A Randomized, Open-Label Study to Evaluate the Pharmacokinetics and Safety of Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc; BIIB031) Manufactured at 15K Scale and at Different Vial Strengths in Previously Treated Subjects With Severe Hemophilia A
Phase: PHASE3
Conditions: Severe Hemophilia A
Sponsor: Bioverativ Therapeutics Inc.

 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
1 
 
 
 
 
 
 
 
Biogen MA Inc. 
250 Binney Street 
Cambridge, MA 02142 
United States 
 
PROTOCOL NUMBER: 
997HA309 
Biogen Idec Research Limited 
Innovation House 
70 Norden Road 
Maidenhead Berkshire 
SL6 4AY 
United Kingdom 
 
PHASE OF DEVELOPMENT: 
3b 
 
 
PROTOCOL TITLE:  A Randomized, Open-Label Study to Evaluate the 
Pharmacokinetics and Safety of Recombinant Factor VIII Fc Fusion Protein 
(rFVIIIFc; BIIB031) Manufactured at 15K Scale and at Different Vial Strengths in 
Previously Treated Subjects With Severe Hemophilia A 
 
 
EUDRA CT NO: 
 
2014-003895-21  
 
 
DATE: 
21 September 2015 
Version 1.1 
FINAL 
 
Supersedes previous Version 1 dated 08 April 2015, for participating sites in the United States. 
 
 
 

Protocol 997HA309 
 
Version 1.1 
Pharmacokinetics and Safety of rFVIIIFc 15K Product 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
3 
 
TABLE OF CONTENTS 
1. 
SPONSOR INFORMATION .......................................................................................8 
2. 
LIST OF ABBREVIATIONS.......................................................................................9 
3. 
SYNOPSIS .................................................................................................................11 
4. 
STUDY SCHEMATIC AND SCHEDULE OF EVENTS FOR STUDY 
997HA309 ...................................................................................................................19 
4.1. 
Study Schematic .........................................................................................................19 
4.2. 
Schedule of Events .....................................................................................................21 
4.2.1. 
Screening ....................................................................................................................22 
4.2.2. 
Pharmacokinetic Assessments ....................................................................................24 
4.2.3. 
Treatment Period ........................................................................................................26 
4.2.4. 
Surgery Visits .............................................................................................................28 
5. 
INTRODUCTION ......................................................................................................30 
5.1. 
Profile of Previous Experience With rFVIIIFc ...........................................................31 
5.2. 
Study Rationale ...........................................................................................................33 
5.3. 
Rationale for Dose and Schedule Selection ................................................................34 
5.4. 
Potential Risks and Benefits .......................................................................................34 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................35 
6.1. 
Objectives ...................................................................................................................35 
6.1.1. 
Primary Objectives .....................................................................................................35 
6.1.2. 
Secondary Objectives .................................................................................................35 
6.2. 
Endpoints ....................................................................................................................35 
6.2.1. 
Primary Endpoint ........................................................................................................35 
6.2.2. 
Secondary Endpoints ..................................................................................................35 
7. 
STUDY DESIGN .......................................................................................................37 
7.1. 
Study Overview ..........................................................................................................37 
7.2. 
Study Specifics ...........................................................................................................38 
7.2.1. 
Inhibitor Testing .........................................................................................................38 
7.2.2. 
Anti-rFVIIIFc Antibody Testing ................................................................................38 
7.3. 
Overall Study Duration and Follow-Up .....................................................................38 
7.3.1. 
Screening ....................................................................................................................38 

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7.3.2. 
Pharmacokinetic Assessments ....................................................................................39 
7.3.3. 
Treatment ....................................................................................................................39 
7.3.4. 
Follow-Up ...................................................................................................................40 
7.4. 
Study Stopping Rules .................................................................................................40 
7.5. 
End of Study ...............................................................................................................40 
8. 
SELECTION OF SUBJECTS ....................................................................................41 
8.1. 
Inclusion Criteria ........................................................................................................41 
8.2. 
Exclusion Criteria .......................................................................................................42 
9. 
ENROLLMENT, REGISTRATION, AND RANDOMIZATION ............................44 
9.1. 
Screening and Enrollment ...........................................................................................44 
9.2. 
Randomization and Registration of Subjects ..............................................................44 
9.3. 
Blinding Procedures ....................................................................................................44 
10. 
STUDY TREATMENT ..............................................................................................45 
10.1. 
Treatment Schedule ....................................................................................................45 
10.1.1. 
Pharmacokinetic Assessments ....................................................................................45 
10.1.2. 
Treatment Period ........................................................................................................48 
10.1.3. 
Bleeding Episodes ......................................................................................................49 
10.1.4. 
Surgery ........................................................................................................................49 
10.2. 
Modification of Dose and/or Treatment Schedule ......................................................52 
10.3. 
Precautions ..................................................................................................................52 
10.4. 
Compliance .................................................................................................................52 
10.5. 
Concomitant Therapy and Procedures ........................................................................52 
10.5.1. 
Concomitant Therapy .................................................................................................52 
10.5.2. 
Concomitant Procedures .............................................................................................53 
10.6. 
Continuation of Treatment ..........................................................................................53 
11. 
STUDY TREATMENT MANAGEMENT ................................................................54 
11.1. 
rFVIIIFc ......................................................................................................................54 
11.1.1. 
rFVIIIFc Preparation ..................................................................................................55 
11.1.2. 
rFVIIIFc Storage .........................................................................................................55 
11.1.3. 
rFVIIIFc Handling and Disposal ................................................................................55 
11.1.4. 
rFVIIIFc Accountability .............................................................................................56 

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12. 
DISCONTINUATION OF STUDY TREATMENT AND/OR 
WITHDRAWAL OF SUBJECTS FROM THE STUDY ...........................................57 
13. 
PHARMACOKINETIC ASSESSMENTS .................................................................59 
13.1. 
Pharmacokinetic (rFVIIIFc Activity) Assessments ....................................................59 
14. 
SAFETY ASSESSMENTS ........................................................................................60 
14.1. 
Clinical Safety Assessments .......................................................................................60 
14.2. 
Laboratory Assessments .............................................................................................60 
14.3. 
Retention of Plasma Samples .....................................................................................60 
15. 
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES .................................................................................................62 
15.1. 
Definitions ..................................................................................................................62 
15.1.1. 
Serious Pretreatment Event .........................................................................................62 
15.1.2. 
Adverse Event .............................................................................................................62 
15.1.3. 
Serious Adverse Event ................................................................................................62 
15.2. 
Safety Classifications ..................................................................................................63 
15.2.1. 
Investigator Assessment of Events .............................................................................63 
15.2.2. 
Relationship of Events to Study Treatment ................................................................63 
15.2.3. 
Severity of Events .......................................................................................................63 
15.2.4. 
Expectedness of Events ..............................................................................................64 
15.3. 
Monitoring and Recording Events ..............................................................................64 
15.3.1. 
Serious Pretreatment Events .......................................................................................64 
15.3.2. 
Adverse Events ...........................................................................................................64 
15.3.3. 
Serious Adverse Events ..............................................................................................64 
15.3.4. 
All Events ...................................................................................................................65 
15.3.5. 
Immediate Reporting of Serious Adverse Events .......................................................66 
15.3.5.1. 
Deaths .........................................................................................................................66 
15.3.6. 
Suspected Unexpected Serious Adverse Reactions ....................................................66 
15.4. 
Procedures for Handling Special Situations ...............................................................67 
15.4.1. 
Pregnancy ...................................................................................................................67 
15.4.2. 
Overdose .....................................................................................................................67 
15.4.3. 
Medical Emergency ....................................................................................................67 
15.4.3.1. 
Unblinding for Medical Emergency ...........................................................................67 

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15.5. 
Contraception Requirements ......................................................................................67 
15.6. 
Safety Responsibilities ................................................................................................67 
15.6.1. 
The Investigator ..........................................................................................................67 
15.6.2. 
Biogen .........................................................................................................................68 
16. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ...........69 
16.1. 
Demography and Baseline Disease Characteristics ....................................................69 
16.2. 
Pharmacokinetics ........................................................................................................69 
16.2.1. 
Analysis Populations ..................................................................................................70 
16.2.1.1. 
Pharmacokinetic Analysis Set (PKAS) ......................................................................70 
16.2.1.2. 
Sequential Pharmacokinetic Subgroup .......................................................................70 
16.2.2. 
Methods of Analysis ...................................................................................................70 
16.3. 
Safety ..........................................................................................................................71 
16.3.1. 
Analysis Population ....................................................................................................71 
16.3.2. 
Methods of Analysis ...................................................................................................71 
16.3.2.1. 
Inhibitor Development ................................................................................................71 
16.4. 
Interim Analyses .........................................................................................................72 
16.5. 
Sample Size Considerations .......................................................................................72 
17. 
ETHICAL REQUIREMENTS ...................................................................................73 
17.1. 
Declaration of Helsinki ...............................................................................................73 
17.2. 
Ethics Committee ........................................................................................................73 
17.3. 
Subject Information and Consent ...............................................................................73 
17.4. 
Subject Data Protection ..............................................................................................74 
17.5. 
Compensation for Injury .............................................................................................74 
17.6. 
Conflict of Interest ......................................................................................................74 
17.7. 
Registration of Study and Disclosure of Study Results ..............................................74 
18. 
ADMINISTRATIVE PROCEDURES .......................................................................75 
18.1. 
Study Site Initiation ....................................................................................................75 
18.2. 
Quality Assurance .......................................................................................................75 
18.3. 
Monitoring of the Study..............................................................................................75 
18.4. 
Study Funding .............................................................................................................75 
18.5. 
Publications .................................................................................................................75 

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19. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION ........................76 
19.1. 
External Contract Organizations .................................................................................76 
19.1.1. 
Contract Research Organization .................................................................................76 
19.1.2. 
Interactive Response Technology ...............................................................................76 
19.1.3. 
Electronic Data Capture ..............................................................................................76 
19.1.4. 
Central Laboratories for Laboratory Assessments .....................................................76 
19.1.5. 
Central Facility for Other Assessments ......................................................................76 
19.2. 
Study Committees .......................................................................................................77 
19.3. 
Changes to Final Study Protocol ................................................................................77 
19.4. 
Ethics Committee Notification of Study Completion or Termination ........................77 
19.5. 
Retention of Study Data ..............................................................................................77 
19.6. 
Study Report Signatory...............................................................................................77 
20. 
REFERENCES ...........................................................................................................78 
21. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL .........................................80 
 
LIST OF TABLES 
Table 1: 
Instructions for Treatment of Bleeding Episodes, Washout, and PK 
Sampling During the PK Assessment .........................................................................46 
Table 2: 
rFVIIIFc Dosing for Treatment of Bleeding ..............................................................49 
Table 3: 
rFVIIIFc Dosing for Perioperative Management .......................................................51 
 
LIST OF FIGURES 
Figure 1: 
Study Design ...............................................................................................................20 
 

Protocol 997HA309 
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1. 
SPONSOR INFORMATION 
This study is being conducted by Biogen MA Inc. (Biogen).  Biogen is the sponsor of the study, 
responsible for initiating and managing the study. 
Biogen MA Inc. 
250 Binney Street 
Cambridge, MA  02142 
United States 
 
Biogen Idec Research Limited 
Innovation House 
70 Norden Road 
Maidenhead, Berkshire  
SL6 4AY 
United Kingdom 
Biogen Australia Pty Ltd 
Suite 1, Level 5,  
123 Epping Road 
North Ryde, NSW 2113 
Australia 
 
 
 
 
For urgent medical issues in which the study’s Medical Director should be contacted, please 
refer to the Study Reference Guide’s Official Study Contact List for complete contact 
information. 
Biogen may transfer any or all of its study-related responsibilities to a contract research 
organization (CRO) and other third parties; however, Biogen retains overall accountability for 
these activities. 

Protocol 997HA309 
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2. 
LIST OF ABBREVIATIONS 
 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ASA 
acetylsalicylic acid 
AST 
aspartate aminotransferase 
aPTT 
activated partial thromboplastin time 
AUCinf 
area under the concentration-time curve from time zero to infinity 
BSA 
body surface area 
BU 
Bethesda unit 
BUN 
blood urea nitrogen 
CI 
confidence interval 
CL 
clearance 
Cmax 
maximum activity 
CHMP 
Committee for Medicinal Products for Human Use 
CRO 
contract research organization 
DHA 
Directions for Handling and Administration 
EDC 
electronic data capture 
eCRF 
electronic case report form 
ED 
exposure day 
EMA 
European Medicines Agency 
FcRn 
neonatal Fc receptor 
FVIII 
coagulation factor VIII 
GCP 
Good Clinical Practice 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IgG 
immunoglobulin G 
IgG1 
immunoglobulin G1 
IR 
incremental recovery 
IV 
intravenous 
IXRS 
Interactive Voice/Web Response System 
MRT 
mean residence time 
PK 
pharmacokinetic 
PK1 
pharmacokinetic assessment 1, with 2K rFVIIIFc 
PK2 
pharmacokinetic assessment 2, with 15K rFVIIIFc 
PK3 
pharmacokinetic assessment 3, with 15K rFVIIIFc 

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PT 
prothrombin time 
PTP 
previously treated patient 
PVG 
pharmacovigilance 
rFVIIIFc 
recombinant factor VIII Fc fusion protein 
SABR 
Safety and Benefit-Risk Management 
SAE 
serious adverse event 
SUSAR 
suspected unexpected serious adverse reaction 
TP 
Treatment Period 
t½ 
half-life 
ULN 
upper limit of normal 
Vss 
volume of distribution at steady state 
vWF 
von Willebrand factor 
WBC 
white blood cell 
WFH 
World Federation of Hemophilia 
WHO 
World Health Organization 
2K 
2000 liter (i.e., the bioreactor scale for the manufacturing of the drug 
substance that is ultimately packaged into vials that constitute the 
finished 2K drug product) 
15K 
15,000 liter (i.e., the bioreactor scale the manufacturing of the drug 
substance that is ultimately packaged into vials that constitute the 
finished 15K drug product) 

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3. 
SYNOPSIS 
This is a brief summary.  For details refer to the body of the protocol. 
Protocol Number: 
997HA309 
Protocol Title: 
A Randomized, Open-Label Study to Evaluate the 
Pharmacokinetics and Safety of Recombinant Factor VIII Fc 
Fusion Protein (rFVIIIFc; BIIB031) Manufactured at 15K 
Scale and at Different Vial Strengths in Previously Treated 
Subjects with Severe Hemophilia A 
Version Number: 
1 
Name of Study Treatment: 
rFVIIIFc (Eloctate; Elocta; BIIB031) 
Study Indication: 
Hemophilia A 
Phase of Development: 
3b 
Rationale for the Study: 
Biogen is increasing the scale of manufacture of rFVIIIFc 
drug substance from a 2000 L (2K) to a 15,000 L (15K) 
bioreactor.  In addition, at the 15K scale, Biogen is 
increasing the highest manufactured vial strength from 
3000 IU/vial to 6000 IU/vial, to provide more vial strength 
options. 
The purpose of this study is to compare the PK of rFVIIIFc 
drug product manufactured at the 15K scale with the PK of 
rFVIIIFc manufactured at the current scale (2K).  The study 
will also characterize the PK of rFVIIIFc 15K product in 
1000 IU vials and 6000 IU vials, characterize the PK of 15K 
rFVIIIFc after 13 weeks of prophylactic dosing, and 
evaluate the safety of 15K rFVIIIFc during extended 
prophylaxis/treatment for at least 26 weeks. This study is 
designed to be in accordance with the European Medicines 
Agency (EMA) requirements for clinical investigation of 
recombinant and human plasma-derived factor VIII products 
[EMA (EMA/CHMP/BPWP/144533/2009) 2011].   
Study Objectives and 
Endpoints: 
Objectives 
Primary:    

Protocol 997HA309 
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The primary objective of the study is as follows: 
 To compare the PK of rFVIIIFc manufactured at 
the current scale of 2000 L (2K) to the PK of 
rFVIIIFc manufactured at the 15,000 L (15K) 
scale in previously treated subjects with severe 
hemophilia A 
Secondary: 
Secondary objectives are as follows: 
1. to characterize the PK of 15K rFVIIIFc at the 15K 
baseline and after 13 weeks of treatment 
2. to characterize the PK of 15K rFVIIIFc at 
1000 IU/vial and 6000 IU/vial strengths  
3. to evaluate the safety of 15K rFVIIIFc  
Endpoints 
Primary: 
The primary endpoint includes the following PK parameters 
for pharmacokinetic assessment 1 with rFVIIIFc 
manufactured at 2K scale (PK1) and for pharmacokinetic 
assessment 2 with rFVIIIFc manufactured at 15K scale 
(PK2), including: 
 area under the concentration-time curve from 
time zero to infinity (AUCinf)  
 incremental recovery (IR)  
as estimated from the coagulation factor VIII (FVIII) 
activity data, measured by the one-stage (aPTT) clotting 
assay. 
Secondary:  
 
The secondary endpoints include the following: 
1. PK parameters, including but not be limited to 
AUCinf, IR, the maximum FVIII activity (Cmax), 
half-life (t½), clearance (CL), volume of distribution 
at steady state (Vss), and mean residence time 

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(MRT).   
PK will be assessed using the one-stage (aPTT) clotting 
assay and the two-stage chromogenic assay. 
PK parameters will be assessed for the following 
 15K rFVIIIFc at the 15K baseline (i.e., at PK2) 
and after 13 weeks of treatment (at 
pharmacokinetic assessment 3, with 15K 
rFVIIIFc [PK3]) 
 15K rFVIIIFc at 1000 IU/vial and 6000 IU/vial 
strengths 
 2K rFVIIIFc (at PK1) and 15K rFVIIIFc (at 
PK2) [except AUCinf and IR, which are included 
in the primary endpoint] 
2. Development of inhibitors as measured by the 
Nijmegen-modified Bethesda assay 
3. Evaluation of adverse events (AEs) and serious 
adverse events (SAEs) 
Study Design: 
Overview: 
This is an open-label, multicenter, randomized study.  A 
minimum of 16 subjects who are at least 12 years of age and 
have had at least 150 exposure days (150 EDs) to any FVIII 
product will complete 3 PK assessments and a 26-week 
treatment period.  Approximately 24 subjects may be 
enrolled in order to obtain the necessary number of 
evaluable subjects as defined in Section 7.5. 
In this study, subjects will have PK assessments of 2K 
rFVIIIFc at the 1000 IU/vial strength (PK1) followed by PK 
assessment of either 15K rFVIIIFc (1000 IU/vial strength) 
or 15K rFVIIIFc (6000 IU/vial strength) at PK2.  After 
13 weeks of treatment with15K rFVIIIFc (1000 IU/vial or 
6000 IU/vial strength) will be re-evaluated at 
Pharmacokinetic assessment 3 (PK3).  Following PK3, 
subjects will continue prophylactic dosing until they reach 
26 weeks of treatment with 15K rFVIIIFc (total, starting 
from the PK2 assessment). 

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Safety will be assessed over the course of the study.  All 
bleeding episodes and dosing information will be captured 
in the study diary that the subject (or the subject’s caregiver) 
will maintain throughout the study. 
After completion of the study, eligible subjects living in 
countries where rFVIIIFc is not commercially available will 
be offered enrollment into extension study 8HA01EXT.   
Screening, PK Assessments, Treatment, and Follow-Up: 
Pharmacokinetic Assessment 1 (PK1):  Subjects will 
undergo washout (96 hours of washout for a short-acting 
FVIII product, or 120 hours of washout for a long-acting 
FVIII product) prior to the first PK assessment.  Following 
screening and washout, all subjects will undergo a 96-hour 
PK assessment with 50 IU/kg of rFVIIIFc manufactured at 
the 2K scale using 1000 IU/vial.   
Pharmacokinetic Assessment 2 (PK2):  It is recommended 
that the second PK assessment be performed within 2 to 
6 weeks after the first.  However, prophylaxis and treatment 
of bleeding episodes are permitted during the intervening 
period, provided that subjects undergo a minimum of 
120 hours of washout of rFVIIIFc prior to the PK2 
assessment. 
Subjects will be randomized in a 1:1 ratio to 2 groups for the 
second PK assessment:   
 Group 1 will receive 15K rFVIIIFc (1000 IU/vial 
strength), 50 IU/kg. 
 Group 2 will receive 15K rFVIIIFc (6000 IU/vial 
strength), 50 IU/kg. 
Treatment Period (TP):  After PK2, subjects will begin 
receiving treatment with rFVIIIFc (15K vials), for at least 
26 weeks.  After 13 weeks in the treatment period, subjects 
will undergo washout in preparation for the PK3 
assessment.  Following the PK3 assessment, they will 
resume treatment, until they reach a minimum of 26 weeks. 
Pharmacokinetic Assessment 3 (PK3):  Subjects will 
undergo a minimum of 120 hours of washout prior to the 
third PK assessment.  Subjects will undergo a third PK 
assessment with 15K rFVIIIFc (50 IU/kg) at the same vial 

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strength they received in PK2.  If PK3 does not occur within 
13 weeks after PK2, a Treatment Period visit will be 
performed in its place. 
Rationale for Dose and 
Schedule Selection: 
The 50 IU/kg dose was used in the Phase 3 Study 
(997HA301) PK assessment and is consistent with the EMA 
guidance [EMA (EMA/CHMP/BPWP/144533/2009) 2011]. 
Prophylactic  treatment dose and regimen:  
Following PK2 assessments, subjects will receive 
prophylactic treatment.  
The specific choice of the dosing regimen for any given 
subject and the subsequent dose or interval adjustment will 
be based on the subject’s response and will be at the 
Investigator’s discretion.  Subjects may use any of 
5 available 15K vial strengths during the treatment phase.   
Suggested prophylactic starting dosing regimens are: 
 50 IU/kg every 3 to 5 days  
OR  
 65 IU/kg weekly  
The proposed prophylactic starting regimens are based on 
the results of the Phase 3 study (997HA301) in adults and 
adolescents.   
Vial Strength 
The EMA guidance [EMA 
(EMA/CHMP/BPWP/144533/2009) 2011] requires that, for 
products marketed at different strengths, the 
pharmacokinetics of the lowest and highest concentration 
should be investigated unless otherwise justified. 
The 1000 IU/vial strength was chosen as the lowest strength 
for this study following CHMP agreement that it is the 
lowest strength suitable for PK assessment at a dose of 
50 IU/kg, although vial strengths as low as 250 IU are 
produced.   
The 6000 IU/vial strength was selected as the highest 

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strength for this study because it is the highest vial strength 
of 15K rFVIIIFc currently intended for commercialization. 
Study Location: 
Multinational (approximately 3 countries) 
Number of Planned Subjects: 
Approximately 24 enrolled subjects (12 in Group 1 and 
12 in Group 2) are planned, in order to obtain the necessary 
number of evaluable subjects as defined in Section 7.5.   
Study Population: 
This study will be conducted in subjects who are male 
previously treated patients (PTPs) ≥12 years of age with 
severe hemophilia A (FVIII <1%) and ≥150 EDs to any 
recombinant and/or plasma-derived FVIII and/or 
cryoprecipitate products. 
Detailed criteria are described in Section 8. 
Treatment Groups: 
Treatment of approximately 24 subjects is planned.   
All subjects will undergo an initial PK assessment with 
rFVIIIFc manufactured at the 2K scale (1000 IU/vial)[PK1].   
On Day 1 of PK1, subjects will be randomized (for the 
purposes of the subsequent PK2 and PK3 assessments) to 
2 groups of approximately 12 subjects each, both receiving 
drug product manufactured at the 15K scale: 
 Group 1 will receive 15K rFVIIIFc (1000 IU 
vials) for PK2 and PK3.   
 Group 2 will receive 15K rFVIIIFc (6000 IU 
vials) for PK2 and PK3.   
In the treatment period that follows PK2, all subjects will 
receive treatment with 15K rFVIIIFc for a minimum of 
26 weeks, during which time subjects will be offered the 
option of prophylactic treatment.   
Duration of Treatment and 
Follow-Up: 
The duration of a subject’s participation will be 
approximately 43 weeks, including up to 8 weeks of 
screening, 3 PK assessments, a minimum of 26 weeks of 
prophylactic dosing, and a follow-up telephone call 7 (+7) 
days after the last dose of rFVIIIFc during the Treatment 
Period.  A subject’s participation in the study may be 
extended due to the treatment of bleeding episodes or 

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surgery. 
Criteria for Evaluation:  
 
Pharmacokinetics: 
 
 
 
 
FVIII activity will be assessed using the following assays: 
 One-stage (aPTT) clotting assay 
 Two-stage chromogenic assay 
PK parameters will include but not be limited to AUCinf, IR, 
Cmax, t½, CL, Vss, and MRT. 
Safety: 
The safety profile of rFVIIIFc will be assessed based on the 
following criteria: 
 Nijmegen-modified Bethesda assay for the 
development of inhibitors 
 AEs and SAEs 
Statistical Methods: 
 
Natural log transformed primary PK endpoints (AUCinf [if 
data permit] and IR following rFVIIIFc dosing for 2K and 
15K at the 15K baseline measured by the one-stage (aPTT) 
clotting assay) will be analyzed using a mixed effect model 
with period and treatment as fixed effects and subject as a 
random effect.  Estimates of the adjusted mean differences 
(15K/2K) and corresponding 90% confidence intervals (CIs) 
will be obtained from the model.  The adjusted mean 
differences and 90% CIs for the differences will be back 
transformed (exponentiated) to provide estimates of the ratio 
of adjusted geometric means (15K/2K) and 90% CIs for the 
ratios.   
For descriptive purposes only, similar analyses may be 
performed for the other secondary PK parameters measured 
by the one-stage (aPTT) assay and for all relevant PK 
parameters measured by the two-stage chromogenic assay.   
Comparability of the 2 manufacturing scales will be 
concluded if the 90% CIs for the ratio of adjusted geometric 
means for both AUCinf and IR fall within the range of (68%, 
146%). 
In addition, the PK endpoints (including AUCinf, IR, Cmax, 

Protocol 997HA309 
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18 
 
t1/2, CL, Vss, and MRT) will be summarized descriptively by 
manufacturing scale, vial strength, and by type of assay 
(one-stage [aPTT] clotting assay and two-stage chromogenic 
assay).  Summary statistics will include, but not be limited 
to the mean, CI, standard deviation, median, minimum and 
maximum values and the geometric means (antilog of the 
means of the logs) and coefficients of variation. 
Safety endpoints, including AEs and SAEs, will be 
summarized descriptively using standard listings. 
The occurrence of inhibitors will be provided in a listing. 
Interim Analysis: 
Interim analyses of PK and/or safety data may be conducted 
during the study, for example, as required to support 
regulatory submissions, future studies, and/or publications. 
Sample Size Determination: 
The sample size is consistent with the EMA guidance for 
PK assessment of hemophilia products, and has sufficient 
power to demonstrate comparability between the primary 
PK endpoints. 
Study Stopping Rules: 
Biogen may terminate this study for safety reasons at any 
time, after informing Investigators.  The study will be 
discontinued if an unacceptable risk is identified that 
precludes continued treatment with rFVIIIFc. 

Protocol 997HA309 
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Pharmacokinetics and Safety of rFVIIIFc 15K Product 
 
CONFIDENTIAL 
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19 
 
4. 
STUDY SCHEMATIC AND SCHEDULE OF EVENTS FOR 
STUDY 997HA309 
4.1. 
Study Schematic 

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Randomization on PK1 Day 1
Final study visitf
Where rFVIIIFc is not 
commercially 
available, eligible 
subjects may enroll in 
the 
Extension Study 
(8HA01EXT)
Screening 
Up to 8 weeks
Current Prophylaxis 
or On Demand 
Regimen
Washouta
Abbreviations: 2K=rFVIIIFc produced at 2000 L scale; 15K=rFVIIIFc produced at 15,000 L scale; PK=Pharmacokinetic sampling period
aMinimum of 96 hours of washout for a  short-acting FVIII product, or 120 hours of washout for a long-acting FVIII product.
bApproximately N=24 subjects may be enrolled in order to complete the study as described in Section 7.5. 
cIf more than 2 bleeds occur during the PK1 assessment period, it will not be rescheduled. The subject may continue on the study in the treatment period.
dSee Section 10.1.2, for dosing regimens and Section 4.2 for time windows. 
eThe 120-hour washout period for PK2 may begin at the time of the PK1 injection and include the period when the patient is undergoing the PK1 assessment if no additional treatments are needed for bleeds before the 
PK2 assessment. 
fThere will be a follow up phone call 7 + 7 days after the last dose of rFVIIIFc during the treatment period unless the subject has already enrolled into the extension study, Study 8HA01EXT, by that time.  
Treatment Period
Prophylactic Dosing for 26 Weeks total, 15K Productd
Treatment Period
Prophylactic Dosing for 26 Weeks total, 15K Productd
Minimum 120-hour 
washout prior to 
PK3 injection
PK2
15K Product
1000 IU/vial
50 IU/kg
n=1
n=12b
PK2
15K Product
1000 IU/vial
50 IU/kg
n=12b
Group 1
PK3
At 13 Weeks
15K Product
1000 IU/vial
50 IU/kg
PK3
At 13 Weeks
15K Product
1000 IU/vial
50 IU/kg
PK2
15K Product
6000 IU/vial
50 IU/kg
n=12b
PK2
15K Product
6000 IU/vial
50 IU/kg
n=12b
Group 2
PK3
At 13 Weeks
15K Product
6000 IU/vial
50 IU/kg
PK3
At 13 Weeks
15K Product
6000 IU/vial
50 IU/kg
PK1
2K Productc
1000 IU/vial
50 IU/kg
n=2
n 24b
PK1
2K Productc
1000 IU/vial
50 IU/kg
n=24b
Minimum 120-hour washout Prior to PK2 injectione

Protocol 997HA309 
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4.2. 
Schedule of Events 
Each subject will participate in the following visits:  Screening; PK1 period (visits on Days 1, 2, 
3, 4, and 5); PK2 period (visits on Days 1, 2, 3, 4, and 5); a PK3 period (visits on Days 1, 2, 3, 4, 
and 5); the Final Study Visit; and a final study telephone call.  In addition, unscheduled visits 
may be conducted for inhibitor monitoring, as well as perisurgical visits (as described in the 
Schedule of Events tables).  If PK3 does not occur within 13 weeks after PK2, a TP visit will be 
performed in its place.

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4.2.1. 
Screening 
Tests and Assessments 
Screening 
 
Week -8 to 01 
Informed consent and assent2 
X 
Assessment of subject eligibility3 
X 
Demographics4 
X 
Medical, surgical, and hemophilia history5 
X 
Physical examination 
X 
Height 
X 
Weight 
X 
Vital signs6 
X 
CD4 count, viral load7 
X 
Hematology8, 9 
X 
Blood chemistry8, 10  
X 
PT and vWF antigen8 
X 
Nijmegen-modified Bethesda assay (inhibitor assay)8, 11, 12  
X 
Anti-rFVIIIFc antibody8, 12 
X 
FVIII activity (one-stage [aPTT] clotting and two-stage 
chromogenic assays)8, 12 
X 
Serum and plasma samples8, 13 
X 
Study diary training/administration/review 
X 
Subject’s completion of study diary 
   ongoing         
SAEs14 
X 
Concomitant therapy/procedures recording15 
ongoing 
 
FVIII = coagulation factor VIII; PT=prothrombin time; rFVIIIFc = recombinant coagulation factor VIII Fc fusion protein; SAE=serious adverse event; 
vWF = von Willebrand factor. 
NOTE: See Figure 1 for the relative timing of the Screening, the 3 PK periods, and the treatment period. 

Protocol 997HA309 
 
 
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Pharmacokinetics and Safety of rFVIIIFc 15K Product 
 
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1 Subjects should attend screening at trough for FVIII activity testing (to confirm severe hemophilia A, i.e., endogenous FVIII <1%).  The Screening period can 
be extended for subjects who have a bleeding episode requiring treatment with FVIII within 96 hours prior to Day 1.  Subjects must then repeat the washout.  If 
screening is prolonged more than 8 weeks, then the inhibitor, biochemistry, hematology, vital signs, and physical examination screening assessments must be 
repeated to ensure continued eligibility. 
2 Informed consent must be obtained from the subject or the subject’s legal guardian prior to any study-related procedures, including any instruction to washout 
current therapy specifically for entry into the study.  Subject assent must also be obtained, if applicable (i.e., if the subject is under 18 years of age). 
3 Eligibility should be assessed for all criteria pending the central laboratory screening results at screening and should be re-confirmed prior to Day 1 of 
pharmacokinetic assessment 1 (PK1).   
4 Includes sex, race, date of birth (year only), and ethnicity as permitted by local regulations. 
5 Medical history should include smoking and alcohol consumption habits.  Hemophilia history includes (but is not limited to) the date of diagnosis; severity of 
disease; genotype; number of prior exposures to FVIII; types of FVIII products administered; current dose and regimen of FVIII; last dose of FVIII received; 
inhibitor history; allergic/anaphylaxis history; and hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) serology.   
6 Vital signs include blood pressure, pulse, respiratory rate, and temperature (°C), and should be taken after the subject has been resting supine for 5 minutes. 
7 CD4 count and viral load are required at screening for all subjects known to be HIV antibody positive.  If no results are available from within 26 weeks prior to 
screening, the CD4 count and viral load must be performed at the central laboratory. 
8 Testing will be performed by the central laboratory. 
9 Hematology includes:  white blood cell (WBC) count, differential, platelet count, hemoglobin, and hematocrit. 
10 Blood chemistry includes:  electrolytes (sodium, potassium, and chloride), glucose, total protein, total bilirubin, ALT (alanine aminotransferase), AST 
(aspartate aminotransferase), ALP (alkaline phosphatase), BUN (blood urea nitrogen), and serum creatinine. 
11 For study eligibility, subjects must have no history of a positive inhibitor test, clinical signs of decreased response to FVIII administrations, or measurable 
inhibitor activity using the Nijmegen-modified Bethesda assay (≥0.6 Bethesda units [BU]/mL is considered positive) at screening.   
12 A washout of at least 48 hours is recommended prior to sample collection (for FVIII inhibitor testing purposes).  Separate blood samples will be obtained for 
inhibitor testing and for anti-rFVIIIFc antibody testing.  If inhibitor development is suspected during the study, additional testing will be performed for 
inhibitor status and anti-rFVIIIFc antibodies.  If the results are positive, an independent confirmatory sample will be collected 2 to 4 weeks later for testing. 
13Samples will be archived for testing (if required) for immunology or further coagulation assays, for clarification of any clinical or laboratory AE, or for 
genotype analysis in case of inhibitor development. 
14 Before treatment, report SAEs only. 
15 Medications administered up to 30 days prior to screening will be recorded. 
 

Protocol 997HA309 
 
 
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Pharmacokinetics and Safety of rFVIIIFc 15K Product 
 
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24 
 
4.2.2. 
Pharmacokinetic Assessments 
 
PK11, PK2, and PK3 
Tests and Assessments 
PK Day 1 
PK Days 2-5 
Hours (postdose) 
Predose2 
Dosing 
0.5 h 
(±5 min) 
1 h 
(±10 min) 
6 h 
(±10 min) 
24 h 
(±60 min) 
48 h 
(±60 min) 
72 h 
(±60 min) 
96 h 
(±60 min) 
Assessment of subject eligibility3 
X 
 
 
 
 
 
 
 
 
Randomization4 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
Vital signs5 
X 
 
X 
 
 
 
 
 
 
Nijmegen-modified Bethesda assay (inhibitor assay) 6, 7 
X 
 
 
 
 
 
 
 
 
Anti-rFVIIIFc antibody6,7  
X 
 
 
 
 
 
 
 
 
FVIII activity (one-stage [aPTT] clotting and two-stage 
chromogenic assays)8 
X 
 
X 
X 
X 
X 
X 
X 
X 
rFVIIIFc in-clinic administration 
 
X 
 
 
 
 
 
 
 
rFVIIIFc dosing/dispensation/accountability9 
 
 
 
 
 
 
 
 
X 
Study diary training/administration/review 
X 
 
 
 
 
 
 
 
 
Subject’s completion of study diary 
<<<<<<<<<<<<<<<<<         Ongoing        >>>>>>>>>>>>>>>>>> 
AE/SAE monitoring and recording 
<<<<<<<<<<<<<<<<<       Ongoing; Monitor and record at all visits       >>>>>>>>>>>>> 
Concomitant therapy/procedures recording 
<<<<<<<<<<<<<<<<<         Ongoing; Monitor and record at all visits       >>>>>>>>>>>>>>>>>> 
AE = adverse event; FVIII = coagulation factor VIII; h = hours; min = minutes; PK1, PK2, orPK 3 = pPharmacokinetic aAssessment 1, 2, or 3; PT = prothrombin time; 
rFVIIIFc = recombinant coagulation factor VIII Fc fusion protein; SAE = serious adverse event;TP  =  Treatment Period.  
NOTE:  See Figure 1 for the relative timing of the Sscreening period, the 3 PK periods, and the treatment periods.  PK3 will occur 14 weeks ± 7 days following PK2. 
1 If more than 2 bleeding episodes occur during the PK1 assessment period, the PK assessment will not be rescheduled.  The subject may continue on the study 
in the TP. 
2 Washout periods:  Before PK1, a minimum of 96 hours (for a short-acting product; or 120 hours of washout for a long-acting product such as rFVIIIFc).  
Before PK2 and PK3, a minimum of 120 hours.  The 120-hour washout period for PK2 may begin at the time of the PK1 injection and may include the period 
when the subject is undergoing the PK1 assessment if no additional treatments are needed for bleeding episodes before the PK2 assessment.    
3 Eligibility should be assessed for all criteria pending the central laboratory screening results at screening and should be re-confirmed prior to Day 1 of PK1.   
4 On Day 1 of PK1, subjects will also be randomized in a 1:1 ratio to receive either 1000 IU/kg or 6000 IU/kg of 15K rFVIIIFc (a single intravenous [IV] 
injection of 50 IU/kg) in the subsequent PK2 and PK3 assessments. 

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5 Vital signs include blood pressure, pulse, respiratory rate, and temperature (°C), and should be taken after the subject has been resting supine for 5 minutes; 
measured pre-injection and 30 minutes ±15 minutes from the start of the injection at dosing visits. 
6 A washout of at least 48 hours is recommended prior to sample collection (for FVIII inhibitor testing purposes).  The blood sample should be collected at 
trough on Day 1 of each injection, before the i.e.,  pre-injection is given.  Separate blood samples will be obtained for inhibitor testing and for anti-rFVIIIFc 
antibody testing.  If inhibitor development is suspected during the study, additional testing will be performed for both inhibitor status and anti-rFVIIIFc 
antibodies.  If the results are, and if positive, an independent confirmatory sample will be collected 2 to 4 weeks later for testing at the central laboratory. 
7 Testing will be performed by the central laboratory. 
8 Samples for measurement of FVIII activity should be drawn at the post-dosing times specified at the top of each column. 
9 Subjects will receive supplies of rFVIIIFc for home administration from the study site.  Each time, the study site staff will perform full medication exchange 
and accountability with the subject or the subject’s caregiver.  After the third PK assessment, the subject will continue to receive 15K rFVIIIFc until he reaches 
a minimum of 26 weeks of treatment with 15K rFVIIIFc in total.   

Protocol 997HA309 
 
 
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4.2.3. 
Treatment Period 
Tests and Assessments 
Treatment Period 
Visit1 
13 Weeks  
After PK2 Injection 
(14 weeks ± 7 days)  
Final Study Visit2 
26 weeks (+7 days)  
After PK2 Injection or  
at Early Termination 
Follow-Up  
7 (+ 7) days after last dose3 
Weight 
X 
X 
 
Physical examination 
X 
X 
 
rFVIIIFc dosing/dispensation/accountability4 
X 
X 
 
Nijmegen-modified Bethesda assay (inhibitor assay)5, 6 
X 
X 
 
Anti-rFVIIIFc antibody5, 6 
X 
X 
 
Hematology5, 7 
X 
X 
 
Blood chemistry5, 8 
X 
X 
 
Subject diary review  
X 
X 
X 
Telephone call3 
X 
X 
X 
AE/SAE monitoring and recording 
Monitor and record at all visits; telephone call every 8 weeks 
Concomitant therapy/procedures recording 
Monitor and record at all visits; telephone call every 8 weeks 
AE=adverse event; FVIII = coagulation factor FVIII; rFVIIIFc = recombinant coagulation factor VIII Fc fusion protein; PK1, PK2, PK3 = pharmacokinetic assessment 1, 2, or 3; 
SAE = serious adverse event; TP = Treatment Period   
NOTE: See the Figure 1 for the relative timing of the Screening period, the 3 PK periods, and the treatment period.  
1 This visit is needed only if the PK3 assessment period does not occur as scheduled after 13 weeks (14 weeks ± 7 days).  
2 A Final Study Visit will be performed if the subject is at the end of the Treatment Period (after a minimum of 26 weeks following the PK2 injection), the 
subject terminates from the study early, or the Sponsor declares the end of study.  If subjects terminate from study early, all end-of-study assessments will be 
done at the Termination Visit.   
3 There will be a telephone call every 8 weeks to monitor AEs and SAEs.  A Follow-Up Telephone Call is required 7 (+ 7) days after the last dose of rFVIIIFc 
during the Treatment Period to monitor AEs, SAEs, and concomitant medications and therapies.  Any subject who terminates early or is withdrawn from study 
for any reason is required to undergo the follow-up telephone visit 7 (+ 7) days after the last dose, if possible.  This follow-up is not required if the subject has 
entered directly into extension study 8HA01EXT. 

Protocol 997HA309 
 
 
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27 
 
4 Subjects will receive supplies of rFVIIIFc for home administration from the study site. Each time study treatment is dispensed, the study site staff will perform 
full medication exchange and accountability with the subject or the subject’s caregiver. 
5 Testing will be performed by the central laboratory. 
6 A washout of at least 48 hours is recommended prior to sample collection (for FVIII inhibitor testing purposes).  Separate blood samples will be obtained for 
inhibitor testing and for anti-rFVIIIFc antibody testing.  If inhibitor development is suspected during the study, additional testing will be performed for 
inhibitor status and anti-rFVIIIFc antibodies.  If the results are positive, an independent confirmatory sample will be collected 2 to 4 weeks later for testing at 
the central laboratory. 
7 Hematology includes:  white blood cell (WBC) count, differential, platelet count, hemoglobin, and hematocrit. 
8 Blood chemistry includes:  electrolytes (sodium, potassium, and chloride), glucose, total protein, total bilirubin, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), blood urea nitrogen (BUN), and serum creatinine. 
 

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28 
 
4.2.4. 
Surgery Visits 
Tests and Assessments1 
Presurgery  
Visit 1 
Visit 22 
Visit 33 
Visit 43 
Week -12 to Week -1 Before 
Surgery 
Day of 
Surgery 
1-2 Weeks After 
Surgery 
Last Postoperative 
Visit 
Physical examination 
X 
X 
 
X 
Weight 
X 
X 
X 
X 
Vital signs (temperature, blood pressure, pulse rate, 
respiratory rate) 
 
X 
 
 
Hematology4, 5 
X 
X 
X 
X 
Blood chemistry4, 6 
X 
X 
X 
X 
FVIII activity (one-stage [aPTT] clotting and two-stage 
chromogenic assays) 4,7 
X 
X 
X 
X 
Nijmegen-modified Bethesda assay (inhibitor testing) 4,8  
X 
X 
X 
X 
Anti-rFVIIIFc antibody assay4, 8  
X 
X 
X 
X 
Bleeding and dosing information collected9 
X 
X 
X 
X 
rFVIIIFc administration 
X 
X 
X 
X 
AE/SAE monitoring and recording  
X 
X 
X 
X 
Concomitant therapy/procedures recording 
X 
X 
X 
X 
AE=adverse event; FVIII = coagulation factor FVIII; rFVIIIFc = recombinant coagulation factor VIII Fc fusion protein; SAE = serious adverse event 
 
1 All tests and assessments should be collected for major surgery and minor surgery, where available.  Subjects may be allowed to have a PK assessment 
performed by the central laboratory prior to surgery if needed in the opinion of the Investigator. 
2 All assessments to be performed prior to surgery. 
3 Visit 3 (1 to 2 weeks after surgery) and Visit 4 (last post-operative visit) are not performed for subjects who undergo minor surgery.  For major surgery, Visit 4 
occurs when the subject resumes a regular rFVIIIFc regimen as determined by the Investigator, and is not required if resumption of the regular rFVIIIFc 
regimen occurs at Visit 3. 
4 Testing will be performed by the central laboratory.   
5 Hematology includes WBC, differential, platelet count, hemoglobin, and hematocrit. 

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6 Blood chemistry includes:  electrolytes (sodium, potassium, and chloride), glucose, total protein, total bilirubin, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), blood urea nitrogen (BUN), and serum creatinine. 
7 FVIII activity levels should be measured prior to the pre-operative (loading) dose of rFVIIIFc, and at 30 minutes ± 5 minutes after dosing.  A repeat sample 
will be taken approximately 6 to 9 hours after this dose, but may alternatively follow the local standard of care for determination of subsequent rFVIIIFc 
dosing.  During the subject’s hospitalization, FVIII activity will be measured daily at the local laboratory, and a plasma aliquot will be prepared for each blood 
sample drawn for subsequent analysis at the central laboratory.  One-stage (aPTT) clotting and two-stage chromogenic assays to be performed at central 
laboratory. 
8 Inhibitor and anti-rFVIIIFc antibody testing to be performed 2 to 4 weeks prior to surgery, pre-operatively on the day of surgery, 1 to 2 weeks after surgery, 
and at the last post-operative visit (for minor surgery, testing is not performed at the last 2 timepoints).  A washout of at least 48 hours is recommended prior to 
sample collection (for FVIII inhibitor testing purposes).  Separate blood samples will be obtained for inhibitor testing and for anti-rFVIIIFc antibody testing.  If 
inhibitor development is suspected during the study, additional testing will be performed for inhibitor status and anti-rFVIIIFc antibodies, and if positive, a 
confirmatory sample will be collected 2 to 4 weeks later for testing.   
9 Information to be collected will include number of injections and dose per injection to maintain hemostasis during the surgical period, estimated blood loss 
(mL) during surgery and post-operative period, and number of blood product units transfused during surgery. 
 
 

Protocol 997HA309 
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5. 
INTRODUCTION  
Study 997HA309 is designed to investigate the pharmacokinetic (PK) profile of rFVIIIFc 
manufactured at the 15K scale relative to the PK of rFVIIIFc manufactured at the current scale 
(2K).  The study will also characterize the PK of 15K rFVIIIFc in 6000 IU vials, the highest vial 
strength currently intended for commercialization, and the lower, 1000 IU vial strength, in 
accordance with European Medicines Agency (EMA) guidance [EMA 
(EMA/CHMP/BPWP/144533/2009) 2011].  The study will provide 26 weeks of safety and PK 
data about treatment with 15K rFVIIIFc.  The study population will consist of eligible male, 
previously treated subjects aged ≥12 years with severe hemophilia A.   
Overview of Hemophilia A  
Hemophilia A is an X-chromosome-linked bleeding disorder caused by mutations and/or 
deletions in the F8 gene resulting in a deficiency of coagulation factor VIII (FVIII) activity 
[Bolton-Maggs and Pasi 2003; Mannucci and Tuddenham 2001].  The coagulation disorder 
occurs predominantly in males and affects approximately 1 in 5,000 male births [Skinner 2012]. 
The severity of disease is characterized by the endogenous level of FVIII measured in the 
plasma.  Severe hemophilia A is defined as a coagulation activity of FVIII in plasma (FVIII:C) 
level of <1% (<1 IU/dL).  Individuals with severe hemophilia A experience frequent bleeding 
and recurrent spontaneous bleeding into the soft tissue and joints, leading to joint damage and 
severe disability.  Repeated bleeding into muscles and joints, which often begins in early 
childhood, results in hemophilic arthropathy and irreversible joint damage.  Damage can lead to 
limited mobility of joints, muscle atrophy, and chronic pain [Rodriguez-Merchan 2003]. 
FVIII and factor IX work in concert to activate factor X, a central step in the clotting cascade.  
The coagulation cascade has 2 pathways, the Contact Activation Pathway (Intrinsic Pathway) 
and the Tissue Factor Pathway (Extrinsic Pathway).  The plasma factors are activated in a 
cascade one after the other until the soluble plasma protein fibrinogen is transformed into a 
fibrinous clot. 
Therapies for Hemophilia A  
There is no cure for hemophilia A, so treatment focuses on the replacement of FVIII with the 
intravenous (IV) administration of FVIII-containing coagulation products to promote clotting.  
The goal of treatment with FVIII-containing coagulation products is to raise the circulating level 
of FVIII to the lowest effective level to achieve either resolution of bleeding (on-demand 
treatment) or prevention of bleeding (prophylactic treatment) [MASAC 2009; WFH 2005].  The 
frequency of administration of FVIII products varies across patients and is tailored to the 
patient’s clinical status, taking into consideration the type of bleeding episode, frequency of 
bleeding, and goal of treatment for the subject.  The dose of FVIII required also varies and has 
been based on observations over the years as well as guidelines established by organizations such 

Protocol 997HA309 
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31 
 
as the National Hemophilia Foundation of the United States and the World Federation of 
Hemophilia [WFH 2005]. 
The use of FVIII-containing plasma-derived coagulation products for people with hemophilia A, 
available for almost 40 years, has led to vast improvements in quality of life and has increased 
life expectancy.  Manufacturing methods for plasma-derived products are now considered to be 
highly effective in reducing the risk of transmission of enveloped viruses such as human 
immunodeficiency virus (HIV) and hepatitis B and C.  However, these methods may not be 
effective in reducing the risk of nonenveloped viruses, such as hepatitis A and parvovirus B19.  
Recombinant coagulation products developed more recently with no animal or human 
plasma-derived proteins have a safety advantage with a minimal risk of disease transmission 
[Mannucci and Tuddenham 2001]. 
Priorities for improving hemophilia A therapy include the development of more convenient 
dosing options and development of modified FVIII agents with longer half-life (t½) to decrease 
injection frequency.  Current therapy is focused on home therapies, which, taken 
prophylactically or administered at the onset of a bleeding episode, reduce short-term disability 
and long-term joint damage and improve patients’ quality of life and functional independence 
[Colvin 2008].  
rFVIIIFc is a novel recombinant Fc fusion protein comprised of a single molecule of B domain 
deleted FVIII attached to the Fc domain of human immunoglobulin G1 (IgG1).  This type of 
construct has been termed a monomeric Fc fusion protein [Dumont 2006].  The Fc enables 
binding to the neonatal Fc receptor (FcRn), which is responsible for protecting 
immunoglobulin G (IgG) from degradation and confers IgG the 3-week t½ observed in humans 
[Ghetie and Ward 2000; Roopenian and Akilesh 2007].  The FcRn is present in humans 
throughout life and protects IgG from catabolism [Junghans and Anderson 1996].  rFVIIIFc was 
designed to offer a longer circulating t½ than currently available FVIII products, aiming to 
provide hemophilia A patients with prolonged protection and prophylaxis from bleeding with 
less frequent dosing. 
rFVIIIFc has marketing authorization for the treatment of individuals with hemophilia A in the 
United States and several additional countries.  
5.1. 
Profile of Previous Experience With rFVIIIFc 
Nonclinical Experience 
A number of nonclinical comparability studies support the scale-up from the 2000 L to the 
15,000 L bioreactor scale, including PK, pharmacology, and immunogenicity studies in the 
HemA mouse model and in vitro studies of activation and inactivation rates.   These studies 
found that PK parameters, ex vivo efficacy, and the immunogenic potential of rFVIIIFc 
produced at the 2 scales were comparable in HemA mice.  The 2000 L drug substance and 
15,000 L drug substance were also similar in biochemical assays, including activation by 
thrombin and inactivation by activated protein C. 

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For further details regarding other nonclinical studies conducted with rFVIIIFc, see the rFVIIIFc 
Investigator’s Brochure. 
Clinical Experience 
Study 998HA101, a completed Phase 1/2a study, investigated the safety and PK of a single dose 
of rFVIIIFc given as an IV injection to subjects with severe hemophilia A and compared the PK 
of rFVIIIFc with Advate® (antihemophilic factor [Recombinant], Plasma/Albumin-Free Method, 
[INN] octocog alfa).  PK profiles were performed for Advate at 2 dose levels (25 and 65 IU/kg), 
followed by PK profiles for rFVIIIFc at equivalent doses.  rFVIIIFc was well tolerated.  No 
clinically significant changes in safety parameters occurred and most adverse events (AEs) were 
mild and resolved without sequelae by the end of the study.  No subject developed antibodies or 
inhibitors during the study period.  Compared with Advate, rFVIIIFc demonstrated significantly 
longer t½, increased systemic exposure, and a reduction in CL, with comparable Cmax and 
recovery.    
Study 997HA301, a Phase 3 study in previously treated subjects aged 12 years or older with 
severe hemophilia A, has also been completed.  A total of 164 subjects (including 13 subjects 
aged 12 to 17 years) received at least 1 dose of rFVIIIFc.  This included 146 subjects treated for 
at least 26 weeks and 23 subjects treated for at least 39 weeks, for a total of 102.05 subject-years 
on study.  Compared with Advate, rFVIIIFc demonstrated improved PK activity, as indicated by 
a 53% longer t½, a 56% increase in systemic exposure, and a 36% reduction in CL, with 
comparable Cmax and incremental recovery (one-stage [aPTT] clotting assay).  rFVIIIFc was well 
tolerated.  No subject developed an inhibitor to rFVIIIFc.  Common AEs observed were 
consistent with those expected in patients with hemophilia A.  Adverse drug reactions were 
generally mild and manageable, and the majority were not treatment limiting.  One nonserious 
event of rash required discontinuation of treatment and resolved.  There were no Grade 2 or 
greater allergic reactions or serious vascular thrombotic events.  No treatment-related SAEs were 
observed.   
Study 8HA02PED (referred to as the pediatric study) is a completed, open-label, multicenter 
study evaluating the safety, PK, and efficacy of rFVIIIFc in previously treated pediatric patients 
with severe hemophilia A who were <12 years of age and had at least 50 exposure days (EDs) to 
FVIII products prior to enrollment.  A total of 71 male subjects enrolled (36 subjects <6 years of 
age and 35 subjects 6 to <12 years of age).  A total of 60 subjects completed the week 26 visit 
(i.e., 26 weeks of prophylactic treatment for all but 1 subject) to attain at least 50 EDs.  A total of 
53 subjects (23 subjects <6 years of age and 30 subjects 6 to <12 years of age) underwent an 
evaluation of the PK profile of both prestudy FVIII and rFVIIIFc.  No subject developed an 
inhibitor during the study, including 61 subjects with at least 50 EDs to rFVIIIFc. There were no 
reports of anaphylaxis or serious hypersensitivity events associated with rFVIIIFc; and no 
vascular thrombotic events were reported.  Assessment of the PK of rFVIIIFc revealed 12.28 and 
13.45 hours t½ for the <6 years of age cohort and 6 to <12 years of age cohort, respectively.   
Study 997HA307 is an ongoing randomized, open-label crossover study to evaluate the 
pharmacokinetics of 2 vial strengths of rFVIIIFc in previously treated subjects with severe 

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hemophilia A, who are ≥12 years of age and had >150 EDs to FVIII products prior to 
enrollment.  Approximately 16 subjects will be enrolled to ensure that at least 12 subjects 
provide evaluable PK profiles for both vial strengths being tested (1000 IU/vial and 3000 
IU/vial). 
Study 8HA01EXT (referred to as the extension study) is an open-label, multicenter extension to 
both the Phase 3 study (997HA301) and the pediatric study (8HA02PED), as well as to other 
studies in which subjects have received rFVIIIFc.  The extension study is evaluating the 
long-term safety and efficacy of rFVIIIFc for prophylaxis and episodic treatment of bleeding 
episodes in previously treated patients (PTPs) with hemophilia A.   
For further details regarding the clinical studies conducted with rFVIIIFc, see the rFVIIIFc 
Investigator’s Brochure. 
5.2. 
Study Rationale 
Biogen is increasing the scale of manufacture of rFVIIIFc drug substance from 2000 L (2K) to 
15,000 L (15K).  The purpose of this study is to compare the PK of rFVIIIFc manufactured at the 
15K scale with the PK of rFVIIIFc manufactured at the current scale (2K), in order to investigate 
whether there were any effects of changes in the manufacturing process on the activity of 
rFVIIIFc.  In addition, at the 15K scale, Biogen is increasing the highest manufactured vial 
strength from 3000 IU/vial to 6000 IU/vial.  The study will also characterize the PK of 15K 
rFVIIIFc in 1000 IU and 6000 IU vials, will characterize the PK of 15K rFVIIIFc after 13 weeks 
of prophylactic dosing, and will evaluate safety of 15K rFVIIIFc during the extended 
prophylaxis/treatment for at least 26 weeks.  This study will provide clinical data to complement 
nonclinical, bioanalytical, and physicochemical comparability data on rFVIIIFc from the 2K and 
15K scale product. 
This study is designed to be in accordance with the European Medicines Agency (EMA) 
requirements for clinical investigation of recombinant and human plasma-derived factor VIII 
products [EMA (EMA/CHMP/BPWP/144533/2009) 2011], particularly with regard to the 
following: 
 A PK assessment of the pre-change product (i.e., 2K rFVIIIFc) versus the post-
change product (i.e., 15K rFVIIIFc) will be performed.   
 A PK assessment of the post-change product (i.e., rFVIIIFc manufactured at the 15K 
scale) after 13 weeks of dosing will be performed.   
 Subjects will complete a minimum of 26 weeks of dosing with 15K rFVIIIFc.  
 The PK of the lowest and highest vial strengths is being investigated.  Although vial 
strengths as low as 250 IU are produced, the 1000 IU/vial strength was chosen for this 
study because it is the lowest strength suitable for PK assessment at a dose of 

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50 IU/kg.  The 6000 IU vial represents the highest vial strength intended for 
commercialization and, therefore, was selected for this study.   
5.3. 
Rationale for Dose and Schedule Selection 
The dose for the PK assessments  (50 IU/kg) is within the 25 to 50 IU/kg specified in EMA 
guidance [EMA (EMA/CHMP/BPWP/144533/2009) 2011] and is the same as that used in the 
Phase 3 study (997HA301) for PK assessment. 
In the treatment period that follows PK2, all subjects will receive a minimum of 26 weeks of 
prophylactic treatment with 15K rFVIIIFc.  The specific choice of the dose for any given subject, 
and the subsequent dose adjustment, will be based on the subject’s response and will be at the 
Investigator's discretion.  The recommended dosing regimens are as follows: 
 50 IU/kg rFVIIIFc every 3 to 5 days.  The dose may be adjusted in the range of 25 to 
65 IU/kg at 3 to 5 day intervals.   
 65 IU/kg rFVIIIFc once weekly   
5.4. 
Potential Risks and Benefits 
See the Investigator’s Brochure for descriptions of the potential risks and benefits of rFVIIIFc.   

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6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Objectives 
6.1.1. 
Primary Objectives 
The primary objective of the study is to compare the PK of rFVIIIFc manufactured at the current 
scale of 2000 L (2K) to the PK of rFVIIIFc manufactured at the 15,000 L (15K) scale in 
previously treated subjects with severe hemophilia A. 
6.1.2. 
Secondary Objectives 
Secondary objectives are as follows: 
 To characterize the PK of 15K rFVIIIFc at the 15K baseline and after 13 weeks of 
treatment 
 To characterize the PK of 15K rFVIIIFc at 1000 IU/vial and 6000 IU/vial strengths  
 To evaluate the safety of 15K rFVIIIFc 
6.2. 
Endpoints 
6.2.1. 
Primary Endpoint 
The primary endpoint includes the following PK parameters following dosing in PK1 (rFVIIIFc 
manufactured at 2K scale) and in PK2 (rFVIIIFc manufactured at 15K scale) at the 15K baseline, 
including: 
  AUCinf 
  IR 
as estimated from the coagulation factor VIII (FVIII) activity data, as measured by the one-stage  
(aPTT) clotting assay. 
6.2.2. 
Secondary Endpoints 
The secondary endpoints include the following: 
1. PK parameters, including but not be limited to AUCinf, IR, Cmax, t½, CL, Vss, and MRT.  
PK will be assessed using the one-stage (aPTT) clotting assay and the two-stage 
chromogenic assay for the following: 

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 15K rFVIIIFc before treatment (at PK2) and after 13 weeks of treatment (at PK3) 
 15K rFVIIIFc at 1000/vial and 6000 IU/vial strengths 
 2K rFVIIIFc (at PK1) and 15K rFVIIIFc (at PK2) [only Cmax, t½, CL, Vss, and MRT; 
other parameters comprise the primary endpoint] 
2. The development of inhibitors as measured by the Nijmegen-modified Bethesda assay 
3. Evaluation of AEs and SAEs  

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7. 
STUDY DESIGN 
7.1. 
Study Overview 
This will be a randomized, open-label, multicenter study to evaluate the PK of a single dose of 
rFVIIIFc manufactured at 2 different scales (2K and 15K) and 15K rFVIIIFc.  PK of rFVIIIFc 
produced at different vial strengths will be evaluated at the 15K baseline (PK2) and after 
13 weeks on the study (PK3).  Subjects will receive treatment with 15K rFVIIIFc for at least 
26 weeks while on study, and will be followed for safety during that time.  Subjects will be PTPs 
who are ≥12 years of age.  Approximately 24 subjects will be enrolled in order to obtain the 
necessary number of evaluable subjects as defined in Section 7.5. 
After eligibility is confirmed, subjects will undergo PK assessments at clinic visits, when safety 
assessments, drug accountability, and review of dosing and bleeding data will also be performed.   
Prior to the first PK assessment (PK1) subjects will undergo a minimum washout period of 
96 hours (for short-acting products) or 120 hours (for long-acting products).  In the event that 
bleeding occurs during the washout period, the subject must repeat the washout.  
Subjects will then undergo the PK1 assessment with 2K rFVIIIFc (a single IV injection of 
50 IU/kg using 1000 IU/vial material).  During the PK1 assessment period, subjects will also be 
randomized in a 1:1 ratio to receive either 1000 IU/kg or 6000 IU/kg of 15K rFVIIIFc (a single 
IV injection of 50 IU/kg) in the subsequent PK2 and PK3 assessments.  If more than 2 bleeding 
episodes occur during the PK1 assessment, the PK assessment will not be rescheduled, and the 
subject may proceed to the 26-week Treatment Period.   
Just prior to the PK2 and PK3 injections, there will be a minimum washout of 120 hours.  It is 
recommended that the second PK assessment, PK2, be performed within 2 to 6 weeks after the 
first (Section 10.1.1).  There are no limits on the number of bleeding episodes during the 
washouts and the PK2 and PK3 assessment periods.  Subjects who cannot complete all 3 PK 
assessments may continue to the 26-week Treatment Period.   
After PK2 (irrespective of PK evaluability), subjects will begin treatment with 15K rFVIIIFc for 
at least 26 weeks (Section 10.1.2).  During treatment, subjects will be offered prophylaxis 
(dosing either every 3 to 5 days or once-weekly) using 15K rFVIIIFc.  Subjects will be allowed 
to switch from one regimen to another if approved by the Investigator and will be allowed to use 
any of several available vial strengths.   
After 13 weeks on treatment, there will be a third PK assessment (PK3) with the same vial 
strength of 15K rFVIIIFc that the subject previously received.  The subject will continue to 
receive 15K rFVIIIFc for a minimum of 26 weeks of treatment with 15K rFVIIIFc in total.  After 
completion of the study, eligible subjects living in countries where rFVIIIFc is not commercially 
available will be offered enrollment into extension study 8HA01EXT.   

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Discontinued subjects or subjects unable to complete all 3 PK assessments may be replaced if 
needed to attain the number of subjects required to complete the study as described in Section 
7.5.   
See Figure 1 for a schematic of the study design. 
7.2. 
Study Specifics 
7.2.1. 
Inhibitor Testing 
For FVIII inhibitor testing, a washout of at least 48 hours is recommended.  Inhibitor testing will 
be performed at screening, prior to each PK dose (or at the 14 week ± 7 day visit if PK3 does not 
take place at 13 weeks; see Section 4.2.3), and at the Final Study Visit.  If inhibitor development 
is suspected at any time during the study (for example, if the expected plasma FVIII activity 
levels are not attained or if bleeding is not controlled as expected following dosing), inhibitor 
testing will be performed by the central laboratory.  The definition of a positive result for 
inhibitor is any inhibitor (≥0.6 BU/mL) identified and confirmed on 2 separate samples drawn 
approximately 2 to 4 weeks apart.  Both tests must be performed by the central laboratory using 
the Nijmegen-modified Bethesda assay.  
A confirmed positive inhibitor will result in withdrawal of the subject from the study.   
7.2.2. 
Anti-rFVIIIFc Antibody Testing 
In order to characterize non-neutralizing antibodies that may react with rFVIIIFc, an exploratory 
assay that differentiates between antibodies with specificities for rFVIIIFc, full-length FVIII 
(Advate), or Fc will be used to test for the presence of anti-drug antibody in study subjects.  The 
electrochemiluminescent assay used for this test is approximately 10- to 20-fold more sensitive 
than the Nijmegen-modified Bethesda assay.  At the same timepoints when samples are drawn 
for inhibitor testing, a blood sample will be collected for testing of anti-rFVIIIFc antibody (see 
Section 4.2.2 and Section 4.2.3).   
7.3. 
Overall Study Duration and Follow-Up 
The study period will consist of screening, 3 PK assessment periods, a treatment period, and 
follow-up. 
7.3.1. 
Screening 
Subject eligibility for the study will be determined within 8 weeks prior to study entry.  The 
Screening Period will also include the washout of FVIII prior to initial study dosing.  During 
screening, subjects will continue with their prior FVIII product and treatment regimen.  
However, prior to the first rFVIIIFc PK assessment, subjects must have a washout of at least 
96 hours for a short-acting FVIII product, or at least 120 hours of washout for a long-acting 
FVIII product.  The Screening Period can be extended for subjects who require treatment with 

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FVIII for a bleeding episode within 4 days (96 hours) prior to the first injection on Day 1 of PK1 
or during the PK1 assessment periods.  Subjects will be given diaries at the Screening Visit and 
will be instructed to start recording all injections and bleeding episodes.  Further details will be 
provided in the Diary Instruction Manual.   
If screening is longer than 8 weeks, then the inhibitor, biochemistry, hematology, vital signs, and 
physical examination screening assessments must be repeated to ensure continued eligibility.  
The reason for prolongation of screening should be clearly documented. 
Eligibility should be assessed for all criteria pending the central laboratory screening results at 
screening and should be re-confirmed prior to Day 1 of PK1.   
7.3.2. 
Pharmacokinetic Assessments 
A washout period with no FVIII treatment will be required prior to each injection of rFVIIIFc for 
all PK assessments (96 hours for short-acting products or 120 hours for long-acting products).   
Eligible subjects will report to the study site for the PK assessments.  Every subject is expected 
to participate in all 3 PK assessments:  
 PK1: At the first visit, the subject will receive a single IV injection of 2K rFVIIIFc 
(50 IU/kg of 1000 IU/vial) in the clinic under medical supervision.  PK sampling will 
occur just before the PK injection and at 7 time points:  0.5 hour (±5 minutes); 1 hour 
and 6 hours (±10 minutes); and 24, 48, 72, and 96 hours (±60 minutes).  The subject 
will receive 50 IU/kg of 15K rFVIIIFc at either the 1000 IU/vial or 6000 IU/vial 
strength in subsequent PK assessments.  
 PK2: The second PK assessment will be performed, preferably, within 2 to 6 weeks 
after the first PK assessment.  PK sampling will occur just before the PK injection 
and at 7 time points:  0.5 hour (±5 minutes); 1 hour and 6 hours (±10 minutes); and 
24, 48, 72, and 96 hours (±60 minutes) after each injection.   
 PK3: After 13 weeks (14 weeks ± 1 week) on treatment with 15K rFVIIIFc, the 
subject will have a third PK assessment at the same vial strength as in PK2.  PK 
sampling will occur just before the PK injection and at 7 time points:  0.5 hour (±5 
minutes); 1 hour and 6 hours (±10 minutes); and 24, 48, 72, and 96 hours (±60 
minutes) after each injection.   
7.3.3. 
Treatment 
Subjects will receive supplies of rFVIIIFc from the study site for home administration, either at 
study site visits for PK assessments or between study visits consistent with Section 11.  Subjects 
will be provided rFVIIIFc for a total of at least 26 weeks of treatment, unless the end-of-study 
criteria have been reached (Section 7.5).  After that time, eligible subjects living in countries 

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where rFVIIIFc is not commercially available will be offered enrollment into extension study 
8HA01EXT.    
Dosing regimens are described in detail in Section 10.1.2.    
7.3.4. 
Follow-Up 
There will be a Follow-up Telephone Call 7 (+7) days after the last dose of rFVIIIFc during the 
Treatment Period, unless the subject has entered directly into extension study 8HA01EXT by 
that time.   
7.4. 
Study Stopping Rules 
Biogen may terminate this study for safety reasons at any time, after informing Investigators.  
Biogen (or designee) will notify Investigators when the study is to be placed on hold, completed, 
or terminated.  The study will be discontinued if an unacceptable risk is identified that precludes 
continued treatment with rFVIIIFc. 
7.5. 
End of Study 
The study will be considered complete when  
 At least 16 subjects (8 in each arm) have evaluable PK data AND  
 At least 12 subjects have had at least 26 weeks of treatment with 15K rFVIIIFc.   
When this occurs, all ongoing subjects will return to the clinic for end-of-study assessments (see 
Section 4.2.3).  End of study will occur when the last subject has had his last visit (Last Subject 
Last Visit [LSLV]). 

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8. 
SELECTION OF SUBJECTS 
8.1. 
Inclusion Criteria 
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at Screening, or at the timepoint specified in the individual eligibility criterion listed:   
1. Ability of the subject or his/her 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 confidential health information in accordance 
with national and local subject privacy regulations.  Parental or guardian consent is 
required for subjects who are less than 18 years of age or unable to give consent, or as 
applicable per local laws.  Subjects who are less than 18 years of age may provide assent 
in addition to the parental/guardian consent, if appropriate. 
2. Male, age ≥12 years old at the time of informed consent, and weighing at least 40 kg. 
3. Have severe hemophilia A, defined as <1 IU/dL (<1%) endogenous FVIII as determined 
by one-stage clotting assay from the central laboratory at Screening.  If the screening 
result is ≥1%, then the severity of hemophilia A may be confirmed by documented 
historical evidence from a certified clinical laboratory demonstrating <1% FVIII:C as 
determined by the one-stage clotting assay from the medical record. 
4. Previously treated subject, defined as having at least 150 documented prior EDs to any 
recombinant and/or plasma-derived FVIII and/or cryoprecipitate products at Day 1.  
Fresh frozen plasma treatment must not be considered in the count for documented EDs. 
5. No history of a positive inhibitor test or clinical signs of decreased response to FVIII 
administrations.  Family history of inhibitors will not exclude the subject. 
6. No measurable inhibitor activity using the Nijmegen-modified Bethesda assay 
(≥0.6 BU/mL is considered positive) at Screening. 
7. Willingness and ability of the subject or a surrogate (a caregiver or a family member 
≥18 years of age) to complete training in the use of the study diary and to complete the 
study diary in a timely manner throughout the study. 
8. Platelet count ≥100,000 platelets/μL at Screening (test performed by the central 
laboratory and reviewed prior to Day 1 of the first PK assessment). 
The following inclusion criteria refer to tests performed within 26 weeks prior to 
Screening.  If not available, the test should be conducted by the central laboratory, 
sampled at Screening and reviewed prior to Day 1 of the first PK assessment. 

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9. CD4 lymphocytes >200 mm3 if known as HIV antibody positive at Screening.  
10. Viral load of <400 copies/mL if known HIV antibody positive at Screening. 
8.2. 
Exclusion Criteria 
Candidates will be excluded from study entry if any of the following exclusion criteria exist at 
Screening, or at the timepoint specified in the individual criterion listed: 
1. Current enrollment in any interventional clinical study in which an investigational drug or 
approved therapy for investigational use is administered within 30 days prior to the 
Baseline Visit OR prior participation in any of the following Biogen studies:  998HA101, 
997HA301, 8HA02PED, 997HA307, and 8HA01EXT.   
2. Previous participation in this study. 
3. Inability to comply with study requirements in the opinion of the Investigator. 
4. Any concurrent clinically significant major disease that, in the opinion of the Investigator 
or Biogen, makes the subject unsuitable for participation in the study. 
5. Other coagulation disorder(s) in addition to hemophilia A. 
6. History of hypersensitivity or anaphylaxis associated with FVIII or IV immunoglobulin 
administration. 
7. Currently taking (or likely to require during the study) acetylsalicylic acid (ASA), except 
for low-dose ASA as prophylaxis (other non-steroidal anti-inflammatory drugs are 
permitted). 
8. Concurrent systemic treatment with immunosuppressive drugs within 12 weeks prior to 
Day 1 of the first PK assessment.  Exceptions to this include:  ribavirin for treatment of 
HCV, and/or systemic steroids (a total of 2 courses of pulse treatments lasting no more 
than 7 days within 12 weeks prior to Day 1) and/or inhaled steroids. 
9. Major surgery within the previous 8 weeks. 
10. Abnormal renal function (serum creatinine >2.0 mg/dL) [test performed by the central 
laboratory and reviewed prior to Day 1 of the first PK assessment]. 
11. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5 × upper 
limit of normal (ULN) [test performed by the central laboratory and reviewed prior to 
Day 1 of the first PK assessment]. 
12. Serum total bilirubin >3 × ULN (test performed by the central laboratory and reviewed 
prior to Day 1 of the first PK assessment). 

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13. Other unspecified reasons that, in the opinion of the Investigator or Biogen, make the 
subject unsuitable for enrollment. 
 

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9. 
ENROLLMENT, REGISTRATION, AND RANDOMIZATION 
9.1. 
Screening and Enrollment 
Subjects (or their legally authorized representative [e.g., parent or legal guardian], where 
applicable) must provide informed consent/assent before any screening tests are performed (see 
Section 17.3).  Participating study sites are required to document all screened candidates initially 
considered for inclusion in this study.  If a subject is excluded from the study, the reasons for 
exclusion will be documented in the subject’s source documents and on the screening log.  
Subjects will be registered as screened in the Interactive Voice/Web Response System (IXRS) 
following completion of all screening assessments. 
The Screening Period can be extended for subjects who have a bleeding episode requiring 
treatment with FVIII during the washout period prior to the first injection on Day 1 of PK1 
Injection 1 (see Section 7.3.1  for details). 
Once the required washout is complete and all inclusion and exclusion criteria have been met 
(see Section 8.1 and Section 8.2), the subject will be enrolled into the study and randomized as 
described in Section 9.2. 
Discontinued subjects or subjects unable to complete all 3 PK assesments may be replaced if 
needed to attain the number of subjects required to complete the study as described in 
Section 7.5.   
9.2. 
Randomization and Registration of Subjects 
Subjects will be enrolled after all screening assessments have been completed and after the 
Investigator has verified that the subjects are eligible per criteria in Sections 8.1 and 8.2.  No 
subject may begin treatment prior to assignment of a unique identification number (registration).  
Any subject identification numbers that are assigned will not be reused even if the subject does 
not receive treatment.  As confirmation, the Investigator will receive written verification of the 
subject’s registration by mail or fax.   
Subjects will be randomized on Day 1 of PK1 via the IXRS.  The randomization will determine 
their PK2 and PK3 group assignments, to 1 of 2 groups, in a 1:1 ratio.  Subjects will receive 
either 1000 IU/vial or 6000 IU/vial of 15K rFVIIIFc.  
Refer to the Study Reference Guide for details on registration and randomization. 
9.3. 
Blinding Procedures 
Not applicable. 

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10. 
STUDY TREATMENT 
The Sponsor will provide rFVIIIFc to sites via its designated distributors. 
Refer to Section 11 for specifics on the preparation, storage, handling, disposal, and 
accountability of study treatment. 
10.1. 
Treatment Schedule 
Refer to and follow the Directions for Handling and Administration (DHA).  
Refer to Figure 1 for a schematic of the study design and to Section 4.2 for study schedules.   
During the PK assessment, rFVIIIFc injections will be prepared and administered in the clinic by 
study personnel.  During the Treatment Period, rFVIIIFc injections will be prepared and 
administered at home.     
10.1.1. 
Pharmacokinetic Assessments 
The PK assessments will be performed following a single dose of rFVIIIFc, as follows: 
 PK1: 2K rFVIIIFc, 1000 IU/vial, 50 IU/kg 
 PK2 and PK3:  
o Group 1 will receive 15K rFVIIIFc, 1000 IU/vial, 50 IU/kg for both 
assessments. 
o Group 2 will receive 15K rFVIIIFc, 6000 IU/vial, 50 IU/kg for both 
assessments. 
Assignment of study treatment kits appropriate to a particular subject’s PK assessment is 
described in Section 11.1.4 .  
Following the minimum washout (96 hours of washout for a short-acting product, or 120 hours 
of washout for a long-acting product such as rFVIIIFc) and confirmation of eligibility, subjects 
will receive their first injection of rFVIIIFc (on Day 1 of PK1).  At the time of the PK1 
assessment, subjects will be randomized in a 1:1 ratio to receive 15K rFVIIIFc at either the 
1000 IU/vial or the 6000 IU/vial strength in the subsequent PK2 and PK3 assessments.   
Treatment of bleeding episodes is permitted during the PK1 assessment.  Prophylaxis and 
treatment of bleeding episodes is permitted in the period between PK1 and PK2 if needed.  
Subjects must use only 2K 1000 IU/vial rFVIIIFc and must undergo a minimum of 120 hours of 
washout of rFVIIIFc prior to the PK2 assessment.  It is recommended that the PK2 assessment 

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be performed within 2 to 6 weeks after the PK1 assessment.  Washout is also required prior to 
the PK3 assessment. 
Study procedures to be carried out during PK assessments are summarized in Section 4.2.2.  
Blood samples for PK analysis will be collected just prior to the injection and at the following 
timepoints:  0.5 hour (±5 minutes); 1 hour and 6 hours (±10 minutes); and 24, 48, 72, and 
96 hours (±60 minutes) after each injection.  In cases of bleeding episodes during the PK 
assessment, subjects should be treated according to Table 1  and Table 2.  There will be a limit of 
2 bleeding episodes (i.e., a total of 3 attempts to perform the PK assessment) for PK1, but no 
limit on the number of bleeding episodes during PK2 and PK3 (see Table 1).  If PK assessments 
cannot be completed, the subject will enter the Treatment Period (see Section 10.1.2) and may be 
replaced. 
Subjects who experience a bleed during a PK sampling period should complete the required 
washout and reschedule the planned PK injection followed by blood sampling for PK assessment 
as soon as is feasible following resolution of the bleed.  Instructions for handling bleeding 
episodes during the PK assessments are provided in Table 1.  Additional information on bleeding 
episodes is provided in Section 10.1.3.   
Table 1: 
Instructions for Treatment of Bleeding Episodes, Washout, and PK Sampling 
During the PK Assessment 
If a bleeding episode occurs: 
During the 
washout prior to 
PK1 
Washout 
 Bleeding episodes can be treated with prestudy FVIII product. 
 Washout is 96 hours for a short-acting product, or 120 hours for a 
long-acting product. 
 Washout may be repeated.  The 8-week Screening Period can be 
extended if necessary. 
After the PK1 
injection and 
before the 96-hour 
sample 
Washout 
 Bleeding episodes must be treated with 2K rFVIIIFc 1000 IU/kg 
(Table 2). 
 New washout of at least 120 hours is then required before the PK1 
Injection is repeated.   
 Additional attempts at washout are permitted.  However, if more than 
2 bleeding episodes occur during the PK1 assessment period, the PK 
will not be rescheduled, and the subject may be replaced.  The subject 
may continue on the study in the Treatment Period. 

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If a bleeding episode occurs: 
After the PK1 
Injection and prior 
to the 96-hour 
sample (cont’d.) 
PK Sampling 
 Collection of PK samples to 96 hours is required. 
During the 120-
hour washout 
period between 
PK1 and PK2 
Washout 
 Bleeding episodes must be treated with 2K rFVIIIFc 1000 IU/kg 
(Table 2).   
 New washout of at least 120 hours is then required before PK2 
injection. 
 Additional attempts at washout are permitted.  It is recommended 
PK2 be performed within 2 to 6 weeks following PK1. 
After the PK2 
injection and 
before the 96-hour 
sample 
Washout 
 
Any bleeding episode after the PK2 injection is treated with 15K 
rFVIIIFc at any of the available vial strengths (Table 2). 
 
Washout of at least 120 hours is then required before the PK2 
Injection is repeated. 
 
Additional attempts at washout are permitted. Completion of the 
second PK within 2 to 6 weeks following PK1 is recommended. 
PK Sampling 
 
Collection of PK samples to 96 hours is required. 
Between PK2 and 
PK3 
Washout 
 
Any bleeding episode after the PK2 injection is treated with 15K 
rFVIIIFc at any of the available vial strengths (Table 2).  
 
Washout of at least 120 hours is then required before the PK3 
Injection. 
 
Additional attempts at washout are permitted. 

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If a bleeding episode occurs: 
After the PK3 
injection and 
before the 96-hour 
sample 
Washout 
 
Any bleeding episode after the PK3 injection is treated with 15K 
rFVIIIFc at any of the available vial strengths (Table 2).   
 
Washout of at least 120 hours is then required before PK3 Injection is 
repeated. 
 
Additional attempts at washout are permitted.   
PK Sampling 
 
Collection of PK samples to 96 hours is required. 
After PK3, 
through the end 
study 
Any bleeding episode after the PK3 injection is treated with 15K rFVIIIFc 
at any of the available vial strengths (Table 2). 
10.1.2. 
Treatment Period 
After completing the PK2 assessment, all subjects (whether or not evaluable for PK) will begin 
receiving treatment with 15K rFVIIIFc exclusively.  Subjects will receive prophylactic dosing.  
The specific choice of regimen for any given subject and any subsequent dose adjustments will 
be based on the subject’s response and will be at the Investigator’s discretion.  Subjects may use 
any of 5 available 15K vial strengths during the treatment phase. 
Recommended starting dosing regimens include the following: 
 A prophylactic regimen at a starting dose of 50 IU/kg of rFVIIIFc given every 3 to 
5 days.  Further dose and interval adjustments will be based on individual clinical 
response per Investigator's discretion.  Dosing may be adjusted in the range of 25 to 
65 IU/kg at 3 to 5 day intervals.  
 A prophylactic regimen of 65 IU/kg administered every 7 days may be considered for 
appropriate subjects who will be selected based on the opinion of the Investigator.   
Subjects will be allowed to switch from one regimen to another if approved by the Investigator 
and will be allowed to use any of the several available vial strengths.   
Study procedures to be carried out during the Treatment Period are summarized in Section 4.2.3.  
Information on study treatment (injection date, time, dose, and whether the injection was for 
prophylaxis or a bleeding episode) will be recorded in the subject’s study diary.  The 
subject/subject’s caregiver should enter study diary information in a timely manner to facilitate 
appropriate medical review and dosing guidance.   

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After 13 weeks in the treatment period, subjects will undergo washout in preparation for the PK3 
assessment using 15K rFVIIIFc in either 1000 IU or 6000 IU vials (see Section 10.1.1).  
Following the PK3 assessment, subjects will resume to treatment in the Treatment Period until 
they complete a total of at least 26 weeks of treatment.  A subject’s participation in the study 
may be extended due to the treatment of bleeding episodes or surgery. 
After study completion, in countries where rFVIIIFc is not commercially available, eligible 
subjects will be offered enrollment into a long-term safety and efficacy extension study 
(8HA01EXT).  All subjects will have a follow-up telephone call 7 (+7) days after the last dose of 
rFVIIIFc during the Treatment Period, unless they have entered directly into Study 8HA01EXT 
by that time.     
Refer to the Directions for Handling and Administration (DHA) for additional instructions. 
10.1.3. 
Bleeding Episodes 
If a subject has a bleeding episode during the study, the Investigator should be notified.  The 
Investigator will provide guidance on the dosing for treatment of bleeding episodes as described 
in Table 2.  The impact of the treatment of bleeding episodes on planned PK assessments is 
described in Table 1.   
Table 2: 
rFVIIIFc Dosing for Treatment of Bleeding 
Severity of Bleed 
Desired Peak Factor VIII 
Level (IU/dL or % of normal) 
Dose (IU/kg)/  
Frequency of Doses (hrs) 
Minor and Moderate 
 
For example: joint, superficial 
muscle/no neurovascular 
compromise (except iliopsoas), 
deep laceration and renal. 
superficial soft tissue, mucous 
membranes 
40 to 60 
20 to 30 IU/kg 
 
Repeat every 24-48 hours until 
bleeding is resolved 
Major 
 
For example:  iliopsoas and 
deep muscle with neurovascular 
injury, or substantial blood loss, 
retroperitoneum, CNS, throat 
and neck, gastrointestinal 
80 to 100 
40 to 50 IU/kg  
 
Repeat every 12-24 hours until 
bleeding is resolved. 
Adapted from [WFH 2012]. 
Subsequent dosage and duration of treatment depends on the individual clinical response, the severity of the factor 
VIII deficiency, and the location and extent of bleeding. 
10.1.4. 
Surgery 
For subjects who require emergent or elective surgery during the study period, the dose and 
regimen of rFVIIIFc will be that deemed appropriate by the Investigator for the type of surgery 
to be performed, following the guidance in Table 3.  

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All major surgeries must take place in a center that can provide study treatment, trained study 
personnel, post-operative assessments, and hematological consult by the Investigator or 
Co-Investigator.  If the surgery does not occur in such a setting, the subject will be withdrawn 
from the study.   
In addition, subjects who require major surgery may receive rFVIIIFc if: 
1. The surgery occurs within the contracted institution for the trial and/or a separate 
agreement has been executed, permitting the use of study drug and Biogen’s rights to 
data generated in the trial at an alternative institution deemed appropriate by the Principal 
Investigator, AND 
2. The Investigator and/or appropriate qualified/licensed delegate is available to: 
a. Administer all rFVIIIFc doses required during surgery and during postoperative 
rehabilitation (if applicable).   
b. Provide medical oversight and guidance throughout the duration of the 
preoperative and intraoperative periods.   
Surgeries, elective or emergent, will be classified as major or minor, as follows: 
 Major surgery is defined as any surgical procedure (elective or emergent) that usually, 
but not always, involves general anesthesia and/or respiratory assistance, in which a 
major body cavity is penetrated and exposed, or a substantial impairment of physical or 
physiological functions is produced (e.g., laparotomy, thoracotomy, craniotomy, joint 
replacement, or limb amputation).   
 Minor surgery is defined as any surgical procedure (elective or emergent) that does not 
involve general anesthesia and/or respiratory assistance (e.g., minor dental extractions, 
incision, and drainage of abscess, joint or other injections, or simple excisions).   
All major surgeries will be reported as SAEs.   
Study procedures to be carried out before, during, and after surgery are summarized in 
Section 4.2.4.  Inhibitor testing should be performed 2 to 4 weeks prior to the scheduled surgery, 
preoperatively on the day of surgery, 1 to 2 weeks after surgery, and at the last postoperative 
visit (for minor surgery, testing is not performed at the last 2 timepoints).  On the day of surgery, 
subjects will be given a preoperative loading dose of rFVIIIFc as a bolus, and, in the case of 
emergency surgery, as soon as possible prior to the procedure.  Predose FVIII activity levels will 
be sampled followed by FVIII peak (recovery) samples 30 ± 5 minutes post-dosing.   
A repeat sample will be taken approximately 6 to 9 hours after this dose, but may alternatively 
follow the local standard of care for the determination of subsequent rFVIIIFc dosing.  During 
the subject’s hospitalization, FVIII activity will be measured daily at the local laboratory, and a 

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plasma aliquot will be prepared for each blood sample drawn so that subsequent analysis at the 
central laboratory can be performed. 
Doses higher than 65 IU/kg may be used in the context of surgery to achieve the required FVIII 
levels to prevent bleeding.  However, the maximum number of daily or every-other-day doses 
will not exceed the predicted accumulated Cmax of approximately 200% of normal (normal 
ranges are 50% to 150% FVIII activity).  All surgical dosing plans will be discussed with and 
approved by the Sponsor Medical Monitor before surgery.  All doses administered in the hospital 
will be captured in the electronic case report form (eCRF).   
During surgery and the postoperative period, the following information will be collected: 
 number of injections and dose per injection to maintain hemostasis during the surgical 
period 
 estimated blood loss (mL) during surgery and the postoperative period 
 number of blood product units transfused during surgery 
Bleeding caused directly by surgery should not be reported, although undesired or unexpected 
bleeding during or after surgery should be recorded on the eCRF.   
Table 3: 
rFVIIIFc Dosing for Perioperative Management 
Type of Surgery 
Target Factor VIII Level 
(IU/dL or % of normal) 
Dose (IU/kg)/Frequency of 
Doses (hr)  
Minor 
 
Minor operations, including 
uncomplicated dental 
extraction 
50 to 80 
25 to 40 IU/kg 
 
A single infusion may be 
sufficient.  Repeat every 
24 hours as needed to control 
bleeding. 
Major 
 
Major operations including 
intra-abdominal and joint 
replacement surgery 
80 to 120 
An initial preoperative dose of 
40 to 60 IU/kg  followed by a 
repeat dose of 40 to 50 IU/kg 
after 8 to 24 hours and then 
every 24 hours to maintain 
FVIII activity within the target 
range. 
 

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10.2. 
Modification of Dose and/or Treatment Schedule 
Subjects will also receive 26 weeks of treatment with 15K rFVIIIFc starting after PK2.  Two 
regimens are recommended based on existing data collected during the clinical development 
program (Section 10.1.2) but will be chosen and subsequently adjusted based on the subject’s 
response, and at the Investigator’s discretion.   
Information on all of the potential modifications to the dose and treatment schedule can be found 
in Section 10.1. 
10.3. 
Precautions 
The first dose of rFVIIIFc will be given in the clinic.  Subjects will be provided with specific 
guidance by the Investigator on what to do if they experience a lack of efficacy or AEs at home, 
including how to seek emergency medical treatment.   
For details regarding the risks and benefits of rFVIIIFc, see the rFVIIIFc Investigator’s 
Brochure. 
10.4. 
Compliance 
Compliance with treatment dosing is to be monitored and recorded by site staff. 
Injections for PK assessments will be administered in the clinic under controlled conditions by 
the investigational staff and recorded in the eCRF to ensure that accurate injection times are 
recorded for PK profiling.   
During the treatment period, subjects or their caregivers will record treatment in a dosing diary 
that will be reviewed periodically by study site staff and the Clinical Monitor.  The subject or the 
subject’s caregiver will record both routine doses and doses for the treatment of bleeding 
episodes in the study diary.  Diary data will be reviewed on a regular basis by site staff. 
10.5. 
Concomitant Therapy and Procedures 
The use of concomitant therapies or procedures defined in Section 10.5.1 and Section 10.5.2 and 
the reason for all concomitant procedures must be recorded on the subject’s eCRF, according to 
instructions for eCRF completion.  AEs related to administration of these therapies or procedures 
must be documented on the appropriate eCRF. 
10.5.1. 
Concomitant Therapy 
A concomitant therapy is any drug or substance administered between 30 days prior to the 
Screening Visit and 7 days after the last dose of rFVIIIFc during the Treatment Period for that 
subject.   
Subjects should be instructed to inform the Investigator if they start any new medications. 

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Allowed Concomitant Therapy 
Therapy considered necessary for the subject’s welfare may be given at the discretion of the 
Investigator.  All such therapy must be recorded in the eCRF.   
Disallowed Concomitant Therapy 
No other drug under investigation may be used concomitantly with the study treatment.  Subjects 
are not allowed to participate concurrently in another clinical study. 
The following concomitant medications are not permitted during the study: 
 ASA, except for low-dose ASA, defined as a dose of ≤81 mg, as prophylaxis. 
 Current systemic treatment with chemotherapy and/or other immunosuppressant 
drugs, with the following exceptions:  medications to treat hepatitis and/or HIV, 
treatment with systemic steroids and/or inhaled steroids (with approval of the Sponsor 
Medical Monitor) and/or nonsteroidal anti-inflammatory drugs other than high-dose 
ASA, and routine immunizations. 
 Any other FVIII product (see the exceptions listed in Section 12). 
10.5.2. 
Concomitant Procedures 
A concomitant procedure is any therapeutic intervention (e.g., surgery/biopsy, physical therapy) 
or diagnostic assessment (e.g., blood gas measurement, bacterial cultures) performed between 
the time the subject is enrolled in the study and the follow-up telephone call 7 (+7) days after the 
last dose of rFVIIIFc during the Treatment Period. 
10.6. 
Continuation of Treatment  
Subjects who complete this study in countries where rFVIIIFc is not commercially available will 
be offered enrollment into extension study 8HA01EXT if they meet all of the inclusion and 
exclusion criteria.  All subjects will have a follow-up telephone call 7 (+7) days after the last 
dose of rFVIIIFc during the Treatment Period unless they have entered directly into Study 
8HA01EXT by that time.     
 
 

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11. 
STUDY TREATMENT MANAGEMENT 
The Sponsor or designee will arrange for all shipments of study treatment from the distribution 
center to the study site.  After shipment of study materials arrives at the site, the Investigator 
must ensure that the shipment receipt is recorded in the IXRS and investigational medicinal 
product records in a timely manner.   
Study site staff should follow the DHA for specific instructions on the handling, preparation, 
administration, and disposal of the study treatment.  The DHA supersedes all other references 
(e.g., protocol, Investigator’s Brochure). 
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 11.1.4.  Dose and dosing regimen of study treatment will be determined by the 
Investigator.   
Study treatment must be dispensed only by a pharmacist, appropriately qualified staff, or 
designee.  Study treatment is to be dispensed only to subjects enrolled in this study or their legal 
guardian.  Once study treatment is prepared for a subject, it can be administered only to that 
subject.  Study treatment vials are for one-time use only; any study treatment remaining in the 
vial should not be used for another subject. 
Subjects will receive supplies of rFVIIIFc from the study site for home administration, either at 
study site visits for PK assessments, or between study visits.  Between study visits, the subject or 
the subject’s caregiver must return to the study site for dispensation of rFVIIIFc and 
administration supplies before the earliest expiration date of drug in the subject’s inventory.  
This is to maintain adequate drug supplies for his treatment, including an adequate supply to treat 
breakthrough bleeding or due to delays scheduling clinic visits.  Each time, the study site staff 
will perform full medication exchange and accountability with the subject or the subject’s 
caregiver. 
11.1. 
rFVIIIFc 
rFVIIIFc is supplied in a kit that contains several components, including, but not limited to, 
lyophilized drug, a diluent, a vial adapter, and an infusion set (see DHA for further details).  The 
lyophilized 2K product is provided in 1 strength in a 10 mL clear glass vial containing 
1000 IU/vial of rFVIIIFc. The lyophilized 15K product is provided in 5 different strengths in a 
10-mL clear glass vial containing 250, 1000, 2000, 3000, or 6000 IU/vial of rFVIIIFc.  In 
addition to the rFVIIIFc, the formulation of the lyophilized product contains 
 L-Histidine, 
 sodium chloride, 
 calcium chloride dihydrate, 
 (w/v) sucrose, and 
 (w/v) 
polysorbate 20, and is the same for all 5 strengths.  The diluent is 
 sterile water for injection 
for reconstitution of rFVIIIFc prior to administration to subjects.  The study treatment will be 
labeled according to the requirements of local law and legislation.  Label text will be approved 

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according to Biogen procedures, and a copy of the labels will be made available to the study site 
upon request. 
The label will include conditions for storage, lot number, potency, and other pertinent 
information such as manufacturer, protocol number, and caution statement.  For sites 
participating in the United States, the expiration date is provided in the Pharmacy Manual.  
rFVIIIFc should not be used after the expiration date. 
11.1.1. 
rFVIIIFc Preparation 
Once a subject is identified as eligible for the study and assigned a unique subject number, the 
individual preparing the rFVIIIFc should first carefully review the instructions provided in the 
DHA or Information for Patients before preparing the dose assigned for the subject.  The study 
Pharmacist or designated staff member will be required to prepare a drug retain if any drug 
remains in a vial following preparation of the dose for the PK assessment.  Instructions for 
preparing the drug retain are described in the Pharmacy Manual. 
The Pharmacist or designated staff member will provide the Investigator or clinical staff with 
enough rFVIIIFc kits for the subject’s dosing regimen.  This will be documented according to the 
requirements in Section 11.1.4. 
If the packaging is damaged, or if there is anything unusual about the appearance or attributes of 
the vials of rFVIIIFc or syringes containing the diluent, the study treatment should not be used.  
The vial or syringe in question should be returned to and saved at the study site, and the problem 
immediately reported to the Sponsor. 
11.1.2. 
rFVIIIFc Storage 
At the study site, study treatment must be stored in a secure location.  The rFVIIIFc kit is to be 
stored at 2ºC to 8ºC in a monitored, locked refrigerator with limited access, or the room in which 
the refrigerator resides must be locked.  The Information for Patients will describe proper storage 
conditions for the study drug that subjects take home with them. 
For the most up-to-date storage requirements, follow the instructions provided in the DHA. 
11.1.3. 
rFVIIIFc Handling and Disposal 
The Investigator must return all used and unused kits of rFVIIIFc as instructed by the Sponsor.  
The instructions for return will be provided at the time the request is made by the Biogen (or its 
designee). 
If the Sponsor requests the study site to destroy unused rFVIIIFc kits, the 
institution/Investigator(s) must notify the Sponsor, in writing, of the method of destruction, the 
date of destruction, and the location of destruction. 

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11.1.4. 
rFVIIIFc Accountability 
Accountability for study treatment is the responsibility of the Investigator.  The study site must 
maintain accurate records demonstrating dates and amount of study treatment received, to whom 
dispensed (subject by subject accounting), amount returned by the subject, and accounts of any 
study treatment accidentally or deliberately destroyed.  These records will be routinely reviewed 
by the Clinical Monitor during the monitoring visits. 
Unless otherwise notified, all vials (used and unused) must be saved for study treatment 
accountability.  The subject/caregiver should return all vials (used and unused) at each clinic 
visit for full medication exchange and accountability.  At the end of the study, reconciliation 
must be made between the amount of drug product supplied, dispensed, and subsequently 
destroyed or returned to the Sponsor.  A written explanation must be provided by the site to the 
Sponsor for any discrepancies. 
The IXRS system will be used to randomize subjects to Group 1 (15K rFVIIIFc, 1000 IU/vial) or 
Group 2 (15K rFVIIIFc, 6000 IU/vial) for PK2 and PK3.  For these PK assessments, the IXRS 
will direct the site to dispense a specific dosing kit number that is appropriate to that particular 
subject’s PK dosing group. Therefore, it is critical that the study site follow the instructions of 
the IXRS system in dispensing kits for the PK assessments. 
 

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12. 
DISCONTINUATION OF STUDY TREATMENT AND/OR 
WITHDRAWAL OF SUBJECTS FROM THE STUDY 
If more than 2 bleeding episodes occur during the PK1 assessment period, the PK assessment 
will not be rescheduled.  However, the subject may continue on the study in the Treatment 
Period.   
Discontinued subjects or subjects unable to complete all 3 PKs may be replaced if needed to 
attain the number of subjects required to complete the study as described in Section 7.5.   
A subject must permanently discontinue rFVIIIFc treatment and be withdrawn from the study for 
any of the following reasons: 
 A Grade 2 or greater allergic drug reaction occurs in association with administration 
of rFVIIIFc, as defined below by the Recommendations for Grading of Acute and 
Sub-Acute Toxic Effects on the World Health Organization (WHO) scale [WHO 
1979]:  
o Grade 2 Bronchospasm related to rFVIIIFc; no parenteral therapy needed  
o Grade 3 Bronchospasm related to rFVIIIFc; parenteral therapy required 
o Grade 4 Anaphylaxis related to rFVIIIFc 
 An inhibitor is identified and confirmed by a second test conducted at the central 
laboratory within 2 to 4 weeks of the first positive test using the Nijmegen-modified 
Bethesda assay.  
 Use of FVIII products other than rFVIIIFc occurs, unless it occurs prior to 
randomization according to the instructions in Table 1, in an emergency and/or as a 
result of 1 accidental use, and the Sponsor agrees to retain the subject in the study.  
Use must be recorded in the subject’s Study diary and electronic case report form, 
and the Investigator should contact the Sponsor Medical Monitor.  
 The subject withdraws consent.  
 The parent or legal guardian withdraws the subject from the study. 
 The subject experiences a medical emergency that necessitates permanent 
discontinuation of study treatment.  
 The subject is unwilling or unable to comply with the protocol. 
 At the discretion of the Investigator for medical reasons. 

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The reason for discontinuation of study treatment and withdrawal from the study must be 
recorded in the subject’s eCRF. 
Subjects who discontinue treatment should remain in the study to complete protocol required 
tests and assessments as described in Section 4.2 and then must be permanently withdrawn from 
the study.   
 
 
 
 

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13. 
PHARMACOKINETIC ASSESSMENTS 
13.1. 
Pharmacokinetic (rFVIIIFc Activity) Assessments 
All PK samples collected will be analyzed for FVIII activity (one-stage [aPTT] clotting assay 
and two-stage chromogenic assay) in plasma at a central laboratory.  Assay methods as well as 
procedures for collecting, processing, storing, and transporting to the central laboratory are fully 
described in the Study Laboratory Manual.  See Section 4 for the timing of all assessments. 
PK endpoints will include but not be limited to AUCinf, IR, Cmax, t1/2, CL, Vss, and MRT. 
The PK of FVIII activity will be assessed using the following: 
 One-stage (aPTT) clotting assay 
 Two-stage chromogenic assay 

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14. 
SAFETY ASSESSMENTS 
Refer to Section 4 for the timing of all safety assessments. 
14.1. 
  Clinical Safety Assessments 
The following clinical assessments will be performed: 
 Physical examinations  
 Weight 
 Concomitant therapy  
 AE and SAE recording 
Refer to Section 4.2 for the timing of assessments. 
14.2. 
Laboratory Assessments 
The following laboratory assessments will be performed: 
 Inhibitor testing 
 rFVIIIFc antibody testing 
 Hematology: white blood cell (WBC) count, differential, platelet count, hemoglobin, 
hematocrit  
 Blood chemistry: electrolytes (sodium, potassium, and chloride), glucose, total 
protein, total bilirubin, ALT, AST, alkaline phosphatase (ALP), blood urea nitrogen 
(BUN), and serum creatinine.  
Refer to Section 4.2 for the timing of assessments.   
Procedures for collecting, processing, storing, and transporting to the laboratory are fully 
described in the Study Laboratory Manual.   
14.3. 
Retention of Plasma Samples 
Plasma samples from each subject obtained at each rFVIIIFc PK sampling timepoint will be 
aliquoted into 2 vials where possible.  These 2 aliquots will be shipped to the central laboratory 
in separate shipments (the second aliquot being a back-up sample in case of damage or loss 
during shipping).  Back-up samples may be used, if clinically or scientifically indicated, for 

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retesting in the event that a subject develops an inhibitor, is suspected of having developed an 
inhibitor, or has an anaphylactic reaction to the study treatment, or if additional tests for 
assessment of coagulation parameters or safety parameters are required.  A blood sample will 
also be collected at study start to be used for any additional immunologic/serologic testing as 
needed. 
In addition to this, samples will be retained until after completion of review by competent 
authorities in accordance with [EMA (EMA/CHMP/BPWP/144533/2009) 2011] in the case of a 
positive inhibitor or clinical suspicion of inhibitor. 
No samples will be used for genetic analyses except FVIII genotype retesting in case of detection 
of inhibitors. 
The total blood sample volume will not exceed 20 mL at any one time. 

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15. 
SAFETY DEFINITIONS, RECORDING, REPORTING, AND 
RESPONSIBILITIES 
Throughout the course of the study, every effort must be made to remain alert to possible AEs.  
If an AE occurs, the first concern should be for the safety of the subject.  If necessary, 
appropriate medical intervention should be provided. 
At the signing of the ICF, each subject or his legally authorized representative and/or main 
caregiver must be given the names and telephone numbers of study site staff for reporting AEs 
and medical emergencies. 
15.1. 
Definitions 
15.1.1. 
Serious Pretreatment Event 
A serious pretreatment event is any event that meets the criteria for SAE reporting (as defined in 
Section 15.1.3) and occurs after the subject signs the ICF, but before administration of study 
treatment. 
15.1.2. 
Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and that does not necessarily have a causal relationship 
with this treatment.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product. 
Bleeding episodes in this patient population are not considered AEs.  Bleeding episodes that 
meet a serious criterion (Section 15.1.3) should be reported as an SAE.  All bleeding episodes 
will be captured in the study diary the subject will be maintaining throughout the study period.   
15.1.3. 
Serious Adverse Event 
An SAE is any untoward medical occurrence that at any dose: 
 Results in death 
 In the view of the Investigator, places the subject at immediate risk of death (a 
life-threatening event); however, this does not include an event that, had it occurred 
in a more severe form, might have caused death 
 Requires inpatient hospitalization or prolongation of existing hospitalization 

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 Results in persistent or significant disability/incapacity 
 Results in a congenital anomaly/birth defect 
All major surgeries will be reported as SAEs.  An SAE may also be any other medically 
important event that, in the opinion of the Investigator, may jeopardize the subject or may 
require intervention to prevent one of the other outcomes listed in the definition above.  
(Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or convulsions occurring at home that do not require an inpatient 
hospitalization.) 
15.2. 
Safety Classifications 
15.2.1. 
Investigator Assessment of Events 
All events must be assessed to determine the following: 
 If the event meets the criteria for an SAE as defined in Section 15.1.3. 
 The relationship of the event to study treatment as defined in Section 15.2.2. 
 The severity of the event as defined in Section 15.2.3. 
15.2.2. 
Relationship of Events to Study Treatment 
The following definitions should be considered when evaluating the relationship of AEs and 
SAEs to the study treatment. 
Relationship of Event to Study Treatment 
Not related 
An AE will be considered “not related” to the use of the investigational drug if there is 
not a reasonable possibility that the event has been caused by the product under 
investigation.  Factors pointing toward this assessment include but are not limited to:  the 
lack of reasonable temporal relationship between administration of the drug and the 
event, the presence of a biologically implausible relationship between the product and the 
AE, or the presence of a more likely alternative explanation for the AE. 
Related 
An AE will be considered “related” to the use of the investigational drug if there is a 
reasonable possibility that the event may have been caused by the product under 
investigation.  Factors that point toward this assessment include but are not limited to:  a 
positive rechallenge, a reasonable temporal sequence between administration of the 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. 
15.2.3. 
Severity of Events 
The following definitions should be considered when evaluating the severity of AEs and SAEs: 

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Severity of Event 
Mild 
Symptom(s) barely noticeable to subject or does not make subject uncomfortable; does 
not influence performance or functioning; prescription drug not ordinarily needed for 
relief of symptom(s) but may be given because of personality of subject. 
Moderate 
Symptom(s) of a sufficient severity to make subject uncomfortable; performance of daily 
activity is influenced; subject is able to continue in study; treatment for symptom(s) may 
be needed. 
Severe 
Symptom(s) cause severe discomfort; symptoms cause incapacitation or significant 
impact on subject’s daily life; severity may cause cessation of treatment with study 
treatment; treatment for symptom(s) may be given and/or subject hospitalized. 
15.2.4. 
Expectedness of Events 
Expectedness of all AEs will be determined by Biogen (or designee) according to the 
Investigator’s Brochure for rFVIIIFc.   
15.3. 
Monitoring and Recording Events 
15.3.1. 
Serious Pretreatment Events 
A serious pretreatment event experienced by the subject after signing and dating the ICF, but 
before administration of study treatment, is to be recorded on the SAE form and faxed to 
Quintiles Pharmacovigilance (PVG) within 24 hours of the study site staff becoming aware of 
the event (see Section15.3.5). 
15.3.2. 
Adverse Events 
Any AE experienced by the subject between the time of the first dose of study drug, rFVIIIFc, 
and the final follow-up telephone call (7 [+ 7] days after last dose of rFVIIIFc) is to be recorded 
on the eCRF, regardless of the severity of the event or its relationship to study treatment. 
In addition, any known, untoward event that occurs subsequent to the AE reporting period that 
the Investigator assesses as possibly related to the investigational medication/product should also 
be reported as an AE. 
15.3.3. 
Serious Adverse Events 
Any SAE experienced by the subject between the time of signing the ICF through the final 
telephone follow-up call is to be recorded on the eCRF and SAE form, regardless of the severity 
of the event or its relationship to study treatment.  SAEs must be collected for up to 14 days after 
the end of the Treatment Period and reported to Quintiles PVG within 24 hours as described in 
Section 15.3.5.  Follow-up information regarding an SAE also must be reported within 24 hours. 

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For subjects not entering the extension study 8HA01EXT, SAEs that occur up to 14 days after 
the subject’s last dose of rFVIIIFc must also be recorded on the SAE form.  SAEs must be 
reported to the designated personnel as detailed in the study file. 
Any SAE that is ongoing when the subject completes or discontinues the study will be followed 
by the Investigator until the event has resolved, stabilized, or returned to baseline status. 
In this study, the following events are considered medically important and must be reported as 
SAEs: 
 A subject develops an inhibitor, as defined in Section 7.2.1. 
 A Grade 2 or greater allergic drug reaction in association with administration of 
rFVIIIFc, as defined below by the Recommendations for Grading of Acute and Sub-
Acute Toxic Effects on the WHO scale [WHO 1979]:  
o Grade 2 
Bronchospasm related to rFVIIIFc; no parenteral therapy needed 
o Grade 3 
Bronchospasm related to rFVIIIFc; parenteral therapy required 
o Grade 4 
Anaphylaxis related to rFVIIIFc 
 A subject develops a vascular thrombotic event in association with the administration 
of rFVIIIFc, with the exception of IV injection site thrombophlebitis.   
 Major surgery. 
Subjects will be informed of early symptoms and signs of thrombotic phenomena, including pain 
and/or tenderness along a vein, swelling of an arm or leg without pain or tenderness, redness 
along a vein, low fever without any known reason (such as a cold or flu), sudden shortness of 
breath or difficulty breathing or coughing, sudden chest pain, sudden severe headache or changes 
in vision, and numbness or tingling in arms or legs.  If such an event occurs while the subject is 
at home, the subject will be instructed to seek immediate medical care. 
15.3.4. 
All Events 
All events must be assessed to determine the following: 
 If the event meets the criteria for an SAE as defined in Section 15.3.3. 
 The relationship of the event to study treatment as defined in Section 15.2.2. 
 The severity of the event as defined in Section 15.2.3. 

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15.3.5. 
Immediate Reporting of Serious Adverse Events 
In order to adhere to all applicable laws and regulations for reporting an SAE, the study site must 
formally notify Quintiles PVG within 24 hours of the study site staff becoming aware of the 
SAE.  At the same time, the event should be recorded in the eCRF.  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 has signed the ICF and 14 days after the 
final dose of study treatment must be reported to Biogen SABR (or designee) within 24 hours of 
the study site staff becoming aware of the event.  Thereafter, the event should be reported only if 
the Investigator considers it related to study treatment. 
A report must be submitted to Biogen SABR (or designee) regardless of the following: 
 Whether or not the subject has undergone study-related procedures 
 Whether or not the subject has received study treatment 
 The severity of the event 
 The relationship of the event to study treatment 
To report initial or follow-up information on an SAE, fax a completed SAE form to Quintiles 
PVG at the country specific fax number provided in the Study Reference Guide. 
15.3.5.1. 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 Biogen SABR.  The term death should be reported as an 
SAE only if the cause of death is not known and cannot be determined. 
15.3.6. 
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are SAEs that are unexpected and 
judged by the Investigator or Biogen to be related to the study treatment administered.  Biogen 
SABR (or designee) will report SUSARs to the appropriate regulatory authorities and 
Investigators as required, according to local law. 

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15.4. 
Procedures for Handling Special Situations 
15.4.1. 
Pregnancy 
The population under study is male; therefore, pregnancies will not be tracked.   
Congenital abnormalities/birth defects in the offspring of male subjects should be reported if 
study drug-exposed conception occurs.   
15.4.2. 
Overdose 
An overdose is any dose of study treatment given to a subject or taken by a subject that exceeds 
100 IU/kg.  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 Biogen 
SABR (or designee) within 24 hours of the site becoming aware of the overdose.  An overdose 
must be reported to Biogen SABR (or designee) even if the overdose does not result in an AE.  If 
an overdose results in an AE, the AE must be recorded.  If an overdose results in an SAE, both 
the SAE and Overdose forms must be completed and faxed to Biogen SABR (or designee).  All 
study treatment-related dosing information must be recorded on the dosing eCRF. 
15.4.3. 
Medical Emergency 
In a medical emergency requiring immediate attention, study site staff will apply appropriate 
medical intervention, according to current standards of care.  The Investigator (or designee) 
should contact the study’s Medical Director.  Refer to the Study Reference Guide’s Official 
Study Contact List for complete contact information. 
15.4.3.1. Unblinding for Medical Emergency 
Not Applicable. 
15.5. 
Contraception Requirements 
Pregnancy reporting is described in Section 15.4.1. 
15.6. 
Safety Responsibilities 
15.6.1. 
The Investigator 
The Investigator’s responsibilities include the following: 
 Monitor and record all AEs, including SAEs, regardless of the severity or relationship 
to study treatment. 
 Determine the seriousness, relationship, and severity of each event, as possible. 

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 Determine the onset and resolution dates of each event. 
 Complete an SAE form for each SAE and fax it to Biogen SABR (or designee) within 
24 hours of the study site staff becoming aware of the event. 
 Pursue SAE follow-up information actively and persistently.  Follow-up information 
must be reported to Biogen SABR (or designee) within 24 hours of the study site staff 
becoming aware of new information. 
 Ensure all AE and SAE reports are supported by documentation in the subjects’ 
medical records. 
 Pursue AE follow-up information, if possible, until the event has resolved or become 
stable. 
 Report SAEs to local ethics committees, as required by local law. 
The Investigator may delegate responsibilities for study-related tasks where appropriate to 
individuals sufficiently qualified by education, training, and experience, in accordance with 
International Conference on Harmonisation (ICH) Good Clinical Practice (GCP).  The 
Investigator should maintain a list of the appropriately qualified persons to whom significant 
trial-related duties have been delegated. 
15.6.2. 
Biogen 
Biogen’s responsibilities include the following: 
 Before study site activation and subject enrollment, the Clinical Monitor or the 
Sponsor’s designee is responsible for reviewing with study site staff the definitions of 
AE and SAE, as well as the instructions for monitoring, recording, and reporting AEs 
and SAEs. 
 Biogen (or designee) 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. 
16.1. 
Demography and Baseline Disease Characteristics 
The analysis of demography and baseline disease characteristics will be based on the Safety 
Analysis Set.  A description of the Safety Analysis Set is provided in Section 16.3.1.  
Demographic and baseline disease characteristics will be summarized categorically and with 
descriptive statistics, as appropriate, for each treatment sequence group and overall. 
Demographic data to be tabulated will include age, race, hemophilia history, genotype, and other 
disease-specific measures.  
Baseline disease characteristics, based on general medical and surgical and hemophilia histories, 
will be summarized by group and overall, as follows: general medical and surgical history will 
be summarized by the number and percentage of subjects with a medical history in each of the 
major body system classifications; hemophilia history data to be tabulated will include genotype 
and other disease- and treatment-specific measures. 
16.2. 
Pharmacokinetics 
Primary PK parameters include the following, for 2K rFVIIIFc (PK1) and for 15K rFVIIIFc at 
the 15K baseline (PK2): 
 AUCinf 
 IR 
as estimated from the coagulation factor VIII (FVIII) activity data, as  measured by the one-stage 
(aPTT) clotting assay. 
Secondary PK parameters include but will not be limited to AUCinf, IR, Cmax, t½, CL, Vss, and 
MRT.   
These parameters will be assessed using the one-stage (aPTT) clotting assay and the two-stage 
chromogenic assay. 
PK parameters will be assessed for the following: 

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 15K rFVIIIFc at the 15K baseline (i.e., at PK2) and after 13 weeks of treatment (at 
PK3) 
 15K rFVIIIFc at 1000 IU/vial and 6000 IU/vial 
 2K rFVIIIFc (at PK1) and 15K rFVIIIFc (at PK2) [except AUCinf and IR, which are 
included in the primary endpoint] 
16.2.1. 
Analysis Populations 
16.2.1.1. Pharmacokinetic Analysis Set (PKAS) 
The Pharmacokinetic Analysis Set (PKAS) is defined as all subjects with evaluable PK profiles. 
A PK profile for a given injection is considered evaluable if all PK parameters can be determined 
in at least 1 of the 2 assays. 
16.2.1.2. Sequential Pharmacokinetic Subgroup 
The Sequential Pharmacokinetic Subgroup will consist of all subjects who have evaluable PK 
profiles for PK2 and for at least 1 ofPK1 and PK3. 
16.2.2. 
Methods of Analysis 
Natural log transformed primary PK endpoints (AUCinf [if data permit] and IR following 
rFVIIIFc dosing for 2K and for 15K at the 15K baseline measured by the one-stage [aPTT] 
assay) will be analyzed using a mixed effects model with period and treatment as fixed effects 
and subject as a random effect.  Estimates of the adjusted mean differences (15K-2K) and 
corresponding 90% CIs will be obtained from the model.  The adjusted mean differences and 
90% CIs for the differences will be back transformed (exponentiated) to provide estimates of the 
ratio of adjusted geometric means (15K/2K) and 90% CIs for the ratios.   
For descriptive purposes only, similar analyses may be performed for secondary PK parameters 
measured by the one-stage (aPTT) assay and for all relevant PK parameters measured by the 
two-stage chromogenic assay.  
Comparability of the 2 manufacturing scales will be concluded if the 90% CIs for the ratio of 
adjusted geometric means for both primary PK endpoints (AUCinf  and IR following rFVIIIFc 
dosing for 2K and for 15K at the 15K baseline measured by the one-stage [aPTT] assay) fall 
within the range of (68%, 146%). 
The FVIII activity data will be tabulated over time for each subject and summarized by scale (2K 
[PK1], 15K [PK2] or 15K [PK3]) and vial strength (1000 IU/vial, 6000 IU/vial or overall) using 
descriptive statistics.  Mean FVIII activity will be plotted over time for each scale (with 
combined vial strengths) and each available combination of scale and vial strength. 

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The rFVIIIFc PK parameters will be listed for each subject, and summary statistics for the PK 
endpoints (including AUCinf, IR, Cmax, t1/2, CL, Vss, and MRT) will be summarized descriptively 
by manufacturing scale (2K [PK1], 15K [PK2] or 15K [PK3]), vial strength (1000 IU/vial, 
6000 IU/vial, or overall), and by assay (one-stage [aPTT] clotting assay and two-stage 
chromogenic assay).  Summary statistics for AUCinf and IR measured by the one-stage (aPTT) 
clotting assay and the two-stage chromogenic assay will include but not be limited to the mean, 
CI, standard deviation, median, minimum, and maximum values, as well as the geometric means 
(antilog of the means of the logs) and coefficients of variation.  Similar analyses will be 
performed for the other secondary PK parameters measured by the one-stage (aPTT) assay and 
for all relevant PK parameters measured by the two-stage chromogenic assay.  Arithmetic mean 
activity by sampling timepoint will be listed side by side for each scale (with combined vial 
strengths) and each available combination of scale and vial strength. 
16.3. 
Safety 
16.3.1. 
Analysis Population 
The Safety Population will include all subjects who receive at least 1 dose of rFVIIIFc. 
16.3.2. 
Methods of Analysis 
For the analysis of safety, data from the PK assessment and treatment period will be combined, 
unless specified otherwise.  The incidence of AEs will be tabulated overall, by severity, and by 
relationship to treatment.  Subject listings will be provided for all AEs, SAEs, and AEs resulting 
in discontinuation of the study treatment or withdrawal from the study, drug interruption, and 
deaths.  Additional listings will include but not be limited to the following assessments:  bleeding 
episodes during the treatment period, injections to treat a bleeding episode, all injections and 
treated bleeding episodes, dose and consumption, and compliance and exposure.  Injections and 
bleeding episodes during the surgical period will be flagged where appropriate.  The treatment 
and surgical/rehabilitation periods will be defined in the Statistical Analysis Plan for the purpose 
of determining the study periods during which data will be used for select analyses.  Findings in 
clinical laboratory values will be summarized by descriptive statistics.  Listings of vital signs and 
abnormal laboratory test results will be provided. 
The total number of EDs of rFVIIIFc will be summarized overall.  An ED is a 24-hour period in 
which 1 or more rFVIIIFc injections are given. 
Data collected during surgeries will be listed.  The listings will include, but not be limited to, 
injections and dose per injection to maintain hemostasis during the surgical period, estimated 
blood loss (mL) during surgery and the postoperative period, and transfusions. 
16.3.2.1. Inhibitor Development 
Data for subjects who develop inhibitors following initial rFVIIIFc administration will be 
provided in a listing. 

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16.4. 
Interim Analyses 
Interim analyses of PK and/or safety data may be conducted during the study as required to 
support regulatory submissions, future studies, and/or publications.  
Due to the open-label nature of this study, all personnel involved in conducting the interim 
analyses will have access to treatment assignments. 
16.5. 
Sample Size Considerations 
The minimum sample size in this study (16 subjects) is consistent with the EMA guidance for 
PK assessment of hemophilia products [EMA (EMA/CHMP/BPWP/144533/2009) 2011]. 
 
 

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

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or subject’s legally authorized representative (e.g., parent or legal guardian), as applicable, in 
accordance with local practice and regulations.   
The background of the proposed study, the procedures, the benefits and risks of the study, and 
that study participation is voluntary for the subject must be explained to the subject (or the 
subject’s legally authorized representative).  The subject must be given sufficient time to 
consider whether to participate in the study. 
In addition, 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.  The signed and dated ICF will be retained with the 
study records.  Local regulations must be complied with in respect to the final disposition of the 
original (wet signature) and copies of the signed and dated ICFs. 
Confirmation of informed consent and assent, if applicable, must also be documented in the 
subject’s medical record.   
17.4. 
Subject Data Protection 
Prior to any testing under this protocol, including screening tests and assessments, candidates 
must also provide all authorizations required by local law (e.g., Protected Health Information 
authorization in North America). 
The subject will not be identified by name in the eCRF or in any study reports, and these reports 
will be used for research purposes only.  Biogen, its partner(s) and designee(s), ethics 
committees, and various government health agencies may inspect the records of this study.  
Every effort will be made to keep the subject’s personal medical data confidential. 
17.5. 
Compensation for Injury 
Biogen 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 
Biogen) with the subject before the subject makes a decision to participate in the study. 
17.7. 
Registration of Study and Disclosure of Study Results 
Biogen will register the study and post study results regardless of outcome on a publicly 
accessible website in accordance with the applicable laws and regulations. 

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18. 
ADMINISTRATIVE PROCEDURES 
18.1. 
Study Site Initiation 
The Investigator must not screen any subjects prior to completion of a study initiation visit, 
conducted by Biogen (or designee).  This initiation visit will include a detailed review of the 
protocol and study procedures. 
18.2. 
Quality Assurance 
During and/or after completion of the study, quality assurance officers named by Biogen or the 
regulatory authorities may wish to perform onsite audits.  The Investigator will be expected to 
cooperate with any audit and to provide assistance and documentation (including source data) as 
requested. 
18.3. 
Monitoring of the Study 
The Investigator must permit study-related monitoring by providing direct access to source data 
and to the subjects’ medical histories. 
The Clinical Monitor(s) will visit the Investigator(s) at regular intervals during the study and 
after the study has completed, as appropriate. 
During these visits, eCRFs and supporting documentation related to the study will be reviewed 
and any discrepancies or omissions will be resolved.   
Monitoring visits must be conducted according to the applicable ICH and GCP guidelines to 
ensure protocol adherence, quality of data, study treatment accountability, compliance with 
regulatory requirements, and continued adequacy of the investigational site and its facilities. 
18.4. 
Study Funding 
Biogen is the Sponsor of the study and is funding the study.  All financial details are provided in 
the separate contract(s) between the institution, Investigator and Biogen.   
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 
Biogen may transfer any or all of its study-related responsibilities to a contract research 
organization (CRO) and other third parties; however, Biogen retains overall accountability for 
these activities. 
19.1.1. 
Contract Research Organization  
A CRO, Quintiles, will be responsible for administrative aspects of the study including but not 
limited to study initiation, monitoring, 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 Response Technology 
An IXRS will be used in this study.  Before subjects are screened or enrolled, Biogen or the 
IXRS vendor will provide each study site with the necessary training, a user manual, and access 
rights to the system.  Specific details regarding IXRS are provided in the Study Reference Guide. 
19.1.3. 
Electronic Data Capture 
Subject information will be captured and managed by study sites on eCRFs by a Web-based 
electronic data capture tool OR remote data capture tool developed and supported by the 
Electronic Data Capture (EDC) vendor and configured by Quintiles.  In addition, subjects in the 
study will have a study diary to record information regarding each dose of rFVIIIFc administered 
by the subject for any reason. All doses given in the clinic will be entered on the eCRF by the 
site staff. 
19.1.4. 
Central Laboratories for Laboratory Assessments 
Central laboratories have been selected by Biogen to analyze all laboratory samples being 
collected for this study.  Specifics regarding the requirements for laboratory specimen collection, 
handling, and analysis are provided in the Study Laboratory Manual, which is part of the Study 
Reference Guide. 
19.1.5. 
Central Facility for Other Assessments 
Three laboratories – LabCorp, Esoterix, and the Assay Services Laboratory (ASL) at Biogen – 
have been selected by Biogen as central laboratories for this study. 

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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 
law, such modifications must also be approved by the appropriate regulatory agency prior to 
implementation. 
However, Biogen may, at any time, amend this protocol to eliminate an apparent immediate 
hazard to a subject.  In this case, the appropriate regulatory authorities will be notified 
subsequent to the modification. 
In the event of a protocol modification, the ICF may require similar modifications (see 
Sections 17.2 and 17.3). 
19.4. 
Ethics Committee Notification of Study Completion or Termination 
Where required, the regulatory authorities and ethics committees must be notified of completion 
or termination of this study, and sent a copy of the study synopsis in accordance with necessary 
timelines. 
19.5. 
Retention of Study Data 
The minimum retention time for study records will meet the strictest standard applicable to that 
site, as dictated by any institutional requirements or local laws or regulations.  Prior to 
proceeding with destruction of records, the Investigator must notify Biogen in writing and 
receive written authorization from Biogen to destroy study records.  In addition, the Investigator 
must notify Biogen of any changes in the archival arrangements including but not limited to 
archival at an offsite facility or transfer of ownership if the Investigator leaves the site. 
19.6. 
Study Report Signatory 
Biogen 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 Biogen. 
Biogen will follow all applicable local regulations pertaining to study report signatories. 

Protocol 997HA309 
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20. 
REFERENCES 
Bolton-Maggs PH, Pasi KJ. Haemophilias A and B. Lancet. 2003;361(9371):1801-9. 
Colvin BT, Astermark J, Fischer K, et al. European principles of haemophilia care. Haemophilia. 
2008;14(2):361-74. 
Dumont JA, Low SC, Peters RT, et al. Monomeric Fc fusions: impact on pharmacokinetic and 
biological activity of protein therapeutics. BioDrugs. 2006;20(3):151-60. 
European Medicines Agency. Guideline on the clinical investigation of recombinant and human 
plasma-derived factor VIII products. EMA/CHMP/BPWP/144533/2009. July 21, 2011. 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2011/08/WC500
109692.pdf. 
Ghetie V, Ward ES. Multiple roles for the major histocompatibility complex class I- related 
receptor FcRn. Annu Rev Immunol. 2000;18:739-66. Epub 2000/06/03. 
Junghans RP, Anderson CL. The protection receptor for IgG catabolism is the beta2-
microglobulin-containing neonatal intestinal transport receptor. Proc Natl Acad Sci U S A. 
1996;93(11):5512-6. 
Mannucci PM, Tuddenham EG. The hemophilias--from royal genes to gene therapy. N Engl J 
Med. 2001;344(23):1773-9. 
MASAC Recommendation #190 Concerning Products Licensed for the Treatment of Hemophilia 
and Other Bleeding Disorders. March 2009 (Replaced by Recommendation #215, November 
2012). New York, NY: National Hemophilia Foundation. 
http://www.hemophilia.org/NHFWeb/Resource/StaticPages/menu0/menu5/menu57/masac190.pd
f. 
Rodriguez-Merchan EC. Management of musculoskeletal complications of hemophilia. Semin 
Thromb Hemost. 2003;29(1):87-96. 
Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol. 
2007;7(9):715-25. Epub 2007 Aug 17. 
Skinner MW. WFH: Closing the global gap--achieving optimal care. Haemophilia. 2012;18 
Suppl 4:1-12. 

Protocol 997HA309 
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Pharmacokinetics and Safety of rFVIIIFc 15K Product 
 
 
CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen MA Inc. 
79 
 
WFH Report on the Annual Global Survey 2004. Montreal, Quebec: World Federation of 
Hemophilia; 2005. 
WFH. Guidelines for the management of hemophilia. 2nd edition. Montréal, Québec: World 
Federation of Hemophilia; 2012. p. 1-76. 
WHO. WHO handbook for reporting results of cancer treatment. WHO Offset Publication No. 
48. Geneva, Switzerland: World Health Organization; 1979. p. 1-46. 
 
 

Protocol 997HA309 
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Pharmacokinetics and Safety of rFVIIIFc 15K Product 
 
 
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21. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL 
I have read the foregoing protocol, “Protocol 997HA309: A Randomized, Open-Label Study to 
Evaluate the Pharmacokinetics and Safety of Recombinant Factor VIII Fc Fusion Protein 
(rFVIIIFc; BIIB031) Manufactured at 15K Scale and at Different Vial Strengths in Previously 
Treated Subjects with Severe Hemophilia A,” and agree to conduct the study according to the 
protocol and the applicable ICH guidelines and GCP regulations, and to inform all who assist me 
in the conduct of this study of their responsibilities and obligations. 
 
 
 
____________________________________________________ 
Investigator’s Signature 
 
 
 
Date 
 
 
____________________________________________________ 
Investigator’s Name (Print) 
 
 
 
____________________________________________________ 
Study Site (Print)