A SINGLE COUNTRY, MULTICENTER, OPEN-LABEL AND NON-RANDOMIZED CLINICAL TRIAL WITH MOROCTOCOG ALFA (AF-CC) PROPHYLAXIS AND TREATMENT OF BLEEDING EPISODES IN PREVIOUSLY TREATED PATIENTS WITH MODERATE AND SEVERE HEMOPHILIA A FOR A DURATION OF 8 WEEKS
Phase: PHASE4
Conditions: Hemophilia A
Sponsor: Pfizer

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 1
A SINGLE COUNTRY, MULTICENTER, OPEN-LABEL AND NON-RANDOMIZED 
CLINICAL TRIAL WITH MOROCTOCOG ALFA (AF-CC) PROPHYLAXIS AND 
TREATMENT OF BLEEDING EPISODES IN PREVIOUSLY TREATED PATIENTS 
WITH MODERATE AND SEVERE HEMOPHILIA A FOR A DURATION OF 
8 WEEKS
Protocol Number:
B1831097
Medicinal Product:
Moroctocog alfa (AF-CC)
United States (US) Investigational New 
Drug (IND) Number:
Not Applicable
European Clinical Trial Database 
(EudraCT) Number:
Not Applicable
Universal Trial Number:
Not Applicable
Phase:
Phase 4
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in writing, 
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or 
disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In the event 
of any actual or suspected breach of this obligation, Pfizer must be promptly notified.
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 2
Document History
Document
Version Date
Summary of Changes
Original protocol
10-April-2019
Not Applicable (N/A)
Protocol 
Amendment 1
16-September-2019
The following changes were made as part 
of Protocol Amendment 1:
Removal of the word “pragmatic” from the 
study title.
Addition of text throughout the protocol to 
clarify that samples taken for factor VIII 
(FVIII) development could be analyzed at 
the local laboratory or central laboratory.
Modification of footnote of Table 1 
(Schedule of Assessments) to clarify that at 
Screening, assessment for FVIII activity 
and inhibitor assessment will be conducted 
at the local laboratory and that a duplicate 
blood sample will be assessed by the 
central laboratory for confirmation of 
FVIII activity and inhibitor assessment.
Modification of text defining 
immunocompromised subjects due to 
human immunodeficiency virus (HIV) 
infection in exclusion criterion #9, 
changing the limit of the viral load above 
or equal to 400,000 copies to above or 
equal to 100,000 copies/mL.
Addition of exclusion criterion #11 to 
exclude subjects who have planned use of 
any non-study medication for the treatment 
of hemophilia (such as other factor 
replacement agents, bypassing agents, or 
non-factor treatments [for example, anti-
tissue factor pathway inhibitors]).
Addition of text clarifying that any subject 
using non-study medication for the 
treatment of hemophilia during their 
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 3
participation in the study will be 
withdrawn from the study, but patients 
who have a bleed away from the study site 
and are not treated by the investigator and 
need non-study treatment, will not be 
withdrawn from the study.
Addition of text clarifying that subjects 
will be withdrawn from the study if their 
central laboratory result for inhibitor 
assessment at screening does not confirm 
eligibility per the local laboratory result.
Addition of text to Section 5.4 to permit a 
dosing variance of ±5 IU/kg throughout the 
study in order to simplify dosing and 
minimizing potential waste.
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.
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 4
Abbreviations
This is a list of abbreviations used in the protocol. All of these abbreviations may or may not 
be used in the protocol.
Abbreviation
Term
ABR
annualized bleeding rate
AE
adverse event
AF-CC
albumin-free cell culture
ALT
alanine transaminase
AST
aspartate transaminase
BUN
blood urea nitrogen
CD4+
cluster of differentiation 4 positive 
CDSCO
Central Drugs Standard Control Organization 
CI
confidence interval
CRF
case report form
CSA
clinical study agreement
DNA
deoxyribonucleic acid
EC
ethics committee
eCRF
electronic case report form
EDs
exposure days
EDP
exposure during pregnancy
EudraCT
European Clinical Trial Database 
FVIII
factor VIII
GCP
Good Clinical Practice
HIV
human immunodeficiency virus
ICH
International Council for Harmonisation
IND
investigational new drug
INR
international normalized ratio
IRB
institutional review board
IU
international units
IV
intravenous 
LFT
liver function test
LPD
local product document
LSLV
last subject last visit 
MedDRA
medical dictionary for regulatory activities
PT
prothrombin time
SAE
serious adverse event
SAP
statistical analysis plan
SRSD
single reference safety document
TFC
total factor consumption
ULN
upper limit of normal
US
United States 
WHO
World Health Organization
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 5
PROTOCOL SUMMARY
Background and Rationale
Hemophilia A (congenital factor VIII deficiency) is an X-linked recessive disorder caused by 
a congenital deficiency of coagulation factor VIII clotting activity.  Patients with hemophilia 
A are usually treated by replacing the missing or defective factor VIII for treatment or 
prevention of hemorrhage.  
The current protocol outlines a post-approval study to fulfill the Central Drugs Standard 
Control Organization (CDSCO) written request for supplementary information relating to the 
use of moroctocog-alfa (Albumin-free cell culture [AF-CC]) in Indian subjects with 
hemophilia A.  The additional information will include safety and efficacy of 
moroctocog-alfa (AF-CC) in Indian patients with a diagnosis of congenital moderate or
severe hemophilia A (factor VIII [FVIII]:C ≤5%).
Objectives and Endpoints
Primary Objective
To study the safety of moroctocog alfa (AF-CC) when administered for prophylaxis with
respect to incidence of FVIII inhibitor development.
Secondary Objectives
•
To evaluate the incidence of adverse events (AEs) and serious adverse events (SAEs) 
in subjects receiving a moroctocog alfa (AF-CC) prophylaxis. 
•
To evaluate the efficacy of moroctocog alfa (AF-CC) during a prophylaxis regimen. 
•
To evaluate the total annualized consumption of moroctocog alfa (AF-CC) by
subjects following a prophylaxis regimen.
•
To evaluate the efficacy of moroctocog alfa (AF-CC) for the treatment of 
breakthrough bleeding episodes (on-demand treatment) while following a prophylaxis
regimen.
Primary Endpoint
The primary endpoint will be the proportion of subjects who develop FVIII inhibitor 
(≥0.6 BU/mL), as confirmed by central laboratory testing, during the course of the study.
Secondary Endpoints
•
Incidence of AEs;
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 6
•
Incidence of SAEs;
•
Annualized bleeding rate (ABR) during prophylaxis;
•
Annualized total factor consumption (TFC) in international units (IU) and annualized 
TFC by weight (IU/kg) of moroctocog alfa (AF-CC) measured during the up to 
8 weeks of treatment, by reason for infusion and total units consumed (across all 
reasons);
•
Number of moroctocog alfa (AF-CC) infusions used to treat each bleed.
Study Design
This is a single-country, multicenter, open-label, interventional study which will be 
conducted in India.  Subjects will be monitored according to local standard of care, which 
should be in accordance with the local product document (LPD).
At least 50 male subjects aged ≥12 years to ≤65 years with moderate or severe hemophilia 
A (FVIII:C ≤5%) who have had at least 50 exposure days (EDs) to FVIII-containing products 
will be enrolled in the study.
The overall treatment duration for each subject will be up to 8 weeks, with up to a 4-week 
screening period and a subsequent post-treatment 28 day safety observation period.  Subjects 
are requested to continue in the study until at least 24 EDs or a period of up to 8 weeks on 
moroctocog alfa (AF-CC) treatment had occurred (whichever occurs first).  Subjects will be 
treated with a dose and regimen of moroctocog alfa (AF-CC) prophylaxis in accordance with 
the LPD.  
Study Treatments
Moroctocog alfa (AF-CC) will be administered by the investigator or a delegate at Visits 2
and 3.  For administration between study visits, the product will be administered in 
accordance with procedures provided by their physicians.  Subjects or caregivers/parents of 
subjects will be trained on how to administer moroctocog alfa (AF-CC) away from the study 
site, as applicable.  
Statistical Methods
Sample Size
No formal statistical sample size computation will be performed for this study.  The sample 
size rationale is based on the written request of the CDSCO. 
At least 50 subjects will be enrolled to participate in the study.  
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 7
Statistical Analyses
Efficacy Analyses
Efficacy analyses will be conducted on all subjects who receive at least one dose of 
moroctocog alfa (AF-CC) and have data evaluable for the efficacy assessment.  The efficacy 
results of this study will be presented using descriptive statistics. 
Safety Analyses 
All safety analyses will be performed according to Pfizer Data Standards on all subjects who 
receive at least one dose of moroctocog alfa (AF-CC). 
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 8
SCHEDULE OF ACTIVITIES 
The Schedule of Activities (Table 1) provides an overview of the protocol visits and procedures.  Refer to STUDY PROCEDURES
and ASSESSMENTS sections of the protocol for detailed information on each procedure and assessment required for compliance with 
the protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities, in order to conduct 
evaluations or assessments required to protect the wellbeing of the subject.
Table 1.
Schedule of Assessments
Visit Identifier
Visit 1
Screening
(Screening/Baseline)
(Within 28 days of 
Visit 2)
Visit 2
(Day 1)
Visit 3
(Day 24-32)
Visit 4
(Day 52-60)a
End of Study 
Visit
(Day 80-88)b
Written informed consent/assentc
X
Review inclusion/exclusion criteria
X
Demographic datad
X
Physical examinatione
X
X
X
X
X
Vital signsf
X
X
X
X
X
Hemophilia A historyg
X
Medical historyh
X
Laboratory assessments: coagulation, hematology, 
biochemistry tests, factor VIII inhibitori
X
X
Documentation of testing for HIV and CD4j
X
Moroctocog alfa (AF-CC) administrationk
X
X
Recording of AEsl
X
X
X
X
X
Concomitant treatments and therapiesm
X
X
X
X
X
Subject infusion logn
X
X
X
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 9
Visit Identifier
Visit 1
Screening
(Screening/Baseline)
(Within 28 days of 
Visit 2)
Visit 2
(Day 1)
Visit 3
(Day 24-32)
Visit 4
(Day 52-60)a
End of Study 
Visit
(Day 80-88)b
AE=adverse event; CD4=cluster of differentiation 4; eCRF=electronic case report form; ED=exposure day; FVIII=factor VIII; HIV=human immunodeficiency virus.
a.
Visit 4 should occur 3 (+7) days after the final dose; ie, subjects are requested to continue participation until 24 EDs or 8 weeks of treatment has been reached 
(whichever occurs first).  As 24 EDs approaches, the timing of Visit 4 should be discussed with the subject.
b.
The End of Study Visit can occur earlier if a subject achieves the requested 24 EDs sooner than 8 weeks.  As the 24th ED approaches, the end of study should be 
discussed with the subject.
c.
Signed informed consent must be obtained prior to any procedures or collection of study data.
d.
Demographic data to be captured will include sex, year of birth, race and ethnicity.  Age will be calculated as “year at screening visit minus birth year”.
e.
As per site-specific practice.  
f.
Vital signs assessments should include height, weight, heart rate, blood pressure, and body temperature.
g.
Record hemophilia A history, eg, date of diagnosis and severity of hemophilia A and previous use of factor VIII (prior EDs).
h.
Recording of medical history will include: co-morbidities and surgical history.
i.
Coagulation (with residual activity for factor FVIII), hematology, biochemistry tests will be performed by the local laboratory per local routine clinical practice.  
Samples for FVIII activity and inhibitor assessment will also be collected for analysis by local laboratory and central laboratory. At Screening, assessment for FVIII 
activity and inhibitor assessment will be conducted at the local laboratory.  A duplicate blood sample will be assessed by the central laboratory for confirmation of FVIII 
activity and inhibitor assessment. If a subject’s central laboratory result does not confirm eligibility for Inhibitory assessment per the local laboratory result, the subject 
will be withdrawn from the study.
j.
Serological tests for HIV and CD4 will be performed as per local routine clinical practice.  Consent for HIV testing is to be taken per local standard practice and also the 
information on the result must be shared only with the subject/caregiver.  If a subject tests positive for HIV, assessment of CD4 will be performed.
k.
Moroctocog alfa (AF-CC) will be administered by the investigator or a delegate at Visits 2 and 3.  Administration between study visits will be in accordance with 
procedures provided by the investigator.  Subjects or caregivers/parents of subjects will be trained on how to administer moroctocog alfa (AF-CC), as applicable.  Based 
on the subject infusion log, the investigator will assess the EDs at each visit and if there were any changes in dose.  All infusions and any related bleeding episode 
information will be recorded.
l.
SAEs will be recorded from when a subject provides informed consent through to the last subject visit.  AEs (serious and nonserious) should be recorded on the eCRF 
from the time the subject has taken at least 1 dose of study treatment through the last subject visit.  
m.
All concomitant treatments and therapies should be recorded.
n.
Subject infusion log dispensed at Visit 2 and reviewed at each visit (discussion with subject and documentation in source about any concomitant medications, study
compliance issues, and investigational product administration).  In addition, information on bleeds/infusions in the subject infusion log will be transcribed at the site into 
the eCRF.
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 10
TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................13
1. INTRODUCTION ...............................................................................................................14
1.1. Mechanism of Action/Indication.............................................................................14
1.2. Background and Rationale ......................................................................................14
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................14
2.1. Objectives................................................................................................................14
2.1.1. Primary Objective.......................................................................................14
2.1.2. Secondary Objectives .................................................................................14
2.2. Endpoints.................................................................................................................15
2.2.1. Primary Endpoint........................................................................................15
2.2.2. Secondary Endpoints ..................................................................................15
3. STUDY DESIGN.................................................................................................................15
4. SUBJECT SELECTION......................................................................................................16
4.1. Inclusion Criteria.....................................................................................................16
4.2. Exclusion Criteria....................................................................................................16
4.3. Randomization Criteria ...........................................................................................17
4.4. Life Style Guidelines...............................................................................................17
5. STUDY INTERVENTION..................................................................................................17
5.1. Allocation to Intervention/Treatment......................................................................17
5.2. Drug Supplies..........................................................................................................17
5.2.1. Dosage Form(s) and Packaging..................................................................17
5.3. Preparation and Dispensing.....................................................................................18
5.4. Administration.........................................................................................................19
5.5. Drug Storage ...........................................................................................................20
5.6. Drug Accountability................................................................................................21
5.7. Concomitant Treatment(s).......................................................................................21
6. STUDY PROCEDURES .....................................................................................................21
6.1. Screening – Visit 1 (within 28 Days prior to Day 1) ..............................................21
6.2. Study Period ............................................................................................................22
6.2.1. Visit 2 (Day 1) ............................................................................................22
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 11
6.2.2. Visit 3 (Day 24-32).....................................................................................23
6.2.3. Visit 4 (Day 52-60, or earlier) ....................................................................23
6.3. End of Study Visit (Day 80-88 or earlier)...............................................................24
6.4. Subject Withdrawal.................................................................................................24
7. ASSESSMENTS..................................................................................................................25
7.1. Efficacy Assessments..............................................................................................25
7.1.1. Total Factor VIII Consumption and Bleeds................................................25
7.2. Safety Assessments .................................................................................................25
7.2.1. Laboratory Evaluations...............................................................................25
7.2.2. Vital Signs and Physical Examination........................................................26
8. ADVERSE EVENT REPORTING......................................................................................26
8.1. Adverse Events........................................................................................................26
8.2. Reporting Period .....................................................................................................27
8.3. Definition of an Adverse Event...............................................................................27
8.4. Medication Errors....................................................................................................28
8.5. Abnormal Test Findings..........................................................................................28
8.6. Serious Adverse Events...........................................................................................29
8.7. Protocol-Specified Serious Adverse Events............................................................29
8.8. Potential Cases of Drug-Induced Liver Injury ........................................................29
8.9. Additional Safety Information ................................................................................31
8.9.1. Medically Important Events .......................................................................31
8.10. Hospitalization ......................................................................................................31
8.11. Severity Assessment..............................................................................................32
8.12. Causality Assessment............................................................................................32
8.13. Exposure During Pregnancy..................................................................................33
8.14. Withdrawal Due to Adverse Events (See Also Section on Subject 
Withdrawal)...............................................................................................................34
8.15. Eliciting Adverse Event Information ....................................................................34
8.16. Reporting Requirements........................................................................................34
8.17. Serious Adverse Event Reporting Requirements..................................................35
8.18. Nonserious Adverse Event Reporting Requirements............................................35
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 12
8.19. Sponsor Reporting Requirements to Regulatory Authorities................................35
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................35
9.1. Sample Size Determination.....................................................................................36
9.2. Data Sources............................................................................................................36
9.3. Effectiveness Analysis ............................................................................................36
9.3.1. Analysis of Primary Endpoint ....................................................................36
9.3.2. Analysis of Secondary Endpoints...............................................................37
9.3.2.1. Annualized Bleeding Rate During Prophylaxis ........................37
9.3.2.2. Number of Moroctocog alfa (AF-CC) Infusions Used to 
Treat Each Bleed ...............................................................................37
9.3.2.3. Annualized Total Factor Consumption of Moroctocog 
Alfa (AF-CC).....................................................................................37
9.4. Analysis of Other Endpoints ...................................................................................38
9.5. Safety Analysis........................................................................................................38
9.6. Data Monitoring Committee ...................................................................................38
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................38
11. DATA HANDLING AND RECORD KEEPING .............................................................39
11.1. Case Report Forms/Electronic Data Record .........................................................39
11.2. Record Retention...................................................................................................39
12. ETHICS..............................................................................................................................40
12.1. Institutional Review Board (IRB)/Ethics Committee (EC)...................................40
12.2. Ethical Conduct of the Study ................................................................................40
12.3. Subject Information and Consent..........................................................................40
12.4. Subject Recruitment ..............................................................................................42
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................42
13. DEFINITION OF END OF STUDY.................................................................................42
13.1. End of Study in all Participating Countries...........................................................42
14. SPONSOR DISCONTINUATION CRITERIA ................................................................42
15. PUBLICATION OF STUDY RESULTS..........................................................................42
15.1. Communication of Results by Pfizer ....................................................................42
15.2. Publications by Investigators ................................................................................43
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 13
16. REFERENCES ..................................................................................................................44
LIST OF TABLES
Table 1.
Schedule of Assessments............................................................................8
Table 2.
Maintenance of Factor VIII Activity for Various Hemorrhagic 
Events .......................................................................................................19
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 14
1. INTRODUCTION
1.1. Mechanism of Action/Indication
Coagulation factor VIII (recombinant) (moroctocog alfa [Albumin-free cell culture 
(AF-CC)]), is a purified B-Domain deleted recombinant FVIII protein produced by 
recombinant deoxyribonucleic acid (DNA) technology.  It will be marketed in India as 
Xynthophilia®.1
Moroctocog-alfa (AF-CC) is indicated in India for the control and prevention of hemorrhagic 
episodes and for routine and surgical prophylaxis in patients with hemophilia A (congenital 
factor VIII deficiency or classic hemophilia).1
1.2. Background and Rationale
Hemophilia A (congenital factor VIII deficiency) is an X-linked recessive disorder caused by 
a congenital deficiency of coagulation factor VIII clotting activity. Patients with hemophilia 
A are usually treated by replacing the missing or defective factor VIII for treatment or 
prevention of hemorrhage. Xyntha (moroctocog alfa, AF-CC) first received regulatory 
approval on 21 February 2008 in the United States.1 Xyntha is a trade name of moroctocog 
alfa (AF-CC) used in some other countries. Xynthophilia is the trade name for moroctocog 
alfa (AF-CC) in India. Moroctocog alfa (AF-CC) was approved for use in the European 
Union under the trade name ReFacto AF on 26 February 2009.2 At present, moroctocog alfa 
(AF-CC) pre-filled syringe is approved in 87 countries and marketed in 53 countries. 
The current protocol outlines a post-approval study to fulfill the Central Drugs Standard 
Control Organization (CDSCO) written request for supplementary information relating to the 
use of moroctocog-alfa (AF-CC) in Indian subjects with hemophilia A. The additional 
information will include safety and efficacy of moroctocog-alfa (AF-CC) in Indian subjects
with a diagnosis of congenital moderate or severe hemophilia A (FVIII:C ≤5%).
Complete information for this compound may be found in the Single Reference Safety 
Document (SRSD), which for this study is the local product document (LPD).1
2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
2.1.1. Primary Objective
To study the safety of moroctocog alfa (AF-CC) when administered for prophylaxis with 
respect to incidence of FVIII inhibitor development.
2.1.2. Secondary Objectives
•
To evaluate the incidence of adverse events (AEs) and serious adverse events (SAEs) 
in subjects receiving moroctocog alfa (AF-CC) prophylaxis.
•
To evaluate the efficacy of moroctocog alfa (AF-CC) during a prophylaxis regimen.
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 15
•
To evaluate the total annualized consumption of moroctocog alfa (AF-CC) by
subjects following a prophylaxis regimen.
•
To evaluate the efficacy of moroctocog alfa (AF-CC) for the treatment of 
breakthrough bleeding episodes (on-demand treatment) while following a prophylaxis 
regimen.
2.2. Endpoints
2.2.1. Primary Endpoint
The primary endpoint will be the proportion of subjects who develop FVIII inhibitor 
(≥0.6 BU/mL), as confirmed by central laboratory testing, during the course of the study.
2.2.2. Secondary Endpoints
•
Incidence of AEs;
•
Incidence of SAEs;
•
Annualized bleeding rate (ABR) during prophylaxis;
•
Annualized total factor consumption (TFC) in international units (IU) and annualized 
TFC by weight (IU/kg) of moroctocog alfa (AF-CC) measured during the up to 
8 weeks of treatment, by reason for infusion and total units consumed (across all 
reasons);
•
Number of moroctocog alfa (AF-CC) infusions used to treat each bleed.
3. STUDY DESIGN
This is a single-country, multicenter, open-label, interventional study which will be 
conducted in India.  
At least 50 male subjects aged ≥12 years to ≤65 years with moderate or severe hemophilia A 
(FVIII:C ≤5%) who have had at least 50 exposure days (EDs) to FVIII-containing products 
will be enrolled in the study.
The overall treatment duration for each subject will be up to 8 weeks, with up to a 4-week 
screening period and a subsequent post-treatment 28-day safety observation period.  Subjects 
are requested to continue in the study until 24 exposure days (EDs) or a period of up to 
8 weeks on moroctocog alfa (AF-CC) treatment had occurred (whichever occurs first).  
Subjects will be treated with a dose and regimen of prophylaxis in accordance with the LPD.1
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 16
4. SUBJECT SELECTION
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom the protocol intervention is 
considered appropriate by their health care provider and consistent with the LPD.
4.1. Inclusion Criteria
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:
1. Male subjects ≥12 years to ≤65 years with a diagnosis of congenital moderate or
severe hemophilia A (FVIII:C ≤5%).
2. Documented history of at least 50 exposure days (EDs) to FVIII-containing products.
3. Evidence of a personally signed and dated informed consent document indicating that 
the subject (or a legally acceptable representative, parent(s)/legal guardian) has been 
informed of all pertinent aspects of the study.  For minors under the age of legal 
consent in India, assent of the participating child needs to be documented for the age 
range 12 to 18 in addition to the parental informed consent.
4.2. Exclusion Criteria
Subjects presenting with any of the following will not be included in the study:
1. Prior history of inhibitor to FVIII or positive inhibitor testing (≥0.6 BU/mL) during 
Screening.  Clinical signs or symptoms of decreased response to FVIII.
2. Known hypersensitivity to the active substance or any of the excipients.
3. Known allergic reaction to hamster proteins.
4. Presence of any bleeding disorder in addition to hemophilia A.
5. Participation in other studies involving investigational drug(s) (Phases 1-4) within 
30 days before the current study begins and/or during study participation.
6. Planned surgery within 6 months from the start of the study.
7. Unsuitable to participate in study for any other reason as assessed by the investigator; 
including any disorder, except for conditions associated with hemophilia A, which in 
the investigator’s opinion might jeopardize subject’s safety or compliance with the 
protocol.
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 17
8. Subjects (or a legally acceptable representative) is not able to understand study 
documents and study procedure.
9. Immunocompromised subjects due to human immunodeficiency virus (HIV) infection 
(defined as viral load above or equal to 100,000 copies/mL; and for HIV+ subjects:
cluster of differentiation 4 positive (CD4+) lymphocyte count below or equal to 
200/μL). HIV status and CD4+ lymphocyte count results may be obtained at 
screening or from available medical records; results must be not older than 6 months
prior to screening.
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, subjects who have been previously enrolled into the study, or subjects 
who are Pfizer employees directly involved in the conduct of the study.
11. Planned use of any non-study medication for treatment of hemophilia (eg, other factor
replacement agents, bypassing agents, or non-factor treatments [such as anti-tissue 
factor pathway inhibitors]).
4.3. Randomization Criteria
Not applicable as this is a single-arm, non-randomized study.
4.4. Life Style Guidelines 
Not applicable.
5. STUDY INTERVENTION 
5.1. Allocation to Intervention/Treatment
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular subject or affect the order in which subjects are enrolled.
The investigator will assign subject identification numbers sequentially to the subjects as 
they are screened for the study.  This identification number will be retained throughout the 
study.  A subject number must never be reassigned or reused for any reason.  The 
investigator must maintain a log linking the subject number to the subject’s name.
5.2. Drug Supplies
5.2.1. Dosage Form(s) and Packaging
Moroctocog alfa (AF-CC) is a freeze-dried lyophilized powder for reconstitution in a 
single-use vial.  Investigational product will be provided by Pfizer as white to off-white 
lyophilized powder which will be clear to slightly opalescent, colorless solution upon 
reconstitution with sterile 0.9% sodium chloride solution provided in the kit for intravenous 
injection. 
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 18
The label attached to each moroctocog alfa (AF-CC) vial and diluent container minimally 
states the product name and amount, potency (drug only), lot number, directions for storage, 
and name of manufacturer (the diluent may not have all this information).  Labels may 
contain other information, such as expiry date, as required by local regulatory guidelines.
 
 
 
 
 
 
5.3. Preparation and Dispensing
Pfizer will provide the investigators with a sufficient amount of moroctocog alfa (AF-CC).  
Once moroctocog alfa (AF-CC) is dispensed to a subject it must not be re-dispensed to 
another subject.  The product should be prepared, reconstituted, and used in accordance with 
procedures provided by their physicians.  For instructions, subjects should follow the 
recommendations in the Administration and Reconstitution sections of the local product 
document (LPD).  At each visit before Visit 4, the subject should receive a sufficient quantity 
of investigational product in order to last until their next visit.  Further information on 
moroctocog alfa (AF-CC) will be provided in the Investigational Product Manual.
CCI
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 19
5.4. Administration
Moroctocog alfa (AF-CC) will be administered by the investigator or a delegate at Visits 2
and 3.  For administration between study visits, the product will be administered in 
accordance with procedures provided by their physicians.  Subjects or caregivers/parents of 
subjects will be trained on how to administer moroctocog alfa (AF-CC) away from the study 
site, as applicable.
Prophylaxis:
Moroctocog alfa (AF-CC) should be administered prophylactically in previously treated 
patients at a dose of 30 ± 5 IU/kg given 3 times weekly in accordance with the LPD.1
On-Demand Treatment:
The amount to be administered and the frequency of administration should always be tailored 
to the clinical effectiveness in individual subjects.
In the case of the following hemorrhagic events, consideration should be given to 
maintaining the factor VIII activity at or above the plasma levels (in % of normal or in 
IU/dL) for the indicated period, as outlined in Table 2.
Table 2 can be used to guide dosing in bleeding events and surgery. 
Table 2.
Maintenance of Factor VIII Activity for Various Hemorrhagic Events
Type of Hemorrhage
Factor VIII Level Required 
(% or IU/dL)
Frequency of Doses (h)/ 
Duration of Therapy (d)
Minor
Early hemarthrosis, superficial 
muscle or soft
tissue and oral bleeds.
20-40
Repeat every 12 to 24 hours as 
necessary until resolved.
At least 1 day, depending upon 
the severity of the hemorrhage.
Moderate
Hemorrhages into muscles. Mild 
head trauma capitus. Minor 
operations including tooth 
extraction.
Hemorrhages into the oral cavity.
30-60
Repeat infusion every 
12-24 hours for 3- 4 days or until 
adequate hemostasis is achieved. 
For tooth extraction a single 
infusion plus oral antifibrinolytic 
therapy within 1 hour may be 
sufficient.
Major
Gastrointestinal bleeding.
Intracranial, intraabdominal
or intrathoracic hemorrhages.
Fractures.
Major operations.
60-100
Repeat infusion every 8-24 hours 
until threat is resolved or in the 
case of surgery, until adequate 
local hemostasis is achieved, then 
continue therapy for at least 
another 7 days.
Source: LPD.1
IU=international unit; LPD=local product document.
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 20
In the interest of simplifying dosing and minimizing potential waste, a dosing variance of 
±5 IU/kg is permitted throughout the study.
5.5. Drug Storage 
The investigator, or an approved representative, eg, study coordinator, will ensure that all 
investigational products, including any comparative agents and/or marketed products are 
stored in a secured area with controlled access under recommended storage conditions and in 
accordance with applicable regulatory requirements.
Moroctocog alfa (AF-CC) should be stored in its original container and in accordance with 
the storage conditions stated on the label.  The reconstituted solution of moroctocog alfa 
(AF-CC) may be stored at room temperature prior to infusion.  The reconstituted solution of 
moroctocog alfa (AF-CC) does not contain preservative and should be infused within 3 hours 
after reconstitution.  
Storage conditions stated in SRSD (ie, LPD) will be superseded by the storage conditions 
stated in the labeling.
Site systems must be capable of measuring and documenting (for example, via a log), at a 
minimum, daily minimum and maximum temperatures for all site storage locations (as 
applicable, including frozen, refrigerated and/or room temperature products).  This should be 
captured from the time of investigational product receipt throughout study, on all business 
days.  Even for continuous monitoring systems, a log or site procedure which ensures active 
daily evaluation for excursions should be available.  The operation of the temperature 
monitoring device and storage unit (for example, refrigerator), as applicable, should be 
regularly inspected to ensure it is maintained in working order.  
Any excursions from the product label storage conditions should be reported upon discovery. 
The site should actively pursue options for returning the product to labeled storage 
conditions, as soon as possible.  Deviations from the storage requirements, including any 
actions taken, must be documented and reported to the sponsor.  
Once an excursion is identified, the investigational product must be quarantined and not used 
until the sponsor provides documentation of permission to use the investigational product.  
Specific details regarding information the site should report for each excursion will be 
provided to the site. 
Receipt of materials, door opening and closing, and other routine handling operations where 
the product(s) are briefly out of labeled temperature range are not considered excursions.
Site staff will instruct subjects (or caregivers if applicable) on storage requirements for take 
home medications including how to report temperature excursions. 
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 21
5.6. Drug Accountability
The investigator’s site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the drug supplies.  When investigational product is taken home by the 
subject, any unused products must be returned to the investigator by the subject at Visit 4.
All used and unused vials of moroctocog alfa (AF-CC) and unused diluent syringes will be 
used for investigational product accountability.  Used diluent syringes will not be returned to 
the study center for test article accountability due to the potential risk of blood 
contamination. Therefore, each returned used moroctocog alfa (AF-CC) vial indirectly 
accounts for a diluent syringe used by the subject. The investigator can use a 1:1 ratio of 
used drug vials to account for used diluent syringes. The investigator uses this information to 
maintain an accurate and complete moroctocog alfa (AF-CC) investigational product 
accountability log.  
Administration of moroctocog alfa (AF-CC) by subjects or their caregivers away from the 
study site should be captured in the Subject Infusion Log.
The monitor will review drug accountability during routine monitoring visits. Drug 
accountability will be done at all study visits after Day 1 until Visit 4. Any discrepancies 
must be investigated and their resolution documented.  At the completion or termination of 
the study, a final drug accountability review and reconciliation must be performed. Any 
discrepancies that cannot be reconciled must be documented in writing in the study file.
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site). If destruction is authorized to take place at the study site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer and all destruction must be adequately documented.
5.7. Concomitant Treatment(s)
The use of permitted concomitant medication must be in accordance with the study drug 
label. The use of concomitant treatments will be recorded throughout the study.
6. STUDY PROCEDURES
6.1. Screening – Visit 1 (within 28 Days prior to Day 1)
The following information and assessments will be collected and documented at screening 
for each subject:
•
Obtain written informed consent/assent;
•
Review of eligibility criteria (as described in Sections 4.1 and 4.2).;
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 22
•
Demographic data (sex, year of birth, race and ethnicity); age will be calculated as 
“year at screening visit minus birth year”;
•
Physical examination;
•
Vital signs (height, weight, heart rate, blood pressure, and body temperature);
•
Record hemophilia A history (date of diagnosis and severity of hemophilia A and 
previous factor VIII use [prior EDs]);
•
Medical history (including co-morbidities and surgical history);
•
Laboratory assessments (coagulation [with residual activity for factor VIII], 
hematology, and biochemistry (via local laboratory) and blood samples drawn for 
factor VIII activity and inhibitor testing (via local laboratory and central laboratory).
At Screening, assessment for FVIII activity and inhibitor assessment will be 
conducted at the local laboratory.  A duplicate blood sample will be assessed by the 
central laboratory for confirmation of FVIII activity and inhibitor assessment.  If a 
subject’s central laboratory result does not confirm eligibility for Inhibitory 
assessment per the local laboratory result, the subject will be withdrawn from the 
study.
•
Documentation of testing for HIV (for HIV+ subjects: cluster of differentiation 
4 [CD4] viral load);
•
Recording of SAEs;
•
Concomitant treatments and therapies.
6.2. Study Period
6.2.1. Visit 2 (Day 1)
The following information and assessments will be collected and documented for each 
subject:
•
Physical examination;
•
Vital signs (weight, heart rate, blood pressure, and body temperature);
•
Moroctocog alfa (AF-CC) administration by the investigator or delegate
(administration between study visits will be in accordance with procedures provided 
by the investigator.  Subjects or caregivers/parents of subjects will be trained on how
to administer moroctocog alfa [AF-CC], as applicable);
•
Recording of AEs;
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 23
•
Concomitant treatments and therapies;
•
Dispensing of Subject Infusion Log and instruct on its use (discussion with subject 
and documentation in source about any concomitant medications, study compliance 
issues, and investigational product administration. In addition, information on 
bleeds/infusions will be transcribed into the electronic CRF [eCRF]).
6.2.2. Visit 3 (Day 24-32)
The following information and assessments will be collected and documented for each 
subject:
•
Physical examination;
•
Vital signs (weight, heart rate, blood pressure, and body temperature);
•
Moroctocog alfa (AF-CC) administration by the investigator or delegate
(administration between study visits will be in accordance with procedures provided 
by the investigator.  Subjects or caregivers/parents of subjects will be trained on how
to administer moroctocog alfa [AF-CC], as applicable);
•
Recording of AEs;
•
Concomitant treatments and therapies;
•
Review of Subject Infusion Log and transcription of bleeds/infusions data into the
eCRF.
6.2.3. Visit 4 (Day 52-60, or earlier)
It should be noted that this visit will occur between Day 52 and Day 60 or earlier and should
occur 3 (+7) days after the final dose of moroctocog alfa (AF-CC) (if the requested number 
of EDs are reached [24 EDs or 8 weeks of treatment, whichever occurs first]).  As 24 ED 
approaches, the timing of Visit 4 should be discussed with the subject.  
The following information and assessments will be collected and documented for each 
subject:
•
Physical examination;
•
Vital signs (weight, heart rate, blood pressure, and body temperature);
•
Laboratory assessments (coagulation [with residual activity for factor VIII], 
hematology, and biochemistry (via local laboratory) and blood samples drawn for 
factor VIII activity and inhibitor testing (via local laboratory and central laboratory);
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 24
•
Recording of AEs;
•
Concomitant treatments and therapies;
•
Review of Subject Infusion Log and transcription of bleeds/infusions data into the 
eCRF.
6.3. End of Study Visit (Day 80-88 or earlier)
It should be noted that this visit will occur between approximately Day 80 and Day 88 or 
earlier if the requested number of EDs is reached (24 EDs before Day 60).  As the 24th ED
approaches, the end of study should be discussed with the subject.  The following 
information and assessments will be collected and documented for each subject:
•
Physical examination;
•
Vital signs (weight, heart rate, blood pressure, and body temperature);
•
Recording of AEs;
•
Concomitant treatments and therapies;
6.4. Subject Withdrawal
Subjects may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator. Any subject who uses non-study 
medication for the treatment of hemophilia (eg, other factor replacement agents, bypassing 
agents, or non-factor treatments [such as anti-tissue factor pathway inhibitors]) will be 
considered to have a protocol violation and will be withdrawn from the study.  The exception 
to this would be for subjects who require non-study treatment for a bleed away from the 
study site.  This would be considered a protocol deviation rather than a protocol violation that 
would not require withdrawal from the study.
Subjects will be withdrawn from the study if their central laboratory result for inhibitor 
assessment at screening does not confirm eligibility per the local laboratory result.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  All attempts to contact the subject and information received during contact attempts 
must be documented in the subject’s medical record. If possible, subjects who withdraw 
from the study, and who do not withdraw consent, should be requested to return to the study 
center to have the procedures listed under Visit 4 completed. In any circumstance, every 
effort should be made to document subject outcome, if possible.  The investigator should 
inquire about the reason for withdrawal, request the subject to return for a final visit, if 
applicable, and follow up with the subject regarding any unresolved AEs.
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 25
If the subject withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected.  The sponsor may retain and continue to use any data collected before such 
withdrawal of consent.
7. ASSESSMENTS
Every effort should be made to ensure that protocol required assessments and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances, outside the control of the investigator that may make it unfeasible to perform 
an assessment. In these cases, the investigator must take all steps necessary to ensure the 
safety and well-being of the subject.  When a protocol required assessment cannot be 
performed, the investigator will document the reason for the missed assessment and any 
corrective and preventative actions which s/he has taken to ensure that required processes are 
adhered to as soon as possible.  These will be documented as protocol deviations.  The study 
team must be informed of these incidents in a timely manner.  The assessments described in 
this section will be performed at times defined in the schedule of assessments (Table 1) and 
Section 6 of this protocol.
7.1. Efficacy Assessments
7.1.1. Total Factor VIII Consumption and Bleeds
Subjects/caregivers or the investigator or his/her delegate will record all moroctocog alfa 
(AF-CC) infusions, including each prophylaxis infusion (and dose) and those administered to 
treat a bleeding episode in the Subject Infusion Log. For on-demand infusions (ie, to treat a 
bleeding episode), the date and time that the bleeding event occurs, type/etiology of bleed
(eg, spontaneous or traumatic), location of bleed, and details of each infusion (dose)
administered to resolve the bleed) will be recorded.  
7.2. Safety Assessments
Safety assessments throughout the study will include collection of AEs, laboratory safety 
testing, vital signs, and physical examination at the time points specified in (Table 1
[schedule of assessments]), but can be conducted at other time points at the investigator’s 
discretion.
7.2.1. Laboratory Evaluations
Laboratory evaluations, according to local laboratory and/or central laboratory assessment,
will be conducted at the time points specified in Table 1.
•
Hematology (local laboratory): measurement of complete blood count, including 
hemoglobin, hematocrit, white blood cell count and differential, and red blood cell 
and platelet count.
•
Coagulation: FVIII activity (local laboratory and central laboratory), international 
normalized ratio (INR; local laboratory), and prothrombin time (PT; local laboratory).
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 26
•
Biochemistry (local laboratory): aspartate transaminase (AST), alanine transaminase 
(ALT), total bilirubin, alkaline phosphatase, blood urea nitrogen (BUN), creatinine, 
uric acid, albumin, total protein, glucose (fasting), calcium, sodium, potassium, and 
chloride.
•
Laboratory assessment for factor VIII inhibitor antibodies (local laboratory and 
central laboratory).
7.2.2. Vital Signs and Physical Examination
Vital Signs and physical examinations will be conducted at the time points specified in 
Table 1.
•
Vital signs: to include height, weight, blood pressure, heart rate, and body temperature.
•
Supine blood pressure should be measured, after the subject has been at rest for at 
least 5 minutes, using a digital or mercury sphygmomanometer with a cuff 
appropriate to the subject’s arm girth.
•
Physical examination: to include general appearance, skin, head/eyes/ears/nose/throat, 
heart, lungs, breasts, abdomen, extremities, neurological, back/spinal, and lymph nodes.  
This will be conducted by a physician, trained physician’s assistant, or nurse practitioner 
as acceptable according to local regulations.
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of 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 nonserious AE 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.  
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 27
8.2. Reporting Period
For SAEs, 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.  AEs and 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 AEs and 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 nonserious) should be recorded on the eCRF from the time the subject has 
taken at least 1 dose of study treatment through the last subject visit.
8.3. 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;
•
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;
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 28
•
Exposure during pregnancy (EDP);
•
Exposure via breastfeeding;
•
Medication error;
•
Occupational exposure.
In this population, bleeding episodes are not considered AEs. Bleeding episodes should be 
reviewed by the investigator and those that meet the criteria of serious should be reported as 
an SAE.
8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong drug, by the wrong subject, at the wrong time, or at the wrong dosage strength.  Such 
medication errors occurring to a study participant are to be captured on the adverse event 
(AE) page of the eCRFs 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 and, if applicable, any associated AE(s) are captured on an 
AE eCRF page (refer to the ADVERSE EVENT REPORTING section for further details).  
8.5. 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
•
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 AE by the investigator or sponsor.
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 29
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require
reporting as an AE.
8.6. Serious Adverse Events
An SAE 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.
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.  The important medical event should be reported as serious, 
if it is determined that the event may jeopardize the subject or may require intervention to 
prevent one of the other AE outcomes.
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.
In addition, FVIII inhibitor development (defined as a titer ≥0.6 BU/mL confirmed by central 
laboratory testing) will be considered an SAE.
8.7. 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 8.17).
8.8. Potential Cases of Drug-Induced Liver Injury
Liver function tests (LFTs) are not required as a routine safety monitoring procedure in this 
study.  However, should an investigator deem it necessary to run LFTs because of clinical 
sign/symptom presentation in a subject, such LFT results should be handled and followed up 
as described below. 
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 30
Abnormal values in AST and/or 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 values ≥3 times the upper limit of 
normal (× ULN) concurrent with a total bilirubin value ≥2 × ULN with no evidence 
of hemolysis and an alkaline phosphatase value ≤2 × ULN or not available;
•
For subjects with preexisting ALT OR AST OR total bilirubin values above the 
ULN, the following threshold values should be used in the definition mentioned 
above:
•
For subjects with preexisting AST or ALT baseline values above the normal 
range: AST or ALT values ≥2 times the baseline values and ≥3 × ULN, or 
≥8 × ULN (whichever is smaller).
•
Concurrent with
•
For subjects with preexisting values of total bilirubin above the normal range: 
Total bilirubin level increased by 1 × ULN or ≥3 × 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 
exposure, sexual history, travel history, history of contact with a jaundiced person, surgery, 
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 liver function test (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.
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 31
8.9. Additional Safety Information
8.9.1. Medically Important Events
For this study, the medically important events are any confirmed FVIII inhibitor 
development (defined as a titer ≥0.6 BU/mL confirmed by central laboratory testing).  These 
events must be reported as SAEs.
8.10. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation to 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 
AE is not in itself an SAE.  Examples include: 
•
Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of persistent pre-treatment laboratory abnormality);
•
Social admission (eg, subject has no place to sleep);
•
Administrative admission (eg, for yearly physical examination);
•
Protocol-specified admission during a study (eg, for a procedure required by the study
protocol);
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 32
•
Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);
•
Hospitalization for observation without a medical AE;
•
Preplanned 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 noninvasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.
8.11. Severity Assessment
If required on the AE eCRFs, the investigator will use the adjectives MILD, MODERATE, 
or SEVERE to describe the maximum intensity of the AE.  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 AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.12. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
nonserious); the investigator must record the causal relationship in the eCRF, 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 
AE; 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 Section 8.16).  If the investigator's causality 
assessment is "unknown but not related to investigational product," this should be clearly 
documented on study records.  
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 33
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and eCRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
8.13. Exposure During Pregnancy
For investigational products and for marketed products, an exposure during pregnancy 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; 
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).
2. A male subject has been exposed (eg, because of treatment or environmental 
exposure) to the investigational product prior to or around the time of conception 
and/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 a Serious Adverse Event (SAE) Report Form 
and Exposure During Pregnancy (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 until pregnancy termination) and notify Pfizer of the outcome as a follow-up to 
the initial EDP supplemental 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 preprocedure test 
findings are conclusive for a congenital anomaly and the findings are reported).
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 34
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, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported as SAEs 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 SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to 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 in the source 
documents that the subject was given the Pregnant Partner Release of Information Form to 
provide to his partner.
8.14. Withdrawal Due to Adverse Events (See Also Section on Subject Withdrawal)
Withdrawal due to AE should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE eCRF 
page.  
When a subject withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.15. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study subject/parent/legally acceptable representative.  In addition, each study 
subject/parent/legally acceptable representative will be questioned about AEs. Bleeding 
episodes are not considered AEs (further details are provided in Section 8.3).
8.16. 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.
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 35
8.17. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.
In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available AE information.  This time frame also 
applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of exposure during pregnancy and exposure via 
breastfeeding cases.  
In the rare event that the investigator does not become aware of the occurrence of an SAE 
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 or her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames 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 SAEs is more detailed than that captured 
on the AE eCRF.  In general, this will include a description of the AE 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, 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.
8.18. Nonserious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the eCRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE eCRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE 
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the eCRFs as well as on the form for collection of SAE information.
8.19. Sponsor Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a statistical analysis plan (SAP), which will be maintained by the 
sponsor.  This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment.
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 36
9.1. Sample Size Determination
No formal statistical sample size computation will be performed for this study.  The sample 
size rationale is based on the written request of the CDSCO. 
At least 50 subjects will be enrolled to participate in the study.  With a sample size of 50, if 
FVIII inhibitors were detected, the corresponding exact two-sided 90% confidence intervals 
(CIs) for the proportion of subjects who developed FVIII inhibitors would be:
Observed cases
Observed rate
90% CI (%)
1
2%
(0.10, 9.14)
2
4%
(0.72, 12.06)
3
6%
(1.66, 14.78)
9.2. Data Sources 
The investigator will first record the study data in source documents, such as medical records
which will include treatment data, during subjects scheduled visits. Another source 
document will be the Subject Infusion Log from which bleeding assessment, investigational 
product infusion that may occur outside hospital or clinic and other information will be 
captured during this study. Each subject will be identified by a single number that will be 
maintained throughout the study. The investigator or the delegate will then enter the 
applicable study data and Subject Infusion Log data into the eCRFs.
9.3. Effectiveness Analysis
Efficacy analyses will be conducted on all subjects who receive at least one dose of 
moroctocog alfa (AF-CC) and have data evaluable for the efficacy assessment.  The efficacy 
results of this study will be presented using descriptive statistics. The following descriptive 
statistics will be used:
•
For continuous endpoints: sample size, mean, standard deviation, median, minimum 
and maximum;
•
For binary or categorical endpoints: sample size, frequency and percentage 
(proportion).
Data collected after a subject develops FVIII inhibitor (≥0.6 BU/mL), as confirmed by 
central laboratory testing, will not be considered evaluable for efficacy, but may be analyzed 
for safety.
9.3.1. Analysis of Primary Endpoint 
Not applicable, since all efficacy endpoints are secondary endpoints in this study.
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 37
9.3.2. Analysis of Secondary Endpoints
The secondary efficacy endpoints assessed during this study are described in this section.
9.3.2.1. Annualized Bleeding Rate During Prophylaxis
The ABR will be derived for each subject by using the following formula:
ABR = number of bleeds/(Treatment interval duration/365.25).
The number of bleeds for each subject for the ABR calculation includes all bleeds requiring 
treatment with moroctocog alfa (AF-CC) during the treatment interval duration (up to 
8 weeks of treatment, or sooner, once 24 EDs are achieved).  Treatment interval duration is 
calculated as the number of days beginning on Visit 2 (“Day 1”, provided an infusion was 
given) up to Visit 4. Additionally, ABRs will be summarized by bleed type (eg, spontaneous 
or traumatic) and by bleed location (eg, joint, soft tissue/muscle).
9.3.2.2. Number of Moroctocog alfa (AF-CC) Infusions Used to Treat Each Bleed
The investigational product infusion log case report form will be used to determine the 
number of investigational product infusions administered to treat a bleed.  This will be 
calculated by adding the initial (on-demand) infusion to any subsequent (on-demand) 
infusions for the same bleed (same bleed start date/time).  
If there is more than one bleed location (eg, ankle and joint) with identical bleed start date 
and time, it will be treated as one bleed occurrence.
Summary statistics will be reported using the number of infusions as a continuous variable.  
In addition, frequency tables will be provided for each of the categories (1, 2, 3, 4, or 
>4 infusions needed to treat the bleed), in which the numerator is the number of bleeds 
falling into each category, and the denominator is the total number of new bleeds across all 
subjects.  The number of subjects contributing data (ie, the number of subjects with any new 
bleed) for the analysis will also be reported.
9.3.2.3. Annualized Total Factor Consumption of Moroctocog Alfa (AF-CC)
The total amount (IU) infused for each moroctocog alfa (AF-CC) infusion recorded in the 
investigational product infusion log CRF will be summed to calculate the TFC for each 
subject. The annualized TFC of moroctocog alfa (AF-CC) will be derived for each subject 
by using the following formula: 
Annualized TFC = TFC / (Treatment interval duration/365.25).
In addition, for each infusion, IU/kg will be calculated, using the most recently recorded 
weight measurement, and annualized TFC by weight (IU/kg) will be summarized similarly, 
by reason for infusion, and for the total.
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 38
9.4. Analysis of Other Endpoints
Not applicable.
9.5. Safety Analysis
All safety analyses will be performed according to Pfizer Data Standards on all subjects who 
receive at least one dose of moroctocog alfa (AF-CC). 
The primary safety endpoint is the proportion of subjects with central-laboratory-confirmed 
positive FVIII inhibitor, defined as ≥0.6 BU/mL, developed during the course of the study. 
Only subjects with a confirmed positive FVIII inhibitor will count towards the numerator of 
the derived proportion. The denominator will be the total number of subjects at risk for 
developing an inhibitor during the study, who received at least one dose of moroctocog alfa 
(AF-CC).  The corresponding two-sided 90% CIs will be reported. Secondary safety 
endpoints include the occurrence of AEs and SAEs.
Safety data will be tabulated and listed according to Pfizer’s standard reporting algorithms.  
Additional analyses may be done for safety endpoints if needed.  The Medical Dictionary for 
Regulatory Activities (MedDRA) will be used to code AEs and concomitant medications will 
be coded using the World Health Organization (WHO) drug dictionary.
9.6. Data Monitoring Committee
Not Applicable.
10. QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, Pfizer or its agent will conduct periodic monitoring visits to ensure 
that the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on eCRFs is accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.
The study site may be subject to review by the Institutional Review Board (IRB)/Ethics 
Committee (EC), and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 39
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term case report form (CRF) should be understood to refer to 
either a paper form or an electronic data record or both, depending on the data collection 
method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer. The investigator shall ensure that the 
CRFs are securely stored at the study site in encrypted electronic form and will be secured in 
a locked room to prevent access by unauthorized third parties.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs is true. Any corrections to entries made in the CRFs or source 
documents must be dated, initialed and explained (if necessary) and should not obscure the 
original entry. 
In most cases, the source documents are the subject’s chart in the hospital or the physician's 
office.  In these cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.
In addition, the Subject Infusion Log will be a source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, eg, eCRFs and hospital records), all original signed informed 
consent/assent documents, copies of all eCRFs, safety reporting forms, source documents, 
and detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls reports).  The records should be 
retained by the investigator according to International Council for Harmonisation (ICH), 
according to local regulations, or as specified in the Clinical Study Agreement (CSA), 
whichever is longer. The investigator must ensure that the records continue to be stored 
securely for so long as they are retained.
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 40
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations.
The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board (IRB)/Ethics Committee (EC)
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/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.
12.2. 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), the Declaration of Helsinki (World Medical 
Association 1996 & 2008), and Schedule Y, Drugs and Cosmetics Act 1940 and Rules 1945. 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local India regulatory requirements and laws.
12.3. Subject Information and Consent
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of subject personal data. Such 
measures will include OMITTING subject names or other directly identifiable data in any 
reports, publications, or other disclosures, except where required by applicable laws. 
The personal data will be stored at the study site in encrypted electronic form and will be 
password protected to ensure that only authorized study staff have access.  The study site will 
implement appropriate technical and organizational measures to ensure that the personal data 
can be recovered in the event of disaster.  In the event of a potential personal data breach, the 
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 41
study site shall be responsible for determining whether a personal data breach has in fact 
occurred and, if so, providing breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, when study data is compiled for transfer to Pfizer and other authorized parties, 
subject names, addresses, and other identifiable data will be replaced by a numerical code 
consisting of 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 their numerical code to the subject’s actual identity.  In case of data transfer, Pfizer 
will maintain high standards of confidentiality and protection of subject personal data 
consistent with applicable privacy laws.
The informed consent/assent documents must be in compliance with ICH GCP, local India 
regulatory requirements, and legal requirements, including applicable privacy laws.
The informed consent/assent documents used during the informed consent process must be 
reviewed by the sponsor, approved by the IRB/EC before use, and available for inspection.
The investigator must ensure that each study subject, or his or her 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, as permitted by the IRB/EC and consistent with local regulatory and 
legal requirements, then 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/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 India law, they must be re-consented 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.   
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 42
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each subject or the 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.
12.4. Subject Recruitment
Advertisements approved by ethics committees and investigator databases may be used as 
recruitment procedures. 
12.5. Reporting of Safety Issues 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 ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF STUDY
13.1. End of Study in all Participating Countries
End of Study in all participating countries (India) is defined as Last Subject Last Visit 
(LSLV).
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, drug safety problems, or at the discretion of Pfizer.  
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating subjects and 
the hospital pharmacy (if applicable) within 7 days.  As directed by Pfizer, all study materials 
must be collected and all eCRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. 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), www.pfizer.com, and/or the 
European Clinical Trials Database (EudraCT), www.ctri.nic.in (Clinical Trials Registry 
-India), and other public registries in accordance with applicable local laws/regulations. 
www.clinicaltrials.gov.
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 43
Pfizer posts clinical trial Basic Results on www.clinicaltrials.gov for all Pfizer-sponsored 
interventional studies that evaluate the safety and/or efficacy of a Pfizer product.
15.2. Publications by Investigators
Pfizer has no objection to publication by investigator of any information collected or 
generated by investigator, whether or not the results are favorable to the investigational drug. 
However, to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure before it is submitted or otherwise disclosed.
The investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc.) 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 (other than the Study results themselves) before disclosure.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all centers. 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, investigator is free to publish separately, subject to the other requirements 
of this section.
For all publications relating to the study, institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
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 Clinical Study Agreement between 
Pfizer and the institution.  In this section entitled Publications by Investigators, the defined 
terms shall have the meanings given to them in the Clinical Study Agreement.
CCI

Xynthophilia® (Moroctocog alfa [AF-CC], B Domain Deleted Recombinant FVIII)
B1831097
Final Protocol Amendment 1, 16 September 2019
PFIZER CONFIDENTIAL
Page 44
16. REFERENCES
1.
Moroctocog alfa (AF-CC) LPDXYN042018.
2.
Commission of the European Communities. Commission decision of 26.2.2009 
Amending the Marketing Authorisation for “ReFacto AF- Moroctocog Alfa”, a 
Medicinal Product for Human Use, Granted by Decision C(1999)938.
CCI

'RFXPHQW $SSURYDO 5HFRUG
'RFXPHQW 1DPH
	
      	
'RFXPHQW 7LWOH
	
      	
6LJQHG %\
'DWH*07
6LJQLQJ &DSDFLW\
%%	
 &'&	
() *
PPD