An Open-Label, Multicenter Evaluation of the Long-Term Safety and Efficacy of Recombinant Human Coagulation Factor VIII Fusion Protein (rFVIIIFc) in the Prevention and Treatment of Bleeding Episodes in Previously Treated Subjects With Hemophilia A
Phase: PHASE3
Conditions: Hemophilia A
Sponsor: Bioverativ Therapeutics Inc.

CONFIDENTIAL 
The information contained herein may not be used, disclosed, or published without the written consent of 
Biogen Idec MA Inc. 
1 
 
 
 
 
 
Biogen Idec MA Inc.
14 Cambridge Center
  Cambridge, MA 02142, USA 
 
 
PROTOCOL NUMBER: 
8HA01EXT 
Biogen Idec Research Limited
Innovation House
70 Norden Road
Maidenhead Berkshire
SL6 4AY
United Kingdom
PHASE OF DEVELOPMENT: 
3 
 
 
PROTOCOL TITLE: An Open-Label, Multicenter Evaluation of the Long-Term Safety and 
Efficacy of Recombinant Human Coagulation Factor VIII Fusion Protein (rFVIIIFc) in the 
Prevention and Treatment of Bleeding Episodes in Previously Treated Subjects With 
Hemophilia A 
 
EUDRA CT NO: 
 
2011-003072-37 
 
DATE: 
26 August 2013 
Version 3 
FINAL 
Supersedes previous Version 2 dated 20 June 2012  
 

Protocol 8HA01EXT 
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Long Term Use of rFVIIIFc
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TABLE OF CONTENTS 
1. 
SPONSOR INFORMATION AND CONTACT INFORMATION .............................9 
2. 
LIST OF ABBREVIATIONS.....................................................................................11 
3. 
SYNOPSIS .................................................................................................................12 
4. 
SCHEDULE OF EVENTS FOR STUDY 8HA01EXT .............................................20 
5. 
INTRODUCTION ......................................................................................................27 
5.1. 
Profile of Previous Experience ...................................................................................27 
5.1.1. 
Therapies for Hemophilia A .......................................................................................27 
5.1.2. 
rFVIIIFc ......................................................................................................................28 
5.1.3. 
Summary of Clinical Experience With rFVIIIFc .......................................................28 
5.2. 
Study Rationale ...........................................................................................................29 
5.3. 
Rationale for Dose and Schedule Selection ................................................................30 
5.3.1. 
On-Demand Regimen .................................................................................................30 
5.3.2. 
Prophylaxis Regimens ................................................................................................30 
5.3.2.1. 
Option 1:  Tailored Prophylaxis .................................................................................30 
5.3.2.2. 
Option 2:  Weekly Prophylaxis ...................................................................................31 
5.3.2.3. 
Option 3: Personalized Prophylaxis ............................................................................31 
5.3.3. 
Surgery and Rehabilitation .........................................................................................31 
5.4. 
Potential Risks and Benefits .......................................................................................32 
6. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................33 
6.1. 
Objectives ...................................................................................................................33 
6.1.1. 
Primary Objective .......................................................................................................33 
6.1.2. 
Secondary Objectives .................................................................................................33 
6.2. 
Endpoints ....................................................................................................................33 
6.2.1. 
Primary Endpoint ........................................................................................................33 
6.2.2. 
Secondary Endpoints ..................................................................................................33 
6.2.3. 
Major Surgery Endpoints ............................................................................................33 
6.2.4. 
Patient-Reported Outcome Endpoints ........................................................................34 
7. 
STUDY DESIGN .......................................................................................................35 
7.1. 
Study Overview ..........................................................................................................35 

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7.1.1. 
Dose-Limiting Toxicity ..............................................................................................36 
7.1.2. 
Inhibitor Testing .........................................................................................................36 
7.1.3. 
Anti-rFVIIIFc Antibody Testing ................................................................................36 
7.1.4. 
Bleeding Episodes ......................................................................................................37 
7.1.4.1. 
Information to be Recorded ........................................................................................37 
7.1.4.2. 
Procedure to Treat the Bleeding Episode ...................................................................38 
7.1.4.3. 
Dose and/or Interval Modification Following Bleeding Episodes .............................39 
7.2. 
Overall Study Duration and Follow-Up .....................................................................39 
7.2.1. 
Screening ....................................................................................................................39 
7.2.2. 
Treatment ....................................................................................................................40 
7.2.3. 
Follow-Up ...................................................................................................................40 
7.3. 
Study Stopping Rules .................................................................................................40 
7.4. 
End of Study ...............................................................................................................40 
8. 
SELECTION OF SUBJECTS ....................................................................................41 
8.1. 
Inclusion Criteria ........................................................................................................41 
8.2. 
Exclusion Criteria .......................................................................................................41 
9. 
ENROLLMENT AND REGISTRATION PROCEDURES ......................................42 
9.1. 
Enrollment and Screening ...........................................................................................42 
9.2. 
Registration of Subjects ..............................................................................................42 
9.3. 
Blinding Procedures ....................................................................................................42 
10. 
TREATMENT OF SUBJECTS ..................................................................................43 
10.1. 
Study Treatment Schedule and Administration ..........................................................43 
10.1.1. 
Prophylaxis Regimens ................................................................................................43 
10.1.2. 
On-Demand Regimen .................................................................................................44 
10.1.3. 
Surgery ........................................................................................................................44 
10.2. 
Treatment Precautions ................................................................................................45 
10.3. 
Modification of Dose and/or Treatment Schedule ......................................................45 
10.3.1. 
Prophylaxis Regimen ..................................................................................................45 
10.3.2. 
On-Demand Regimen .................................................................................................45 
10.4. 
Treatment Compliance ................................................................................................45 
10.5. 
Concomitant Therapy and Procedures ........................................................................46 

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10.5.1. 
Concomitant Therapy .................................................................................................46 
10.5.1.1. 
Allowed Concomitant Therapy ...................................................................................46 
10.5.1.2. 
Disallowed Concomitant Therapy ..............................................................................46 
10.5.2. 
Concomitant Procedures .............................................................................................46 
10.6. 
Continuation of Treatment ..........................................................................................47 
11. 
WITHDRAWAL OF SUBJECTS FROM STUDY TREATMENT AND/OR 
THE STUDY ..............................................................................................................48 
11.1. 
Discontinuation of Study Treatment ...........................................................................48 
11.2. 
Withdrawal of Subjects From Study ...........................................................................49 
12. 
STUDY TREATMENT MANAGEMENT ................................................................50 
12.1. 
rFVIIIFc (BIIB031) ....................................................................................................50 
12.1.1. 
rFVIIIFc Preparation ..................................................................................................50 
12.1.2. 
rFVIIIFc Storage .........................................................................................................50 
12.1.3. 
rFVIIIFc Handling and Disposal ................................................................................51 
12.1.4. 
rFVIIIFc Accountability .............................................................................................51 
13. 
EFFICACY ASSESSMENTS ....................................................................................52 
13.1. 
Clinical Efficacy Assessments ....................................................................................52 
13.2. 
Laboratory Efficacy Assessments ...............................................................................52 
13.3. 
Pharmacokinetic Assessments ....................................................................................53 
13.4. 
Pharmacodynamic Assessments .................................................................................53 
13.5. 
Additional Assessments ..............................................................................................53 
13.5.1. 
Hemophilia Joint Health Score ...................................................................................53 
13.5.2. 
Patient-Reported Outcomes ........................................................................................53 
13.5.3. 
Health Outcomes Related to Hemophilia ...................................................................54 
13.5.4. 
Optional Laboratory Assessment ................................................................................54 
13.5.5. 
Archive Plasma Samples ............................................................................................54 
14. 
SAFETY ASSESSMENTS ........................................................................................55 
14.1. 
Clinical Safety Assessments .......................................................................................55 
14.2. 
Laboratory Safety Assessments ..................................................................................55 
15. 
SAFETY DEFINITIONS, MONITORING, AND REPORTING .............................56 
15.1. 
Definitions ..................................................................................................................56 
15.1.1. 
Serious Pretreatment Event .........................................................................................56 

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15.1.2. 
Adverse Event .............................................................................................................56 
15.1.3. 
Serious Adverse Event ................................................................................................56 
15.2. 
Monitoring and Recording Events ..............................................................................57 
15.2.1. 
Serious Pretreatment Events .......................................................................................57 
15.2.2. 
Adverse Events ...........................................................................................................57 
15.2.3. 
Serious Adverse Events ..............................................................................................57 
15.2.4. 
All Events ...................................................................................................................58 
15.2.5. 
Immediate Reporting of Serious Adverse Events .......................................................58 
15.2.5.1. 
Deaths .........................................................................................................................59 
15.3. 
Safety Classifications ..................................................................................................59 
15.3.1. 
Relationship of Events to Study Treatment ................................................................59 
15.3.2. 
Severity of Events .......................................................................................................60 
15.3.3. 
Expectedness of Events ..............................................................................................60 
15.4. 
Procedures for Handling Special Situations ...............................................................60 
15.4.1. 
Overdose .....................................................................................................................60 
15.4.2. 
Medical Emergency ....................................................................................................61 
15.4.3. 
Pregnancy ...................................................................................................................61 
15.4.4. 
Regulatory Reporting ..................................................................................................61 
15.5. 
Investigator Responsibilities .......................................................................................61 
15.6. 
Sponsor Responsibilities .............................................................................................62 
16. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ...........63 
16.1. 
Description of Objectives ...........................................................................................63 
16.1.1. 
Primary Objective(s) ...................................................................................................63 
16.1.2. 
Secondary Objective(s) ...............................................................................................63 
16.2. 
Description of Endpoints ............................................................................................63 
16.2.1. 
Primary Endpoint ........................................................................................................63 
16.2.2. 
Secondary Endpoints ..................................................................................................63 
16.3. 
Demography and Baseline Disease Characteristics ....................................................63 
16.4. 
Efficacy .......................................................................................................................64 
16.4.1. 
Analysis Population ....................................................................................................64 
16.4.2. 
General Methods of Analysis .....................................................................................64 

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16.4.3. 
Endpoints Analysis .....................................................................................................64 
16.4.3.1. 
Annualized Bleeding Episodes and Annualized rFVIIIFc Consumption ...................64 
16.4.3.2. 
Other Efficacy Endpoints ...........................................................................................64 
16.4.3.3. 
Surgery Endpoints ......................................................................................................64 
16.4.4. 
Additional/Exploratory Analysis ................................................................................65 
16.5. 
Patient-Reported and Health Outcomes ......................................................................65 
16.5.1. 
Analysis Population ....................................................................................................65 
16.5.2. 
Methods of Analysis ...................................................................................................65 
16.5.2.1. 
Patient-Reported Outcomes ........................................................................................65 
16.5.2.2. 
Health Outcomes ........................................................................................................65 
16.6. 
Safety ..........................................................................................................................65 
16.6.1. 
Analysis Population ....................................................................................................65 
16.6.2. 
Methods of Analysis ...................................................................................................65 
16.7. 
Inhibitor Formation Data ............................................................................................66 
16.7.1. 
Analysis Population ....................................................................................................66 
16.7.2. 
Methods of Analysis ...................................................................................................66 
16.8. 
Optional Laboratory Assessments ..............................................................................66 
16.9. 
Interim Analyses .........................................................................................................66 
16.10. 
Sample Size Considerations .......................................................................................66 
17. 
ETHICAL REQUIREMENTS ...................................................................................67 
17.1. 
Declaration of Helsinki ...............................................................................................67 
17.2. 
Ethics Committee ........................................................................................................67 
17.3. 
Subject Information and Consent ...............................................................................67 
17.4. 
Subject Data Protection ..............................................................................................68 
17.5. 
Compensation for Injury .............................................................................................68 
17.6. 
Conflict of Interest ......................................................................................................68 
17.7. 
Registration of Study and Disclosure of Study Results ..............................................68 
18. 
ADMINISTRATIVE PROCEDURES .......................................................................69 
18.1. 
Study Site Initiation ....................................................................................................69 
18.2. 
Study Supplies ............................................................................................................69 
18.3. 
Quality Assurance .......................................................................................................69 

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18.4. 
Monitoring of the Study..............................................................................................69 
18.5. 
Study Funding .............................................................................................................69 
18.6. 
Publications .................................................................................................................69 
19. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION ........................70 
19.1. 
External Contract Organizations .................................................................................70 
19.1.1. 
Contract Research Organization .................................................................................70 
19.1.2. 
Interactive Voice/Web Response System ...................................................................70 
19.1.3. 
Electronic Data Capture ..............................................................................................70 
19.1.4. 
Central Laboratories for Laboratory Assessments .....................................................70 
19.2. 
Changes to Final Study Protocol ................................................................................70 
19.3. 
Ethics Committee Notification of Study Completion or Termination ........................71 
19.4. 
Retention of Study Data ..............................................................................................71 
19.5. 
Study Report Signatory...............................................................................................71 
20. 
REFERENCES ...........................................................................................................72 
21. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL .........................................74 
22. 
APPENDIX A:  RFVIIIFC DOSING GUIDELINE FOR TREATMENT OF 
BLEEDING EPISODES .............................................................................................75 
23. 
APPENDIX B:  HEMOPHILIA JOINT HEALTH SCORE (HJHS) .........................76 
24. 
APPENDIX C:  SUBJECT
PONSE TO 
TREATMENT OF BLEEDING .................................................................................79 
25. 
APPENDIX D:  PHYSICI
NT OF RESPONSE ..........80 
26. 
APPENDIX E:  PHYSICIAN ASSESSMENT OF RESPONSE TO 
TREATMENT DURING SURGERY ........................................................................81 
27. 
APPENDIX F:  PATIENT REPORTED OUTCOMES .............................................82 
 
LIST OF TABLES 
Table 1: 
Screening and Treatment Period .................................................................................20 
Table 2: 
Surgery Visits .............................................................................................................25 
 

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1. 
SPONSOR INFORMATION AND CONTACT INFORMATION 
This study is sponsored by Biogen Idec MA Inc. 
Biogen Idec MA Inc. 
14 Cambridge Center 
Cambridge, MA 02142 
USA 
Phone:  +1 617-679-2000 
Fax:  +1 617-679-2617 
Biogen Idec Research Ltd. 
Innovation House 
70 Norden Road 
Maidenhead, Berkshire  
SL6 4AY 
United Kingdom 
Phone:  +44-1628 501000 
Fax:  +44-1628 501010 
 
Biogen Idec Japan Ltd. 
Atago Green Hills Mori 
Tower 26F 
5-1Atago 2-chome 
Minato-ku  
Tokyo 105-6226 
Japan 
Phone:  +81 3 6402-7800 
Fax:  +81 3 6402-7850 
 
Biogen Idec Canada 
90 Burnahamthorpe Road West 
Suite 1100 
Mississauga, Ontario L5B 3C3 
Canada 
Phone:  +1 905-804-1444 
Fax:  +1 905-897-3222 
 
 
 
Biogen Idec Australia Pty Ltd 
Suite 1, Level 5, 123 Epping Rd 
North Ryde, NSW 2113 
Australia 
Phone: +61 2 8875 3900 
Fax: +61 2 9889 1162 
 
 
Primary contact for urgent medical issues: 
, Medical Research: 
 
Biogen Idec MA Inc. 
 
  
 
 
 
 
 
 
 
Secondary contact for urgent medical issues: 
Medical Research 
 
, MD 
Biogen Idec MA Inc. 
 
  
 
 
 
 
 
 
 

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Other Contacts: 
Clinical Research Organization: 
 
Quintiles 
 
 
4820 Emperor Boulevard 
 
 
Durham, NC 27703 USA 
 
Pharmacovigilance/SAE Reporting  
Quintiles Lifecycle Safety 
 
Local telephone and fax numbers for reporting to Quintiles Pharmacovigilance from each 
participating country will be provided separately to each site to be retained in th
Study File. 
 
Please refer to the Study Reference Manual, Official Study Contact List for complete contact 
information. 

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2. 
LIST OF ABBREVIATIONS  
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
CHO-KLAT 
Canadian Hemophilia Outcomes-
 
Cmax 
Maximum activity 
CRO 
Contract research organization 
DHA 
Directions for Handling and Administration 
eCRF 
Electronic case report form 
ED 
Exposure day(s) 
EDC 
Electronic data capture 
eDiary 
Electronic patient diary 
EOT 
End of Treatment 
FcRn 
Neonatal Fc receptor 
FVIII 
Factor VIII 
FVIII:C 
Factor VIII coagulant activity 
GCP 
Good Clinical Practice 
HJHS 
Hemophilia Joint Health Score 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IU 
International Units 
IV 
Intravenous 
IXRS 
Interactive Voice and Web Response System 
kg 
Kilogram 
PHI 
Protected health information 
PK 
Pharmacokinetics 
PTP 
Previously treated patient 
QoL 
Quality of life 
rFVIIIFc 
Recombinant human Factor VIII 
SAE 
Serious adverse event 
SUSAR 
Suspected unexpected serious adverse event 
t1/2 
Half-life 
WBC 
White blood count 
WFH 
World Federation of Hemophilia 
WHO 
World Health Organization 

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3. 
SYNOPSIS 
This is a brief summary.  For details refer to the body of the protocol.   
 
Protocol Number: 
8HA01EXT 
Protocol Title: 
An Open-Label, Multicenter Evaluation of the Long-Term Safety 
and Efficacy of Recombinant Human Coagulation Factor VIII 
Fusion Protein (rFVIIIFc) in the Prevention and Treatment of 
Bleeding Episodes in Previously Treated Subjects With 
Hemophilia A. 
Version Number: 
3 
Name of Study Treatment: 
rFVIIIFc (BIIB031) 
Study Indication: 
Hemophilia A 
Phase of Development: 
3 
Rationale for the Study: 
To evaluate the long-term safety of rFVIIIFc for prevention and 
on-demand treatment of bleeding episodes in subjects with 
hemophilia A, and to allow subjects from the A-LONG pivotal 
study (997HA301), the pediatric study (8HA02PED), or any other 
rFVIIIFc study to continue treatment with rFVIIIFc.  
Study Objectives and Endpoints: 
Objectives 
Primary:    
The primary objective of the study is to evaluate the long-term 
safety of rFVIIIFc in subjects with hemophilia A. 
Secondary:  
The secondary objective of the study is to evaluate the efficacy of 
rFVIIIFc in the prevention and treatment of bleeding episodes in 
subjects with hemophilia A.  
Endpoints 
Primary:  
The occurrence of inhibitor development 
Secondary: 
 
The annualized number of bleeding episodes 
(spontaneous and traumatic) per subject 
 
The annualized number of spontaneous joint bleeding 
episodes per subject 
 
The total number of days of exposure per subject per 
year 
 
The consumption of rFVIIIFc as total dose per kg per 
subject per year  

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the
response to his treatment regimen using a 4-point 
scale 
 
the treatment of 
bleeding episodes using a 4-point scale 
Major Surgery Endpoints: 
 
Investigator/Surgeon assessment of hemostatic 
response to surgery using the 4-point bleeding 
response scale 
 
Number of injections and dose per injection to 
maintain hemostasis during the surgical period 
 
Estimated blood loss (mL) during surgery and 
post-operative period 
 
Number of blood product units transfused during 
surgery 
Patient-Reported Outcomes Endpoints  
Subjects will only take the Quality of Life (QoL) measurements 
that they completed during the parent study, which could include: 
 
Haem-A-QoL  
 
Haemo-QoL  
 
Hemo-Sat-Patient Satisfaction Scale for 
parents/guardians, Version 15 
 
Canadian Hemophilia Outcomes-
Assessment Tool (CHO-KLAT)  
o Children, Version 2.0 (for children 
previously enrolled in study 8HA02PED who 
are less than 18 years of age).   
o Proxy, Version 2.0p (for parents/guardians of 
children previously enrolled in study 
8HA02PED and who are less than 18 years 
of age) 
 
EQ-5D-Y  
 
EQ-5D-3L  
Subjects will only take the health outcomes measurements related 
to hemophilia that they completed during the parent study, which 
could include: 
 
Number of hospitalizations, excluding planned 
hospitalizations, elective surgery documented at 
Visit 1, and emergent surgery 
 
Number of emergency room visits  
 
Number of physician visits excluding study visits  

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Number of hospitalization days 
 
Number of days off work, school, daycare, or 
preschool  
 
Number of days off work for subject or 
parent/caregiver  
Study Design: 
This is an open-label, multicenter, long-term study of intravenous 
(IV) administration of rFVIIIFc in previously treated patients with 
hemophilia A, who have completed the A-LONG study 
(997HA301), the pediatric study (8HA02PED), or any other trial 
with rFVIIIFc.  Treatment will be administered as tailored 
prophylaxis (individualized), weekly (modified) prophylaxis, 
personalized prophylaxis, or on-demand (episodic) regimens.  
The regimens will hereafter be referred to as tailored prophylaxis, 
weekly prophylaxis, personalized prophylaxis, or on-demand. 
Rationale for Dose and Schedule 
Selection: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subjects will follow a tailored prophylaxis, weekly prophylaxis, 
personalized prophylaxis, or on-demand regimen.  The choice of 
regimen will be based on the clinical profile of the subject and by 
the trough or peak (recovery) values, if needed, as observed in the 
preceding study.  Subjects 12 years of age or older are allowed to 
change from prophylaxis to on-demand, or from on-demand to 
prophylaxis during the study.  However, subjects less than 12 
years of age will receive only a tailored or personalized 
prophylactic regimen.  All treatment regimen changes will be 
discussed between the Investigator and the subject (and 
parent/guardian, as applicable).  All treatment regimen changes 
require the approval of the Sponsor Medical Monitor.   
The starting dose in study 8HA01EXT may be based on a 
dose and dosing interval from the preceding rFVIIIFc 
study.  In the completed Phase 3 study 997HA301 subjects 
initiated a dosing regimen of 25 IU/kg on Day 1 and 50 IU/kg on 
Day 4.  The dose for each subject was subsequently adjusted 
between 25 IU/kg and 65 IU/kg and was given every 3 to 5 days 
The 
maximum dose allowed was 65 IU/kg every 3 days.  In the 
pediatric study, 8HA02PED, a dosing regimen with starting doses 
of 25 IU/kg on Day 1 and 50 IU/kg on Day 4 are being evaluated, 
with dose adjustments up to maximum prophylactic dose of 
80 IU/kg and frequency of administration up to every 2 days if 
necessary to maintain adequate FVIII activity trough levels and 
prevent spontaneous bleeding events.  
Treatment Regimen: 
Details for each dosing regimen, including, if applicable, date of 
change, new dose and/or dosing interval, and reason(s) for the 
regimen change will be recorded on the appropriate eCRF each 
time a change is made by the Investigator. 
On-Demand Regimen 
The individual dose of rFVIIIFc to treat bleeding episodes will be 

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bleeding event, and in some cases, FVIII peak (recovery) levels.  
Pharmacokinetic (PK) data and dosing levels from the preceding 
studies can also be used to guide dosing decisions.  Subjects less 
than 12 years of age will receive a tailored or personalized 
prophylactic regimen and will not have the option to receive an 
on-demand regimen, but can receive an on-demand regimen once 
they reach the age of 12 years during the study. 
 
Prophylaxis Dosing Regimens 
 
Option 1:  Tailored Prophylaxis 
The Investigator may consider the following options to target a 
FVIII trough of up to 5%, but is encouraged to use the lowest 
effective dose targeting a FVIII trough level between 1% and 3%.  
If bleeding episodes occur at FVIII trough levels of 1% to 3%, 
further adjustments to dose or interval over the course of the 
study will target trough levels of up to 5%. 
Dosing is approximately 25 IU/kg to 65 IU/kg every 3 to 5 days, 
or dosing 2 times per week at approximately 20 IU/kg to 65 IU/kg 
on Day 1 and 40 IU/kg to 65 IU/kg on Day 4.  The dosing interval 
preceding rFVIIIFc study, and/or his individual PK (if available), 
and FVIII trough and/or peak (recovery) values.  For pediatric 
subjects <12 years of age, dose levels may be increased to a 
maximum prophylactic dose of 80 IU/kg and dose intervals 
decreased to every 2 days. 
 
Option 2:  Weekly Prophylaxis  
Dosing is approximately 65 IU/kg at weekly intervals.  The dose 
preceding rFVIIIFc study and/or his individual PK (if available), 
and FVIII trough and/or peak (recovery) values.  Subjects less 
than 12 years of age will not have the option to receive a weekly 
prophylaxis regimen, but can receive a weekly prophylaxis 
regimen once they reach the age of 12 years during the study. 
 
Option 3:  Personalized Prophylaxis 
If optimal prophylaxis dosing cannot be achieved using either of 
the above options, the Investigator may further personalize dosing 
to meet the needs of individual subjects.  The personalized 
prophylaxis dosing option will require consultation with the 
Medical Monitor.  The Investigator may consider the following 
personalized dosing options: 
- 
activity. 
- 
Targeting a FVIII trough level of >3%, if the 

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bleeding history and/or activity level requires.
- 
Dosing less frequently. 
The Investigator is not limited to the options above, and should 
consult the Medical Monitor for further consideration of a 
 
Surgery: 
 
If a subject requires surgery during this study, either emergent or 
elective, he may be treated with the dose and regimen of rFVIIIFc 
deemed appropriate for the type of surgery.   
All major surgeries must take place in a center that can provide 
study treatment, trained study personnel, post-operative 
assessments, and hematological consultation by the Investigator 
or Co-Investigator.  If surgery does not take place in such a 
setting, the subject will be withdrawn from the study.  Specific 
provisions apply when a subject requires major surgery. 
Surgeries, elective or emergent, will be classified as major and 
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. 
Rehabilitation period 
If surgery-related dosing is to be continued during post-operative 
rehabilitation, the dose of rFVIIIFc will be adjusted to achieve a 
FVIII trough at a sufficient level to maintain hemostasis, 
including during physical therapy.  These doses will be captured 
(eDiary).   
Subjects will return to a regular rFVIIIFc regimen once all dosing 
for the post-operative period has been completed.  For subjects 
undergoing major surgery, a visit is required 1-2 weeks after 
surgery (Visit 3, not required for minor surgery).  Visit 4 (Last 
Post-Operative Visit) occurs when the subject returns to a regular 
rFVIIIFc regimen as determined by the Investigator, and is 
required only if the subject did not return to a regular rFVIIIFc 

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regimen at Visit 3.  
Study Location: 
Global 
Number of Planned Subjects: 
Approximately 194 subjects are planned to be treated in the study. 
Study Population: 
This study will be conducted in previously treated adult and 
pediatric subjects with hemophilia A.   
Detailed criteria are described in the body of the protocol. 
Treatment Regimens: 
Treatment regimens are defined as follows: 
 
On-Demand:  all subjects enrolled in the trial and 
treated using an on-demand regimen 
 
Prophylaxis:  all subjects enrolled in the trial and 
treated using a tailored prophylaxis, weekly 
prophylaxis, or personalized prophylaxis regimen 
There will also be a surgery subgroup, which is defined as a 
subset of subjects from the prophylaxis and on-demand regimens 
who have major surgery during the course of the trial. 
Duration of Treatment and 
Follow-up: 
Subjects first dosed with rFVIIIFc when <12 years of age will be 
followed to at least 100 EDs, even if rFVIIIFc becomes 
commercially available.   
All subjects will have the opportunity to continue in this study for 
up to 4 years or until rFVIIIFc is commercially available in the 
applicable participating country.  
Definition of Dose-Limiting 
Toxicity: 
No dose-limiting toxicity for rFVIIIFc has been identified. 
Statistical Methods: 
 
In general, the data for subjects who enroll from the parent studies 
will have their data integrated with their data from 8HA01EXT.  A 
parent study is defined as a study where subjects may be enrolled 
into 8HA01EXT after study completion or at a time specified in the 
protocol.     
Demography and Baseline Disease Characteristics 
The analysis of demography and baseline disease characteristics will 
be based on the Safety Analysis Set.   
Demographics and baseline disease characteristics will be 
summarized categorically and/or with descriptive statistics, as 
appropriate, using the data at the entry of the parent studies. 
Efficacy 
Subjects who receive at least 1 dose of rFVIIIFc will be included in 
the Full Analysis Set (FAS).  Efficacy analyses will be based on the 
FAS. 
For subjects who have surgeries during the study, their efficacy data 
during the surgical period (including rehabilitation period) will be 
analyzed separately.  The efficacy 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 

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select efficacy analyses.  Data on bleeding and rFVIIIFc 
consumption will be based on the efficacy period; surgical 
evaluations will be based on the surgical/rehabilitation period. 
Bleeding episodes will be annualized for each subject first, then 
summarized and tabulated by treatment arm, treatment regimen, or 
age cohort, as appropriate, in the parent studies.  These analyses will 
also be performed for each type of bleed (spontaneous and 
traumatic).  The number of spontaneous joint bleeding episodes and 
the consumption of rFVIIIFc will be annualized in a similar fashion 
and tabulated. 
Analysis of surgery endpoints will be performed for subjects who 
had surgeries during the study, either emergently or electively.  
Summary statistics of surgery endpoints will be provided for the 
surgical/rehabilitation period. 
Patient-Reported and Health Outcomes 
Endpoints for patient-reported outcomes (Haem-A-QoL, Haemo-
QoL, Hemo-Sat-Patient, CHO-KLAT Children, CHO-KLAT Proxy, 
EQ-5D-Y and EQ-5D-3L) will be analyzed in a separate report.  
These endpoints will be analyzed by summarizing actual values and 
change from baseline as appropriate. 
Summary statistics of health outcome endpoints will be tabulated at 
each collection timepoint. 
Safety 
The Safety Population will include all subjects with at least 1 dose of 
rFVIIIFc.  For the analysis of safety, data in 8HA01EXT will be 
integrated with the parent studies, unless specified otherwise.  The 
incidence of AEs will be tabulated overall, by severity, and by 
relationship to treatment.  In addition, the incidence of AEs will be 
presented by exposure day (ED) intervals.  Findings in clinical lab 
values will be summarized by descriptive statistics.   
The proportion of subjects with inhibitors during rFVIIIFc 
administration will be provided with the exact (Clopper-Pearson) 
2-sided, 95% confidence interval.   
Interim Analyses: 
Interim analyses will be conducted during the study, as needed.   
Analyses will be descriptive in nature.  No formal comparisons are 
planned and no hypotheses will be formally tested. 
Due to the open-label nature of this study, personnel involved in 
conducting the interim analyses will have access to treatment 
assignments. 
Sample Size Determination: 
This is an extension study.  Sample size is based on sample sizes of 
Studies 997HA301 (N=144) and 8HA02PED (N=50), and may be 
increased based upon subject participation in other rFVIIIFc studies. 
Study Stopping Rules: 
The Sponsor may terminate this study at any time, after informing 
Investigators. 
Study stopping is required if any of  the following occur: 

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Three subjects develop high-titer inhibitor (i.e., 
.00 BU/mL) identified and confirmed on 2 separate 
samples drawn approximately 2 to 4 weeks apart and 
performed by the central laboratory using the Nijmegen-
modified Bethesda assay.  This number can be adjusted 
based on sample size when more subjects might be 
included into this trial from other rFVIIIFc studies. 
 
An unexpected, serious, or unacceptable risk to study 
subjects 
If the study is stopped, the events will be investigated, enrollment 
will be stopped, and current subjects will stop dosing with rFVIIIFc.  
Surveillance Team, it is 
determined that the study should be permanently discontinued, then 
subjects will attend a final visit. 
 

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4. 
SCHEDULE OF EVENTS FOR STUDY 8HA01EXT 
Table 1: 
Screening and Treatment Period 
Tests and Assessments2 
Visit 
11 
 
Visit 2 
Month 6 
(±2 weeks) 
Visit 3 
Month 12 
(±2 weeks) 
Visit 4 
Month 18 
(±2 weeks) 
Visit 5 
Month 24 
(±2 weeks) 
Visit 6 
Month 30 
(±2 weeks) 
Visit 7 
Month 36 
(±2 weeks) 
Visits Semi-Annually 
(Every 6 months) 
(±2 weeks) 
Informed Consent and Assent Forms 
X 
 
 
 
 
 
 
 
Eligibility Verification 
X 
 
 
 
 
 
 
 
Medical and Surgical History and Demographics3 
X 
 
 
 
 
 
 
 
Physical Examination and Vital Signs 4 
X 
 
X 
 
X 
 
X 
X 
Height 
X 
 
X 
 
X 
 
X 
X 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
rFVIIIFc Dosing/Dispensation/Accountability5 
X 
X 
X 
X 
X 
X 
X 
X 
Nijmegen-modified Bethesda Assay (inhibitor assay)6 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-rFVIIIFc antibody6 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 6,7 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Chemistry 6, 8 
X 
X 
X 
X 
X 
X 
X 
X 
FVIII Activity 6, 9 
X 
X 
X 
X 
X 
X 
X 
X 
DNA-Based Testing10 
X 
 
 
 
 
 
 
 
QoL Questionnaires11 
X 
X 
X 
X 
X 
X 
X 
X 
Health Outcomes12 
X 
X 
X 
X 
X 
X 
X 
X 
Subject eDiary Review  
X 
X 
X 
X 
X 
X 
X 
X 
Bleeding Episodes Treated in Clinic 
<<<<<<<<<<<<<<<<<< ongoing >>>>>>>>>>>>>>>> 
 to the 
Treatment Regimen 
X 
X 
X 
X 
X 
X 
X 
X 
HJHS 14 
X 
 
X 
 
X 
 
X 
X 

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AE/SAE Monitoring and Recording 
X 
Monitor and record at all visits; telephone call every 2 months for AE/SAE assessments 
Concomitant Therapy/Procedures Recording 
X 
Monitor and record at all visits; telephone call every 2 months   

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Table 1: 
Screening and Treatment Period (Continued) 
Tests and Assessments2 
Unscheduled Visit13 
Final Study Visit/ 
Early Termination Visit 
Follow-Up15 
7 (+7) days after last dose 
Physical Examination and Vital Signs 4 
 
X 
 
Height 
 
X 
 
Weight 
 
X 
 
rFVIIIFc Dosing/Dispensation/Accountability5 
X 
X 
 
Nijmegen-modified Bethesda Assay (inhibitor assay)6 
 
X 
 
Anti-rFVIIIFc antibody6 
 
X 
 
Hematology 6, 7 
 
X 
 
Blood Chemistry 6, 8 
 
X 
 
FVIII Activity 6, 9 
 
X 
 
QoL Questionnaires11 
 
X 
 
Health Outcomes12 
 
X 
 
Subject eDiary Review  
X 
X 
 
Bleeding Episodes Treated in Clinic 
<<<<<<<<<<<<<<<<<< ongoing >>>>>>>>>>>>>>>> 
 
 to the 
Treatment Regimen 
X 
X 
 
HJHS 14 
 
X 
 
AE/SAE Monitoring and Recording 
Monitor and record at all visits; telephone call every 2 months for 
AE/SAE assessments 
X 
Concomitant Therapy/Procedures Recording 
Monitor and record at all visits; telephone call every 2 months  
X 
Table footnotes are presented on page 23.

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Footnotes for Screening and Treatment Period 
1. 
End of Treatment (EOT) visit for the preceding study may serve as the Screening Visit for the extension study.  Written informed consent and subject 
assent, if applicable, for participation in the extension study must be obtained at this visit before any extension study-related procedures are conducted.  
Parents/legal guardians should receive the informed consent information prior to this visit to allow adequate time for review at home, and discussion 
with the Investigator and/or designee.  Data on medical history, demographics, screening tests, ongoing adverse events (AEs) and concomitant therapy, 
and EOT tests and assessments will be transferred from the preceding rFVIIIFc studies.  Thus, it will not be necessary to repeat these assessments at 
Visit 1.  An HJHS or modified HJHS assessment, as appropriate, should be performed at Visit 1 in ALL subjects.  Study eligibility must be verified prior 
to study enrollment.  Subjects who enroll with a gap of greater than 37 days following EOT Visit of the previous study should have all laboratory 
assessments performed and reviewed by the Investigator at Visit 1, prior to dosing with rFVIIIFc, to assess safety and inclusion/exclusion parameters. 
The time required for Visit 1 may span a sufficient interval to allow for laboratory results to be reviewed and confirmed as suitable by the Investigator, 
and may require more than 1 clinic visit prior to dosing with rFVIIIFc. 
2. 
For future subjects that enroll into ASPIRE, assessments will be only those conducted in the parent study.  
3. 
Medical and surgical history includes any significant medical condition and/or any significant surgical histories that have occurred since the subject 
enrolled in the parent study. 
4. 
Physical examination and vital signs.  Physical examination to include:  skin, head, eyes, ears, nose, throat (HEENT); lymph; neck; chest/lungs; heart; 
vascular; abdomen; musculoskeletal; neurological; extremities; and joints.  Vital signs to include: temperature, blood pressure, pulse rate, and 
respiratory rate.  Following Visit 7, physical examination and vital signs continue to be performed only annually. 
5. 
Subjects will receive supplies of rFVIIIFc for home administration from the study site at and between visits; each time, the study site staff will perform 
full medication exchange and accountability with the subject
.  See Section 12 for information on planning and process for 
dispensation, and on supplies accountability. 
6. 
To be performed at the central laboratory.  FVIII activity is determined by one-stage aPTT clotting assay and two-stage chromogenic assay performed at 
the central laboratory.  For FVIII inhibitor and rFVIIIFc antibody testing, a wash out of at least 48 hours is recommended.  For subjects who have fewer 
than 50 exposure days (EDs) with rFVIIIFc following completion of Visit 1, a visit may be conducted to perform inhibitor testing at the time subjects 
reach 10 to 15 EDs, 50 to 75 EDs, and 100 to 125 EDs, as applicable.  If the timing does not coincide with a scheduled visit, an unscheduled visit may 
be conducted.  A portion of the blood sample collected will be stored for future anti-rFVIIIFc antibody testing.  Samples will be archived for testing (if 
required) for immunology or further coagulation assays, or for clarification of any clinical or laboratory AE.  Inhibitor and rFVIIIFc antibody testing 
should also be done when deemed clinically relevant. 
7. 
Hematology includes:  white blood cell count (WBC), differential, platelet count, hemoglobin, hematocrit. 
8. 
Blood chemistry includes:  electrolytes (sodium, potassium, chloride), glucose, total protein, total bilirubin, alanine aminotransferase (ALT), aspartate 
aminotransferase (AST), alkaline phosphatase (ALP), blood urea nitrogen (BUN), and serum creatinine. 
9. 
Tailored prophylaxis, weekly prophylaxis, and personalized prophylaxis regimens:  FVIII activity to be measured at trough immediately prior to the 
injection, and at peak (recovery) 30 (±3) minutes from the start of injection.  On-demand regimen:  FVIII activity to be measured at the discretion of the 
Investigator. 
10. 
The sample for DNA-based testing is optional and may be collected at any time during the study, not exclusively at Visit 1. 

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11. 
Patient-reported outcomes should be completed only if they were conducted during the parent study:  Questionnaires to be completed every 6 months at 
scheduled clinic visits.  Questionnaires will be provided under separate cover. 
12. 
Changes in patient-reported health outcomes conducted during the parent study to be queried 
electronic patient diary (eDiary) on an 
ongoing basis, and details to be recorded in the electronic case report form (eCRF). 
13. 
Unscheduled visits may be necessary during the study, as determined by the Investigator, for reasons that may include repeating safety assessments, 
repeating blood sampling if required, or changing dose/regimen.  For subjects from the pediatric study (8HA02PED) who undergo major surgery and 
enter the extension study before completing their Last Post-Operative Visit, an unscheduled visit may be conducted to perform the Last Post-Operative 
Visit assessments when the subjects switch from their post-surgery dosing regimen to a regimen outlined in Section 5.3 (see Section 5.3.3 for list of 
assessments).  For subjects who have fewer than 50 EDs with rFVIIIFc following completion of Visit 1, a visit may be conducted to perform inhibitor 
testing at the time subjects reach 10 to 15 EDs, 50 to 75 EDs, and 100 to 125 EDs, as applicable.  If the timing does not coincide with a scheduled visit, 
an unscheduled visit may be conducted. 
14. 
Subjects entering the extension study from 997HA301 should continue to use the Modified Hemophilia Joint Health Score.  Subjects entering the 
extension study from 8HA02PED should continue to use the HJHS Version 2.1.  HJHS and modified HJHS should only be completed if they were 
conducted during the parent study.  Following Visit 7, the HJHS assessment continues to be performed annually.  The HJHS assessment is not required 
at Final Study Visit if it was performed within the last 9 months. 
15. 
A follow-up telephone visit is required 7 (+7) days after the last dose of rFVIIIFc to monitor AEs, SAEs, and concomitant medications and therapies.  
This 7 day follow-up visit is not required if a subject ends his participation in the extension study to enroll into another rFVIIIFc study, however, a final 
visit/early termination visit is required. 
 

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Table 2: 
Surgery Visits 
Tests and Assessments1 
Pre-Surgery2 
Visit 1 
Week -12 to Week -1 prior to 
Surgery 
Visit 2 
Day of 
Surgery 
 
Visit 3 
1-2 Weeks Post 
Surgery8 
 
Visit 4 
Last Post-Operative 
Visit8 
 
Physical Examination 
X 
X 
 
X 
Weight 
X 
X 
X 
X 
Vital Signs (temperature, blood pressure, pulse rate, 
respiratory rate) 
 
X1 
 
 
Hematology3 
X 
X 
X 
X 
Blood Chemistry3 
X 
X 
X 
X 
4 
<<<<<<<<         ongoing as applicable       >>>>>> 
Investigator/Surgeon Assessment of Hemostatic Response5 
 
X 
 
 
FVIII Activity6 
X 
X 
X 
X 
Nijmegen-modified Bethesda Assay (inhibitor testing)7 
X 
X 
X 
X 
Anti-rFVIIIFc Antibody Assay7 
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 
Table footnotes are presented on page 25.

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Footnotes for Surgery Visits 
1. 
All tests and assessments should be collected for major surgery and minor surgery, where available.  Subjects may be allowed to have a PK 
evaluation performed by the central laboratory prior to surgery if needed in the opinion of the Investigator. 
2. 
To be assessed prior to surgery. 
3. 
To be performed at the central laboratory.  Hematology includes:  WBC, differential, platelet count, hemoglobin, and hematocrit.  Blood chemistry 
includes:  electrolytes (sodium, potassium, and chloride), glucose, total protein, total bilirubin, ALT, AST, ALP, BUN, and serum creatinine.   
4. 
Subjects who require post-operative rFVIIIFc treatment for a bleeding episode at home will record their assessment of response to treatment in the 
eDiary; this assessment is to be made approximately 8 to 12 hours from the time the rFVIIIFc injection was given to treat the bleeding episode and 
prior to any additional doses of rFVIIIFc given for the same bleeding episode. 
5. 
 during surgery using a 4-point scale.  This assessment 
will be done within 24 hours after surgery.  See Appendix C and Appendix E. 
6. 
FVIII activity levels should be measured prior to the pre-operative (loading) dose of rFVIIIFc, and at 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 determination of subsequent 
rFVIIIFc 
VIII 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. 
7. 
Inhibitor and anti-rFVIIIFc antibody testing to be performed 2 to 4 weeks prior to surgery, pre-operatively on the day of surgery, 1-2 weeks after 
surgery, and at the last post-operative visit (for minor surgery, testing is not performed at the last 2 timepoints).  For FVIII inhibitor and antibody 
testing, a wash out of at least 48 hours is recommended.  
8. 
Visit 3 (1-2 Weeks Post 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 returns to a regular rFVIIIFc regimen as determined by the Investigator, and is not required if the return to 
a regular rFVIIIFc regimen occurs at Visit 3. 
 

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5. 
INTRODUCTION  
8HA01EXT is an extension study designed to assess the long-term safety and efficacy of 
recombinant factor VIII fusion protein (rFVIIIFc) in previously treated subjects with hemophilia 
A.  Male subjects of all ages who have completed a preceding study of rFVIIIFc (997HA301, 
8HA02PED, or any other rFVIIIFc study) may be eligible for enrollment in this study. 
The Note for Guidance on the Clinical Investigation of Recombinant Factor VIII and Human 
Plasma-derived FVIII Products [CPMP, 2009] was followed in the development of this protocol. 
5.1. 
Profile of Previous Experience 
Hemophilia A is an X-chromosome-linked bleeding disorder caused by mutations and/or 
deletions in the F8 gene resulting in a deficiency of FVIII activity [Mannucci, 2001; Bolton-
Maggs and Pasi, 2003].  The coagulation disorder occurs predominantly in males and affects 
approximately 1 in 10,000 males.  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.   
5.1.1. 
Therapies for Hemophilia A 
There is no cure for hemophilia A, so treatment focuses on the replacement of FVIII with the 
intravenous (IV) administration of FVIII-containing coagulation products to promote clotting.  
The goal of treatment with FVIII-containing coagulation products is to raise the circulating level 
of FVIII to the lowest effective level to achieve either resolution of bleeding (on-demand 
treatment) or prevention of bleeding (prophylaxis treatment) [WFH, 2005; MASAC, March 
2009].  The frequency of administration of FVIII products varies across patients and is tailored to 
s, 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 and guidelines established by organizations such as 
the National Hemophilia Foundation of the United States and the World Federation of 
Hemophilia (WFH [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 

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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 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, 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 (t1/2) 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 
al independence 
[Colvin, 2008]. 
5.1.2. 
rFVIIIFc 
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 IgG from 
degradation and confers IgG the 3-week t1/2 observed in humans [Ghetie and Ward 2000; 
Roopenian 2007].  The FcRn is present in humans throughout life and protects IgG from 
catabolism [Junghans 1996].  rFVIIIFc was designed to offer a longer circulating t1/2 than 
currently available FVIII products, aiming to provide hemophilia A patients with prolonged 
protection and prophylaxis from bleeding with less frequent dosing. 
5.1.3. 
Summary of Clinical Experience With rFVIIIFc 
A completed Phase 1/2a study (998HA101) investigated the safety of a single dose of rFVIIIFc 
given as an IV injection over 10 minutes to subjects with severe hemophilia A and compared the 
pharmacokinetics (PK) of rFVIIIFc with Advate® (antihemophilic factor [Recombinant], 
Plasma/Albumin-Free Method, [INN] octocog alfa).   
Two dose levels, 25 IU/kg and 65 IU/kg, were evaluated, with 6 subjects receiving Advate 
25 IU/kg, and 10 receiving Advate 65 IU/kg.  Following a 3-day PK profile for the Advate 
25 IU/kg dose group and a 4-day profile for the Advate 65 IU/kg dose group, these subjects then 
crossed over to receive an equivalent dose of rFVIIIFc.  A 7-day PK profile was performed after 
the 25 IU/kg dose.  Following the rFVIIIFc 65 IU/kg dose, subjects underwent a 10-day PK 
profile.  A 28-day safety observation period followed the rFVIIIFc dose, and included inhibitor 
testing at 14 and 28 days post-dosing. 
Safety and tolerability were assessed in all 16 subjects, including FVIII inhibitors and 
anti-FVIIIFc antibodies, vital signs, hematology, clinical chemistry, and coagulation parameters. 
When compared with Advate at both dose levels, rFVIIIFc was well-tolerated.  No clinically 
significant changes in safety parameters occurred and most adverse events (AEs) were mild and 
resolved without sequelae by the end of the study.  No subject developed antibodies or inhibitors 
during the study period.  Compared with Advate, rFVIIIFc demonstrated significantly improved 

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activity, as indicated by longer t1/2, increased systemic exposure, and a reduction in clearance, 
with comparable maximum plasma activity (Cmax) and recovery.  Improved FVIII activity 
resulted in an increased time to 1% above baseline, approximately 50% to 74% longer at doses 
of 25 IU/kg and 65 IU/kg, respectively (one-stage aPTT clotting assay); and 51% to 79% longer 
at 25 IU/kg and 65 IU/kg, respectively (chromogenic assay). 
In addition, a Phase 3 study in previously treated subjects age 12 years or older with severe 
hemophilia A has recently been completed (Study 997HA301).  A total of 164 subjects 
(including 13 subjects aged 12 to 17 years) in the Phase 3 study received at least 1 dose of 
rFVIIIFc.  This included 146 subjects treated for at least 26 weeks and 23 subjects treated for at 
least 39 weeks, for a total of 102.05 person-years on study.   
Compared with Advate, rFVIIIFc demonstrated improved PK activity, as indicated by a 53% 
longer t1/2, a 56% increase in systemic exposure, and a 36% reduction in CL, with comparable 
Cmax and recovery (one-stage aPTT clotting assay).   
rFVIIIFc was well tolerated in the Phase 3 study.  No subject developed an inhibitor to rFVIIIFc.  
Common AEs observed were consistent with those expected in patients with hemophilia A.  
Adverse drug reactions were mild and manageable, and the majority were not treatment limiting.  
One nonserious event of rash required discontinuation of treatment and resolved.  There was no 
Grade 2 or greater allergic reactions or serious vascular thrombotic events.  No treatment-related 
serious adverse events (SAEs) were observed.   
Study 8HA02PED (referred to as the pediatric study) is an open-label, multicenter study 
evaluating the safety, PK, and efficacy of rFVIIIFc in previously treated pediatric patients with 
severe hemophilia A, who are <12 years of age, and have at least 50 EDs to FVIII products prior 
to enrollment.  Approximately 50 male subjects (25 subjects <6 years of age and 25 subjects 6 to 
<12 years of age) are planned to complete at least 26 weeks of prophylactic treatment to attain at 
least 50 EDs.  At least 24 of these subjects (12 subjects <6 years of age and 12 subjects 6 to 
<12 years of age) will undergo an evaluation of the PK profile of pre-study FVIII and rFVIIIFc.  
Subjects who complete this study will be offered enrollment into the extension trial described in 
this protocol. 
For further details regarding the clinical studies conducted with rFVIIIFc, please refer to the 
rFVIIIFc Investi
 
5.2. 
Study Rationale 
The results of the Phase 1/2a study, the nonclinical data [Dumont, 2009], and the Phase 3 study 
support further investigation of repeat administration of rFVIIIFc in the prevention and treatment 
of bleeding episodes in hemophilia A subjects.  This extension study will evaluate the long-term 
safety of rFVIIIFc in subjects with hemophilia A and will allow subjects from the A-LONG 
(997HA301) pivotal study, the pediatric study (8HA02PED), and other studies to continue 
treatment with rFVIIIFc. 

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5.3.
Rationale for Dose and Schedule Selection
Subjects 12 years of age or older will follow either a tailored prophylaxis (individualized), 
weekly (modified) prophylaxis, personalized prophylaxis, or on-demand (episodic) regimen 
based on the clinical profile of the subject and by the trough and/or peak (recovery) values, if 
needed, as observed in the preceding study.  Subjects are allowed to change treatment regimens 
(for example, from prophylaxis to on-demand, or from on-demand to prophylaxis) during the 
study.  Subjects less than 12 years of age will receive 1 of 2 prophylactic regimens, tailored or 
personalized, and will not have the option to change to a weekly prophylactic or on-demand 
regimen, unless they reach the age of 12 years during the study, at which time they can be use 
any of the 4 treatment regimens.  All treatment regimen changes will be discussed between the 
Investigator and the subject (and parent/guardian, as applicable).  All treatment regimen changes 
require the approval of the Sponsor Medical Monitor.  All regimen changes must occur at a 
scheduled or unscheduled clinic visit following assessment by the Investigator, and must be 
documented at that visit.  Details (including date of change, new dose and/or dosing interval, and 
reasons for the change) will be recorded on electronic case report forms (eCRFs). 
rFVIIIFc study.  In the completed Phase 3 study, 997HA301, doses between 20 IU/kg and 
65 IU/kg were evaluated and shown to successfully maintain a trough level >1% and/or control 
bleeding.  In the pediatric study, 8HA02PED, a regimen consisting of starting doses of 25 IU/kg 
on Day 1 and 50 IU/kg on Day 4 of rFVIIIFc is used initially.  This dosing regimen may be 
adjusted as indicated by enrollment PK, subsequent FVIII activity trough levels, or bleeding 
patterns: the dose may be adjusted up to a maximum prophylactic dose of 80 IU/kg and the 
frequency of administration up to every 2 days, if necessary to maintain adequate FVIII activity 
trough levels and prevent spontaneous bleeding events.  
5.3.1. 
On-Demand Regimen 
The individual dose of rFVIIIFc 
condition, type and severity of the bleeding event, and if indicated, FVIII levels.  
PK 
profile and dosing levels from the predecessor studies may also be used to guide dosing 
decisions.  Subjects <12 years of age entering from another rFVIIIFc study will not be offered 
this option, but can receive an on-demand regimen once they reach the age of 12 years during the 
study. 
Please refer to Appendix A for guidance on dosing decisions. 
5.3.2. 
Prophylaxis Regimens   
Details for each dosing option, including, if applicable, date of change, new dose and/or dosing 
interval, and reason(s) for the regimen change will be recorded on the appropriate eCRF each 
time a change is made. 
5.3.2.1. 
Option 1:  Tailored Prophylaxis 
The Investigator may consider the following options for tailored prophylaxis to target a FVIII 
trough of up to 5%, but is encouraged to use the lowest effective dose targeting a FVIII trough 

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level between 1% and 3%.  If bleeding episodes occur at FVIII trough levels of 1% to 3%, 
further adjustments to dose or interval over the course of the study will target trough levels of up 
to 5%. 
Dosing is approximately 25 IU/kg to 65 IU/kg every 3 to 5 days, or dosing 2 times per week at 
approximately 20 IU/kg to 65 IU/kg on Day 1 and 40 IU/kg to 65 IU/kg on Day 4.  The dose and 
study, and/or his individual PK (if available), and FVIII trough and/or peak (recovery) values.  In 
pediatric subjects, doses may be adjusted up to a maximum prophylactic dose of 80 IU/kg and the 
interval decreased to every 2 days, if necessary to maintain adequate FVIII activity trough levels and 
prevent spontaneous bleeding events. 
5.3.2.2. 
Option 2:  Weekly Prophylaxis  
Dosing is approximately 65 IU/kg at weekly intervals.  The dose should be based on the 
available), and FVIII trough and/or peak (recovery) values.  Subjects <12 years of age entering 
from another rFVIIIFc study will not be offered this option, but can receive a weekly prophylaxis 
regimen once they reach the age of 12 years during the study. 
5.3.2.3. 
Option 3: Personalized Prophylaxis 
If optimal prophylaxis dosing cannot be achieved using either of the above options, the 
Investigator may further personalize dosing to meet the needs of individual subjects. 
The Investigator may consider the following personalized dosing options: 
 
 
 Targeting a FVIII trough level of >3%, if the bleeding history and/or activity level 
requires. 
 Dosing less frequently. 
The Investigator is not limited to the options above, and should consult the Medical Monitor for 
ized prophylaxis dosing option 
will require consultation with the Medical Monitor. 
5.3.3. 
Surgery and Rehabilitation 
If a subject requires emergent or elective surgery while participating in this study, he may be 
treated with the dose and regimen of rFVIIIFc deemed appropriate for the type of surgery.  All 
major surgeries will be reported as SAEs. 
All major surgical procedures must take place in a center that can provide study treatment, 
trained study personnel, post-operative assessments, and hematological consultation by the 
Investigator or Co-Investigator.  If the surgery does not occur in such a setting, the subject will 
be withdrawn from the study.  See Section 10.1.3 for provisions when a subject requires major 
surgery.  

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If surgery-related dosing is continued during post-operative rehabilitation and/or physical 
therapy, the dose of rFVIIIFc will be adjusted to achieve a FVIII trough at a sufficient level to 
maintain hemostasis. 
Subjects will return to a regular rFVIIIFc regimen once all dosing for the post-operative 
rehabilitation period has been completed.  For subjects undergoing major surgery, a visit is 
required 1-2 weeks after surgery (Visit 3, not required for minor surgery).  Visit 4 (Last 
Post-Operative Visit, not required for minor surgery) occurs when the subject returns to a regular 
rFVIIIFc regimen as determined by the Investigator, and is required only if the subject did not 
return to a regular rFVIIIFc regimen at Visit 3. 
The surgical period will begin w
e surgery 
(i.e., the pre-surgery dose).  This is the pre-operative period of the surgery.  The intra-operative 
period is defined as the time the surgery begins to the time the surgery completes.  The 
post-operative care period is defined as the time period following the completion of the surgery 
through the last dose of rFVIIIFc given for the surgery, as judged by the Investigator/Surgeon, 
including doses given to prevent bleeding during the post-operative rehabilitation period. 
For subjects from the pediatric study (8HA02PED) who undergo major surgery and enter the 
extension study before completing their Last Post-Operative Visit from the prior rFVIIIFc study, 
an unscheduled visit may be conducted to perform the Last Post-Operative Visit assessments 
when the subjects switch from their post-surgery dosing regimen to a regular rFVIIIFc regimen 
(as outlined in Sections 5.3.1 and 5.3.2).  The following assessments must be performed at that 
time: 
 Physical examination 
 Weight 
 Hematology 
 
ssessment of response 
 FVIII activity (to be measured at trough immediately prior to the injection and at peak 
[recovery] 30 [±3] minutes from the start of injection) 
 Subject eDiary review 
 Nijmegen-modified Bethesda assay (inhibitor assay) 
 rFVIIIFc administration and accountability 
 AE/SAE monitoring and recording  
 Concomitant therapy/procedures recording 
5.4. 
Potential Risks and Benefits 
Ple
benefits of rFVIIIFc. 

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6. 
STUDY OBJECTIVES AND ENDPOINTS 
6.1. 
Objectives  
6.1.1. 
Primary Objective 
The primary objective of the study is to evaluate the long-term safety of rFVIIIFc in subjects 
with hemophilia A. 
6.1.2. 
Secondary Objectives 
The secondary objective of the study is to evaluate the efficacy of rFVIIIFc in the prevention and 
treatment of bleeding episodes in subjects with hemophilia A. 
6.2. 
Endpoints 
6.2.1. 
Primary Endpoint 
The primary endpoint is the occurrence of inhibitor development 
6.2.2. 
Secondary Endpoints 
The secondary endpoints are as follows: 
 The annualized number of bleeding episodes (spontaneous and traumatic) per subject 
 The annualized number of spontaneous joint bleeding episodes per subject 
 The total number of days of exposure per subject per year 
 The consumption of rFVIIIFc as total dose per kg per subject per year  
 
response to his treatment regimen 
using a 4-point scale 
 Subject  assessment of response to the treatment of bleeding episodes using a 4-point 
scale 
6.2.3. 
Major Surgery Endpoints 
The major surgery endpoints are as follows: 
 Investigator/Surgeon assessment of hemostatic response to surgery using the 4-point 
bleeding response scale 
 Number of injections and dose per injection to maintain hemostasis during the 
surgical period. 
 Estimated blood loss (mL) during surgery and post-operative period 
 Number of blood product units transfused during surgery 

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6.2.4. 
Patient-Reported Outcome Endpoints 
The following patient-reported outcomes will be assessed.  Subjects will only take the 
questionnaires that they completed during the parent study.  If a subject goes outside of the age 
range for a questionnaire, they should no longer complete the questionnaire.  The Investigator 
will administer the age-appropriate questionnaire at the appropriate visits. 
Quality of Life (QoL) questionnaires: 
 Haem-A-QoL  
 Haemo-QoL  
 Hemo-Sat-Patient Satisfaction Scale for parents/guardians, Version 15 
 Canadian Hemophilia Outcomes-
(CHO-KLAT)  
o Children, Version 2.0 (for children previously enrolled in study 8HA02PED 
who are less than 18 years of age).   
o Proxy, Version 2.0p (for parents/guardians of children previously enrolled in 
study 8HA02PED and who are less than 18 years of age) 
 EQ-5D Y  
 EQ-5D-3L 
Health outcomes related to hemophilia will include: 
 Number of hospitalizations excluding planned hospitalizations, elective surgery 
documented at Visit 1, and emergent surgery 
 Number of emergency room visits  
 Number of physician visits, excluding study visits 
 Number of hospitalization days  
 Number of days off work, school, day care, or preschool  
 Number of days off work for the parent or caregiver  
 

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7. 
STUDY DESIGN 
7.1. 
Study Overview 
This is an open-label, multi-center, long-term study of IV administration of rFVIIIFc in 
previously treated patients (PTPs) with hemophilia A who have completed the A-LONG study 
(997HA301), the pediatric study (8HA02PED), or any other study with rFVIIIFc.  This is a 
global study and will be offered to those countries participating in these studies.   
Based on estimated sample sizes from these studies, approximately 194 subjects from the 
ongoing A-LONG study and the pediatric study may be eligible to enroll in this extension study.  
The End of Treatment (EOT) Visit of the previous study may serve as the initial visit of the 
extension study.  Assessments performed at this visit will be used to confirm eligibility for 
participation in the extension study. 
Study visits are scheduled at 6-month (±2 weeks) intervals following completion of Visit 1.  
Unscheduled visits may occur as deemed necessary by the Investigator.  For subjects who enter 
the extension study and undergo surgery before completing their Last Post-Operative Visit from 
the prior rFVIIIFc study, the Last Post-Operative Visit assessments will be performed when the 
subjects switch from their post-surgery dosing regimen to a regimen outlined in Section 5.3 (see 
Section 5.3.3 for list of assessments).  For subjects who have fewer than 50 exposure days (EDs) 
with rFVIIIFc following completion of Visit 1, a visit may be conducted to perform inhibitor 
testing at the time subjects reach 10-15 EDs, 50-75 EDs, and 100-125 EDs, as applicable.  If the 
timing does not coincide with a scheduled visit, an unscheduled visit may be conducted. 
For subjects undergoing surgery, post-operative clinic visits may be more frequent.   For subjects 
undergoing major surgery, a visit is required 1-2 weeks after surgery (Visit 3, not required for 
minor surgery).  Visit 4 is required only if subjects who had major surgery did not return to a 
regular rFVIIIFc regimen as determined by the Investigator at Visit 3.  All major surgeries will 
be reported as SAEs.  Scheduled visits will include safety and efficacy assessments, and FVIII 
activity measurements to assess trough and peak (recovery) (Section 4).  In addition, the site will 
continue to contact study subjects and/or caregivers by telephone on a bimonthly basis to review 
AEs, treatment compliance, and use of concomitant medications and therapies. 
Treatment will be administered as tailored prophylaxis, weekly prophylaxis, personalized 
prophylaxis, or as an on-demand regimen.  Subjects 12 years of age or older will be able to 
switch from one regimen to another at scheduled or unscheduled visits during the study, per 
Investigator discretion.  Subjects less than 12 years of age will receive 1 of 2 prophylactic 
regimens, tailored or personalized, and will not have the option to change to a weekly 
prophylactic or on-demand regimen, unless they reach the age of 12 years during the study, at 
which time they can use any of the 4 treatment regimens.  
To ensure accuracy of FVIII trough/peak (recovery) and inhibitor testing, subjects following a 
prophylaxis regimen should schedule clinic visits 48 hours after the previous dose of rFVIIIFc, 
whenever possible. 

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Subjects first dosed with rFVIIIFc when <12 years of age will be followed to at least 100 EDs, 
even if rFVIIIFc becomes commercially available.   
All subjects will have the opportunity to continue in this study for up to 4 years or until rFVIIIFc 
is commercially available in the applicable participating country.   
7.1.1. 
Dose-Limiting Toxicity 
No dose-limiting toxicities have been identified to date in humans receiving a single dose of 
rFVIIIFc up to 65 IU/kg.  Also, no dose-limiting toxicities were observed in the preclinical 
animal studies where repeat doses of up to 1000 IU/kg were evaluated.   
Doses higher than 65 IU/kg may be used in this study, such as in surgery, to achieve the required 
FVIII levels to prevent bleeding.  However, the maximum dose during surgery will not exceed 
the predicted accumulated Cmax of approximately 200% of normal (normal ranges are 50-150% 
FVIII activity).  In pediatric subjects, dose adjustments up to a maximum prophylactic dose of 
80 IU/kg and frequency of administration up to every 2 days can be used if necessary to maintain 
adequate FVIII activity trough levels and prevent spontaneous bleeding events.   
An overdose of rFVIIIFc is defined as any single prophylactic dose >100 IU/kg (see Section 
15.4.1).   
7.1.2. 
Inhibitor Testing 
If inhibitor development is suspected at any time during the study (for example, 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 
 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 high-titer inhibitor is defined as 
 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. 
When an inhibitor test is performed at the local laboratory, an aliquot of the sample must be sent 
in parallel to the central laboratory. 
For FVIII inhibitor testing, a wash out of at least 48 hours is recommended. 
For subjects who have fewer than 50 exposure days (EDs) with rFVIIIFc following completion 
of Visit 1, a visit may be conducted to perform inhibitor testing at the time subjects reach 10-15 
EDs, 50-75 EDs, and 100-125 EDs, as applicable.  If the timing does not coincide with a 
scheduled visit, an unscheduled visit may be conducted. 
7.1.3. 
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.  

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The electrochemiluminescent assay (ECLA) used for this test is approximately 10-to 20-fold 
more sensitive than the Nijmegen-modified Bethesda assay.  A blood sample will be stored for 
future testing of anti-rFVIIIFc antibody at the same time points that samples are drawn for 
inhibitor testing, or for any clinical event deemed relevant to anti-rFVIIIFc testing (see Table 1 
and Table 2).  
7.1.4. 
Bleeding Episodes 
If a subject experiences a bleeding event at any time during study treatment, he or his caregiver 
should follow the guidance for treatment of bleeds, a document to be provided to each subject 
and/or caregiver.  Guidance for study staff is provided in Appendix A.  The type of bleed and 
each injection and injection dose 
electronic patient diary (eDiary). 
In this study, when a subject reports a bleed or hemorrhage, and is treated with study drug, it will 
be classified as spontaneous or traumatic by the subject
eDiary will serve as the 
source document for bleeding episodes while on study.  
In this study, a bleed will be defined as follows:  a bleeding episode starts from the first sign of a 
bleed and ends no more than 72 hours after the last treatment for the bleed, within which any 
symptoms of bleeding at the same location, or injections less than or equal to 72 hours apart, are 
considered the same bleed.  Any injection to treat the bleed, taken more than 72 hours after the 
preceding one, will be considered the first injection to treat a new bleed at the same location.  
Any bleeding at a different location is considered a separate bleed regardless of time from last 
injection. 
Spontaneous bleeding episodes:  Bleeding episodes should be classified as spontaneous if a 
subject records a bleeding event when there is no known contributing factor such as definite 
the Investigator.  Both spontaneous bleeding episodes (the occurrence of hemorrhage where 
neither the subject nor a caregiver can identify a reason) and traumatic bleeding episodes 
(hemorrhage occurring secondary to an event such as trauma or strenuous activity) will be 
collected.  Target joints can have spontaneous bleeding episodes.  
Traumatic bleeding episodes:  Bleeding episodes should be classified as traumatic if a subject 
records a bleeding event when there is a known or believed reason for the bleed.  For example, if 
a subject were to exercise strenuously and then have a bleed in the absence of any obvious 
injury, the bleed would still be recorded as a traumatic bleed.  Target joint bleeding episodes can 
be traumatic if a known action led to bleeding into the joint. 
7.1.4.1. 
Information to be Recorded 
The incidence of bleeding in this study will be obtained from eDiaries and any medical records 
while the subject is receiving study treatment.  
eDiary information in a timely manner to facilitate appropriate medical review and dosing 
guidance.  The clinical sites and monitors will ensure that there is consistency between the 
eDiary record and eCRFs.  During the clinical visits and telephone calls with the 
subject/
, and 

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/
document it in (
on, and 
(b) the eCRF, documenting the new classification of the bleed according to the Investigator, and 
whether or not 
spontaneous  or traumatic  will be used (if 
 
Bleeding episodes will not be reported as AEs; however, the concomitant events associated with 
a bleed may be reported as an AE if appropriate (i.e., a fracture in an elbow).  Both spontaneous 
bleeding episodes and traumatic bleeding episodes will be collected.  
The following information will also be documented in the eDiary: 
 The type of bleeding episode (e.g., spontaneous, traumatic, or related to increased 
physical activity).   
 The date the bleeding event occurred. 
 The dose administered for the bleeding episode, including any repeat doses. 
 The location of the bleed (joint, internal, skin/mucosa, or muscle). 
 The reason for administering the dose (medical or nonmedical reasons [e.g., strenuous 
activity or other reason]) 
7.1.4.2. 
Procedure to Treat the Bleeding Episode 
The dose of rFVIIIFc to treat the bleeding episode 
condition, known PK information from the previous study or FVIII trough/peak (recovery) 
measurements in this study, type and severity of the bleeding event (see Appendix A for 
guidance on dosing), and input from the Sponsor, if necessary. 
Subjects 
episode with a single dose of rFVIIIFc.  Most bleeding episodes should resolve with a single 
dose of rFVIIIFc.  If a subject has one spontaneous bleed and the Investigator is concerned the 
trough level is too low, the Investigator should contact the Sponsor to discuss next steps for this 
subject.  
 If the bleeding episode stops with a single IV dose of rFVIIIFc, the subject should 
return to his previous dosing regimen and will be treated with his next dose of rFVIIIFc 
as previously scheduled, even if this results in consecutive daily doses.   
 If the bleeding episode does not stop within 24 hours with the single IV dose of 
rFVIIIFc, the subject or the subject
uld consult with the Investigator for 
an optimal rFVIIIFc dose and dosing interval, and should administer a second dose (first 
follow-up dose) no less than 24 hours after the initial dose.  Administration of the second 
dose of rFVIIIFc as follow-up treatment will be determined by the Investigator based on 
 Appendix A for rFVIIIFc dosing 
guidance.  Once the bleeding event stops, the subject will return to his previous dosing 

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regimen and will be treated with his next dose of rFVIIIFc as previously scheduled, even 
if this results in consecutive daily doses.   
 If the bleeding event does not stop with 2 doses (initial and follow-up treatments) of 
rFVIIIFc, the subject or the subject s caregiver should contact the Investigator for 
advice.  Following consultation with the Investigator, a third dose of rFVIIIFc will be 
administered 24 hours after the administration of the second dose of rFVIIIFc.  The third 
dose (second follow-up dose) may be at the same dose as the second dose or a dose 
 to 
Appendix A for rFVIIIFc dosing guidance.  Once the bleeding event resolves, the subject 
will return to his previous dosing regimen and will be treated with his next dose of 
rFVIIIFc as previously scheduled, even if this results in consecutive daily doses.   
If the bleeding event still has not stopped after 3 doses (initial and 2 follow-up doses) of 
rFVIIIFc, the Investigator should contact the Sponsor Medical Monitor to discuss the next steps 
for treatment of the subject. 
7.1.4.3. 
Dose and/or Interval Modification Following Bleeding Episodes 
Dose and/or interval modification following bleeding episodes can occur if a subject experiences 
moderate or major spontaneous bleeding episodes over a rolling 8-week period.  The 
Investigator can adjust the rFVIIIFc dose as follows: 
 If an increase is required, the dose may be increased in increments of at least 5 IU/kg. 
 The dose and/or interval may be adjusted after discussion with the Sponsor Medical 
Monitor. 
 See Section 5.3 for description of regimen changes.  
7.2. 
Overall Study Duration and Follow-Up 
The study period will consist of Screening and Treatment.   
Subjects first dosed with rFVIIIFc when <12 years of age will be followed to at least 100 EDs, 
even if rFVIIIFc becomes commercially available.   
All subjects will have the opportunity to participate in this study for up to 4 years or until 
rFVIIIFc is commercially available in the applicable participating country.    
7.2.1. 
Screening 
Subject eligibility for the study will be determined prior to enrollment (Visit 1). The EOT Visit 
for the preceding study may act as Visit 1 for this study, however, if there is a gap of >37 days 
following the EOT Visit of the preceding study, all laboratory assessments for Visit 1 must be 
performed and eligibility confirmed prior to dosing with rFVIIIFc.   
Informed consent for the extension study may be reviewed and obtained during the EOT Visit of 
the previous study, and if not then consent must be obtained at Visit 1.  

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7.2.2. 
Treatment 
Eligible subjects will self-administer rFVIIIFc according to their assigned treatment regimen.  
Caregivers or Sponsor-approved designees may also administer rFVIIIFc.  Where appropriate, 
rFVIIIFc may be administered in the clinic. 
7.2.3. 
Follow-Up 
A final study visit will be conducted approximately 147 (+7) days after the last dose of rFVIIIFc.  
This 7 day follow-up visit is not required if a subject ends his participation in the extension study 
to enroll into another rFVIIIFc study. 
7.3. 
Study Stopping Rules 
The Sponsor may terminate this study at any time, after informing Investigators.  Investigators 
will be notified by the Sponsor or designee if the study is placed on hold, completed, or closed. 
The study must be stopped in the following cases: 
 
.00 BU/mL) inhibitor, as defined in 
Section 7.1.2.  This number can be adjusted based on sample size when more subjects 
might be included into this trial from other rFVIIIFc studies. 
 An unexpected, serious, or unacceptable risk to the study subjects. 
If the study is stopped, the events will be investigated, enrollment will be stopped, and current 
subjects will stop dosing with rFVIIIFc.  If, in consultation with the Sponso
Surveillance Team, it is determined that the study should be permanently discontinued, then 
subjects will attend a final visit.   
7.4. 
End of Study 
The end of study is last subject, last visit. 
 

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8. 
SELECTION OF SUBJECTS 
8.1. 
Inclusion Criteria 
To be eligible to participate in this study, candidates must meet the following eligibility criteria 
at the time of signing the informed consent at Visit 1 of the study, or at the EOT of the previous 
study:   
1. Ability to understand the purpose and risks of the study and provide signed and dated 
informed consent and authorization to use protected health information (PHI) 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. Subjects who have completed the studies 997HA301, 8HA02PED, or other studies with 
rFVIIIFc. 
8.2. 
Exclusion Criteria 
Candidates will be excluded from study entry if any of the following exclusion criteria exist at 
the time of signing the informed consent at Visit 1 of the study, or at the EOT of the previous 
study: 
1. Confirmed high-
, as defined in Section 7.1.2.  
2. Current enrollment in any other study. 
3. Inability to comply with study requirements. 
4. Other unspecified reasons that, in the opinion of the Investigator or Biogen Idec, make 
the subject unsuitable for enrollment. 
 

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9. 
ENROLLMENT AND REGISTRATION PROCEDURES 
9.1. 
Enrollment and Screening 
Adult subjects must provide written informed consent and pediatric subjects may provide written 
assent (as appropriate), before any screening tests or assessments are performed.  For subjects 
less than 18 years of age, or, for subjects otherwise unable to provide written informed consent, 
parents or legal guardian(s) must obtain the informed consent form and return to the clinic 
following review to discuss and sign the consent/assent forms as appropriate.  At the time of 
consent/assent, the subject will be enrolled into the study.  This will occur following successful 
completion of the EOT assessments for the previous rFVIIIFc study.  Participating study sites are 
required to document all screened candidates initially considered for inclusion in this study.  If a 
source documents and on the screening log. 
9.2. 
Registration of Subjects 
Subjects will be registered at Visit 1 after all assessments for the EOT Visit of the previous 
rFVIIIFc study have been completed and after the Investigator has verified that they are eligible 
per criteria in Sections 8.1 and 8.2.  Subjects will retain their previous study identification 
number.  Subject identification numbers previously assigned will not be reused for another 
subject, even if a subject does not receive treatment. 
Refer to the Study Reference Manual for details on registration. 
As confirmation, the Sponsor or designee will provide the Investigator with written verification 
email or fax.   
9.3. 
Blinding Procedures 
Not applicable:  This is an open-label study. 

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10. 
TREATMENT OF SUBJECTS 
The Sponsor will provide rFVIIIFc to the study sites via designated distributors. 
Refer to Section 12 (Study Treatment Management) for specifics on the preparation, storage, 
handling, disposal, and accountability of study treatment. 
10.1. 
Study Treatment Schedule and Administration 
Instructions for preparation and administration of rFVIIIFc are provided in the Drug Handling 
and Administration (DHA) Manual. 
rFVIIIFc will be administered over several minutes by slow IV injection.  The rate of 
taken as soon as possible or per the instructions of the Investigator.   
Subjects 12 years of age or older will follow either a tailored prophylaxis, weekly prophylaxis, 
personalized prophylaxis, or an on-
PK profiles and dosing levels from the prior rFVIIIFc study.  Subjects will be allowed to change 
from a prophylaxis regimen to on-demand and from on-demand to prophylaxis during this study.  
All treatment regimen changes will be discussed between the Investigator and the subject (and 
parent/guardian, as applicable).  All treatment regimen changes require the approval of the 
Sponsor Medical Monitor.  
Subjects less than 12 years of age will receive 1 of 2 prophylactic regimens, tailored or 
personalized, and will not have the option to change to a weekly prophylactic or on-demand 
regimen, unless they reach the age of 12 years during the study, at which time they can be use 
any of the 4 treatment regimens.   
10.1.1. 
Prophylaxis Regimens 
The tailored prophylaxis regimen may comprise weekly doses of 25 IU/kg to 65 IU/kg rFVIIIFc 
every 3 to 5 days or dosing 2 times per week at approximately 20 IU/kg to 65 IU/kg rFVIIIFc on 
Day 1 and 40 IU/kg to 65 IU/kg rFVIIIFc on Day 4.  In pediatric subjects, dose adjustments up 
to a maximum prophylactic dose of 80 IU/kg and frequency of administration up to every 2 days 
can be used if necessary to maintain adequate FVIII activity trough levels and prevent 
spontaneous bleeding events. 
The weekly prophylaxis dosing regimen comprises once weekly dosing of approximately 65 
IU/kg rFVIIIFc. 
If optimal prophylaxis dosing cannot be achieved using either of the above options, the 
Investigator may further personalize dosing to meet the needs of individual subjects.  The 
personalized prophylaxis dosing option will require consultation with the Sponsor Medical 
Monitor. 
Please refer to Section 5.3.2 for descriptions of the tailored prophylaxis, weekly prophylaxis, and 
personalized prophylaxis dosing options. 

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10.1.2. 
On-Demand Regimen 
The individual dose of rFVIIIFc 
condition and the type and severity of the bleeding event.  Please refer to Appendix A for on-
demand dosing guidelines.  Subjects less than 12 years of age entering from another rFVIIIFc 
study will not have the option of an on-demand regimen, but can receive an on-demand regimen 
once they reach the age of 12 years during the study. 
10.1.3. 
Surgery 
For subjects who require emergent or elective surgery during the study period, the dose and 
regimen of rFVIIIFc shall be that deemed appropriate for the type of surgery to be performed. 
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 d
to data generated in the trial at an alternative Institution deemed appropriate by the 
Principal Investigator.   
2. The Investigator and/or appropriate qualified/licensed delegate is available to 
a. Administer all rFVIIIFc doses required during surgery and during post-operative 
rehabilitation (if applicable).   
b. Provide medical oversight and guidance throughout the duration of the pre-operative 
and the intra-operative 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.   
Inhibitor testing should be performed 2 to 4 weeks prior to the scheduled surgery, pre-
operatively on the day of surgery, 1-2 weeks post-surgery, and at the last post-operative visit (for 
minor surgery, testing is not performed at the last 2 timepoints).  On the day of surgery, subjects 
will be given a pre-operative loading dose of rFVIIIFc as a bolus, and, in the case of emergency 

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surgery, as soon as possible prior to the procedure.  Pre-dose 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 determination of subsequent rFVIIIFc dosing.  During the 
VIII activity will be measured daily at the local laboratory, and a 
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 eCRF. 
Bleeding caused directly by surgery should not be reported, although undesired or unexpected 
bleeding during or after surgery should be recorded on the eCRF. 
10.2. 
Treatment Precautions 
Precautions should be taken with any FVIII product.   
The subject will be provided with specific instructions by the Investigator on what to do in the 
event of an overdose, allergic reaction, bronchospasm, or anaphylaxis while at home including 
how to seek emergency medical treatment. 
10.3. 
Modification of Dose and/or Treatment Schedule 
10.3.1. 
Prophylaxis Regimen 
Please refer to Section 5.3 for details on prophylaxis regimens. 
10.3.2. 
On-Demand Regimen 
rFVIIIFc 
cal condition, type 
and severity of the bleeding episode, and in some cases, FVIII peak (recovery) levels.  A 
previous rFVIIIFc studies may also be used to 
guide dosing decisions. 
Specific guidance for treatment of bleeding episodes is presented in Appendix A. 
10.4. 
Treatment Compliance 
Compliance with treatment dosing is to be monitored by site staff. 
Subjects will record both routine doses and doses for the treatment of bleeding episodes in the 
eDiary.  Diary data will be reviewed on a regular basis by site staff. 

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10.5.
Concomitant Therapy and Procedures
10.5.1. 
Concomitant Therapy 
A concomitant therapy is any drug or substance administered from 30 days prior to Visit 1 until 
7 (+7) days after the last dose of rFVIIIFc in this extension study.  Concomitant medications, 
for eCRF completion.  AEs related to administration of these therapies or procedures must be 
documented on the appropriate eCRF. 
10.5.1.1. Allowed Concomitant Therapy 
Investigator.   
Allowed therapies include treatment for hepatitis and/or HIV, routine immunizations, treatment 
with systemic steroids and/or inhaled steroids (with approval of the Sponsor Medical Monitor), 
and/or non-steroidal anti-inflammatory drugs including only low dose acetylsalicylic acid 
81 mg) (with approval of the Sponsor Medical Monitor). 
All allowed therapies must be recorded in the eCRF. 
10.5.1.2. Disallowed Concomitant Therapy 
No other investigational drug may be used concomitantly with the study treatment.   
The following concomitant medications are not permitted during the study: 
 Acetylsalicylic acid doses >81 mg (other non-steroidal anti-inflammatory drugs are 
permitted). 
The use of low-dose acetylsalicylic acid may be allowed, with approval of the Sponsor 
Medical Monitor, for subjects who have (or develop) a medical condition requiring this 
treatment and who remain under the medical supervision of the prescribing physician 
during the course of the study. 
 Current systemic treatment with chemotherapy and/or other immunosuppressant drugs 
(unless advised otherwise after consult with the Medical Monitor) 
 Any other FVIII product (with exceptions listed in Section 11.1) 
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 until the study is completed/terminated by the 
Sponsor, and unless the subject is being followed for study-related toxicity. 
eCRF, according to instructions for eCRF completion.  AEs related to administration of these 
therapies or procedures must be documented on the appropriate eCRF. 

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10.6.
Continuation of Treatment
If rFVIIIFc is proven to be beneficial, all regulatory requirements regarding post-study access 
will be met.   
Subjects first dosed with rFVIIIFc when <12 years of age will be followed to at least 100 EDs, 
even if rFVIIIFc becomes commercially available.   
All subjects will have the opportunity to continue in this study for up to 4 years or until rFVIIIFc 
is commercially available in the applicable participating country. 

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11. 
WITHDRAWAL OF SUBJECTS FROM STUDY TREATMENT 
AND/OR THE STUDY 
11.1. 
Discontinuation of Study Treatment 
A subject must permanently discontinue rFVIIIFc for any of the following reasons: 
 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 World Health Organization WHO scale [WHO 
handbook, 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 high-titer inhibitor (
), as defined in Section 7.1.2. 
 Use of FVIII products other than rFVIIIFc, unless it occurs in 1 life-threatening 
emergency and/or as a result of 1 accidental use, and the Sponsor agrees to retain the 
subject in the study.  
investigator should contact the Sponsor Medical Monitor. 
 Any condition a subject develops that precludes him from complying with the study 
procedures.  
 The subject experiences a medical emergency that necessitates discontinuation of 
treatment. 
 Clinical judgment of the Investigator:  a subject may have treatment permanently 
to continue with the study treatment. 
 The parent or legal guardian can withdraw the subject from the study at will at any 
time. 
 The subject and/or his parent/guardian withdraw consent.   
 At the discretion of the Investigator or Sponsor for noncompliance. 
The reaso
 eCRF. 
For any subject who no longer responds to treatment with rFVIIIFc, as determined by the 
Investigator, a decision will be made with the Sponsor whether to continue the subject on the 
study. 
Subjects who discontinue treatment should remain in the study to complete protocol-required 
tests and assessments, and then must be permanently withdrawn from the study. 

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11.2.
Withdrawal of Subjects From Study
Subjects must be withdrawn from the study for any 1 of the following reasons: 
 The subject and/or parent/guardian withdraw consent.   
 The subject and/or parent/guardian are unwilling or unable to comply with the 
protocol. 
 The subject meets any of the criteria defined in Section 11.1. 
 eCRF. 
Subjects who discontinue study treatment and are withdrawn from the study will not be replaced. 
If the decision is made to withdraw the subject from the study, the final study visit/early 
termination visit will be performed as described in Section 4 (Table 1). 

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12. 
STUDY TREATMENT MANAGEMENT 
Please refer to the DHA for full details regarding rFVIIIFc. 
Study treatment must be stored in a secure location.  Accountability for study treatment is the 
responsibility of the Investigator.  More details concerning this responsibility are included in 
Section 12.1.4.  Study treatment must only be dispensed by designated study staff.  Study 
treatment is to be dispensed only to subjects, to parents/legal guardians of subjects enrolled in 
this study, or to Sponsor-approved designees.  Once study treatment is dispensed to a subject, it 
can only be administered 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. 
Study site staff should refer to the DHA located in the Study Reference Manual for specific 
instructions on the handling, preparation, administration, and disposal of the study treatment.  
The DHA supersedes all other references (e.g., Investigator
Brochure). 
 must return to the investigational site for 
dispensation of rFVIIIFc and administration supplies before the earliest expiration date of drug 
This is to maintain adequate drug supplies for his treatment, including 
an adequate supply to treat breakthrough bleeding or due to delays in scheduling clinic visits.  
12.1. 
rFVIIIFc (BIIB031) 
rFVIIIFc lyophilized powder is provided in a clear glass vial containing 250, 500, 1000, 2000, or 
3000 IU of rFVIIIFc (nominal strengths).  Not all strengths may be available at the start of the 
study.  In addition to the rFVIIIFc, the formulation of the lyophilized drug product contains 
 L-histidine, 
 sodium chloride,
 calcium chloride dehydrate, 
 sucrose, and
 polysorbate 20, and is the same for all strengths.  The prefilled 
diluent syringe contained 3 mL sterile water for injection for reconstitution of rFVIIIFc prior to 
administration.   
The label will comply with local labeling requirements. 
12.1.1. 
rFVIIIFc Preparation 
The individual preparing rFVIIIFc should first carefully review the instructions provided in the 
DHA (if site staff), or in subject information materials provided by the site. 
If the packaging is damaged, or if there is anything unusual about the appearance or attributes of 
the vials or drug, it should not be used.  The vial in question should be saved by the subject or 
site, and then immediately reported by the site to the Sponsor. 
12.1.2. 
rFVIIIFc Storage 
Site stocks of rFVIIIFc kits should be stored at 2 C to 8 C in a monitored, locked refrigerator 
with limited access, or the room in which the refrigerator resides must be locked and with limited 
access.   

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12.1.3. 
rFVIIIFc Handling and Disposal 
The Investigator must return all unused vials/kits of rFVIIIFc as instructed by the Sponsor.  The 
instructions for return will be provided to the site at the time the request is made by the Sponsor. 
If the Sponsor requires the study site to destroy unused rFVIIIFc kits, the Institution/Principal 
Investigator(s) must notify the Sponsor, in writing, of the method of destruction, the date of 
destruction, and the location of destruction. 
12.1.4. 
rFVIIIFc Accountability 
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.   
for full medication exchange and accountability.  At the end of the study, reconciliation must be 
made between the amount of rFVIIIFc supplied, dispensed, and subsequently returned to the 
Sponsor.  A written explanation must be provided for any discrepancies. 

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13. 
EFFICACY ASSESSMENTS 
For future subjects that enroll into ASPIRE, no additional assessments will be added other than 
those conducted in the parent study. 
13.1. 
Clinical Efficacy Assessments 
 
The following clinical tests/assessments will be performed to assess the efficacy of rFVIIIFc. 
For all subjects: 
 Number of bleeding episodes reported by each subject 
during 
the study period 
o Recording of bleeding episodes in the hospital in the eCRF by the 
Surgeon/Investigator; recording of all other bleeding episodes in the eDiary by 
the 
 
 Dose and dosing interval adjustments 
 Assessment of response to treatment using a 4-point scale in the eDiary (Appendix C) 
o Assessment of response to bleeding episodes using 4-point scale by 
Investigator for individual bleeding episodes treated in the clinic; assessment 
of all other bleeding episodes in the eDiary by the 
caregiver 
 
n using a 
4-point scale (Appendix D) 
For subjects undergoing surgery, in addition to the above: 
 Investigator/Surgeon assessment of hemostatic response using the 4-point bleeding 
response scale (see Appendix E)  
 Number of injections and dose per injection to maintain hemostasis during the 
surgical period 
 Number of blood product units transfused during surgery 
 Estimated blood loss (mL) during surgery and post-operative period 
Refer to Section 4 for the timing of assessments. 
13.2. 
Laboratory Efficacy Assessments 
The following laboratory tests/assessments will be performed to assess the efficacy of rFVIIIFc: 
 FVIII activity (determined by one-stage aPTT clotting assay and two-stage 
chromogenic assay performed at the central laboratory)  

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FVIII peak (recovery) and/or trough measurements, if applicable
Refer to Section 4 for the timing of assessments. 
13.3. 
Pharmacokinetic Assessments 
Not applicable. 
13.4. 
Pharmacodynamic Assessments 
Not applicable. 
13.5. 
Additional Assessments 
In addition to the efficacy assessments above, the following tests will be performed. 
13.5.1. 
Hemophilia Joint Health Score 
Joint assessment will be conducted at Visit 1 using a modified Hemophilia Joint Health Score 
(HJHS) for adult subjects.  This assessment is based on the scoring system used in a joint scoring 
reliability study in boys with hemophilia [Hilliard et al, 2006].  It has been used as a tool to 
evaluate musculoskeletal outcomes in a cohort of 20 boys, aged 4 to 17 years [Saulyte 
Trakeymieine, 2010].  Modifications were included to adapt the HJHS scoring system to an adult 
hemophilia population and according to comments in a recent validation study by the 
International Hemophilia Prophylaxis Study Group [Feldman et al, 2011].   
Pediatric subjects will continue to use the HJHS, Version 2.1, and a joint assessment will be 
conducted at Visit 1.  Version 2.1 was published as an appendix to a validation study of Version 
1.0 [Feldman et al, 2011]. 
HJHS and modified HJHS should only be performed if they were conducted during the parent 
study. 
13.5.2. 
Patient-Reported Outcomes 
Only patient reported outcomes that were completed during the parent study should be 
completed during the current study.  If a subject goes outside of the age range for a 
questionnaire, they should no longer complete the questionnaire.  The following patient-reported 
outcome assessments will be performed, if applicable, for all subjects every 6 months, where 
linguistic validations exist in which the subject and/or parent/guardian is fluent.  
Parents/guardians will perform these assessments for pediatric subjects as appropriate.  The 
Investigator will administer the following age-appropriate questionnaires at the appropriate 
visits: 
 Haem-A-QoL [von Mackensen & Gringeri 2009] 
 Haemo-QoL [von Mackensen et al. 2004] 
 Hemo-Sat-Patient Satisfaction Scale for parents/guardians, Version 15 [Mapi 
Research Institute, 2009] 

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CHO-KLAT [CHO-KLAT, 2009]
o Children, Version 2.0 (for children previously enrolled in study 8HA02PED 
who are less than 18 years of age).   
o Proxy, Version 2.0p (for parents/guardians of children who were previously 
enrolled in study 8HA02PED and who are less than 18 years of age) 
 EQ-5D-Y [EQ-5D-Y, 2011] 
 EQ-5D-3L [EuroQol 1990] 
13.5.3. 
Health Outcomes Related to Hemophilia 
Health outcomes will include the following assessments: 
 Number of hospitalizations, excluding planned hospitalizations, elective surgery 
documented at Visit 1, and emergent surgery 
 Number of emergency room visits  
 Number of physician visits, excluding study visits  
 Number of hospitalization days  
 Number of days off work, school, daycare, or preschool  
 Number of days off work for a parent/caregiver  
13.5.4. 
Optional Laboratory Assessment 
For subjects who give their consent (or whose parent/guardian gives consent for pediatric 
subjects), a sample of blood will be collected during the study to conduct an analysis of genetic 
risk factors in the hemophilia A patient population.  This exploratory laboratory assessment 
consists of DNA testing with full genome sequence. 
13.5.5. 
Archive Plasma Samples 
From the volume of blood (approximately 20 mL) taken at each visit, samples for FVIII activity 
will be collected for each subject at each visit for back-up and archiving.  Samples will be 
archived for testing (if required) for immunologic assays including anti-rFVIIIFc antibodies or 
further coagulation assays, or for clarification of any clinical or laboratory AE. 

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14. 
SAFETY ASSESSMENTS 
For future subjects that enroll into ASPIRE, no additional assessments will be added other than 
those conducted in the parent study. 
14.1. 
Clinical Safety Assessments 
The following clinical assessments will be performed to assess the safety profile of rFVIIIFc: 
 Physical examination 
 Medical and surgical history (from previous study and updated) 
 Height 
 Weight 
 Concomitant therapy and procedures  
 AE and SAE  
Refer to Section 4 for the timing of assessments. 
14.2. 
Laboratory Safety Assessments 
The following laboratory tests will be performed by the central laboratory to assess the safety 
profile of rFVIIIFc: 
 Hematology:  White blood cell count (WBC), differential, platelet count, hemoglobin, 
hematocrit 
 Blood chemistry:  sodium, potassium, chloride, glucose, total protein, total bilirubin, 
alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline 
phosphatase (ALP), blood urea nitrogen (BUN), and serum creatinine 
 Nijmegen-modified Bethesda assay for development of inhibitors 
Refer to Section 4 for the timing of assessments. 
 

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15. 
SAFETY DEFINITIONS, MONITORING, AND REPORTING 
Throughout the course of the study, every effort must be made to remain alert to possible AEs.  
If an AE occurs, the first concern should be for the safety of the subject.  If necessary, 
appropriate medical intervention should be provided. 
At the signing of the informed consent form (ICF), each subject 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 not applicable in this extension study as all AEs occurring up to 
subject consent in 
. 
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. 
Bleeds in this patient population are not considered as 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 eDiary 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 
 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 

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an emergency room or convulsions occurring at home that do not require an inpatient 
hospitalization). 
15.2. 
Monitoring and Recording Events 
15.2.1. 
Serious Pretreatment Events 
A serious pretreatment event is not applicable in this extension study as all AEs occurring up to 
subject consent in 
.  
15.2.2. 
Adverse Events 
Any AE experienced by the subject during participation in this extension study is to be recorded 
on the eCRF.   
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. 
15.2.3. 
Serious Adverse Events 
Any SAE experienced by the subject between the day of signing the ICF through the last visit is 
to be recorded on an SAE Form, regardless of the severity of the event or its relationship to study 
treatment.  SAEs must be reported to Quintiles.  SAEs that occur up to 21 
last dose of rFVIIIFc must also be recorded on the SAE Form eCRF.  SAEs must be reported to 
the designated personnel as detailed in the study file. 
Any SAE ongoing when the subject completes the study or discontinues from the study will be 
followed by the Investigator until the event has resolved, stabilized, or returned to baseline 
status. 
In this study, the following events are considered medically important and must be reported as 
SAEs: 
 A subject develops an inhibitor, as defined in Section 7.1.2. 
 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 handbook, 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.   
All major surgery should be captured as an SAE. 

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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. 
15.2.4. 
All Events 
All events must be assessed to determine the following: 
 If the event meets the criteria for an SAE as defined in Section 15.1.3. 
 The relationship of the event to study treatment as defined in Section 15.3.1. 
 The severity of the event as defined in Section 15.3.2. 
15.2.5. 
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 Pharmacovigilance within 24 hours of the study site staff becoming 
ting 
information and procedures are used and followed appropriately. 

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Reporting Information for SAEs 
Any Serious Event that occurs between the time that the subject has signed the ICF and up to 
21 days after the final dose of study treatment must be reported to Quintiles Pharmacovigilance 
within 24 hours of the study site staff becoming aware of the event. 
A report must be submitted to Quintiles Pharmacovigilance regardless of the following: 
 whether or not the subject has undergone study-related procedures 
 whether or not the subject has received study treatment 
 the severity of the event 
 the relationship of the event to study treatment 
To report initial or follow-up information on a Serious Event, fax a completed SAE form to the 
following:   
Fax:  Please fax to Quintiles Pharmacovigilance at the country-specific fax number 
provided in the Study Manual. 
   
15.2.5.1. Deaths 
Death is an outcome of an event.  The event that resulted in death should be recorded and 
reported on the appropriate eCRF.  All causes of death must be reported as SAEs.  The 
Investigator should make every effort to obtain and send death certificates and autopsy reports to 
Quintiles Pharmacovigilance.   
15.3. 
Safety Classifications 
15.3.1. 
Relationship of Events to Study Treatment 
The following definitions should be considered when evaluating the relationship of AEs and 
SAEs to the study treatment:   

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Relationship of Event to Study Treatment 
Not related 
drug if there is not a possibility that the event has been caused by the product under 
investigation.  Factors pointing toward this assessment include, but are not limited to:  
the lack of reasonable temporal relationship between administration of the drug and 
the event, the presence of a biologically implausible relationship between the product 
and the adverse event (e.g., the event occurred before administration of drug), or the 
presence of a more likely alternative explanation for the adverse event. 
Related 
An adverse event wil
there is a possibility that the event may have been caused by the product under 
investigation.  Factors that point toward this assessment include, but are not limited to:  
a positive rechallenge, a reasonable temporal sequence between administration of the 
drug and the event, a known response pattern of the suspected drug, improvement 
following discontinuation or dose reduction, a biologically plausible relationship 
between the drug and the adverse event, or a lack of an alternative explanation for the 
adverse event. 
15.3.2. 
Severity of Events 
The following definitions should be considered when evaluating the severity of AEs and SAEs: 
Severity of Event 
Mild 
Symptom(s) barely noticeable to subject or does not make subject uncomfortable; 
does not influence performance or functioning; prescription drug not ordinarily 
needed for relief of symptom(s) but may be given because of personality of subject. 
Moderate 
Symptom(s) of a sufficient severity to make subject uncomfortable; performance of 
daily activity is influenced; subject is able to continue in study; treatment for 
symptom(s) may be needed. 
Severe 
Symptom(s) cause severe discomfort; symptoms cause incapacitation or significant 
 daily life; severity may cause cessation of treatment with study 
treatment; treatment for symptom(s) may be given and/or subject hospitalized. 
15.3.3. 
Expectedness of Events 
Expectedness of all AEs will be determined according to the 
 for 
rFVIIIFc.   
15.4. 
Procedures for Handling Special Situations 
15.4.1. 
Overdose 
An overdose is any single dose of study treatment given to a subject or taken by a subject that 
exceeds the maximum dose described in the protocol, 100 IU/kg.  Overdoses are not considered 
AEs; however, all overdoses should be recorded on an Overdose Form and faxed to Quintiles 
Pharmacovigilance within 24 hours.  An overdose should be reported even if it does not result in 

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an AE.  Overdoses do not need to be recorded in the eCRF; dosing information is recorded on 
the eCRF. 
15.4.2. 
Medical Emergency 
In a medical emergency requiring immediate attention, study site staff will apply appropriate 
medical intervention, according to current standards of care.  The Investigator or designee should 
contact the Sponsor Medical Director for this study, Cheryl Pikora, MD, PhD, MPH at 
+1 781-228-0553 (mobile)/ or Geoffrey Allen, MD at +1 781-558-0857 (mobile). 
15.4.3. 
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 when 
study drug-exposed conception occurs. 
15.4.4. 
Regulatory Reporting 
Suspected Unexpected Serious Adverse Reactions (SUSARs) are SAEs that are unexpected and 
judged by the Investigator or the Sponsor to be related to the study treatment administered. 
The Sponsor/designee will report SUSARs to the appropriate regulatory authorities and 
Investigators as required, according to local law. 
15.5. 
Investigator Responsibilities 
ilities include the following: 
 Monitor and record all AEs, including SAEs, regardless of the severity or relationship 
to study treatment. 
 Determine the seriousness, relationship, and severity of each event. 
 Determine the onset and resolution dates of each event. 
 Report congenital abnormalities/birth defects in the offspring of male subjects when 
study drug-exposed conception occurs.  
 Complete an SAE form for each serious event and fax it to Quintiles 
Pharmacovigilance within 24 hours of the study site staff becoming aware of the 
event. 
 Pursue SAE follow-up information actively and persistently.  Follow-up information 
must be reported to Quintiles Pharmacovigilance within 24 hours of the study site 
staff becoming aware of new information. 
 Ensure all AE and SA
medical records. 
 Report SAEs to local ethics committees, as required by local law. 

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15.6.
Sponsor Responsibilities
Sponsor
 
 Before study site activation and subject enrollment, the Clinical Monitor or Sponsor 
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. 
 The Sponsor/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 
In general, the data for subjects who enroll from parent studies will be integrated with their data 
from 8HA01EXT.  A parent study is defined as a study where subjects may be enrolled into 
8HA01EXT after study completion or at a time specified in the protocol.   
All statistical analyses will be descriptive in nature.  No formal comparison is planned and no 
hypothesis will be formally tested.  Continuous variables will be summarized and presented by 
number, mean, median, standard deviation, minimum and maximum, and where appropriate, 
with the 25th and 75th percentiles.  Categorical variables will be summarized by the number and 
percentage in each category.   
16.1. 
Description of Objectives 
16.1.1. 
Primary Objective(s)  
See Section 6.1.1 
ves. 
16.1.2. 
Secondary Objective(s)  
See Section 6.1.2 
 
16.2. 
Description of Endpoints 
16.2.1. 
Primary Endpoint 
See Section 6.2.1 for full descriptions of study endpoints. 
16.2.2. 
Secondary Endpoints 
See Sections 6.2.2 and 6.2.3 
s. 
16.3. 
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 16.6.1. 
Demographic and baseline disease characteristics will be summarized categorically and/or with 
descriptive statistics, as appropriate, using the data at the entry of the parent studies.  
Demographic data to be tabulated will include, but not be limited to, age, weight, height, body 
mass index, ethnicity, and race.   
Baseline disease characteristics, based on general medical and surgical, hemophilia, and bleeding 
histories, will be summarized by 8HA01EXT treatment regimen 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. 

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16.4.
Efficacy
16.4.1. 
Analysis Population 
All subjects who consent to participate in 8HA01EXT will be included in the All-enrolled 
Analysis Set. 
Subjects who receive at least 1 dose of rFVIIIFc will be included in the Full Analysis Set (FAS).  
Efficacy analyses will be based on the FAS. 
16.4.2. 
General Methods of Analysis 
All efficacy endpoints are secondary.  No imputation will be applied to any missing efficacy 
data.  For subjects who need/select to have surgeries during the study, their efficacy data during 
surgical period (including rehabilitation period) will be analyzed separately.  The efficacy 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 efficacy analyses.  Data 
on bleeding and rFVIIIFc consumption will be based on the efficacy period; surgical evaluations 
will be based on the surgical/rehabilitation period. 
Analysis of efficacy endpoints that are visit-based will include data from all study visits, whether 
or not in the efficacy period, unless a visit is coincidental with a surgical/rehabilitation period for 
a major surgery, in which case it would be excluded. 
16.4.3. 
Endpoints Analysis 
16.4.3.1. Annualized Bleeding Episodes and Annualized rFVIIIFc Consumption 
Bleeding episodes will be annualized for each subject first, then summarized and tabulated by 
treatment arm, treatment regimen, or age cohort, as appropriate, in the parent studies, and by 
treatment regimen in 8HA01EXT.  These analyses will also be performed for each type of bleed 
(spontaneous and traumatic).  The number of spontaneous joint bleeding episodes and the 
consumption of rFVIIIFc will be annualized in a similar fashion and tabulated. 
Summaries of these data will be based on the FAS. 
16.4.3.2. Other Efficacy Endpoints  
The response to treatment for bleeding will be summarized by the number and percentage of 
bleeding episodes with each response (excellent, good, moderate, no response).  These data will 
be summarized overall and for subgroups of interest during each study based on the FAS.   
16.4.3.3. Surgery Endpoints  
Analysis of surgery endpoints will be performed for subjects who had surgeries during the study, 
either emergently or electively.  Summary statistics of surgery endpoints will be provided for the 
surgical/rehabilitation period.   

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16.4.4. 
Additional/Exploratory Analysis 
The number of injections and the dose per injection required to resolve bleeding will be 
summarized on both a per-bleeding-episode and a per-subject basis, where the per-subject basis 
will be determined as the overall average across all bleeding episodes for a given subject.  These 
data will be summarized overall and for subgroups of interest during each study based on 
the FAS. 
Other efficacy analyses can be conducted for exploratory purposes. 
16.5. 
Patient-Reported and Health Outcomes 
16.5.1. 
Analysis Population 
The FAS will be used for the analysis of patient-reported and health outcomes.    
16.5.2. 
Methods of Analysis 
16.5.2.1. Patient-Reported Outcomes 
Questionnaires for patient-reported outcomes are described in Section 13.5.2. 
Endpoints for patient-reported outcomes (Haem-A-QoL, Haemo-QoL, Hemo-Sat-P, CHO-KLAT 
Children, CHO-KLAT Proxy, EQ-5D-Y and EQ-5D-3L) will be analyzed in a separate report. 
These endpoints will be analyzed by summarizing actual values, change from baseline and 
percent change from baseline, as appropriate. 
16.5.2.2. Health Outcomes 
Summary statistics of health outcome endpoints will be tabulated at each collection timepoint.   
16.6. 
Safety 
16.6.1. 
Analysis Population 
The Safety Population will include all subjects with at least 1 dose of rFVIIIFc.   
16.6.2. 
Methods of Analysis 
For the analysis of safety, data in 8HA01EXT will be integrated with the parent studies, unless 
specified otherwise.  The incidence of AEs will be tabulated overall, by severity, and by 
relationship to treatment.  In addition, the incidence of AEs will be presented by exposure day 
(ED) intervals.  An ED is a 24-hour period in which one or more rFVIIIFc injections are given.  
Subject listings will be provided for all AEs, SAEs, AEs resulting in discontinuation of the study 
treatment or withdrawal from the study, and deaths.  Findings in clinical lab values will be 
summarized by descriptive statistics.  Listings of abnormal laboratory test results will be 
provided.  
The total number of EDs of rFVIIIFc will be summarized by treatment regimen and overall for 
8HA01EXT, and overall using combined data from the parent studies and 8HA01EXT. 

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16.7.
Inhibitor Formation Data
16.7.1. 
Analysis Population 
The Safety Population (as defined in Section 16.6.1) will be the basis for analyses of inhibitor 
formation. 
16.7.2. 
Methods of Analysis 
The proportion of subjects with inhibitors during rFVIIIFc administration will be provided with 
the exact (Clopper-Pearson) 2-sided, 95% confidence interval.  Any subject with an inhibitor 
following the initial rFVIIIFc administration will be counted in the numerator; however, only 
subjects who have completed at least 50 EDs and 100 EDs from their initial rFVIIIFc 
administration will be included in the denominator.  Unless all subjects complete at least 50 EDs, 
the proportion of subjects with inhibitors will also be calculated using all subjects, regardless of 
the amount of exposure to rFVIIIFc, in the denominator. 
16.8. 
Optional Laboratory Assessments 
Optional laboratory assessment consisting of DNA testing with full genome sequence data may 
be analyzed to evaluate genetic risk factors in the hemophilia A patient population.  The analysis, 
however, will be in a separate report and will not be included as part of any CSR or interim CSR 
of 8HA01EXT. 
16.9. 
Interim Analyses 
Interim analyses will be conducted during the study, as needed. Analyses will be descriptive in 
nature.  No formal comparisons are planned and no hypotheses will be formally tested.  
Due to the open-label nature of this study, personnel involved in conducting the interim analyses 
will have access to treatment assignments.   
16.10. 
Sample Size Considerations 
This is an extension study.  The sample size is based on the planned sample sizes of Studies 
997HA301 (N=144) and 8HA02PED (N=50), and may be increased based upon subject 
participation in other rFVIIIFc studies or upon enrollment being greater than expected in studies 
997HA301 and/or 8HA02PED.   

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17. 
ETHICAL REQUIREMENTS 
The Sponsor and the Investigator must comply with all instructions, regulations, and agreements 
in this protocol and applicable International Conference on Harmonisation (ICH) and Good 
Clinical Practice (GCP) guidelines and conduct the study according to local regulations. 
17.1. 
Declaration of Helsinki 
The Investigator and Sponsor must adhere to the principles set forth by the Declaration of 
Helsinki dated October 2008. 
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.   
If the Investigator makes any changes to the ICF, the Sponsor must approve the changes before 
the ICF is submitted to the ethics committee.  A copy of the approved ICF must be provided to 
the Sponsor.  After approval, the ICF must not be altered without the agreement of the relevant 
ethics committee and the Sponsor. 
It is the responsibility of the Principal Investigator(s) to ensure that all aspects of institutional 
review are conducted in accordance with current governmental regulations. 
The Sponsor 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 the Sponsor. 
17.3. 
Subject Information and Consent 
Prior to performing any study-related activities under this protocol, including screening tests and 
assessments, written informed consent with the approved ICF must be obtained from the subject 
in accordance with local practice and 
regulations.  Written informed consent must be obtained from all subjects participating in a 
clinical study conducted by the Sponsor. 
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.  The subject 
must be given sufficient time to consider whether to participate in the study. 
A copy of the ICF, signed and dated by the subject, must be given to the subject.  Confirmation 
any testing under this protocol, including screening tests and assessments. 

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Each consent form should contain an authorization allowing the Principal Investigator(s) and the 
Sponsor to use and disclose PHI (i.e., subject-identifiable health information) in compliance with 
local law. 
The signed consent form will be retained with the study records. 
For subjects who are under 18 years of age (or legally a minor per local regulations), or who are 
otherwise unable to provide written informed consent, a parental/guardian consent will be 
obtained, the contents of which will be identical to that of the standard adult consent.  Written 
subject assent will also be obtained from those subjects who are able to read and understand the 
assent form, a brief summary of the study process, benefits, and risks. 
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., PHI authorization in North 
America). 
The subject will not be identified by name in the eCRF or in any study report, and these reports 
will be used for research purposes only.  The Sponsor, 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 kee
 
17.5. 
Compensation for Injury 
The Sponsor maintains appropriate insurance coverage for clinical trials and will follow 
applicable local compensation laws. 
17.6. 
Conflict of Interest 
The Investigators should address any potential conflicts of interest (e.g., financial interest in the 
Sponsor) with the subject before the subject makes a decision to participate in the study. 
17.7. 
Registration of Study and Disclosure of Study Results 
The Sponsor 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 the Sponsor or designee.  This initiation visit will include a detailed review of the 
protocol and study procedures. 
18.2. 
Study Supplies 
The Sponsor will supply the rFVIIIFc while subjects participate in this study (see Section 12).  
Since study subjects will be required to maintain accurate records of each dose of rFVIIIFc 
administered during the study, the Sponsor will provide personal eDiaries to the study sites for 
subjects to use to record study information. 
18.3. 
Quality Assurance 
During and/or after completion of the study, quality assurance officers named by the Sponsor or 
the regulatory authorities may wish to perform on-site audits.  The Investigator will be expected 
to cooperate with any audit and to provide assistance and documentation (including source data) 
as requested. 
18.4. 
Monitoring of the Study 
The Principal Investigator(s) must permit study-related monitoring by providing direct access to 
ies. 
The Clinical Monitor(s) will visit the Investigator(s) at regular intervals during the course of 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.   
Section 19.1.3 will be used as source data. 
The 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. 
18.5. 
Study Funding 
The Sponsor will pay the clinic or institution where the study is conducted for the costs of 
running the study.  All financial details are provided in the separate contract(s) between the 
Institution/Investigator and the Sponsor.   
18.6. 
Publications 
Details are included in the clinical trial agreement for this study. 

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19. 
FURTHER REQUIREMENTS AND GENERAL INFORMATION 
19.1. 
External Contract Organizations 
19.1.1. 
Contract Research Organization  
A contract research organization (CRO) will be responsible for administrative aspects of the 
study including, but not limited to, study initiation, monitoring, and management of SAE reports 
and data management.  Before subjects are screened at each study site, the CRO will review 
study responsibilities with the Investigators and other study site staff, as appropriate. 
19.1.2. 
Interactive Voice/Web Response System 
Interactive Voice and Web Response System (IXRS) will be used in this study.  Before subjects 
are screened or enrolled, the IXRS vendor will provide each study site with appropriate training 
and a user manual. 
19.1.3. 
Electronic Data Capture 
Subject information will be captured and managed by study sites on eCRFs by a web-based 
electronic data capture (EDC) tool (eDiary) developed and supported by the EDC vendor and 
configured by the Sponsor.   
Data entered by subjects using the eDiary will be downloaded to the database. 
19.1.4. 
Central Laboratories for Laboratory Assessments 
Central laboratories have been selected by the Sponsor to analyze all hematology, blood 
chemistry, inhibitor, and antibody samples collected for this study.  Specifics regarding the 
requirements for laboratory specimen collection, handling, and analysis are provided in the study 
Laboratory Manuals, which are part of the Study Manual. 
19.2. 
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, the Sponsor may, at any time, amend this protocol to eliminate an apparent immediate 
hazard to a subject.  In this case, the appropriate regulatory authorities will be notified 
subsequent to the modification. 
In the event of a protocol modification, the subject consent form may require similar 
modifications (see Sections 17.2 and 17.3). 

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19.3.
Ethics Committee Notification of Study Completion or Termination
Where required, the Health Authorities and ethics committees must be notified of completion or 
termination of this study, and sent a copy of the study synopsis in accordance with necessary 
timelines. 
19.4. 
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 Idec in writing and 
receive written authorization from Biogen Idec to destroy study records.  In addition, the 
Investigator must notify Biogen Idec of any changes in the archival arrangements including, but 
not limited to, archival at an off-site facility or transfer of ownership if the Investigator leaves the 
site. 
19.5. 
Study Report Signatory 
The Sponsor will designate one of the participating Study Investigators as a signatory for the 
study report.  This determination will be made by several factors, including, but not limited to, 
the Investigator's experience and reputation in the studied indication, the Investigator's 
contribution to the study in terms of design, management, and/or subject enrollment, or by other 
factors determined to be relevant by the Sponsor. 
The Sponsor will follow all applicable local regulations pertaining to study report signatories.   

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20. 
REFERENCES 
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Canadian Hemophilia Outcomes-Kids' Life Assessment Tool, Version 2.0.  2009 
Canadian Hemophilia Outcomes-Kids' Life Assessment Tool-Proxy, Version 2.0.  2009 
Colvin BT, Astermark J, Fischer K, et al.  European principles of haemophilia care.  
Haemophilia 2008;14:361 374 
Committee for Proprietary Medicinal Products (CPMP).  Note for Guidance on the Clinical 
Investigation of Recombinant Factor VIII and FIX Products.  CPMP/BPWG/156/99. 
London, 23 July 2009 
Dumont J et al. Factor VIII-Fc fusion protein shows extended half-life and hemostatic 
activity in hemophilia A dogs.  Abstract.  Blood 2009;114:265-268 
Dumont JA, Low SC, Peters RT, Bitonti AJ.  Monomeric Fc fusions: impact on 
pharmacokinetic and biological activity of protein therapeutics.  BioDrugs 2006:20:151-160 
EQ-5D-Y, Version 4.0.  2011 
The EuroQol Group.  EuroQol-a new facility for the measurement of health-related quality 
of life.  Health Policy 1990;16(3):199-208 
Feldman BM et al.  Validation of a new pediatric joint scoring system from the International 
Hemophilia Prophylaxis Study Group:  Validity of the hemophilia joint health score (HJHS).  
Arthritis Care Res. (Hoboken) 2011;63(2):223-230. 
Ghetie V, Ward ES.  Multiple roles for the major histocompatibility complex class I-related 
receptor FcRn.  Annu Rev Immunol. 2000;18:739-766 
Hemophilia Joint Health Score, Version 2.1, 2011. 
Hilliard P et al.  Hemophilia joint health score reliability study.  Haemophilia 
2006;12(5) :518-525 
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microglobulin-containing neonatal intestinal transport receptor.  Proc Natl Acad Sci. 
1996;93:5512-5516  
Mannucci PM, Tuddenham EGD.  The hemophiliac: from royal genes to gene therapy.  
N Engl J Med. 2001;344:1773-1779 
Mapi Research Institute.  Hemo-Sat Patient Satisfaction Scale for parents, Version 15.  2009 
MASAC Recommendation 190, Concerning Products Licensed for Hemophilia and Other 
Bleeding Disorders, March 2009.  National Hemophilia Foundation, www.hemophilia.org. 
Rodriguez-Merchan EC.  Management of musculo-skeletal complications of hemophilia.  
Semin Thromb Hemost. 2003;29:87-96 

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Roopenian DC, Akilesh S.  FcRn: the neonatal Fc receptor comes of age.  Nature Rev 
Immunol. 2007;7:715-725 
Saulyte Trakymiene S, Ingerslev J, Rageliene L.  Utility of the Haemophilia Joint Health 
Score in the study of episodically treated boys with severe haemophilia A and B in 
Lithuania.  Haemophilia 2010;16(3):479-486 
Von Mackensen S, Bullinger M, Haemo-QoL Group.  Development and testing of an 
instrument to assess the Quality of Life of Children with Haemophilia in Europe (Haemo-
QoL).  Haemophilia 2004;10(Suppl 1):17-25 
Von Mackensen S, Gringeri A.  Quality of Life in Hemophilia.  In: Preedy VR & Watson 
RR. (eds.) Handbook of Disease Burdens and Quality of Life Measures.  Heidelberg: 
Springer, 2009;Vol.3, Chap.12:1895-1920 
World Federation of Hemophilia.  Guidelines for the management of hemophilia.  World 
Federation of Hemophilia 2005 (www.wfh.org) 
World Health Organization handbook for reporting results of cancer treatment.  1979 

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21. 
SIGNED AGREEMENT OF THE STUDY PROTOCOL 
I have read the foregoing 
An Open-Label, Multicenter, Evaluation of the Long-Term 
Safety and Efficacy of Recombinant Human Coagulation Factor VIII Fusion Protein (rFVIIIFc) 
in the Prevention and Treatment of Bleeding Episodes in Previously Treated Subjects with 
Hemophilia A
Version 3, 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. 
 
 
 
____________________________________________________ 
 
 
 
 
Date 
 
 
____________________________________________________ 
 
 
 
 
____________________________________________________ 
Study Site (Print) 

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22. 
APPENDIX A:  rFVIIIFc DOSING GUIDELINE FOR 
TREATMENT OF BLEEDING EPISODES 
The following table provides guidance for dosing with rFVIIIFc for bleeding episodes.  Subjects 
should consult with the Investigator for an optimal rFVIIIFc level and dosing frequency, but 
should take only 1 follow-up dose not less than 24 hours after the initial dose.  For Major 
bleeding episodes the subjects will be instructed to administer treatment and contact the study 
staff as soon as possible. 
 
DOSING GUIDELINES FOR rFVIIIFc THERAPY IN HEMOPHILIA A 
 
 
 
 
 
        
        Factor VIII 
    
       
 
 
 
 
             Level Required 
 
 
 
 
    
       Type of Hemorrhage 
 
      
 (%) 
__________________________________________________________________________ 
 
Minor 
Epistaxis 
 
 
 
 
20-40  
 
 
 
 
Hemarthroses, uncomplicated 
 
20-40  
 
 
 
 
 
 
Superficial muscular  
 
 
20-40  
 
 
 
 
Superficial soft tissue  
 
 
20-40  
 
 
 
 
 
 
 
Moderate 
Epistaxis 
 
 
 
 
30-60  
 
 
 
 
     
Intramuscular with dissection  
 
30-60  
 
 
 
 
     
Soft tissue with dissection 
 
 
30-60  
 
 
 
 
     
Mucous membranes  
 
 
30-60  
 
 
 
 
     
Dental extractions 
 
 
 
30-60  
 
 
 
 
     
Hematuria 
 
 
 
 
30-60  
 
 
 
 
     
Hemarthroses, with limited motion  
40-80  
 
 
 
 
Major 
Epistaxis  
 
 
 
 
80-100  
 
 
 
 
Pharynx 
 
 
 
 
80-100  
 
 
 
 
 
 
Retropharynx  
 
 
 
80-100  
 
 
          
 
Retroperitoneum 
 
 
 
80-100  
 
 
 
 
 
 
Surgery 
 
 
 
 
80-100  
 
 
 
CNS 
 
 
 
 
 
80-100  
 
 
 
 
 
 

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23. 
APPENDIX B:  HEMOPHILIA JOINT HEALTH SCORE (HJHS) 
 
Appendix B1: 
Modified HJHS for Subjects Transferring from 
Study 997HA301 
 
This modified HJHS is based on the scoring system used in a joint scoring reliability study in 
boys with hemophilia [Hilliard et al., 2006].  The modifications were done to adapt the scoring 
system to an adult hemophilia population and according to comments in a recent validation study 
by the international hemophilia prophylaxis study group [Feldman et al., 2011].  This version is 
for use only with subjects who were previously enrolled in study 997HA301.   
Six joints (left ankle-LA, right ankle-RA, left elbow-LE, right elbow-RE, left knee-LK, right 
knee-RK) will be scored on a scale from 0 to 19 according to the following criteria:  swelling, 
duration, muscle atrophy, crepitus, flexion loss, extension loss, instability, joint pain, and 
strength.  Gait will be scored on a scale from 0 to 2 based on walking and climbing stairs.  The 
total score will be the sum of scores from all 6 joints plus the gait score (range from 0 to 116 
with 0 being normal and 116 being the most severe disease). 
SCORING DETAILS 
1. Joint scoring will be done separately for the 6 joints (LA, RA, LE, RE, LK, RK) 
according to these categories and scales (range is 0-19 for each joint and 0-114 for all six 
joints): 
Swelling 
0=none 
1=mild 
2=moderate 
3= severe 
Duration of swelling 
0=no swe
 
1= >6 months 
Muscle atrophy 
0=none 
1=mild 
2=severe 
Crepitus on motion 
0=absent 

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1=present 
Flexion loss (includes plantarflexion of ankles) 
0=none* 
1= mild* 
2= moderate* 
3= severe* 
Extension loss (includes dorsiflexion of ankles) 
0= none* 
1= mild* 
2= moderate* 
3= severe*  
*  Use the following as guidance for scoring flexion loss and extension loss at knees and 
elbows:  
None:  approximately 0-5 degrees 
Mild:  approximately 5-10 degrees 
Moderate:  approximately 11-20 degrees 
Severe:  approximately >20 degrees 
Instability 
0=none 
1=significant pathologic joint laxity 
 
Joint pain 
0=no pain (either through range or at end range of motion) 
1=present 
Strength 
0=normal (holds position against gravity and maximum resistance) 
1=minimal decrease (holds position against gravity and moderate resistance, but not 
maximum resistance) 
2=mild decrease (holds position against gravity or minimal resistance) 
3=moderate decrease (able to move joint if gravity eliminated) 
4=severe decrease (trace or no muscle contraction) 

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2. Gait will be scored once (range is 0-2):
0=No difficulty with walking or climbing up/down stairs 
1=No difficulty with walking, but difficulty with stairs 
2=Difficulty with walking and with stairs 
 
Total score = sum of all joint scores plus the gait score (range is 0-116) 
 
Appendix B2. 
HJHS Version 2.1 for All Other Subjects 
 
Pediatric subjects previously enrolled in study 8HA02PED or subjects from any other rFVIIIFc 
study will continue to use HJHS Version 2.1 (Hemophilia Joint Health Score, Version 2.1, 
2011). 

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24. 
APPENDIX C:  
ASSESSMENT OF RESPONSE TO 
TREATMENT OF BLEEDING 
bleeding episode using the following 4-point scale (excellent, good, moderate, or none).  This 
assessment is to be made approximately 8 to 12 hours from the time the injection was given to 
treat the bleeding episode and prior to any additional doses of rFVIIIFc given for the same 
bleeding episode.  In this study, a bleed will be defined as follows:  a bleeding episode starts 
from the first sign of a bleed and ends no more than 72 hours after the last treatment for the 
bleed, within which any symptoms of bleeding at the same location, or injections less than or 
equal to 72 hours apart, are considered the same bleed.  Any injection to treat the bleed, taken 
more than 72 hours after the preceding one, will be considered the first injection to treat a new 
bleed at the same location.  Any bleeding at a different location is considered a separate bleed 
regardless of time from last injection.  Response could also be assessed by the Physician for 
those subjects who were treated in the hospital with rFVIIIFc for major bleeds or post-surgery 
until discharge from the hospital. 
 Excellent:  Abrupt pain relief and/or improvement in signs of bleeding within 
approximately 8 hours after the initial injection 
 Good:  Definite pain relief and/or improvement in signs of bleeding within approximately 
8 hours after an injection, but possibly requiring more than one injection after 24  48 
hours for complete resolution 
 Moderate:  Probable or slight beneficial effect within 8 hours after the initial injection 
and requires more than one injection 
 None:  No improvement, or condition worsens within approximately 8 hours after the 
initial injection 
The following evaluations will determine the level of hemostasis achieved with rFVIIIFc 
treatment during surgery: 
 Number of injections and dose per injection required to maintain hemostasis during the 
surgical period 
 Estimated blood loss during surgery (intra-operative period) 
 Number and type of blood component transfusions required during surgery 
 

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25. 
APPENDIX D:  P
GLOBAL ASSESSMENT OF 
RESPONSE 
is rFVIIIFc regimen using 
the following 4-point scale: 
 
 
usual dose of rFVIIIFc
that usually observed. 
 Effective:  most bleeding episodes responded to the same number of injections and 
dose, but some required more injections or higher doses, or there was a minor 
increase in the rate of breakthrough. 
 Partially Effective:  bleeding episodes most often required more injections and/or 
higher doses than expected, or adequate breakthrough bleeding prevention during 
prophylaxis required more frequent injections and/or higher doses. 
 Ineffective:  routine failure to control hemostasis or hemostatic control require 
additional agents. 
Investigators should consider the following, if available, when making the assessment: 
 Frequency of rFVIIIFc injections 
 Response to rFVIIIFc injection 
 Information reported in the eDiary by the subject 

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26. 
APPENDIX E:  PHYSICIAN ASSESSMENT OF RESPONSE TO 
TREATMENT DURING SURGERY 
The Investigator/Surgeon who completed the minor or major surgical procedures will assess the 
rFVIIIFc treatment using a 4-point clinical scale.  This 
includes observations during surgery.  This assessment will be done within 24 hours after the 
surgery. 
Excellent:  intra-operative and post-operative blood loss similar to (or less than) the 
non-hemophilic patient.   
 No extra doses of rFVIIIFc needed AND 
 Blood component transfusions required are similar to person without hemophilia 
Good:  intra-operative and/or post-operative bleeding slightly increased over expectations for the 
non-hemophilic patient, but the difference is not clinically significant. 
 Intra-operative blood loss no more than than expected for person without hemophilia 
AND 
 No extra doses of rFVIIIFc needed AND 
 Blood component transfusions required are similar to person without hemophilia 
Fair:  intra-operative and/or post-operative blood loss is increased over expectation for the 
person without hemophilia and additional treatment is needed. 
 Intra-operative blood loss greater than expected for person without hemophilia OR 
 Extra dose of rFVIIIFc needed OR 
 Increased blood component transfusion requirement  
Poor/none:  significant intra-operative and/or post-operative bleeding that is substantially 
increased over expectations for the person without hemophilia, requires intervention, and is not 
explained by a surgical/medical issue other than hemophilia 
 Intra-operative blood loss greater than for the person without hemophilia OR 
 Unexpected hypotension or unexpected transfer to intensive care unit due to bleeding 
OR 
Substantially increased blood component transfusion requirement 

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27. 
APPENDIX F:  PATIENT REPORTED OUTCOMES 
The following QoL questionnaires will be presented under separate cover: 
 Haem-A-QoL  
 Haemo-QoL  
 Hemo-Sat-P Patient Satisfaction Scale for parents/guardians, Version 15 
 CHO-KLAT 
o Children, Version 2.0 (for children previously enrolled in study 8HA02PED who 
are less than 18 years of age).   
o Proxy, Version 2.0p (for parents/guardians of children who were previously 
enrolled in study 8HA02PED and who are less than 18 years of age) 
 EQ-5D Y  
 EQ-5D 3L