A Phase 1/2a, Open-Label, Dose-Escalation Study to Determine the Safety, Tolerability, and Pharmacokinetics of a Single Intravenous Injection of rFVIIIFc-VWF-XTEN (BIVV001) in Previously Treated Adults With Severe Hemophilia A
Phase: PHASE1
Conditions: Hemophilia A
Sponsor: Bioverativ, a Sanofi company

CONFIDENTIAL
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Bioverativ Therapeutics Inc.
1
Bioverativ Therapeutics Inc.
225 Second Avenue
Waltham, MA 02451
PROTOCOL NUMBER:
Protocol 242HA101
PHASE OF DEVELOPMENT:
1/2a
PROTOCOL TITLE: A Phase 1/2a, Open-Label, Dose-Escalation Study to Determine 
the Safety, Tolerability, and Pharmacokinetics of a Single Intravenous Injection 
of rFVIIIFc-VWF-XTEN (BIVV001) in Previously Treated Adults with Severe 
Hemophilia A
EUDRA CT NUMBER:
2017-001140-34
DATE:
04 January 2018
Version 6.0 
Supersedes Version 5.0 dated 29 November 2017.
NCT03205163

Protocol 242HA101 
BIWOOl (rFVIIIFc-VWF-XTEN) Safety and Pharmacokinetics Study 
SPONSOR SIGNATURE PAGE 
Protocol 242HA101 was approved by: 
 
 
Bioverativ Therapeutics, Inc. 
CONFIDENTIAL 
DSTAN )<ts 
Date 
Version 6.0 
The information contained herein may not be used, disclosed, or published without the written consent of 
Bioverativ Therapeutics Inc. 
2 

Protocol 242HA101
Version 6.0
BIVV001 (rFVIIIFc-VWF-XTEN) Safety and Pharmacokinetics Study
CONFIDENTIAL
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TABLE OF CONTENTS
SPONSOR SIGNATURE PAGE ....................................................................................................2
1.
SYNOPSIS ...................................................................................................................9
2.
LIST OF ABBREVIATIONS.....................................................................................13
3.
SPONSOR INFORMATION .....................................................................................15
4.
INTRODUCTION......................................................................................................16
4.1.
Overview of Hemophilia A ........................................................................................16
4.2.
Current Therapies for Hemophilia A..........................................................................16
4.3.
Profile of Previous Experience With BIVV001 .........................................................17
4.3.1.
Nonclinical Experience...............................................................................................18
4.3.2.
Clinical Experience.....................................................................................................18
4.4.
Study Rationale...........................................................................................................18
4.5.
Rationale for Dose and Schedule Selection................................................................19
5.
SCHEDULES OF ACTIVITIES ................................................................................21
6.
STUDY OBJECTIVES AND ENDPOINTS..............................................................37
6.1.
Primary Objective and Endpoints...............................................................................37
6.2.
Secondary Objective and Endpoints...........................................................................37
6.3.
Exploratory Objective and Endpoints.........................................................................37
7.
STUDY DESIGN .......................................................................................................38
7.1.
Study Overview ..........................................................................................................38
7.1.1.
Dose-Limiting Toxicity ..............................................................................................41
7.2.
Overall Study Duration and Follow-Up .....................................................................41
7.2.1.
Screening Period (Including Initial Wash Out) ..........................................................41
7.2.2.
Low-Dose Cohort .......................................................................................................41
7.2.3.
Escalation to High-Dose Cohort.................................................................................42
7.2.4.
High-Dose Cohort.......................................................................................................42
7.2.5.
Safety Observation Period ..........................................................................................43
7.3.
Study Duration for Subjects........................................................................................44
7.4.
Responsibilities of Study Site Personnel....................................................................44
7.5.
Substudy Design .........................................................................................................44
7.6.
Study Stopping Rules .................................................................................................44
7.6.1.
Dose and Enrollment Suspension...............................................................................44

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7.6.2.
Dose and Enrollment Termination..............................................................................45
7.7.
End of Study ...............................................................................................................46
8.
SELECTION OF SUBJECTS ....................................................................................47
8.1.
Inclusion Criteria ........................................................................................................47
8.2.
Exclusion Criteria.......................................................................................................48
9.
SCREENING AND ENROLLMENT ........................................................................50
9.1.
Screening ....................................................................................................................50
9.2.
Enrollment ..................................................................................................................50
9.3.
Blinding Procedures....................................................................................................51
10.
DISCONTINUATION OF STUDY TREATMENT AND WITHDRAWAL 
OF SUBJECTS FROM THE STUDY........................................................................52
10.1.
Withdrawal of Subjects From Study...........................................................................52
10.1.1.
Criteria for Subject Withdrawal From Study Prior to BIVV001 
Administration............................................................................................................52
10.1.2.
Criteria for Subject Withdrawal From Study After BIVV001 Administration..........53
10.1.3.
General Considerations...............................................................................................53
10.2.
Lost to Follow-Up.......................................................................................................53
11.
STUDY TREATMENT USE .....................................................................................55
11.1.
Regimen......................................................................................................................55
11.1.1.
Regimen for Low-Dose Cohort (Advate and BIVV001 25 IU/kg Single 
Doses) .........................................................................................................................55
11.1.2.
Regimen for High-Dose Cohort (Advate and BIVV001 65 IU/kg Single 
Doses) .........................................................................................................................56
11.2.
Modifications of Dose and/or Treatment Schedule....................................................56
11.2.1.
Modifications to BIVV001 and/or Advate Doses ......................................................56
11.2.2.
Modifications to BIVV001 and/or Advate Dose Administration...............................57
11.2.2.1.
Allergic Reactions ......................................................................................................57
11.2.2.2.
Anaphylactic Reactions ..............................................................................................57
11.2.2.3.
Bleeding Episodes ......................................................................................................57
11.2.3.
Modifications to Treatment Schedule.........................................................................57
11.3.
Precautions..................................................................................................................57
11.3.1.
Bleeding Episodes ......................................................................................................57
11.4.
Compliance.................................................................................................................58

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11.5.
Concomitant Therapy and Procedures........................................................................58
11.5.1.
Concomitant Therapy .................................................................................................58
11.5.1.1.
Allowed Concomitant Therapy...................................................................................58
11.5.1.2.
Disallowed Concomitant Therapy..............................................................................58
11.5.2.
Concomitant Procedures.............................................................................................59
11.5.3.
Recording of Concomitant Therapies and/or Procedures...........................................59
11.6.
Continuation of Treatment..........................................................................................59
12.
STUDY TREATMENT MANAGEMENT................................................................60
12.1.
BIVV001.....................................................................................................................60
12.2.
Advate.........................................................................................................................60
13.
EFFICACY AND PHARMACOKINETIC ASSESSMENTS...................................61
13.1.
Clinical Efficacy Assessments....................................................................................61
13.2.
Laboratory Efficacy Assessments...............................................................................61
13.3.
Pharmacokinetic Assessments....................................................................................61
13.4.
Pharmacodynamic Assessments.................................................................................61
13.5.
Pharmacogenetic and Genetic Assessments...............................................................61
13.6.
Exploratory Assessment .............................................................................................62
14.
SAFETY ASSESSMENTS ........................................................................................63
14.1.
Clinical Safety Assessments.......................................................................................63
14.2.
Laboratory Safety Assessments..................................................................................63
14.3.
Immunogenicity Assessments ....................................................................................64
15.
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES .................................................................................................65
15.1.
Definitions ..................................................................................................................65
15.1.1.
Serious Pretreatment Event.........................................................................................65
15.1.2.
Adverse Event.............................................................................................................65
15.1.3.
Serious Adverse Event................................................................................................66
15.2.
Safety Classifications..................................................................................................66
15.2.1.
Investigator Assessment of Events.............................................................................66
15.2.2.
Relationship of Events to Study Treatment................................................................66
15.2.3.
Severity of Events.......................................................................................................67
15.2.4.
Expectedness of Events ..............................................................................................67

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15.3.
Monitoring and Recording Events..............................................................................67
15.3.1.
Adverse Events ...........................................................................................................67
15.3.2.
Serious Adverse Events..............................................................................................68
15.3.3.
Immediate Reporting of Serious Adverse Events.......................................................69
15.3.3.1.
Deaths .........................................................................................................................69
15.3.4.
Suspected Unexpected Serious Adverse Reactions....................................................69
15.4.
Procedures for Handling Special Situations ...............................................................70
15.4.1.
Pregnancy ...................................................................................................................70
15.4.2.
Overdose.....................................................................................................................70
15.4.3.
Medical Emergency....................................................................................................70
15.4.3.1.
Unblinding for Medical Emergency...........................................................................70
15.5.
Contraception Requirements ......................................................................................70
15.6.
Safety Responsibilities................................................................................................70
15.6.1.
Investigator Responsibilities.......................................................................................70
15.6.2.
Bioverativ Responsibilities.........................................................................................71
16.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE...........72
16.1.
Description of Objectives and Endpoints ...................................................................72
16.2.
Demographics and Baseline Disease Characteristics .................................................72
16.3.
Efficacy.......................................................................................................................72
16.4.
Pharmacokinetics........................................................................................................72
16.4.1.
Analysis Population....................................................................................................72
16.4.2.
Methods of Analysis...................................................................................................72
16.5.
Pharmacodynamics.....................................................................................................73
16.6.
Biomarker Analyses/Pharmacogenetics .....................................................................73
16.7.
Safety..........................................................................................................................73
16.7.1.
Analysis Population....................................................................................................73
16.7.2.
Methods of Analysis...................................................................................................73
16.8.
Immunogenicity..........................................................................................................74
16.8.1.
Analysis Population....................................................................................................74
16.8.2.
Methods of Analysis...................................................................................................74
16.9.
Interim Analyses.........................................................................................................74
16.10.
Sample Size Considerations .......................................................................................74

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17.
ETHICAL REQUIREMENTS ...................................................................................76
17.1.
Declaration of Helsinki...............................................................................................76
17.2.
Ethics Committee........................................................................................................76
17.3.
Subject Information and Consent ...............................................................................76
17.4.
Subject Data Protection ..............................................................................................77
17.5.
Compensation for Injury.............................................................................................77
17.6.
Conflict of Interest......................................................................................................77
17.7.
Registration of Study and Disclosure of Study Results..............................................78
18.
ADMINISTRATIVE PROCEDURES.......................................................................79
18.1.
Study Site Initiation....................................................................................................79
18.2.
Quality Control and Quality Assurance......................................................................79
18.3.
Monitoring of the Study..............................................................................................79
18.4.
Study Funding.............................................................................................................80
18.5.
Publications.................................................................................................................80
19.
FURTHER REQUIREMENTS AND GENERAL INFORMATION........................81
19.1.
External Contract Organizations.................................................................................81
19.1.1.
Contract Research Organization.................................................................................81
19.1.2.
Interactive Response Technology...............................................................................81
19.1.3.
Electronic Data Capture..............................................................................................81
19.1.4.
Central Laboratories for Laboratory Assessments .....................................................81
19.1.5.
Central Facility for Other Assessments ......................................................................81
19.2.
Study Committees.......................................................................................................82
19.2.1.
Data Safety Monitoring Committee............................................................................82
19.3.
Changes to Final Study Protocol ................................................................................82
19.4.
Ethics Committee Notification of Study Completion or Termination........................82
19.5.
Retention of Study Data..............................................................................................82
19.6.
Study Report Signatory...............................................................................................82
20.
REFERENCES ...........................................................................................................83
21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL.........................................87
LIST OF TABLES
Table 1:
Screening Schedule (Both BIVV001 Low-Dose and High-Dose Cohorts)................21

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Table 2:
Advate Dosing and Pharmacokinetics Sampling Schedule (Both Low-Dose 
and High-Dose Cohorts).............................................................................................24
Table 3:
BIVV001 Dosing and Pharmacokinetics Sampling Schedule (BIVV001 
Low-Dose Cohort Only).............................................................................................26
Table 4:
BIVV001 Dosing and Pharmacokinetics Sampling Schedule (BIVV001 
High-Dose Cohort Only) ............................................................................................29
Table 5:
End-of-Study / Early Termination Evaluation Schedule for Advate and 
BIVV001 (Both Low-Dose and High Dose Cohorts).................................................32
Table 6:
Instructions for Washout, Dosing, and Pharmacokinetic Sampling...........................34
Table 7:
Instructions for Treatment of Bleeding Episodes .......................................................35
Table 8:
Confidence Intervals for Given Observed Geometric Mean Time to 1% 
Above Baseline for FVIII Activity.............................................................................74
LIST OF FIGURES
Figure 1:
Study Design...............................................................................................................40

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1.
SYNOPSIS
Protocol Title
A Phase 1/2a, Open-Label, Dose-Escalation Study to Determine 
the Safety, Tolerability, and Pharmacokinetics of a Single Intravenous 
Injection of rFVIIIFc-VWF-XTEN (BIVV001) in Previously Treated 
Adults with Severe Hemophilia A
Protocol Number
Protocol 242HA101
Version Number
Name of Study 
Treatment
Study Phase
Study Indication
Study Rationale
6.0
Recombinant coagulation factor VIII Fc - von Willebrand factor -
XTEN fusion protein (rFVIIIFc-VWF-XTEN; BIVV001) 
1/2a
Severe Hemophilia A
Severe hemophilia A (<1 IU/dL [<1%] endogenous factor VIII [FVIII] 
activity level) accounts for approximately 30% to 50% of all cases of 
hemophilia A. The World Health Organization, the World Federation 
of Hemophilia, and other international expert consensus groups 
recommend FVIII prophylactic therapy to prevent bleeding and related 
joint and musculoskeletal disease [Berntorp 1995; Berntorp 2003; 
Srivastava 2013; National Hemophilia Federation (NHF) 2016], 
and FVIII prophylaxis is considered the standard of care for patients 
with severe hemophilia A.
Prior to the introduction of recombinant coagulation factor VIII Fc 
(rFVIIIFc), FVIII products were generally administered every 2 to 
3 days due to the short half-life (t½) of the protein: approximately 10 to 
12 hours in adults [Fijnvandraat 1997; White 1997; Tarantino 2004; 
Blanchette 2008]. The longer mean t½ of rFVIIIFc — 19.7 hours 
(95% confidence interval: 17.4, 22.0) in adults [Eloctate USPI 2017], 
which allows for less frequent administration: every 3 to 5 days. 
Nevertheless, there is still a need for further improvement in FVIII 
therapy via the development of products with longer half-life, as the 
burden of a demanding treatment regimen remains an obstacle to 
adoption of and adherence to prophylaxis. Next-generation extended 
half-life (EHL) FVIII products — which could reduce the frequency of 
bleeding episodes with less frequent administration due to their 
prolonged periods of prophylactic coverage — would potentially 
address these challenges and in turn could improve the quality of life 
for hemophilia patients [Collins 2009]. 

Protocol 242HA101
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BIVV001 (rFVIIIFc-VWF-XTEN), designed to be a next-generation 
EHL blood clotting FVIII, is a recombinant fusion protein consisting of 
single chain FVIII, the Fc domain of human immunoglobulin G1, the 
FVIII-binding D′D3 domain of von Willebrand factor (VWF), and 
2 XTEN polypeptide linkers. BIVV001 is the first rFVIII engineered to 
be independent of VWF, and has been shown to have a longer half-life 
compared with current FVIII and rFVIII products in nonclinical 
studies.
Study Objectives 
and Endpoints
The primary objective is to assess the safety and tolerability of a single 
intravenous (IV) dose of BIVV001 in adult previously treated patients 
(PTPs) with severe hemophilia A.
The primary endpoints are as follows:

The occurrence of adverse events (AEs).

The occurrence of clinically significant abnormalities in laboratory
tests, including development of inhibitors (neutralizing antibodies 
directed against FVIII) as determined via the Nijmegen-modified 
Bethesda assay.
The secondary objective is to characterize the pharmacokinetics (PK) 
of BIVV001 after a single IV administration compared with the PK of 
Advate®, with FVIII activity determined by the one-stage (activated 
partial thromboplastin time [aPTT]) clotting assay.
The secondary endpoints are PK parameters, including but not limited 
to the following: maximum activity (Cmax); half-life (t½); clearance; 
volume of distribution at steady state (Vss); area under the 
concentration-time curve from time 0 to infinity (AUC∞); mean 
residence time (MRT); incremental recovery (IR); time to 1% above 
baseline for FVIII activity.
Study Design
This is a Phase 1/2a, open-label, dose-escalation, multicenter study 
designed to evaluate the safety, tolerability, and PK of a single IV dose 
of BIVV001 in PTPs with severe hemophilia A. 
Subjects will be dosed with a single IV dose of Advate followed 
by a PK sampling period. After a brief washout period, each subject 
will be administered a single dose of BIVV001 followed by a PK 
sampling period. Subjects will also undergo safety observation for 28 
days following BIVV001 administration, which includes inhibitor 
assessments 14 and 28 days after BIVV001 dosing.
Two BIVV001 doses will be evaluated in this study: 25 IU/kg single 
dose (low-dose cohort) and 65 IU/kg single dose (high-dose cohort).

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A step-wise dosing and dose-escalation procedure will be utilized 
to minimize the potential of adverse reactions in multiple subjects:
1. For the low-dose cohort, data collected for inhibitor test results 
and other available safety assessments through 28 days 
post-BIVV001 dose for Subject 1 must be reviewed before 
permitting administration of BIVV001 to Subject 2, and the 
same data through 28 days post-BIVV001 dose must be 
reviewed before permitting administration of BIVV001 to 
Subject 3. After BIVV001 administration to Subject 3, data will 
be reviewed for inhibitor test results and other available safety 
assessments through 14 days post-BIVV001 dose, before 
permitting administration of BIVV001 to Subject 4 [Abbas
2007]. For Subjects 4 through 8 of this cohort, an interval of at 
least 72 hours must elapse between BIVV001 dose 
administrations to successive subjects.
2. Before proceeding to the high-dose cohort, the Sponsor and the 
Data Safety Monitoring Committee (DSMC) will review 
available data obtained from the low-dose cohort to determine 
whether it is appropriate to begin administration of the higher 
BIVV001 dose.
3. For the high-dose cohort, data collected for inhibitor test results 
and other available safety assessments through 28 days post-
BIVV001 dose for Subject 1 must be reviewed before 
permitting administration of BIVV001 to Subject 2, and the 
same data through 28 days post-BIVV001 dose must be 
reviewed before permitting administration of BIVV001 to 
Subject 3. After BIVV001 administration to Subject 3, data will 
be reviewed for inhibitor test results and other available safety 
assessments through 14 days post-BIVV001 dose, before 
permitting administration of BIVV001 to Subject 4 [Abbas
2007]. For Subjects 4 through 10 of this cohort, an interval of at 
least 96 hours must elapse between BIVV001 administrations to 
successive subjects.
Study Locations
Approximately 10 sites in North America and Asia. 
Number of 
Planned Subjects
A total of approximately 18 adult males will be enrolled and treated.
Study Population
Adult male subjects (18 to 65 years of age) with severe hemophilia A 
(defined as <1 IU/dL [<1%] endogenous FVIII) who have had at least 
150 exposure days (EDs) to the FVIII product.

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Detailed entry criteria for each cohort are described in Section 8.
Treatment Groups
Approximately 8 subjects in the low-dose cohort (Advate 25 IU/kg 
single dose and BIVV001 25 IU/kg single dose).
Approximately 10 subjects in the high-dose cohort (Advate 65 IU/kg 
single dose and BIVV001 65 IU/kg single dose).
Duration of 
Treatment and 
Follow-up
The total time on study for each subject in the low- and high-dose cohorts
will range from approximately 60 to 156 days, depending on the length 
of Screening Period and the cohort to which the subject is assigned.

Up to 28 days for screening and washout of prestudy FVIII 
therapy prior to Advate dosing (this period may be extended up to 
120 days with prior Sponsor approval). If the Screening Period 
extends beyond 56 days, screening assessments must be repeated 
as specified in Table 1 prior to dosing with Advate.

At least 3 days (low-dose cohort) of Advate PK sampling/washout 
following Advate dose administration

At least 4 days (high-dose cohort) of Advate PK sampling/washout
following Advate dose administration

28 days of safety observation (which includes 10 to 14 days of 
BIVV001 PK sampling) following BIVV001 dose administration.

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2.
LIST OF ABBREVIATIONS
ADA
anti-drug antibody
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ASA
Acetylsalicylic acid
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
AUC∞
area under the concentration-time curve from time 0 to infinity
BU
Bethesda units
BUN
blood urea nitrogen
CHMP
Committee for Medicinal Products for Human Use
CI
confidence interval
CL
clearance
Cmax
maximum activity
CRF
case report form
DHA
Directions for Handling and Administration
DLT
dose-limiting toxicity
DSMC
Data Safety Monitoring Committee
ED
exposure day
EHL
extended half-life
EMA
European Medicines Agency
EOS
end of study
ET
early termination
FVIII
factor VIII
γGT
gamma-glutamyl transferase
GCP
Good Clinical Practice
HBV
hepatitis B virus
Hct
hematocrit
HCV
hepatitis C virus
HemA
FVIII-deficient (mouse strain)
Hgb
hemoglobin
HIV
human immunodeficiency virus
IB
(BIVV001) Investigator Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IGF-1
insulin-like growth factor type 1
IgG1
immunoglobulin G1
INR
international normalized ratio
IR
incremental recovery
IRT
Interactive Response Technology

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14
IU
international units
IV
intravenous(ly)
MASAC
Medical and Scientific Advisory Council
MedDRA
Medical Dictionary for Regulatory Activities
MRT
mean residence time
NHF
National Hemophilia Foundation
NOAEL
no-observed adverse effect level
NSAID
non-steroidal anti-inflammatory drug
PK
pharmacokinetics
PT
prothrombin time
PTE
pretreatment event
PTP
previously treated patient
RBC
red blood cell
rFVIII
recombinant coagulation factor VIII
rFVIIIFc
recombinant coagulation factor VIII Fc
rFVIIIFc-VWF-XTEN
recombinant coagulation factor VIII Fc – von Willebrand factor –
XTEN fusion protein (BIVV001)
rhGh
recombinant human growth factor
SAE
serious adverse event
SUSAR
suspected unexpected serious adverse reaction
t½
half-life
TAT
thrombin anti-thrombin
ULN
upper limit of normal
USPI
United States Prescribing Information
Vss
volume of distribution at steady state
VWF
von Willebrand factor
VWF:RCo
von Willebrand factor ristocetin cofactor
WBC
white blood cell
WHO
World Health Organization

Protocol 242HA101
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3.
SPONSOR INFORMATION
This study is sponsored by Bioverativ Therapeutics Inc. (Bioverativ). Refer to the Study 
Reference Guide for complete information for all study contacts. 
Bioverativ Therapeutics Inc.
225 Second Avenue
Waltham, MA 02451
USA
Bioverativ Japan Ltd.
Nihonbashi 1-chome Mitsui 
Building 14F
4-1 Nihonbashi 1-chome
Chuo-ku, Tokyo
103-0027 Japan
For urgent medical issues in which the study’s Medical Director should be contacted, please 
refer to the Study Reference Guide for complete contact information.
Bioverativ may transfer any or all of its study-related responsibilities to IQVIA, contract research 
organizations, and/or other third parties; however, Bioverativ retains overall accountability for 
these activities.

Protocol 242HA101
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4.
INTRODUCTION
In this study, approximately 18 males (18 to 65 years of age, inclusive) with severe hemophilia A 
(defined as <1 IU/dL [<1%] endogenous factor VIII [FVIII]) will be administered a single 
intravenous (IV) dose of 25 IU/kg or 65 IU/kg BIVV001 (rFVIIIFc-VWF-XTEN) at 
approximately 10 sites in North America and Asia to evaluate the safety and tolerability of 
BIVV001. Additionally, this study will evaluate the pharmacokinetics (PK) of BIVV001 (single 
dose) and compare it to the PK of single-dose administration of the commercially available 
recombinant FVIII (rFVIII) product Advate®.
4.1.
Overview of Hemophilia A
Hemophilia A is an X-chromosome linked bleeding disorder that occurs predominantly in males, 
and is characterized by a functional FVIII deficiency caused by a variety of mutations occurring 
in the gene that encodes FVIII [Furie and Furie 1990; Graw 2005]. The worldwide prevalence of 
hemophilia A is estimated to be 1 in 10,000, whereas the worldwide incidence is approximately 
1 in 5,000 male births [Roosendaal and Lafeber 2003]. Hemophilia A appears to be equally 
distributed around the world [World Federation of Haemophilia 2011; Skinner 2012]. The 
severity of the disease is characterized by the endogenous level of FVIII calculated in plasma.
Severe hemophilia A (<1% endogenous FVIII activity level; <1 IU/dL) accounts for 
approximately 30% to 50% of all cases of hemophilia A [Aznar 2009; Centers for Disease 
Control and Prevention (CDC) 2011; United Kingdom Haemophilia Centre Doctors' 
Organisation (UKHCDO) 2011].
Individuals with severe hemophilia experience frequent bleeding episodes into major joints, 
soft tissue, and muscle, either spontaneously or following trauma. Signs and symptoms of 
hemophilia A include joint swelling, joint and muscle pain, as well as mucosal, gastrointestinal, 
and post-circumcision bleeding. Repeated bleeding episodes can lead to debilitating long-term 
complications, including hemophilic arthropathy from bleeding into the joints. The disease can 
be acutely life threatening; intracranial hemorrhage can result in disability and death, and is the 
leading cause of hemorrhagic death in individuals with hemophilia [Witmer 2011]. Another 
severe complication is the development of target joints from inflammation due to prior bleeding.
Patients are more susceptible to recurrent bleeding into that same joint, ultimately leading to 
disabling arthropathy. Significant effects on physical/psychosocial well-being, quality of life, 
and financial burden have been reported in patients with severe hemophilia [Lee 2010]. 
4.2.
Current Therapies for Hemophilia A
Currently, no cure is available for hemophilia A. Current standard of care focuses on replacement 
therapy with plasma-derived FVIII or rFVIII products. Although FVIII and rFVIII products have 
similar efficacy and safety profiles, rFVIII products are more commonly used because they 
are not associated with the theoretical risk of pathogen transmission.

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The FVIII treatment of hemophilia A can be episodic or prophylactic. Clinical studies have
shown that routine prophylactic therapy is superior in delaying/preventing the development 
of arthropathy, as well as in controlling bleeding frequency [Nilsson 1992; Aledort 1994; 
Manco-Johnson 2007]. For these reasons, the World Health Organization (WHO), the World 
Federation of Hemophilia, and other international expert consensus groups recommend FVIII 
prophylaxis to prevent bleeding and reduce secondary joint and musculoskeletal disease 
[Berntorp 1995; Berntorp 2003; Srivastava 2013; National Hemophilia Federation (NHF) 2016].
As prophylactic regimens were initially developed, a target trough of 1% factor activity was 
adopted based on the observation of a significantly decreased frequency of bleeding in moderate 
hemophilia A patients, who have factor activity levels of 1% to 5% of the endogenous FVIII 
level.
For effective prophylaxis, FVIII products with protein half-lives (t½) of 10 to 12 hours are 
generally administered every 2 to 3 days in adults [Fijnvandraat 1997; White 1997; 
Tarantino 2004; Blanchette 2008]. Newer extended half-life (EHL) PEGylated FVIII products 
have mean t½ ranging from 14 to 19.6 hours in adults; these include glycoPEGylated FVIII 
(N8-GP), Cys variant-PEGylated FVIII (BAY 94-9027), and amino group-PEGylated FVIII 
(BAX855) [Tiede 2013; Coyle 2014; Konkle 2015]. The recombinant FVIII-Fc fusion protein 
(rFVIIIFc; Eloctate®), has a longer mean t½ of 19.7 hours (95% CI: 17.4, 22.0) in adults [Eloctate 
United States Package Insert [USPI] 2017], which allows for less frequent administration:
every 3 to 5 days.
Nevertheless, there is still a need for further improvement. FVIII administration is challenging, 
particularly in children with hemophilia A, due to the requirement for venous access, dosing 
compliance due to time commitment, and the cost associated with frequent administration 
[Blanchette 2008]. Additionally, children have higher body-weight-normalized clearance (CL) 
and shorter half-life, necessitating more frequent injections. Even with the EHL FVIII products 
that are currently available, the burden of a demanding regimen remains an obstacle to adoption 
of and adherence to prophylaxis. Products with even longer half-life would offer the opportunity 
for reduced time below threshold FVIII activity levels at which there may be an increased risk of 
bleeding events [Collins 2009].
BIVV001 (rFVIIIFc-VWF-XTEN) is a recombinant fusion protein consisting of single chain 
FVIII, the Fc domain of human immunoglobulin G1 (IgG1), the FVIII-binding D′D3 domain 
of von Willebrand factor (VWF), and 2 XTEN linkers. It is believed that the plasma half-life 
of FVIII is prolonged by its interaction with VWF. All current EHL rFVIII products interact with 
VWF and have comparable circulating half-lives, consistent with upper limits on the half-life 
of rFVIII variants owing to the approximate 15-hour half-life of endogenous VWF [Pipe 2016].
BIVV001 is the first rFVIII engineered to be independent of VWF, theoretically extending its 
half-life. Nonclinical studies of BIVV001 have demonstrated that its half-life is significantly 
prolonged compared with current FVIII products.
4.3.
Profile of Previous Experience With BIVV001
See the BIVV001 Investigator Brochure (IB) for detailed information on relevant nonclinical 
studies.

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4.3.1.
Nonclinical Experience
The PK of BIVV001 have been characterized in FVIII-deficient (HemA) mice, normal Sprague 
Dawley rats, and normal Cynomolgus monkeys. The results from these studies demonstrated that 
the half-life of BIVV001 was 2.8-fold, 3.6-fold, and 4.1-fold longer than that of Advate in each 
of these species, respectively.
Nonclinical efficacy of BIVV001 has been evaluated using 2 bleeding models in HemA mice:
a tail clip model to evaluate acute efficacy and a tail vein transection model to evaluate 
prophylactic efficacy. In the tail clip study, the observed in vivo activity of BIVV001 was 
comparable to that of Advate, and both demonstrated significantly decreased blood loss 
compared to the vehicle control. In the tail vein transection study, BIVV001 demonstrated 
a 3-fold increase in its duration of protective activity compared to that observed for Advate, 
which is consistent with the prolonged half-life of BIVV001 observed in nonclinical PK studies.
In 4-week, repeated-dose toxicology studies in normal Sprague Dawley rats and normal 
Cynomolgus monkeys, no unexpected toxicity findings were observed for BIVV001.
No adverse findings were observed that were directly attributed to BIVV001 administration.
The no-observed adverse event level (NOAEL) was determined to be BIVV001 750 IU/kg, 
which was the highest dose level administered IV in these studies. Adverse findings 
were observed in monkeys; however, these were directly related to antibody formation to BIVV001 
and cross-reactivity with endogenous FVIII, resulting in acquired hemophilia. The development 
of antibodies is an expected finding, as BIVV001 is a foreign protein to monkeys.
4.3.2.
Clinical Experience
This drug has not yet been evaluated in humans.
4.4.
Study Rationale
BIVV001 has been designed to be a next-generation EHL blood clotting FVIII. This 
first-in-human study will evaluate the safety and tolerability of a single IV dose of BIVV001 in 
subjects with severe hemophilia A (defined as <1 IU/dL [<1%] endogenous FVIII). In addition, 
this study will provide data on the PK of this drug compared with that of Advate, which was 
chosen as a comparator because it is a commonly prescribed rFVIII replacement product. The
results of this study will inform the design of Phase 3 clinical studies.
BIVV001 has not yet been evaluated in humans. As described in Section 4.3.1, nonclinical 
studies have shown that BIVV001 has an EHL compared with current FVIII products.
Additionally, in silico tools were utilized in the design and preparation of BIVV001 to assess 
and reduce the immunogenic potential of this fusion protein [Chhabra 2016].
BIVV001 was engineered to include an rFVIIIFc containing a B-domain deleted human FVIII 
covalently linked to the Fc domain of human IgG1. 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 half-life than endogenous FVIII. The fusion of Fc to human FVIII 

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utilized a proven approach for increasing the half-life of therapeutic proteins, including several 
approved drugs [Jazayeri 2012; Wu 2014]. 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 half-life imposed by VWF [Saenko and Scandella 1995; Yee 2014; 
Lenting 2016]. The D′D3 domain has not been reported to interact with other targets.
Finally, BIVV001 also includes 2 XTEN linkers (unstructured polypeptides): the first is located 
in the B-domain region of FVIII (connecting the heavy and light chains of FVIII), while 
the second is located between the D′D3 and Fc domains. These XTEN linkers are designed 
to extend the half-life of the fusion protein and reduce clearance [Schellenberger 2009], which 
has been demonstrated in studies where XTEN linkers have been joined to other protein drugs.
An allometric scaling analysis of Exenatide-XTEN showed that the fusion of XTEN to the 
compound would result in a t½ of 139 hours in humans versus 2.4 hours for Exenatide alone 
[Schellenberger 2009; Byetta USPI 2015]. These analyses were confirmed in a Phase 1, 
placebo-controlled study of Exenatide-XTEN single dose in 52 patients with type 2 diabetes 
mellitus: the average t½ of Exenatide-XTEN was 128 hours in these patients [Cleland 2012]. In a 
study conducted in rats, the half-life of T-20 — an anti-retroviral peptide indicated for patients 
with human immunodeficiency virus (HIV) — was increased nearly 20-fold when fused to 
XTEN linkers [Ding 2014]. In a study of 50 adult humans with growth hormone deficiency, the 
half-life of a recombinant human growth factor (rhGH) fused with XTEN was 30- to 60-fold 
longer than that previously observed for rhGH alone. Moreover, efficacy responses (assessed via 
observation of ample levels of insulin-like growth factor type 1 [IGF-1]) persisted for a full 
month after a single dose of rhGH-XTEN was administered; in contrast, rhGH typically must 
be administered daily to maintain efficacy [Yuen 2013]. In a study of 68 pediatric patients with 
growth hormone deficiency, a single dose of rhGH-XTEN resulted in a sustained IGF-1 response 
for up to 1 month [Moore 2016].
Nonclinical single-dose PK studies demonstrated BIVV001 half-life that was approximately 
3-fold longer than that of Advate in all species tested. This first-in-human study of BIVV001 is 
being conducted to evaluate the safety and tolerability of a single intravenous injection of 
BIVV001 at either 25 IU/kg or 65 IU/kg and assess whether BIVV001 demonstrates a similar 
half-life prolongation compared with Advate in adult males with severe hemophilia A.
4.5.
Rationale for Dose and Schedule Selection
There will be 2 dose cohorts in this study:

Low-dose cohort: Approximately 8 subjects will receive a single IV dose of Advate 
25 IU/kg followed by a single IV dose of BIVV001 25 IU/kg

High-dose cohort: Approximately 10 subjects will receive a single IV dose of Advate 
65 IU/kg followed by a single IV dose of BIVV001 65 IU/kg
The low-dose level for this study is based on nonclinical study results for BIVV001 and clinical 
and nonclinical results for marketed FVIII products, including rFVIIIFc (Eloctate).

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The high-dose level is determined by the upper limit of the physiological plasma FVIII activity 
level of 150 IU/dL in healthy subjects and taking into account an anticipated incremental 
recovery (IR) of 2 IU/dL per IU/kg (based on values typically observed for FVIII products, 
including rFVIIIFc). Data from nonclinical studies have shown a BIVV001 procoagulation 
capacity per IU similar to those of other FVIII products.
The 2 dose levels considered for this study are expected to approximately bracket the therapeutic 
dose range. The physiological plasma FVIII activity level in healthy subjects is between 
50 and 150 IU/dL. The low dose (25 IU/kg) for this study is expected to provide a peak activity 
level close to the lower limit of this range and the high dose (65 IU/kg) to achieve a peak activity 
level under the upper limit, taking into account an anticipated IR of 2 IU/dL per IU/kg, as 
described above. Four-week, repeated-dose toxicity studies of BIVV001 in rats and monkeys 
revealed a NOAEL of 750 IU/kg (Section 4.3.1), which is a dose level that is 30 times (30×) 
higher than the low dose for this study, and approximately 11.5× higher than the high dose.
As this is the first study of BIVV001 in humans, a step-wise dosing and data review/monitoring
procedure (described in Section 7.1) will be followed in both the low-dose and high-dose cohorts 
to minimize the potential of adverse reactions occurring in several subjects. Additionally, 
following completion of dosing and data collection for the low-dose cohort, the Sponsor 
and an independent Data Safety Monitoring Committee (DSMC) will review all available data 
to determine the appropriateness of escalation to the higher BIVV001 dose; refer to Section 7.1
and Figure 1 for details.

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5.
SCHEDULES OF ACTIVITIES
Table 1:
Screening Schedule (Both BIVV001 Low-Dose and High-Dose Cohorts)
Tests and Assessments1
Screening Visit (Visit 1)2
Repeat Screening Visit if >56 Days Elapse 
Prior to Advate Dosing3
Day -28 to Day 1
Informed Consent4
X
Assessment of Subject Eligibility5
X
X
Demographics6
X
Medical, Surgical, and Hemophilia History7
X
X
CD4 Count, Viral Load (if known HIV+)8
X
X
HIV, HBV, and HCV Status9
X
X
Genotype, including 
 
10 (Optional)
X
Physical Examination (Including Height)
X
X
Vital Signs11
X
X
Weight
X
X
Hematology12
X
X
Clinical Chemistry13
X
X
Urinalysis14
X
X
Coagulation and Thrombosis Markers15
X
X
FVIII Activity (one-stage [aPTT-based] clotting and two-
stage chromogenic assays)16
X
X

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Tests and Assessments1
Screening Visit (Visit 1)2
Repeat Screening Visit if >56 Days Elapse 
Prior to Advate Dosing3
Day -28 to Day 1
X
X
Nijmegen-Modified Bethesda Assay for Inhibitor16
X
X
Anti-rFVIIIFc-VWF-XTEN Antibody16
X
X
Serum and Plasma Samples17 (Optional)
X
X
Adverse Event / Serious Adverse Event Reporting18
Ongoing: Monitor and record at all visits
Concomitant Treatment/Procedure Recording19
Ongoing: Monitor and record at all visits
BIV001 = rFVIIIFc-VWF-XTEN (recombinant coagulation factor VIII Fc - von Willebrand factor - XTEN fusion protein), BU = Bethesda units, FVIII = Factor 
VIII, HBV = hepatitis B virus, HCV = hepatitis C virus, HIV = human immunodeficiency virus, 
 
1
Unscheduled visits may be necessary during the study to repeat any blood sampling if required.
2
Screening may be accomplished over the course of more than 1 study visit if needed. The Screening Period may be extended up to 120 days with prior 
Sponsor approval. If the Screening Period extends beyond 56 days, screening assessments must be repeated as specified in the Repeat Screening Visit 
column prior to dosing with Advate. Repeat laboratory assessments do not require site visit; samples may be collected via a home-nursing visit. Non 
laboratory assessments may be conducted on the same day as Advate dosing. See Table 6 for instructions for washout prior to the Advate dose. See Table 7
for instructions for treatment of bleeding, if applicable.
3
This visit need not be performed at the site.  See Footnote 2 for details regarding Repeat Screening Visits.
4
Informed consent from the subject or the subject’s legal guardian MUST be obtained prior to any study-related procedures, including washout of current 
therapy specifically for entry into the study. Subject assent must also be obtained where applicable (according to the study site’s geographic region).
5
For Repeat Screening Visit, update with any changes since original Screening Visit.
6
Demographics include sex, race, ethnicity, and date of birth (year only), as permitted by local regulations. Race and ethnicity will be collected for reasons 
described in Section 17.4.
7
Includes 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.
8
For subjects 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.
9
For subjects who have been historically negative, assess HIV, HBV, and HCV status with central laboratory test.
10
Collection of samples for genotype analysis (as permitted by local regulations and ethics committees) will be governed by a separate informed consent form 
(ICF). 
 Subjects may opt out of these assessments.
11
Vital signs include blood pressure, pulse rate, respiratory rate, and temperature (°C). Vital signs should be taken after the subject has been resting supine for 
5 minutes. Vital signs should also be taken at any unscheduled visit.

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12
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 any FVIII dosing, including dosing with the most recent prior FVIII 
(prestudy FVIII).
13
Clinical chemistry parameters include alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamyl 
transferase (GGT), bilirubin, blood urea nitrogen (BUN), creatinine, glucose, total protein, sodium, potassium, and chloride. Blood samples for clinical 
chemistry analysis will be collected prior to any FVIII dosing, including dosing with the most recent prior FVIII (prestudy FVIII).
14
Urinalysis parameters include specific gravity, pH, color, appearance, leukocyte esterase, protein, glucose, ketones, occult blood, bilirubin, urobilinogen, 
nitrite, and microscopic examination of urine sediment. Urine samples for urinalysis will be collected prior to any FVIII dosing, including dosing with the 
most recent prior FVIII (prestudy FVIII).
15
Coagulation and thrombosis markers include prothrombin time (PT), activated partial thromboplastin time (aPTT), D-dimer, international normalized ratio 
(INR), thrombin anti-thrombin (TAT) complex, prothrombin fragment 1.2, and the von Willebrand comprehensive panel (which includes assessments of 
von Willebrand Factor [VWF] ristocetin cofactor activity, and VWF antigen). Analysis of VWF multimers will be for future testing. Blood samples for 
analysis of coagulation and thrombosis markers will be collected prior to any FVIII dosing, including dosing with the most recent prior FVIII (prestudy 
FVIII). 
16
Trough sample only (collected prior to any prestudy FVIII dosing), to confirm severe hemophilia A (i.e., endogenous FVIII <1%) and to confirm that 
washout has occurred prior to inhibitor testing. This sample should be collected at the same time point as the inhibitor and anti-drug antibody (ADA) 
samples. Washout of at least 96 hours (for subjects on conventional FVIII product) and 120 hours (for subjects on EHL product) prior to sample collection
is required. Separate samples for anti-rFVIIIFc-VWF-XTEN antibody (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). Inhibitor and ADA samples will be collected 
prior to dosing on the day of any prestudy FVIII dosing. 
All inhibitor assays, including the assay for the Screening Visit and any confirmatory assays, will be performed by the central laboratory using 
the Nijmegen-modified Bethesda assay. If a Nijmegen-modified Bethesda assay result returns as ≥0.6 BU/mL, a separate sample must be collected 
and tested for confirmation of inhibitor development within 2 to 4 weeks. 
Testing for potential antibody 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 Fc, FVIII, D′D3, or XTEN.
17
Samples will be collected prior to any prestudy FVIII dosing and will be archived for testing by the central laboratory (if required) for future research, e.g., 
immunology assays, further coagulation assays, or clarification of any clinical or laboratory AE, etc. These tests will be governed by a separate ICF; 
subjects may opt out of these assessments.
18
Adverse events and serious adverse events (SAEs) occurring after signing of ICF through the End of Study (EOS)/ Early Termination (ET) evaluations will 
be recorded on the case report form (CRF). Adverse events and SAEs should also be recorded at unscheduled visits.
19
Concomitant medications and procedures from up to 30 days prior to screening through the EOS/ET evaluations will be recorded on the CRF.

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Table 2:
Advate Dosing and Pharmacokinetics Sampling Schedule (Both Low-Dose and High-Dose Cohorts)
Tests and Assessments1
Advate Dosing Visit (Visit 2; Day 1)2
Advate PK Visits
(Visits 3 Through 5)
Visit 2
Visit 3
Visit 4
Visit 5
Predose
Advate 
Dosing
30 min
(±5 min)
1 h
(±10 min)
6 h
(±10 min)
24 h
(±1 h)
48 h
(±2 h)
72 h
(±2 h)
Assessment of Subject Eligibility
X
Vital Signs3
X
X
X
X
X
X
X
Weight4
X
Hematology5
X
Clinical Chemistry6
X
Urinalysis7
X
Coagulation and Thrombosis Markers8
X
X
X
X
FVIII Activity (one-stage clotting assay and chromogenic assay)
X 2
X
X
X
X
X
X
X
X
X
X
X
X
X
Nijmegen-Modified Bethesda Assay for Inhibitor9
X 
Anti-rFVIIIFc-VWF-XTEN Antibody9
X
Serum and Plasma Samples10 (Optional)
X
Advate Dosing (in clinic)
X
Adverse Event / Serious Adverse Event Recording11
Ongoing: Monitor and record at all visits
Concomitant Treatment/Procedure Recording12
Ongoing: Monitor and record at all visits

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BIV001 = rFVIIIFc-VWF-XTEN (recombinant coagulation factor VIII Fc - von Willebrand factor - XTEN fusion protein), BU = Bethesda units, FVIII = Factor 
VIII, PK = pharmacokinetics. 
1
Unscheduled visits may be necessary during the study to repeat any blood sampling if required.
2
See Table 6 for instructions for washout prior to the Advate and BIVV001 doses. See Table 7 for instructions for treatment of bleeding, if applicable. PK 
sampling time points are measured relative to the start of injection. The predose sample should be taken within 30 minutes prior to the Advate injection.
3
Vital signs include blood pressure, pulse rate, respiratory rate, and temperature (°C). Vital signs should be taken after the subject has been resting supine for 
5 minutes. Vital signs should also be taken at any unscheduled visit.
4
On the dosing day, weight will be used to calculate the Advate dose.
5
Hematology parameters include RBC count, WBC count and differential, platelet count, Hgb, and Hct. Blood samples for hematology analysis will be 
collected prior to any FVIII dosing, including dosing with the most recent prior FVIII (prestudy FVIII).
6
Clinical chemistry parameters include ALT, AST, ALP, GGT, bilirubin, BUN, creatinine, glucose, total protein, sodium, potassium, and chloride. Blood 
samples for clinical chemistry analysis will be collected prior to any FVIII dosing, including dosing with the most recent prior FVIII (prestudy FVIII).
7
Urinalysis parameters include specific gravity, pH, color, appearance, leukocyte esterase, protein, glucose, ketones, occult blood, bilirubin, urobilinogen, 
nitrite, and microscopic examination of urine sediment. Urine samples for urinalysis will be collected prior to any FVIII dosing, including dosing with the 
most recent prior FVIII (prestudy FVIII).
8
Coagulation and thrombosis markers include PT, aPTT, D-dimer, INR, TAT complex, prothrombin fragment 1.2, and the von Willebrand comprehensive 
panel (which includes assessments of von Willebrand Factor [VWF] ristocetin cofactor activity, and VWF antigen., Analysis of VWF multimers will be for 
future testing. Blood samples for analysis of coagulation and thrombosis markers will be collected prior to any FVIII dosing, including dosing with the 
most recent prior FVIII (prestudy FVIII).
9
Washout of at least 96 hours for conventional products and at least 120 hours for EHL products prior to sample collection is required. Separate samples for 
anti-rFVIIIFc-VWF-XTEN antibody (anti-drug antibody; 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). Inhibitor and ADA samples will be collected prior to dosing on 
the day of Advate dosing.
All inhibitor assays, including the assay for the Screening Visit and any confirmatory assays, will be performed by the central laboratory using 
the Nijmegen-modified Bethesda assay. If a Nijmegen-modified Bethesda assay result returns as ≥0.6 BU/mL, a separate sample must be collected 
and tested for confirmation of inhibitor development within 2 to 4 weeks.
Testing for potential antibody 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 Fc, FVIII, D′D3, or XTEN.
10
Samples will be archived for testing by the central laboratory (if required) for future research, e.g., immunology assays, further coagulation assays, or 
clarification of any clinical or laboratory AE, etc. These tests will be governed by a separate ICF; subjects may opt out of these assessments.
11
Adverse events and SAEs occurring after signing of the (ICF through the EOS/ET evaluations will be recorded on the CRF. Adverse events and SAEs
should also be recorded at unscheduled visits.
12
Concomitant medications and procedures from up to 30 days prior to screening through the EOS/ET evaluations will be recorded on the CRF.

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Table 3:
BIVV001 Dosing and Pharmacokinetics Sampling Schedule (BIVV001 Low-Dose Cohort Only)
Tests and 
Assessments1
BIVV001 Dosing Visit2
(After Advate Dosing Visit)
BIVV001 PK Visits (Visits 7 Through 13a) 
and 14-Day Inhibitor Test Visit (Visit 14)1
Visit 
7
Visit 
8
Visit 
9
Visit 
10
Visit 
11
Visit 
12
Visit 
13a
14-Day 
Inhibitor 
Test
Visit3
Visit 64
Visit 14
Pre-
dose
BIVV001 
Dosing 
10
min
(±2 
min)
30 
min
(±5 
min)
1 h
(±10
min)
3 h
(±10 
min)
6 h 
(±10 
min)
9 h 
(±10 
min)
24 h 
(±1 h)
48 h
(±2 h)
72 h
(±2 h)
96 h
(±2 h)
120 h
(±2 h)
168 h
(±2 h)
240 h 
(±2 h)
336 h 
(±24 h for 
low-dose 
cohort)
Vital Signs5
X
X
X
X
X
X
X
X
X
X
Weight6
X
X
Hematology7
X
X
Clinical Chemistry8
X
X
Urinalysis9
X
X
Coagulation and 
Thrombosis 
Markers10
X
X
X
X
X
FVIII Activity
(one-stage clotting 
assay and 
chromogenic assays)
X 2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Nijmegen-Modified 
Bethesda Assay for 
Inhibitor11
X
X

Protocol 242HA101
Version 6.0
BIVV001 (rFVIIIFc-VWF-XTEN) Safety and Pharmacokinetics Study
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Bioverativ Therapeutics Inc.
27
Tests and 
Assessments1
BIVV001 Dosing Visit2
(After Advate Dosing Visit)
BIVV001 PK Visits (Visits 7 Through 13a) 
and 14-Day Inhibitor Test Visit (Visit 14)1
Visit 
7
Visit 
8
Visit 
9
Visit 
10
Visit 
11
Visit 
12
Visit 
13a
14-Day 
Inhibitor 
Test
Visit3
Visit 64
Visit 14
Pre-
dose
BIVV001 
Dosing 
10
min
(±2 
min)
30 
min
(±5 
min)
1 h
(±10
min)
3 h
(±10 
min)
6 h 
(±10 
min)
9 h 
(±10 
min)
24 h 
(±1 h)
48 h
(±2 h)
72 h
(±2 h)
96 h
(±2 h)
120 h
(±2 h)
168 h
(±2 h)
240 h 
(±2 h)
336 h 
(±24 h for 
low-dose 
cohort)
Anti-rFVIIIFc-
VWF-XTEN 
Antibody11
X
X
Serum and Plasma 
Samples12
(Optional)
X
X
BIVV001 Dosing 
(in clinic)
X
Adverse Event / 
Serious Adverse 
Event Recording13
Ongoing: Monitor and record at all visits
Concomitant 
Treatment/ 
Procedure 
Recording14
Ongoing: Monitor and record at all visits
BIV001 = rFVIIIFc-VWF-XTEN (recombinant coagulation factor VIII Fc – von Willebrand factor – XTEN fusion protein), BU = Bethesda units, 
FVIII = Factor VIII. 
1
Unscheduled visits may be necessary during the study for safety and/or to repeat any blood sampling if required.
2
See Table 6 for instructions for washout prior to the BIVV001 dose. See Table 7 for instructions for treatment of bleeding, if applicable. PK sampling time 
points are measured relative to the start of injection. The predose sample should be taken within 30 minutes prior to the BIVV001 injection.
3
Subjects may resume treatment with their prestudy FVIII after completion of Visit 14 activities.
4
Visit 6 may be combined with Visit 5 for subjects in the low-dose cohort. If Visits 5 and 6 are combined, Visit 5 assessments may be performed at Visit 6.

Protocol 242HA101
Version 6.0
BIVV001 (rFVIIIFc-VWF-XTEN) Safety and Pharmacokinetics Study
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Bioverativ Therapeutics Inc.
28
5
Vital signs include blood pressure, pulse rate, respiratory rate, and temperature (°C). Vital signs should be taken after the subject has been resting supine 
for 5 minutes. Vital signs should also be taken at any unscheduled visit.
6
On the dosing day, weight will be used to calculate the BIVV001 dose.
7
Hematology parameters include RBC count, WBC count and differential, platelet count, Hgb, and Hct. Blood samples for hematology analysis will be 
collected prior to any FVIII dosing, including dosing with the most recent prior FVIII (prestudy FVIII).
8
Clinical chemistry parameters include ALT, AST, ALP, GGT, bilirubin, BUN, creatinine, glucose, total protein, sodium, potassium, and chloride. Blood 
samples for clinical chemistry analysis will be collected prior to any FVIII dosing, including dosing with the most recent prior FVIII (prestudy FVIII).
9
Urinalysis parameters include specific gravity, pH, color, appearance, leukocyte esterase, protein, glucose, ketones, occult blood, bilirubin, urobilinogen, 
nitrite, and microscopic examination of urine sediment. Urine samples for urinalysis will be collected prior to any FVIII dosing, including dosing with the 
most recent prior FVIII (prestudy FVIII).
10
Coagulation and thrombosis markers include PT, aPTT, D-dimer, INR, TAT complex, prothrombin fragment 1.2, and the von Willebrand comprehensive 
panel (which includes assessments of VWF ristocetin cofactor activity, and VWF antigen. Analysis of VWF multimers will be for future testing. Blood 
samples for analysis of coagulation and thrombosis markers will be collected prior to any FVIII dosing, including dosing with the most recent prior FVIII 
(prestudy FVIII).
11
Washout of at least 3 days (72 hours) prior to sample collection is required. See Table 7 for instructions for treatment of bleeding. Separate samples for 
anti-rFVIIIFc-VWF-XTEN antibody (anti-drug antibody; 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). Inhibitor and ADA samples will be collected prior to dosing 
on the day of BIVV001 dosing.
All inhibitor assays, including the assay for the Screening Visit and any confirmatory assays, will be performed by the central laboratory using 
the Nijmegen-modified Bethesda assay. If a Nijmegen-modified Bethesda assay result returns as ≥0.6 BU/mL, a separate sample must be collected 
and tested for confirmation of inhibitor development within 2 to 4 weeks.
Testing for potential antibody 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 Fc, FVIII, D′D3, or XTEN.
12
Samples will be archived for testing by the central laboratory (if required) for future research, e.g., immunology assays, further coagulation assays, 
clarification of any clinical or laboratory AE, etc. These tests will be governed by a separate ICF; subjects may opt out of these assessments.
13
Adverse events and SAEs occurring after signing of ICF through the EOS/ET evaluations will be recorded on the CRF. Adverse events and SAEs should 
also be recorded at unscheduled visits.
14
Concomitant medications and procedures from up to 30 days prior to screening through the EOS/ET evaluations will be recorded on the CRF.

Protocol 242HA101
Version 6.0
BIVV001 (rFVIIIFc-VWF-XTEN) Safety and Pharmacokinetics Study
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Bioverativ Therapeutics Inc.
29
Table 4:
BIVV001 Dosing and Pharmacokinetics Sampling Schedule (BIVV001 High-Dose Cohort Only)
Tests and 
Assessments1
BIVV001 Dosing Visit2
(After Advate Dosing Visit)
BIVV001 PK Visits (Visits 7 Through 13b) 
and 14-Day Inhibitor Test Visit (Visit 14)1
Visit 
7
Visit 
8
Visit 
9
Visit 
10
Visit 
11
Visit 
12
Visit 
13a
Visit 
13b
14-Day 
Inhibitor 
Test Visit
3
Visit 6
Visit 14
Pre-
dose
BIVV001 
Dosing 
10 
min 
(±2 
min)
30 
min 
(±5 
min)
1 h 
(±10 
min)
3 h
(±10 
min)
6 h 
(±10 
min)
9 h 
(±10 
min)
24 h 
(±1 h)
48 h
(±2 h)
72 h
(±2 h)
96 h
(±2 h)
120 h
(±2 h)
168 h
(±2 h)
240 h 
(±2 h)
288 h
(±2 h)
336 h 
(±24 h for 
high-dose 
cohort)
Vital Signs4
X
X
X
X
X
X
X
X
X
X
Weight5
X
X
Hematology6
X
X
Clinical Chemistry 7
X
X
Urinalysis8
X
X
Coagulation and 
Thrombosis 
Markers9
X
X
X
X
X
FVIII Activity 
(one-stage clotting 
assay and 
chromogenic assay)
X2
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

Protocol 242HA101
Version 6.0
BIVV001 (rFVIIIFc-VWF-XTEN) Safety and Pharmacokinetics Study
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Bioverativ Therapeutics Inc.
30
Tests and 
Assessments1
BIVV001 Dosing Visit2
(After Advate Dosing Visit)
BIVV001 PK Visits (Visits 7 Through 13b) 
and 14-Day Inhibitor Test Visit (Visit 14)1
Visit 
7
Visit 
8
Visit 
9
Visit 
10
Visit 
11
Visit 
12
Visit 
13a
Visit 
13b
14-Day 
Inhibitor 
Test Visit
3
Visit 6
Visit 14
Pre-
dose
BIVV001 
Dosing 
10 
min 
(±2 
min)
30 
min 
(±5 
min)
1 h 
(±10 
min)
3 h
(±10 
min)
6 h 
(±10 
min)
9 h 
(±10 
min)
24 h 
(±1 h)
48 h
(±2 h)
72 h
(±2 h)
96 h
(±2 h)
120 h
(±2 h)
168 h
(±2 h)
240 h 
(±2 h)
288 h
(±2 h)
336 h 
(±24 h for 
high-dose 
cohort)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Nijmegen-Modified 
Bethesda Assay for 
Inhibitor10
X
X
Anti-rFVIIIFc-
VWF-XTEN 
Antibody10
X
X
Serum and Plasma 
Samples11
(Optional)
X
X
BIVV001 Dosing 
(in clinic)
X
Adverse Event / 
Serious Adverse 
Event Recording12
Ongoing: Monitor and record at all visits
Concomitant 
Treatment/ 
Procedure 
Recording13
Ongoing: Monitor and record at all visits

Protocol 242HA101
Version 6.0
BIVV001 (rFVIIIFc-VWF-XTEN) Safety and Pharmacokinetics Study
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Bioverativ Therapeutics Inc.
31
BIV001 = rFVIIIFc-VWF-XTEN (recombinant coagulation factor VIII Fc - von Willebrand factor - XTEN fusion protein), BU = Bethesda units, FVIII = Factor 
VIII, PK = pharmacokinetics. 
1
Unscheduled visits may be necessary during the study to repeat any blood sampling if required.
2
See Table 6 for instructions for washout prior to the BIVV001 dose. See Table 7 for instructions for treatment of bleeding, if applicable. PK sampling time 
points are measured relative to the start of injection. The predose sample should be taken within 30 minutes prior to the BIVV001 injection.
3
For the high-dose cohort, the 14-day Inhibitor Test Visit will coincide with the 336 hour (14 day) visit for BIVV001 PK sampling at Visit 14. Subjects may 
resume treatment with their prestudy FVIII after completion of Visit 14 activities. 
4
Vital signs include blood pressure, pulse rate, respiratory rate, and temperature (°C). Vital signs should be taken after the subject has been resting supine for 
5 minutes. Vital signs should also be taken at any unscheduled visit.
5
On the dosing day, weight will be used to calculate the BIVV001 dose.
6
Hematology parameters include RBC count, WBC count and differential, platelet count, Hgb, and Hct. Blood samples for hematology analysis will be 
collected prior to any FVIII dosing, including dosing with the most recent prior FVIII (prestudy FVIII).
7
Clinical chemistry parameters include ALT, AST, ALP, GGT, bilirubin, BUN, creatinine, glucose, total protein, sodium, potassium, and chloride. Blood 
samples for clinical chemistry analysis will be collected prior to any FVIII dosing, including dosing with the most recent prior FVIII (prestudy FVIII).
8
Urinalysis parameters include specific gravity, pH, color, appearance, leukocyte esterase, protein, glucose, ketones, occult blood, bilirubin, urobilinogen, 
nitrite, and microscopic examination of urine sediment. Urine samples for urinalysis will be collected prior to any FVIII dosing, including dosing with the 
most recent prior FVIII (prestudy FVIII).
9
Coagulation and thrombosis markers include PT, aPTT, D-dimer, INR, TAT complex, prothrombin fragment 1.2, and the von Willebrand comprehensive 
panel (which includes assessments of VWF ristocetin cofactor activity, and VWF antigen). Analysis of VWF multimers will be for future testing. Blood 
samples for analysis of coagulation and thrombosis markers will be collected prior to any FVIII dosing, including dosing with the most recent prior FVIII 
(prestudy FVIII).
10
Washout of at least 4 days (96 hours) prior to sample collection is required. See Table 7 for instructions for treatment of bleeding. Separate samples for 
anti-rFVIIIFc-VWF-XTEN antibody (anti-drug antibody; 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). Inhibitor and ADA samples will be collected prior to dosing on 
the day of BIVV001 dosing.
All inhibitor assays, including the assay for the Screening Visit and any confirmatory assays, will be performed by the central laboratory using 
the Nijmegen-modified Bethesda assay. If a Nijmegen-modified Bethesda assay result returns as ≥0.6 BU/mL, a separate sample must be collected 
and tested for confirmation of inhibitor development within 2 to 4 weeks.
Testing for potential antibody 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 Fc, FVIII, D′D3, or XTEN.
11
Samples will be archived for testing by the central laboratory (if required) for future research, e.g., immunology assays, further coagulation assays, 
clarification of any clinical or laboratory AE, etc. These tests will be governed by a separate ICF; subjects may opt out of these assessments.
12
Adverse events and SAEs occurring after signing of the ICF through the EOS/ET evaluations will be recorded on the CRF. Adverse events and SAEs 
should also be recorded at unscheduled visits.
13
Concomitant medications and procedures from up to 30 days prior to screening through the EOS/ET evaluations will be recorded on the CRF.

Protocol 242HA101
Version 6.0
BIVV001 (rFVIIIFc-VWF-XTEN) Safety and Pharmacokinetics Study
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Bioverativ Therapeutics Inc.
32
Table 5:
End-of-Study / Early Termination Evaluation Schedule for Advate and BIVV001 (Both Low-Dose 
and High Dose Cohorts)
Tests and Assessments 1
End of Study/Early Termination2
Visit 15 3
Post-Advate Follow-Up Safety
Telephone Call 4
28 days (±5 days) after BIVV001 dose 
Physical Examination
X
Vital Signs5
X
Weight
X
Hematology6
X
Clinical Chemistry7
X
Urinalysis8
X
Coagulation and Thrombosis Markers9
X
FVIII Activity (one-stage clotting assay and chromogenic assay)
X 
X
Nijmegen-Modified Bethesda Assay for Inhibitor10
X
Anti-rFVIIIFc-VWF-XTEN Antibody10
X
Serum and Plasma Samples11 (Optional)
X
Follow-Up Safety Telephone Call
X
Adverse Event / Serious Adverse Event Recording12
Ongoing: Monitor and record at all visits
Concomitant Treatment/Procedure Recording13
Ongoing: Monitor and record at all visits

Protocol 242HA101
Version 6.0
BIVV001 (rFVIIIFc-VWF-XTEN) Safety and Pharmacokinetics Study
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Bioverativ Therapeutics Inc.
33
BIV001 = rFVIIIFc-VWF-XTEN (recombinant coagulation factor VIII Fc – von Willebrand factor – XTEN fusion protein), BU = Bethesda units, 
FVIII = Factor VIII, PK = pharmacokinetics.
1
Unscheduled visits may be necessary during the study to repeat any blood sampling if required.
2
If a subject is withdrawn from the study early, the Investigator will make every effort to complete and report the reason(s) for withdrawal as thoroughly as 
possible on the subject’s CRF. Subjects who withdraw from the study may be replaced; refer to Section 10.1.3.
3
The activities listed in this column will be performed for the following subjects: those who were administered BIVV001 and successfully completed 
the 28-day safety observation period; those who were administered BIVV001 but were withdrawn from the study (for any reason other than withdrawal 
of consent) prior to completing the 28-day safety observation period (refer to Section 10.1.2). Subjects who complete these activities (whether performed 
at the conclusion of the 28-day safety observation period or as an early-termination visit) are not required to participate in the post-Advate follow-up safety 
telephone call.
4
The post-Advate follow-up safety telephone call is required for subjects who were withdrawn from the study (for any reason other than withdrawal of 
consent) prior to BIVV001 administration (refer to Section 10.1.1 for withdrawal criteria). The telephone call must be completed between 7 to 14 days from 
the time of Advate administration, or as soon as possible thereafter.
5
Vital signs include blood pressure, pulse rate, respiratory rate, and temperature (°C). Vital signs should be taken after the subject has been resting supine 
for 5 minutes. Vital signs should also be taken at any unscheduled visit.
6
Hematology parameters include RBC count, WBC count and differential, platelet count, Hgb, and Hct. Blood samples for hematology analysis will be 
collected prior to any FVIII dosing, including dosing with the most recent prior FVIII (prestudy FVIII).
7
Clinical chemistry parameters include ALT, AST, ALP, GGT, bilirubin, BUN, creatinine, glucose, total protein, sodium, potassium, and chloride. Blood 
samples for clinical chemistry analysis will be collected prior to any FVIII dosing, including dosing with the most recent prior FVIII (prestudy FVIII).
8
Urinalysis parameters include specific gravity, pH, color, appearance, leukocyte esterase, protein, glucose, ketones, occult blood, bilirubin, urobilinogen, 
nitrite, and microscopic examination of urine sediment. Urine samples for urinalysis will be collected prior to any FVIII dosing, including dosing with the 
most recent prior FVIII (prestudy FVIII).
9
Coagulation and thrombosis markers include PT, aPTT, D-dimer, INR, TAT complex, prothrombin fragment 1.2, and the von Willebrand comprehensive 
panel (which includes assessments of VWF ristocetin cofactor activity, and VWF antigen. Analysis of VWF multimers will be for future testing. Blood 
samples for analysis of coagulation and thrombosis markers will be collected prior to any FVIII dosing, including dosing with the most recent prior FVIII 
(prestudy FVIII).
10 Washout of at least 48 hours prior to the inhibitor test is required. Separate samples for anti-rFVIIIFc-VWF-XTEN antibody (anti-drug antibody; 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). Inhibitor and ADA samples will be collected prior to dosing on the day of any prestudy FVIII dosing.
All inhibitor assays, including the assay for the Screening Visit and any confirmatory assays, will be performed by the central laboratory using 
the Nijmegen-modified Bethesda assay. If a Nijmegen-modified Bethesda assay result returns as ≥0.6 BU/mL, a separate sample must be collected 
and tested for confirmation of inhibitor development within 2 to 4 weeks.
Testing for potential antibody 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 Fc, FVIII, D′D3, or XTEN.
11 Samples will be archived for testing by the central laboratory (if required) for future research, e.g., immunology assays, further coagulation assays, 
clarification of any clinical or laboratory AE, etc. These tests will be governed by a separate ICF; subjects may opt out of these assessments. 
12 Adverse events and SAEs occurring after signing of the ICF through the EOS/ET evaluations will be recorded on the CRF. Adverse events and SAEs should 
also be recorded at unscheduled visits.
13 Concomitant medications and procedures from up to 30 days prior to screening through the EOS/ET evaluations will be recorded on the CRF.

Protocol 242HA101
Version 6.0
BIVV001 (rFVIIIFc-VWF-XTEN) Safety and Pharmacokinetics Study
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Bioverativ Therapeutics Inc.
34
Table 6:
Instructions for Washout, Dosing, and Pharmacokinetic Sampling
The following steps are to be followed if no bleeding episode occurs:
Screening
Subjects may continue prophylaxis with their most recent previous FVIII product (referred to as prestudy FVIII), except during the following activities:

The washout prior to Screening test of FVIII activity and inhibitor tests and prior to Advate dose administration: this washout duration must be at 
least 96 hours (4 days) if the prestudy FVIII is a conventional product; it must be at least 120 hours (5 days) if the prestudy FVIII is an EHL 
product.
Advate PK sampling

PK sampling duration is 72 hours (3 days) for both the low-dose and high-dose cohort.
Washout prior to BIVV001 dose

Washout duration is at least 72 hours (3 days) after a low dose of Advate; the duration is at least 96 hours (4 days) after a high dose of Advate. This 
washout duration may overlap with the Advate PK sampling period.
BIVV001 dose and PK sampling

The BIVV001 dose must be administered 3 (+1) days in the low-dose cohort after the Advate dose, and 4 (+1) days in the high-dose cohort after the 
Advate dose.

PK sampling duration is 10 days for the low-dose cohort and 14 days for the high-dose cohort. 
After completion of Visit 14 activities (which include the 14-day inhibitor test)

Subjects may resume treatment with their prestudy FVIII therapy

If the subject resumes prestudy FVIII during this time, a washout of at least 48 hours is required prior to sample collection for the End of Study 
(EOS)/Early Termination (ET) inhibitor test
BIV001 = rFVIIIFc-VWF-XTEN (recombinant coagulation factor VIII Fc - von Willebrand factor - XTEN fusion protein), FVIII = Factor VIII, 
PK = pharmacokinetics.

Protocol 242HA101
Version 6.0
BIVV001 (rFVIIIFc-VWF-XTEN) Safety and Pharmacokinetics Study
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Bioverativ Therapeutics Inc.
35
Table 7:
Instructions for Treatment of Bleeding Episodes
Investigator must instruct the subject on the pre-study FVIII regimen for treatment of bleeding episodes. Please refer to the Study 
Reference Guide for details regarding the treatment of bleeding episodes during the study.
If the bleed occurs:
Take the following action(s):
During screening prior to the pre-Advate 
washout1
Treat the bleeding episode with prestudy FVIII
Subsequent steps as described in Table 6
During washout prior to Advate dose 1
Treat the bleeding episode with prestudy FVIII
If 1 bleeding episode occurs during this period:

Repeat washout prior to Advate:

Washout duration may be modified to at least 96 hours (4 days) if the prestudy FVIII is a 
conventional product; washout duration is at least 120 hours (5 days) if EHL product

Subsequent steps as described in Table 6
If more than 1 bleeding episode occurs during this period: discontinue the subject from further study 
participation.2 As these events occurred prior to study enrollment, the subject will be designated a screen failure.
During the PK sampling period for 
Advate
Treat the bleeding episode with prestudy FVIII
If 1 bleeding episode occurs during this period:

Repeat washout prior to Advate:

Washout duration may be modified to at least 96 hours (4 days) if the prestudy FVIII is a 
conventional product; washout duration is at least 120 hours (5 days) if EHL product 

Repeat Advate dose and PK sampling

Subsequent steps as described in Table 6
If more than 1 bleeding episode occurs or more than 28 days elapse as a result of a bleeding episode between the 
Advate dose and the planned BIVV001 dose: discontinue further study treatment and end further PK sampling.2
The subject must participate in a post-Advate follow-up safety telephone call (Table 5; Section 10.1.1) to be 
officially withdrawn from the study. 

Protocol 242HA101
Version 6.0
BIVV001 (rFVIIIFc-VWF-XTEN) Safety and Pharmacokinetics Study
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Bioverativ Therapeutics Inc.
36
If the bleed occurs:
Take the following action(s):
During the washout prior to BIVV001 
dose and after completion of Advate 
PK sampling (if applicable)
Treat the bleeding episode with prestudy FVIII
If no more than 28 days elapse between the Advate dose and the planned BIVV001 dose:

Repeat washout prior to BIVV001

Washout duration is at least 96 hours (4 days) after the FVIII dose for a conventional product 
or at least 120 hours (5 days) if EHL product 

Subsequent steps as described in Table 6
If more than 1 bleeding episode occurs or 28 days elapse as a result of a bleeding event between the Advate dose 
and the planned BIVV001 dose: discontinue further study treatment and end further PK sampling.2 The subject 
must participate in a post-Advate follow-up safety telephone call (Table 5; Section 10.1.1) to be officially
withdrawn from the study. 
During the PK sampling period for 
BIVV001
Treat the bleeding episode with prestudy FVIII.
End further PK sampling. The subject will remain in the study to complete the remaining inhibitor and other 
safety assessments of the 28-day safety observation period and the EOS/ET evaluations (Table 5).2
During follow-up after completion of 
Visit 14 activities 
After completion of Visit 14 activities (which includes the 14-day inhibitor test), subjects may resume treatment 
with their prestudy FVIII.

Treat the bleeding episode with prestudy FVIII

If a subject experiences two or more spontaneous bleeds between Day 14 and Day 28, the 
investigator will notify the sponsor.

If the subject resumes prestudy FVIII during this time, a washout of at least 48 hours is required 
prior to sample collection for the EOS/ET inhibitor test.
BIV001 = rFVIIIFc-VWF-XTEN (recombinant coagulation factor VIII Fc - von Willebrand factor - XTEN fusion protein), FVIII = Factor VIII, 
PK = pharmacokinetics.
1
The Screening Period (including the washout prior to Advate) may be extended up to 120 days with prior Sponsor approval. If the Screening Period extends 
beyond 56 days, screening assessments must be repeated as specified in Table 1 prior to dosing with Advate. Repeat laboratory assessments do not require 
site visit; samples may be collected via a home-nursing visit. Non-laboratory assessments may be conducted on the same day as Advate dosing.
2
Replace the subject if needed to ensure that at least 6 subjects from the low-dose cohort and at least 8 subjects from the high-dose cohort provide evaluable 
PK and inhibitor data.

Protocol 242HA101
Version 6.0
BIVV001 (rFVIIIFc-VWF-XTEN) Safety and Pharmacokinetics Study
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Bioverativ Therapeutics Inc.
37
6.
STUDY OBJECTIVES AND ENDPOINTS
6.1.
Primary Objective and Endpoints
The primary objective is to assess the safety and tolerability of a single IV administration 
of BIVV001 in adult previously treated patients (PTPs) with severe hemophilia A.
The primary endpoints are as follows:

The occurrence of adverse events (AEs) 

The occurrence of clinically significant abnormalities in laboratory tests, including 
development of inhibitors (neutralizing antibodies directed against FVIII) 
as determined by the Nijmegen-modified Bethesda assay.
6.2.
Secondary Objective and Endpoints 
The secondary objective is to characterize the PK of BIVV001 after a single IV administration 
compared with the PK of Advate, with FVIII activity determined by the one-stage (activated 
partial thromboplastin time [aPTT]-based) clotting assay.
The secondary endpoints are PK parameters, including but not limited to the following:
maximum activity (Cmax); t½; CL; volume of distribution at steady state (Vss); area under the 
concentration-time curve from time 0 to infinity (AUC∞); mean residence time (MRT); IR; 
and time to 1% above baseline for FVIII activity.
6.3.
Exploratory Objective and Endpoints 
The exploratory objective is to characterize the PK of BIVV001 after a single IV administration 
compared with the PK of Advate, with FVIII activity determined by the two-stage chromogenic 
assay.
The exploratory endpoints are PK parameters, including but not limited to the following: Cmax, 
t½, CL, Vss, AUC∞, MRT, IR, and time to 1% above baseline for FVIII activity. 

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7.
STUDY DESIGN
7.1.
Study Overview
This is a Phase 1/2a, open-label, dose-escalation, multicenter study designed to evaluate the 
safety, tolerability, and PK of a single IV dose of BIVV001 in subjects with severe hemophilia A 
who have received at least 150 exposure days (EDs) of prior FVIII treatment. 
Approximately 18 male PTPs aged 18 to 65 years will be enrolled: approximately 8 subjects 
in the low-dose cohort (Advate 25 IU/kg and BIVV001 25 IU/kg) and approximately 10 subjects 
in the high-dose cohort (Advate 65 IU/kg and BIVV001 65 IU/kg). Each subject will be dosed 
with Advate followed by a PK sampling period. Following a brief washout period, each subject 
will then be administered BIVV001 followed by a PK sampling period. Subjects will undergo 
safety observation for 28 days following the injection of BIVV001, including sample collection 
for inhibitor assessments 14 and 28 days after the injection of BIVV001 (refer to Figure 1
and Sections 11.1.1 and 11.1.2 for details on treatment and sample collection regimens).
Only subjects who are able to provide adequate samples for PK and inhibitor characterization 
following both Advate and BIVV001 dosing will be considered to be evaluable; additional 
subjects will be enrolled as needed to ensure that at least 6 subjects in the low-dose cohort 
and 8 subjects in the high-dose cohort provide evaluable PK and inhibitor data.
To minimize the potential of adverse reactions occurring in several subjects, the following 
step-wise procedures will be utilized to administer BIVV001:
1. For the low-dose cohort, data collected for inhibitor test results and other available safety 
assessments through 28 days post-BIVV001 dose for Subject 1 must be reviewed before 
permitting administration of BIVV001 to Subject 2, and the same data through 28 days 
post-BIVV001 dose must be reviewed before permitting administration of BIVV001 to 
Subject 3. After BIVV001 administration to Subject 3, data will be reviewed for inhibitor 
test results and other available safety assessments through 14 days post-BIVV001 dose, 
before permitting administration of BIVV001 to Subject 4 [Abbas 2007]. For Subjects 4
through 8 of this cohort, an interval of at least 72 hours must elapse between BIVV001 
dose administrations to successive subjects.
2. Before proceeding to the high-dose cohort, the Sponsor and the DSMC will review 
available data obtained from the low-dose cohort to determine whether it is appropriate 
to begin administration of the higher BIVV001 dose.
3. For the high-dose cohort, data collected for inhibitor test results and other available safety 
assessments through 28 days post-BIVV001 dose for Subject 1 must be reviewed before 
permitting administration of BIVV001 to Subject 2, and the same data through 28 days 
post-BIVV001 dose must be reviewed before permitting administration of BIVV001 to 
Subject 3. After BIVV001 administration to Subject 3, data will be reviewed for inhibitor 
test results and other available safety assessments through 14 days post-BIVV001 dose, 

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before permitting administration of BIVV001 to Subject 4 [Abbas 2007]. For Subjects 4 
through 10 of this cohort, an interval of at least 96 hours must elapse between BIVV001 
administrations to successive subjects. 
Refer to Figure 1 for a schematic of the study design.

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Figure 1:
Study Design 

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7.1.1.
Dose-Limiting Toxicity
Each subject in this study will receive a single IV dose of Advate (either 25 IU/kg or 65 IU/kg) 
and a single IV dose of BIVV001 (either 25 IU/kg or 65 IU/kg). Investigators will not be asked 
to determine dose-limiting toxicities (DLTs) in this study. Certain postdose events may result 
in a meeting between the Sponsor and DSMC to determine the appropriateness of dosing 
subsequent subjects. For details, refer to Section 7.6.1 (dose suspension) and Section 7.6.2
(dose termination).
7.2.
Overall Study Duration and Follow-Up
The study will consist of 3 periods: a 28-day screening period (extendable to 120 days; refer to 
Section 7.2.1); an Advate dosing and PK sampling period (which also includes an Advate 
washout that may overlap with PK sampling); a BIVV001 dosing and PK sampling period, and 
a 28-day safety observation period (in which PK sampling and safety observation will overlap 
during the first 10 to 14 days of this period). 
It is anticipated that subjects in the low-dose cohort will visit the study clinic approximately 4 to 
15 times, depending on how many home nursing visits occur: 4 of these visits will include medical 
evaluation and sample collection, while the other 11 visits will include sample collection only 
(refer to Table 2 and Table 3). For subjects in the high-dose cohort, it is anticipated that they will 
visit the clinic approximately 4 to 16 times, depending on how many home nursing visits occur:
4 of these visits will include medical evaluation and sample collection, while the other 12 visits 
will include sample collection only (refer to Table 2 and Table 4).
7.2.1.
Screening Period (Including Initial Wash Out)
The Screening Period for determination of subject eligibility is scheduled within 28 days prior 
to the dose of Advate (and may be extended up to 120 days with prior Sponsor approval); refer 
to Table 1. If the Screening Period extends beyond 56 days, screening assessments must be 
repeated as specified in Table 1 prior to dosing with Advate. The Screening Period includes 
washout of the subject’s prior FVIII treatment (hereinafter referred to as the prestudy FVIII) 
prior to screening assessments and prior to the Advate dosing and PK sampling period. Prestudy 
FVIII washout duration is at least 96 hours (4 days) from the most recent prestudy FVIII dose for 
subjects who received a conventional FVIII product and at least 120 hours (5 days) for subjects 
who received an EHL FVIII product (rFVIIIFc or other products). Washout procedures for 
conventional FVIII products may be modified if the subject experiences a bleeding episode. 
Refer to Table 6 for detailed washout instructions; refer to Table 7 for detailed instructions on 
the treatment of bleeding episodes. Subjects who do not meet eligibility requirements at 
screening will not be allowed to repeat screening at a later date. 
7.2.2.
Low-Dose Cohort
In the low-dose cohort, Advate and BIVV001 dosing will begin at 25 IU/kg. All doses of Advate 
and BIVV001 will be administered IV by the Investigator or his/her designee under medical 

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supervision, with an injection duration of 8 ± 2 minutes. Details describing the treatment and 
sample collection regimen for the low-dose cohort are provided in Section 11.1.1. 
The following are the key elements of the low-dose cohort:

After completing the Screening Period, subjects will receive a single IV dose of 
Advate followed by a 72-hour (3-day) PK sampling period; see Table 2. 

Prophylactic dosing with prestudy FVIII therapy is not permitted between Advate and 
BIVV001 dosing. 

After washout of Advate, subjects will receive a single open-label IV dose of 
25 IU/kg BIVV001 followed by a 240-hour (10-day) sampling period (see Table 3). 

To minimize the potential of adverse reactions occurring in several subjects, a 
step-wise dosing and data review/monitoring procedure will be followed between 
BIVV001 administrations to successive subjects in the low-dose cohort.

BIVV001 25 IU/kg must be administered 3 (+1) days following administration of 
25 IU/kg Advate. 

If the dose of BIVV001 cannot be administered per these guidelines, the 
administration of BIVV001 may occur within a window of up to 4 additional days at 
the discretion of the Investigator, i.e., up to 7 days following 25 IU/kg Advate. 

The Investigator must notify the sponsor and provide rationale if the dose of 
BIVV001 is administered beyond 96 hours (4 days) following Advate administration.

If a bleeding event is detected between Advate dosing and BIVV001 dosing, no more 
than 28 days may elapse between Advate and BIVV001 dosing (refer to the 
instructions in Table 7).
7.2.3.
Escalation to High-Dose Cohort
Upon availability of data from the low-dose cohort, the Sponsor and the DSMC will review the 
data and decide on the appropriateness of escalation to the high dose (65 IU/kg) as detailed in the 
DSMC charter. If the Sponsor and DSMC determine that dose escalation can proceed, additional 
new subjects will be enrolled in the high-dose cohort. 
7.2.4.
High-Dose Cohort
In the high-dose cohort, Advate and BIVV001 dosing will begin at 65 IU/kg. All doses of 
Advate and BIVV001 will be administered IV by the Investigator or his/her designee under 
medical supervision, with an injection duration of 8 ± 2 minutes. Details describing the treatment 
and sample collection regimen for the high-dose cohort are provided in Section 11.1.2. 

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The following are the key elements of the high-dose cohort:

After completing the Screening Period, subjects will receive a single IV dose of 
Advate followed by a 72-hour (3-day) sampling period (see Table 2).

Prophylactic dosing with prestudy FVIII therapy is not permitted between Advate and 
BIVV001 dosing. 

After washout of Advate, subjects will receive a single open-label IV dose of 
BIVV001 followed by a 336-hour (14-day) sampling period (see Table 4).

As with the low-dose cohort, an identical, step-wise dosing and data 
review/monitoring procedure will be followed between BIVV001 administrations to 
successive subjects in the high-dose cohort (Section 7.1).

BIVV001 65 IU/kg must be administered 4 (1) days following administration of 65 
IU/kg Advate.

If the dose of BIVV001 cannot be administered per these guidelines, the 
administration of BIVV001 may occur within a window of up to 4 days at the 
discretion of the Investigator, i.e. up to 8 days following 65 IU/kg Advate.

The Investigator must notify the sponsor and provide rationale if the dose of 
BIVV001 is administered beyond 120 hours (5 days) following Advate 
administration.

If a bleeding event is detected between Advate dosing and BIVV001 dosing, no more 
than 28 days may elapse between Advate and BIVV001 dosing (refer to the 
instructions in Table 7).
7.2.5.
Safety Observation Period
The 28-day safety observation period starts on the day the subject receives the single IV dose 
of BIVV001 and overlaps with the PK sampling period for BIVV001.
Subjects may resume treatment with their prestudy FVIII product during the 28-day safety 
observation period after completing Visit 14 activities (which include the 14-day inhibitor test; 
refer to Table 3 and Table 4).
Final assessments for the study are performed in the End of Study (EOS)/Early Termination (ET) 
evaluations; see Table 5. Subjects who are withdrawn from the study (for reasons other 
than withdrawal of consent) prior to BIVV001 administration will be asked to participate 
in a post-Advate follow-up safety telephone call; see Table 5 and Section 10.1.1. Subjects 
who are administered BIVV001 and either complete the 28-day safety observation period 
or are withdrawn from the study (for reasons other than withdrawal of consent) prior 
to completion of the safety observation period (see Section 10.1.2) will be asked to submit 

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to Visit 15 procedures (Table 5). The post-Advate follow-up safety telephone call is not required 
for subjects who complete Visit 15 procedures.
7.3.
Study Duration for Subjects
The total time on study for each subject is expected to range from approximately 60 to 156 days, 
depending on the length of Screening Period and the cohort to which the subject is assigned. 
Time on study is comprised of the following:

Up to 28 days for screening and washout of prestudy FVIII therapy prior to Advate 
dosing (the screening period may be extended up to 120 days with prior Sponsor 
approval). If the Screening Period extends beyond 56 days, screening assessments 
must be repeated as specified in Table 1 prior to dosing with Advate.

At least 3 days (low-dose cohort) or 4 days (high-dose cohort) of Advate 
PK sampling/washout following Advate dose administration

28 days of safety observation (which includes 10 to 14 days of BIVV001 
PK sampling) following BIVV001 dose administration.
Further details are provided in the Section 5. Durations may vary for scheduling reasons or if a 
bleeding episode occurs; see Table 7 for further details regarding treatment of a bleeding episode.
The end-of-study date for a subject is the last study visit or the last follow-up telephone 
conversation.
7.4.
Responsibilities of Study Site Personnel 
Refer to Study Reference Guide.
7.5.
Substudy Design
No substudies are planned for this study.
7.6.
Study Stopping Rules
The Sponsor may terminate the study at any time, after informing Investigators, Institutional 
Review Boards/Ethics Committees (ECs), and applicable regulatory agencies. Investigators will 
be notified by the Sponsor (or designee) if enrollment and dosing are suspended, completed, 
or closed.
7.6.1.
Dose and 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 will be investigated prior to enrollment 
or dosing of any additional subjects.

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The events requiring dose and enrollment suspension are as follows:

Development of inhibitor (a result of ≥0.6 Bethesda units per mL [BU/mL] identified 
and confirmed by a second test on an independent sample collected within 2 weeks to 
4 weeks of the first positive sample, with both tests performed by the central 
laboratory using the Nijmegen-modified Bethesda assay) following administration of 
BIVV001.

A low VWF ristocetin cofactor (VWF:RCo < 30 IU/dL identified and confirmed by a 
second test on an independent sample collected 1 to 4 weeks after the first low result, 
with both tests performed by the central laboratory) following the administration of 
BIVV001.

Two or more subjects experience serious adverse events (SAEs) that are assessed 
by the Investigator to be related to BIVV001

The Investigator, Sponsor, Medical Monitor, and/or DSMC determine that an event 
or current data warrant further evaluation by the DSMC. 
Actions to be taken for subjects already participating in the study at the time of dose and 
enrollment suspension will depend on whether the suspension occurred prior to or after 
the subject received BIVV001:
a.
Subjects who have not yet received BIVV001 will suspend further study procedures 
(including BIVV001 administration); subjects who have received Advate will 
complete the procedures described for the Advate PK sampling period.
b. Subjects who have received BIVV001 will remain on the protocol schedule 
(to complete the BIVV001 PK sampling period, the 28-day safety observation period, 
and the EOS/ET evaluations), unless the DSMC, Investigator, Sponsor, or Medical 
Monitor advise otherwise (i.e., longer duration and/or additional follow-up is needed).
The DSMC will review the data concerning the event and subject, with input from the 
Investigator, along with all other available data. Based on the results of its investigation, 
the DSMC and/or Sponsor will determine appropriate follow-up and decide whether study 
enrollment and dosing should resume.
7.6.2.
Dose and Enrollment Termination
The occurrence of specific study events will require that further enrollment in the study 
and further dosing be terminated. If study enrollment and dosing are terminated, the Investigators 
will be notified and the DSMC will review the available data. 
The events requiring dose and enrollment termination are as follows:

Unacceptable inhibitor frequency, including high-titer inhibitor frequency, as advised 
by the Sponsor and/or DSMC following administration of BIVV001

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
Death at any time during the study that is assessed by the Investigator and/or Sponsor 
to be related to BIVV001

The Investigator, Sponsor, Medical Monitor, and/or DSMC determine that an event 
or current data warrant termination of dosing and enrollment.
Actions to be taken for subjects already participating in the study at the time of dose 
and enrollment termination will depend on whether the termination occurred prior 
to or after the subject received BIVV001:
a.
Subjects who have not yet received BIVV001 will stop further study procedures 
(including BIVV001 administration) and will be asked to perform the EOS/ET 
evaluations (including the post-Advate follow-up safety telephone call); see Table 5.
b. Subjects who have received BIVV001 will remain on the protocol schedule 
(to complete the BIVV001 PK sampling period, the 28-day safety observation period, 
and the EOS/ET evaluations; see Table 5), unless the DSMC, Investigator, Sponsor, 
or Medical Monitor advise otherwise (i.e., longer duration and/or additional follow up 
is needed).
Bioverativ will notify Investigators and IQVIA when the study is to be placed on hold, 
completed, or terminated.
7.7.
End of Study
The EOS is the last visit or the last follow-up telephone call of the last subject.

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8.
SELECTION OF SUBJECTS
8.1.
Inclusion Criteria
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at screening, or at the time point specified in the individual eligibility criterion listed:
1. Ability of the subject, or his legally authorized representative (e.g., parent or legal 
guardian) if applicable in accordance with local regulations, to understand the purpose 
and risks of the study and provide signed and dated informed consent/assent and 
authorization to use confidential health information in accordance with national and local 
subject privacy regulations.
2. Male, aged 18 to 65 years, inclusive, at the time of informed consent.
3. Severe hemophilia A, defined as <1 IU/dL (<1%) endogenous FVIII at screening as 
determined by the one-stage clotting assay from the central laboratory. If the initial 
screening result is ≥1%, then a repeat endogenous FVIII activity level will be performed 
using the using the one stage clotting assay from the central laboratory. If the repeated result 
is <1 IU/dL (<1%), then the subject will meet this inclusion requirement.
4. Previous treatment for hemophilia A, defined as at least 150 documented prior EDs to 
any recombinant and/or plasma-derived FVIII and/or cryoprecipitate products at Day 1.
Fresh frozen plasma treatment must not be considered in the count for documented 
exposure days.
5. Platelet count ≥100,000 cells/μL at screening (test performed by the central laboratory 
and reviewed prior to the Day 1 Advate dose).
6. A subject known to be human immunodeficiency virus (HIV) antibody positive, either 
previously documented or identified from screening assessments, must have the 
following results prior to Day 1 Advate dose.
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. 
Subjects who have previously tested negative for HIV must have a repeat test by the 
central laboratory during Screening. 

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8.2.
Exclusion Criteria
Candidates will be excluded from study entry if any of the following exclusion criteria exist 
at screening, or at the time point specified in the individual criterion listed:
Medical History
1. Any concurrent clinically significant major disease that, in the opinion of the 
Investigator, would make the subject unsuitable for enrollment. 
2. Serious active bacterial or viral infection (other than chronic hepatitis or HIV) present 
within 30 days of screening.
3. Other known coagulation disorder(s) in addition to hemophilia A.
4. History of hypersensitivity or anaphylaxis associated with any FVIII product.
5. Known or suspected allergy to mice, hamsters, or any ingredient in Advate
6. History of a positive inhibitor test or clinical signs of decreased response to FVIII 
administrations. Family history of inhibitors will not exclude the subject.
The following medical history exclusion criteria refer to tests performed by the central laboratory 
on samples collected at screening. Results must be reviewed prior to the Day 1 Advate dose to 
confirm eligibility:
7. Measurable inhibitor activity, using the Nijmegen-modified Bethesda assay, 
with ≥0.6 BU/mL considered a positive result.
8. VWF:RCo <50 IU/dL
9. Abnormal renal function, defined as serum creatinine >2.0 mg/dL.
10. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5 × upper 
limit of normal (ULN).
11. Serum total bilirubin >3 × ULN.
Medications and Procedures
12. Previous participation in this study.
13. Current enrollment or participation within 30 days prior to screening in any other 
investigational study.
14. Treatment within 12 weeks prior to screening with a monoclonal antibody therapeutic, 
an Fc fusion protein other than rFVIIIFc, or IV immunoglobulin.

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15. Vaccination within 30 days of screening. 
16. Treatment with acetylsalicylic acid (ASA) within 2 weeks prior to screening or treatment 
with non-steroidal anti-inflammatory drugs (NSAIDs) at or above the maximum dose 
specified in the regional prescribing information for each product.
17. 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, with the exception of systemic corticosteroid treatment 
given daily or on alternate days at 20 mg/day of prednisone or its equivalent 
for >14 days. Local, topical, and/or inhaled steroid use is permitted.
18. Major surgery within 8 weeks prior to screening or likely to require surgery during 
the study. 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 (e.g., laparotomy, thoracotomy, 
craniotomy, joint replacement, or limb amputation).
Other
19. Inability to comply with study requirements as assessed by the Investigator.
20. Other unspecified reasons that, in the opinion of the Investigator or Sponsor, 
make the subject unsuitable for enrollment.

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9.
SCREENING AND ENROLLMENT
9.1.
Screening 
Subjects (or their legally authorized representative, e.g., parent or legal guardian) must provide 
informed consent before any screening tests are performed, including washout of current therapy 
specifically for entry into the study (see Table 1 and Section 17.3). Subject assent must also be 
obtained if applicable in the site’s geographic region. Participating study sites are required to 
document all screened candidates initially considered for inclusion in the study. Subjects will 
be registered as screened in the Interactive Response Technology (IRT) system following 
completion of all screening assignments.
The screening period for determination of subject eligibility for the study is scheduled within 
28 days prior to Advate single-dose administration. Screening may be accomplished over the 
course of more than 1 study visit if needed. Additionally, the Screening Visit may be extended 
up to 120 days with prior Sponsor approval. If the Screening Period extends beyond 56 days, 
screening assessments must be repeated as specified in Table 1 prior to dosing with Advate. See 
Table 6 for washout instructions prior to the Advate dose. See Table 7 for instructions for 
treatment of bleeding, if applicable.
Screen failures are defined as subjects who sign the informed consent form (ICF) but are not 
subsequently dosed with Advate. If a subject is considered a screen failure, the reasons for 
exclusion must be documented in the subject’s 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 demography, screen failure details, eligibility criteria, and any SAEs. Individuals 
who do not meet the criteria for participation in this study (i.e., a screen failure) will not be 
rescreened.
9.2.
Enrollment 
Subjects will be enrolled via IRT after all screening assessments have been completed and 
after the Investigator has verified that the subjects are eligible per criteria in Sections 8.1 and 8.2. 
Subjects will be assigned a unique identification number that will be used on study-related 
documents pertaining to the subject, and will be administered their Advate dose (25 IU/kg 
or 65 IU/kg) on the day of their official enrollment in the study. Any subject identification 
numbers that are assigned will not be reused even if the subject does not receive treatment 
or withdraws from the study.
Refer to the Study Reference Guide for details on enrollment.

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9.3.
Blinding Procedures
Not applicable. This is an open-label study.

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10.
DISCONTINUATION OF STUDY TREATMENT AND 
WITHDRAWAL OF SUBJECTS FROM THE STUDY
Every effort will be made to keep subjects in the study; however, if a subject is withdrawn from 
the study early, the Investigator will make every effort to complete and report the reason(s) for 
withdrawal as thoroughly as possible.
The reason(s) for discontinuation of study treatment and withdrawal from the study must be 
recorded in the subject’s case report form (CRF). Subjects who discontinue study treatment 
and withdraw from the study will not be allowed to enroll again at a later date.
Determination of whether a subject should discontinue further treatment and withdraw from 
the study will depend on whether a discontinuation criterion occurs prior to or after the subject 
received BIVV001.
Subjects who withdraw from the study may be replaced; refer to Section 10.1.3. 
10.1.
Withdrawal of Subjects From Study
10.1.1.
Criteria for Subject Withdrawal From Study Prior to BIVV001 Administration
A subject must permanently discontinue further treatment and will be withdrawn from the study 
for any of the following reasons:

The subject withdraws consent prior to receiving BIVV001.

More than 1 bleeding episode occurs during the pre-Advate washout.

More than 1 bleeding episode occurs between Advate and BIVV001 dosing.

More than 28 days elapse as a result of a bleeding event between the Advate dose and 
the planned BIVV001 dose.

Any of the following events occur before the BIVV001 dose:

The Investigator or Sponsor notes a significant noncompliance with protocol 
procedures. 

The subject requires major surgery, as defined in the exclusion criteria.

The Investigator and/or Sponsor determines that the subject must discontinue 
further treatment due to an intolerable toxicity, a medical emergency, or other 
medical reasons. 

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Subjects who received Advate but discontinue treatment prior to receiving BIVV001 for reasons 
other than withdrawal of consent will be asked to participate in a post-Advate follow-up safety 
telephone call as part of the withdrawal from the study. If a subject who is withdrawn from the 
study has an ongoing SAE, the SAE should be followed until the event has resolved, stabilized, 
or returned to baseline status. Further details on actions for subjects who are discontinued from 
the study are provided in Table 5.
10.1.2.
Criteria for Subject Withdrawal From Study After BIVV001 Administration
Once subjects receive BIVV001, they will be strongly encouraged to remain in the study 
to perform the remaining protocol-required assessments (PK sampling, inhibitor tests, and other 
safety assessments of the 28-day safety observation period and the EOS evaluations), unless they 
withdraw consent.
For any subjects who are withdrawn from the study prior to completion of the 28-day safety 
observation period (for reasons other than withdrawal of consent), EOS (Visit 15) procedures 
must be performed at the time of study withdrawal. If a subject who is withdrawn from the study 
has an ongoing SAE, the SAE should be followed until the event has resolved, stabilized, or 
returned to baseline status. Further details on actions for subjects who are withdrawn from the 
study are provided in Table 5.
10.1.3.
General Considerations
Subjects who experience a discontinuation criterion or withdraw consent before completing 
adequate PK and/or inhibitor sampling for both Advate and BIVV001 will be replaced if needed 
to ensure that evaluable PK and FVIII inhibitor data are obtained from at least 6 subjects in the 
low-dose cohort and 8 subjects in the high-dose cohort.
10.2.
Lost to Follow-Up
Subjects will be considered lost to follow-up if they repeatedly fail to return for scheduled visits 
and are unable to be contacted by the study site. 
The following actions must be taken if a subject fails to return to the clinic for a required study 
visit:

The site must attempt to contact the subject and reschedule the missed visit as soon 
as possible, counsel the subject on the importance of maintaining the assigned visit 
schedule, and ascertain whether the subject wishes to and/or should continue in the 
study.

Should the subject be unreachable by telephone, the Investigator or designee must 
make every effort to regain contact with the subject. These contact attempts should be 
documented in the subject’s medical record.

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
In cases in which the subject is deemed lost to follow-up, then the subject will 
be considered to have withdrawn from the study with a primary reason of lost 
to follow-up.

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11.
STUDY TREATMENT USE
Bioverativ will provide BIVV001 to all study sites; sites will be expected to procure their own 
supplies of Advate for use in the study. Section 12 provides summaries for storage, handling, 
preparation, disposal, and accountability information for both BIVV001 and Advate.
11.1.
Regimen
Refer to Figure 1 for a schematic of study design and to Section 5 for study schedules.
All study visits will be performed as outpatient visits. All Advate and BIVV001 doses will be 
administered via slow, manual IV injections over a duration of 8 ± 2 minutes. Treatments will be 
administered by the Investigator or designated personnel at each study site, where emergency 
medical equipment must be readily available.
Details for each study cohort are listed below:
11.1.1.
Regimen for Low-Dose Cohort (Advate and BIVV001 25 IU/kg Single Doses)

Approximately 8 eligible, consenting subjects will undergo a screening period 
of up to 28 days (extendable to 120 days with prior Sponsor approval). If the 
Screening Period extends beyond 56 days, screening assessments must be repeated as 
specified in Table 1 prior to dosing with Advate. The screening period includes 
a washout period of 4 to 5 days without FVIII treatment. Prior to Advate dosing, 
a minimum of 4 days (96 hours) must have elapsed since the subject’s last dose 
of conventional FVIII products. For subjects who were taking an EHL FVIII product, 
the washout period before Advate administration must be a minimum of 5 days 
(120 hours) (Table 1).

Subjects will receive a single IV dose of Advate 25 IU/kg (Table 2).

Subjects will complete a 72-hour PK sampling period at designated predose and 
postdose time points (Table 2).

Subjects will complete a 72-hour washout period following Advate administration 
(this washout period may overlap with the PK sampling period; Table 6), then receive 
a single IV dose of BIVV001 25 IU/kg (Table 3).

Following BIVV001 25 IU/kg single-dose administration, subjects will complete 
a 10-day PK sampling period at designated predose and postdose time points 
(Table 3).

Following BIVV001 25 IU/kg single-dose administration, subjects will complete 
a 28-day (±5 days) safety observation period (Table 5). Please note that the first 

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10 days of this observation period overlaps with the 10-day PK sampling period 
(above). 
Once the evaluation criteria for the low-dose cohort have been met, the Sponsor and the DSMC 
will review the data and determine if it is acceptable to proceed to the high-dose cohort 
as detailed in the DSMC charter. 
11.1.2.
Regimen for High-Dose Cohort (Advate and BIVV001 65 IU/kg Single Doses)

Approximately 10 eligible, consenting subjects will undergo a screening period of up 
to 28 days (extendable to 120 days with prior Sponsor approval). If the Screening 
Period extends beyond 56 days, screening assessments must be repeated as specified 
in Table 1 prior to dosing with Advate. The screening period includes a washout 
period of 4 to 5 days without FVIII treatment. Prior to Advate dosing, a minimum of 
4 days (96 hours) must have elapsed since the subject’s last dose of conventional 
FVIII products. For subjects who were taking an EHL FVIII product, the washout 
period before Advate administration must be a minimum of 5 days (120 hours) 
(Table 1).

Subjects will receive a single IV dose of Advate 65 IU/kg (Table 2).

Subjects will complete a 72-hour PK sampling period at designated predose and 
postdose time points (Table 2).

Subjects will complete a 96-hour washout period following Advate administration 
(this washout period may overlap with the PK sampling period; Table 6), then receive 
a single IV dose of BIVV001 65 IU/kg (Table 4).

Following BIVV001 65 IU/kg single-dose administration, subjects will complete 
a 14-day PK sampling period at designated predose and postdose time points 
(Table 4).

Following BIVV001 65 IU/kg single-dose administration, subjects will complete 
a 28-day (±5 days) safety observation period (Table 5). Please note that the first 
14 days of this observation period overlaps with the 14-day PK sampling period 
(above). 
11.2.
Modifications of Dose and/or Treatment Schedule
11.2.1.
Modifications to BIVV001 and/or Advate Doses
Doses will be calculated for each subject according to the subject’s assigned dose of Advate 
or BIVV001 from the body weight obtained from the subject immediately prior to scheduled 
Advate and BIVV001 dose administrations (Table 2, Table 3, and Table 4).

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11.2.2.
Modifications to BIVV001 and/or Advate Dose Administration 
11.2.2.1.
Allergic Reactions
If any subject develops signs or symptoms of an allergic-type reaction during the administration 
of Advate or BIVV001, the injection will be immediately terminated and appropriate medical 
care will be initiated (if necessary). If the reaction occurs during Advate administration, 
the subject will be withdrawn from the study. If the reaction occurs during BIVV001 
administration, PK assessments and the safety observation period should be completed, 
at the discretion of the Investigator. Refer to Table 5 and Section 10.1 for detailed information on 
subject withdrawal requirements.
11.2.2.2.
Anaphylactic Reactions
If any subject develops signs or symptoms of an anaphylactic reaction during the administration 
of Advate or BIVV001, the injection will be immediately stopped, and appropriate medical care 
will be administered. If any signs or symptoms of shock are observed, the current medical 
standards of treatment should be administered. If the reaction occurs during Advate 
administration, the subject will be withdrawn from the study. If the reaction occurs 
during BIVV001 administration, PK assessments and the safety observation period 
should be completed, at the discretion of the Investigator. Refer to Table 5 and Section 10.1
for detailed information on subject withdrawal requirements.
11.2.2.3.
Bleeding Episodes
Refer to Table 7 for instructions on appropriate responses to bleeding episodes.
11.2.3.
Modifications to Treatment Schedule
See Section 7.1 for details regarding the study’s stepwise dosing and dose escalation procedures. 
11.3.
Precautions
BIVV001 is being administered for the first time to humans; thus, all subjects will be observed 
closely for safety following administration of BIVV001 as described in Sections 7.1, 14, and 15.
Whether and which side effects may occur is unknown. Clinical safety data are available for 
commercially available rFVIII products, including Advate [Advate USPI 2015; Adynovate USPI 
2016; Eloctate USPI 2017].
11.3.1.
Bleeding Episodes
As this is a safety and PK study, the doses of Advate and BIVV001 being administered are not 
intended to provide the subject optimal protection from new bleeding episodes. Refer to Table 7
for detailed instructions on the treatment of bleeding episodes that occur during this study. 
Bleeding episodes will be reported on the CRF.

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11.4.
Compliance
All doses of Advate and BIVV001 will be administered by study site staff.
11.5.
Concomitant Therapy and Procedures
11.5.1.
Concomitant Therapy
A concomitant therapy is any drug or substance administered between the time that the subject 
is enrolled in the study and the end of the 28-day safety observation period.
11.5.1.1.
Allowed Concomitant Therapy
If a subject requires treatment for a bleeding episode during the study, the subject’s prestudy 
FVIII product should be used for treatment. Refer to Table 7 for instructions on appropriate 
responses to bleeding episodes. Subjects are also permitted to resume their prestudy FVIII 
regimen after completion of Visit 14 activities (see Table 3 and Table 4).
It is preferred for this study not to include subjects requiring concomitant medications. However, 
subjects taking medication routinely for a pre-existing condition should be on a regimen that has 
been stable for at least 3 weeks, and dosage changes should not be anticipated during the 
observation period for this study. Prestudy stable NSAID doses below the maximum dose 
specified in the regional prescribing information at the time of enrollment are permitted. All 
concurrent prescription and non-prescription medications including over-the-counter and 
alternative preparations (including herbal remedies, vitamins, and health food supplements) 
should be recorded at baseline and throughout the treatment and follow-up periods. 
11.5.1.2.
Disallowed Concomitant Therapy 
No FVIII injections are permitted within 4 days prior to the injection of Advate or BIVV001.
No premedication for pain or pyrexia relief are to be administered for injections of the drugs.
Should premedications be contemplated, this will be discussed on a case-by-case basis with the 
Medical Monitor and the Sponsor’s Clinical Operations representative before administration.
With the exception of a subject resuming prestudy FVIII regimen after the completion of all 
Visit 14 activities (Section 11.5.1.1), no drugs interfering with hemostasis (such as tranexamic 
acid, warfarin, and heparin), experimental drugs, blood products (such as red blood cells [RBCs], 
platelets, and fresh frozen plasma), and drugs affecting immune function (such as interferon, 
ribavirin, immunizations, systemic steroids, and chemotherapy) may be taken during the 
subject’s participation in this study; subjects requiring such medications and/or products will be 
discontinued from the study (Section 10). Acetylsalicylic acid is not allowed. Non-steroidal 
anti-inflammatory drugs [NSAIDs] at or above the maximum dose specified in the regional 
prescribing information for each product are not allowed.

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11.5.2.
Concomitant Procedures
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
the time that the subject is enrolled in the study and the end of the 28-day safety observation 
period.
11.5.3.
Recording of Concomitant Therapies and/or Procedures
The use of concomitant therapies or procedures (defined in Section 11.5.1 or Section 11.5.2) 
must be recorded on the subject’s CRF according to the instructions for its completion. Any AEs 
related to administration of these therapies or procedures must be documented on the appropriate 
CRF.
11.6.
Continuation of Treatment 
There is no provision to provide additional treatment with Advate or BIVV001 after the study.

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12.
STUDY TREATMENT MANAGEMENT
12.1.
BIVV001
BIVV001 drug product will be supplied as
 
 which will also be supplied by 
Bioverativ. For this study, each vial of drug product includes 1000 IU of BIVV001 along with 
the following excipients:
 
. Please refer to the 
BIVV001 Directions for Handling and Administration (DHA) or BIVV001 IB for additional 
details. 
BIVV001 will be manufactured, handled, and stored in accordance with applicable Good 
Manufacturing Practice. BIVV001 vials will be labeled according to the requirements of local 
law and legislation. Label text will be approved according to Bioverativ procedures, and copies 
of the labels will be made available to the study site upon request.
Study site staff should follow the BIVV001 DHA for specific instructions on its storage, 
handling, preparation, administration, disposal, and accountability. 
BIVV001 must be dispensed only by a pharmacist or appropriately qualified staff. BIVV001 
is to be dispensed only to subjects enrolled in this study. Once BIVV001 is prepared 
for a subject, it can be administered only to that subject. BIVV001 doses will be administered 
by the Investigator or designated personnel at each study site, where emergency medical 
equipment must be readily available. BIVV001 preparations are for one-time use only; study site 
staff should not use any leftover BIVV001 remaining in the vial for another subject.
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 
(subject-by-subject accounting), and accounts of any BIVV001 accidentally or deliberately 
destroyed or lost. Unless otherwise notified, all BIVV001 vials (used and unused) must be saved 
for BIVV001 accountability. By the end of the study, reconciliation must be made between the 
amount of BIVV001 supplied, dispensed, and subsequently destroyed, lost, or returned to 
Bioverativ. A written explanation must be provided for any discrepancies.
12.2.
Advate
Advate is available as a lyophilized powder in single-use vials containing nominally 250, 500, 
1000, 1500, 2000, 3000, or 4000 IU. The 250 to 1500 IU strengths come with 2 mL of Sterile 
Water for Injection; the 2000 to 4000 IU strengths come with 5 mL of Sterile Water for 
Injection. 
Study site staff should follow the regional product label for Advate for instructions on its storage, 
preparation, administration, handling, disposal, and accountability requirements.

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13.
EFFICACY AND PHARMACOKINETIC ASSESSMENTS
See Section 5 for the timing of all assessments.
Tests and evaluations affecting endpoints and/or analyses may need to be repeated if the original 
results are lost or damaged. Duplicate samples for key laboratory assessments will be collected 
as a backup in case the original sample is lost or not evaluable. In cases where duplicate samples 
are no longer available, subjects may be asked to return to the clinic to repeat the evaluations. 
13.1.
Clinical Efficacy Assessments
No formal clinical efficacy assessments will be performed.
13.2.
Laboratory Efficacy Assessments
No formal laboratory efficacy assessments will be performed. However, the PK evaluation will 
provide an initial understanding of the efficacy of BIVV001 in humans, consistent with the view 
from the European Medicines Agency (EMA) guidelines that PK data are considered the most 
important surrogate markers for efficacy of a new FVIII product [EMA 2016].
13.3.
Pharmacokinetic Assessments
One-stage (aPTT-based) clotting assay and two-stage chromogenic coagulation assays will be 
performed to assess FVIII activity (referred to as PK) following both Advate and BIVV001 
administration. The PK of BIVV001 single dose will be assessed and compared to that of Advate 
single dose via the estimation of parameters including but not limited to the following: Cmax, t½, 
CL, Vss, AUC∞, MRT, IR, and time to 1% above baseline for FVIII activity. 
Pharmacokinetics sampling schedules for Advate administration, BIVV001 25 IU/kg 
administration, and BIVV001 65 IU/kg are presented in Table 2, Table 3, and Table 4, 
respectively. 
13.4.
Pharmacodynamic Assessments
No pharmacodynamic assessments are planned for this study.
13.5.
Pharmacogenetic and Genetic Assessments
Where local regulations and EC approval allow, an optional sample will be collected at screening 
for genotype analysis, including 
, to aid in 
interpreting the potential risk of inhibitor development. The sample will not be needed if 
previously documented. Collection of samples and previously documented genotype information 
for genotype analysis will be governed by a separate ICF; genotype will not be a criterion for 
inclusion or exclusion.

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The DNA samples will be coded with the subject’s identification number and stored for 15 years 
or a duration dictated by local, national, or regional laws or regulations. No genotyping or 
genetic data will be provided to the subject. Subjects may withdraw consent and request to have 
their sample destroyed at any time and no further genetic data will be generated; any data already 
generated will not be destroyed.
13.6.
Exploratory Assessment
 
 
 

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14.
SAFETY ASSESSMENTS
Refer to Section 5 for the timing of all safety assessments.
Tests and evaluations affecting endpoints and/or analyses may need to be repeated if the original 
results are lost or damaged. Duplicate samples for key laboratory assessments will be collected 
as a backup in case the original sample is lost or not evaluable. In cases where duplicate samples 
are no longer available, subjects may be asked to return to the clinic to repeat the evaluations.
The total estimated blood sample volume collected from a subject will not exceed approximately 
87 mL at one time and 330 mL over the duration of the study.
14.1.
Clinical Safety Assessments
The following clinical assessments will be performed to evaluate the safety profile of BIVV001:

Medical, surgical, and hemophilia history

Physical examinations

Vital sign measurements: systolic and diastolic blood pressure, pulse rate, respiratory 
rate, and temperature. Vital sign measurements should be taken after the subject has 
been resting (supine position) for at least 5 minutes. Postdose vital sign measurements 
should be taken before PK sample collection. Vital signs should also be taken at any 
unscheduled visit.

Body weight measurements. On Advate and BIVV001 dosing days (Visits 2 and 6, 
respectively), body weight measurements will be used to calculate the Advate and 
BIVV001 doses to be prepared and administered.

Concomitant therapy and procedure recording

AE and SAE recording.
14.2.
Laboratory Safety Assessments
Samples will be analyzed using Good Laboratory Practice-validated assays.
The following laboratory assessments will be performed to evaluate the safety profile of BIVV001:

Hematology: red blood cell (RBC) count; white blood cell (WBC) count and 
differential; platelet count; hemoglobin (Hgb); and hematocrit (Hct)

Clinical chemistry: alanine aminotransferase (ALT); aspartate aminotransferase 
(AST); alkaline phosphatase (ALP); gamma-glutamyl transferase (GGT); bilirubin; 

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blood urea nitrogen (BUN); creatinine; glucose; total protein; sodium; potassium; 
and chloride

Urinalysis: specific gravity; pH; color; appearance; leukocyte esterase; protein; 
glucose; ketones; occult blood; bilirubin; urobilinogen; nitrite; and microscopic 
examination of urine sediment

Coagulation and thrombosis markers: prothrombin time (PT); aPTT; D-dimer; 
international normalized ratio; thrombin anti-thrombin complex; prothrombin 
fragment 1.2; and the von Willebrand comprehensive panel, which includes 
assessments of VWF ristocetin cofactor activity, and VWF antigen. Analysis of VWF 
multimers will be for future testing.

Detection of FVIII inhibitors, as determined by the Nijmegen-modified Bethesda 
assay. A subject’s blood will be considered to be positive for FVIII inhibitor when an 
initial test result of ≥0.6 BU/mL is identified and confirmed by a subsequent test 
result from an independent blood sample collected within 2 to 4 weeks of the first 
positive sample. 
14.3.
Immunogenicity Assessments
Blood samples will be collected for the detection and analysis of anti-rFVIIIFc-VWF-XTEN 
antibodies at the following visits: 

Screening visit (Visit 1) and, if necessary, Repeat Screening Visit

Advate dosing visit (Visit 2) – sample collected predose

BIVV001 dosing visit (Visit 6) – sample collected predose

14-day inhibitor visit (Visit 14) – this visit must occur 336 ± 24 hours after BIVV 
dose administration

EOS visit (Visit 15) or ET visit.
Testing for potential antibody formation will be performed at a central laboratory using a 
validated rFVIIIFc-VWF-XTEN-specific anti-drug antibody assay. Confirmed positive samples 
will be further characterized for antibodies specific to Fc, FVIII, D′D3, or XTEN.

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15.
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES
Throughout the course of the study, every effort must be made to remain alert to possible AEs. If 
an AE occurs, the first concern should be for the safety of the subject. If necessary, appropriate 
medical intervention should be provided.
At the signing of the ICF, each subject (or his legally authorized representative and/or main 
caregiver) must be given the names and telephone numbers of study site staff for reporting AEs 
and medical emergencies.
15.1.
Definitions
15.1.1.
Serious Pretreatment Event
A serious pretreatment event (PTE) is any event that meets the criteria for SAE reporting (as 
defined in Section 15.1.3), occurs after the subject signs the ICF, but occurs before the 
administration of Advate or BIVV001.
15.1.2.
Adverse Event
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product.
Determination of whether an abnormal laboratory value and/or vital sign result meets 
the definition of an AE will be made by the Investigator. Abnormal results are not considered 
AEs unless one or more of the following criteria are met:

The result meets the criteria for an SAE

The result requires the subject to receive specific corrective therapy

The result is considered by the Investigator or the subject’s treating hematologist to 
be clinically significant
Bleeding episodes in this patient population are not considered AEs; however, the concomitant 
events associated with a bleeding episode should be reported as AEs as appropriate (e.g., an 
elbow fracture). Bleeding episodes that meet a serious criterion (Section 15.1.3) should be 
reported as an SAE.

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15.1.3.
Serious Adverse Event
An SAE is any untoward medical occurrence that at any dose:

Results in death

In the view of the Investigator, places the subject at immediate risk of death (a 
life-threatening event); however, this does not include an event that, had it occurred 
in a more severe form, might have caused death

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Results in a congenital anomaly/birth defect

Is a medically important event
A medically important event is an AE that, in the opinion of the Investigator, may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the definition 
above.
15.2.
Safety Classifications
15.2.1.
Investigator Assessment of Events
All events must be assessed to determine the following:

If the event meets the criteria for an SAE as defined in Section 15.1.3

The relationship of the event to study treatment as defined in Section 15.2.2

The severity of the event as defined in Section 15.2.3
15.2.2.
Relationship of Events to Study Treatment
The following definitions should be considered when evaluating the relationship of AEs 
and SAEs to the study treatment:

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Relationship of Event to Study Treatment
Not related
An AE will be considered “not related” to the use of the investigational product 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 investigational 
product and the AE, the presence of a biologically implausible relationship between the 
product and the AE, or the presence of a more likely alternative explanation for the AE.
Related
An AE will be considered “related” to the use of the investigational product if there is a 
reasonable 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 
investigational product and the AE, a known response pattern of the suspected product, 
improvement following discontinuation or dose reduction, a biologically plausible
relationship between the product and the AE, or a lack of an alternative explanation for 
the AE.
15.2.3.
Severity of Events
The following definitions should be considered when evaluating the severity of AEs and SAEs:
Severity of Event
Mild
Symptoms barely noticeable to subject or does not make subject uncomfortable; does not 
influence performance or functioning; prescription drug not ordinarily needed for relief of 
symptoms but may be given because of personality of subject.
Moderate
Symptoms of a sufficient severity to make subject uncomfortable; performance of daily 
activity is influenced; subject is able to continue in study; treatment for symptoms may be 
needed.
Severe
Symptoms cause severe discomfort; symptoms cause incapacitation or significant impact 
on subject’s daily life; severity may cause cessation of treatment with study treatment; 
treatment for symptoms may be given and/or subject hospitalized.
15.2.4.
Expectedness of Events
Expectedness of all AEs will be determined by Bioverativ according to the BIVV001 IB.
15.3.
Monitoring and Recording Events
15.3.1.
Adverse Events
Any AE experienced by the subject between the time that they sign the ICF through the end of the 
28-day safety observation period is to be recorded on the CRF, regardless of the severity of the 
event or its relationship to Advate or BIVV001. At each study visit, the Investigator will assess 
the subject for AEs and will record any new AEs or updates to previously reported AEs on the 
CRF.
All AEs experienced by the subject should be followed until they have resolved, stabilized, 
or returned to baseline in subsequent visits.

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15.3.2.
Serious Adverse Events
Any SAE experienced by the subject between the time of the signing of the ICF and the end of 
the 28-day safety observation period is to be recorded on an SAE form, regardless of the severity 
of the event or its relationship to study treatment. SAEs must be reported to IQVIA
Pharmacovigilance within 24 hours as described in Section 15.3.3. Follow-up information 
regarding an SAE also must be reported within 24 hours.
Subjects will be followed for all SAEs until the end of the 28-day safety observation period.
Thereafter, the event should be reported to IQVIA Pharmacovigilance only if the Investigator 
considers the SAE to be related to study treatment.
Any SAE that is ongoing when the subject completes or discontinues the study will be followed 
by the Investigator until the event has resolved, stabilized, or returned to baseline status.
In this study, the following events are considered medically important and must be reported as 
SAEs:

A subject develops an inhibitor (Section 7.6.1)

A subject develops a Grade 2 or greater allergic reaction in association with 
administration of BIVV001 defined as follows using the Recommendations for 
Grading of Acute and Subacute Toxic Effects on the World Health Organization 
(WHO) scale [WHO 1979]:

Grade 2: bronchospasm, no parenteral therapy needed

Grade 3: bronchospasm, parenteral therapy required

Grade 4: anaphylaxis

A subject develops a vascular thrombotic event, with the exception of IV injection 
site thrombophlebitis.
Allergic reactions, including anaphylaxis, have been reported with FVIII products. The subject 
(and the subject's parents/caregivers, if applicable) should be informed of early symptoms and 
signs of hypersensitivity reactions, including difficulty breathing, chest tightness, swelling of the 
face, rash, or hives. If such an event occurs while the subject is at home, the subject will be 
instructed to seek immediate medical care.
The subject (and the subject's parents/caregivers, if applicable), should be informed of early 
symptoms and signs of thrombotic phenomena, including pain and/or tenderness along a vein, 
unexpected swelling of an arm or leg without pain or tenderness, redness along a vein, low fever 
without any known reason (such as a cold or flu), sudden shortness of breath or difficulty 
breathing, or coughing, sudden chest pain, sudden severe headache or changes in vision, and 
numbness or tingling in arms or legs. If such an event occurs while the subject is at home, the 

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subject (and the subject's parents/caregivers, if applicable) will be instructed to seek immediate 
medical care.
15.3.3.
Immediate Reporting of Serious Adverse Events
To adhere to all applicable laws and regulations for reporting an SAE, the study site must 
formally notify IQVIA Pharmacovigilance within 24 hours of the study site staff becoming 
aware of the SAE. It is the Investigator’s responsibility to ensure that the SAE reporting 
information and procedures are used and followed appropriately.
Reporting Information for SAEs
A report must be submitted to IQVIA Pharmacovigilance regardless of the following:

Whether or not the subject has undergone study-related procedures

Whether or not the subject has received study treatment

The severity of the event

The relationship of the event to study treatment
To report initial or follow-up information on an SAE, fax or email a completed SAE form; refer 
to the Study Reference Guide for complete contact information.
Any SAE must also be entered in the CRF in the same time frame.
15.3.3.1.
Deaths
Death is an outcome of an event. The event that resulted in death should be recorded on the 
appropriate CRF. 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 to IQVIA Pharmacovigilance. The term death should be reported 
as an SAE only if the cause of death is not known and cannot be determined.
15.3.4.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are unexpected 
and judged by the Investigator or Bioverativ to be related to the study treatment administered.
Bioverativ (or designee) will report SUSARs to the appropriate regulatory authorities and 
Investigators as required, according to local law.

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15.4.
Procedures for Handling Special Situations
15.4.1.
Pregnancy
The population under study is male; therefore, pregnancies will not be tracked. Congenital 
abnormalities and birth defects in the offspring of male subjects should be reported as an SAE 
if conception occurred during the study treatment period.
15.4.2.
Overdose
An overdose is any dose of study treatment administered to a subject or taken by a subject that 
exceeds the dose assigned to the subject according to the protocol. Overdoses are not considered 
AEs and should not be recorded as an AE on the CRF; however, all overdoses must be recorded 
on an Overdose form and faxed or emailed to IQVIA Pharmacovigilance within 24 hours of the 
site becoming aware of the overdose. An overdose must be reported to IQVIA
Pharmacovigilance even if the overdose does not result in an AE. If an overdose results in an 
AE, the AE must be recorded. If an overdose results in an SAE, both the SAE and Overdose 
forms must be completed and faxed or emailed to IQVIA Pharmacovigilance. All study 
treatment-related dosing information must be recorded on the dosing CRF.
15.4.3.
Medical Emergency
In a medical emergency requiring immediate attention, study site staff will apply appropriate 
medical intervention, according to current standards of care. The Investigator (or designee) 
should contact the study’s Medical Director. Refer to the Study Reference Guide for complete 
contact information.
15.4.3.1.
Unblinding for Medical Emergency
Not applicable, as this is an open-label study.
15.5.
Contraception Requirements
There are no contraception requirements for this study.
15.6.
Safety Responsibilities
15.6.1.
Investigator Responsibilities
The Investigator’s responsibilities include the following:

Monitor and record all AEs, including SAEs, on the CRF regardless of the severity or 
relationship to study treatment.

Determine the seriousness, relationship, and severity of each event.

Determine the onset and resolution dates of each event.

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
Complete an SAE form for each SAE and fax or email it to IQVIA
Pharmacovigilance within 24 hours of the study site staff becoming aware of the 
event.

Pursue SAE follow-up information actively and persistently. Follow-up information 
must be reported to IQVIA Pharmacovigilance within 24 hours of the study site staff 
becoming aware of new information.

Ensure all AE and SAE reports are supported by documentation in the subjects’ 
medical records.

Pursue AE follow-up information until the event has resolved or become stable.
Record AE follow-up information, including resolution, on the CRF, as applicable.

Report SAEs to local ECs, as required by local law.
15.6.2.
Bioverativ Responsibilities
Bioverativ’s responsibilities include the following:

Before a site can enroll any subjects, the Clinical Monitor or the Sponsor’s designee 
is responsible for reviewing with study site staff the definitions of AE and SAE, 
as well as the instructions for monitoring, recording, and reporting AEs and SAEs.

Bioverativ is to notify all appropriate regulatory authorities, central ECs, and 
Investigators of SAEs, as required by local law, within required time frames.

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16.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
16.1.
Description of Objectives and Endpoints
The objectives of the study and the endpoints to be analyzed are described in Section 6.
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a statistical analysis plan. In general, unless otherwise stated, continuous 
variables will be summarized by descriptive statistics, including: number, mean, median, 
standard deviation, minimum, and maximum. Categorical variables and response variables will 
be presented with the number and percentage in each category. Additionally, exploratory 
statistical tests may be applied to study data to generate hypotheses to be tested in subsequent 
trials.
16.2.
Demographics and Baseline Disease Characteristics
Demographic and other baseline disease characteristics will be summarized using descriptive 
statistics by dose level and overall. Number of observations, mean, standard deviation, median, 
minimum, and maximum will be presented for continuous parameters. Categorical parameters 
will be displayed using counts and percentages within each category. Data to be tabulated will 
include, but not be limited to, age, race, medical history, and other disease specific measures. All 
data will be summarized by drug and dose level group.
16.3.
Efficacy
No formal clinical efficacy assessments will be performed.
16.4.
Pharmacokinetics
16.4.1.
Analysis Population
The PK analysis set is defined as all subjects who complete the relevant blood sample collections 
(following Advate or BIVV001 administration), enabling acceptable determination of all key PK 
parameters, as determined by the PK scientist.
16.4.2.
Methods of Analysis
In general, descriptive statistics including number of observations, mean, standard deviation, 
median, minimum, and maximum will be presented for continuous parameters. Summary 
descriptive statistics and individual subject listings will be presented for all PK parameters (listed 
in Section 6.2) by drug and dose level group. Various exploratory statistical tests may be applied 
to study data to generate hypotheses to be tested in subsequent trials.

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FVIII activity-versus-time profiles will be plotted for each subject, and mean activity-versus-time 
profiles will be plotted at each dose level for BIVV001 and Advate for the one-stage clotting 
assays and chromogenic assays, on both the linear and logarithmic scale. Individual PK parameter 
estimates will be listed for each subject and summarized descriptively by drug and dose level 
group for both assays. Summary descriptive statistics will include the number of observations, 
arithmetic and geometric means and their associated confidence intervals (CIs), standard 
deviation, coefficient of variation, median, minimum, and maximum.
An analysis of variance model with factors for drug and subject will be used to compare BIVV001 
to Advate for the analysis of selected PK parameters, including but not limited to Cmax, t½, CL, Vss, 
AUC∞, MRT, IR, and time to 1% above baseline for FVIII activity. Analyses will be performed for 
each dose level separately. PK parameters will be log-transformed for these analyses, and 
estimated means, mean differences, and CIs on the log scale will be exponentiated to obtain 
estimates for geometric means, geometric mean ratios, and CIs, respectively, on the original scale.
In addition, untransformed PK parameters will be used to calculate arithmetic means and 
arithmetic mean ratios.
16.5.
Pharmacodynamics
No pharmacodynamics assessments are planned for this study.
16.6.
Biomarker Analyses/Pharmacogenetics
No biomarker analyses or pharmacogenetics assessments are planned for this study.
16.7.
Safety
16.7.1.
Analysis Population
All subjects who receive at least 1 dose of Advate or BIVV001 will be evaluable for the analysis 
of safety.
16.7.2.
Methods of Analysis
Adverse events will be classified using Medical Dictionary for Regulatory Activities (MedDRA) 
system organ class and preferred term. Tabulations of AEs by frequency, relatedness, and 
severity will be presented. Data will be presented for each drug and by dose level group. Subject 
listings will be provided for SAEs.
Changes from baseline in clinical laboratory parameters and vital signs will be summarized 
over time using descriptive statistics for each drug and dose level group.

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16.8.
Immunogenicity
16.8.1.
Analysis Population
All subjects who receive at least 1 dose of Advate or BIVV001 will be evaluable for the analysis 
of immunogenicity.
16.8.2.
Methods of Analysis
The number and percentage of subjects who are positive at the end of the study for inhibitor 
and anti-rFVIIIFc antibodies will be presented for each drug and by dose level group.
All inhibitor and antibody data will also be listed by subject.
16.9.
Interim Analyses
No formal interim analyses are planned. At least one interim analysis is planned at the 
conclusion of the low-dose cohort and will be descriptive in nature.
Additional analyses may be performed to support dose regimen planning for future studies. 
16.10.
Sample Size Considerations
The sample size for this study is based on the need to establish the initial safety profile 
of BIVV001 and characterize its PK profile. The number of subjects who have severe 
hemophilia A is small; thus, the determination of sample size for this study is constrained by 
subject availability. Approximately 18 subjects will be enrolled and treated. Additional subjects 
may be enrolled to ensure that at least 6 subjects from the low-dose cohort and 8 subjects from 
the high-dose cohort provide evaluable PK (defined in Section 16.4.1) and inhibitor data.
 
 

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17.
ETHICAL REQUIREMENTS
Bioverativ, IQVIA, and the Investigator must comply with all instructions, regulations, 
and agreements in this protocol and applicable International Council for Harmonisation (ICH) 
and Good Clinical Practice (GCP) guidelines, and conduct the study according to local regulations.
The Investigator may delegate responsibilities for study-related tasks where appropriate to 
individuals sufficiently qualified by education, training, and experience, in accordance with 
applicable ICH and GCP guidelines. The Investigator should maintain a list of the appropriately 
qualified persons to whom significant study-related duties have been delegated. The Investigator 
is responsible for supervising those individuals and for implementing procedures to ensure the 
integrity of the tasks performed and any data generated.
17.1.
Declaration of Helsinki
This study will be performed in alignment with the ethical principles outlined in the Declaration 
of Helsinki.
17.2.
Ethics Committee
The Investigator must obtain EC approval of the protocol, ICF, and other required study 
documents prior to starting the study. IQVIA will submit documents on behalf of the 
investigational sites in countries other than the US.
If the Investigator makes any changes to the ICF, Bioverativ must approve the changes before 
it is submitted to the EC. A copy of the approved ICF must be provided to Bioverativ. After 
approval, the ICF must not be altered without the agreement of the relevant EC and Bioverativ.
It is the responsibility of the Investigators to ensure that all aspects of institutional review 
are conducted in accordance with current applicable regulations.
Bioverativ must receive a letter documenting EC approval, which specifically identifies the 
protocol, protocol number, and ICF, prior to the initiation of the study. Protocol amendments will 
be subject to the same requirements as the original protocol.
A progress report must be submitted to the EC at required intervals and not less than annually.
At the completion or termination of the study, the investigational site must submit a close-out
letter to the EC and Bioverativ.
17.3.
Subject Information and Consent
Prior to performing any study-related activities under this protocol, including screening tests and 
assessments, written informed consent with the approved ICF must be obtained from the subject 

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or subject’s legally authorized representative (e.g., parent or legal guardian), as applicable, in 
accordance with local practice and regulations.
The background of the proposed study, the procedures, the benefits and risks of the study, 
and that study participation is voluntary for the subject must be explained to the subject 
(or the subject’s legally authorized representative). The subject must be given sufficient time 
to consider whether to participate in the study.
Subjects will be informed that their race and ethnicity will be collected and will be used during 
analysis of study results. A copy of the signed and dated ICF or assent must be given to the 
subject or the subject’s legally authorized representative. The original signed and dated ICF will
be retained with the study records. Local regulations must be complied with in respect to the 
final disposition of the original (wet signature) and copies of the signed and dated ICFs.
Confirmation of informed consent or assent must also be documented in the subject’s medical 
record.
17.4.
Subject Data Protection
Prior to any testing under this protocol, including screening tests and assessments, candidates 
must also provide all authorizations required by local law (e.g., Protected Health Information 
authorization in North America).
The race and ethnicity of subjects 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 [Astermark 2005; Carpenter 2012]. Additionally, differential responses to FVIII 
products may occur in different haplotypes of FVIII that also differ across racial and ethnic 
groups [Viel 2009].
Study reports will be used for research purposes only. The subject will not be identified by name in 
CRFs, study-related forms, study reports, or any related publications. Bioverativ, its partners and 
designees, ECs, and various government health agencies may inspect the records of this study.
Every effort will be made to keep the subject’s personal medical data confidential.
17.5.
Compensation for Injury
Bioverativ maintains appropriate insurance coverage for clinical studies and will follow 
applicable local compensation laws.
17.6.
Conflict of Interest
The Investigators should address any potential conflicts of interest (e.g., financial interest 
in Bioverativ or IQVIA) with the subject before the subject makes a decision to participate in the 
study.

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17.7.
Registration of Study and Disclosure of Study Results
Bioverativ will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations.

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18.
ADMINISTRATIVE PROCEDURES
18.1.
Study Site Initiation
The Investigator must not screen any subjects prior to completion of a study initiation visit, 
which will be conducted by IQVIA. This initiation visit will include a detailed review of the 
protocol and study procedures.
18.2.
Quality Control and Quality Assurance
Quality control procedures will be implemented at each stage of data handling to ensure that 
all data are reliable and have been processed correctly. Data anomalies will be communicated 
to the sites for clarification and resolution, as appropriate. 
During and/or after completion of the study, quality assurance officers named by 
Bioverativ or the regulatory authorities may wish to perform onsite audits or inspections.
The Investigator will be expected to cooperate with any audit or inspection and to provide 
assistance and documentation (including source data) as requested.
18.3.
Monitoring of the Study
The Investigator must permit study-related monitoring by providing direct access to source data 
and to the subjects’ medical histories. Source data must be attributable, legible, original, 
accurate, contemporaneous, and complete. Changes to source data must be traceable, not obscure 
the original entry, and be explained if necessary (e.g., with an audit trail). The Investigator 
should maintain a record of the location(s) of essential documents.
The Clinical Monitor will visit the study site at regular intervals during the study and after the 
study has completed, as appropriate. A clinical site monitoring plan will detail who performs 
the monitoring, how often, and the extent of review. It also will provide the monitoring strategy, 
with emphasis on subject safety, data integrity, and critical data and processes. During such 
visits, CRFs, supporting documentation, and essential documentation related to the study will be 
reviewed and any discrepancies or omissions will be resolved. Remote evaluation of data 
(centralized monitoring) may also be conducted and reported as defined in the monitoring plan.
Monitoring visits must be conducted according to the applicable ICH and GCP guidelines 
to ensure the protection of subject rights and well-being, protocol adherence, quality of data 
(accurate, complete, and verifiable), study treatment accountability, compliance with regulatory 
requirements, and continued adequacy of the investigational site and its facilities.

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18.4.
Study Funding
Bioverativ is the Sponsor of the study and is funding the study. All financial details are provided 
in the separate contracts between the institution, Investigator, and Bioverativ.
18.5.
Publications
Details are included in the clinical trial agreement for this study.

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19.
FURTHER REQUIREMENTS AND GENERAL INFORMATION
19.1.
External Contract Organizations
Bioverativ will ensure oversight of any study-related duties and functions carried out on its 
behalf and will specify in writing all duties and functions that are transferred.
19.1.1.
Contract Research Organization 
IQVIA will be responsible for administrative aspects of the study, including but not limited to 
study initiation (including review of study responsibilities with study site Investigators and staff), 
monitoring, management of SAE reports, and data management. Contract research organizations 
will be used to prepare and publish the clinical study report.
19.1.2.
Interactive Response Technology
Interactive response technology (IRT) will be used in this study. Before subjects are screened 
or enrolled, the IRT vendor or Sponsor designee will provide each study site with the necessary 
training, a user manual, and access rights to the system. Specific details regarding the IRT 
system are provided in the Study Reference Guide.
19.1.3.
Electronic Data Capture
Subject information will be captured and managed by study sites on electronic CRFs by a 
web-based electronic data capture tool developed and supported by IQVIA and configured by 
Bioverativ. It is recommended that data be entered into the electronic data capture system within 
5 business days, including batched records and records with source documents. 
19.1.4.
Central Laboratories for Laboratory Assessments
Central laboratories have been selected by Bioverativ to analyze all laboratory samples being 
collected for this study. Specifics regarding the requirements for laboratory specimen collection, 
handling, and analysis are provided in the Study Laboratory Manual, which is part of the Study 
Reference Guide.
19.1.5.
Central Facility for Other Assessments
LabCorp (which includes Covance and Esoterix) has been selected by Bioverativ as the central 
laboratory for this study.

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19.2.
Study Committees
19.2.1.
Data Safety Monitoring Committee 
An independent DSMC will evaluate the safety data from the study on an ongoing basis.
The DSMC and the Sponsor will also evaluate safety data to determine whether it is appropriate 
to escalate from the low-dose BIVV001 cohort to the high-dose BIVV001 cohort. The specifics 
regarding the DSMC organization and procedures will be outlined in a DSMC charter.
19.3.
Changes to Final Study Protocol
All protocol amendments must be submitted to the EC and regulatory authorities if required by 
local law. Protocol modifications that affect subject safety, the investigational scope, or the 
scientific quality of the study must be approved by the EC before implementation of such 
modifications to the conduct of the study. If required by local law, such modifications must also 
be approved by the appropriate regulatory agency before implementation. However, Bioverativ 
may, at any time, amend this protocol to eliminate an apparent immediate hazard to a subject. In 
this case, the appropriate regulatory authorities will be notified subsequent to the modification.
In the event of a protocol modification, the ICF may require similar modifications (refer 
to Sections 17.2 and 17.3).
19.4.
Ethics Committee Notification of Study Completion or Termination
Where required, the regulatory authorities and ECs must be notified of completion or termination 
of this study, and sent a copy of the study synopsis in accordance with necessary timelines.
19.5.
Retention of Study Data
The minimum retention time for study records will meet the strictest standard applicable to that 
site, as dictated by any institutional requirements or local, national, or regional laws or 
regulations. Prior to proceeding with destruction of records, the Investigator must notify 
Bioverativ in writing and receive written authorization from Bioverativ to destroy study records.
In addition, the Investigator must notify Bioverativ of any changes in the archival arrangements 
including but not limited to archival at an offsite facility or transfer of ownership if the 
Investigator leaves the site.
19.6.
Study Report Signatory
Bioverativ will designate one or more of the participating Investigators as a signatory for the 
study report. This determination will be made by several factors, including but not limited to, the 
Investigator's experience and reputation in the studied indication; the Investigator's contribution 
to the study in terms of design, management, and/or subject enrollment; or by other factors 
determined to be relevant by Bioverativ.
Bioverativ will follow all applicable local regulations pertaining to study report signatories.

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20.
REFERENCES
Abbas AK, Lichtman AH, Pillai S. Cellular and Molecular Immunology, 6ª ed, Editor Saunders 
2007
Advate United States Prescribing Information [USPI], May 2015, Baxter International Inc. The 
most recent version is available at: 
http://www.shirecontent.com/PI/PDFs/ADVATE_USA_ENG.pdf.
Adynovate United States Prescribing Information [USPI], December 2016, Baxalta US Inc. The 
most recent version is available at: 
http://www.shirecontent.com/PI/PDFs/ADYNOVATE_USA_ENG.pdf.
Aledort LM, Haschmeyer RH, Pettersson H. A longitudinal study of orthopaedic outcomes for 
severe factor-VIII-deficient haemophiliacs. The Orthopaedic Outcome Study Group. J Intern 
Med. 1994;236(4):391-9.
Astermark J, Oldenburg J, Escobar M, et al. The Malmö International Brother Study (MIBS). 
Genetic defects and inhibitor development in siblings with severe hemophilia A. Haematologica. 
2005;90(7):924-31.
Aznar JA, Lucia F, Abad-Franch L, et al. Haemophilia in Spain. Haemophilia. 
2009;15(3):665-75.
Berntorp E, Astermark J, Björkman S, et al. Consensus perspectives on prophylactic therapy for 
haemophilia: summary statement. Haemophilia. 2003;9(Suppl 1):1-4.
Berntorp E, Boulyjenkov V, Brettler D, et al. Modern treatment of haemophilia. Bull World 
Health Organ. 1995;73(5):691-701.
Blanchette VS, Shapiro AD, Liesner RJ, et al. Plasma and albumin-free recombinant factor VIII: 
pharmacokinetics, efficacy, and safety in previously treated pediatric patients. J Thromb 
Haemost. 2008;6(8):1319-26.
Byetta United States Prescribing Information [USPI], February 2015, AstraZeneca 
Pharmaceuticals LP. The most recent version is available at: 
https://www.azpicentral.com/byetta/pi_byetta.pdf
Carpenter SL, Michael Soucie J, Sterner S, et al. Increased prevalence of inhibitors in Hispanic 
patients with severe haemophilia A enrolled in the Universal Data Collection database. 
Haemophilia. 2012;18(3):e260-5.

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Centers for Disease Control and Prevention (CDC). Summary Report of UDC Activity National, 
Patient Demographics (Hemophilia). 2011. Available at: 
https://www2a.cdc.gov/ncbddd/htcweb/UDC_Report/UDC_Report.asp.
 
Chhabra ES, Simon J, Zuben S, et al. Application of in silico antigenicity prediction methods to 
avoid neo-epitopes during the designing of BIIB073, a next-generation long-acting recombinant 
Factor VIII (rFVIII) molecule. Haemophilia. 2016;22(Suppl 4):18.
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Protocol 242HA101
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BIVV001 (rFVIIIFc-VWF-XTEN) Safety and Pharmacokinetics Study
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Bioverativ Therapeutics Inc.
85
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Bioverativ Therapeutics Inc.
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Protocol 242HA101
Version 6.0
BIVV001 (rFVIIIFc-VWF-XTEN) Safety and Pharmacokinetics Study
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of 
Bioverativ Therapeutics Inc.
87
21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL
I have read the foregoing protocol, “A Phase 1/2a, Open-Label, Dose-Escalation Study to 
Determine the Safety, Tolerability, and Pharmacokinetics of a Single Intravenous Injection 
of rFVIIIFc-VWF-XTEN (BIVV001) in Previously Treated Adults with Severe Hemophilia A,” 
and agree to conduct the study according to the protocol and the applicable ICH guidelines and 
GCP regulations, and to inform all who assist me in the conduct of this study of their 
responsibilities and obligations.
____________________________________________________
Investigator’s Signature
Date
____________________________________________________
Investigator’s Name (Print)
____________________________________________________
Study Site (Print)