................................... 26 
2.2.3.1 
Study 242HA101 ............................................................................................................................ 26 
2.2.3.2 
Study 242HA102 ............................................................................................................................ 27 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 28 
2.3.1 
Benefit assessment ........................................................................................................................ 28 
2.3.2 
Risk assessment ............................................................................................................................ 29 
2.3.3 
Overall benefit: risk conclusion ...................................................................................................... 29 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 30 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 31 
4 
STUDY DESIGN ............................................................................................................................ 32 
4.1 
OVERALL DESIGN ........................................................................................................................ 32 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 34 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 35 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 36 
4.5 
STUDY STOPPING RULES .......................................................................................................... 37 
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4.5.1 
Criteria for dose and/or enrollment suspension ............................................................................. 37 
5 
STUDY POPULATION .................................................................................................................. 38 
5.1 
INCLUSION CRITERIA .................................................................................................................. 38 
5.2 
EXCLUSION CRITERIA ................................................................................................................ 39 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 40 
5.4 
SCREEN FAILURES...................................................................................................................... 41 
6 
STUDY INTERVENTION ............................................................................................................... 42 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 42 
6.1.1 
Investigational medicinal product(s) ............................................................................................... 42 
6.1.2 
Study treatment schedule and administration ................................................................................ 43 
6.1.3 
Treatment of bleeding episodes during prophylactic treatment regimen ....................................... 43 
6.1.4 
Surgical dosing ............................................................................................................................... 44 
6.1.5 
Bleeding episodes that occur prior to the baseline and during PK sampling period ..................... 45 
6.1.6 
BIVV001 dosing calculations ......................................................................................................... 45 
6.1.6.1 
Definitions of nominal strength versus actual potency ................................................................... 45 
6.1.6.2 
Calculation and recording of actual versus nominal dosing .......................................................... 46 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 46 
6.2.1 
Study drug packaging and labelling ............................................................................................... 47 
6.2.2 
Study drug storage ......................................................................................................................... 47 
6.2.3 
Study drug preparation .................................................................................................................. 47 
6.2.4 
Study drug administration .............................................................................................................. 47 
6.2.5 
Study drug accountability ............................................................................................................... 47 
6.2.6 
Study drug handling and disposal .................................................................................................. 47 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 48 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 48 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 48 
6.6 
DOSE MODIFICATION .................................................................................................................. 49 
6.7 
INTERVENTION AFTER THE END OF THE STUDY ................................................................... 49 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 50 
7.1 
DISCONTINUATION OF STUDY INTERVENTION ...................................................................... 50 
7.1.1 
Definitive discontinuation ............................................................................................................... 50 
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7.1.2 
Temporary discontinuation ............................................................................................................. 51 
7.1.2.1 
Rechallenge ................................................................................................................................... 51 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 51 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 52 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 53 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 53 
8.1.1 
Electronic patient diary supply and training ................................................................................... 53 
8.1.2 
Bleeding episodes data .................................................................................................................. 53 
8.1.3 
Assessment of clinical response to BIVV001 treatment for bleeding episodes ............................. 55 
8.1.4 
Physician’s global assessment (PGA) ........................................................................................... 55 
8.1.5 
Hemophilia joint health score (HJHS) ............................................................................................ 56 
8.1.6 
Investigator’s target joint assessment ............................................................................................ 56 
8.1.7 
Assessment of response to surgery ............................................................................................... 56 
8.1.8 
Samples for future scientific research ............................................................................................ 58 
8.2 
SAFETY ASSESSMENTS ............................................................................................................. 58 
8.2.1 
Physical examinations ................................................................................................................... 58 
8.2.2 
Vital signs ....................................................................................................................................... 59 
8.2.3 
Clinical safety laboratory assessments .......................................................................................... 59 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................... 60 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 60 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 60 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 60 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 61 
8.3.5 
Deaths ............................................................................................................................................ 61 
8.3.6 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 61 
8.3.7 
Adverse event of special interest ................................................................................................... 62 
8.3.8 
Guidelines for reporting product complaints .................................................................................. 62 
8.4 
TREATMENT OF OVERDOSE ...................................................................................................... 62 
8.5 
PHARMACOKINETICS .................................................................................................................. 63 
8.6 
PHARMACODYNAMICS ............................................................................................................... 64 
8.7 
GENETICS ..................................................................................................................................... 64 
8.8 
BIOMARKERS ............................................................................................................................... 64 
8.9 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 65 
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8.9.1 
Inhibitor development ..................................................................................................................... 65 
8.9.2 
Anti-drug antibodies ....................................................................................................................... 65 
8.10 
CAREGIVER- AND/OR PATIENT-REPORTED CLINICAL OUTCOME ASSESSMENTS 
AND MEDICAL RESOURCE UTILIZATION .................................................................................. 65 
8.10.1 
Caregiver- and/or patient-reported clinical outcome assessments ................................................ 65 
8.10.1.1 PROMIS instruments ..................................................................................................................... 67 
8.10.1.2 Hemophilia quality of life questionnaire (Haemo-QoL) .................................................................. 67 
8.10.1.3 EuroQoL-Youth (EQ-5D-Y) ............................................................................................................ 67 
8.10.1.4 Caregivers interviews ..................................................................................................................... 68 
8.10.2 
Healthcare resource utilization ....................................................................................................... 68 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 69 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 69 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 69 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 69 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 70 
9.4.1 
General considerations .................................................................................................................. 70 
9.4.2 
Primary endpoint(s) ........................................................................................................................ 70 
9.4.3 
Secondary endpoint(s) ................................................................................................................... 70 
9.4.4 
Tertiary/exploratory endpoint(s) ..................................................................................................... 73 
9.4.5 
Other analyse(s) ............................................................................................................................. 73 
9.5 
INTERIM ANALYSES .................................................................................................................... 73 
9.6 
DATA MONITORING COMMITTEE (DMC) ................................................................................... 73 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 74 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 74 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 74 
10.1.2 
Financial disclosure........................................................................................................................ 75 
10.1.3 
Informed consent process .............................................................................................................. 75 
10.1.4 
Data protection ............................................................................................................................... 76 
10.1.5 
Dissemination of clinical study data ............................................................................................... 77 
10.1.6 
Data quality assurance .................................................................................................................. 77 
10.1.7 
Source documents ......................................................................................................................... 78 
10.1.8 
Study and site start and closure ..................................................................................................... 78 
10.1.9 
Publication policy ........................................................................................................................... 79 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 79 
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10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................ 81 
10.3.1 
Definition of AE .............................................................................................................................. 81 
10.3.2 
Definition of SAE ............................................................................................................................ 82 
10.3.3 
Recording and follow-up of AE and/or SAE ................................................................................... 83 
10.3.4 
Reporting of SAEs.......................................................................................................................... 85 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION .............................................................................................................................. 86 
10.5 
APPENDIX 5: OVERDOSE ........................................................................................................... 86 
10.6 
APPENDIX 6: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 86 
10.7 
APPENDIX 7: ADDITIONAL APPENDICES .................................................................................. 86 
10.7.1 
Definitions of minor and major surgery .......................................................................................... 86 
10.7.2 
Definitions of minor, moderate, and major bleeding episodes ....................................................... 87 
10.7.3 
Hemophilia joint health score (HJHS) ............................................................................................ 88 
10.7.4 
Washout and blood sampling summary ......................................................................................... 89 
10.7.5 
Caregiver - and/or patient-reported clinical outcome assessments ............................................... 91 
10.7.5.1 PROMIS instruments ..................................................................................................................... 91 
10.7.5.2 Haemo-QoL .................................................................................................................................... 97 
10.7.5.3 EuroQoL 5-dimension 5-level youth (EQ-5D-Y) .......................................................................... 107 
10.7.5.4 Caregivers interviews guide ......................................................................................................... 113 
10.7.6 
Healthcare resource utilization (HRU) ......................................................................................... 122 
10.8 
APPENDIX 8: ABBREVIATIONS ................................................................................................. 123 
10.9 
APPENDIX 9: PROTOCOL AMENDMENT HISTORY ................................................................ 124 
11 
REFERENCES ............................................................................................................................. 125 
 
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LIST OF TABLES  
Table 1 - Overall schedule of activities from screening to safety follow-up call or visit ................................ 15 
Table 2 - PK sampling schedule of activities (PK subgroup) ........................................................................ 20 
Table 3 - Surgical schedule of activities ........................................................................................................ 21 
Table 4 - Objectives and endpoints ............................................................................................................... 30 
Table 5 - Overview of study interventions administered ............................................................................... 42 
Table 6 - BIVV001 weight-based vial and injection rate recommendations .................................................. 43 
Table 7 - Intravenous BIVV001 treatment ..................................................................................................... 45 
Table 8 - ISTH assessment of treatment of acute bleeds ............................................................................. 55 
Table 9 - Physician’s global assessment ...................................................................................................... 55 
Table 10 - ISTH hemostatic response for surgical procedures scale ........................................................... 58 
Table 11 - List of caregiver- and/or patient-reported clinical outcome assessments .................................... 66 
Table 12 - Populations for analyses .............................................................................................................. 69 
Table 13 - Protocol-required laboratory assessments .................................................................................. 80 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 14 
Figure 2 - Overall design and components of BIVV001 ................................................................................ 23 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
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 pediatric patients <12 years of age with severe hemophilia A 
Short title: 
Safety, efficacy and PK of BIVV001 in pediatric patients with hemophilia A 
(XTEND-Kids) 
Rationale:  
BIVV001 is designed to be a new class of blood clotting Factor VIII (FVIII). Preclinical and 
clinical experience indicate that BIVV001 has an extended half-life (t½), which can achieve and 
maintain higher sustained factor activity levels than currently available treatments, with less 
frequent administration. 
This study is being conducted to determine the safety, efficacy, and pharmacokinetics (PK) of 
BIVV001 administered as once-weekly (QW) prophylaxis treatment in previously treated 
pediatric patients <12 years of age with severe hemophilia A. 
Objectives and endpoints  
 
Objectives 
Endpoints 
Primary 
• 
To evaluate the safety of BIVV001 in previously 
treated pediatric participants with hemophilia A 
• 
The occurrence of inhibitor development (neutralizing 
antibodies directed against FVIII as determined via 
the Nijmegen modified Bethesda assay) 
Secondary 
• 
To evaluate the efficacy of BIVV001 as a prophylaxis 
treatment  
• 
Annualized bleeding rate (ABR) (for treated, for 
untreated, for all bleeding episodes) and by type and 
location 
• 
Percentage of participants who maintain FVIII activity 
levels over 1%, 3%, 5%, 10%, 15%, and 20% at 
Day 7 
• 
To evaluate the efficacy of BIVV001 in the treatment 
of bleeding episodes 
• 
Number of injections and dose of BIVV001 to treat a 
bleeding episode  
• 
Percentage of bleeding episodes treated with a single 
injection of BIVV001 
• 
Assessment of response to BIVV001 treatment of 
individual bleeding episodes based on the 
International Society on Thrombosis and 
Haemostasis (ISTH) 4-point response scale 
• 
Physician’s global assessment (PGA) of participant’s 
response to BIVV001 treatment based on a 4-point 
response scale 
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Objectives 
Endpoints 
• 
To evaluate BIVV001 consumption for prevention and 
treatment of bleeding episodes 
• 
Total annualized BIVV001 consumption 
per participant 
• 
To evaluate the effect of BIVV001 prophylaxis on joint 
health outcomes 
• 
Annualized joint bleeding rate (AJBR)  
• 
Target joint resolution at Week 52, based on ISTH 
criteria  
• 
Change from Baseline to Week 52 in total score and 
domain scores (eg, swelling and strength) assessed 
by the Hemophilia Joint Health Score (HJHS) 
• 
To evaluate the effect of BIVV001 prophylaxis on 
Quality of Life (QoL) outcomes 
• 
Changes in Haemophilia Quality of Life 
Questionnaire for Children (Haemo-QoL) total score 
and physical health domain score from baseline to 
Week 52 (≥4 years old) and via parent proxy version 
(≥4 years old) 
• 
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 
• 
To evaluate the safety and tolerability of BIVV001 
treatment 
• 
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 
• 
The occurrence of embolic and thrombotic events 
• 
To assess the pharmacokinetics (PK) of BIVV001 
based on the one-stage activated partial 
thromboplastin time (aPTT) and two-stage 
chromogenic FVIII activity assays 
• 
PK parameters including, but not limited to, maximum 
activity (Cmax), elimination half-life (t1/2), total 
clearance (CL), total clearance at steady state (CLss), 
volume of distribution at steady state (Vss), area 
under the activity time curve (AUC), dose-normalized 
area under the activity-time curve (DNAUC), mean 
residence time (MRT), incremental recovery (IR), 
trough activity (Ctrough), time above predefined FVIII 
activity levels 
Abbreviations: ABR = annualized bleeding rate; AE = adverse event; AJBR = annualized joint bleeding rate; aPTT = activated partial 
thromboplastin time; AUC = area under the activity time curve; CL = total clearance; CLss = total clearance at steady state; Cmax = maximum 
activity; Ctrough = trough activity; DNAUC = dose-normalized area under the activity-time curve; HJHS = Hemophilia Joint Health Score; 
IR = incremental recovery; ISTH = International Society on Thrombosis and Haemostasis; MRT = mean residence time; PGA = Physician’s 
global assessment; PK = pharmacokinetics; QoL = Quality of Life; SAE = serious adverse event; t1/2 = half-life; Vss = volume of distribution at 
steady state. 
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Overall design: 
This is a multinational, multicenter, open-label Phase 3 study of the safety, efficacy, and PK of 
intravenous (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 <6 years 
and 6 to <12 years age cohorts, where participants will receive BIVV001 at a dose of 50 IU/kg 
IV QW for 52 weeks. Approximately 65 participants will be enrolled to achieve at least 
50 participants (25 participants <6 years of age and 25 participants 6 to <12 years of age) 
completing approximately 52 weeks of treatment to obtain at least 50 exposure days (EDs). 
Enrollment in a planned open-label extension study will be offered to participants after 
completion of this study. 
Following a washout period (at least 3 to 4 days, depending on age), the first 24 participants from 
the 2 age cohorts (at least 12 participants <6 years of age and at least 12 participants 6 to 
<12 years of age) will undergo PK sampling after their first dose of BIVV001 (Baseline). For all 
participants included in the PK subgroup, existing PK information with the participant’s pre-study 
FVIII product (t1/2 and incremental recovery [IR]) should be available. 
Participants who undergo major surgery during the study will be included in the surgery subset. 
The definition of major surgery is included in Appendix 7, Section 10.7.1. 
Disclosure Statement: This is a single arm treatment study that is open label for PTPs <12 years 
of age with severe hemophilia A. 
Number of participants: 
Approximately 65 PTPs will be enrolled to obtain at least 50 participants with at least 50 EDs at 
the end of the study. The first 24 participants (the first 12 [<6 years] and first 12 [6 to <12 years]) 
will be included in the PK subgroup.  
Intervention groups and duration: 
Participants will receive QW dose of BIVV001 for 52 weeks. 
Study intervention(s) 
Investigational medicinal product(s) 
• Study drug: Recombinant coagulation Factor VIII Fc-von Willebrand Factor-XTEN 
Fusion Protein. 
• Route(s) of administration: IV 
• Dose regimen: 50 IU/kg IV QW for 52 weeks. 
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Statistical considerations: 
Primary endpoint:  
The primary endpoint is the occurrence of inhibitor development, defined as an inhibitor result of 
≥0.6 Bethesda units [BU]/mL that is confirmed by a second test result 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. The incidence 
of inhibitor formation for all (≥0.6 BU/mL), “high (≥5.0 BU/mL)” and “low (≥0.6 BU/mL and 
<5.0 BU/mL)” titer inhibitors from the central laboratory will be summarized for each age cohort 
and overall; a 95% confidence interval (CI) using Clopper-Pearson method will be calculated for 
each incidence.  
For the incidence calculations, 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 to BIVV001. The calculation will also be 
performed with a denominator that includes all participants with a valid inhibitor test following at 
least 25 EDs to BIVV001 and a denominator that includes all participants with a valid inhibitor 
test, regardless of how many days they were exposed to BIVV001. 
Main secondary endpoints:  
Participants who receive at least 1 dose of BIVV001 will be included in the Full Analysis Set 
(FAS). Efficacy analyses will be based on the FAS. The efficacy and surgical/rehabilitation 
periods will be defined in the statistical analysis plan (SAP) for the purpose of determining the 
study periods during which data will be used for selected efficacy analyses. Data on bleeding and 
BIVV001 consumption will be based on the efficacy period; surgical evaluations will be based on 
the surgical/rehabilitation period. 
Analysis of efficacy endpoints that are visit-based will include data from all study visits, whether 
or not in the efficacy period, unless a visit is coincidental with a surgical/rehabilitation period for 
a major surgery, in which case it would be excluded. 
Annualized Bleeding Rate (ABR) 
The mean and 95% CI of annualized bleeding rate (ABR) will be estimated using a 
Negative-Binomial model. The model will include number of treated bleeding episodes during the 
efficacy period as response variable, log-transformed duration of efficacy period as offset variable 
to account for variable duration. Individual ABR will also be calculated for each patient. 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. 
Bleeding episodes that occur during surgical/rehabilitation period will be excluded and 
summarized separately.  
In addition, ABR will be summarized descriptively by type of bleed (spontaneous or traumatic) 
and location of bleed (joint, muscle, internal, or skin/mucosa).  
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Hemophilia Joint Health Score 
Changes in total Hemophilia Joint Health Score (HJHS) score and specific domains such as 
swelling and strength will be summarized descriptively. 
Secondary Safety Endpoints 
All safety analyses will be performed on the Safety Analysis Set. Safety will be assessed through 
descriptive summaries of adverse events (AEs), serious adverse events (SAEs), laboratory results, 
physical examination, and vital signs.  
The incidence of AEs will be summarized by system organ class and preferred term for each age 
cohort and overall. Clinical laboratory values will be summarized for change from baseline, shifts, 
and potentially clinically significant abnormalities. 
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.  
Pharmacokinetics 
Any participant with adequate BIVV001 PK data will be included in the PK Analysis Set. A 
noncompartmental analysis will be performed for each participant's BIVV001 baseline PK profile. 
Any participant who does not have adequate PK data will be excluded from the PK analysis. An 
additional participant will be enrolled in the PK subgroup to ensure that at least 24 participants 
have adequate PK data for analysis. Instructions for wash-out and PK sampling are provided in 
Appendix 7, Section 10.7.4. 
Pharmacokinetic parameters of BIVV001 activity including but not limited to the maximum 
activity (Cmax), t½, total clearance (CL), total clearance at steady state (CLss), volume of 
distribution at steady state (Vss), area under the activity-time curve (AUC), dose-normalized area 
under the activity-time curve (DNAUC), mean residence time (MRT), IR, trough activity (Ctrough) 
and time above 1% FVIII activity measured by activated partial thromboplastin time (aPTT) 
clotting assay and chromogenic assay will be determined for BIVV001. Pharmacokinetic 
parameters will be summarized for each age cohort for BIVV001 with geometric means and their 
corresponding 95% CIs. 
Other Secondary endpoints 
All other secondary endpoints will be summarized descriptively.  
The number and percentage of participants achieving trough FVIII activity levels above 1%, 3%, 
5%, 10%, 15%, and 20% will be summarized. 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 and 
chromogenic assay. Participants with trough samples that are outside 168 ±5 hours from the 
previous dose will be excluded from this analysis. 
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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. 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. 
The consumption of BIVV001 will be annualized and summarized. 
The number of injections and total dose of BIVV001 to treat a bleeding episode will be 
summarized 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. 
The participant’s response to treatment of individual bleeding episodes will be summarized as the 
number and percentage of bleeding episodes with each response (excellent, good, moderate, or 
none). 
The physician’s global assessment of the participant’s overall response to BIVV001 treatment will 
be summarized for each study visit and across all visits as the number and percentage classified as 
excellent, effective, partially effective, and ineffective. 
For Haemo-QoL, total score and physical health domain score will be summarized descriptively 
over time. 
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. 
Data Monitoring Committee: Yes 
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1.2 
SCHEMA  
Figure 1 - Graphical study design  
Day 1
Screening
BIVV001 i.v.
Weekly Prophylaxis
(n=65) 
PTPs <12 years of age with severe hemophilia A
Baseline
Week 4
±7 days
Week 13
±7 days
Week 26
±7 days
Week 39
±7 days
Week 52
±7 days
Week -8 
To Day 1
Safety
FUa
EOS
 
Abbreviations: EOS = end of study; FU = follow-up; IV = intravenous; PTP = previously treated patient. 
a The safety follow-up call or visit will occur 2 to 3 weeks after the last dose of BIVV001, unless the participant enrolls in the open-label extension study. 
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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, b 
(Week -8 to 
Day 1) 
Baselineb 
BIVV001 
Day 1 
Week 4c 
±7 days 
Week 13c 
±7 days 
Week 26c 
±7 days 
Week 39c 
±7days 
Week 52 
±7 days 
EOS/ETc 
Unscheduled 
visitd 
Safety follow-
up call or 
visite 
Informed consentf 
X 
 
 
 
 
 
 
 
 
Assessment of eligibility 
X 
X 
 
 
 
 
 
 
 
Demographicsg 
X 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
 
 
Height 
X 
 
 
 
X 
 
X 
 
 
Medical, surgical, and hemophilia 
historyh 
X 
 
 
 
 
 
 
 
 
FVIII activity (1-stage aPTT assay)j 
X 
 
 
 
 
 
 
 
 
Genotypei 
 
 
 
X 
 
 
 
 
 
In-clinic BIVV001 dosingk 
 
X 
X 
X 
X 
X 
X 
 
 
Safety 
Physical exam 
X 
X 
X 
 
X 
 
X 
X 
 
Vital signsl 
X 
X 
X 
 
X 
 
X 
X 
 
HIV, HBV, and HCV statusm 
X 
 
 
 
 
 
 
 
 
CD4 count, viral loadn 
X 
 
 
 
 
 
 
 
 
Hematologyo 
X 
X 
X 
X 
X 
X 
X 
 
 
Coagulation parametersp 
 
X 
 
 
X 
 
X 
 
 
Clinical chemistryq 
X  
X 
X 
X 
X 
X 
X 
 
 
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Tests and assessments 
Screeninga, b 
(Week -8 to 
Day 1) 
Baselineb 
BIVV001 
Day 1 
Week 4c 
±7 days 
Week 13c 
±7 days 
Week 26c 
±7 days 
Week 39c 
±7days 
Week 52 
±7 days 
EOS/ETc 
Unscheduled 
visitd 
Safety follow-
up call or 
visite 
von Willebrand Comprehensive Panelr 
 
X 
X 
X 
X 
X 
X 
 
 
Nijmegen-modified Bethesda assay 
(inhibitor assay)j 
X 
X 
X 
X 
X 
X 
X 
 
 
Anti-rFVIIIFc-VWF-XTEN Antibody 
(ADA)j 
X 
X 
X 
X 
X 
X 
X 
 
 
Adverse event/serious adverse event 
recordings 
<<ongoing; monitor and record at all visits>> 
Prior and concomitant medications 
and concomitant therapies and 
procedurest 
<<ongoing; monitor and record at all visits>> 
Monthly telephone callu 
<<ongoing; once per month, after Week 4>> 
Efficacy 
HJHS joint assessments (≥4 years 
old)v 
 
X 
 
 
X 
 
X 
 
 
Investigator’s target joint assessment 
 
X 
 
 
 
 
 
 
 
Physician’s global assessment of 
response to treatment (PGA) 
 
 
 
X 
 
 
X 
 
 
Investigator’s assessment of 
participant’s response to treatment of 
bleeding episodes at the study sitew 
 
<<ongoing>> 
 
Left-over serum and plasma samples 
material preserved for future 
researchx (optional) 
X 
X 
X 
X 
X 
X 
X 
 
 
Electronic patient diary (ePD) 
training/administration/reviewy 
X 
X 
<<ongoing>> 
 
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Tests and assessments 
Screeninga, b 
(Week -8 to 
Day 1) 
Baselineb 
BIVV001 
Day 1 
Week 4c 
±7 days 
Week 13c 
±7 days 
Week 26c 
±7 days 
Week 39c 
±7days 
Week 52 
±7 days 
EOS/ETc 
Unscheduled 
visitd 
Safety follow-
up call or 
visite 
Caregiver completion of ePD including 
at-home dosing, bleeding episodes, 
and assessment of response to 
bleeding episodesz 
 
<<ongoing>> 
 
Pharmacokinetics 
Pharmacokinetic samplingaa 
 
X 
(for participants 
in the PK 
subgroup) 
 
 
 
 
 
 
 
FVIII peak and trough samplingbb 
 
X 
(for participants 
not in the PK 
subgroup) 
X 
X 
X 
X 
X 
 
 
Caregiver- and/or Patient-Reported Clinical Outcome Assessments (COA) 
PROMIS-SF Assessmentscc 
 
X 
 
 
X 
 
X 
 
 
Haemo-QoLdd 
 
X 
 
 
X 
 
X 
 
 
EQ-5D-Yee 
 
X 
 
 
X 
 
X 
 
 
Caregiver interviews (only in selected 
countries) 
 
 
 
 
 
 
X  
(or subsequent 
post-study 
follow-up visit) 
 
 
Healthcare Resource Utilization 
 
X 
 
 
X 
 
X 
 
 
Abbreviations: AE = Adverse event; ADA = anti-drug antibody; ALP = alkaline phosphatase; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin assay; AST = aspartate aminotransferase; 
BIVV001 = rFVIIIFc-VWF-XTEN (recombinant coagulation Factor VIII Fc - von Willebrand factor - XTEN fusion protein); BU = Bethesda units; BUN = blood urea nitrogen; COA = clinical outcome assessment; 
eCRF = electronic Case Report Form; EOS = End of study; ePD = electronic patient diary; EQ-5D-Y = EuroQoL-Youth; ET = early termination; FVIII = Factor VIII; GGT = gamma glutamyl transferase; HBV = hepatitis 
B virus; Hct=hematocrit; HCV = hepatitis C virus; Hgb = hemoglobin; HIV = human immunodeficiency virus; HJHS = Hemophilia Joint Health Score; HLA = Human leukocyte antigen; ICF = informed consent form; 
ISTH=International Society on Thrombosis and Haemostasis; PGA = Physician's Global Assessment; PK = pharmacokinetics; PROMIS = Patient-Reported Outcomes Measurement Information System; RBC = red 
blood cell; SAE = serious adverse events; VWF = von Willebrand; WBC = white blood cell. 
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a Washout prior to the Screening inhibitor test is at least 48 hours to obtain interpretable test results. 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. Individuals who do not meet the criteria for participation in this study (screen failure) may be rescreened twice maximum. Individuals who rescreen will sign the informed consent form 
(ICF) again and repeat all screening assessments.  
b Washout prior to BIVV001 Day 1 dose administration is at least 96 hours (4 days) for 6 to <12 years participants and at least 72 hours (3 days) for <6 years participants. The washout period prior to Day 1 BIV001 
dose administration may be modified at the discretion of the Investigator based on individual PK data and clinical phenotype in consultation with the medical monitor. Separate samples for anti-rFVIIIFc-VWF-XTEN 
antibody 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). 
c Participants should schedule their study visits to be 7 ±1 day after the previous prophylactic dose of BIVV001. 
d 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. Vital signs should be taken after the participant has been resting supine for 5 minutes. If BIVV001 is being administered at an unscheduled visit, vital signs will be 
measured pre-injection and 30 (+/-15) minutes from the start of injection. If an unscheduled visit occurs only for purposes of prophylactic administration of BIVV001, collection of physical exam and vital sign data is 
not required. 
e This call or visit will occur 2 to 3 weeks after the last dose of BIVV001, unless the participant enrolls in the open-label extension study. 
f 
Informed consent from 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. Participant assent 
must also be obtained where applicable (according to the study site’s local regulations). 
g 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 
h 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. 
i 
Collection of samples for genotype analysis (as permitted by local regulations and ethics committees) will be governed by a separate ICF. Human leukocyte antigen (HLA) genotype will not be needed if previously 
documented. If blood volume is limiting, this assessment may be performed at a subsequent visit. The participant’s parent/legal guardian may provide consent in order to receive this testing at any time during the 
Treatment Period. 
j 
Washout prior to scheduled visits other than screening and baseline should be at least 7 ±1 days. Inhibitor and anti-drug antibody (ADA) samples will be collected prior to BIVV001 dosing. Separate samples for 
ADA testing will be collected at the same time point 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 Bethesda units (BU)/mL, a separate sample must be collected and tested for confirmation of inhibitor development within 2 to 4 weeks. 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.  
k Participants will have BIVV001 doses given at each applicable scheduled visit delivered via a slow push intravenous injection at a rate of administration recommended in the protocol (Section 6.1.2) and 
determined by the participant’s comfort level. Injection start and stop time will be recorded in the electronic Case Report Form (eCRF). Other doses may be self/caregiver administered at home (or in clinic).  
l 
Vital signs include blood pressure, pulse rate, respiratory rate, and oral, tympanic, axillary or temporal 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.  
m 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. 
n 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. 
o 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. 
p Coagulation parameters include activated partial thromboplastin time (aPTT). 
q Clinical chemistry parameters include alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT), bilirubin, blood urea nitrogen (BUN), 
creatinine, nonfasting glucose, total protein, sodium, potassium, and chloride. Blood samples for clinical chemistry analysis will be collected prior to BIVV001 dosing. 
r 
The von Willebrand (VWF) comprehensive panel includes assessments of von Willebrand Factor ristocetin cofactor activity and VWF antigen. Blood samples for analysis of VWF comprehensive panel will be 
collected prior to any BIVV001 dosing. 
s Adverse events (AEs) and serious adverse events (SAEs) occurring after signing of the ICF through the Safety Follow-Up Call or Visit will be recorded on the eCRF.  
t 
Prior 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 eCRF. Pain medication 
related to Hemophilia and administered within 2 weeks prior to the visit will be recorded on the eCRF. 
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u In addition to scheduled clinic visits, telephone calls are planned approximately once a month, after Week 4, 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. 
v 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 the International Society on 
Thrombosis and Haemostasis (ISTH) criteria. 
w For bleeding episodes initially treated at the study sites, the Investigator will contact the caregiver approximately 72 hours from the time the BIVV001 injection was administered to treat the bleeding episode at the 
study site and record the caregiver'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, caregivers will record 
response to bleeding episodes in the ePD. 
x 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/caregivers will sign an additional consent for this research. 
y At the screening visit, caregivers will be shown and trained on the ePD device to ensure understanding of obligation to enter data during the trial. Devices will be given to caregivers at the baseline visit. 
z  Caregivers will record all bleeding episodes in the ePD beginning at Baseline. Assessment of response to bleeding episodes will be performed using a 4-point bleeding response scale. The caregiver 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 caregiver's response to treatment via the eCRF.  
aa The first 12 participants in each age cohort will undergo PK sampling after the first dose of BIVV001 (Baseline). Thereafter, PK sampling at Baseline will be optional. See PK sampling details in Table 2.  
bb Trough and peak samples are collected within 30 minutes prior to rFVIIIFc-VWF-XTEN dosing and 15 (±3) minutes post-injection, respectively. This trough sample should be collected at the same time point as the 
trough inhibitor and ADA samples taken predose. 
cc  Patient-Reported Outcomes Measurement Information System (PROMIS) Assessments to include Pain Intensity, Pain Interference (PROMIS Pediatric-SF Pain Interference <18 years old), and Physical Function 
(PROMIS Pediatric-SF Physical Activity <18 years old). The PROMIS instruments will be administered to participants ≥8 years old and to parent proxy for participants aged 5-12 years. 
dd The Haemo-QoL children version will be administered to participants ≥4 years old and the parent will be administered a parent proxy version (≥4 years old). 
ee The EQ-5D-Y children version will be administered to participants ≥8 years old and the parent version will be administered to parent proxy (for participants 4-7 years old). 
 
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Table 2 - PK sampling schedule of activities (PK subgroup)  
Assessmentsa 
Pre-dose 
Post-dosec  
Day 1 Week 1b 
Day 1 Week 1 
Day 2 
Day 4 
Day 8d 
15 minutes 
(±3) minutes 
3 hours 
(±15 minutes) 
24 hours 
(±2 hours) 
72 hours 
(±5 hours) 
168 hours 
(±5 hours) 
FVIII activity (measured by 
one-stage clotting aPTT and 
two-stage chromogenic 
assays)e 
X 
X 
X 
X 
X 
X 
Abbreviations: aPTT = activated partial thromboplastin assay; FVIII = Factor VIII; PK = pharmacokinetics. 
NOTE: Initial dosing of BIVV001 is in the clinic on Day 1 Week 1. 
a For a subset of participants who are in the PK subgroup (n=24). Baseline PK sampling can be conducted optionally after full enrollment of the PK subgroup in other participants at the discretion of investigator 
through central laboratory. 
b Washout of at least 96 hours (4 days) for 6 to <12 years participants and at least 72 hours (3 days) for <6 years participants prior to sample collection is required. Pre-dose samples are collected within 30 minutes 
prior to dosing. 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 of the next dose of BIVV001. Study drug can be taken after assessments on Day 8. 
e Details regarding sample handling and volume in relation to body weight are provided in the Central Laboratory Manual.
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Table 3 - 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 
Xd 
X 
 
 
Vital signse 
Xd 
X 
 
 
Laboratory safety panelsf 
Xd 
Xh 
 
 
FVIII activity (1-stage clotting aPTT 
and 2-stage chromogenic assays)g 
Xd 
Xi 
Xi 
 
Nijmegen-modified Bethesda Assay 
(inhibitor assay) 
Xd 
Xh 
 
 
Anti-rFVIIIFc-VWF-XTEN 
Antibody (ADA) 
Xd 
Xh 
 
 
BIVV001 surgical administration 
 
Xj 
Xj 
 
BIVV001 between-clinic visit 
administration(s) 
<continued> 
 
 
 
ePD training review 
Xd 
 
 
 
Participant’s assessment of 
response in ePD including 
assessment of response to a bleedk 
<<ongoing as applicable>> 
 
Surgeon’s/Investigator’s 
assessment of response to surgeryl 
 
 
X 
 
Investigator’s assessment of 
response to a bleeding episodem 
<<ongoing as applicable>> 
Adverse events/serious adverse 
event recording 
<<continuous>> 
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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 
Concomitant medications, 
therapies, and procedures 
<<continuous>> 
Abbreviations: ADA = anti-drug antibody; ALP = alkaline phosphatase; ALT = alanine aminotransferase; aPTT = activated partial thromboplastin assay; AST = aspartate aminotransferase; BIVV001 = rFVIIIFc-VWF-
XTEN (recombinant coagulation Factor VIII Fc - von Willebrand factor - XTEN fusion protein); BUN = blood urea nitrogen; eCRF = electronic Case Report Form; EOS = end of study; ePD = electronic patient diary; 
FVIII = Factor VIII; GGT = gamma glutamyl transferase; Hct = hematocrit; Hgb = hemoglobin; RBC = red blood cell; VWF = von Willebrand; WBC= white blood cell. 
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 For minor surgeries only, the post-operative follow-up may be conducted via a phone call 24 hours following surgery for the surgeon/investigator’s assessment of response to surgery. For major surgeries and if 
clinically warranted and at the discretion of the surgeon/investigator for minor surgeries, the participant will be brought back into the clinic 24 hours post surgery for BIVV001 activity sampling (pre-dose if an 
administration of BIVV001 is planned) and for the surgeon/investigator’s assessment of response. Following the 24-hour post-operative study assessment, caregivers will follow the recommended postoperative 
treatment regimen as per Investigator’s advice. 
c 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 treatment. 
At the end of the perioperative period, caregivers will be instructed to resume their child's pre-surgery treatment regimen and to register treatment accordingly in the ePD. For participants who undergo major surgery 
at the end of the study (EOS), 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. 
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 (VWF) comprehensive panel includes assessments of von Willebrand Factor 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. 
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 6.1.4. 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’s caregiver should record response in the ePD, including assessment of response to a bleed, approximately 
72 hours from the time the BIVV001 injection was administered to treat the bleeding episode.  
l 
Investigator’s/surgeon’s assessments of participant’s response to surgery with BIVV001, using a bleeding response scale when participant has completed the surgical period, which includes the 24-hour 
postoperative time period. 
m For bleeding episodes treated in-clinic/hospital, the investigator will contact the caregiver approximately 72 hours from the time the BIVV001 injection was administered to treat the bleeding episode and record the 
caregiver's assessment of response to BIVV001 treatment on the eCRF using a 4-point bleeding response scale. 
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2 
INTRODUCTION  
Recombinant coagulation Factor VIII Fc - von Willebrand factor - XTEN fusion protein 
(rFVIIIFc-VWF-XTEN) (BIVV001; BIIB073) is designed to be a new class of blood clotting 
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), FVIII-binding D’D3 domain of 
human von Willebrand factor (VWF), and 2 XTEN polypeptide linkers (Figure 2) (1). The Fc, 
VWF, and XTEN linker portions of the molecule are each designed to extend the t½ of the FVIII 
molecule in plasma. 
Figure 2 - Overall design and components of BIVV001  
 
2.1 
STUDY RATIONALE  
BIVV001 is designed to be a new class of blood clotting FVIII. Preclinical and clinical experience 
indicate that BIVV001 has an extended half-life, which can achieve and maintain higher sustained 
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 
as QW prophylaxis treatment in PTPs <12 years of age with severe hemophilia A. 
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2.2 
BACKGROUND  
Hemophilia A is a congenital X-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 (2, 3). The worldwide prevalence of hemophilia A is estimated to be 
1 in 10,000 and worldwide incidence is approximately 1 in 5000 male births (4). Hemophilia A 
appears to be equally distributed across the world (5, 6, 7). 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 (8, 9, 10). 
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 (7). 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 (11). Significant effects on physical and psychosocial well-being and quality of life 
(QoL) and substantial financial burden have been reported in patients with severe hemophilia 
(12).  
2.2.1 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 (13, 14). In the 1970s and 1980s, techniques were 
developed to eliminate infectious agents, including treatment with heat and detergent, as well as 
immunoaffinity chromatography (15). 
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 (16). 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 (17) and randomized 
clinical trials (18, 19, 20) 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 (21, 22). With prophylactic treatment, annual median 
bleeding rates of less than 10 to as low as 1 bleeding episode per year have been reported (21). As 
a result, prophylaxis treatment regimens are being adopted as the standard of care in many 
countries, with episodic treatment as an alternative option. 
The use of a prophylaxis regimen in young children with hemophilia improves their long-term 
clinical outcome by preventing joint bleeding in the early years of life and subsequent hemophilic 
arthropathy (18, 23, 24). This was confirmed by a prospective, randomized controlled study 
comparing the joint outcome between episodic and prophylactic regimens in children. At 6 years 
of age, children on a prophylaxis regimen had significantly less joint damage than children treated 
with an on-demand regimen (18). 
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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 (25). This also includes 
newer generation extended half-life FVIII therapies that still require 2 to 3 injections per week to 
maintain activity levels ≥1% (26). 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 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 (27). 
Next-generation 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 
QoL 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 (28). Indeed, it is well established that the accepted minimum target of FVIII 
activity trough level (1%-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 (26, 29, 30). The ability to increase patient protection by 
achieving higher sustained levels of factor activity remains a critical need for patients (31) and 
follows recommendations from World Federation of Hemophilia (WFH) (5). 
2.2.2 BIVV001  
BIVV001 is a recombinant fusion protein consisting of single-chain FVIII, the Fc domain of 
IgG1, the FVIII-binding D’D3 domain of VWF, and 2 XTEN linkers. It is believed that the 
plasma t½ of FVIII is prolonged by its interaction with VWF. All current extended half-life 
recombinant FVIII (rFVIII) products interact with VWF and have comparable circulating t½, 
owing to the approximate 15-hour t½ of endogenous VWF (32, 33). BIVV001 is the first rFVIII 
engineered to be independent of VWF, theoretically extending its t½. Nonclinical and clinical 
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 BDD human FVIII covalently 
linked to the Fc domain of human IgG1 that is currently approved for individuals with hemophilia 
A (34). 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 (35, 36). 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 (33, 37). The D’D3 domain has not been reported to interact with 
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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 t½ of the 
fusion protein by altering the hydrodynamic radius of the molecule, which in turn reduces its 
clearance (38). 
2.2.3 Brief summary of clinical data of BIVV001  
The BIVV001 clinical development program includes two completed studies: a Phase 1/2a study 
(242HA101) and a Phase 1 study (242HA102) evaluating the safety, tolerability, and PK of 
BIVV001 administered as single and repeat IV doses, respectively. In Study 242HA101, 
15 participants received a single dose of BIVV001 and in Study 242HA102, 24 participants 
received a total of 4 doses of BIVV001. 
A Phase 3 open-label, multicenter study of the safety, efficacy and PK of BIVV001 in previously 
treated adults and adolescents ≥12 years of age with severe hemophilia A (EFC16293) is currently 
on-going. 
2.2.3.1 Study 242HA101  
Study 242HA101 was a First in Human 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 PTPs with 
severe hemophilia A. Participants received a single IV dose of 25 IU/kg or 65 IU/kg rFVIII 
comparator (Advate) 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 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 hypersensitivity or anaphylaxis. Overall, single dose BIVV001 was well tolerated and 
no safety concerns were identified. 
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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 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 t1/2 was 37.6 hours for 
BIVV001 compared with 9.1 hours for Advate based on FVIII activity measured by the one-stage 
aPTT assay (geometric mean ratio [GMR]=4.1 [95% CI: 2.9, 5.8]; p <0.001) in the low-dose 
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 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, 17.0% at 7 days and 1.1% at 14 days, 
based on the one-stage aPTT assay. The geometric mean t1/2 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 (GMR=3.2 [95% CI: 2.8, 3.8]; p <0.001) in the high-dose cohort. 
2.2.3.2 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. Participants were 
enrolled into either Cohort 1 or Cohort 2 and received a total of 4 once-weekly doses 
(Days 1, 8, 15, and 22) of BIVV001 at 50 IU/kg or 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 (168 hours) sample taken prior to dosing on Days 8, 15, and 22. Of the 
24 participants enrolled in the study, all 24 received a total of 4 doses of BIVV001.  
Safety results 
Repeat doses of BIVV001 were well tolerated and no safety concerns were identified. No 
inhibitor development to FVIII was detected and there were no reports of hypersensitivity, 
anaphylaxis, or vascular thrombotic events. Of the 24 participants included in the Safety Analysis 
Set, 12 participants (50.0%) were reported to have experienced at least 1 TEAE, with a total of 
25 TEAEs reported. No study drug-related TEAEs, TEAEs leading to study discontinuation, 
TESAEs or deaths were reported during the study. The most common (≥2 subjects overall) 
TEAEs reported were rhinitis (4 subjects [16.7%]), arthralgia (2 subjects [8.3%]), upper 
respiratory tract infection (2 subjects [8.3%]), and headache (2 subjects [8.3%]). All other TEAEs 
were reported in 1 subject (4.2%), each. The reported TEAEs were generally consistent with those 
anticipated in a population of adult subjects with severe hemophilia A. 
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Pharmacokinetic results 
The mean t1/2 based on one-stage clotting and chromogenic assays, respectively, was 41.25 and 
43.87 hour following 50 IU/kg; and 37.31 and 42.51 hour following 65 IU/kg. The Cmax and 
Incremental Recovery [IR] for one-stage and chromogenic assay were comparable on Days 1 and 
22 indicating consistent recovery within dose level (50 and 65 IU/kg QW treatment). Following 
4 weekly doses of BIVV001, no accumulation of BIVV001 was observed. The one-stage FVIII 
Ctrough was 9.16% with 50 IU/kg and 10.8% with 65 IU/kg whereas chromogenic FVIII activity 
Ctrough was 6.51% with 50 IU/kg and 7.37% with 65 IU/kg dosing. On Day 22 with QW dosing, 
the one-stage and chromogenic FVIII activity was maintained above 10% for 162.75 and 
141.16 hour, respectively at 50 IU/kg; and 172.53 and 146.70 hour, respectively at 65 IU/kg. The 
results of this study confirm a prolonged t1/2 of BIVV001, between 37-44 hours, with minimal 
accumulation for weekly dosing regimens of 50 IU/kg and 65 IU/kg. After the weekly 50 IU/kg 
dose, mean steady state FVIII activity levels 3, 5 and 7 days following drug administration were 
46%, 22%, and 9%, respectively (one-stage clotting assay). After the weekly 65 IU/kg dose, mean 
steady state FVIII activity levels 3, 5, and 7 days following drug administration were 
69%, 27% and 12%, respectively (one-stage clotting assay). 
A more detailed description of the chemistry, pharmacology, and safety of BIVV001 is provided 
in the BIVV001 Investigator’s Brochure (IB). 
2.3 
BENEFIT/RISK ASSESSMENT  
2.3.1 Benefit assessment  
BIVV001 is designed to be a new class of blood clotting FVIII engineered to be independent of 
VWF. New classes of 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 adherence and outcomes, including QoL for individuals with hemophilia A. In 
addition to the patient burden that results from frequent administration (25) it is well established 
that the currently accepted FVIII activity trough level (1%-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 (18, 26, 30). The 
ability to increase patient protection by achieving higher sustained levels of factor activity 
remains a critical need for patients (31) and follows recommendations from the World Federation 
of Hemophilia (5). BIVV001 has the potential to achieve and maintain substantially higher factor 
activity levels than currently available therapies, with less frequent administration, which would 
represent a major advance in hemophilia management. 
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2.3.2 Risk assessment  
There is a long history of therapeutic use of rFVIII products in the treatment of hemophilia A, 
with a well-recognized and understood safety profile. Patients treated with other rFVIII products 
have reported adverse reactions that include hypersensitivity, anaphylaxis, and development of 
inhibitors. Based on the currently available non-clinical (in vivo and in vitro) and clinical data, it 
is expected that BIVV001 will have a safety profile similar to other rFVIII products. 
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). Single and repeat doses BIVV001 were well tolerated and no safety concerns 
were identified.  
2.3.3 Overall benefit: risk 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 t1/2 that offers increased protection in the treatment of individuals with 
hemophilia A. 
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3 
OBJECTIVES AND ENDPOINTS  
Table 4 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
• 
To evaluate the safety of BIVV001 in previously 
treated pediatric participants with hemophilia A 
• 
The occurrence of inhibitor development (neutralizing 
antibodies directed against FVIII as determined via the 
Nijmegen modified Bethesda assay 
Secondary 
• 
To evaluate the efficacy of BIVV001 as a 
prophylaxis treatment  
• 
Annualized bleeding rate (ABR) (for treated, for 
untreated, for all bleeding episodes) and by type and 
location 
• 
Percentage of participants who maintain FVIII activity 
levels over 1%, 3%, 5%, 10%, 15%, and 20% at Day 7 
• 
To evaluate the efficacy of BIVV001 in the 
treatment of bleeding episodes 
• 
Number of injections and dose of BIVV001 to treat a 
bleeding episode  
• 
Percentage of bleeding episodes treated with a single 
injection of BIVV001 
• 
Assessment of response to BIVV001 treatment of 
individual bleeding episodes based on the International 
Society on Thrombosis and Haemostasis (ISTH) 4-point 
response scale 
• 
Physician’s global assessment (PGA) of participant’s 
response to BIVV001 treatment based on a 4-point 
response scale 
• 
To evaluate BIVV001 consumption for prevention 
and treatment of bleeding episodes 
• 
Total annualized BIVV001 consumption per participant 
• 
To evaluate the effect of BIVV001 prophylaxis on 
joint health outcomes 
• 
Annualized joint bleeding rate (AJBR)  
• 
Target joint resolution at Week 52, based on ISTH 
criteria  
• 
Change from Baseline to Week 52 in total score and 
domain scores (eg, swelling and strength) assessed by 
the Hemophilia Joint Health Score (HJHS) 
• 
To evaluate the effect of BIVV001 prophylaxis on 
Quality of Life (QoL) outcomes 
• 
Changes in Haemophilia Quality of Life Questionnaire 
for Children (Haemo-QoL) total score and physical 
health domain score from baseline to Week 52 
(≥4 years old) and via parent proxy version (≥4 years 
old) 
• 
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 
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Objectives 
Endpoints 
• 
To evaluate the safety and tolerability of BIVV001 
treatment 
• 
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 
• 
The occurrence of embolic and thrombotic events 
• 
To assess the PK of BIVV001 based on the 
one-stage activated partial thromboplastin time 
(aPTT) and two-stage chromogenic FVIII activity 
assays 
• 
PK parameters including, but not limited to, maximum 
activity (Cmax), elimination half-life (t1/2), total clearance 
(CL), total clearance at steady state (CLss), volume of 
distribution at steady state (Vss), area under the activity 
time curve (AUC), dose-normalized area under the 
activity-time curve (DNAUC), mean residence time 
(MRT), incremental recovery (IR), trough activity (Ctrough), 
time above predefined FVIII activity levels 
Tertiary/Exploratory 
• 
To assess the impact of BIVV001 treatment on 
caregiver- and/or patient-reported clinical outcome 
assessments measurements and health resource 
utilization  
• 
Changes in PROMIS-SF Physical Function measures 
from Baseline to Week 52 (≥8 years old) and via parent 
proxy version (≥ 5 years old) 
• 
Changes in PROMIS Pain Intensity measures from 
Baseline to Week 52 (≥8 years old) and via parent proxy 
version (≥ 5 years old) 
• 
Changes in PROMIS Pediatric-SF Pain Interference 
measures from Baseline to Week 52 (≥8 years old) and 
via parent proxy version (≥ 5 years old) 
• 
Changes in EuroQoL 5-dimension 5-level Youth 
(EQ-5D-Y) from Baseline to Week 52 (≥8 years old) and 
via parent proxy version (4-7 years old) 
• 
Caregiver interviews at Week 52 (or subsequent 
post-study follow-up visit) 
• 
Changes in healthcare resource utilization and 
productivity 
Abbreviations: ABR = annualized bleeding rate; AE = adverse event; AJBR = annualized joint bleeding rate; aPTT = activated partial 
thromboplastin time; AUC = area under the activity time curve; CL = total clearance; CLss = total clearance at steady state; Cmax = maximum 
activity; Ctrough = trough activity; DNAUC = dose-normalized area under the activity-time curve; EQ-5D-Y = EuroQoL-Youth; FVIII = factor VIII; 
Haemo-QoL = Haemophilia Quality of Life Questionnaire for Children and Adolescents; HJHS = Hemophilia Joint Health Score; 
IR = incremental recovery; ISTH = International Society on Thrombosis and Haemostasis; MRT = mean residence time; PGA = Physician’s 
global assessment; PROMIS = Patient-Reported Outcomes Measurement Information System, QoL = Quality of Life; SAE = serious adverse 
event; t1/2 = half-life; Vss = volume of distribution at steady state. 
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 risks to participant safety. 
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This is a multinational, multicenter, open-label Phase 3 study of the safety, efficacy, and PK of IV 
BIVV001 in PTPs <12 years of age with severe hemophilia A (defined as <1 IU/dL [<1%] 
endogenous FVIII). The study is comprised of one arm where participants will receive BIVV001 
at a dose of 50 IU/kg IV QW for 52 weeks.  
Overall, approximately 65 participants will be enrolled to achieve at least 50 participants  
(25 participants <6 years of age and 25 participants 6 to <12 years of age) completing 
approximately 52 weeks of treatment to obtain at least 50 EDs.  
Following a washout period (at least 3 to 4 days, depending on age), the first 24 participants from 
2 age cohorts (at least 12 participants <6 years of age and at least 12 participants 6 to <12 years of 
age) will undergo PK sampling after their first dose of BIVV001 (Baseline). For all participants 
included in the PK subgroup, existing PK information with the participant’s pre-study FVIII 
product (t1/2 and IR) should be available. 
Participants 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 Appendix 7, Section 10.7.1.  
Enrollment in a planned open-label extension study will be offered to participants after 
completion of this study.  
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 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 informed consent form 
(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) for 6 to <12 years participants and at least 72 hours 
(3 days) for <6 years participants. The washout prior to the Day 1 BIVV001 dose administration 
may be modified at the discretion of the Investigator based on individual PK data and clinical 
phenotype in consultation with medical monitor. 
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Participants will be registered as screened in the Interactive Response Technology (IRT) system 
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 65 patients will be 
enrolled. 
Participants will receive BIVV001 as weekly prophylaxis for 52 weeks. Additional doses will be 
given as necessary to treat breakthrough bleeding episodes according to Section 6.1.3. Selected 
doses will be given in clinic according to the Schedule of Activities ([SoA]; Table 1). Other doses 
will be administered by the participant or caregiver at home, or in clinic. 
Participant’s caregivers 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. Participant’s caregivers will be prompted to 
enter bleeding location, type (spontaneous or traumatic), reasons for dosing (prophylaxis or 
treatment of a bleeding episode), symptoms and response to treatment. An ePD training will be 
completed at the study site at the Baseline visit. Training of caregivers should be documented in 
the appropriate source record. The ePD refresher training should also be provided at any point 
during the study.  
The first 12 participants in each age cohort (<6 years of age to 12 years and 6 to <12 years of age) 
will undergo PK sampling after the first dose of BIVV001 (Baseline) (see Table 2 for details). 
After full enrollment of the PK subgroup, optional participation in the PK subgroup is offered. All 
other participants will have trough and peak samples only (collected within 30 minutes prior to 
BIVV001 dosing and 15 (±3) minutes post injection). 
Participants who undergo major surgery during the study will be included in the surgery 
subgroup. 
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 all participants 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.  
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The first 12 participants in each age cohort (<6 years of age to 12 years and 6 to <12 years of age) 
will undergo PK sampling after the first dose of BIVV001 (Baseline), including samples at Day 1, 
Day 2, Day 4 and Day 8 (Table 2). All other participants will have trough and peak sample only 
(collected within 30 minutes prior to BIVV001 dosing and 15 (±3) minutes post-injection at each 
visit where a BIV001 injection is scheduled.  
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 (±7) days post-Baseline, or earlier if EOS has been declared. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
BIVV001 is designed to be a new class of blood clotting FVIII. Preclinical and clinical experience 
indicate that BIVV001 has an extended t1/2, which can achieve and maintain higher sustained 
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 
as prophylaxis treatment in PTPs <12 years of age with severe hemophilia A at a weekly dose of 
50 IU/kg. 
The study will enroll PTPs with severe hemophilia A aged <12 years. The study design takes into 
consideration the published guidelines for the clinical investigation of recombinant and human 
plasma-derived FVIII products per the European Medicines Agency (EMA) guidelines (39).  
Participants should have been treated with any recombinant and/or plasma-derived FVIII, or 
cryoprecipitate for at least 150 EDs for patients aged 6-11 years and at least 50 EDs for patients 
aged <6 years. 
Participants will receive prophylactic BIVV001 at QW dosing interval for 52 weeks.  
The primary endpoint is the occurrence of inhibitor development (neutralizing antibodies directed 
against FVIII as determined via the Nijmegen-modified Bethesda assay. The incidence of 
inhibitor formation for all (≥0.6 BU/mL), “high (≥5.0 BU/mL)” and “low (≥0.6 BU/mL and  
<5.0 BU/mL)”, titer inhibitors from the central laboratory will be summarized for each age cohort 
and overall; a 95% CI using Clopper-Pearson method will be calculated for each incidence.  
The efficacy of BIVV001 as a prophylactic treatment will also be assessed and the secondary 
efficacy endpoints will include ABR. The 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.  
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4.3 
JUSTIFICATION FOR DOSE  
The dose of 50 IU/kg IV QW was selected as the prophylactic dose in both age cohorts  
(6 to <12 years and <6 years). The dosing regimen was chosen to optimize protection against 
bleeds and reduce the treatment burden on participants and their families. The dose was selected 
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. The population PK model with adult 
data was extrapolated to pediatric subjects with allometric exponents driven by body weight 
(
). Pediatric simulations with body weight ranges from historical hemophilia 
trials were performed to understand steady state kinetics of BIVV001 in 6-12 years and <6 years 
age cohorts. Physiologically-based pharmacokinetic model were also evaluated to understand the 
effect of age ontogeny on BIVV001 PK profile in younger subjects.  
At a dose of 50 IU/kg QW in the 6 to <12 years age cohort, the population PK model predicted a 
mean time above 40% (normal or near-normal FVIII activity levels) for 
 days with the 
one-stage aPTT assay and for 
 days with the chromogenic assay, providing a sustained level of 
protection. The population means for Cmax were in the upper physiological range of FVIII activity 
with 
 and
 IU/dL for the one-stage aPTT assay and the chromogenic assay, respectively. 
The population means for Ctrough were 
 and 
 IU/dL  days post-dose, for the one-stage 
aPTT assay and the chromogenic assay, respectively. 
At a dose of 50 IU/kg QW in the <6 years cohort, the population PK model predicted a mean time 
above 40% (normal or near-normal FVIII activity levels) for 
 days with the one-stage aPTT 
assay and for 
 days with the chromogenic assay, providing a sustained level of protection. The 
population means for Cmax were in the upper physiological range of FVIII activity with 
 and 
 IU/dL for one-stage aPTT assay and chromogenic assay, respectively. The population means 
for Ctrough were 
 and 
 IU/dL for one-stage aPTT assay and chromogenic assay, 
respectively. 
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 (40). BIVV001 is the first FVIII replacement therapy to overcome the t1/2 limitations of 
VWF (32) and could thus allow for higher sustained levels of protection. Therefore, 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, while decreasing the burden of treatment.  
Development of a new class of FVIII replacement therapy whose t1/2 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 
pediatric patients with hemophilia A targeted FVIII activity levels of ≥1% with 2 or 3 times 
dosing weekly (19). 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 
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does not eliminate the considerable long-term joint damage associated with severe hemophilia A, 
albeit it does delay its onset (26, 41). Manco-Johnson and colleagues recently evaluated 
prophylaxis use in the United States in relation to bleeding rates and joint health outcomes (29). 
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 magnetic resonance imaging at an early age (18) 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 (42). Thus, the continued development of joint 
damage despite prophylactic treatment suggests that current treatment regimens targeting FVIII 
activity trough levels of ≥1% are inadequate (31). Recommendations from World Federation of 
Hemophilia have supported the maintenance of higher FVIII activity levels (5). 
The dose of BIVV001 recommended for treating bleeding episodes and surgical management 
follows published treatment guidelines to achieve minimum FVIII activity levels (6). 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 treatment of 
bleeding episodes and surgery as defined by the WFH guidelines (6). 
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 3 to 
4 days post-dose. Using the same dose for treatment of bleeding episodes as for the prophylactic 
treatment regimen is recommended to avoid complexity and dosing errors. It is anticipated that 
most bleeding episodes will require treatment with 1 dose of BIVV001. Based on the 
investigator’s judgement, 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 Appendix 7, Section 10.7.2 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 
are recommended. 
4.4 
END OF STUDY DEFINITION  
End of Study will occur when both of the following criteria have been met: 
• At least 50 participants (25 participants <6 years of age and 25 participants 6 to <12 years 
of age) have reached 50 EDs and have completed a valid inhibitor test after the 50th ED. 
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• 24 participants (12 participants <6 years of age and 12 participants 6 to <12 years of age) 
in the PK subgroup have completed the BIVV001 PK profile with adequate estimate of 
terminal t1/2. 
Once this milestone has been achieved, all ongoing study participants will return to the study 
center for the EOS/Early Termination (ET) visit assessments.  
At the EOS, eligible patients will have the option to participate in a long-term extension study. 
4.5 
STUDY STOPPING RULES  
The Sponsor may terminate the study at any time, after informing Investigators, Institutional 
Review Boards (IRB)/Independent Ethics Committees (IEC), and applicable regulatory agencies. 
Investigators will be notified by the Sponsor (or designee) if enrollment and dosing are 
suspended, completed, or closed.  
At the EOS, eligible patients will have the option to participate in a long-term extension study. 
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 2 or more participants following administration of BIVV001 
(See Section 8.3.7 for definition of inhibitor development). 
• The Investigator and Sponsor (or Sponsor alone) determine that an event or current data 
warrant further evaluation. 
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5 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
INCLUSION CRITERIA  
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
I 01. Participant must be younger than 12 years of age, 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 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 for patients aged  
6-11 years and above 50 EDs for patients aged <6 years. 
I 04. For the PK subgroup only: existing PK information with the participant’s pre-study FVIII 
product (t1/2 and IR) should be available, or alternatively, historic PK assessments deemed 
adequate for calculating t1/2 and IR PK by the Sanofi PK scientist.  
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 
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 caregiver to complete training in the use of the study ePD 
and to use the ePD throughout the study. 
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Weight  
I 08. Weight above or equal to 10 kg. 
Sex 
I 09. Male 
a) Male participants 
No contraceptive measures required for this study. 
Informed Consent 
I 10. Ability of the participant or his 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. Serious active bacterial, viral or fungal infection (other than chronic hepatitis or HIV) 
present within 30 days of Screening. 
E 02. Other known coagulation disorder(s) in addition to hemophilia A. 
E 03. History of hypersensitivity or anaphylaxis associated with any FVIII product. 
E 04. History of a positive inhibitor (to FVIII) 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 05. Positive inhibitor test result, defined as ≥0.6 BU/mL at Screening. 
E 06. Active renal disease (per the discretion of the Investigator and medical records) at 
Screening. 
E 07. Active hepatic disease (per the discretion of the Investigator and medical records) at 
Screening.  
Prior/concomitant therapy 
E 08. Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) above the maximum dose 
specified in the regional prescribing information within 2 weeks prior to Screening. 
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E 09. Treatment with acetylsalicyclic acid (ASA) or other non-NSAIDs anti-platelet therapies 
within 2 weeks prior to Screening.  
E 10. 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.  
E 11. Emicizumab use within the 20 weeks prior to Screening.  
Prior/concurrent clinical study experience 
E 12. Previous enrolment in this study; participants who fail Screening may rescreen (maximum 
of 2 rescreenings). 
E 13. 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 14. 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 15. Any country-related specific regulation that would prevent the participant from entering 
the study.  
E 16. 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 17. 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 18. A 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. 
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 
BIVV001 dosing could be chosen prior to a weekly recurring physical activity. 
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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 date of informed consent/assent, demography, screen 
failure reasons, eligibility criteria, and any AEs. 
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 source documents and on the Screening log. Reasons for 
screen failure will be captured in the Interactive Response System. 
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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 5 - Overview of study interventions administered  
ARM name 
Prophylaxis 
Intervention name 
rFVIIIFc-VWF-XTEN (BIVV001) 
Type 
Drug 
Dose formulation 
Lyophilized powder in a sterile vial that requires reconstitution with Sterile Water for 
Injection (diluent)  
Unit dose strength(s) 
250, 500, 1000, 2000 IU per vial 
Dosage level(s) 
50 IU/Kg every week  
Route of administration 
Intravenous 
IMP and NIMP 
IMP 
Packaging and labeling 
Study intervention will be provided in vials. Each vial will be labeled as required per 
country requirement 
[Current/Former name(s) or 
alias(es)] 
--- 
Abbreviations: IMP = Investigational medicinal product; NIMP = noninvestigational medicinal product. 
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 nominally contains 250, 500, 1000, 2000 IU of BIVV001 in 
the formulation buffer (10 mM L-histidine, 250 mM L-arginine-HCl, 5mM CaCl2, 5% (w/v) 
sucrose, 0.05% (w/v) polysorbate 80, pH 7.0). Please refer to the BIVV001 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 the caregivers and/or legal guardians of participants enrolled in this study. 
Once BIVV001 is prepared for a participant, it can only be administered 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 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. 
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6.1.2 Study treatment schedule and administration  
Instructions for the preparation and administration of BIVV001 are provided in the Pharmacy 
Manual and the Information for Patients. 
The prophylactic treatment regimen is QW (every 7 days) dosing with 50 IU/kg BIVV001. This 
dose was determined based on population PK model and appropriate simulations to understand 
steady state kinetics of BIVV001. The aim of the 50 IU/kg QW treatment regimen is to provide 
sustained FVIII activity levels in the normal to mild hemophilic range and to decrease treatment 
burden with QW dosing. 
The dosing interval in the younger age cohort (<6 years) may be reduced by 1 or 2 days if 
clinically warranted at the discretion of the investigator and only after consultation with the study 
medical monitor. For participants who have their BIVV001 dosing interval reduced, the washout 
period prior to inhibitor tests must be adjusted accordingly. 
BIVV001 will be delivered via a slow push IV injection at a rate of administration listed in 
Table 6 and determined by the participant’s comfort level. BIVV001 formulation contains sucrose 
and the injection durations listed in Table 6 are consistent with recommendations on infusion 
rates. Overall, the recommended maximum total injection time should be ≤15 minutes for all 
doses.  
Table 6 - BIVV001 weight-based vial and injection rate recommendations  
Participant weight 
Minimum injection duration per vial 
Maximum total injection time 
10-<20 kg 
6 minutes per vial 
15 min 
20-<30 kg 
3 minutes per vial 
15 min 
≥30 kg 
2 minutes per vial 
15 min 
 
Any missed of BIVV001 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. 
6.1.3 Treatment of bleeding episodes during prophylactic treatment regimen  
The participant’s caregiver will be instructed by the clinic on how to treat a bleeding episode at 
home and record this in the ePD (for a definition of bleeding episode refer to Section 8.1.2). 
Bleeding episodes requiring treatment will be treated with a single dose of 50 IU/kg, as described 
in Table 7.  
Major bleeding episodes will be treated in the hospital/clinic or at home, as applicable. The 
participant’s caregivers will be instructed to consult the investigational site prior to dosing any 
follow-up injection. Administration of a second dose of BIVV001 as follow-up treatment will be 
determined by the Investigator and participant’s caregivers 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 
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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 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 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. 
6.1.4 Surgical dosing  
Minor surgeries can be performed while participating in this trial by administering a dose of 
50 IU/kg BIVV001 (Table 7).  
Participants who undergo major surgery during the study will be included in the surgery subset. 
Definitions for major and minor surgery are listed in Appendix 7, Section 10.7.1.  
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 7. 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. No continuous infusion of 
BIVV001 will be allowed for 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. 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 the WFH Guidelines. 
Post-operatively, FVIII activity levels should be monitored by daily measurements of FVIII 
activity locally as long as the patient is hospitalized. FVIII levels should be maintained at 
recommended levels and duration according to WFH Guidelines. 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 t1/2 of BIVV001, the frequency of dosing in the post-surgical period may be extended 
after the first week post-surgery.  
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Table 7 - 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 within 2 to 3 days 
of a recent prophylactic dose, a 30 IU/kg dose may also be 
used. 
Minor surgery 
50 IU/kg 
Single dose prior to surgery 
Major surgery, only 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 Appendix 7 (Section 10.7.2) for definitions of minor, moderate, and major bleeding episodes. 
6.1.5 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 in Table 7. 
Detailed guidelines for washout and sampling details are provided in Appendix 7, Section 10.7.4. 
6.1.6 BIVV001 dosing calculations  
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. 
6.1.6.1 Definitions of nominal strength versus actual potency  
The nominal strength is the target potency of the vial (that is, 250 IU, 500 IU, 1000 IU, 2000 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.) 
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6.1.6.2 Calculation and recording of actual versus nominal dosing  
Actual potency must be used for dose calculations for the following: 
Baseline PK and Peak/Trough at Week 4: 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 Pharmacy 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: 
Peak/Trough after Week 4 and 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 Pharmacy 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 clinical research associate [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. BIV001 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. 
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 Pharmacy manual. 
Any quality issue noticed with the receipt or use of an investigational medicinal product (IMP) 
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. 
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A potential defect in the quality of IMP 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 and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP/NIMP to a third party (except for DTP 
shipment, for which a courier company has been approved by the Sponsor), allow the IMP/NIMP 
to be used other than as directed by this clinical trial protocol, or dispose of IMP/NIMP 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 Sanofi 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 Pharmacy Manual for specific instructions on its 
storage. 
6.2.3 Study drug preparation  
The study site staff should follow the BIVV001 Pharmacy Manual for specific instructions on its 
preparation. 
6.2.4 Study drug administration  
The study site staff should follow the BIVV001 Pharmacy Manual 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 
(participant-by-participant accounting), and accounts of any BIVV001 accidentally or deliberately 
destroyed or lost. The study site staff should follow the BIVV001 Pharmacy Manual 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 
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must be provided for any discrepancies. The study site staff should follow the BIVV001 
Pharmacy Manual for specific instructions on its disposal. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
Not applicable as this is an open-label 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. Confirmation of destruction will be provided to the Sponsor. 
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 from the time of signature of the ICF 
through the Safety Follow-Up Call or Visit will be recorded in the eCRF along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
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 from the time of signature of the ICF throughout the treatment 
and follow-up periods.  
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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. NSAIDs at doses above the maximum dose specified in local prescribing information.  
2. Acetylsalicyclic acid (ASA) or other non-NSAIDs anti-platelet therapies. 
3. Systemic treatment with chemotherapy and/or other immunosuppressive drugs (except for 
the treatment of 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 a14-day duration. 
Local, topical, and/or inhaled steroid use is permitted.  
4. Any other FVIII product.  
5. Emicizumab. 
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.  
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 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.  
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
Participants or their caregivers 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 
the assessments at the EOS/ET visit as specified in the 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 8.3.7 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 
• The participant or his caregivers withdraws consent  
The Investigator may confer with the Sponsor or Study Medical Manager before discontinuing 
dosing in the participant. 
Participants or their caregivers may decide that IMP be discontinued. 
If a participant discontinues dosing due to an AE or SAE, the event should be followed as 
described in Section 8.3.3. When a participant discontinues IMP dosing, the primary reason must 
be recorded in the appropriate section of the eCRF.  
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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 ET/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  
• Participants may withdraw from the study at any time at their own or their caregiver’s 
request or may be withdrawn at any time at the discretion of the Investigator or Sponsor 
for safety, behavioral, compliance, or administrative reasons.  
• 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 (Table 1) for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed. The participant will 
be permanently discontinued both from the study intervention and from the study at that 
time. 
• If the participant or his parents withdraw consent for disclosure of future information, the 
Sponsor may retain and continue to use any data collected before such a withdrawal of 
consent. 
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• If a participant withdraws from the study, he or his parents 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 or their caregivers 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 or his caregivers may withdraw 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. 
Preferably the patient should withdraw consent in writing and, if the patient or the patient’s 
representative refuses or is physically unavailable, the site should document and sign the reason 
for the patient’s failure to withdraw consent in writing. 
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 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/caregiver 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/caregiver (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/caregiver 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. 
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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. 
8.1 
EFFICACY ASSESSMENTS  
Planned time points for all efficacy assessments are provided in the SoA (Table 1). 
8.1.1 Electronic patient diary supply and training  
Participant’s caregiver will be supplied with an 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. Participant’s caregiver will be prompted to enter bleeding 
location, type (spontaneous or traumatic), reasons for dosing (prophylaxis or treatment of a 
bleeding episode), symptoms and response to treatment. An ePD training will be completed at the 
study site at the Baseline visit. Training of caregivers should be documented in the appropriate 
source record. The ePD refresher training should also be provided at any point during the study.  
8.1.2 Bleeding episodes data  
In this study, a standardized definition of a bleeding episode based on International Society on 
Thrombosis and Haemostasis (ISTH) criteria will be used (43). 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.  
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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. 
• Follow up injection: if an additional injection 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's caregiver, the Investigator will 
review the bleeding episode data in the ePD. If the Investigator judges that the classification by 
the participant's 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's 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's 
caregiver completion and Investigator review of the participant’s ePD are captured by the 
participant's caregiver using the ePD. The date and details of injection and bleeding 
episodes will be recorded by the participant's caregiver in the ePD within 7 days of the 
episode. 
• Bleeding episodes in-clinic/hospital and doses to treat bleeds given at the clinic/hospital 
are captured by the Investigator in the eCRF. 
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• Electronic patient diary (ePD) Review and Training: Investigator or designee to review 
ongoing ePD data and perform participant retraining as necessary.  
• 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/hospital: 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. 
8.1.3 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 (43) (Table 8). 
The assessment should be performed approximately 72 hours after the initial treatment for the 
bleeding episode. 
Table 8 - 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 
8.1.4 Physician’s global assessment (PGA)  
The Physician’s global assessment (PGA) is an assessment of the participant’s response to 
treatment using a 4-point response scale (Table 9). 
Table 9 - 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. 
Ineffective 
• 
Routine failure to control hemostasis or hemostatic control required additional agents. 
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8.1.5 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 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 (Section 10.7.3). 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 used in children aged 
≥4 years at Baseline, Week 26 and Week 52.  
8.1.6 Investigator’s target joint assessment  
The Investigator will assess target joints at Baseline according to the 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.  
8.1.7 Assessment of response to 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 must have 6 EDs to BIVV001 and a negative inhibitor test within 4 weeks prior to 
surgery to be eligible for the surgery subgroup. 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 7. 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 6.1.4. 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. 
Following a 24-hour post-operative study assessment, participants will follow the recommended 
postoperative treatment regimen as per Investigator’s advice.  
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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. 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 be treated with BIVV001 during the minor intervention 
according to the guidelines on surgical dosing found in Section 6.1.4. 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 eCRF. Any doses administered 
outside of the clinic/hospital 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 
pre-surgery treatment regimen. 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 (Table 10). This includes observations during surgery and the 24-hour post-operative 
time period so this assessment will be done 24 hours after the surgery. 
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Table 10 - 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 
8.1.8 Samples for future scientific research  
Additional serum and plasma samples will be collected and archived (along with unused backup 
samples) for testing by the central laboratory for future scientific research.  
This research will enable a better understanding of the factors contributing to clinical outcomes 
and immunological responses during treatment with BIV001 in patients with Hemophilia A and 
may include the following investigations: clotting experiments (thrombin generation assays, fibrin 
generation assay and clotting assays with additional clotting reagents), tests to clarify any clinical 
or laboratory AE and viral analyses. 
 
 
 
 
This is optional, and only participants who provided assent and who had their parent’s consent for 
sample collection and use of unused samples for future research will have their samples archived. 
8.2 
SAFETY ASSESSMENTS  
Planned time points for all safety assessments are provided in the SoA (Table 1). 
8.2.1 Physical examinations  
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. 
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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. 
• 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 eCRF. 
• 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. Refer to Section 1.3 for vital 
sign collection timepoints.  
8.2.3 Clinical safety laboratory assessments  
• See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and 
to the SoA (Table 1) 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 eCRF. 
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 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. 
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- 
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 eCRF. 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
The definitions of an AE and 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 
up on 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 Time period and frequency for collecting AE and SAE information  
All AEs and SAEs will be collected from the signing of the ICF until the safety follow-up call or 
visit at the time points specified in the SoA (Section 1.3). 
All SAEs and adverse events of special interest (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. 
8.3.2 Method of detecting AEs and SAEs  
The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures 
for completing and transmitting SAE reports are provided in 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.  
8.3.3 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 
non-serious AEs of special interest (as defined in Section 8.3.7), 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 provided in Appendix 3 (Section 10.3). 
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8.3.4 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, IRB/IEC, and Investigators. 
• Adverse events that are considered expected will be specified in the reference safety 
information (IB).  
• Suspected unexpected serious adverse reactions (SUSARs) are reported to regulatory 
authorities, Investigators, and IRBs/IECs as follows: 
- 
For SUSARs that are life-threatening or result in death, reporting is no later than 
7 days after first knowledge by the Sponsor, with all relevant follow-up information 
subsequently reported within an additional 8 days 
- 
For SUSARs, other than those that are life-threatening or result in death, reporting is 
no later than 15 days after first knowledge by the Sponsor 
• An Investigator who receives an Investigator safety report describing a SAE, SUSAR or 
any other specific safety information (eg, summary or listing of SAEs) from the Sponsor 
will review and then file it along with IB and will notify the IRB/IEC, if appropriate 
according to local requirements. It is the responsibility of the Sponsor to assess whether an 
event meets the criteria for a SUSAR, and therefore, is expedited to regulatory authorities. 
8.3.5 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.  
8.3.6 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) should be reported as an SAE. All bleeding episodes after 
signature of the ICF will be captured in the ePD that the participant’s caregivers will be 
maintaining throughout the study period. 
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8.3.7 Adverse event of special interest  
An 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. 
• Symptomatic overdose (serious or nonserious) with IMP/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. 
• Other project specific AESI(s) 
- 
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 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 
- 
A participant develops an embolic or thrombotic event, except for injection site 
thrombophlebitis. 
8.3.8 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. 
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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 eCRF. 
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 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 Appendix 7, Section 10.7.4. If a participant has a bleed during the PK time period 
(Table 2), the participant's caregiver should enter the bleed into the ePD, contact the Investigator 
as soon as possible and follow the criteria given in Appendix 7, Section 10.7.4. 
The first 24 participants from the 2 age cohorts (12 participants <6 years of age and 
12 participants 6 to <12 years of age) will undergo an evaluation of the PK profile of BIVV001 
and will be included in the PK subgroup. After completing the baseline PK assessments, these 
24 participants will begin QW 50 IU/kg prophylactic treatment with BIVV001. Any participant 
who does not have adequate PK data will be excluded from the PK analysis. Additional 
participants may be enrolled to ensure that at least 24 participants have adequate PK data for 
analysis. The remaining participants will proceed directly to QW prophylactic treatment. Baseline 
PK sampling can be conducted in other participants at the discretion of investigator through the 
central laboratory. 
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. 
PK Subgroup: At least 12 participants <6 years of age and at least 12 participants 6 to <12 years 
of age 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 6.1.6.1) 
• Baseline PK sampling at BIVV001 Day 1: Pre-injection and 15 (±3) minutes, 3 hours  
(±15 minutes), 24 (±2) hours [Day 2], 72 (±5) hours [Day 4], and 168 (±5) hours [Day 8] 
from the start of the injection  
See Table 2 for details of PK sampling of first 12 participants in each age cohort. If a participant 
has a bleed during the PK time period above, the participant's caregiver should enter the bleed into 
the ePD and contact the Investigator as soon as possible. 
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Peak and trough sampling: Participants in the PK subgroup in both age cohorts will have trough 
and peak sampling at all scheduled visits subsequent to Day 1. Participants not included in the PK 
subgroup in both age cohorts will have trough and peak sampling at all scheduled visits including 
Day 1. 
PK assessments will be based on FVIII activity levels determined by one-stage aPTT clotting 
assay and two-stage chromogenic assay performed at all scheduled visits. The first 12 participants 
in each age cohort will undergo PK sampling at Day 1. Refer to Appendix 7, Section 10.7.4 for 
PK sampling completion criteria. 
Pharmacokinetic sampling will be used to estimate PK parameters, including but not limited to the 
following: Cmax, t1/2, CL, CLss, AUC, Vss, MRT, IR, Ctrough and time above predefined FVIII 
activity levels.  
8.6 
PHARMACODYNAMICS  
Pharmacodynamic parameters will be 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 (44). 
Where local regulations and EC allow approval, for participants whose FVIII genotype is not 
known, an optional sample will be collected at Week 13 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 or 
participant's caregiver may withdraw consent and request to have the participant’s 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. 
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8.9 
IMMUNOGENICITY ASSESSMENTS  
8.9.1 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. 
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. 
8.9.2 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. 
8.10 
CAREGIVER- AND/OR PATIENT-REPORTED CLINICAL OUTCOME ASSESSMENTS 
AND MEDICAL RESOURCE UTILIZATION  
8.10.1 Caregiver- and/or patient-reported clinical outcome assessments  
Table 11 shows the concepts of clinical outcome assessments (COAs) along with their related 
questionnaires to be used in the study. The Sponsor or designee will provide the translations for 
all caregiver- and/or patient-reported COA instruments, where translations are available. Where 
available, the COAs will be distributed to children <12 years and their caregivers (proxy) as 
specified in the SoA (Table 1). If an instrument is not available in the participant’s language, the 
instrument will not be completed. All caregiver or Patient Reported Clinical Outcome assessment 
are collected via an electronic tablet and transmitted to a third-party vendor data server over 
public networks using encrypted data. 
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Table 11 - List of caregiver- and/or patient-reported clinical outcome assessments  
Concept 
Questionnaire 
Administered to 
Endpoint 
Assessment 
Schedule 
Pain and Physical 
Function (PROMIS 
Instruments) 
PROMIS instruments: 
1. 
PROMIS Pediatric NRS-Pain 
Intensity (participants  
≥8 years old) 
2. 
PROMIS Pediatric-Pain 
Interference-SF (participants 
≥8 years old) 
3. 
PROMIS Pediatric- Physical 
Activity-SF (participants  
≥8 years old) 
4. 
PROMIS Parent Proxy NRS - 
Pain Intensity (participants  
5 to <12 years old) 
5. 
PROMIS Parent Proxy- Pain 
Interference-SF (participants 
5 to <12 years old) 
6. 
PROMIS Parent Proxy- 
Physical Activity-SF 
(participants 5 to <12 years 
old) 
Children version for 
participants ≥8 years 
old and parent proxy 
version (participants  
5 to <12 years old). 
Exploratory 
 
Baseline, 
Weeks 26, 52 
Hemophilia specific  
Haemo-QoL 
1. 
Haemo-QoL kids (4-7 years) 
2. 
Haemo-QoL kids (8 to 
<12 years) 
3. 
Haemo-QoL parent proxy (for 
participants 4-7 years) 
4. 
Haemo-QoL parent proxy (for 
participants 8 to <12 years) 
 
Children version for 
participants (≥4 years 
old) and via parent 
proxy version (≥4 years 
old)  
Note:There are 
separate Haemo-QoL 
versions for participants 
and parent proxy based 
on age of participant 
(for participants  
4-7 years and for 
participants 8 to 
<12 years) 
Secondary (total 
and physical 
health score) 
Baseline, 
Weeks 26, 52 
Health status 
EQ-5D-Y 
1. 
EQ-5D-Y kids (8 to <12 years) 
2. 
EQ-5D-Y parent proxy (for 
participants 4-7 years) 
Children version for 
participants ≥8 years 
old and parent version 
for proxy parent 
(participants aged  
4-7 years). 
Exploratory 
Baseline, 
Weeks 26, 52 
Experience with 
treatment and 
impact 
Caregiver interviews (in a subset of 
caregivers of patients) 
Caregivers (all ages) 
Exploratory 
Week 52 (or 
subsequent 
follow-up visit) 
Abbreviations: EQ-5D-Y = EuroQoL-Youth; Haemo-QoL = Haemophilia Quality of Life Questionnaire for Children and Adolescents; 
PROMIS = Patient-Reported Outcomes Measurement Information System. 
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8.10.1.1 PROMIS instruments  
Patient-Reported Outcomes Measurement Information System (PROMIS) is a system of reliable 
and precise measures of participant-reported heath status (45). 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 or 11-point Numeric Rating Scale with and a recall period of the past 7 days. The PROMIS 
instruments will be administered at Baseline and Weeks 26 and 52 in children aged 8 to <12 and 
parent proxy for ages 5-12. 
PROMIS Pediatric Numeric Rating Scale Pain Intensity v1.0 
The PROMIS Pediatric Numeric Rating Scale Pain Intensity v1.0 is a single item rating scale. 
(refer Appendix 7, Section 10.7.5.1.1 and Section 10.7.5.1.4 for children and parent version, 
respectively). The estimated completion time is <1 minute.  
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 (refer to Appendix 7, Section 10.7.5.1.2 and Section 10.7.5.1.5 
for children and parent version, respectively). The estimated time of completion is 1 minute. 
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 (refer to Appendix 7, Section 10.7.5.1.3 and Section 10.7.5.1.6 for 
children and parent version, respectively). The estimated completion time is 1-2 minutes. 
8.10.1.2 Hemophilia quality of life questionnaire (Haemo-QoL)  
The Hemophilia Quality of Life Questionnaire (Haemo-QoL) questionnaire for children with 
hemophilia is available for participants <17 years of age. Estimated completion time is less than 
10 minutes (46). The instrument (children's short versions by age groups: 4-7 years - 16 items 
[Section 10.7.5.2.1]; 8 to <12 years - 35 items [Section 10.7.5.2.2] and parent’s short versions: 
4-7 years - 16 items [Section 10.7.5.2.3]; 8 to <12 years - 35 items [Section 10.7.5.2.4]) will be 
administered to participants and their caregivers at Baseline and Weeks 26 and 52. 
8.10.1.3 EuroQoL-Youth (EQ-5D-Y)  
The EuroQoL-5D-Youth (EQ-5D-Y) comprises of 5 dimensions (mobility, looking after myself, 
doing usual activities, having pain or discomfort, feeling worried, sad or unhappy) with 3 levels 
and a visual analogue scale and is a qualitative measure of health outcomes. The EQ-5D-Y will be 
administered to children aged 8 to <12 years (Section 10.7.5.3.1) and parent proxy version will be 
used for children aged 4-7 years (Section 10.7.5.3.2). 
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8.10.1.4 Caregivers interviews  
Semi-structured interviews (Appendix 7, Section 10.7.5.4) will be conducted in a subset of 
caregivers of children (ie, caregivers from English speaking countries, including but not limited to 
the USA. Non English-speaking countries may be included based on feasibility) in the study at the 
last visit or a subsequent follow-up visit to evaluate their expectations from treatment, perception 
of treatment impact on the daily lives and functioning of children and their caregivers. The 
interviews will be conducted by trained interviewers based on a structured interview guide. 
8.10.2 Healthcare resource utilization  
Healthcare resource utilization (HRU) associated with medical encounters and attributable to 
Hemophilia A will be collected in the eCRF 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 Appendix 7, Section 10.7.6. Medical resource 
utilization data associated with medical encounters will be collected in the eCRF by the 
Investigator and study-site personnel for all participants throughout the study. Protocol-
mandated procedures, tests, and encounters are excluded. 
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9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES  
In general, all statistical analyses will be descriptive in nature. No formal comparison is planned 
and no hypothesis will be formally tested. For the primary endpoint, the proportion of participants 
who experience any inhibitor during the study will be calculated including an exact (Clopper-
Pearson) 2-sided, 95% CI. Continuous endpoints will be summarized using the number of 
observations, mean, standard deviation (SD), median, minimum, and maximum with the 25th and 
75th percentiles, where appropriate. Categorical endpoints will be summarized by counts and 
percentages. All data will be summarized for each age cohort (<6 years and 6 to <12 years) and 
overall. 
9.2 
SAMPLE SIZE DETERMINATION  
The determination of the number of participants is based on clinical rather than statistical 
considerations. Taking into consideration the guideline from Committee for Medicinal Products 
for Human Use (EMEA/CHMP/BPWP/144533/2009 rev.2), approximately 65 PTPs will be 
enrolled to obtain at least 50 participants with at least 50 EDs at the end of the study. All 
participants completing or remaining at the end of study will be offered participation in the 
planned extension trial. 
At least 12 participants in each age cohort need to have completed adequate blood sample 
collection to assess key PK parameters. 
9.3 
POPULATIONS FOR ANALYSES  
The following populations are defined (Table 12): 
Table 12 - Populations for analyses  
Population 
Description 
Screened 
All participants who sign the ICF 
Full Analysis Set 
All participants who take at least 1 dose of study intervention 
Safety Analysis Set 
The safety analysis 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.  
Abbreviations: ICF = informed consent form; PK = pharmacokinetics. 
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9.4 
STATISTICAL ANALYSES  
9.4.1 General considerations  
The SAP will be finalized prior to database lock and will include a more technical and detailed 
description of the statistical analyses described in this section. This section is a summary of the 
planned statistical analyses of the most important endpoints including primary and secondary 
endpoints. 
9.4.2 Primary endpoint(s)  
The primary endpoint is the occurrence of inhibitor development, defined as an inhibitor result of 
>0.6 BU/mL that is confirmed by a second test result 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. The incidence of inhibitor 
formation for all (≥0.6 BU/mL), “high (≥5.0 BU/mL)” and “low (≥0.6 BU/mL and <5.0 BU/mL)” 
titer inhibitors from the central laboratory will be summarized for each age cohort and overall; a 
95% CI using Clopper-Pearson method will be calculated for each incidence.  
For the incidence calculations, 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 to BIVV001. The calculation will also be 
performed with a denominator that includes all participants with a valid inhibitor test following at 
least 25 EDs to BIVV001 and a denominator that includes all participants with a valid inhibitor 
test, regardless of how many days they were exposed to BIVV001. 
9.4.3 Secondary endpoint(s)  
Participants who receive at least 1 dose of BIVV001 will be included in the FAS. Efficacy 
analyses will be based on the FAS. The efficacy and surgical/rehabilitation periods will be defined 
in the SAP for the purpose of determining the study periods during which data will be used for 
selected efficacy analyses. Data on bleeding and BIVV001 consumption will be based on the 
efficacy period; surgical evaluations will be based on the surgical/rehabilitation period. 
Analysis of efficacy endpoints that are visit-based will include data from all study visits, whether 
or not in the efficacy period, unless a visit is coincidental with a surgical/rehabilitation period for 
a major surgery, in which case it would be excluded. 
Annualized Bleeding Rate (ABR) 
The mean and 95% CI of ABR will be estimated using a Negative-Binomial model. The model 
will include number of treated bleeding episodes during the efficacy period as response variable, 
log-transformed duration of efficacy period as offset variable to account for variable duration. 
Individual ABR will also be calculated for each patient. 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. Bleeding episodes that occur 
during surgical/rehabilitation period will be excluded and summarized separately.  
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In addition, ABR will be summarized descriptively by type of bleed (spontaneous or traumatic) 
and location of bleed (joint, muscle, internal, or skin/mucosa).  
Hemophilia Joint Health Score 
Changes in total HJHS score and specific domains such as swelling and strength will be 
summarized descriptively. 
Secondary Safety Endpoints 
All safety analyses will be performed on the Safety Analysis Set. Safety will be assessed through 
descriptive summaries of AEs, SAEs, laboratory results, physical examination, and vital signs.  
The incidence of AEs will be summarized by system organ class and preferred term for each age 
cohort and overall. Clinical laboratory values will be summarized for change from baseline, shifts, 
and potentially clinically significant abnormalities. 
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. 
Medical adjudication of the search results will also be performed according to the below 
definition. 
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, computed tomography venogram, magnetic resonance 
angiography, or computed tomography angiography to be included as part of medical 
adjudication. 
An indwelling central venous access device is a well-established risk factor for thrombosis (47) 
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 (48) and will 
not be included as part of medical adjudication. 
Pharmacokinetics 
Any participant with adequate BIVV001 PK data will be included in the PK Analysis Set. A 
noncompartmental analysis will be performed for each participant's BIVV001 baseline PK profile. 
At least 24 participants will be enrolled in the PK group. Instructions for wash-out and PK 
sampling are provided in Appendix 7, Section 10.7.4. 
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Pharmacokinetic parameters of BIVV001 activity including but not limited to Cmax, CL, CLss, Vss, 
AUC, DNAUC, MRT, IR, Ctrough and time above 1% FVIII activity measured by aPTT clotting 
assay and chromogenic assay will be determined for BIVV001. Pharmacokinetic parameters will 
be summarized for each age cohort for BIVV001 with geometric means and their corresponding 
95% CIs. 
Other Secondary endpoints 
All other secondary endpoints will be summarized descriptively.  
The number and percentage of participants achieving trough FVIII activity levels above 1%, 3%, 
5%, 10%, 15%, and 20% will be summarized. 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 and 
chromogenic 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. 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. 
The consumption of BIVV001 will be annualized and summarized. 
The number of injections and total dose of BIVV001 to treat a bleeding episode will be 
summarized 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. 
The participant’s response to treatment of individual bleeding episodes will be summarized as the 
number and percentage of bleeding episodes with each response (excellent, good, moderate, or 
none). 
The physician’s global assessment of the participant’s overall response to BIVV001 treatment will 
be summarized for each study visit and across all visits as the number and percentage classified as 
excellent, effective, partially effective, and ineffective. 
For Haem-A-QoL, total score and physical health domain score will be summarized descriptively 
over time. 
Surgical endpoints will be summarized descriptively for the surgical subgroup. Continuous 
endpoints will be summarized using the number of non-missing values (n), mean, SD, median, 
minimum, and maximum. Categorical endpoints will be summarized by counts and percentages. 
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9.4.4 Tertiary/exploratory endpoint(s)  
Table 11 shows the concepts of measurement and their related COAs (caregiver- and/or patient-
reported) questionnaires to be used in the study. All endpoints for COAs and health outcomes 
related to hemophilia (except for Haemo-QoL) are exploratory in nature. All endpoints for COAs 
and health outcomes related to hemophilia will be analyzed in a separate report by summarizing 
actual values and change from baseline as appropriate. If the final sample size is sufficient, then 
these summaries will also be presented stratified by previous episodic and previous prophylaxis 
treatment. 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 over time. 
9.4.5 Other analyse(s)  
Other analyses if any can be conducted for exploratory purposes and the details of the analyses 
will be defined in the SAP. 
9.5 
INTERIM ANALYSES  
Interim analyses may be conducted for regulatory purposes, as needed. The SAP will describe the 
planned interim analyses in detail. 
9.6 
DATA MONITORING COMMITTEE (DMC)  
An independent external Data Monitoring Committee (DMC) will be responsible for evaluating 
and monitoring the safety and tolerability of the study drug on an ongoing basis during the study. 
The specifics regarding the DMC organization and procedures will be outlined in the DMC 
Charter.  
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS  
10.1.1 Regulatory and ethical considerations  
• 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 International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines 
- 
Applicable laws and regulations (eg, data protection law as General Data Protection 
Regulation - GDPR) 
• 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 Determining whether an incidental finding should be 
returned to a participant and, if it meets the appropriate criteria, to ensure the finding is 
returned (an incidental finding is a previously undiagnosed medical condition that is 
discovered unintentionally and is unrelated to the aims of the study for which the tests 
are being performed). The following should be considered when determining the return 
of an incidental finding: 
- 
The return of such information to the study participant and his parents (and/or his 
designated healthcare professional, if so designated by the participant his parents is 
consistent with all applicable national, state, or regional laws and regulations in the 
country where the study is being conducted, and  
- 
The finding reveals a substantial risk of a serious health condition or has 
reproductive importance, AND has analytical validity, AND has clinical validity.  
- 
The participant in a clinical study and his parents has the right to opt out of being 
notified by the Investigator of such incidental findings. In the event that the 
participant or his parents have opted out of being notified and the finding has 
consequences for other individuals, eg, the finding relates to a communicable 
disease, Investigators should seek independent ethical advice before determining 
next steps. 
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- 
In case the participant or his parents have decided to opt out, the Investigator must 
record in the site medical files that he or his parents do not want to know about 
such findings. 
- 
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. 
As applicable, according to Directive 2001/20/EC, the Sponsor will be responsible for obtaining 
approval from the Competent Authorities of the EU Member States and/or Ethics Committees, as 
appropriate, for any amendments to the clinical trial that are deemed as “substantial” (ie, changes 
which are likely to have a significant impact on the safety or physical or mental integrity of the 
clinical trial participants or on the scientific value of the trial) prior to their implementation. 
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. 
10.1.3 Informed consent process  
• The Investigator or his/her representative will explain the nature of the study to the 
participant and his legally authorized representative and answer all questions regarding the 
study.  
• Participants must be informed that their participation is voluntary. Participants (if 
applicable) and their legally authorized representative will be required to sign a statement 
of informed consent/assent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center.  
• The participant or participant’s legally authorized representative (eg, parent or legal 
guardian) must be provided with informed consent/assent document(s) prior to the 
screening visit to allow adequate time for review and opportunity to discuss the study with 
the investigator/designee. After reviewing, parents/legal guardians and participants (if 
applicable) will come to the clinic to sign the informed consent/assent. Participants (where 
applicable) and/or parents legal guardians must provide consent/assent before any 
screening assessments are performed. 
• 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. 
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• Participants must be re-assented, and their legally authorized representative 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 and their legally authorized representative are required to sign a 
new ICF, when applicable. 
The ICF will contain a separate section that addresses the use of remaining mandatory samples or 
new extra samples for optional exploratory research. The Investigator or authorized designee will 
explain to each participant's caregiver the objectives of the exploratory research. Participants and 
their caregivers will be told that they are free to refuse participation and may withdraw their 
consent at any time and for any reason during the storage period. A separate consent will be 
required to document a participant's caregiver/participant (where applicable) agreement to allow 
any remaining specimens to be used for exploratory research. The participant/caregiver who 
decline participation in this optional research will not provide this separate consent. 
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 (General 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 
names or any information which would make the participant identifiable will not be 
transferred to the Sponsor. 
• 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 (49, 50). Additionally, differential responses to FVIII 
products may occur in different haplotypes of FVIII that also differ across racial and 
ethnic groups (51). 
• The participant and his legally authorized representative must be informed that participant 
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/participant's caregiver as described in the informed consent.  
• The participant and his legally authorized representative must be informed that participant 
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. 
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• 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. 
• Participant data are intended to be used for the whole drug development program from 
collection to reimbursement.  
10.1.5 Dissemination of clinical study data  
Sanofi shares information about clinical trials and results on publically 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 clinicaltrialregister (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 case 
report form (CRF) and ePD 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.  
• 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). 
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• 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 start and closure  
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open and will be the study start date. 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for 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 
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- 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator 
- 
Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the caregiver/participant and 
should assure appropriate participant therapy and/or follow-up. 
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 13 will be performed by the central laboratory.  
• Blood samples will be obtained as blood volume permits and should not exceed the blood 
volume collection limit of 3% of total blood volume over a 4 weeks period. The specific 
requirements for blood sampling and minimum interval between visits are described in the 
laboratory manual. Sampling should be prioritized for safety labs and PK. 
• 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 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. 
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Table 13 - Protocol-required laboratory assessments  
Laboratory assessments 
Parameters 
Hematology 
 
 
Platelet count 
 
Red blood cell (RBC) count 
 
Hemoglobin 
 
Hematocrit 
 
White blood cell (WBC) count with differential: 
 
Neutrophils 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
Clinical chemistry 
 
 
Blood urea nitrogen (BUN) 
 
Creatinine 
 
Glucose (nonfasting) 
 
Potassium 
 
Sodium 
 
Chloride 
 
Aspartate aminotransferase (AST) 
 
Alanine aminotransferase (ALT) 
 
Alkaline phosphatase (ALP) 
 
Gamma glutamyl transferase (GGT) 
 
Total and direct bilirubin 
 
Total protein 
Von Willebrand (VWF) 
comprehensive panel 
 
 
VWF ristocetin cofactor activity 
 
VWF antigen 
Immunogenicity 
 
 
Nijmegen modified Bethesda inhibitor assay 
 
Anti-drug Antibodies (ADA) 
 
ADA subtype (FVIII, Fc, D’D3, or XTEN) 
Coagulation parameters 
 
 
Activated partial thromboplastin time (aPTT)  
Other screening tests 
 
 
HIV (HIV-1 antibodies, HIV-2 antibodies, and HIV-1 p24 antigen), HBV (HBV surface 
antigen, anti-HBV surface antibody and anti-HBV core antibody) and HCV (anti-HCV 
antibodies) for patients who have been historically negative 
 
CD4 count and viral load (for patients known to be HIV positive) 
Abbreviations: ADA = Anti-drug Antibodies; ALP = Alkaline phosphatase; ALT = Alanine aminotransferase; aPTT = activated partial 
thromboplastin time; AST = Aspartate aminotransferase; BUN = Blood urea nitrogen; GGT= Gamma glutamyl transferase; HBV = hepatitis B 
virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; RBC = Red blood cell; SAE = serious adverse event; VWF = Von 
Willebrand; WBC = White blood cell 
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Investigators must document their review of each laboratory safety report. 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING  
10.3.1 Definition of AE  
AE definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
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 
• Any abnormal laboratory test results (eg, hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, electrocardiography [ECG], radiological scans, vital signs 
measurements), including those 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 AEs or SAEs if they fulfil the definition of an AE or SAE.  
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Events NOT meeting the AE definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• Medical or surgical procedure (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. 
10.3.2 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 
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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. 
- 
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. 
10.3.3 Recording and follow-up of AE and/or SAE  
AE and SAE recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (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. 
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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 
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. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The Investigator will also consult the 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. 
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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. 
• The Investigator will submit any updated SAE data to the Sponsor (or representative) 
within 24 hours of receipt of the information. 
10.3.4 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 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 are 
not available. 
• In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
• Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames. 
• Contacts for SAE reporting can be found in Study Manual. 
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10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION  
Not applicable. 
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 (Section 8.3.1). 
Asymptomatic overdoses are not considered AEs and should not be recorded as an AE on the 
CRF. 
10.6 
APPENDIX 6: COUNTRY-SPECIFIC REQUIREMENTS  
Not applicable. 
10.7 
APPENDIX 7: ADDITIONAL APPENDICES  
10.7.1 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. 
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) 
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It is recommended that any elective non-dental major surgery be performed at a study site, when 
possible. 
10.7.2 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 
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10.7.3 Hemophilia joint health score (HJHS)  
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10.7.4 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. 
Washout and pk sampling requirements 
Screening: 
all participants 
Washout 
• 
First attempt: Washout of at least 48 hours before Screening inhibitor test to obtain interpretable 
test resultsa. Repeat this washout if participant treats a bleed prior to 48 hours (follow second 
attempt). 
• 
Second attempt: Conduct same washout as first attempt. 
• 
If the second attempt at washout fails, additional attempts may be considered after consultation 
with the medical monitora. 
 
 
Baseline PK sampling: PK subgroup 
Day 1 Baseline PK 
sampling: 
12 subjects 
<6 years of age  
Washout 
• 
First attempt: Washout of at least 72 hours (3 days); repeat this washout if participant treats a 
bleed prior to 72 hours (follow second attempt)a. 
• 
Additional attempt(s): Conduct same washout as first attempta. 
• 
If the second attempt at washout fails, additional attempts may be considered after consultation 
with the medical monitor. 
 
PK Sampling 
• 
First attempt: PK sampling period with collection of PK samples (Table 2) to 168 hours (Day 8) is 
required. If a participant treats a bleeding episode after receiving the dose of BIVV001 for PK 
evaluation but prior to completing the PK sampling period, PK sampling will be stopped at the time 
of the bleed and a second attempt (repeat) PK sampling period should be conducted.  
• 
Second attempt: Participants are required to undergo a 240 hour (10 Day) washout from the prior 
BIVV001 dose, which is then followed by the PK sampling period with collection of PK samples 
(Table 2) to 168 hours (Day 8). 
• 
If the second attempt at PK sampling period fails due to the participant treating a bleed prior to 
collection of the 168-hour (Day 8) sample, the participant will remain in the study but will no longer 
be included in the PK subgroup. The participant will be replaced in the PK subgroup and will 
continue with prophylactic BIVV001 dosing regimen. 
Day 1 Baseline PK 
sampling: 
12 subjects 6 to 
<12 years of age 
Washout 
• 
First attempt: Washout of at least 96 hours (4 days); repeat this washout if participant treats a 
bleed prior to 96 hours (follow second attempt)a. 
• 
Additional attempt(s): Conduct same washout as first attempt. If the second attempt at washout 
fails, additional attempts may be considered after consultation with the medical monitora. 
PK Sampling 
• 
First attempt: PK sampling period with collection of PK samples (Table 2) to 168 hours (Day 8) is 
required. If a participant treats a bleeding episode after receiving the dose of BIVV001 for PK 
evaluation but prior to completing the PK sampling period, PK sampling will be stopped at the time 
of the bleed and a second attempt PK sampling period should be conducted.  
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• 
Second attempt: Participants are required to undergo a 240 hour washouta after previous dose, 
which is then followed by the PK sampling period with collection of PK samples (Table 2) to 
168 hours (Day 8). 
• 
If the second attempt at PK sampling period fails due to the participant treating a bleed prior to 
collection of the168-hour (Day 8) sample, the participant will remain in the study but will no longer 
be included in the PK subgroup. The participant will be replaced in the PK subgroup and will 
continue with prophylactic BIVV001 dosing regimen. 
 
 
Peak and trough 
sampling: All 
Participants 
except PK 
subgroup at Day 1 
Washout 
• 
First attempt: Washout of at least 72 hours (3 days) or 96 hours (4 days) for < 6 yr and 6 to <12 yr 
participants, respectively; repeat this washout if participant treats a bleed prior to 72 hours and 
96 hours for <6 yr and 6 to <12 yr participants respectively (follow second attempt)a. 
• 
Additional attempts: Conduct same washout as first attempt. 
• 
If the second attempt at washout fails, additional attempt may be considered after consultation with 
the medical monitor. 
PK Sampling 
• 
Collection of sample at trough (immediately pre-injection) and peak at 15 ±3 mins from start of 
injection. If the participant is being treated for an acute bleeding prior to collection of the peak and 
trough sample collection, no repeat sampling is needed and the patient will remain in the study and 
collect peak and trough at the next scheduled visit. 
Peak and trough 
sampling: All 
Participants after 
Day 1 
Washout 
• 
No washout required. Participants should visit clinic 7 ±1 day after previous dose. 
• 
If the participant has treated a bleeding episode since his last dose, the scheduled visit should be 
postponed for 7 ±1 day after previous dose. 
PK Sampling 
• 
Collection of sample at trough (immediately pre-injection) and peak at 15 ±3 mins from start of 
injection. If the participant treats a bleed prior to collection of the peak and trough sample 
collection, no repeat sampling is needed and the participant will remain in the study and collect 
peak and trough at the next scheduled visit. 
a 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 
 
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10.7.5 Caregiver - and/or patient-reported clinical outcome assessments  
10.7.5.1 PROMIS instruments  
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10.7.5.1.2 PROMIS Pediatric-SF v2.0 - pain interference 8a  
 
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10.7.5.1.3 PROMIS Pediatric-SF v1.0 - physical activity 8a  
 
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10.7.5.1.4 PROMIS parent proxy numeric rating scale pain intensity v1.0  
 
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10.7.5.1.5  PROMIS parent proxy-sf v2.0 - pain interference 8a  
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10.7.5.1.6 PROMIS parent proxy-sf v1.0 - physical activity 8a  
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10.7.5.2 Haemo-QoL  
10.7.5.2.1 Haemo-QoL short children version (4-7 years)  
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10.7.5.2.2 Haemo-QoL short children version (8 to <12 years)  
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10.7.5.2.3 Haemo-QoL parent proxy short version (children 4-7 years)  
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10.7.5.2.4 Haemo-QoL parent proxy short version (children 8 to <12 years)  
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10.7.5.3 EuroQoL 5-dimension 5-level youth (EQ-5D-Y)  
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10.7.5.4 Caregivers interviews guide  
 
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10.7.6 Healthcare resource utilization (HRU)  
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10.8 
APPENDIX 8: ABBREVIATIONS  
 
ABR: 
annualized bleeding rate 
AE: 
adverse event 
AESI: 
adverse events of special interest 
AJBR: 
annualized joint bleeding rate 
aPTT: 
activated partial thromboplastin time 
ASA: 
acetylsalicyclic acid 
AUC: 
area under the activity-time curve 
BDD: 
B-domain deleted 
BU: 
Bethesda units 
Cavg: 
average activity after reaching steady state 
CI: 
confidence interval 
CIOMS: 
Council for International Organizations of Medical Sciences  
CL: 
total clearance 
CLss: 
total clearance at steady state 
Cmax: 
maximum activity 
COA: 
clinical outcome assessment 
CONSORT: 
consolidated standards of reporting trials 
CRA: 
clinical research associate 
CRF: 
case report form 
CTCAE: 
common terminology criteria for adverse events 
Ctrough: 
trough activity 
DMC: 
Data and Safety Monitoring Committee 
DNAUC: 
dose-normalized area under the activity-time curve 
DRE: 
disease related event 
ECG: 
electrocardiography 
eCRF: 
electronic case report form 
ED: 
exposure day 
EMA: 
European Medicines Agency 
EOS: 
end of study 
ePD: 
electronic patient diary 
EQ-5D-Y: 
EuroQoL-Youth 
ET: 
early termination 
FAS: 
full analysis set 
FVIII: 
factor VIII 
GCP: 
Good Clinical Practice 
GMP: 
Good Manufacturing Practice 
GMR: 
geometric mean ratio 
Haemo-QoL: 
hemophilia quality of life questionnaire 
HCV: 
hepatitis C virus 
HIV: 
human immunodeficiency virus 
HJHS: 
hemophilia joint health score 
HLA: 
human leukocyte antigen 
HRU: 
healthcare resource utilization 
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IB: 
investigator's brochure 
ICF: 
informed consent form 
ICH: 
International Council for Harmonization  
IEC: 
Independent Ethics Committee 
IgG1: 
immunoglobulin G1 
IMP: 
investigational medicinal product 
IR: 
incremental recovery 
IRB: 
Institutional Review Board 
IRT: 
interactive response technology 
ISTH: 
International Society on Thrombosis and Haemostasis 
IV: 
intravenous 
MRT: 
mean residence time 
NIH: 
National Institute of Health 
NSAID: 
non-steroidal anti-inflammatory drug 
PGA: 
physician's global assessment 
PK: 
pharmacokinetics 
PROMIS: 
patient-reported outcomes measurement information system 
PTP: 
previously treated patient 
QoL: 
quality of life 
QW: 
once-weekly 
rFVIII: 
recombinant factor VIII 
SAE: 
serious adverse event 
SAP: 
statistical analysis plan 
SD: 
standard deviation 
SUSAR: 
suspected unexpected serious adverse reaction 
t1/2: 
half-life 
Vss: 
volume of distribution at steady state 
VWF: 
von Willebrand factor 
WFH: 
World Federation of Hemophilia 
 
10.9 
APPENDIX 9: PROTOCOL AMENDMENT HISTORY  
Not applicable. 
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22. Valentino LA, Mamonov V, Hellmann A, Quon DV, Chybicka A, Schroth P, et al. A 
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23. Aznar JA, Magallon M, Querol E, Gorina E, Tusell JM. The orthopaedic status of severe 
hemophiliacs in Spain. Haemophilia. 2000;6(3):170-6. 
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survey of the orthopaedic status of severe haemophilia A and B patients in France. 
Haemophilia. 2000;6(1):23-32. 
25. Mair FS, May CR. Thinking about the burden of treatment. BMJ. 2014;349:g6680. 
26. Oldenburg J. Optimal treatment strategies for hemophilia: achievements and limitations of 
current prophylactic regimens. Blood. 2015;125(13):2038-44. 
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27. 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. 
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28. 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 
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29. Manco-Johnson MJ, Soucie J M, Gill JC. Prophylaxis usage, bleeding rates, and joint 
outcomes of hemophilia, 1999 to 2010: a surveillance project. Blood. 2017;129(17):2368-74. 
30. Soucie JM, Monahan PE, Kulkarni R, Konkle BA, Mazepa MA, US Hemophilia Treatment 
Center Network. The frequency of joint hemorrhages and procedures in nonsevere hemophilia 
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31. Jimenez-Yuste V, Auerswald G, Benson G, Lambert T, Morfini M, Remor E, et al. Achieving 
and maintaining an optimal trough level for prophylaxis in haemophilia: the past, the present 
and the future. Blood Transfus. 2014;12:314-9. 
32. Pipe SW, Montgomery RR, Pratt KP, Lenting PJ, 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. 
33. 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- 
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34. Eloctate [package insert]. Waltham (MA): Bioverativ Therapeutics Inc.; 2017. 
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36. Benjamin WU, Sun YN. Pharmacokinetics of peptide-Fc fusion proteins. J Pharm Sci. 
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37. 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 
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38. 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;27(12):1186-90. 
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investigation of recombinant and human plasma-derived factor VIII products. 2018. 
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40. Lambert T, Benson G, Dolan G, Hermans C, Jimenez-Yuste V, Ljung R, et al. Practical 
aspects of extended half-life products for the treatment of haemophilia. Ther Adv Hematol. 
2018;9(9):295-308. 
41. Oldenburg J, Kulkarni R, Srivastava A, Mahlangu JN, Blanchette VS, Tsao E, et al. Improved 
joint health in subjects with severe hemophilia A treated prophylactically with recombinant 
factor VIII Fc fusion protein. Hemophilia. 2018;24(1):77-84. 
42. Oldenburg J, Zimmerman R, Katsarou O, Theodossiades G, Zanon E, Niemann B, et al. 
Controlled, cross-sectional MRI evaluation of joint status in severe haemophilia A patients 
treated with prophylaxis vs on demand. Haemophilia. 2015;21(2):171-9. 
43. 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. 
44. Oldenburg J, Pavlova A. Genetic risk factors for inhibitors to factors VIII and IX. 
Haemophilia. 2006;12(6):15-22. 
45. 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. Med Care. 2007;45(5 Suppl 1); S3-11. 
46. 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;8 Suppl 2:47-54. 
47. Baskin JL, Pui CH, Reiss U, Wilimas JA, Metzger ML, Ribeiro RC, et al. Management of 
occlusion and thrombosis associated with longterm indwelling central venous catheters. 
Lancet. 2009;374(9684):159-69. 
48. 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. 
49. 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. 
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I. Increased prevalence of inhibitors in Hispanic patients with severe haemophilia A enrolled 
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in black patients with hemophilia. N Engl J Med. 2009;360(16):1618-27. 
 
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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 
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partnership or other entity 
According to template: QSD-002643 VERSION 8.0 (16-JUN-2020) 
Page 1 
STATISTICAL ANALYSIS PLAN 
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 pediatric patients <12 years of age 
with severe hemophilia A 
Protocol number: 
EFC16295 
Compound number 
(INN/Trademark): 
BIVV001 
Study phase: 
Phase 3 
Short title: 
Safety, efficacy and PK of BIVV001 in pediatric patients 
with hemophilia A (XTEND-Kids) 
Statistician: 
Statistical project 
leader: 
Date of issue: 
23-Aug-2021 
Regulatory agency identifier number(s): 
IND: 
EudraCT: 
WHO: 
017464 
2020-000769-18 
U1111-1244-0558
NCT04759131 
Total number of pages: 53 
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Statistical Analysis Plan  
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF TABLES ........................................................................................................................................... 5 
LIST OF FIGURES .......................................................................................................................................... 5 
VERSION HISTORY ....................................................................................................................................... 6 
1 
INTRODUCTION .............................................................................................................................. 7 
1.1 
STUDY DESIGN .............................................................................................................................. 7 
1.2 
OBJECTIVE AND ENDPOINTS ...................................................................................................... 8 
2 
SAMPLE SIZE DETERMINATION ................................................................................................ 10 
3 
ANALYSIS POPULATIONS .......................................................................................................... 11 
4 
STATISTICAL ANALYSES ........................................................................................................... 12 
4.1 
GENERAL CONSIDERATIONS .................................................................................................... 12 
4.1.1 
Definition of study periods .............................................................................................................. 12 
4.1.1.1 
Treatment period ............................................................................................................................ 13 
4.1.1.2 
Efficacy period ................................................................................................................................ 13 
4.1.1.3 
Surgical/rehabilitation period .......................................................................................................... 14 
4.1.1.4 
Safety period .................................................................................................................................. 15 
4.2 
PARTICIPANT DISPOSITIONS ..................................................................................................... 15 
4.3 
PRIMARY ENDPOINT ANALYSIS ................................................................................................ 16 
4.3.1 
Definition of endpoint ..................................................................................................................... 16 
4.3.2 
Main analytical approach ............................................................................................................... 16 
4.3.3 
Supplementary analyses ................................................................................................................ 17 
4.4 
SECONDARY ENDPOINT ANALYSIS .......................................................................................... 17 
4.4.1 
Annualized bleeding rate (ABR) ..................................................................................................... 18 
4.4.1.1 
Definition of endpoint ..................................................................................................................... 18 
4.4.1.2 
Main analytical approach ............................................................................................................... 19 
4.4.1.3 
Sensitivity analyses ........................................................................................................................ 19 
4.4.1.4 
Subgroup analyses ........................................................................................................................ 19 
4.4.2 
ABR by type and location ............................................................................................................... 19 
4.4.3 
ABR based on all bleeding episodes ............................................................................................. 20 
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4.4.4 
Percentage of participants who maintain FVIII activity levels ........................................................ 20 
4.4.5 
Number of injections and dose of BIVV001 to treat a bleeding episode ....................................... 20 
4.4.6 
Percentage of bleeding episodes treated with a single injection of BIVV001 ................................ 21 
4.4.7 
Assessment of response to BIVV001 treatment of bleeding episodes .......................................... 21 
4.4.8 
Physician’s global assessment of participant’s response to BIVV001 treatment .......................... 21 
4.4.9 
Annualized BIVV001 consumption ................................................................................................. 22 
4.4.10 
Annualized joint bleeding rate ........................................................................................................ 22 
4.4.11 
Target joint resolution..................................................................................................................... 22 
4.4.12 
Hemophilia Joint Health Score ....................................................................................................... 22 
4.4.13 
Haemo-QoL (≥4 years old) ............................................................................................................ 24 
4.4.14 
Surgery endpoints .......................................................................................................................... 24 
4.4.14.1 Investigators’ or Surgeons’ assessment of participant’s hemostatic response to BIVV001 
treatment ........................................................................................................................................ 24 
4.4.14.2 Number of injections and dose to maintain hemostasis for major surgery .................................... 25 
4.4.14.3 Total BIVV001 consumption for major surgery .............................................................................. 25 
4.4.14.4 Number and type of blood component transfusions for major surgery .......................................... 25 
4.4.14.5 Estimated blood loss for major surgery.......................................................................................... 25 
4.5 
EXPLORATORY ENDPOINTS ANALYSES .................................................................................. 25 
4.5.1 
PROMIS instruments ..................................................................................................................... 25 
4.5.2 
EuroQoL-Youth (EQ-5D-Y) ............................................................................................................ 26 
4.5.3 
Caregiver interviews....................................................................................................................... 27 
4.5.4 
Healthcare resource utilization (HRU) ........................................................................................... 27 
4.6 
MULTIPLICITY ISSUES ................................................................................................................ 27 
4.7 
SAFETY ANALYSES ..................................................................................................................... 27 
4.7.1 
Extent of exposure ......................................................................................................................... 27 
4.7.1.1 
Overall exposure ............................................................................................................................ 28 
4.7.1.2 
Compliance .................................................................................................................................... 28 
4.7.2 
Adverse events .............................................................................................................................. 30 
4.7.3 
Additional safety assessments ....................................................................................................... 32 
4.7.3.1 
Laboratory variables....................................................................................................................... 33 
4.7.3.2 
Vital signs and physical examination ............................................................................................. 35 
4.8 
OTHER ANALYSES....................................................................................................................... 35 
4.8.1 
Pharmacokinetic analyses ............................................................................................................. 35 
4.8.2 
Additional Immunogenicity analysis ............................................................................................... 37 
4.8.2.1 
Anti-drug antibody .......................................................................................................................... 37 
4.9 
INTERIM ANALYSES .................................................................................................................... 38 
5 
SUPPORTING DOCUMENTATION .............................................................................................. 39 
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5.1 
APPENDIX 1 LIST OF ABBREVIATIONS ..................................................................................... 39 
5.2 
APPENDIX 2 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS .................................................................................................. 39 
5.3 
APPENDIX 3 DATA HANDLING CONVENTIONS ........................................................................ 41 
5.4 
APPENDIX 4 POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA .......... 44 
5.5 
APPENDIX 5 QUESTIONNAIRE SCORING ................................................................................. 47 
5.5.1 
Appendix 5.1 PROMIS instruments ............................................................................................... 47 
5.5.2 
Appendix 5.2 Haemo-Qol ............................................................................................................... 50 
6 
REFERENCES ............................................................................................................................... 53 
 
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LIST OF TABLES  
Table 1 - Major changes in statistical analysis plan ........................................................................................ 6 
Table 2 - Objectives and endpoints ................................................................................................................. 8 
Table 3 - Populations for analyses ................................................................................................................ 11 
Table 4 - HJHS domains ............................................................................................................................... 23 
Table 5 - Direction of change indicating clinical concern for laboratory tests ............................................... 34 
Table 6 - Analyses window definition ............................................................................................................ 43 
Table 7 - Threshold levels for potentially clinically significant hematology abnormalities ............................. 44 
Table 8 - Threshold levels for potentially clinically significant chemistry abnormalities ................................ 45 
Table 9 - Threshold levels for potentially clinically significant coagulation abnormalities ............................. 46 
Table 10 - Threshold levels for potentially clinically significant vital sign abnormalities ............................... 46 
Table 11 - Conversion table for PROMIS instruments .................................................................................. 48 
 
LIST OF FIGURES  
Figure 1 - Study schema ................................................................................................................................. 7 
 
 
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VERSION HISTORY  
This statistical analysis plan (SAP) for Study EFC16295 is based on the protocol dated 
15-May-2020.  
The first participant was enrolled on 22-Mar-2021.  
Table 1 - Major changes in statistical analysis plan  
SAP Version 
Approval Date 
Changes 
Rationale 
1.0 
Current version 
Not Applicable  
Original version 
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1 
INTRODUCTION 
1.1 
STUDY DESIGN 
This is a multinational, multicenter, open-label Phase 3 study of the safety, efficacy and 
pharmacokinetics (PK) of 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 <6 years and 6 to <12 years age cohorts, where participants will receive 
BIVV001 at a dose of 50 IU/kg IV QW for 52 weeks. Approximately 65 participants will be 
enrolled to achieve at least 50 participants (25 participants <6 years of age and 25 participants 6 to 
<12 years of age) completing approximately 52 weeks of treatment to obtain at least 50 exposure 
days (EDs). Enrollment in a planned open-label extension study will be offered to participants 
after completion of this study. 
Day 1
Screening
BIVV001 i.v.
Weekly Prophylaxis
(n=65) 
PTPs <12 years of age with severe hemophilia A
Baseline
Week 4
±7 days
Week 13
±7 days
Week 26
±7 days
Week 39
±7 days
Week 52
±7 days
Week -8 
To Day 1
Safety
FUa
EOS
Abbreviations: EOS = end of study; FU = follow-up; IV = intravenous; PTP = previously treated patient. 
a The safety follow-up call or visit will occur 2 to 3 weeks after the last dose of BIVV001, unless the participant enrolls in the open-label 
extension study. 
All enrolled participants will come in to scheduled visits at Baseline (Day 1), Week 4, Week 13, 
Week 26, Week 39 and Week 52. 
Following a washout period (at least 3 to 4 days, depending on age), the first 24 participants from 
the 2 age cohorts (at least 12 participants <6 years of age and at least 12 participants 6 to 
<12 years of age) will undergo PK sampling after their first dose of BIVV001 (Baseline). 
In addition, participants 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. 
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Statistical Analysis Plan  
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Participants will be offered enrollment in an open-label extension study after completion of this 
study based on eligibility criteria. 
1.2 
OBJECTIVE AND ENDPOINTS  
Table 2 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
• 
To evaluate the safety of BIVV001 in 
previously treated pediatric participants with 
hemophilia A 
• 
The occurrence of inhibitor development (neutralizing 
antibodies directed against FVIII as determined via the 
Nijmegen modified Bethesda assay 
Secondary 
• 
To evaluate the efficacy of BIVV001 as a 
prophylaxis treatment  
• 
Annualized bleeding rate (ABR) (for treated)  
• 
ABR by type and location 
• 
ABR for all bleeding episodes (including untreated 
bleeding episodes)  
• 
Percentage of participants who maintain FVIII activity 
levels over 1%, 3%, 5%, 10%, 15%, and 20% 
• 
To evaluate the efficacy of BIVV001 in the 
treatment of bleeding episodes 
• 
Number of injections and dose of BIVV001 to treat a 
bleeding episode  
• 
Percentage of bleeding episodes treated with a single 
injection of BIVV001 
• 
Assessment of response to BIVV001 treatment of 
individual bleeding episodes based on the International 
Society on Thrombosis and Haemostasis (ISTH) 4-point 
response scale 
• 
Physician’s global assessment (PGA) of participant’s 
response to BIVV001 treatment based on a 4-point 
response scale 
• 
To evaluate BIVV001 consumption for 
prevention and treatment of bleeding episodes 
• 
Total annualized BIVV001 consumption per participant 
• 
To evaluate the effect of BIVV001 prophylaxis 
on joint health outcomes 
• 
Annualized joint bleeding rate (AJBR)  
• 
Target joint resolution at Week 52, based on ISTH criteria  
• 
Change from Baseline to Week 52 in total score and 
domain scores (eg, swelling and strength) assessed by 
the Hemophilia Joint Health Score (HJHS) 
• 
To evaluate the effect of BIVV001 prophylaxis 
on Quality of Life (QoL) outcomes 
• 
Changes in Haemophilia Quality of Life Questionnaire for 
Children (Haemo-QoL) total score and physical health 
domain score from baseline to Week 52 (≥4 years old) 
and via parent proxy version (≥4 years old) 
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Objectives 
Endpoints 
• 
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 
• 
To evaluate the safety and tolerability of 
BIVV001 treatment 
• 
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 
• 
The occurrence of embolic and thrombotic events 
• 
To assess the PK of BIVV001 based on the 
one-stage activated partial thromboplastin 
time (aPTT) and two-stage chromogenic FVIII 
activity assays 
• 
PK parameters including, but not limited to, maximum 
activity (Cmax), elimination half-life (t1/2), total clearance 
(CL), total clearance at steady state (CLss), volume of 
distribution at steady state (Vss), area under the activity 
time curve (AUC), dose-normalized area under the 
activity-time curve (DNAUC), mean residence time 
(MRT), incremental recovery (IR), trough activity (Ctrough), 
time above predefined FVIII activity levels 
Tertiary/Exploratory 
• 
To assess the impact of BIVV001 treatment 
on caregiver- and/or patient-reported clinical 
outcome assessments measurements and 
health resource utilization  
• 
Changes in PROMIS-SF Physical Function measures 
from Baseline to Week 52 (≥8 years old) and via parent 
proxy version (≥ 5 years old) 
• 
Changes in PROMIS Pain Intensity measures from 
Baseline to Week 52 (≥8 years old) and via parent proxy 
version (≥ 5 years old) 
• 
Changes in PROMIS Pediatric-SF Pain Interference 
measures from Baseline to Week 52 (≥8 years old) and 
via parent proxy version (≥ 5 years old) 
• 
Changes in EuroQoL 5-dimension 5-level Youth 
(EQ-5D-Y) from Baseline to Week 52 (≥8 years old) and 
via parent proxy version (4-7 years old) 
• 
Caregiver interviews at Week 52 (or subsequent post-
study follow-up visit) 
• 
Changes in healthcare resource utilization  
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2 
SAMPLE SIZE DETERMINATION  
The determination of the number of participants is based on clinical rather than statistical 
considerations. Taking into consideration the guideline from Committee for Medicinal Products 
for Human Use (EMEA/CHMP/BPWP/144533/2009 rev.2), approximately 65 PTPs will be 
enrolled to obtain at least 50 participants with at least 50 EDs at the end of the study. All eligible 
participants completing or remaining at the end of study will be offered participation in the 
planned extension trial. 
At least 12 participants in each age cohort need to have completed adequate blood sample 
collection to assess key PK parameters. 
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3 
ANALYSIS POPULATIONS  
The following populations for analyses are defined:  
Table 3 - 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 take at least 1 dose of study intervention. 
All analyses of demographics, baseline characteristics, and efficacy will be based on the 
FAS, unless otherwise specified. 
Safety Analysis Set 
The safety analysis is the same as the Full Analysis Set and will include all participants who 
receive at least one dose of study drug.  
All analyses of safety will be based on the Safety Analysis Set, unless otherwise specified. 
Per Protocol Set 
A subset of the Full Analysis Set including participants who do not have important protocol 
deviations potentially impacting efficacy. 
The Per Protocol Set will be utilized for sensitivity analysis of the efficacy endpoint of 
annualized bleeding rate.  
PK Analysis Set (PKAS) 
All participants who have completed adequate blood sample collection to assess key PK 
parameters, as determined by the PK scientist. 
Surgery Subgroup  
All participants who have undergone major surgery after the first dose of study drug. 
 
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4 
STATISTICAL ANALYSES  
All summaries and statistical analyses will be generated using SAS Version 9.0 or higher. 
4.1 
GENERAL CONSIDERATIONS  
Unless otherwise specified, all data will be summarized for each age cohort (<6 years and 6 to 
<12 years) and overall. 
The surgery subgroup will be included in baseline tables as well as the overall AE summary. 
When the surgery subgroup is included in a summary table, participants who participated in the 
surgery subgroup will be included in the columns for age cohort and the surgery subgroup but will 
only be counted once in the overall column. 
Baseline 
Baseline is defined as the last non-missing measurement taken prior to the first dose of study drug, 
excluding measurements taken during a surgical/rehabilitation period. For HJHS, if there are no 
measurements taken prior to the first dose of the drug, and the first measurement is taken no more 
than 7 days after the first dosing, then this first measurement will be considered as baseline for HJHS. 
Study Day 
Study day is defined as the number of days relative to the date of the first dose of study drug. The 
first dose of study drug is Day 1. Study day will be calculated as (date of event – first dose date 
+1) if the date of event is on or after the first dose date or (date of event – first dose date) if the 
date of event is before the first dose date. If the date of event is missing or partial, the 
corresponding study day will be left blank. 
Exposure Day 
One exposure day (ED) is defined as a 24-hour period in which a participant receives 1 or more 
doses of study drug, with the time of the first injection of study drug defined as start of the ED.  
4.1.1 Definition of study periods  
This section defines the study periods used for different analyses, including treatment period, 
efficacy period, surgical/rehabilitation period, and safety period.  
All analyses and summaries relating to bleeding and consumption will be based on the efficacy 
period (Section 4.1.1.2); 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 period (Section 4.1.1.1), excluding data 
that occurs during any major surgical/rehabilitation period to avoid confounding the treatment 
effect. Analysis of efficacy endpoints that are visit-based will not include visits that are 
coincidental with a major surgical/rehabilitation period. 
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Surgical evaluations will be based on the surgical/rehabilitation period (Section 4.1.1.3). 
All safety analyses will be based on the safety period (Section 4.1.1.4). Unless otherwise 
specified, adverse events and laboratory evaluations occurred during major surgical/rehabilitation 
periods will not be included in the safety summaries.  
4.1.1.1 Treatment period  
The treatment period is defined as the actual treatment that the participant follows.  
The start date and time of the treatment period is defined as the date and time of the first dose of 
study drug (or, if the time is not available, at 00:01 on the day of the first dose). The end date and 
time of the treatment period is defined as 23:59 on the day of the last dose of study drug. 
The duration of treatment period is the time period from the start of the treatment period to the 
end of that treatment period. The total duration will be calculated in minutes and converted to 
days as the number of minutes divided by 1440. 
4.1.1.2 Efficacy period  
The efficacy period will be used for the evaluation of bleeding and consumption endpoints. For a 
participant to have an evaluable efficacy period over the duration of study, he/she must have at 
least 2 prophylactic dose of study drugs. The efficacy period is defined as the treatment period 
interrupted for PK periods, surgical/rehabilitation periods (major and minor) and large injection 
intervals as described below. 
Adjustments Due to PK sampling period(s) 
For participants undergoing PK sampling after their first dose of BIVV001, the efficacy period 
starts with the date and time of the first prophylactic dose following the completed PK sampling 
period (168 hours), and ends with the end of the treatment period as defined in Section 4.1.1.1. 
That is, if the initial PK sampling period is incomplete due to an aborted collection of blood 
samples following the PK injection (eg, because of a bleeding episode that required treatment), 
then the efficacy period will begin following a subsequent fully executed PK sampling period. 
Adjustments Due to Surgical/Rehabilitation Periods 
For analysis purposes, the efficacy period will be adjusted for all surgical/rehabilitation periods 
(major and minor). The start and end of the efficacy period are adjusted as follows: 
• For all participants, the efficacy period continues up to 1 minute before the start of a 
surgical/rehabilitation period. 
• For participants on a prophylactic regimen following the end of a surgical/rehabilitation 
period, the efficacy period for the prophylactic regimen re-starts at the first prophylactic 
dose following the end of the surgical/rehabilitation period. 
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Bleeding episodes that occur during the surgical/rehabilitation period will be attributed to the 
surgical/rehabilitation period and hence not counted towards the ABR. 
Adjustments Due to Large Injection Intervals  
For analysis purposes, the efficacy period will also be adjusted to account for large intervals 
between injections resulting from missing data. A large interval is defined as >28 days between 
any 2 adjacent BIVV001 injections within a prophylactic treatment regimen, and any such 
intervals will be removed from the efficacy period. The efficacy period prior to each such interval 
will end at the time of the last injection prior to the interval and restart at the time of the next 
prophylaxis injection. The efficacy period will be adjusted for each identified interval that is not 
within a surgical/rehabilitation period.  
4.1.1.3 Surgical/rehabilitation period  
The broadest span of time for the surgical/rehabilitation period is from the first dose of BIVV001 
given for the surgery (ie, the pre-surgery dose) up to 1 minute before the first regular prophylactic 
dose after the last day of postoperative care/rehabilitation.  
Since not all participants will have these events, specific considerations for the start and end of the 
surgical/rehabilitation period are as follows: 
Start of the surgical/rehabilitation period: 
• If there is more than one pre-surgical dose, then the first one should be selected (a pre-
surgical dose can be administered on the day or the day before surgery). 
• If there is no pre-surgical dose but there was a prophylactic dose, or a dose given for 
“OTHER” reason prior to the surgery on the day of or the day before surgery, then the last 
of these doses should be selected. 
• If there is no pre-surgical dose or no prophylactic dose on the day before surgery, then 
select the start date/time of the surgery. If the time was not recorded, then select the date 
and impute 00:01 for the time. 
End of the surgical/rehabilitation period: 
• If the participant resumed the prophylactic regimen following the surgical/rehabilitation 
period, then the end of the surgical/rehabilitation period is 1 minute before the first regular 
prophylactic dose after the latest date and time among the following (impute 23:59 if time 
is not available): 1) discharge from the hospital, 2) end of perioperative period follow-up 
phone call, and 3) end of a two-week period (one-week for minor surgeries) after the 
resumption of weekly prophylaxis treatment. 
• If the participant did not resume the prophylactic regimen following the 
surgical/rehabilitation period (eg, the participant received no further prophylactic doses), 
then the end of the surgical/rehabilitation period is imputed as 23:59 on the last date 
among the following: 1) discharge from the hospital, 2) end of perioperative period 
follow-up phone call, and 3) end of a two-week period (one-week for minor surgeries) 
after the last surgical dose. 
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• If the overall end of study is declared while the participant is still in the 
surgical/rehabilitation period, then select the date of the end-of-study visit and impute 
23:59 for the time if a time is not provided. 
Two exceptions are noted: 
• If 2 (or more) major surgeries are performed without an intervening discharge from the 
hospital, then the first surgical/rehabilitation period will end 1 minute before the start of 
the next surgery and the second surgical/rehabilitation will end as described above. The 
same will also apply among overlapping minor surgeries. 
• If minor surgery is performed during postoperative care or rehabilitation of a major 
surgery then the surgical/rehabilitation period for the minor surgery will start and end on 
the day of the minor surgery, at 00:01 and 23:59, respectively, if times are not otherwise 
provided or recorded as 00:00. The surgical/rehabilitation period for the major surgery will 
include the minor surgery (ie, the surgical/rehabilitation period for the major surgery does 
not stop and restart around the minor surgery) and will end as otherwise defined. 
The surgical/rehabilitation period will be determined in the same manner for both major and 
minor surgeries. 
4.1.1.4 Safety period  
The safety period is defined as beginning at the first dose of study drug. For participants who 
enroll in the open-label extension study after completion of this study, the safety period ends at 
the end of their treatment period as defined in Section 4.1.1.1. For participants who do not enroll 
in the extension study, the safety period ends at the Safety Follow-up Call or Visit. If the Safety 
Follow-up Call or Visit is missing, then the safety period ends at the last ePD entry, the last study 
visit, or the last documented participant contact, whichever occurs latest.  
4.2 
PARTICIPANT DISPOSITIONS  
Disposition of participants will be summarized using the All-Enrolled Analysis Set. The number 
(%) of participants included in each of the analysis populations listed in Table 3 will be 
summarized by age cohort and overall. The number of participants who completed the study and 
the number of participants who discontinued from the study early, including the primary reason 
for discontinuation, will be tabulated by age cohort and overall. 
Separate summaries of enrollment by country/region and site and the number of participants 
attending each visit will be provided using the All-Enrolled Analysis Set by age cohort and 
overall. Disposition, including date of last visit and reason for early discontinuation, for 
participants who did not complete the study, will be provided in a listing by participant using the 
All-Enrolled Analysis Set. 
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Protocol deviations 
The number of participants with major protocol deviations will be summarized by age cohort and 
overall for the FAS. Major protocol deviations that occurred during a major surgical/rehabilitation 
period will be presented separately in the summary.  
Important protocol deviations impacting efficacy assessment will be identified by the study team 
from the following protocol deviation categories and will be finalized before the database lock: 
• Entered the study even though entry criteria were not satisfied 
• Developed withdrawal criteria during the study but were not withdrawn 
• Received the wrong treatment or incorrect dose 
• Received an excluded concomitant treatment 
• Persistent misuse of the ePD device impacting interpretation of data based on medical 
review 
Important protocol deviations will be summarized by age cohort and overall for the FAS. 
Participants who have at least one important protocol deviation will be excluded from the Per 
Protocol Set. 
4.3 
PRIMARY ENDPOINT ANALYSIS  
4.3.1 Definition of endpoint  
The primary endpoint for this study is the occurrence of inhibitor development, defined as an 
inhibitor result of >0.6 BU/mL that is confirmed by a second test result 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. The date of 
inhibitor development is the date of the sample with the first positive test result which was 
subsequently confirmed by the second sample.  
Results from blood samples collected during surgical/rehabilitation periods for the purpose of 
determining the presence of an inhibitor will be included in this analysis. 
4.3.2 Main analytical approach  
The overall incidence of positive inhibitor formation will be calculated as: 
Number of participants with an inhibitor 
Number of participants reaching ED milestone or who have an inhibitor 
The primary analysis of inhibitor development is based on all participants who have reached at 
least 50 EDs and had at least one inhibitor test performed at or beyond this milestone. For the 
incidence calculation, any participant who develops an inhibitor following the initial BIVV001 
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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 to BIVV001.  
The calculation will also be performed with a denominator that includes all participants with a valid 
inhibitor test following at least 25 EDs to BIVV001 and a denominator that includes all participants 
with a valid inhibitor test, regardless of how many days they were exposed to BIVV001. 
The incidence of positive inhibitor formation will be summarized for each age cohort and overall; 
an exact 95% confidence interval (CI) will be calculated using the Clopper-Pearson method for 
each incidence.  
4.3.3 Supplementary analyses  
The incidence of inhibitor formation will also be analyzed by type of inhibitor. 
• A positive low titer inhibitor is defined as an inhibitor test and confirmatory test, both with 
results of ≥0.60 and <5.00 BU/mL. 
• A positive high titer inhibitor is defined as an inhibitor test and confirmatory test, both 
with results of ≥5.00 BU/mL. 
Participants with discordant 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 third 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. 
In either case, the date of the inhibitor is the date of the sample with the first positive test result. 
Summaries will be provided for participants with high-titer inhibitors and participants with low-
titer inhibitors, separately, as defined above. Similar to the primary analysis, the supplementary 
analyses will be based on all participants who have reached at least 1, 25 and 50 EDs and had at 
least one inhibitor test performed at or beyond this milestone.  
The incidence rates and the corresponding 95% CIs will be provided, for each age cohort and 
overall, using the same method as applied to the primary analysis.  
4.4 
SECONDARY ENDPOINT ANALYSIS  
All secondary efficacy endpoints will be summarized descriptively based on the FAS and 
presented by age cohort and overall, unless otherwise specified.  
All analyses of bleeding endpoints will be based on treated bleeding episodes, except for the 
summary of ABR for all bleeds which will include both treated and untreated bleeds. 
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Analysis of efficacy endpoints that are visit-based will include data from all study visits, whether 
or not in the efficacy period, unless a visit is coincidental with a surgical/rehabilitation period for 
a major surgery, in which case it would be excluded. 
4.4.1 Annualized bleeding rate (ABR)  
4.4.1.1 Definition of endpoint  
Data for bleeding events will be collected by each participant via an ePD or, in the case of bleeds 
occurring and/or treated at the study site, on the eCRF and will include type of bleed, location of 
bleed, and treatment dates, if applicable. This information will be used to derive efficacy 
endpoints on bleeding.  
During the course of the study, the Investigator is given the opportunity to disagree with the 
classification of bleeding episode as given by the caregiver, and the caregiver is subsequently 
given the opportunity to agree or disagree with the reclassification (spontaneous, traumatic, or not 
a bleed). If the caregiver agrees with the Investigator’s assessment, then all analyses of bleeding 
will be based on the Investigator’s determination of the bleeding type, whether or not the change 
was made to the participant’s records.  
Bleeding episodes of an unknown type will be included in the determination of the annualized 
bleeding rate and in summaries based on bleeding episodes but, unless specified otherwise, will 
not be included in summary tables where endpoints are summarized by type of bleed.  
Definition of a bleeding episode (based on treated bleeds) 
All primary analyses of bleeding endpoints will be based on treated bleeds consistent with ISTH 
criteria (1) using the following standardized definition: 
In the analysis of treated bleeds, a bleeding episode starts from the first sign of bleeding and ends 
no more than 72 hours after the last injection to treat the bleed, within which any subsequent 
bleeding at the same location, injections ≤72 hours apart, are considered 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 bleed, taken >72 hours after the preceding one, will be 
considered the first injection to treat a new bleeding episode in the same location. Any subsequent 
bleeding or injection at a different location will be considered a separate bleeding episode, 
regardless of the time from the last injection. 
Annualized bleeding rate 
The ABR for each individual participant is calculated using the following formula:  
ABR = Number of treated bleeding episodes during the efficacy period × 365.25 
Total number of days during the efficacy period 
A bleeding episode is counted in the analysis if it was treated with BIVV001. All types of 
bleeding episodes (spontaneous, traumatic, and type unknown) will be included in determining the 
annualized number.  
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4.4.1.2 Main analytical approach  
The mean and 95% CI of ABR will be estimated using a Negative-Binomial model. The model 
will include number of treated bleeding episodes during the efficacy period as response variable, 
log-transformed duration of efficacy period as offset variable to account for variable duration. 
Individual ABR will also be calculated for each participant and summarized descriptively. The 
summaries will be presented by age cohort and overall for the FAS.  
4.4.1.3 Sensitivity analyses  
Sensitivity analysis of the ABR will also be performed using the Per Protocol Set, as well as using 
the FAS including participants with an efficacy period of at least 26 weeks. 
4.4.1.4 Subgroup analyses  
To assess the homogeneity of the treatment effect across various subgroups, analyses of the ABR 
will be performed across the following subgroups (categories with fewer than 5 participants may 
be combined with other categories): 
• By bleeding phenotype at Baseline (estimated bleeds in prior 12 months, 0, >0-5, >5-10, 
>10) 
• By number of target joints (none present, ≤ median of number present, > median of 
number present) 
• By dosing and dosing interval compliance (<80%, ≥80%) 
The estimated mean ABR and the corresponding 95% CI will be provided, for each subgroup, 
using the same method as applied to the primary analysis. Forest plots will be provided.  
4.4.2 ABR by type and location  
ABR will be summarized descriptively by type and location for the following subsets of treated 
bleeds: 
• Type of bleeding (spontaneous, traumatic, unknown) 
• Location of bleeding (joint, muscle, internal, skin/mucosa)  
• Location and type of bleeding (joint spontaneous, joint traumatic, muscle spontaneous, 
muscle traumatic, internal spontaneous, internal traumatic, skin/mucosa spontaneous, 
skin/mucosa traumatic) 
The estimated mean ABR and the corresponding 95% CI will be provided, for each subset, using 
the same method as specified above. These tables will be presented by age cohort and overall for 
the FAS. 
As a description of the raw data collected in this study, the unadjusted number of bleeding 
episodes per participant will be summarized using categorical (0, 1, 2, 3, 4, 5, and >5) and 
descriptive statistics overall and by bleed type (spontaneous, traumatic, unknown). The number 
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and percentage of participants experiencing a bleeding episode will be summarized categorically 
overall and by type of bleed (spontaneous, traumatic, unknown) as well as by bleed location 
(joint, muscle, internal, skin/mucosa, and unknown) for each bleed type; percentages will be 
based on the number of participants with an efficacy period. The total participant years followed 
during the efficacy period will be provided in order to put the un-annualized numbers in 
perspective. 
4.4.3 ABR based on all bleeding episodes   
ABR will be summarized for all bleeds (treated and untreated) by age cohort and overall. All 
types of bleeding episodes (spontaneous, traumatic, and unknown) will be included, regardless of 
whether treatment was used or not. The estimated mean ABR and the corresponding 95% CI will 
be provided, using the same method as described in Section 4.4.1.2. 
Definition of a bleeding episode (based on all bleeds) 
The definition of all bleeds will follow the ISTH criteria, accounting for both treated and 
untreated bleeds, based on the date and time of the bleed as follows: 
In the analysis of all bleeds, a bleeding episode starts from the first sign of a bleed (treated and 
untreated) and ends no more than 72 hours after the last injection to treat the bleed or the last 
untreated bleed at the same location, within which any sign of bleeding (treated and untreated) at 
the same location, injections ≤72 hours apart, are considered the same bleeding episode.  
Any injection or untreated bleed, occurring >72 hours after the preceding one, will be considered 
the start of a new bleeding episode. Any subsequent injection or untreated bleed at a different 
location will be considered a separate bleeding episode, regardless of the time from the last 
injection or bleed.  
4.4.4 Percentage of participants who maintain FVIII activity levels  
The number and percentage of participants achieving steady-state trough FVIII activity levels 
above 1%, 3%, 5%, 10%, 15%, and 20% will be summarized by age cohort and overall. 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 aPTT-based one-stage assay and chromogenic assay. Participants with trough samples 
that are outside 168 +/-5 hours from the previous dose will be excluded from this analysis. 
4.4.5 Number of injections and dose of BIVV001 to treat a bleeding episode  
The number of injections and total dose of BIVV001 (IU/kg) to treat a bleeding episode will be 
determined on both a per-bleeding episode and per-participant basis. A bleeding episode is 
considered resolved when treatment for the bleeding is no longer needed. 
Per bleeding episode: The total number of injections will consider all injections, including initial 
and follow-up injections, in a bleeding episode. The total dose of BIVV001 will be the sum of 
these doses. The number of injections to treat a bleeding episode will be summarized across all 
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bleeding episodes both categorically (1, 2, 3, 4, >4; 1, >1; and ≤2, >2) and with descriptive 
statistics. The total dose of BIVV001 used to treat a bleeding episode will be summarized using 
descriptive statistics. 
Per participant: The number of injections and total dose of BIVV001 to treat each bleeding 
episode, as determined for the per-bleeding episode summaries, will be averaged across all 
bleeding episodes for each participant. The average number of injections required for resolution of 
a bleeding episode will be summarized both categorically (1 to <2, 2 to <3, 3 to <4, and ≥4; and 
1 to <2, ≥2) and with descriptive statistics. The averages for the per-participant total dose of 
BIVV001 used to treat a bleeding episode will be summarized using descriptive statistics. 
4.4.6 Percentage of bleeding episodes treated with a single injection of BIVV001  
The number and percentage of bleeding episodes treated with a single injection of BIV001 will be 
determined on a per-bleeding episode basis. The number and percentage of bleeding episodes 
treated with a single injection of BIVV001 will be summarized by age group and overall for the 
FAS. 
4.4.7 Assessment of response to BIVV001 treatment of bleeding episodes  
Participants will provide an assessment of response to each injection of BIVV001 for treating a 
bleed using a 4-point scale of excellent, good, moderate, and none, based on ISTH standardized 
definitions in hemophilia (1). Response categories of excellent and good will be presented 
combined as well as individually.  
The assessment of response will be summarized first on a per injection basis. The number and 
percentage of injections in each response category will be tabulated based on all injections; 
percentages will be based on the total number of injections for treating a bleed for which a 
response was provided.  
As a supplemental analysis, the assessment of response will also be summarized on a per bleeding 
episode basis by presenting the number and percentage of first injections to treat a bleeding 
episode for which the response to the treatment was categorized as excellent, good, moderate, or 
no response. Percentages will be based on the number of bleeding episodes for which a response 
was provided for the first injection. 
The participant’s assessment of response during the efficacy period will be summarized by age 
cohort as well as overall for the FAS. 
4.4.8 Physician’s global assessment of participant’s response to BIVV001 treatment  
The physician’s global assessment of the participant’s response to BIVV001 treatment will be 
summarized by age cohort and overall for each study visit as the number and percentage of 
participants classified as excellent, effective, partially effective, and ineffective. Percentages will 
be based on number of participants for whom an assessment was provided at the respective visit. 
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This table will also include a cumulative tabulation across all scheduled study visits; participants 
can be included in this tabulation once for each visit. Percentages for this collection of responses 
throughout the study will be based on the total number of assessments across all visits.  
4.4.9 Annualized BIVV001 consumption  
The consumption of BIVV001 will be annualized and summarized by age cohort and overall for 
the FAS. The total annualized BIVV001 consumption (IU/kg) will be calculated for each 
participant using the following formula: 
Annualized consumption = 
Total IU/kg of BIVV001 during the efficacy period × 365.25 
Total number of days during the efficacy period 
The total amount of BIVV001 received will be the sum of the nominal IU/kg administered for 
each injection based on the units of BIVV001 as recorded from the participant’s ePD and eCRF 
and the participant’s most recent weight.  
Total annualized BIVV001 consumption will be determined for the efficacy period, ie, excluding 
the PK assessments and surgery/rehabilitation periods (major or minor).  
4.4.10 Annualized joint bleeding rate  
The annualized joint bleeding rate (AJBR) will be summarized descriptively by age cohort and 
overall as described in Section 4.4.1.  
4.4.11 Target joint resolution  
Participants will be assessed for target joints at screening by the investigator. 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. Resolution is achieved when 
≤2 bleeds occur into that joint during 12 months of continuous exposure (1).  
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 per age cohort and overall. 
Determination of resolution will be based on the number of spontaneous bleeding episodes into 
that joint as well as based on the number of total bleeding episodes into that joint (regardless of 
type). In this analysis, only participants who have at least 12 months of exposure (defined as 
duration of dosing ≥52 weeks) to BIVV001 will be included. Target joints on which surgery was 
performed on or before the end of the participant’s 12 months of exposure will be censored.  
4.4.12 Hemophilia Joint Health Score  
Hemophilia Joint Health Score (HJHS) is a functional measure of joint health using ankle, knee 
and elbow (to access flexion, extension, range of movement, muscle strength, swelling, duration 
of swelling, crepitus, gait, pain, and muscle atrophy). The assessment is administered by a 
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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 
used in children aged ≥4 years at Baseline, Week 26 and Week 52. Details of the questionnaire are 
provided in protocol Appendix 6 (Section 10.7.3).  
Table 4 - HJHS domains  
Range 
Left 
elbow 
Right 
elbow 
Left 
knee 
Right 
knee 
Left 
ankle 
Right 
ankle 
Domain 
total 
Swelling 
0-3 
0-3 
0-3 
0-3 
0-3 
0-3 
0-18 
Duration 
0-1 
0-1 
0-1 
0-1 
0-1 
0-1 
0-6 
Muscle Atrophy 
0-2 
0-2 
0-2 
0-2 
0-2 
0-2 
0-12 
Crepitus on motion 
0-2 
0-2 
0-2 
0-2 
0-2 
0-2 
0-12 
Flexion loss 
0-3 
0-3 
0-3 
0-3 
0-3 
0-3 
0-18 
Extension loss 
0-3 
0-3 
0-3 
0-3 
0-3 
0-3 
0-18 
Joint pain 
0-2 
0-2 
0-2 
0-2 
0-2 
0-2 
0-12 
Strength 
0-4 
0-4 
0-4 
0-4 
0-4 
0-4 
0-24 
Joint Total 
0-20 
0-20 
0-20 
0-20 
0-20 
0-20 
 
The HJHS assessment includes the scoring of six joints (left ankle, right ankle, left elbow, right 
elbow, left knee, and right knee) on a scale from 0 to 20 according to the following criteria: 
swelling, duration of swelling, muscle atrophy, crepitus of motion, flexion loss, extension loss, 
joint pain, and strength (Table 4). Gait will be scored on a scale from 0 to 4 based on the number 
of skills that are not within the normal limits. The total score will be the sum of scores from all six 
joints plus the gait score (range from 0 to 124, with 0 being normal and 124 being the most severe 
disease).  
The total joint score (ie, sum of scores from all six joints) will be defined and derived as follows: 
• The total joint score will be set as missing if any one of the individual item score at any 
joint is missing; 
• The total joint score will be set as missing if scores are evaluated within 2 weeks after a 
joint or muscle bleeding episode; and 
• The total joint score will be re-derived if surgery is performed on a joint. The scores for 
that joint will be replaced with the scores of the same joint at the last visit prior to the 
surgery using the last observation carried forward (LOCF) technique. Then, the total joint 
score in the subsequent visits are re-derived using the abovementioned scores.  
The individual domain score (ie, sum of scores from all six joints for each domain) will be 
calculated using the same rules as above for all domains. 
The total joint score, gait scores, and total score (calculated as the sum of total joint score and gait 
score), as well as change from baseline will be summarized by age cohort and overall. In addition, 
individual domain scores and change from baseline will be summarized by age cohort and overall.  
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4.4.13 Haemo-QoL (≥4 years old)  
Four HAEMO-QoL questionnaires are used in this study and administered at Baseline, Weeks 26 
and 52. Details of the questionnaires are provided in protocol Appendix 6 (Section 10.7.5.2).  
• Haemo-QoL kids short version (4-7 years) 
• Haemo-QoL kids short version (8 to <12 years) 
• Haemo-QoL parent proxy short version (for participants 4-7 years)  
• Haemo-QoL parent proxy short version (for participants 8 to <12 years) 
Each HAEMO-QoL questionnaire for 4-7 years will be summarized by calculating a total score, 
and each questionnaire for 8 to <12 years will be summarized in terms of subscale scores and a 
total score according to the recommendations of the questionnaire authors. As specified in 
Appendix 5.2 Haemo-Qol (Section 5.5.2), questions will either have been coded or will be re-
coded to ensure that high scores represent a low quality of life and low scores represent a high 
quality of life. These scores are then transformed to produce a Transformed Scale Score (TSS). 
This score is scaled, as a percentage, from 0 to 100%, with higher TSS values representing a 
worse quality of life for each sub-score and total score summary measurement.  
When missing data are presented, a subscale/total score can only be calculated if at least 50% of 
questions for that subscale/questionnaire are answered (non-missing and not “Not Applicable”).  
For each HAEMO-QoL questionnaire, the total score and individual subscale scores based on the 
TSS will be summarized descriptively for the actual value and change from baseline by visit for 
each age cohort and overall.  
4.4.14 Surgery endpoints   
An overall summary of surgeries will be provided which summarizes the number of major and 
minor surgeries and (%) of participants with at least one major surgery and (%) of participants 
with at least one minor surgery. 
All major and minor surgeries in detail will be provided in the data listings. 
4.4.14.1 Investigators’ or Surgeons’ assessment of participant’s hemostatic response to 
BIVV001 treatment  
The Investigators’/Surgeons’ assessment of the participant’s hemostatic response to BIVV001 
treatment will be collected at 24 hours post-surgery based on the ISTH 4-point response scale and 
will be summarized categorically and using descriptive statistics for all major surgeries for 
participants in the surgery subgroup. Categorically, the number and percentage of surgeries given 
each rating will be tabulated. Percentages will be based on the number of surgeries for which a 
response was provided. Since the response is given as an ordered ordinal scale, the responses have 
also been given a numeric score (Excellent=1, Good=2, Fair=3, Poor/none=4). A lower average 
score indicates a better Investigators’/Surgeons’ assessment of the participants’ response to 
surgery with BIVV001 treatment. Descriptive statistics will be provided using the numeric value 
of the 4-point scale. 
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4.4.14.2 Number of injections and dose to maintain hemostasis for major surgery 
The number of injections, mean dose per injection (IU/kg), and total dose (IU/kg) required to 
maintain hemostasis during surgery will be summarized for all major surgeries for participants in 
the surgery subgroup. The number of injections per surgery will be summarized categorically 
(0, 1, 2, 3, 4, >4) and with descriptive statistics. Percentages for the categorical summary will be 
based on the number of major surgeries. The mean dose per injection and total dose required to 
maintain hemostasis will be summarized using descriptive statistics. The mean dose per injection 
will be determined as the average dose across all injections per major surgery (including the 
loading dose); the total dose will be determined as the sum across all injections (including the 
loading dose) per major surgery. 
4.4.14.3 Total BIVV001 consumption for major surgery 
Total consumption (IU/kg) per major surgery on the day of surgery, for the first 2 weeks 
following surgery (Days 1-3, 4-14, and 1-14), and for the overall surgical/rehabilitation period 
will be summarized using descriptive statistics for all major surgeries for the surgery subgroup. 
The day of surgery refers to the calendar day of the surgery and includes the loading dose given 
for that surgery. The first 2 weeks following surgery begins the day after surgery and extends for 
14 calendar days. The overall surgical/rehabilitation period is defined in Section 4.1.1.3. Total 
BIVV001 consumption will be determined as the sum of all doses administered during the 
referenced time periods. 
4.4.14.4 Number and type of blood component transfusions for major surgery 
The number of transfusions per surgery (regardless of the type of transfusion), the number of 
transfusions summed across all surgeries for each type of transfusion, and the number of 
surgeries requiring each type of transfusion will be summarized categorically for all major 
surgeries for the surgery subgroup. Percentages in the categorical summaries will be based on the 
number of major surgeries for which the respective data is available. 
4.4.14.5 Estimated blood loss for major surgery 
The estimated total blood loss during and post each major surgical procedure will be summarized 
using descriptive statistics for all major surgeries for the surgery subgroup. 
4.5 
EXPLORATORY ENDPOINTS ANALYSES  
4.5.1 PROMIS instruments 
Six PROMIS instruments are used in this study and administered at Baseline, Weeks 26 and 52. 
Details for each instrument are provided in protocol Appendix 6 (Section 10.7.5.1). 
•
PROMIS Pediatric NRS Pain Intensity (v1.0 Pain Intensity 1a; ≥8 years old)
•
PROMIS Pediatric-SF Pain Interference (v2.0 Pain Interference 8a; ≥8 years old)
•
PROMIS Pediatric-SF Physical Activity (v1.0 Physical Activity 8a; ≥8 years old)
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• PROMIS Parent Proxy NRS Pain Intensity (v1.0 Pain Intensity 1a; 5 to <12 years old)  
• PROMIS Parent Proxy-SF Pain Interference (v2.0 Pain Interference 8a; 5 to <12 years old) 
• PROMIS Parent Proxy-SF Physical Activity (v1.0 Physical Activity 8a; 5 to <12 years 
old) 
The two PROMIS instruments on pain intensity each uses an 11-point Numeric Rating Scale 
(NRS) ranging in value from 0 to 10, with 0 indicating no pain and 10 indicating worse pain. The 
NRS will be summarized descriptively for the actual value and change from baseline by visit for 
each age cohort and overall.  
For each of the other four PROMIS instruments, each question has five response options ranging 
in value from one to five. To find the total raw score for an instrument with all questions 
answered, sum the values of the response to each question. All questions must be answered in 
order to produce a valid total score. The total raw score is then converted into a T-score for each 
participant using an instrument-specific Conversion Table (see APPENDIX 5.1 PROMIS 
instruments [Section 5.5.1]). The T-score rescales the raw score into a standardized score with a 
mean of 50 and a standard deviation (SD) of 10. Therefore, a person with a T-score of 40 is one 
SD below the mean. 
A higher PROMIS T-score represents more of the concept being measured. For negatively-
worded concepts like Pain Intensity and Pain Interference, a T-score of 60 is one SD worse than 
average. By contrast, for positively-worded concepts like Physical Function and Physical Activity, 
a T-score of 60 is one SD better than average. 
T-scores for each of the four PROMIS instruments will be summarized descriptively for the actual 
value and change from baseline by visit for each age cohort and overall.  
4.5.2 EuroQoL-Youth (EQ-5D-Y)  
The EuroQol-5D-Youth (EQ-5D-Y) and its parent proxy version will be used for children aged 
8 to <12 years and children aged 4-7 years, respectively, at Baseline, Weeks 26 and 52. Both 
instruments consist of 3 pages: the title page, the EQ-5D-Y descriptive system and the EQ visual 
analogue scale (VAS). A copy of the questionnaires is provided in protocol Appendix 6 
(Section 10.7.5.3). 
Both the EQ-5D-Y children and parent proxy versions will be analyzed according to the 
recommendations of the authors (see www.euroqol.org). The descriptive system contains 
5 dimensions (mobility, looking after myself, doing usual activities, having pain or discomfort, 
feeling worried, sad or unhappy), each with 3 response categories (no problems, some problems, 
and a lot of problems). The number and percentage of participants in each response category will 
be tabulated by age cohort and overall. Percentages are based on the number of participants for 
whom an assessment is provided at the respective visit.  
The EQ visual analogue scale is a visual scale from 0-100 to record a respondent’s overall self-
rated health state. The respondent is asked to mark an “X” on the scale then record the 
corresponding number; 0 refers to the worst possible health state, 100 refers to the best possible 
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health state. The EQ VAS will be summarized for the observed response and change from 
baseline by visit for each age cohort and overall. 
4.5.3 Caregiver interviews  
The caregiver interviews data is not the scope of this SAP and will be analyzed in a separate 
report. 
4.5.4 Healthcare resource utilization (HRU)  
The number (0, 1-2, 3-4, >4) and percentage of healthcare visits by type (office visit, hospital ER 
visit, hospitalization, and ICU stay) will be summarized by-visit and age cohort and overall for the 
FAS. 
4.6 
MULTIPLICITY ISSUES  
All analyses are descriptive in nature and therefore adjustments for multiplicity will not be 
applied.  
4.7 
SAFETY ANALYSES  
The summary of safety results will be presented by age cohort as well as overall for the Safety 
Analysis Set. The analysis of the safety variables will be essentially descriptive, and no systematic 
testing is planned. 
4.7.1 Extent of exposure  
The extent of exposure and compliance will be assessed and summarized by age cohort and 
overall. In addition, study drug administered will be listed by participant including the reason for 
administration, date and time of administration, and dose. A listing of lot numbers and nominal 
potency of the lots will be provided by participant.  
Except for PK doses, the unit body weight dose (IU/kg) for analysis of dosing will be calculated 
as the total IU (nominal dose) for each injection divided by the participant’s most recent weight in 
kg prior to the dose of study drug. 
PK doses are calculated using the actual potency of the vial (between 80% to 125% of nominal 
strength) and used partial vials where necessary. Therefore, PK doses in the analysis are similarly 
calculated using the exact number of complete and partial vials, the volume and actual potency of 
each vial and the participant’s most recent weight: 
Dose (IU/kg) = ( Total volume administered ) × Actual Potency of Vial 
Volume of vial 
Weight (kg) 
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4.7.1.1 Overall exposure  
The extent of investigational medicinal product (IMP) exposure will be assessed by the number of 
injections and exposure days to BIVV001 and duration of BIVV001 dosing based on the Safety 
Analysis Set.  
Number of Injections and Exposure Days to BIVV001 
For any participant, the total number of days of exposure to BIVV001 will be accumulated from 
the time of their first on-study injection of BIVV001. An ED is a 24-hour period in which one or 
more BIVV001 injections are given. The 24-hour window starts from the first injection on study 
and then for subsequent injections, it starts from an injection taken after/outside of a previously 
identified ED. 
The total number of EDs on BIVV001 for each participant will be summarized categorically 
(<5, 5-<10, 10-<25, 25-<50 and ≥50; and ≥1, ≥5, ≥10, ≥25, ≥50) and with descriptive statistics for 
the Safety Analysis Set.  
The total number of injections per participant will be summarized overall and by reason for 
injection (prophylactic regimen, spontaneous bleed, traumatic bleed, follow-up injection, surgical 
or other) using descriptive statistics for the Safety Analysis Set. 
Duration of BIVV001 Dosing 
The duration of BIVV001 dosing will be calculated from the start date time of the treatment dose 
to the end date time, as defined in Section 4.1.1.1. Any interruptions to dosing will not be 
accounted for when calculating this duration. 
Duration of BIVV001 dosing (weeks) will be summarized using descriptive statistics for the 
Safety Analysis Set. Weeks will be represented in the descriptive statistics as if these were data 
collected with 1 decimal place. The number and percentage of participants whose duration of 
dosing was at least 13, 26, 39, and 52 weeks will be summarized. 
4.7.1.2 Compliance  
Compliance will be assessed during the efficacy period and will be summarized for the FAS by 
age cohort and overall. Except for doses administered in the clinic, study treatment may be 
administered by the participant or a caregiver. Data from the eCRF and ePD will be considered 
for the analysis of treatment received and participants’ compliance with the study protocol.  
Compliance of prophylaxis injections 
The compliance rate of each participant during the efficacy period will be calculated in 2 ways: 
As dose compliance and as dosing interval compliance. Compliance will first be determined on a 
per-injection basis and then on a per-participant basis. That is, compliance for an individual dose 
or dosing interval will be determined and then the overall percentage of doses and dosing intervals 
that were in compliance will be determined for each participant. 
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For the purpose of evaluating compliance, the following will be considered per injection: 
• The nominal dose taken compared to the study dose (50 IU/kg for prophylaxis treatment) 
• The actual day of treatment compared to the study day of treatment (weekly for 
prophylaxis treatment) 
An individual dose will be considered compliant if it is within 80%-125% of the study dose 
(50 IU/kg). An individual dosing interval will be considered compliant if the time between two 
prophylactic doses is within 36 hours of the study dosing interval (7 days).  
The actual dosing intervals will be calculated as the length of time between consecutive 
prophylactic doses that are not separated by a bleeding episode or surgical/rehabilitation period 
(date / time of dosex+1 – date / time of dosex). The actual time between doses will be determined in 
minutes and converted to days as the number of minutes divided by 1440. The absolute value of 
the difference between the actual dosing interval and the study dosing interval of 7 days must be 
≤1.5 day (+/-36 hours) in order to be compliant.  
All prophylactic injections will be used to determine prophylactic dose compliance; only the 
prophylactic dosing intervals that are not separated by a bleeding episode or surgical/rehabilitation 
period will be used to evaluate prophylactic interval compliance. Large injection intervals as 
defined in Section 4.1.1.2 will be included in the interval compliance calculation. Dose and dosing 
interval compliance rates per participant will be determined as follows: 
Dose compliance rate = 
Number of doses taken within 80%-125% 
of study dose 
× 100 
Total number of doses 
where the percentage of a study dose is calculated as: (nominal dose taken / study dose) × 100. 
Dose interval compliance rate = 
Number of doses taken within +/-36 hours of 
study day/time 
× 100 
Total number of intervals 
Both participant dose and dosing interval compliance rates will be summarized as continuous 
variables using descriptive statistics as well as categorically (<80%, ≥80%) for the FAS. 
A participant is considered “dose compliant” or “dosing interval compliant” if his respective rate 
is at least 80%. Based on this, participants will be further classified into the following mutually 
exclusive categories for overall compliance to their prophylactic treatment as: 
• Both dose and interval compliant 
• Dose compliant or interval compliant (but not both) 
• Neither dose nor interval compliant 
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Compliance of ePD contemporaneous data entry 
Injections (for prophylaxis or a bleed) and untreated bleeds must be entered into the ePD within 
7 days from the date of the injection or the untreated bleed. Injections or untreated bleeds entered 
outside the 7-day window will be reported as protocol deviations. Descriptive statistics of the 
percentage of the participants with fewer than 80% of their total individual ePD records entered 
within this 7-day window and those with ≥80% of records meeting this criterion will be presented 
for the FAS as well as a summary of % compliance to this criterion by participant. 
4.7.2 Adverse events  
General common rules for adverse events 
Summaries of adverse events will be presented by age cohort as well as overall for the Safety 
Analysis Set.  
All adverse events will be coded using the version of Medical Dictionary for Regulatory 
Activities (MedDRA) in effect at Sanofi at the time of database lock.  
The primary focus of adverse event reporting will be on treatment-emergent adverse events 
(TEAEs). TEAEs are AEs that developed, worsened or became serious during the treatment-
emergent period. Pretreatment adverse events will be listed separately.  
An AE with incomplete or missing date/time of onset (occurrence, worsening, or becoming 
serious) will be classified as a TEAE unless there is definitive information to determine it is a 
pre-treatment AE. Details on classification of adverse events with missing or partial onset dates 
are provided in Appendix 3 (Section 5.3). 
TEAEs that occurred during major surgical/rehabilitation periods will be included in the overall 
(top-line) summary of TEAEs but not in any of the other TEAE tables. The exception to this rule 
is that TEAEs occurring during a major surgical/rehabilitation period with an onset date on the 
day the surgical/rehabilitation period starts or on the day of the surgery (whichever comes earlier) 
will be included in the TEAE summaries. Consideration is given to AEs with an onset date at the 
start of the surgical/rehabilitation period in the event the pre-surgical dose was administered the 
day before the surgery.  
TEAE incidence tables will present by system organ class (SOC) and preferred term (PT).  
Listings will be provided for all AEs, SAEs, AEs resulting in discontinuation of study treatment 
and/or from the study, and deaths. AEs that are emergent prior to the first BIVV001 treatment, 
AEs that are emergent during a major or minor surgical/rehabilitation period, and AEs that are 
emergent on the day the major surgical/rehabilitation period starts will be flagged.  
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Analysis of all adverse events 
Overall summary of treatment-emergent adverse events 
An overall (top-line) summary of TEAEs will be provided which summarizes number of TEAEs, 
treatment-emergent serious adverse events (TESAEs) and treatment emergent adverse events of 
special interest (TEAESI) and (%) of participants with any: TEAE, related TEAE, TESAE, related 
TESAE, TEAESI, related TEAESI, TEAE leading to death, and TEAE leading to treatment 
discontinuation. 
Analysis of all treatment-emergent adverse events 
The following TEAE summaries will be generated for the safety population. 
• TEAEs by SOC and PT 
• TEAEs by PT in descending order of incidence 
• TEAEs by relationship, presented by SOC and PT. AEs with a missing relationship will be 
counted as “Related” in the summary table, as described in Appendix 3 (Section 5.3). 
A participant will be counted once for each SOC and PT based on the highest relationship 
within that SOC and PT, respectively. 
• TEAEs by maximal severity, presented by SOC and PT. AEs with a missing severity will 
be counted as “Severe” in the summary table, as described in Appendix 3 (Section 5.3). 
A participant will be counted once for each SOC and PT based on the greatest severity 
within that SOC and PT, respectively. 
Analysis of all treatment emergent serious adverse event(s) 
• TESAEs by SOC and PT 
• TESAEs by PT in descending order of incidence 
• TESAEs by relationship and SOC and PT 
Analysis of all treatment emergent adverse events of special interest 
• TEAESIs by SOC and PT  
• TEAESIs by relationship and SOC and PT 
Analysis of all treatment-emergent adverse event(s) leading to treatment discontinuation 
• TEAEs leading to treatment discontinuation, by SOC and PT 
Analysis of treatment-emergent adverse event(s) occurring during a major or minor 
surgical/rehabilitation period 
• All TEAEs occurring during a major or minor surgical/rehabilitation period will be 
provided in a listing. The following categories will be flagged separately: 
- 
TEAEs occurring during a major surgical/rehabilitation period, excluding AEs with an 
onset date on the day the surgical/rehabilitation period starts  
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- 
TEAEs occurring during a major surgical/rehabilitation period with an onset date on 
the day the surgical/rehabilitation period starts 
- 
TEAEs occurring during a minor surgical/rehabilitation period 
Subgroup analysis  
- 
All TEAEs will also be provided by demographic factors including: race (White, 
Black, Asian, Other), geographic location (Asia/Pacific, Europe, North America) 
Analysis of deaths 
A listing of AEs with an outcome of death will be provided.  
Embolic and Thrombotic Events 
The occurrence of embolic and thrombotic events will be described by age cohort and overall. 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 following definition: 
• 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 
(2) 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 (3) and 
will not be included as part of medical adjudication 
4.7.3 Additional safety assessments  
By-visit summaries of laboratory variables and vital signs will be presented by age cohort and 
overall for the Safety Analysis Set. Shifts and potentially clinically significant laboratory 
abnormality (PCSA) summaries will be presented by age cohort and overall for the Safety 
Analysis Set.  
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4.7.3.1 Laboratory variables  
Blood samples for clinical laboratories will be taken at all scheduled visits. Clinical laboratory 
values will be analyzed after conversion into standard international units; international units will 
be used in all listings and tables. Data collected at local laboratories will be only included in the 
PCSA analysis and listing, and shift summary. 
The laboratory parameters will be classified as follows:  
• Hematology  
- 
Red blood cell (RBC) count 
- 
White blood cell (WBC) count and differential 
- 
Hemoglobin (Hgb) 
- 
Hematocrit (HCT) 
- 
Platelet count 
• Clinical chemistry  
- 
Alanine aminotransferase (ALT) 
- 
Aspartate aminotransferase (AST) 
- 
Alkaline phosphatase (ALP) 
- 
Gamma glutamyl transferase (GGT) 
- 
Bilirubin 
- 
Blood Urea Nitrogen (BUN) 
- 
Creatinine 
- 
Glucose  
- 
Total protein 
- 
Potassium 
- 
Sodium 
- 
Chloride 
• von Willebrand Comprehensive panel 
- 
VWF ristocetin cofactor activity 
- 
VWF antigen 
All laboratory evaluations will be summarized for the Safety Analysis Set. Laboratory evaluations 
taken during major surgical/rehabilitation periods will not be included in the summaries. In the 
event of retests or repeat assessments at the same time point, the last non-missing evaluable 
measurement will be used for the purpose of analysis. Laboratory values of the form “<x” 
(ie, below the lower limit of quantification [LLOQ]) or “>x” (ie, above the upper limit of 
quantification [ULOQ]) will be imputed as “x” in the calculation of summary statistics but 
displayed as “<x” or “>x” in the listings. 
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Change from baseline 
The summary statistics (including number, mean, median, standard deviation, minimum and 
maximum) of all laboratory variables (central laboratory values and changes from baseline) will 
be calculated for each visit by age cohort and overall.  
Shifts 
Each participant’s laboratory values will be classified according to whether the test result is “low” 
(below the lower limit of normal [LLN]), “normal” (within the normal range), or “high” (above 
the upper limit of normal [ULN]). Shift tables will be constructed based on both the minimum and 
maximum post baseline values for each participant. Data collected from unscheduled visits will be 
included in the determination of the per participant minimum and maximum values.  
A separate table will be provided which summarizes the results of the shift tables in which the 
number and percentage of participants with a shift to low (from normal, high, or unknown) and 
the number of participants with a shift to high (from normal, low, or unknown) will be tabulated; 
percentages will be based on the number of participants at risk. The number at risk for a shift to 
low (high) is the number of participants whose baseline value was not low (high), including 
unknown, who had at least one post-baseline value. Only directions of change indicating a clinical 
concern will be included in this table summarizing the shifts. The direction of concern is provided 
in Table 5. 
Table 5 - Direction of change indicating clinical concern for laboratory tests  
Laboratory test  
Direction 
Laboratory test  
Direction 
Chemistry 
Hematology 
Liver 
 
White blood cells 
Low and High 
ALP 
High 
Lymphocytes 
Low and High 
ALT/SGPT 
High 
Neutrophils 
Low and High 
AST/SGOT 
High 
Monocytes 
Low and High 
Total bilirubin 
High 
Eosinophils 
Low and High 
GGT 
High 
Basophils 
Low and High 
Renal 
 
Red blood cells 
Low and High 
Blood urea nitrogen 
High 
Hemoglobin 
Low and High 
Creatinine 
High 
Hematocrit 
Low and High 
Electrolytes 
 
Platelets 
Low and High 
Sodium 
Low and High 
 
 
Potassium 
Low and High 
Coagulation 
Chloride 
Low and High 
VWF antigen 
Low 
Other 
 
VWF:RCo activity 
Low 
Glucose 
Low and High 
 
 
Total protein 
Low and High 
 
 
 
 
 
 
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Potentially Clinically Significant Laboratory Abnormalities 
Abnormal laboratory values will also be evaluated by determining the number and percentage of 
participants with at least one PCSA over the course of the study that also represents a worsening 
from baseline. The PCSA values are defined as abnormal values considered medically important 
by the Sponsor according to predefined criteria/thresholds based on literature review and defined 
by the Sponsor for clinical laboratory tests and vital signs (APPENDIX 4 [Section 5.4]). 
Participants who have a post baseline laboratory value that meets the criteria for being potentially 
clinically significant but do not have a baseline value will be included in the numerator for 
determining the percentage of participants with an abnormality. Percentages will be based on the 
number of participants with at least one post baseline value for the given laboratory test. Data 
collected from unscheduled visits will be included in this analysis. 
4.7.3.2 Vital signs and physical examination  
Vital signs will be taken at Baseline, Weeks 4, 26 and 52. Vital signs include temperature, pulse 
rate, respiratory rate and blood pressure. All vital sign evaluations will be summarized for the 
Safety Analysis Set. Data from unscheduled visits and vital sign measurements taken during 
major surgical/rehabilitation periods will not be included in any summary but will be included in 
the listings and flagged.  
Change from baseline 
The summary statistics (including number, mean, median, standard deviation, minimum and 
maximum) of all vital sign variables (and changes from baseline) will be calculated for each visit 
by age cohort and overall for the Safety Analysis Set. Evaluations taken during major 
surgical/rehabilitation periods will not be included in any summary.  
Potentially Clinically Significant Vital Sign Abnormalities (PCSA) 
Frequencies and percentages of participants with potentially clinically significant abnormalities 
will be summarized by age cohort and overall. Percentages will be based on the number of 
participants with a baseline and at least one post baseline value. Vital sign abnormality thresholds 
are defined in APPENDIX 4 (Section 5.4). 
All physical examination findings are presented in a by-participant data listing. 
4.8 
OTHER ANALYSES  
4.8.1 Pharmacokinetic analyses  
All PK analyses will be performed based on the PK analysis set (PKAS). 
If a repeat PK profile is required due to bleeding (or other reason) during the PK evaluations, then 
only the repeat profile will be used for the summary of the FVIII activity levels and in the analysis 
of PK summary parameters. Data from incomplete profiles will be included in data listings. 
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Actual sampling times, doses, and injection durations will be used for PK analysis. Nominal 
sampling times and doses will be used for the creation of tables, figures and listings.  
FVIII activity values for each timepoint will be corrected for baseline activity at Day 1 using the 
residual decay function. The detailed methodology used to correct baseline activity will be 
provided either in the clinical study report or PK report. PK parameters will be computed using 
baseline corrected FVIII activity values. 
PK parameters will be estimated using FVIII activity values measured by aPTT-baseline one-
stage clotting assay, and values measured by chromogenic coagulation assay. 
For participants undergo PK sampling at Day 1, for each participant using noncompartmental 
methods the following pharmacokinetic parameters will be included but not limited to: maximum 
FVIII activity (Cmax), terminal half-life (t1/2), total clearance (CL), clearance at steady state 
(CLss), volume of distribution at steady state (Vss), area under the plasma FVIII activity-time 
curve from time zero to end of dosing period (AUC0-tau), dose-normalized area under the activity-
time curve (DNAUC), mean residence time (MRT), incremental recovery (IR), trough activity 
(Ctrough) and time to 1% FVIII activity level. 
The detailed methodology for computing PK parameters using noncompartmental method will be 
described in the CSR or PK report. The detailed methodology for computing PK parameters using 
population PK method will be described in the population PK report. 
The population PK analysis will be presented separately from the main CSR. Population PK 
analysis will be described fully in the population PK analysis plan and will be finalized before 
database lock. 
For the PKAS the following analyses will be performed: 
• For each assay type, a summary table of FVIII activity levels will be provided for 
BIVV001 at scheduled PK visits and time points for the PK subgroup (Baseline 
BIVV001). Summary descriptive statistics will include the number of non-missing values, 
mean, geometric mean, standard deviation, percent coefficient of variation, minimum, and 
maximum. In these summaries, values below the LLOQ will be imputed as zero. 
• For each assay type, individual PK parameters will be listed for each participant and 
summarized descriptively for the PK subgroup (Baseline BIVV001). Any FVIII 
assessments flagged by the PK scientist as being implausible and excluded from 
computation of PK parameters will be excluded from summaries but included in listings. 
The listings will indicate which values, if any, were excluded from summaries. A separate 
listing of excluded values, together with the reason for exclusion will be provided. 
In addition, for each assay type, the peak and trough concentrations will be summarized by visit 
for the FAS. The incremental recovery will also be summarized by visit for the FAS. Summary 
descriptive statistics will include the number of non-missing values, mean, geometric mean, 
median, Q1, Q3, standard deviation, percent coefficient of variation, minimum, and maximum. In 
these summaries, values below the LLOQ will be imputed as zero. 
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4.8.2 Additional Immunogenicity analysis  
4.8.2.1 Anti-drug antibody  
Participant’s ADA status (see definitions below) will be summarized on the safety analysis set. A 
participant with at least one anti-drug antibody (ADA) result available in the database is 
considered evaluable. 
Participant’s ADA status 
• Pre-existing ADA: participant with at least one ADA positive prior to 
receiving BIVV001.  
- 
Treatment-boosted ADA: participant with pre-existing ADA positive and the ADA 
titer level anytime post-baseline is significantly higher than that at baseline. The post-
baseline titer value that is at least 4-fold of pre-existing ADA titer value is considered 
significant. 
- 
Unclassified ADA: participant with pre-existing ADAs that cannot be classified as 
treatment-boosted ADA because of missing titer(s).  
• Treatment-induced ADA: participant with all ADA negative (or missing) prior to 
receiving BIVV001 and at least one ADA positive at any time post-baseline.  
• Treatment-emergent ADA: participant with treatment-induced or treatment boosted ADA. 
ADA kinetics: 
ADA response duration is defined as the date of last treatment-induced or treatment-boosted ADA 
sample minus date of first treatment-induced or treatment-boosted ADA sample +1. ADA 
response duration will be calculated only for participants with at least two treatment-induced or 
treatment-boosted ADA samples, irrespective of negative samples. 
In case of participants with only one treatment-induced or treatment-boosted ADA, the ADA 
duration will be imputed to 0.  
ADA response will be classified in the following categories for each participant: 
• Persistent ADA response: an ADA response duration greater or equal than 16 weeks 
• Transient ADA responses: an ADA response duration less than 16 weeks and the last 
sample in the study is not treatment-induced nor treatment-boosted. 
• Indeterminate ADA response: ADA response that is neither persistent nor transient.  
The number and percentage of participants with pre-existing ADA, treatment-boosted, 
unclassified, treatment-induced ADA, and treatment emergent ADA will be summarized by age 
cohort and overall for the Safety Analysis Set. The number and percentage of participants with 
different ADA kinetic status (ie, persistent, transient, indeterminate) will be summarized by age 
cohort and overall for the Safety Analysis Set. Median and 25th/75th quantiles, minimal and 
maximal of the ADA titer for pre-existing ADA, treatment-boosted, unclassified, treatment-
induced ADA, and treatment emergent ADA will be provided. 
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A listing will be provided for confirmed positive anti-BIVV001 antibody information, including 
sample collection date and time, and ADA characterization testing. To evaluate the potential 
impact of ADAs and PK parameters, PK parameters for participants who have incidence of ADA 
positive (i.e., treatment-boosted or treatment-induced), along with the group mean of participants 
who are ADA negative at all times will be tabulated. As needed, FVIII activity level over time for 
participants who have incidence of ADA positive (ie, treatment-boosted or treatment-induced), 
along with the group mean of participants who are ADA negative at all times may be evaluated. 
4.9 
INTERIM ANALYSES  
Interim PK analyses will take place for each of the individual age cohorts (<6 years and 
6-12 years) once evaluable PK data are available for a minimum of 6 participants in each the 
cohort.  
An interim safety, PK and efficacy analysis will be performed after 12 participants are enrolled in 
the older age cohort (6-12 years). The PK analysis will be conducted once each of the 
12 participants from the older age cohort complete the first dose of BIVV001; the safety and 
efficacy analysis will be conducted once the12 participants from the older age cohort have 
reached 25 EDs to BIVV001.  
In addition, for the purposes of regulatory submission, an interim analysis of key safety data, PK 
data and selected efficacy data for this study will be performed when the pivotal adult/adolescent 
study EFC16293 is completed.  
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5 
SUPPORTING DOCUMENTATION  
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS  
 
ED: 
exposure day 
SAP: 
statistical analysis plan 
5.2 
APPENDIX 2 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS  
Demographic characteristics 
Demographic variables include sex, date of birth (year of birth only), height, weight, body mass 
index (BMI), race, ethnicity and geographic location.  
Demographic characteristics will be summarized by age cohort, including the surgery subgroup, 
and overall for the FAS using descriptive statistics.  
Hemophilia history 
The following hemophilia history variables will be summarized by age cohort, including the 
surgery subgroup, and overall for the FAS using descriptive statistics: 
• Age at diagnosis of severe hemophilia (years)  
• Family inhibitor history (Yes, No) 
• Blood type (A, B, AB, O) 
• Rh factor (Positive, Negative) 
• Lowest documented historical FVIII level (<1%, ≥1%) 
• FVIII genotype (Intron 22 inversion, Intro 1 inversion, Frameshift, Missense, Nonsense, 
Other mutation, Unknown) 
• HIV status (Positive, Negative, Unknown) 
• Hepatitis B (HBV) status (Positive, Negative, Unknown)  
• Hepatitis C (HCV) status (Positive, Negative, Unknown) 
• Vaccination history in past 12 months (Yes, No, and if Yes, how many)  
• Types of FVIII products previously administered (FVIII plasma derived, FVIII 
recombinant, FVIII cryoprecipitate, Non FVIII product) 
• Age at start of first prophylaxis regimen 
• Number of prior exposure days to FVIII (<50, 50-<100, 100-<150 and ≥150; <150, ≥150) 
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• Number of bleeds in the past 12 months 
• Number of joint bleeds in the past 12 months  
• Number of spontaneous joint bleeds in the past 12 months  
• Number of traumatic joint bleeds in the past 12 months 
• Number of target joint at baseline  
Medical and surgical history 
Medical (or surgical) history will be collected at screening and will be coded using the version of 
Medical Dictionary for Regulatory Activities (MedDRA) in effect at Sanofi at the time of 
database lock. 
The number and percentage of participants with any medical and surgical history will be 
summarized for each body system by age cohort, including the surgery subgroup, and overall 
using the Safety Analysis Set. A participant will be counted only once if the participant reported 
one or more occurrences of the same body system.  
Prior or concomitant medications 
All medications taken in the 30 days prior to the time the participant enrolls in the study and until 
the Safety Follow Up Call or Visit are to be reported on the eCRF. 
Medications will be identified as being prior and/or concomitant based on the start and stop dates 
compared to the first dose of study drug. Prior medications are those taken before the first dose of 
study drug. Concomitant medications are those administered during or after the first dose of study 
drug. A medication that started prior to the first dose of study drug and was ongoing during and/or 
after the first dose of study drug will be classified as both prior and concomitant.  
No imputation of medication start/end dates will be performed. If the start/end date is missing or 
partial, the corresponding study day will be left blank. However, inferences will be made from the 
partial and missing dates to classify the medications as prior and/or concomitant as follows. 
If a concomitant medication start day is missing then the medication will be assumed to be both a 
prior and a concomitant medication unless the start month and/or year or medication stop date can 
be used to determine if a medication is concomitant or prior, as follows:  
• If the medication start day is missing, but the month and year precede the month and year 
of the first treatment and the medication stop date is before the date of first treatment, then 
the medication will be classified as prior only.  
• If the medication start month is missing, but the year precedes the year of first treatment 
and the medication stop date is before the date of first treatment, then the medication will 
be classified as prior only. 
• If the medication start day is missing and the month and/or year are on or after the month 
and year of the first treatment, then the medication will be classified as concomitant only.  
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All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version in effect at Sanofi at the time of database lock. 
Separate summaries will be provided for prior and concomitant medications. Prior and 
concomitant medications will be presented by age cohort and overall for the Safety Analysis Set. 
Summaries will be based on the number and percentage of participants taking medications by 
WHO-DD standardized medication text. Within each WHO-DD standardized medication text a 
participant will be counted once even if he/she reported taking the medication more than once.  
Concomitant medications taken for hemophilia-related pain 
Concomitant medications taken for hemophilia-related pain will be summarized by age cohort and 
overall for the Safety Analysis Set. Summaries will be based on the number and percentage of 
participants taking pain medications by class (acetaminophen/paracetamol, NSAIDs, opioids, 
other).  
In addition, the number of days pain medication was used for hemophilia-related pain in the past 
2 weeks will be summarized categorically (0 [None], 1-3, 4-7, 8-14) for each study visit by age 
cohort and overall.  
5.3 
APPENDIX 3 DATA HANDLING CONVENTIONS  
Electronic Patient Diary (ePD) Data 
Participant recorded diary data will be handled taking into consideration previous audit findings 
and industry standards to control changes to participant reported data. Only changes defined as 
not requiring participant confirmation and that are supported by site source documentation will be 
allowed.  
The following programming algorithms are allowable to address record consolidation and true 
duplicate removal. 
1) 
Record consolidation: 
When a dose requires more than one vial and these vials are erroneously recorded in the 
ePD/eCRF as separate injections, albeit within a short time window, the change to consolidate 
these multiple records into one record is called single vial consolidation. The programming 
algorithm to identify and consolidate the records is as follows: 
• Identify all injection records within 60 minutes of one another where the variables 
(injection date/times, lot numbers, number of vials, and vials strength in nominal IU) are 
not exactly the same on each record. There are four scenarios: 
- 
Date and time of injections are not exactly same, and lot numbers, number of vials, and 
vials strength in nominal IU are not the same. 
- 
Date and time of injections are not exactly same, but lot numbers, number of vials, and 
vials strength in nominal IU are the same. 
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- 
Date and time of injections are exactly same, but lot numbers, number of vials, and 
vials strength in nominal IU are not the same. 
- 
Date and time of injections are exactly same, and lot numbers, number of vials, and 
vials strength in nominal IU are the same and these duplicates occurred for reasons 
which cannot be attributed to administrative issues as specified below 
• Consolidate injections as follows: 
- 
Record with earliest injection date/time retained with corresponding contextual 
information 
- 
Combine/sum values related to the dose (eg, lot numbers, number of vials, volume 
injected, nominal and actual dose) into the single retained record 
If injections identified with the above algorithm have distinctly different reasons (eg, one injection 
is recorded as bleeding or surgery and another is recorded as prophylaxis, or OTHER), then the 
records should NOT be consolidated. However, if one record has reason or bleed information 
missing, then consolidation can be performed. 
2) 
True duplicates removal: 
When injections are identified in the ePD with exactly the same date/times, bleed information if 
applicable (type, location, and sublocation), lot numbers, number of vials, and vials strength in 
nominal IU, these may have resulted due to administrative issues and are therefore true duplicates. 
There are three types of administrative issues as follows: 
• Technical transmission issue 
• Entry of same record into 2 different devices 
• Records duplicated in ePD and eCRF which remain despite attempts to correct the data via 
the query process  
The programming algorithm to identify and delete the duplicates is as follows: 
• Identify all injections that have exactly the same date/times, reasons for injection, bleed 
information (if applicable), lot numbers, number of vials, and vials strength in nominal IU 
• Remove the duplicates and keep a single record  
As with single vial consolidation, if injections identified as duplicates have distinctly different 
reasons (eg, one injection is recorded as bleeding or surgery and another is recorded as 
prophylaxis or OTHER), then these cannot be considered duplicates and removed. However, if 
one reason is missing, then they can be considered duplicates and removed. 
Algorithm for determining analysis visit windows for PRO and HJHS observations  
A scheduled measurement will be used if it is available. Otherwise, the following analysis 
window will decide how the unscheduled and EOS/ET visits will be used in the analyses of PRO 
and HJHS variables. 
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A measurement (unscheduled or EOS/ET) will be used if it is available and measurement date is 
within the analysis window. 
After applying these time windows, if multiple assessments are associated to the same time point, 
the closest from the targeted study day will be used. If the difference is a tie, the value after the 
targeted study day will be used. If multiple valid values exist within a same day, then the first 
value of the day will be selected.   
Table 6 - Analyses window definition  
Scheduled visit post 
baseline 
Target study day 
Derived Window in study days 
Lower bound 
Upper bound 
Baseline 
1 
-INF 
1(7 for HJHS) 
Week 26 
182 
2 (8 for HJHS) 
272 
Week 52 
364 
273 
- 
Handling of adverse events with missing or partial date/time of onset 
No imputation of adverse event onset/end dates will be performed. If the onset/end date is missing 
or partial, the corresponding study day will be left blank. However, inferences will be made from 
the partial and missing dates to classify the adverse events as treatment-emergent or not as 
follows: 
• If the onset day of an adverse event is missing and the onset month and year of the AE are 
either the same as or later than the month and year of the first treatment, the AE will be 
considered a TEAE. 
• If the onset day of an adverse event is missing and the onset month and year of the AE 
precede the month and year of the first treatment, the AE will not be considered a TEAE. 
• If the onset month of an adverse event is missing and the onset year of the AE is either the 
same as or later than the year of first treatment, the AE will be considered a TEAE. 
• If the onset month of an adverse event is missing and the onset year of the AE precedes the 
year of first treatment, the AE will not be considered a TEAE. 
• If the onset day, month, and year of an adverse event are missing, the AE will be 
considered a TEAE.  
• If start date is partial but the stop date can be determined to be before the start of the first 
dose of study drug, then the AE will not be considered a TEAE. 
Handling of adverse events with missing relationship to investigational product 
If the assessment of relationship to study drug is missing, the event will be counted as “related” in 
the frequency tables of treatment-emergent adverse events by relationship to study drug. 
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Handling of adverse events with missing severity 
If the assessment of severity is missing, the event will be counted as “severe” in the frequency 
tables of treatment-emergent adverse events by severity.  
Unscheduled visits 
Unscheduled visit measurements of laboratory data and vital signs will not be included in the by-
visit summaries but will be used for computation of baseline, maximum or minimum on-treatment 
values, and PCSAs.  
5.4 
APPENDIX 4 POTENTIALLY CLINICALLY SIGNIFICANT ABNORMALITIES CRITERIA  
Table 7 - Threshold levels for potentially clinically significant hematology abnormalities  
Parameter 
name 
Age 
Low 
High 
White Blood Cells 
6 to <12 years old 
<5.0 Giga/L or 5,000/mm3 
>17.0 Giga/L or 17 000/mm3 
24 months/2 years to <6 years old 
<3.0 Giga/L or 3,000/mm3 
>16.0 Giga/L or 16 000/mm3 
28 days/1 month to 23 months old 
<4.0 Giga/L or 4000/mm3 
>20.0 Giga/L or 20 000/mm3 
Birth/0 to 27 days old 
<4.0 Giga/L or 4000/mm3 
>25.0 Giga/L or 25 000/mm3 
Neutrophils 
6 to <12 years old 
<1.2 Giga/L or 1200/mm3 
>1 ULN 
24 months/2 years to <6 years old 
<1.2 Giga/L or 1200/mm3 
>1 ULN 
28 days/1 month to 23 months old 
<1.0 Giga/L or 1000/mm3 
(1-3 months) 
<1.2 Giga/L or 1200/mm3 
(3-24 months) 
>1 ULN 
Birth/0 to 27 days old 
<4.0 Giga/L or 4000/mm3 
(1 day old) 
<1.5 Giga/L or 1500/mm3 
(2-7 days old) 
<1.25 Giga/L or 1250/mm3 
(>7 day-1 month old) 
>1 ULN 
Lymphocytes 
6 to <12 years old 
<1.0 Giga/L or 1000/mm3 
>8.0 Giga/L or 8000/mm3 
24 months/2 years to <6 years old 
<1.0 Giga/L or 1000/mm3 
>9.5 Giga/L or 9500/mm3 
28 days/1 month to 23 months old 
<2.0 Giga/L or 2000/mm3 
>13.5 Giga/L or 13 500/mm3 
Birth/0 to 27 days old 
<1.2 Giga/L or 1200/mm3 
>17.0 Giga/L or 17 000/mm3 
Hemoglobin 
24 months/2 years to <12 years old 
<1.55 mmol/L or  
10.0 g/dL or any decrease 
>0.31 mmol/L or 2 g/dL 
28 days/1 month to 23 months old 
<1.40 mmol/L or 9.0 g/dL or 
any decrease  
>0.31 mmol/L or 2 g/dL 
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Parameter 
name 
Age 
Low 
High 
Birth/0 to 27 days old 
<8.6 mmol/L or 12.0 g/dL or 
any decrease  
>0.31 mmol/L or 2 g/dL 
Hematocrit 
24 months/2 years to <12 years old 
<0.32 l/l or 32% 
>0.47 l/l or 47% 
28 days/1 month to 23 months old 
<0.29 l/l or 29% 
>0.42 l/l or 42% 
Birth/0 to 27 days old 
<0.39 l/l or 40% 
>0.61 l/l or 47% 
Platelet count 
<12 years 
<100 Giga/L or 100 000/mm3 
>700 Giga/L or 700 000/mm3 
N/A = not applicable 
Table 8 - Threshold levels for potentially clinically significant chemistry abnormalities  
Parameter name 
Age 
PCS low 
PCS high 
Sodium 
<12 years 
≤129 mmol/L or 129mEq/L 
≥150 mmol/L or 150mEq/L 
Potassium 
24 months/2 years to 
<12 years old 
≤3.5 mmol/L or 3.5 mEq/L 
≥5.5 mmol/L or 5.5 mEq/L 
28 days/1 month to 
23 months old 
≤3.5 mmol/L or 3.5 mEq/L 
≥6.0 mmol/L or 6.0 mEq/L 
Birth/0 to 27 days old 
≤3.0 mmol/L or 3.0 mEq/L 
≥7.0 mmol/L or 7.0 mEq/L 
Chloride 
<12 years 
≤80 mmol/L or 80mEq/L 
≥115 mmol/L or 115 mEq/L 
ALT/SGPT 
<12 years 
N/A 
≥3 x ULN 
AST/SGOT 
<12 years 
N/A 
≥3 x ULN 
Alkaline phosphatase 
<12 years 
N/A 
≥1.5 x ULN 
Total Bilirubin 
<12 years 
N/A 
≥1.3 x ULN 
Creatinine   
6 years to <12 years old 
N/A 
≥90 µmol/L or 1.1 mg/dL 
Birth/0 to <6 years old 
N/A 
≥53 µmol/L or 0.6 mg/dL 
Creatinine Clearance 
<12 years 
50% of normal 
<60 mL/min/1.73m2 (after 
1 year old) 
 
Uric Acid 
<12 years 
≤2.0 mg/dL or 119 µmol/L 
≥8.0 mg/dL or 476 µmol/L 
Blood urea nitrogen 
(BUN) 
28 days/1 month to 
12 years old 
N/A 
≥6.4 mmol/L or 18 mg/dL 
Birth/0 to <27 days old 
N/A 
≥4.3 mmol/L or 12 mg/dL 
Bicarbonate 
<12 years 
≤16 mmol/L or 16 mEq/L 
≥30 mmol/L or 30 mEq/L 
Glucose 
<12 years 
<2.7 mmol/L or 50 mg/dL 
(Hypoglycaemia) 
≥7 mmol/L or 120 mg/dL 
(Hyperglycaemia and fasted after 
>12 hours of fast) 
≥10.0 mmol/L or 180 mg/dL (unfasted) 
Calcium total 
<12 years 
≤2.0 mmol/L or 8.0 mg/dL 
≥2.9 mmol/L or 11.6 mg/dL 
Calcium ionized 
<12 years 
≤1.0 mmol/L or 4.0 mg/dL 
≥1.4 mmol/L or 5.6 mg/dL 
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Parameter name 
Age 
PCS low 
PCS high 
Total Cholesterol 
<12 years 
N/A 
≥6.20 mmol/L or 240 mg/dL 
Triglycerides 
<12 years 
N/A 
≥4.0 mmol/L or 350 mg/dL 
Lipasemia 
<12 years 
N/A 
≥2 ULN 
Amylasemia 
<12 years 
Hypoglycaemia <2.7 mmol/L 
or 50 mg/dL  
Hyperglycaemia ≥7 mmol/L or 
120 mg/dL (fasted after >12 hours of 
fast);  
>10.0 mmol/L or 180 mg/dL (unfasted) 
CRP 
<12 years 
N/A 
>2 ULN or  
>10 mg/L (if ULN not provided) 
N/A = not applicable, ULN = upper limit of normal 
Table 9 - Threshold levels for potentially clinically significant coagulation abnormalities  
Parameter name 
Age 
Low 
High 
VWF antigen 
All 
< LLN 
N/A 
VWF:RCo activity 
All 
< LLN 
N/A 
N/A = not applicable, ULN = upper limit of normal 
Table 10 - Threshold levels for potentially clinically significant vital sign abnormalities  
Variable 
Age 
Low 
High 
Systolic Blood 
Pressure 
6 to <12 years old 
≤80 mmHg and decrease 
from baseline ≥20 mmHg  
≥108 mmHg and increase from 
baseline ≥20 mmHg  
24 months/2 years to <6 years old 
≤70 mmHg and decrease 
from baseline ≥20 mmHg 
≥101 mmHg and increase from 
baseline ≥20 mmHg 
28 days/1 month to 23 months old 
≤70 mmHg and decrease 
from baseline ≥20 mmHg  
≥98 mmHg and increase from baseline 
≥20 mmHg  
Birth/0 to 27 days old 
≤60 mmHg and decrease 
from baseline ≥20 mmHg 
≥85 mmHg and increase from baseline 
≥20 mmHg 
Diastolic Blood 
Pressure 
6 to <12 years old 
≤48 mmHg and decrease 
from baseline ≥10 mmHg  
≥72 mmHg and increase from baseline 
≥10 mmHg  
24 months/2 years to <6 years old 
≤34 mmHg and decrease 
from baseline ≥10 mmHg 
≥59 mmHg and increase from baseline 
≥10 mmHg 
28 days/1 month to 23 months old 
≤34 mmHg and decrease 
from baseline ≥10 mmHg 
≥54 mmHg and increase from baseline 
≥10 mmHg 
Birth/0 to 27 days old 
≤34 mmHg and decrease 
from baseline ≥10 mmHg 
≥50 mmHg and increase from baseline 
≥10 mmHg 
Orthostatic 
hypotension 
< 12 years 
SBP : St - Su ≤-20 mmHg  
DBP : St - Su ≤-10 mmHg 
N/A 
Sa02 
<12 years 
≤95% 
N/A 
Weight 
<12 years 
N/A 
≥5% weight loss from baseline 
Heart Rate 
6 to <12 years old 
≤50 bpm and decrease from 
baseline ≥20 bpm  
≥120 bpm and increase from baseline 
≥20 bpm  
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Variable 
Age 
Low 
High 
24 months/2 years to <6 years old 
≤75 bpm and decrease from 
baseline ≥20 bpm  
≥140 bpm and increase from baseline 
≥20 bpm  
28 days/1 month to 23 months old 
≤80 bpm and decrease from 
baseline ≥20 bpm  
≥175 bpm and increase from baseline 
≥20 bpm  
Birth/0 to 27 days old 
≤90 bpm and decrease from 
baseline ≥20 bpm  
≥190 bpm and increase from baseline 
≥20 bpm  
Temperature  
<12 years 
N/A 
Ear/temporal artery: ≥100.4◦F/38.0◦C 
Oral: ≥99.5◦F/37.5◦C 
Axillary: ≥99◦F/37.2◦C 
Respiration Rate 
6 to <12 years old 
<18 per minute  
>30 per minute 
24 months/2 years to <6 years old 
<22 per minute 
>34 per minute 
28 days/1 month to 23 months old 
<24 per minute 
>40 per minute 
Birth/0 to 27 days old 
<30 per minute 
>60 per minute 
5.5 
APPENDIX 5 QUESTIONNAIRE SCORING  
5.5.1 Appendix 5.1 PROMIS instruments  
Six PROMIS instruments are used in this study: 
a) PROMIS Pediatric NRS Pain Intensity (v1.0 Pain Intensity 1a; ≥8 years old) 
b) PROMIS Parent Proxy NRS Pain Intensity (v1.0 Pain Intensity 6b; 5 to <12 years old)  
c) PROMIS Pediatric-SF Pain Interference (v2.0 Pain Interference 8a; ≥8 years old)  
d) PROMIS Parent Proxy-SF Pain Interference (v2.0 Pain Interference 8a; 5 to <12 years old) 
e) PROMIS Pediatric-SF Physical Activity (v1.0 Physical Activity 8a; ≥8 years old) 
f) PROMIS Parent Proxy-SF Physical Activity (v1.0 Physical Activity 8a; 5 to <12 years 
old) 
For PROMIS instruments c) - f), within each instrument, each question has five response options 
ranging in value from one to five. To find the total raw score for an instrument with all questions 
answered, sum the values of the response to each question. All questions must be answered in 
order to produce a valid total score. For pain intensity forms, the items are not calibrated and do 
not produce a T-score. Instead, raw response scores (0 to 10) should be used for analyses. For 
other forms, total raw score is then converted into a T-score for each participant using an 
instrument-specific Conversion Table as provided in Table 11. The T-score rescales the raw score 
into a standardized score with a mean of 50 and a standard deviation (SD) of 10. Therefore, a 
person with a T-score of 40 is one SD below the mean. 
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Statistical Analysis Plan  
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Table 11 - Conversion table for PROMIS instruments  
(c) PROMIS Pediatric-SF Pain 
Interference (≥8 years) 
 
(d) PROMIS Pediatric-SF 
Physical Activity (≥8 years) 
 
(e) PROMIS-SF Pain 
Interference (5 to <12 years) 
 
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Statistical Analysis Plan  
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(f) PROMIS Parent Proxy-SF 
Physical Activity (5 to 
<12 years) 
 
 
 
 
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Statistical Analysis Plan  
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5.5.2 Appendix 5.2 Haemo-Qol  
The Haemo-Qol questionnaires for children aged 4-7 years will be summarized in terms of a total 
score, and the questionnaires for children aged 8 to <12 years will be summarized in terms of 
subscale scores and a total score according to the recommendations of the questionnaire authors.  
When missing data are presented, a subscale/total score can only be calculated if at least 50% of 
questions for that subscale/questionnaire are answered (non-missing and not “Not Applicable”).  
Haemo-QoL (age group I; 4-7 years old) 
The Haemo-Qol questionnaire for participants with hemophilia who are 4-7 years of age consists 
of 16 items for past 4 weeks time period. 
Haemo-QoL (age group II; 8 to <12 years old) 
The Haemo-Qol questionnaire for participants with hemophilia who are 8-<12 years of age 
consists of 35 items pertaining to 9 subscales for past 4 weeks time period. 
 
Time Period 
Subscales for Haemo-QoL 
No. of 
questions 
No. of non-missing 
items required to 
calculate subscale 
In the past 4 weeks 
1. Physical health 
4 
2 
 
2. Feeling 
4 
2 
 
3. View of yourself 
4 
2 
 
4. Family 
4 
2 
 
5. Friends 
3 
2 
 
6. Other persons 
4 
2 
 
7. Sports and school  
4 
2 
 
8. Dealing with hemophilia 
4 
2 
 
9. Treatment 
4 
2 
 
Total Score 
35 
18 
Haemo-QoL parent proxy (age group I; 4-7 years) 
The Haemo-QoL questionnaire for parents of participants with hemophilia who are 4-7 years of 
age consists of 16 items for past 4 weeks time period. 
Haemo-QoL parent proxy (age group II; 8 to <12 years) 
The Haemo-QoL questionnaire for parents of participants with hemophilia who are 8 to <12 years 
of age consists of 35 items pertaining to 9 subscales for past 4 weeks time period. 
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Statistical Analysis Plan  
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Time Period 
Subscales for Haem-A-QoL 
No. of 
questions 
No. of non-missing 
items required to 
calculate subscale 
In the past 4 weeks 
1. Physical health 
4 
2 
 
2. Feeling 
4 
2 
 
3. View of yourself 
4 
2 
 
4. Family 
4 
2 
 
5. Friends 
3 
2 
 
6. Other persons 
4 
2 
 
7. Sports and school  
4 
2 
 
8. Dealing with hemophilia 
4 
2 
 
9. Treatment 
4 
2 
 
Total Score 
35 
18 
Scoring algorithm 
Per the algorithm on http://www.haemoqol.de/manual.htm, to correctly score the questionnaires, 
each version has to be identified and the appropriate scoring list has to be selected. High score 
represent low quality of life and scoring involves the following steps: 
1. Assigning numbers to the response scale  
1= never, 2=seldom, 3=sometimes, 4=often, 5=always 
For negatively worded items, the above classification can be applied in which higher values 
represent a lower quality of life. For positively worded items, the score has to be recoded (see 
below).  
2. Recoding positively worded items 
Positively worded items in table have to be recoded so that numeric values assigned are reversed: 
1=always, 2=often, 3=sometimes, 4=seldom, 5= never  
By recoding, high scores in positively worded items reflect not higher but lower quality of life. 
The then unidirectional values can subsequently be added to yield the summed scores according to 
the scoring list. 
3. Producing the raw score  
A raw subscale score is produced by summing up all items within a subscale. Its range lies 
between the lowest possible (number of items (n) x 1) and highest possible (number of items (n) 
x 5) value of the respective scale. 
The raw total score is produced by the addition of all items (instead of the subscale items only) of 
the questionnaire (again paying attention to the recoding procedure - see Steps 1 and 2).  
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Statistical Analysis Plan  
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4. Transferring a raw score to a Transformed Scale Score (TSS) between 0 and 100  
Creating a Transformed Scale Score (TSS) makes it possible to express the score as a percentage 
between the lowest (0) and the highest (100) possible value. To obtain the TSS the following 
transformation rule has to be applied: 
TSS = 100 x ((raw score – minimal possible raw score) / possible range of raw scores) where: 
• minimal possible raw score = number of questions answered × 1 
• maximal possible raw score = number of questions answered × 5 
• possible range of raw scores = maximum possible raw score - minimal possible raw score 
Example: A raw score of 12 on the “Physical Health” scale is to be transformed: 
• When all 4 questions were answered: 
- 
minimal possible score=4 
- 
maximal possible score=20 
- 
range of scores=16 
- 
TSS=(12-4)/16 = 50 
• When 3 of the 4 questions were answered: 
- 
minimal possible score=3 
- 
maximal possible score=15 
- 
range of scores=12 
- 
TSS=(12-3)/12 = 75 
Transformed scores can be produced from raw subscale and raw total scores.  
The total and subscale scores based on TSS will be presented in outputs. 
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Statistical Analysis Plan  
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6 
REFERENCES  
1. Blanchette VS, Key NS, Ljung LR, Manco-Johnson MJ, van den Berg HM, Srivastava A, et 
al. Definitions in hemophilia: communication from the SSC of the ISTH. J Thromb Haemost. 
2014;12(11):1935-9. 
2. Baskin JL, Pui CH, Reiss U, Wilimas JA, Metzger ML, Ribeiro RC, et al.  Management of 
occlusion and thrombosis associated with long-term indwelling central venous catheters.  
Lancet. 2009;374(9684):159-69.  
3. 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. 
 
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