An Open-label Study To Evaluate Prophylaxis Treatment, And To Characterize The Efficacy, Safety, And Pharmacokinetics Of B-domain Deleted Recombinant Factor Viii Albumin Free (Moroctocog Alfa [Af-cc]) In Children With Hemophilia A
Phase: PHASE3
Conditions: Hemophilia A
Sponsor: Pfizer

Moroctocog alfa (AF-CC) 
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AN OPEN-LABEL STUDY TO EVALUATE PROPHYLAXIS TREATMENT, AND 
TO CHARACTERIZE THE EFFICACY, SAFETY, AND PHARMACOKINETICS 
OF B-DOMAIN DELETED RECOMBINANT FACTOR VIII ALBUMIN FREE 
(MOROCTOCOG ALFA [AF-CC]) IN CHILDREN WITH HEMOPHILIA A
Date of Original Protocol:
09 Mar 2007
Amendment 1:
12 Jun 2007
Amendment 2:
27 Aug 2007
Amendment 3:
22 Jan 2009
Amendment 4:
15 Sep 2009
Amendment 5:
20 Jul 2010
Amendment 6: 
10 Mar 2011
Amendment 7: 
31 Aug 2011
Amendment 8: 
19 Oct 2012
Amendment 9: 
29 Jan 2013
Amendment 10: 
02 Oct 2015
Sponsor:
Wyeth Pharmaceuticals Inc. acting through its division Wyeth Research, a 
Pfizer Company
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities, institutional review boards/ethics committees 
(IRBs/ECs), etc. 

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TABLE OF CONTENTS
1. DISCLOSURE STATEMENT..............................................................................................7
2. CONTACTS ..........................................................................................................................7
3. ABBREVIATIONS ...............................................................................................................7
4. DEFINITIONS.......................................................................................................................9
5. SYNOPSIS...........................................................................................................................16
6. STUDY OVERVIEW..........................................................................................................20
7. STUDY FLOWCHART 1: ROUTINE PROPHYLAXIS (RP) COHORT STUDY 
PROCEDURES...................................................................................................................21
8. STUDY FLOWCHART 2: PHARMACOKINETIC ASSESSMENT VISIT 2 
(DAY 1) ..............................................................................................................................23
9. BACKGROUND INFORMATION AND RATIONALE...................................................24
9.1. The History of ReFacto and Moroctocog alfa (AF-CC) .........................................24
9.2. Manufacturing Changes for Moroctocog alfa (AF-CC)..........................................24
9.3. Clinical Experience With Moroctocog alfa (AF-CC) .............................................25
9.4. Rationale for the Current Moroctocog alfa (AF-CC) Study 
(3082B2-313-WW)....................................................................................................26
10. OBJECTIVES....................................................................................................................28
10.1. Primary Objective .................................................................................................28
10.2. Secondary Objectives............................................................................................28
11. STUDY DESIGN...............................................................................................................28
11.1. Description ............................................................................................................28
11.2. Approximate Duration of Subject Participation....................................................29
11.3. Approximate Duration of Study............................................................................29
11.4. Approximate Number of Subjects.........................................................................30
12. SELECTION OF SUBJECTS............................................................................................30
12.1. Inclusion Criteria...................................................................................................30
12.2. Exclusion Criteria..................................................................................................32
12.3. Life Style Guidelines.............................................................................................33
12.4. Sponsor’s Qualified Medical Personnel................................................................33
13. PRIOR TREATMENT.......................................................................................................34
14. CONCOMITANT TREATMENT.....................................................................................34
14.1. Prohibited ..............................................................................................................34

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14.2. Permitted ...............................................................................................................34
15. PROCEDURES..................................................................................................................35
15.1. Study Procedures for RP Cohort ...........................................................................35
15.1.1. Consent/Assent .........................................................................................35
15.1.2. Payment of Subjects .................................................................................35
15.1.3. Study Visit 1 (Screening Visit) - RP Cohort ............................................36
15.1.4. Screening Period Activities and Randomization - RP Cohort..................37
15.1.5. Study Visit 2 (Day 1) - Segment 1 - RP Cohort .......................................38
15.1.5.1. Pharmacokinetic Assessment (if Applicable) - Segment 1 
- RP Subject Cohort...........................................................................38
15.1.5.2. Study Drug Dispensed - RP Cohort ........................................39
15.1.6. Subject Activities Between Successive Study Visits (Visit 2 
Through Visit 11), and Activities of Study Contacts 4, 6, 8, and 10 -
Segment 1 - RP Cohort ....................................................................................39
15.1.7. Study Visits 3, 5, 7, and 9 (Study Months 1, 3, 6, and 9) –
Segment 1 - RP Cohort ....................................................................................40
15.1.8. Study Visit 11 (Study Month 12) - RP Cohort .........................................41
15.1.8.1. Start of Segment 2 - RP Cohort...............................................42
15.1.8.2. Study Drug Dispensed – Segment 2 - RP Cohort ...................42
15.1.9. Subject Activities Between Successive Study Visits (Visit 11 
Through Visit 19), and Activities of Study Contacts 12, 14, 16, and 18 -
Segment 2 - RP Cohort ....................................................................................43
15.1.10. Study Visits 13, 15, and 17 (Months 15, 18, and 21) - Segment 2 -
RP Cohort.........................................................................................................43
15.1.11. Final Study Visit (Visit 19, Month 24) - Segment 2 – RP Cohort .........44
15.1.12. Final Study Contact (Visit 20) – RP Cohort...........................................45
15.2. Study Procedures for Pharmacokinetic Assessment .............................................45
15.3. Procedures Following Early Termination or Other Potential Events....................47
15.3.1. Early Termination.....................................................................................47
15.3.2. Factor VIII Inhibitor Development...........................................................47
15.3.3. Regimen Escalation ..................................................................................48
15.3.4. Unplanned, Required Surgery ..................................................................48
15.4. Total Volume of Blood Collected .........................................................................50
16. TEST ARTICLE AND ADMINISTRATION...................................................................50

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16.1. Moroctocog alfa (AF-CC) Administration for Pharmacokinetic Assessment ......50
16.2. Moroctocog alfa (AF-CC) Administration for Rechallenge .................................50
16.3. Moroctocog alfa (AF-CC) Administration for Hemophilia A Treatment.............50
16.3.1. Moroctocog alfa (AF-CC) Administration for On-Demand 
Treatment of Breakthrough Bleeds..................................................................51
16.3.2. Moroctocog alfa (AF-CC) Administration for Prophylaxis .....................51
16.4. Formulation, Packaging, and Labeling .................................................................52
16.5. Storage and Stability .............................................................................................52
16.6. Preparation ............................................................................................................52
16.7. Drug Accountability..............................................................................................52
16.8. Subject Compliance...............................................................................................53
17. SAFETY ............................................................................................................................53
17.1. Factor VIII Inhibitors ............................................................................................54
17.2. Antibodies to Moroctocog alfa (AF-CC) Components.........................................55
18. EFFICACY ........................................................................................................................55
18.1. Bleeding ................................................................................................................55
18.1.1. Types of Bleeding.....................................................................................55
18.1.2. Location of Bleeds....................................................................................56
18.1.3. Treatment of Bleeds..................................................................................56
18.2. Less Than Expected Therapeutic Effect................................................................57
19. PHARMACOKINETICS...................................................................................................59
19.1. Pharmacokinetic Analysis.....................................................................................59
19.2. Pharmacokinetic Methods.....................................................................................59
20. PHARMACODYNAMICS ...............................................................................................60
21. LABORATORY DETERMINATIONS............................................................................60
22. STATISTICS .....................................................................................................................60
22.1. Safety Variables ....................................................................................................61
22.2. Efficacy Variables.................................................................................................61
22.3. Pharmacokinetic Variables....................................................................................61
22.4. Subject Populations in the Analysis of Study Variables.......................................62
22.4.1. Safety Variables........................................................................................62
22.4.2. Efficacy Variables ....................................................................................62

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22.4.3. Pharmacokinetic Variables .......................................................................62
22.5. Analysis of Study Variables..................................................................................62
22.5.1. General......................................................................................................62
22.5.2. Safety Variables........................................................................................62
22.5.3. Efficacy Variables ....................................................................................63
22.5.4. Pharmacokinetic Variables .......................................................................64
22.6. Interim Analysis and Report .................................................................................64
22.7. Statistical Power and Sample Size Considerations ...............................................65
23. SUBJECT IDENTIFICATION..........................................................................................66
24. TEST ARTICLE ACCOUNTABILITY, RECONCILIATION, AND RETURN ............66
25. RANDOMIZATION..........................................................................................................66
26. ADVERSE EVENT REPORTING....................................................................................67
26.1. Adverse Events......................................................................................................67
26.2. Reporting Period ...................................................................................................67
26.3. Definition of an Adverse Event.............................................................................67
26.3.1. Hemophilia Events....................................................................................68
26.4. Abnormal Test Findings........................................................................................68
26.5. Serious Adverse Events.........................................................................................69
26.5.1. Protocol-Specified Serious Adverse Events.............................................70
26.5.2. Potential Cases of Drug-Induced Liver Injury (Potential Hy’s Law 
Cases)...............................................................................................................70
26.6. Hospitalization ......................................................................................................71
26.7. Severity Assessment..............................................................................................72
26.8. Causality Assessment............................................................................................72
26.9. Exposure During Pregnancy..................................................................................73
26.10. Occupational Exposure .......................................................................................74
26.11. Withdrawal Due to Adverse Events (See Also Section 27 - Subject 
Discontinuation or Withdrawal)................................................................................74
26.12. Eliciting Adverse Event Information ..................................................................74
26.13. Reporting Requirements......................................................................................75
26.13.1. Serious Adverse Event Reporting Requirements ...................................75
26.13.2. Non-Serious Adverse Event Reporting Requirements ...........................75
26.13.3. Sponsor’s Reporting Requirements to Regulatory Authorities ..............75

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26.14. Medication Errors................................................................................................75
27. SUBJECT DISCONTINUATION OR WITHDRAWAL.................................................76
27.1. Reporting of Safety Issue and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................76
28. STUDY SUSPENSION, TERMINATION, AND COMPLETION..................................77
29. ETHICS..............................................................................................................................77
29.1. Institutional Review Board/Ethics Committee......................................................77
29.2. Ethical Conduct of the Study ................................................................................77
29.3. Subject Information and Consent..........................................................................77
30. PROTOCOL AMENDMENTS .........................................................................................78
31. QUALITY CONTROL AND ASSURANCE ...................................................................79
32. DIRECT ACCESS, DATA HANDLING, AND RECORD-KEEPING ...........................79
32.1. Investigator............................................................................................................79
32.2. Sponsor..................................................................................................................79
33. SUBJECT INJURY ...........................................................................................................80
34. PRESTUDY DOCUMENTATION...................................................................................80
35. RECORDS RETENTION..................................................................................................81
36. SAMPLE RETENTION ....................................................................................................81
37. CLINICAL STUDY REPORT ..........................................................................................81
38. PUBLICATION OF STUDY RESULTS..........................................................................81
38.1. Communication of Results by Pfizer ....................................................................81
38.2. Publications by Investigators ................................................................................82
39. REFERENCES ..................................................................................................................83
40. APPENDICES ...................................................................................................................86
APPENDICES
Appendix 1. Guidelines for On-Demand Treatment With Moroctocog alfa (AF-CC)............86

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1. DISCLOSURE STATEMENT
Restricted Distribution of Documents
This document contains information that is confidential and proprietary to the Sponsor.  This 
information is being provided to you solely for the purpose of evaluating and/or conducting a 
clinical study for the Sponsor.  You may disclose the contents of this document only to study 
personnel under your supervision, institutional review boards (IRBs)/independent ethics 
committees (IECs), or duly authorized representatives of regulatory agencies for this purpose 
under the condition that they maintain confidentiality.  The contents of this document may 
not be used in any other clinical study, disclosed to any other person or entity, or published 
without the prior written permission of the Sponsor.  The foregoing shall not apply to 
disclosure required by any regulations; however, you will give prompt notice to the Sponsor 
of any such disclosure.  All other nonpublic information provided by the Sponsor, as well as 
any information that may be added to this document, also is confidential and proprietary to 
the Sponsor and must be kept in confidence in the same manner as the contents of this 
document.
2. CONTACTS
NOTE: Emergency Contact, Regional Contact and Global Study Team Contact information 
is located in the Study Reference Manual.
3. ABBREVIATIONS
Abbreviation
Term
ABR
Annualized bleed rate
AE
Adverse event
ALT
Alanine aminotransferase
ANOVA
Analysis of variance
AST
Aspartate aminotransferase 
AUC
Area under the curve to infinity
AUCt
Area under the curve to last measurable concentration
AUMC
Area under moment curve
BDDrFVIII
B-Domain deleted recombinant factor VIII, commercially 
available as ReFactoor as, the investigational drug 
moroctocog alfa (AF-CC), (marketed in certain regions of the 
world as Xyntha)
BU
Bethesda unit
CFR
Code of Federal Regulations
CHO
Chinese hamster ovary cells (host cell line for moroctocog alfa 
[AF-CC] production)
CL
Clearance
C0.5 hr
FVIII:C at 0.5 hours after the start of the study drug infusion
CRF
Case report form
CSA
Clinical study agreement
Ct
FVIII:C observed at a specified time (t)

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Abbreviation
Term
E-DMC
External-Data Monitoring Committee
eCRF
Electronic case report form
ED
Exposure day
EIU
Exposure in-utero
ELISA
Enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EDP
Exposure during pregnancy
FDA
United States Food and Drug Administration
FVIII
Factor VIII
FVIII:C
Factor VIII activity in plasma
GCP
Good clinical practice
HIV
Human immunodeficiency virus
HSA
Human serum albumin
IEC
Independent ethics committee
IND
Investigational new drug application
INR
International normalized ratio
IRB
Institutional review board
ITT
Intent to treat
IV
Intravenous
IVIG
Intravenous immunoglobulin
LETE
Less than expected therapeutic effect
LLN
Lower limit of normal
mITT
Modified intent to treat
moroctocog alfa 
(AF-CC)
B Domain Deleted Recombinant FVIII, Albumin Free
MRT
Mean residence time
NSAID
Nonsteroidal anti-inflammatory drug
OD
On-demand
OS
One-stage FVIII activity assay
pdFVIII
Plasma-derived FVIII
PK
Pharmacokinetics
PT
Prothrombin time
PTP
Previously treated patient
PUP
Previously untreated patient
rFVIII
Recombinant FVIII
RP
Routine prophylaxis
SAE
Serious adverse event
SD
Standard deviation
t½
Terminal phase half-life
ULN
Upper limit of normal
Vss
Steady state volume of distribution
WHO
World Health Organization

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4. DEFINITIONS
Term
Definition
Anti-CHO antibodies
Antibodies to proteins derived from the Chinese hamster ovary 
(CHO) host cell line used to produce moroctocog alfa (AF-CC).
Anti-FVIII antibodies
Neutralizing and nonneutralizing antibodies to FVIII.
Anti-TN8.2 
antibodies
Antibodies to the affinity ligand (TN8.2) used during the 
moroctocog alfa (AF-CC) purification process.
Bleeding episode
Hemorrhage (bleeding) caused by injury or occurring 
spontaneously at 1 or more anatomic sites. A bleeding episode is 
documented by a subject/caregiver’s report in the Subject Diary 
(or by the investigator in the subject’s source document). A 
subject/caregiver’s report does not need to be independently 
verified.
Bleeding
(breakthrough)
Bleeding occurring since last routine prophylactic dose of 
FVIII therapy. 
Bleeding 
(spontaneous)
Bleeding occurring in the absence of known injury or any 
antecedent cause.
Bleeding
(traumatic)
Bleeding occurring because of an injury or activity that would lead 
to a bleed in a hemophilic patient (for example, exercise).
Caregiver
For the purpose of this protocol, a person who provides for and/or 
oversees the general care of the subject.  The person may 
administer study drug to the subject for home use and performs 
many activities required by this protocol including, but not limited 
to, reporting of bleeds and study drug usage.  The person could be 
a parent, other family member, or legal acceptable representative. 
Case report form
A printed or electronic document designed to record all the 
protocol-required information to be reported to the Sponsor on 
each study subject.
Central laboratory
The reference laboratory designated by the Sponsor to analyze 
selected samples as described in this protocol. There may be 
multiple central laboratories.

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Term
Definition
Completed subject
Any subject who completes the study activities through the Final 
Study Contact and who is not withdrawn early.
Designee
A person with the appropriate qualifications to whom a task has 
been delegated without relinquishing responsibilities of the 
specified person/role. 
Exposure day (ED)
Any day during which the subject receives study drug. One (1), or 
more than 1, dose of study drug may be administered on a single 
ED.
FVIII inhibitor
(confirmed)
A neutralizing antibody to FVIII with a titer of ≥0.6 BU/mL in a 
sample assayed at the central laboratory using the Nijmegen assay.
FVIII inhibitor
(de novo)
Development of a confirmed FVIII inhibitor during the course of 
the study in a subject with no prior clinical history of FVIII 
inhibitor, or prior history of measurable inhibitor activity by 
Bethesda Inhibitor Assay or by any other method.
FVIII inhibitor
(history of)
A history of FVIII inhibitor (clinical or laboratory-based 
assessment).  For laboratory-based assessments, any measured 
Bethesda inhibitor titer of ≥0.6 BU/mL, regardless of the 
laboratory normal range, or any measured Bethesda inhibitor titer 
greater than the ULN for the laboratory performing the assay.
FVIII replacement 
product
A concentrated recombinant or plasma-derived formulation of the 
Factor VIII protein made for use in the treatment and prevention 
of bleeding in patients with hemophilia A (for the purposes of this 
protocol fresh frozen plasma, cryoprecipitate and blood are not 
considered FVIII replacement products).
Hematology panel
Measurement of the complete blood count, which includes 
hemoglobin, hematocrit, white blood cell count and differential, 
red blood cell and platelet count.
Incremental recovery
The IU/dL of FVIII:C increase per IU/kg of FVIII infusion.
Independent ethics 
committee (IEC)
Throughout this document, the term ethics committee refers to all 
appropriate and properly constituted committees or boards 
recognized to be the appropriate regulatory agencies for approving 
clinical studies. These include independent ethics committees and 
institutional review boards.

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Term
Definition
Intent-to-treat 
population
The intent-to-treat population consists of subjects who sign the 
consent/assent form.  (Screen failures are excluded).
Investigator
A person, with the appropriate qualifications, responsible for the 
conduct of the study at a study site. 
Lack of efficacy
Failure of expected pharmacologic action or therapeutic benefit.
Less than expected 
therapeutic effect, 
LETE (on-demand)
Less than Expected Therapeutic Effect (LETE) occurs in the 
on-demand setting if the subject/caregiver records 2 successive 
“No Response” ratings after 2 successive infusions of study drug, 
respectively. The infusions must have been administered within
24 hours of each other for treatment of the same bleeding event in 
the absence of confounding factors as described in this protocol. 
Less than expected 
therapeutic effect, 
LETE (prophylaxis)
Less than Expected Therapeutic Effect (LETE) occurs in the 
prophylaxis setting if there is a spontaneous bleed within 48 hours 
(≤48 hours) after a regularly scheduled prophylactic dose of study 
drug (which was not used to treat a bleed) in the absence of 
confounding factors as described in this protocol.
Less than expected 
therapeutic effect, 
LETE (low recovery)
Lower than expected recovery of FVIII in the opinion of the 
investigator following injection of study drug in the absence of 
confounding factors as described in this protocol. 
Medical records
Legal documentation (written or electronic) of a patient's medical 
history, current illness, diagnosis, treatments, and/or other medical 
data that is maintained by the investigator. For the purposes of 
this study, these can serve as source documents.
Modified 
intent-to-treat 
population 
The modified intent-to-treat population consists of subjects who 
receive at least 1 dose of study drug (moroctocog alfa [AF-CC]).
Monitor
A person, with the appropriate qualifications and assigned by the 
Sponsor, to oversee the progress of a study, and to ensure that it is
conducted, recorded, and reported in accordance with the protocol 
and other applicable requirements. 
On-demand (OD) 
Subject
A study subject that practices on-demand therapy with moroctocog 
alfa (AF-CC) for the first segment of the study, followed by 
routine prophylaxis for the second segment.

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Term
Definition
On-demand treatment
Treatment of hemorrhages, as needed, by administering an 
unscheduled bolus infusion of study drug to stop bleeding and 
control hemostasis.
Patient
For the purposes of this protocol, a person with hemophilia A. 
Previously treated 
patients (PTPs)
Patients who have received FVIII replacement therapy. For the 
purposes of this study, PTPs are those who have accrued 
20 exposure days to any FVIII replacement product.
Previously untreated 
patients (PUPs)
Patients who have not received any FVIII replacement therapy or 
any blood products.
Prophylaxis 
FVIII replacement therapy administered at a routine interval such 
as every other day, for a prolonged period of time, to prevent 
occurrence of spontaneous musculoskeletal bleeding episodes.
Regimen A
Study drug prophylaxis regimen of 45 5 IU/kg, administered 
twice per week.  The interval between prophylactic infusions 
should be 3 to 4 days, and should not exceed 4 days. 
Regimen B
Study drug prophylaxis regimen of 25 5 IU/kg, administered 
every other day.  The interval between prophylactic infusions 
should be approximately 48 hours (eg, an appropriate dosing 
schedule for Regimen B is as follows Monday, Wednesday, 
Friday, Sunday, Tuesday, Thursday, Saturday, Monday…etc). 
Regimen escalation
During prophylaxis, criteria for prophylaxis regimen escalation are 
the occurrence, over a 4-week period (and in the absence of a 
confirmed FVIII inhibitor), of (a) 2 or more spontaneous bleeds 
into a major joint and/or target joint, OR (b) 3 or more 
spontaneous bleeds (consisting of joint bleeds and/or significant
soft tissue/muscle or other site bleeds). If either criterion is met, 
the subject will be escalated to a more intense prophylaxis regimen 
of 45 ±5 IU/kg, administered every other day.  Subjects who meet 
dose escalation criteria while on this more intensive regimen may 
dose escalate to a higher intensity regimen designated by the 
investigator.  Significant spontaneous bleeds are defined as those 
that lead to a transient or persistent loss of function.

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Term
Definition
Regulation
The term regulation refers to all applicable regulations, laws, and 
guidelines.  The regulations may be international, national, or local 
and may include but are not limited to the Code of Federal 
Regulations; the European Clinical Trials Directive; the Good 
Clinical Practice: Consolidated Guideline (Canada); the 
International Conference on Harmonisation Guideline for Good 
Clinical Practice; the Pharmaceutical Affairs Law and Good 
Clinical Practice (Japan); the Therapeutic Goods Administration 
Annotated International Conference on Harmonisation Guidelines 
(Australia); the World Medical Association Declaration of 
Helsinki: Ethical Principles for Medical Research Involving 
Human Subjects; and other regulations if they apply.
Regulatory agency
The term regulatory agency refers to all health and regulatory 
agencies with oversight responsibility for the study.  These may be 
international, national, or local and may include but are not limited 
to the Australian Therapeutic Goods Administration (TGA); the 
Canadian Health Products and Food Branch (HPFB); the European 
Medicines Agency (EMA); the Japanese Ministry of Health, 
Labor, and Welfare (MHLW); the Japanese Pharmaceuticals and 
Medical Devices Agency (PMDA); the US Food and Drug 
Administration (FDA); and other regulatory agencies if they 
apply.
Routine Prophylaxis 
(RP) Subject
A study subject that practices routine prophylaxis therapy with 
moroctocog alfa (AF-CC) according to the randomly assigned 
regimens for the first and second segments of the study.
Screening period
Interval starting from the signing of the informed consent/assent 
(study visit 1) and extending up to study day 1 (study visit 2).  
There are up to approximately 35 screening days.
Serum chemistry
Measurement of sodium, potassium, chloride, CO2 (serum 
bicarbonate), ALT, AST, calcium, glucose, creatinine, blood urea 
nitrogen (BUN), (total) bilirubin, phosphorus, alkaline 
phosphatase, total protein, amylase, cholesterol and albumin.
Source 
documentation
Original documents, data, and/or records (eg, patient medical 
record, Subject Diary).
Sponsor
The term Sponsor refers but is not limited to the sponsors listed in 
the front of this document and any contract research organization 
that is being used for the study.

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Term
Definition
Study drug
Test article, moroctocog alfa (AF-CC) (marketed in certain regions 
of the world as Xyntha®), and the solutions and materials 
accompanying moroctocog alfa (AF-CC) preparations.
Study start date
Date that the first study subject provides informed consent/assent.
Study end date
Date of Final Study Contact for the last subject.
Study Reference 
Manual(s) 
A general term describing instructions and materials for 
completing study activities. Supplied to study sites by the Sponsor 
in addition to this protocol.
Study Site
The location(s) where study-related activities are actually 
conducted.
Subject
A participant in a clinical study.  A subject may be healthy or have 
a disease.  For obtaining informed consent, this term also includes 
a legally acceptable representative where applicable. 
Subject Diary
Collection of forms (or electronic data) filled out directly by the 
subject or caregiver while the subject is away from the study site. 
The forms will collect information on infusions, bleeding and 
bleeding response to study drug, adverse events and other required 
study information. The diary is turned in at each study visit and 
replaced with a new diary. For the purposes of this study, can 
serve as source documents.
Target joint
A major joint (eg, hip, elbow, shoulder, knee, ankle) into which 
repeated bleeding occurs (frequency of 3 or more bleeding 
episodes over 6 months), and/or clinical signs and/or symptoms of 
underlying target joint damage (synovitis, persistent swelling, 
effusion, limitation of range of motion, eg any objective limitation 
or joint held in flexion or “frozen”).
Test article
Any drug, comparator, placebo, nutritional product, dietary 
supplement, herbal product, vaccine, biologic product, or device 
used in the Sponsor’s studies.  For test article accountability, this 
term applies to such articles when they are required by the 
protocol and supplied (shipped) by the Sponsor (including diluents 
such as sterile water for injection). 
Time on study
Time from signing the informed consent/assent to last study 
contact reported for study participation.
TN8.2
The affinity ligand used during the moroctocog alfa (AF-CC) 
purification process.

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Term
Definition
Treatment phase of 
the study
Period of time during which subject receives study drug.  The 
period starts at study visit 2 (day 1) and ends at the Final Study 
Visit (visit 15, month 18 or visit 19, month 24, depending on the 
cohort into which the subject is enrolled).
Washout
The time between the last dose of FVIII replacement product or 
blood product (eg, fresh frozen plasma, cryoprecipitate, blood) and 
the collection of FVIII activity or other laboratory information. 
For this study, the minimal washout time is 72 hours. The intent 
of the washout is to allow complete clearance of previous FVIII 
replacement therapy from the blood.

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5. SYNOPSIS
Study Title: An Open-Label Study to Evaluate Prophylaxis Treatment, and to Characterize the Efficacy, 
Safety, and Pharmacokinetics of B-Domain Deleted Recombinant Factor VIII Albumin Free (moroctocog 
alfa [AF-CC]) in Children With Hemophilia A
Protocol 
Number
3082B2-313-WW – Amendment 10
Phase 
3
Type
Interventional
Condition/Disease: Hemophilia A
Approximate
Number of Subjects
80 Subjects
56 RP subjects 
24 OD subjects, OD 
Cohort Closed
Duration of Subject 
Participation
26 months (RP Subjects)
20 or 26 months (OD 
Subjects) Cohort Closed
Number of Study 
Centers
Approximately 40
globally
Duration of Study
8 years; includes 26 
months after last RP 
subject enrolled
Rationale: While prophylaxis therapy with factor VIII (FVIII) products has increasingly been prescribed 
worldwide, direct clinical information on optimal prophylaxis dosing strategies is limited.  Therefore, this 
study will directly evaluate the efficacy of moroctocog alfa (AF-CC), a recombinant FVIII product in 
clinical development, prophylaxis to reduce bleed rates relative to moroctocog alfa (AF-CC) on-demand 
therapy, and will compare the clinical outcomes of a high- versus low-frequency prophylaxis dosing regimen 
in a randomized crossover design.  In addition, younger hemophilia A patients may respond differently to 
FVIII therapy compared with older children and adults.  Thus, it is important to continue to characterize the 
pharmacokinetics (PK) of moroctocog alfa (AF-CC) in patients with hemophilia. In addition to the FVIII 
PK data following moroctocog alfa (AF-CC) administration already collected in this study from children 
younger than 6 years of age, additional opportunity for PK data collection is being provided.  Furthermore, 
the efficacy and safety of moroctocog alfa (AF-CC) during routine prophylaxis treatment will be described 
in these young patients.
Enrollment into the on-demand (OD) cohort has been closed.  To date, there are data indicating that 
prophylaxis therapy controls bleeding episodes better than on-demand therapy.  Because of availability of 
FVIII:C PK data following Xyntha administration in children with the Food and Drug Administration (FDA)
approval, enrollment into the PK assessment is optional. Given that prophylaxis has replaced OD therapy as 
the preferred standard of medical care, the study will continue enrollment into the routine prophylaxis (RP) 
cohort to assess the effect of a high (25 IU/kg every other day) versus low (45 IU/kg twice per 
week)-frequency dosing schedule on the efficacy of moroctocog alfa (AF-CC) prophylaxis for male subjects 
6 months to <16 years of age.
Primary Objective:
To demonstrate that moroctocog alfa (AF-CC) prophylaxis reduces annualized bleeding rates (ABRs) 
relative to on-demand therapy.  Enrollment into the on-demand (OD) cohort has been closed.
Secondary Objectives:
To assess the effect of a high (25 IU/kg every other day)- versus low (45 IU/kg twice per week)-frequency 
dosing schedule on the efficacy of moroctocog alfa (AF-CC) prophylaxis.
To continue to characterize the PK of FVIII after moroctocog alfa (AF-CC) administration in children 
6 months to <16 years of age.
To describe moroctocog alfa (AF-CC) efficacy and safety in children, including characterization of the 
incidence of “less than expected therapeutic effect”.
Design: This 2-segment study will be an open-label, multicenter trial.  There will have been two cohorts 
enrolled into the study; one in which the subject practices on-demand therapy for the first segment of the 
study, followed by routine prophylaxis for the second segment, and, another cohort in which the subject 
practices routine prophylaxis for both segments.  Study subjects will be hereafter referred to by their 

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segment 1 treatment modality: on-demand (OD) subjects and routine prophylaxis (RP) subjects.  Enrollment 
for the OD cohort has been closed.  Enrollment for the RP cohort is ongoing.
All RP subjects will practice prophylaxis with moroctocog alfa (AF-CC) study drug according to one of two
randomly assigned moroctocog alfa (AF-CC) regimens, each delivering approximately 90 IU/kg/week, but 
differing in dosing schedule.  Randomization will be stratified by hemophilia A severity: FVIII activity 
<1% or 1-2% (central laboratory screening result).  Each segment will be 12 months in duration. In the first 
segment, subjects will be randomly assigned to Regimen A: 45 5 IU/kg, administered twice per week or 
Regimen B: 25 5 IU/kg, administered every other day.
After completion of the first segment, all subjects will cross over to the second prophylactic regimen for 
segment 2.  Subjects who received Regimen A in segment 1 will follow Regimen B in segment 2.  
Conversely those subjects who received Regimen B in segment 1 will follow Regimen A in segment 2.
During prophylaxis, a subject’s treatment will be escalated to a higher intensity prophylaxis regimen 
comprised of the most intensive components of both regimens A and B (45 5 IU/kg, administered every 
other day) if criteria justifying regimen escalation are met: over a 4-week period, the occurrence of 2 or 
more spontaneous joint bleeds or the occurrence of 3 or more spontaneous bleeds (consisting of joint bleeds, 
and/or significant soft tissue/muscle or other site bleeds).  Subjects who meet dose escalation criteria while 
on this more intensive regimen may dose escalate to a higher intensity regimen designated by the 
investigator.  During prophylaxis, subjects will also use moroctocog alfa (AF-CC), as needed, for the 
treatment of bleeds (ie, on-demand), should they occur.
Clinical and laboratory examinations, including assessments for FVIII inhibitor development, will be 
conducted during the course of the study.
Moroctocog alfa (AF-CC) efficacy and safety will be assessed over the entire treatment period.
A subset of subjects may participate in assessments for FVIII PK characterization after administration of 
moroctocog alfa (AF-CC).  This subset of subjects will undergo a baseline PK assessment, receiving a single 
open-label dose of moroctocog alfa (AF-CC) (50 5 IU/kg, rounded to the closest complete vial) with blood 
sampled for FVIII activity measurements before and at 0.5, 8, 24, 28 (optional), and 32 hours after the start 
of infusion. 
Main Inclusion Criteria: Males 6 months to <16 years of age at the time of screening visit with 
moderately severe to severe hemophilia A (FVIII activity 2%), with previous FVIII replacement therapy 
experience (20 exposure days).
Main Exclusion Criteria: Current or history of FVIII inhibitor.
Concomitant Treatment: Regular medication, other than FVIII concentrates, may continue unchanged.
Test Articles(s) and Administration: Moroctocog alfa (AF-CC) study drug; single 50 5 IU/kg (rounded to 
closest complete vial) intravenous infusions administered for PK assessment;either 45 IU/kg twice per week 
or 25 IU/kg every other day for prophylaxis treatment (or according to investigator prescription in the event 
that escalation criteria are met while the subject is practicing the initial protocol-defined escalated regimen).
Safety Evaluation: Safety variables will be as follows: the incidence of adverse events (by severity and by 
relationship to moroctocog alfa (AF-CC)); the incidence of FVIII inhibitor development, development of 
antibodies to moroctocog alfa (AF-CC), CHO cell proteins, and TN8.2.  Laboratory-based assessments for 
FVIII inhibitor will be conducted at intervals of approximately every 3 months.
Efficacy Evaluation: Efficacy variables will include ABR, number of moroctocog alfa (AF-CC) infusions 
per bleed, response of bleed to moroctocog alfa (AF-CC) treatment (4-point scale of assessment), time 

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interval between bleed onset and prior moroctocog alfa (AF-CC) routine prophylaxis dose, incidence of 
prophylaxis regimen escalation, incidence of less than expected therapeutic effect (LETE), consumption of 
moroctocog alfa (AF-CC), and compliance with assigned prophylaxis regimen.  All subjective assessments 
will be provided by the caregiver or investigator.
Pharmacokinetics: FVIII activity in plasma (FVIII:C) will be analyzed using noncompartmental methods 
and the following PK parameters calculated for each subject: FVIII:C 0.5 hours after the beginning of the 
infusion (C0.5hr), incremental recovery, area-under-the FVIII:C-time curve to the last measureable FVIII:C 
(AUCt) and AUC extrapolated to infinity (AUC∞), terminal phase half-life (t½), clearance (CL), steady-state 
volume of distribution (Vss), and mean residence time (MRT). Summary statistics of each parameter will be 
reported.
Statistical Considerations, General: This study will provide descriptive safety, efficacy and PK data of 
moroctocog alfa (AF-CC) treatment in previously treated pediatric patients at least 6 months to <16 years of 
age. The sample size of each cohort of the study was based on the statistical comparison of ABR between 
the first and second segments.  Additional information regarding sample size estimates is provided below.
Statistical Considerations, Primary Objective: The primary objective of this study is to demonstrate a 
mean change in ABR during a period of protocol-defined moroctocog alfa (AF-CC) prophylaxis 
(~25 5 IU/kg, administered every other day) compared to a period of on-demand therapy with moroctocog 
alfa (AF-CC).  Only subjects who practice on-demand therapy with moroctocog alfa (AF-CC) during 
segment 1, before starting protocol-defined moroctocog alfa (AF-CC) prophylaxis in segment 2, will be 
included in this analysis.  For these subjects, an analysis of variance (ANOVA) will be conducted to 
compare the mean ABR during their on-demand and prophylaxis treatment periods.  In a completed ReFacto 
Previously Untreated Patients (PUP) study (3082A1-301-WW), a reduction in the ABR was observed for 
subjects during their periods of prophylaxis (2 infusions per week) compared to their periods of on-demand 
therapy (reduction of 5.7 6.9 bleeds per year [11.85 to 6.15 bleeds per year], ABR decrease of 48%, N=39).  
Based upon this experience, a more conservative decrease in ABR of 40% (corresponding to a mean change 
of 4.75 bleeds per year) and a standard deviation of 7 were selected for use in sample size calculations.  A 
sample size of 18 OD subjects who practice on-demand therapy in segment 1, followed by prophylaxis in 
segment 2, provides 80% power to detect such a difference using a 2-sided alpha level of 0.05.  Due to an 
expected attrition rate of up to 25%, approximately 24 OD subjects, who practice on-demand therapy during 
segment 1, were planned to be enrolled to ensure that 18 are evaluable for the comparison of ABRs in the 
on-demand versus the prophylaxis setting.  Because enrollment into the OD cohort has been closed, all 
available data will be analyzed.
Statistical Considerations, Secondary Objectives: A secondary objective is to evaluate the effect of 
dosing schedule on prophylactic efficacy. For the comparison of high-versus low-frequency prophylaxis 
dosing schedule, a subset analysis of data from the completed ReFacto PUP study (Wyeth protocol 
3082A1-301-WW) revealed an ABR of 5.7 5.2 (N=26) in patients receiving a high-frequency prophylaxis 
regimen (3 infusions per week) compared to an ABR of 7.1 4.1 (N=13) in patients receiving a 
lower-frequency prophylaxis regimen (2 infusions per week).  However, the treatment assignment was not 
randomized and prophylaxis regimens were not controlled in that study.  To avoid selection bias and 
inter-patient variability affecting outcome, two protocol-defined prophylaxis regimens (a high- and a 
low-frequency dosing regimen) will be assessed in a crossover design. Assuming an intra-class correlation 
of 30% and a standard deviation of 6 bleeds per year based on this previous ReFacto PUP study, a 
within-subject standard deviation of 5 bleeds per year was used for sample size calculations for the 
comparison between the 2 protocol-defined prophylaxis regimens (A and B).  Given this, 36 RP cohort 
subjects are needed to provide 80% power to demonstrate equivalence of the two regimens.  Allowing for an 
attrition rate of 25%, approximately 48 RP subjects need to be enrolled to support this objective.
Based on a sample size re-estimation using data from the ongoing study, a difference of means of 1.3 bleeds 
per year between the two protocol-defined prophylaxis regimens with a corresponding standard deviation of 
the difference of 6.5 was obtained requiring 38 subjects to provide 80% power to demonstrate equivalence 

Moroctocog alfa (AF-CC) 
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Final Amendment 10, 02 October 2015
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of the two regimens (A and B).  Allowing for an attrition rate of 30%, approximately 56 RP subjects would 
need to be enrolled. The two prophylaxis regimens will be considered equivalent if the limits of the 2-sided 
90% confidence interval for the difference in observed mean ABRs fall wholly within the interval defined by 
fewer than 4 bleeds per year.
FVIII:C pharmacokinetics after administration of moroctocog alfa and moroctocog alfa (AF-CC) have been 
well described in a wide range of ages.  Younger patients (median age 10 8.3 months, N=59) had lower 
recoveries than older patients (median age 26 12 years, N=101), with mean values of 1.5 0.6 and 
2.4 0.4 IU/dL per IU/kg, respectively.  Younger children have also been observed to have higher clearance 
of FVIII:C when adjusted by weight and shorter half-lives.  A secondary objective of this study allows for 
continued characterization of the FVIII:C PK after administration of moroctocog alfa (AF-CC) in children 
younger than 16 years of age, thus improving our understanding the FVIII:C pharmacokinetics in children.  
Descriptive statistics of single-dose PK parameters will define this characterization.  Subjects opting to 
participate are required to be 6 months to <16 years of age at the time of the baseline PK assessment.
Interim Report and Analysis: An independent data monitoring committee will provide guidance during the 
course of the study, with review intervals of approximately every 6 months.  Prior to study completion, 
selected (safety, efficacy and/or PK) data from this study may be summarized and reported to regulatory 
authorities to support regulatory submissions or requests. The analyses for these summaries would be based 
on descriptive statistics.
Per discussions with the FDA, a final report for the OD cohort will be submitted comparing prophylaxis 
efficacy and safety versus on-demand therapy according to Section 3.3 of the statistical analysis plan.
Additionally, after approximately 38 evaluable RP subjects, who practiced prophylaxis for both segment 1
and segment 2, complete the study, a final report for the RP cohort will be submitted.
Ethical Considerations: This study will be conducted in accordance with applicable laws and regulations 
including, but not limited to, the International Conference on Harmonisation Guideline for Good Clinical 
Practice (GCP) and the ethical principles that have their origins in the Declaration of Helsinki.  The 
institutional review board (IRB)/independent ethics committee (IEC) must review and approve the protocol 
and informed consent form (ICF) before any subjects are enrolled.  Before any procedures specified in the 
protocol are performed, the subject’s legally authorized representative must sign and date the 
IRB/IEC-approved informed consent form.

Moroctocog alfa (AF-CC) 
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Final Amendment 10, 02 October 2015
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6. STUDY OVERVIEW
CC
These 56 subjects will crossover to the other moroctocog alfa 
(AF-CC) prophylaxis regimen
     these 28 subjects switch to regimen B 
    these 28 subjects switch to regimen A
A 2-Segment, Open-Label Study (N = 80 Subjects)
Cohort Used 
for 
Comparison 
of 2 
Prophylaxis 
Regimens
Regimen A: 45 IU/kg, twice per week;
Regimen B: 25 IU/kg, every other day
Segment 1
(12 months)
Segment 2
(12 months)
Cohort Used for 
Comparison of 
On-Demand to 
Prophylaxis
Cohort closed 
These 24 subjects will switch to protocol-defined 
moroctocog alfa (AF-CC) prophylaxis (24 subjects switch to 
regimen B)
Segment 1
(6 months)
Pharmacokinetic
Characterization
Optional
Subjects from either of the 
subject populations (cohorts) 
defined above and below 
participate in a baseline PK 
assessment
(visit 2)
24 subjects who report on-demand therapy 
as current treatment at time of screening
will continue on-demand therapy with 
moroctocog alfa (AF-CC) according to 
investigator prescription
56 subjects will practice 1 of 2 protocol-defined moroctocog alfa 
(AF-CC) prophylaxis regimens
28 subjects randomized to regimen A 
28 subjects randomized to regimen B
CROSSOVER
Segment 2
(12 months)

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7. STUDY FLOWCHART 1: ROUTINE PROPHYLAXIS (RP) COHORT STUDY PROCEDURES
Study Proceduresa
Screeningb
SEGMENT 1 (Routine Prophylaxis Treatment Phase)
Study Visit/Contact ID
1
2
3
4
5
6
7
8
9
10
Study Intervalc
(Day –35
to –1)
Day1
Mo.1
(1wk)
Mo.2
(1wk)
Mo.3
(1wk)
Mo.4.5
(1wk)
Mo.6
(1wk)
Mo.7.5
(1wk)
Mo.9
(1wk)
Mo.10.5
(1wk)
Informed consent/assent
X
Demographics, medical 
history, 
hemophilia A information
X
Physical examinationd
X
72-hour FVIII washout
X
72-hour FVIII washout
X
72-hour FVIII washout
X
72-hour FVIII washout
X
72-hour FVIII washout
X
CD4 cell count (HIV 
subjects only)
X
PT or INR 
X
Hematology panele
X
Xe
Serum chemistrye
X
FVIII activity (FVIII:C)f
Xa,f
X
X
X
X
X
FVIII inhibitorf
Xa,f
X
X
X
X
X
Anti-FVIII antibodyf
Xf
X
X
X
X
X
Anti-CHO antibodyf
Xf
X
Anti-TN8.2 antibodyf
Xf
X
Subject diaryg
X
X
X
X
X
X
PK assessmenth (optional)
Xh
Randomization to regimeni
Xi
Study drug dispensed
X
X
X
X
X
Study drug accountability
X
X
X
X
Telephone contactj
X
X
X
X
Concomitant medicationsk
COLLECTED at EACH VISIT/CONTACT
Adverse eventsk
COLLECTED at EACH VISIT/CONTACT

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Page 22
STUDY FLOWCHART 1: Routine Prophylaxis (RP) COHORT study procedures (Continued)
Study Proceduresa
SEGMENT 2 (Routine Prophylaxis Treatment Phase)
Final 
Contact
Study Visit/Contact ID
11
12
13
14
15
16
17
18
19
20
Study Intervalc
Mo.12
(1wk)
Mo.13.5
(1wk)
Mo.15
(1wk)
Mo.16.5
(1wk)
Mo.18
(1wk)
Mo.19.5
(1wk)
Mo.21
(1wk)
Mo.22.5
(1wk)
Mo.24
(1wk)
Mo.25
(+10 
days)
Informed consent/assent
Demographics, medical 
history, 
hemophilia A information
Physical examinationd
72-hour FVIII washout
X
72-hour FVIII washout
X
72-hour FVIII washout
X
72-hour FVIII washout
X
72-hour FVIII washout
X
CD4 cell count
X
PT or INR 
Hematology panele
X
X
Serum chemistrye
X
X
FVIII activity (FVIII:C)f
X
X
X
X
X
FVIII inhibitorf
X
X
X
X
X
Anti-FVIII antibodyf
X
X
X
X
X
Anti-CHO antibodyf
X
X
Anti-TN8.2 antibodyf
X
X
Subject diaryg
X
X
X
X
X
PK assessmenth (optional)
Randomization to regimeni
Study drug dispensed
X
X
X
X
Study drug accountability
X
X
X
X
X
Telephone contactj
X
X
X
X
X
Concomitant medicationsk
COLLECTED at EACH VISIT/CONTACT
Adverse eventsk
COLLECTED at EACH VISIT/CONTACT
Abbreviations: Mo = month; wk = week; PT = prothrombin time; INR = international normalized ratio for prothrombin time; FVIII = factor VIII;
CHO = Chinese hamster ovary; TN8.2 = affinity ligand used in study drug purification process; PK = pharmacokinetic.
a.
All testing will be performed by the central laboratory.  The local laboratory will also perform FVIII activity and FVIII inhibitor testing to confirm eligibility.
b.
Screening period.  Interval starting from the signing of the informed consent/assent and extending up to visit 2 (day 1).  There are up to approximately 35 days in this 
interval (day -35 to day -1).
c.
Study day or month.  Visits/contacts 3 (month 1) through 19 (month 24) to be conducted within ± 1 week of indicated study month.  Final Study Contact (Visit 20, month 
25) to be conducted at least 28 days (+10 days) from Final Study Visit (Visit 19, month 24).
d.
Includes collection of vital signs and weight.  Also includes collection of height at visits 1 (Screening) and 11 (month 12).
e.
See Protocol Definitions.  For visit 2 (day 1), hematology panel is only collected for subjects participating in the optional PK assessment.
f.
Subjects will observe a minimum 72-hour FVIII washout before sample collection.  For screening purposes, subjects will be instructed to return to the clinic following a 

Moroctocog alfa (AF-CC) 
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Page 23
72-hour FVIII washout for this sample collection if the washout was not observed before the initial screening visit.
g.
Subject diary dispensed and/or collected.  Subject diary is reviewed at each visit (information about adverse events, concomitant medications, study compliance, study drug 
infusions and assessments, less than expected therapeutic effect, and dose escalation and/or changes, if applicable, is reviewed).
h.
See Study Flowchart 2 for activities related to this assessment.
i.
Randomization will occur only after study eligibility criteria have been confirmed and documented.  Only those subjects who will practice prophylaxis during both study 
segments will be randomized to 1 of the 2 protocol-defined prophylaxis regimens to be followed for 12 months during segment 1; these subjects will then crossover to the 
other protocol-defined prophylaxis regimen for 12 months during segment 2.
j.
Information about adverse events, concomitant medications, dose escalation and/or changes, if applicable, and study compliance will be collected during these contacts.  
Can be conducted at appropriately scheduled clinic visits if preferred.
k.
Collected at each visit/contact from the time the consent/assent form is signed to the final study contact.
8. STUDY FLOWCHART 2: PHARMACOKINETIC ASSESSMENT VISIT 2 (DAY 1)
Study Proceduresa
Predose: -2-0 hr
Dose: 0 hr
0.5 hr (± 3 min)
8 hr (± 48 min)
24 hr (± 1 hr)
28 hrb (± 1 hr)
32 hr (± 1 hr)
Physical exam and Weight
X
Vital signs
X
X
Blood sample collections for:
FVIII activity
72-hour FVIII washout
X
X
X
X
X
X
FVIII inhibitor
X
Anti-FVIII antibody
X
Anti-CHO antibody
X
Anti-TN8.2 antibody
X
Hematology panelc
X
Study drug administration
(50 5 IU/kg, rounded to nearest 
complete vial)
X
Concomitant medications
COLLECTED for the COURSE of the ASSESSMENT
Adverse events
COLLECTED for the COURSE of the ASSESSMENT
Abbreviations: FVIII=factor VIII; hr=hour; min=minute; CHO=Chinese hamster ovary; TN8.2=affinity ligand used in study drug purification process.
a.
Optional pharmacokinetic assessment is conducted at visit 2 (day 1).  Subjects must be in a nonbleeding state for this assessment.  All testing will be 
performed by the central laboratory.
b.
The 28-hour sample collection is optional.
c.
See Protocol Definitions.

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9. BACKGROUND INFORMATION AND RATIONALE
9.1. The History of ReFacto and Moroctocog alfa (AF-CC)
Hemophilia A is an X-linked recessive disease in which clotting factor VIII (FVIII) is 
deficient or inactive.  Patients with a low level of FVIII have an increased tendency to bleed.  
When the levels of FVIII are very low (≤2% of normal), spontaneous bleeding episodes may 
occur.  Infusing patients with a concentrated formulation of the missing FVIII protein can 
control the bleeding.  Until the late 1980s, such concentrates were produced exclusively from 
human (or porcine) plasma.  However, a combination of the risk of transmission of viral 
diseases, especially the human immunodeficiency virus (HIV), and rapidly evolving 
recombinant technology drove the development of recombinant DNA-derived coagulation 
products.  Recombinant DNA technology also provides the potential to produce virtually 
unlimited quantities of virally safe products.
The first recombinant FVIII products (rFVIII) were referred to as “full-length” in that they 
were derived from plasmid DNA expression constructs containing the entire coding sequence 
of the FVIII protein.  Later, it was observed that removal of the central B domain of FVIII 
increased the manufacturing yield without compromising the biological activity of the 
molecule.1,2  To enhance the production of rFVIII, a B-domain deleted (BDD) rFVIII was 
developed.  This culminated in the licensure of ReFacto®.  The active substance of ReFacto 
is a recombinant B-domain deleted, murine monoclonal-antibody purified, solvent-detergent 
treated, and albumin-free formulated FVIII, (BDDrFVIII).  The amino acid sequence is 
comparable to the 90 + 80 kDa form of FVIII and posttranslational modifications are similar 
to those of the plasma-derived molecule.3, 4  ReFacto has functional characteristics 
comparable to those of endogenous Factor VIII.3, 4, 5
9.2. Manufacturing Changes for Moroctocog alfa (AF-CC)
ReFacto was manufactured using 2 raw materials that carry with them a minor but finite risk 
of introducing viral contaminants into the process stream.  Human serum albumin (HSA) was 
used in the cell culture medium, and the purification process used a murine monoclonal 
antibody that was manufactured by a process employing bovine and human-derived 
components.  To address these potential risks, Wyeth developed an alternative manufacturing 
process for ReFacto which included (1) the use of a reformulated, HSA-free cell culture 
medium for growth and production, (2) the use of a chemically synthesized polypeptide 
affinity ligand (TN8.2) in a column chromatography purification step in lieu of the murine 
monoclonal-antibody purification step, and (3) the addition of a virus-retaining membrane to 
the final manufacturing steps.  These manufacturing changes expanded upon the 
comprehensive multifaceted viral safety program already in place for ReFacto.6, 7  This 
improved process eliminates the use of all human or animal-derived proteins at any stage of 
the manufacturing process, and the new product has been designated moroctocog alfa 
(AF-CC).

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Final Amendment 10, 02 October 2015
Page 25
Later, additional changes were also incorporated into the manufacturing process for 
moroctocog alfa (AF-CC), coincident with a manufacturing site transfer, to allow use of the 
common one-stage (OS) assay for monitoring moroctocog alfa (AF-CC) replacement 
therapy.
The BDDrFVIII DNA construct and the final formulation are identical for ReFacto and 
moroctocog alfa (AF-CC).  Biochemical characterizations indicate that the active substance, 
BDDrFVIII, produced by both manufacturing processes (ReFacto and moroctocog alfa 
[AF-CC]) is comparable with respect to structure and function.
ReFacto/moroctocog alfa (AF-CC) has been licensed for use since 1999 in the European 
Union (EU) and since 2000 in the United States (US).  In the EU moroctocog alfa (AF-CC) is 
marketed under the trade name ReFacto AF.  In the US, moroctocog alfa (AF-CC) is 
distributed under the trade name Xyntha.  Globally, as of August 2014, moroctocog alfa 
(AF-CC) was approved in 48 countries and marketed in 19 countries.8
9.3. Clinical Experience With Moroctocog alfa (AF-CC)
Extensive clinical trial experience had already been compiled for moroctocog alfa (AF-CC) 
before the last manufacturing changes (ie, before the modifications facilitating use of the OS 
assay and the change of manufacturing site): a pharmacokinetic crossover study showed 
bioequivalence to ReFacto (study 3082B1-305-GL); and 2 open-label, single-arm studies 
were initiated to assess safety and efficacy in previously treated patients (PTPs) at least 
6 years of age (studies 3082B1-306-GL [study 306] and 3082B1-307-GL [study 307]).  
Results from study 306 showed moroctocog alfa (AF-CC) to be safe and efficacious for 
hemophilia A treatment in 110 PTPs (median moroctocog alfa (AF-CC) exposure days [EDs] 
= 58), and study 307 demonstrated the long-term safety of moroctocog alfa (AF-CC) in 98 of 
these PTPs who elected to participate in this extension study after completing study 
306 (median moroctocog alfa [AF-CC] EDs = 169 over median duration of 521 days).
The safety and efficacy of moroctocog alfa (AF-CC) manufactured with the most recent 
manufacturing changes (ie, modifications allowing use of the OS assay and new 
manufacturing site), has been evaluated in 2 clinical trials in PTPs at least 12 years of age, 
completed study 3082B2-310-WW (study 310) and completed study 3082B2-311-WW 
(study 311).
Study 310 was an open-label safety and efficacy evaluation of moroctocog alfa (AF-CC) for 
the control and prevention of bleeding in PTPs with severe or moderately severe hemophilia 
A during moroctocog alfa (AF-CC) prophylaxis treatment.  In this open-label study, patients 
used moroctocog alfa (AF-CC) according to an assigned routine prophylaxis regimen, 
accruing a minimum of 50 EDs over a 6-month period.  The 310 study also included a 
comparative pharmacokinetic evaluation.  While prior pharmacokinetic studies have 
demonstrated the bioequivalence of ReFacto and the full-length plasma-derived FVIII 
(pdFVIII) using the chromogenic substrate assay,9 a double-blind, crossover evaluation in the 
310 study used the OS assay to demonstrate the bioequivalence of moroctocog alfa (AF-CC) 
and a full-length recombinant FVIII product (Advate®).

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Study 311 was also an open-label study with the primary efficacy objective of characterizing 
the ability of moroctocog alfa (AF-CC) to support patients during and after surgery.  The 
safety and efficacy of moroctocog alfa (AF-CC) was assessed in patients with severe or 
moderately severe hemophilia A undergoing major elective surgery.  Factor VIII infusions 
were administered as bolus injections or as a continuous infusion, over a period of at least 
6 days following the surgical procedure.
Collectively, results from studies 310 and 311 support the use of moroctocog alfa (AF-CC) 
for the control and prevention of bleeding episodes, and for surgical prophylaxis in PTPs 
with hemophilia A.
9.4. Rationale for the Current Moroctocog alfa (AF-CC) Study (3082B2-313-WW)
While studies 310 and 311 are designed to evaluate the safety and efficacy of moroctocog 
alfa (AF-CC) in PTPs who are 12 years of age or older, the current study will provide these 
data for moroctocog alfa (AF-CC) treatment in pediatric PTPs who are younger than 6 years 
of age.  Because early treatment may be necessary in patients with the more severe forms of 
hemophilia A, it is important to demonstrate product safety and efficacy in the youngest 
patients.
Prophylaxis therapy (ie, the regularly scheduled administration of a factor replacement 
product for the prevention of bleeding) is widely advocated as the optimal treatment modality 
for patients affected with the more severe forms of hemophilia A.  Several studies have 
concluded that it is preferable to on-demand therapy, as prophylaxis affords lower bleeding 
rates, better retention of joint integrity, and quality of life improvements (eg, fewer
hospitalizations and greater academic achievement).10, 11, 12, 13, 14  In view of the established 
benefits of prophylaxis in pediatric patients with hemophilia, the National Hemophilia 
Foundation (NHF),15 the World Federation of Hemophilia (WFH),16 and the World Health 
Organization (WHO) now endorse prophylaxis.  Despite the increasing collection of data 
favoring prophylaxis over on-demand therapy, more specific questions still exist.  For 
example, direct clinical information on optimal prophylaxis dosing strategies is limited.  
Recently, the Cochrane collaboration recommended conducting additional prospective, 
randomized controlled trials to determine optimal prophylactic regimens and to assess the 
effectiveness of clotting factors.17  Although many of the favorable outcomes associated with 
prophylaxis are best achieved when the therapy is initiated at an early age, perceived dosing 
frequency requirements are often a major obstacle for its practice in pediatric populations.  
Thus, corollary data, establishing associations between dosing frequency and effective 
prophylaxis, would be especially meaningful for younger patients. 
To achieve its objectives, this study evaluates moroctocog alfa (AF-CC) in the context of two
settings.  A cohort of subjects was enrolled who practiced on-demand therapy for a 6-month 
period during segment 1, then switched to prophylaxis with moroctocog alfa (AF-CC) for a 
12-month period in segment 2, practicing a protocol-defined regimen (25 5 IU/kg, 
administered every other day). This regimen has been well characterized and has 
demonstrated efficacy relative to on-demand therapy, although in a different patient 
population.12  A second cohort, comprising all other subjects, will practice a single 
moroctocog alfa (AF-CC) treatment modality, prophylaxis, during this study, but treatment 

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will include practice of each of the two protocol-defined regimens; these subjects will follow 
one of the two randomly assigned protocol-defined regimens for a 12-month period
(segment 1), and then will crossover to the other regimen for a second 12-month treatment 
period (segment 2).  Study subjects will be hereafter referred to by their segment 1 treatment 
modality: on-demand (OD) subjects and routine prophylaxis (RP) subjects.  This study 
design allows direct evaluation of moroctocog alfa (AF-CC) in the prophylaxis and 
on-demand settings, as well as a direct comparison between 2 different moroctocog alfa 
(AF-CC) prophylaxis-dosing schedules.  The duration of moroctocog alfa (AF-CC) treatment 
in this study (18 - 24 months depending on the cohort) ensures that sufficient experience with 
moroctocog alfa (AF-CC) is obtained.
Pharmacokinetic assessment of FVIII:C after FVIII therapy has shown lower FVIII:C
recovery, in young children. For moroctocog alfa, this has also been observed: a mean
incremental recovery of 1.5 0.6 IU/dL per IU/kg, in 59 children with median age 10 8.3 
months was reported compared with mean incremental recovery of 2.4 0.4 IU/dL per IU/kg
in 101 patients with a median age of 26 12 years.18  Younger patients also have higher 
clearance, when adjusted for body size and shorter half-lives compared with older children 
and adults.  A secondary objective of this study is to continue to characterize the 
pharmacokinetics of moroctocog alfa (AF-CC) in pediatric patients.  To achieve this 
objective, a subset of enrolled subjects will participate in a pharmacokinetic assessment 
conducted at the start of the study.
Another secondary objective of this study is to define the safety and efficacy of moroctocog 
alfa (AF-CC) in pediatric patients, including the characterization of the incidence of “less 
than expected therapeutic effect”.
Enrollment into the on-demand (OD) cohort has been closed.  To date, there are data 
indicating that prophylaxis therapy controls bleeding episodes better than on-demand 
therapy.  Subsequent to the initiation of this protocol, Xyntha has been approved for 
on-demand use in children. The availability of the completed pharmacokinetic assessment in 
the submission means enrollment into the pharmacokinetic (PK) assessment is optional.
Given that prophylaxis has replaced OD therapy as the preferred standard of medical care, 
the study will continue enrollment into the RP cohort to assess the effect of a high (25 IU/kg 
every other day) versus low (45 IU/kg twice per week) frequency dosing schedule on the 
efficacy of moroctocog alfa (AF-CC) prophylaxis for male subjects 6 months to <16 years 
of age. 
Refer to the most recent version of the investigator’s brochure for a summary of findings 
from nonclinical studies that potentially have clinical significance and from clinical studies 
that are relevant to the study.  Also refer to the most recent version of the investigator’s 
brochure for a summary of the known and potential risks and benefits, if any, to human 
subjects.

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10. OBJECTIVES
10.1. Primary Objective
To demonstrate that moroctocog alfa (AF-CC) prophylaxis reduces annualized bleeding rates 
relative to on-demand therapy.  Enrollment into the on-demand (OD) cohort has been closed.
10.2. Secondary Objectives

To assess the effect of a high (25 IU/kg every other day)- versus low (45 IU/kg 
twice per week)-frequency dosing schedule on the efficacy of moroctocog alfa 
(AF-CC) prophylaxis.

To continue to characterize the PK of FVIII:C after administration of moroctocog 
alfa (AF-CC) in children 6 months to <16 years of age.  Enrollment into the PK
assessment is optional.

To describe moroctocog alfa (AF-CC) efficacy and safety in children, including 
characterization of the incidence of “less than expected therapeutic effect” (see 
Section 18.2).
11. STUDY DESIGN
11.1. Description
There will have been two cohorts enrolled into the study; one in which the subject practices 
on-demand therapy for the first segment of the study, followed by routine prophylaxis for the 
second segment, and, another cohort in which the subject practices routine prophylaxis for 
both segments.  Study subjects will be hereafter referred to by their segment 1 treatment 
modality: on-demand (OD) subjects and routine prophylaxis (RP) subjects.  Enrollment into 
the OD cohort has been closed. Enrollment for the RP cohort is ongoing.
Enrollment for the RP cohort will continue and will be conducted as an open-label, 
multicenter trial of moroctocog alfa (AF-CC) in approximately 56 subjects (6 months to 
<16 years of age) with moderately severe to severe hemophilia A.  The study will be 
conducted in two 12-month segments (Also refer to Section 6).
At study start, a subset of subjects may participate in optional assessments to characterize the 
PK of FVIII after moroctocog alfa (AF-CC) administration.  Subjects who are eligible and 
opt to participate will undergo a baseline PK assessment, receiving a single open-label dose 
of moroctocog alfa (AF-CC) (50 5 IU/kg rounded to the nearest complete vial) with blood 
sampled for FVIII activity measurements before and at 0.5, 8, 24, 28 (optional), and 32 hours 
after the start of the infusion. 
All RP subjects will practice prophylaxis with moroctocog alfa (AF-CC) according to 1 of 
2 randomly assigned moroctocog alfa (AF-CC) regimens, each delivering approximately 
90 IU/kg/week, but differing in dosing schedule.  Randomization will be stratified by 
hemophilia A severity: FVIII activity <1% or 1-2% (central laboratory screening result).  
Each segment will be 12 months in duration.

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In the first segment, subjects will be randomly assigned to Regimen A: 45 5 IU/kg, 
administered twice per week or Regimen B: 25 5 IU/kg, administered every other day.
For regimen A, the interval between prophylactic infusions should be 3 to 4 days, and should 
not exceed 4 days.  For regimen B, the interval between prophylactic infusions should be 
approximately 48 hours (eg, an appropriate dosing schedule for Regimen B is as follows 
Monday, Wednesday, Friday, Sunday, Tuesday, Thursday, Saturday, Monday…etc). 
After completion of the first segment, all subjects will cross over to the alternate prophylactic 
regimen for segment 2.  Subjects who received Regimen A in segment 1 will follow 
regimen B in segment 2.  Conversely, those subjects who received Regimen B in segment 1 
will follow Regimen A in segment 2.
During prophylaxis, a subject’s treatment will be escalated to a higher intensity prophylaxis 
regimen comprised of the most intensive components of both regimens A and B 
(45 5 IU/kg, administered every other day) if criteria justifying regimen escalation are met 
(see Section 15.3.3).  Subjects who meet dose escalation criteria while on this more intensive 
regimen may dose escalate to a higher intensity regimen designated by the investigator.  The 
subject will follow the assigned regimen(s) until the respective 12-month period of 
prophylaxis with study drug has been completed (segment 1 or 2); the 12-month period is 
inclusive of treatment time on all the prophylaxis regimens assigned during the respective 
study segment.  During prophylaxis, subjects will also use moroctocog alfa (AF-CC), as 
needed, for the treatment of bleeds (ie, on-demand), should they occur.
Clinical and laboratory examinations, including assessments for FVIII inhibitor development, 
will be conducted during the course of the study.
11.2. Approximate Duration of Subject Participation
Subjects enrolled in the OD subject cohort participated in the study for approximately 
20 or 26 months, while subjects enrolled in the RP cohort will participate in the study for 
approximately 26 months.  This includes approximately 35 days for screening, a 6-month or 
12-month treatment period during segment 1, a 12-month treatment period during segment 2, 
and approximately 1 month (at least 28 days) for a final safety follow-up assessment (Final 
Study Contact).  Completion of the Final Study Contact concludes the subject’s participation 
in the study.
11.3. Approximate Duration of Study
The duration of this study will be approximately 98 months (including 26 months after the 
last RP subject is enrolled).  The end of the study is the Final Study Contact of the last 
subject (Final Study Contact occurs at least 28 days after the Final Study Visit).  A final 
safety follow-up assessment is performed during the Final Study Contact; this follow-up 
assessment includes the reporting of any adverse events that may have occurred during the 
time between the Final Study Visit and the Final Study Contact and also includes the 
reporting of medications used during this period.

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11.4. Approximate Number of Subjects
Approximately 56 subjects will be enrolled in the RP cohort of this study at approximately 
40 sites globally. Approximately 24 subjects were enrolled in the OD cohort.  Enrollment in 
the OD cohort has been closed. Subjects withdrawn from the study will not be replaced, 
regardless of the reason for withdrawal.
12. SELECTION OF SUBJECTS
Subjects (and legal acceptable representative, if required) must participate in the informed 
consent/assent process and sign and date the informed consent/assent form before any study 
procedures or screening activities specified in this protocol are performed (the informed 
consent/assent form for signature must have been approved by both the institutional review 
board (IRB)/independent ethics committee (IEC) and the Sponsor).  Prospective subjects may 
be notified of the study’s existence, but no study procedures may be performed before 
obtaining informed consent/assent.  The investigator will maintain a subject-screening 
logbook at the study site.  All subjects screened at the study site will be entered into the 
logbook (see Section 23).
After obtaining informed consent/assent, the investigator and monitor determine a subject’s 
eligibility by history and specific laboratory assays.  The central laboratory will be used for 
all screening blood tests.  The local laboratory will also be used specifically for 2 tests: 
FVIII activity (FVIII:C) and FVIII inhibitor.  Local laboratory measurements of FVIII:C and 
FVIII inhibitor will be used by the investigator to assess eligibility, although parallel samples 
will be analyzed at the central laboratory and will also be used to confirm eligibility for 
subjects.  (NOTE: During the treatment phase of the study, all tests for FVIII:C and/or FVIII 
inhibitor performed at the local laboratory should have duplicate samples from the same 
phlebotomy shipped to the central laboratory for analyses.  The treatment phase starts at 
visit 2 and ends at the Final Study Visit.)  If the local or central laboratory results for either 
FVIII:C or FVIII inhibitor show the subject is ineligible, the subject will be considered a 
screen failure.  The Sponsor’s clinician may be consulted regarding eligibility of particular 
subjects if circumstances warrant further discussion.
12.1. Inclusion Criteria
For all subjects participating in the study:
1. Male subjects with moderately severe to severe hemophilia A (FVIII:C 2%) by both
the local laboratory and the central laboratory at screening.
2. A negative FVIII inhibitor by both the local laboratory and the central laboratory at 
screening (for local laboratory, a Bethesda inhibitor titer less than the upper limit of 
normal [ULN] for the laboratory performing the assay and is not reported to be 
≥0.6 Bethesda Units [BU]/mL; for central laboratory, Bethesda inhibitor titer 
<0.6 BU/mL by Nijmegen assay).
3. A medical history negative for a past FVIII inhibitor (see Protocol Definitions).

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4. Age 6 months to <16 years at the time of screening visit (study visit 1).
5. Previous experience of FVIII therapy (20 exposure days to any FVIII replacement 
product [see Protocol Definitions]).
6. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 5.0 × ULN, 
and bilirubin 2 mg/dL (<35 mol/L).
7. Serum albumin the lower limit of normal (LLN).
8. Serum creatinine 1.25 × ULN.
9. Platelet count 100,000/L.
10. Absolute CD4 count >400/L for subjects with HIV only.
11. Prothrombin time (PT) 1.25 × ULN, or international normalized ratio (INR) 1.5.
12. The subject is not receiving treatment for HIV or hepatitis infection, or the subject is 
on a stable antiviral regimen at the time of signing the consent/assent form (ie, stable 
dosing for at least 3 months before signing the consent/assent form).
13. The subject is able to comply with the mandatory 72-hour FVIII washout preceding 
each FVIII:C and FVIII inhibitor assessment during the study.
14. Male subjects able to father children must agree to use a highly effective method of 
contraception throughout the study and for at least 28 days after the last dose of 
assigned treatment. 
15. Evidence of a personally signed and dated informed consent/assent document 
indicating that the subject (or a legally acceptable representative/parent(s)/legal 
guardian) has been informed of all pertinent aspects of the study.
16. Subjects who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures.
The Sponsor’s clinician should be consulted about prospective subjects with complex 
medical or laboratory histories relevant to inclusion criteria.
Additional criteria for subjects participating in the PK assessment:
1. Male subjects as described immediately above except they must have a FVIII:C of 
1% confirmed by the central laboratory screening test.
2. Age 6 months to <16 years at time of PK assessment (study visit 2).
3. The subject’s size is sufficient to permit PK-related phlebotomy.

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4. The subject is able to comply with the procedures conducted during the PK 
assessment, including a mandatory 72-hour washout period preceding the PK 
assessment. 
12.2. Exclusion Criteria
1. A history of FVIII inhibitor (clinical or laboratory-based assessment).  For laboratory 
assessments, any measured Bethesda inhibitor titer 0.6 BU/mL, regardless of the 
laboratory normal range, or any measured Bethesda inhibitor titer greater than the 
ULN for the laboratory performing the assay.
2. Presence of a bleeding disorder in addition to hemophilia A.
3. Treatment with any investigational drug or device within 30 days before the time of 
signing the consent/assent form.
4. Major or orthopedic surgery planned to occur within the period following the signing 
of the consent/assent form to the Final Study Contact (ie, during the course of the 
study).
5. Regular (eg, daily, every other day) use of antifibrinolytic agents or medications 
known to influence platelet function such as aspirin or certain nonsteroidal 
anti-inflammatory drugs (NSAIDs).
6. Regular, concomitant therapy with immunomodulating drugs (eg, intravenous 
immunoglobulin [IVIG], routine systemic corticosteroids).
7. Known hypersensitivity to hamster protein.
8. Any condition(s) that compromises the subject’s ability to comply with and/or 
perform study-related activities or that poses a clinical contraindication to study 
participation (these conditions include, but are not limited to, inadequate medical 
history to assure study eligibility; inability to properly store study drug; expectation 
of poor compliance in study related documentation).
9. Unwilling or unable to follow the terms of the protocol.
10. Subjects who are investigational site staff members directly involved in the conduct 
of the study and their family members, site staff members otherwise supervised by the 
investigator, or subjects who are Pfizer employees directly involved in the conduct of 
the study.
11. Male subjects able to father children who are unwilling or unable to use a highly 
effective method of contraception as outlined in this protocol for the duration of the 
study and for at least 28 days after the last dose of investigational product or longer 
based upon the compound’s half-life characteristics.

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The Sponsor’s clinician should be consulted about prospective subjects with complex clinical 
or laboratory histories relevant to Exclusion Criteria.
12.3. Life Style Guidelines 
All male subjects who are able to father children and are sexually active and at risk for 
pregnancy must agree to use a highly effective method of contraception consistently and 
correctly for the duration of the active treatment period and for at least 28 days after the last 
dose of investigational product.  The investigator or his or her designee, in consultation with 
the subject, will select/will confirm that the subject has selected an appropriate method of 
contraception for the individual subject and his partner from the permitted list of 
contraception methods (see below) and instruct the subject in its consistent and correct use.  
Subjects need to affirm that they meet the criteria for correct use of at least 1 of the selected 
methods of contraception.  The investigator or his/her designee will discuss with the subject 
the need to use highly effective contraception consistently and correctly according to the 
schedule of activities and document such conversation in the subject’s chart.  In addition, the 
investigator or his or her designee will instruct the subject to call immediately if the selected 
contraception method is discontinued or if pregnancy is known or suspected in the subject or 
the subject’s partner. 
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of oral, inserted, injected, implanted or transdermal hormonal 
methods of contraception is allowed provided the subject plans to remain on the 
same treatment throughout the entire study and has been using that hormonal 
contraceptive for an adequate period of time to ensure effectiveness.
2. Correctly placed copper -containing intrauterine device (IUD). 
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, 
cream, or suppository).  For countries where spermicide is not available or condom 
plus spermicide is not accepted as highly effective contraception, this option is not 
appropriate.
All sexually active male subjects must agree to prevent potential transfer of and exposure to 
drug through semen to their partners by using a condom consistently and correctly, beginning 
with the first dose of investigational product and continuing for at least 28 days after the last 
dose.
12.4. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the supporting study documentation.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card. The contact card contains, 

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at a minimum, protocol and investigational compound identifiers, subject study numbers, 
contact information for the investigational site, and contact details for a contact center in the 
event that the investigational site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
subject’s participation in the study. The contact number can also be used by investigational 
staff if they are seeking advice on medical questions or problems; however, it should be used 
only in the event that the established communication pathways between the investigational 
site and the study team are not available. It is therefore intended to augment, but not replace, 
the established communication pathways between the investigational site and the study team 
for advice on medical questions or problems that may arise during the study. The contact 
number is not intended for use by the subject directly, and if a subject calls that number, he 
or she will be directed back to the investigational site.
13. PRIOR TREATMENT
All treatment received within 30 days before signing the consent/assent form will be 
recorded.
14. CONCOMITANT TREATMENT
14.1. Prohibited
Concomitant treatment with FVIII concentrates, other than moroctocog alfa (AF-CC) study 
drug, is not allowed during the treatment phase of this study: the treatment phase starts at 
visit 2 (day 1) and ends at the Final Study Visit (ie, visit 19, month 24 for RP subjects).  
After completion of the treatment phase of this study, subjects may use the FVIII concentrate 
of their choice and should not use study drug.
Subjects should not receive drugs with antiplatelet effects (eg, aspirin) or use certain NSAIDs 
to a degree that, in the opinion of the investigator or Sponsor’s clinician, affects the 
hemostatic function of the subject, and/or affects the subject’s FVIII therapy.
The regular use of immunomodulating drugs (eg, IVIG, routine systemic corticosteroids) is 
prohibited.
14.2. Permitted
The subject’s regular medication, other than FVIII concentrates, may continue unchanged, 
and will be recorded.  Analgesics, as well as other therapy considered necessary for the 
subject’s well-being during the study, may be given at the discretion of the investigator.  
Subjects must use only study drug (moroctocog alfa [AF-CC]) for FVIII therapy during the 
treatment phase of this study: the treatment phase starts at visit 2 (day 1) and ends at the Final 
Study Visit 19, month 24 for RP subjects).
Subjects with HIV and/or hepatitis virus infection(s) will be permitted to continue with any 
stable, noninvestigational treatment throughout the study.  Licensed antiviral medications, 
including but not limited to protease inhibitors, interferon, and ribavirin, are permitted 
provided subjects are on stable dosing for at least 3 months before the signing of the 

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consent/assent form.  Subjects must remain on a stable regimen of antivirals over the course 
of this study.  The Sponsor’s clinician should be consulted about prospective subjects with 
circumstances that may conflict with these criteria regarding antiviral medications.
Major surgery or orthopedic surgery planned to occur within the period following the signing 
of the consent/assent form to the Final Study Contact (ie, during the course of this study) is 
an exclusion criterion for this study.  Required minor surgery, or major/orthopedic surgical 
procedures which were unplanned at the time of signing the consent/assent form, will be 
allowed during the course of this study, pending approval from the Sponsor’s clinician.  
Moroctocog alfa (AF-CC) study drug will be the only FVIII replacement product used to 
achieve and maintain normal hemostasis through a surgical procedure.  See Section 15.3.4
for further details.
15. PROCEDURES 
The following description provides information on the procedures and activities of 
subjects/caregivers and investigators (or designees) as the study proceeds.  
[NOTE: Enrollment has been closed in the OD cohort.  Details of the OD cohort can be 
found in Amendment 9 of this protocol.  The RP cohort enrollment remains active and PK 
assessment portion continues as optional.]  Due to the young age of some subjects in this 
study, many activities will be performed by a subject’s caregiver (eg, reporting of bleeds and 
study drug usage); where applicable in this protocol, the term subject will also refer to 
caregiver.  Please also refer to Sections 7 and 8 for an overview of study procedures.
15.1. Study Procedures for RP Cohort
Please also refer to the study flowchart in Section 7, for an overview of study procedures.
15.1.1. Consent/Assent
All subjects must review and sign a consent form that has been approved by both the 
appropriate IRB/IEC and the Sponsor (the consent form must be approved by the sponsor as 
well as the IRB/IEC before it can be used for the trial at that site).  Where deemed 
appropriate by the IRB/IEC, the subject should also sign an assent form (the assent form must 
be approved by the Sponsor as well as the IRB/IEC before it can be used for the trial at that 
site).  Subjects who are under the legal age of consent, must have a legally acceptable 
representative review, approve and sign consent for the study (also see Section 29.3).  The
consent process must explain to the subject (and legal acceptable representative) that they 
may withdraw their consent/assent at any time for any reason.  A note (dated and timed) must 
be made in the patient’s medical record that the subject is participating in this study and that 
consent/assent was obtained.  Collection of adverse events (AEs), as well as bleeds and 
medications, begins after the signing of the consent/assent form and completion of the 
medical history.  Signing the consent/assent form marks the start of study participation.
15.1.2. Payment of Subjects
Subjects may be reimbursed for expenses related to study activities.  Any payments must 
meet applicable law and regulations and be approved by the relevant IRBs/IECs.

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15.1.3. Study Visit 1 (Screening Visit) - RP Cohort
Following consent/assent, subjects will undergo the following screening activities to 
determine if they are eligible for the study.  Results from the central laboratory, designated 
by the Sponsor, will be used to determine eligibility as noted.  Local laboratory test results 
will also be used to determine eligibility as noted.  Screening procedures will collect the 
following:

Obtain informed consent/assent.

Demographic information, medical history (including HIV status and history of 
hepatitis infections), medication history (including hepatitis vaccinations), and 
hemophilia A history.

Current hemophilia A treatment information (eg, prophylaxis or on-demand therapy).

Complete physical examination including vital signs (temperature [Celsius], blood 
pressure, pulse, and respiration), body weight (kilograms), and height (centimeters).

Blood sample for:

CD4 cell count (central laboratory) for subjects with HIV only.

PT or INR (central laboratory).

Hematology panel (see Protocol Definitions; central laboratory).

Serum chemistry (see Protocol Definitions; central laboratory).

FVIII:C (after a 72-hour FVIII washout; local and central laboratories; results 
from both local and central laboratories must meet inclusion criteria).

FVIII inhibitor (after a 72-hour FVIII washout; local and central laboratories; 
results from both local and central laboratories must meet inclusion criteria).

anti-FVIII antibody (see Protocol Definitions; collected after a 72-hour FVIII 
washout; frozen and sent to central laboratory for enzyme-linked immunosorbent 
assay [ELISA] analysis).

anti-CHO antibody (see Protocol Definitions; collected after a 72-hour FVIII 
washout; frozen and sent to central laboratory for ELISA analysis).

anti-TN8.2 antibody (see Protocol Definitions; collected after a 72-hour FVIII 
washout; frozen and sent to central laboratory for ELISA analysis).
All screening procedures that do not require a 72-hour FVIII washout may occur during the 
initial screening visit.  Subjects will be instructed to return to the clinic following the 72-hour 
FVIII washout for relevant screening sample collections if the minimum 72-hour FVIII 
washout was not observed before the initial screening visit. If a subject experiences a bleed 

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during the 72-hour washout, he should be treated with his usual FVIII therapy and then have 
a repeat 72-hour FVIII washout before relevant screening sample collections.
FVIII:C and FVIII inhibitor testing will be performed at both the local and the central 
laboratories.  Subjects must have FVIII:C 2% by both the local laboratory and the central 
laboratory.  Subjects must have negative FVIII inhibitor tests by both the local laboratory and 
the central laboratory (for local laboratory, a Bethesda inhibitor titer < ULN for the 
laboratory performing the assay and is not reported to be 0.6 Bethesda Units [BU]/mL; for 
central laboratory, Bethesda inhibitor titer <0.6 BU/mL by Nijmegen assay).  Once results 
are received, subjects who are deemed eligible will return for visit 2 (day 1) within 
approximately 35 days after the screening visit.
Subjects who do not meet study eligibility criteria will be considered screen failures (please 
refer to the Study Reference Manual for data recording instructions for screen failures).  In 
the event that contradictory FVIII:C or FVIII inhibitor results are reported by the local and 
central laboratories, a subject is ineligible for the study if either the local or central 
laboratory results do not meet study eligibility criteria (eg, if a subject is ineligible for the 
study based on the central laboratory results for FVIII:C or FVIII inhibitor, the subject will 
be considered a screen failure even if the local laboratory results indicate the subject is 
eligible; similarly, if a subject is ineligible for the study based on the local laboratory results 
for FVIII:C or FVIII inhibitor, the subject will be considered a screen failure even if the 
central laboratory results indicate the subject is eligible).
Please refer to the Study Reference Manual for further details on the collection and shipping 
of all samples collected at this and other visits.
Subjects will receive the appropriate materials (ie, Subject Diary) and instructions to record 
any AEs, bleeds, and concomitant medication use.
15.1.4. Screening Period Activities and Randomization - RP Cohort
During the screening period (interval of up to approximately 35 days, starting from the 
signing of the informed consent/assent and extending up to visit 2, day 1), subjects should 
adhere to their usual therapies (including FVIII therapy) prescribed by the investigator.  All 
AEs, bleeds, and medications must be recorded in the Subject Diary (issued at visit 1, 
Screening).
After study eligibility has been confirmed, and prior to visit 2, day 1, subjects will be 
randomized.  Allocation of subjects to treatment assignments will be performed through an 
interactive voice or web-based response system.  RP subjects will practice prophylaxis 
during both study segments and will be randomly assigned in a 1:1 ratio to 1 of 2 treatment 
sequences (AB or BA) defining the prophylaxis regimens to be practiced for 12 months each 
during segments 1 and 2, respectively:
A: 45 5 IU/kg, administered twice per week
B: 25 5 IU/kg, administered every other day

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For regimen A, the interval between prophylactic infusions should be 3 to 4 days, and should 
not exceed 4 days.  For regimen B, the interval between prophylactic infusions should be 
approximately 48 hours (eg, an appropriate dosing schedule for Regimen B is as follows 
Monday, Wednesday, Friday, Sunday, Tuesday, Thursday, Saturday, Monday…etc). 
Randomization will be stratified by hemophilia A severity: FVIII activity <1% or 1-2% 
(central laboratory screening result).  The randomizations will be performed as specified in 
the Study Reference Manual.
15.1.5. Study Visit 2 (Day 1) - Segment 1 - RP Cohort
After confirmation of eligibility, the subject will be notified by the investigator and arrange 
to return for visit 2 (day 1).  Visit 2 (day 1) should occur within approximately 35 days after 
visit 1 (Screening).  Only subjects who have met the eligibility criteria for the study should 
have visit 2 (day 1).
This visit requires a 72-hour FVIII washout.  The subject should not have exogenous FVIII:C 
at the time of the visit.  Therefore, depending on the last FVIII dose before the beginning of 
the FVIII washout, an interval longer than 72 hours may be needed.  If a subject sustains a 
bleed requiring treatment during the 72-hour FVIII washout, the necessary treatment should 
be administered using the subject’s usual FVIII replacement product.  Once the bleed has 
been adequately treated, visit 2 must be rescheduled, and must be preceded by a new 
72-hour FVIII washout.
The subject will be examined, measured for weight (kilograms), have vital signs taken 
(including temperature [Celsius], blood pressure, pulse, and respiration), and will have blood 
samples collected for:

FVIII:C (central laboratory).

FVIII inhibitor (central laboratory).

anti-FVIII antibody (central laboratory).

anti-CHO antibody (central laboratory).

anti-TN8.2 antibody (central laboratory).
At this visit, the subject will turn in his Subject Diary.  The investigator (or designee) will 
review the Subject Diary with the subject, and inquire about and record AEs, bleeds, and use 
of medications.  In addition to the information obtained from those sources, the subject 
should be asked the following nonspecific question: “How have you been feeling since your 
last visit?”  Signs and symptoms should be recorded using standard medical terminology.
15.1.5.1. Pharmacokinetic Assessment (if Applicable) - Segment 1 - RP Subject Cohort
Please refer to Section 15.2 and study flowchart 2 in Section 8 for PK-related study 
procedures.

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15.1.5.2. Study Drug Dispensed - RP Cohort
Study drug (moroctocog alfa [AF-CC] and accessory supplies) will first be dispensed to the 
subject at this visit.  The investigator (or designee) will provide study drug according to the 
subject’s treatment modality, prophylaxis, and using the subject’s weight recorded that day 
(see Study Reference Manual for guidelines of dose selection based on the subject’s 
measured body weight; dispensed supplies also include supplies for treatment of any bleeds).  
RP subjects will be following the protocol-defined regimen to which they have been 
randomly assigned (A or B), therefore the investigator (or designee) will review the assigned 
regimen, and information related to regimen escalation (criteria for, and subsequent action; 
see Section 15.3.3) with the subject.  For regimen A, the interval between prophylactic 
infusions should be 3 to 4 days, and should not exceed 4 days.  For regimen B, the interval 
between prophylactic infusions should be approximately 48 hours (eg, an appropriate dosing 
schedule for Regimen B is as follows Monday, Wednesday, Friday, Sunday, Tuesday, 
Thursday, Saturday, Monday…etc).  All subjects will receive instructions for study drug 
reconstitution and administration, and the appropriate materials (ie, Subject Diary) and 
instructions to collect data on his home treatment (ie, infusions, bleeding events, response to 
infusions, etc).  All instructions given to the subject will be documented in the subject’s 
source document.  Subjects may now commence treatment with study drug (moroctocog alfa 
[AF-CC]).  For subjects who opt to participate in the PK assessment, moroctocog alfa 
(AF-CC) treatment should not commence until after the final PK sample collection 
(ie, 32 hour collection).  (NOTE: Treatment with study drug may occur before the final PK 
sample collection if a subject experiences a bleeding episode during the assessment; in the 
event that this occurs, the bleed is to be stabilized with study drug.)  Only moroctocog alfa 
(AF-CC) may be used for FVIII replacement therapy from this point through the remainder 
of the treatment phase of this study; the treatment phase starts at visit 2 (day 1) and ends at 
the Final Study Visit (visit 19, month 24).
15.1.6. Subject Activities Between Successive Study Visits (Visit 2 Through Visit 11), 
and Activities of Study Contacts 4, 6, 8, and 10 - Segment 1 - RP Cohort
Subjects will use moroctocog alfa (AF-CC) for hemophilia A treatment (protocol-defined 
prophylaxis [including treatment of any bleed, if necessary, during prophylaxis]).  Subjects 
will document all of their infusions (dose, time of infusion, and reason) and all bleeding 
episodes in the Subject Diary.  In addition, subjects will record the efficacy of a study drug 
infusion given on-demand for treatment of a bleed using a 4-point ordinal scale of 
“Excellent,” “Good,” “Moderate,” and “No Response” in the Subject Diary (please refer to 
Section 18.1.3 for description of scale).  Subjects will also document any AEs or use of 
concomitant medications in the Subject Diary.  Subjects will save used study drug vials; used 
study drug vials are returned at each study visit.  Approximately 4 weeks (1 week) after 
study visit 3, and approximately 6 weeks (±1 week) after study visits 5, 7, and 9, 
respectively, the investigator (or designee) will contact the subject by telephone in order to 
collect information regarding the occurrence of any AEs, the use of concomitant medications, 
and study compliance.  During these contacts, the investigator (or designee) will also review 
the subject’s hemophilia A treatment (ie, investigator-prescribed on-demand therapy, or 
protocol-defined prophylaxis).  The investigator (or designee) will also review information 
related to regimen escalation (criteria for, and subsequent action; see Section 15.3.3) with the 

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subject and will ensure that the criteria for regimen escalation had not been met.  In addition, 
any change in a subject’s prophylaxis regimen must be recorded; changes in the prophylaxis 
regimen should only occur in the event that escalation criteria are met.  These study contacts, 
following study visits 3, 5, 7, and 9 are referred to as study contacts 4, 6, 8, and 10, 
respectively. (Note: Study contact information may be collected at an appropriately 
scheduled clinic visit, if the subject or the investigator prefers).
15.1.7. Study Visits 3, 5, 7, and 9 (Study Months 1, 3, 6, and 9) – Segment 1 - RP Cohort
Approximately 1, 3, 6, and 9 months after visit 2 (day 1), the subject will return to the clinic 
for study visits 3, 5, 7, and 9, respectively.  If the study visit occurs outside of the 
recommended study visit window (ie, 1 week) the reason must be documented in the 
subject’s source document.
These visits require a 72-hour FVIII washout; thus, for subjects assigned to prophylaxis 
regimen B, an interruption in the every-other-day dosing frequency is required.  The subject 
should not have exogenous FVIII:C at the time of the visit.  Therefore, depending on the last 
FVIII dose before the beginning of the FVIII washout, an interval longer than 72 hours may 
be needed.  If a subject sustains a bleed requiring treatment during the 72-hour FVIII 
washout, the necessary treatment should be administered using moroctocog alfa (AF-CC).  
Once the bleed has been adequately treated, the study visit must be rescheduled, and must be 
preceded by a new 72-hour FVIII washout.
The subject will be examined, measured for weight (kilograms), have vital signs taken 
(including temperature [Celsius], blood pressure, pulse, and respiration), and will have blood 
samples collected for:

FVIII:C (central laboratory).

FVIII inhibitor (central laboratory).

anti-FVIII antibody (central laboratory).
The subject will turn in his used study drug vials, account for all study drug he has received, 
and turn in his Subject Diary.  The investigator (or designee) will review the Subject Diary 
with the subject, and inquire about and record AEs, concomitant medications, or any study 
drug infusions for efficacy assessments.  In addition to the information obtained from those 
sources, the subject should be asked the following nonspecific question: “How have you been 
feeling since your last visit?”  Signs and symptoms should be recorded using standard 
medical terminology.  During the review, the investigator (or designee) will inquire about 
study compliance, review information related to less than expected therapeutic effect (LETE) 
(see Section 18.2 for criteria), and will review the subject’s hemophilia A treatment 
(ie, protocol-defined prophylaxis).  The investigator (or designee) will also review 
information related to regimen escalation (criteria for, and subsequent action; see 
Section 15.3.3) with the subject and will ensure that the criteria for regimen escalation had 
not been met.  In addition, any change in a subject’s prophylaxis regimen must be recorded; 

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changes in the prophylaxis regimen should only occur in the event that escalation criteria are 
met. 
Additional study drug will be dispensed as needed, and a new Subject Diary will be issued.
15.1.8. Study Visit 11 (Study Month 12) - RP Cohort
Approximately 12 months after visit 2 (day 1), the subject will return to the clinic for study 
visit 11.  If the study visit occurs outside of the recommended study visit window 
(ie, 1 week), the reason must be documented in the subject’s source document.
For RP subjects, visit 11 (month 12) marks the subject’s completion of the first 12-month 
moroctocog alfa (AF-CC) treatment period (segment 1).  Visit 11 (month 12) also marks the 
start of the second 12-month moroctocog alfa (AF-CC) treatment period (segment 2) for 
these subjects.
This visit requires a 72-hour FVIII washout; thus, for subjects assigned to prophylaxis 
regimen B, an interruption in the every-other-day dosing frequency is required.  The subject 
should not have exogenous FVIII:C at the time of the visit.  Therefore, depending on the last 
FVIII dose before the beginning of the FVIII washout, an interval longer than 72 hours may 
be needed.  If a subject sustains a bleed requiring treatment during the 72-hour FVIII 
washout, the necessary treatment should be administered using moroctocog alfa (AF-CC).  
Once the bleed has been adequately treated, visit 11 must be rescheduled, and must be 
preceded by a new 72-hour FVIII washout.
The subject will be examined, measured for weight (kilograms) and height (centimeters), 
have vital signs taken (including temperature [Celsius], blood pressure, pulse, and 
respiration), and will have blood samples collected for:

Hematology panel (see Protocol Definitions; central laboratory).

Serum chemistry (see Protocol Definitions; central laboratory).

FVIII:C (central laboratory).

FVIII inhibitor (central laboratory).

anti-FVIII antibody (central laboratory).

anti-CHO antibody (central laboratory).

anti-TN8.2 antibody (central laboratory).
The subjects will turn in their used study drug vials, account for all study drug received, and 
turn in their Subject Diary.  The investigator (or designee) will review the Subject Diary with 
the subject, and inquire about and record AEs, concomitant medications, or any study drug 
infusions for efficacy assessments.  In addition to the information obtained from those 

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sources, the subject should be asked the following nonspecific question: "How have you been 
feeling since your last visit?"  Signs and symptoms should be recorded using standard 
medical terminology.  During the review, the investigator (or designee) will inquire about 
study compliance, review information related to LETE (see Section 18.2 for criteria), and 
will review the subject’s hemophilia A treatment (ie, protocol-defined prophylaxis).  The 
investigator (or designee) will also review information related to regimen escalation (criteria 
for, and subsequent action; see Section 15.3.3) with the subject and will ensure that the 
criteria for regimen escalation had not been met.  In addition, any change, that may have 
occurred since the last study contact (study contact 10), in a subject’s prophylaxis regimen 
must be recorded; changes in the prophylaxis regimen should only occur in the event that 
escalation criteria are met.
15.1.8.1. Start of Segment 2 - RP Cohort
RP subjects following 1 of the 2 protocol-defined regimens to which they were randomly 
assigned during the screening period (see Section 15.1.4), will now crossover to the other 
protocol-defined regimen.
The investigator (or designee) will review the assigned prophylaxis regimen, and information 
related to regimen escalation (criteria for, and subsequent action; see Section 15.3.3) with the
subject.  For regimen A, the interval between prophylactic infusions should be 3 to 4 days, 
and should not exceed 4 days.  For regimen B, the interval between prophylactic infusions 
should be approximately 48 hours (eg, an appropriate dosing schedule for Regimen B is as 
follows Monday, Wednesday, Friday, Sunday, Tuesday, Thursday, Saturday, Monday…etc).  
The instructions given to the subject will be documented in the subject’s source document.
15.1.8.2. Study Drug Dispensed – Segment 2 - RP Cohort
Study drug (moroctocog alfa [AF-CC] and accessory supplies) will be dispensed to the 
subject.  The investigator (or designee) will provide study drug for prophylaxis treatment 
(and for treatment of any bleeds) using the subject’s weight recorded that day (see Study 
Reference Manual for guidelines of dose selection based on the subject’s measured body 
weight).  The investigator will review instructions for study drug reconstitution and 
administration with the subject.  The subject will also receive a new Subject Diary and 
instructions to collect data on his home treatment (ie, infusions, bleeding events, response to 
infusions, etc).  The instructions given to the subject will be documented in the subject’s 
source document.
Subjects should now commence moroctocog alfa (AF-CC) prophylaxis according to the 
assigned regimen (A or B).  RP subjects following 1 of the 2 protocol-defined regimens to 
which they were randomly assigned during the screening period (see Section 15.1.4), will
now crossover to the other protocol-defined regimen.  These subjects will follow the assigned 
prophylaxis regimen for a 12-month period.  Only moroctocog alfa (AF-CC) study drug may 
be used for FVIII replacement therapy during this 12-month period (ie, through the 
remainder of the treatment phase of this study which ends at the Final Study Visit [visit 19, 
month 24]).

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15.1.9. Subject Activities Between Successive Study Visits (Visit 11 Through Visit 19), 
and Activities of Study Contacts 12, 14, 16, and 18 - Segment 2 - RP Cohort
Subjects should adhere to their assigned moroctocog alfa (AF-CC) prophylaxis regimen.  
Subjects should also use study drug for the treatment of a bleed, if necessary.  Subjects will 
document all their infusions (dose, time of infusion, and reason) and all bleeding episodes in 
the Subject Diary.  In addition, subjects will record the efficacy of a study drug infusion 
given on-demand for treatment of a bleed using a 4-point ordinal scale of “Excellent,” 
“Good,” “Moderate,” and “No Response” in the Subject Diary (please refer to Section 18.1.3
, for description of scale).  Subjects will also document any AEs or use of concomitant 
medications in the Subject Diary.  Subjects will save used study drug vials (used study drug 
vials are returned at each study visit).  Approximately 6 weeks (1 week) after study 
visits 11, 13, 15 and 17, respectively, the investigator (or designee) will contact the subject 
by telephone in order to collect information regarding the occurrence of any AEs, the use of 
concomitant medications, study compliance, and to ensure that the criteria for regimen 
escalation had not been met (see Section 15.3.3 for criteria and subsequent action).  The 
investigator (or designee) will also review the subject’s assigned prophylaxis regimen, and 
information related to regimen escalation with the subject during these contacts.  Any change 
in a subject’s prophylaxis regimen must be recorded; changes in the prophylaxis regimen 
should only occur in the event that escalation criteria are met.  The study contacts, following 
visits 11, 13, 15 and 17, are referred to as study contacts 12, 14, 16, and 18, respectively.  
(Note: Study contact information may be collected at an appropriately scheduled clinic visit, 
if the subject or the investigator prefers).
15.1.10. Study Visits 13, 15, and 17 (Months 15, 18, and 21) - Segment 2 - RP Cohort
Approximately 15, 18, and 21 months after visit 2 (day 1), the subject will return to the clinic 
for study visits 13, 15, and 17, respectively.  If the study visit occurs outside of the 
recommended study visit window (ie, 1 week) the reason must be documented in the 
subject’s source document.
These visits require a 72-hour FVIII washout; thus, for subjects assigned to prophylaxis 
regimen B, an interruption in the every-other-day dosing frequency is required.  The subject 
should not have exogenous FVIII:C at the time of the visit.  Therefore, depending on the last 
FVIII dose before the beginning of the FVIII washout, an interval longer than 72 hours may 
be needed.  If a subject sustains a bleed requiring treatment during the 72-hour FVIII 
washout, the necessary treatment should be administered using moroctocog alfa (AF-CC).  
Once the bleed has been adequately treated, the study visit must be rescheduled, and must be 
preceded by a new 72-hour FVIII washout.
The subject will be examined, measured for weight (kilograms), have vital signs taken 
(including temperature [Celsius], blood pressure, pulse, and respiration), and will have blood 
samples collected for:

FVIII:C (central laboratory).

FVIII inhibitor (central laboratory).

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
anti-FVIII antibody (central laboratory).
The subject will turn in his used study drug vials, account for all study drug he has received, 
and turn in his Subject Diary.  The investigator (or designee) will review the Subject Diary 
with the subject, and inquire about and record AEs, concomitant medications, or any study 
drug infusions for efficacy assessments.  In addition to the information obtained from those 
sources, the subject should be asked the following nonspecific question: "How have you been 
feeling since your last visit?"  Signs and symptoms should be recorded using standard 
medical terminology.  During the review, the investigator (or designee) will inquire about 
study compliance, review information related to LETE (see Section 18.2 for criteria), and 
ensure that the criteria for regimen escalation had not been met (see Section 15.3.3 for 
criteria and subsequent action).  The investigator (or designee) will also review the subject’s
assigned prophylaxis regimen, and information related to regimen escalation with the subject.  
Any change in a subject’s prophylaxis regimen must be recorded; changes in the prophylaxis 
regimen should only occur in the event that escalation criteria are met.
Additional study drug will be dispensed as needed, and a new Subject Diary will be issued.
15.1.11. Final Study Visit (Visit 19, Month 24) - Segment 2 – RP Cohort
Approximately 24 months after visit 2 (day 1), RP subjects will return to the clinic for study 
visit 19 (month 24).  If the study visit occurs outside of the recommended study visit window 
(ie, 1 week), the reason must be documented in the subject’s source document.
Visit 19 is the Final Study Visit; it coincides with the subject’s completion of the second 
12-month treatment period (segment 2), and marks the conclusion of the treatment phase of 
the study.  At the conclusion of the treatment phase, subjects will resume their usual FVIII 
replacement therapy and will not use study drug.
This visit requires a 72-hour FVIII washout.  The subject should not have exogenous FVIII:C 
at the time of the visit.  Therefore, depending on the last FVIII dose before the beginning of 
the FVIII washout, an interval longer than 72 hours may be needed.  If a subject sustains a 
bleed requiring treatment during the 72-hour FVIII washout, the necessary treatment should 
be administered using moroctocog alfa (AF-CC).  Once the bleed has been adequately 
treated, visit 19 must be rescheduled, and must be preceded by a new 72-hour FVIII 
washout.
The subject will be examined, measured for weight (kilograms), have vital signs taken 
(including temperature [Celsius], blood pressure, pulse, and respiration), and will have blood 
samples collected for:

CD4 cell count (central laboratory).

Hematology panel (see Protocol Definitions; central laboratory).

Serum chemistry (see Protocol Definitions; central laboratory).

FVIII:C (central laboratory).

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
FVIII inhibitor (central laboratory).

anti-FVIII antibody (central laboratory).

anti-CHO antibody (central laboratory).

anti-TN8.2 antibody (central laboratory).
The subject will turn in all study drug vials (used and unused) and all unused diluent, 
account for all study drug he has received, and turn in his Subject Diary.  The investigator (or 
designee) will review the Subject Diary with the subject, and inquire about and record AEs, 
concomitant medications, or any study drug infusions for efficacy assessments.  In addition 
to the information obtained from those sources, the subject should be asked the following 
nonspecific question: "How have you been feeling since your last visit?"  Signs and 
symptoms should be recorded using standard medical terminology.  During the review, the 
investigator (or designee) will also inquire about study compliance, and review information 
related to LETE (see Section 18.2 for criteria).  Any change, that may have occurred since 
the last study contact (study contact 18), in a subject’s prophylaxis regimen must be 
recorded; changes in the prophylaxis regimen should only occur in the event that escalation 
criteria are met (see Section 15.3.3 for criteria).
At the end of visit 19, the subject makes an appointment for a Final Study Contact (visit 20) 
that must occur at least 28 days (+10 days) after the Final Study Visit (visit 19).
15.1.12. Final Study Contact (Visit 20) – RP Cohort
At least 28 days (+10 days) after the Final Study Visit (visit 19), the investigator 
(or designee) will contact the subject by telephone in order to collect information regarding 
the occurrence of any AEs and the use of medications.  In addition, the subject should be 
asked the following nonspecific question: "How have you been feeling since your last visit?"  
Signs and symptoms should be recorded using standard medical terminology.  Completion of 
this telephone contact concludes the subject’s participation in the study.  (Note: Final study 
contact information may be collected at an appropriately scheduled clinic visit, if the subject 
or the investigator prefers).
15.2. Study Procedures for Pharmacokinetic Assessment
Please also refer to study Flowchart 2 in Section 8, for an overview of PK-related study 
procedures.
Some subjects will participate in a PK assessment.  This is optional for subjects who are 
<16 years of age at the time of visit 2, who meet the additional PK eligibility criteria outlined 
in Section 12.1, and who enroll at a study site participating in the PK assessments.  
Consenting, PK-eligible subjects will be enrolled sequentially into the PK portion of the 
study.  Thus, if applicable, subjects will begin activities for the PK assessment as described 
below (also refer to Section 8).  Subjects must be in a nonbleeding state for this assessment.

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The procedures for visit 2, detailed previously in Section 15.1.5 for RP subjects 
(ie, examination and collection of weight, vital signs, AEs, medications, and blood samples), 
should occur within 2 hours before study drug administration for PK assessment.  In addition 
to the blood sample collections, subjects participating in the PK assessment will also have a 
blood sample collected, within 2 hours before study drug administration, for:

Hematology panel (see Protocol Definitions; central laboratory).
An intravenous (IV) catheter (temporary) will be inserted in 1 arm for the purpose of 
collecting blood samples for the PK assessment.  The catheter may be removed as needed.  
Unless the infusion is administered through a central catheter, blood samples must be drawn 
from the arm contralateral to the arm in which the infusion is administered.  If an indwelling 
catheter (eg, Port-A-Cath) is in place, it may be used for the infusion only.  In no case may 
blood samples be obtained via the catheter through which the study drug was administered.
Heparin should not be used to flush indwelling catheters during PK study drug administration 
or PK sampling.
The subject will receive a single 50 5 IU/kg, rounded to the nearest vial, intravenous (IV) 
infusion of moroctocog alfa (AF-CC), given over no more than 2 minutes.  The time of study 
drug reconstitution will be recorded.  The dose, prepared from a single lot, will be calculated 
based on the subject's actual body weight as measured that day (see Study Reference Manual 
for specific guidelines for PK dose based on the subject’s measured body weight).  The start 
and stop time of the infusion will be recorded.  The residual volume of dose remaining in the 
tubing, if any, should be immediately flushed into the subject as described in the Study 
Reference Manual.  Time 0 is the time when the study drug infusion begins.
Blood samples for FVIII:C determinations, to be used for PK analysis, will be drawn at 
0.5 hours (3 minutes), 8 hours (48 minutes), 24 hours (1 hour), 28 hours (1 hour), and 
32 hours (1 hour) after the start of the study drug infusion (refer to study flow chart in 
Section 8).  The blood sample to be drawn at 28 hours is optional.  The exact times of the 
actual PK sample blood draws will be recorded in the source documents.  All samples 
collected during the PK assessment must be prepared and identified in the manner described 
in the Study Reference Manual.
Just before (ie, within approximately 20 minutes of) the 0.5 and 24-hour PK sample 
collection times, vital signs (including temperature [Celsius], blood pressure, pulse, and 
respiration) will be collected.
Any AEs and concomitant medications should be recorded throughout the PK assessment in 
the subject’s source document.
If a subject experiences a bleeding episode during the PK assessment, the subject is to be 
stabilized with study drug.  The samples collected should be processed as directed.

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15.3. Procedures Following Early Termination or Other Potential Events
15.3.1. Early Termination
Subjects who are withdrawn or who voluntarily withdraw from the study subsequent to the 
screening period will have an accelerated Final Study Visit.  At this accelerated visit, all data 
specified for the Final Study Visit (see Section 15.1.11 for RP subjects) will be collected.  
The accelerated Final Study Visit should occur, if possible, within 7 days after a subject’s 
last infusion of study drug.  A Final Study Contact should occur at least 28 days after the 
accelerated Final Study Visit, as described in Section 15.1.12 for RP subjects.
15.3.2. Factor VIII Inhibitor Development
For the purposes of this study, a subject will be considered to have developed a FVIII 
inhibitor after receiving study drug if he has an inhibitor titer of 0.6 BU/mL in a sample 
assayed at the central laboratory using the Nijmegen assay; these criteria define a confirmed
FVIII inhibitor for this study.  In the event that a subject develops a confirmed FVIII 
inhibitor, the investigator will contact the Sponsor. The Sponsor and the investigator will 
determine whether the subject will remain in the study or be withdrawn from the study.
Subjects withdrawn from the study will complete the procedures of the Final Study Visit and 
Final Study Contact as described in Section 15.1.11 and 15.1.12 for RP subjects.  In addition 
to the Final Study Visit procedures described in Section 15.1.11 for RP subjects, subjects 
with a confirmed FVIII inhibitor should be rechallenged, unless medically contraindicated, 
with a single moroctocog alfa (AF-CC) infusion of 50 5 IU/kg at the Final Study Visit, 
following the 72-hour FVIII washout required for this visit (see Study Reference Manual for 
instructions regarding study drug reconstitution, administration, and data recording).
All blood sample collections required at the Final Study Visit (see Section 15.1.11 for RP 
subjects), as well as the physical examination and collections of weight and vital signs, will 
occur before the moroctocog alfa (AF-CC) infusion for rechallenge.  A blood sample will be 
collected at 0.5 hours (±3 minutes) after administration of the rechallenge infusion and sent 
to the central laboratory for FVIII: C analysis.  Vital signs (including temperature [Celsius], 
blood pressure, pulse, and respiration) will be collected just before (ie, within approximately 
20 minutes of) the 0.5-hour sample collection.  Three (3) to 5 days (inclusive of a 72-hour 
FVIII washout if possible) after the moroctocog alfa (AF-CC) infusion for rechallenge, blood 
samples will be collected for FVIII:C, FVIII inhibitor, and anti-FVIII antibody testing at the 
central laboratory.  Samples collected for the rechallenge analysis must be prepared and 
identified according to instructions provided in the Study Reference Manual.  After at least 
28 days following the Final Study Visit, the subject will complete the procedures of the Final 
Study Contact, as described in Section 15.1.12 for RP subjects.
NOTE: All tests for FVIII:C and/or FVIII inhibitor performed at the local laboratory should 
have duplicate samples from the same phlebotomy shipped to the central laboratory for 
analyses.  In cases of FVIII inhibitor development, these duplicate analyses will continue 
until the Final Study Contact.  Thus, a duplicate sample of all samples tested at the local 
laboratory for FVIII inhibitor development should also be sent to the central laboratory for 
confirmatory testing.  Aliquots of plasma samples will be stored in a -70°C or colder freezer.  
See Section 17.1 for additional discussion regarding FVIII inhibitor development.

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15.3.3. Regimen Escalation
During prophylaxis (segments 1 and/or 2), a subject’s prophylaxis regimen will be escalated 
if criteria are met.  The criteria for regimen escalation will be the occurrence of either of the 
following:
a.
2 or more spontaneous (atraumatic) bleeds into major joints (such as elbow, ankle, or 
knee joint) and/or into other target joints over a 4-week (28-day) period in the 
absence of a confirmed FVIII inhibitor.
OR
b. 3 or more spontaneous (atraumatic) bleeds (consisting of joint bleeds and/or 
significant soft tissue/muscle or other site bleeds) over a 4-week (28-day) period in 
the absence of a confirmed FVIII inhibitor.
Significant spontaneous bleeds are defined as those that lead to a transient or persistent loss 
of function.19  The loss of function may be transient and may evidence itself by a reluctance 
of the subject to utilize the affected body part in usual activities be it on account of pain, 
associated swelling or limitation in motion.  This specification is intended to prevent regimen 
escalation based upon clinically insignificant or minor bleeding episodes (eg, ecchymoses, 
epistaxis). 
The investigator will review these criteria with the subject/caregiver at the time study drug is 
first dispensed for protocol-assigned prophylaxis treatment, during telephone contacts, and at 
study visits.  In the event that any of the criteria for regimen escalation are met, the 
subject/caregiver must contact the investigator as soon as possible, and the investigator will 
confirm that the subject has met criteria.  The subject’s treatment will be escalated to a higher 
intensity prophylaxis regimen comprised of the most intensive components of both regimens 
A and B: 45 5 IU/kg, administered every other day.  The investigator will provide the 
subject/caregiver with instructions for the new, more intense prophylaxis regimen.  The 
subject will now follow the protocol-assigned regimen escalation, and arrangements for 
adequate study drug supplies will be made.  Further prophylaxis regimen escalations will be 
prescribed by the investigator with each recurrence of escalation criteria.  The subject will 
follow the assigned regimen(s) until the respective 12-month period of prophylaxis with 
study drug has been completed (segment 1 or 2); the 12-month period is inclusive of 
treatment time on all the prophylaxis regimens assigned during the respective study segment.
15.3.4. Unplanned, Required Surgery
As indicated, major surgery or orthopedic surgery planned to occur within the period 
following signing of the consent/assent form to the Final Study Contact (ie, during the course 
of this study) is an exclusion criterion for this study and only required minor surgery, or 
major/orthopedic surgical procedures which were unplanned at the time of signing the 
consent/assent form, may be allowed during the course of this study. 

Major surgical intervention- surgery involving open abdominal, intracranial and 
orthopedic procedures, including synovectomies and liver biopsies. Retroperitoneal, 

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thoracic, pharyngeal, retropharyngeal and invasive dental procedures involving 
complicated extractions are also considered major surgery.  For other major surgeries 
contact the Sponsor’s physician clinician.

Minor surgical intervention- surgery that includes laparoscopic abdominal procedures 
such as laparoscopic cholecystectomies or laparoscopic appendectomies.  Central 
venous catheter placement is also considered minor surgery.  For other minor 
surgeries contact the Sponsor’s physician clinician.
In the event that a minor surgery or an unplanned major or orthopedic surgery is required, the 
investigator will contact the Sponsor’s clinician.  The clinician will determine whether the 
subject will remain on the study or be withdrawn.  If withdrawn, the subject should follow 
procedures required for all withdrawn subjects (see Section 15.3.1).  Subjects who remain on 
the study will temporarily cease their current study drug treatment regimen (ie, 
investigator-prescribed on-demand therapy or protocol-assigned prophylaxis), and will 
instead receive study drug in bolus injection, as prescribed by the investigator, to achieve and 
maintain normal hemostasis through the surgical period.  Administration of study drug by 
continuous infusion will not be allowed during surgery or during the post surgical wound 
healing period. Moroctocog alfa (AF-CC) study drug will be the only FVIII replacement 
product used during the surgical period. 
The surgical period includes pre-, intra-, and postoperative periods; the surgical period begins 
with the administration of any preparatory study drug infusion for the surgery, and ends 
when the subject has recovered and is ready to resume his investigator-prescribed on-demand 
therapy or protocol-assigned prophylaxis with moroctocog alfa (AF-CC).  The investigator 
should refer to the Study Reference Manual for dosing guidelines for surgery.  After 
reviewing the dosing guidelines for surgery provided in the Study Reference Manual, the 
investigator will designate the appropriate study drug dose, and treatment duration for the 
surgical period, and should inform the Sponsor’s clinician in advance.  In addition to any 
AEs and concomitant medications (including any transfusions), the administration time and 
dose of all study drug infusions will be recorded during the surgical period.  The subject’s 
estimated blood loss and any nonpharmacological treatments will also be reported.
Samples for FVIII:C measurements will be collected within 15 to 30 minutes before the 
preoperative moroctocog alfa (AF-CC) infusion; approximately 30 minutes after completion 
of the preoperative infusion (and before the first surgical incision); just before any 
intraoperative infusion; approximately 30 minutes after completion of any intraoperative 
infusion; and daily during the in-hospital, postoperative period (ie, FVIII trough levels to be 
obtained before an infusion).  The time of the collection of samples for FVIII:C measurement 
will be recorded as well as the time of infusion of all doses.  NOTE: During the surgical 
period, all tests for FVIII:C and/or FVIII inhibitor performed at the local laboratory should 
have duplicate samples from the same phlebotomy shipped to the central laboratory for 
analyses.
Subjects will resume study drug treatment, as prescribed by their investigator (for on-demand 
therapy) or as defined by their protocol-assigned regimen (for prophylaxis), following the 

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surgical period.  The surgical period will not count as time on the treatment periods of this 
study; as such, study visits may need to be rescheduled accordingly.  For subjects whose 
surgical period exceeds 4 weeks, the Sponsor’s clinician will be contacted to discuss the 
suitability of the subject’s continued participation in the study.
15.4. Total Volume of Blood Collected
For each subject who participates in the study, the total volume of blood collected over the 
study period is detailed in the following table. 
Study Participation
Blood Volume (mL)
Study Visit/Contact ID
1
2
3
5
7
9
11
13
15
17
19
Total
RP Subject
20
13
9
9
9
9
18
9
9
9
20
134
RP Subject + PK
20
42a
9
9
9
9
18
9
9
9
20
163
Abbreviations: RP Subject = Routine Prophylaxis treatment during segment 1 followed by Routine Prophylaxis treatment 
during segment 2; RP Subject + PK = Routine Prophylaxis treatment and Pharmacokinetic Assessment during segment 1 
followed by Routine Prophylaxis treatment during segment 2.
a.
42 mL total.  Approximately 28 mL on day 1 of PK assessment and 14 mL on day 2 of PK Assessment (Visit 2).
16. TEST ARTICLE AND ADMINISTRATION
Study drug, moroctocog alfa (AF-CC), will be labeled according to local regulations.  The 
Sponsor will not ship clinical supplies until a signed approval letter from the IRB/IEC has 
been received and a contractual agreement has been signed by the Sponsor and the study site.
16.1. Moroctocog alfa (AF-CC) Administration for Pharmacokinetic Assessment
A single IV infusion of study drug at a dosage of 50 5 IU/kg rounded to the nearest 
complete vial, will be administered over no more than 2 minutes for PK assessment.  The 
dose, prepared from a single lot, will be calculated based on the subject's actual body weight 
as measured on the day of study drug administration (see Study Reference Manual for 
specific guidelines for PK and recovery dose based on the subject’s measured body weight).  
The time of study drug reconstitution will be recorded.  The start and stop time of the 
infusion will be recorded.
16.2. Moroctocog alfa (AF-CC) Administration for Rechallenge
In addition to the Final Study Visit procedures described in Section 15.1.11 for RP subjects, 
subjects with a confirmed FVIII inhibitor should be rechallenged, unless medically 
contraindicated, with a single moroctocog alfa (AF-CC) study drug infusion of 50 ±5 IU/kg 
at the Final Study Visit, following the 72-hour FVIII washout required for this visit (see 
Study Reference Manual for instructions regarding study drug reconstitution, administration, 
and data recording).
16.3. Moroctocog alfa (AF-CC) Administration for Hemophilia A Treatment
In total, RP subjects will use moroctocog alfa (AF-CC) study drug, in an open-label manner, 
for a 24-month period.  In segment 1, all subjects will use moroctocog alfa (AF-CC) 
according to 1 of 2 randomly assigned prophylactic regimens.  Segment 1 for RP subjects 

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will be 12 months in duration.  All subjects will then use moroctocog alfa (AF-CC) for 
prophylaxis during segment 2, as specified in Section 16.3.2.  Prophylaxis subjects will cross 
over to the other protocol-assigned prophylaxis regimen during segment 2.  During 
prophylaxis, subjects will also use moroctocog alfa (AF-CC), as needed, for the treatment of 
bleeds (ie, on-demand).  See Section 16.3.1 and 16.3.2 for administration guidelines and 
recommendations for on-demand and prophylaxis dosing, respectively.
Moroctocog alfa (AF-CC) study drug will be administered as a bolus intravenous infusion. If 
an indwelling catheter (eg, Port-A-Cath) is in place, it may be used for moroctocog alfa 
(AF-CC) study drug infusions, when appropriate.
16.3.1. Moroctocog alfa (AF-CC) Administration for On-Demand Treatment of 
Breakthrough Bleeds
All bleeding episodes will be treated (on-demand) at the discretion of the 
caregiver/investigator.  Treatment guidelines, based on current recommendations for 
on-demand treatment with the licensed product Xyntha®, are provided in Appendix 1.  
A subject’s specific circumstances should be considered when determining a specific dose.  
The dose will be prepared using the actual potency on the label of the study drug to be 
administered and the subject's most recent actual body weight as measured during the study.
16.3.2. Moroctocog alfa (AF-CC) Administration for Prophylaxis
Subjects will be advised to routinely administer the prophylaxis dose in the morning, in 
advance of their day’s activities.  The dose will be prepared using the actual potency on the 
label of the study drug to be administered and the subject's most recent actual body weight as 
measured during the study.  See Study Reference Manual for guidelines of dose selection 
based on the subject’s measured body weight.
Subjects will use moroctocog alfa (AF-CC) for prophylaxis according to the assigned 
regimen, A or B:
A: 45 5 IU/kg, administered twice per week
B: 25 5 IU/kg, administered every other day
For regimen A, the interval between prophylactic infusions should be 3 to 4 days, and should 
not exceed 4 days.  For regimen B, the interval between prophylactic infusions should be 
approximately 48 hours (eg, an appropriate dosing schedule for Regimen B is as follows 
Monday, Wednesday, Friday, Sunday, Tuesday, Thursday, Saturday, Monday…etc). 
The dosage and dosing frequency of these regimens are consistent with ReFacto and 
moroctocog alfa (AF-CC) clinical data, and with recommendations for prophylactic dosing in 
the literature.3,12,19,20,21  (See Study Reference Manual for specific dose selections for 
regimens A and B based on the subject’s measured body weight).  A subject’s treatment will 
be escalated to a more intensive prophylaxis regimen (45 5 IU/kg, administered every other 
day, initially, and if dose escalation criteria are met while on this more intensive regimen the 
subsequent regimen escalation will be investigator-designated) if criteria justifying regimen 

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escalation are met (see Section 15.3.3).  Guidance for prophylaxis treatment is offered in the 
investigator’s brochure.
16.4. Formulation, Packaging, and Labeling
The study drug, moroctocog alfa (AF-CC), is formulated as a sterile, nonpyrogenic, 
lyophilized powder preparation for IV injection.  Study drug will be available in single-use 
vials containing the labeled amount of actual FVIII activity (IU).  Each vial of study drug 
contains nominally 250 IU, 500 IU, 1000 IU, or 2000 IU per vial.
16.5. Storage and Stability
Moroctocog alfa (AF-CC) as packaged: Study drug should be stored under refrigeration at a 
temperature of 2 °C to 8 °C (36 °F to 46 °F).  It is stable for up to 3 months at 25 °C. The 
product should not be returned to refrigeration once it has been stored at 25 °C. Freezing of 
diluent or study drug should be avoided to prevent damage.  The study drug should be stored 
to protect from light.  Study drug should not be used after the expiry date on the label.
Investigators and site staff are reminded to check temperatures daily and ensure that 
thermometers are working correctly as required for proper storage of investigational 
products. These include thermometers for both the room storage and refrigerator storage.
Deviations from the storage requirements, including any actions taken, must be documented 
and reported to the Sponsor. Once a deviation is identified, the study drug must be 
quarantined and not used until the Sponsor provides documentation of permission to use the 
study drug.
Moroctocog alfa (AF-CC) after reconstitution: The reconstituted moroctocog alfa (AF-CC) 
solution does not contain a preservative and should be used within 3 hours after 
reconstitution.  The reconstituted solution should not be refrigerated. 
16.6. Preparation
The investigator (or designee) should follow specific reconstitution and administration 
procedures detailed in the Study Reference Manual for study drug preparation during the 
study. Caregivers should follow the specific reconstitution and administration procedures 
provided by the investigator during the study.
16.7. Drug Accountability
The US Food and Drug Administration (FDA) and other regulatory agencies require 
accounting for the disposition of all investigational drugs received by each study site.  
Information on drug disposition required by law consists of the date received, date 
administered, quantity administered, and the subject to whom the drug was administered.  
The investigator is responsible for the accounting for all unused study drug and diluent and 
all used study drug.  (NOTE: Used diluent syringes will not be returned for test article 
accountability due to the potential risk of blood contamination.  Therefore, each returned 
study drug vial indirectly accounts for each diluent syringe used by the subject).  Study drug 
may not be given to nonstudy patients under any circumstances.

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Supplies will be shipped to the study site at appropriate intervals, depending on subject 
accrual. The site will use the Dispensing and Inventory Record provided by the Sponsor to 
document study drug disposition.  This record must be maintained either in the pharmacy or 
in another area approved by the Sponsor’s monitor.  Drug accountability will be reviewed by 
a monitor during routine monitoring visits and interim drug returns will be performed as 
needed.  Each time a dose is prepared (for the PK assessment) or vials are dispensed for a 
subject, the following information must be recorded: the subject’s study number, the number 
of vials dispensed, the date dispensed, the number of the lot from which the dose was 
prepared, and the initials of the person preparing the dose. The doses prepared for subjects at 
the study site for the PK assessment will be documented on a worksheet to be kept at the 
study site.
The investigator (or designee) will instruct each subject or parent/legal acceptable 
representative to whom drug is dispensed, to return used study drug vials at each study visit, 
and to return all study drug vials (used and unused) and all unused diluent syringes at the 
Final Study Visit.
At the termination of the study, a final drug accountability review and reconciliation must be 
completed and any discrepancies must be investigated and their resolution documented. 
All used and unused study drug vials and all unused diluent syringes may be returned to the 
Sponsor.  Alternatively, all used and unused study drug vials and unused diluent syringes 
may be destroyed at site, per the local requirements, after the site and Sponsor have 
performed drug accountability.
16.8. Subject Compliance
The investigator or the Sponsor’s clinician may withdraw a subject if he or she decides that a 
subject’s noncompliance is damaging to the study or the subject’s best interests.  No 
predetermined percentage of missing vials or data will define a subject as “noncompliant.”  
The final study report will document and report the impact of extensive noncompliance on 
study conclusions.  Vial counts, Subject Diaries, and verbal information will be used to 
determine subject compliance.  Subjects who are withdrawn for noncompliance or any other 
reason will have an accelerated Final Study Visit.  All data specified in Section 15.1.11 for 
RP subjects will be collected.  The Final Study Visit for subjects who are withdrawn or 
withdraw, if possible, should occur within 7 days after their last infusion of study drug.  A 
Final Study Contact should also occur at least 28 days after the Final Study Visit, as 
described in Section 15.1.12 for RP subjects.
17. SAFETY
The Sponsor may stop the study for any reason; the reason for study cessation will be 
documented.
This study will use an External Data Monitoring Committee (E-DMC).  The E-DMC will 
periodically review data from the study to ensure subject safety according to the Charter. 
The E-DMC includes physicians experienced in the management of hemophilia who are not 
investigators in the study, including at least one who is also experienced in the treatment of 

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children with hemophilia.  The E-DMC also includes a statistician experienced in the review 
of clinical trials.  The schedule of the E-DMC review will be determined by the E-DMC with 
review intervals of approximately every 6 months.  Additional meetings may be held at the 
discretion of the E-DMC or upon request by the Sponsor.  The E-DMC members will be 
provided demography data, safety data inclusive of inhibitor formation data, laboratory data 
including factor VIII inhibitor assay results, and relevant efficacy data, in advance of the 
meetings. The recommendations made by the E-DMC to alter the conduct of the study will 
be forwarded to Pfizer for final decision.  Pfizer will forward such decisions, which may 
include summaries of aggregate analyses of endpoint events and of safety data which are not 
endpoints, to regulatory authorities, as appropriate. 
Safety variables in the study are listed in Section 22.1.  The following describes the 
collection of safety data for 1 of these variables in greater detail.
17.1. Factor VIII Inhibitors
For the purposes of this study, a subject will be considered to have developed a FVIII 
inhibitor after receiving study drug if he has a titer of ≥0.6 BU/mL in a sample assayed at the 
central laboratory using the Nijmegen assay; these criteria define a confirmed FVIII inhibitor 
for this study.  Confirmed FVIII inhibitors will be further categorized as low titer or high 
titer.  Low-titer inhibitors are defined as those inhibitors with titers between 0.6 to <5 BU/mL 
in a sample assayed at the central laboratory using the Nijmegen assay.  High-titer inhibitors 
are defined as those inhibitors with a titer of 5 BU/mL assayed at the central laboratory 
using the Nijmegen assay.  If a FVIII inhibitor resolves (by the Nijmegen assay at the central 
laboratory) at or before a subject’s final assessment it will be further classified as transient.
Investigators must report all FVIII inhibitors in the same expedited manner as outlined for 
serious adverse events (SAEs; see Section 26.13.1).  The Sponsor will report all confirmed 
FVIII inhibitors to regulatory authorities in the same manner as unexpected, related SAEs.
If a subject has a local laboratory assay that is considered positive for FVIII inhibitor by the 
investigator in spite of a negative central laboratory result, or the investigator considers the 
subject to have developed a FVIII inhibitor for other reasons based on clinical grounds 
(although all suspected FVIII inhibitors should also be supported by laboratory evidence; the 
investigator may perform additional laboratory tests for FVIII inhibitor as appropriate in his 
medical judgment), then the finding will be reported in the manner of and recorded as an 
SAE.  Reports or assays received by the Sponsor, which are suggestive of a FVIII inhibitor, 
will be confirmed by the study’s central laboratory before communication with regulatory 
authorities.  In addition, for purposes of the analyses of this study, any FVIII inhibitor report 
not confirmed by the central laboratory (ie, sample did not have a titer of 0.6 BU/mL by the 
Nijmegen assay) will count as an SAE, but will not count as a FVIII inhibitor. 
In the event that subjects develop a confirmed FVIII inhibitor, the investigator will contact 
the Sponsor. The Sponsor and the investigator will determine whether the subject will 
remain in the study or be withdrawn from the study. Subjects withdrawn from the study will
complete the procedures of the Final Study Visit and Final Study Contact as described in 
Sections 15.1.11 and 15.1.12.

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FVIII inhibitor development is a safety variable for this study.  The incidence of FVIII 
inhibitor (ie, number of subjects with confirmed FVIII inhibitor development) will be 
reported.
17.2. Antibodies to Moroctocog alfa (AF-CC) Components
Patient serum samples will be collected and tested for the development of antibodies (both 
neutralizing and nonneutralizing) to moroctocog alfa (AF-CC), antibodies to CHO cell 
proteins derived from the cell line used in manufacture of moroctocog alfa (AF-CC), and 
antibodies to TN8.2, the affinity ligand used in purification of moroctocog alfa (AF-CC), 
using a validated ELISA.
18. EFFICACY
Specific efficacy variables for this study are listed in Section 22.2.  The following describes 
the collection of some variables in detail.
18.1. Bleeding
The incidence of bleeding treated with FVIII replacement infusion(s) will be obtained from 
Subject Diaries and medical records.  Where relevant, investigators (or designee) and 
monitors will ensure that there is consistency between the subject’s medical record and/or 
Subject Diaries and the electronic case report forms (eCRFs).  Such bleeding episodes will 
not be reported as AEs although the concomitant events associated with a bleed may be 
reported as an AE if appropriate (eg, a fracture).  In the rare instance in which a bleeding 
episode also meets the criteria for a Serious Adverse Event, then the bleeding episode should 
be recorded as an AE. Only bleeding episodes that are considered serious and meet the SAE 
criteria should be listed on the AE case report form (CRF) page.  If the bleeding episode 
qualifies as an SAE and is treated with study drug, then in addition to recording the bleed 
event on the AE eCRF, the bleed event should also be recorded on the Bleed log as there is 
information captured on the Bleed log that is not captured on the AE eCRF (eg, infusion 
information and response to study drug).
Both spontaneous bleeding episodes and traumatic bleeding episodes will be collected.
18.1.1. Types of Bleeding
For the purposes of this study, a bleed treated with study drug will be classified as either 
spontaneous or traumatic.  The subject’s diary or medical record will serve as the source 
document for bleeding episodes while on study.  Investigators (or designee) and/or monitors 
will review the Subject Diary and medical records to assist in classification if necessary.  The 
criteria for spontaneous and traumatic bleeds are described below.
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 
trauma, antecedent “strenuous” activity, or “overuse”.  The determination of “strenuous” or 
“overuse” is at the discretion of the subject/caregiver/investigator.  For example, if a subject 
were to wake up in the morning and note he was bleeding, a “spontaneous” bleed would be 
recorded.  Target joints can have spontaneous bleeding episodes.  Incidences of spontaneous 

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bleeding episodes define regimen escalation criteria during prophylaxis (see Section 15.3.3).  
For this purpose, spontaneous bleeds are further categorized as “significant”.  Significant 
spontaneous bleeds are defined as those that lead to a transient or persistent loss of function 
(see Section 15.3.3).
Traumatic Bleeding Episodes: Bleeding episodes should be classified as traumatic if a 
subject records a bleeding event when there is a known or presumed 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 be recorded as a traumatic bleed.  Target joint bleeding 
episodes can be traumatic if a known action led to bleeding into the joint.
18.1.2. Location of Bleeds
For the purposes of this study, when subjects report a bleed treated with study drug, the 
location of the bleed should be recorded in the Subject Diary or medical record.  Bleeds will 
be reported as occurring in 1 of the following locations: joint, muscle/soft tissue, or other.  
Each individual location of multiple-site bleeds will be reported.  For joint bleeds, the 
specific joint will be reported.  Parameters to identify joint bleeds include: pain on joint 
motion, limitation of motion, and visible swelling of joint.
18.1.3. Treatment of Bleeds
Typically, a bleed would be treated with an (on-demand) infusion of study drug.  The 
specific treatment with study drug is at the discretion of the subject/caregiver/investigator but 
all doses and infusions of study drug will be recorded and reported.
The subject/caregiver/investigator will assess efficacy of study drug in treating a bleed by 
recording their assessments of efficacy through the use of the 4-point On-Demand 
Hemostasis Efficacy Rating Scale, described below.  The 4-point response scale for 
on-demand treatment of a bleeding episode, is defined as follows:

Excellent: Definite pain relief and/or improvement in signs of bleeding starting within 
8 hours after an infusion, with no additional infusion administered.

Good: Definite pain relief and/or improvement in signs of bleeding starting within 
8 hours after an infusion, with at least one additional infusion administered for 
complete resolution of the bleeding episode. 
or,
Definite pain relief and/or improvement in signs of bleeding starting after 8 hours 
following the infusion, with no additional infusion administered.

Moderate: Probable or slight improvement starting after 8 hours following the 
infusion, with at least one additional infusion administered for complete resolution of 
the bleeding episode.

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
No Response: No improvement at all between infusions or during the 24 hour 
interval following an infusion, or condition worsens.
18.2. Less Than Expected Therapeutic Effect
All bleed and study drug infusion response data will be reported and analyzed (see 
Sections 22.2 and 22.5.3).  The following text describes criteria defining a specific subset of 
these data that will also be reported and referred to “Less than expected therapeutic effect”.
“Less than expected therapeutic effect” (LETE) is an efficacy variable of this study.  LETE 
can occur in 3 specific circumstances.  All types of LETE in aggregate and individually will 
be summarized as part of the efficacy information collected in this study.  The following 
criteria define LETE.
Less than Expected Therapeutic Effect in the On-Demand Setting
LETE occurs in the on-demand setting if the subject records 2 successive “No Response” 
ratings after 2 successive study drug infusions, respectively.  The infusions must have been 
administered within 24 hours (24 hours) of each other for treatment of the same bleeding 
event in the absence of confounding factors (described below).  Therefore, LETE in the 
on-demand setting is based on the response to treatment of a bleed.  The only confounding 
factors are as follows:

Known presence or subsequent identification of a FVIII inhibitor.

Known inadequate dose for the type and/or severity of bleed in the opinion of the 
investigator.

Delay of greater than 4 hours between onset of bleed to infusion.

Delay of greater than 24 hours before administration of a follow-up infusion.

Known compromised study drug.

Faulty administration of study drug.

The subject has an underlying, predisposing condition responsible for the bleed in the 
opinion of the investigator (eg, kidney stones or use of medications known to impair 
platelet function, such as aspirin or NSAIDs).
For the purposes of this study, LETE in the on-demand setting will be summarized only from 
eCRFs.  In the absence of identified confounding factors, monitors will query a site if 
2 “No Response” ratings occur for 2 infusions which are given within 24 hours (≤24 hours) 
for the same bleed and LETE is not noted.
Less than Expected Therapeutic Effect in the Prophylaxis Setting

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LETE occurs in the prophylaxis setting if there is a spontaneous bleed within 48 hours 
(≤48 hours) after a regularly scheduled prophylactic dose of study drug (which was not used 
to treat a bleed) in the absence of confounding factors.  Therefore, LETE in the prophylaxis 
setting is the occurrence of a bleed.  The only confounding factors are as follows:

Known presence or subsequent identification of a FVIII inhibitor.

Known inadequate prophylactic dose (ie, a dose less than that prescribed in subject’s 
regimen).

Known lack of adherence to the prescribed prophylaxis regimen.

Bleed occurs in a target joint identified at the start of the study.

Known compromised study drug.

Faulty administration of study drug.

The subject has an underlying, predisposing condition responsible for the bleed in the 
opinion of the investigator (eg, kidney stones or use of medications known to impair 
platelet function, such as aspirin or NSAIDs).
For the purposes of this study, LETE in the prophylaxis setting will be summarized only 
from eCRFs.  In the absence of identified confounding factors, monitors will query a site if a 
spontaneous bleed within 48 hours (≤48 hours) of a prophylactic dose is recorded and LETE 
is not noted.
Less than Expected Therapeutic Effect (Low Recovery)
LETE can also be lower than expected recovery of FVIII in the opinion of the investigator 
following infusion of study drug in the absence of confounding factors.  There are no planned 
recovery measurements outside the PK assessment that subjects may undergo at study start.  
During the course of this study, additional recovery measurements should be done only for 
assessment of a possible FVIII inhibitor.  (NOTE: During the treatment phase of the study, 
all tests for FVIII:C and/or FVIII inhibitor performed at the local laboratory should have 
duplicate samples from the same phlebotomy shipped to the central laboratory for analyses.)  
Therefore, LETE (Low Recovery) can happen only if a recovery measurement is performed 
for clinical management of a subject and an inhibitor is not confirmed by the central 
laboratory.  The only confounding factors for low recovery are as follows:

Known presence or subsequent identification of a FVIII inhibitor.

Known compromised study drug.

Faulty administration of study drug.

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19. PHARMACOKINETICS 
19.1. Pharmacokinetic Analysis
FVIII:C will be analyzed by a central laboratory using a one-stage method (mnemonic 
CB-0052).  Using a sample volume of 0.5 mL, the range of quantitation is 
0.0100-0.8300 IU/mL.  The upper limit of quantitation is slightly variable and depends upon 
the potency of the lot of calibrator.  Stability of the samples has been shown for 3 freeze/thaw 
cycles.  The coefficient of variations for precision of the calibrators in method development 
was less than 12.4% and the accuracy ranged between 89 and 115% of the expected 
amount.22
19.2. Pharmacokinetic Methods
The plasma FVIII activity (FVIII: C)-versus-time curves after administration of moroctocog 
alfa (AF-CC) will be characterized, using standard noncompartmental methods.  FVIII:C at 
0.5 hours after the start of study drug infusion (C0.5 hr) will be directly determined from the 
observed FVIII:C data.  The terminal-phase disposition (elimination) rate constant (z) will 
be estimated by regression of the terminal log-linear phase of the FVIII:C-versus-time curve.  
The terminal phase half-life (t½) will be calculated as:
t½ = ln2 / z
The areas under the FVIII:C-versus-time curves (AUCt) and under the moment curve 
(AUMCt) to last measurable activity (Ct) will be calculated using the trapezoidal method. 
The area under the curve from 0 to infinity (AUC) will be estimated as:
AUC= AUCt + Ct / z
Similarly, area under the moment curve from 0 to infinity (AUMC) will be estimated as:
AUMC= AUMCt + [(Ct t) / z] + [Ct / (z)2]
where, t is the time corresponding to the last measurable Ct.
The clearance (CL) will be calculated as:
CL = Dose/AUC
where, Dose = IU/kg of study drug administered.
The mean residence time (MRT) will be calculated as:
MRT = AUMC/AUC- TI/2
where, TI is the duration of infusion.
The volume of distribution at steady state (Vss) will be calculated as:

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Vss = CL MRT.
Incremental recovery, is estimated using the following formula:
Incremental recovery = (C0.5 hr-C0)/Dose
where,
C0 =  FVIII:C at time 0 (time before start of study drug infusion)
Dose = IU/kg of study drug administered.
The FVIII:C concentrations measured in this study may be combined with similar data from 
other studies to perform a population pharmacokinetic analysis using nonlinear mixed effects 
modeling (NONMEM).
20. PHARMACODYNAMICS
There are no planned pharmacodynamic evaluations. 
21. LABORATORY DETERMINATIONS
Samples for required assays may be collected according to the procedures at the clinical trial 
study site.  Samples taken for the central laboratory will be collected according to the 
schedule outlined in Section 7, 8 and 15 of this protocol.  Sample collection, storage, and 
shipping information can be found in the Study Reference Manual supplied by the Sponsor.  
All clinically important abnormal laboratory test values identified after study drug 
administration will be followed until the condition stabilizes or until the end of the subject’s 
participation in the study; any clinically important abnormal laboratory test value should be 
reported as an AE (or SAE if appropriate, see Sections 26.4 for reporting abnormal test 
findings as AEs and 26.13.1 for SAE criteria).
22. STATISTICS
Additional details of the analysis will be provided in the statistical analysis plan and/or the 
clinical study report.  This may include details of missing, and if applicable, unused and 
spurious data.  Deviations from the statistical plan will be reported in the clinical study 
report.
Safety and efficacy analyses for the OD cohort (on-demand therapy in segment 1, followed 
by the prescribed prophylaxis regimen in segment 2), will be done independently from the 
analyses for the RP cohort (randomized to follow prophylaxis regimens in both 
segments 1 and 2).  PK characterization will be presented for all subjects (in either cohort) 
who provided PK data.  In addition, select tables will be provided for all subjects in the 
study, regardless of cohort.

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22.1. Safety Variables

Incidence of AEs (by severity and by relationship to moroctocog alfa [AF-CC]).

Incidence of confirmed FVIII inhibitor development.

Incidence of development of antibodies to moroctocog alfa (AF-CC), CHO cell 
proteins, and TN8.2.
22.2. Efficacy Variables

Annualized bleed rate (ABR).

Number of moroctocog alfa (AF-CC) infusions per bleed.

Response of bleed to moroctocog alfa (AF-CC) treatment (4-point scale of 
assessment, see Section 18.1.3).

Time interval between bleed onset and prior moroctocog alfa (AF-CC) prophylaxis 
dose.

Incidence of prophylaxis regimen escalation.

Incidence of LETE (see Section 18.2).

Consumption of moroctocog alfa (AF-CC).

Compliance with assigned prophylaxis regimen.
Note: All subjective assessments will be provided by the caregiver or investigator.
22.3. Pharmacokinetic Variables
Primary variables:

Terminal phase half-life (t½).

Clearance (CL).

Incremental recovery.
Secondary PK variables:

maximum concentration (FVIII:C at 0.5 hours after study drug infusion [C0.5 hr]).

area under the curve to infinity (AUC).

area under the curve to last measurable concentration (AUCt).

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
steady-state volume of distribution (Vss).

mean residence time (MRT).
22.4. Subject Populations in the Analysis of Study Variables
22.4.1. Safety Variables
The safety analyses will be performed on the intent-to-treat (ITT) population.  This 
population includes all subjects who sign the informed consent/assent form.  Screen failures 
will not be included in the ITT population.
Analysis of the incidence of confirmed FVIII inhibitor development will be performed on the 
modified intent-to-treat (mITT) population.  The mITT population consists of the subset of 
ITT subjects who received at least one dose of study drug. 
22.4.2. Efficacy Variables
The efficacy analyses will be performed on the ITT population.  This population includes all 
subjects who sign the informed consent/assent form.  Screen failures will not be included in 
the ITT population.  If a subject develops a confirmed FVIII inhibitor, his data will be 
included up to the time an inhibitor is determined to be present.
Efficacy analyses will also be performed on per-protocol populations.  The statistical analysis 
plan will define per-protocol populations.
22.4.3. Pharmacokinetic Variables
All FVIII:C data will be reported.  Individual pharmacokinetic analysis will be performed on 
all subjects for whom an adequate pharmacokinetic profile has been obtained.
22.5. Analysis of Study Variables 
22.5.1. General
A discussion of the statistical methods by which the study hypotheses will be tested is 
provided below (see section 22.5.3).  In addition, continuous variables for PK, efficacy, and 
safety analyses will be summarized by descriptive statistics.  Categorical variables will be 
presented in frequency tables, with counts and percentages provided for each category.  
Missing data will be reported as such and no imputation will be made.  Additional details of 
the study analyses will be provided in the statistical analysis plan.
22.5.2. Safety Variables

The number (%) of subjects experiencing any AE will be reported.  AEs will be 
summarized by body system and preferred term regardless of the relationship to 
moroctocog alfa (AF-CC).  The incidence of AEs by severity and the incidence of 
AEs by the relatedness to moroctocog alfa (AF-CC) will also be summarized.

The number (%) of subjects who develop a confirmed FVIII inhibitor will be 
reported, and categorized by inhibitor titer (ie, high or low).

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22.5.3. Efficacy Variables
The annualized bleed rate (ABR) is the primary endpoint for testing the primary objective of 
the study, as well as for testing one of the secondary objectives of the study.  ABRs will 
reflect the incidence of bleeds treated with FVIII replacement therapy.  To avoid potential 
bias related to prior treatment, the first month of each protocol-defined prophylaxis treatment 
will serve as a washout period; ABR analyses will be performed with and without data from 
this washout period. 

For the primary objective of demonstrating that moroctocog alfa (AF-CC) 
prophylaxis reduces the ABR relative to on-demand therapy, the null hypothesis is 
that prophylactic treatment does not reduce the ABR relative to on-demand treatment.  
The alternative hypothesis is that prophylactic therapy does reduce the ABR.

To test the hypothesis, an analysis of variance (ANOVA) will be conducted to 
compare the mean ABR between subjects in on-demand (segment 1) and prophylaxis 
(segment 2) treatment regimens.  Only subjects who practice on-demand therapy with 
moroctocog alfa (AF-CC) during segment 1, before starting the protocol-defined 
moroctocog alfa (AF-CC) prophylaxis in segment 2, will be included in this analysis.  
The ANOVA will include factors for treatment regimen (study segment 1 or 2).  The 
model will also include a blocking factor for subjects to ensure that the comparison of 
ABRs from each treatment regimen is performed on a within subject basis.  The 
p-value for treatment regimen calculated in ABR of the ITT population will be used 
to test the null hypothesis; a p-value less than 0.05 will be considered significant.

For the secondary objective of assessing the effect of a high- versus low-frequency 
dosing schedule on the efficacy of moroctocog alfa (AF-CC) prophylaxis, the null 
hypothesis is that there is a difference in mean ABR between the two prophylaxis 
regimens.  The alternative hypothesis is that the two prophylaxis regimens are similar 
enough to be considered clinically equivalent.  To test this hypothesis, the two
protocol-defined prophylaxis regimens (a high- and a low-frequency dosing regimen) 
will be assessed in a crossover design.  Only subjects who practice protocol-defined 
prophylaxis regimens in segment 1 and 2, respectively: the low- followed by the 
high-frequency dosing regimen (AB), or the high- followed by the low-frequency 
dosing regimen (BA) will be included in this analysis.
The 90% 2-sided confidence interval (CI) for the mean difference in ABRs for 
the 2 prophylaxis regimens for ITT subjects will be constructed using the t 
distribution with n-1 degrees of freedom (n equals the number of subjects) to 
assess the equivalence of these 2 regimens.  Equivalence will be demonstrated 
if the limits of the 90% CI fall wholly within the interval of (–4, 4) bleeds per 
year.

ABR will also be presented as descriptive statistics (n, mean, SD, median, minimum, 
and maximum).  ABRs will be summarized by bleed type (ie, spontaneous or 
traumatic), by bleed location (eg, joint, soft tissue/muscle), and by treatment period
(ie, on-demand therapy or prophylaxis). 

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Additional efficacy variables:

Number of study drug infusions used to treat a bleed will be summarized by bleed 
location and by dose (IU/kg) administered at the first infusion.

The 4-point response (efficacy rating) for study drug-treated bleeds will be 
summarized, and any successive ratings of “No Response” will also be reported.  The 
response to the first study drug infusion to treat a bleed will be tabulated by the total 
number of infusions needed for bleed resolution.  First infusion responses will also be 
summarized by bleed location and by administered dose (IU/kg).

The time between onset of a bleed and prior moroctocog alfa (AF-CC) routine 
prophylaxis infusion will be summarized by the following categories: 24, >24-48, 
>48-72, and >72 hours.

The number (%) of subjects requiring prophylaxis regimen escalation during 
protocol-defined prophylaxis will be provided, and will be reported for each 
protocol-defined regimen.

The number (%) of subjects reporting LETE (see Section 18.2) will be provided.

For consumption of moroctocog alfa (AF-CC) per bleed, first infusion (IU/kg) and 
total dose (IU/kg) administered for the bleed will be summarized by bleed location 
(joint, soft tissue/muscle, multiple sites, and other).  For consumption of moroctocog 
alfa (AF-CC) over time, the number of infusions, exposure days (ED), and dose 
(IU/kg and IU) per infusion will be summarized by reason of dosing (ie, on-demand 
or prophylaxis).  Descriptive statistics (n, mean, SD, median, minimum, and 
maximum) will be provided.

Descriptive statistics will be provided to summarize subject compliance to their 
assigned prophylaxis regimen (dose [IU/kg] and dose frequency [number of infusions 
per week]).  The number of infusions and the number of days (and weeks) on each 
assigned prophylaxis regimen will be presented for each subject.
22.5.4. Pharmacokinetic Variables
All PK variables (see Section 19.1, 22.3) will be summarized by descriptive statistics 
(number [n], mean, median, standard deviation [SD], standard error [SE], minimum and 
maximum, coefficient of variance [CV %], geometric mean, and 95% confidence intervals 
[CI]).
Graphic exploration of potential relationships between age, weight, body-surface area and 
body mass index and CL, Vss, t½ and incremental recovery will be performed.
22.6. Interim Analysis and Report
An independent E-DMC will periodically review data from the study to ensure subject safety, 
with review intervals of approximately every 6 months.  See Section 17 for more information 
regarding the E-DMC.

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Prior to study completion, selected (safety, efficacy and/or PK) data from this study may be 
summarized and reported to regulatory authorities to support regulatory submissions or 
requests. The analyses for these summaries would be based on descriptive statistics. 
Per discussions with the FDA, a final report for the OD cohort will be submitted comparing 
prophylaxis efficacy and safety versus on-demand therapy according to section 3.3 of the 
statistical analysis plan.  Additionally, after approximately 38 evaluable RP subjects, who 
practiced prophylaxis for both segment 1 and segment 2, complete the study, a final report 
for the RP cohort will be submitted.
22.7. Statistical Power and Sample Size Considerations
The sample size of each cohort of the study is based on the statistical comparison of ABR 
between the first and second segments.  Data from a previous ReFacto PUP study (Wyeth 
protocol 3082A1-301-WW) guided assumptions for the sample size estimates for objectives 
of this study.  Additional information regarding each of these sample size estimates is 
provided below.
In the completed ReFacto 3082A1-301-WW PUP study, a reduction in the ABR was 
observed for subjects during their periods of prophylaxis (2 infusions per week) compared 
to their periods of on-demand therapy (reduction of 5.7 6.9 bleeds per year, [11.85 to 
6.15 bleeds per year], ABR decrease of 48%, N=39).  Based upon this experience, a more 
conservative decrease in ABR of 40% (corresponding to a mean change of 4.75 bleeds per 
year) and a standard deviation of 7 were selected for use in power calculations for the 
comparison of ABRs in the on-demand versus prophylaxis setting for this study (see 
Section 22.4.2 for description of statistical analysis).  A sample size of 18 OD subjects who 
practice on-demand therapy in segment 1, followed by prophylaxis in segment 2, provides
80% power to detect such a difference using a 2-sided alpha level of 0.05.  Due to an 
expected attrition rate of up to 25%, approximately 24 OD subjects, who practice on-demand 
therapy during segment 1, were planned to be enrolled to ensure that 18 are evaluable for the 
comparison of ABRs in the on-demand versus prophylaxis setting.  Because enrollment into 
the OD cohort has been closed, all available data will be analyzed.
For the RP cohort, the comparison of high- versus low-frequency prophylaxis dosing 
schedules, a subset analysis of data from the completed ReFacto PUP study (Wyeth protocol 
3082A1-301-WW) revealed an ABR of 5.7 5.2 (N=26) in patients receiving a 
high-frequency prophylaxis regimen (3 infusions per week) compared to an ABR of 
7.1 4.1 (N=13) in patients receiving a lower-frequency prophylaxis regimen (2 infusions per 
week).  However, the treatment assignment was not randomized and prophylaxis regimens 
were not controlled in that study.  To avoid selection bias and inter-patient variability 
affecting outcome, two protocol-defined prophylaxis regimens (a high- and a low-frequency 
dosing regimen) will be assessed in a crossover design. Assuming an intraclass correlation 
of 30% and a standard deviation of 6 bleeds per year based on this previous ReFacto PUP 
study, a within-subject standard deviation of 5 bleeds per year was used for sample size 
calculations for the comparison between the two protocol-defined prophylaxis regimens 
(A and B).  Given this, 36 RP subjects are needed to provide 80% power to demonstrate 
equivalence of the two regimens (see Section 22.5.3 for description of statistical analysis).  

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Allowing for an attrition rate of 25%, approximately 48 RP subjects need to be enrolled to 
support this objective.
Based on a sample size re-estimation using data from this ongoing study, a difference of 
means of 1.3 bleeds per year between the two protocol-defined prophylaxis regimens (A and 
B) with a corresponding standard deviation of the difference of 6.5 was obtained requiring 
38 subjects to provide 80% power to demonstrate equivalence of the two regimens.  
Allowing for an attrition rate of 30%, approximately 56 RP subjects need to be enrolled.  The 
two prophylaxis regimens will be considered equivalent if the limits of the 2-sided 90% 
confidence interval for the difference in observed mean ABRs fall wholly within the interval 
defined by fewer than 4 bleeds per year.
23. SUBJECT IDENTIFICATION
Subjects will be numbered sequentially using the site number and their sequence number.  
Each subject in the study must be assigned a unique subject number and must keep that 
number throughout the study even if he transfers to another site.  A subject who discontinues 
or is withdrawn (including screen failures), who reenrolls at a later time must be assigned a 
new subject number.  A number must never be reassigned or reused for any reason.  The 
investigator must maintain a log (see Section 12) linking the subject number to the subject’s 
name.  The investigator must follow all applicable privacy laws in order to protect a subject’s 
privacy and confidentiality.  Information that could identify a subject will be masked on 
material received by the Sponsor.
24. TEST ARTICLE ACCOUNTABILITY, RECONCILIATION, AND RETURN
The investigator must maintain a complete and current dispensing and inventory record that 
has been supplied by the Sponsor.  All used and unused vials of study drug, and unused 
diluent must be returned by the subject/caregiver to the study site in the original containers.  
See Section 16.7 for further details.
25. RANDOMIZATION
Randomization for assignment of a treatment regimen(s) to be followed during this study will 
be performed during the screening period (interval of up to approximately 35 days, starting 
from the signing of the informed consent/assent and extending up to visit 2) after 
confirmation of study eligibility, and as specified in the Study Reference Manual.  All
subjects will practice prophylaxis for both segments of the study, will be randomly assigned 
in a 1:1 ratio to 1 of 2 treatment sequences (AB or BA) defining the prophylaxis regimens to 
be practiced during segments 1 and 2, respectively: the low- followed by the high-frequency 
dosing regimen (AB), or the high- followed by the low-frequency dosing regimen (BA).  
Randomization will be stratified by hemophilia A severity: FVIII activity <1% or 1-2% 
(central laboratory screening result).  Allocation of subjects to treatment assignments will be 
performed using an interactive voice or web-based response system.  Dropouts after 
randomization will not be replaced.

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26. ADVERSE EVENT REPORTING
For safety information on moroctocog alfa (AF-CC), refer to the most recent version of the 
Single Reference Safety Document, which for this study is the investigator’s brochure.
26.1. Adverse Events
All observed or volunteered adverse events (AEs) regardless of treatment group or suspected 
causal relationship to the investigational product(s) will be reported as described in the 
following sections. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a 
serious adverse event (SAE) requiring immediate notification to Pfizer or its designated 
representative.  For all AEs, sufficient information should be obtained by the investigator to 
determine the causality of the AE.  The investigator is required to assess causality.  
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the Sponsor, any non-serious adverse event 
that is determined by the Sponsor to be serious will be reported by the Sponsor as an SAE.  
To assist in the determination of case seriousness further information may be requested from 
the investigator to provide clarity and understanding of the event in the context of the clinical 
study.
26.2. Reporting Period
For SAEs, and confirmed FVIII inhibitors, the active reporting period to Pfizer or its 
designated representative begins from the time that the subject provides informed consent, 
which is obtained prior to the subject’s participation in the study, ie, prior to undergoing any 
study-related procedure and/or receiving investigational product, through and including 
28 calendar days after the last administration of the investigational product.  SAEs occurring 
to a subject after the active reporting period has ended should be reported to the sponsor if 
the investigator becomes aware of them; at a minimum, all SAEs that the investigator 
believes have at least a reasonable possibility of being related to investigational product are 
to be reported to the sponsor.
AEs (serious and non-serious) should be recorded on the case report form (CRF) from the 
time the subject has taken at least 1 dose of investigational product through the subject’s last 
visit.
26.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to:  

Abnormal test findings;

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
Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease.

Drug abuse;

Drug dependency;
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breast feeding;

Medication Error;

Occupational exposure.
26.3.1. Hemophilia Events
Hemophilia Events are certain AEs that are likely to occur due to the subject’s hemophilia.  
For example, pain, swelling, or decreased range of motion due to a bleed may be an expected 
consequence of hemophilia (per Section 18.1, the bleeding episode itself is not reported as an 
AE, unless the bleeding episode meets the criteria for a Serious Adverse Event).  
Investigators will be asked to determine if an AE is expected because of the subject’s 
hemophilia.  Bleeding or bruising, not due to the subject’s hemophilia, will be recorded as an 
AE, and not a hemophilia event.  Hemophilia events that require hospitalization or meet other 
SAE criteria should be reported as SAEs. 
26.4. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE are as follows: 

Test result is associated with accompanying symptoms, and/or

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
Test result requires additional diagnostic testing or medical/surgical intervention, 
and/or

Test result leads to a change in study dosing (outside of protocol-stipulated dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy, and/or

Test result is considered to be an adverse event by the investigator or Sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an adverse event.  Any abnormal test result that is determined to be an error does 
not require reporting as an adverse event.
26.5. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect.
Lack of efficacy should be reported as an AE when it is associated with an SAE.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the subject or may require intervention to prevent one of the other adverse event outcomes, 
the important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
The following event must be considered medically important and has the same reporting 
requirements as SAEs:

Confirmed FVIII inhibitor development.  For the purposes of this study, a confirmed 
FVIII inhibitor is a Nijmegen assay result of 0.6 BU/mL at the central laboratory.

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26.5.1. Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs in this study.  All SAEs will be reported by the 
investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see Section 26.13.1 Serious Adverse Event Reporting Requirements). 
26.5.2. Potential Cases of Drug-Induced Liver Injury (Potential Hy’s Law Cases)
Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) 
levels concurrent with abnormal elevations in total bilirubin level that meet the criteria 
outlined below in the absence of other causes of liver injury are considered potential cases of 
drug-induced liver injury (potential Hy’s Law cases) and should always be considered 
important medical events. 
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the subject’s individual baseline values and underlying conditions.  Subjects who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

Subjects with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT 3 times the upper limit of normal 
(x ULN) concurrent with a total bilirubin value 2 x ULN with no evidence of 
hemolysis and an alkaline phosphatase 2 x ULN or not available.

For subjects with preexisting ALT OR AST OR total bilirubin values above the 
upper limit of normal, the following threshold values should be used in the definition 
mentioned above:

For subjects with pre-existing AST or ALT baseline values above the normal 
range: AST or ALT 2 times the baseline values and 3 x ULN, or 8 x ULN 
(whichever is smaller).

Concurrent with

For subjects with pre-existing values of total bilirubin above the normal range: 
Total bilirubin level increased from baseline by an amount of at least 1 x ULN or
if the value reaches 3 x ULN (whichever is smaller).
The subject should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history and physical assessment.
In addition to repeating measurements of AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, prothrombin time (PT)/international normalized ratio (INR) and alkaline 
phosphatase.  A detailed history, including relevant information, such as review of ethanol, 
acetaminophen, recreational drug and supplement consumption, family history, occupational 
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blood transfusion, history of liver or allergic disease, and work exposure, should be collected.  
Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary tract) 
may be warranted.  All cases confirmed on repeat testing as meeting the laboratory criteria 
defined above, with no other cause for LFT abnormalities identified at the time should be 
considered potential Hy’s Law cases irrespective of availability of all the results of the 
investigations performed to determine etiology of the abnormal LFTs.  Such potential Hy’s 
Law cases should be reported as SAEs.
26.6. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance.
Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
adverse event is not in itself a serious adverse event.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new adverse event or with a worsening of the preexisting condition 
(eg, for work-up of persistent pre-treatment lab abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical exam);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

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
Optional admission not associated with a precipitating clinical adverse event (eg, for 
elective cosmetic surgery);

Hospitalization for observation without a medical AE;

Pre-planned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject.
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not 
be reported as adverse events.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an adverse event.  For example, an 
acute appendicitis that begins during the adverse event reporting period should be reported as 
the adverse event, and the resulting appendectomy should be recorded as treatment of the 
adverse event.
26.7. Severity Assessment
If required on the adverse event CRFs, the investigator will use the adjectives MILD,
MODERATE, or SEVERE to describe the maximum intensity of the adverse event.  For 
purposes of consistency, these intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an adverse event.  A severe 
event is not necessarily a serious event.  For example, a headache may be severe (interferes 
significantly with subject's usual function) but would not be classified as serious unless it met 
one of the criteria for serious adverse events, listed above.
26.8. Causality Assessment
The investigator’s assessment of causality must be provided for all adverse events (serious 
and non-serious); the investigator must record the causal relationship in the CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements if applicable.  An investigator’s causality assessment is the determination of 
whether there exists a reasonable possibility that the investigational product caused or 
contributed to an adverse event; generally the facts (evidence) or arguments to suggest a 
causal relationship should be provided.  If the investigator does not know whether or not the 
investigational product caused the event, then the event will be handled as “related to 
investigational product” for reporting purposes, as defined by the Sponsor (see the 
Section 26.13 on Reporting Requirements).  If the investigator's causality assessment is 
“unknown but not related to investigational product”, this should be clearly documented on 
study records. 
In addition, if the investigator determines a serious adverse event is associated with study 
procedures, the investigator must record this causal relationship in the source documents and 

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CRF, as appropriate, and report such an assessment in accordance with the serious adverse 
event reporting requirements, if applicable.
26.9. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (also referred to as exposure in-utero [EIU]) occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product; 
2. An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).
3. A male has been exposed (eg, due to treatment or environmental exposure) to the 
investigational product prior to or around the time of conception or is exposed during 
his partner’s pregnancy.
If a study subject or study subject’s partner becomes or is found to be pregnant during the 
study subject’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer drug safety unit on an SAE report form and an EDP supplemental 
form, regardless of whether an SAE has occurred.  In addition, the investigator must submit 
information regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a 
subject reports that she is pregnant and has been exposed to a cytotoxic product by inhalation 
or spillage) using the EDP supplemental form.  This must be done irrespective of whether an 
AE has occurred and within 24 hours of awareness of the exposure.  The information 
submitted should include the anticipated date of delivery (see below for information related 
to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion or (pregnancy termination) and notify Pfizer of the outcome as a follow up to the
initial EDP Form.  In the case of a live birth, the structural integrity of the neonate can be 
assessed at the time of birth.  In the event of a termination, the reason(s) for termination 
should be specified and, if clinically possible, the structural integrity of the terminated fetus 
should be assessed by gross visual inspection (unless pre-procedure test findings are 
conclusive for a congenital anomaly and the findings are reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live born baby, a terminated fetus, an intrauterine fetal demise, or neonatal death]), the 
investigator should follow the procedures for reporting serious adverse events.

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Additional information about pregnancy outcomes that are reported as serious adverse events 
follows: 

“Spontaneous abortion” includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as serious adverse events.  In addition, infant deaths after 1 month should 
be reported as serious adverse events when the investigator assesses the neonatal 
death as related or possibly related to exposure to the investigational product.
Additional information regarding the exposure during pregnancy may be requested by the 
investigator.  Further follow-up of birth outcomes will be handled on a case-by-case basis 
(eg, follow-up on preterm infants to identify developmental delays).  In the case of paternal 
exposure, the investigator will provide the study subject with the Pregnant Partner Release of 
Information Form to deliver to his partner.  The Investigator must document on the Form that 
the subject was given this letter to provide to his partner.
26.10. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to the drug safety unit within 24 hours of the 
investigator’s awareness, using the SAE report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a subject enrolled in the study, 
the information is not reported on a CRF; however, a copy of the completed SAE report form 
is maintained in the investigator site file.
26.11. Withdrawal Due to Adverse Events (See Also Section 27 - Subject 
Discontinuation or Withdrawal)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page.
When a subject withdraws because of a serious adverse event, the serious adverse event must 
be reported in accordance with the reporting requirements defined below.
26.12. Eliciting Adverse Event Information
The investigator is to report all directly observed adverse events and all adverse events 
spontaneously reported by the study subject.  In addition, each study subject will be 
questioned about adverse events.

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26.13. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
26.13.1. Serious Adverse Event Reporting Requirements
If a serious adverse event occurs, or confirmed FVIII Inhibitor, Pfizer is to be notified within 
24 hours of investigator awareness of the event.  In particular, if the serious adverse event is 
fatal or life-threatening, notification to Pfizer must be made immediately, irrespective of the 
extent of available AE information.  This timeframe also applies to additional new 
information (follow-up) on previously forwarded serious adverse event reports as well as to 
the initial and follow-up reporting of EDP, exposure via breastfeeding and occupational 
exposure cases. 
In the rare event that the investigator does not become aware of the occurrence of a serious 
adverse event immediately (eg, if an outpatient study subject initially seeks treatment 
elsewhere), the investigator is to report the event within 24 hours after learning of it and 
document the time of his/her first awareness of the adverse event.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the timeframes for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 
expedited fashion.  This information collected for serious adverse events is more detailed 
than that captured on the AE CRF.  In general, this will include a description of the adverse 
event in sufficient detail to allow for a complete medical assessment of the case and 
independent determination of possible causality.  Information on other possible causes of the 
event, such as concomitant medications and vaccines and/or illnesses must be provided.  In 
the case of a subject death, a summary of available autopsy findings must be submitted as 
soon as possible to Pfizer or its designated representative. 
26.13.2. Non-Serious Adverse Event Reporting Requirements
All adverse events will be reported on the adverse event page(s) of the CRF.  It should be 
noted that the form for collection of serious adverse event information is not the same as the 
AE CRF.  Where the same data are collected, the forms must be completed in a consistent 
manner.  For example, the same adverse event term should be used on both forms.  AEs
should be reported using concise medical terminology on the CRFs as well as on the form for 
collection of serious adverse event information.
26.13.3. Sponsor’s Reporting Requirements to Regulatory Authorities
Adverse event reporting, including suspected unexpected serious adverse reactions, will be 
carried out in accordance with applicable local regulations.
26.14. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong subject, at the wrong time, or at the wrong dosage strength.  

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Such medication errors occurring to a study participant are to be captured on the medication 
error CRF, which is a specific version of the AE page, and on the SAE form when 
appropriate.  In the event of medication dosing error, the sponsor should be notified 
immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving subject exposure to the investigational product.

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the AE page 
and, if applicable, any associated AE(s) are captured on an AE CRF page. 
27. SUBJECT DISCONTINUATION OR WITHDRAWAL
Reasons why a subject may discontinue or be withdrawn from the study include, but are not 
limited to, AE, subject request, protocol violation, subject noncompliance, study termination 
by the Sponsor, and if the investigator believes it is not in the subject’s best interest to 
continue participating in the study.  Discontinued or withdrawn subjects will not be replaced.  
Subjects will be withdrawn from the study by the Sponsor if screening laboratory results 
performed at the central laboratory indicate the subject was not eligible for the study.  This 
will occur even if the local laboratory results indicate the subject is eligible.  Subjects will be 
withdrawn from the study if a FVIII inhibitor, confirmed by the central laboratory, develops 
during the study.  Except for screen failures, when a subject discontinues or is withdrawn, the 
investigator will directly notify the Sponsor and, when possible, will perform the procedures 
indicated for the Final Study Visit and Final Study Contact, see Section 15.1.11 and 15.1.12.  
For subjects who are withdrawn due to confirmed FVIII inhibitor development, see 
Section 15.3.2 for procedures.
27.1. Reporting of Safety Issue and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
Competent Authority in any area of the World, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of the 
investigational product, Pfizer should be informed immediately. 
In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study subjects against any immediate hazard, and of 
any serious breaches of this protocol or of International Conference on Harmonisation (ICH)
Good Clinical Practice (GCP) that the investigator becomes aware of.

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28. STUDY SUSPENSION, TERMINATION, AND COMPLETION
The Sponsor may suspend or terminate the study or part of the study at any time for any 
reason.
If the investigator suspends or terminates the study, the investigator will promptly inform the 
Sponsor and the IRB/IEC and provide them with a detailed written explanation.  The 
investigator will also return all test article, test article containers, and other study materials to 
the Sponsor.  Upon study completion, the investigator will provide the Sponsor, IRB/IEC, 
and regulatory agency with final reports and summaries as required by regulations.  For 
investigational new drug (IND) studies, the investigator must submit a written report to the 
Sponsor and the IRB/IEC within 3 months after the completion or termination of the study. 
29. ETHICS
29.1. Institutional Review Board/Ethics Committee
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent/assent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/ethics committee (EC). All 
correspondence with the IRB/EC should be retained in the investigator file.  Copies of 
IRB/EC approvals should be forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
29.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 1996 & 2008).
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
29.3. Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where 
required by law. 
When study data are compiled for transfer to Pfizer and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by a numerical code based on a 
numbering system provided by Pfizer in order to de-identify study subjects.  The study site 
will maintain a confidential list of subjects who participated in the study, linking each 

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subject’s numerical code to his actual identity.  In case of data transfer, Pfizer will maintain 
high standards of confidentiality and protection of subjects’ personal data consistent with 
applicable privacy laws.
The informed consent/assent documents must be in compliance with ICH GCP, local 
regulatory requirements, and legal requirements, including applicable privacy laws.
The informed consent/assent documents used during the informed consent process must be 
reviewed and approved by the sponsor, approved by the IRB/EC before use, and available for 
inspection.
The investigator must ensure that each study subject or his legally acceptable representative, 
or parent(s) or legal guardian if a minor, is fully informed about the nature and objectives of 
the study and possible risks associated with participation. 
Whenever consent is obtained from a subject’s legally acceptable representative/parent(s) or 
legal guardian, the subject’s assent (affirmative agreement) must subsequently be obtained 
when the subject has the capacity to provide assent, as determined by the IRB/EC.  If the 
investigator determines that a subject’s decisional capacity is so limited he/she cannot 
reasonably be consulted, then, as permitted by the IRB/EC and consistent with local 
regulatory and legal requirements, the subject’s assent may be waived with source 
documentation of the reason assent was not obtained.  If the study subject does not provide 
his or her own consent, the source documents must record why the subject did not provide 
consent (eg, minor, decisionally impaired adult), how the investigator determined that the 
person signing the consent was the subject’s legally acceptable representative, the consent 
signer’s relationship to the study subject (eg, parent, spouse), and that the subject’s assent 
was obtained, or waived.  If assent is obtained verbally it must be documented in the source 
documents.
If the study includes minor subjects who reach the age of majority during the study, as 
recognized under local law, they must re-consent as adults to remain in the study.  If the 
enrollment of ‘emancipated minors’ is permitted by the study age criteria, the IRB/EC, and 
local law, they must provide documentation of legal status to give consent without the 
permission of a parent or legal guardian.
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject's legally acceptable representative, parent(s) or legal guardian and 
the subject’s assent, when applicable, before any study-specific activity is performed.  The 
investigator will retain the original of each subject's signed consent/assent document.
30. PROTOCOL AMENDMENTS
Any significant change in the study requires a protocol amendment.  An investigator must 
not make any changes to the study without IRB/IEC and Sponsor approval except when 
necessary to eliminate apparent immediate hazards to the subjects.  A protocol change 
intended to eliminate an apparent immediate hazard to subjects may be implemented 
immediately, but the change must then be documented in an amendment, reported to the 

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IRB/IEC within 5 working days, and submitted to the appropriate regulatory agency in the 
required time frame.  All protocol amendments must be reviewed and approved by the 
Sponsor and the investigator.
31. QUALITY CONTROL AND ASSURANCE
The Sponsor performs quality control and assurance checks on all clinical studies that it 
sponsors.  Before enrolling any subjects in this study, Sponsor personnel and the investigator 
review the protocol, the investigator’s brochure, the eCRFs and instructions for their 
completion, the procedure for obtaining informed consent/assent, and the procedure for 
reporting AEs and SAEs.  A qualified representative of the Sponsor will monitor the conduct 
of the study by visiting the study site and by contacting the study site by telephone, fax, mail, 
or e-mail.  During these study site visits, information recorded in the eCRFs is verified 
against source documents.
32. DIRECT ACCESS, DATA HANDLING, AND RECORD-KEEPING
32.1. Investigator
The investigator will permit study-related monitoring, audits, IRB/IEC review, and 
regulatory inspections by providing direct access to source data and documents.
All information will be recorded on source documents.  The subject’s medical record is 
considered to be the source document for the study unless it is information collected 
specifically for this study and recorded directly in the subject’s Subject Diary or in eCRFs.  
All required data will be recorded in the eCRFs.  All eCRF data must be submitted to the 
Sponsor throughout and at the end of the study.  Remote data capture will be used to record 
and transmit data electronically to the Sponsor.
Central laboratory data will be transmitted directly to the Sponsor.  There may be no prior 
written or electronic record for these data.
If an investigator retires, relocates, or otherwise withdraws from conducting the study, the 
investigator must notify the Sponsor to agree upon an acceptable storage solution.  
Regulatory agencies will be notified with the appropriate documentation.  An updated Form 
1572 will be filed with the Sponsor for any changes in the study personnel reported in the 
current Form 1572.
32.2. Sponsor
The eCRF data are stored in a database and processed electronically.  The Sponsor clinician 
reviews the data for safety information.  The data are reviewed for legibility, completeness, 
and logical consistency.  Automated validation programs identify missing data, out-of-range 
data, and other data inconsistencies.  Requests for data clarification are forwarded to the 
investigative site for resolution.  By participating in this study, the investigator (and their 
designated staff) accepts responsibility for resolving questions about study data to the best of 
their ability.

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33. SUBJECT INJURY
In general, subject to specific provisions in the Clinical Study Agreement (CSA), if a subject 
is injured as a direct result of a test article, the Sponsor will pay for reasonable and necessary 
medical treatment for the injury, to the extent that such expenses are not covered by the 
subject’s medical insurance, a government program, or other responsible third party.  If laws 
or regulations of the locality in which the study is taking place require additional payment of 
expenses, the Sponsor shall comply with such laws or regulations.  Where applicable, the 
Sponsor has taken specific national insurance.
34. PRESTUDY DOCUMENTATION
The investigator must provide the Sponsor with the following documents BEFORE enrolling 
any subjects:

Completed and signed Form 1572.

All applicable country-specific regulatory forms.

Current (within 2 years) signed and dated curricula vitae for the investigator, 
subinvestigators, and other individuals having significant investigator responsibility 
who are listed on the form 1572 or equivalent, or the clinical study information form.

Copy of the IRB/IEC approval letter for the protocol and informed consent.  All 
advertising, recruitment, and other written information provided to the subject must 
be approved by the IRB/IEC.  Written assurance of continuing approval (at least 
annually) as well as a copy of the annual progress report submitted to the IRB/IEC 
must also be provided to the Sponsor.

Copy of the IRB/IEC-approved informed consent document to be used.

Where applicable, a list of the IRB/IEC members and their qualifications, and 
a description of the committee’s working procedure.

Copy of the protocol sign-off page signed by the investigator.

Fully executed CSA.

Where applicable, a financial disclosure form.

A written document containing the name, location, certification number, and date of 
certification of the laboratory to be used for laboratory assays and those of other 
facilities conducting tests.  This document should be returned along with the 
statement of investigator form (Form 1572).  The Sponsor must be notified if the 
laboratory is changed or if any additional laboratory is to be used.

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
List of normal laboratory values and units of measure for all laboratory tests required 
by the protocol.  This is required for each laboratory to be used during the study.  The 
Sponsor must be notified if normal values or units of measurement change.
35. RECORDS RETENTION
The investigator shall retain and preserve 1 copy of all data generated in the course of the 
study, specifically including but not limited to those defined by GCP as essential, for the 
longer of (i) 2 years after the last marketing authorization for the study drug has been 
approved or the Sponsor has discontinued its research with respect to such drug or (ii) such 
longer period as required by applicable global regulatory requirements.  At the end of such 
period, the investigator shall notify the Sponsor in writing of its intent to destroy all such 
material.  The Sponsor shall have 30 days to respond to the investigator’s notice, and the 
Sponsor shall have a further opportunity to retain such materials at the Sponsor’s expense.
36. SAMPLE RETENTION
Samples may be used for purposes related to this research, such as repeat testing is needed.  
The samples will be stored for up to 15 years after the end of the study and then destroyed.  
In addition, identifiable samples can be destroyed at any time at the request of the subject.
37. CLINICAL STUDY REPORT
As appropriate, an investigator will be selected to act as the signatory for the clinical study 
report.  This investigator will be selected based on clinical experience and understanding of 
the product.
38. PUBLICATION OF STUDY RESULTS
38.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies conducted in patients that evaluate the safety and/or efficacy of a Pfizer 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are submitted for posting within 1 year of the primary completion date for studies in 
adult populations or within 6 months of the primary completion date for studies in pediatric 
populations.

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Primary completion date is defined as the date that the final subject was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical study concluded according to the prespecified protocol or was 
terminated.
EudraCT
Pfizer posts EU Basic Results on EudraCT for all Pfizer-sponsored interventional studies that 
are in scope of EU requirements.  EU Basic Results are submitted for posting within 1 year 
of the primary completion date for studies in adult populations or within 6 months of the 
primary completion date for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
38.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by 
principal investigator of the results of the study based on information collected or generated 
by principal investigator, whether or not the results are favorable to the Pfizer product.  
However, to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “Publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before they are 
submitted for publication or otherwise disclosed.  If any patent action is required to protect 
intellectual property rights, the investigator agrees to delay the disclosure for a period not to 
exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all study sites, and that any subsequent publications by the
principal investigator will reference that primary publication.  However, if a joint manuscript 
has not been submitted for publication within 12 months of completion or termination of the 
study at all participating sites, the investigator is free to publish separately, subject to the 
other requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 

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Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any Attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.
39. REFERENCES
1.
Eaton DL, Wood WI, Eaton D, et al.  Construction and characterization of an active 
factor VIII variant lacking the central one-third of the molecule.  Biochemistry. 1986; 
25: 8343 8347.
2.
Toole JJ, Pittman DD, Orr EC, Murtha P, Wasley LC, Kaufman RJ.  A large region 
(~95 kDa) of human factor VIII is dispensable for in vitro procoagulant activity.  Proc 
Natl Acad Sci USA. 1986; 83: 5939-5942.
3.
Wyeth investigator’s brochure: ReFacto (moroctocog alfa), [WAY-167652].
4.
Sandberg H, Almstedt A, Brandt J, et al.  Structural and functional characterization of B 
domain deleted recombinant factor VIII.  Semin Hematol. 2001; 38(2 Suppl 4): 4-12.
5.
Brinkhous K, Sandberg H, Widlund L, et al.  Preclinical pharmacology of albumin-free 
B domain deleted recombinant factor VIII.  Semin Thromb Hemost. 2002; 28(3): 
269-272.
6.
Kelley BD, Booth J, Tannatt M, et al.  Isolation of a peptide ligand for affinity 
purification of factor VIII using phage display.  J Chromatogr A. 2004; 1038: 121-130.
7.
Kelley BD, Tannatt M, Magnusson R, Hagelberg S, Booth J.  Development and 
validation of an affinity chromatography step using a peptide ligand for cGMP 
production of factor VIII.  Biotechnol Bioeng. 2004; 87: 400-412.
8.
Pfizer Inc. Periodic Safety Update Report #20 for moroctocog alfa AF-CC, 27 August 
2013 to 26 August 2014.  Collegeville, PA.  15-Oct-2014.
9.
Kessler CM, Gill JC, White GC, et al.  B-domain deleted recombinant factor VIII 
preparations are bioequivalent to a monoclonal antibody purified plasma-derived factor 
VIII concentrate: a randomized, three-way crossover study.  Haemophilia. 2005; 11: 
84 91.

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10.
Aledort LM, Haschmeyer RH, Pettersson H.  A longitudinal study of orthopaedic 
outcomes for severe factor-VIII-deficient haemophiliacs.  J Intern Med. 1994; 236: 
391 399.
11.
Liesner RJ, Khair K, Hann IM. The impact of prophylactic treatment on children with 
severe haemophilia.  Br J Haematol. 1996; 92: 973-978.
12.
Manco-Johnson MJ, Abshire TC, Shapiro AD, et al.  Prophylaxis versus Episodic 
Treatment to Prevent Joint Disease in Boys with Severe Hemophilia.  N Engl J Med. 
2007; 357;6: 535 544.
13.
Nilsson IM, Berntorp E, Lofqvist T, Pettersson H.  Twenty-five years' experience of 
prophylactic treatment in severe haemophilia A and B.  J Intern Med. 1992; 232: 25-32.
14.
Shapiro AD, Donfield SM, Lynn HS, et al.  Defining the impact of hemophilia: the 
academic achievement in children with hemophilia study.  Pediatrics. 2001; 108: 
105 110.
15.
Srivastava A, Giagrande P, Poon MC, McGraw A, Weideln J. WFH Guidelines for the
management of hemophilia. Available at: 
http://www.wfh.org/2/docs/Publications/Diagnosis_and_Treatment/Guidelines_Mng_H
emophilia.pdf
16.
Berntorp E, Bouyjenkov V, Brettler D. Modern treatment of haemophilia. Bull World 
Health Organ. 1995; 73:691-701.
17.
Iorio A, Marchesini E, Marcucci M, Stobart K, Chan AKC.  Clotting factor concentrates 
given to prevent bleeding and bleeding-related complications in people with hemophilia 
A or B (Review).  The Cochrane Library.  2011, Issue 9.  
http://www.thecochranelibrary.com
18.
Aronstam A, McLellan DS, Wassef M, Mbatha PS.  Effect of height and weight on the 
in vivo recovery of transfused factor VIII.  J Clin Pathol 1982; 35:289 - 291.
19.
Feldman BM, Pai M, Rivard GE, et al.  Tailored prophylaxis in severe hemophilia A: 
interim results from the first 5 years of the Canadian hemophilia primary prophylaxis 
study. J.  Thromb Haemost. 2006; 4: 1228-1236.
20.
Medical and Scientific Advisory Council (MASAC).  MASAC Recommendation #117: 
Recommendation concerning prophylaxis (prophylactic administration of clotting factor 
concentrate to prevent bleeding).  May 2001 [cited 2006 April]; Available from: 
http://www.hemophilia.org.
21.
Lofqvist T, Nilsson IM, Berntorp E, Pettersson H.  Haemophilia prophylaxis in young 
patients - a long-term follow-up.  J Intern Med. 1997; 241: 395-400.

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22.
Gooding A.  ReFacto AF:  Bioanalytical analysis in human plasma and human serum in 
support of Wyeth Protocol 3082B2-311-WW.  Wyeth Research.  RPT 74903.  2008).

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40. APPENDICES
Appendix 1. Guidelines for On-Demand Treatment With Moroctocog alfa (AF-CC)
Guidelines for On-Demand Treatment With Moroctocog alfa (AF-CC), Based on 
Current Recommendations for On-Demand Therapy With the Licensed Product 
Xyntha®
Type of Bleeding Episode
FVIII Level Required
(IU/dL or % of normal)
Frequency of Doses (hours)/
Duration of Therapy (days)
Minor
Early hemarthrosis, minor
muscle or oral bleeds.
20-40
Repeat infusion every 12 to 
24 hours as necessary until 
resolved for at least 1 day, 
depending upon the severity of 
the bleeding episode.
Moderate
Bleeding into muscles.
Mild head trauma.
Bleeding into the oral
cavity.
30-60
Repeat infusion every 12 to 
24 hours for 3 to 4 days, or 
until adequate local hemostasis 
is achieved.
Major
Gastrointestinal bleeding.
Intracranial, intra-abdominal
or intrathoracic
bleeding.
Fractures.
60-100
Repeat infusion every 8 to 
24 hours until bleeding is
resolved