An Open-Label, Multicenter Evaluation of the Safety and Efficacy of Recombinant Coagulation Factor VIII Fc Fusion Protein (rFVIIIFc; BIIB031) in the Prevention and Treatment of Bleeding in Previously Untreated Patients With Severe Hemophilia A
Phase: PHASE3
Conditions: Hemophilia A
Sponsor: Bioverativ, a Sanofi company

CONFIDENTIAL
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Therapeutics Inc
1
PROTOCOL NUMBER:
997HA306
PHASE OF DEVELOPMENT:
3
Bioverativ Therapeutics Inc.
225 Second Avenue
Waltham, MA 02451
United States
PROTOCOL TITLE: An Open-Label, Multicenter Evaluation of the Safety and Efficacy of 
Recombinant Coagulation Factor VIII Fc Fusion Protein (rFVIIIFc; BIIB031) in the Prevention and 
Treatment of Bleeding in Previously Untreated Patients With Severe Hemophilia A
EUDRA CT NO:
2013-005512-10
DATE:
12 February 2018
Version 6
FINAL
Supersedes previous Version 5 dated 23 February 2017
NCT02234323

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TABLE OF CONTENTS
1.
SPONSOR INFORMATION .....................................................................................10
2.
LIST OF ABBREVIATIONS.....................................................................................11
3.
SYNOPSIS .................................................................................................................13
4.
STUDY SCHEMATIC AND SCHEDULE OF ACTIVITIES FOR STUDY 
997HA306...................................................................................................................19
4.1.
Study Schematic .........................................................................................................20
4.2.
Schedules of Activities ...............................................................................................21
4.2.1.
Schedule of Activities: Screening and Baseline Incremental Recovery Visit............21
4.2.2.
Treatment Period Visits..............................................................................................22
4.2.2.1.
Schedule of Activities: Episodic and Prophylaxis Regimens.....................................23
4.2.2.2.
Schedule of Activities: Exposure Day Milestone Visits.............................................25
4.2.2.3.
Schedule of Activities: Immune Tolerance Induction................................................26
4.2.2.4.
Schedule of Activities: Pharmacokinetic Sampling for Half-life 
Determination .............................................................................................................28
4.2.2.5.
Schedule of Activities: Post-Immune Tolerance Complete Success Visits................29
4.2.2.6.
Schedule of Activities: Surgery Visits........................................................................31
5.
INTRODUCTION......................................................................................................33
5.1.
Profile of Previous Experience ...................................................................................33
5.1.1.
Therapies for Hemophilia A.......................................................................................33
5.1.2.
rFVIIIFc......................................................................................................................34
5.1.3.
Summary of Nonclinical Experience with rFVIIIFc ..................................................34
5.1.4.
Summary of Clinical Experience With rFVIIIFc .......................................................35
5.2.
Study Rationale...........................................................................................................37
5.3.
Rationale for Dose and Schedule Selection................................................................37
5.4.
Potential Risks and Benefits.......................................................................................38
6.
STUDY OBJECTIVES AND ENDPOINTS..............................................................39
6.1.
Objectives ...................................................................................................................39
6.1.1.
Primary Objective.......................................................................................................39
6.1.2.
Secondary Objectives .................................................................................................39
6.1.3.
Exploratory Objective.................................................................................................39
6.2.
Endpoints....................................................................................................................39

Protocol 997HA306
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6.2.1.
Primary Endpoint........................................................................................................39
6.2.2.
Secondary Endpoints ..................................................................................................39
6.2.3.
Exploratory Endpoints................................................................................................40
7.
STUDY DESIGN .......................................................................................................41
7.1.
Study Overview ..........................................................................................................41
7.2.
Study Specifics ...........................................................................................................42
7.2.1.
Dose-Limiting Toxicity ..............................................................................................42
7.3.
Overall Study Duration and Follow-Up .....................................................................42
7.3.1.
Screening ....................................................................................................................42
7.3.2.
Treatment....................................................................................................................42
7.3.3.
Follow-Up...................................................................................................................43
7.4.
Study Stopping Rules .................................................................................................43
7.5.
End of Study ...............................................................................................................43
8.
SELECTION OF SUBJECTS ....................................................................................45
8.1.
Inclusion Criteria ........................................................................................................45
8.2.
Exclusion Criteria.......................................................................................................45
8.3.
Minimum Criteria for Enrollment ..............................................................................46
9.
ENROLLMENT AND REGISTRATION .................................................................47
9.1.
Screening ....................................................................................................................47
9.1.1.
Screening Assessments...............................................................................................47
9.2.
Enrollment of Subjects ...............................................................................................48
9.3.
Registration of Subjects..............................................................................................48
9.4.
Blinding Procedures....................................................................................................48
10.
TREATMENT OF SUBJECTS..................................................................................49
10.1.
Study Treatment Schedule and Administration..........................................................49
10.1.1.
Definitions of Nominal Strength Versus Actual Potency...........................................50
10.2.
Treatment....................................................................................................................51
10.2.1.
Incremental Recovery.................................................................................................51
10.2.1.1.
Baseline Incremental Recovery Assessments.............................................................51
10.2.1.2.
Assessment of FVIII Activity During Interim Visits .................................................51
10.2.2.
Episodic Treatment.....................................................................................................51
10.2.3.
Prophylaxis Treatment................................................................................................52

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10.2.4.
Bleeding Episodes ......................................................................................................52
10.2.5.
Inhibitor Testing .........................................................................................................55
10.2.5.1.
Definition of Negative and Positive Inhibitors...........................................................56
10.2.5.2.
Positive Inhibitors.......................................................................................................56
10.2.6.
Anti-rFVIIIFc Antibody Testing ................................................................................57
10.2.7.
Immune Tolerance Induction Therapy .......................................................................58
10.2.7.1.
Assessment of Incremental Recovery and Half-Life During Immune 
Tolerance Induction Therapy......................................................................................58
10.2.7.2.
Treatment of Bleeding Episodes During Immune Tolerance Induction 
Therapy.......................................................................................................................59
10.2.7.3.
Interruption of Immune Tolerance Induction Therapy...............................................59
10.2.7.4.
Immune Tolerance Induction Therapy Outcomes ......................................................59
10.2.7.5.
Transition to a Prophylactic Regimen Following Immune Tolerance 
Induction Therapy Success (Tapering Period) ...........................................................62
10.2.7.6.
Monitoring for Relapse...............................................................................................63
10.2.8.
Surgery........................................................................................................................63
10.2.8.1.
Definitions of Major and Minor Surgery....................................................................64
10.2.8.2.
Definition of the Surgical Period................................................................................64
10.2.8.3.
Rehabilitation Period ..................................................................................................66
10.3.
Treatment Precautions ................................................................................................66
10.4.
Modification of Dose and/or Treatment Schedule......................................................66
10.5.
Non-Medical Treatment With rFVIIIFc .....................................................................66
10.6.
End of Treatment ........................................................................................................66
10.7.
Treatment Compliance................................................................................................67
10.8.
Concomitant Therapy and Procedures........................................................................68
10.8.1.
Concomitant Therapy .................................................................................................68
10.8.1.1.
Allowed Concomitant Therapy...................................................................................68
10.8.1.2.
Disallowed Concomitant Therapy..............................................................................68
10.8.2.
Concomitant Procedures.............................................................................................69
10.9.
Continuation of Treatment..........................................................................................69
11.
WITHDRAWAL OF SUBJECTS FROM THE STUDY...........................................70
12.
STUDY TREATMENT MANAGEMENT................................................................72
12.1.
rFVIIIFc (BIIB031) ....................................................................................................72

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12.1.1.
rFVIIIFc Preparation ..................................................................................................72
12.1.2.
rFVIIIFc Storage at Site..............................................................................................73
12.1.3.
rFVIIIFc Handling and Disposal ................................................................................73
12.1.4.
rFVIIIFc Accountability.............................................................................................73
13.
EFFICACY AND PHARMACOKINETIC ASSESSMENTS...................................74
13.1.
Clinical Efficacy Assessments....................................................................................74
13.2.
Laboratory Efficacy Assessments...............................................................................74
13.3.
Pharmacokinetic Assessments....................................................................................74
13.4.
Additional Assessments..............................................................................................75
13.4.1.
Factor VIII Genotyping (Optional).............................................................................75
13.4.2.
Whole Blood for Exploratory Assays for Inhibitor Positive Subjects........................75
13.4.3.
Health Outcomes Related to Hemophilia ...................................................................75
14.
SAFETY ASSESSMENTS ........................................................................................77
14.1.
Clinical Safety Assessments.......................................................................................77
14.2.
Laboratory Safety Assessments..................................................................................77
14.3.
rFVIIIFc-Specific Safety Assessments.......................................................................78
14.4.
Archive Samples.........................................................................................................78
14.4.1.
Archive Plasma Samples ............................................................................................78
14.4.2.
Archive Genotyping Samples (Optional) ...................................................................78
14.4.3.
Sample Volumes.........................................................................................................79
15.
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES .................................................................................................80
15.1.
Definitions ..................................................................................................................80
15.1.1.
Adverse Event.............................................................................................................80
15.1.2.
Serious Adverse Event................................................................................................80
15.1.2.1.
Serious Pretreatment Event.........................................................................................81
15.2.
Safety Classifications..................................................................................................81
15.2.1.
Investigator Assessment of Events.............................................................................81
15.2.2.
Relationship of Events to Study Treatment................................................................81
15.2.3.
Severity of Events.......................................................................................................81
15.2.4.
Expectedness of Events ..............................................................................................82
15.3.
Monitoring and Recording Events..............................................................................82

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15.3.1.
Adverse Events ...........................................................................................................82
15.3.2.
Serious Adverse Events..............................................................................................82
15.3.3.
Immediate Reporting of Serious Adverse Events.......................................................83
15.3.3.1.
Deaths .........................................................................................................................84
15.3.4.
Suspected Unexpected Serious Adverse Reactions....................................................84
15.4.
Procedures for Handling Special Situations ...............................................................84
15.4.1.
Overdose.....................................................................................................................84
15.4.2.
Medical Emergency....................................................................................................85
15.4.3.
Unblinding for Medical Emergencies.........................................................................85
15.5.
Safety Responsibilities................................................................................................85
15.5.1.
Investigator Responsibilities.......................................................................................85
15.5.2.
Bioverativ Responsibilities.........................................................................................86
16.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE...........87
16.1.
Demography and Baseline Disease Characteristics....................................................87
16.2.
Efficacy.......................................................................................................................87
16.2.1.
Analysis Population....................................................................................................87
16.2.2.
General Methods of Analysis .....................................................................................87
16.2.3.
Analysis of Efficacy Endpoints ..................................................................................88
16.2.4.
Additional/Exploratory Analysis of Efficacy Endpoints............................................89
16.3.
Pharmacokinetics........................................................................................................89
16.4.
Pharmacodynamics.....................................................................................................89
16.5.
Safety..........................................................................................................................89
16.5.1.
Analysis Population....................................................................................................89
16.5.2.
Methods of Analysis...................................................................................................89
16.5.2.1.
Occurrence of Inhibitor Development........................................................................89
16.5.2.2.
Adverse Events ...........................................................................................................90
16.5.2.3.
Other Safety Parameters .............................................................................................90
16.6.
Immune Tolerance Induction......................................................................................90
16.7.
Interim Analyses.........................................................................................................90
16.8.
Sample Size Considerations .......................................................................................90
17.
ETHICAL REQUIREMENTS ...................................................................................91
17.1.
Declaration of Helsinki...............................................................................................91

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17.2.
Ethics Committee........................................................................................................91
17.3.
Subject Information and Consent ...............................................................................91
17.4.
Subject Data Protection ..............................................................................................92
17.5.
Compensation for Injury.............................................................................................92
17.6.
Conflict of Interest......................................................................................................93
17.7.
Registration of Study and Disclosure of Study Results..............................................93
18.
ADMINISTRATIVE PROCEDURES.......................................................................94
18.1.
Study Site Initiation....................................................................................................94
18.2.
Quality Assurance.......................................................................................................94
18.3.
Monitoring of the Study..............................................................................................94
18.4.
Study Funding.............................................................................................................94
18.5.
Publications.................................................................................................................94
19.
FURTHER REQUIREMENTS AND GENERAL INFORMATION........................95
19.1.
External Contract Organizations.................................................................................95
19.1.1.
Contract Research Organization.................................................................................95
19.1.2.
Interactive Voice and Web Response System ............................................................95
19.1.3.
Electronic Data Capture..............................................................................................95
19.1.4.
Central Laboratories for Laboratory Assessments .....................................................95
19.2.
Study Committees.......................................................................................................95
19.2.1.
Independent Data Safety Monitoring Committee.......................................................95
19.3.
Changes to Final Study Protocol ................................................................................96
19.4.
Ethics Committee Notification of Study Completion or Termination........................96
19.5.
Retention of Study Data..............................................................................................96
19.6.
Study Report Signatory...............................................................................................96
20.
REFERENCES ...........................................................................................................97
21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL.........................................99
APPENDIX A.
RFVIIIFC DOSING GUIDELINES FOR BLEEDING EPISODES..............100
APPENDIX B.
ASSESSMENT OF RESPONSE TO BLEEDING .........................................101
APPENDIX C.
PHYSICIAN’S GLOBAL ASSESSMENT.....................................................102
APPENDIX D.
PHYSICIAN ASSESSMENT OF RESPONSE TO TREATMENT 
DURING SURGERY...............................................................................................103
APPENDIX E.
OBJECTIVES AND THEIR ASSOCIATED ENDPOINTS AND 
ASSESSMENTS.......................................................................................................104

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LIST OF TABLES
Table 1:
Comparison of PK Parameters of rFVIIIFc by Age Category: Geometric 
Mean (95% Confidence Interval) ...............................................................................36
Table 2:
Examples of Recommended Blood Draw Volume Limits .........................................79
LIST OF FIGURES
Figure 1:
Study Design...............................................................................................................20
Figure 2:
Immune Tolerance Induction Assessment Algorithm................................................62
Figure 3:
Primary Objective, Endpoints and Assessments ......................................................104
Figure 4:
Secondary Objectives, Endpoints, and Assessments................................................105
Figure 5:
Exploratory Objectives, Endpoints, and Assessments..............................................106

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1.
SPONSOR INFORMATION
This study is sponsored by Bioverativ Therapeutics Inc. Refer to the Study Reference Manual 
that contains all study contacts for complete contact information.
Bioverativ Therapeutics Inc.
225 Second Avenue
Waltham, MA 02451
Phone:
Fax:
For urgent medical issues in which the study’s Medical Director should be contacted, please 
refer to the Study Reference Guide’s Official Study Contact List for complete contact 
information.
Bioverativ may transfer any or all of its study-related responsibilities to a contract research 
organization (CRO) and other third parties; however, Bioverativ retains overall accountability 
for these activities.

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2.
LIST OF ABBREVIATIONS
ABR
annualized bleeding rate
ADR
adverse drug reaction
AE
adverse event
aPCC
activated prothrombin complex concentrate
aPTT
activated partial thromboplastin time
BU
Bethesda unit
CHMP
Committee for Medicinal Products for Human Use
CI
confidence interval
CL
clearance
CRO
contract research organization
DHA
Directions for Handling and Administration
DLT
dose-limiting toxicity
DNAUC
dose-normalized area under the curve
DSMC
Data Safety Monitoring Committee
eCRF
electronic case report form
ED
exposure day
EMA
European Medicines Agency
EOS
End of Study
EOT
End of Treatment
EPD
electronic patient diary
ET
early termination
F8
target gene for hemophilia A
FAS
Full Analysis Set
FcRn
neonatal Fc receptor
FVIII
coagulation factor VIII
FVIII:C
coagulation activity of coagulation factor VIII in plasma
GCP
Good Clinical Practice
HIV
human immunodeficiency virus
ICF
informed consent form
ICH
International Council for Harmonisation
IgG1
immunoglobulin G1
IR
incremental recovery
ITI
immune tolerance induction
IV
intravenous
IU
international units
IXRS
Interactive Voice/Web Response System
MRT
mean residence time
PHI
protected health information
PK
pharmacokinetic(s)
PTP
previously treated patient
PUP
previously untreated patient

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rFVIIa
recombinant activated factor VII
rFVIII
recombinant coagulation factor VIII
rFVIIIFc
recombinant coagulation factor VIII Fc fusion protein
SAE
serious adverse event
SAP
statistical analysis plan
SUSAR
suspected unexpected serious adverse reaction
t½
half-life
Vss
volume of distribution at steady state
WHO
World Health Organization

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3.
SYNOPSIS
This is a brief summary. For details refer to the body of the protocol.
Protocol Number:
997HA306
Protocol Title:
An Open-Label, Multicenter Evaluation of the Safety and 
Efficacy of Recombinant Coagulation Factor VIII Fc Fusion 
Protein (rFVIIIFc; BIIB031) in the Prevention and 
Treatment of Bleeding in Previously Untreated Patients 
With Severe Hemophilia A
Version Number:
6
Name of Study Treatment:
Antihemophilic Factor, Recombinant Coagulation Factor 
VIII Fc Fusion Protein (rFVIIIFc; BIIB031)
Study Indication:
Hemophilia A
Phase of Development:
3
Rationale for the Study:
The use of a prophylaxis regimen in young children starting 
prior to the onset of frequent joint bleeding is currently the 
recommended standard of care in hemophilia due to the 
demonstrated benefit on long-term outcomes [Aznar 2000; 
Manco-Johnson 2007; Molho 2000]. Currently available 
coagulation factor VIII (FVIII) replacement therapies are 
limited by short elimination half-life (t½).
The purpose of this study is to investigate the safety and 
efficacy of rFVIIIFc in previously untreated patients (PUPs) 
in accordance with the European Medicines Agency (EMA) 
Committee for Medicinal Products for Human Use (CHMP) 
guideline on the clinical investigation of recombinant and 
human plasma-derived factor VIII products [EMA 
(EMA/CHMP/BPWP/144533/2009) 2011].
Study Objectives and 
Endpoints:
Objectives
Primary: 
The primary objective of the study is to evaluate the safety 
of rFVIIIFc in previously untreated subjects with severe 
hemophilia A.
Secondary: 

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The secondary objectives of the study are as follows:

To evaluate the efficacy of rFVIIIFc in the 
prevention and treatment of bleeding episodes in 
PUPs

To evaluate rFVIIIFc consumption for the 
prevention and treatment of bleeding episodes in 
PUPs

To describe experience with the use of rFVIIIFc 
for immune tolerance induction (ITI) in subjects 
with inhibitors
The exploratory objectives of the study are 

To evaluate the effect of rFVIIIFc based on 
patient-reported outcomes and health resource 
utilization

To assess the efficacy of rFVIIIFc for 
perioperative management
Endpoints
The primary endpoint of the study is the occurrence of 
inhibitor development.
The secondary endpoints of the study are as follows:

The annualized number of bleeding episodes per 
subject.

The annualized number of spontaneous joint 
bleeding episodes per subject.

The number of injections and dose per injection 
of rFVIIIFc required to resolve a bleeding 
episode.

Assessments of response to treatment with 
rFVIIIFc for bleeding episodes, using the 4-point 
bleeding response scale.

The total number of exposure days (EDs) per 
subject per year.

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
Total annualized rFVIIIFc consumption per 
subject for the prevention and treatment of 
bleeding episodes.

rFVIIIFc incremental recovery (IR)

Response to ITI with rFVIIIFc 
(complete success, partial success, failure, early 
withdrawal)
Exploratory endpoints in the study include, but are not 
limited to

Health Outcomes

Investigator/Surgeon’s Assessment of Response
Study Design:
An open-label, single-arm, multicenter study evaluating the 
safety and efficacy of rFVIIIFc in previously untreated 
pediatric subjects with severe hemophilia A when used 
according to local standard of care for implementation of a 
prophylaxis regimen, including an optional preceding 
episodic (on-demand) treatment regimen. The duration of 
episodic treatment is at the Investigator’s discretion, in 
accordance with local standard of care. Surgery is allowed 
during the study. ITI is allowed during the study for subjects 
developing a positive inhibitor after exposure to rFVIIIFc.
Separate consent is required before starting an ITI regimen.
For subjects with inhibitors, the end of treatment will be 
defined based on the outcome of ITI therapy and the 
completion of any required tapering regimen and monitoring 
periods. The study will end after at least 90 subjects have 
reached at least 50 EDs with rFVIIIFc.
Subjects may be enrolled and receive study drug after 
samples for factor VIII activity and inhibitor testing at the 
central laboratory have been drawn, and diagnosis of severe 
hemophilia A with less than 1% factor VIII activity has been 
established based on local labs. However, any such subject 
must be withdrawn if the central laboratory screening results 
indicate factor VIII activity ≥1%, or a positive inhibitor. 
Rationale for Dose and 
Schedule Selection:
In the completed Phase 3 study (Study 997HA301) multiple 
doses of up to 65 IU/kg were well tolerated, with an adverse 
event (AE) profile generally consistent with that expected in 
patients with hemophilia A. Safety data from the completed 

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pediatric study in subjects <12 years of age (Study 
8HA02PED), which allowed for doses up to 80 IU/kg and a 
minimum dosing interval of 2 days, showed a safety profile 
generally consistent with the results of the Phase 3 study.
The dose for initiation of prophylaxis may be chosen by the 
Investigator within the range of 25 to 80 IU/kg. The dose 
can be adjusted based on the subject’s response to dosing in 
the range of 25 to 65 IU/kg at 3 to 5 day intervals.
Adjustments to the dose and interval of rFVIIIFc can be 
made in this study based on available PK data including 
FVIII activity levels, level of physical activity, and bleeding 
pattern, in accordance with local standards of care for a 
prophylactic regimen. Based on data from the completed 
clinical studies, and knowledge of increased clearance of 
factor concentrates in children <6 years of age, more 
frequent or higher doses of up to 80 IU/kg may be required.
The dose for treatment of bleeding episodes will target peak 
plasma FVIII activity of approximately 40% to 100%, in 
accordance with local standards.
Subjects will be eligible to undergo ITI with rFVIIIFc if 

They develop a positive high titer inhibitor 
(≥5.00 Bethesda Units [BU]/mL) 
or 

They develop a positive low titer inhibitor 
(≥0.60 and <5.00 BU/mL) and experience poorly 
controlled bleeding despite increased rFVIIIFc 
doses, or require bypassing agents to treat 
bleeding.
The ITI regimen will approximate the high-dose treatment 
arm of the International ITI Study protocol, and will utilize 
single injections of rFVIIIFc at a dose of 200 IU/kg, daily, 
consistent with current ITI guidelines [Valentino 2015]. 
This dosing regimen is also supported by the results of a 
prospective clinical trial that compared subjects treated with 
FVIII for ITI at a high dose (200 IU/kg/day) and a low dose 
(50 IU/kg/3 times per week). Results from this study [Hay 
and DiMichele 2012] demonstrated that the times to achieve 
negative inhibitor titer, normal FVIII recovery, and FVIII 
tolerance were shorter in subjects treated with the high dose 

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of FVIII, compared to subjects treated with the low dose. 
Furthermore, subjects treated with the high dose for ITI had 
a lower rate of intercurrent bleeding and fewer 
hospitalizations due to bleeding than subjects treated with 
the low dose. Since clearance is expected to be very rapid in 
the presence of inhibitors, irrespective of the type of FVIII 
product, the high dose of 200 IU/kg/day evaluated in the 
International ITI Study will be used in the present study to
maximize the potential for rapid tolerization while 
minimizing bleeding-related adverse events.
Study Location:
Multinational
Number of Planned Subjects:
At least 90 pediatric PUPs are expected to reach at least 50 
EDs with rFVIIIFc at the end of the study.
Study Population:
This study will be conducted in male, previously untreated 
subjects <6 years of age with severe hemophilia A.
Detailed entry criteria are described in the protocol.
Treatment Groups:
This is a single-arm study. Subjects who develop inhibitors 
after exposure to rFVIIIFc study drug may meet additional 
criteria that make them eligible for treatment with an ITI 
regimen on the study.
Duration of Treatment and 
Follow-up:
Individual subject study participation is expected to be 
approximately 6 months to 3 years including screening and 
follow-up. For each subject, the treatment period is no less 
than 50 EDs to the study treatment, unless the subject 
develops an inhibitor or the end of study (EOS) is declared.
Statistical Methods:
In general, all statistical analyses will be descriptive in 
nature. No formal comparison is planned, and no hypothesis 
will be formally tested. Continuous variables will be
summarized and presented by the number of observations, 
mean, median, standard deviation, minimum, and 
maximum. Categorical variables will be summarized by the 
number and percentage in each category.
Subjects with at least 1 dose of rFVIIIFc will be included in 
the Full Analysis Set (FAS) and the Safety Analysis Set.
Efficacy analyses will be based on the FAS, and safety 
analyses will be based on the Safety Analysis Set. Subjects 
developing a confirmed positive inhibitor test after exposure 
to rFVIIIFc study drug will have their efficacy and safety 

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data included up to the time of the last negative inhibitor 
test; efficacy and safety data collected after the time of the 
last negative inhibitor test will be summarized separately.
Summary statistics will be presented for safety and efficacy 
endpoints. The proportion of subjects developing inhibitors 
will be presented with a 95% confidence interval. For 
efficacy purposes, the number of bleeding episodes will be 
annualized. The summary statistics of annualized bleeding 
episodes and the subject’s response to treatment will be 
presented separately for episodic and prophylaxis treatment.
Other statistical analyses may be conducted for exploratory 
purposes.
Interim Analysis:
An interim analysis of safety and efficacy data will be 
conducted when at least 50 subjects have completed at least 
50 EDs and undergone inhibitor testing. Additional interim 
analyses may be conducted during the study, as needed.
Analyses will be descriptive in nature. No formal 
comparisons are planned, and no hypotheses will be 
formally tested.
Sample Size Determination:
Because the size of the hemophilia population is limited, the 
sample size is based on clinical rather than statistical 
considerations. Taking into account the CHMP Guideline 
[EMA (EMA/CHMP/BPWP/144533/2009) 2011] and in an 
effort to enroll a sufficient number of subjects to assess the 
efficacy and safety of rFVIIIFc in this population of 
primarily very young children, approximately 105 subjects 
will be dosed with rFVIIIFc to achieve at least 90 subjects 
with no less than 50 EDs by the completion of the study. 
Study Stopping Rules:
Study stopping is required for the following:

Unacceptable inhibitor incidence as advised by 
the Data Safety Monitoring Committee (DSMC).

Detection of an unexpected, serious, or 
unacceptable risk to the study subjects.

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4.
STUDY SCHEMATIC AND SCHEDULE OF ACTIVITIES FOR 
STUDY 997HA306

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Safety and Efficacy of rFVIIIFc in Previously Untreated Patients With Hemophilia A
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4.1.
Study Schematic
Figure 1:
Study Design
EOT = End of Treatment; ET = Early Termination; ITI = immune tolerance induction
a Subjects may not enter the study if they have received any injections of factor prior to the Confirmation of Eligibility.
b Screening Visit and Baseline Incremental Recovery Visit may be performed as 2 separate visits OR all activities necessary for screening, confirmation of eligibility, and the 
baseline incremental recovery visit may be performed at the same visit.
c If screening assessments cannot be completed within 8 weeks, some assessments may need to be repeated as described in Section 7.3.1.
d The most common scenarios for EOT are shown; however, EOT may occur under other circumstances as defined by the protocol, for example, when the End Of Study is declared 
for the study or upon early withdrawal of a subject. (Section 10.6)
eSee Section 10.2.5 for criteria.
fSee the ITI Outcome Algorithm in Figure 2.

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4.2.
Schedules of Activities
4.2.1.
Schedule of Activities: Screening and Baseline Incremental Recovery Visit
Activities
Screening
Baseline Incremental Recovery
Visita
Predose
Postdose
Informed Consent
X
Demographicsb
X
Medical and Surgical Historyc
X
Physical Examination
X
Height
X
Weight
X
X
Vital Signsd
X
X
X
Health Outcome
X
Hematologye
X
Blood Chemistryf
X
Viral Analysisg
X
Nijmegen-Modified Bethesda Assay (Inhibitor 
Assay)h,i
X
Xi
FVIII Activityh
X
FVIII Activity for Incremental Recoveryj
Xi
X
Anti-rFVIIIFc Antibody
X
Xi
F8 Genotypingk
X
Injection Site Inspection
X
EPD Review, including rFVIIIFc Dosing 
Accountability
Monitor and record at all visits
rFVIIIFc Clinic Dosing
X
Assessment of Response in EPD by Parent/Caregiverl
Monitor and record at all visits
Physician's Assessment of Response to Individual 
Bleeding Episodes Treated in Clinic
Monitor and record at all visits
Adverse Eventsm
Monitor and record at all visits
Serious Adverse Eventsn
X
Monitor and record at all visits
Concomitant Therapy/ Procedures Recordingo
X
Monitor and record at all visits
AE = adverse event; DHA=Directions for Handling and Administration; ED = exposure day; EPD = electronic 
patient diary; ET = Early Termination; F8 = target gene for hemophilia A; FVIII = coagulation factor VIII; 
HIV = human immunodeficiency virus; ICF = informed consent form; IR = incremental recovery; rFVIIIFc = 
recombinant coagulation factor VIII Fc fusion protein; SAE = serious adverse event.
a
The Baseline IR Visit activities may be completed on the same day as Screening, or they may be completed as a 

Protocol 997HA306
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part of a separate visit as shown. Baseline IR requires a washout from rFVIIIFc of at least 24 hours prior to 
the predose sample collection. 
b
Race and ethnicity will be included among the demographic data collected in this study, for reasons described 
in Section 17.4.
c
Medical and surgical history includes any significant medical condition and/or any significant surgical histories, 
plus the following: HIV infection status (if positive, viral load, cluster of differentiation 4 [CD4] count, and 
platelets; based on laboratory results within the last 6 months), hepatitis B infection status, hepatitis C 
infection status, medication history, and any other congenital immunodeficiency. Medical history should also 
include any exposure to blood components or other factor replacement products prior to Screening and the 
time when the subject meets all eligibility criteria, since these would exclude the subject.
d
Vital signs include blood pressure, pulse rate, respiratory rate, and temperature (°C). Postdose assessments 
following in-clinic injections should be taken approximately 20 minutes after the end of the rFVIIIFc 
injection.
e
Hematology includes white blood cell count and differential, red blood cell, hemoglobin, hematocrit, and 
platelet count.
f
Blood chemistry includes sodium, potassium, chloride, total protein, total bilirubin, gamma glutamyl 
transferase, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, blood urea nitrogen, 
serum creatinine, and glucose.
g
Sample to be used to determine seropositivity at Screening, should subject be diagnosed with HIV, hepatitis B, 
or hepatitis C during the study.
h
See minimum criteria for enrollment, Section 8.3.
i
The predose activity, anti-drug antibody, and inhibitor testing are only required for subjects who received at 
least 1 dose of FVIIIFc (or 1 accidental dose of a factor VIII product) between enrollment and the dose for the 
baseline IR assessment.
j
Volume and units of factor infused at Baseline IR must be calculated and recorded using the actual potency as 
described in Section 10.1.1 (and in the DHA). The dose of factor for the IR baseline is 25 IU/kg (Section 
10.2.1.1). Blood samples will be taken at trough (predose; 30 minutes prior to the start of the rFVIIIFc 
injection) and postdose at 30 (±5) minutes after the start of the rFVIIIFc injection.
k
If genotype is not known and the parent/legal guardian provides separate consent for genotyping, a sample will 
be drawn for analysis during the Predose Baseline IR Visit. If blood volume is limiting, this assessment may 
be performed at a subsequent visit (Section 4.2.2.1). The subject’s parent/legal guardian may provide consent 
in order to receive this testing at any time during the Treatment Period.
l
The subject’s parent/caregiver must enter dosing information into the EPD as soon as possible after an 
injection and within a maximum of 7 days following the injection (Section 10.2.4.1.4). It is recommended 
that parents/caregivers enter dosing information immediately after an injection.
m
AEs are to be monitored and recorded from the time of first dose of rFVIIIFc.
n
SAEs are to be monitored and recorded from the time of signing informed consent form.
o
For subjects who are receiving breast milk, maternal concomitant medications will also be collected at the same 
time points as other concomitant therapies, unless the breast milk is derived from a source other than the 
mother or the mother has not consented.
4.2.2.
Treatment Period Visits
Subjects on episodic or prophylactic treatment in this study will participate in regular interim 
visits for follow up (Section 4.2.2.1), as well as follow up at specific ED milestones 
(Section 4.2.2.2). Subjects on ITI will participate in an ITI-specific schedule of interim visits 
(Section 4.2.2.3, and, if applicable, Section 4.2.2.4 and Section 4.2.2.5). Subjects requiring 
surgery will also participate in specialized visits (Section 4.2.2.6).

Protocol 997HA306
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Safety and Efficacy of rFVIIIFc in Previously Untreated Patients With Hemophilia A
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4.2.2.1.
Schedule of Activities: Episodic and Prophylaxis Regimens
Interim visits will be scheduled for all of the subjects on this study. Subjects on episodic and 
prophylaxis regimens will follow the schedule of activities below. 
Activities
Interim Visits
ET/ 
EOT
Visit
Final 
Safety 
Follow-
Up 
Visit/
Tele-
phone
Callc
Episodic Regimen
Visits every 12 (±2) weeksa
Prophylaxis Regimen
Visits every 
12 (±2) weeksb
Predose
Postdose
Predose
Postdose
Physical Examination
X
X
X
Height
X
Weight
X
X
X
Vital Signsd
X
X
X
X
X
Health Outcomee
X
X
X
Hematologyf
X
X
X
Blood Chemistryg
X
X
X
Nijmegen-Modified Bethesda 
Assay (Inhibitor Assay)h
X
X
Xj
FVIII Activityi
X
X
Anti-rFVIIIFc Antibody
X
X
X
F8 Genotypingj
If needed
Injection Site Inspectionk
X
X
X
Physician’s Global 
Assessment of Response
X
X
rFVIIIFc Clinic Dosingl
X
X
X
EPD Review, including 
rFVIIIFc Dosing 
Accountabilitym,n
<<<< ONGOING; Monitor and record at all visits; telephone call every 
month>>>
Assessment of Response in 
EPD by Caregiverm,n
<<< ONGOING; Monitor and record at all visits; telephone call every 
month>>>
Physician's Assessment of 
Response to Individual 
Bleeding Episodes Treated in 
Clinick
<<< ONGOING; Monitor and record at all visits; telephone call every 
month>>> 
Adverse Eventsn,o
<<< ONGOING; Monitor and record at all visits; telephone call every month>>> 
Serious Adverse Eventsn,p
<<< ONGOING; Monitor and record at all visits; telephone call every month>>> 

Protocol 997HA306
Version 6
Safety and Efficacy of rFVIIIFc in Previously Untreated Patients With Hemophilia A
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Activities
Interim Visits
ET/ 
EOT
Visit
Final 
Safety 
Follow-
Up 
Visit/
Tele-
phone
Callc
Episodic Regimen
Visits every 12 (±2) weeksa
Prophylaxis Regimen
Visits every 
12 (±2) weeksb
Predose
Postdose
Predose
Postdose
Concomitant Therapy/ 
Procedures Recordingq
<<< ONGOING; Monitor and record at all visits; telephone call every month>>> 
AE = adverse event; DHA=Directions for Handling and Administration; ED = exposure day; EOT = end of 
treatment; EPD = electronic patient diary; ET = Early Termination; F8 = target gene for hemophilia A; 
FVIII = coagulation factor VIII; HIV = human immunodeficiency virus; ICF = informed consent form; rFVIIIFc = 
recombinant coagulation factor VIII Fc fusion protein; SAE = serious adverse event.
a
For subjects on episodic treatment who have had no infusions of factor since the previous visit, blood draws 
will only be required every 24 weeks, rather than every 12 weeks.
b
If an investigator chooses to have the subject temporarily withdraw from treatment with rFVIIIFc and delay the 
start of ITI, the subject should continue to participate in Interim visits every 12 ± 2 weeks (per the 
prophylaxis regimen).
c
A follow-up telephone call or in-person visit is required 7 to 14 days after the last dose of rFVIIIFc to monitor 
AEs, SAEs, and concomitant medications and procedures.
d
Vital signs include blood pressure, pulse rate, respiratory rate, and temperature (°C). Assessments for in-clinic 
injections should be taken prior to and approximately 20 minutes after the end of the rFVIIIFc injection. 
e
Health outcome assessments will be performed every other visit during episodic and prophylaxis regimens, that 
is, every 24 weeks.
f
Hematology includes white blood cell count and differential, red blood cell, hemoglobin, hematocrit, and 
platelet count.
g
Blood chemistry includes sodium, potassium, chloride, total protein, total bilirubin, gamma glutamyl 
transferase, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, blood urea nitrogen, 
serum creatinine, and glucose.
h
An unscheduled visit may be required to repeat inhibitor testing under this protocol if the ET/EOT Visit 
inhibitor test is not evaluable or to obtain a sample to confirm a positive inhibitor test result.
i
Samples for FVIII activity will only be taken if the subject receives an rFVIIIFc injection during the site visit 
and is in a non-bleeding state. Volume and units of factor infused must be calculated and recorded using the 
nominal strength as described Section 10.1.1 (and in the DHA). Predose sample is to be collected within 30 
minutes prior to the start of rFVIIIFc injection; postdose sample is to be taken 30 (±5) minutes after the start 
of the rFVIIIFc injection.
j
If the subject’s genotype was not already known at Screening and the sample could not be drawn due to blood 
volume limitations at the Predose Baseline IR Visit, this assessment may be performed at the first Interim 
Visit. If the subject develops an inhibitor on the study, a sample may be drawn for this testing at any time 
during the Treatment Period. The parent/legal guardian must provide separate consent for genotyping.
k
Injection site inspection is to be performed only if the subject receives an rFVIIIFc injection during a clinic 
visit.
l
Clinic dosing is applicable only if warranted.
m
The subject’s parent/caregiver must enter dosing information into the EPD as soon as possible after an 
injection and within a maximum of 7 days following the injection (Section 10.2.4.1.4). It is recommended 
that parents/caregivers enter dosing information immediately after an injection.
n
In addition to scheduled clinic visits, telephone calls are planned approximately once a month for study site 
staff to check on each subject’s status. During the monthly phone call, the subject’s parent/caregiver will also 
be reminded about the requirement for timely EPD data entry, and assessments of “spontaneous” and 
“traumatic” bleeds will be noted.
o
AEs to be monitored and recorded from the time of first dose of rFVIIIFc.
p
SAEs to be monitored and recorded from the time of signing ICF. 
q
For subjects who are receiving breast milk, maternal concomitant medications will also be collected at the same 

Protocol 997HA306
Version 6
Safety and Efficacy of rFVIIIFc in Previously Untreated Patients With Hemophilia A
CONFIDENTIAL
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Therapeutics Inc.
25
time points as other concomitant therapies, unless the breast milk is derived from a source other than the 
mother or the mother has not consented.
4.2.2.2.
Schedule of Activities: Exposure Day Milestone Visits
In addition to the assessments at the interim visits described in Section 4.2.2.1, subjects must 
undergo testing for inhibitors at the ED milestones shown below. Testing for inhibitors may be 
combined with a scheduled interim visit. However, if an interim visit does not occur within the 
time windows below, the subject must return to the clinic to have the samples collected. In 
addition, if inhibitor development is suspected at any time during the study (e.g., the expected 
plasma factor VIII activity levels are not attained or if bleeding is not controlled with an 
expected dose), the subject will be tested for inhibitors by the central laboratory. 
Visits at
Activities
5 ED 
(5±1 
ED)
10 ED 
(10 to 15 
ED)
20 ED 
(20 to 25 
ED)
50 ED
(50 to 55 
ED)
Nijmegen-Modified 
Bethesda Assay 
(Inhibitor Assay)
X
X
X
X
ED = exposure day

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Safety and Efficacy of rFVIIIFc in Previously Untreated Patients With Hemophilia A
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4.2.2.3.
Schedule of Activities: Immune Tolerance Induction
The following schedule applies to subjects who are eligible for ITI, as described in Section 10.2.5.2. The specific follow up tests to be 
performed following ITI depend on the outcome of ongoing testing as described in Section 10.2.7.4 and Figure 2.
Activities
Pre-ITI 
Assessment
(ITI Day 0)
Week 2 
Visit
(at 2 wks 
±3 days)
ITI Visits
Every 4 Weeks
(±2 Weeks) 
Every 4 Weeks
(±2 Weeks) 
Every 4 Weeks 
(±2 Weeks)
Starting at ITI Week 4,
Until negative titer is 
confirmed
Starting at time of 
confirmed negative titer,
Until IR ≥66% of 
expected is confirmed
Starting at time of IR 
confirmed ≥66 % Until 
ITI Complete Successa
OR 
33 Months of treatment
Informed Consentb
X
Physical Examination
X
X
X
X
X
Weight (kg)
X
X
X
X
X
Vital Signsc
X
X
X
X
X
Hematologyd,e
X
X
X
X
Blood Chemistrye,f
X
X
X
X
rFVIIIFc Dosingg
X
X
X
X
X
Nijmegen-Modified Bethesda Assay (Inhibitor 
Assay)h
X
X
X
X
X
Blood Sample for Exploratory Biomarker 
Characterizationi
X
X
X
X
FVIII Activity for Incremental Recovery j
X
X
X
Half-life Evaluation (Factor VIII activity only 
to be done every 12 weeks once IR ≥66% 
confirmed)k
Xl
Anti-rFVIIIFc Antibody
X
X
X
X
X
EPD Review, including rFVIIIFc Dosing 
Accountabilitym
X
X
X
X
X
Injection Site Inspectionn
X
X
X
X
X
Adverse Events
<<<ONGOING; Monitor and record at all visits; telephone call every month>>>

Protocol 997HA306
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Safety and Efficacy of rFVIIIFc in Previously Untreated Patients With Hemophilia A
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Serious Adverse Events
<<<ONGOING; Monitor and record at all visits; telephone call every month>>>
Concomitant Therapy/Procedures Recordingo
<<<ONGOING; Monitor and record at all visits; telephone call every month>>>
AE = adverse event; DHA=Directions for Handling and Administration; EOT = end of treatment; ET = early termination; FVIII = coagulation factor VIII; ITI = 
immune tolerance induction; rFVIIIFc = recombinant coagulation factor VIII Fc fusion protein; SAE = serious adverse event.
a
See Section 10.2.7.4.2 for criteria for complete success.
b
Informed consent must be obtained prior to the ITI assessments beginning at Week 0.
c
Vital signs include blood pressure, pulse rate, respiratory rate, and temperature (°C). Postdose assessments following in-clinic rFVIIIFc injections should 
be taken approximately 20 minutes after the end of the injection. 
d
Hematology includes white blood cell count and differential, red blood cell, hemoglobin, hematocrit, and platelet count.
e
From the start of the ITI treatment period through the time of ITI complete success, samples may be drawn every other month for testing.
f
Blood chemistry includes sodium, potassium, chloride, total protein, total bilirubin, gamma glutamyl transferase, aspartate aminotransferase, alanine 
aminotransferase, alkaline phosphatase, blood urea nitrogen, serum creatinine, and glucose.
g
Clinic dosing is applicable only if warranted.
h
The definitive Nijmegen assay for each timepoint must be performed by the central laboratory.
i
A whole blood sample will be collected every other month during ITI treatment and at the time when the ITI outcome is declared (complete success, 
partial success, or failure), for exploratory assays related to immune response during ITI. Up to 10-mL (minimum 3 mL) will be collected, as allowable 
based on patient weight and institutional practice regarding blood draw restrictions for pediatric patients.
j
Predose samples for incremental recovery (IR) calculations are to be taken when the subject is in a non-bleeding state and after at least a 24-hour washout. 
Volume and units of factor infused must be calculated and recorded using the actual potency as described in Section 10.1.1 (and in the DHA). Predose 
sample is to be collected within 30 minutes before the start of the 50 IU/kg rFVIIIFc injection; postdose sample is to be taken 30 (±5) minutes after the 
start of the rFVIIIFc injection. IR assessments will be performed at the central laboratory.
k
rFVIIIFc PK assessments for half-life determination are to be performed when the subject is in a non-bleeding state and after at least a 72-hour washout. 
See Section 4.2.2.4.
l
The rFVIIIFc PK assessments for half-life will be performed at 12-week intervals, only after IR determinations of ≥66% of expected value on 
2 consecutive months. The first rFVIIIFc PK assessment will occur 12 weeks after IR≥66% of expected value is confirmed; subsequent PK assessments 
will be performed every 12 weeks thereafter for subjects who have not yet achieved the criteria for ITI complete success.
m
The subject’s parent/caregiver must enter dosing information into the EPD as soon as possible after an injection and within a maximum of 7 days
following the injection (Section 10.2.4.1.4). It is recommended that parents/caregivers enter dosing information immediately after an injection.
n
Injection site inspection is only to be performed if the subject receives an rFVIIIFc injection during a clinic visit.
o
For subjects who are receiving breast milk, maternal concomitant medications will also be collected at the same time points as other concomitant 
therapies, unless the breast milk is derived from a source other than the mother or the mother has not consented.

Protocol 997HA306
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Safety and Efficacy of rFVIIIFc in Previously Untreated Patients With Hemophilia A
CONFIDENTIAL
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4.2.2.4.
Schedule of Activities: Pharmacokinetic Sampling for Half-life Determination
Subjects with a confirmed negative inhibitor titer and confirmed IR ≥66% of expected who have 
not yet achieved the criteria for ITI complete success will undergo PK evaluation for t½ every 
12 weeks as described in Figure 2; monitoring for inhibitor and IR will continue on a monthly 
basis. Subjects must not have received an injection of rFVIIIFc within at least 72 hours of the 
predose sample collection. The PK dose will be 50 IU/kg of rFVIIIFc. Volume and units of 
factor infused must be calculated and recorded using the actual potency as described in the DHA 
(see Section 10.1.1).
The following Schedule of Activities applies only to subjects requiring PK assessments for 
determination of t½ as described in Section 10.2.7.4.2, Section 10.2.7.4.3, and Section 10.2.7.6. 
Time in Relation to rFVIIIFc Dosing
Activities
Pre
dosea
0
30 min
(± 5 min)
3 hr 
(± 10 min)
6 hr 
(± 10 min)
24 hrs 
(± 60 min)
48 hrs 
(± 60 min)
72 hrs 
(± 2 hrs)
rFVIII Dosing
X
PK Assessments
b
X
X
X
X
X
X
X
Hr=hours; min=minutes
a
Predose sample is to be collected within 30 minutes prior to the start of rFVIIIFc injection.
b
Timepoints for PK assessment are measured from start of the rFVIIIFc injection.

Protocol 997HA306
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Safety and Efficacy of rFVIIIFc in Previously Untreated Patients With Hemophilia A
CONFIDENTIAL
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4.2.2.5.
Schedule of Activities: Post-Immune Tolerance Complete Success Visits 
The following Schedule of Activities applies only to subjects who meet the criteria for ITI 
complete success described in Section 10.2.7.4.2 and Section 10.2.7.5.
Tapering Period 
Visits Every 4 Weeks
Follow-up Monitoring for Relapse
Visits Every 12 Weeksa
Activities
Month 1 
(± 1 wk)
Month 2 
(± 1 wk)
Month 3 
(± 1 wk)
Month 6 
(± 2 wks)
Month 9 
(± 2 wks)
Month 12 
(± 2 wks)
Physical Examination
X
X
X
X
X
X
Weight (kg)
X
X
X
X
X
X
Vital Signsb
X
X
X
X
X
X
Hematologyc
X
X
X
X
X
Blood Chemistryd
X
X
X
X
X
Nijmegen-Modified 
Bethesda Assay (Inhibitor 
Assay)e
X
X
X
X
X
X
Blood Sample for 
Exploratory Biomarker 
Characterizationf 
X
rFVIIIFc Dosing
X
X
X
X
X
X
FVIII Activity for 
Incremental Recoveryk
X
X
X
X
X
X
FVIII Activity for Half-life 
Determinationg,h
X
EPD Review, including 
rFVIIIFc Dosing 
Accountabilityi
X
X
X
X
X
X
Anti-rFVIIIFc Antibody
X
X
X
X
X
X
Injection Site Inspectionj
X
X
X
X
X
X
Adverse Eventsi
<ONGOING; Monitor and record at all visits >
Serious Adverse Eventsi
<ONGOING; Monitor and record at all visits >
Concomitant Therapy/ 
Procedures Recordingi
<ONGOING; Monitor and record at all visits >
AE = adverse event; aPTT=activated partial thromboplastin; EOT = end of treatment; EPD=electronic patient diary; 
ET = early termination; FVIII = coagulation factor VIII; ITI = immune tolerance induction; rFVIIIFc = 
recombinant coagulation factor VIII Fc fusion protein; wk = week.
a
The timing of the ET/EOT visit (Section 10.6) will vary for subjects fulfilling the criteria for ITI complete 
success, as described in Section 10.2.7.4.2. The minimum tapering period is 12 weeks. Subjects who develop 
inhibitors during the tapering phase (i.e., who relapse) will proceed immediately to the ET/EOT visit.
b
Vital signs include blood pressure, pulse rate, respiratory rate, and temperature (°C). Postdose assessments 
following in-clinic injections should be taken approximately 20 minutes after the end of the rFVIIIFc 
injection.

Protocol 997HA306
Version 6
Safety and Efficacy of rFVIIIFc in Previously Untreated Patients With Hemophilia A
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Bioverativ 
Therapeutics Inc.
30
c
Hematology includes white blood cell count and differential, red blood cell, hemoglobin, hematocrit, and 
platelet count.
d
Blood chemistry includes sodium, potassium, chloride, total protein, total bilirubin, gamma glutamyl 
transferase, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, blood urea nitrogen, 
serum creatinine, and glucose.
e
An unscheduled visit may be required to repeat inhibitor testing under this protocol in order to obtain a sample 
to confirm a positive inhibitor test result.
f
A whole blood sample will be drawn at the end of the tapering period, for exploratory assays related to 
immune response. Up to 10 mL of whole blood (minimum 3 mL) should be collected, as allowable based on 
patient weight and institutional practice regarding blood draw restrictions for pediatric patients.
g
Volume and units of factor infused must be calculated and recorded using the actual potency as described in 
Section 10.1.1(and in the DHA).
h
Half-life evaluation is performed under circumstances described in Section 10.2.7.4.3 , Figure 2, and Section 
10.2.7.6. For the PK sampling schedule, see Section 4.2.2.4.
i
Telephone call every month during the Follow-up Monitoring period.
j
Injection site inspection is to be performed only if the subject receives an rFVIIIFc injection during a clinic 
visit.
k
Blood samples will be taken at predose (within 30 minutes prior to the start of the rFVIIIFc injection) and 
postdose (30 ±5 minutes after the start of the rFVIIIFc injection).

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4.2.2.6.
Schedule of Activities: Surgery Visits
Activities
Pre-Surgery 
(Week -4 to 
Week -2)a
Preoperative 
Assessment/Day 
of Surgeryb
Postoperative 
Visit (1 to 
2 Weeks After 
Surgery)c
Last 
Postoperative 
Visitd
Physical Examination
X
X
X
Weight (kg)
X
X
X
X
Vital Signse
X
X
Hematologyf
Xg
X
X
Blood Chemistryh
Xg
X
X
FVIII Activityi
Xg
Xg
X
X
Nijmegen-Modified Bethesda 
Assay (Inhibitor Assay)
Xg
Xg
X
X
rFVIIIFc Clinic Dosingj
X
X
X
X
Anti-rFVIIIFc Antibody
Xg
Xg
X
X
EPD Review, including rFVIIIFc 
Dosing Accountability
X
X
Xk
X
Investigator/Surgeon’s Assessment 
of Responsel
X
X
AE/SAE Monitoring and 
Recording
X
X
X
X
Concomitant Therapy/Procedures 
Recordingm
X
X
X
X
AE = adverse event; EOT = end of treatment; EPD = electronic patient diary; ET = early termination; 
FVIII = coagulation factor VIII; rFVIIIFc = recombinant coagulation factor VIII Fc fusion protein; SAE = serious 
adverse event.
a
Not required for emergent surgery.
b
If surgery is delayed by ≥8 weeks, preoperative assessments must be repeated. These include assessments of 
FVIII activity and Nijmegen-modified Bethesda assay. For minor surgery, the Investigator is to be in contact 
with the subject’s parent/caregiver to determine when the subject should return to the regular prophylaxis 
regimen.
c
Visit is required for major surgeries only.
d
This visit is required for major surgeries only. This visit occurs when the Investigator determines that the 
subject can return to the regular pre-surgery regimen. This visit is not required if the return to the regular 
pre-surgery regimen occurs at the Postoperative Visit (1 to 2 weeks after surgery). If the subject is 
withdrawn from the study, then he will complete the ET/EOT Visit assessments (Section 4.2.2.1) at least 
2 weeks after surgery.
e
Vital signs include blood pressure, pulse rate, respiratory rate, and temperature (°C). Postdose assessments 
following in-clinic injections should be taken approximately 20 minutes after the end of the rFVIIIFc 
injection.
f
Hematology includes white blood cell count and differential, red blood cell, hemoglobin, hematocrit, and 
platelet count.
g
For minor surgeries, this is only to be performed if indicated by the nature of the procedure, according to local 
standard of care.
h
Blood chemistry includes sodium, potassium, chloride, total protein, total bilirubin, gamma glutamyl 

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transferase, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, blood urea nitrogen, 
serum creatinine, and glucose.
i
Samples for the determination of predose FVIII activity levels will be collected prior to the dose of rFVIIIFc 
given for the surgery. FVIII activity levels will be sampled 30 (±5) minutes after the start of the rFVIIIFc 
injection. For major surgeries, a repeat blood draw for FVIII activity should be taken approximately 9 hours 
after the start of the injection but may alternatively follow local standard of care for determining when the 
next dose of rFVIIIFc should be administered. While hospitalized, blood will be drawn daily to be tested at 
the local laboratory for FVIII activity so that monitoring of the subject can occur in real time.
j
Clinic dosing is applicable only if warranted.
k
Subjects who require postoperative treatment with rFVIIIFc at home for a bleeding episode will have their 
assessment of response to treatment recorded in the EPD.
l
For minor surgeries, assessment of response is conducted on the day of surgery. For major surgeries, 
assessment occurs 24 hours after surgery and at the Postoperative Visit (1 to 2 weeks after surgery). See 
Appendix D.
m
For subjects who are receiving breast milk, maternal concomitant medications will also be collected at the 
same time points as other concomitant therapies, unless the breast milk is derived from a source other than 
the mother or the mother has not consented.

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5.
INTRODUCTION
In this study, previously untreated male subjects with severe hemophilia A will receive 
recombinant coagulation factor VIII Fc fusion protein (rFVIIIFc; BIIB031) according to local 
standard of care for implementation of a prophylaxis regimen, including an optional preceding 
episodic (on-demand) treatment regimen. The European Medicines Agency (EMA) Committee 
for Medicinal Products for Human Use (CHMP) guideline on the clinical investigation of 
recombinant and human plasma-derived factor VIII products [EMA 
(EMA/CHMP/BPWP/144533/2009) 2011] was followed in the development of this protocol.
5.1.
Profile of Previous Experience
Hemophilia A is an X-linked bleeding disorder caused by mutations and/or deletions in the target 
gene for hemophilia A (F8) resulting in a deficiency of coagulation factor VIII (FVIII) activity 
[Bolton-Maggs and Pasi 2003; Mannucci and Tuddenham 2001]. Hemophilia A occurs 
predominantly in males and the worldwide incidence is approximately 1 case per 5000 male 
births. The severity of disease is characterized by the endogenous level of FVIII measured in the 
plasma. Severe hemophilia A is defined as a coagulation activity of FVIII in plasma (FVIII:C) of 
<1% (<1 IU/dL). Individuals with severe hemophilia A experience frequent bleeding and 
recurrent spontaneous bleeding into the soft tissue and joints, leading to joint damage and severe 
disability. Repeated bleeding into muscles and joints, which often begins in early childhood, 
results in hemophilic arthropathy and irreversible joint damage. Damage can lead to limited 
mobility of joints, muscle atrophy, and chronic pain [Rodriguez-Merchan 2003].
5.1.1.
Therapies for Hemophilia A
There is no cure for hemophilia A, so treatment focuses on the replacement of FVIII with the 
intravenous (IV) administration of FVIII-containing coagulation products to promote clotting.
The goal of treatment with FVIII-containing coagulation products is to raise the circulating level 
of FVIII to the lowest effective level to achieve either resolution of bleeding (on-demand 
treatment) or prevention of bleeding (prophylaxis treatment) [MASAC 2009; WFH 2005]. The 
frequency of administration of FVIII products varies across patients and is tailored to the 
patient’s clinical status, taking into consideration the type of bleeding episode, frequency of 
bleeding, and goal of treatment for the patient. The dose of FVIII required also varies and has 
been based on observations over the years and guidelines established by organizations such as 
the National Hemophilia Foundation of the United States and the World Federation of 
Hemophilia [WFH 2005].
The use of FVIII-containing plasma-derived coagulation products for people with hemophilia A, 
available for almost 40 years has led to vast improvements in quality of life and has increased 
life expectancy. Manufacturing methods for plasma-derived products are now considered to be 
highly effective in reducing the risk of transmission of enveloped viruses such as human 
immunodeficiency virus (HIV) and hepatitis B and C viruses. However, these methods may not 
be effective in reducing the risk of non-enveloped viruses, such as hepatitis A and parvovirus 

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B19. Recombinant coagulation products developed more recently with no animal or human 
plasma-derived proteins have a safety advantage with a minimal risk of disease transmission 
[Mannucci and Tuddenham 2001].
Priorities for improving hemophilia A therapy include the development of more convenient 
dosing options and development of modified FVIII agents with a longer half-life (t½) to decrease 
injection frequency. Current therapy is focused on home therapies, which, when taken 
prophylactically or administered at the onset of a bleeding episode, reduce short-term disability 
and long-term joint damage and improve patients’ quality of life and functional independence 
[Colvin 2008].
5.1.2.
rFVIIIFc
rFVIIIFc is a novel recombinant Fc fusion protein consisting of a single molecule of B-domain 
deleted FVIII attached to the Fc domain of human immunoglobulin G1. This type of construct 
has been termed a monomeric Fc fusion protein [Dumont 2006]. The Fc enables binding to the 
neonatal Fc receptor (FcRn), which is responsible for protecting immunoglobulin G (IgG) from 
degradation and confers IgG the 3-week t½ observed in humans [Ghetie and Ward 2000; 
Roopenian and Akilesh 2007]. The FcRn is present in humans throughout life and protects IgG 
from catabolism [Junghans and Anderson 1996]. rFVIIIFc was designed to offer a longer 
circulating t½ than currently available FVIII products, aiming to provide hemophilia A patients 
with prolonged protection and prophylaxis from bleeding with less frequent dosing.
5.1.3.
Summary of Nonclinical Experience with rFVIIIFc
rFVIIIFc was evaluated in a comprehensive nonclinical program, which included 
pharmacokinetics (PK), pharmacology, and toxicology studies. The nonclinical program 
provided the following critical results:

Improved PK parameters (e.g., increased elimination t½) were observed for rFVIIIFc 
in several animal species, and administered rFVIIIFc retained its functional activity 
while present in the circulation.

Prolonged pharmacodynamics and efficacy were observed for rFVIIIFc in 2 animal 
species deficient in FVIII.

Similar potency was found for rFVIIIFc and recombinant FVIII (rFVIII) in an acute 
bleeding model.

The toxicology program established that there were no adverse toxicological findings 
directly related to the effects of rFVIIIFc in 2 relevant species (rats and monkeys).

The safety margin is 10-fold based on a comparison of no-observed-adverse-effect 
levels (1000 IU/kg) with the highest anticipated routine clinical dose of 100 IU/kg.
See the Investigator’s Brochure for detailed information on nonclinical studies.

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5.1.4.
Summary of Clinical Experience With rFVIIIFc
Three clinical studies, including a Phase 1/2a study (Study 998HA101), a Phase 3 study in 
previously treated patients (PTPs) [Study 997HA301], and a Phase 3 pediatric study (Study 
8HA02PED) have been completed. Ongoing clinical studies include an extension study (Study 
8HA01EXT) and this PUPs study (Study 997HA306). 
A completed Phase 1/2a study (Study 998HA101) investigated the safety of a single dose of 
rFVIIIFc given as an IV injection over 10 minutes to subjects with severe hemophilia A and 
compared the PK of rFVIIIFc with Advate® (Antihemophilic Factor [Recombinant], 
Plasma/Albumin-Free Method, [INN octocog alfa]). Inhibitor-positive subjects were excluded.
Two dose levels, 25 and 65 IU/kg, were evaluated, with 6 subjects receiving Advate 25 IU/kg, 
and 10 subjects receiving Advate 65 IU/kg. Following a 3-day PK profile for the Advate 
25 IU/kg dose group and a 4-day PK profile for the Advate 65 IU/kg dose group, these subjects 
then crossed over to receive an equivalent dose of rFVIIIFc. A 7-day PK profile was performed 
after the 25 IU/kg dose. Following the rFVIIIFc 65 IU/kg dose, subjects underwent a 10-day PK 
profile. A 28-day safety observation period followed the rFVIIIFc dose and included inhibitor 
testing at 14 and 28 days post-dosing.
Safety and tolerability were assessed in all 16 subjects, including FVIII inhibitors and 
anti-FVIIIFc antibodies, vital signs, hematology, blood chemistry, and coagulation parameters.
When compared with Advate at both dose levels, rFVIIIFc was well tolerated. No clinically 
significant changes in safety parameters occurred, and most adverse events (AEs) were mild and 
resolved without sequelae by the end of the study. No subject developed antibodies or inhibitors 
during the study period. Compared with Advate, rFVIIIFc demonstrated a significantly longer t½, 
an increased systemic exposure, and a reduction in clearance (CL) with comparable volume of 
distribution and recovery. The t½ and mean residence time (MRT) of rFVIIIFc were both 
prolonged by 1.54-fold at 25 IU/kg and by 1.70- and 1.71-fold, respectively, at 65 IU/kg, relative 
to equivalent doses of Advate in this study.
Phase 3 Study 997HA301 was a study of previously treated subjects aged 12 years or older with 
severe hemophilia A, in which a total of 164 subjects (including 13 subjects aged 12 to 17 years) 
received at least 1 dose of rFVIIIFc. This included 146 subjects treated for at least 26 weeks and 
23 subjects treated for at least 39 weeks, for a total of 102.05 person-years on study. Inhibitor-
positive subjects were excluded.
Compared with Advate, rFVIIIFc demonstrated a 53% longer t½, a 56% increase in systemic 
exposure, and a 36% reduction in CL, with comparable steady state volume of distribution and 
recovery (1-stage activated partial thromboplastin time [aPTT] clotting assay).
rFVIIIFc was generally well tolerated in the Phase 3 study. No subject developed an inhibitor to 
rFVIIIFc. Adverse drug reactions (ADRs) were defined as AEs assessed by the Investigator as 
related to the treatment with rFVIIIFc followed by medical review. The most common ADRs 
observed in the Phase 3 study (incidence >1%) were arthralgia and malaise. No serious adverse 
events (SAEs) were assessed as related to rFVIIIFc treatment by the Investigator. One 

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nonserious event of rash was assessed as related to rFVIIIFc, resulted in discontinuation of study 
treatment and resolved. There were no Grade 2 or greater allergic reactions or serious vascular 
thrombotic events. Overall, the AE profile was consistent with the background characteristics of 
the hemophilia A population.
Efficacy data from the Phase 3 study showed that rFVIIIFc was effective in the control and 
prevention of bleeding episodes and in perioperative management (surgical prophylaxis). For 
further details, see the rFVIIIFc Investigator’s Brochure.
Study 8HA02PED (referred to as the pediatric study) was an open-label, multicenter study 
evaluating the safety, PK, and efficacy of rFVIIIFc in previously treated pediatric patients with 
severe hemophilia A, who were <12 years of age, and had at least 50 exposure days (EDs) to 
FVIII products prior to enrollment. The results from this study suggest that rFVIIIFc was well 
tolerated and effective for the control and prevention of bleeding when administered for routine 
prophylaxis using an individualized regimen. The pattern of treatment-emergent AEs reported 
during the study was typical of the population studied, and no unique safety issues were 
identified. No subject developed an inhibitor to rFVIIIFc. Efficacy data showed that rFVIIIFc 
was effective in the control and prevention of bleeding episodes and in perioperative 
management. A review of rFVIIIFc PK parameters by age group demonstrated an increase in the 
mean body-weight-normalized CL and a decrease in the mean t½,, MRT, and dose-normalized 
area under the curve (DNAUC) estimates for children <12 years of age compared to adults and 
adolescents ≥12 years of age (see Table 1).
Table 1:
Comparison of PK Parameters of rFVIIIFc by Age Category: Geometric 
Mean (95% Confidence Interval)
Pediatric Study (8HA02PED)
Phase 3 Study (997HA301)
<6 Years
(N = 23)
6 to <12 Years
(N = 31)
12 to 17 Years
(N = 11)
≥18 Years
(N = 144)
IR (IU/dL per IU/kg)
1.901
(1.785, 2.024)
2.299
(2.042, 2.587)
1.807
(1.561, 2.092)
1.925
(1.849, 2.004)
DNAUC
(IU*h/dL per IU/kg)
28.93
(25.59, 32.72)
38.37
(33.20, 44.35)
38.15
(33.96, 42.87)
43.30
(40.82, 45.93)
t½ (h)
12.28
(10.99, 13.72)
13.45
(11.45, 15.81)
16.04
(13.90, 18.53)
17.14
(16.37, 17.94)
MRT (h)
16.76
(15.11, 18.60)
19.00
(16.21, 22.26)
22.67
(19.67, 26.13)
24.37
(23.30, 25.49)
CL (mL/h/kg)
3.456
(3.056, 3.908)
2.607
(2.256, 3.012)
2.621
(2.333, 2.945)
2.310
(2.177, 2.450)
Vss (mL/kg)
57.9
(54.1, 62.0)
49.5
(44.1, 55.6)
59.4
(52.7, 67.0)
56.3
(54.5, 58.2)
CL = clearance; DNAUC = dose-normalized area under the curve; IR= incremental recovery; MRT = mean 
residence time; PK = pharmacokinetic; rFVIIIFc = recombinant coagulation factor VIII Fc; t½ = terminal half-life; 
Vss = volume of distribution at steady state.

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Study 8HA01EXT (referred to as the extension study) is an open-label, multicenter extension to 
both the Phase 3 study (Study 997HA301) and the pediatric study (Study 8HA02PED) as well as 
other studies in which subjects have received rFVIIIFc. The extension study is evaluating the 
long-term safety and efficacy of rFVIIIFc for prophylaxis and episodic treatment of bleeding 
episodes in previously treated patients with hemophilia A. The safety observations in the 
extension study are, so far, consistent with those from the Phase 3 study.
For further details regarding the clinical studies conducted with rFVIIIFc, and for descriptions of 
the potential risks and benefits of rFVIIIFc, see the rFVIIIFc Investigator’s Brochure.
5.2.
Study Rationale
The use of a prophylaxis regimen in young children starting prior to the onset of frequent joint 
bleeding is currently the recommended standard of care in hemophilia due to the demonstrated 
benefit on long-term outcomes [Aznar 2000; Manco-Johnson 2007; Molho 2000]. Currently 
available FVIII replacement therapies are limited by short elimination t½.
The purpose of this study is to investigate the safety and efficacy of rFVIIIFc in previously 
untreated patients (PUPs) in accordance with the EMA CHMP guideline on the clinical 
investigation of recombinant and human plasma-derived factor VIII products [EMA 
(EMA/CHMP/BPWP/144533/2009) 2011].
5.3.
Rationale for Dose and Schedule Selection
In the completed Phase 3 study (Study 997HA301), multiple doses of up to 65 IU/kg were well 
tolerated, with an AE profile generally consistent with that expected in patients with 
hemophilia A. Safety data from the completed pediatric study (Study 8HA02PED), which 
allowed for doses up to 80 IU/kg and a minimum dosing interval of 2 days, showed a safety 
profile consistent with the results of the Phase 3 study.
The dose for prophylaxis may be selected and adjusted based on the subject’s response to dosing 
(i.e., available PK data, including FVIII activity levels, level of physical activity, and bleeding 
pattern), in the range of 25 to 65 IU/kg at 3 to 5 day intervals. However, based on data from the 
completed clinical studies, and knowledge of increased clearance of factor concentrates in 
children <6 years of age, more frequent or higher doses of up to 80 IU/kg may be required. 
Prophylactic dose titration outside the range of 25 to 80 IU/kg requires discussion with the 
Sponsor and documentation of rationale.
The dose for treatment of bleeding episodes will target peak plasma FVIII activity of 
approximately 40% to 100%, in accordance with local standards.
Subjects will be eligible to undergo immune tolerance induction (ITI) with rFVIIIFc if

They develop a positive high titer inhibitor (≥5.00 Bethesda Units [BU]/mL), or 

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
They develop a positive low titer inhibitor (≥0.60 and <5.00 BU/mL) and experience 
poorly controlled bleeding despite increased rFVIIIFc doses, or require bypassing 
agents to treat bleeding.
The ITI regimen will approximate the high-dose treatment arm of the International ITI Study 
protocol [Hay and DiMichele 2012] and will utilize single injections of rFVIIIFc 200 IU/kg, 
daily, consistent with current ITI guidelines [Valentino 2015]. This dosing regimen is also 
supported by the results of a prospective clinical trial (the International ITI Study) that compared 
subjects treated with FVIII for ITI at a high dose (200 IU/kg/day) and a low dose (50 IU/kg/ 
3 times per week). Results from this study [Hay and DiMichele 2012] demonstrated that the 
times to achieve negative inhibitor titer, normal FVIII recovery, and FVIII tolerance were shorter 
in subjects treated with the high dose of FVIII, compared to subjects treated with the low dose. 
Furthermore, subjects treated with the high dose for ITI had a lower rate of intercurrent bleeding 
and fewer hospitalizations due to bleeding than subjects treated with the low dose. Since 
clearance is expected to be very rapid in the presence of inhibitors, irrespective of the type of 
FVIII product, the high dose of 200 IU/kg/day evaluated in the International ITI Study will be 
used in the present study to maximize the potential for rapid tolerization while minimizing 
bleeding-related adverse events.
If a subject requires surgery while participating in this study, the subject may be treated with the 
dose and regimen of rFVIIIFc deemed appropriate by the Investigator for the type of surgery. All 
major surgeries will be reported as serious adverse events (SAEs). 
5.4.
Potential Risks and Benefits
See the current Investigator’s Brochure for descriptions of the potential risks and benefits of 
rFVIIIFc.

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6.
STUDY OBJECTIVES AND ENDPOINTS
6.1.
Objectives
6.1.1.
Primary Objective
The primary objective of the study is to evaluate the safety of rFVIIIFc in previously untreated 
subjects with severe hemophilia A.
6.1.2.
Secondary Objectives
The secondary objectives of the study are as follows:

To evaluate the efficacy of rFVIIIFc in the prevention and treatment of bleeding 
episodes in PUPs

To evaluate rFVIIIFc consumption for the prevention and treatment of bleeding 
episodes in PUPs

To describe experience with the use of rFVIIIFc for ITI in subjects with inhibitors
6.1.3.
Exploratory Objective
The exploratory objectives are 

To evaluate the effect of rFVIIIFc based on patient-reported outcomes and health 
resource utilization

To assess the efficacy of rFVIIIFc for perioperative management
6.2.
Endpoints
6.2.1.
Primary Endpoint
The primary endpoint of the study is the occurrence of inhibitor development.
6.2.2.
Secondary Endpoints
The secondary endpoints of the study are as follows:

The annualized number of bleeding episodes per subject

The annualized number of spontaneous joint bleeding episodes per subject

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
Assessments of response to treatment with rFVIIIFc for bleeding episodes, using the 
4-point bleeding response scale

The total number of EDs per subject per year

Total annualized rFVIIIFc consumption per subject for the prevention and treatment 
of bleeding episodes

The number of injections and dose per injection of rFVIIIFc required to resolve a 
bleeding episode

rFVIIIFc incremental recovery (IR)

Response to ITI with rFVIIIFc (complete success, partial success, failure, early 
withdrawal)
For additional information about the correspondence between the objectives and their associated 
endpoints and assessments, see Appendix E.
6.2.3.
Exploratory Endpoints
The exploratory endpoints include, but are not limited to

Health Outcomes

Investigator/Surgeon’s Assessment of Response

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7.
STUDY DESIGN
7.1.
Study Overview
This is an open-label, single-arm, multicenter study evaluating the safety and efficacy of 
rFVIIIFc in previously untreated pediatric subjects with severe hemophilia A when used 
according to local standard of care. Following the confirmation of eligibility, the Investigator has 
the option to treat eligible subjects episodically (on-demand) prior to initiating a prophylaxis 
regimen. The duration of episodic treatment is at the Investigator’s discretion, in accordance with 
local standard of care. At least 90 previously untreated subjects are planned to complete the 
study after reaching at least 50 EDs with rFVIIIFc. 
Baseline IR may be conducted along with other baseline assessments on the same day as 
screening, once the subject has been enrolled, or as part of a separate baseline IR visit, as long as 
the subject has not yet had more than 3 doses of rFVIIIFc. 
Subjects with a documented plasma FVIII activity of <1% may be enrolled on the basis of local 
laboratory results and may receive study drug after samples for factor VIII activity level and 
inhibitors, for testing at the central laboratory, have been obtained. However, any such subject 
must be withdrawn if the central laboratory screening results indicate factor VIII activity level 
≥1% or a positive inhibitor. 
Major and minor surgery are allowed during the study (Section 10.2.8).
ITI with rFVIIIFc is allowed during the study for those subjects developing, after exposure to 
rFVIIIFc study drug, a positive high titer inhibitor (≥5.00 BU/mL) or a positive low titer 
inhibitor (≥0.60 and <5.00 BU/mL) with poorly controlled bleeding despite increased rFVIIIFc 
doses or requiring bypassing agents to treat bleeding (Section 10.2.5.2). 
Because of the risk of allergic reactions with FVIII concentrates, the initial administrations of 
rFVIIIFc should be performed under medical observation where proper medical care for allergic 
reactions could be provided. The first injection of rFVIIIFc study drug after the Screening Visit 
must be administered by the Investigator or a qualified delegate. Thereafter, study treatment may 
be administered by a parent/caregiver or by a qualified medical professional under the direction 
of the Investigator. Study treatment may also be injected in the hospital during surgery or during 
hospitalization due to major bleeding. 
See Figure 1 for a schematic of the study design. Section 4.2 provides schedules for the activities 
required for each study visit. Section 10 describes the treatment of subjects during the study. 

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7.2.
Study Specifics
7.2.1.
Dose-Limiting Toxicity
No dose-limiting toxicity (DLT) has been identified to date in humans receiving doses of 
rFVIIIFc up to 80 IU/kg. Also, no DLTs were observed in the nonclinical animal studies where 
repeated doses of up to 1000 IU/kg were evaluated. Single injections of rFVIIIFc up to 
100 IU/kg are allowed 
 
 based on the individual subject’s recovery and/or age-specific PK data for 
rFVIIIFc (see Table 1). Single, daily injections of rFVIIIFc 200 IU/kg will be allowed in the ITI 
regimen, since exposure is expected to be much lower in subjects undergoing ITI due to the 
presence of inhibitors. 
7.3.
Overall Study Duration and Follow-Up
The study period will consist of screening, treatment, and follow-up. Individual subject study 
participation is expected to be approximately 6 months to 3 years, including screening and 
follow-up. For subjects who do not develop an inhibitor, the treatment period is no less than 
50 EDs to the study treatment. 
One ED is defined as a 24-hour period in which a subject receives 1 or more doses of rFVIIIFc, 
with the time of the first injection of rFVIIIFc defined as the start of the ED. 
See Figure 1 for a schematic of the study design.
7.3.1.
Screening
Subject eligibility for the study will be determined within 8 weeks from the start of screening 
activities (Section 4.2.1, that is, all activities other than informed consent, which can occur prior 
to the subject’s birth). 
If more than 8 weeks elapse and screening activities have not been completed, the Nijmegen 
inhibitor and factor VIII antibody blood draws must be repeated. Other screening assessments 
that have not yet been completed must be completed within an additional 8 weeks
Potential subjects may be enrolled and receive study drug as long as they meet the minimum 
criteria for enrollment (Section 8.3). If the central lab factor VIII level is ≥1% or the central 
screening inhibitor test result is subsequently found to be positive, the subject must be 
withdrawn.
7.3.2.
Treatment
Enrolled subjects will report to the study site for 2 kinds of required visits during the Treatment 
Period:

Scheduled Interim Visits: every 12 (±2) weeks by calendar date (Section 4.2.2.1).
Subjects who develop high titer inhibitors will switch to a schedule of ITI Induction 

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Visits (Section 4.2.2.3 and, if applicable, Section 4.2.2.4) and, if they subsequently meet 
ITI complete success criteria within 33 months, will receive a tapering regimen and 
participate in Post-ITI Success Visits (Section 4.2.2.5).

ED Milestone Visits: at 5 (±1) EDs, 10 to 15 EDs, 20 to 25 EDs, and 50 to 55 EDs 
(Section 4.2.2.2).
In addition, telephone calls with the subject’s parents/caregivers are planned approximately once 
a month. (Section 10.2.4.1.4).
Subjects who develop inhibitors may be eligible for 33 months of Immune Tolerance Induction 
Therapy (ITI), followed by a tapering off regimen of 3 months and follow up monitoring for 
9 months (for a total of 12 months of monitoring post-ITI success) (Section 10.2.7, 
Section 4.2.2.4 and Section 4.2.2.5).
7.3.3.
Follow-Up
Subjects are to return to the study site for the Early Termination/End of Treatment Visit 
(ET/EOT), followed by a final safety follow up visit or telephone call within 7 to 14 days 
following the ET/EOT Visit.
7.4.
Study Stopping Rules
Bioverativ may terminate this study at any time, after informing Investigators. Investigators will 
be notified by Bioverativ or designee if the study is suspended, stopped, or closed.
Study stopping is required for the following:

Unacceptable inhibitor incidence as determined by the Data Safety Monitoring 
Committee (DSMC; see Section 19.2)

Detection of an unexpected, serious, or unacceptable risk to the study subjects
Data regarding frequency of inhibitor development will be reviewed by the DSMC at regular 
intervals. If, after consideration of subject-specific risk factors (e.g., genotype), the DSMC
judges that the observed rate of inhibitor formation is unacceptable, compared with that reported 
for commercially available rFVIII concentrates, the study will be stopped.
If the study is stopped, the events will be investigated, enrollment will be stopped, and current 
subjects will stop dosing with rFVIIIFc. If, in consultation with the DSMC, it is determined that 
the study should be permanently discontinued, then subjects will attend a final visit.
7.5.
End of Study
The end of the study (EOS) will occur after at least 90 subjects have reached at least 50 EDs with 
rFVIIIFc. Once this milestone has been achieved, all ongoing study subjects will return to the 
study center for the ET/EOT Visit assessments. 

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The end of treatment for individual subjects is described in Section 10.6.

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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 the time of screening, or at the time point specified in the individual eligibility criterion listed:
1. Ability of the subject's legally authorized representative (e.g., their parent or legal 
guardian) to understand the purpose and risks of the study and provide signed and dated 
informed consent and authorization to use confidential health information in accordance 
with national and local subject privacy regulations.
2. Male, age <6 years at the time of informed consent.
3. Weight ≥3.5 kg.
4. Severe hemophilia A defined as <1 IU/dL (<1%) endogenous FVIII documented in the 
medical record or as tested during the Screening Period. Any subject who is enrolled 
based on results of the local laboratory must be withdrawn if the central laboratory 
screening results indicate a baseline FVIII activity level ≥1% of normal.
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:
1. Any exposure to blood components, factor VIII replacement products, including 
commercially available rFVIIIFc at any time prior to or during screening.
2. History of positive inhibitor testing. A prior history of inhibitors is defined based on a 
patient’s historical positive inhibitor test using the local laboratory Bethesda value for a 
positive inhibitor test (that is, equal to or above lower level of detection).
5. History of hypersensitivity reactions associated with any rFVIIIFc administration.
6. Other coagulation disorder(s) in addition to hemophilia A.
7. Any concurrent clinically significant major disease that, in the opinion of the 
Investigator, would make the subject unsuitable for enrollment (e.g. HIV infection with 
CD4 lymphocyte count <200 µL or a viral load >200 particles/ µL, or any other known 
congenital or acquired immunodeficiency).
8. Current systemic treatment with chemotherapy and/or other immunosuppressant drugs.
Use of corticosteroids for 1) the treatment of asthma or 2) management of acute allergic 
or otherwise life-threatening episodes is allowed with the exception of systemic 

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corticosteroid treatment given to children daily or on alternate days at ≥2 mg/kg per day 
of prednisone or its equivalent or ≥20 mg/day if the duration is longer than 14 days. 
9. Participation within the past 30 days in any other clinical study involving investigational 
treatment.
10. Current enrollment in any other clinical study involving investigational treatment.
11. Inability to comply with study requirements.
12. Other unspecified reasons that, in the opinion of the Investigator or Bioverativ, make the 
subject unsuitable for enrollment.
8.3.
Minimum Criteria for Enrollment
A subject may be enrolled as a subject when the following minimal criteria have been met:

Diagnosis of severe hemophilia A with factor VIII <1% has been documented by 
local labs.

Laboratory data already present in the medical record are acceptable.

Samples have been drawn for central laboratory testing for inhibitors and factor VIII 
activity.

The results are not required at the time of enrollment.

If central laboratory testing of the screening laboratory sample subsequently 
reveals a factor VIII activity level >1% or a positive inhibitor, the subject will 
discontinue treatment and be withdrawn per Section 11.

The patient has met the remaining eligibility criteria described in the inclusion and 
exclusion criteria (Section 8.1 and Section 8.2) including the lack of exposure to 
blood components and factor VIII replacement products prior to enrollment.

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9.
ENROLLMENT AND REGISTRATION 
9.1.
Screening
9.1.1.
Screening Assessments
The subject's legally authorized representative [e.g., parent or legal guardian], must be provided 
with the informed consent document(s) prior to the Screening Visit to allow adequate time for 
review and an opportunity to discuss the study with the Investigator/designee. After reviewing, 
parents/legal guardians will come into the clinic to sign the informed consent. 
Parents/legal guardians of subjects must provide consent before any screening assessments are 
performed (see Section 17.3). 
Subjects will be assigned a unique identification number as soon as informed consent has been 
obtained or at the Screening Visit. A centralized Interactive Web Response System (IXRS; see 
Section 19.1.2) will assign a unique 6-digit subject identification number to each subject. The 
unique number consists of the 3-digit site number (e.g., 105) and a sequential 3-digit subject 
number (e.g., 004). This number will be assigned regardless of whether the subject will be 
eligible for enrollment and subsequent treatment or not and will remain with the subject as the 
study-specific subject identifier. Any subject identification numbers that are assigned will not be 
reused even if the subject does not receive treatment. The study site is responsible for 
maintaining a current log of subject number assignments in order to avoid assignment errors, 
such as duplicating or skipping numbers. If a subject is excluded from the study, the reasons for 
exclusion will be documented in the subject’s source documents and on the screening log. The 
subject’s unique identification number must be entered on all study documentation (sample 
containers, drug accountability logs, source documents, etc.). As confirmation, the IXRS will 
provide the Investigator with written verification of the allocation of subject identification 
number by email or fax. See the Study Reference Manual for the IXRS User Manual.
Screening assessments should be completed within a total of 8 weeks from the start of the 
screening activities (not including informed consent, which can occur earlier) (Section 4.2.1). If 
more than 8 weeks have elapsed, and the subject has not been enrolled in the study, See Section 
7.3.1. As part of the screening process, the Investigator must have sufficient documentation of a 
subject’s medical history to ensure previously untreated status. 
Subjects weighing <6 kg may require that blood draws for laboratory tests be collected over 
multiple days in order to comply with maximum allowable blood draw volumes.
Alternatively, individual investigators may choose to collect all screening samples using a single 
blood draw, after weighing the risk associated with multiple venipuncture attempts versus that of 
drawing all required samples at a single time. If the option of a single blood draw is chosen, the 
Investigator must document the rationale (Section 14.4.3). Stored plasma samples (e.g., cord 

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blood, or blood obtained for diagnostic testing prior to the signature of the ICF) may be used at 
screening if:

The samples were drawn within 28 days prior to the shipment day.

The samples were collected and processed per the site’s standard of care.

The samples can be processed as specified in the Laboratory Manual.
Participating study sites are required to document all screened candidates initially considered for 
inclusion in this study. If a subject is excluded from the study, the reasons for exclusion will be 
documented in the subject’s source documents and on the screening log.
9.2.
Enrollment of Subjects
Subjects will be considered enrolled when the Investigator has verified that they are eligible 
according to the criteria in Sections 8.1 and 8.2 (see Section 9.1.1). Using the IXRS, the status of 
the subject should be updated to indicate the enrollment prior to dispensing study drug to the 
subject. 
As confirmation, the IXRS will provide the Investigator with written verification of the subject’s 
enrollment by email or fax.
After enrollment, the subject should be treated only with rFVIIIFc study treatment. Subjects 
treated with another FVIII concentrate must permanently discontinue study treatment and be
withdrawn from the study, although exceptions are allowed for 1 emergency or accidental use.
9.3.
Registration of Subjects
At the Screening Visit, an IXRS will be used to assign each subject a unique 6-digit subject 
identification number (see Section 9.1.1). See the Study Reference Manual for additional details 
about registration.
9.4.
Blinding Procedures
Not applicable. This is an open-label study.

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10.
TREATMENT OF SUBJECTS
Bioverativ will provide rFVIIIFc to the study sites via its designated distributors.
10.1.
Study Treatment Schedule and Administration
During the Treatment Period, subjects will be treated with rFVIIIFc according to schedules 
described in Section 4.2. See Figure 1 for a schematic of the study design and Section 7.3 for a 
description of the study duration.
Instructions for the preparation and administration of rFVIIIFc are provided in the Directions for 
Handling and Administration (DHA) and the Information for Patients. Dosing will be calculated 
as summarized in Section 10.1.1. See Section 12 for specifics on the preparation, storage, 
handling, disposal, and accountability of study treatment.
rFVIIIFc will be delivered via a slow push IV injection over several minutes, at a rate of 
administration determined by the subject’s comfort level. Any missed doses should be taken as 
soon as possible or according to the instructions of the Investigator. 
Because of the risk of allergic reactions with FVIII concentrates, the initial administration of 
rFVIIIFc should, according to the Investigator’s judgment, be performed under medical 
observation, where proper medical care for allergic reactions could be provided.
Parents/caregivers will be instructed to administer subsequent rFVIIIFc doses at home or to have 
it be administered by a qualified professional under the direction of the Investigator.
During the clinic visits and monthly telephone calls, the study site staff will verify whether or not 
a bleeding episode has occurred, and was “spontaneous” or “traumatic” (Section 10.2.4.1.4).
During the monthly phone call, the subject’s parent/caregiver will also be reminded about 
requirement that EPD data be entered as soon as possible, and within a maximum of 7 days 
following an injection.
Additional visits may be necessary during the study to test for inhibitors, test for recovery, repeat 
safety assessments, repeat any blood sampling if required for study purposes, or perform PK 
assessments if needed for surgical planning or adjustment of dosing regimen. Investigators are to 
report all inhibitor assessments performed throughout the study on the eCRF. 
Subjects requiring surgery will also be followed via specialized visits (Section 4.2.2.6).
Treatment will continue until the subject has reached at least 50 EDs to rFVIIIFc, discontinues 
due to inhibitor development, completes ITI (with follow-up, if applicable), or the end of study is 
declared. The end of the study for all subjects is described in Section 7.5.

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10.1.1.
Definitions of Nominal Strength Versus Actual Potency
This section explains when the actual potency or nominal strength is to be used for dose 
calculations. The definitions of these terms and the types of dose calculations in this study are 
described below. 
Definitions

The nominal strength is the target potency of the vial (that is, 250 IU, 500 IU, 1000 
IU, or 2000 IU per vial).

The actual potency is the true potency of the vial as measured by a validated potency 
assay. (Actual potency may vary between 80 to 125% of nominal strength.) 
Calculation and Recording of Actual versus Nominal Dosing
Actual potency must be used for dose calculations for the following:

For partial vial use (Actual Potency dosing), including the dose used for the 
calculation of Baseline IR, the dose used for IR and t1/2 assessments during ITI, 
and any other doses using partial vials. The actual potency shown on the vial must be 
used to calculate the units of rFVIIIFc and the volume to inject. Actual potency 
dosing is required for the dose of 25 IU/kg that is used to measure Baseline IR.
Note: The instructions and worksheets provided in the DHA manual must be used to calculate 
the volume for administration based on actual potency (unless an equivalent alternative site-
specific template is approved by the responsible CRA prior to use). The actual potency shown on 
the vial must be used to calculate the volume for administration.
Nominal strength must be used for dose calculations for the following:

Dosing for prophylactic treatment or treatment of bleeds, as well as the dose used 
for FVIII activity at interim visits. The nominal strength should be used for 
calculations. Whole vials should be used to achieve the target dose, rounded to the 
nearest 250 IU. These calculations should be discussed with the parent/caregiver 
during regular monthly phone calls. 
Note: The instructions and worksheets provided in the DHA manual must be used to calculate 
the number of vials for administration based on nominal strength (unless an equivalent 
alternative site-specific template is approved by the responsible CRA prior to use).

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10.2.
Treatment
10.2.1.
Incremental Recovery
10.2.1.1.
Baseline Incremental Recovery Assessments
Baseline IR assessments described in Section 4.2.1 may be completed on the same day as 
Screening, or they may be completed as a part of a separate visit. Baseline IR requires a washout 
from rFVIIIFc of at least 24 hours prior to the predose sample collection.
For the Baseline IR measurement, a dose of 25 IU/kg will be given in clinic as an IV injection. 
The actual potency of rFVIIIFc must be used to calculate the units and volume of rFVIIIFc 
infused for the IR visit dose. (For additional details, see the DHA, as well as Section 10.1 of this 
protocol). rFVIIIFc will be delivered via a slow push IV injection over several minutes, at a rate 
of administration determined by the subject’s comfort level. 
Blood samples will be taken at trough (predose; within 30 minutes of the injection) and at 
30 (±5) minutes after the start of the rFVIIIFc injection for the assessment of IR, and measured 
by the one-stage aPTT clotting assay and the chromogenic assay. The predose activity does not 
have to be collected if the subject has not received any dose of any product containing FVIII 
(including a blood transfusion) between screening and the dose for the baseline IR assessment.
10.2.1.2.
Assessment of FVIII Activity During Interim Visits
If an injection is administered during an Interim Visit, predose and postdose samples will also be 
taken for dose adjustment purposes. The subject should be in a non-bleeding state.
The subject’s current prophylactic dose of rFVIIIFc may be used for FVIII activity assessments 
at interim visits. Nominal strength should be used to calculate the units and volume of rFVIIIFc 
infused at Interim Visits. (For additional details, see the DHA, as well as Section 10.1.1 of this 
protocol).
rFVIIIFc will be delivered via a slow push IV injection over several minutes, at a rate of 
administration determined by the subject’s comfort level.
Blood samples will be taken Predose (within 30 minutes prior to the start of the injection) and 
postdose (30 (±5) minutes after the start of the rFVIIIFc injection), measured by the one-stage 
aPTT clotting assay and the chromogenic assay. According to the local standard of care, an IV 
access device may be offered to facilitate sample collection. The IV access device must not be 
flushed with heparin between injection of rFVIIIFc and the collection of the samples. 
Dosing for ITI IR is discussed separately in Section 10.2.7.1.
10.2.2.
Episodic Treatment 
The Investigator has the option to treat the subject episodically, starting after the confirmation of 
eligibility and lasting until a prophylactic regimen is initiated. Dosing will be determined by the 

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Investigator using the guidelines in Appendix A. The duration of episodic treatment is at the 
Investigator’s discretion and should be based upon the Investigator’s treatment plan for the 
subject in accordance with the local standard of care. However, given global standards of care, it 
is expected that the prophylactic regimen will be initiated prior to or immediately following a 
third episode of hemarthrosis [Berntorp 1995; Manco-Johnson 2007; MASAC 2007]. The date of 
transition from episodic treatment to a prophylaxis regimen must be captured on the electronic 
case report form (eCRF).
10.2.3.
Prophylaxis Treatment
It is anticipated that subjects will begin a prophylaxis regimen prior to or immediately following 
the occurrence of a third hemarthrosis (joint bleed). The dose for initiation of prophylaxis may be 
chosen by the Investigator within the range of 25 to 80 IU/kg. However, based on data from the 
completed clinical studies, and knowledge of increased clearance of factor concentrates in 
children <6 years of age, more frequent or higher doses of up to 80 IU/kg may be required to 
minimize breakthrough bleeding events. The dose can be adjusted based on the subject’s 
response to dosing in the range of 25 to 65 IU/kg at 3 to 5 day intervals. Adjustments to the dose 
and dosing interval can be made based upon available IR data, subsequent FVIII activity levels, 
level of physical activity, and bleeding pattern, in accordance with local standards of care for a 
prophylactic regimen.
Parents/caregivers will be instructed to administer rFVIIIFc at home or to have it be administered 
by a qualified professional under the direction of the Investigator. Treatment will continue until 
the subject has reached at least 50 EDs to rFVIIIFc study drug, completed follow up of an ITI 
regimen, or the end of study is declared, see Section 7.5). 
10.2.4.
Bleeding Episodes
10.2.4.1.1. Definition of a Bleeding Episode
In this study, a bleeding episode will be defined as follows: A bleeding episode starts from the 
first sign of a bleed and ends no more than 72 hours after the last injection to treat the bleed, 
within which any symptoms of bleeding at the same location, injections less than or equal to 
72 hours apart, are considered the same bleeding episode. Any injection to treat the bleeding 
episode, taken more than 72 hours after the preceding one, will be considered the first injection 
to treat a new bleeding episode in the same location. Any bleeding at a different location is 
considered a separate bleeding episode, regardless of the time from the last injection.
In this study, when a subject reports a bleeding episode or hemorrhage and is treated with study 
drug, it will be classified as 1 of 2 types: spontaneous or traumatic. The subject’s electronic 
patient diary (EPD) will serve as the source document for bleeding episodes while on study.
Spontaneous bleeding episodes: Bleeding episodes should be classified as spontaneous if a 
parent/caregiver records a bleeding event when there is no known contributing factor such as a 
definite trauma or antecedent “strenuous” activity. The determination of “strenuous” is at the 

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discretion of the Investigator, and the parent/caregiver/subject needs to be instructed by the 
Investigator.
Traumatic bleeding episodes: Bleeding episodes should be classified as traumatic if the 
parent/caregiver records a bleeding episode even when there is a known or believed reason for 
the bleed. For example, if a subject were to exercise strenuously and then have a bleeding 
episode in the absence of any obvious injury, the bleeding episode would still be recorded as 
traumatic. Target joint bleeding episodes can be traumatic if a known action led to bleeding into 
the joint. The Investigator should consider whether events resulting in a traumatic bleeding 
episode qualify as AEs and should be reported as such.
10.2.4.1.2. Procedure to Treat the Bleeding Episode
After meeting eligibility criteria, all bleeding episodes should be treated with study drug, either 
as part of an episodic treatment regimen or on an as-needed basis on the background of 
prophylactic treatment. Dosing calculations should be performed as described in the DHA and as 
summarized in Section 10.1.1, with respect to the use of nominal strength for the administration 
of whole vials and actual potency for the administration of partial vials. 
The subject’s parents/caregivers should be instructed to treat at the first sign of a bleeding 
episode and with a single dose of rFVIIIFc. Most bleeding episodes should resolve with a single 
dose of rFVIIIFc.
The dose of rFVIIIFc to treat the bleeding episode will be based on the subject’s clinical 
condition, known PK information (including Table 1), type and severity of the bleeding event 
(see Appendix A for guidance on dosing), and input from the Medical Monitor, if necessary.

If the bleeding episode resolves with a single IV dose of rFVIIIFc, the subject will return 
to the schedule of dosing used prior to the bleeding episode.

If the bleeding episode does not resolve within 24 hours with the single IV dose of 
rFVIIIFc, the subject’s parents/caregivers should contact the Investigator for advice.
Administration of a second dose of rFVIIIFc as follow-up treatment will be determined 
by the Investigator based on the subject’s clinical condition. Once the bleeding event 
resolves, the subject will return to the rFVIIIFc dosing schedule used prior to the 
bleeding episode.

If the bleeding episode does not resolve with 2 doses (initial and follow-up treatments) of 
rFVIIIFc, the subject’s parents/caregivers should contact the Investigator for advice. A 
third dose of rFVIIIFc will be administered within 24 hours after the administration of the 
second dose of rFVIIIFc. The repeat dose may be at the same dose or a dose determined 
by the Investigator based on the subject’s clinical condition. Once the bleeding event 
resolves, the subject will return to the rFVIIIFc dosing schedule used prior to the 
bleeding episode.

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
If the bleeding event has still not resolved with 3 doses (initial and 2 follow-up 
treatments) of rFVIIIFc, the Investigator should consult with the Medical Monitor to 
determine if the subject should be withdrawn from the study (see Section 11).
10.2.4.1.3. Dose and/or Interval Modification Following Bleeding Episodes
See Section 10.2.4.1.2 for guidance on dose and/or interval modification.
10.2.4.1.4. Information to be Recorded
The incidence of bleeding in this study will be obtained from EPDs, eCRFs, and medical records.
Information on dosing and bleeding episodes treated with rFVIIIFc study drug prior to the 
subject being issued with an EPD upon confirmation of eligibility (Section 8.3) should be 
recorded in the eCRF (including date and location of bleed, type of bleeding episode, dose, date 
of injection, and response to treatment).
Bleeding episodes will not be reported as AEs; however, the concomitant events associated with 
a bleeding episode should be reported as AEs as appropriate (e.g., a fracture in an elbow).
All injections administered during a study site visit must be recorded in the eCRF. An injection 
administered during a clinic visit must not be recorded in the EPD. Injections cannot be logged 
in both places. All injections performed while the subject is in the hospital for surgery must be 
recorded in the eCRF.
The subject’s parent/caregiver must enter dosing information into the EPD as soon as possible 
after an injection and within a maximum of 7 days following the injection, to ensure data 
integrity, and to facilitate appropriate medical review and dosing guidance. It is recommended 
that parents/caregivers enter dosing information immediately after an injection.
The clinical sites and Clinical Monitors will ensure that there is consistency between the 
subject’s medical record, IXRS, source documents, EPD, and eCRFs. During the clinic visits and 
monthly telephone calls with the subject’s parents/caregivers, the Investigator will verify 
whether or not a bleeding episode has occurred and was “spontaneous” or “traumatic.” The 
subject’s parent/caregiver will also be reminded about timely EPD completion during the 
monthly phone call.
If, following this discussion, the Investigator judges that the classification by the subject’s 
parents/caregivers was incorrect, the Investigator will document it in the subject’s medical 
records with the rationale for the new classification, and the eCRF, documenting the new 
classification of the bleeding episode according to the Investigator and whether or not the 
subject’s parents/caregivers agreed with this new classification. With regard to dose changes, the 
Investigator’s classification of spontaneous or traumatic will be used (if different from the 
classification recorded in the EPD by the parent/caregiver). Both spontaneous and traumatic 
bleeding episodes will be collected.
Information collected in the EPD will include, but not be limited to, the following:

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
The type of bleeding episode (that is, spontaneous or traumatic) and if related to 
sports activity or physical activity

The date the bleeding event occurred

The dose administered to treat the bleeding episode including any repeat doses

The location of the bleed

The reason for administering the dose (medical or nonmedical reasons [e.g., training 
for administration of study treatment])

The caregiver’s rating of treatment response
10.2.5.
Inhibitor Testing
Subjects must be tested for the formation of inhibitors to rFVIIIFc under the following 
circumstances:

At each clinic visit (Section 4.2.2.1). If for some reason, the inhibitor test could not be 
performed on the scheduled visit, an additional visit should be schedule to perform 
the test. 

At specific ED milestones (Section 4.2.2.2). Inhibitor testing at these ED milestones 
may be combined with scheduled study visits. However, if they do not align with a 
scheduled study visit, an additional visit must be scheduled to complete this testing. 

If required by the local standard of care or at the Investigator's discretion. Additional 
unscheduled testing may be performed under these circumstances.

If inhibitor development is suspected at any time during the study (e.g., the expected 
plasma FVIII activity levels are not attained or if bleeding is not controlled with an 
expected dose). The subject will be tested for inhibitors by the central laboratory.

Perioperatively (Section 4.2.2.6). For minor surgeries, testing for inhibitors will only 
be performed if indicated by the nature of the procedure, according to local standard 
of care.

At ITI visits (Section 4.2.2.3) and Post-ITI Complete Success Visits (Section 4.2.2.5)

At the ET/EOT Visit (Section 4.2.2.1). A valid inhibitor test result is required from 
the ET/EOT Visit. If the ET/EOT Visit inhibitor test is not evaluable, or if a sample is 
needed to obtain a sample to confirm a positive inhibitor test result, an unscheduled 
visit may be required to repeat inhibitor testing under this protocol 
The results will be recorded on the eCRF.

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10.2.5.1.
Definition of Negative and Positive Inhibitors
10.2.5.1.1. Negative Inhibitor
A negative inhibitor is defined as an inhibitor test with a result of <0.6 BU/mL.
10.2.5.1.2. Positive Inhibitor
A positive inhibitor test result is defined as an inhibitor test result of ≥0.60 BU/mL that is 
confirmed by a second test result of ≥0.60 BU/mL from a separate sample, drawn approximately 
2 to 4 weeks following the date when the original sample was drawn. Both tests must be 
performed by the central laboratory using the Nijmegen-modified Bethesda assay.

A positive low titer inhibitor is defined as an inhibitor test with a result of ≥0.60 and 
<5.00 BU/mL.

A positive high titer inhibitor is defined as ≥5.00 BU/mL.
Subjects with discrepant inhibitor test results (initial low titer result followed by high titer result 
or initial high titer result followed by low titer result) should have repeat inhibitor testing 
performed by the central laboratory from a separate sample, drawn approximately 2 to 4 weeks 
following the previous sample.

If 2 of 3 test results are <5.00 BU/mL, the inhibitor is considered low titer.

If 2 of 3 test results are ≥5.00 BU/mL, the inhibitor is considered high titer.
10.2.5.2.
Positive Inhibitors
Subjects developing positive inhibitors will be further classified as having low or high titer
inhibitors and followed as described below. Subjects with confirmed or suspected inhibitors may
receive bypassing agents. For more information on the use of bypassing agents see 
Section 10.2.5.2.3.
10.2.5.2.1. Low Titer Inhibitors
At the discretion of the Investigator, subjects developing positive low titer inhibitors (≥0.60 and 
<5.00 BU/mL) may continue on study at the same or higher dose per injection of rFVIIIFc.
These subjects will continue with the schedule of assessments in Section 4.2.2.1 . 
The subject will be eligible for ITI if the Investigator determines that bleeding is no longer 
adequately controlled despite increased rFVIIIFc doses or if bypassing agents are required to 
treat bleeding in a subject with a positive low titer inhibitor (see Section 5.3). Subjects 
undergoing an ITI regimen will follow the schedule of assessments in Section 4.2.2.3. If the 
subject declines to undergo or continue ITI, he will be withdrawn from the study. 

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10.2.5.2.2. High Titer Inhibitors
Subjects developing positive high titer inhibitors (≥5.00 BU/mL) will be eligible for ITI 
(see Section 10.2.7). Subjects undergoing an ITI regimen will follow the schedule of assessments 
in Section 4.2.2.3. If the subject declines to undergo or continue ITI, he will be withdrawn from 
the study.
10.2.5.2.3. Use of Bypassing Agents
Subjects with confirmed or suspected inhibitors may receive bypassing agents (aPCC [FEIBA] 
or rFVIIa [NovoSeven]) at the discretion of the Investigator and within labeled dosing 
recommendations for the specific bypassing agent. The Investigator may prescribe bypassing 
agents for active bleeding or if there is a high clinical suspicion of bleeding or potential for 
bleeding. When possible, bleeding should be confirmed via physical examination and/or imaging 
prior to administration of a bypassing agent; Confirmation of bleeding should not cause any 
unnecessary delay in the start of treatment, as judged by the Investigator. In the event of an 
emergency, prior consultation with the Investigator is not required before administration of a 
bypassing agent; however, the Investigator must be notified of such use. 
In subjects with low-titer inhibitors, bleeding events may be controlled with increased doses of 
replacement FVIII to overwhelm the inhibitor by antigen excess. In subjects with high-titer 
inhibitors, bleeding may be treated with bypassing agents, which can bypass FVIII inhibition. 
During the study, the Investigator will determine if increased doses of replacement FVIII or use 
of bypassing agents is appropriate.   
During ITI treatment, subjects may also receive bypassing agents as needed for active bleeding 
or if there is a high clinical suspicion of bleeding or potential for bleeding. The use of bypassing 
agents in the setting of ITI requires awareness of FVIII activity levels and close monitoring for 
cessation of bleeding events. 
It is recommended that Investigators discontinue the use of bypassing agents once the inhibitor 
titer is <0.6 BU/mL (negative titer, or values considered negative per local laboratory reference) 
or once rFVIIIFc provides sufficient hemostatic control, as judged by the Investigator. 
The prophylactic use of bypassing agents in subjects with confirmed or suspected inhibitors must 
be communicated to the Sponsor Medical Monitor with documentation of rationale.
All use of bypassing agents must be documented in the appropriate section of the eCRF.  
10.2.6.
Anti-rFVIIIFc Antibody Testing
Blood samples will be collected for anti-rFVIIIFc antibody 
 testing 
according to the Schedules of Activities (Section 4.2 ). Samples may also be collected and 
archived at the time of any clinical event deemed relevant to rFVIIIFc antibody testing. 
 
 

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10.2.7.
Immune Tolerance Induction Therapy
Subjects who develop high titer inhibitors as defined in Section 10.2.5.2.2 and choose to remain 
in the study will undergo ITI with rFVIIIFc, as described below. Subjects with low titer 
inhibitors as defined in Section 10.2.5.2.1 will be eligible for ITI if the Investigator determines 
that bleeding is no longer adequately controlled despite increased rFVIIIFc doses or if bypassing 
agents are required to treat bleeding in a subject with a positive low titer inhibitor (see
Section 5.3). Separate consent is required before starting an ITI regimen. 
The timing of ITI initiation in patients with a peak inhibitor titer of >10 BU/mL, including 
patients who experience serious or life-threatening bleeding or have frequent mild to moderate 
bleeding, will be based on the Investigator’s clinical judgement.
If an investigator chooses to have the subject temporarily suspend treatment with rFVIIIFc, and 
delay the start of ITI, the subject should continue to participate in Interim visits every 
12 ± 2 weeks (per the prophylaxis schedule in Section 4.2.2.1).
The ITI regimen will approximate the high-dose treatment arm of the International ITI Study 
protocol [Hay and DiMichele 2012] and will utilize single injections of rFVIIIFc 200 IU/kg, 
daily. Concomitant immunomodulation will not be allowed during ITI therapy.
ITI outcomes will be assessed on an ongoing basis as described in Section 10.2.7.4.
Additional informed consent must be obtained prior to the ITI assessments beginning at Day 0.
Immune tolerance induction therapy assessments will be performed according to the schedule as 
described in Section 4.2.2.3.
10.2.7.1.
Assessment of Incremental Recovery and Half-Life During Immune Tolerance 
Induction Therapy
Upon the confirmation of a negative inhibitor titer, IR and t½ will be performed per the schedule 
of assessments (Section 4.2.2.3). Doses given for the purposes of full PK measurements (that is, 
t½), and IR will be calculated and recorded using the actual potency written on the vial as 
described in Section 10.1.1. IR and t½ assessments will be based on the one-stage clotting assay.
The IR and t1/2 will be calculated by the Sponsor and provided to the PI.
For PK assessments, the subject must not be currently bleeding:

Blood samples for recovery assessments will be taken predose (within 30 minutes 
prior to the start of the injection) and at 30 (±5) minutes after the start of a 50 IU/kg 
injection of rFVIIIFc. Subjects are required to have at least a 24-hour washout prior 
to the predose sample collection.

For PK assessments to determine t½, subjects must not have received an injection of 
rFVIIIFc within at least 72 hours of the predose sample collection. Sampling will 
occur at the following time points: predose and 30 (±5) minutes; 3 and 6 hours 
(±10 minutes); and 24 hours (±60 minutes), 48 hours (±60 minutes), and 72 hours 

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(±2 hours) after a 50 IU/kg injection of rFVIIIFc. Subjects should not have any 
additional doses of rFVIIIFc during the PK sampling period. If additional doses are 
required for clinical care, please immediately inform the Sponsor, as the t1/2
assessments must be repeated.
Whole blood will be drawn for exploratory assays related to immune response during ITI, 
starting with a sample collected at the pre-ITI assessment visit. A whole blood sample will be 
drawn every other month during ITI, at the time of the confirmation of complete success, partial 
success, or failure, and at the end of tapering (if applicable). Up to 10 mL of whole blood 
(minimum 3 mL) should be collected, as allowable by patient weight and institutional practice 
regarding blood draw restrictions for pediatric patients.
10.2.7.2.
Treatment of Bleeding Episodes During Immune Tolerance Induction Therapy
At the Investigator’s discretion, activated prothrombin complex concentrates, recombinant 
activated coagulation factor VII, and rFVIIIFc can be used to treat active bleeding or to provide 
surgical hemostasis during ITI.
10.2.7.3.
Interruption of Immune Tolerance Induction Therapy
Interruptions of ITI should be avoided wherever possible and not exceed a maximum of 2 weeks.
Subjects who discontinue ITI after less than 33 months will be withdrawn from study, unless 
they have already met the criteria for successful immune tolerance described in Section 10.2.7.4 .
10.2.7.4.
Immune Tolerance Induction Therapy Outcomes
The outcome of ITI (complete success, partial success, or failure) will be assessed in the study 
via the algorithm provided in Figure 2. Potential outcomes are defined below. 
10.2.7.4.1. Reference Incremental Recovery Values for ITI 
The reference IR Value (expected recovery), which is the basis for one of the criteria for 
complete ITI success, is defined below:

For subjects who have a baseline IR value, ≥66% of the subject’s baseline value 
(if the subject’s baseline IR value was obtained via the Baseline IR visit), OR 

 
10.2.7.4.2. Definitions of Complete Success, Partial Success, and Failure of Immune 
Tolerance Induction Therapy
Complete Success: 

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Complete ITI success requires that all of the following criteria be met:
1. Negative inhibitor titers in 2 consecutive determinations at least 1 month apart
13. IR ≥66% of expected in 2 consecutive determinations at least 1 month apart
14. t½ ≥6 hours 
Subjects may meet the criteria for complete success in less than 33 months. 
Subjects fulfilling the criteria for complete success will transition to a “tapering” regimen over a 
minimum period of 12 weeks with the aim of starting a prophylactic rFVIIIFc regimen, as 
described in Section 10.2.7.5, and will be monitored for relapse for up to 9 months as described 
in Section 4.2.2.5. 
Partial Success:
The determination of partial success will be made only for subjects who have completed 
33 months of ITI but who do not fulfill the criteria for complete success.
To achieve partial success, the following criteria must be met after subjects have completed 
33 months of ITI:
1. Negative inhibitor titers on 2 consecutive tests within 2 months of each other 
AND
15. Either of the following but not both:

IR ≥66% of expected 
OR

t½ ≥6 hours
If the subject has 2 negative inhibitor tests but recovery is <66% of the subject’s baseline value 
(if known) 
, then the subject may 
remain on ITI at the discretion of the Investigator, up to a total duration of ITI of 33 months.
Failure:
ITI failure is defined as the inability to meet criteria for Complete Success or Partial Success 
after 33 months on ITI.
10.2.7.4.3. Algorithm for Determining the Outcome of Immune Tolerance Induction
Assessments to be performed during the ITI regimen are described in Section 10.2.7.4.
Additional assessments may be required, per Figure 2 below and the Schedule of Assessments in 
Section 4.2.2.3.

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If subjects begin the ITI regimen but discontinue the regimen without meeting the criteria for 
successful immune tolerance, they will be withdrawn from the study. (See Section 11) 

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Figure 2:
Immune Tolerance Induction Assessment Algorithm
Perform these assessments until Negative Titer is Confirmed:a
Inhibitor Titer at 2 weeks
Inhibitor Titer at 4 weeks
For Up to 33 Months
Positive Inhibitor Titerb
Confirmed Negative Inhibitor Titer 
(2 consecutive determinations at least 1 month apart)b
Qualification for ITI Regimen (Positive Inhibitor Titer)
ITI Success Criteriac Reached 
Within 33 Months or Less
Proceed Immediately to Tapering Regimene
ITI Success Criteriac NOT Reached 
after 33 Months
Proceed to End of Treatment Visita
Perform these assessments after Negative Titer is 
Confirmed:
Perform these assessments for the remainder of the 
ITI Period after ≥66% reached:
IR that is ≥66% of expected valuec
(2 consecutive determinations at least 1 month apart)
Inhibitor Titer every 4 weeks
Inhibitor Titer every 4 weeks
IR every 4 weeks
t½ every 12 weeksd
Inhibitor Titer every 4 weeks
t½ ≥6 hours
IR every 4 weeks
aSee Section 4.2.2.3 for complete Schedule of Activities for ITI.
bSee Section 10.2.5 for definitions of a positive low and high titer inhibitors.
cSee Section 10.2.7.4.1 for the definition of expected values, and Section 10.2.7.4.2 for ITI success criteria.
dSee Section 4.2.2.4 for Schedule of Activities for Half-Life Determination
eSee Section 4.2.2.5 for Schedule of Activities for Tapering Regimen.
10.2.7.5.
Transition to a Prophylactic Regimen Following Immune Tolerance Induction 
Therapy Success (Tapering Period)
Subjects fulfilling the criteria for complete ITI success will transition (“taper off”) to a 
prophylactic regimen over a minimum period of 3 months. The duration of the tapering period 

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may be modified by the Investigator with the Sponsor’s medical monitor’s approval based on the 
subject’s clinical response.
The suggested “tapering” schedule is similar to that used on the International ITI Study protocol 
[Hay and DiMichele 2012]:
Prophylaxis Regimen during Follow-up: Based on clinical response, adjust the prophylaxis 
regimen in the range of 25 to 65 IU/kg every 3 to 5 days, utilizing more frequent dosing or doses 
up to 80 IU/kg, as required.
10.2.7.6.
Monitoring for Relapse
During the 9-month period following the end of the tapering off (Section 10.2.7.5), the subjects 
will be monitored for relapse via blood samples processed by the central laboratory using the 
Nijmegen-modified Bethesda assay for inhibitor detection, as well as IR assessments. The 
inhibitor titer and IR will be measured every 3 months for the follow up period. rFVIIIFc half-
life assessments will be performed 12 months after ITI success. 
If any of these tests indicate the possibility of an inhibitor at any time between the start of 
tapering through the beginning of prophylaxis, the tests must be repeated within 2 to 4 weeks to 
confirm relapse.
Relapse is defined as any of the following, occurring within 12 months following complete ITI 
success, based on the International ITI criteria [Hay and DiMichele 2012]:

A positive inhibitor (≥0.6 BU/mL using the Nijmegen assay) that is confirmed by a 
second test result of ≥0.60 BU/mL from a separate sample, drawn approximately 2 to 
4 weeks following the date when the original sample was drawn.

 
 

t½ <6 hours.
10.2.8.
Surgery
For subjects who require emergent or elective surgery during the study period, the target FVIII 
levels for the proposed procedure will be those deemed appropriate by the Investigator for the 

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type of surgery to be performed. Recommendations for the appropriate dosing regimen of 
rFVIIIFc during the surgery may be discussed between the Investigator and the Medical Monitor 
taking factors such as standard doses of FVIII for the type of surgery, the clinical status of the 
subject, and IR data for the subject into consideration.
All doses administered in the hospital will be captured in the eCRF. The subject’s 
parent/caregiver should not enter these doses in the EPD.
See Section 4.2.2.6 for the surgery visit schedule.
10.2.8.1.
Definitions of Major and Minor Surgery
Surgeries, elective or emergent, will be classified as major and minor as follows:

Major surgery is defined as any surgical procedure in which a major body cavity is 
penetrated and exposed or for which a substantial impairment of physical or 
physiological function is produced (e.g., laparotomy, thoracotomy, craniotomy, joint 
replacement, or limb amputation).

Minor surgery is defined as any surgical procedure that does not qualify as major (e.g., 
minor dental extractions, incision and drainage of abscess, port placement, or simple 
excisions).
10.2.8.2.
Definition of the Surgical Period 
The surgical period includes Preoperative, Intraoperative, and Postoperative Periods:

The preoperative period of the study (that is, the beginning of the surgical period) begins 
with the first dose of rFVIIIFc given for the surgery. For elective surgeries, this is the 
pre-surgery dose.

The intraoperative period is defined as the time from when the surgery begins to the time 
when the surgery is completed.

The postoperative period is defined as the time period following the end of surgery 
through the last dose of rFVIIIFc given for the surgery, as judged by the 
Investigator/Surgeon, including doses given to prevent bleeding during the postoperative 
period.
10.2.8.2.1. Minor Surgery
Minor surgery is allowed at any time during the study.
For minor surgeries, pre-surgery assessments of FVIII trough and recovery, inhibitor, and 
anti-rFVIIIFc antibody, and hematology and blood chemistry on the day of surgery are only to be 
performed if indicated by the nature of the procedure, according to local standard of care.

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If FVIII activity levels and inhibitor formation assessments are indicated, predose samples will 
be collected prior to the dose of rFVIIIFc given for the surgery, and FVIII recovery levels will be 
sampled 30 (±5) minutes after the start of the rFVIIIFc injection.
Bleeding caused directly by surgery should not be reported, although undesired or unexpected 
bleeding during or after surgery should be recorded on the eCRF. The Investigator or Surgeon’s 
assessment of response will be conducted on the day of surgery.
The Investigator will contact the subject’s parent/caregiver after the day of surgery to determine 
when the subject returns to his regular dosage regimen.
10.2.8.2.2. Major Surgery
Major surgery will only be allowed in the study after the subject has had at least 3 injections of 
rFVIIIFc without safety concerns. If a subject needs to undergo major surgery prior to 
3 injections, they will be withdrawn from the study. The Investigator must consult with 
Bioverativ in advance of the surgery. 
All major surgeries must take place in a center that can provide study treatment, trained study 
personnel, postoperative assessments, and hematological consult by the Investigator or 
Sub-Investigator. If surgery does not take place in such a setting, the subject will be withdrawn 
from the study.
In addition, subjects who require major surgery may receive rFVIIIFc if:
1. The surgery occurs within the contracted institution for the study and/or a separate 
agreement has been executed, permitting the use of study drug and Bioverativ’s rights to 
data generated in the study at an alternative institution deemed appropriate by the 
Principal Investigator or designee.
2. The Investigator and/or appropriate qualified/licensed delegate is available to:
a.
Administer all rFVIIIFc doses required during surgery and during postoperative 
rehabilitation (if applicable).
b. Provide medical oversight and guidance throughout the duration of the preoperative 
and the intraoperative periods.
All major surgeries will be reported as SAEs, even if the surgery does not otherwise meet the 
definition of an SAE.
Samples for determination of predose FVIII activity levels and inhibitor formation will be 
collected prior to the dose of rFVIIIFc given for the surgery, and FVIII recovery levels will be 
sampled 30 (±5) minutes after the start of the rFVIIIFc injection.
For major surgeries, a repeat blood draw for FVIII activity should be taken approximately 
9 hours after the start of the injection, but may alternatively follow local standard of care for 
determining when the next dose of rFVIIIFc should be administered. While hospitalized, blood 

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will be drawn daily to be tested at the local laboratory for FVIII activity so that monitoring of the 
subject can occur in real time.
Bleeding caused directly by surgery should not be reported, although undesired or unexpected 
bleeding during or after surgery should be recorded on the eCRF. The Investigator or Surgeon’s 
assessment of response is conducted 24 hours after surgery and at the Postoperative Visit (1 to 
2 weeks after surgery).
A postoperative visit will be required following major surgery.
10.2.8.3.
Rehabilitation Period
If surgery-related dosing is to be continued during postoperative rehabilitation, the dose of 
rFVIIIFc will be adjusted to achieve a trough at a sufficient level to maintain hemostasis, 
including during physical therapy. These doses will be captured in the subject’s EPD.
Subjects will return to their pre-surgery regimen once all dosing for the postoperative period has 
been completed.
10.3.
Treatment Precautions
Medications and resuscitation equipment for the emergency management of anaphylactic 
reactions must be available where the subject’s first injection of rFVIIIFc is being performed.
The subject’s first injection must be performed by the Investigator or by qualified medical 
personnel identified by the Investigator. In addition, the parents/caregivers will be provided with 
specific instructions by the Investigator on what to do should such an event occur while at home, 
including how to seek emergency medical treatment.
10.4.
Modification of Dose and/or Treatment Schedule
Information on modifications to the dose and treatment schedule can be found in 
Section 10.2.4.1.2.
10.5.
Non-Medical Treatment With rFVIIIFc
During the study, subjects’ parents/caregivers may attend training sessions on administration of 
rFVIIIFc. Administration of rFVIIIFc to subjects for training purposes will be considered 
non-medical treatment. Such training is permitted and must be recorded in the EPD. However, 
administration of the first dose of rFVIIIFc must be performed under supervision in the clinic.
Data from this time period will be excluded from the analysis of consumption.
10.6.
End of Treatment
The End of Treatment (EOT) for individual subjects is defined as follows:

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
Any individual subject who completes at least 50 EDs of rFVIIIFc and is not on an 
ITI regimen is considered to have completed treatment.

A subject undergoing ITI with rFVIIIFc is considered to have completed treatment if 
either of the following occurs:

The subject has achieved complete ITI success (as defined in Section 10.2.7.4)
and has completed the tapering and monitoring periods described in
Section 10.2.7.5 and Section 4.2.2.5.

The subject has completed 33 months on an ITI regimen without achieving 
complete ITI success (that is, ITI failure or partial ITI success) [Section 10.2.7.4,
Figure 2].
Individual subjects may also have to end treatment because 1 of the following has occurred:
1. The subject has met criteria for early withdrawal (Section 11). 
2. Study stopping rules have been met (Section 7.4).
3. EOS has been reached (Section 7.5).
Upon ending treatment for any of the reasons described above, the subject will return to the site 
for the ET/EOT visit.
The Final Safety Follow-up Visit (by telephone or in person) will be conducted within 7 to 
14 days after the last dose of rFVIIIFc to assess the subject’s status, collect AEs and/or SAEs and 
concomitant medications and procedures and follow up on open AEs and SAEs. (Section 4.2.2.1)
10.7.
Treatment Compliance
Compliance with treatment dosing is to be monitored and recorded by site staff. The instructions 
provided in the DHA must be followed, as summarized in 10.1.1.
For the doses that will be administered at the study site, the study treatment will be administered 
under controlled conditions by the investigational staff; therefore, full compliance with study 
treatment is anticipated.
For between-visit administration, subjects’ parents/caregivers or a qualified medical professional 
under the direction of the Investigator will administer rFVIIIFc and will record treatment in the 
EPD. The EPD will be reviewed during periodic calls to the subject’s parents/caregiver and at 
each clinic visit.

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10.8.
Concomitant Therapy and Procedures
The use of concomitant therapies or procedures defined below must be recorded on the subject’s 
eCRF according to instructions for eCRF completion. AEs related to administration of these 
therapies or procedures must be documented on the appropriate eCRF.
10.8.1.
Concomitant Therapy
A concomitant therapy is any drug or substance administered from 30 days prior to the Screening 
Visit through the Final Safety Follow-up Visit/Telephone Call. For subjects who are receiving 
breast milk, the mother will provide consent to collect the concomitant medications that she is 
taking (as part of the main parental consent). The mother’s concomitant medications will not be 
collected if the breast milk is derived from a source other than the mother, if the mother will not 
consent, or if the mother is no longer breastfeeding. The list of disallowed concomitant 
medications in Section 10.8.1.2 does not apply to the mother's medications.  
The subject’s parents/caregivers should be instructed that the child not start taking any new 
medications, including nonprescription drugs and herbal preparations, unless they have received 
permission from the Investigator. 
10.8.1.1.
Allowed Concomitant Therapy
Therapy considered necessary for the subject’s welfare, including routine immunizations, may be 
given at the discretion of the Investigator. Bypassing agents (e.g., aPCC [FEIBA], rFVIIa 
[NovoSeven]) are allowed in subjects with confirmed or suspected inhibitors as outlined in 
Section 10.2.5.2. All such therapy must be recorded in the eCRF. The prophylactic use of 
bypassing agents in subjects with confirmed or suspected inhibitors must be communicated to 
the Sponsor Medical Monitor with documentation of rationale. 
10.8.1.2.
Disallowed Concomitant Therapy
No other drug under investigation may be used concomitantly with the study treatment. Subjects 
are not allowed to participate concurrently in another clinical study.
The following concomitant medications are not permitted during the study:

Acetylsalicylic acid.

Current systemic treatment with chemotherapy and/or other immunosuppressant 
drugs. Use of corticosteroids for the treatment of asthma or management of acute 
allergic episodes is allowed with the exception of systemic corticosteroid treatment 
given to children daily or on alternate days at ≥2 mg/kg per day of prednisone or its 
equivalent or ≥20 mg/day if the duration is longer than 14 days. 

Concomitant immunomodulation will not be allowed during ITI therapy.

Emicizumab (Hemlibra)

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
Any other FVIII product (exception allowed for 1 emergency or accidental use).
10.8.2.
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 from 
30 days prior to the Screening Visit until the Final Safety Follow-up Visit/Telephone Call. The 
reason for all concomitant procedures performed during the study will be documented in the 
medical records and recorded in the eCRF.
10.9.
Continuation of Treatment
No further provisions are made for access to the study treatment. If rFVIIIFc is proven to be 
beneficial, all regulatory requirements regarding post study access will be met.

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11.
WITHDRAWAL OF SUBJECTS FROM THE STUDY
A subject must permanently discontinue study treatment and be withdrawn from the study if any 
of the following occur:
1. The subject is found to have a factor VIII activity ≥1% or a positive inhibitor based on 
central laboratory results obtained during the screening period.
2. The subject develops a positive inhibitor following enrollment and is eligible for ITI (as 
defined in Section 10.2.5.1) AND opts not to undergo or continue ITI. 
3. A subject who is in the tapering period (or the subsequent follow-up monitoring period) 
develops inhibitors (that is, has a relapse) (Section 4.2.2.5).
4. The subject develops a Grade 2 or greater allergic drug reaction in association with the 
administration of rFVIIIFc, as defined by the Recommendations for Grading of Acute 
and Subacute Toxic Effects on the World Health Organization (WHO) scale [WHO 
Handbook 1979]:

Grade 2: bronchospasm; no parenteral therapy needed

Grade 3: bronchospasm; parenteral therapy required

Grade 4: anaphylaxis
5. The subject uses FVIII products other than rFVIIIFc (exception allowed for 1 emergency 
or accidental use).
6. The subject receives concomitant immunomodulation.
7. The subject develops any condition that precludes him from complying with the study 
procedures.
8. The subject experiences a medical emergency that necessitates discontinuation of 
treatment.
9. It is not in the subject’s best interest to continue with the study treatment, in the judgment 
of the Investigator. 
10. The parent/legal guardian decides to withdraw the subject from the study.
At the discretion of the Investigator, a subject may be withdrawn due to noncompliance. 
The reason for the subject’s withdrawal from the study must be recorded in the subject’s eCRF.

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For any subject who is not responding to treatment with rFVIIIFc, as determined by the 
Investigator, a decision will be made with the Bioverativ Medical Monitor whether to continue 
the subject in the study. If the decision is made to withdraw the subject from the study, the 
ET/EOT Visit assessments will be performed as described in Section 4.2.2.1 and Section 10.6.

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12.
STUDY TREATMENT MANAGEMENT
Study site staff should follow the DHA, which contains specific instructions on the handling, 
preparation, administration, and disposal of rFVIIIFc. The DHA supersedes all other 
references (e.g., Investigator’s Brochure, Protocol).
The study treatment, rFVIIIFc, must be stored in a secure location. Accountability for study 
treatment is the responsibility of the Investigator. More details concerning this responsibility are 
included in Section 12.1.4.
Study treatment must be dispensed only by a pharmacist or medically qualified staff. Study 
treatment is to be dispensed only to parents/legal guardians of subjects enrolled in this study or 
Sponsor-approved designees. Once study treatment is prepared for a subject, it can only be 
administered to that subject. Study treatment vials are for 1-time use only; any study treatment 
remaining in the vial after preparation of a dose should not be used for another subject.
12.1.
rFVIIIFc (BIIB031)
rFVIIIFc is supplied in a kit that contains several components, including, but not limited to, 
lyophilized drug, a diluent, a vial adapter, and an infusion set (see DHA for further details). The 
lyophilized drug product is provided in 4 different strengths in a glass vial containing 250, 500, 
1000, or 2000 IU of rFVIIIFc per vial. In addition to the rFVIIIFc, the formulation of the 
lyophilized drug product contains 
 L-histidine, 
 sodium chloride, 
 calcium 
chloride dihydrate, 
 sucrose, and 
 polysorbate 20 and is the same for 
all 4 strengths. The diluent is sterile water for injection for reconstitution of rFVIIIFc prior to 
administration to subjects.
The label will comply with local labeling requirements.
12.1.1.
rFVIIIFc Preparation
At the first visit when study product is given, the individual preparing the study treatment should 
first carefully review the instructions provided in the DHA before preparing the dose assigned 
for the subject.
The pharmacist or medically qualified staff member will provide the Investigator or clinical staff 
with enough rFVIIIFc kits for treatment until the subject’s next clinic visit. This will be 
documented according to Section 12.1.4.
If the packaging is damaged, or if there is anything unusual about the appearance or attributes of 
the vials of rFVIIIFc or syringes containing the diluent, it should not be used. The vial or syringe 
in question should be saved at the study site and the problem immediately reported to the 
Clinical Monitor.

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12.1.2.
rFVIIIFc Storage at Site
The study treatment, rFVIIIFc, must be stored in a secure location. The rFVIIIFc kit should be 
stored on site at 2°C to 8°C in a monitored and locked refrigerator with limited access. If the 
refrigerator does not have a lock, the refrigerator must be located in a locked room. For the most 
up-to-date storage requirements, follow the instructions provided in the DHA.
12.1.3.
rFVIIIFc Handling and Disposal
The Investigator must return all used and unused kits of rFVIIIFc as instructed by Bioverativ
unless approved for onsite destruction. The instructions for returning the kits will be provided at 
the time the request is made by Bioverativ. 
If any Bioverativ supplies are to be destroyed at the study site, the institution or appropriate site 
personnel must obtain prior approval from Bioverativ, by providing, in writing, the destruction 
policy or details of the method of destruction. After such destruction, Bioverativ must be 
notified, in writing, of the details of the study treatment destroyed (e.g., lot or kit numbers, 
quantities), the date of destruction, and proof of destruction. 
12.1.4.
rFVIIIFc Accountability
Accountability for study treatment is the responsibility of the Investigator. The study site must 
maintain accurate records demonstrating dates and amount of study treatment received, to whom 
dispensed (subject-by-subject accounting), amount returned by the subject, and accounts of any 
study treatment accidentally or deliberately destroyed. These records will be routinely reviewed 
by the Clinical Monitor during the monitoring visits.
Unless otherwise notified, the subject’s parents/legal guardians should return all vials (used and 
unused) at each clinic visit for full medication exchange and accountability. At the end of the 
study, reconciliation must be made between the amount of drug product supplied, dispensed, and 
subsequently destroyed, lost, or returned to Bioverativ. A written explanation must be provided 
to Bioverativ for any discrepancies.

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13.
EFFICACY AND PHARMACOKINETIC ASSESSMENTS
See Section 4.2 for the timing of assessments.
13.1.
Clinical Efficacy Assessments
The following clinical tests/assessments will be performed to assess the efficacy of rFVIIIFc:

Recording of bleeding episodes at Baseline IR Visit, other clinic visits, and during 
hospitalizations in the eCRF by the Investigator; recording of all other bleeding episodes 
in the EPD by the parent or caregiver. 

Assessment of response to bleeding episodes using the 4-point scale by the Investigator 
for individual bleeding episodes treated in the clinic; assessment of all other bleeding 
episodes in the EPD by the parent or caregiver. See Appendix B.

Physician’s global assessment of the subject’s response to his treatment regimen using 
the 4-point scale. See Appendix D.
13.2.
Laboratory Efficacy Assessments
Not applicable.
13.3.
Pharmacokinetic Assessments
Samples are to be collected for PK assessments before and after the rFVIIIFc injection at the 
Baseline IR Visit, and at all Interim Visits during the prophylaxis regimen when rFVIIIFc is 
administered in the clinic. Samples collected will be analyzed for FVIII activity at a central 
laboratory. Procedures for collecting, processing, storing, and transporting to the central 
laboratory are fully described in the Study Laboratory Manual. 
For subjects undergoing surgery, samples are to be collected according to the schedule in 
Section 4.2.2.6. While hospitalized, blood will be drawn daily to be tested at the local laboratory 
for FVIII activity so that monitoring of the subject can occur in real time.
For subjects undergoing ITI, FVIII activity for trough level assessments is to be taken at each 
visit. FVIII activity for IR assessments while the subject is inhibitor positive is at the discretion 
of the Investigator. After a confirmed negative inhibitor in subjects undergoing ITI, samples are 
to be collected for the calculation of IR and assessment of t½ according to the schedule shown in 
Section 4.2.2.3. See Section 10.2.7 for details of assessments. Samples collected will be analyzed 
for FVIII activity at a central laboratory. 
See Section 4.2 for the timing of assessments.

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13.4.
Additional Assessments
13.4.1.
Factor VIII Genotyping (Optional)
There is 1 target gene for hemophilia A. The name of the target gene is F8. Genotyping may 
provide information regarding the predisposition of genotypic subpopulations to experience 
different bleeding frequencies. The development of an inhibitor to treatment with factor 
concentrates is the single most serious complication of factor replacement. One of the decisive 
risk factors for the development of inhibitors is the type of mutation (e.g., full or missense) that 
codes for a protein that may be absent, truncated, or present but not functional. There is a 
correlation between the resultant protein and the likelihood of developing inhibitors to factor 
replacement [Oldenburg and Pavlova 2006].
For subjects whose F8 genotype is not known, a sample will be drawn for analysis at the 
Baseline IR Visit (or at a subsequent visit if blood volume is limiting at the Baseline IR Visit 
[Section 4.2.1 and Section 4.2.2.1]). Genotyping requires separate consent from the subject’s 
parents/legal guardians. This is not an inclusion or exclusion criterion; refusal of the subject’s 
parents/legal guardians, or local laws precluding this test, would not exclude the subject from the 
study. The subject’s parent/legal guardian may provide consent in order to receive this testing at 
any time during the Treatment Period.
The central laboratory will provide genotyping kits to the sites. The central laboratory will 
receive and forward the genotyping samples to Puget Sound Blood Center Hemostasis Reference 
Laboratory at periodic intervals for analysis. Analysis will take approximately 1 month, and the 
Investigator at the site will be informed of the result.
Additionally, residual blood cell pellets (buffy coat and erythrocytes) from plasma samples will 
be archived and may be used, if clinically or scientifically indicated, for 
 
Genotyping samples will be retained 
indefinitely (unless prohibited by local law).
13.4.2.
Whole Blood for Exploratory Assays for Inhibitor Positive Subjects
Whole blood samples will be collected to
 
 in inhibitor positive subjects. Samples will 
be taken at the following time points: at the pre-ITI assessment visit; every other month during 
ITI; at the declaration of success, partial success or failure; and at the end of tapering (if 
applicable). A minimum of 3 mL and a maximum of 10 mL of whole blood should be collected 
at each time point, as allowable by patient weight and institutional practice regarding blood draw 
restrictions for pediatric patients. These samples will be stored indefinitely (unless prohibited by 
local law).
 
13.4.3.
Health Outcomes Related to Hemophilia
Assessments of health outcomes related to hemophilia may include:

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
Number of hemophilia-related hospitalizations, excluding planned hospitalizations 
documented at screening

Number of hemophilia-related hospitalization days

Number of hemophilia-related emergency room visits

Number of hemophilia-related physician visits excluding study visits

Number of days off school or day care (kindergarten)

Number of days off work for parent/legal guardian or caregiver (demographic data for 
caregivers may be collected at the Screening Visit)

Primary method of administering rFVIIIFc

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14.
SAFETY ASSESSMENTS
See Section 4.2 for the timing of assessments.
14.1.
Clinical Safety Assessments
The following clinical assessments will be performed to evaluate the safety profile of rFVIIIFc:

Physical examination

Medical and surgical history

Height

Weight

Vital sign measurements (blood pressure, pulse rate, respiratory rate, and 
temperature)

Concomitant therapy and procedure recording, including concomitant medications 
taken by the mother of any subject who is receiving breast milk, unless the breast 
milk is derived from a source other than the mother or the mother has not consented.

AE and SAE recording
See Section 4.2 for the timing of assessments.
14.2.
Laboratory Safety Assessments
The following laboratory tests will be performed to evaluate the safety profile of rFVIIIFc. All 
samples will be analyzed at a central laboratory. Procedures for collection, processing, storing, 
and transporting the samples are fully described in the Study Laboratory Manual.

Hematology: white blood cell count and differential, red blood cell, hemoglobin, 
hematocrit, and platelet count

Blood chemistry: sodium, potassium, chloride, total protein, total bilirubin, gamma 
glutamyl transferase, aspartate aminotransferase, alanine aminotransferase, alkaline 
phosphatase, blood urea nitrogen, serum creatinine, and glucose
Subjects of low body weight may require screening blood draws over multiple days in order to 
comply with maximum allowable blood draw volumes [European Commission 2008].
Alternatively, individual investigators may choose to collect all screening samples using a single 
blood draw, after weighing the risk associated with multiple venipuncture attempts versus that of 

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drawing all required samples at a single time. If the option of a single blood draw is chosen, the 
Investigator must document the rationale.
14.3.
rFVIIIFc-Specific Safety Assessments
The following assessments will be performed to determine the safety of rFVIIIFc:

Neutralizing antibody development (inhibitor) measured by the Nijmegen-modified 
Bethesda assay
See Section 4.2 for the timing of assessments.
14.4.
Archive Samples
14.4.1.
Archive Plasma Samples
Primary and backup plasma samples from each subject obtained at each sampling time point for 
inhibitor and anti-rFVIIIFc testing will be will be aliquoted into 2 vials where possible. These 
2 aliquots will be shipped to the central laboratory in separate shipments (the second aliquot 
being a back-up sample in case of damage or loss during shipping). Where the backup sample is 
not used, it will be stored (archived) and may be used, if clinically or scientifically indicated, for 
the following:
1. Testing for coagulation parameters
2. Lupus anticoagulant
3. Additional testing in the event that a subject develops an inhibitor, or is suspected of 
having developed an inhibitor, or has an anaphylactic reaction to the study treatment

In the event of a subject developing an inhibitor to rFVIIIFc (titer 
≥0.60 BU/mL), additional testing will include FVIII-specific inhibitors
4. Testing for immunology or further coagulation assays or for clarification of any 
clinical or laboratory AE
In addition to this, a portion of the above samples will continue to be archived until after 
completion of review by competent authorities in accordance with EMA guidance [EMA 
(EMA/CHMP/BPWP/144533/2009) 2011] in the case of a positive inhibitor or clinical suspicion 
of inhibitor.
14.4.2.
Archive Genotyping Samples (Optional)
Residual blood cell pellets (buffy coat and erythrocytes) from plasma samples for genotyping at 
baseline or the first interim visit (see Section 13.4.1) will be archived and may be used, if 
clinically or scientifically indicated, 
 

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Genotyping samples will be retained indefinitely (unless prohibited by local law). 
14.4.3.
Sample Volumes
The volume of blood taken from the subjects should comply with European Commission 
guidance [European Commission 2008], namely the study-related blood loss should not exceed 
3% of the total blood volume during a period of 4 weeks and should not exceed 1% at any single 
time. Examples of recommended blood draw volume limits per the European Commission 
guidance are provided in Table 2. Local and/or regional guidelines regarding blood draw 
volumes may also apply.
Subjects weighing <6 kg may require screening blood draws over multiple days in order to 
comply with maximum allowable blood draw volumes [European Commission 2008].
Alternatively, individual investigators may choose to collect all screening samples using a single 
blood draw, after weighing the risk associated with multiple venipuncture attempts versus that of 
drawing all required samples at a single time. If the option of a single blood draw is chosen, the 
Investigator must document the rationale.
Table 2:
Examples of Recommended Blood Draw Volume Limits
Subject Weight (kg) 
Blood Draw Limitsa (mL)
Single Occasionb
4 weeksb
3.5 
2.8
8.4
4.0 
3.2
9.6
4.5 
3.6
10.8
5.0 
4.0
12.0
5.5 
4.4
13.2
6.0 
4.8
14.4
6.5 
5.2
15.6
7.0 
5.6
16.8
7.5 
6.0
18.0
8.0 
6.4
19.2
8.5 
6.8
20.4
9.0 
7.2
21.6
9.5 
7.6
22.8
10.0 
8.0
24.0
a Based on an estimated blood volume of 80 mL/kg
b Based on European Commission guidance [European Commission 2008] recommending that blood draw volumes 
not exceed 1% of total blood volume on a single occasion or 3% over a 4-week period.

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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 informed consent form (ICF), each subject’s 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.
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.
Bleeding episodes in this patient population are not considered as AEs. Bleeding episodes that 
meet a serious criterion (see Section 15.1.2) should be reported as an SAE. All bleeding episodes 
after the Baseline IR Visit will be captured in the EPD that the subject’s parents/caregivers will 
be maintaining throughout the study period. 
15.1.2.
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, or

Results in a congenital anomaly/birth defect
An SAE may also be any other medically important event that, in the opinion of the Investigator, 
may jeopardize the subject or may require intervention to prevent one of the other outcomes 

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listed in the definition above. (Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or convulsions occurring at home that do not 
require an inpatient hospitalization.)
15.1.2.1.
Serious Pretreatment Event
A serious pretreatment event is any event that meets the criteria for SAE reporting (as defined in 
Section 15.1.2) and occurs after the subject’s parents/legal guardians sign the ICF, but before 
administration of study treatment. A serious pretreatment event is to be recorded on the SAE 
Form and faxed to Quintiles Pharmacovigilance within 24 hours of the study site staff becoming 
aware of the event (see Section 15.3.3).
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 15.1.2.

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:
Relationship of Event to Study Treatment
Not related
An adverse event will be considered “not related” to the use of the investigational drug if 
there is not a reasonable possibility that the event has been caused by the product under 
investigation. Factors pointing toward this assessment include, but are not limited to: the 
lack of reasonable temporal relationship between administration of the drug and the 
event, the presence of a biologically implausible relationship between the product and the 
adverse event (e.g., the event occurred before administration of drug), or the presence of a 
more likely alternative explanation for the adverse event.
Related
An adverse event will be considered “related” to the use of the investigational drug if 
there is a possibility that the event may have been caused by the product under 
investigation. Factors that point toward this assessment include, but are not limited to: a 
positive rechallenge, a reasonable temporal sequence between administration of the drug 
and the event, a known response pattern of the suspected drug, improvement following 
discontinuation or dose reduction, a biologically plausible relationship between the drug 
and the adverse event, or a lack of an alternative explanation for the adverse event.
15.2.3.
Severity of Events
The following definitions should be considered when evaluating the severity of AEs and SAEs:

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Severity of Event
Mild
Symptom(s) barely noticeable to subject or does not make subject uncomfortable; does 
not influence performance or functioning; prescription drug not ordinarily needed for 
relief of symptom(s) but may be given because of personality of subject.
Moderate
Symptom(s) of a sufficient severity to make subject uncomfortable; performance of daily 
activity is influenced; subject is able to continue in study; treatment for symptom(s) may 
be needed.
Severe
Symptom(s) 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 symptom(s) may be given and/or subject hospitalized.
15.2.4.
Expectedness of Events
Expectedness of all AEs will be determined according to the Investigator’s Brochure for 
rFVIIIFc.
15.3.
Monitoring and Recording Events 
15.3.1.
Adverse Events 
Any AE experienced by the subject between the time of first dose of study treatment and the 
Safety Follow-up Visit/Telephone Call is to be recorded on the eCRF, regardless of the severity 
of the event or its relationship to study treatment. All AEs experienced by the subject should be 
followed up until they have resolved, stabilized, or returned to baseline in subsequent visits.
In addition, any known, untoward event that occurs subsequent to the AE reporting period that 
the Investigator assesses as possibly related to the investigational medication/product should also 
be reported as an AE.
15.3.2.
Serious Adverse Events
Any SAE experienced by the subject between the time of signing the ICF and the Safety Follow-
up Visit/Telephone Call 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 Quintiles Pharmacovigilance and 
the designated personnel within 24 hours as described in Section 15.3.3. Follow up information 
regarding an SAE must be reported within 24 hours. 
Any SAE ongoing when the subject completes the study or discontinues from 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, as defined in Section 10.2.5.

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
A subject develops a Grade 2 or greater allergic reaction in association with 
administration of rFVIIIFc defined as follows using the Recommendations for 
Grading of Acute and Subacute Toxic Effects on the WHO scale [WHO Handbook 
1979]:

Grade 2: bronchospasm; no parenteral therapy needed

Grade 3: bronchospasm; parenteral therapy required

Grade 4: anaphylaxis

A subject develops a vascular thrombotic event in association with the administration 
of rFVIIIFc, with the exception of IV injection site thrombophlebitis

A subject undergoes major surgery
Allergic reactions, including anaphylaxis, have been reported with FVIII products. The subject’s 
parents/caregivers (and the subject, 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 parents/caregivers 
should be instructed to seek immediate medical care for the subject.
The subject’s parents/legal guardians (and the subject, if appropriate) will be informed of the 
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 
parents/legal guardians will be instructed to seek immediate medical care for the subject.
15.3.3.
Immediate Reporting of Serious Adverse Events
In order to adhere to all applicable laws and regulations for reporting an SAE, the study site must 
formally notify Quintiles 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
Any Serious Event that occurs between the time that the parents/legal guardians have signed the 
informed consent and 7 to 14 days after the last dose of rFVIIIFc (up to final safety follow-up 
visit/telephone call) must be reported to Quintiles Pharmacovigilance within 24 hours of the 
study site staff becoming aware of the event.
A report must be submitted regardless of the following:

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
Whether or not the subject has undergone study-related procedures

Whether or not 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 a Serious Event, fax a completed SAE form to 
Quintiles Pharmacovigilance at the country-specific fax numbers provided in the Study 
Reference Manual.
Any SAE must also be entered in the eCRF in the same timeframe.
15.3.3.1.
Deaths
Death is an outcome of an event. The event that resulted in death should be recorded and 
reported on the appropriate eCRF. All causes of death must be reported as SAEs within 24 hours 
of the site becoming aware of the event. The Investigator should make every effort to obtain and 
send death certificates and autopsy reports to Quintiles 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, according to local law. 
15.4.
Procedures for Handling Special Situations
15.4.1.
Overdose
For the purposes of this study, any prophylactic dose greater than 150 IU/kg will be considered
an overdose. Doses greater than 150 IU/kg will not be considered overdoses if they are given as 
part of episodic treatment, treatment of a bleeding episode, surgical management, or during the 
ITI regimen. 
Overdoses are not considered AEs; however, all overdoses should be recorded on an Overdose 
Form and faxed to Quintiles Pharmacovigilance within 24 hours. An overdose should be reported 
even if it does not result in an AE. Overdoses do not need to be recorded in the eCRF; dosing 
information is recorded in the eCRF.

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15.4.2.
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’s Official 
Study Contact List for complete contact information.
15.4.3.
Unblinding for Medical Emergencies
Not applicable.
15.5.
Safety Responsibilities
15.5.1.
Investigator Responsibilities
The Investigator’s responsibilities include the following:

Monitor and record all AEs, including SAEs, 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.

Complete an SAE form for each serious event and fax it to Quintiles 
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 Quintiles 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 and SAE follow-up information until the event has resolved or become 
stable.

Report SAEs to local ethics committees, as required by local law.
The Investigator may delegate responsibilities for study-related tasks where appropriate to 
individuals sufficiently qualified by education, training, and experience, in accordance with 
International Council for Harmonisation (ICH) - Good Clinical Practice (GCP). The Investigator 
should maintain a list of the appropriately qualified persons to whom significant study-related 
duties have been delegated.

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15.5.2.
Bioverativ Responsibilities
Bioverativ’s responsibilities include the following:

Before study site activation and subject enrollment, the Clinical Monitor or 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 ethics 
committees, 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
In general, all statistical analyses will be descriptive in nature. No formal comparison is planned 
and no hypothesis will be formally tested. Continuous variables will be summarized and 
presented by the number of observations, mean, median, standard deviation, minimum, and 
maximum. Categorical variables will be summarized by the number and percentage in each 
category.
The objectives and endpoints are as described in Section 6.
16.1.
Demography and Baseline Disease Characteristics
The analysis of demography and baseline disease characteristics will be based on the Safety 
Analysis Set. A description of the Safety Analysis Set is provided in Section 16.5.1.
Demographics and baseline disease characteristics will be summarized categorically and/or with 
descriptive statistics, as appropriate.
Demographic data to be tabulated will include, but not be limited to, age, race, weight, and 
geographic location.
Baseline disease characteristics, based on general medical and surgical, hemophilia, and bleeding 
histories, will be summarized as follows. General medical and surgical history will be 
summarized by the number and percentage of subjects with a medical history in each of the 
major body system classifications. Hemophilia history data to be tabulated will include but not 
be limited to genotype, types of blood products previously used, and other disease- and 
treatment-specific measures. Bleeding history will include a summary of the number and types of 
bleeding episodes subjects experienced during the 3 months prior to this study.
16.2.
Efficacy
16.2.1.
Analysis Population
Subjects who receive at least 1 dose of rFVIIIFc will be included in the Full Analysis Set (FAS).
Efficacy analyses will be based on the FAS, including the data collected on or after the time of 
the first injection of rFVIIIFc study drug.
Subjects developing a confirmed positive inhibitor test after exposure to rFVIIIFc (the Inhibitor 
Subgroup) will have their efficacy data included up to the time of the last negative inhibitor test; 
efficacy data collected after the time of the last negative inhibitor test will be summarized 
separately.
16.2.2.
General Methods of Analysis
All efficacy endpoints are secondary. No imputation will be applied to any missing efficacy data.

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The efficacy and surgical/rehabilitation periods will be defined in the statistical analysis plan 
(SAP) for the purpose of determining the study periods during which data will be used for select 
efficacy analyses. Data on bleeding and rFVIIIFc consumption will be based on the efficacy 
period; surgical evaluations will be based on the surgical/rehabilitation period.
Analysis of efficacy endpoints that are visit-based will include data from all study visits whether 
or not in the efficacy period, unless that visit is coincidental with a surgical/rehabilitation period 
for a major surgery, in which case it would be excluded.
16.2.3.
Analysis of Efficacy Endpoints
Annualized Bleeding Episodes and Annualized rFVIIIFc Consumption
Bleeding episodes during the efficacy period will be annualized on a per-subject basis and 
summarized by treatment regimen (episodic or prophylaxis regimen) and overall. This 
annualized bleeding rate (ABR) will be calculated as the total number of bleeding episodes 
experienced by a subject divided by the total number of days in their efficacy period for each 
treatment regimen or overall as appropriate, multiplied by 365.25. The per-subject ABR will also 
be summarized for type of bleed (spontaneous or traumatic), location of the bleed, and 
spontaneous joint bleeding episodes, and for other subgroups of interest. The consumption of 
rFVIIIFc will be annualized in a similar fashion and summarized overall as well as for subgroups 
of interest.
Other Efficacy Endpoints
The number of injections and dose per injection required to resolve bleeding will be summarized 
on both a per-bleeding-episode and a per-subject basis, where the per-subject basis will be 
determined as the average over all bleeding episodes for a given subject.
The response to treatment for bleeding will be summarized by the number and percentage of 
bleeding episodes with each response (excellent, good, moderate, or none).
These data will be summarized overall and for subgroups of interest.
Other Efficacy Assessments
The total dose administered to resolve a bleeding episode will be calculated and summarized in 
addition to, and in the same manner as, the specified endpoints of number of injections and dose 
per injection for resolution of bleeding.
The Investigator’s assessment of the subject’s overall response to his rFVIIIFc regimen will be 
summarized for each study visit and across all visits for the number and percentage of outcomes 
classified as excellent, effective, partially effective, and ineffective. Summaries will be provided 
overall.
Treatment with rFVIIIFc, bleeding episodes, blood loss, and transfusions administered for major 
and minor surgeries will be provided in data listings. These assessments will be made during the 

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various components of the surgical/rehabilitation period as appropriate (surgery, postoperative 
care, and rehabilitation).
16.2.4.
Additional/Exploratory Analysis of Efficacy Endpoints
Other efficacy analyses may be conducted for exploratory purposes, including summary of 
exploratory endpoints (health outcomes, Investigator/Surgeon's Assessment of Response).
16.3.
Pharmacokinetics
IR data will be listed and summarized by visit. For each subject, the observed IR estimated at 
each applicable visit will be averaged and summarized.
PK parameters, such as IR and t½, derived from assessments during ITI will be listed for each 
applicable subject. PK parameters (IR and t½) for subjects undergoing ITI will be determined by 
real-time analyses of the FVIII activity data measured by the one-stage clotting assay to facilitate 
assessment of ITI outcome.
16.4.
Pharmacodynamics
Not applicable.
16.5.
Safety
Unless specified otherwise in the SAP, safety data will be summarized overall. Subjects 
developing a confirmed positive inhibitor test after exposure to rFVIIIFc study drug (the 
Inhibitor Subgroup) will have their safety data included up to the time of the last negative 
inhibitor test; safety data collected after the time of the last negative inhibitor test will be 
summarized separately.
16.5.1.
Analysis Population
The Safety Analysis Set is defined as all subjects who receive at least 1 dose of rFVIIIFc study 
drug. Safety analyses will be based on the Safety Analysis Set, including the data collected on or 
after the time of the first injection of rFVIIIFc.
16.5.2.
Methods of Analysis
16.5.2.1.
Occurrence of Inhibitor Development
The proportion of subjects who develop an inhibitor during the study will be determined along 
with the exact (Clopper-Pearson) 2-sided, 95% confidence interval. Any subject who develops an 
inhibitor following the initial rFVIIIFc administration will be included in the numerator; 
however, only subjects with a valid inhibitor test following at least 10 EDs of rFVIIIFc study 
drug will be included in the denominator. One ED is defined as a 24-hour period in which a 
subject receives 1 or more doses of rFVIIIFc, with the time of the first injection of rFVIIIFc 
defined as the start of the ED.

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16.5.2.2.
Adverse Events
AEs will be coded using the Medical Dictionary for Regulatory Activities. The incidence of AEs 
will be summarized by system organ class and preferred term. Summaries will be for all AEs as 
well as by severity and relationship to treatment. Subject listings will be provided for all AEs, 
SAEs, AEs resulting in discontinuation of study treatment and/or from the study, and deaths.
Unless otherwise specified in the study SAP, AEs and SAEs occurring during treatment with the 
ITI regimen will be summarized and listed separately.
16.5.2.3.
Other Safety Parameters
Clinical laboratory values will be summarized for change from baseline, shifts, and potentially 
clinically significant abnormalities. Threshold levels for potentially clinically significant 
laboratory abnormalities will be provided in the SAP. Listings of abnormal laboratory test results 
will be provided.
Vital signs will be summarized by the number and percentage of subjects with abnormalities.
Abnormal values will be defined in the SAP. A listing of abnormal vital signs will be provided.
Duration of exposure and the total number of EDs to rFVIIIFc per subject will be summarized 
overall based on the Safety Analysis Set.
16.6.
Immune Tolerance Induction
For each subject undergoing ITI, the outcome (complete success, partial success, failure, and 
early withdrawal during the monitoring period will be listed and summarized. Additional 
summaries, including the percentage of subjects with relapse (as defined in Section 10.2.7.6), 
will be documented in the study SAP.
16.7.
Interim Analyses
An interim analysis of safety and efficacy data will be conducted when at least 50 subjects have 
completed at least 50 EDs and undergone inhibitor testing. Additional interim analyses may be 
conducted during the study, as needed. Analyses will be descriptive in nature. No formal 
comparisons are planned, and no hypotheses will be formally tested.
16.8.
Sample Size Considerations
Because the size of the hemophilia population is limited, the sample size is based on clinical 
rather than statistical considerations. Taking into account the CHMP Guideline [EMA 
(EMA/CHMP/BPWP/144533/2009) 2011] and in an effort to enroll a sufficient number of 
subjects to assess the efficacy and safety of rFVIIIFc in this population of primarily very young 
children, approximately 105 subjects will be dosed with rFVIIIFc to achieve at least 90 subjects 
with no less than 50 EDs by the completion of the study.

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17.
ETHICAL REQUIREMENTS
Bioverativ and the Investigator must comply with all instructions, regulations, and agreements in 
this protocol and applicable ICH and 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.
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 ethics committee approval of the protocol, informed consent form 
(ICF), and other required study documents prior to starting the study. Bioverativ will submit 
documents on behalf of the investigational sites in countries other than the United States.
If the Investigator makes any changes to the ICF, Bioverativ must approve the changes before 
the ICF is submitted to the ethics committee. 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 
ethics committee and Bioverativ.
It is the responsibility of the Principal Investigator(s) to ensure that all aspects of institutional 
review are conducted in accordance with current governmental regulations.
Bioverativ must receive a letter documenting ethics committee 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 ethics committee 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 ethics committee 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

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subject’s legally authorized representative, as applicable, in accordance with local practice and 
regulations. Consent must also be obtained from breastfeeding mothers of subjects.
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’s 
parents/legal guardians. The subject’s parents/legal guardians must be given sufficient time to 
consider whether to participate in the study.
Subjects’ parents/legal guardians will be informed that the subject’s race and ethnicity will be 
collected and will be used during analysis of study results. (See Section 17.4.)
A copy of the ICF, signed and dated by the subject’s parents/legal guardians, must be given to 
them. Confirmation of a subject’s legally authorized representative’s informed consent must also 
be documented in the subject’s medical record prior to any testing under this protocol, including 
screening tests and assessments.
Each consent form should contain an authorization allowing the Principal Investigator(s) and 
Bioverativ to use and disclose PHI (that is, subject-identifiable health information) in compliance 
with local law.
The signed consent form will be retained with the study records.
17.4.
Subject Data Protection
Prior to any testing under this protocol, including screening tests and assessments, candidates 
(including study subjects and their breastfeeding mothers, if applicable) must also provide all 
authorizations required by local law (e.g., PHI authorization in North America).
During the study, subjects’ race and ethnicity will be collected. These data may be used in the 
analysis of the safety and/or pharmacokinetic profile of the study treatment. In cross sectional 
analyses of different ethnic groups, differences in the occurrence of inhibitors have been 
observed [Astermark 2005; Carpenter 2012]. Differential responses to Factor VIII products may 
occur in different haplotypes of FVIII that also differ across racial and ethnic groups [Viel 2009].
The subject will not be identified by name in the eCRF or in any study reports, and these reports 
will be used for research purposes only. Bioverativ, its partner(s) and designee(s), ethics 
committees, 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 trials and will follow applicable 
local compensation laws.

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17.6.
Conflict of Interest
The Investigators should address any potential conflicts of interest (e.g., financial interest in 
Bioverativ) with the subject before the subject makes a decision to participate in the study.
17.7.
Registration of Study and Disclosure of Study Results
Bioverativ will register the study and poststudy 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, 
conducted by Bioverativ or designee. This initiation visit will include a detailed review of the 
protocol and study procedures.
18.2.
Quality Assurance
During and/or after completion of the study, quality assurance officers named by Bioverativ or 
the regulatory authorities may wish to perform on-site audits. The Investigator will be expected 
to cooperate with any audit 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.
The Clinical Monitor(s) will visit the Investigator(s) at regular intervals during the study and 
after the study has completed, as appropriate.
During these visits, eCRFs and supporting documentation related to the study will be reviewed 
and any discrepancies or omissions will be resolved.
Monitoring visits must be conducted according to the applicable ICH and GCP guidelines to 
ensure protocol adherence, quality of data, study treatment accountability, compliance with 
regulatory requirements, and continued adequacy of the investigational site and its facilities.
18.4.
Study Funding
Bioverativ is the Sponsor of the study and is funding the study. All financial details are provided 
in the separate contract(s) 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
19.1.1.
Contract Research Organization 
A contract research organization (CRO) will be responsible for administrative aspects of the 
study including, but not limited to, study initiation, monitoring, management of SAE reports, 
data management, and the coordination of an independent external DSMC. Before subjects are 
screened at each study site, the CRO will review study responsibilities with the Investigators and 
other study site staff, as appropriate.
19.1.2.
Interactive Voice and Web Response System
An IXRS will be used in this study. Before subjects are screened or enrolled, the appropriate 
training will be provided to the study staff by Bioverativ and the IXRS vendor. A user manual 
will also be provided. Specific details regarding IXRS are provided in the Study Reference 
Manual.
19.1.3.
Electronic Data Capture
Subject information will be captured and managed by study sites on eCRFs by a Web-based 
electronic data capture tool developed and supported by the CRO assisting with the conduct of 
the study and configured by Bioverativ. Data should be entered into the EDC within 5 business 
days, including batched records and records with source documents.
Subjects’ parents/caregivers in the study will have EPDs to record information regarding each 
dose of rFVIIIFc administered to the subject for any reason. EPD data must be entered within 
no more than 7 days (Section 10.2.4.1.4).
19.1.4.
Central Laboratories for Laboratory Assessments
Central laboratories have been selected by Bioverativ to analyze all the laboratory samples being 
collected in the study. Specifics regarding the requirements for laboratory specimen collection, 
handling, and analysis are provided in the Laboratory Manuals.
19.2.
Study Committees
19.2.1.
Independent Data Safety Monitoring Committee
An independent, external DSMC is responsible for evaluating and monitoring the safety and 
tolerability of the study drug on an ongoing basis during the study. The specifics regarding the 
DSMC organization and procedures will be outlined in the DSMC Charter.

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19.3.
Changes to Final Study Protocol
All protocol amendments must be submitted to the ethics committee and regulatory authorities if 
required by local law. Protocol modifications that affect subject safety, the scope of the 
investigation, or the scientific quality of the study must be approved by the ethics committee 
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 prior to 
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 (see 
Sections 17.2 and 17.3).
19.4.
Ethics Committee Notification of Study Completion or Termination
Where required, the regulatory authorities and ethics committees 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 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 of the participating Study 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
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, Magallón M, Querol F, et al. The orthopaedic status of severe haemophiliacs in Spain. 
Haemophilia. 2000;6(3):170-6.
Berntorp E, Boulyjenkov V, Brettler D, et al. Modern treatment of haemophilia. Bull World 
Health Organ. 1995;73(5):691-701.
Bolton-Maggs PH, Pasi KJ. Haemophilias A and B. Lancet. 2003;361(9371):1801-9.
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.
Colvin BT, Astermark J, Fischer K, et al. European principles of haemophilia care. Haemophilia. 
2008;14(2):361-74.
Dumont JA, Low SC, Peters RT, et al. Monomeric Fc fusions: impact on pharmacokinetic and 
biological activity of protein therapeutics. BioDrugs. 2006;20(3):151-60.
European Medicines Agency. Guideline on the clinical investigation of recombinant and human 
plasma-derived factor VIII products. EMA/CHMP/BPWP/144533/2009. July 21, 2011. 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2011/08/WC500
109692.pdf.
European Commission. Ethical considerations for clinical trials on medicinal products conducted 
with the paediatric population. 2008. p. 34.
Ghetie V, Ward ES. Multiple roles for the major histocompatibility complex class I- related 
receptor FcRn. Annu Rev Immunol. 2000;18:739-66. Epub 2000/06/03.
Hay CRM, DiMichele DM. The principal results of the International Immune Tolerance Study: a 
randomized dose comparison. Blood. 2012;119(6):1335-1344.
Junghans RP, Anderson CL. The protection receptor for IgG catabolism is the beta2-
microglobulin-containing neonatal intestinal transport receptor. Proc Natl Acad Sci U S A. 
1996;93(11):5512-6.
Manco-Johnson MJ, Abshire TC, Shapiro AD, et al. Prophylaxis versus episodic treatment to 
prevent joint disease in boys with severe hemophilia. N Engl J Med. 2007;357(6):535-44.

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Mannucci PM, Tuddenham EG. The hemophilias--from royal genes to gene therapy. N Engl J 
Med. 2001;344(23):1773-9.
MASAC Recommendation #179 Concerning Prophylaxis (Regular Administration of Clotting 
Factor Concentrate to Prevent Bleeding). November 2007 (Replaces #170). New York, NY: 
National Hemophilia Foundation. 
http://www.hemophilia.org/NHFWeb/Resource/StaticPages/menu0/menu5/menu57/masac179.pd
f. Accessed December 03, 2012.
MASAC Recommendation #190 Concerning Products Licensed for the Treatment of Hemophilia 
and Other Bleeding Disorders. March 2009 (Replaced by Recommendation #215, November 
2012). New York, NY: National Hemophilia Foundation. 
http://www.hemophilia.org/NHFWeb/Resource/StaticPages/menu0/menu5/menu57/masac190.pd
f.
Molho P, Rolland N, Lebrun T, et al. Epidemiological survey of the orthopaedic status of severe 
haemophilia A and B patients in France. The French Study Group. 
secretariat.haemophiles@cch.ap-hop-paris.fr. Haemophilia. 2000;6(1):23-32.
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2006;12(Suppl 6):15-22.
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2007;7(9):715-25. Epub 2007/08/19.
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induction in patients with haemophilia a and inhibitors. Haemophilia. 2015;21(5):559-67.
Viel KR, Ameri A, Abshire TC, et al. Inhibitors of factor VIII in black patients with hemophilia. 
N Engl J Med. 2009;360(16):1618-27.
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Organization Offset Publication No. 48; 1979. 
http://whqlibdoc.who.int/offset/WHO_OFFSET_48.pdf. Accessed November 30, 2012.

Protocol 997HA306
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Safety and Efficacy of rFVIIIFc in Previously Untreated Patients With Hemophilia A
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Bioverativ 
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99
21.
SIGNED AGREEMENT OF THE STUDY PROTOCOL
I have read the foregoing protocol, “An Open-Label, Multicenter Evaluation of the Safety and 
Efficacy of Recombinant Coagulation Factor VIII Fc Fusion Protein (rFVIIIFc; BIIB031) in the 
Prevention and Treatment of Bleeding in Previously Untreated Patients 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)

Protocol 997HA306
Version 6
Safety and Efficacy of rFVIIIFc in Previously Untreated Patients With Hemophilia A
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100
APPENDIX A. rFVIIIFc DOSING GUIDELINES FOR BLEEDING 
EPISODES
The following table describes the recommended target activities of rFVIIIFc for bleeding 
episodes.
DOSING GUIDELINES FOR rFVIIIFc THERAPY IN HEMOPHILIA A
   
    Factor VIII
    
Level Required
   Type of Hemorrhage
  
(%)
__________________________________________________________________________
Minor
Epistaxis
20-40
Hemarthroses, uncomplicated
20-40
Superficial muscular
20-40
Superficial soft tissue
20-40
Moderate
Epistaxis
30-60
Intramuscular with dissection
30-60
Soft tissue with dissection
30-60
Mucous membranes
30-60
Dental extractions
30-60
Hematuria
30-60
Hemarthroses, with limited motion
40-80
Major
Epistaxis 
80-100
Pharynx
80-100
Retropharynx
80-100
Retroperitoneum
80-100
Surgery
80-100
Central Nervous System
80-100

Protocol 997HA306
Version 6
Safety and Efficacy of rFVIIIFc in Previously Untreated Patients With Hemophilia A
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101
 
 
 
 
 
 
 
 
 
 

Protocol 997HA306
Version 6
Safety and Efficacy of rFVIIIFc in Previously Untreated Patients With Hemophilia A
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Therapeutics Inc.
102
 
 
 
 
 
 
 

Protocol 997HA306
Version 6
Safety and Efficacy of rFVIIIFc in Previously Untreated Patients With Hemophilia A
CONFIDENTIAL
The information contained herein may not be used, disclosed, or published without the written consent of Bioverativ 
Therapeutics Inc.
103
 
 
 
 
 
 
 
 
 
 
 
 

Protocol 997HA306
Version 6
Safety and Efficacy of rFVIIIFc in Previously Untreated Patients With Hemophilia A
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APPENDIX E. OBJECTIVES AND THEIR ASSOCIATED ENDPOINTS
AND ASSESSMENTS
Figure 3:
Primary Objective, Endpoints and Assessments

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Figure 4:
Secondary Objectives, Endpoints, and Assessments
Objectives
Endpoints
Assessments

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Safety and Efficacy of rFVIIIFc in Previously Untreated Patients With Hemophilia A
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Figure 5:
Exploratory Objectives, Endpoints, and Assessments