Clinical trial NCT01454739
Conditions: Hemophilia A
Keywords: rFVIIIFc A-LONG Extension
Sponsor: Bioverativ Therapeutics Inc.
Start date: 2011-12-01; Completion date: 2017-10-01
Enrollment: 240 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the study is to evaluate the long-term safety of recombinant human Factor VIII Fc fusion protein (rFVIIIFc) in participants with hemophilia A. The secondary objective of the study is to evaluate the efficacy of rFVIIIFc in the prevention and treatment of bleeding episodes in participants with hemophilia A.

Detailed description:
Participant will follow either a prophylaxis or on-demand regimen. The starting dose in this study will be determined by the clinical profile of the participant in the preceding studies A-LONG - 997HA301 (NCT01181128), pediatric study 8HA02PED (NCT01458106), 997HA307 (NCT02083965) and 997HA309 (NCT02502149).

Arms: arm 1: The individual dose of rFVIIIFc to treat bleeding episodes will be based on participant's clinical condition, type and severity of the bleeding event, and if indicated, Factor VIII (FVIII) levels. arm 2: Tailored prophylaxis, Weekly prophylaxis or Personalized prophylaxis available.
Interventions: intervention 1: rFVIIIFc
Intervention descriptions: intervention 1: Administered as specified in the treatment arm.

Protocol documents:
Prot_000.pdf: 
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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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 
Bolton-Maggs P, Pasi J.  Haemophilias A and B.  Lancet 2003;361:1801-1809 
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 
-
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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73 
 
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  
 
 

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8HA01EXT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 




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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................7 
1. 
INTRODUCTION ........................................................................................................9 
2. 
DESCRIPTION OF OBJECTIVES AND ENDPOINTS ...........................................10 
2.1. 
Study Objectives .........................................................................................................10 
2.1.1. 
Primary Objective .......................................................................................................10 
2.1.2. 
Secondary Objective ...................................................................................................10 
2.2. 
Study Endpoints ..........................................................................................................10 
2.2.1. 
Primary Endpoint ........................................................................................................10 
2.2.2. 
Secondary Efficacy Endpoints ....................................................................................10 
2.2.3. 
Major Surgery Endpoints ............................................................................................10 
2.2.4. 
Endpoints Based on Patient-reported Outcomes ........................................................11 
3. 
STUDY DESIGN .......................................................................................................12 
3.1. 
Overall Study Design and Plan ...................................................................................12 
3.2. 
Treatment ....................................................................................................................12 
3.2.1. 
Regimens ....................................................................................................................13 
3.2.1.1. 
Episodic Regimen .......................................................................................................13 
3.2.1.2. 
Prophylaxis Regimens ................................................................................................13 
3.2.2. 
Surgery and Rehabilitation .........................................................................................14 
3.3. 
Number of Subjects ....................................................................................................14 
3.3.1. 
Sample Size ................................................................................................................14 
3.3.2. 
Study Sample ..............................................................................................................14 
3.3.3. 
Procedures for Discontinuing Treatment and Removal of Subjects from the 
Study ...........................................................................................................................14 
3.3.4. 
End of Study ...............................................................................................................15 
3.3.5. 
Randomization and Blinding ......................................................................................15 
4. 
ANALYSIS POPULATIONS ....................................................................................16 
4.1. 
All-enrolled Analysis Set ............................................................................................16 
4.2. 
Full Analysis Set (FAS) ..............................................................................................16 
4.3. 
Safety Analysis Set .....................................................................................................16 
4.4. 
Surgery Subgroup .......................................................................................................16 
5. 
DATA HANDLING ...................................................................................................17 
5.1. 
General Principles .......................................................................................................17 


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5.1.1. 
Description of Study Days ..........................................................................................18 
5.1.2. 
Data Analysis ..............................................................................................................20 
5.1.3. 
Handling of Missing Data ...........................................................................................20 
5.2. 
Data Summaries ..........................................................................................................20 
5.2.1. 
Continuous Variables ..................................................................................................20 
5.2.2. 
Categorical Variables ..................................................................................................21 
5.3. 
Study Periods ..............................................................................................................21 
5.3.1. 
Treatment Regimens for Analysis ..............................................................................21 
5.3.2. 
Efficacy Period ...........................................................................................................23 
5.3.3. 
Surgical/Rehabilitation Period ....................................................................................25 
5.3.4. 
Safety Period ...............................................................................................................27 
5.4. 
Electronic Patient Diary (EPD) Data ..........................................................................27 
6. 
STUDY SUBJECTS ...................................................................................................28 
6.1. 
Disposition of Subjects ...............................................................................................28 
6.2. 
Demography and Baseline Disease Characteristics ....................................................28 
6.2.1. 
Demography ...............................................................................................................28 
6.2.2. 
General Medical and Surgical History .......................................................................28 
6.2.3. 
Physical Examination .................................................................................................29 
6.3. 
Protocol Deviations ....................................................................................................29 
6.4. 
Non-study Drug Medications .....................................................................................29 
6.4.1. 
Concomitant Medications ...........................................................................................29 
6.4.2. 
Other Therapies and Procedures .................................................................................30 
6.5. 
Study Drug ..................................................................................................................30 
6.5.1. 
Exposure .....................................................................................................................30 
6.5.1.1. 
Duration of rFVIIIFc Dosing, Number of Injections and Exposure Days to 
rFVIIIFc ......................................................................................................................30 
6.5.1.2. 
Last Prescribed Dose and Dosing Frequency .............................................................30 
6.5.2. 
Change of Treatment Regimens .................................................................................30 
6.5.3. 
Prophylactic Dose (IU/kg) and Dosing Interval (days) ..............................................31 
6.5.4. 
Consumption ...............................................................................................................32 
6.5.5. 
Compliance .................................................................................................................32 
6.5.5.1. 
Compliance in the Treatment of Bleeding Episodes ..................................................32 
6.5.5.2. 
Compliance of Prophylactic Injections .......................................................................33 


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6.5.5.3. 
Compliance of EPD Contemporaneous data entry .....................................................34 
7. 
EFFICACY AND PHARMACOKINETIC ANALYSIS ...........................................35 
7.1. 
General Efficacy Principles ........................................................................................35 
7.1.1. 
Bleeding Episodes ......................................................................................................35 
7.1.2. 
Multiplicity .................................................................................................................36 
7.2. 
Primary Endpoint ........................................................................................................36 
7.3. 
Secondary Endpoints ..................................................................................................36 
7.3.1. 
Annualized Bleeding Rate ..........................................................................................36 
7.3.2. 
Total Number of Days of Exposure ............................................................................37 
7.3.3. 
Total Annualized rFVIIIFc Consumption ..................................................................37 
7.3.4. 
Physician’s Global Assessment of the Subject’s Response to His rFVIIIFc 
Regimen ......................................................................................................................37 
7.3.5. 
Subject’s Assessment of Response to rFVIIIFc Injections for Bleeding ...................38 
7.4. 
Additional Assessments ..............................................................................................39 
7.4.1. 
Number of Injections and Dose of rFVIIIFc to Resolve a Bleeding Episode ............39 
7.4.2. 
Time from Last Injection of rFVIIIFc to a Bleeding Episode ....................................39 
7.4.3. 
Time Between the First and Second Injection to Treat a Bleeding Episode ..............40 
7.4.4. 
Hemophilia Joint Health Score ...................................................................................40 
7.5. 
Endpoints Based on Patient-reported Outcomes ........................................................41 
7.5.1. 
HAEMO-QoL and HAEM-A-QoL .............................................................................41 
7.5.2. 
Hemo-Sat Patient Satisfaction Scale ..........................................................................42 
7.5.3. 
CHO-KLAT ................................................................................................................42 
7.5.4. 
EQ-5D Youth Questionnaire ......................................................................................42 
7.5.5. 
EQ-5D-3L Questionnaire ............................................................................................43 
7.5.6. 
Health-Economic Parameters .....................................................................................43 
7.6. 
Surgery Data ...............................................................................................................44 
7.6.1. 
Investigators’/Surgeons’ Assessment of Hemostatic Response to Surgery 
Using the 4-point Bleeding Response Scale ...............................................................45 
7.7. 
Pharmacokinetic Assessments ....................................................................................45 
8. 
SAFETY ANALYSIS ................................................................................................46 
8.1. 
Primary Endpoint ........................................................................................................46 
8.2. 
Adverse Events ...........................................................................................................46 
8.2.1. 
Overall Summary of Treatment-emergent Adverse Events ........................................47 


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8.2.2. 
Treatment-emergent Adverse Events .........................................................................48 
8.2.3. 
Adverse Events in Descending Order of Incidence ....................................................48 
8.2.4. 
Severity of Adverse Events ........................................................................................48 
8.2.5. 
Relationship of Adverse Events to Study Drug ..........................................................48 
8.2.6. 
Serious Adverse Events ..............................................................................................48 
8.2.7. 
Adverse Events Leading to Treatment Discontinuation or Withdrawal From 
the Study .....................................................................................................................49 
8.2.8. 
Deaths on Study ..........................................................................................................49 
8.3. 
Clinical Laboratory Evaluations .................................................................................49 
8.3.1. 
Hematology and Chemistry ........................................................................................49 
8.3.1 .1  
Change from Study 8HA01EXT Baseline ..................................................................49 
8.3.1.2  
Shifts ...........................................................................................................................49 
8.3.1.3  
Potentially Clinically Significant Laboratory Abnormalities .....................................50 
8.3.2. 
Inhibitor Development ................................................................................................52 
8.3.3 
Incidence of Anti-rFVIIIFc Antibodies ......................................................................52 
8.4. 
Vital Signs ..................................................................................................................52 
9. 
SENSITIVITY IMPACT ASSESSMENT .................................................................54 
9.1  
Data Record Changes .................................................................................................56 
9.2  
Existing Outputs to be Re-run ....................................................................................56 
9.3 
 New Outputs to be Created ........................................................................................57 
10. 
REFERENCES ...........................................................................................................58 
11. 
INDEPENDENT DATA SAFETY MONITORING COMMITTEE .........................59 
LIST OF TABLES, LISTINGS, AND FIGURES .........................................................................60 
APPENDIX A. SUBJECT’S ASSESSMENT OF RESPONSE TO TREATMENT OF 
BLEEDING ................................................................................................................66 
APPENDIX B. SURGERY RESPONSE SCALE ......................................................................67 
APPENDIX C. SCORING ALGORITHM FOR HAEM-A-QOL AND HAEMO-QOL ...........68 
APPENDIX D. EQ-5D-3L QUESTIONNAIRE SCORE DEFINITIONS .................................93 
APPENDIX E. CHO-KLAT SCORING ALGORITHM AND QUESTIONNAIRES...............94 
APPENDIX F. HEMO-SAT SCORING ALGORITHM AND QUESTIONNAIRE ...............104 
APPENDIX G. EQ-5D-Y QUESTIONNAIRE SCORE DEFINITIONS ................................111 
APPENDIX H. HEMOPHILIA JOINT HEALTH SCORE (HJHS) ........................................112 
 


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LIST OF ABBREVIATIONS 
AE 
adverse event 
ALP 
Alkaline phosphatase 
ALT  
alanine aminotransferase 
AST  
aspartate aminotransferase 
BMI 
body mass index 
BU 
Bethesda Units 
BUN  
blood urea nitrogen 
CHO-KLAT 
Canadian Hemophilia Outcomes-Kids’ Life Assessment Tool 
CRF  
Case Report Form 
dL 
deciliter 
DSMC 
Data Safety Monitoring Committee 
eCRF  
Electronic Case Report Form 
ED 
exposure day 
EPD 
electronic patient diary 
FAS 
Full Analysis Set 
FVIII 
factor VIII 
GGT 
gamma glutamyl transferase 
HCV 
Hepatitis C 
HIV  
human immunodeficiency virus 
IU  
International Unit 
IV  
intravenous 
IXRS  
Interactive Voice/Web Response System 
kg  
kilogram 
MedDRA  
Medical Dictionary for Regulatory Activities 
MRT  
mean residence time 
PK  
pharmacokinetic 
QoL 
quality of life 
RBC  
red blood cell count 
rFVIIIFc 
recombinant coagulation factor VIII Fc fusion protein 
SAE  
serious adverse event 


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SAP 
statistical analysis plan 
SOC 
system organ class 
SVC 
Single Vial Consolidation 
TEAE 
treatment-emergent adverse event 
vWF 
von Willebrand factor 
WBC  
white blood cell count 
 


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1. 
INTRODUCTION 
Hemophilia A is an X-chromosome-linked bleeding disorder caused by mutations and/or 
deletions in the factor VIII (FVIII) 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 level of 
FVIII coagulant activity (FVIII:C) in plasma 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]. 
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 
[episodic] treatment) or prevention of bleeding (prophylaxis treatment) [WFH, 2005; MASAC, 
March 2009].  The frequency of administration of FVIII products varies between patients and is 
tailored to the patient’s clinical status, taking into consideration the type of bleeding episode, 
frequency of bleeding, and the 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]. 
This statistical analysis plan is for the purpose of providing an analysis of long term safety and 
efficacy data on rFVIIIFc to support the generation of long-term data on safety, efficacy and 
other patient reported outcomes.  The analysis is based on study 8HA01EXT data only.  Study 
subjects refer only to those subjects enrolled into this study from parent studies 997HA301, 
8HA02PED, 997HA307, and 997HA309.  A parent study is defined as a study where subjects 
may be enrolled into 8HA01EXT after study completion.   
 
 


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2. 
DESCRIPTION OF OBJECTIVES AND ENDPOINTS 
2.1. 
Study Objectives 
2.1.1. 
Primary Objective  
The primary objective of the study is to evaluate the long-term safety of rFVIIIFc in subjects 
with hemophilia A. 
2.1.2. 
Secondary Objective  
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. 
2.2. 
Study Endpoints 
2.2.1. 
Primary Endpoint  
The primary endpoint is the occurrence of inhibitor development. 
2.2.2. 
Secondary Efficacy 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  
 Physician’s global assessment of the subject’s response to his treatment regimen 
using a 4-point scale 
 Subject’s assessment of response to the treatment of bleeding episodes using a 4-point 
scale 
2.2.3. 
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 the post-operative period 
 Number of blood product units transfused during surgery 
 


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2.2.4. 
Endpoints Based on Patient-reported Outcomes 
Subjects will only take the questionnaires that they completed during the parent study.  Subjects 
who go outside of the age range for a questionnaire should no longer complete the questionnaire.  
The Investigator will administer the age-appropriate questionnaire at the appropriate visits.  The 
following patient-reported outcomes will be assessed.   
Quality of Life (QoL) questionnaires: 
 Haem-A-QoL  
 Haemo-QoL  
 Hemo-Sat-Patient Satisfaction Scale for parents/guardians, Version 15 
 Canadian Hemophilia Outcomes-Kids’ Life 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 (referred to as EQ-5D Youth for children in study 8HA02PED) 
 EQ-5D-3L (referred to as EQ-5D in study 997HA301) 
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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3. 
STUDY DESIGN 
3.1. 
Overall Study Design and Plan 
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 that plans to 
enroll subjects into this study after study completion or at a time specified in the protocol.  This 
is a global study and will be offered to those countries participating in the parent studies. 
Based on final and estimated sample sizes from these studies, approximately 214 subjects from 
studies 997HA301, 8HA02PED, 997HA307, and 997HA309 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 
undergo surgery, 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 3.2.1.   
For subjects undergoing surgery, post-operative clinic visits may be more frequent.   For subjects 
undergoing major surgery, a visit (Visit 3) is required 1-2 weeks after surgery (not required for 
minor surgery).  A last post-operative visit (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 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.   
Subjects first dosed with rFVIIIFc when <12 years of age in the parent study will be followed to 
at least 100 EDs in total across parent and extension study, even if rFVIIIFc becomes 
commercially available.   
3.2. 
Treatment 
Subjects 12 years of age or older will follow either a tailored prophylaxis, weekly prophylaxis, 
personalized prophylaxis, or 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 parent study.  Subjects are 
allowed to change treatment regimens (for example, from tailored prophylaxis to episodic, or 
from episodic to tailored prophylaxis) at scheduled or unscheduled visits 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 episodic 
regimen, unless they reach the age of 12 years during the study, at which time they can use any 
of the 4 treatment regimens.  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). 


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3.2.1. 
Regimens 
3.2.1.1. 
Episodic Regimen 
The individual dose of rFVIIIFc to treat bleeding episodes will be based on the subject’s clinical 
condition, type and severity of the bleeding event, and if indicated, FVIII levels.  A subject’s PK 
profile and dosing levels from the parent study 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 episodic regimen once they reach the age of 12 years during the study. 
3.2.1.2. 
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. 
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 
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 options are: 
 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 interval should be based on the subject’s clinical profile observed in the preceding 
rFVIIIFc 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. 
Option 2:  Weekly Prophylaxis  
Dosing is approximately 65 IU/kg at weekly intervals.  The dose should be based on the 
subject’s clinical profile observed in the parent rFVIIIFc study, and/or his individual PK (if 
available), and FVIII trough and/or peak (recovery) values.  Subjects <12 years of age at entry to 
8HA01EXT will not be offered this option initially but may be prescribed this 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 Investigator may consider the following personalized dosing options: 
 Addition of “prevention” doses prior to strenuous activity 


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 Targeting a FVIII trough level of >3%, if the bleeding history and/or activity level 
requires 
 Dosing less frequently 
3.2.2. 
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.  If a 
subject had a major surgery before the implementation of Protocol Amendment 2, only major 
surgeries that were not prescheduled were to be reported as SAEs.  However, for subjects having 
a major surgery after the implementation of Protocol Amendment 2, all major surgeries were to 
be reported as SAEs. 
3.3. 
Number of Subjects   
3.3.1. 
Sample Size 
As this is an extension study, the sample size was based on the planned sample sizes of studies 
997HA301 (N=144), 8HA02PED (N=50), 997HA307 (N=12), and 997HA309 (N=8, the subset 
of subjects from Australia and New Zealand only).  This might be increased based upon 
enrollment being greater than expected in these studies. 
3.3.2. 
Study Sample 
Subject inclusion and exclusion criteria can be found in Sections 8.1 and 8.2 of the protocol. 
3.3.3. 
Procedures for Discontinuing Treatment and Removal of Subjects from the 
Study 
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 (≥5.00 BU/mL) 
 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.   
 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. 


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 Clinical judgment of the Investigator:  a subject may have treatment permanently 
discontinued, if in the opinion of the Investigator, it is not in the subject’s best interest 
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 reason for discontinuation of study treatment must be recorded in the subject’s 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. 
3.3.4. 
End of Study  
The end of study is defined as the last subject’s last visit. This will occur once all subjects have 
completed the study, discontinued prematurely, switched to commercially available rFVIIIFc 
when it becomes available in the applicable participating country, or switched to EAP (Expanded 
Access Program).  
3.3.5. 
Randomization and Blinding 
This is an open-label study with no blinding or randomization.   


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4. 
ANALYSIS POPULATIONS 
For the purpose of the analysis, analysis populations will consist of subjects who enrolled into 
study 8HA01EXT from parent studies 997HA301, 8HA02PED, 997HA307, and 997HA309.   
4.1. 
All-enrolled Analysis Set 
All subjects who consent to participate in 8HA01EXT will be included in the All-enrolled 
Analysis Set.  
4.2. 
Full Analysis Set (FAS) 
Subjects who receive at least 1 dose of rFVIIIFc in study 8HA01EXT will be included in the Full 
Analysis Set (FAS).  Analyses of efficacy will be performed on the FAS.   
4.3. 
Safety Analysis Set  
Subjects who receive at least 1 dose of rFVIIIFc in study 8HA01EXT will be included in the 
Safety Analysis Set. 
4.4. 
Surgery Subgroup 
Surgery subgroup is defined as subjects who have undergone major surgery or have major 
surgical/rehabilitation periods described in Section 5.3.3 during study 8HA01EXT.   


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5. 
DATA HANDLING 
This study is being conducted under the sponsorship of Biogen.  Data management is being 
performed under contract with Quintiles in collaboration with Bioverativ.  Statistical analysis is 
being performed by Bioverativ, using SAS® version 9.3 or higher and, where appropriate, 
additional validated software.  This statistical analysis plan (SAP) is based on protocol Version 
3, dated 26 August 2013 and will detail analyses to be performed and summaries to be produced 
for the final Clinical Study Report (CSR). 
5.1. 
General Principles 
The following rules will be followed for all applicable analyses contained in this SAP, unless 
specified otherwise. 
Because the subjects from studies 997HA301/997HA307/997HA309 and study 8HA02PED are 
in different age groups (i.e. ≥12 years of age for studies 997HA301/997HA307/997HA309 and 
<12 years of age for study 8HA02PED) and may therefore have different safety and efficacy 
profiles, analyses will be performed separately for the groups of subjects from the parent study or 
parent studies combined, as described in the table below.  Further, the table categories (i.e. age 
cohort, treatment regimen, etc) by type of analyses for each grouping are also detailed unless 
specified otherwise. 
Groups of subjects from the parent study 
or parent studies combined 
Categories by type of analyses 
8HA02PED 
Baseline/Concomitant therapy and procedures: 
Age cohort and overall; treatment regimen 
(including surgery subgroup) and overall  
Exposure: 
Age cohort and overall; treatment regimen and 
overall  
Efficacy: 
Age cohort; treatment regimen 
Patient-reported outcomes: 
Age cohort and overall; visit 
Compliance/surgery/Safety: 
Visit (if applicable) 
997HA301 
Baseline/Concomitant therapy and procedures: 
Treatment regimen (including surgery subgroup) 
and overall 
Exposure: 
Treatment regimen and overall  
Efficacy: 
Treatment regimen 
997HA301/997HA307/997HA309 combined 


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Patient-reported outcomes: 
Visit  
Compliance/surgery subgroup/Safety: 
Visit (if applicable) 
Overall 
Compliance/Surgery/Safety: 
Visit (if applicable) 
Where treatment regimen (which is defined as treatment regimen in study 8HA01EXT) is: 
 Tailored prophylaxis 
 Weekly prophylaxis 
 Personalized prophylaxis 
 Episodic 
Age cohort for subjects from study 8HA02PED is as reported for that study, namely: 
 <6 years old 
 6 to <12 years old 
Summaries of study 8HA01EXT data will be produced using standard summary statistics.  
Listings will also only include data from study 8HA01EXT and the treatment regimen associated 
with each data point, unless specified otherwise.  Data collected at unscheduled visits will be 
included in the definition of the maximum and minimum post-baseline values. 
Unless specified otherwise, for the purpose of analyses involving change from baseline during 
8HA01EXT, baseline will be defined as the last non-missing measurement (that can be used for 
data analysis) taken prior to or on the date of 8HA01EXT study Study Day 1 (see Section 5.1.1 
for a description of study days).  Eligible subjects will be enrolled at End of Treatment (EOT) 
visit of their parent study (997HA301, 8HA02PED, 997HA307, or 997HA309), which will serve 
as the Baseline Visit for this extension study (Visit 1).  Baseline visit assessments may have been 
repeated if there was a gap in study treatment (e.g. a gap of greater than 37 days following the 
EOT Visit for the previous study).  Post-baseline values are defined as any assessment taken 
after 8HA01EXT Study Day 1 (see Section 5.1.1 for a description of study days).  In the case of 
unscheduled visits being taken for the same visit number assigned, the latest available non-
missing assessment for that visit will be used for by-visit summaries. 
Data collected at the local laboratories will be excluded from the analyses of laboratory data but 
will be included in the data listing.  
5.1.1. 
Description of Study Days 
Definition of Gap 
A gap is calculated as:  
Date of Visit 1 for study 8HA01EXT – date of the last day of the parent study, 
where the last day of the parent study is defined as either 1) the date of the last rFVIIIFc dose for 
subjects on a prophylactic regimen in study 997HA301, 8HA02PED, 997HA307, or 997HA309, 
or only had PK injections in study 997HA307 or 997HA309, or 2) the date of the last non-safety 
follow-up study visit for subjects on the episodic regimen in study 997HA301 or 997HA307 or 


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subjects who ended the study in a surgical/rehabilitation period in study 997HA301, 8HA02PED, 
997HA307, or HA997309. 
A listing will be provided for subjects from studies 997HA301, 997HA307 and 997HA309 who 
had a gap of greater than 7 days and subjects from study 8HA02PED who had a gap of greater 
than 4 days.  These gaps were identified because for the majority of the subjects, the FVIII 
activity is below 1% after 7 days for subjects from studies 997HA301 997HA307, and 
997HA309 and below 1% after 4 days for subjects from study 8HA02PED.  In addition, the 
definition of Study Day 1 will be somewhat different for these subjects with a longer gap, as 
described below.  
For simplicity, the gap of greater than 7 days for subjects from studies 997HA301, 997HA307, 
and 997HA309 and the gap of greater than 4 days for subjects from study 8HA02PED will be 
referred to as the gap of greater than 7 or 4 days.  
Definition of 8HA01EXT Study Day 1  
8HA01EXT Study Day 1 will be used as a reference date to calculate the study day relative to 
the start of study 8HA01EXT.  The definition of 8HA01EXT Study Day 1 depends on the length 
of the gap.   
For 8HA01EXT subjects with no gap or a gap of less than or equal to 7 or 4 days: 
In general, 8HA01EXT Study Day 1 is defined as the last day of the parent study, i.e. either 1) 
the day of the last rFVIIIFc dose for subjects on a prophylactic regimen in study 997HA301, 
8HA02PED, 997HA307, or 997HA309, or 2) the day of the last non-safety follow-up study visit 
for subjects on the episodic regimen in study 997HA301 or 997HA307 or subjects who ended 
the study in a surgical/rehabilitation period in study 997HA301, 8HA02PED, 997HA307, or 
997HA309. 
For subjects from studies 997HA307 and 997HA309 who only had PK injections (i.e. no 
injections in treatment phase) and enroll in 8HA01EXT on a prophylactic regimen, the 
8HA01EXT Study Day 1 is either 1) the day of the first study visit if there is a prophylactic dose 
on that day, or 2) the day of the last non-safety follow-up study visit in studies 997HA307 and 
997HA309 if there is no prophylactic dose on the day of the first study visit in 8HA01EXT. 
For 8HA01EXT subjects with a gap of greater than 7 or 4 days: 
8HA01EXT Study Day 1 is defined as either 1) the date of the first rFVIIIFc dose in study 
8HA01EXT for subjects on a prophylactic regimen at the start of study 8HA01EXT, or 2) the 
day of the first study visit for subjects starting study 8HA01EXT on the episodic regimen or in a 
surgical/rehabilitation period.   
Definition of Study Day 
The following definition of Study Day will be used in the analysis: 
 8HA01EXT Study Day: day relative to 8HA01EXT Study Day 1, as defined above.  
The start/stop day of events will be calculated as (date of event – date of Study Day 1 + 1) if the 
date of the event is on or after the Study Day 1 date, or (date of event – date of Study Day 1) if 
the date of the event is before the Study Day 1 date.  Study Day -1 is the day immediately 
preceding Study Day 1.  There is no Study Day 0 in this study.       


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5.1.2. 
Data Analysis 
Unit body weight dose (IU/kg) for analysis of dosing will be calculated as the total IU (nominal 
dose) for each injection divided by the subject’s most recent weight in kilograms prior to the 
dose of study drug.   
Summaries on change from baseline by study visit will be based on subjects who have both study 
8HA01EXT baseline and post-baseline values at the visit being summarized.  Each of the post-
baseline timepoint summaries will contain a row that provides the mean baseline value for the 
subjects included in that visit summary. There will also be a row for the baseline median where 
indicated on the table shells.   
5.1.3. 
Handling of Missing Data 
Aside from the following, no imputation of study data will be performed.   
 The episodic treatment regimen at the start of study 8HA01EXT will be imputed for 
the scenario specified in Section 5.3.1. 
 The end of PK period of the parent study (997HA307 or 997HA309) and start of 
study 8HA01EXT will be imputed for the scenario specified in Section 5.3.1. 
 The occurrence of a new bleeding episode will be imputed if >72 hours lapse between 
2 consecutive injections administered to treat a bleed.  Details are provided in Section 
7.1.1.   
For CHO-KLAT, if a subject has data missing at a particular visit, the total score can still be 
estimated provided at least 27 of the 35 questions have been answered.  If a subject’s data cannot 
be used to calculate an overall score that subject will also be excluded from summaries of 
individual domains at that visit and will be flagged as excluded from summaries in analysis 
dataset.  Details are provided in Section 7.5.3 and Appendix E. 
For HAEMO-QoL and HAEM-A-QoL, Hemo-Sat, EQ-5D-Y and EQ-5D-3L, if a subject has 
data missing at a particular visit for a domain, the total score and subscores will still be estimated 
provided the questionnaire makes provision for missing domains in the calculation algorithm of 
overall score. If a subject’s data cannot be used to calculate an overall score that subject will also 
be excluded from summaries of individual domains at that visit and will be flagged as excluded 
from summaries in data listings.  Details are provided in Sections 7.5.1, 7.5.2, 7.5.4 and 7.5.5 
Appendix C, F, G, and D, respectively. 
For the analysis of AEs and concomitant medications/procedures, if the stop/start date of an 
AE/concomitant medication is missing or partial, the corresponding study day will be left blank.  
However, inferences will be made from the partial and missing dates to classify medications as 
concomitant, AEs as treatment emergent (or not) and AEs during surgical/rehabilitation period.  
These inferences are described in Sections 6.4.1 and 8.2, respectively. 
5.2. 
Data Summaries 
5.2.1. 
Continuous Variables  
Continuous variables will be summarized using descriptive statistics including the number of 
non-missing values (n), mean, standard deviation (SD), median, minimum, and maximum.  


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Where specified in the table shells, the 25th and 75th percentiles will also be provided.  Means, 
medians, and the 25th and 75th percentiles will be presented to one decimal place beyond that 
with which the data was captured.  SDs will be presented to two decimal places beyond that with 
which the data was captured.  Minimum and maximum will be displayed to the same number of 
decimal places as that with which the data was captured.   
Unless impractical within a given table, statistics will be aligned by the decimal place in the 
summary tables (even though not necessarily displayed in this manner in the table shells). 
5.2.2. 
Categorical Variables 
Categorical variables will be summarized by counts and percentages.  All percentages will be 
rounded to one decimal place.  The percentage will be suppressed when the count is zero.  
Unless specified otherwise, the denominator for all percentages will be the number of subjects 
(or other experimental unit, e.g. bleeding episodes) in each treatment regimen or overall with 
non-missing data for a given summarization.  This number (n) will be included with categorical 
summaries unless the same variable is also being summarized with descriptive statistics, in 
which case ‘n’ will already be provided.   
5.3. 
Study Periods 
5.3.1. 
Treatment Regimens for Analysis 
For the purpose of analysis, the treatment regimen in study 8HA01EXT means the actual 
treatment regimen(s) that subjects follow over the course of the study (i.e., not necessarily the 
regimen they started on).  For example, a subject who starts the study on the tailored prophylaxis 
regimen and switches to the weekly prophylaxis regimen will appear in both the tailored 
prophylaxis and weekly prophylaxis regimens in the summaries based on the time he spent in the 
respective regimens.   
Start and End of Treatment Regimens 
At the start of study 8HA01EXT, the start date and time of the starting treatment regimen is 
8HA01EXT Study Day 1 with starting time defined below:  
For 8HA01EXT subjects with no gap or a gap of less than or equal to 7 or 4 days: 
In general, starting time is defined as either 1) 1 minute after the last rFVIIIFc dose on 
8HA01EXT Study Day 1 for subjects on a prophylactic regimen in study 997HA301, 
8HA02PED, 997HA307, or 997HA309, or 2) 23:59 on 8HA01EXT Study Day 1 for subjects on 
the episodic regimen in study 997HA301/997HA307 or subjects who ended the study in a 
surgical/rehabilitation period in study 997HA301, 8HA02PED, 997HA307, or 997HA309. 
For subjects from study 997HA307/997HA309 who only had PK injections (i.e. no injections in 
treatment phase) and enroll in 8HA01EXT on a prophylactic regimen, the start time is either 1) 
the time of the prophylactic dose on Study Day 1, or 2) 23:59 on Study Day 1 if there is no 
prophylactic dose on Study Day 1. The time between 23:59 and 1 minute before the first 
prophylactic dose in study 8HA01EXT will be imputed as PK period.  
For 8HA01EXT subjects with a gap of greater than 7 or 4 days: 


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Start time is defined as either 1) time of the first rFVIIIFc dose on 8HA01EXT Study Day 1 for 
subjects on a prophylactic regimen at the start of study 8HA01EXT, or 2) 00:01 on 8HA01EXT 
Study Day 1 for subjects starting study 8HA01EXT on the episodic regimen or in a 
surgical/rehabilitation period.   
The above definition of the start date and time of the starting treatment regimen is applicable for 
all subjects with the following exceptions: 
 For subjects who were on the episodic treatment arm in study 997HA301or 
997HA307, or only had PK injections in study 997HA307 or 997HA309, and started 
study 8HA01EXT on the episodic regimen, if there was any dose on 8HA01EXT 
Study Day 1, then the episodic treatment regimen in study 8HA01EXT will start at 
the time of that dose.   
 For subjects who were on the episodic treatment arm in study 997HA301 or 
997HA307 and switched to a prophylactic regimen at study 8HA01EXT start, and 
had a gap of less than 7 days: 
o If there was no prophylactic dose on the last non-safety follow-up study visit, 
then the prophylactic treatment regimen in study 8HA01EXT will start at the 
time of the first prophylactic dose in study 8HA01EXT.  The interval from the 
starting time on 8HA01EXT Study Day 1 (i.e., 23:59 on the day of the last 
non-safety follow-up study visit) through 1 minute before the first 
prophylactic dose in study 8HA01EXT will be imputed as the episodic 
treatment regimen in study 8HA01EXT.   
o If there was a prophylactic dose on the last non-safety follow-up study visit, 
then the start of the prophylactic regimen in study 8HA01EXT will be the 
time of that prophylactic dose.  In this case, the time from the start of the 
prophylactic regimen to 23:59 on that day, i.e. the end of the episodic regimen 
in studies 997HA301 and 997HA307, will be attributed to both study 
997HA301/997HA307 and study 8HA01EXT.  If there were bleeding 
episodes during this overlap of time, they would have been attributed to 
studies 997HA301 and 997HA307.   
The end of the last treatment regimen (for subjects who have not changed treatment regimens, it 
will be the same treatment regimen as they started) will be either 1) the date and time of the last 
rFVIIIFc dose for subjects whose last treatment regimen was prophylactic or if they were in a 
surgical/rehabilitation period in study 8HA01EXT, or 2) 23:59 on the day of the last non-safety 
follow-up study visit for subjects whose last treatment regimen in study 8HA01EXT was 
episodic. 
Treatment Regimen Changes 
During study 8HA01EXT, when a treatment regimen changes, the date of the prescribed change 
will be recorded on the ‘Treatment Regimen Assignment Change Details (TRS2)’ form in the 
eCRF.  In the following sections, new treatment regimen refers to the one that the subject was 
changed to, and the previous treatment regimen refers to the one immediately before the new 
treatment regimen.  The start date and time of the new treatment regimen and the end date and 
time of the previous treatment regimen are defined in the following three scenarios: 


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 From one prophylactic regimen to a new prophylactic regimen, the new prophylactic 
regimen starts at the date and time of the first prophylactic dose in the new 
prophylactic regimen.  The previous prophylactic regimen ends 1 minute before that.  
If the time of the first prophylactic dose in the new prophylactic regimen is not 
available, the new prophylactic regimen will start at 00:01 on the day of the first 
prophylactic dose in the new prophylactic regimen, and the previous prophylactic 
regimen will end at 23:59 on the day prior to that.   
 From the episodic regimen to a prophylactic regimen, the prophylactic regimen starts 
at the date and time of the first prophylactic dose in the prophylactic regimen.  The 
episodic regimen ends 1 minute before that.  If the time of the first prophylactic dose 
in the prophylactic regimen is not available, the prophylactic regimen will start at 
00:01 on the day of the first prophylactic dose in the prophylactic regimen, and the 
episodic regimen will end at 23:59 on the day prior to that. 
 From a prophylactic regimen to the episodic regimen, if there is no prophylactic dose 
on the day of treatment regimen change recorded in the eCRF, the episodic regimen 
starts at 00:01 on the day of treatment regimen change, and the prophylactic regimen 
ends at 23:59 on the day prior to the day of treatment regimen change.  If there is a 
prophylactic dose on the day of treatment regimen change, the episodic regimen starts 
1 minute after that prophylactic dose, and the prophylactic regimen ends on the date 
and time of that prophylactic dose.    
Duration of a Treatment Regimen 
The duration of a given treatment regimen is the time period from the start of the treatment 
regimen to the end of that treatment regimen in study 8HA01EXT.  The duration will stop and 
start for each treatment regimen change.  If a subject is treated in a given treatment regimen more 
than once in study 8HA01EXT, the total durations in the same treatment regimen will be added 
together.  For example, during study 8HA01EXT, if a subject is treated with the tailored 
prophylaxis regimen and then the weekly prophylaxis regimen and then goes back to the tailored 
prophylaxis regimen, then his total duration in the tailored prophylaxis regimen will be the sum 
of the two durations in the tailored prophylaxis regimen.  Further details will be provided for 
individual analysis where needed.  
The total duration of time allocated to each treatment regimen will be calculated in minutes and 
converted to days as the number of minutes divided by 1440.   
5.3.2. 
Efficacy Period 
The efficacy period in study 8HA01EXT will be used for the evaluation of bleeding and 
consumption endpoints.  For a subject to have an evaluable efficacy period over the duration of 
study 8HA01EXT, he must have >0 day of treatment for an episodic regimen, and at least 2 
prophylactic injections for prophylactic regimens.  
The start and end, and the total duration of the efficacy period for a given treatment regimen in 
8HA01EXT is the same as the start and end, and the total duration of that treatment regimen 
defined in Section 5.3.1 with the following exception to the definition of start, and the 
adjustments necessary due to surgical/rehabilitation periods.   


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Exception to the Definition of Start 
For subjects who entered study 8HA01EXT during a surgical/rehabilitation period, if they are to 
be on a prophylactic regimen in study 8HA01EXT, then the efficacy period for the prophylactic 
regimen will start at the time of the first prophylactic dose following the end of the 
surgical/rehabilitation period (see Section 5.3.3).  If they are to be on the episodic regimen in 
study 8HA01EXT, then the efficacy period for the episodic treatment regimen will start at 00:01 
on the day following the end of the surgical/rehabilitation period (see Section 5.3.3). 
Adjustments Due to Surgical/Rehabilitation Periods 
For analysis purposes, the efficacy period for a given treatment regimen will be adjusted for all 
surgical/rehabilitation periods (major and minor).  The start and end of the efficacy period for a 
given treatment regimen are adjusted as follows: 
 For subjects on a prophylactic regimen before the start of a surgical/rehabilitation 
period, the efficacy period for the prophylactic regimen continues up to the last dose 
(for prophylaxis or a bleed) before the start of the surgical/rehabilitation period. 
 For subjects on the episodic regimen before the start of a surgical/rehabilitation 
period, the efficacy period for the episodic regimen continues up to 1 minute before 
the start of a surgical/rehabilitation period. 
 For subjects on a prophylactic regimen following the end of a surgical/rehabilitation 
period, the efficacy period for the prophylactic regimen starts or re-starts (depending 
on whether there is a treatment regimen change during the surgical/rehabilitation 
period) at the first prophylactic dose following the end of the surgical/rehabilitation 
period. 
 For subjects on the episodic regimen following the end of a surgical/rehabilitation 
period, the efficacy period for the episodic regimen starts or re-starts (depending on 
whether there is a treatment regimen change during the surgical/rehabilitation period) 
at 00:01 on the day following the end of the surgical/ rehabilitation period. 
Start and end dates/times for the efficacy period for given treatment regimens and treatment 
regimen changes will be adjusted for each surgery (major or minor) as necessary.   
For subjects on a prophylactic regimen before the start of a surgical/rehabilitation period, the 
interval of time between the last dose before a surgical/rehabilitation period and the start of the 
surgical/rehabilitation period will not be attributed to the efficacy period for the prophylactic 
regimen.  By definition, there should not be any treated bleeding episodes in this interval of time.   
For subjects on a prophylactic regimen following the end of a surgical/rehabilitation period, 
bleeding episodes that occur after discharge from a rehabilitation facility but before the next 
prophylactic dose will be attributed to the surgical/rehabilitation period and hence not counted 
towards the annualized bleeding rate.   
Adjustments Due to Large Injection Intervals  
For analysis purposes, the efficacy period will also be adjusted to account for large intervals 
between injections resulting from missing data.  Time between any 2 adjacent rFVIIIFc 
injections of greater than 28 days within a prophylactic treatment regimen will be removed from 
the efficacy period. The efficacy period prior to each such interval will end at the time of the first 


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injection of this interval and restart (or start if it is the first interval of a treatment regimen) at the 
time of the second injection of this interval.  The efficacy period will be adjusted for each 
identified interval that is not within a surgical/rehabilitation period. Treatment regimens 
considered for large interval adjustment include tailored prophylaxis, weekly prophylaxis and 
personalized prophylaxis regimen with at least 2 routine prophylactic injections (additional 
injections are not considered due to the sporadic nature of these injections).  No adjustment for 
large injection intervals will be made for episodic treatment regimens.   
5.3.3. 
Surgical/Rehabilitation Period 
The broadest span of time for the surgical/rehabilitation period in study 8HA01EXT is from the 
first dose of rFVIIIFc in study 8HA01EXT given for the surgery (i.e., the pre-surgery dose) up to 
1 minute before the first regular prophylactic dose after the last day of postoperative 
care/rehabilitation for subjects on prophylactic regimens and up to 23:59 on the last day of the 
surgical/rehabilitation period for subjects on the episodic regimen.  If dose(s) labeled for a 
surgical reasons which do not correspond to a surgery will be re-classified as ‘OTHER’ and will 
not be used in the determination of the surgical/rehabilitation period.  Since not all subjects will 
have these events, specific considerations for the start and end of the surgical/rehabilitation 
period are as follows: 
Start of the surgical/rehabilitation period: 
 Date/time of the first pre-surgical dose.  In general, if an injection for a pre-surgical 
dose is recorded in the eCRF, the reason for the injection should be labeled as 
“prophylaxis pre-operative”.  If an injection for pre-surgical dose is recorded in the 
EPD, the reason will be labeled as “surgical prophylaxis”.  If the date/time of surgery 
is complete, a pre-surgery dose is any dose labeled for a surgical reason on the day of, 
or the day before surgery, which is prior to the start date/time of the surgery.  If the 
time of surgery is missing or 00:00 (as sometime occurs for minor surgeries), only 
injections labeled as “prophylaxis pre-operative” on the day of surgery should be 
taken as a pre-surgical dose along with any other doses labeled for a surgical reason 
on the day before surgery.  If there is more than one pre-surgical dose, then the first 
one should be selected (a pre-surgical dose can be administered the day before the 
surgery). 
 If there is no pre-surgical dose but there was a prophylaxis dose or dose given for 
“OTHER” reason prior to the surgery on the day of or the day before surgery, the last 
of these doses should be selected. 
 If there is no pre-surgical dose or a prophylaxis dose prior to the surgery on the day of 
or the day before surgery then select the start date/time of the surgery.  If the time was 
not recorded or recorded as 00:00 then select the date and impute 00:01 for the time. 
End of the surgical/rehabilitation period: 
If the treatment regimen after the surgical/rehabilitation period is a prophylactic regimen, then 
the end of the surgical/rehabilitation period is 


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 1 minute before the first prophylactic dose on or after the last date among the dates 
for discharge from the hospital, post-operative visit 1, post-operative visit 2, the end 
of rehabilitation. 
 If all of the dates mentioned above are missing, then select the first prophylactic dose 
after the date/time for the end of surgery.  If the surgery time was not recorded or 
recorded as 00:00, then select the surgery date and impute 23:59 for the time.  If the 
end date of the surgery is missing, then select the start date of the surgery and impute 
23:59 for the time. 
 If there are no prophylaxis doses following the latter of the 6 dates mentioned above, 
then select the latter of the dates and impute 23:59 for the time if otherwise there is no 
time associated with the given date (e.g., the subject completed the 
surgical/rehabilitation period but received no further prophylactic doses). 
 If the overall end of study is declared while the subject is still in the 
surgical/rehabilitation period, then select the date of the end of study and impute 
23:59 for the time.   
If the treatment regimen after the surgical/rehabilitation period is the episodic regimen, then the 
end of the surgical/rehabilitation period is 
 Imputed as 23:59 on the last date among the dates for discharge from the hospital, 
post-operative visit 1, post-operative visit 2, and the end of rehabilitation 
 If all of the dates mentioned above are missing, then the select the date of the end of 
surgery and impute 23:59 for the time.  If the end date of the surgery is missing, then 
select the start date of the surgery and impute 23:59 for the time. 
Two exceptions are noted: 
 If 2 (or more) major surgeries are performed without an intervening discharge from 
the hospital, then the first surgical/rehabilitation period will end 1 minute before the 
start of the next surgery and the second surgical/rehabilitation period will end as 
described above. 
 If minor surgery is performed during postoperative care or rehabilitation then the 
surgical/rehabilitation period for the minor surgery will start and end on the day of the 
minor surgery, at 00:01 and 23:59, respectively, if times are not otherwise provided or 
recorded as 00:00.  The surgical/rehabilitation period for the major surgery will 
include the minor surgery (ie, the surgical/rehabilitation period for the major surgery 
does not stop and restart around the minor surgery) and will end as otherwise defined. 
Within the total surgical/rehabilitation period, the time is divided into: 
 Intraoperative period:  from the date/time of the pre-surgery rFVIIIFc dose to the 
date/time of the end of surgery   
 Postoperative care period:  from the date and time plus 1 minute following the end of 
surgery to the last dose of rFVIIIFc given for the surgery, including doses given to 
prevent bleeding during the postoperative period 


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 Postoperative rehabilitation period:  from the date following the last day of 
postoperative care to the end of the surgical period as described above 
The surgical/rehabilitation period will be determined in the same manner for both major and 
minor surgeries.   
5.3.4. 
Safety Period 
The safety period is defined as the period from 8HA01EXT Study Day 1 to the last recorded 
date.  The end of the safety period will be imputed as 23:59 for the time on the last recorded date 
in the analysis database.  The last recorded date is either the date of the last study visit, last 
telephone call, or the date of the last dose, whichever comes last.  
5.4. 
Electronic Patient Diary (EPD) Data 
 
From approximately 25 Apr of 2016, EPD data cannot be queried for changes which require 
subject confirmation.  However a subset of data issues needing changes which do not require 
subject confirmation may be handled programmatically.  One such issue falls under the heading 
of Single Vial Consolidation (SVC) and occurs when a dose consists of an injection which uses 
more than one vial and these vials are erroneously recorded in the EPD as separate injections, 
albeit within a short time window.  As a scenario where these are actually 2 separate doses 
within a short space of time is medically implausible, these vials can be consolidated into a 
single record for the dose.  The programming algorithm can be summarized as follows 
 
 Identify all injection records within 60 minutes of one another (fields for identification 
are subject ID and injection date/time)  
 Exclude all examples of true duplicates, based upon records with a selected number of 
key fields identical (fields for identification are subject ID, injection date/time, nominal 
dose, and lot numbers)  
 For the remaining pairs of records: 
Exclude them if the reasons for injections are different from each other with the 
following three types of scenarios: 1) bleed and prophylaxis/additional/OTHER, 2) 
surgery and prophylaxis/additional/OTHER, and 3) one with the reason that is not 
provided. Otherwise, 
o Record with earliest injection date/time retained with corresponding contextual 
information 
o Combine/sum field values related to the dose (e.g. lot numbers, number of vials, 
volume injected, nominal and actual dose) into the single retained record 


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6. 
STUDY SUBJECTS 
6.1. 
Disposition of Subjects 
Subject disposition will be summarized for study 8HA01EXT for subjects from each parent 
study and overall.  This table will present the number of subjects in the All-enrolled Analysis 
Set, the number and percentage of subjects enrolled in the Full Analysis Set (FAS) including the 
number of subjects with an efficacy period, the number of subjects within each treatment 
regimen, the number and percentage of subjects in the Safety Analysis Set, and the number and 
percentage of subjects in the surgery subgroup.  The number of subjects with the status of 
completed, and discontinued from the study, including the primary reason for those who 
discontinued, will be tabulated.  Subject disposition, including the date of the last visit and the 
reason for early termination for subjects who did not complete the study, will be provided in a 
data listing. 
The number and percentage of enrolled subjects will be summarized by country, site and 
treatment regimen using All-enrolled Analysis Set.  The number of subjects attending each visit 
in study 8HA01EXT will be summarized overall by planned visit using the Safety Analysis Set.  
The summary for each study visit will include only those subjects for whom the visit evaluations 
reflect the designated visit on the study (i.e., including subjects for whom this visit represents the 
end-of-study visit due to early termination). 
6.2. 
Demography and Baseline Disease Characteristics 
Demographics and baseline disease characteristics will be summarized using the Safety Analysis 
Set.   
6.2.1. 
Demography 
Demographic characteristics including age (years), geographic location, height (cm), weight 
(kg), and body mass index (kg/m2) will be summarized using the data at entry into study 
8HA01EXT.  Race and ethnicity will also be included in the summary using the data at the entry 
into the parent study.  Geographic locations are defined as Europe, North America, and other.  
For subjects from studies 997HA301/997HA307, Europe includes Austria, Belgium, Germany, 
France, United Kingdom, Italy, Spain, Sweden and Switzerland.  North America includes 
Canada and the United States.  Other countries include Australia, Brazil, Hong Kong, India, 
Japan, Israel, New Zealand and South Africa.  For subjects from study 8HA02PED, Europe 
includes Ireland, the Netherlands, Poland, and the United Kingdom.  North America includes the 
United States.  Other countries include Australia, Hong Kong, and South Africa.   For subjects 
from study 997HA309, there are only two countries: Australia and New Zealand, which will be 
categorized as ‘Other’.  
6.2.2. 
General Medical and Surgical History 
An updated medical and surgical history is collected at the first visit of study 8HA01EXT.  A 
summary of this updated medical and surgical history by body system for the Safety Analysis Set 


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will be presented.  A subject will be counted only once if they reported one or more occurrences 
in the same body system.  
6.2.3. 
Physical Examination  
Physical examination continues to be performed annually in this extension study. A listing of 
subjects with an abnormal status will be presented. 
6.3. 
Protocol Deviations 
All protocol deviations will be recorded throughout study 8HA01EXT.  Major and minor 
protocol deviations/violations are to be pre-specified prior to database lock.  All major protocol 
deviations during study 8HA01EXT will be summarized by study 8HA01EXT treatment 
regimen, the surgery subgroup, and overall using the FAS.  Protocol deviations that occurred 
during surgical/rehabilitation periods will be attributed to the surgery subgroup only.  All 
deviations, both major and minor, will be provided in a data listing.  
In addition, another set of protocol deviations (PDs) will be determined using the EPD dataset 
created for the impact analysis, where changes requiring subject confirmation have been reverted 
to the original pre-change state.  Details specific to the impact analysis will be provided in 
Sections 9 below.  This set of PDs will be summarized and listed in a similar manner to the 
primary set, for the FAS. 
6.4. 
Non-study Drug Medications 
6.4.1. 
Concomitant Medications 
Two listings will be provided, one for concomitant medications taken through the Final Study 
Visit/Early Termination Visit and the other for concomitant medications taken after the Final 
Study Visit/Early Termination Visit and prior to the Follow-up visit/phone call. 
Concomitant medications will be summarized using for the Safety Analysis Set. 
Concomitant medications are those administered on or after 8HA01EXT Study Day 1, or 
administered prior to 8HA01EXT Study Day 1 and ongoing at the start of 8HA01EXT Study 
Day 1.  They will be characterized based on the start and end dates relative to 8HA01EXT Study 
Day 1.  Medications reported for a subject will be classified as concomitant unless they can be 
excluded as such, as follows: 
 Medications with a start date after the follow-up visit will not be considered 
concomitant. 
 For partial dates, if a concomitant medication start day is missing then the medication 
will be assumed to be a concomitant medication unless the start month and/or year or 
medication stop date can be used to determine if a medication is concomitant, as 
follows.   
 If the concomitant medication start day is missing, but the month and year are 
before the start month and year of 8HA01EXT Study Day 1 and the concomitant 
medication stop date is before the date of 8HA01EXT Study Day 1, then the 
medication will not be classified as concomitant.   


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 If the day of the start date is missing and the month and year are after the month 
and year of 8HA01EXT Study Day 1, then the medication will be classed as 
concomitant.   
 If the month of the start date is missing and the year is before the start year of 
8HA01EXT Study Day 1 and the stop date is before the date of 8HA01EXT 
Study Day 1, then the medication will not be classified as concomitant. 
Concomitant medications will be coded using World Health Organization drug enhanced 
dictionary version March 2011. 
6.4.2. 
Other Therapies and Procedures 
Other therapies administered and concomitant procedures performed in study 8HA01EXT will 
be summarized using for the Safety Analysis Set as well as will be listed. 
6.5. 
Study Drug  
Study treatment regimens are described in Section 3.2.  The listing of all study drug administered 
will include the reason for administration (prophylaxis [regular or additional], treatment of a 
bleeding episode, surgery, other).  Subject-level information on dosing with study drug will also 
be provided in a data listing.   
Treatment with study drug, (exposure, prophylactic dose, prophylactic dosing interval, and 
consumption) will be summarized using the FAS.   
6.5.1. 
Exposure 
6.5.1.1. 
Duration of rFVIIIFc Dosing, Number of Injections and Exposure Days to 
rFVIIIFc 
Two summaries of exposure will be produced.  Details of the summaries are described in Section 
7.3.2. 
6.5.1.2. 
Last Prescribed Dose and Dosing Frequency  
Subjects’ last prescribed dose and dosing frequency will be summarized as a cross tabulation of 
dosing frequency by dose (IU/kg) in which the number and percentage of subjects who were last 
prescribed each combination of dose and dosing frequency (every 2, 3, 4, or 5 days or twice 
weekly) will be tabulated.  A summary table will be provided for the overall prophylaxis regimen 
consisting of the tailored prophylaxis and weekly prophylaxis regimens in study 8HA01EXT.  
The last prescribed dose will also be summarized for each dosing frequency using descriptive 
statistics.  If no dose (dosing frequency) changes were prescribed, then a subject’s starting dose 
(dosing frequency) will be used.  The dose for the twice weekly regimen will be the average of 
the two doses given. Percentages will be based on the number of subjects in each prophylactic 
regimen (ie, not on the number of subjects in each dosing frequency category). 
6.5.2. 
Change of Treatment Regimens  
 


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For the changes in treatment regimens in study 8HA01EXT described in Section 5.3.1, the 
number of subjects with at least one treatment regimen change, the regimen first changed to, and 
the number of changes will be summarized by starting treatment regimen in study 8HA01EXT 
and overall.  
6.5.3. 
Prophylactic Dose (IU/kg) and Dosing Interval (days) 
Because prophylactic dosing in study 8HA01EXT is based on variable doses and dosing 
intervals, the amount of rFVIIIFc received prophylactically will be summarized as an average 
weekly dose.  Descriptive statistics will be provided using the FAS for each prophylactic 
regimen.   
The average weekly prophylactic dose (IU/kg) and the prophylactic dosing interval will be based 
on prophylactic doses that are not separated by a bleeding episode.  Data to be included in the 
calculations, specifically the prophylactic doses and the total duration of prophylaxis treatment, 
will come strictly from intervals representing 2 consecutive prophylactic doses (PR) during the 
efficacy period (see Section 5.3.2 for a description of the efficacy period).  The sum of doses at 
PRx and the sum of interval durations (PRx+1 minus PRx) will be determined across all evaluable 
intervals of PRx to PRx+1.  As such, when a bleeding episode is encountered, the interval stops at 
the prophylactic dose prior to the event and continues with the first prophylactic dose after the 
event.  The last PR dose during a given treatment regimen will be the end of the last interval used 
for these calculations.  The start and stop time of a treatment regimen and the calculation of total 
duration in that treatment regimen are described in Section 5.3.1.  If a subject is treated in a 
given treatment regimen more than once during study 8HA01EXT, the sum of doses at PRx, sum 
of days in PR intervals, sum of days in PR intervals and number of PR intervals will be 
calculated across all durations in that treatment regimen before the average weekly prophylactic 
dose and dosing interval are calculated using the formulae below. 
Average weekly prophylactic dose =
Sum of doses at PRx  
x 7 
Sum of days in PR intervals 
 
Average prophylactic dosing interval = 
Sum of days in PR intervals 
Number of PR intervals 
 
For the personalized prophylaxis regimen, additional injections administered will also be 
included in the average weekly prophylactic dose and average dosing interval calculations. 
Prophylactic dosing will be further characterized by the number of prescribed changes in the 
dose and the number of prescribed changes in the dosing interval while on a given prophylaxis 
treatment regimen.  If both dose and dosing interval change, they will be included in each 
summary.  Dose and dosing interval changes are based on recommendations made by the 
Investigator and may or may not reflect whatever modifications a subject actually made to his 
dosing regimen.  The number of prescribed changes in the dose level and the number of 
prescribed changes in the dosing schedule will be summarized categorically (0, 1, 2, 3, 4, >4) 
and with descriptive statistics.  If a subject is treated in a given treatment regimen more than 
once during study 8HA01EXT, then the total number of changes will be across all durations in 
that treatment regimen.  


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6.5.4. 
Consumption 
The total annualized rFVIIIFc consumption (IU/kg) will be calculated for each subject using the 
following formula: 
Annualized consumption = 
Total IU/kg of study drug received  
during the efficacy period 
x 365.25 
Total number of days during the efficacy period 
 
The total amount of rFVIIIFc received will be the sum of the nominal IU/kg administered for 
each injection based on the units of rFVIIIFc as recorded from the subject’s diary and eCRF and 
his most recent weight. 
Total annualized rFVIIIFc consumption will be determined for each treatment regimen during 
the efficacy period (i.e., excluding surgery/rehabilitation periods [major and minor surgeries]).   
For personalized prophylaxis regimen, additional injections administered will be included in the 
consumption calculations.  
Consumption is a secondary endpoint in this study.  A description of how consumption will be 
summarized is provided in Section 7.3.3. 
6.5.5. 
Compliance 
Prophylactic dose compliance will assess adherence to the Investigator’s recommendations for 
dosing.  Prophylactic dose compliance will be assessed during the efficacy period. 
The prophylactic dose compliance rate will be summarized for overall prophylaxis regimen for 
the FAS.  See Section 6.5.5.2 for further details on prophylactic dose compliance. 
Except for doses administered in the clinic, study treatment may be administered by a caregiver 
or self-administered by the older children in the study.     
Data from the eCRF and EPD will be considered for the analysis of treatment received and 
subjects’ compliance with the study protocol; compliance has been defined by the Sponsor.  
Compliance with prestudy FVIII will not be a considered measurement for this study. 
6.5.5.1. 
Compliance in the Treatment of Bleeding Episodes 
Bleeding episodes are defined in Section 7.1.1.  All bleeding episodes during the efficacy period 
for which there is a date and time for both the onset of the bleed and treatment of the bleed will 
be evaluated for compliance.  Compliance will first be determined on a per-bleed basis and then 
on a per-subject basis.  That is, compliance for each bleeding episode will be determined and 
then the overall percentage of bleeding episodes for which treatment was in compliance will be 
determined for each subject.   
The definition of compliance for the treatment of an individual bleeding episode, as specified by 
the Sponsor, is no more than 8 hours between the onset of the bleed and the initiation of 
treatment for the bleed.  Thus, the compliance rate for the treatment of bleeding episodes will be 
measured by determining the proportion of injections administered within a maximum of 8 hours 
of the initial sign of a bleed, as follows: 


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Treatment of bleed 
compliance rate = 
Number of first injections to treat a bleed taken within  
8 hours of the first sign of a bleed 
x 100 
Total number of evaluable bleeding episodes 
The following circumstances result in a bleeding episode being considered not evaluable for the 
determination of this compliance rate: 
 the type of bleed has been classified as Unknown based on the definition of a 
bleeding episode (>72 hours between consecutive injections) since there is no onset 
time 
 a missing bleed time for a spontaneous or traumatic bleed  
 a bleed time that was recorded as being after the time of treatment 
Bleeding episodes for which the first injection for treatment was with non-study drug will be 
included in the evaluation of compliance.  Inclusion of bleeding episodes treated with non-study 
drug is discussed in Section 7.1.1. 
Descriptive statistics of the per-subject compliance rate as well as a categorical summary of these 
data (<80%, ≥80%) will be presented for overall treatment regimen for the FAS.   
6.5.5.2. 
Compliance of Prophylactic Injections 
The compliance rate of each subject to the prescribed prophylactic dosing regimen during the 
efficacy period will be calculated in 2 ways, as dose compliance and as dosing interval 
compliance.  Compliance will first be determined on a per-injection basis and then on a per-
subject basis.  That is, compliance for an individual dose or dosing interval will be determined 
and then the overall percentage of doses and dosing intervals that were in compliance will be 
determined for each subject.   
For the purpose of evaluating compliance, the following will be considered per injection: 
 the nominal dose taken compared to the nominal dose prescribed  
 the actual day of treatment compared to the prescribed day of treatment 
An individual dose will be considered compliant if it is within 80% to 125% of the prescribed 
dose.  An individual dosing interval will be considered compliant if the time between two 
prophylactic doses is within 24 hours of the prescribed dosing interval.  Prescribed dose and 
dosing intervals are according to the Investigator.  Instructions provided to the subject by the 
Investigator regarding dose or dosing interval changes will be used to determine compliance as 
of the date the information was provided to the subject. 
The actual dosing intervals will be calculated as the length of time between consecutive 
prophylactic doses (date/time of PRx+1 – date/time of PRx).  PRx+1 and PRx are also discussed in 
Section 6.5.3.  The actual time between doses will be determined in minutes and converted to 
days as the number of minutes divided by 1440.  The prescribed dosing interval will be taken 
from the eCRF as recorded by the Investigator.  The absolute value of the difference between the 
actual and prescribed dosing intervals must be ≤1 day (+/- 24 hours) in order to be compliant. 
All prophylactic injections will be used to determine prophylactic dose compliance; only the 
prophylactic injections used to determine the average prophylactic dosing interval (i.e., intervals 


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not separated by a bleeding episode or surgical/rehabilitation period), as detailed in Section 
6.5.3, will be used to evaluate prophylactic interval compliance.  Dose and dosing interval 
compliance rates per subject will be determined as follows: 
 
Dose compliance rate = 
Number of doses taken within 80% to 125%  
of prescribed dose 
x 100 
Total number of doses 
where the percentage of a prescribed dose is calculated as:  (nominal dose taken/prescribed 
dose) x100 
and the ‘nominal dose taken’ will be determined from the nominal potency labeled on the 
vials used by the subject for each injection of rFVIIIFc.  
Dose interval compliance rate = 
Number of doses taken within +/- 24 hours  
of prescribed day/time 
x 100 
Total number of intervals 
 
A subject is considered ‘dose compliant’ or ‘dosing interval compliant’ if his respective rate is at 
least 80%. 
Descriptive statistics of the percentage of nominal doses taken per subject within the 80% to 
125% range for dosing compliance as well as frequencies for the dose compliance rate (<80%, 
≥80%) will be presented for overall prophylaxis regimen for the FAS.  Similarly, descriptive 
statistics of the percentage of doses taken per subject within ±24 hours of the prescribed day as 
well as frequencies of the dosing interval compliance rate (<80%, ≥80%) will be presented for 
the FAS. 
Based on their per-subject compliance rates for dose and dosing interval (each <80%, ≥80%), 
subjects will be further classified into the following mutually exclusive categories for overall 
compliance to their prophylactic treatment as: 
 Both dose and interval compliant 
 Dose compliant or interval compliant (but not both) 
 Neither dose nor interval compliant 
6.5.5.3. 
Compliance of EPD Contemporaneous data entry 
Injections must be entered into the EPD within 7 days from the date of the injection.  Injections 
entered outside the 7-day window will be reported as protocol deviations.  Descriptive statistics 
of the percentage of the subjects with fewer than 80% of their total individual EPD records 
entered within this 7-day window and those with 80% or greater of records that met this criteria 
will be presented for overall treatment regimen for the FAS. 
The analysis of ABR, duration of dosing, and adverse events in safety, as described in Sections 
7.3.1, 7.3.2, and 8.2.1 respectively, will be presented by subgroups based upon this percentage. 


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7. 
EFFICACY AND PHARMACOKINETIC ANALYSIS 
7.1. 
General Efficacy Principles 
Unless specified otherwise, only data occurring during the efficacy period will be used in 
analyses and summaries relating to bleeding, consumption, and compliance in the treatment of 
bleeding episodes; efficacy data collected during the surgical/rehabilitation periods (major and 
minor) will not be included (see Section 5.3.1).   
7.1.1. 
Bleeding Episodes 
Bleeding episodes will be recorded in both the EPD and eCRF; this information will be used to 
derive the secondary efficacy endpoints.  During the course of the study the investigator was 
given the opportunity to disagree with the type of bleed (spontaneous, traumatic) as classified by 
the subject/caregiver and the subject/caregiver was subsequently given the opportunity to agree 
or disagree with the reclassification.  If the subject/caregiver agreed with the Investigator’s 
assessment, then all analyses subset by type of bleed will be based on the Investigator’s 
determination of the bleed type whether or not the change was made to the subject’s records. 
A standardized definition of a bleeding episode has been applied to this study, 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.  For the purpose of analysis, the latter injection will be associated 
with a new bleeding episode and classified as type=Unknown.  The location(s) associated with 
the original bleeding episode will be carried forth to the new bleeding episode; the onset date and 
time of bleeding will be unknown and hence considered missing. Any bleeding at a different 
location is considered a separate bleeding episode regardless of the time from the last injection. 
This algorithm will also apply when a follow-up injection was recorded subsequent to a 
prophylactic injection.  If the follow-up injection was administered >72 hours after the previous 
injection to treat a bleeding episode (type=spontaneous, traumatic, follow-up), then the follow-up 
injection will be classified as a new bleeding episode as described above. 
Bleeding at a different location will occur when the general bleeding location is different (e.g., in 
a joint for the original bleeding episode and subsequently in a muscle) or in a sub-location not 
initially present if in the same location category (e.g., right elbow for the original bleeding 
episode and subsequently in the right and left elbows).  Conversely, a bleeding episode that 
originally occurs in the right elbow and left knee and is reported as a new bleed within 72 hours 
as being only in the right elbow will be considered to be in the same location and hence not 
counted as a new bleeding episode.  
A bleeding episode that occurs in multiple locations will be counted as a single event when 
determining the overall annualized number of bleeding episodes.  However, in summaries by 
bleeding location, the bleeding episode will be counted in each location for which it is reported 
with the exception that bleeding that occurs in more than one sub-location of the same location 
category (e.g., 2 or more different joints) will be counted as just one for that location category.  


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Only bleeding episodes that were treated with at least one dose of FVIII (whether rFVIIIFc or a 
non-study drug) will be included in the analysis of endpoints evaluating bleeding.  That is, 
bleeding episodes that were not treated at all will not be included.  Bleeding episodes that were 
treated with non-study medication will be included in the determination of the annualized 
bleeding rate.  The handling of bleeding episodes treated with non-study FVIII for other 
endpoints is discussed in Sections 7.4.1. 
Bleeding episodes of an unknown type will be included in the determination of the annualized 
bleeding rate and in summaries based on bleeding episodes but, unless specified otherwise, will 
not be included in summary tables where endpoints are summarized by type of bleed.   
The per-subject annualized number of bleeding episodes, hereafter referred to as the annualized 
bleeding rate (ABR), will be calculated for each subject using the following formula:  
ABR = 
Number of bleeding episodes during the efficacy period 
x 365.25 
Total number of days during the efficacy period 
7.1.2. 
Multiplicity 
Multiplicity is not a concern in this study since no statistical tests are being performed on the 
efficacy endpoints. 
7.2. 
Primary Endpoint 
There are no primary efficacy endpoints in this study. 
7.3. 
Secondary Endpoints 
7.3.1. 
Annualized Bleeding Rate 
The ABR will be summarized using categorical (e.g. 0, >0-5, >5-10, >10-20, etc.) and 
descriptive statistics for the FAS.  All types of bleeding episodes (spontaneous, traumatic, and 
type unknown) will be included in determining the annualized number. 
As a description of the raw data collected in this study, the unadjusted number of bleeding 
episodes per subject will be summarized using categorical (e.g. 0, 1-3, 4-6, 7-10, 11-15, etc.) and 
descriptive statistics over all bleeding episodes and by type of bleed (spontaneous, traumatic, and 
type unknown).  The number and percentage of subjects experiencing a bleeding episode will be 
summarized categorically for any bleeding episode and for each type of bleed by location (joint, 
muscle, internal, skin/mucosa, unknown); percentages will be based on each treatment regimen 
in study 8HA01EXT for FAS.  Of note, the number of subjects with a bleeding episode for 
which the location is unknown will be tabulated in these summaries but no further analysis of 
unknown bleeding locations is planned.  The total subject years followed will be provided in 
order to put the unadjusted numbers in perspective. 
In addition, summaries of the ABR will also be provided for the following subgroups: 
 type of bleed (spontaneous, traumatic) 
 location of the bleed (joint, muscle, internal, skin/mucosa) 
For the purpose of analysis bleeding episodes with a location of iliopsoas will be 


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treated as a muscle bleed; however, the location will be displayed as iliopsoas in the 
listings. 
 other combinations of type and location of bleed (spontaneous muscle, spontaneous 
internal, spontaneous skin/mucosa, traumatic joint, traumatic muscle, traumatic 
internal, traumatic skin/mucosa) 
 target joint at screening in the parent study 
 contemporaneous entry compliance of </≥ 80%, as described in Section 6.5.5.3. 
7.3.2. 
Total Number of Days of Exposure  
The total number of exposure days (EDs) along with the duration of dosing to rFVIIIFc and total 
number of injections per subject will be summarized.  The summary will use the Safety Analysis 
Set; these data will be summarized. 
In this summary, for any subject, the total number of EDs, duration of dosing to rFVIIIFc, and 
total number of injections will be calculated from the start date and time of the the starting 
treatment regimen to the end date and time of the last treatment regimen in study 8HA01EXT.  
The start and end of treatment regimens are defined in Section 5.3.1.  An ED is a 24-hour period 
in which one or more rFVIIIFc injections are given.  The 24-hour window starts from the first 
rFVIIIFc injection on the study and then for subsequent injections, it starts from an injection 
taken after/outside of a previously identified ED.   
The total number of EDs on rFVIIIFc for each subject will be summarized categorically (<50, 
50-<100, 100-<150, 150-<200, 200-<250, etc.) and with descriptive statistics.  The total number 
of injections per subject will be summarized using descriptive statistics.   
Any interruptions to dosing will be ignored for the purposes of calculating the interval.  The 
number and percentage of subjects whose duration of dosing was at least 13 weeks, at least 26 
weeks, at least 39 weeks, at least 52 weeks, and at least 78 weeks will be tabulated based on the 
integer part of the calculated week.   
Duration of rFVIIIFc dosing (weeks) will also be summarized using descriptive statistics.  
Weeks will be represented in the descriptive statistics as if these were data collected with 1 
decimal place.   
This table will also be presented by subgroup based upon contemporaneous entry compliance of 
</≥ 80%, as described in Section 6.5.5.3.  
7.3.3. 
Total Annualized rFVIIIFc Consumption  
The secondary endpoint of total annualized rFVIIIFc consumption per subject for the prevention 
and treatment of bleeding episodes will be summarized for the FAS.  See Section 6.5.4 for 
details on the annualized rFVIIIFc consumption derivation.   
7.3.4. 
Physician’s Global Assessment of the Subject’s Response to His rFVIIIFc 
Regimen 
Investigators will record assessments of each subject’s response to his rFVIIIFc regimen at each 
scheduled visit using the following 4-point scale: 


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1=Excellent: bleeding episodes responded to ≤ the usual number of injections or ≤ the usual 
dose of rFVIIIFc, or the rate of breakthrough bleeding during prophylaxis was ≤ that 
usually observed.  
2=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.  
3=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.  
4=Ineffective: routine failure to control hemostasis or hemostatic control requires 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  
The physician’s global assessment of the subject’s response will be summarized by visit for 
overall treatment regimen for the FAS.  The number and percentage of subjects in each response 
category will be tabulated.  Percentages will be based on the number of subjects for whom an 
assessment was provided at the respective visit. This table will also include a cumulative 
tabulation across all scheduled study visits; subjects can be included in this tabulation up to all 
visits, once for each visit.  Percentages for this collection of responses throughout the study will 
be based on the total number of assessments across all visits.  In addition, these assessments will 
be provided in a data listing.  
7.3.5. 
Subject’s Assessment of Response to rFVIIIFc Injections for Bleeding 
Each subject or subject’s caregiver will provide an assessment of response to each administration 
of rFVIIIFc for each bleeding episode using the 4-point scale of excellent, good, moderate, and 
none (see Appendix A for further details; ‘none’ means that there was no improvement, not that 
the subject did not provide a response).  Response categories of excellent and good will be 
presented combined as well as individually.  The number and percentage of injections in each 
response category will be tabulated based on all injections.  Two summaries will be provided.  In 
the first summary percentages will be based on the total number of injections administered for 
bleeding episodes for which a response was provided.  In the second summary percentages will 
be based on the total number of bleeding episodes whether or not a response was provided.  As a 
supplemental analysis, similar summaries will be provided based on just the first injection 
administered after each bleeding episode using both approaches to determine the percentages.   
 The subject’s assessment of response will be summarized for the FAS.  


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7.4. 
Additional Assessments 
7.4.1. 
Number of Injections and Dose of rFVIIIFc to Resolve a Bleeding Episode 
The number of injections, average dose per injection (IU/kg), and total dose (IU/kg) required to 
resolve a bleeding episode will be determined on both a per-bleeding episode and per-subject 
basis.  See Section 7.1.1 for details on the definition of a bleeding episode.  A bleeding episode is 
considered resolved when treatment for the bleeding is no longer needed. 
Per bleeding episode:  The total number of injections will include the initial injection for a 
spontaneous bleed (SB), a traumatic bleed (TB), or a bleed of unknown type plus all injections 
identified as follow-up (FU) treatment for that bleed.  For each bleed, the average dose per 
injection will be calculated as the average of all doses (IU/kg) administered among the 
SB/TB/Unknown and FU injections administered to treat that bleed; the total dose will be the 
sum of these doses.  The number of injections required for the resolution of a bleeding episode 
will be summarized across all bleeding episodes in study 8HA01EXT both categorically (1, 2, 3, 
>3; 1, >1; and ≤2, >2) and with descriptive statistics.  The average dose per injection and total 
dose required for resolution of a bleeding episode will be summarized using descriptive statistics. 
Per subject:  The number of injections, average dose per injection, and total dose required to 
resolve each bleeding episode, as determined for the per-bleeding episode summaries, will be 
averaged across all bleeding episodes in study 8HA01EXT for each subject.  The average 
number of injections required for resolution of a bleeding episode will be summarized both 
categorically (1 to <2, 2 to <3, and ≥3) and with descriptive statistics.  The averages for the per-
subject average dose per injection and total dose required for resolution of a bleeding episode 
will be summarized using descriptive statistics. 
Bleeding episodes that were treated with both study and non-study medication will be included 
in the determination of the number of injections required to resolve the bleeding episode but not 
in either the average dose per injection or total dose required. 
For the above analysis, data from the FAS will be summarized. 
7.4.2. 
Time from Last Injection of rFVIIIFc to a Bleeding Episode 
The time (in days) between a spontaneous bleeding episode and the most recent previous 
prophylaxis injection of rFVIIIFc, will be calculated and summarized using descriptive statistics.  
Time will be determined in minutes and then converted to days as total minutes divided by 1440.  
Of note, the reference time for the bleeding episode is the onset of the bleed and not the time 
treatment for the bleed was first administered.  The definition of a new bleeding episode can be 
found in Section 7.1.1. 
The time from the last prophylactic injection to a new spontaneous bleeding episode will be 
determined on both a per-bleeding episode and per-subject basis.  Each evaluable spontaneous 
bleeding episode will be included as a separate observation in the summary statistics for the per-
bleeding episode evaluation.  Evaluable bleeding episodes are those for which both a date and 
time are available for both the onset of the bleeding episode and the previous prophylactic 
injection.  For the per-subject evaluations, times will be averaged across all evaluable 
spontaneous bleeding episodes per subject and descriptive statistics will be provided for this per-
subject average time. 


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Bleeding episodes that were treated with non-study medication will be included in these 
analyses, regardless of which treatment was administered first, if all other information needed to 
calculate the endpoint value is available.  
7.4.3. 
Time Between the First and Second Injection to Treat a Bleeding Episode 
In order to characterize the resolution of bleeding episodes treated with rFVIIIFc, the time 
between the first and second injections to treat a bleeding episode will be determined on both a 
per-bleeding episode and a per-subject basis.   
Per bleeding episode:  The time (in hours) between the first and second injections to treat a bleed 
will be summarized using descriptive statistics across all bleeding episodes, including those with 
type=Unknown, that required at least 2 injections for resolution.   
Per subject:  The number of hours between the first and second injections to treat a bleeding 
episode, as determined for the per-bleeding episode summaries, will be averaged across all 
evaluable bleeding episodes per subject.  Descriptive statistics will be provided for the per-
subject average times.  
Additionally, the time between the first and second injections to treat a bleed will be summarized 
per bleeding episode and per subject by type of bleed (spontaneous, traumatic) using descriptive 
statistics.  
Bleeding episodes that were treated with non-study medication will be included in the 
determination of the time between the first and second injections.  
7.4.4. 
Hemophilia Joint Health Score 
Joint assessment will be collected using a modified Hemophilia Joint Health Score (HJHS) for 
adult subjects and use the HJHS for pediatric subjects.  
The Modified HJHS assessment includes the scoring of six joints (left ankle, right ankle, left 
elbow, right elbow, left knee, right knee) 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).  
The HJHS assessment includes the scoring of six joints (left ankle, right ankle, left elbow, right 
elbow, left knee, and right knee) on a scale from 0 to 20 according to the following criteria: 
swelling, duration of swelling, muscle atrophy, crepitus of motion, flexion loss, extension loss, 
joint pain, and strength. Gait will be scored on a scale from 0 to 4 based on the number of skills 
that are not within the normal limits. The total score will be the sum of scores from all six joints 
plus the gait score (range from 0 to 124, with 0 being normal and 124 being the most severe 
disease).   
 
The total and gait scores and change from study 8HA01EXT baseline will be summarized by 
visit for overall treatment regimen for Safety Analysis Set.  The study 8HA01EXT baseline is 
defined above in Section 5.1. 
Modified HJHS and HJHS scoring details are given in Appendix H. 


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7.5. 
Endpoints Based on Patient-reported Outcomes 
The following patient-reported outcomes will be assessed and data listings will be provided.  
Analyses involving baseline value will be based on study 8HA01EXT Baseline (as defined 
above in Section 5.1).  
7.5.1. 
HAEMO-QoL and HAEM-A-QoL 
The questionnaires will be analyzed according to the recommendations of the questionnaire 
authors (see http://www.haemoqol.de).  Details of the questionnaire are provided in Appendix C.   
The algorithm for deriving the sub scores is given in Appendix C.  
The HAEMO-QoL questionnaire for Children and Teenagers aged 13-16 contains 12 sub-
grouped sections, which will count as 12 separate sub-scores.  Further details on the sub-scores 
are contained in Appendix C.  The following sub-sections make up the 12 sub-scores of the 
HAEMO-QoL questionnaire:  
Time Period 
Sub-scores for HAEMO-QoL 
During the past month 
 1. Physical health 
 
 2. Feeling 
 
 3. View of yourself 
 
 4. Family 
 
 5. Friends 
 
 6. Perceived support 
 
 7. Others persons 
 
 8. Sports and school 
 
 9. Dealing with hemophilia 
 
10. Treatment 
 
11. Future 
 
12. Relationships 
The HAEM-A-QoL questionnaire for Adults contains 10 sub-grouped sections, which will count 
as 10 separate sub-scores.  The following sub-sections make up the 10 sub-scores of the 
HAEM-A-QoL questionnaire:  
Time Period 
Sub-scores for HAEM-A-QoL 
During the past 
month 
 1. Physical health 
 
 2. Feeling of yourself 
 
 3. View 
 
 4. Sports and leisure 
 
 5. Work and school 
 
 6. Dealing with hemophilia 
 
 7. Treatment  
Recently 
 8. Future 
 
 9.  Family planning 
 
10.  Partnership and sexuality 
As specified in Appendix C, questions will either have been coded or will be re-coded to ensure 
that high scores represent a low quality of life and low scores represent a high quality of life.  
These scores are then transformed to produce a Transformed Scale Score (TSS).  This score is 


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scaled, as a percentage, from 0 to 100%, with higher TSS values representing a worst quality of 
life for each sub-score and total score summary measurement. 
For both the HAEMO-QoL and HAEM-A-QoL questionnaires the total scores and individual 
sub-scores based on the TSS will be summarized for the observed value and change from study 
8HA01EXT baseline for the FAS. 
7.5.2. 
Hemo-Sat Patient Satisfaction Scale 
A copy of the questionnaire and further details on the subscales and the calculation of the 
subscores are contained in Appendix F.   
As specified in Appendix F, questions will either have been coded or will need to be re-coded to 
ensure that high scores represent a low satisfaction and low scores represent a high satisfaction.  
These scores are then transformed to produce a Transformed Scale Score (TSS).  This score is 
scaled as a percentage from 0 to 100% for each sub-score and total score, with higher TSS values 
representing a worst satisfaction. 
The total score and individual subscores based on the TSS will be summarized for the observed 
response and change from baseline using descriptive statistics for the FAS.  A negative change 
from baseline represents an improvement in satisfaction.  Summaries will be at each visit.  See 
Section 5.1.3 for details of when questionnaire results should be excluded from tabulated 
summaries. 
7.5.3. 
CHO-KLAT 
Two forms of the assessment tool were administered for subjects from 8HA02PED, one to the 
subjects (Child Self-report Questionnaire), and one to the parent/caregiver (Parent/Proxy 
Questionnaire).   
A copy of the questionnaires and details on their scoring are provided in Appendix E.  As 
specified in Appendix E, questions will either have been coded or will need to be re-coded to 
ensure that high scores represent a high quality of life and low scores represent a low quality of 
life.  These scores are then transformed to produce a Transformed Scale Score (TSS).  This score 
is scaled, as a percentage, from 0 to 100%, with higher TSS values representing a better quality 
of life. 
The total score based on the TSS will be summarized for the observed response and change from 
study 8HA01EXT baseline using descriptive statistics for subjects ≥5 years old in study 
8HA02PED.  A positive change from baseline represents an improvement in quality of life.  
Summaries will be at each visit.    See Section 5.1.3 and Appendix E for details of when 
questionnaire results should be excluded from tabulated summaries. 
7.5.4. 
EQ-5D Youth Questionnaire 
The EQ-5D™ is a standardized instrument used to measure health outcome.  EQ-5D-Y is a 
version of this instrument developed for use in children aged 7 to 12 years old. 
The questionnaire will be analyzed according to the recommendations of the authors (see 
www.euroqol.org).  EQ-5D-Y consists of 2 pages – a 5 dimension descriptive system and the EQ 
visual analogue scale.  The elements of the questionnaire are provided in Appendix G. 


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The descriptive system contains 5 categories: mobility; looking after myself; doing usual 
activities; having pain or discomfort; and feeling worried, sad, or unhappy.  Each category has 
3 levels of response representing no problems, some problems, and a lot of problems.   
The EQ visual analogue scale is a visual scale from 0 to 100 used to record a subject’s overall 
self-rated health state.  The subject is asked to mark an ‘X’ on the scale then record the 
corresponding number; 0 refers to the worst possible health state, 100 refers to the best possible 
health state.   
The EQ visual analogue scale will be summarized for the observed response and change from 
study 8HA01EXT baseline using descriptive statistics for children 7 to <12 years of age for the 
FAS.  Subjects for whom the baseline value is zero will be excluded from this analysis.  See 
Section 5.1.3 for details of when questionnaire results should be excluded from tabulated 
summaries. 
7.5.5. 
EQ-5D-3L Questionnaire 
The questionnaire will be analyzed according to the recommendations of the authors (see 
www.euroqol.org).  EQ-5D consists of 2 pages – a 5 dimension descriptive system and the EQ 
visual analogue scale.  A copy of the questionnaire is provided in Appendix D. 
The descriptive system contains 5 categories: mobility, self-care, usual activities, 
pain/discomfort and anxiety/depression.  These categories are scored on a scale of 1 to 3, with 1 
being the best response, and 3 being the worst response.  A total score can also be calculated for 
the EQ-5D-3L questionnaire. For ease of interpretation, these scores will be transformed into a 0-
100 scale by using the following steps: 
 Sum all of the sub-category scores (can take values from 5-15) and divide by the 
maximum possible score overall (3 x 5 categories = 15).  If all questions within each sub-
category are missed, exclude these from analysis. 
 The total score is calculated as: 100 * (subject total score/maximum possible score) 
The 5 categories and total will be summarized for the observed response and change from the 
study 8HA01EXT baseline for the FAS.  See Section 5.1.3 for details of when questionnaire 
results should be excluded from tabulated summaries. 
The EQ visual analogue scale is a visual scale from 0-100 to record a respondent’s overall self-
rated health state.  The respondent is asked to mark an ‘X’ on the scale then record the 
corresponding number; 0 refers to the worst possible health state, 100 refers to the best possible 
health state.  This will also be presented alongside the 5 dimension descriptive system scores.  
The EQ visual analogue scale will be summarized for the observed response and change from the 
study 8HA01EXT baseline for the FAS.  See Section 5.1.3 for details of when questionnaire 
results should be excluded from tabulated summaries. 
7.5.6. 
Health-Economic Parameters 
Health-economic assessments consist of the following items based on the time period since the 
last visit at which they were assessed: 
 Number of hospitalizations excluding planned hospitalizations, elective surgery 
documented at Visit 1, and emergent surgery 


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 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 
The previous visit for the Visit 1 refers to the previous visit in the parent study where applicable.   
These data will be tabulated categorically at each visit for overall treatment regimen for the FAS. 
Information collected on the questionnaire relates to both hemophilia and non-hemophilia related 
events.  Thus, in addition to summarizing the hemophilia-related health resource utilization, the 
utilization for hemophilia- and non-hemophilia related events will be combined and the total 
summarized for the last 4 assessments listed above. 
7.6. 
Surgery Data 
Due to the small overall size of the Surgery Subgroup as described in Section 4.4, efficacy 
analyses will predominantly be based on assessment of subject data listings.   
The following information will be provided in the data listings: 
 Dates/times for the various components of the surgical rehabilitation period (hospital 
admission, surgery, discharge) 
 The surgical procedure performed, blood loss, drainage  
 Blood products used including details for type of transfusion, date/time administered, 
and amount given 
 Surgeon’s/investigator’s assessment of hemostatic response to rFVIIIFc 
 Dosing during surgery, on the day of surgery, and for the first 14 days post-surgery 
(Days 1-3, Days 4-14, and Days 1-14)  
o during surgery:  number of injections, average dose per injection, and total 
dose required to maintain hemostasis 
o day of surgery:  total dose required to maintain hemostasis 
o post-surgery:  total rVIIIFc administered, the total number of injections, and 
the minimum and maximum intervals of time between injections 
 The number of injections required to maintain hemostasis and average daily dose on 
the day of surgery and for Days 1-3 and Days 4-14 following surgery 
 Injections and bleeding episodes during surgery and for the first 14 days following 
surgery, FVIII levels, reason for injection, nominal dose, hours since the last 
injection, and if any additional treatment was given to treat the bleed 
The following information will be summarized for the FAS: 


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 Number of injections and mean and total dose per injection required to maintain 
hemostasis during the major surgical period  
 Estimated blood loss during major surgery  
 Total rFVIIIFc consumption (IU/kg) per major surgery 
 Number of bleeds after surgery per major surgery 
In addition, minor surgeries will be summarized and listed where possible in a similar manner for 
the FAS. 
During surgery includes the pre-surgery dose given for the surgery.  The day of surgery refers to 
the calendar day of the surgery and includes the pre-surgery dose given for the surgery, even if it 
was given on the previous day.  Day 1 refers to the day following surgery.  The average dose per 
injection will be determined as the average dose across all injections during the referenced time 
period.  Total dose will be determined as the sum of all doses administered during the referenced 
time period. 
7.6.1. 
Investigators’/Surgeons’ Assessment of Hemostatic Response to Surgery Using 
the 4-point Bleeding Response Scale 
The Investigators’/Surgeons’ assessment (using the 4-point surgery response scale detailed in 
Appendix 2) of the subject’s hemostatic response to rFVIIIFc within 24 hours post-surgery will 
be summarized categorically for all major surgeries for the FAS.  Categorically, the number and 
percentage of surgeries given each rating will be tabulated.  Percentages will be based on the 
number of surgeries for which a response was provided.   
The above data will be summarized for both major and minor surgeries in 8HA01EXT.  
7.7. 
Pharmacokinetic Assessments 
FVIII activity levels data will be provided in a listing.   


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8. 
SAFETY ANALYSIS 
Safety data will be summarized for subjects from the parent study or subjects from the parent 
studies combined along with the overall total.  The analysis population for safety analyses is 
defined in Section 4.3.   
Adverse events (AEs) will be summarized for subjects from each parent study and overall for all 
subjects in study 8HA01EXT, regardless of treatment arm for subjects from studies 997HA301, 
997HA307, and 997HA309, age cohort for subjects from study 8HA02PED, and treatment 
regimen in study 8HA01EXT.   
In addition, all data from study 8HA01EXT will be provided in data listings.   
8.1. 
Primary Endpoint 
The primary safety endpoint is the occurrence of inhibitor development as determined from the 
Nijmegen-modified Bethesda assay.  A listing of inhibitor test results will be provided.  
8.2. 
Adverse Events 
AEs will be classified using the Medical Dictionary for Regulatory Activities (MedDRA) system 
organ classes and preferred terms.  MedDRA version 15.0 will be used throughout the study.  All 
AEs will be listed.   
In general, AEs will be analyzed based on incidence, defined as the proportion of subjects who 
had at least one occurrence of an event out of the number of subjects in the Safety Analysis Set.    
All adverse event listings will include the onset and resolution study days relative to 8HA01EXT 
Study Day 1.  AEs that are emergent during a major surgical/rehabilitation period, AEs that are 
emergent on the day of surgery and AEs that occur during the gap of greater than 7 or 4 days will 
be flagged.  In addition, a separate listing will be provided for AEs that are emergent during a 
major surgical/rehabilitation period. 
AEs occurring during a major surgical/rehabilitation period with an onset date on the day the 
surgical/rehabilitation period starts or on the day of the surgery will be included in the 
summaries of the study AEs but excluded from the summaries or listings of AEs occurring 
during a major surgical/rehabilitation period.  Consideration is given to AEs with an onset date at 
the start of the surgical/rehabilitation period in the event the pre-surgical dose was administered 
the day before the surgery.   
Events of overdose will not be included in the AE summary tables unless they are reported as 
adverse events. 
The algorithm for the determination of AEs that are emergent during a major 
surgical/rehabilitation period, AEs with an onset date on the day of the surgical/rehabilitation 
period starts or on the day of the surgery, and AEs that are emergent during a treatment regimen 
period when an onset date is partially or completely missing is described below. 
 If the onset date of an adverse event is present, then the date of onset will be compared 
with the start/stop dates of the major surgical/rehabilitation period and treatment regimen 
period to determine whether the adverse event is during a major surgical/rehabilitation 


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period, on the day of the surgical/rehabilitation period starts or on the day of the surgery, 
or during a treatment regimen period.  If the onset of the adverse event is on the day of 
the treatment regimen change, then it will be attributed to the previous treatment regimen.  
 If the onset day of an adverse event is missing and the onset month and year of the AE 
are completely within a major surgical/rehabilitation period or a treatment regimen 
period, then the AE will be attributed to that major surgical/rehabilitation period or that 
treatment regimen period.  For example, the onset of an AE is recorded as 2013-03.  A 
major surgical/rehabilitation period for that subject needs to cover at least from 00:01 on 
the later date of 2013-03-01 and 8HA01EXT Study Day 1 to 23:59 on the earlier date of 
2013-03-31 and the end of his safety period for that AE to be attributed to that major 
surgical/rehabilitation period.  Similarly, if the start and stop time of a treatment regimen 
do not completely cover the possible range of the onset of AE, then the treatment regimen 
for that AE will be set to unknown.  Regardless of the above, the AE will not be 
attributed to the day the major surgical/rehabilitation period starts or the day of the major 
surgery because the exact date is missing. 
 If the onset day and month of an adverse event are missing and the onset year of the AE 
is completely within a major surgical/rehabilitation period or a treatment regimen period, 
then the AE will be attributed to that major surgical/rehabilitation period or that treatment 
regimen period.  For example, the onset of an AE is recorded as 2013.  A major 
surgical/rehabilitation period for that subject needs to cover at least from 00:01 on the 
later date of 2013-01-01 and 8HA01EXT Study Day 1 to 23:59 on the earlier date of 
2013-12-31 and the end of his safety period for that AE to be attributed to that major 
surgical/rehabilitation period.  Similarly, if the start and stop time of a treatment regimen 
do not completely cover the possible range of the onset of AE, then the treatment regimen 
for that AE will be set to unknown.  Regardless of the above, the AE will not be 
attributed to the day the major surgical/rehabilitation period starts or the day of the major 
surgery because the exact date is missing. 
 If the AE onset date is completely missing, the AE will be considered to be outside any 
major surgical/rehabilitation period and the treatment regimen for that AE will be set to 
unknown.   
8.2.1. 
Overall Summary of Treatment-emergent Adverse Events 
An overall summary of treatment-emergent adverse events (TEAEs) will be provided which 
tabulates the number and percentage of subjects who experienced a TEAE, related TEAE, 
treatment-emergent SAE, or treatment-emergent related SAE; the number and percentage of 
subjects who discontinued treatment or withdrew from the study due to an AE; and the number 
and percentage of subjects who died.  This table will also be presented by subgroup based upon 
contemporaneous entry compliance of </≥ 80%, as described in Section 6.5.5.3.     
AEs that occurred during major surgical/rehabilitation periods will be included in the overall 
summary of AEs (in the surgery subgroup column) but not in any of the other AE summary 
tables. 


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8.2.2. 
Treatment-emergent Adverse Events 
In general, an AE will be regarded as treatment-emergent if it was present prior to receiving the 
first injection of rFVIIIFc in the parent study and subsequently worsened in severity, or was not 
present prior to receiving the first injection but subsequently appeared before the subject’s last 
visit on study or the follow-up phone call, whichever came later (or the date of withdrawal/loss 
to follow-up).   
All AEs that occurred on or after the 8HA01EXT Study Day 1 will be considered treatment-
emergent in study 8HA01EXT, regardless of the gap between the parent study and study 
8HA01EXT.  AEs that were treatment-emergent in the parent studies and carried over to study 
8HA01EXT without worsening in severity will be considered the same AEs and will not be 
counted again in study 8HA01EXT.   
The incidence of TEAEs will be summarized by system organ class (SOC) and preferred term.  
Unless specified otherwise, SOCs and preferred terms within each SOC will be presented 
alphabetically.  For the purpose of summarization, a subject is counted once in a SOC or 
preferred term if the subject reported one or more events in that SOC or preferred term.  Unless 
specified otherwise, percentages will be based on the number of subjects in the Safety Analysis 
Set.  
8.2.3. 
Adverse Events in Descending Order of Incidence 
A table will be provided which displays TEAE preferred terms in descending order of incidence.  
Only preferred terms will be included in this table (i.e., the display will not include SOCs). 
A similar table will be provided for severe TEAEs.  AEs for which the assessment of severity is 
missing will be included in this table. 
8.2.4. 
Severity of Adverse Events 
AEs are classified by the Investigator for severity (“Mild”, “Moderate”, and “Severe”).  A 
summary of TEAEs by system organ class, preferred term, and severity will be presented.  AEs 
with a missing severity will be counted as “Severe” in the summary table.  A subject will be 
counted once for each SOC and preferred term based on the greatest severity within that SOC 
and preferred term, respectively. 
8.2.5. 
Relationship of Adverse Events to Study Drug 
AEs are classified by the Investigator for relationship to study drug (“Not related” and 
“Related”).  A summary of TEAEs by SOC, preferred term, and relationship will be presented.  
AEs with a missing relationship will be counted as “Related” in the summary table.  A subject 
will be counted once for each SOC and preferred term based on the highest relationship within 
that SOC and preferred term, respectively. 
8.2.6. 
Serious Adverse Events 
Any AE reported as resulting in death, immediate risk of death (life threatening), inpatient 
hospitalization or prolongation of existing hospitalization, persistent or significant 
disability/incapacity, or a congenital/anomaly/birth defect will be classified as an SAE by the 
Investigator.  An SAE may also be any other medically important event that, in the opinion of 


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the Investigator, may jeopardize the subject or may require intervention to prevent one of the 
other outcomes listed above.  
All SAEs will be listed; treatment-emergent SAEs will be summarized by system organ class and 
preferred term. 
8.2.7. 
Adverse Events Leading to Treatment Discontinuation or Withdrawal From the 
Study 
AEs leading to treatment discontinuation or withdrawal from the study will be listed.  All AEs 
reported on the AE log for the item “Was the subject terminated from this study due to this AE” 
with a response of “Yes” or “Action Taken with Study Drug” with a response of “Drug 
Withdrawn” will be included.   
8.2.8. 
Deaths on Study 
A listing of deaths occurring on study 8HA01EXT will be provided. 
8.3. 
Clinical Laboratory Evaluations 
Analyses for laboratory data involving baseline value will be based on study 8HA01EXT 
Baseline (as defined above in Section 5.1).   
All summaries will be structured such that the hematology and chemistry tests are presented in 
the order shown in the tables provided in Section 8.3.1. 
All laboratory data will be provided in data listings; abnormal values relative to laboratory 
normal ranges will be identified.  Laboratory evaluations taken during major 
surgical/rehabilitation periods will be included in the listings and flagged.   
8.3.1. 
Hematology and Chemistry 
Hematology measurements that will be collected and listed include white blood cell count 
(WBC), differential, hemoglobin, hematocrit, and platelet count. 
Chemistry measurements that will be collected and listed include electrolytes (sodium, 
potassium, chloride), glucose, total protein, total bilirubin, alanine aminotransferase (ALT), 
aspartate aminotransferase (AST), alkaline phosphatase (ALP) [collected for subjects from 
study 997HA301 only], blood urea nitrogen (BUN), and serum creatinine.  
8.3.1 .1  
Change from Study 8HA01EXT Baseline 
Hematology and chemistry results at baseline and post baseline visits, along with change from 
baseline, will be summarized with descriptive statistics for Safety Analysis Set.       
8.3.1.2  
Shifts 
Each subject’s laboratory values will be classified according to whether the test result is “low” 
(below the lower limit of normal [LLN]), “normal” (within the normal range), “high” (above the 
upper limit of normal [ULN]).  Shift tables will be constructed based on both the minimum and 
maximum post-baseline values for each subject.  Data collected from unscheduled visits will be 
included in the determination of the per subject minimum and maximum values.  A separate 
table will be provided which summarizes the results of the shift tables in which the number and 


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percentage of subjects with a shift to low (from normal, high, or unknown) and the number of 
subjects with a shift to high (from normal, low, or unknown) will be tabulated; percentages will 
be based on the number of subjects at risk.  The number at risk for a shift to low (high) is the 
number of subjects whose baseline value was not low (high), including unknown, who had at 
least one post-baseline value.  Only directions of change indicating a clinical concern will be 
included in this table summarizing the shifts.  The direction of concern is provided in Table 1. 
Table 1: 
Direction of Change Indicating Clinical Concern for Laboratory Tests 
Laboratory Test  
Direction 
Laboratory Test  
Direction 
Chemistry 
Hematology 
Liver 
 
White blood cells 
Low and High 
ALT/SGPT 
High 
Lymphocytes 
Low and High 
AST/SGOT 
High 
Neutrophils 
Low and High 
Total bilirubin 
High 
Monocytes 
Low and High 
GGT 
High 
Eosinophils 
Low and High 
Renal 
 
Basophils 
Low and High 
Blood urea nitrogen 
High 
Red blood cells 
Low and High 
Creatinine 
High 
Hemoglobin 
Low and High 
Electrolytes 
 
Hematocrit 
Low and High 
Sodium 
Low and High 
Platelets 
Low and High 
Potassium 
Low and High 
 
 
Chloride 
Low and High 
 
 
Other 
 
 
 
Glucose 
Low and High 
 
 
Total protein 
Low and High 
 
 
 
 
 
 
8.3.1.3  
Potentially Clinically Significant Laboratory Abnormalities 
Abnormal laboratory values will also be evaluated by determining the number and percentage of 
subjects with at least one potentially clinically significant laboratory abnormality over the course 
of the study that also represents a worsening from baseline.  The potentially clinically significant 
levels are based on Grade 2 or higher thresholds from the Common Toxicity Criteria for Adverse 
Events (CTCAE v 4.02 2009) where possible, or were defined by Bioverativ’s Safety and 
Benefit Risk Management group.  Subjects who have a post baseline laboratory value that meets 
the criteria for being potentially clinically significant but do not have a baseline value will be 
included in the numerator for determining the percentage of subjects with an abnormality.  
Percentages will be based on the number of subjects with at least one post baseline value for the 
given laboratory test.  Threshold levels for potentially clinically significant laboratory 
abnormalities are provided in Table 2 (hematology) and Table 3 (chemistry).  Data collected 
from unscheduled visits will be included in this analysis. 


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Table 2: 
Threshold Levels for Potentially Clinically Significant Hematology 
Abnormalities 
Subjects from studies 997HA301/997HA307/997HA309 
 
Low 
High 
White blood cells 
<3.0 × 109/L 
≥16 × 109/L 
Lymphocytes 
<0.8 × 109/L 
>12 × 109/L 
Neutrophils 
<1.5 × 109/L 
>13.5 × 109/L 
Monocytes 
NA 
>2.5 × 109/L 
Eosinophils 
NA 
>1.6 × 109/L 
Basophils 
NA 
>1.6 × 109/L 
Hemoglobin 
≤115 g/L 
≥190 g/L 
Hematocrit 
≤37% 
≥60% 
Platelet count 
≤75 × 109/L 
≥700 × 109/L 
 
 
 
Subjects from study 8HA02PED 
                                   Low                          High 
Neutrophils 
<1.5 × 109/L 
NA 
Eosinophils 
NA 
>1.6 × 109/L 
Hemoglobin 
<100 g/L 
Increase in >20 g/L above ULN 
Hematocrit 
<30% 
≥60% 
Platelet count 
≤75 × 109/L 
≥700 × 109/L 
NA = not applicable 
Table 3: 
Threshold Levels for Potentially Clinically Significant Chemistry 
Abnormalities 
Subjects from studies 997HA301/997HA307/997HA309 
 
Low              
High 
Liver 
 
 
ALT/SGPT 
NA 
≥3 × ULN 
AST/SGOT 
NA 
≥3 × ULN 
Total bilirubin 
NA 
≥34.2 µmol/L 
 
 
 
Renal 
 
 
Blood urea nitrogen 
NA 
≥10.7 mmol/L 
Creatinine 
NA 
≥176.8 µmol/L 
 
 
 
Electrolytes 
 
 
Sodium 
≤126 mmol/L 
≥156 mmol/L 
Potassium 
≤3 mmol/L 
≥6 mmol/L 
Chloride 
≤90 mmol/L 
≥118 mmol/L 
 
 
 
Other 
 
 
Glucose 
≤2.22 mmol/L 
≥9.71 mmol/L 
Total protein 
≤45 g/L 
≥100 g/L 
 
 
 
Subjects from study 8HA02PED 
                                                   Low                           High 
Liver 
 
 
ALT/SGPT 
NA 
>3 × ULN 


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AST/SGOT 
NA 
>3 × ULN 
Total bilirubin 
NA 
>1.5 × ULN 
 
 
 
Renal 
 
 
Creatinine 
NA 
>1.5 × ULN 
 
 
 
Electrolytes 
 
 
Chloride 
≤90 mmol/L 
≥118 mmol/L 
 
 
 
Other 
 
 
Glucose 
<3.1 mmol/L 
>8.9 mmol/L 
Total protein 
≤45 g/L 
≥100 g/L 
NA = not applicable, ULN = upper limit of normal 
8.3.2. 
Inhibitor Development 
Inhibitor results of the Nijmegen-modified Bethesda Assay from the central lab will be listed.  
Results from blood samples collected during surgical/rehabilitation periods for the purpose of 
determining the presence of an inhibitor will be included.  
A positive inhibitor occurs where a subject has a value ≥0.6 Bethesda Units (BU/mL) confirmed 
on re-testing between 2 and 4 weeks later.  Both tests must be performed by the central 
laboratory. 
A “low” titer inhibitor occurs where a subject has a value between 0.6 and <5.0 Bethesda Units 
(BU/mL) confirmed on re-testing between 2 and 4 weeks later. 
A “high” titer inhibitor occurs where a subject has a value ≥5.0 Bethesda Units (BU/mL) 
confirmed on re-testing within 2 to 4 weeks. 
8.3.3 Incidence of Anti-rFVIIIFc Antibodies 
The development of anti-rFVIIIFc antibodies will be assessed as the number and percentage of 
subjects negative throughout the study, positive at any time following study 8HA01EXT Study 
Day 1, and positive at the final evaluation.  Percentages will be based on the number of subjects 
who are antibody negative prior to study 8HA01EXT baseline and have at a post baseline 
antibody evaluation for the referenced time point or time interval.   
Results from blood samples collected during surgical/rehabilitation periods for the purpose of 
determining the presence of anti-rFVIIIFc antibodies will be included in this analysis. 
In addition to a listing of all anti-rFVIIIFc antibody results, a separate listing of all results from 
subjects with at least one positive outcome during the study, including at baseline, will be 
provided. 
8.4. 
Vital Signs 
Vital signs (systolic and diastolic blood pressure, pulse, respiratory rate, and oral temperature) 
will be summarized for the observed values and change from baseline using descriptive statistics 
for the Safety Analysis Set.     


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The number and percentage of subjects with clinically relevant post-baseline abnormalities will 
be presented.  The criteria for clinically relevant post-baseline abnormalities are shown below in 
Table 4.   
Table 4  Criteria to Determine Clinically Relevant Abnormalities in Vital Signs 
Vital Sign 
Criteria for Abnormalities 
Temperature 
>38oC and an increase from pre-dosing of at least 1oC 
Pulse  
120 beats per minute post-baseline, or 
an increase from pre-dosing of more than 20 beats per minute, or 
<50 beats per minute post-baseline, or 
a decrease from pre-dosing of more than 20 beats per minute 
Systolic Blood Pressure 
>180 mmHg post-baseline, or  
an increase from pre-dosing of more than 40 mmHg, or  
<90 mmHg post-baseline, or  
a decrease from pre-dosing of more than 30 mmHg 
Diastolic Blood Pressure 
>105 mmHg post-baseline, or  
an increase from pre-dosing of more than 30 mmHg, or 
<50 mmHg post-baseline, or  
a decrease from pre-dosing of more than 20 mmHg 
A listing of all vital signs (added height and weight) will be provided, including from 
unscheduled visits and during surgical/rehabilitation periods.  Vital signs collected during 
surgical/rehabilitation periods as well as those occurring on the day of surgery will be flagged in 
this listing. 


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9. 
Sensitivity Impact Assessment 
As proposed under the MHRA CAPA commitment, an analysis will be performed to assess the 
impact of the EPD query process and addition of manually created records on the results of study 
8HA01EXT.  The analysis will include summary tables that will be re-run plus any additional 
summary tables or listings required for inclusion in the final clinical study report (CSR).  
Background 
Subject recorded diary data was queried via a defined process which originally required 
confirmation with the subject of all changes.  Subsequently, it was identified that this did not 
occur in all cases nor was this actually necessary for all types of change.  In 2014, it was agreed 
that only certain categories of changes required subject confirmation, and a process implemented 
to ensure adequate documentation to support those changes was available.  After a subsequent 
MHRA audit in 2015, further consideration was given to the timing of changes relative to the 
actual data generation, reliable subject recall period, and still lack of appropriate documentation 
to support changes in all cases.  Therefore, taking into consideration these findings and industry 
standards to limit changes of subject reported data, the query process was updated to only allow 
changes defined as not requiring subject confirmation.  Although changes classified as 
SVC/L60 did not require subject confirmation (as agreed with MHRA in 2014), these changes 
will no longer be made directly into the data, but will be applied via a programmatic data 
convention (details described in Section 5.4).   
The Total Query Report (TQR) documents all changes to the EPD data.  The changes in this 
report were classified according to a pre-defined list (see table below).   
Code 
Description 
Requires subject 
confirmation 
LN 
Minor lot # change (addition/deletion of spaces or hyphens) and 
Major lot # change (any other changes to lot #) 
N 
D/EPD 
Duplicate entry in EPD by subject - deleted 
Y 
D/CRF 
Entry in EPROLOG is also in CRF/INFORM as in-clinic dose 
N 
Dose 
Vials added or removed 
Y 
SVC 
Single vials combined - entered as separate injections in error  
Y 
SVC/L60 
Single vials combined - entered as separate injections in error – 
injection time range for combined records is < 60 mins  
To be applied via 
programmatic data 
convention during 
analysis as 
described in 
Section 5.4 
Error 
Subject entered in error - entry deleted 
Y 
DTOI 
Date and/or time of injection corrected 
Y 
Pre-Fc 
Entries deleted as prior to first dose with Fc (not required per 
protocol) 
N 
Train 
Entries deleted as training/prior to first dose with Fc (not 
required per protocol) 
N 
Test subject 
Subject does not exist - entries deleted 
N 


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Code 
Description 
Requires subject 
confirmation 
Inj Reason 
Reason of injection changed (other than routine prophylaxis or 
other to surgical prophylaxis if a confirmed minor/major surgery or 
procedure is capture in the eCRF during the defined surgical period 
or date of procedure; or from new bleed to follow up) 
Y 
Inj Reason 
Surgery 
Injection reason from routine prophylaxis or other to surgical 
prophylaxis  
N 
BLD LOC 
Change in Bleed Location 
Y 
BLD TYP 
Change in Bleed Type 
Y 
BLD SYM 
Change in Bleed Symptoms 
Y 
DTOB 
Date and/or time of bleed corrected 
Y 
Activity 
Change in Physical Activity question 
Y 
TRT SD 
Amendment to Treat with Study Drug item: “Did you inject 
with rFVIIIFc (Study Drug)?”  
Y 
TRT BLD 
Amendment to Treat Bleed item: “How did the bleed respond to 
injection on ...” 
Y 
Abandon 
Query request was raised but then cancelled by site 
N 
In-clinic 
administratio
n 
In-clinic administration entered in EPD and corrected in  
reference to source records 
N 
NBTFU 
Injection to treat the bleed is < 72 h of the previous injection to 
treat the existing bleed 
New bleed deleted, follow up inj to existing bleed added (per 
protocol definition) 
N 
Tx Arm/Reg 
Change in treatment arm or regimen 
N 
ADMIN 
Changes made by site to data fields that the site would have 
entered originally and/or are administrative. E.g. study name or 
data entered into an incorrect field and corrected, data entered 
that is not required, expiry date of IMP extended, data field 
changes that are duplicated due to multiple site staff involved in 
the query process or similar, correction of injection reason 
related to treatment arm, e.g. routine prophylaxis to weekly 
dose for subjects on a weekly regimen 
N 
 
In certain circumstances, where subjects could not enter records directly into the EPD for any 
reason, records were requested to be created manually by the site according to a pre-defined 
documented process which included SDV by CRA.   However, it was subsequently identified 
that confirmation of SDV could not be provided.   Records were re-SDVed at site to determine 
whether source was available, or whether contemporaneous documentation of confirmation with 
the subject was available. (Not discussed further in this SAP).    
For the impact assessment, all data record changes requiring subject confirmation will be set 
back to the original values.  Although changes classified as SVC/L60 did not require subject 
confirmation (as agreed with MHRA in 2014), these changes will no longer be made directly into 


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the data, but will be applied via a programmatic data convention (described in Section 5.4).  
Manually created data without complete SDV of the record versus a paper diary will be 
considered unsupported by SDV at site, and will be removed for the purpose of the impact 
assessment.  SDTM and ADAM datasets will be re-created and certain statistical analyses re-run.  
Endpoints covered under the impact assessment include: 
 exposure 
 annualized number of bleeding episodes per subject (ABR) 
 subjects assessment of response to treatment with rFVIIIFc for bleeding episodes 
 number of injections and dose per injection of rFVIIIFc required to resolve a bleeding 
episode 
 prophylactic dose and dosing interval  
9.1  
Data Record Changes 
A summary of the number and percentage of data record changes and manually created records 
by record and subject will be produced, overall and by change classification, and whether 
contemporaneous confirmation with subject was required. 
In addition, a listing of the data record changes (to include value pre-change, value post-change, 
change classification and contemporaneous subject confirmation flags) will be produced. 
9.2  
Existing Outputs to be Re-run 
The summary tables will be regenerated based on updated ADAM datasets are shown in Table 5. 
Table 5: Summary Tables Rerun With the Updated Datasets 
Outputs 
Summary Table titles 
Program file name 
Disposition 
Disposition 
T-DISPOSITION.SAS 
Exposure 
Summary of exposure 
T-EX-SUM.SAS.SAS 
 
Summary of prophylactic dose 
(IU/kg) 
T-EX-PROPHY-DOSE.SAS 
 
Summary of prophylactic dose 
and interval 
T-EX-PROPHY-DOSE-INT.SAS 
ABR 
Summary of annualized 
bleeding rate 
T-ABR-SUM.SAS 
Subject response to 
treatment of bleed 
Summary of subject's 
assessment of response to 
rFVIIIFc injections for the 
treatment of bleeding episodes    
T-SUBJ-ASSESS-RESP-
BLD.SAS 


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Injections and dose 
required for resolution of 
a bleeding episode 
Summary of number of 
injections required for 
resolution of a bleeding 
episode 
T-INJ-RES-BLD.SAS 
Injections and dose 
required for resolution of 
a bleeding episode 
Summary of dose (IU/kg) of 
rFVIIIFc for resolution of 
bleeds 
T-DOSE-RES-BLD.SAS 
9.3 
New Outputs to be Created 
Additional listings that are required to support the re-run of existing summary tables for the 
impact assessment will be created.   
The following by subject listings will be created:  
 Listing of derived bleeding and injection endpoints per subject – from original and 
impact assessment  
 Listing of dose endpoints – from original and impact assessment 
 Listing of exposure – from original and impact assessment 
The following listings may be created if the results of the impact analysis require further 
investigation at a bleed or injection level: 
 Listing of derived bleeding endpoints based on individual bleeding episodes – from 
impact assessment  
 Listing of injections to treat a bleed – from impact assessment  
 


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10. 
REFERENCES 
Bolton-Maggs P, Pasi J. Haemophilias A and B. Lancet. 2003;361:1801–09. 
Guideline on the clinical investigation of recombinant and human plasma-derived factor VIII 
products. Committee for Proprietary Medicinal Products (CPMP). CPMP/BPWP/144533/2009. 
London,  (draft 23 July 2009 ,adoption of guideline by CHMP 21 July 2011). 
Mannucci PM, Tuddenham EGD. The hemophiliac: from royal genes to gene therapy. N Engl J 
Med. 2001;344:1773-1779. 
MASAC recommendations concerning the treatment of 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. 
WFH Guidelines- Guidelines for the management of hemophilia. World Federation of 
Hemophilia. 2005.www.wfh.org. 
 


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11. 
INDEPENDENT DATA SAFETY MONITORING COMMITTEE 
There will be no independent data safety monitoring committee for this study. 
 


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LIST OF TABLES, LISTINGS, AND FIGURES 
List of Tables (Table titles are suggested.  If appropriate, table titles may change during their 
creation.) 
Summary of disposition 
Subjects from study 997HA301:  
Summary of subjects attending each visit 
Summary of demographic and baseline characteristics 
Summary of medical and surgical history 
 
Summary of concomitant medications 
Summary of major protocol deviations 
Summary of major protocol deviations based one EPD data in the original pre-change state 
Summary of exposure 
Summary of exposure by EPD entry compliance 
Summary of last prescribed dose and dosing frequency 
Summary of changes in study 8HA01EXT treatment regimens 
Summary of prophylactic dose (IU/kg) 
Summary of prophylactic dosing interval 
Summary of annualized rFVIIIFc consumption (IU/kg) 
Summary of bleeding episodes 
Summary of annualized bleeding rate 
Summary of annualized bleeding rate by type of bleeds  
Summary of annualized bleeding rate by location and type of bleeds 
 
Summary of annualized bleeding rate by the presence of target joints at screening in parent study 
Summary of annualized bleeding rate by EPD entry compliance 
Summary of subject’s assessment of response to rFVIIIFc injections for the treatment of 
bleeding episodes 
Summary of number of injections required for resolution of a bleeding episode 
Summary of dose (IU/kg) of rFVIIIFc for resolution of bleeds 
Summary of number of days from the last prophylaxis injection to a spontaneous bleeding 
episode 
Summary of time (hours) between first and second injection to treat a bleeding episode 
Summary of time (hours) between first and second injection to treat a bleeding episode by type 
of bleed 
 
Subjects from study 997HA301 and studies 997HA301/997HA307/997HA309 combined: 
Summary of results and change from study 8HA01EXT baseline: HAEMO-QoL total score and  
sub-score (Children and Teenagers aged 13-16) 
Summary of results and change from study 8HA01XT baseline: HAEM-A-QoL total score and 
sub-score (Adults) 
Summary of EQ-5D-L descriptive system 
Summary of results and change from study 8HA01EXT baseline: EQ-5D-L visual analogue scale 
Summary of hemophilia-related health economic parameters 
Summary of health economic parameters for all physician and emergency room visits 
Summary of results and changes from study 8HA01EXT baseline: Modified Hemophilia Joint 


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Health Score (HJHS) 
Subjects from studies 997HA301/997HA307/997HA309 combined:  
Summary of subjects attending each visit 
Summary of demographic and baseline characteristics 
Summary of medical and surgical history 
Summary of concomitant medications 
Summary of major protocol deviations 
Summary of major protocol deviations based one EPD data in the original pre-change state 
Summary of exposure 
Summary of exposure by EPD entry compliance 
Summary of last prescribed dose and dosing frequency 
Summary of changes in study 8HA01EXT treatment regimens 
Summary of prophylactic dose (IU/kg) 
Summary of prophylactic dosing interval 
Summary of annualized rFVIIIFc consumption (IU/kg) 
Summary of bleeding episodes 
Summary of annualized bleeding rate 
Summary of annualized bleeding rate by type of bleeds 
Summary of annualized bleeding rate by location and type of bleeds 
Summary of annualized bleeding rate by the presence of target joints at screening in parent study 
Summary of annualized bleeding rate by EPD entry compliance 
Summary of subject’s assessment of response to rFVIIIFc injections for the treatment of 
bleeding episodes 
Summary of number of injections required for resolution of a bleeding episode 
Summary of dose (IU/kg) of rFVIIIFc for resolution of bleeds 
Summary of number of days from the last prophylaxis injection to a spontaneous bleeding 
episode 
Summary of time (hours) between first and second injection to treat a bleeding episode 
Summary of time (hours) between first and second injection to treat a bleeding episode by type 
of bleed 
 
Subjects from study 8HA02PED: 
Summary of subjects attending each visit 
Summary of demographic and baseline characteristics 
Summary of medical and surgical history 
Summary of concomitant medications 
Summary of major protocol deviations 
Summary of major protocol deviations based one EPD data in the original pre-change state 
Summary of exposure 
Summary of exposure by ePD entry compliance 
Summary of last prescribed dose and dosing frequency 
Summary of changes in study 8HA01EXT treatment regimens 
Summary of prophylactic dose (IU/kg) 
Summary of prophylactic dosing interval 
Summary of annualized rFVIIIFc consumption (IU/kg) 
Summary of bleeding episodes 


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Summary of annualized bleeding rate 
Subjects from study 8HA02PED: Summary of annualized bleeding rate by type of bleeds 
Subjects from study 8HA02PED: Summary of annualized bleeding rate by location and type of 
bleeds 
Subjects from study 8HA02PED: Summary of annualized bleeding rate by the presence of target 
joints at screening in parent study 
Subjects from study 8HA02PED: Summary of annualized bleeding rate by ePD entry compliance 
Summary of subject’s assessment of response to rFVIIIFc injections for the treatment of 
bleeding episodes 
Summary of number of injections required for resolution of a bleeding episode 
Summary of dose (IU/kg) of rFVIIIFc for resolution of bleeds 
Summary of results and change from study 8HA01EXT baseline: CHO-KLAT total score from 
the Child Self-report Questionnaire 
Summary of results and change from study 8HA01EXT baseline: CHO-KLAT total score from 
the Parent/Proxy Questionnaire 
Summary of results and change from study 8HA01EXT baseline: Hemo-Sat total score and 
subscores 
Summary of EQ-5D-Y descriptive system 
Summary of results and change from study 8HA01EXT baseline: EQ-5D-Y visual analogue 
scale 
Summary of hemophilia-related health-economic parameters 
Summary of health economic parameters for all physician and emergency room visits 
Summary of results and changes from study 8HA01EXT: Hemophilia Joint Health Score (HJHS) 
 
Overall groups of subjects in 8HA01EXT (as described in Section 5.1): 
Summary of compliance for the treatment of bleeding episodes 
Summary of prophylactic dose compliance 
Summary of prophylactic dosing interval compliance 
Summary of prophylactic compliance 
Summary of EPD entry compliance 
Overall summary of rFVIIIFc treatment-emergent adverse events 
Summary of rFVIIIFc treatment-emergent adverse events by preferred term in descending order 
of incidence 
Summary of rFVIIIFc treatment-emergent adverse events by relationship to treatment 
Summary of rFVIIIFc treatment-emergent serious adverse events 
Summary of anti-rFIIIVFc antibodies 
Surgery subgroup – Summary of Investigators'/Surgeons' assessment of subjects' hemostatic 
response to rFVIIIFc post major surgery 
Surgery subgroup – Number of injections and dose required to maintain hemostasis during major 
surgery 
Surgery subgroup - Estimated total blood loss during major surgery 
Surgery subgroup – Total rFVIIIFc consumption (IU/kg) per major surgery 
Surgery subgroup - summary of number of bleeds after surgery per major surgery 
Summary of Investigators'/Surgeons' assessment of subjects' hemostatic response to rFVIIIFc 
post minor surgery 
Number of injections and dose required to maintain hemostasis during minor surgery 


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Estimated total blood loss during minor surgery 
Total rFVIIIFc consumption (IU/kg) per minor surgery 
Summary of number of bleeds after surgery per minor surgery 
Summary of laboratory results and change from study 8HA01EXT baseline: Hematology 
Shifts from study 8HA01EXT baseline to minimum/maximum post-baseline value for laboratory 
results: Hematology 
Summary shifts from study 8HA01EXT baseline to minimum/maximum post-baseline value for 
laboratory results: Hematology 
Summary of potentially clinically significant laboratory abnormalities: Hematology 
Summary of laboratory results and change from study 8HA01EXT baseline: Blood Chemistry 
from study 8HA01EXT baseline to minimum/maximum post-baseline value for laboratory 
results: Blood Chemistry 
Summary of shifts from study 8HA01EXT baseline to minimum/maximum post-baseline value 
for laboratory results: Blood Chemistry 
Summary of potentially clinically significant laboratory abnormalities: Blood Chemistry 
Summary of vital sign results and change from study 8HA01EXT baseline 
Summary of clinical abnormalities from study 8HA01EXT baseline in vital signs 
List of Listings (Listing titles are suggested.  If appropriate, listing titles may change during 
their creation.) 
Listing of subjects with large gap between the parent study and study 8HA01EXT 
Listing of subject disposition 
Listing of major and minor protocol deviations 
Listing of major and minor protocol deviations based one EPD data in the original pre-change 
state 
Listing of demographic and baseline characteristics  
Listing of medical and surgical history 
Listing of prior and concomitant medications 
Listing of medications taken after the End of Study Visit 
Listing of other therapy or concomitant procedures 
Listing of prescribed dose and dosing regimen changes 
Listing of the Investigator’s classification of bleeding episodes which differed from the 
subject’s/caregiver’s classification 
Listing of weight 
Listing of all injections and treated bleeding episodes 
Listing of derived bleeding endpoints based on individual bleeding episodes 
Listing of derived bleeding and injection endpoints based on subjects 
Listing of compliance in treatment of bleed 
Listing of exposure 
Listing of injections to treat a bleed 
Listing of the by-subject summary of the assessment of response to rFVIIIFc for the treatment of 
bleeding episodes 
Listing of dose and consumption endpoints 
Listing of the number of bleeding episodes during the efficacy period 
Listing of physician’s assessment of the subject’s global response to his treatment regimen 
Listing of major surgery information – hospitalization data  


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Listing of major surgery information – blood loss 
Listing of major surgery information – dosing during and for the first 14 days post-surgery 
Listing of major surgery information – transfusions and surgeon’s assessment of hemostatic 
response to rFVIIIFc 
Listing of minor surgery information – hospitalization data 
Listing of minor surgery information – blood loss 
Listing of minor surgery information – dosing during and on the day of surgery 
Listing of minor surgery information – transfusions and surgeon’s assessment of hemostatic 
response to rFVIIIFc 
Listing of injections and bleeding episodes during and for the first 14 days following major 
surgery 
Listing of FVIII activity levels 
Listing of adverse events 
Listing of adverse events reported during major surgical/rehabilitation periods 
Listing of serious adverse events 
Listing of adverse events leading to discontinuation of treatment and/or the study 
Listing of adverse events reported in study 8HA01EXT that started before 8HA01EXT Study 
Day 1 but were not reported in the parent study 
Listing of deaths 
Listing of laboratory normal ranges 
Listing of laboratory values: Hematology (WBC and differential, absolute count) 
Listing of laboratory values: Hematology (WBC and differential [%]) 
Listing of laboratory values: Hematology (red blood cell parameters and platelet count) 
Listing of abnormal laboratory values based on the normal range: Hematology 
Listing of abnormal laboratory values based on potentially clinically significant abnormalities: 
Hematology 
Listing of laboratory values: Blood Chemistry (liver and renal parameters)  
Listing of laboratory values: Blood Chemistry (electrolytes and other parameters) 
Listing of abnormal laboratory values based on the normal range: Blood Chemistry 
Listing of abnormal laboratory values based on potentially clinically significant abnormalities: 
Blood Chemistry 
Listing of laboratory values: Inhibitor results 
Listing of laboratory values: Anti-rFVIIIFc antibodies 
Listing of vital sign measurements 
Listing of abnormal findings from physical examination 
Listing of CHO-KLAT questionnaire (Part 1 of 4) 
Listing of CHO-KLAT questionnaire (Part 2 of 4) 
Listing of CHO-KLAT questionnaire (Part 3 of 4) 
Listing of CHO-KLAT questionnaire (Part 4 of 4) 
Listing of CHO-KLAT total score 
Listing of Hemo-Sat questionnaire (Ease and convenience)  
Listing of Hemo-Sat questionnaire (Efficacy, Burden, General satisfaction) 
Listing of Hemo-Sat questionnaire (Specialist/Nurses, Center/Hospital) 
Listing of Hemo-Sat total score and sub-scores 
Listing of EQ-5D-Y descriptive system 
Listing of HAEMO-QoL questionnaire (Part x of 6) - Children and Teenagers aged 13-16  


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Listing of HAEMO-QoL questionnaire (Total and sub-scores) - Children and Teenagers aged 13-
16 
Listing of HAEM-A-QoL questionnaire (Part x of 2) - Adults  
Listing of HAEM-A-QoL total score and sub-score - Adults 
Listing of EQ-5D-L descriptive system 
Listing of hemophilia-related health-economic parameters 
Sensitivity Impact Assessment (Tables and Listings): 
Summary of data record changes by classification and contemporaneous subject confirmation 
Listing of data record changes 
Listing of derived bleeding and injection endpoints per subject – from original and impact 
assessment 
Listing of dose endpoints – from original and impact assessment 
Listing of exposure – from original and impact assessment 
Listing of derived bleeding endpoints based on individual bleeding episodes – from impact 
assessment 
Listing of injections to treat a bleed – from impact assessment 
Disposition – from impact assessment 
Summary of exposure – from impact assessment 
Summary of prophylactic dose (IU/kg) Prophylactic dose and interval – from impact assessment 
Summary of annualized bleeding rate – from impact assessment 
Summary of subject's assessment of response to rFVIIIFc injections for the treatment of bleeding 
episodes - – from impact assessment                                 
Summary of number of injections required for resolution of a bleeding episode - – from impact 
assessment 
Summary of dose (IU/kg) of rFVIIIFc for resolution of bleeds - – from impact assessment 
 
Data to be Provided in Listings Upon Request 
None 
 
List of Figures 
None 


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APPENDIX A. SUBJECT’S ASSESSMENT OF RESPONSE TO 
TREATMENT OF BLEEDING 
Using the eDiary, each subject or the subject’s caregiver will rate the treatment response to any 
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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APPENDIX B. SURGERY RESPONSE SCALE 
This surgery scale is used for the investigators’/surgeons’ assessments of response to surgery 
with rFVIIIFc treatment. 
Excellent:  intra-operative and postoperative blood loss similar to (or less than) a person without 
hemophilia.   
 No extra doses of rFVIIIFc needed AND 
 Blood component transfusions required are similar to a person without hemophilia 
Good:  intra-operative and/or postoperative bleeding slightly increased over expectations for a 
person without hemophilia, but the difference is not clinically significant. 
 Intra-operative blood loss no more than expected for a person without hemophilia AND 
 No extra doses of rFVIIIFc needed AND 
 Blood component transfusions required are similar to a person without hemophilia 
Fair:  intra-operative and/or postoperative blood loss is increased over expectation for a person 
without hemophilia and additional treatment is needed. 
 Intra-operative blood loss greater than expected for a person without hemophilia OR 
 Extra dose of rFVIIIFc factor needed OR 
 Increased blood component transfusion requirement  
Poor/none:  significant intra-operative and/or postoperative bleeding that is substantially 
increased over expectations for a person without hemophilia, requires intervention, and is not 
explained by a surgical/medical issue other than hemophilia 
 Intra-operative blood loss greater than for a 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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APPENDIX C. SCORING ALGORITHM FOR HAEM-A-QOL AND 
HAEMO-QOL 
Per the algorithm on http://www.haemoqol.de/manual.htm, to correctly score the 
questionnaires, each version has to be identified and the appropriate scoring list has to be 
selected. Basically high score represent low quality of life and scoring involves the following 
steps: 
1. Assigning numbers to the response scale, which is applicable to both age groups (children 
and teenagers aged 13-16 and adults>16)  
 
1= never, 2=rarely, 3=sometimes, 4=often, 5=all the time 
 
For negatively worded items, the above classification can be applied in which higher values 
represent a lower quality of life. For positively worded items, the score has to be recoded (see 
below).  
 
2. Recoding positively worded items 
 
Positively worded items in the subscales table have to be recoded so that numeric values 
assigned are reversed: 
 
1=all the time, 2=often, 3=sometimes, 4=rarely, 5= never  
 
By recoding, high scores in positively worded items reflect not higher but lower quality of life. 
The then unidirectional values can subsequently be added to yield the summed scores according 
to the Scoring list for the respective questionnaire. 
 
3. Producing the Raw score  
 
A Raw subscale score is produced by summing up all items within a subscale. Its range lies 
between the lowest possible (number of items (n) x 1) and highest possible (number of items (n) 
x 5) value of the respective scale. 
  
The Raw total score is produced by the addition of all items (instead of the subscale items only) 
of the questionnaire (again paying attention to the recoding procedure – see steps 1 and 2).  
 
4. Transferring a raw score to a Standardized score  
A Standardized score is produced by dividing the raw score by the number of items in the sub scale or 
total.  This allows comparison between subscales. 


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5. Transferring a raw score to a Transformed Score between 0 and 100  
Creating a transformed score makes it possible to express the score as a percentage between the lowest 
(0) and the highest (100) possible value. To obtain the transformed score the following transformation 
rule has to be applied: 
Transformed score= 100 x ((raw score – minimal possible raw score) / possible range of raw scores) 
where: 
 minimal possible raw score = number of questions answered × 1 
 maximal possible raw score = number of questions answered × 5 
 possible range of raw scores = maximum possible raw score - minimal possible raw score 
Example: A raw score of 20 on the “Physical Health” Scale is to be transformed: 
 when all 7 questions were answered: 
o minimal possible score=7 
o maximal possible score=35 
o range of scores=28 
o TSS=20-7/28 = 46.4 
 when 6 of the 7 questions were answered: 
o minimal possible score=6 
o maximal possible score=30 
o range of scores=24 
o TSS=20-6/24 = 58.3 
Transformed scores can be produced from raw subscale and raw total scores.  
The total transformed score will be presented in outputs. 
6. Presentation of scores 
The transformed scores for subscale and total will be presented in the outputs. 
7. Subscales 
The following sub score categories are included for the HAEMO-QoL (Children and Teenagers 
aged 13-16) questionnaire: 


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Time Period 
Sub-scores for HAEMO-QoL 
No. of 
questions 
No. of non-
missing items 
required to 
calculate subscale 
During the past 
month 
 1. Physical health 
7 
6 
 
 2. Feeling 
8 
6 
 
 3. View of yourself 
10 
8 
 
 4. Family 
8 
6 
 
 5. Friends 
4 
3 
 
 6. Perceived Support 
4 
3 
 
 7. Other person 
6 
5 
 
 8. Sports and School 
9 
7 
 
 9. Dealing with Hemophilia 
7 
6 
 
10. Treatment 
8 
6 
 
11. Future 
4 
3 
 
12. Relationships 
2 
2 
 
 
 
 
 
Total Score 
77 
63 
 
The following sub score categories are included for the HAEMO-A-QoL (Adults) questionnaire: 
Time Period 
Sub-scores for HAEM-A-QoL 
No. of 
questions 
No. of non-
missing items 
required to 
calculate subscale 
During the past 
month 
 1. Physical Health 
5 
4 
 
 2. Feeling 
4 
3 
 
 3. View of yourself 
5 
4 
 
 4. Sports and leisure 
5 
4 
 
 5. Work and school 
4 
3 
 
 6. Dealing with hemophilia 
3 
3 
 
 7. Treatment  
8 
6 
Recently 
 8. Future 
5 
4 
 
 9.  Family planning 
4 
3 
 
10. Partnership and sexuality 
3 
3 
 
 
 
 
 
Total Score 
46 
38 
 
8. Sub score Items  
Provided below is a copy of both questionnaires.  Items are highlighted when they require re-
coding as detailed in point 2 above. 


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HAEMO QoL Child and Teen Questionnaire  
[III,kids,long] – CIII-HAEMO-QOL-USA/English –Final Version-29 Jun 07 


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We would like to find out about your physical health... 
During the past 7 days... 
never 
rarely 
some-
times 
often 
all the 
time 
1. 
... I felt ill 
 
 
 
 
 
2. 
... I was in pain 
 
 
 
 
 
3. 
... I was tired and worn-out  
 
 
 
 
 
4. 
... I felt strong and full of energy  
 
 
 
 
 
5. 
... I was afraid that my illness might get 
worse  
 
 
 
 
 
... then about how you’ve been feeling in general... 
During the past 7 days... 
never 
rarely 
some-
times 
often 
all the 
time 
1. 
... I had fun and laughed a lot  
 
 
 
 
 
2. 
... I was bored 
 
 
 
 
 
3. 
... I felt alone  
 
 
 
 
 
4. 
... I felt scared or unsure of myself  
 
 
 
 
 
5. 
... I was sad because of my illness  
 
 
 
 
 
... and how you have been feeling about yourself. 
During the past 7 days... 
never 
rarely 
some-
times 
often 
all the 
time 
1. 
... I took pride in myself 
 
 
 
 
 
2. 
... I felt on top of the world 
 
 
 
 
 
3. 
... I felt content with myself 
 
 
 
 
 
4. 
... I had lots of good ideas 
 
 
 
 
 
5. 
... I was able to cope well with my illness
 
 
 
 
 
 


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The next questions are about your family... 
During the past 7 days... 
never 
rarely 
some-
times 
often 
all the 
time 
1. 
... I got along well with my parents 
 
 
 
 
 
2. 
... I felt fine at home  
 
 
 
 
 
3. 
... we argued at home 
 
 
 
 
 
4. 
... I felt restricted by my parents 
 
 
 
 
 
5. 
... my parents treated me like a baby 
because of my illness 
 
 
 
 
 
... and then about your friends. 
During the past 7 days... 
never 
rarely 
some-
times 
often 
all the 
time 
1. 
... I did things together with my friends  
 
 
 
 
 
2. 
... I was popular with my friends 
 
 
 
 
 
3. 
... I got along well with my friends 
 
 
 
 
 
4. 
... I felt different from other people 
 
 
 
 
 
5. 
... I did not want others to notice my 
illness 
 
 
 
 
 
Now, we would like to find out about school. 
During the past 7 days... 
never 
rarely 
some-
times 
often 
all the 
time 
1. 
... doing my schoolwork was easy 
 
 
 
 
 
2. 
... I found school interesting 
 
 
 
 
 
3. 
... I worried about my future 
 
 
 
 
 
4. 
... I worried about getting bad marks or 
grades  
 
 
 
 
 
5. 
... I missed something at school 
because of my illness 
 
 
 
 
 


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NOW WE WOULD LIKE TO ASK YOU SEVERAL QUESTIONS ABOUT YOUR 
HEMOPHILIA 
Here we would like to find out about your BLEEDS (JOINT BLEEDS) 
 
1. 
How frequent were your bleeds in the past month? 
 
 no bleeds 
 1 
 2 
 more than 2 
How many?___ 
The following questions should only be answered if you had bleeds. 
2. 
How much were you troubled by bleeds during the past month? 
 
 not at all 
 a little 
 moderately 
 a lot 
 
3. 
How severe were your bleeds during the past month?  
(If you had several bleeds, please answer for the most severe bleed.) 
 
 slight 
 moderate 
 severe 
 very severe 
 
4. 
Did you feel a strange sensation in your joints before you had a bleed? 
 
 never 
 rarely 
 sometimes 
 often 
 always 
5. 
Did you have to stay quiet (e.g., lie in bed) when you had bleeds? 
 
 never 
 rarely 
 sometimes 
 often 
 always 
6. 
When you had bleeds, did you inform your parents immediately? 
 
 never 
 rarely 
 sometimes 
 often 
 always 
 
We would like to find out who gave you your INJECTIONS 
 
In the past month... 
never 
rarely 
some-
times 
often 
all the 
time 
1.  
... I injected myself 
 
 
 
 
 
2. 
... my mother injected me 
 
 
 
 
 
3. 
... my father injected me 
 
 
 
 
 
4. 
... a nurse injected me 
 
 
 
 
 
5. 
... a doctor injected me 
 
 
 
 
 


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Note: Questions 3, 4, 6 and 10 are positively worded and are recoded so that numeric values 
assigned are reversed: 
 
1=all the time, 2=often, 3=sometimes, 4=rarely, 5= never  


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Note: Questions 1 to 4 of the FRIENDS subscale are positively worded and are recoded so that 
numeric values assigned are reversed: 
1=all the time, 2=often, 3=sometimes, 4=rarely, 5= never  


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Note: Questions 1 to 4 of the SUPPORT subscale are positively worded and are recoded so that 
numeric values assigned are reversed: 
1=all the time, 2=often, 3=sometimes, 4=rarely, 5= never  


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Note: Questions 4, 6 and 7 are positively worded and are recoded so that numeric values 
assigned are reversed: 
1=all the time, 2=often, 3=sometimes, 4=rarely, 5= never  


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Note: Questions 1 to 7 are positively worded and are recoded so that numeric values assigned are 
reversed: 
1=all the time, 2=often, 3=sometimes, 4=rarely, 5= never  


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Note: Questions 1, 2 and 3 of the TREATMENT subscale and Questions 2 and 4 of the FUTURE 
subscale are positively worded and are recoded so that numeric values assigned are reversed: 
1=all the time, 2=often, 3=sometimes, 4=rarely, 5= never  


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Open Questions 
 
1. 
How much are you bothered by your hemophilia? 
 
 not at all 
 a little 
 moderately 
 considerably 
 very much 
 
2. 
What bothers you most about hemophilia? Please write down some things: 
 _____________________________________________________________ 
 _____________________________________________________________ 
 _____________________________________________________________ 
 
3. 
What did you think of the questionnaire?  
(Please put a mark on the line between “0” and “100” to show what you think of  
the questionnaire.) 
 
0 
100 
 
| 
| 
 
very poor 
very good 
 
4. 
Have we forgotten anything that is important to you? 
 _____________________________________________________________ 
 _____________________________________________________________ 
 _____________________________________________________________ 
 
5. 
How long did it take to fill out the questionnaire? 
About ___________ minutes
 
Great job - congratulations! 
 
THANK YOU FOR YOUR ASSISTANCE! 


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HAEM-A-QoL Adult Questionnaire  
CIII-Haemo – QOL - USA/English – Final version – 29 June 07. 


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HAEM-A- QOL 
 
Questionnaire for Adults 
 
Dear Patient, 
 
We would like to find out how you have been feeling during the past weeks. Please 
be so kind as to answer the following questions in this questionnaire, designed 
specifically for people with hemophilia.  
Please follow the instructions below when answering the questions: 
 Please read each question carefully. 
 Think about how things have been for you over the past weeks. 
 Put an “X” in the box corresponding to the answer that fits you best.  
 Only mark one box for each question.  
 There are no right or wrong answers.  
 It’s what you think that matters. 
 There are some aspects that might not concern you (Sports & Leisure, 
Family Planning, Work & School, e.g., if you don’t work or don’t go to 
school). In such a case, please mark the answer category “not applicable.”
 
All your answers will be treated with the strictest confidence! 
Date of completion: __ / __ / __ (month/ day/ year)


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1. Here we would like to find out about hemophilia and your  
PHYSICAL HEALTH 
 
In the past month... 
never 
rarely 
sometimes
often 
all the time
1. 
... my swellings hurt 
 
 
 
 
 
2. 
... I had pain in my joints 
 
 
 
 
 
3. 
... it was painful for me to 
move 
 
 
 
 
 
4. 
... I had difficulty walking as 
far as I wanted to 
 
 
 
 
 
5. 
… I needed more time to get 
ready because of my 
condition 
 
 
 
 
 
2. and now about how you have been FEELING because of your hemophilia  
In the past month... 
never 
rarely 
sometimes
often 
all the time
1. 
... my hemophilia was a 
burden for me 
 
 
 
 
 
2. 
... my hemophilia made me 
angry 
 
 
 
 
 
3. 
... I was worried because of 
my hemophilia 
 
 
 
 
 
4. 
... I felt excluded  
 
 
 
 
 
 


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Note: Questions 2 and 5 of the VIEW OF YOURSELF subscale and Question 3 of the SPORTS 
AND LEISURE subscale are positively worded and are recoded so that numeric values assigned 
are reversed: 
1=all the time, 2=often, 3=sometimes, 4=rarely, 5= never  


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Note: Questions 1 and 2 of the WORK AND SCHOOL subscale and Questions 1 to 3 of the 
DEALING WITH HEMOPHILIA subscale are positively worded and are recoded so that 
numeric values assigned are reversed: 
1=all the time, 2=often, 3=sometimes, 4=rarely, 5= never  


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Note: Question 8 is positively worded and is recoded so that numeric values assigned are 
reversed: 
1=all the time, 2=often, 3=sometimes, 4=rarely, 5= never  


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Note: Question 2 of the FUTURE subscale is positively worded and is recoded so that numeric 
values assigned are reversed: 
1=all the time, 2=often, 3=sometimes, 4=rarely, 5= never  
 


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10. What about PARTNERSHIP AND SEXUALITY? 
 Recently... 
never 
rarely 
sometimes 
often 
all the time
1. 
... I have been finding it difficult to 
date because of my hemophilia 
 
 
 
 
 
2 
... I have been insecure in my 
relationships with women 
because of my hemophilia 
 
 
 
 
 
3. 
… I haven't been able to have a 
normal relationship because of 
my hemophilia 
 
 
 
 
 
 
 
THANK YOU FOR YOUR ASSISTANCE! 
 
 
 
 
 
 
 
 


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APPENDIX D. EQ-5D-3L QUESTIONNAIRE SCORE DEFINITIONS 
 
Domain 
Response 
Score 
Mobility 
I have no problems in walking about 
1 
 
I have some problems in walking about 
2 
 
I am confined to bed 
3 
Self-care 
I have no problems with self-care 
1 
 
I have some problems washing or dressing myself 
2 
 
I am unable to wash or dress myself 
3 
Usual activities 
I have no problems with performing my usual 
activities 
1 
 
I have no problems with performing my usual 
activities 
2 
 
I am unable to perform my usual activities 
3 
Pain/discomfort 
I have no pain or discomfort 
1 
 
I have moderate pain or discomfort 
2 
 
I have extreme pain or discomfort 
3 
Anxiety/depression
I am not anxious or depressed 
1 
 
I am moderately anxious or depressed 
2 
 
I am extremely anxious or depressed 
3 


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APPENDIX E. CHO-KLAT SCORING ALGORITHM AND 
QUESTIONNAIRES 
 
1. Scoring 
The items presented in the CHO-KLAT questionnaire are worded in both positive and negative 
directions whereas the responses to the questions are consistently scored as 1=Never, 2=Rarely, 
3=Sometimes, 4=Often, and 5=Always.  Therefore, the negatively-worded questions need to be 
rescored as 5=Never, 4=Rarely, 3=Sometimes, 2=Often, and 1=Always so that a high score 
represent a high quality of life.  After the rescoring the unidirectional values can be added to 
yield a total score. 
Positively worded questions include numbers 1, 2, 7, 12 through 14, 19 through 22, 29, 30, and 
35.   
Negatively worded questions include numbers 3 through 6, 8 through 11, 15 through 18, 23 
through 28, and 31 through 34. 
Questions 23 through 35 include an additional response that indicates that the question is not 
applicable to the respondent.  A response indicating that the situation is not applicable to the 
subject for questions 23, 24, 26 through 29, and 34 should receive a score of 5.  A response 
indicating that the situation is not applicable to the subject for questions 22, 25, 30 through 33, 
and 35 should be scored as missing data as these situations have neither a positive nor negative 
impact on quality of life. 
 
2. Producing the raw total score 
The raw total score is produced by summing up all of items that were answered.  Its range lies 
between the number of items answered × 1 and the number of items answered × 5.  The highest 
possible score is 175.  Applying a minimum data rule of 75%, at least 27 questions must be 
answered in order to obtain a total score. 
 
3. Transferring the raw total score to a Transformed Score between 0 and 100  
Creating a transformed score makes it possible to express the score as a percentage between the 
lowest (0) and the highest (100) possible value.  To obtain the transformed score the following 
transformation rule has to be applied: 
Transformed score= 100 × ((raw score – minimal possible raw score) / possible range of raw 
scores) where: 
 minimal possible raw score = number of questions answered × 1 
 maximal possible raw score = number of questions answered × 5 
 possible range of raw scores = maximum possible raw score - minimal possible raw 
score 


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Example 1: A raw total score of 60 is to be transformed when 30 questions were answered: 
 minimal possible score=30 
 maximal possible score=150 
 range of scores=120 
 TSS=100× (60-30)/120 = 25.0 
Example 2: A raw total score of 110 is to be transformed when 28 questions were answered: 
 minimal possible score=28 
 maximal possible score=140 
 range of scores=112 
 TSS=100× (110-28)/112 = 73.2 
The total transformed score will be summarized. 
A copy of the questionnaire is provided below.  Items are highlighted when they require re-
coding as detailed in point 1 above. 
CHO-KLAT Child Self-report Questionnaire 
 
 


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CHO-KLAT Parent/Proxy 
Questionnaire
 


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APPENDIX F. HEMO-SAT SCORING ALGORITHM AND 
QUESTIONNAIRE 
The Hemo-Sat Patient Satisfaction scale is a 35-item questionnaire encompassing 6 subscales 
regarding the subject’s and parent/caregiver’s satisfaction with various aspects of the treatment 
and care the subject. 
1. Scoring 
The items presented in the Hemo-Sat questionnaire are worded in both positive and negative 
directions whereas the responses to the questions are consistently scored as 1=Totally agree, 
2=Somewhat agree, 3=Neither agree nor disagree, 4=Somewhat disagree, and 5=Totally 
disagree.  Therefore, the negatively-worded questions need to be rescored as 5=Totally agree, 
4=Somewhat agree, 3=Neither agree nor disagree, 2=Somewhat disagree, and 1=Totally disagree 
so that a high score represent a high satisfaction with the treatment.  After the rescoring the 
unidirectional values can be added to yield 6 subscores and a total score. 
Negatively worded questions include numbers 9 through 11.  The 32 remaining questions are all 
positively worded. 
2. Producing the raw total and subscale scores  
The raw total score is produced by summing up all of items that were answered across all 35 
questions.  Its range lies between the number of items answered × 1 and the number of items 
answered × 5.  The highest possible score is 175.  Applying a minimum data rule of 75%, at least 
27 questions must be answered in order to obtain a total score. 
Similarly, a raw subscale score is produced by summing up all items that were answered within a 
subscale.  The range of values lies between the number of items that were answered × 1 and the 
number of items that were answered × 5 in a given subscale.  The minimum number of questions 
answered for each subscale, applying a minimum data rule of 75%, is as follows: 
 
Hemo-Sat Subscale 
Number 
of 
questions 
Number of non-missing 
items required to 
calculate subscale 
 1. Ease and convenience 
11 
9 
 2. Efficacy 
6 
5 
 3. Burden 
4 
3 
 4. Specialist/Nurses 
7 
6 
 5. Center/Hospital 
5 
4 
 6. General satisfaction with the treatment 
2 
2 
 
 
 
Total score 
35 
27 
 
3. Transferring a raw score to a Standardized (average) score 
The Standardized score is the average of all items with a nonmissing score.  That is, missing 
items do not contribute to either the numerator or denominator.  This effectively imputes the 


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mean of all nonmissing items for the items that are missing, allowing for a comparison between 
subscales. 
4. Transferring a raw score to a Transformed Score between 0 and 100  
Creating a transformed score makes it possible to express the score as a percentage between the 
lowest (0) and the highest (100) possible value.  To obtain the transformed score the following 
transformation rule has to be applied: 
Transformed score= 100 × ((raw score – minimal possible raw score) / possible range of raw 
scores) where: 
 minimal possible raw score = number of questions answered × 1 
 maximal possible raw score = number of questions answered × 5 
 possible range of raw scores = maximum possible raw score - minimal possible raw 
score 
Example 1: A raw score of 17 on the “Center/Hospital” subscale is to be transformed when all 5 
of the questions were answered: 
 minimal possible score=5 
 maximal possible score=25 
 range of scores=20 
 TSS=100×(17-5)/20 = 60.0 
Example 2: A raw score of 20 on the “Specialist/Nurse” subscale is to be transformed when 6 of 
the 7 questions were answered: 
 minimal possible score=6 
 maximal possible score=30 
 range of scores=24 
 TSS=100×(20-6)/24 = 58.3 
The total and subscale transformed score will be summarized. 
A copy of the questionnaire is provided below.  Items are highlighted when they require re-
coding as detailed in point 1 above. 
 


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HEMO-SAT QUESTIONNAIRE 
 
 
 
 


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APPENDIX G. EQ-5D-Y QUESTIONNAIRE SCORE DEFINITIONS 
 
Domain 
Response 
Mobility 
I have no problems walking about 
 
I have some problems walking about 
 
I have a lot of problems walking about 
Looking after myself 
I have no problems washing or dressing myself 
 
I have some problems washing or dressing myself 
 
I have a lot of problems washing or dressing myself 
Doing usual activities 
I have no problems doing my usual activities 
 
I have some problems doing my usual activities 
 
I have a lot of problems doing my usual activities 
Having pain/discomfort 
I have no pain or discomfort 
 
I have some pain or discomfort 
 
I have a lot of pain or discomfort 
Feeling worried, sad or unhappy 
I am not worried, sad, or unhappy 
 
I am a bit worried, sad, or unhappy 
 
I am very worried, sad, or unhappy 
How good is your health today 
 
 
 


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APPENDIX H. HEMOPHILIA JOINT HEALTH SCORE (HJHS) 
Modified HJJS for adult subjects 
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 swellling 
0=no swelling or < 6 months 
1= >6 months 
Muscle atrophy 
0=none 
1=mild 
2=severe 
Crepitus on motion 
0=absent 
1=present 
Flexion loss (includes plantarflexion of ankles) 
0=none* 
1= mild* 
2= moderate* 
3= severe* 
Extension loss (includes dorsiflexion of ankles) 


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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) 
 
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) 


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HJHS for pediatric subjects 
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 20 according to the following criteria:  swelling, 
duration of swelling, muscle atrophy, crepitus of motion, flexion loss, extension loss, joint pain, 
and strength.  Gait will be scored on a scale from 0 to 4 based on the number of skills not within 
the normal limits.  The total score will be the sum of scores from all 6 joints plus the gait score 
(range from 0 to 124 with 0 being normal and 124 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 0-20 for each joint and 0-120 for all six 
joints): 
Swelling 
0 = no swelling 
1 = mild 
2 = moderate 
3 = severe 
Duration of swelling 
0 = no swelling or <6 months 
1 = ≥6 months 
Muscle atrophy 
0 = none 
1 = mild 
2 = severe 
Crepitus on motion 
0 = none 
1 = mild 
2 = severe 
Flexion loss  
0 = <5° 
1 = 5° - 10° 
2 = 11° - 20° 
3 = >20° 
Extension loss  


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0 = <5° 
1 = 5° - 10° 
2 = 11° - 20° 
3 = >20° 
Joint pain 
0 = no pain through active range of motion 
1 = no pain through active range; only pain on gentle overpressure or palpation 
2 = pain through active range 
Strength 
0 = holds test position against gravity with maximum resistance (gr. 5) 
1 = holds test position against gravity with moderate resistance (but breaks with maximal 
resistance (gr. 4) 
2 = holds test position with minimal resistance (gr. 3+), or holds test position against 
gravity (gr. 3) 
3 = able to partially complete ROM against gravity (gr. 3-/2+), or able to move through 
ROM gravity eliminated (gr. 2), or thorough partial ROM gravity eliminated (gr. 2-) 
4 = trace (gr. 1) or no muscle contraction (gr. 0) 
NE = non-evaluable 
2. Gait will be scored once (range is 0-4): 
0 = all skills are within normal limits 
1 = One skill is not within normal limits 
2 = Two skills are not within normal limits 
3 = Three skills are not within normal limits 
4 = No skills are within normal limits 
NE = non-evaluable 
 
Total score = sum of all joint scores plus the gait score (range is 0-124)