A Non-controlled, Open-Label, Multicenter, Study of Efficacy of rFVIIIFc for Immune Tolerance Induction (ITI) in Severe Hemophilia A Subjects With Inhibitors Undergoing the First ITI Treatment
Phase: PHASE4
Conditions: Hemophilia A With Inhibitors
Sponsor: Bioverativ, a Sanofi company

CONFIDENTIAL 
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Bioverativ. 
Page 1 
Bioverativ Therapeutics Inc. 
225 Second Avenue 
Waltham, MA 02451 
TRACKING NUMBER: 
997HA402 
PHASE OF DEVELOPMENT: 
4 
PROTOCOL TITLE: A Non-Controlled, Open-Label, Multicenter, Study of Efficacy of 
rFVIIIFc for Immune Tolerance Induction (ITI) in Severe Hemophilia A Subjects 
With Inhibitors Undergoing the First ITI Treatment 
EUDRA CT NO: 
2017-000373-36 
DATE: 
11 Jul  2019 
Version 3.0 
Supersedes Version 2.0 dated 09 February 2018 and Version 2.1 dated 02 March 2018. 
VV-CLIN-0542000 3.0
NCT03093480

Protocol 997HA402 
Version 3.0 
rFVIIIFc Immune Tolerance Induction Study 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Bioverativ Therapeutics Inc. 
Page 2 
SPONSOR SIGNATURE PAGE 
 
 
 
 
 
 
VV-CLIN-0542000 3.0

Protocol 997HA402 
Version 3.0 
rFVIIIFc Immune Tolerance Induction Study 
 
CONFIDENTIAL 
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Bioverativ Therapeutics Inc. 
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TABLE OF CONTENTS 
1. 
SPONSOR INFORMATION .....................................................................................11 
2. 
LIST OF ABBREVIATIONS.....................................................................................12 
3. 
SYNOPSIS .................................................................................................................14 
4. 
STUDY SCHEMATIC AND SCHEDULE OF ACTIVITIES ..................................19 
4.1. 
Study Schematic .........................................................................................................19 
4.2. 
Schedules of Activities ...............................................................................................20 
5. 
INTRODUCTION ......................................................................................................31 
5.1. 
Overview of Immune Tolerance Induction in the Clinical Management of 
Hemophilia A ..............................................................................................................31 
5.2. 
Profile of Previous Experience With rFVIIIFc for Immune Tolerance 
Induction .....................................................................................................................33 
5.2.1. 
Previous Nonclinical and Clinical Experience With rFVIIIFc for Immune 
Tolerance Induction ....................................................................................................33 
5.2.2. 
Nonclinical Experience ...............................................................................................33 
5.2.3. 
Clinical Experience .....................................................................................................34 
5.3. 
Study Rationale ...........................................................................................................34 
5.4. 
Rationale for Dosing Regimen ...................................................................................35 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................36 
6.1. 
Primary Objective and Endpoint ................................................................................36 
6.2. 
Secondary Objectives and Endpoints .........................................................................36 
6.3. 
Exploratory Objectives and Endpoints .......................................................................37 
7. 
STUDY DESIGN .......................................................................................................38 
7.1. 
Study Overview ..........................................................................................................38 
7.2. 
Overall Study Duration and Follow-Up .....................................................................38 
7.2.1. 
Screening ....................................................................................................................38 
7.2.2. 
Immune Tolerance Induction Period ..........................................................................39 
7.2.2.1. 
Use of Bypassing Agents ............................................................................................40 
7.2.2.2. 
ITI Outcome ................................................................................................................41 
7.2.3. 
Downtitration (Dose Adjustment) Between ITI Treatment and the Tapering 
Period ..........................................................................................................................44 
7.2.4. 
Tapering Period ..........................................................................................................44 
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7.2.5. 
Follow-Up ...................................................................................................................45 
7.2.6. 
End of Treatment/End of Study ..................................................................................45 
7.2.7. 
Final Safety Follow-Up ..............................................................................................46 
7.3. 
Unscheduled Visits .....................................................................................................46 
7.4. 
Study Stopping Rules .................................................................................................46 
7.5. 
End of Study ...............................................................................................................46 
8. 
SELECTION OF SUBJECTS ....................................................................................47 
8.1. 
Inclusion Criteria ........................................................................................................47 
8.2. 
Exclusion Criteria .......................................................................................................47 
9. 
ENROLLMENT AND REGISTRATION, STUDY PROCEDURES .......................49 
9.1. 
Screening, Enrollment ................................................................................................49 
9.2. 
Registration of Subjects ..............................................................................................49 
10. 
DISCONTINUATION OF STUDY TREATMENT AND WITHDRAWAL 
OF SUBJECTS FROM THE STUDY ........................................................................50 
11. 
STUDY TREATMENT ..............................................................................................51 
11.1. 
Dosing Regimen and Administration .........................................................................51 
11.1.1. 
Administration of rFVIIIFc ........................................................................................52 
11.1.2. 
Calculation and Recording of Dosing Based on Actual Potency and Dosing 
Based on Nominal Strength ........................................................................................52 
11.1.3. 
Prior and Concomitant Therapy ..................................................................................53 
11.1.4. 
Allowed Concomitant Therapy ...................................................................................53 
11.2. 
Compliance .................................................................................................................53 
11.3. 
Excluded Concomitant Therapies and Procedures .....................................................53 
12. 
STUDY TREATMENT MANAGEMENT ................................................................55 
12.1. 
rFVIIIFc Stability and Storage ...................................................................................55 
12.1.1. 
rFVIIIFc Preparation ..................................................................................................55 
12.1.2. 
rFVIIIFc Handling and Disposal ................................................................................55 
12.2. 
rFVIIIFc Accountability .............................................................................................56 
13. 
EFFICACY AND PHARMACOKINETIC ASSESSMENTS ...................................57 
13.1. 
Clinical Efficacy Assessments ....................................................................................57 
13.1.1. 
Assessment of Inhibitor Titers ....................................................................................57 
13.1.2. 
Assessment of Incremental Recovery .........................................................................57 
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13.1.2.1. 
FVIII Activity .............................................................................................................57 
13.1.2.2. 
Calculations ................................................................................................................58 
13.1.3. 
Assessment of rFVIIIFc Half-Life..............................................................................59 
13.1.3.1. 
Sampling for rFVIIIFc t½ ............................................................................................59 
13.1.3.2. 
Calculations ................................................................................................................60 
13.1.4. 
Assessment of Bleeding Episodes ..............................................................................60 
13.1.4.1. 
Definition of a Bleeding Episode ...............................................................................60 
13.1.4.2. 
Data to Be Captured ....................................................................................................61 
13.2. 
Medical History Assessments .....................................................................................61 
13.3. 
Demography ...............................................................................................................62 
13.4. 
Pharmacoeconomic Assessments ...............................................................................62 
13.5. 
Exploratory Laboratory Assessments .........................................................................62 
13.5.1. 
Assessment of Mechanisms Underlying Inhibitor Development ...............................62 
13.5.2. 
Anti-rFVIIIFc Antibody Assessment .........................................................................62 
13.5.3. 
Immune Cell Characterization ....................................................................................63 
13.5.4. 
Analysis of FVIII Mutation and Human Leukocyte Antigen Allotyping ...................63 
13.5.5. 
Future Scientific Research ..........................................................................................64 
14. 
SAFETY ASSESSMENTS ........................................................................................65 
14.1. 
Clinical Safety Assessments .......................................................................................65 
14.2. 
Laboratory Safety Assessments ..................................................................................65 
14.3. 
Vital Signs ..................................................................................................................66 
14.4. 
Physical Examination .................................................................................................66 
14.5. 
Sample Volumes .........................................................................................................66 
15. 
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES .................................................................................................68 
15.1. 
Definitions ..................................................................................................................68 
15.1.1. 
Adverse Event .............................................................................................................68 
15.1.2. 
Serious Adverse Event ................................................................................................69 
15.2. 
Safety Classifications ..................................................................................................69 
15.2.1. 
Investigator Assessment of Events .............................................................................69 
15.2.2. 
Relationship of Events to Study Treatment ................................................................70 
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rFVIIIFc Immune Tolerance Induction Study 
 
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15.2.3. 
Severity of Events .......................................................................................................70 
15.2.4. 
Expectedness of Events ..............................................................................................70 
15.3. 
Monitoring and Recording Events ..............................................................................71 
15.3.1. 
Adverse Events ...........................................................................................................71 
15.3.2. 
Serious Adverse Events ..............................................................................................71 
15.3.3. 
Immediate Reporting of Serious Adverse Events .......................................................72 
15.3.3.1. 
Deaths .........................................................................................................................72 
15.3.4. 
Suspected Unexpected Serious Adverse Reactions ....................................................72 
15.4. 
Procedures for Handling Special Situations ...............................................................73 
15.4.1. 
Contraception ..............................................................................................................73 
15.4.2. 
Reporting Pregnancy ..................................................................................................73 
15.4.3. 
Overdose .....................................................................................................................73 
15.4.4. 
Medical Emergency ....................................................................................................74 
15.5. 
Safety Responsibilities ................................................................................................74 
15.5.1. 
Investigator Responsibilities .......................................................................................74 
15.5.2. 
Sponsor .......................................................................................................................74 
16. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ...........75 
16.1. 
Sample Size Considerations .......................................................................................75 
16.2. 
Efficacy .......................................................................................................................75 
16.2.1. 
Analysis Populations ..................................................................................................75 
16.2.2. 
Methods of Analysis ...................................................................................................75 
16.2.2.1. 
Primary Endpoint Analysis .........................................................................................75 
16.2.2.2. 
Secondary Endpoints Analysis ...................................................................................76 
16.2.2.3. 
Pharmacokinetics ........................................................................................................77 
16.2.2.4. 
Exposure and Duration of Treatment .........................................................................77 
16.2.2.5. 
Demography and Baseline Disease Characteristics ....................................................77 
16.3. 
Interim Analyses .........................................................................................................77 
16.4. 
Safety ..........................................................................................................................77 
16.4.1. 
Analysis Populations ..................................................................................................77 
16.4.2. 
Methods of Analysis ...................................................................................................77 
16.4.2.1. 
Adverse Events ...........................................................................................................77 
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16.4.2.2. 
Clinical Laboratory Results ........................................................................................77 
16.4.2.3. 
Vital Signs ..................................................................................................................77 
16.5. 
Subgroup Analysis ......................................................................................................78 
17. 
ETHICAL REQUIREMENTS ...................................................................................79 
17.1. 
Declaration of Helsinki ...............................................................................................79 
17.2. 
Ethics Committee ........................................................................................................79 
17.3. 
Subject Information and Consent ...............................................................................79 
17.4. 
Subject Data Protection ..............................................................................................80 
17.5. 
Compensation for Injury .............................................................................................80 
17.6. 
Conflict of Interest ......................................................................................................80 
17.7. 
Registration of Study and Disclosure of Study Results ..............................................81 
18. 
ADMINISTRATIVE PROCEDURES .......................................................................82 
18.1. 
Study Site Initiation ....................................................................................................82 
18.2. 
Quality Assurance .......................................................................................................82 
18.3. 
Monitoring of the Study..............................................................................................82 
18.4. 
Study Funding .............................................................................................................82 
18.5. 
Publications .................................................................................................................82 
19. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION ........................83 
19.1. 
External Contract Organizations .................................................................................83 
19.1.1. 
Contract Research Organization .................................................................................83 
19.1.2. 
Interactive Web Response System ..............................................................................83 
19.1.3. 
Electronic or Remote Data Capture ............................................................................83 
19.1.4. 
Central Laboratory for Assessments ...........................................................................83 
19.2. 
Study Committees .......................................................................................................83 
19.3. 
Changes to Final Study Protocol ................................................................................83 
19.4. 
Ethics Committee Notification of Study Completion or Termination ........................84 
19.5. 
Retention of Study Data ..............................................................................................84 
19.6. 
Study Report Signatory...............................................................................................84 
20. 
REFERENCES ...........................................................................................................85 
21. 
INVESTIGATORS SIGNED AGREEMENT OF STUDY PROTOCOL .................90 
APPENDIX A. PROTOCOL AMENDMENT HISTORY .........................................................91 
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Protocol 997HA402 
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Protocol Version 1.1 (specific for Canada) ....................................................................................91 
Protocol Version 2.0 (Global, except Canada) ..............................................................................92 
Protocol Version 2.1 (specific for Canada) ....................................................................................92 
The amendment summary describing every change is available upon request. .......................................92 
APPENDIX B. COUNTRY SPECIFIC REQUIREMENTS ......................................................93 
Country-specific requirements for Canada ....................................................................................93 
 
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Protocol 997HA402 
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LIST OF TABLES  
Table 1: 
Schedule of Activities for Screening Visit and ITI Period .........................................20 
Table 2: 
Schedule of Activities for the Tapering and Follow-Up Periods After 
Successful Tolerization ...............................................................................................26 
Table 3: 
Sampling Schedule for Pharmacokinetic Evaluation (Half-Life) ...............................30 
Table 4 
Example of a Dose Adjustment Schedule: Negative Inhibitor, Not All 
Success Criteria Met ...................................................................................................51 
Table 5 
Example of a Dose Tapering Schedule: All 3 Success Criteria Met ..........................52 
Table 6 
Examples of Recommended Blood Draw Volume Limits .........................................67 
 
LIST OF FIGURES  
Figure 1: 
997HA402 Study Design ............................................................................................19 
Figure 2 
Flow Diagram for Assessment of ITI Outcome .........................................................43 
 
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
 
DOCUMENT HISTORY 
 
Document 
Country/countries 
impacted by amendment 
Date 
Protocol Version 3    
All, including Canada 
11 July 2019 
Protocol Version 2.1   
(from Version 1.1) 
Canada 
02 March 2018 
Protocol Version 1.1   
(from Version 1) 
Canada 
06 July 2017 
Protocol Version 2 
All 
09 February 2018 
Protocol Version 1 
All 
19 January 2017 
 
Present amendment to the protocol (11-July-2019) 
This is a global amendment to the protocol V2.0 and V2.1,  and includes specific requirements 
for Canada in Appendix B. 
OVERALL RATIONALE FOR THE AMENDMENT 
The primary reason for this amendment to Protocol 997HA402 is to reduce the number of 
subjects to be enrolled, to clarify the timing for subjects moving from interim ITI visits to ITI 
outcome assessment visits, and to clarify sample collection schedules for ADA. Additional 
updates have been made for Canada and these country-specific changes are outlined in 
Appendix B. 
PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Section # and Name 
Description of Change 
Brief Rationale 
Synopsis, Section 7.1, and 
Section 16.1. 
 
Following texts or similar texts have been added in the 
sections:  
This study will enroll up to 17 subjects, Or 
Approximately, 17 subjects will be treated 
The primary reason for this 
amendment  to Protocol 997HA402 
is to reduce the number of subjects 
to be enrolled, to clarify the timing 
for subjects moving from interim ITI 
visits to ITI outcome assessment 
visits, and to clarify sample 
collection schedules for ADA, and to 
incorporate requests by Health 
Canada. 
Section 4.2, Section 7.2.2, 
Section 7.2.2.2, and Section 
13.1.2.1 
Clarification for the timing for subjects moving from 
interim ITI visits to ITI outcome assessment visits was 
added to the sections and Table 1, Table 1 footnote 13, 
Table 2 footnote 11, and Figure 2 were updated.  
Section 4.2 and Section 
13.5.2 
ADA sample collection has been clarified in Table 1, 
footnote 10. 
Section 4.2, Section 8.1, 
Section 13.5.4, Section 14.2, 
Section 15.4.1, Section 
15.5.1, and Appendix B 
Specific changes for Canada from Protocol 1.1 and 2.1 
 
Two new appendix sections have also been created to display history of protocol amendments (Appendix A) and country specific 
requirements (Appendix B). 
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Protocol 997HA402 
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rFVIIIFc Immune Tolerance Induction Study 
 
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1. 
SPONSOR INFORMATION  
This study is sponsored by Bioverativ Therapeutics Inc. (Sponsor). Refer to the Study Reference 
Manual that contains all study contacts for complete contact information.  
 
Bioverativ Therapeutics Inc. 
225 Second Avenue 
Waltham, MA 02451 
USA 
 
Bioverativ Japan Ltd. 
Nihonbashi 1-chome Mitsui Building 14F 
4-1 Nihonbashi 1-chome 
Chuo-ku, Tokyo 
103-0027 Japan 
 
For urgent medical issues in which the study’s Medical Director should be contacted, please 
refer to the Study Reference Manual Official Study Contact List for complete contact 
information. 
Sponsor may transfer any or all of its study-related responsibilities to contract research 
organization (CRO) and other third parties; however, Sponsor retains overall accountability for 
these activities. 
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Protocol 997HA402 
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rFVIIIFc Immune Tolerance Induction Study 
 
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2. 
LIST OF ABBREVIATIONS  
ADA 
anti-drug antibody 
AE 
adverse event 
aPCC 
activated prothrombin complex concentrate 
aPTT 
activated partial thromboplastin time 
BU 
Bethesda Unit 
CD4 
cluster of differentiation 4 
CHO 
Chinese hamster ovary 
CRO 
contract research organization 
DHA 
Directions for Handling and Administration 
ED 
exposure day 
EDC 
electronic data capture  
EHL 
extended half-life 
EOT 
end of treatment 
EPD 
electronic patient diary 
FEIBA 
factor eight inhibiting bypassing activity 
FVIII 
coagulation factor VIII 
GCP 
Good Clinical Practice 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HLA 
human leukocyte antigen 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IITR 
International ITI Registry 
IQR 
interquartile range 
IR 
incremental recovery 
ITI 
immune tolerance induction 
ITIFAS 
ITI full analysis set 
IU 
international units 
IV 
Intravenous 
IXRS 
Interactive Web Response System 
NAITR 
North American ITI Registry 
NGNA 
N-glycolylneuraminic acid 
pdFVIII 
plasma-derived FVIII 
PK 
pharmacokinetics 
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 
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Protocol 997HA402 
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SUSAR 
suspected unexpected serious adverse reaction 
tt½  
half-life 
TPFAS 
Tapering Period full analysis set 
ULN 
upper limit of normal 
USA 
United States of America 
VWF 
von Willebrand factor 
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3. 
SYNOPSIS  
Tracking Number: 
997HA402 
Protocol Title: 
A Non-Controlled, Open-Label, Multicenter, Study of 
Efficacy of rFVIIIFc for Immune Tolerance Induction 
(ITI) in Severe Hemophilia A Subjects with Inhibitors 
Undergoing the First ITI Treatment 
Version Number: 
2.0 
Name of Study Treatment: 
Antihemophilic factor VIII (recombinant) Fc fusion protein; 
rFVIIIFc; Eloctate®; Elocta® 
Study Indication: 
Hemophilia A, ITI 
Phase of Development: 
4 
Rationale for the Study: 
Hemophilia A (coagulation factor VIII [FVIII] deficiency) 
is a rare X-linked bleeding disorder and the most common 
type of hemophilia. The most serious treatment 
complication for patients with hemophilia A is the 
development of inhibitory immunoglobulin antibodies to 
FVIII. Inhibitors result in rapid clearance of infused FVIII 
and marked reduction, or absence, of efficacy of FVIII 
treatment. FVIII-bypassing agents such as activated 
prothrombin complex concentrate (aPCC [FEIBA]) or 
recombinant activated factor VII (rFVIIa [NovoSeven]) are 
used to treat acute bleeding in patients with high-titer 
inhibitors, but inhibitor eradication remains the goal of 
long-term management. 
Immune tolerance induction (ITI) therapy using frequent 
administration of high doses of FVIII is the only proven 
strategy shown to achieve antigen-specific tolerance 
(Kempton et al., 2014; Valentino et al., 2015). ITI usually 
attempts to eliminate high-responding FVIII inhibitors 
(≥5 Bethesda Unit [BU] titer). ITI regimens employ 
different doses and dosing frequencies of FVIII, and they 
may or may not involve adjunctive immunomodulatory 
therapy (Franchini et al., 2011; Valentino et al., 2015). 
Currently, a range of FVIII products and dosing regimens 
are used for ITI because there is no clear consensus on an 
optimal regimen (Franchini et al., 2011). 
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In the International ITI Study, a prospective randomized 
study comparing a high-dose (200 international units 
[IU]/kg/day) and a low-dose (50 IU/kg 3 times per week) 
FVIII regimen, subjects in the high-dose arm achieved a 
negative titer (median 4.6 months [interquartile range (IQR) 
2.8 to 13.8] vs. 9.2 months [IQR 4.9 to 17.0]; p = 0.017) and 
a normal recovery (median 6.9 months [IQR 3.5 to 12.0] vs. 
13.6 months [IQR 8.7 to 19.0]; p = 0.001) significantly 
more rapidly than subjects in the low-dose arm. High-dose 
subjects also experienced significantly fewer bleeding 
episodes than low-dose subjects, and for this reason, the 
data safety monitoring board recommended study 
termination (Hay & DiMichele, 2012). 
These findings and limited experience in patients with 
hemophilia who have inhibitors have led to an interest in 
investigating the use of the Extended Half-Life (EHL) 
recombinant coagulation factor VIII Fc fusion protein 
(rFVIIIFc) in ITI. rFVIIIFc was approved in the United 
States of America (USA), Canada, and Japan in 2014 with 
the name of Eloctate and in Europe in 2015 with the name 
of Elocta. 
Study Objectives and 
Endpoints: 
Objectives 
The primary objective of the study is to describe the time to 
tolerization (ITI success, i.e., inhibitor titer <0.6 BU/mL, 
rFVIIIFc incremental recovery [IR] ≥66% of the expected 
IR, and t½ ≥7 hours) with rFVIIIFc in subjects within a 
maximum of 12 months (48 weeks) of ITI treatment.  
The secondary objectives are as follows: 
 To describe the outcome of ITI treatment 
 To describe the relapse rate over the 48-week 
(12-month) period following successful ITI performed 
with rFVIIIFc 
 To describe the intercurrent bleeding during the ITI 
Period and during the 48-week (12-month) period after 
successful ITI performed with rFVIIIFc 
 To describe the safety and tolerability of rFVIIIFc when 
used for ITI  
 To evaluate the impact of ITI treatment with rFVIIIFc on 
health economics and adherence 
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The exploratory objectives are as follows:  
 
 
 
 
 
 
Endpoints 
The primary endpoint of this study is time to tolerization 
with a maximum of 12 months (48 weeks) of ITI treatment 
offered in the study (tolerization defined as inhibitor titer 
<0.6 BU/mL, rFVIIIFc incremental recovery [IR] of ≥66% 
of expected, and half-life [t½] of ≥7 hours). 
The secondary endpoints are as follows: 
 ITI success 
 Confirmed negative titers consisting of 2 
consecutive negative inhibitor assessments within 2 
weeks (±3 days) based on local laboratory results 
<0.6 BU/mL by the Nijmegen-modified Bethesda 
assay; determination of negative titer based on the 
Bethesda assay is acceptable at sites that have not 
yet adopted the Nijmegen-modified Bethesda assay. 
 IR ≥1.32 IU/dL per IU/kg in 2 consecutive 
assessments representing ≥66% of the expected IR 
2 IU/dL per IU/kg.(SmPC; USPI) 
 t½ ≥7 hours. 
 Occurrence of relapse (defined as confirmed positive 
inhibitor titer ≥0.6 BU/mL), abnormal recovery after 
tolerance is achieved, and t½ <7 hours) during the 
Tapering or Follow-Up Periods 
 Number of bleeding episodes during the ITI Period and 
during the 48-week (12-month) period after successful 
ITI performed with rFVIIIFc 
 Adverse events and serious adverse events 
 Number of days away from work or school 
 Number of hospitalization days 
 Adherence (defined as percentage of administered doses 
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versus planned doses) 
 Consumption of rFVIIIFc (measured in total rFVIIIFc 
use) 
The exploratory endpoints are as follows: 
 
  
 
 
  
 
 
The exploratory endpoint
 
 will be reported outside the clinical 
study report. 
Study Design: 
An open-label, single-arm, interventional, multicenter study 
designed to explore the use of rFVIIIFc for ITI in subjects 
with severe hemophilia A, who are undergoing ITI 
treatment for the first time.  
The study consists of 1) a 4-week (1-month) Screening 
Period; 2) a maximum of a 48-week (12-month) ITI Period; 
3) a minimum of a 16-week (4-month) Tapering Period after 
all criteria for tolerization have been met; and 4) a 32-week 
(8-month) Follow-Up Period. Only subjects who achieve 
ITI success will enter the Tapering and Follow-Up Periods. 
During the Tapering and Follow-Up Periods, the subject’s 
dose will be adjusted to achieve the prophylactic dose. 
Study Location and Number 
of Sites: 
Approximately 30 sites in the USA, Europe, Japan, and 
Canada 
Number of Planned Subjects: 
Up to 17 subjects 
Study Population: 
This study will be conducted in male subjects of any age 
with severe hemophilia A and high-titer inhibitors 
(historical peak ≥5 BU/mL), who have been previously 
treated with any plasma-derived FVIII or recombinant 
conventional or EHL FVIII and are undergoing ITI 
treatment for the first time.  
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Detailed criteria are described in Section 8. 
Treatment Groups: 
This is a single-arm study that will enroll up to 17 subjects 
Duration of Treatment and 
Follow-Up: 
Study duration for each subject will vary based on time to 
ITI success. The maximum individual subject study duration 
is expected to be approximately 2 years.  
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4. 
STUDY SCHEMATIC AND SCHEDULE OF ACTIVITIES  
4.1. 
Study Schematic  
Figure 1: 
997HA402 Study Design  
 
Abbreviations: ITI=immune tolerance induction; Max=maximum. 
Only subjects who achieve ITI success within the 48-week (12-month) ITI Period will continue 
into the Tapering and Follow-Up Periods. During the Tapering and Follow-Up Periods, the 
subject’s dose will be adjusted to achieve the prophylactic dose. However, if FVIII peak activity 
levels rise above 200 IU/dL after the inhibitors are negative but before all the ITI success criteria 
are met, the dose may be adjusted according to Investigator judgment to maintain the FVIII peak 
activity levels between 100 and 200 IU/dL. This dose reduction will not be considered part of the 
Tapering Period, and the subject will maintain the schedule of assessments per the ITI Period. 
See Section 11.1 for dosing details. 
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4.2. 
Schedules of Activities  
Table 1: 
Schedule of Activities for Screening Visit and ITI Period  
Activities 
Screening 
Visit 
ITI Period 
EOT for Partial Success or Failure1 
Baseline 
Visit 
(within 4 
weeks of 
Screening) 
Week 2 
Visit 
Interim ITI Visits 
ITI Outcome 
Assessment Visit 
EOT Visit 
Final Safety 
Follow-Up 
Start of 
ITI 
treatment 
2 weeks 
(±3 days) 
from start of 
ITI 
treatment 
Every 4th week 
(±1 week) 
Starting at ITI 
Week 4 until first 
negative titer (<0.6 
BU/mL) is achieved 
OR 48 weeks of ITI 
treatment2 
Every 2nd week 
(±3 days) 
Starting at time of 
first negative 
inhibitor titer until 
ITI success OR 
48 weeks of ITI 
treatment 
 
7 to 14 days 
after EOT 
Visit 
Informed Consent or 
Assent Form 
X 
 
 
 
 
 
 
Assessment of Subject 
Eligibility 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical, Surgical, 
Hemophilia, Inhibitor, 
Bleeding Episodes, and 
ITI History 
X 
 
 
 
 
 
 
Physical Examination 
X 
X 
X 
X 
X 
X 
 
Height (cm) 
X 
 
 
 
 
X 
 
Weight (kg) 
X 
X 
X 
X 
X 
X 
 
Vital Signs3 
X 
X 
X 
X 
X 
X 
 
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Activities 
Screening 
Visit 
ITI Period 
EOT for Partial Success or Failure1 
Baseline 
Visit 
(within 4 
weeks of 
Screening) 
Week 2 
Visit 
Interim ITI Visits 
ITI Outcome 
Assessment Visit 
EOT Visit 
Final Safety 
Follow-Up 
Start of 
ITI 
treatment 
2 weeks 
(±3 days) 
from start of 
ITI 
treatment 
Every 4th week 
(±1 week) 
Starting at ITI 
Week 4 until first 
negative titer (<0.6 
BU/mL) is achieved 
OR 48 weeks of ITI 
treatment2 
Every 2nd week 
(±3 days) 
Starting at time of 
first negative 
inhibitor titer until 
ITI success OR 
48 weeks of ITI 
treatment 
 
7 to 14 days 
after EOT 
Visit 
Hematology (Local 
Laboratory)4 
X 
X 
 
X 
X 
X 
 
Blood Chemistry  
(Local Laboratory)4  
X 
X 
 
X 
X 
X 
 
Urinalysis (Local 
Laboratory)4,5 
X 
X 
 
X 
X 
X 
 
Viral Analysis (HIV, 
HCV, and HBV)  
(Central Laboratory)6  
X 
 
 
 
 
 
 
Blood Sample for 
Analysis of FVIII 
Mutation and HLA 
Allotyping (Central 
Laboratory) (Optional)7 
 
X 
 
 
 
 
 
rFVIIIFc Dosing8 
 
X 
X 
X 
X 
X 
 
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Activities 
Screening 
Visit 
ITI Period 
EOT for Partial Success or Failure1 
Baseline 
Visit 
(within 4 
weeks of 
Screening) 
Week 2 
Visit 
Interim ITI Visits 
ITI Outcome 
Assessment Visit 
EOT Visit 
Final Safety 
Follow-Up 
Start of 
ITI 
treatment 
2 weeks 
(±3 days) 
from start of 
ITI 
treatment 
Every 4th week 
(±1 week) 
Starting at ITI 
Week 4 until first 
negative titer (<0.6 
BU/mL) is achieved 
OR 48 weeks of ITI 
treatment2 
Every 2nd week 
(±3 days) 
Starting at time of 
first negative 
inhibitor titer until 
ITI success OR 
48 weeks of ITI 
treatment 
 
7 to 14 days 
after EOT 
Visit 
Nijmegen-Modified 
Bethesda Inhibitor Assay 
(Both Local and Central 
Laboratories)9  
X 
X 
X 
 
X 
X 
 
Anti-rFVIIIFc Antibody 
(ADA) (Central 
Laboratories)10  
X 
X 
 
X 
X 
X 
 
Blood Sample for Immune 
Cell Characterization 
(Central Laboratory)11 
 
X 
 
X 
 
X 
 
FVIII Activity Level  
(Both Local and Central 
Laboratories)12  
 
 
X 
X 
X 
X 
 
FVIII Activity for IR 
(Both Local and Central 
Laboratories)13  
 
 
 
 
X 
 
 
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Activities 
Screening 
Visit 
ITI Period 
EOT for Partial Success or Failure1 
Baseline 
Visit 
(within 4 
weeks of 
Screening) 
Week 2 
Visit 
Interim ITI Visits 
ITI Outcome 
Assessment Visit 
EOT Visit 
Final Safety 
Follow-Up 
Start of 
ITI 
treatment 
2 weeks 
(±3 days) 
from start of 
ITI 
treatment 
Every 4th week 
(±1 week) 
Starting at ITI 
Week 4 until first 
negative titer (<0.6 
BU/mL) is achieved 
OR 48 weeks of ITI 
treatment2 
Every 2nd week 
(±3 days) 
Starting at time of 
first negative 
inhibitor titer until 
ITI success OR 
48 weeks of ITI 
treatment 
 
7 to 14 days 
after EOT 
Visit 
FVIII Activity for t½ 
Evaluation (Both Local 
and Central Laboratory)14 
 
 
 
 
X 
X 
 
EPD Review, Including 
Review of Bleeding 
Episodes and rFVIIIFc 
Dosing Accountability15  
 
X 
X 
X 
X 
X 
 
Nonserious Adverse 
Events 
 
X 
X 
X 
X 
X 
X 
Serious Adverse Events16 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Therapy/Procedures 
Recording 
X 
X 
X 
X 
X 
X 
X 
 
Abbreviations: ADA=anti-drug antibody; BU=Bethesda Unit; EOT=end of treatment; EPD=electronic patient diary; FVIII=coagulation factor VIII; 
HBV=hepatitis B virus; HCV=hepatitis C virus; HIV=human immunodeficiency virus; HLA=human leukocyte antigen; ICF=informed consent form; 
IR=incremental recovery; ITI=immune tolerance induction; rFVIIIFc=recombinant coagulation factor VIII Fc fusion protein; t½=half-life. 
NOTE: inhibitor titer, FVIII activity level, t½, and IR are all assessed at the local laboratory, with confirmation by the central laboratory. The Investigators will 
use local laboratory results for decision-making purposes. Hematology, blood chemistry, and urinalysis are assessed only at the local laboratory.  
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1 
Subject will be allowed to get the confirmatory test, even if it is after the 48-week (12-month) period, as long as the first test occurred during the 48-week 
(12-month) period. If the second test confirms the results of the first test (<0.6 BU/mL), the date of ITI outcome will be the date of the first value, which 
occurred during the 48-week (12-month) period. Fluctuations in inhibitor levels is common and variability in inhibitor titer is expected. Subjects will be 
treated on a case-by-case basis. 
2 
If, after the initial 3 months (12 weeks), there is no downward trend (at least 20% in the inhibitor titer) over a 6-month (24-week) period that is assessed at 
the Week 36 interim ITI Visit, the subject will be considered a treatment failure and must complete the EOT Visit as soon as possible. The second 
(confirmatory) inhibitor test will occur 2 weeks after the first negative inhibitor test. 
3 
Vital signs include blood pressure, pulse rate, respiratory rate, and body temperature. In the event of in-clinic rFVIIIFc injections, assessments will be taken 
prior to and 20 (±5) minutes after the end of the rFVIIIFc injection (if dosing occurs at the visit). 
4 
Blood samples for determination of hematology and blood chemistry variables and urine dipstick will be collected at Screening Visit, Baseline Visit (before 
the first study treatment administration), and then every 12 weeks (3 months) from the start of the ITI Period through the time of ITI complete success. If the 
subject completes the ITI Period in a duration shorter than 12 weeks (3 months), these assessments must be completed at the end of the ITI Period. 
5 
Dipstick urinalysis, including a protein reading; if the protein reading is positive (≥1+), a full laboratory urinalysis will be required. 
6 
Sample will be collected and tested if there are no HIV testing results available in the medical history 26 weeks (6.5 months) prior to Screening. HCV and 
HBV will only be tested at Screening if there is any indication in the medical record that the subject has prior exposure to plasma-derived coagulation 
factors. For subjects without prior exposure, the sample will be collected and stored at the central laboratory. If the subject is diagnosed with HBV or HCV 
during the study, this sample will be analyzed by the central laboratory to determine seropositivity at Screening. 
7 
This assessment is optional, and requires a separate ICF. For subjects whose FVIII mutation and human leukocyte antigen (HLA) allotype is not documented 
in medical records, samples for analysis of FVIII mutation and HLA allotyping will be collected at the Baseline Visit or at any subsequent visit if blood 
volume is limited at the Baseline Visit for analysis at the central laboratory.  
For Canada specific requirements: see Appendix B. 
8 
Clinic dosing is applicable only if warranted.  
9 
Subjects will be advised to delay administration of their daily dose of rFVIIIFc until after the sample for inhibitor testing is taken. For sites that have not yet 
adopted the Nijmegen-Modified Bethesda Assay, use of the Bethesda Assay is acceptable. 
10 A whole blood sample will be collected at Baseline OR Screening, every fourth week during interim ITI Visits, during assessment of ITI outcome visits, and 
at EOT. A sample for Anti-rFVIIIFc Antibody (ADA) should be collected at Baseline or Screening, and each consecutive visit, except the Week 2 and 
Safety Follow-Up Visits when allowed by the total volume of plasma that can be collected in one day. 
11 A whole blood sample will be collected at ITI Day 1 (Baseline Visit, predose) and at Week 8 (Month 2), as allowable based on subject weight and 
institutional practice regarding blood draw restrictions for pediatric subjects. 
12 A sample for FVIII activity will be collected at visits where samples for IR or t½ assessments are not collected. 
13 IR assessment will only be performed after a negative inhibitor has been confirmed at 2 consecutive visits. The sample for IR is drawn at the visit for the 
confirmatory negative inhibitor titer. However, the interpretation of the IR result will be performed after the negative inhibitor titer is confirmed. The 
predose sample for IR calculations is to be taken when the subject is in a nonbleeding state and after at least a 24-hour washout. See Table 3 for details. 
Subjects will be advised to delay administration of their daily dose of rFVIIIFc until after the sample for IR testing is taken 
14 Subjects will be advised to delay administration of their daily dose of rFVIIIFc until after the sample for t½ is taken. Half-life determination will only be 
performed after IR ≥1.32 IU/dL per IU/kg has been confirmed at 2 consecutive visits or as part of the EOT Visit. t½ determinations are to be performed 
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when the subject is in a nonbleeding state and after at least a 24-hour washout. t½ determination at EOT Visit does not need to be performed if the full 4-
sample t½ assessment was performed within 2 weeks prior to the EOT Visit or if the Investigator determines the subject is an ITI Treatment Failure. 
15 It is recommended that subjects/caregivers enter dosing information immediately after an injection or within a maximum of 7 days. 
16 Serious adverse events are to be monitored and recorded from the time of signing of the ICF. 
 
 
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Table 2: 
Schedule of Activities for the Tapering and Follow-Up Periods After Successful Tolerization  
Activities 
Tapering Period1 
Follow-Up Period1 
EOT2 
Tapering Initiation Visit/Telephone 
Call,3 Week 2, 4, 8, 12, and 16 Visits 
Week 28 and 40 Visits4 
EOT Visit 
Final Safety 
Follow-Up 
Starting at ITI success and 
continuing for a minimum of 16 
weeks 
with visits after 2 weeks (±3 days), 
4 weeks (±1 week), and then every 
4th week (±1 week) 
Week 28 and 40 visits 
(±2 weeks)1 
following ITI success 
Week 48 visit (±2 
weeks) following ITI 
success 
OR 
upon relapse 
7 to 14 days after 
EOT Visit 
Physical Examination 
X 
X 
X 
 
Height (cm) 
 
 
X 
 
Weight (kg) 
X 
X 
X 
 
Vital Signs5 
X 
X 
X 
 
Hematology (Local 
Laboratory) 6, 
X 
 
X 
 
Blood Chemistry (Local 
Laboratory)6 
X 
 
X 
 
Urinalysis (Local 
Laboratory)6,7 
X 
 
X 
 
Nijmegen-Modified Bethesda 
Inhibitor Assay (Both Local 
and Central Laboratories)8 
X 
X 
X 
 
Anti-rFVIIIFc Antibody 
(ADA) (Central Laboratory) 
X 
X 
X 
 
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Activities 
Tapering Period1 
Follow-Up Period1 
EOT2 
Tapering Initiation Visit/Telephone 
Call,3 Week 2, 4, 8, 12, and 16 Visits 
Week 28 and 40 Visits4 
EOT Visit 
Final Safety 
Follow-Up 
Starting at ITI success and 
continuing for a minimum of 16 
weeks 
with visits after 2 weeks (±3 days), 
4 weeks (±1 week), and then every 
4th week (±1 week) 
Week 28 and 40 visits 
(±2 weeks)1 
following ITI success 
Week 48 visit (±2 
weeks) following ITI 
success 
OR 
upon relapse 
7 to 14 days after 
EOT Visit 
Blood Sample for Immune 
Cell Characterization 
(Required) (Central 
Laboratory) 9 
X 
 
X 
 
rFVIIIFc Dosing10 
X  
X 
X 
 
FVIII Activity for IR (Both 
Local and Central 
Laboratories)11 
X 
X 
 
 
FVIII Activity for t½ 
Evaluation (Both Local and 
Central Laboratories)12 
 
 
X 
 
FVIII Activity Level (Both 
Local and Central 
Laboratories)13 
 
X 
X 
 
EPD Review, Including 
Review of Bleeding Episodes 
and rFVIIIFc Dosing 
Accountability14 
X 
X 
X 
 
Nonserious Adverse Events 
X 
X 
X 
X 
Serious Adverse Events 
X 
X 
X 
X 
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Activities 
Tapering Period1 
Follow-Up Period1 
EOT2 
Tapering Initiation Visit/Telephone 
Call,3 Week 2, 4, 8, 12, and 16 Visits 
Week 28 and 40 Visits4 
EOT Visit 
Final Safety 
Follow-Up 
Starting at ITI success and 
continuing for a minimum of 16 
weeks 
with visits after 2 weeks (±3 days), 
4 weeks (±1 week), and then every 
4th week (±1 week) 
Week 28 and 40 visits 
(±2 weeks)1 
following ITI success 
Week 48 visit (±2 
weeks) following ITI 
success 
OR 
upon relapse 
7 to 14 days after 
EOT Visit 
Concomitant Therapy/ 
Procedures Recording 
X 
X 
X 
X 
Abbreviations: EOT=End of Treatment; EPD=electronic patient diary; ET=early termination; FVIII=coagulation factor VIII; IR=incremental recovery; 
ITI=immune tolerance induction; PK=pharmacokinetic; rFVIIIFc=recombinant coagulation factor VIII Fc fusion protein; t½=half-life. 
NOTE: inhibitor titer, FVIII activity level, t½, and IR are all assessed at the local laboratory, with confirmation by the central laboratory. The Investigators will 
use local laboratory results for decision-making purposes. 
Hematology, blood chemistry, and urinalysis are assessed only at the local laboratory. 
1 
During the Tapering and Follow-Up Periods, the subject’s dose will be adjusted to achieve each subject’s prophylactic dose as determined by the 
Investigator. Minimum Tapering Period is 16 weeks (4 months). Subjects who relapse during the Tapering Period (i.e., who have confirmation of inhibitor 
development AND who have confirmed decrease of IR, with or without clinical signs or symptoms) will proceed immediately to the EOT Visit. Subjects 
will be closely monitored during the Tapering Period for potential relapse.   
For Canada specific requirements: see Appendix B. 
2 
Timing of the EOT Visit will vary for subjects, as described in Section 7.2.6. 
3 
Once t½ has been determined to be ≥7 hours, the Investigator may elect to have a Tapering Initiation Visit and/or a Tapering Initiation Telephone Call. If the 
subject has already begun downtitration from the 200 IU/kg/day ITI dose prior to ITI success, the subject will return for the next scheduled visit (the 
Tapering Initiation Visit) 2 weeks from the visit at which t½ was determined to be ≥7 hours. If the subject has not already downtitrated when t½ is 
determined to be ≥7 hours, the Investigator can make a telephone call to instruct the subject to begin downtitrating immediately (Tapering Initiation 
Telephone Call) Subject’s subsequent visit, which will occur 2 weeks from the visit at which t½ was determined to be ≥7 hours, will be the Tapering 
Initiation Visit (see Section 7.2.3).  
4 
Subjects who do not achieve ITI success within 48 weeks (12 months) will proceed to the ET/EOT Visit. Subjects who develop inhibitors during the 
Tapering or the Follow-Up Period (i.e., who relapse) will proceed immediately to the ET/EOT Visit. 
5 
Vital signs include blood pressure, pulse rate, respiratory rate, and body temperature. Postdose assessments following in-clinic injections will be taken prior 
to and 20 (±5) minutes after the end of the rFVIIIFc injection (if dosing occurs at the visit). 
6 
Hematology, blood chemistry, and urine dipstick are to be collected every 12 weeks (3 months) during the Tapering Period. These assessments will also be 
collected at the EOT Visit. 
7 
Dipstick urinalysis, including a protein reading; if the protein reading is positive (≥1+), a full laboratory urinalysis will be required. 
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8 
Subjects will be advised to delay administration of their daily dose of rFVIIIFc until after the sample for inhibitor testing is taken. An unscheduled visit may 
be required to repeat inhibitor testing under this protocol to obtain a sample to confirm a positive inhibitor test result. 
9 
If ITI success is declared, a sample will be collected at the first visit in the Tapering Period. If partial success or failure is declared, a sample will be collected 
at the EOT Visit. The samples will be collected as allowable based on subject weight and institutional practice regarding blood draw restrictions for pediatric 
subjects. 
10 Takes place at each visit in which IR or t½ is being assessed. 
11 Subjects will be advised to delay administration of the remainder of their daily dose of rFVIIIFc until after the sample for IR is taken. Blood samples will be 
collected for analysis of rFVIIIFc activity for assessment of IR starting at the visit for confirmed negative titers and at all consecutive visits, except for those 
visits where samples for rFVIIIFc t½ determination are drawn, as IR will be determined from the same samples. Blood samples will be taken at predose 
(within 30 minutes prior to the start of injection) and postdose (30 ± 5 minutes after the start of injection). If any assessments indicate the possibility of 
relapse at any time during the Tapering or Follow-Up Period, the test must be repeated at the following visit to confirm relapse (i.e., IR <66%).  
12 Subjects will be advised to delay administration of the remainder of their daily dose of rFVIIIFc until after the final post-dose sample for t½ is taken (i.e., up 
to 48 hours post dose). PK assessments for t½ determination are to be performed when the subject is in a nonbleeding state and after at least a 24-hour 
washout (see Table 3).  
13 A sample for FVIII activity can be collected as needed per Investigator discretion. FVIII activity levels can be derived from IR samples; therefore, a separate 
blood draw for FVIII activity assessment is not required.  
14 It is recommended that subjects/caregivers enter dosing information immediately after an injection or within a maximum of 7 days. 
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Details on sampling for rFVIIIFc are described in Section 13.1.3 and Table 3. 
Table 3: 
Sampling Schedule for Pharmacokinetic Evaluation (Half-Life)  
Activities 
Time in Relation to rFVIIIFc Dosing 
 
rFVIIIFc 
Dosing  
50 IU/kg 
Actual 
Potency 
First 
Sample 
Postdose 
Second 
Sample 
Postdose 
Third 
Sample 
Postdose1     
Fourth Sample  
Postdose 
Either 30 h 
OR 48 h Sample 
Predose2  
 
0 
30 min 
(±5 min) 
6 h 
(±10 min) 
24 h 
(±60 min) 
30 h 
(±60 min) 
48 h 
(±60 min) 
rFVIIIFc Dosing 
 
X 
 
 
 
 
 
PK Assessments2 
3     
X 
 
X 
X 
X 
X 
X 
Abbreviations: h=hours; min=minutes; PK=pharmacokinetic; rFVIIIFc=recombinant coagulation factor VIII Fc 
fusion protein. 
NOTE:t½ assessment will also be performed at EOT for all subjects, unless all 4 postdose PK samples (as above) 
were assessed within 2 weeks of EOT or, in the case of subjects who fail ITI treatment. 
1 During the ITI Period, the Investigator may forego the fourth PK sample (i.e., the 30- or 48-hour sample), if, in the 
Investigator’s opinion, the t½ at the third PK sample indicates that a t½ ≥7 hours cannot be achieved. In this case, 
the Investigator will document the decision to forego the fourth sample. 
2 Predose sample is to be collected within 30 minutes prior to the start of the rFVIIIFc injection. 
 3 Timepoints for PK assessment are measured from the start of the factor injection.  
 
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5. 
INTRODUCTION  
In this study, male subjects of all ages with severe hemophilia A and high-titer inhibitors 
(historical peak ≥5 Bethesda Unit [BU]/mL) will receive recombinant coagulation factor VIII Fc 
fusion protein (rFVIIIFc) for first-time immune tolerance induction (ITI) therapy, to eradicate 
and neutralize anti-coagulation factor VIII (FVIII) alloantibodies (inhibitors). 
5.1. 
Overview of Immune Tolerance Induction in the Clinical 
Management of Hemophilia A  
Hemophilia A is a rare X-linked bleeding disorder that is caused by a functional deficiency of 
FVIII, a cofactor in the intrinsic coagulation pathway. Hemophilia A is the most common type of 
hemophilia and is categorized based on endogenous FVIII activity levels as severe 
(<1 international units [IU]/dL), moderate (1 to 5 IU/dL), and mild (>5 to <40 IU/dL) (ISTH 
Factor VIII/IX Scientific Subcommittee (SSC) Working Party on Definitions in Hemophilia, 
2011; Srivastava et al., 2012; White et al., 2001). As there is no available cure for hemophilia A, 
current treatment focuses on replacement therapy with clotting factor concentrates, namely 
plasma-derived FVIII (pdFVIII) or recombinant factor VIII (rFVIII) products.  
The formation of neutralizing anti-FVIII alloantibodies (inhibitors) represents the most serious 
complication related to hemophilia treatment (Kempton et al., 2014). Inhibitors are 
immunoglobulin G antibodies formed against specific epitopes of the FVIII molecule, which can 
neutralize the coagulation activity of FVIII in plasma and reduce the recovery and half-life (t½) 
of FVIII. Inhibitors result in rapid clearance of infused FVIII and marked reduction, or absence, 
of efficacy of FVIII treatment. Approximately 30% of previously untreated patients with severe 
hemophilia A develop inhibitors following exposure to replacement FVIII (Franchini et al., 
2013; Gouw et al., 2013). The presence of an inhibitor makes it more difficult to control bleeding 
because patients no longer respond to standard doses of replacement FVIII. As a result, patients 
with inhibitors are prone to more bleeds, which can lead to severe joint disease and physical 
disability and, consequently, reduced quality of life (Scalone et al., 2006). Patients with 
inhibitors also have a higher risk of mortality due to bleeding complications (Walsh et al., 2015). 
Inhibitors are classified as high-titer or low-titer based on the titer measured by the Bethesda 
assay. Low-titer inhibitors measure <5 BU/mL, are primarily transient (usually spontaneously 
resolve within 6 months but sometimes more slowly), and generally do not reappear upon FVIII 
challenge (Caram et al., 2011; Tagariello et al., 2013). High-titer inhibitors are defined by a peak 
inhibitor titer ≥5 BU/mL and are usually persistent. While it has been reported that 10% of 
patients with a high-titer inhibitor (≥5 BU/mL) had a transient inhibitor that spontaneously 
resolved within 6 months (Tagariello et al., 2013), only 3.4% of patients with a very high-titer 
inhibitor (≥10 BU/mL) had an inhibitor that spontaneously resolved after at least 2 years of 
follow-up (Caram et al., 2011), suggesting that a titer of ≥10 BU/mL is a better predictor for a 
persistent inhibitor.  
In patients with low-titer inhibitors, bleeding episodes may be controlled with increased doses of 
replacement FVIII to overwhelm the inhibitor by antigen excess. In patients with high-titer 
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inhibitors, bleeding episodes are often treated with bypassing agents (activated prothrombin 
complex concentrate [aPCC], FEIBA®, factor eight inhibitor bypassing activity] or recombinant 
activated factor VII [rFVIIa, NovoSeven®]), which can bypass FVIII inhibition, but inhibitor 
eradication remains the goal of long-term management (see Section 7.2.2.1). 
To date, ITI therapy using frequent administration of high doses of FVIII is the only proven 
strategy to achieve antigen-specific tolerance and eradicate FVIII inhibitors. The goal of ITI is to 
tolerize the immune system to FVIII by regular antigen exposure and to restore FVIII 
pharmacokinetics (PK) such that replacement FVIII can be reintroduced at standard doses. A 
successful response to an ITI regimen (i.e., immune tolerance) is based on evaluation of inhibitor 
titer, FVIII recovery, FVIII t½, and elimination of the anamnestic response to FVIII challenge 
(Kempton et al., 2014; Valentino et al., 2015). ITI success rates range from 33% to 88% in 
published studies (Coppola et al., 2009; Dimichele, 2009; Gringeri, 2007; Hay & DiMichele, 
2012; Haya et al., 2001; Jimenez-Yuste et al., 2016; Kreuz, Escuriola Ettingshausen, Vdovin, 
Zozulya, Plyushch, Svirin, Andreeva, Bubanská, et al., 2016; Kurth et al., 2011; Nakar et al., 
2015; Oldenburg et al., 2014). Most ITI studies with reported success rates are based on 
retrospective registries or analyses, which may have limitations with the types of data collected. 
The wide variability in success rates can be attributed to numerous factors, including differences 
in FVIII product types and dosing regimens, patient characteristics, and definitions of success 
and methods for calculating success rates across ITI studies. 
Over the last 30 years, multiple ITI regimens have been developed, and all involve frequent, 
often daily, repetitive exposure to FVIII for months or years. ITI usually attempts to eliminate 
high-responding FVIII inhibitors (≥5 BU/mL titer). ITI regimens employ different doses and 
dosing frequencies of FVIII, and they may or may not involve adjunctive immunomodulatory 
therapy (Franchini et al., 2011; Valentino et al., 2015). Currently, a range of FVIII products and 
dosing regimens are used for ITI because there is no clear consensus on an optimal regimen 
(Franchini et al., 2011). In the only prospective randomized ITI study ever conducted 
(International ITI Study) comparing a high-dose (200 IU/kg/day) and a low-dose (50 IU/kg 3 
times per week) FVIII regimen, subjects in the high-dose arm achieved a negative titer (median 
4.6 months [interquartile range (IQR) 2.8 to 13.8] vs. 9.2 months [IQR 4.9 to 17.0]; p = 0.017) 
and a normal recovery (median 6.9 months (IQR 3.5 to 12.0) vs. 13.6 months (IQR 8.7 to 19.0); 
p = 0.001) significantly more rapidly than subjects in the low-dose arm. High-dose subjects also 
experienced significantly fewer bleeding episodes than low-dose subjects, and for this reason, the 
data safety monitoring board recommended study termination (Hay & DiMichele, 2012). 
Although it is recommended that ITI be initiated once an inhibitor titer is <10 BU/mL (Valentino 
et al., 2015), a recent study suggests that starting ITI as soon as an inhibitor is diagnosed may 
increase the likelihood of ITI success (Nakar et al., 2015). 
Factors that can affect ITI success have been identified in ITI studies. In particular, certain 
patient characteristics, including historical peak inhibitor titer >200 BU/mL, inhibitor titer at ITI 
start ≥10 BU/mL, age at ITI start ≥8 years, time between inhibitor diagnosis and ITI start 
>2 years, and previous ITI failure have been correlated with decreased ITI success and are 
considered high-risk factors for poor ITI outcome (Gringeri, 2007; Hay & DiMichele, 2012; 
Kreuz, Escuriola Ettingshausen, Vdovin, Zozulya, Plyushch, Svirin, Andreeva, Bubanská, et al., 
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2016; Valentino et al., 2015). For example, a statistically significant inverse relationship between 
historical peak inhibitor titer and ITI success was observed in the International ITI Registry 
(IITR; p = 0.004) and North American ITI Registry (NAITR; p = 0.001) (DiMichele et al., 2002; 
Mariani et al., 1994). Immune tolerance was achieved in 82% of patients whose historical peak 
inhibitor titer was <50 BU/mL, compared with 52% and 21% of patients whose historical peak 
inhibitor titer was >200 BU/mL in the IITR and NAITR, respectively (Kroner, 1999). In 
addition, a statistically significant association between inhibitor titer at ITI start (≤10 BU/mL vs. 
>10 BU/mL) and ITI outcome (p = 0.0068) was observed in the Observational ITI Study (Kreuz, 
Escuriola Ettingshausen, Vdovin, Zozulya, Plyushch, Svirin, Andreeva, Bubanská, et al., 2016), 
and an inhibitor titer <10 BU mL at ITI start was the strongest predictor of ITI success in the 
IITR (80% vs. 60%; p < 0.002), NAITR (83% vs 40%; p = 0.001), and a retrospective survey of 
81 patients in the United States (100% vs 78%; p < 0.0001) (Damiano et al., 2000; DiMichele et 
al., 2002; Mariani et al., 1994). 
Reported success rates can reflect different methods for calculation. For example, in the 
International ITI Study, a prospective study conducted in patients without high-risk factors, the 
success rate was 40% (46/115) for all subjects, 47% (37/78) for subjects who completed or 
withdrew from the study, and 70% (46/66) when subjects who were ongoing or withdrawn were 
excluded (Hay & DiMichele, 2012). 
Additional prospective studies are needed to better understand ITI success rates. To date, there 
are few anecdotal case reports that describe the use of rFVIIIFc for the treatment of ITI. This 
prospective study is aimed at assessing the outcomes of ITI therapy with the use of rFVIIIFc. 
5.2. 
Profile of Previous Experience With rFVIIIFc for Immune Tolerance 
Induction  
5.2.1. 
Previous Nonclinical and Clinical Experience With rFVIIIFc for Immune 
Tolerance Induction  
rFVIIIFc is produced in a human cell line (HEK293) as a recombinant B-domain deleted factor 
VIII fused to the Fc domain of human IgG. HEK-produced proteins have the same 
post-translational modifications as native human proteins, in contrast to proteins produced in cell 
lines from other species, such as hamsters (e.g., Chinese hamster ovary [CHO] cells). In such 
proteins, nonhuman glycans (such as N-glycolylneuraminic acid [NGNA]) resulting from the 
post-translational modifications can be potentially immunogenic. NGNA is not found in 
rFVIIIFc.  
Until recently, all rFVIII products were produced in hamster cells (baby hamster kidney or CHO 
cells). Today, in addition to rFVIIIFc, there is only one recently approved rFVIII product 
produced in a human cell line available on the market (Lissitchkov et al., 2015). 
5.2.2. 
Nonclinical Experience  
Nonclinical studies have shown that fusion proteins containing IgG or the Fc domain can induce 
tolerance to the A2 and C2 domains of the FVIII molecule, which are the most frequent epitopes 
targeted by inhibitors. In one study, FVIII-deficient mice were treated with B cells expressing 
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full-length IgG fused to either the A2 or C2 domain (Lei et al., 2005). Inhibitor titers were 
significantly reduced in animals treated with a combination of B cells expressing the A2-IgG and 
C2-IgG fusion proteins compared with control animals. In another study, a fusion protein 
comprising Fc and either the A2 or C2 domain was transplacentally delivered to the progeny of 
FVIII-deficient (HemA) pregnant mice (Gupta et al., 2015). The combination of A2Fc and C2Fc 
fusion proteins led to a significant reduction in inhibitor titers in the offspring of treated mother 
mice compared with the offspring of control mother mice. In both studies, the tolerogenic effect 
of the fusion proteins involved the induction of regulatory T cells.  
In line with the above findings that suggest a role of the Fc domain in tolerance, nonclinical data 
suggest that rFVIIIFc as such can induce tolerance to FVIII. In a nonclinical study, 
FVIII-deficient mice that were pretreated with rFVIIIFc had reduced total anti-FVIII IgG 
antibody and FVIII inhibitor production upon challenge with a high dose of rFVIIIFc 
(Krishnamoorthy et al., 2016). Tolerance induced by rFVIIIFc was associated with a higher 
percentage of regulatory T cells, a lower percentage of pro-inflammatory T cells in the spleen, 
and upregulation of cytokines associated with attenuation of the immune response.  
5.2.3. 
Clinical Experience  
In the clinical setting, there are published case reports of patients who have received rFVIIIFc for 
ITI. Malec and coworkers described 3 patients with severe hemophilia A (ages at initiation of ITI 
were 18 months, 7.5 years, and 10 years) who were started on ITI with rFVIIIFc after detection 
of a high-titer inhibitor. ITI was initiated at a dose of 100 to 200 IU/kg rFVIIIFc with a dosing 
interval of every other day to 3 times per week. ITI led to a negative inhibitor in all 3 children 
within 4 to 12 weeks (Malec et al., 2015) , which is shorter than the median time to negative 
inhibitor reported for other FVIII products (Hay, DiMichele, et al., 2012; Kreuz, Escuriola 
Ettingshausen, Vdovin, Zozulya, Plyushch, Svirin, Andreeva, Bubanska, et al., 2016). Malec and 
coworkers reported the time to tolerization in these 3 patients being 17 weeks, 18 weeks, and 17 
months, respectively (Carcao et al., 2017; Malec et al., 2016). Groomes and coworkers reported a 
15-month-old patient who started ITI on conventional rFVIII products. As the inhibitor titer 
continued to increase, he was switched to rFVIIIFc 50 IU/kg 3 times per week. The inhibitor titer 
had significantly decreased to 0.7 BU/mL after 10 months of ITI at the time of publication 
(Groomes et al., 2016). 
5.3. 
Study Rationale  
Hemophilia management has advanced rapidly in the last few years. Formation of inhibitors still 
remains the main complication of treatment of hemophilia. ITI is the standard of care for 
treatment of inhibitor development for patients with hemophilia A; however, there remains an 
unmet need for a standard dose and a specific product to treat these inhibitors. A range of FVIII 
products and dosing regimens have been studied in a number of generally small retrospective 
registries and 1 prospective study. ITI success rates from these studies range from 33% to 88%, 
due in part to the widely varying definitions of success, FVIII product types used, dose regimens, 
and study populations. The International ITI Study was the only prospective study performed to 
date (Hay & DiMichele, 2012). This study evaluated high-dose (200 IU/kg/day) and low-dose 
(50 IU/kg 3 times per week) ITI regimens in subjects without risk factors associated with poor 
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ITI outcomes. Of the 57 subjects who received high-dose ITI with FVIII, 22 (39%) achieved 
complete success. Based on the results of this study and several registries, Valentino (Valentino 
et al., 2015) published recommendations on ITI treatment. However, there is no clear consensus 
on an optimal regimen, making additional prospective studies necessary.  
Furthermore, rFVIIIFc offers a potential advantage over other replacement FVIII products for 
treating patients with hemophilia A and inhibitors. Based on reports from animal studies, 
Fc-containing fusion proteins have immunomodulatory properties, which may be attributable to 
the ability to upregulate regulatory T cells via epitopes present in the Fc fragment (De Groot et 
al., 2008) and consequently promote tolerance over immune responses that induce 
immunogenicity. These and other nonclinical data (Krishnamoorthy et al., 2016) indicate a 
mechanistic basis for the use of rFVIIIFc for ITI, and promising clinical results from published 
reports (Groomes et al., 2016; Malec et al., 2015) provide initial evidence that rFVIIIFc can 
induce tolerance. 
5.4. 
Rationale for Dosing Regimen  
The proposed dose of rFVIIIFc for ITI (200 IU/kg/day [±8 hours]) is aligned with current ITI 
guidelines (Valentino et al., 2015). 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 achieve faster tolerization with 
fewer bleeding episodes. This dosing regimen is also supported by the results of a prospective 
clinical 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 & 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 with subjects 
treated with the low dose. Furthermore, subjects treated with the high dose of FVIII for ITI had a 
lower rate of intercurrent bleeding and fewer hospitalizations due to bleeding than subjects 
treated with the low dose of FVIII. Anecdotal unpublished reports of cases treated in the United 
States of America (USA) and Canada with 200 IU/kg/day also exist. 
Furthermore, repeated doses of up to 1000 IU/kg evaluated in the nonclinical animal studies have 
shown no dose-limiting toxicities.  
Sustained high FVIII activity levels in plasma (>150 to 200 IU/dL) may increase the risk of 
thrombotic events, although this risk is thought to be low. Therefore, FVIII activity levels in 
plasma will be monitored to provide a basis for dose adjustment of rFVIIIFc when needed. 
During the Tapering and Follow-Up Periods, the subject’s dose will be adjusted to achieve a 
prophylactic dose (see Section 11.1).  
 
 
 
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6. 
STUDY OBJECTIVES AND ENDPOINTS  
6.1. 
Primary Objective and Endpoint  
The primary objective of this study is to describe the time to tolerization (i.e., ITI success) with 
rFVIIIFc in subjects within a maximum of 48 weeks (12 months) of ITI treatment. 
The primary endpoint of this study is time to tolerization with a maximum of 48 weeks (12 
months) of ITI treatment offered in the study (tolerization defined as inhibitor titer <0.6 BU/mL, 
rFVIIIFc incremental recovery [IR] ≥66% of the expected IR, and t½ ≥7 hours). 
6.2. 
Secondary Objectives and Endpoints  
The secondary objectives are as follows: 
 To describe the outcome of ITI treatment 
 To describe the relapse rate over the 48-week (12-month) period following successful 
ITI performed with rFVIIIFc 
 To describe the intercurrent bleeding during the ITI Period and during the 48-week 
(12-month) period after successful ITI performed with rFVIIIFc 
 To describe the safety and tolerability of rFVIIIFc when used for ITI 
 To evaluate the impact of ITI treatment with rFVIIIFc on health economics and 
adherence 
The secondary endpoints are as follows: 
 ITI success  
 Confirmed negative titers consisting of 2 consecutive negative inhibitor 
assessments within 2 weeks (±3 days) based on local laboratory results 
<0.6 BU/mL by the Nijmegen-modified Bethesda assay; determination of 
negative titer based on the Bethesda assay is acceptable at sites that have not yet 
adopted the Nijmegen-modified Bethesda assay  
 IR ≥1.32 IU/dL per IU/kg in 2 consecutive assessments representing ≥66% of the 
expected IR 2 IU/dL per IU/kg (SmPC; USPI) 
 t½ ≥7 hours 
 Occurrence of relapse (defined as confirmed positive inhibitor titer ≥0.6 BU/mL), 
abnormal recovery after tolerance is achieved, and t½ <7 hours) during the Tapering 
or Follow-Up Periods  
 Number of bleeding episodes during the ITI Period and during the 48-week (12-
month) period after successful ITI performed with rFVIIIFc  
 Adverse events (AEs) and serious adverse events (SAEs) 
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 Number of days away from work or school 
 Number of hospitalization days 
 Adherence (defined as percentage of administered doses versus planned doses)  
 Consumption of rFVIIIFc (measured in total rFVIIIFc use) 
6.3. 
Exploratory Objectives and Endpoints  
 
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7. 
STUDY DESIGN  
7.1. 
Study Overview  
This is an open-label, single-arm, interventional, multicenter study designed to explore the use of 
rFVIIIFc for ITI in subjects with severe hemophilia A who have inhibitors, who are undergoing 
ITI treatment for the first time. The study will be conducted at approximately 30 sites in the 
USA, Europe, Japan, and Canada. Approximately 17 subjects will be treated. The maximum 
individual subject study duration is expected to be approximately 2 years (see Figure 1 for a 
schematic of the study design). 
7.2. 
Overall Study Duration and Follow-Up  
The study period will consist of 4 periods: 1) a 4-week (1-month) Screening Period; 2) a 
maximum of a 48-week (12-month) ITI Period; 3) a minimum of a 16-week (4-month) Tapering 
Period after all criteria for tolerization have been met; and 4) a 32-week (8-month) Follow-Up 
Period. The length and the dosing schedules during the Tapering Period are left to the discretion 
of the treating physician. Only subjects who achieve ITI success will enter the Tapering and 
Follow-Up Periods. During the Tapering and Follow-Up Periods, the subject’s dose will be 
adjusted with the aim of tapering the dose to reach the prophylactic dosing regimen within at 
least 12 weeks (3 months) (see Table 5). 
7.2.1. 
Screening  
Subjects will undergo full evaluation to determine their eligibility to participate in the study, 
after the subject or the subject’s legally authorized representative (e.g., parent or legal guardian), 
as applicable, in accordance with local practice and regulations, has signed the informed consent 
form (ICF) (and assent, if applicable). Pediatric subjects who have the capacity should provide 
their assent to participate in the study.  
Subject eligibility for the study will be determined within 4 weeks (1 month) prior to study entry, 
with the exception of informed consent, which may occur earlier. Subjects may be given a 
screening window extension of up to 2 weeks if unable to enroll within the 4-week (1 month) 
Screening Period. Screening laboratory results are valid for up to 6 weeks. Screen failures will be 
allowed to re-screen on a case-by-case basis and will require approval of the Sponsor Medical 
Monitor. Subjects weighing <6 kg may require Screening blood draws over multiple days to 
comply with the 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. 
Subjects who meet all entry criteria will be enrolled and begin treatment at the Baseline Visit 
(see Table 1). A subject will be considered enrolled when the Investigator determines that the 
subject is eligible, and the subject is enrolled in the Interactive Response System (IXRS). Subject 
enrollment in IXRS must occur prior to dispensation of study treatment. 
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7.2.2. 
Immune Tolerance Induction Period  
The first dose of rFVIIIFc ITI will be administered at the Baseline Visit, and treatment will 
continue until ITI success is declared or for a maximum of 48 weeks (12 months). The ITI 
regimen consists of rFVIIIFc 200 IU/kg/day (±8 hours), which may be given as once-daily 
injections or divided into several injections per day at the discretion of the Investigator.  
Subjects will visit the clinic 2 and 4 weeks after enrollment and then every fourth week until 
48 weeks (12 months) or until a negative inhibitor (<0.6 BU/mL) has been obtained. After the 
negative inhibitor results, visits will be scheduled every other week until ITI success or failure is 
declared. 
The Investigator’s assessment of ITI outcome will be based on results from the local laboratory. 
If the local laboratory results are inconclusive, the Investigator may use the central laboratory 
results to determine ITI outcome. During the ITI Period, subjects will undergo procedures and 
assessments at designated visits per Table 1. Samples for inhibitor testing and assessment of 
FVIII activity levels will be analyzed at the local laboratory and at the central laboratory. 
Investigator treatment and assessment of inhibitor status will be based on results from the local 
laboratory. Negative inhibitor testing results must be confirmed (i.e., 2 consistent results at 2 
consecutive assessments). See Section 7.2.2.2 for specific definitions of ITI outcomes. 
The assessment of ITI outcome is illustrated in Figure 2. After the subject has demonstrated a 
negative inhibitor (<0.6 BU/mL) at 2 consecutive assessments within 2 weeks (±3 days) per the 
schedule listed in Table 1, an evaluation of rFVIIIFc IR will be performed at the next scheduled 
visit (the interpretation of the IR result will be performed after the negative inhibitor titer is 
confirmed, but the sample for IR is drawn at the visit for the confirmatory negative inhibitor 
titer). After IR ≥1.32 IU/dL per IU/kg (≥66% of the expected IR) has been obtained at 
2 consecutive assessments within 2 weeks (±3 days), together with a sustained negative inhibitor 
titer (<0.6 BU/mL), PK assessments to determine rFVIIIFc t½ will be performed at the 
subsequent visits until t½ ≥7 hours is attained. If t½ <7 hours is attained, subjects need to return to 
clinic within 2 weeks (±3 days) to complete another t½ assessment until ITI success or 48 weeks 
(12 months).  
Subjects are required to have at least a 24-hour washout prior to the IR and the PK assessment 
for t½. The dose for IR and t½ is 50 IU/kg of rFVIIIFc based on actual potency. Investigators will 
advise subjects to delay any dose of rFVIIIFc until after scheduled inhibitor assessments. 
Investigators will also advise subjects to delay the remainder of their daily dose of rFVIIIFc until 
after IR and t½ assessments have been made.  
Only subjects who achieve confirmed ITI success within 48 weeks (12 months) will continue 
into the Tapering and Follow-Up Periods. Throughout the study, FVIII activity levels above 
200 IU/dL (based on local laboratory values) should be avoided. However, if FVIII activity 
levels rise above 200 IU/dL after the inhibitors are negative but before all of the ITI success 
criteria are met, the dose may be adjusted according to Investigator judgment to maintain the 
FVIII activity levels between 100 and 200 IU/dL. This dose reduction will not be considered part 
of the Tapering Period, and the subject will maintain the schedule of assessments per the ITI 
Period. See Section 11.1 for dosing details. 
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Throughout the ITI Period, rFVIIIFc administration, bypassing agent administration, and any 
bleeding episodes will be collected by the subject and/or his caregiver in a study-specific 
electronic patient diary (EPD). EPD data will be reviewed by the Investigator on an ongoing 
basis and discussed with the subject at each visit. 
7.2.2.1. 
Use of Bypassing Agents  
In the time period between the subject’s signing the ICF and the beginning of ITI treatment, 
treatment with bypassing agents (aPCC [FEIBA] or rFVIIa [NovoSeven]) is permitted.  
During ITI treatment, subjects may also receive bypassing agents as needed for control of active 
bleeding at the discretion of the Investigator and within labeled dosing recommendations for the 
specific bypassing agent. 
The Investigator may also prescribe bypassing agents 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.  
The use of bypassing agents in the setting of ITI requires awareness of FVIII activity levels and 
close monitoring for cessation of bleeding events.  
In subjects with high-titer inhibitors, bleeding may be treated with bypassing agents, which can 
bypass FVIII inhibition. In subjects with low-titer inhibitors, bleeding events may be controlled 
with increased doses of replacement FVIII to overwhelm the inhibitor by antigen excess. 
During the study, the Investigator will determine if increased doses of replacement FVIII or use 
of bypassing agents is appropriate.  
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 is 
permitted; however, the Investigator must inform the Sponsor Medical Monitor and document 
the rationale for such use. 
Throughout the ITI Period, rFVIIIFc administration, bypassing agent administration, and any 
bleeding episodes will be collected by the subject and/or his caregiver in a study-specific EPD. 
EPD data will be reviewed by the Investigator in an ongoing basis and discussed with the subject 
at each visit.  
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7.2.2.2. 
ITI Outcome  
ITI outcome will be assessed on an ongoing basis. Subjects may achieve 1 of 4 outcomes: 
treatment failure, early withdrawal (outcome not determinable) during the ITI Period, partial 
success, or ITI success. 
Early withdrawal (Outcome not determinable) 
 Unable to determine outcome due to withdrawal during the ITI Period 
Treatment failure 
Treatment failure is defined as fulfilling one of the following criteria: 
 No downward trend of at least 20% in the inhibitor titer in a 6-month (24-week) 
period after the initial 3 months (12 weeks) during the ITI Period (assessed at the 
Week 36 [Month 9] Visit).  
 Presence of a sustained positive inhibitor (≥0.6 BU/mL) after 48 weeks (12 months) 
of ITI treatment. 
 Negative inhibitor titer without achieving either of the 2 PK parameters of ITI success 
after 48 weeks (12 months) of ITI treatment:  
 IR ≥1.32 IU/dL per IU/kg OR  
 t½ ≥7 hours 
Subjects who have been determined to have failed ITI will then proceed to the End of Treatment 
(EOT) Visit. 
Partial success 
Partial success is defined as achieving negative inhibitor titer and one of the PK parameters of 
ITI success: IR ≥1.32 IU/dL per IU/kg OR t½ ≥7 hours.  
The determination of partial success will be made only among subjects who have completed the 
maximum period of 48 weeks (12 months) of ITI treatment but do not fulfill the criteria for ITI 
success or treatment failure  
Subjects who have been determined to have achieved only partial success will then proceed to 
EOT Visit. 
ITI success 
ITI success is defined as achieving all 3 of the following criteria based on local laboratory 
results: 
 Confirmed negative inhibitor titer (<0.6 BU/mL by the Nijmegen-modified Bethesda 
assay) based on 2 consecutive negative inhibitor assessments within 2 weeks 
(±3 days); determination of negative titer based on the Bethesda assay is acceptable at 
sites that have not yet adopted the Nijmegen-modified Bethesda assay 
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 IR ≥1.32 IU/dL per IU/kg, representing ≥66% of the expected IR 2 IU/dL per IU/kg 
(SmPC; USPI), at 2 consecutive assessments performed within 2 to 4 weeks 
 t½ ≥7 hours 
 
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Figure 2 
Flow Diagram for Assessment of ITI Outcome  
 
Abbreviations: BU=Bethesda unit; IR=incremental recovery; ITI=immune tolerance induction; t½=half-life. 
After confirmed negative inhibitor titer (<0.6 BU/mL), it is stated ‘Perform these assessments (i.e. inhibitor titer every 2 weeks, and IR every 2 weeks) for the 
remainder of the ITI Period after negative titer (< 0.6 BU/mL) is confirmed’. Although this means that the sample for IR is drawn at the visit for the confirmatory 
negative inhibitor titer, however, the interpretation of the IR result will be performed after the negative inhibitor titer is confirmed.
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7.2.3. 
Downtitration (Dose Adjustment) Between ITI Treatment and the Tapering 
Period  
If FVIII activity levels rise above 200 IU/dL, after the inhibitors are negative but before all of the 
ITI success criteria are met, the dose will be adjusted according to Investigator judgment to 
maintain the FVIII activity levels between 100 and 200 IU/dL. This dose adjustment will not be 
considered part of the Tapering Period, and the subject will maintain the schedule of assessments 
per the ITI Period.  
Once t½ has been determined to be ≥7 hours, the Investigator may have a Tapering Initiation 
Visit and/or a Tapering Initiation Telephone Call. If the subject has already begun downtitration 
from the 200 IU/kg/day ITI dose, the subject will return for the next scheduled visit (the 
Tapering Initiation Visit) 2 weeks from the visit at which t½ was determined to be ≥7 hours. If 
the subject has not already downtitrated when t½ is determined to be ≥7 hours, the Investigator 
can make a telephone call to instruct the subject to begin downtitrating immediately (Tapering 
Initiation Telephone Call). Subject’s subsequent visit, which will occur 2 weeks from the visit at 
which t½ was determined to be ≥7 hours, will be the Tapering Initiation Visit. 
7.2.4. 
Tapering Period  
Subjects who have met the criteria for ITI success will enter the Tapering Period. Further details 
about the recommended dosing regimen for tapering are described in Section 11. Subjects with 
bleeding episodes during the Tapering Period will be tested for recurrence of inhibitors and 
monitored for relapse.  
During the Tapering Period, treatment with bypassing agents may be considered if bleeding is 
unresponsive to treatment with rFVIIIFc (see Section 7.2.2.1). Testing for recurrence of 
inhibitors will be performed throughout the Tapering and Follow-Up Periods.  
Subjects will visit the clinic 2 and 4 weeks after the first visit in the Tapering Period and then 
every fourth week for a minimum of 16 weeks (4 months). The duration of the Tapering Period 
may be modified by the Investigator with the Sponsor Medical Monitor’s approval based on the 
subject’s clinical response. If the Tapering Period exceeds 16 weeks (4 months), unscheduled 
visits will be performed every 4 weeks (1 month) or per the Investigator’s judgment. 
During the Tapering Period, subjects will undergo procedures and assessments at designated 
visits per the schedule of events (see Table 2). At each visit, samples for inhibitor titer and IR 
assessments will be drawn and sent to the local and central laboratories to monitor for relapse.  
If the subject experiences bleeding during the Tapering Period, the treatment of the bleeding will 
be left to the discretion of the Investigator. During the Tapering Period, treatment with bypassing 
agents may be considered if bleeding is unresponsive to treatment with rFVIIIFc (see 
Section 7.2.2.1). 
Throughout the Tapering Period, rFVIIIFc administration, bypassing agent administration, and 
any bleeding episodes will be collected by the subject and/or his caregiver in the EPD. The EPD 
data will be reviewed by the Investigator on an ongoing basis and discussed with the subject at 
each visit. 
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Relapse 
If a subject experiences bleeding episodes that cannot be controlled with the use of rFVIIIFc, 
further investigation for relapse may be warranted.  
Relapse is defined as the occurrence of the following (with or without clinical signs or 
symptoms) after complete ITI success, based on the International ITI criteria (Hay & DiMichele, 
2012): 
 A positive inhibitor (≥0.6 BU/mL using the Nijmegen assay) on 2 consecutive 
assessments performed within 2 to 4 weeks; determination of positive titer based on 
the Bethesda assay is acceptable at sites that have not yet adopted the 
Nijmegen-modified Bethesda assay. 
AND 
 An IR <1.32 IU/dL per IU/kg (representing <66% of the expected IR) on 2 
consecutive assessments performed within 2 to 4 weeks.  
If any assessments indicate the possibility of relapse at any time during the Tapering or 
Follow-Up Period, the tests must be repeated at the following visit to confirm relapse. A subject 
with confirmed relapse (i.e., confirmation of both of the above criteria in 2 consecutive 
assessments) must complete the EOT Visit. At EOT, t½ will be assessed and recorded.  
7.2.5. 
Follow-Up  
After completion of the Tapering Period, subjects will enter the Follow-Up Period, during which 
subjects will be treated prophylactically with the rFVIIIFc dose and interval prescribed by the 
Investigator, according to the label and clinical response of the subject, for 32 weeks (8 months). 
To avoid bleeding episodes and a relapse of the inhibitors, FVIII activity levels should be kept 
≥1 IU/dL. 
If the subject experiences a bleeding episode during the Follow-Up Period, the treatment of the 
bleed will be left to the discretion of the Investigator. Treatment with bypassing agents may be 
considered if bleeding is unresponsive to treatment with rFVIIIFc. Subjects with bleeding 
episodes during the Follow-Up Period will be tested for recurrence of inhibitors (see 
Section 7.2.2.1). 
During the Follow-Up Period, the subject will visit the clinic every 12 weeks (3 months) and 
undergo procedures and assessments as per the schedule of activities (see Table 2). At each visit, 
samples for inhibitor titer and IR assessments will be drawn to monitor for relapse. A subject 
with confirmed relapse criteria will complete the EOT Visit as soon as possible. 
7.2.6. 
End of Treatment/End of Study  
At the EOT Visit, PK assessments to determine rFVIIIFc t½ will be performed. t½ determination 
at EOT Visit does not need to be performed if the full 4-sample t½ assessment was performed 
within 2 weeks prior to the EOT Visit or if the Investigator determines the subject is an ITI 
Treatment Failure (see Section 7.2.2.2). Throughout the Follow-Up Period, rFVIIIFc 
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administration and any bleeding episodes will be collected by the subject and/or his caregiver in 
the EPD. The EPD data will be reviewed by the Investigator on an ongoing basis and discussed 
with the subject at each visit.  
7.2.7. 
Final Safety Follow-Up  
A Final Safety Follow-Up Visit or Follow-Up Telephone Call will take place within 7 to 14 days 
after the EOT Visit to monitor AEs, SAEs, and concomitant medications and procedures. 
7.3. 
Unscheduled Visits  
Subjects may return for an evaluation any time their condition warrants medical attention or to 
repeat safety assessments, protocol-required assessments, including evaluations of inhibitor, IR 
or PK, or any blood sampling, as necessary for study purposes. An unscheduled visit will not 
affect the regular visit schedule and assessments. 
7.4. 
Study Stopping Rules  
Sponsor may terminate this study at any time, after informing the Investigator(s). Sponsor will 
notify Investigator(s) if the study is placed on hold, completed, or terminated. 
Sponsor may also stop the study for futility and not meeting the enrollment targets. 
7.5. 
End of Study  
The end of study is defined as last subject, last visit for final collection of data. 
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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 enrollment: 
1. Ability of the subject or his legally authorized representative (e.g., parent or legal 
guardian) to understand the purpose and risks of the study and provide signed and dated 
informed consent and authorization to use protected health information in accordance 
with national and local subject privacy regulations 
2. Male subjects of any age diagnosed with severe hemophilia A (as confirmed from the 
medical record) 
3. Currently diagnosed with high-titer inhibitors (historical peak ≥5 BU/mL, according to 
medical records) 
4. Previously treated with any pd-FVIII or recombinant conventional or Extended Half-Life 
FVIII 
5. Canada specific requirements: See Appendix B. 
8.2. 
Exclusion Criteria  
Candidates will be excluded from study entry if any of the following exclusion criteria exist at 
the time of enrollment: 
1. Other coagulation disorder(s) in addition to hemophilia A 
2. Previous ITI 
3. History of hypersensitivity or anaphylaxis associated with any FVIII administration 
4. Planned major surgery scheduled during the study unless deferred until after study 
completion (minor surgery such as tooth extraction or insertion/replacement of central 
venous access device is allowed) 
5. Abnormal renal function (serum creatinine >1.5 mg/dL or 2× upper limit of normal 
(ULN) for subject age based on local laboratory range) as assessed by local laboratory 
6. Serum alanine aminotransferase or aspartate aminotransferase >5 × ULN as assessed by 
local laboratory 
7. Serum total bilirubin >3 × ULN as assessed by local laboratory 
8.  Current enrollment or a plan to enroll in any interventional clinical study in which an 
investigational treatment or approved therapy, other than rFVIIIFc, for investigational use 
is administered within 30 days (or 5 half-lives of the agent, whichever is longer) prior to 
the Baseline Visit 
9. Inability to comply with study requirements 
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10. Presence of any medical or psychological condition or laboratory result that, in the 
opinion of the Investigator, can interfere with the subject’s ability to comply with the 
protocol requirements or make the subject not appropriate for inclusion to the study and 
treatment with Elocta®/Eloctate® (rFVIIIFc) 
11. Other unspecified reasons that, in the opinion of the Investigator or Sponsor, make the 
subject unsuitable for enrollment 
12. Unwillingness or inability to comply with the requirements of the protocol, including the 
presence of any condition (physical, mental, or social) that prevents the subject from 
participating in visits as scheduled or entering required information into the EPD in a 
timely manner 
13. Concurrent systemic treatment with immunosuppressive drugs within 12 weeks 
(3 months) prior to Screening. Exceptions to this include ribavirin for treatment of 
hepatitis C virus (HCV), and/or systemic steroids (a total of 2 courses of pulse treatments 
lasting no more than 7 days within 12 weeks [3 months] prior to Day 1) and/or inhaled 
steroids 
14. High risk of cardiovascular, cerebrovascular, or other thromboembolic events, as judged 
by the Investigator 
The following criteria refer to tests performed within 26 weeks (6.5 months) prior to Screening. 
If not available, a new test will be drawn at the Screening Visit. 
15. Cluster of differentiation 4 (CD4) lymphocytes <200 mm3 at Screening, if known as 
human immunodeficiency virus (HIV) antibody positive based on medical history or HIV 
testing 
16. Viral load of >400 copies/mL at Screening, if known as HIV antibody positive based on 
medical history 
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9. 
ENROLLMENT AND REGISTRATION, STUDY PROCEDURES  
Once the investigational site has been activated for study participation, subjects may be enrolled 
if they have met the inclusion criteria in Section 8.1 and have not been excluded based on the 
exclusion criteria in Section 8.2. 
9.1. 
Screening, Enrollment  
Subjects or their legally authorized representative (e.g., parent or legal guardian), where 
applicable, must provide informed consent before any Screening tests or assessments are 
performed. Participating study sites are required to register all screened candidates in this study 
in the IXRS. If a subject is excluded from the study, the reasons for exclusion will be 
documented in the subject’s documents. 
9.2. 
Registration of Subjects  
At the Screening Visit, IXRS will be used to assign each subject a unique 6-digit subject 
identification number (see Section 19.1.2). No subject may begin treatment prior to enrollment. 
Subject identification numbers that have been assigned will not be reassigned to another subject, 
even if the subject does not receive treatment. If a subject is rescreened, the subject may use his 
original number. 
See the Study Reference Manual for details on registration. 
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10. 
DISCONTINUATION OF STUDY TREATMENT AND 
WITHDRAWAL OF SUBJECTS FROM THE STUDY  
Subjects must be withdrawn from the treatment and the study for any one of the following 
reasons: 
 The subject withdraws consent or the parent or legally authorized representative (e.g., 
parent or legal guardian) withdraws consent on behalf of the subject. 
 The subject is unwilling or unable to comply with the protocol. 
 The subject enrolls into another interventional clinical study in which an 
investigational treatment or approved therapy for investigational use is administered. 
 ITI treatment is interrupted for >2 weeks. 
 Emergent or elective surgery. Minor surgery such as tooth extraction or 
insertion/replacement of central venous access device is not a criterion for 
withdrawal. 
 The subject received concomitant immunomodulation. 
 The subject uses FVIII products other than rFVIIIFc (exception allowed for 
1 emergency or accidental use). 
 If, in the clinical judgment of the Investigator or Sponsor, it is not in the subject’s best 
interest to continue with the study treatment. 
The reason for the subject’s withdrawal from the study must be recorded in the subject’s 
electronic case report form (eCRF). When a subject is withdrawn, the date of study treatment 
dose and the date and reason for treatment/study withdrawal (see above) will be clearly described 
in the relevant sections of the eCRF. If a subject is removed from treatment because of an AE, 
the reason for treatment withdrawal will be stated as “adverse event” irrespective of whether this 
was the Investigator’s or the subject’s decision. This subject will be followed until the event has 
resolved, stabilized, or returned to baseline. 
The withdrawn subject will be examined as soon as possible, whenever possible, irrespective of 
the reason for withdrawal. Subjects who are withdrawn will not be replaced. Relevant samples 
will be obtained, and all relevant assessments will be completed, preferably according to the 
schedule for EOT Visit. The eCRF will be completed as much as possible. 
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11. 
STUDY TREATMENT  
The Sponsor will provide rFVIIIFc to sites in all countries. 
11.1. 
Dosing Regimen and Administration  
Refer to and follow the package insert or the Directions for Handling and Administration (DHA). 
See Section 5.4 for the rationale for the selected dosage regimen, dose levels, and treatment 
duration. 
During the ITI Period, the rFVIIIFc dose administered is 200 IU/kg/day (±8 hours), which may 
be given as a once-daily dose or divided into several doses per day. If FVIII activity levels rise 
above 200 IU/dL, after the inhibitors are negative but before all of the ITI success criteria are 
met, the dose will be adjusted according to Investigator judgment to maintain the FVIII activity 
levels between 100 and 200 IU/dL (see Table 4). 
During the Tapering Period (with all 3 tolerization success criteria met), the rFVIIIFc dose 
administered will be adjusted according to Investigator judgment based on the FVIII activity 
levels to maintain the FVIII activity levels between 100 and 200 IU/dL during the initial part of 
the Tapering Period, with the aim of tapering the rFVIIIFc dose to reach a prophylactic dosing 
regimen within 16 weeks (4 months). 
An example of a dose adjustment schedule after the inhibitor titer has become negative and the 
subject has not met all the criteria for a successful tolerization is shown in Table 4. The dose 
adjustment will be individualized according to each subject’s FVIII activity levels during this 
period. 
Table 4 
Example of a Dose Adjustment Schedule: Negative Inhibitor, Not All Success 
Criteria Met  
Peak FVIII Activity Levels 
Dose of rFVIIIFc per Day 
<200 IU/dL 
200 IU/kg/day 
≥200 IU/dL 
100 IU/kg/day 
Abbreviations: FVIII=coagulation factor VIII; rFVIIIFc=recombinant coagulation factor VIII Fc fusion protein. 
 
During the Tapering Period (with all 3 tolerization success criteria met), the aim is to keep FVIII 
activity levels approximately between 100 and 200 IU/dL for at least 4 weeks (1 month), with 
the aim of tapering the dose to reach the prophylactic dosing regimen within at least 12 weeks 
(3 months) (see Table 5). It is recommended that the entire Tapering Period be at least 16 weeks 
(4 months). This schedule is only an example, and each subject’s tapering schedule is left to the 
treating physician’s discretion. 
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Table 5 
Example of a Dose Tapering Schedule: All 3 Success Criteria Met  
Tapering Period 
Dose and Interval 
Weeks 1 to 6 
100 IU/kg QD 
Weeks 6 to 12 
100 IU/kg QOD 
Weeks 12 to 16 
50 IU/kg QOD 
Week 16 onward 
50 IU/kg 3 times per week (prophylaxis) 
Abbreviations: QD=once a day; QOD=every other day. 
 
During the Follow-Up Period, the prophylaxis regimen will be adjusted based on clinical 
response and with the goal of keeping FVIII activity levels ≥1 IU/dL at all time points according 
to Investigator judgment and local practice. 
If the subject misses a dose, the Investigator should be notified, and the Investigator will 
determine when the next dose of rFVIIIFc should be taken. 
Bleeding episodes occurring during the study will be treated per Investigator judgment and 
within labeled dosing recommendations. Concomitant treatment with bypassing agents such as 
aPCC (FEIBA) or rFVIIa (NovoSeven) will be allowed during the ITI Period under certain 
circumstances (see Section 7.2.2.1 for details). 
11.1.1. 
Administration of rFVIIIFc  
After dissolving the powder for injection with the solvent supplied in the pre-filled syringe, 
rFVIIIFc will be delivered via a slow push intravenous (IV) injection over several minutes, at a 
rate of administration determined by the subject’s comfort level. 
Because of the risk of allergic reactions with FVIII concentrates, the initial administration of 
rFVIIIFc will be performed under medical observation, where proper medical care for allergic 
reactions could be provided. Subjects/caregivers will be instructed to administer subsequent 
rFVIIIFc doses at home, except for the dose given prior to assessments of rFVIIIFc t½ and IR, 
which will be administered in the clinic. 
It is recommended that the subject/caregiver enter dosing information on rFVIIIFc and/or FVIII 
bypassing agents into the EPD immediately after an injection or within a maximum of 7 days, to 
ensure data integrity and to facilitate appropriate medical review and dosing guidance. Complete 
instructions for the preparation and administration of rFVIIIFc are provided in the DHA within 
the Study Reference Manual. 
11.1.2. Calculation and Recording of Dosing Based on Actual Potency and Dosing Based on 
Nominal Strength  
Actual potency dosing is required for the dose of 50 IU/kg used to measure IR and t½ during the 
study. The actual potency shown on the vial must be used to calculate the units of rFVIIIFc and 
the volume to inject.  
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Note: The instructions and worksheets provided in the DHA must be used to calculate the 
volume for administration based on actual potency. The actual potency shown on the vial must 
be used to calculate the volume for administration.  
The nominal strength is defined as the target potency of the vial (i.e., 250, 500, 1000, 2000, or 
3000 IU per vial). Nominal strength will be used for all other rFVIIIFc dose calculations, and 
whole vials will be used to achieve the target dose, rounded to the nearest 250 IU.  
11.1.3. Prior and 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. Bypassing agents used during the study are 
considered concomitant therapy and should be recorded as such. For subjects who are receiving 
breast milk, any drug or substance being administered to the mother during the period when she 
is breastfeeding will also be considered a concomitant medication. Maternal concomitant 
medications will also be collected, unless the breast milk is derived from a source other than the 
mother. Maternal concomitant medications will no longer be collected after the discontinuation 
of breastfeeding. 
The subjects or caregivers will be instructed that the subject should not start any new 
medications, including nonprescription drugs and herbal preparations, unless they have received 
permission from the Investigator. 
11.1.4. 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] or rFVIIa 
[NovoSeven]) are allowed in subjects as outlined in Section 7.2.2.1. All such therapy must be 
recorded in the eCRF. The prophylactic use of bypassing agents in subjects requires discussion 
with the Sponsor Medical Monitor and documentation of rationale. 
11.2. 
Compliance  
Compliance with treatment dosing is to be monitored and recorded by site staff. 
The date and time of the rFVIIIFc administrations on Day 1 and the doses given prior to 
assessments of rFVIIIFc t½ and IR, which will be administered in the clinic, will be recorded in 
the eCRF. The date, time, amount of, and reason for rFVIIIFc administrations done outside the 
clinic will be recorded by the subject/caregiver in the EPD. The EPD data will be reviewed on an 
ongoing basis by study site staff and the Clinical Monitor. 
11.3. 
Excluded Concomitant Therapies and 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. AEs related to administration of these procedures 
must be documented on the appropriate eCRF. 
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No other drug under investigation may be used concomitantly with the study treatment. Subjects 
are not allowed to participate concurrently in another interventional 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 the study. 
 Emicizumab® (Hemlibra) 
 Any other FVIII 
During the Tapering Period, treatment with bypassing agents may be considered if bleeding is 
unresponsive to treatment with rFVIIIFc (see Section 7.2.3). It is recommended that subjects be 
tested for inhibitors. See Section 7.2.2.1 for additional details regarding use of bypassing agents. 
Subjects will be instructed to contact their Investigators before taking any new medications, 
including nonprescription drugs and herbal preparations. 
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12. 
STUDY TREATMENT MANAGEMENT  
12.1. 
rFVIIIFc Stability and Storage  
rFVIIIFc is supplied in kits comprising a single-use vial containing nominally 250, 500, 1000, 
2000, or 3000 IU of factor VIII potency, a pre-filled syringe with 3 mL of sterile water for 
injection, and a sterile vial adapter (reconstitution device). The actual amount of rFVIIIFc in IU 
is stated on the label and carton of each vial. Any of the potencies listed may be used. The label 
will include conditions for storage, lot number, and other pertinent information such as Sponsor 
and caution statement. 
Study treatment 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 12.2. 
Study treatment must only be dispensed by a Pharmacist or a medically qualified staff. Study 
treatment is to be dispensed only to a subject (or subject’s legally authorized representative) 
enrolled in this study. 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 cannot be used for another subject. 
Study site staff will refer to the approved package insert and DHA for specific instructions on the 
handling, preparation, administration, and disposal of the study treatment. 
12.1.1. rFVIIIFc Preparation  
The individual preparing rFVIIIFc will first carefully review the instructions provided in the 
approved package insert and the DHA. 
If the packaging is damaged, or if there is anything unusual about the appearance or attributes of 
the vials or drug, it cannot be used. The vial in question will be saved at the study site, and the 
problem will be immediately reported to Sponsor. 
12.1.2. rFVIIIFc Handling and Disposal  
The Investigator must return all used and unused kits of rFVIIIFc as instructed by Sponsor unless 
approved for onsite destruction. The instructions for returning the kits will be provided at the 
time the request is made by Sponsor. 
If any Sponsor supplies are to be destroyed at the study site, the institution or appropriate site 
personnel must obtain prior approval from Sponsor by providing, in writing, the destruction 
policy or details of the method of destruction. After such destruction, the institution/Principal 
Investigator(s) must notify Sponsor, 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. 
 
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12.2. 
rFVIIIFc Accountability  
Accountability for study treatment is the responsibility of the Investigator. The study site must 
maintain accurate records demonstrating the date 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 must 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 Sponsor. A written explanation must be provided to 
Sponsor for any discrepancies. 
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13. 
EFFICACY AND PHARMACOKINETIC ASSESSMENTS  
Laboratory samples will be drawn for assessment of inhibitor titer (Nijmegen-modified Bethesda 
assay) and FVIII activity (1-stage activated partial thromboplastin time [aPTT] assay) and 
analyzed. These samples will be analyzed at the local laboratory and at a central laboratory. The 
Investigators will use local laboratory results for purposes of decision-making. Bethesda assay 
results are acceptable at sites that have not yet adopted the Nijmegen-modified Bethesda assay. 
Laboratory samples will be obtained for local assessment of hematology, blood chemistry, and 
urinalysis. Administration of rFVIIIFc, administration of bypassing agents, occurrence of 
bleeding episodes (spontaneous and traumatic), and associated details will be collected through 
the EPD. If blood volume sufficient for all samples cannot be drawn, please refer to the Study 
Reference Manual for a list of prioritization of samples. 
See Section 4.2 for the timing of all assessments. 
13.1. 
Clinical Efficacy Assessments  
If there is a limitation on blood draw volume, the local laboratory sample will be prioritized. If 
the local laboratory results cannot be interpreted, the Investigator may use the central laboratory 
results. 
Analysis of ITI outcome will be based on the Investigator’s assessment of local laboratory data 
and will be entered into the eCRF. If the local laboratory results cannot be interpreted, the 
Investigator may use the central laboratory results to assess ITI outcome. 
13.1.1. Assessment of Inhibitor Titers  
Sampling procedure and bioanalytical method 
Blood samples for the determination of FVIII inhibitors will be collected at all visits during the 
study. The procedures for blood collection, processing into plasma, storing, and transporting to 
the central laboratory are fully described in the laboratory section of the Study Reference 
Manual. Samples for inhibitor testing and assessment of FVIII activity levels will be analyzed at 
the local laboratory and at a central laboratory. 
Subjects have fulfilled the first criteria for ITI success after confirmation of negative titers 
consisting of 2 consecutive negative inhibitor assessments within 2 weeks (±3 days) based on 
local laboratory results <0.6 BU/mL by the Nijmegen-modified Bethesda assay; determination of 
negative titer based on the Bethesda assay is acceptable at sites that have not yet adopted the 
Nijmegen-modified Bethesda assay. 
13.1.2. Assessment of Incremental Recovery  
13.1.2.1. FVIII Activity  
A blood sample will be collected for monitoring of FVIII activity at each visit where IR or t½ is 
not assessed, starting from Week 2. 
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Sampling for incremental recovery  
Blood samples will be collected for analysis of rFVIIIFc activity for assessment of IR starting at 
the visit for confirmed negative titers and at all consecutive visits, except for those visits at 
which samples for rFVIIIFc t½ determination are drawn, as IR will be determined from the same 
samples. Samples for IR will be analyzed at the investigational site’s local laboratory and 
confirmed at the central laboratory, with results being entered into the eCRF. Testing for IR will 
continue, until 2 consecutive assessments represent ≥66% of the expected IR (≥1.32 IU/dL per 
IU/kg). 
Subjects must not be currently bleeding and are required to have at least a 24-hour washout prior 
to the IR predose sample collection. The sample for IR will be drawn within 30 minutes prior to 
and 30 (±5) minutes after a 50 IU/kg rFVIIIFc injection administered via a slow push IV 
injection over several minutes, at a rate of administration determined by the subject’s comfort 
level. Volume and units of factor infused must be calculated and recorded using the actual 
potency as described in the DHA included in the Study Reference Manual. 
According to the local standard of care, an IV access device may be offered to facilitate sample 
collection. Whenever possible, sites are instructed to avoid the use of heparin when drawing PK 
samples. When this is not possible, sites must follow local protocols to ensure heparin is 
adequately removed prior to the PK sample collection. The IV access device must not be flushed 
with heparin between injection of rFVIIIFc and the collection of the samples. 
Once the sample for IR has been collected, the subjects can be given the remainder of their daily 
ITI dose. 
The procedures for blood collection, processing into plasma, storing, and transporting to the 
central laboratory are fully described in the laboratory section of the Study Reference Manual. 
The plasma samples will be analyzed for FVIII activity at the study’s central laboratory using a 
validated 1-stage clotting assay. 
Subjects have fulfilled the second criterion for ITI success after achieving rFVIIIFc IR ≥1.32 
IU/dL per IU/kg on 2 consecutive assessments performed within 2 weeks (±3 days) (see 
Section 7.2.2.2). 
13.1.2.2. Calculations  
The IR will be calculated as the difference between the FVIII activity level at 30 ± 5 minutes 
postdose (C30min) and the FVIII predose activity level (Cpredose) divided by the dose, i.e., 
IR = (C30min – Cpredose) / Dose. Factor VIII activity levels below the lower limit of quantitation 
will be treated as zero. The actual dose of rFVIIIFc will be used to calculate the IR and t½. 
Calculations of IR will be done by the Investigator or designee according to the instructions in 
the DHA included in the Study Reference Manual. 
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13.1.3. Assessment of rFVIIIFc Half-Life  
13.1.3.1. Sampling for rFVIIIFc t½  
Blood samples will be collected for local and central laboratory analyses of rFVIIIFc activity for 
assessment of rFVIIIFc t½ at the visit after rFVIIIFc IR ≥1.32 IU/dL per IU/kg has been 
confirmed at 2 consecutive assessments performed within 2 weeks (±3 days). The assessment 
will be repeated at each consecutive visit until rFVIIIFc t½ is ≥7 hours and also at the EOT Visit. 
If t½ is <7 hours, subjects need to return to clinic in 2 weeks (±3 days) to complete another t½ 
assessment until ITI success or 48 weeks (12 months). t½ determination at EOT Visit does not 
need to be performed if the complete 4-sample t½ assessment was performed within 2 weeks 
prior to the EOT Visit or if the Investigator determines the subject is an ITI Treatment Failure 
(see Section 7.2.2.2). 
PK assessment of t½ requires sampling at multiple timepoints. During the ITI Period, the 
Investigator may forego the fourth PK sample, i.e., the 30- or 48-hour sample, if, in the 
Investigator’s opinion, the t½ at the third PK sample indicates that a t½ ≥7 hours cannot be 
achieved. In this case, the Investigator will document the decision to forego the fourth sample.  
Samples will be drawn according to the times indicated in Table 3. According to the local 
standard of care, an IV access device may be offered to facilitate sample collection. Whenever 
possible, sites are instructed to avoid the use of heparin when drawing PK samples. When this is 
not possible, sites must follow local protocols to ensure heparin is adequately removed prior to 
the PK sample collection. The IV access device must not be flushed with heparin between 
injection of rFVIIIFc and the collection of the samples. 
Additionally, a saline lock of the infusaport can be used for the 30-minute and 6-hour post-dose 
samples instead of heparin. Heparin may then be used for overnight maintenance of the 
infusaport for the remainder of the samples. Standard technique for clearing the infusaport of 
heparin should be employed prior to the 24- and 30-/48-hour post-dose samples. Sites are 
advised to refer to their local standard of care regarding maintenance of the IV access device. 
Subjects must not be currently bleeding and are required to have at least a 24-hour washout prior 
to the rFVIIIFc t½ predose sample collection. A dose of 50 IU/kg of rFVIIIFc for assessments 
will be delivered via a slow push IV injection over several minutes, at a rate of administration 
determined by the subject’s comfort level. Volume and units of factor infused must be calculated 
and recorded using the actual potency as described in the DHA included in the Study Reference 
Manual. Subjects will not have any additional doses of rFVIIIFc during the PK Sampling Period. 
If emergency dosing is required during the t½ Sampling Period, inform the Sponsor and the t½ 
assessment will be rescheduled. 
Once the final sample for t½ has been collected, the subjects can be given their daily ITI dose. 
Subjects have fulfilled the third and last criterion for ITI success after a FVIII activity t½ 
≥7 hours has been determined by the local and/or central laboratories (see Section 7.2.2.2). 
During the Tapering and Follow-Up Period, if a subject meets the criteria for relapse, he will 
then proceed to the EOT Visit, at which t½ will be assessed.  
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13.1.3.2. Calculations  
Calculations of t½ will be done by the Investigator/designee and Sponsor. Calculations will be 
performed according to the instructions in the DHA included in the Study Reference Manual.  
13.1.4. Assessment of Bleeding Episodes  
13.1.4.1. Definition of a Bleeding Episode  
A bleeding episode starts from the first sign of a bleed and ends no more than 72 hours after the 
last injection of bypass agents or rFVIIIFc to treat the bleeding episode, 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 of bypass agents (or rFVIIIFc during 
tapering or follow-up) 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. 
Type of bleeding episode 
When a subject reports a bleeding episode or hemorrhage, it will be classified as 1 of 2 types: 
spontaneous or traumatic. 
Spontaneous bleeding episodes 
Bleeding episodes will be classified as spontaneous if a subject or caregiver records a bleeding 
event if there is no known contributing factor such as a definite trauma or antecedent “strenuous” 
activity. The determination of “strenuous” is at the discretion of the Investigator, and the 
parent/caregiver/subject needs to be instructed by the Investigator. 
Traumatic bleeding episodes 
Bleeding episodes will be classified as traumatic if the subject or caregiver records a bleeding 
episode even when there is a known or believed reason for the bleed. For example, if a subject 
exercises strenuously and then has 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 will consider whether 
events resulting in a traumatic bleeding episode qualify as AEs and should be reported as such. 
Reporting of bleeding episodes 
Bleeding episodes in this patient population are not considered as AEs. However, the 
concomitant events associated with a bleeding episode will be reported as AEs as appropriate 
(e.g., an elbow fracture). Bleeding episodes that meet a criterion for seriousness will be reported 
as an SAE. All bleeding episodes will be captured in the EPD that the subject maintains 
throughout the study. 
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13.1.4.2. Data to Be Captured  
It is required that the subject/caregiver enter dosing information on rFVIIIFc and/or FVIII 
bypassing agents into the EPD immediately after an injection or within a maximum of 7 days, to 
ensure data integrity and to facilitate appropriate medical review and dosing guidance. 
In the event of a bleeding episode, the following information will be collected in the EPD or 
eCRF and medical records: 
 The type of bleeding episode (i.e., spontaneous or traumatic) and if related to sports 
activity or physical activity 
 The date the bleeding episode occurred 
 The product (rFVIIa, aPCCs, FVIII product [include specific drug name], etc.) and 
dose administered to treat the bleeding episode including any repeat doses 
 The location of the bleeding episode 
The EPD will serve as the source document for bleeding episodes between visits. Bleeding 
episodes during clinical visits will be recorded in the eCRF. 
The clinical sites and Clinical Monitors will ensure that there is consistency between the 
subject’s medical record, dispensing records, source documents, EPD, and eCRFs. During the 
clinic visits, the Investigator will verify whether a bleeding episode has occurred and was 
“spontaneous” or “traumatic.” The subject or caregiver will also be reminded about timely EPD 
completion. 
13.2. 
Medical History Assessments  
Medical, surgical, hemophilia, inhibitor, bleeding episode, and ITI history will be collected at the 
Screening Visit. 
Medical and surgical history includes any significant medical condition and/or any significant 
surgical histories, plus the following: history of allergy/anaphylactic shock, HIV infection status 
(if positive, viral load, CD4 count, and platelets; based on laboratory results within the last 
26 weeks [6.5 months]), hepatitis B virus, HCV, medication history, and any other congenital 
immunodeficiency. 
Hemophilia history includes (but is not limited to) the date of diagnosis; severity of disease, 
family history of hemophilia, and genotype; blood group; number of prior exposures to FVIII; 
last dose regimen; and type of FVIII (recombinant, plasma derived with von Willebrand factor 
(VWF) or plasma derived without VWF prior to inhibitor development. 
Inhibitor history includes peak historical inhibitor titer, age at the time of inhibitor detection, and 
exposure days at inhibitor development. 
Bleeding episode history in the 12 months (48 weeks) prior to Baseline includes date, location, 
type of bleeding episode (e.g., spontaneous or traumatic), and treatment of the bleeding episode. 
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13.3. 
Demography  
Demographic data to be collected will include, but will not be limited to, the subject’s age at 
Screening, sex, race and ethnicity (unless not able to be reported due to local regulations), body 
weight, body length, and geographic location and will be recorded in the eCRF at the Screening 
Visit. The body weight recording will be repeated at each visit as specified in the Schedules of 
Activities (see Section 4.2). Height will also be recorded at Screening and EOT Visit. 
13.4. 
Pharmacoeconomic Assessments  
Consumption will be assessed based on the amount of administered study treatment as recorded 
in the eCRF and in the EPD. 
The date and time of the in-clinic administrations of rFVIIIFc will be recorded in the eCRF by 
the Investigator or designee. The date, time, amount of, and reason for any study treatment 
administrations done outside the clinic will be recorded by the subject/caregiver in the EPD. 
Subject’s days missed from school or work will be recorded in the EPD. Hospitalizations will be 
captured as SAEs. 
13.5. 
Exploratory Laboratory Assessments  
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14. 
 SAFETY ASSESSMENTS   
See Section 4.2 for the timing of all safety assessments. 
14.1. 
Clinical Safety Assessments  
The following clinical assessments will be performed to evaluate the safety profile of rFVIIIFc: 
 Physical examinations 
 Vital sign measurements (body temperature, blood pressure, pulse rate, and 
respiratory rate) should be taken prior to and 20 (±5) minutes after the end of the 
rFVIIIFc injection (if dosing occurs at the visit) 
 Weight and height measurements 
 Concomitant therapy and procedure recording 
 AE and SAE recording 
14.2. 
Laboratory Safety Assessments  
Blood samples for determination of hematology and blood chemistry variables and urine dipstick 
will be collected at Screening Visit, Baseline Visit (before the first study treatment 
administration), and then every 12 weeks (3 months) from the start of the ITI Period through the 
time of ITI complete success. These assessments will be collected every 12 weeks (3 months) 
during the Tapering Period. If the subject completes the ITI Period in a duration shorter than 12 
weeks (3 months), these assessments must be completed at the end of the period. Samples will 
also be collected at the EOT Visit. The date of blood and urine collection will be recorded in the 
eCRF. 
The following laboratory tests will be performed at a local laboratory to assess the safety profile 
of rFVIIIFc: 
 Hematology includes white blood cell count and differential, red blood cell, 
hemoglobin, hematocrit, and platelet count. 
 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. 
 Dipstick urinalysis, including a protein reading; if the protein reading is positive 
(≥1+), a full laboratory urinalysis will be performed. 
Clinically significant abnormal laboratory values should be reported as AEs at the discretion of 
the Investigator. The corresponding result should be entered into the eCRF together with 
information on laboratory variable assessed, date of sample, and normal range from the local 
laboratory. 
For Canada specific requirements:see Appendix B. 
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The volume of blood taken from the subjects: the study-related blood loss should not exceed 3% 
of the total blood volume during a period of 4 weeks (1 month) and should not exceed 1% of the 
total blood volume at any single time (see Table 6 and Section 14.5). 
14.3. 
Vital Signs  
Vital signs (blood pressure [systolic and diastolic], pulse rate, respiratory rate, and body 
temperature) will be assessed at each visit. Vital signs should be taken prior to and 20 (±5) 
minutes after the end of the rFVIIIFc injection (if dosing occurs at the visit). 
Body temperature will be measured using a tympanic thermometer according to each clinic’s 
standard procedures. 
Abnormal vital sign values that the Investigator determines are clinically significant should be 
reported as AEs (see Section 15.1 for details). 
14.4. 
Physical Examination  
A general physical examination will be assessed and recorded as “normal” or “abnormal” at each 
visit. Abnormalities will be specified. Any persisting abnormalities will be stated each time the 
examination is performed. Diagnosis of new abnormalities will be recorded as AEs. If any 
abnormalities are reported at the Screening Visit, they will be recorded as medical history. 
14.5. 
Sample Volumes  
The volume of blood taken from the subjects should comply with the European Commission 
guidance (European Commission, 2008) for recommended blood draw volume limits for 
pediatric patients, that is, the study-related blood loss should not exceed 3% of the total blood 
volume during a period of 4 weeks (1 month) and should not exceed 1% of the total blood 
volume at any single time. Examples of recommended blood draw volume limits per the 
European Commission guidance are provided in Table 6. Local and/or regional guidelines 
regarding blood draw volumes may also apply. 
Subjects of low body weight may require Screening blood draws over multiple days to comply 
with maximum allowable blood draw volumes (see Table 6). 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. 
The laboratory section of the Study Reference Manual will define which laboratory assessments 
to prioritize to ensure that the maximum allowed blood volume is not exceeded. 
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Table 6 
Examples of Recommended Blood Draw Volume Limits  
Subject Weight (kg) 
Blood Draw Limits (mL)1 
Single Occasion 
4 Weeks2 
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 
1 Based on an estimated blood volume of 80 mL/kg. 
2 Based on the European Commission guidance (European Commission, 2008) for recommended blood draw 
volume limits for pediatric patients, recommending that blood draw volumes not exceed 1% of the total blood 
volume on a single occasion or 3% of the total blood volume over a 4-week (1-month) 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 ICF, each subject or his legally authorized representative and/or main 
caregiver must be given the names and telephone numbers of study site staff for reporting AEs 
and medical emergencies. 
SAEs will be collected from the time of signing ICF to the Final Safety Follow-Up 
Visit/Telephone Call. AEs will be collected from the time of the first dose of rFVIIIFc to the 
Final Safety Follow-Up Visit/Telephone Call. 
See Section 4.2 for the timing of all assessments. 
15.1. 
Definitions  
15.1.1. Adverse Event  
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product 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 subject population are not considered AEs. Bleeding episodes that meet 
a serious criterion must be reported as an SAE. All bleeding episodes that occur outside the 
clinic or hospital will be captured in the EPD that the subject or the subject’s caregivers will be 
maintaining throughout the study period. EPD data must be entered within 7 days. 
Determination of whether an abnormal laboratory value meets the definition of an AE will be 
made by the Investigator. Although abnormal laboratory values are typically not considered AEs, 
the following considerations may result in an abnormal laboratory value being considered an AE: 
 A laboratory test result that meets the criteria for an SAE 
 A laboratory test result that requires the subject to receive specific corrective therapy 
 A laboratory abnormality that the Investigator considers to be clinically significant 
Preexisting Conditions 
A preexisting condition (i.e., a disorder present before the AE reporting period started and noted 
on the pretreatment medical history/physical examination form) should not be reported as an AE, 
unless the condition worsens in severity or episodes increase in frequency during the AE 
reporting period. 
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Procedures 
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not be 
reported as AE. However, the medical condition for which the procedure was performed must be 
reported if it meets the definition of an AE. For example, an acute appendicitis that begins during 
the AE reporting period would be reported as the AE and the resulting appendectomy entered in 
the comments section in the eCRF. 
Lack of Efficacy 
If there is a relapse of inhibitor after initial successful ITI, this will be captured as an SAE, 
“relapse of inhibitor” and not as “lack of efficacy.” 
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 subject hospitalization or prolongation of existing hospitalization 
 Results in persistent or significant disability/incapacity 
 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 1 of the other outcomes 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 subject hospitalization.). 
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 of 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. 
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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 Commercial Drug 
Not related 
An AE is considered “not related” to the use of the investigational drug if there is not a 
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 AE (e.g., the event 
occurred before administration of drug), or the presence of a more likely alternative 
explanation for the AE. 
Related 
An AE is 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 
re-challenge, 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 AE, or a lack of an alternative explanation for the AE. 
Abbreviation: AE=adverse event. 
15.2.3. Severity of Events  
The following definitions should be considered when evaluating the severity of AEs and SAEs: 
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; symptom(s) 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 by Sponsor Pharmacovigilance according to the 
Investigator Brochure. 
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15.3. 
Monitoring and Recording Events  
15.3.1. Adverse Events  
Any AE experienced by the subject between the time of the first dose of study treatment and the 
Safety Follow-Up Visit/Telephone Call is to be recorded on the subject’s eCRF, regardless of the 
severity of the event or its relationship to study treatment. 
15.3.2. Serious Adverse Events  
Any SAE experienced by a subject between the time of signature of 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 IQVIA 
Pharmacovigilance and the designated personnel within 24 hours, as described in Section 15.3.3 . 
Follow-up information regarding an SAE also must be reported within 24 hours. 
Bleeding episodes in this patient population are not considered as AEs. However, the 
concomitant events associated with a bleeding episode will be reported as AEs as appropriate 
(e.g., an elbow fracture). Bleeding episodes that meet a criterion for seriousness will be reported 
as an SAE. All bleeding episodes will also be captured in the EPD that the subject maintains 
throughout the study. 
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: 
 Development of a confirmed positive inhibitor (≥0.6 BU/mL) after ITI success, 
during the Tapering and Follow-Up Periods (i.e., relapse of an inhibitor) 
 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 World Health Organization scale 
(WHO, 1979): 
 Grade 2: bronchospasm; no parenteral therapy needed 
 Grade 3: bronchospasm; parenteral therapy required 
 Grade 4: anaphylaxis 
 A subject develops a vascular thrombotic event, with the exception of IV injection 
site thrombophlebitis 
Allergic reactions, including anaphylaxis, have been reported with FVIII products. The 
subjects/caregivers must 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 subjects/caregivers must be instructed to seek 
immediate medical care. 
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The subject and/or the subject’s legally authorized representatives 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, 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 
subject and/or the subject’s caregivers will be instructed to seek immediate medical care for the 
subject. 
15.3.3. Immediate Reporting of Serious Adverse Events  
To adhere to all applicable laws and regulations for reporting an SAE, the study site must 
formally notify IQVIA Pharmacovigilance within 24 hours of the study site staff becoming 
aware of the SAE. It is the Investigator’s responsibility to ensure that the SAE reporting 
information and procedures are used and followed appropriately. 
Reporting Information for SAEs 
Any SAE that occurs between the time that the subject or subject’s parents/legal guardian 
has signed the ICF and 7 to 14 days after the EOT Visit (Final Safety Follow-Up 
Visit/Telephone Call) must be reported to IQVIA Pharmacovigilance within 24 hours of the 
study site staff becoming aware of the event. 
A report must be submitted regardless of the following: 
 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 an SAE, fax a completed SAE form to IQVIA 
Pharmacovigilance at the country-specific fax numbers provided in the Study Reference 
Manual Official Contact List for complete contact information. 
15.3.3.1. Deaths  
Death is an outcome of an event. The event that resulted in death should be recorded 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 IQVIA Pharmacovigilance. The term death will 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 Sponsor to be related to the study treatment administered. 
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Sponsor or designee will report SUSARs to the appropriate regulatory authorities and 
Investigators as required, according to local law. 
15.4. 
Procedures for Handling Special Situations  
15.4.1. 
Contraception  
No animal reproductive studies have been done with rFVIIIFc. The effects of rFVIIIFc on 
pregnancy or the offspring of male subjects are unknown. In accordance with regulatory 
guidance, Sponsor recommends that Investigators discuss the use of contraception with subjects, 
as appropriate. 
For Canada specific changes: See Appendix B. 
15.4.2. Reporting Pregnancy  
Congenital abnormalities/birth defects in the offspring of male subjects will be reported as an 
SAE when study treatment-exposed conception occurs. 
Pregnancy in male subject’s partner shall be reported to IQVIA Pharmacovigilance (at the 
country-specific fax numbers provided in the Study Reference Manual) promptly upon 
awareness by any study personnel, whether associated with an AE or not. Pregnancy itself will 
not be considered an AE. In all reported situations, Sponsor or designee will provide the 
Investigator with a Pregnancy Report Form, which shall be completed and returned by the 
Investigator. Sponsor or designee will make every effort to follow up on the outcome of the 
pregnancy. 
15.4.3. Overdose  
An overdose is any dose of study treatment administered to a subject or taken by a subject that 
exceeds the dose assigned to the subject according to the protocol. Overdoses are not considered 
AEs and should not be recorded as an AE on the eCRF; however, all overdoses must be recorded 
on an Overdose form and faxed to IQVIA Pharmacovigilance within 24 hours of the site 
becoming aware of the overdose. An overdose must be reported to IQVIA Pharmacovigilance 
even if it does not result in an AE. If an overdose results in an AE, the AE must be recorded. If 
an overdose results in an SAE, both the SAE and Overdose forms must be completed and faxed 
to IQVIA Pharmacovigilance. All study treatment-related dosing information must be recorded 
on the dosing eCRF. 
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15.4.4. 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 will 
contact the study’s Medical Monitor. See the Study Reference Manual Official Study Contact 
List for complete contact information. 
15.5. 
Safety Responsibilities  
15.5.1. Investigator Responsibilities  
The Investigator’s responsibilities include the following (see Section 15.1): 
 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. 
 Report congenital abnormalities/birth defects in the offspring of male subjects when 
study treatment-exposed conception occurs. 
 Complete an SAE form for each SAE, and fax it to IQVIA Pharmacovigilance within 
24 hours of the study site staff becoming aware of the event or new information. 
 Ensure that all AE and SAE reports are supported by documentation in the subjects’ 
medical records. 
 Pursue AE follow-up information, if possible, until the event has resolved or become 
stable. 
 Report SAEs to local ethics committees, as required by local law. 
For Canada specific changes, see Appendix B. 
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 
must maintain a list of the appropriately qualified persons to whom significant study-related 
duties have been delegated. 
15.5.2. Sponsor  
Sponsor’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 SAEs. 
 Sponsor 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  
The objectives of the study and the endpoints to be analyzed are listed in Section 6. 
Detailed methodology for summary and statistical analyses of the data collected in this study will 
be documented in a Statistical Analysis Plan (SAP). In general, continuous variables will be 
summarized by descriptive statistics, which includes the number, mean, median, standard 
deviation, minimum, and maximum. Categorical variables and response variables will be 
presented with the number and percentage in each category. Unless otherwise indicated, analysis 
will be performed separately for the ITI, Tapering, and Follow-Up Periods. No formal statistical 
hypothesis testing using inferential statistics will be performed. 
16.1. 
Sample Size Considerations  
Because the number of subjects who have severe hemophilia A and developed inhibitors is 
small, the determination of sample size for this study is constrained by the availability of 
subjects. To describe the duration of time needed to develop tolerization from the onset of ITI, 
the study plans to prospectively enroll up to 17 subjects who are to receive ITI for the first time. 
16.2. 
Efficacy  
16.2.1. Analysis Populations  
For the purpose of statistical analyses, 3 analysis sets are defined based on the following criteria: 
 ITI Full Analysis Set (ITIFAS): This set will include all subjects receiving at least 
1 infusion of rFVIIIFc. All analyses describing efficacy and safety during ITI 
treatment will be based on this analysis set. 
 Tapering Period Full Analysis Set (TPFAS): This set will include all subjects entering 
the tapering phase of the study. All analyses describing efficacy and safety during this 
phase will be based on this analysis set. 
 Follow-Up Period Full Analysis Set: This set will include all subjects entering the 
follow-up phase in the study. All analyses describing efficacy and safety during this 
phase will be based on this analysis set. 
16.2.2. Methods of Analysis  
16.2.2.1. Primary Endpoint Analysis  
The primary endpoint of this study, time to tolerization with a maximum of 12 months 
(48 weeks) of ITI treatment, will be summarized descriptively using minimum, mean, standard 
deviation, median, 25th and 75th quartiles, and maximum. A Kaplan-Meier plot showing 
percentage of subjects who are tolerized against time from the first ITI infusion will also be 
generated. Subjects not achieving ITI success during the 12-month (48-week) ITI Period will be 
censored at the last observed time for this analysis. The ITIFAS will be used for this analysis. 
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Descriptive statistics of the levels of rFVIIIFc inhibitors will be summarized longitudinally for 
all visits during the ITI Period. 
16.2.2.2. Secondary Endpoints Analysis  
ITI success  
The number and proportion of subjects achieving complete ITI success, partial success, or 
treatment failure will be calculated. 
The ITIFAS will be used for this analysis.  
Occurrence of relapse after successful ITI 
Occurrence of relapse will be summarized descriptively by calculating the proportion of subjects 
with ITI success who reach the criteria for relapse. The TPFAS will be used for this analysis. 
Time to relapse will be defined as the duration between ITI success and time of relapse. Time to 
relapse from successful ITI will also be summarized descriptively for subjects who relapsed 
during the Tapering or Follow-Up Period. 
Number of bleeding episodes during ITI, Tapering, and Follow-Up Periods  
The number of bleeding episodes during ITI will be summarized by month using the ITIFAS. 
Descriptive statistics for annualized bleeding rate over both Tapering and Follow-Up Periods 
will also be summarized using the TPFAS. The rate for each subject will be annualized to 
account for potential difference in Tapering and Follow-Up Periods. 
Number of days away from work or school 
Number of days missed from school or work will be summarized descriptively for the ITI Period 
using the ITIFAS and for the combined Tapering and Follow-Up Periods using the TPFAS. 
Number of hospitalization days 
Number of hospitalization days will be summarized descriptively for the ITI Period using the 
ITIFAS and for the combined Tapering and Follow-Up Periods using the TPFAS. 
Adherence 
Adherence with the treatment regimen will be calculated in 2 ways: as dose adherence and as 
dosing frequency adherence. Percentage of administered doses as registered in the EPD versus 
the prescribed doses and percentage of number of days with infusions as registered in the EPD 
compared with the prescribed number of days will be summarized using descriptive statistics for 
each of the 3 periods separately. 
Consumption during ITI 
Consumption during the entire study will be summarized descriptively using the ITIFAS. 
Descriptive statistics will also be provided for each of the periods separately using their 
respective analysis set. 
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16.2.2.3. Pharmacokinetics  
Data listings based on local and central laboratory results of IR and/or t½ for each subject by visit 
will be provided. 
16.2.2.4. Exposure and Duration of Treatment  
Duration of exposure and the total number of exposure days (EDs) to rFVIIIFc will be 
summarized descriptively. An ED is a 24-hour period in which 1 or more rFVIIIFc injections are 
given. 
16.2.2.5. Demography and Baseline Disease Characteristics  
Demographics and baseline characteristics will be summarized with descriptive statistics. 
16.3. 
Interim Analyses  
An interim analysis is planned for when at least 10 subjects have completed at least 24 weeks 
(6 months) of ITI treatment. Subsequent interim analyses will depend on the number of years 
required to recruit the targeted number of subjects.  
16.4. 
Safety  
16.4.1. Analysis Populations  
See Section 16.2.1. 
16.4.2. Methods of Analysis  
16.4.2.1. Adverse Events  
Reported AEs during the study will be coded using Medical Dictionary for Regulatory Activities. 
The number and percentage of subjects with any AEs occurring after the first infusion of 
rFVIIIFc will be summarized in frequency tables by body system, preferred term, and maximum 
severity. Listings of serious SAEs and AEs leading to discontinuation will also be presented. 
Tabulations of AEs and SAEs will be made separately for the ITI Period, the Tapering and 
Follow-Up Periods combined, as well as all 3 periods combined using ITIFAS and TPFAS, 
respectively. Tabulation for all AEs by relatedness across all periods will also be presented. 
16.4.2.2. Clinical Laboratory Results  
Listings of abnormal laboratory test results will be provided. 
16.4.2.3. Vital Signs  
Vital signs will be summarized by the number and percentage of subjects with clinically relevant 
abnormalities. Abnormal values will be defined in the SAP. A listing of abnormal vital signs will 
be provided. 
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16.5. 
Subgroup Analysis  
No particular subgroup analysis of interest has been identified, but exploratory subgroup 
analyses may be performed if considered relevant and sufficient number of subjects in each 
group is available. This will be described in further detail in the SAP. 
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17. 
ETHICAL REQUIREMENTS  
Sponsor and the Investigator must comply with all instructions, regulations, and agreements in 
this protocol and applicable ICH-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-GCP guidelines. The Investigator must 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, ICF, and other required 
study documents prior to starting the study. The Sponsor may submit documents on behalf of the 
investigational sites in countries other than the USA. 
If the Investigator makes any changes to the ICF, Sponsor must first approve the changes before 
the ICF is submitted to the ethics committee. A copy of the approved ICF must be provided to 
Sponsor. After approval, the ICF must not be altered without the agreement of the relevant ethics 
committee and Sponsor. 
It is the responsibility of the Investigator(s) to ensure that all aspects of institutional review are 
conducted in accordance with current governmental regulations. 
Sponsor must receive a letter documenting ethics committee approval, which specifically 
identifies the protocol, tracking number, and ICF version, 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. Documentation of the submission must be provided to Sponsor. 
At the completion or termination of the study, the investigational site must submit a close-out 
letter to the ethics committee and Sponsor. 
17.3. 
Subject Information and Consent  
Prior to performing any study-related activities under this protocol, including Screening tests and 
assessments, written informed consent with the approved ICF must be obtained from the subject 
or subject’s legally authorized representative, as applicable, in accordance with local practice and 
regulations. 
The background of the proposed study, the procedures, the benefits and risks of the study, and 
that study participation is voluntary for the subject must be explained to the subject (or the 
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subject’s legally authorized representative). The subject must be given sufficient time to consider 
whether to participate in the study. 
Subjects will be informed that their race and ethnicity will be collected and will be used during 
analysis of study results (unless not able to be reported due to local regulations) (see 
Section 17.4). 
In addition, pediatric subjects who have the capacity should provide their assent to participate in 
the study. The level of information provided to subjects should match their level of 
understanding as determined by the Investigator and in accordance with applicable regulations 
and guidelines. 
A copy of the signed and dated ICF (and assent, if applicable) must be given to the subject or the 
subject’s legally authorized representative. Confirmation of a subject’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. 
Local regulations must be complied with in respect to the final disposition of the original (wet 
signature) ICF and of copies of the signed and dated ICFs. The original signed ICF 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 
must also provide all authorizations required by local law (e.g., protected health information 
authorization in North America). 
During the study, the subjects’ race and ethnicity will be collected. In cross sectional analyses of 
different ethnic groups, differences in the occurrence of inhibitors have been observed 
(Astermark et al., 2005; Carpenter et al., 2012). Differential responses to FVIII products may 
occur in different haplotypes of FVIII that also differ across racial and ethnic groups (Viel et al., 
2009). 
Study reports will be used for research purposes only. The subject will not be identified by name 
in eCRFs, study-related forms, study reports, or any related publications. Sponsor, its partners 
and designees, 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  
Sponsor maintains appropriate insurance coverage for clinical studies and will follow applicable 
local compensation laws. 
17.6. 
Conflict of Interest  
The Investigators will address any potential conflicts of interest (e.g., financial interest in the 
Sponsor) with the subject before the subject decides to participate in the study. 
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17.7. 
Registration of Study and Disclosure of Study Results  
Sponsor will register the study and poststudy results regardless of outcome on a publicly 
accessible website in accordance with 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 Sponsor or designee and written approval to begin screening. The 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 Sponsor 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  
Sponsor or its designee will conduct on-site visits at the study facilities to monitor various 
aspects of the study. The Investigator must agree to Sponsor-authorized personnel having direct 
access to subject (or associated) files to verify entries made in the eCRF. Adequate space and 
time for monitoring visits must be made available by the Investigator or study staff. The site 
must complete the eCRFs in a timely manner and on an ongoing basis to allow regular review by 
the study team. 
18.4. 
Study Funding  
This study is designed and financed by Sobi and Bioverativ as part of their collaboration 
agreement. Bioverativ is the Sponsor of the study and is funding the study with Sobi. All 
financial details are provided in the separate contract(s) between the institution, Investigator, and 
Sponsor. 
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 CRO will be responsible for the administrative aspects of the study including, but not limited 
to, study initiation, monitoring, and management of SAE reports, and data management. 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 Web Response System  
An IXRS will be used in this study. Before subjects are screened or enrolled, the IXRS vendor 
will provide each study site with the necessary training, a user manual, and access rights to the 
system. 
19.1.3. Electronic or Remote Data Capture  
Subject information will be captured and managed by study sites on eCRFs by a Web-based 
electronic data capture (EDC) tool developed and supported by the CRO assisting with the 
conduct of the study and configured by Sponsor. It is recommended that data be entered into the 
EDC tool within 5 business days, including batched records and records with source documents. 
Subjects and/or his 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 7 days (see Section 13.1.4.2 ). Entries will be made in EPD for at-home 
administration and in the eCRF for in-clinic/scheduled visit administration. 
19.1.4. Central Laboratory for Assessments  
Laboratory samples will be drawn for assessment of inhibitor titer (Nijmegen-modified Bethesda 
assay or Bethesda assay at sites that have not yet adopted the Nijmegen-modified assay), FVIII 
activity (1-stage aPTT assay) for IR and t½, immune cell characterization, viral analysis, optional 
analysis of FVIII mutation and HLA allotyping. These samples will be analyzed at the local 
laboratory and the central laboratory. The Investigators will use local laboratory results for 
purposes of decision-making. 
19.2. 
Study Committees  
Not applicable. 
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 
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law, such modifications must also be approved by the appropriate regulatory agency prior to 
implementation. 
However, Sponsor 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 after the 
amendment. 
In the event of a protocol modification, the subject consent form may require similar 
modifications (see Section 17.3). 
19.4. 
Ethics Committee Notification of Study Completion or Termination  
Where required, the health 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 Sponsor in writing and receive written 
authorization from Sponsor to destroy study records. In addition, the Investigator must notify 
Sponsor of any changes in the archival arrangements including, but not limited to, archival at an 
off-site facility or transfer of ownership if the Investigator leaves the site. 
19.6. 
Study Report Signatory  
Sponsor 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 Sponsor. 
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20. 
REFERENCES  
Astermark, J., Oldenburg, J., Escobar, M., White, G. C., Berntorp, E., & group, M. I. B. S. s. 
(2005). The Malmö International Brother Study (MIBS). Genetic defects and inhibitor 
development in siblings with severe hemophilia A. Haematologica, 90(7), 924-931.  
Caram, C., de Souza, R. G., de Sousa, J. C., Araujo Pereira, T., do Amaral Cerqueira, A. M., van 
der Bom, J. G., et al. (2011). The long-term course of factor VIII inhibitors in patients 
with congenital haemophilia A without immune tolerance induction. Thromb Haemost, 
105(1), 59-65. doi:10.1160/TH10-04-0231 
Carcao, M., Shapiro, A., Staber, J., Hwang, N., Druzgal, C., Lieuw, K., et al. (2017). rFVIIIFc 
for Immune Tolerance Induction in Severe Hemophilia A Patients with Inhibitors - A 
Retrospective Analysis- Poster LB 04. ISTH.  
Carpenter, S. L., Michael Soucie, J., Sterner, S., Presley, R., & Investigators, H. T. C. N. H. 
(2012). Increased prevalence of inhibitors in Hispanic patients with severe haemophilia A 
enrolled in the Universal Data Collection database. Haemophilia, 18(3), e260-265. 
doi:10.1111/j.1365-2516.2011.02739.x 
Coppola, A., Margaglione, M., Santagostino, E., Rocino, A., Grandone, E., Mannucci, P. M., et 
al. (2009). Factor VIII gene (F8) mutations as predictors of outcome in immune tolerance 
induction of hemophilia A patients with high-responding inhibitors. J Thromb Haemost, 
7(11), 1809-1815. doi:10.1111/j.1538-7836.2009.03615.x 
Damiano, M. L., & Hutter, J. J., Jr. (2000). Immune tolerance for haemophilia patients with 
inhibitors: analysis of the western United States experience. The Tri-Regional Nursing 
Group. Haemophilia, 6(5), 526-532.  
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Franchini, M., & Lippi, G. (2011). Immune tolerance induction for patients with severe 
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Gouw, S. C., van der Bom, J. G., Ljung, R., Escuriola, C., Cid, A. R., Claeyssens-Donadel, S., et 
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Gringeri, A. (2007). VWF/FVIII concentrates in high-risk immunotolerance: the RESIST study. 
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Groomes, C. L., Gianferante, D. M., Crouch, G. D., Parekh, D. S., Scott, D. W., & Lieuw, K. 
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Gupta, N., Culina, S., Meslier, Y., Dimitrov, J., Arnoult, C., Delignat, S., et al. (2015). 
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Hay, C. R. M., & DiMichele, D. M. (2012). The principal results of the International Immune 
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Haya, S., López, M. F., Aznar, J. A., Batlle, J., & Group, S. I. T. (2001). Immune tolerance 
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Hofbauer, C. J., Kepa, S., Schemper, M., Quehenberger, P., Reitter-Pfoertner, S., Mannhalter, C., 
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moderate hemophilia A without inhibitors. Blood, 128(2), 293-296. doi:10.1182/blood-
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Hofbauer, C. J., Whelan, S. F., Hirschler, M., Allacher, P., Horling, F. M., Lawo, J. P., et al. 
(2015). Affinity of FVIII-specific antibodies reveals major differences between 
neutralizing and nonneutralizing antibodies in humans. Blood, 125(7), 1180-1188. 
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ISTH Factor VIII/IX Scientific Subcommittee (SSC) Working Party on Definitions in 
Hemophilia. (2011). ISTH Consensus Definitions in Hemophilia [draft]. Updated July 14, 
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Long-term outcome of haemophilia A patients after successful immune tolerance 
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study. Haemophilia, 22(6), 859-865. doi:10.1111/hae.12986 
Kempton, C. L., & Meeks, S. L. (2014). Toward optimal therapy for inhibitors in hemophilia. 
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(2016). First prospective report on immune tolerance in poor risk haemophilia A inhibitor 
patients with a single factor VIII/von Willebrand factor concentrate in an observational 
immune tolerance induction study. Haemophilia, 22(1), 87-95. doi:10.1111/hae.12774 
Kreuz, W., Escuriola Ettingshausen, C., Vdovin, V., Zozulya, N., Plyushch, O., Svirin, P., et al. 
(2016). First prospective report on immune tolerance in poor risk haemophilia A inhibitor 
patients with a single factor VIII/von Willebrand factor concentrate in an observational 
immune tolerance induction study. Haemophilia, 22(1), 87-95. doi:10.1111/hae.12774 
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21. 
INVESTIGATORS SIGNED AGREEMENT OF STUDY PROTOCOL  
I have read the foregoing protocol, “A Non-Controlled, Open-Label, Multicenter, Study of 
Efficacy of rFVIIIFc for Immune Tolerance Induction (ITI) in Severe Hemophilia A Subjects 
With Inhibitors Undergoing the First ITI Treatment” and agree to conduct the study according to 
the protocol and the applicable ICH-GCP guidelines and local 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) 
 
 
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APPENDIX A. PROTOCOL AMENDMENT HISTORY  
The “Protocol Amendment Summary of Changes Table” for the current amendment is located at 
the start of this document (after title page). 
 
The primary reason for this amendment to Protocol 997HA402 (version 3.0) is to reduce the 
number of subjects to be enrolled, to clarify the timing for subjects moving from interim ITI 
visits to ITI outcome assessment visits, and to clarify sample collection schedules for ADA. 
Additional updates have been made for Canada and these country-specific changes are outlined 
in Appendix B. 
 
Previous global and country-specific amendments are outlined below. 
 
Protocol Version 1.1 (specific for Canada)  
Protocol Version 1.1 
(from Version 1.0) 
New texts were added to the following sections:  
Section 8.1, Section 15.5.1   
The primary reason for this 
amendment  to Protocol 997HA402 
was to add the Inclusion Criterion #5 
in response to Health Canada 
Question #2 dated 26 June 2017. 
The Canadian regulatory authority 
requested addition of a requirement 
for study participants to use effective 
contraception, as it is not known 
whether ELOCTATE can affect 
fertility or sperm development in 
hemophilia A patients.This was 
addressed by adding Inclusion 
Criterion #5. 
This change also affected the 
Informed Consent Form, which has 
been updated accordingly. 
The amendment summary 
describing every change is available 
upon request. 
 
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Protocol Version 2.0 (Global, except Canada)  
Protocol Version 2 
(from Version 1.0) 
The changes were introduced in the following sections: 
Synopsis, Section 4.1, Section 4.2.1, Section 5, Section 
6.1, Section 6.2, Section 6.3, Section 7, Section 8.1, 
Section 8.2, Section 9.1, Section 9.2, Section 11, 
Section 12.1, Section 13, Section 14, Section 15, 
Section 16, Section 17, Section 18, Section 19, and in 
Table 1, Table 2, Table 3 and new Section 7.2.2.1, 
Section 7.2.2.2 and Section 7.2.3 have been added.  
The primary reason for this 
amendment  to Protocol 997HA402 
was to provide further clarifications, 
consistency, and a few corrections. 
The amendment summary 
describing every change is available 
upon request. 
 
Protocol Version 2.1 (specific for Canada)  
Protocol Version 2.1 
(from Version 1.1) 
The changes were introduced in the following 
sections/tables: 
Synopsis, Section 4.1, Section 4.2.1, Section 5, Section 
6.1, Section 6.2, Section 6.3, Section 7, Section 8.1, 
Section 8.2, Section 9.1, Section 9.2, Section 11, 
Section 12.1, Section 13, Section 14, Section 15, 
Section 16, Section 17, Section 18, Section 19, and in 
Table 1, Table 2, Table 3 and new sections, Section 
7.2.2.1, Section 7.2.3, Section 13.1.2.1, Section 
13.1.2.2, Section 13.1.3.1, Section 13.1.3.2, Section 
13.5.5, Section 15.4.1, Section 16.3 have been added. 
The primary reason for this 
amendment  to Protocol 997HA402 
was to provide further clarifications, 
consistency, and a few corrections, 
consistent to changes for Version 
2.0 
The amendment summary 
describing every change is 
available upon request.  
 
 
 
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APPENDIX B. COUNTRY SPECIFIC REQUIREMENTS  
 
Country-specific requirements for Canada  
Compared to the global prolocol, the country specific changes for Canada are underlined (for aditions)  
or skriked out (for deletions). 
1. Changes in Protocol Version 3 
Section 4.2 (Table 1, footnote 7) and Section 13.5.4 
This assessment is optional, and requires a separate ICF. For subjects whose FVIII mutation and human 
leukocyte antigen (HLA) allotype is not documented in medical records, samples for analysis of FVIII 
mutation and HLA allotyping will be offered. If subject or subject’s legally authorized representative 
consents, samples for analysis will To be collected at the Baseline Visit or at any subsequent visit if blood 
volume is limited at the Baseline Visit for analysis at the central laboratory. 
Section 4.2 (Table 2, footnote 1)  
During the Tapering and Follow-Up Periods, the subject's dose will be adjusted to achieve each subject's 
prophylactic dose as determined by the Investigator. Minimum Tapering Period is 16 weeks (4 months). 
Subjects who relapse during the Tapering Period (i.e., who have confirmation of inhibitor development 
AND who have confirmed decrease of IR, with or without clinical signs or symptoms) will proceed 
immediately to the EOT Visit where t1/2 will be assessed and recorded. Subjects will be closely monitored 
during the Tapering Period for potential relapse.  
Section 14.2  
Clinically significant abnormal laboratory values should be reported as AEs. at the discretion of the 
Investigator. The corresponding result should be entered into the  eCRF together with information on 
laboratory variable assessed, date of sample, and  normal range from the local laboratory.  
 
2. Changes from Protocol Version 2.1 
Section 15.4.1  
No animal reproductive studies have been done with rFVIIIFc. The effects of rFVIIIFc on pregnancy or 
the offspring of male subjects are unknown. In accordance with regulatory guidance, Sponsor 
recommends that Investigators must discuss the use of contraception with subjects, as appropriate. 
If the subject is fertile and has a female partner of childbearing potential, the subject and partner must use 
effective contraception during the study and continue contraception for 7 days after his last dose of study 
treatment. The study participant must not donate sperm during the study and for 7 days after his last dose 
of study treatment. 
 
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3. Changes from Protocol Version 1.1 
Section 8.1 
To be eligible to participate in this study, candidates must meet the following eligibility criteria at the 
time of enrollment: 
1. Ability of the subject or his legally authorized representative (e.g., parent or legal guardian) to 
understand the purpose and risks of the study and provide signed and dated informed consent and 
authorization to use protected health information in accordance with national and local subject 
privacy regulations 
2. Male subjects of any age diagnosed with severe hemophilia A (as confirmed from the medical 
record) 
3. Currently diagnosed with high-titer inhibitors (historical peak ≥5 BU/mL, according to medical 
records) 
4. Previously treated with any pd-FVIII or recombinant conventional or Extended Half-Life FVIII 
5. If the subject is fertile and has a female partner of childbearing potential, the subject and partner 
must use effective contraception during the study and continue contraception for 7 days after his 
last dose of study treatment. The study participant must not donate sperm during the study and for 
7 days after his last dose of study treatment. 
 
Section 15.5.1  
 
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. 
 
Report congenital abnormalities/birth defects in the offspring of male subjects when study 
treatment-exposed conception occurs. 
 
Report pregnancy in the partner of a male subject when study-treatment-exposed conception 
occurs, whether or not the pregnancy is associated with an AE. 
 
Complete an SAE form for each SAE, and fax it to IQVIA Pharmacovigilance within 
24 hours of the study site staff becoming aware of the event or new information. 
 
Ensure that all AE and SAE reports are supported by documentation in the subjects’ medical 
records. 
 
Pursue AE follow-up information, if possible, until the event has resolved or become stable. 
 
Report SAEs to local ethics committees, as required by local law. 
 
 
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