AN OPEN-LABEL, NON-INVESTIGATIONAL PRODUCT, LEAD-IN STUDY TO EVALUATE AT LEAST 6 MONTHS OF PROSPECTIVE EFFICACY AND SAFETY DATA OF FACTOR IX OR FACTOR VIII PROPHYLAXIS REPLACEMENT THERAPY IN THE USUAL CARE SETTING OF MODERATELY SEVERE TO SEVERE ADULT HEMOPHILIA B SUBJECTS (FIX:C≤2%) WHO ARE NEGATIVE FOR nAb TO AAV VECTOR-SPARK100 AND MODERATELY SEVERE TO SEVERE HEMOPHILIA A ADULT SUBJECTS (FVIII:C≤1%) WHO ARE NEGATIVE FOR nAb TO AAV VECTOR SB-525 CAPSID (AAV6), PRIOR TO THE RESPECTIVE THERAPEUTIC PH 3 GENE THERAPY STUDIES (See Detailed Description Section for Official Protocol Title)
Phase: PHASE3
Conditions: Hemophilia B, Hemophilia A
Sponsor: Pfizer

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AN OPEN-LABEL, NON-INVESTIGATIONAL PRODUCT, MULTI-CENTER, 
LEAD-IN STUDY TO EVALUATE PROSPECTIVE EFFICACY AND SELECTED 
SAFETY DATA OF CURRENT FACTOR IX (FIX) OR FACTOR VIII (FVIII) 
PROPHYLAXIS REPLACEMENT THERAPY IN THE USUAL CARE SETTING OF
MODERATELY SEVERE TO SEVERE ADULT HEMOPHILIA B PARTICIPANTS 
(FIX:C≤2%) WHO ARE NEGATIVE FOR NEUTRALIZING ANTIBODIES TO 
ADENO-ASSOCIATED VIRUS VECTOR-SPARK100 (BENEGENE-1) AND 
MODERATELY SEVERE TO SEVERE HEMOPHILIA A ADULT PARTICIPANTS 
(FVIII:C≤1%) WHO ARE NEGATIVE FOR NEUTRALIZING ANTIBODIES TO 
ADENO-ASSOCIATED VIRUS VECTOR 6 (AAV6), PRIOR TO THE RESPECTIVE 
THERAPEUTIC PHASE 3 GENE THERAPY STUDIES
Investigational Product Number:
Not Applicable (N/A)
Investigational Product Name:
Not Applicable (N/A)
United States (US) Investigational New 
Drug (IND) Number:
017250; 016437 
European Clinical Trials Database 
(EudraCT) Number:
2017-001271-23 
Protocol Number:
C0371004
Phase:
3
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, 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.
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Document History
Document
Version Date
Summary of Changes and Rationale
Amendment 7
17 May 2022
The United Kingdom Ethics Committee 
requested the removal of the phrase “legally 
authorized representative” to avoid potentially 
misleading statements about participant’s 
individual capacity to consent to the study 
(Schedule of Activities [footnote b], and 
Section 4.1, Inclusion Criterion #1 for both 
the Hemophilia A Population and Hemophilia 
B Population).
Clarified that participant with a history of a 
neoplasm (including hepatic malignancy) that 
required treatment (eg, chemotherapy, 
radiotherapy, immunotherapy), is excluded, 
except for adequately treated basal or 
squamous cell carcinoma of the skin or a 
surgically removed benign neoplasm not 
requiring chemotherapy, radiotherapy and/or 
immunotherapy. Any other neoplasm that has 
been cured by resection should be discussed 
between the investigator and sponsor (Section 
4.2, Exclusion Criterion #8).
Increased sample size for hemophilia A 
participant cohort (from 70 to approximately 
80 participants) to support the subsequent 
Phase 3 registration study, C3731003 
(Section 9.1).
The following changes were made to align 
with a PACL dated 19 October 2021:
Clarified that participants with conditions 
associated with increased thromboembolic 
risk such as known inherited or acquired 
thrombophilia, or a history of thrombotic 
events, including venous thromboembolism, 
should be excluded so that it is not open to 
investigator discretion (Section 4.2, Exclusion 
Criterion #7).
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Document
Version Date
Summary of Changes and Rationale
Clarified which medications are permitted and 
medically necessary and according to standard 
of care (Section 5.4).
Amendment 6
23 April 2021
Clarified that, for eligibility for this study 
(C0371004), participation in other studies is 
prohibited only if it involves administration of 
investigational product within the last 
3 months prior to study entry and/or during 
Study C0371002 or C3731003 participation 
(Section 4.2: Exclusion Criterion #9).  This 
allows participants to have their eligibility for 
the subsequent treatment protocols confirmed 
earlier.
Clarified that concomitant use of another 
investigational product is not permitted during 
study participation for consistency with 
clarification to Exclusion Criterion #9 
(Section 5.4).
Clarified the duration of follow-up for 
participants to allow for flexibility of 
enrollment into the subsequent treatment 
protocols (Schedule of Activities and 
Sections 3, 6.3, and 6.5).
Expanded the sample size for hemophilia B 
participants to account for those who do not 
need to be followed for at least 6 months in 
this study (Section 9.1).
Clarified that the participant OR a legally 
authorized representative may obtain consent 
as per local regulations (Section 4.1: Inclusion 
Criterion #1).
Removed the option of remote screening visits 
and home health care services implemented 
via Amendment 5 since processes are not in 
place to support remote informed consent of 
participants (Schedule of Activities and 
Sections 6, 6.1, and 6.2).
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Version Date
Summary of Changes and Rationale
Incorporated administrative changes from the 
2 previous protocol administrative change 
letters (PACLs) dated 12 November 2020 
(Sections 4.4 and 12.3) and 29 January 2021 
(Appendix 4).
Other minor typographical/editorial changes 
were made.
Amendment 5
01 October 2020
Increased sample size for participants with 
hemophilia B to support an additional cohort
planned for the subsequent Phase 3 
registration study, added clarifications on the 
duration of follow-up for individual 
participants to provide flexibility for 
participants who are enrolled beyond the 
minimum threshold of treated participants in 
the treatment protocols, included the option of 
remote screening and baseline visits to 
de-centralize the study visits if permitted by 
local regulations, removed the physical 
examination at the screening visit to facilitate 
the option of remote visits, incorporated 
administrative changes from the 5 previous 
PACLs, and removed AST-to-Platelet Ratio 
Index as an option for liver fibrosis testing as 
it is the least rigorous of the other liver 
fibrosis tests (FibroScan OR 
FibroTest/FibroSURE).
Amendment 4
12 May 2020
A country-specific requirements appendix 
(Appendix 4) was added for Turkey as per 
Turkey MoH requirement that the reference to 
subsequent Phase 3 studies not be included in 
the protocol title, as this is out of the scope of 
the observational study objectives defined in 
the Turkish regulatory guideline. 
Amendment 3
27 June 2019
Including an additional cohort (hemophilia A 
population) as part of the 6-month lead-in 
study, to support the initiation of the 
hemophilia A gene therapy Phase 3 study.  
Incorporate administrative changes from the 
6 previous PACLs. 
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Version Date
Summary of Changes and Rationale
Amendment 2
07 March 2019
The United Kingdom and Ireland Ethics 
Committees are both mandating removal of 
pregnancy language from the protocol and 
corresponding ICD, despite sponsor providing 
a rationale for keeping the pregnancy 
language in the protocol and ICD.  The Ethics 
Committees consider pregnancy reporting or 
follow-up as having no relevance to the study 
since this is a lead-in study and there is no 
exposure to investigational product.
Amendment 1
23 August 2018
Per Health Canada (HC) reporting 
requirements for non-investigational studies 
with marketed products, unusual failure in 
efficacy associated with the FIX replacement 
product in Canadian participants is reportable.  
This is a unique requirement to Health 
Canada.  A country specific amendment for 
Canada will ensure reporting of any Lack of 
Efficacy (LOE) in Canadian participants to 
the Pfizer Drug Safety Unit (DSU) and from 
there to HC (for BeneFIX) or the MAH (for 
products other than BeneFIX) as required).
Original protocol
23 March 2018
Not applicable (N/A)
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs)/ethics committees 
(ECs).
Amendment 8 (31 March 2023)
Overall Rationale for the Amendment: The main reason for Amendment 8 is to increase 
Hemophilia A cohort sample size from 80 to 95 to account for the higher than expected 
attrition rate following the temporary pause in the subsequent Phase 3 study (C3731003)
Description of Change
Brief Rationale
Section # and Name
Substantial Modification(s)
Update the sample size from 
80 to 95 Hemophilia A
participants.
To account for higher than-
expected attrition rate 
following the temporary 
pause in the subsequent 
Phase 3 study (C3731003).  
Section 9.1 Sample Size 
Determination
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Description of Change
Brief Rationale
Section # and Name
Non-substantial Modification(s)
Revised the following text 
to inclusion criterion 5 
“Participants must be on a 
stable FVIII prophylaxis 
replacement therapy 
(recombinant, plasma 
derived or extended half life 
FVIII product) at study 
entry and must have the 
intention to remain on FVIII 
prophylaxis replacement 
therapy for the duration of 
the study. This does not 
include nonfactor treatments 
(eg. Emicizumab), which are 
prohibited, see Section 5.4”
To clarify that non-factor 
treatments are prohibited. 
To clarify that participants 
must be on a stable 
prophylactic FVIII product 
regimen when entering the 
study; this does not include 
nonfactor treatments.  
Section 4.1 Inclusion 
Criteria
Added the words “median 
stiffness” to exclusion 
criterion 5 fibroscan score.
To clarify that Fibroscan 
score corresponds to median 
stiffness.
Section 4.2 Exclusion 
Criteria
Added new exclusion 
criterion 11.
To clarify which therapies 
are prohibited for use during 
the study.
Section 4.2 Exclusion 
Criteria
Added the following new 
text to Disallowed Therapy 
Section ”Bypassing agents 
(eg, factor VIIa, activated 
prothrombin complex 
concentrate) and nonfactor
treatment (eg, emicizumab), 
except in situations where it 
is medically necessitated.”
Added the following new 
text to Disallowed Therapy 
Section “Antifibrinolytics 
(e.g. tranexamic acid, 
aminocaproic acid), except 
where medically indicated.” 
To clarify certain therapies 
are prohibited for use during 
the study and this includes 
bypassing agents, non-factor 
treatment and  
antifibrinolytics.
Section 5.4 Concomitant 
Treatment(s)/Disallowed 
Therapy
Added a new sentence “The 
reasons for preventative 
FIX/FVIII replacement 
To clarify that the reasons
for preventative infusions 
will now be captured and 
this will be done in eCRF.
Section SOA footnote g; 
Section 6.2 Baseline Visit;
Section 6.3 Data Collection
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Description of Change
Brief Rationale
Section # and Name
therapy will be captured in 
eCRF.”
Section 6.5 End of 
Study/Early Termination
Reworded text to clarify 
what AE events are reported 
on the CRF and SAE form 
within the table under AE 
reporting requirement 
section.
To clarify what events need 
to be recorded on CRF as 
well on SAE form.
Section 8.1 AE Reporting 
Requirements
Added updated text from 
April 2023 protocol 
template where applicable. 
To align with current 
protocol template language 
version April 2023 to ensure 
regulatory compliance.
Section 10 (QUALITY 
CONTROL AND 
QUALITY ASSURANCE);
Section 11.1, 11.3  (DATA 
HANDLING AND 
RECORD KEEPING );
Section 12 (ETHICS);
Section 15.1, 15.2 
(PUBLICATION OF 
STUDY RESULTS)
Added “QTL”to 
abbreviation table in 
Appendix 1.
Added FVIIa to abbreviation 
table in Appendix 1.
To align with updated QTL 
text and definition from 
Section 10.
To clarify definition of 
acronyms.
Appendix 1
Added  “New Untreated 
Bleed” definition to 
Appendix 2 to align with 
language in the SAP. 
Minor clarifications for 
consistency with the SAP.
Appendix 2
Incorporated an 
administrative change from 
the protocol administrative 
change letter (PACL#15) 
dated 22 November 2022.
To clarify the definition of a 
bleed that necessitates 
administration of 
coagulation factor within 72 
hours of signs and 
symptoms of bleeding is 
referred to as a “treated 
bleed”.
Appendix 2
TABLE OF CONTENTS
LIST OF FIGURES .................................................................................................................10
APPENDICES .........................................................................................................................11
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SCHEDULE OF ACTIVITIES................................................................................................12
1. INTRODUCTION ...............................................................................................................15
1.1. Mechanism of Action/Indication.............................................................................15
1.2. Background and Rationale ......................................................................................15
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................17
3. STUDY DESIGN.................................................................................................................18
4. PARTICIPANT ELIGIBILITY CRITERIA........................................................................19
4.1. Inclusion Criteria.....................................................................................................19
4.2. Exclusion Criteria....................................................................................................20
4.3. Sponsor’s Qualified Medical Personnel..................................................................23
4.4. Screen Failures ........................................................................................................24
5. STUDY TREATMENTS.....................................................................................................24
5.1. Allocation to Treatment ..........................................................................................24
5.2. Participant Compliance ...........................................................................................24
5.3. FIX or FVIII Replacement Therapy Supplies.........................................................25
5.3.1. Dosage Form(s) and Packaging..................................................................25
5.3.2. FIX or FVIII Replacement Therapy Storage..............................................25
5.4. Concomitant Treatment(s).......................................................................................25
6. STUDY PROCEDURES .....................................................................................................26
6.1. Screening Visit – Screening Phase to Determine nAb Status and Eligibility 
into Data Collection Phase (Day -42 to Day -1)........................................................26
6.2. Baseline Visit – Enrollment into Data Collection Phase (Day 1) ...........................28
6.3. Data Collection – Collection of FIX/FVIII Replacement Therapy and/or 
Safety Events (Day 1 through End of Study/Early Termination For Each 
Participant) ................................................................................................................29
6.4. Interim Phone Call (Approximately Every 30 Days from Day 1 ±1 Week)...........30
6.5. End of Study/Early Termination .............................................................................30
6.6. Participant Withdrawal............................................................................................31
7. ASSESSMENTS..................................................................................................................32
8. ADVERSE EVENT REPORTING......................................................................................32
8.1. Requirements...........................................................................................................32
8.1.1. Additional Details on Recording Adverse Events on the Case Report 
Form (CRF)......................................................................................................34
8.1.2. Eliciting Adverse Event Information..........................................................34
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8.1.3. Withdrawal from the Study Due to Adverse Events (see also the 
Participant Withdrawal section).......................................................................34
8.1.4. Time Period for Collecting AE/SAE Information......................................35
8.1.4.1. Reporting SAEs to Pfizer Safety...............................................35
8.1.4.2. Recording Non-serious AEs and SAEs on the eCRF................35
8.1.5. Causality Assessment .................................................................................35
8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities ..................36
8.2. Definitions...............................................................................................................36
8.2.1. Adverse Events ...........................................................................................36
8.2.2. Serious Adverse Events ..............................................................................36
8.2.3. Hospitalization............................................................................................37
8.3. Severity Assessment................................................................................................38
8.4. Special Situations ....................................................................................................38
8.4.1. Protocol Specified Serious Adverse Events ...............................................38
8.4.2. Exposure to Standard of Care Therapy during Pregnancy and 
Occupational Exposure....................................................................................39
8.4.2.1. Exposure During Pregnancy......................................................39
8.4.2.2. Occupational Exposure .............................................................40
8.4.3. Medication Errors and Lack of Efficacy.....................................................40
8.4.3.1. Medication Errors......................................................................41
8.4.3.2. Lack of Efficacy........................................................................41
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................41
9.1. Sample Size Determination.....................................................................................41
9.2. Efficacy Analysis ....................................................................................................42
9.2.1. Analysis of the Primary Endpoint...............................................................42
9.2.2. Analysis of Secondary Endpoints...............................................................42
9.3. Analysis of Other Endpoints (Exploratory Endpoint).............................................43
9.3.1. nAb Assessment..........................................................................................43
9.4. Safety Analysis........................................................................................................43
9.5. Interim Analysis ......................................................................................................43
9.6. Data Monitoring Committee ...................................................................................43
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................43
11. DATA HANDLING AND RECORD KEEPING .............................................................44
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11.1. Case Report Forms/Electronic Data Record .........................................................44
11.2. Record Retention...................................................................................................45
11.3. Data Protection......................................................................................................45
12. ETHICS..............................................................................................................................46
12.1. Regulatory and Ethical Considerations.................................................................46
12.2. Participant Information and Consent.....................................................................47
12.3. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................47
13. DEFINITION OF END OF TRIAL...................................................................................48
13.1. End of Trial in a Member State.............................................................................48
13.2. End of Trial in All Other Participating Countries.................................................48
14. SPONSOR DISCONTINUATION CRITERIA ................................................................48
15. PUBLICATION OF STUDY RESULTS..........................................................................48
15.1. Dissemination of Clinical Study Data...................................................................48
15.2. Publications by Investigators ................................................................................49
16. REFERENCES ..................................................................................................................51
LIST OF FIGURES
Figure 1.
Study Schematic .......................................................................................19
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APPENDICES
Appendix 1. Abbreviations......................................................................................................52
Appendix 2. Bleed and Factor Replacement Regimen Definitions1,2,3....................................54
Appendix 3. France Country-Specific Requirement................................................................56
Appendix 4. Turkey Country-Specific Requirement...............................................................57
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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the 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 well-being of the participant.
Visit Identifiera
Screening Visit
Baseline Visit
(on-site or remotei; 
start of data 
collection)
Interim Phone Call
End of Study/Early 
Termination Visitj
Visit Window
Day -42 to Day -1
Day 1
Approximately every 30 
days from Day 1 ±1 week
See Footnote j
Informed Consentb
X
Medical History/Hemophilia History and 
Demographyc
X
Vitals (temperature (°C), blood pressure 
(sitting), pulse and respiration), body weight 
(kg) and height (cm)
X
Factor IX/FVIII activity, HBV, HCV, liver 
fibrosis, and HIV serology (viral load and CD4 
count for HIV positive participants only) 
Laboratory Sample Collectiond
X
Neutralizing Antibody (nAb) Laboratory 
Sample Collection for both AAV-Spark-100 
and AAV6e
X
nAb Laboratory Assessmente
X
Eligibility Confirmation
X
Electronic Diary Trainingf
X
Issue Electronic Diary (nAb negative 
participants only)g
X
Review Electronic Diary
X
X
X
Return Electronic Diary
X
Concomitant treatments
X X
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Visit Identifiera
Screening Visit
Baseline Visit
(on-site or remotei; 
start of data 
collection)
Interim Phone Call
End of Study/Early 
Termination Visitj
Serious and non-serious adverse event 
monitoringh
X X
a.
The screening visit should occur within 42 days of the start of the baseline visit (Day 1).  If there is no documentation of baseline Factor IX/VIII activity 
(≤2% or ≤1%, respectively, in participant’s medical record) or no documentation of HBV, HCV, liver fibrosis, and HIV serology (viral load and CD4 count 
for HIV positive participants only) within the last 12 months prior to screening (6 months for HCV), then participants will need to undergo laboratory testing 
prior to baseline visit to determine their status.  The screening period may be extended upon consultation with the sponsor’s medical monitor.  Reason for the 
extension must be recorded in the source documents.  Prior to baseline visit (Day 1), the study site will notify participants of their nAb laboratory results to 
determine participant eligibility to continue in the study and the subsequent data collection phase.  Neutralizing antibody positive participants will be 
discontinued from further participation in the study and nAb negative participants will schedule a baseline visit to continue in the study and the subsequent 
data collection phase.  It is required that the interim phone call(s) will occur approximately every 30 days from baseline visit (Day 1).  These phone calls will 
ensure participant’s study compliance with their electronic diary and standard of care regimen, and monitor participant safety by recording any serious 
adverse events or any protocol specified non serious adverse events (see Section 8.1).
b.
Informed consent should be obtained from participants prior to any study related procedures.  Refer to Section 6.1 for additional details.
c.
Demographics include sex/gender, race, date of birth (month and year only), and ethnicity.  Hemophilia history includes (but is not limited to) date of 
diagnosis, severity, history of inhibitor (FIX inhibitor for hemophilia B participants or FVIII inhibitor for hemophilia A participants), family inhibitor 
history, gene mutation (if available), number of exposure days, number of bleeds and infusions within the last 12 months (where available), and current FIX 
or FVIII treatment and regimen.
d.
If there is no documentation of baseline Factor IX/VIII activity (≤2% or ≤1% respectively in participant’s medical record); or no documentation of 
HBV, HCV, liver fibrosis (FibroScan OR FibroTest/FibroSURE), and HIV serology (viral load and CD4 count for HIV positive participants only) within the 
last 12 months prior to screening (6 months for HCV), then participants will need to undergo laboratory testing prior to baseline visit to determine their 
status.  In the absence of a documented FIX:C or Factor VIII (FVIII:C) activity level (according to the underlying disease) participants will observe a 
minimum 72 hour FIX or FVIII washout for recombinant or plasma derived products or a minimum of 5-10 days or longer for extended half-life products 
prior to the baseline visit.  Depending on when the last FIX or FVIII dose was administered before the beginning of the FIX or FVIII washout, an interval 
longer than 72 hours or 5 10 days may be needed.  The screening visit window may be extended, upon consultation with the sponsor’s medical monitor.  
Reason for the extension must be recorded in the source documents.  If a participant sustains a bleed requiring treatment during the ≥72 hour or ≥5-10 day 
FIX or FVIII washout, the necessary treatment should be administered using the participant’s usual FIX or FVIII replacement product.  Once the bleed has 
been adequately treated, the screening visit must be rescheduled, and must be preceded by a new ≥72 hour or ≥5-10 day FIX or FVIII washout.  
e.
Prior to baseline visit (Day 1), upon the availability of the nAb laboratory results, the study site will notify participants of their nAb laboratory test 
results via a telephone call.  The nAb positive participants (nAb positive against AAV-Spark100 for hemophilia B population or nAb positive against AAV6 
for hemophilia A population) will be contacted to explain what the implications of being nAb positive are and subsequently discontinued from further 
participation in the study.  The nAb negative participants (nAb negative against AAV-Spark100 for hemophilia B population or nAb negative against AAV6 
for hemophilia A population) will be contacted to schedule a baseline visit to issue their electronic diary and continue on with the data collection phase.  In 
the hemophilia B population, the samples collected during the screening visit may be used to test nAb against AAV6, as well as testing for antibodies against 
additional AAVs, at the end of the study (Note: Hemophilia B participants screened prior to Amendment 5 will be reconsented prior to testing their 
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Visit Identifiera
Screening Visit
Baseline Visit
(on-site or remotei; 
start of data 
collection)
Interim Phone Call
End of Study/Early 
Termination Visitj
previously collected samples for nAb against AAV6, as well as testing for antibodies against additional AAVs).  The nAb result against AAV6, as well as 
antibodies against additional AAVs, will not be shared with the hemophilia B participants.  In the hemophilia A population, the samples collected during the 
screening visit may be used to test nAb against AAV-Spark100, as well as testing for antibodies against additional AAVs, at the end of the study.  The nAb 
result against AAV-Spark100, as well as antibodies against additional AAVs, will not be shared with the hemophilia A participants.
f.
Training with respect to operation of the electronic diary including timing and information to be entered by the participant may be conducted at the 
screening or baseline visit.  Refer to Sections 6.1 and 6.2 for additional details.
g.
The electronic diary will capture the following: FIX/FVIII replacement therapy administration (date, time, reason for administration, and dose [IU]); and 
bleeding events (date, location and whether the etiology is spontaneous or traumatic).  See Sections 6.2 and 6.3.  The reasons for preventative FIX/FVIII
replacement therapy will be captured in eCRF.
h.
Adverse events will be recorded from consent through the end of study visit.  Any SAE experienced by the participant from the day of signing the ICD 
through end of study visit is to be recorded, regardless of the severity of the event or its relationship to standard of care therapy.  Protocol specified non 
serious adverse events (re: Section 8.1) are to be recorded from consent through end of study visit regardless of severity of the event or its relationship to 
standard of care therapy.
i.
In the event an on-site clinic study visit cannot be conducted, the investigator and/or site staff can conduct a remote visit (if permitted by local 
regulations).  The remote visit can be conducted with investigator site staff via telehealth (eg, audio,video,video conferencing software).  Refer to Section 6
for additional details.
j.
The duration of follow-up for participants in this study (C0371004) will be at least 6 months until the required number of treated participants in the 
respective treatment protocols (C0371002 and C3731003) are met (refer to Section 9.1 for sample size determination).  Subsequent to reaching the required 
number of participants in the treatment protocols, the exact duration of follow-up for each individual participant may vary.  The end of study visit marks the 
conclusion of the data collection phase and completion of the study for each participant.  Participants withdrawing from the study prematurely will complete 
a termination visit and must have end of study assessments performed unless they have withdrawn consent.
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1. INTRODUCTION
1.1. Mechanism of Action/Indication
The C0371004 study does not involve use of an investigational product.  The study is 
designed to evaluate current Factor IX (FIX) or Factor VIII (FVIII) prophylaxis replacement 
therapy, in the usual care setting of moderately severe to severe adult hemophilia B 
participants (FIX:C≤2%) who are negative for neutralizing antibodies (nAb) to 
adeno-associated virus vector (AAV)-Spark100 OR moderately severe to severe adult 
hemophilia A participants (Factor VIII circulating [FVIII:C] ≤1%) who are negative for nAb 
to AAV6 (capsid portion of SB-525).
1.2. Background and Rationale
Hemophilia B (Christmas disease) and hemophilia A are hereditary X-chromosomal 
recessive bleeding disorders caused by deficiency or absence of coagulation factors: FIX 
(encoded by F9) in hemophilia B and FVIII (encoded by F8) in hemophilia A.2  Hemophilia 
has an estimated frequency of ~1/10,000 births; hemophilia A is more common than 
hemophilia B, representing 80–85% of the total hemophilia population.3
Severity of hemophilia is operationally defined into 3 categories based on circulating FIX or 
FVIII activity levels in the plasma each of which is characterized by different bleeding 
profiles.  Patients with severe hemophilia have factor activity (FIX in hemophilia B and 
FVIII in hemophilia A) levels less than 1% (or <1 IU/dL) of normal while patients with 
moderate hemophilia have factor activity levels 1-5% (1-5 IU/dL) of normal, and mild 
hemophilia patients have factor activity levels over >5-<40% (>5-<40 IU/dL) of normal.1
Hemophilia is characterized by bleeding into muscle, soft tissue, and joints (hemarthroses) 
that occur spontaneously or in response to trauma.  Other types of bleeding events that may 
be observed include intracranial hemorrhage, bleeding following tooth extraction, 
post-surgical bleeding, hematomas and mucosal bleeding.4
Patients with hemophilia B or A are usually managed by replacing the missing or defective 
factor (FIX in hemophilia B and FVIII in hemophilia A) for treatment or prevention of 
hemorrhage.  Current treatment paradigms for both hemophilia B and A rely on replacement 
of the missing clotting Factor IX/VIII using plasma-derived or recombinant factor 
administered in the setting of an acute bleed (on-demand) or at regularly scheduled intervals 
(prophylaxis).  Venous access via peripheral veins remains the only option for the 
administration of Factor IX or VIII replacement therapy.1,2,3
Unmet medical needs associated with current methods of treatment for hemophilia include 
the challenging dose schedule (from 1-4 times per week to twice per month according to 
treatment used- standard half-life/extended half-life), burden to patients and obstacles to 
implementation of prophylaxis associated with replacement factor treatment (standard 
half-life recombinant or plasma derived clotting factor concentrates, long acting clotting 
factor) or new treatment with different mechanism of action (ie, antibodies like 
emicizumab).5
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Gene therapy is a new treatment modality for patients with hemophilia that works via gene 
transfer to target cells (hepatocytes in the case of hemophilia) where Factor IX or Factor VIII 
is then expressed, processed and excreted into the circulation.  This therapy would potentially 
allow patients to realize the benefit of Factor IX or Factor VIII replacement without the need 
for frequent intravenous infusions.
The major benefit of gene therapy is that it may provide persistent treatment of hemophilia 
by continuous endogenous production of functional FIX or FVIII thereby providing relief 
from the medical and life-style burden of recurrent on-demand or routine prophylactic 
protein replacement therapy.
Adeno-associated virus (AAV) based vectors have emerged as the vehicle of choice to 
deliver the Factors IX and VIII genes for gene therapy-based treatment of hemophilia B or 
hemophilia A, respectively.  However, prior infection with naturally occurring AAV induces 
a humoral response which will render AAV-mediated transgene delivery ineffective by 
preventing hepatocyte transduction.
Gene therapy in hemophilia B:
Fidanacogene elaparvovec (PF-06838435; formerly SPK-9001) is an AAV-based vector 
designed by Spark Therapeutics for the treatment of hemophilia B.  It is composed of 
AAV-Spark100 (a bio-engineered AAV capsid derived from a naturally occurring AAV 
serotype) encoding hFIX-Padua that has been shown in vitro and in a small sample of 
patients to be less prone to neutralization than other AAV serotype gene therapy-based 
vectors.  However, these data are of limited scope and the geographic distribution impact on 
neutralizing antibodies is not currently known.
Gene therapy in hemophilia A:
Giroctocogene fitelparvovec (PF-07055480; formerly SB-525) is an AAV-based vector 
designed by Sangamo Therapeutics for the treatment of hemophilia A.  It is composed of 
recombinant adeno-associated virus 2/6 (rAAV2/6) vector encoding the cDNA for the 
B-domain deleted (BDD) human FVIII (hFVIII) that has been shown in vitro and in a small 
sample of patients to be less prone to neutralization than other AAV serotype gene therapy-
based vectors.  However, these data are of limited scope and the geographic distribution 
impact on neutralizing antibodies is not currently known.
The aim of this study is to assess prospective efficacy of FIX or FVIII prophylaxis 
replacement therapy in the usual care setting of moderately severe to severe hemophilia B or 
hemophilia A participants, respectively, whose nAb to AAV-Spark100 (hemophilia B 
participants) and nAb to AAV6 (hemophilia A participants) are below the established 
thresholds (negative).  The FIX and FVIII prophylaxis efficacy data obtained in this study 
will serve as the control for comparison with post gene therapy efficacy for those participants 
that subsequently enroll into and are treated in the respective subsequent Phase 3 gene 
therapy dosing studies (C0371002 hemophilia B and C3731003 hemophilia A).
There is no single reference safety document (SRSD) for this protocol with each product 
supported by their respective approved product label.
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2. STUDY OBJECTIVES AND ENDPOINTS
Primary Objective(s):
Efficacy Endpoint(s):

To establish prospective efficacy data of:

FIX prophylaxis replacement therapy in the 
usual care setting of hemophilia B 
participants, who are negative for nAb to 
AAV-Spark100. 

FVIII prophylaxis replacement therapy in 
the usual care setting of hemophilia A 
participants, who are negative for nAb to
AAV6.
Primary Endpoint 

Annualized bleeding rate (ABR) in 
hemophilia B participants.

Annualized bleeding rate (ABR) in 
hemophilia A participants. 
Secondary Endpoint 

Annualized number of infusions (AIR) in 
hemophilia B participants.

Annualized number of infusions (AIR) in 
hemophilia A participants.
Other Secondary Endpoints 

Dose and total factor consumption in 
hemophilia B participants. 

Dose and total factor consumption in 
hemophilia A participants. 

Number of bleeding events (spontaneous 
and/or traumatic) in hemophilia B participants.

Number of bleeding events (spontaneous 
and/or traumatic) in hemophilia A participants.
Secondary Objective(s):
Safety Endpoint(s):

Evaluate safety (serious adverse events and
medically important events of FIX or FVIII
inhibitor, thrombotic and factor 
hypersensitivity reactions) of FIX replacement
therapy in hemophilia B participants or FVIII 
replacement therapy in hemophilia A
participants.

Incidence of serious adverse events in 
hemophilia B participants.

Incidence of serious adverse events in 
hemophilia A participants. 

Events of Special Interest in hemophilia B 
participants:

FIX inhibitor;

Thrombotic events;

Factor hypersensitivity events.

Events of Special Interest in hemophilia A 
participants:

FVIII inhibitor;

Thrombotic events;
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
Factor hypersensitivity events.
Exploratory Objective(s):
Exploratory Endpoint(s):

Measure the frequency of nAb against
AAV-Spark100 and AAV6 in the respective 
populations assessed (hemophilia B or 
hemophilia A participants).

The frequency and percentage of nAb status to 
AAV-Spark100 or AAV6 (positive, negative).
3. STUDY DESIGN
The C0371004 study will be conducted as an open-label, non-investigational product, 
prospective, multi-center, lead-in study to assess efficacy and selected safety data of current 
Factor IX (FIX) or Factor VIII (FVIII) prophylaxis replacement therapy in the usual care 
setting of moderately severe to severe adult hemophilia B participants (FIX:C≤2%) who are 
negative for nAb to AAV-Spark100 or moderately severe to severe adult hemophilia A 
participants (FVIII:C≤1%) who are negative for nAb to AAV6, prior to the respective 
therapeutic Phase 3 gene therapy studies.
The study consists of two phases: the screening phase will include a laboratory blood draw to 
determine nAb status to both AAV-Spark100 or AAV6 for each respective group of 
participants (hemophilia B or hemophilia A) and the second phase will be the data collection 
phase for those hemophilia B participants who are below the established threshold for nAb to 
AAV-Spark100 or those hemophilia A participants who are below the established threshold 
for nAb to AAV6.  The data collection phase is designed to provide prospective efficacy and 
selected safety data of FIX prophylaxis replacement therapy in the usual setting of those 
hemophilia B participants or FVIII prophylaxis replacement therapy in the usual setting of 
those hemophilia A participants.
Sample size in this study is driven by the need to meet a required number of treated 
participants in the respective treatment protocols (C0371002 and C3731003).  The duration 
of follow-up for participants in this study (C0371004) will be at least 6 months until the 
required number of treated participants in the respective treatment protocols (C0371002 and 
C3731003) are met (refer to Section 9.1 for sample size determination).  Subsequent to 
reaching the required number of participants in the treatment protocols, the duration of 
follow-up for participants recruited into this study (C0371004) may vary.
Participants withdrawn from this study or the subsequent treatment study may be replaced, at 
the discretion of the investigator and sponsor.  The total duration of the study including 
enrollment period will be approximately 60 months.
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Figure 1.
Study Schematic
4. PARTICIPANT ELIGIBILITY CRITERIA
This study can fulfill its objectives only if appropriate participants are enrolled.  The following 
eligibility criteria are designed to select participants for whom participation in the study is 
considered appropriate.  All relevant medical and non-medical conditions should be taken 
into consideration when deciding whether a particular participant is suitable for this protocol.
Participant eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before participants are included in the study.
4.1. Inclusion Criteria
Participants in each population (Hemophilia B or A) must meet all of the inclusion criteria 
for that population to be eligible for enrollment into the study:
Hemophilia B Population:
1. Evidence of a signed and dated informed consent document indicating that the 
participant has been informed of all pertinent aspects of the study.
2. Willing and able to comply with scheduled visits, FIX prophylaxis treatment plan, 
laboratory tests and other study procedures.
3. Males ≥18 and <65 years of age with moderately severe to severe hemophilia B 
and documented FIX activity (≤2%) prior to baseline visit.
4. Previous experience with FIX therapy (≥50 documented exposure days to a 
FIX protein product such as recombinant, plasma-derived or extended half-life 
FIX product).
5. Participants on FIX prophylaxis replacement therapy (recombinant, 
plasma-derived or extended half-life FIX product) must have the intention to 
remain on FIX prophylaxis replacement therapy for the duration of the study.
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6. No known hypersensitivity to FIX replacement product.
7. No history of FIX inhibitor (clinical or laboratory-based assessment) defined as a 
titer ≥0.6 BU/mL, regardless of the laboratory normal range, or any measured 
Bethesda inhibitor titer greater than the upper limit of normal for the laboratory 
performing the assay.  Clinically, no signs or symptoms of decreased response to 
FIX administration.  Participants will not be required to undergo diagnostic 
evaluation of inhibitor status to participate in the study.
Hemophilia A Population:
1. Evidence of a signed and dated informed consent document indicating that the 
participant has been informed of all pertinent aspects of the study.
2. Willing and able to comply with scheduled visits, FVIII prophylaxis treatment 
plan, laboratory tests and other study procedures.
3. Males ≥18 and <65 years of age with moderately severe to severe hemophilia A 
and documented FVIII activity (≤1%) prior to baseline visit.
4. Previous experience with FVIII therapy (≥150 documented exposure days to a
FVIII protein product such as recombinant, plasma-derived or extended half-life
FVIII product). 
5. Participants must be on a stable FVIII prophylaxis replacement therapy
(recombinant, plasma-derived or extended half-life FVIII product) at study entry 
and must have the intention to remain on FVIII prophylaxis replacement therapy 
for the duration of the study. This does not include nonfactor treatments (eg. 
Emicizumab), which are prohibited, see Section 5.4.
6. No known hypersensitivity to FVIII replacement product.
7. No history of FVIII inhibitor (clinical or laboratory-based assessment) defined as a
titer ≥0.6 BU/mL, regardless of the laboratory normal range, or any measured 
Bethesda inhibitor titer greater than the upper limit of normal for the laboratory
performing the assay.  Clinically, no signs or symptoms of decreased response to 
FVIII administration.  Participants will not be required to undergo diagnostic 
evaluation of inhibitor status to participate in the study.
4.2. Exclusion Criteria
Participants with any of the following characteristics/conditions will not be included in the 
study:
1. Anti-AAV-Spark100 neutralizing antibody titer above the established threshold 
performed by a central laboratory during screening in hemophilia B participants or 
Anti-AAV6 neutralizing antibody titer above the established threshold performed 
by a central laboratory during screening in hemophilia A participants.
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2. Lack of participant compliance with documentation of bleeds and/or prophylaxis 
replacement therapy administration.
3. If there is no documentation regarding hepatitis status, as defined below, within the 
last 12 months prior to screening for hepatitis B and 6 months prior to screening 
for hepatitis C, then participants will be required to have the following hepatitis 
testing performed at screening:
a. Hepatitis B screening (acute and chronic):
HBsAg (also referred to as Hepatitis B surface antigen), 
HBV-DNA viral assay (also referred to as a nucleic acid test for Hepatitis B virus 
DNA), and Anti-HBc (also referred to as Total Hepatitis B core antibody).

A participant is not eligible if either HbsAg is positive or HBV-DNA is 
positive/detectable.

Anti-HBc must be obtained in all participants for determination of whether the 
participant had prior hepatitis B.  If the anti-HBc is positive and both HBsAg and 
HBV DNA are negative this would be consistent with a prior infection and the 
participant would be eligible for the study.  Anti-HBc must be obtained in all 
participants to discriminate between those with no prior hepatitis B and those with 
prior infection in the event of reactivation.  FDA has noted reactivation of 
hepatitis B virus exists.

One documented negative HBV-DNA viral load is sufficient to assess eligibility.  
A participant who is currently undergoing anti-viral therapy for hepatitis B is not 
eligible.
b. Hepatitis C (acute or chronic):

A participant who is currently undergoing anti-viral therapy for chronic 
hepatitis C is not eligible.

Participants treated with anti-viral therapy for chronic hepatitis C, must have 
completed anti-viral therapy at least 6 months prior to screening and have a 
negative HCV-RNA at least 6 months prior to screening.

All participants (who are not currently undergoing anti-viral therapy for chronic 
hepatitis C) must have a single HCV-RNA load assay (also referred to as a 
nucleic acid test [NAT] for HCV RNA) obtained during the 6 months preceding 
screening.  This includes participants with prior known chronic hepatitis C who 
have completed treatment with anti-viral therapy.

A participant is not eligible if his HCV-RNA load assay result is 
positive/detectable.
4. Currently on antiviral therapy for hepatitis B or C.
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5. Significant liver disease, as defined by pre-existing diagnosis of portal 
hypertension, splenomegaly, or hepatic encephalopathy.
All participants who do not have the listed pre-existing diagnoses above must have 
the following assessments performed within the last 12 months prior to screening 
and if not will need to be tested for liver fibrosis status at screening: a serum 
albumin level below normal limits and/or significant liver fibrosis by any of the 
following diagnostic modalities: FibroScan median stiffness score >8 kPa units OR 
FibroTest/FibroSURE >0.48*.
* NOTE: If there is concern regarding the validity of any of the liver fibrosis test 
results please contact the medical monitor to discuss whether any additional testing 
needs to be performed (ie, either repeating any test or performing another fibrosis 
test).  Also, note, if a participant has a known history of Gilbert’s syndrome, a 
FibroTest cannot be used for fibrosis testing.
6. Documented serological evidence of human immunodeficiency virus HIV-1 or 
HIV-2 with Cluster of Differentiation 4 positive (CD4+) cell count ≤200 mm3 
within the last 12 months prior to screening.  Participants who are HIV positive 
and stable, have an adequate CD4 count (>200/mm3) and undetectable viral load 
(<50 gc/mL) documented within the preceding 12 months, and are on an 
antiretroviral drug regimen are eligible to enroll.  Participants who have not been 
tested within the prior 12 months of screening will need to be tested for HIV status 
at screening.
7. History of chronic infection or other chronic disease that the investigator deems an 
unacceptable risk. In addition, any participant with conditions associated with 
increased thromboembolic risk such as known inherited or acquired thrombophilia, 
or a history of thrombotic events including but not limited to stroke, myocardial 
infarction, and/or venous thromboembolism, is excluded.
8. Any concurrent clinically significant major disease or condition that the 
investigator deems unsuitable for participation or other acute or chronic medical or 
psychiatric condition including recent (within the past year) or active suicidal 
ideation or behavior or laboratory abnormality that may increase the risk 
associated with study participation or may interfere with the interpretation of study 
results and, in the judgment of the investigator, would make the participant 
inappropriate for entry into this study. In addition, any participant with a history of 
a neoplasm (including hepatic malignancy) that required treatment (eg, 
chemotherapy, radiotherapy, immunotherapy), is excluded, except for adequately 
treated basal or squamous cell carcinoma of the skin or a surgically removed 
benign neoplasm not requiring chemotherapy, radiotherapy and/or immunotherapy. 
Any other neoplasm that has been cured by resection should be discussed between 
the investigator and sponsor.
9. Participation in other studies if involving administration of investigational 
product(s) within the last 3 months prior to study entry and/or during study 
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participation or in a previous gene therapy clinical study within the last 12 months 
prior to screening.

Participants already enrolled in this lead-in study (C0371004) may be allowed to 
participate in the screening and baseline periods of either C0371002 or C3731003 
protocols prior to their completion of the end of study visit in this lead-in study.
10. Any participant who previously received fidanacogene elaparvovec (hemophilia B) 
or giroctocogene fitelparvovec (hemophilia A) or any AAV gene-based therapy.
11. Participants using restricted therapies.  See Section 5.4 for therapies not allowed 
during study participation.
12. Any participant with a planned surgical procedure requiring FIX (hemophilia B) or 
FVIII (hemophilia A) surgical prophylactic factor treatment in the next 24 months.
13. Investigator site staff members directly involved in the conduct of the study and 
their family members, site staff members otherwise supervised by the investigator, 
or participants who are Pfizer employees, including their family members, directly 
involved in the conduct of the study.
NOTE:  The sponsor’s medical team should be contacted if there are any questions 
regarding any of the inclusion or exclusion criteria (Sections: 4.1 and 4.2).
4.3. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the supporting study 
documentation/team SharePoint site/study portal.
To facilitate access to appropriately qualified medical personnel on study related medical 
questions or problems, participants are provided with a study specific contact card.  The 
contact card contains, at a minimum, study protocol identifiers and standard of care 
FIX/FVIII replacement therapy name, participant study numbers, contact information for the 
investigator site, and contact details for a contact center in the event that the investigator site 
staff cannot be reached to provide advice on a medical question or problem originating from 
another healthcare professional not involved in the participant’s participation in the study.  
The contact number can also be used by investigator staff if they are seeking advice on 
medical questions or problems; however, it should be used only in the event that the 
established communication pathways between the investigator site and the study team are not 
available.  It is therefore intended to augment, but not replace, the established communication 
pathways between the investigator site and the study team for advice on medical questions or 
problems that may arise during the study.  The contact number is not intended for use by the 
participant directly, and if a participant calls that number, he or she will be directed back to 
the investigator site.
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4.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently entered in the study.  A minimal set of screen failure information is 
required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities.  Minimal information includes demography, 
screen failure details, eligibility criteria, and any serious adverse event (SAE).
Study participants who do not meet the criteria for participation in this study (for example, 
screening laboratory results and/or FibroScan results) and are deemed a screen failure, may 
be rescreened, because these laboratory and/or Fibroscan results can change over time.  The 
repeated central laboratory and/or Fibroscan results must be available prior to the Baseline 
Visit and be within range for the participant to be eligible.  Rescreened participants are 
required to sign a new ICD and will be assigned a different participant number.
Note: Study participants who are not deemed a screen failure, and have a test value 
(eg, central laboratory and/or Fibroscan) that is outside the range specified by the exclusion 
criteria, repeated by the central laboratory to determine eligibility.  However, the new result 
must be available prior to the Baseline Visit and be within range for the participant to be 
eligible.
5. STUDY TREATMENTS
No investigational product will be administered in this study.  Hemophilia B or 
Hemophilia A participants will remain on their current FIX or FVIII replacement therapy, 
respectively, using their usual prophylaxis regimen.  Investigators can consult the appropriate 
prescribing information for the prophylaxis therapy.
5.1. Allocation to Treatment
The investigator’s knowledge of the participant’s current FIX or FVIII prophylaxis 
replacement therapy regimen should not influence the decision to enroll a particular 
participant or affect the order in which participants are enrolled.  The study will be conducted 
as an open-label and non-randomized trial.
The investigator will assign all participant identification numbers sequentially to their 
participants as they are screened for the study.  This identifying number will be retained 
throughout the study and remains confidential.  A participant number must never be 
reassigned or reused for any reason.  The investigator must maintain a confidential study log 
linking the participant number to the participant’s name.
5.2. Participant Compliance
It is recommended that the study site will review participant compliance on a weekly basis 
but at a minimum monthly to align with the interim phone call to confirm participant 
compliance with electronic diary entry.  The investigator, along with the sponsor will 
determine if a participant should be withdrawn from the study due to a participant’s 
non-compliance which could be damaging to the study results or the participant’s best 
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interests.  Participants who are withdrawn for non-compliance or any other reason will have 
an Early Termination Visit.
5.3. FIX or FVIII Replacement Therapy Supplies
5.3.1. Dosage Form(s) and Packaging
No investigational product will be supplied by the sponsor.  According to the underlying 
disease, participants will continue to administer their respective FIX or FVIII replacement 
therapy using a prophylaxis regimen.  The frequency and dosage for their replacement 
therapy will be based on the approved product label for their respective therapy and adjusted 
solely according to medical and therapeutic necessity at the discretion of the investigator. 
All treatment decisions will follow the general clinical practice/standard of care and will not 
be influenced by the participant taking part in this study.
5.3.2. FIX or FVIII Replacement Therapy Storage 
The respective FIX or FVIII replacement therapy utilized during the course of this study 
should follow the storage conditions stated on the product label.
5.4. Concomitant Treatment(s)
Allowed Therapy
During the study, participants are to continue with their respective FIX or FVIII prophylaxis 
therapy which is part of their usual treatment regimen. In addition, certain non-steroidal 
anti-inflammatory drugs (NSAIDs) are permitted (eg, COX-2 inhibitors and topical 
NSAIDs), along with HIV therapy, where medically necessary and according to standard of 
care.
Once a participant has signed the informed consent, they should be instructed to contact the 
study site to discuss any new medications, including non-prescription drugs and herbal 
preparations, with the investigator prior to taking them for the duration of the study.
Other therapies considered necessary for the participant’s welfare may be given at the 
discretion of the investigator.  All such therapies must be documented in the participant’s 
medical notes and recorded in the electronic case report form (eCRF).
Disallowed Therapy 
The following concomitant medications are not permitted during the study:

Blood products such as red blood cells (RBC), platelets, and fresh frozen plasma, 
except for example during a surgery or another medical condition at discretion of the 
principal investigator (eg, after severe haemorrhage, hypovolemic shock, etc.).  

Medications known to inhibit platelet function (eg, acetylsalicylic acid (aspirin), 
ibuprofen, or naproxen); however, certain NSAIDs are permitted (eg, COX-2 
inhibitors and topical NSAIDs). Please contact the sponsor’s medical monitor if there 
are any questions regarding the use of medications that may prolong bleeding.
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
Concomitant use of another investigational product(s).

Bypassing agents (eg, factor VIIa, activated prothrombin complex concentrate) and 
nonfactor treatment (eg, emicizumab), except in situations where it is medically 
necessitated.

Antifibrinolytics (e.g. tranexamic acid, aminocaproic acid), except where medically 
indicated.
6. STUDY PROCEDURES 
Remote Baseline Visit: If permitted by local regulations, the baseline visit may be conducted 
as a remote visit, where participants do not go to a site to complete the baseline visit but the 
baseline visit can be conducted by the investigator and/or site staff via telehealth (eg, audio, 
video, video conferencing software).  The end of study visit will be conducted on site.
6.1. Screening Visit – Screening Phase to Determine nAb Status and Eligibility into 
Data Collection Phase (Day -42 to Day -1) 
All screening procedures must be completed within 42 days of Day -1.  No study-related 
procedures may be performed until the Informed Consent process is completed.  The 
following procedures will be performed prior to participant enrollment:

Obtain written informed consent.  Collect and record participant demography 
(including date of birth (month and year), sex/gender, race, and ethnicity).

Collect medical history.

Collect hemophilia history including (but is not limited to) date of diagnosis, severity,
history of inhibitor (FIX inhibitor for hemophilia B participants or FVIII inhibitor for 
hemophilia A participants), family inhibitor history, gene mutation (if available), 
number of exposure days, number of bleeds and infusions within the last 12 months 
(where available), and current FIX or FVIII treatment and regimen.

Collect vital signs (temperature [°C], blood pressure [sitting], pulse and respiration), 
body weight (kg) and height (cm).

Collect blood sample for both nAb against AAV-Spark100 (hemophilia B) and 
AAV6 (hemophilia A) nAb assessment (central laboratory).  In the hemophilia B 
population, the samples collected during the screening visit may be used to test nAb 
against AAV6, as well as testing for antibodies against additional AAVs, at the end of 
the study (Note: Hemophilia B participants screened prior to Amendment 5 will be 
reconsented prior to testing their previously collected samples for nAb against AAV6, 
as well as testing for antibodies against additional AAVs).  The nAb result against 
AAV6, as well as antibodies against additional AAVs, will not be shared with the 
hemophilia B participants.  In the hemophilia A population, the samples collected 
during the screening visit may be used to test nAb against AAV-Spark100, as well as 
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testing for antibodies against additional AAVs, at the end of the study.  The nAb 
result against AAV-Spark100, as well as antibodies against additional AAVs, will not 
be shared with the hemophilia A participants.

Approximately 20 mL (4 teaspoons) of blood.

Samples will be collected for the following tests (central laboratory): Factor IX/VIII 
activity (if there is no documentation), HBV, HCV, liver fibrosis (FibroScan OR 
FibroTest/FibroSURE), and HIV serology (viral load and CD4 count for HIV positive 
participants only), only if there is no documentation within the last 12 months prior to 
screening (6 months for HCV):

Approximately 20 mL (4 teaspoons) of blood.

Review inclusion and exclusion criteria.

Record adverse events (reference Section 8.1 for protocol specified adverse event 
reporting) in addition to any research-related injury adverse event arising through 
screening blood draw collection.

Record concomitant treatments (drug and non-drug).
In the absence of a documented FIX:C or FVIII:C level (according to the underlying disease) 
participants will observe a minimum 72-hour FIX or FVIII washout for recombinant or 
plasma derived products or a minimum of 5-10 days or longer for extended half-life products 
prior to the baseline visit.  Depending on when the last FIX or FVIII dose was administered 
before the beginning of the FIX or FVIII washout, an interval longer than 72 hours or 
5-10 days may be needed.  The screening visit window may be extended, upon consultation 
with the sponsor’s medical monitor.  Reason for the extension must be recorded in the source 
documents.  If a participant sustains a bleed requiring treatment during the >72-hour or 
>5-10 day FIX or FVIII washout, the necessary treatment should be administered using the 
participant’s usual FIX or FVIII replacement product.  Once the bleed has been adequately 
treated, the screening visit must be rescheduled, and must be preceded by a new >72-hour or 
>5-10 day FIX or FVIII washout prior to baseline visit (Day 1), upon the availability of the 
nAb laboratory test results, the study site will notify participants of their nAb laboratory test 
results via a telephone call.
Hemophilia B Populations: Neutralizing antibodies against AAV-Spark100 transgene 
product positive participants will be contacted to explain what the implications of being nAb 
positive are and subsequently discontinued from further participation in the study.  
Neutralizing antibodies against AAV-Spark100 negative participants will be contacted to 
schedule a baseline visit to issue their electronic diary and continue on with the data 
collection phase.
Hemophilia A Population: Neutralizing antibodies against AAV6 positive participants will 
be contacted to explain what the implications of being nAb positive are and subsequently 
discontinued from further participation in the study.  Neutralizing antibodies against AAV6 
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negative participants will be contacted to schedule a baseline visit to issue their electronic 
diary and continue on with the data collection phase.
For both the hemophilia B and hemophilia A populations, site staff should conduct electronic 
diary training with the study participant at the screening visit if the baseline visit will be 
conducted remotely.

For Diary and Device Training at Screening Visit:

Site to provide Contact Authorization Form (CAF) for study participant to review and 
sign.

The site will need to log into mPal and add the study participant. Please activate the 
device using the Activation Code (found on the mPal study participant profile in lime 
green letters).  Once Trial Guide is activated, the study participant can navigate to the 
“Diary” tab and complete the “Training Infusion Log” and the “Training Bleed Log”.

Study Participant Eligible (nAb negative):

The site to ship the activated device to the study participant’s home prior to the 
baseline visit.

Study Participant Ineligible (nAb positive):

Please log in to mPal, find and click on the study participant ID and click 
“Archive”.  Select “Screen fail” as the reason for archival.  Clear all push 
notifications from the device and confirm that the Trial Guide mobile application 
has the “Activation Code” screen showing.
6.2. Baseline Visit – Enrollment into Data Collection Phase (Day 1)
Participants who test negative for circulating Immunoglobulin G (IgG) antibody to 
AAV-Spark100 and AAV6 and remain eligible (based on inclusion/exclusion criteria) will be 
given an electronic diary along with instructions on how to complete so that they can begin 
recording their FIX or FVIII replacement therapy efficacy data.  If bleeding episodes or 
treatments are not entered or cannot be entered (ie, device left at home by mistake) in the 
electronic diary during the appropriate time window, data should be entered by the 
investigator (or site staff member) according to the CRF completion guidelines with required 
source documentation in the participant’s medical record. The reasons for preventative 
FIX/FVIII replacement therapy will be captured in eCRF. The bleeding episodes and 
exogenous FIX/FVIII replacement data mentioned above will be referred to as “electronic 
diary data” regardless of how it is collected (ie, via the handheld device or according to the 
CRF completion guidelines).
The following procedures and assessments will be performed:

Confirm eligibility.
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
Record adverse events (reference Section 8.1 for protocol specified adverse event 
reporting) in addition to any research-related injury adverse event arising through 
screening blood draw collection.

Provide electronic diary and training (if not already conducted at the screening visit 
with site staff) with respect to operation of the electronic diary including timing and 
information to be entered by the participant, specifically:

FIX/FVIII replacement therapy administration (date, time, reason for 
administration, and dose international unit [IU]). 

Bleeding events as assessed by the participant (date, time, location and whether 
they are trauma related or spontaneous), should reference Appendix 2 as guidance 
on reporting such events.

Record concomitant treatments (drug and non-drug).

If necessary, FIX/FVIII inhibitor, FIX/FVIII activity can be done at investigator’s 
discretion and per their local usual standard of care.  Whenever FIX/FVIII activity is 
assessed, the time (Date/Hour) of previously administered last dose of FIX/FVIII 
replacement product or blood product should be captured in the electronic diary.
6.3. Data Collection – Collection of FIX/FVIII Replacement Therapy and/or Safety 
Events (Day 1 through End of Study/Early Termination For Each Participant)
Neutralizing antibody negative participants will continue with data collection until the End of 
Study/Early Termination Visit.
Study participants will record their FIX/FVIII replacement therapy administration (date, 
time, reason for administration, and dose [IU] and bleeding events (date, time, location and 
whether they are trauma related or spontaneous), in the electronic diary and should reference 
Appendix 2 as guidance on reporting such events.  If bleeding episodes or treatments are not 
entered or cannot be entered (ie, device left at home by mistake) in the electronic diary 
during the appropriate time window, data should be entered by the investigator (or site staff 
member) according to the CRF completion guidelines with required source documentation in 
the participant’s medical record. The reasons for preventative FIX/FVIII replacement therapy 
will be captured in eCRF. The bleeding episodes and exogenous FIX/FVIII replacement data 
mentioned above will be referred to as “electronic diary data” regardless of how it is 
collected (ie, via the handheld device or according to the CRF completion guidelines).  It is 
recommended that the study site review participant compliance on a weekly basis but at a 
minimum monthly to align with interim phone call to confirm participant compliance with 
electronic diary entry.  The study site should review any change in participant’s FIX/FVIII 
replacement therapy administration, concomitant treatments and report any adverse events 
(reference Section 8.1 for protocol specified adverse event reporting) in addition to any 
research related injury adverse event arising through screening blood draw collection.  The 
study site should enter this data in the eCRF accordingly.  If necessary, FIX/FVIII inhibitor, 
FIX/FVIII activity can be done at the investigator’s discretion and per their local usual 
standard of care.  Whenever FIX/FVIII activity is assessed, the time (Date/Hour) of 
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previously administered last dose of FIX/FVIII replacement product or blood product should 
be captured in the electronic diary as well.
Any unplanned study visits prior to the End of Study/Early Termination Visit will be at the 
discretion of the investigator and may follow the local usual standard of care.  Relevant study 
related data (FIX/FVIII replacement therapy, bleed events, and/or safety events) generated 
from an unplanned visit should be entered in the eCRF.
6.4. Interim Phone Call (Approximately Every 30 Days from Day 1 ±1 Week) 
It is required that the study site call participants approximately every 30 days from baseline 
visit (Day 1).  These phone calls ensure participant’s study compliance with their electronic 
diary and standard of care regimen, and monitor participant safety by recording any serious 
adverse events or any protocol specified non-serious adverse events (see Section 8.1), along 
with any changes to their routine medical care (ie, changes to concomitant therapies) from 
previous interim phone call. 
6.5. End of Study/Early Termination
The end of study visit marks the conclusion of the data collection phase and completion of 
the study for each participant.  Participants withdrawing from the study prematurely will 
complete a termination visit and must have end of study assessments performed unless the 
participants have withdrawn consent.
The following procedures and assessments will be performed.  Participants withdrawing from 
the study prematurely must also have these assessments performed unless the participants 
have withdrawn consent to have any further data collected.

Record serious adverse events and any protocol specified non-serious adverse event 
(see Section 8.1).

Record concomitant treatments (drug and non-drug).

If necessary, FIX/FVIII inhibitor, FIX/FVIII activity can be measured at
investigator’s discretion and per their local usual standard of care.  Whenever 
FIX/FVIII activity is assessed, the time (Date/Hour) of previously administered last 
dose of FIX/FVIII replacement product or blood product should be captured in the 
electronic diary.

The investigator or qualified designee should review the electronic diary with the 
participant for any new data entered since last interim phone call:

FIX/FVIII replacement therapy administration (date, time, reason for 
administration, and dose [IU]). 

The reasons for preventative FIX/FVIII replacement therapy will be captured in 
eCRF.
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
Bleeding events as assessed and reported by the participant (date, time, location 
and whether they are trauma related or spontaneous), should reference 
Appendix 2 as guidance on reporting such events.  Return electronic diary.
6.6. Participant Withdrawal
Withdrawal of consent:
Participants who request to discontinue study participation after collection of the scheduled 
blood sample (to assess nAb status) during the screening phase and/or entry into the data 
collection phase will provide no further information from the time of withdrawal of informed 
consent.  Participants should notify the investigator in writing of the decision to withdraw 
consent from future follow-up, whenever possible.  The withdrawal of consent should be 
explained in detail in the medical records by the investigator.  The sponsor may retain and 
continue to use any data collected before such withdrawal of consent.
In the event that vital status (whether the participant is alive or dead) is not known by the 
investigator from follow-up with the participant, or previously designated family member, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.
Lost to follow-up:
All reasonable efforts must be made to locate participants to determine and report their 
ongoing status.  This includes follow-up with persons authorized by the participant as noted 
above.  Lost to follow-up is defined by the inability to reach the participant after a minimum 
of 2 documented phone calls, faxes, or e-mails as well as lack of response by the participant 
to 1 registered mail letter.  All attempts should be documented in the participant’s medical 
records.  If it is determined that the participant has died, the site will use locally permissible 
methods to obtain the date and cause of death.  If the investigator’s use of a third-party 
representative to assist in the follow-up portion of the study has been included in the 
participant’s informed consent, then the investigator may use a sponsor-retained third-party 
representative to assist site staff with obtaining the participant’s contact information or other 
public vital status data necessary to complete the follow-up portion of the study.  The site 
staff and representative will consult publicly available sources, such as public health 
registries and databases, in order to obtain updated contact information.  If, after all attempts, 
the participant remains lost to follow-up, then the last-known-alive date as determined by the 
investigator should be reported and documented in the participant’s medical records.
Participants 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 or sponsor for safety (see also the 
Withdrawal From the Study Due to Adverse Events section) or behavioral reasons, or the 
inability of the participant to comply with the protocol-required schedule of study visits or 
procedures at a given study site. 
If a participant does not return for a scheduled visit, every effort should be made to contact 
the participant.  All attempts to contact the participant and information received during 
contact attempts must be documented in the participant’s medical record.  In any 
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circumstance, every effort should be made to document participant outcome, if possible.  The 
investigator should inquire about the reason for withdrawal, request that the participant return 
for a final visit, if applicable, and follow-up with the participant regarding any unresolved 
adverse events (AEs).
If the participant 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.
Participants who withdraw from the study may be replaced at the discretion of the 
investigator upon consultation with the sponsor.
7. ASSESSMENTS
The only protocol-required test for this study is the nAb laboratory blood draw during the 
screening visit.
Every effort should be made to ensure tests and procedures are completed as described 
including any screening laboratory tests for Factor IX/VIII activity; HBV, HCV, liver 
fibrosis, and HIV serology (viral load and CD4 count for HIV positive participants only) if 
there is no documentation within the last 12 months prior to screening (6 months for HCV).  
However, it is anticipated that from time to time there may be circumstances outside of the 
control of the investigator that may make it unfeasible to perform the test.  In these cases, the 
investigator will take all steps necessary to ensure the safety and well-being of the 
participant.  When a protocol-required test cannot be performed, the investigator will 
document the reason for this and any corrective and preventive actions that he or she has 
taken to ensure that normal processes are adhered to as soon as possible.  The study team will 
be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
8. ADVERSE EVENT REPORTING
NOTE: Exposure during pregnancy reporting throughout Section 8 is not applicable to 
the United Kingdom and Ireland.  Lack of Efficacy reporting throughout Section 8 is 
only applicable to Canada.
8.1. Requirements
The table below summarizes the requirements for recording safety events on the eCRF and 
for reporting safety events on the Clinical Trial (CT) Serious Adverse Event (SAE) Report 
Form to Pfizer Safety.  These requirements are delineated for 3 types of events: (1) SAEs 
(including protocol specified Events of Special Interest subject to SAE reporting); 
(2) non-serious adverse events (AEs); and (3) scenarios involving exposure to a Pfizer or 
non-Pfizer product (hereafter referred to as “standard of care therapy” including medication 
error, lack of efficacy, exposure during pregnancy, and occupational exposure. 
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Safety Event
Recorded on the eCRF
Reported on the CT SAE 
Report Form to Pfizer Safety 
Within 24 Hours of 
Awareness
SAE
All
All
Protocol Defined Events 
of Special Interest: 
FIX/FVIII Inhibitor, 
thrombotic events, 
FIX/FVIII 
hypersensitivity reactions
All
All
Non-serious AE

Events leading to 
participant withdrawal or 
discontinuation from the 
study 

Events necessitating 
unscheduled visits to the 
clinic
None
Scenarios involving 
exposure to the standard
of care therapy including
medication error, lack of 
efficacy, exposure during
pregnancy, and
occupational exposure
Only AEs/SAEs associated
with exposure during
pregnancy.
All medication errors 
(regardless of whether 
associated with an AE/SAE)
All lack of efficacy 
(regardless of whether 
associated with an AE/SAE)
Occupational exposure is not
recorded.
All exposure during 
pregnancy (and EDP 
supplemental form for EDP),
occupational exposure, lack 
of efficacy* (regardless of 
whether associated with an 
AE/SAE).
*
LOE serious and non-serious events reportable on the CT SAE form to Pfizer safety.
For this protocol all participants will remain on their FIX/FVIII replacement therapy per 
standard of care and will not be receiving an investigational product.  The study comprises a
screening phase with one single blood draw to assess neutralizing antibody status of the 
participant followed by a data collection phase in accordance with routine clinical care.  
Based on the study design, the sponsor will restrict safety data collection to safety events 
outlined in the table above.  Any observed or volunteered event, as outlined in the table 
above and regardless of suspected causal relationship to standard of care therapy will be 
reported as described in the following paragraphs.
Events listed in the table above that require reporting to Pfizer Safety on the CT SAE Report 
Form within 24 hours of awareness of the event by the investigator are to be reported 
regardless of whether the event is determined by the investigator to be related to standard of 
care therapy.  In particular, if the SAE is fatal or life -threatening, notification to Pfizer 
Safety must be made immediately, irrespective of the extent of available event information.  
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This time frame also applies to additional new (follow-up) information on previously 
forwarded reports.  In the rare situation that the investigator does not become immediately 
aware of the occurrence of an event, the investigator must report the event within 24 hours 
after learning of it and document the time of his/her first awareness of the event.
For each event, the investigator must pursue and obtain adequate information both to 
determine the outcome and to assess whether it meets the criteria for classification as an SAE 
(see the Serious Adverse Events section below).  In addition, the investigator may be 
requested by Pfizer Safety to obtain specific follow-up information in an expedited fashion.  
This information is more detailed than that recorded on the eCRF.  In general, this will 
include a description of the event in sufficient detail to allow for a complete medical 
assessment of the case and independent determination of possible causality.  Any information 
relevant to the event, such as concomitant medications and illnesses, must be provided.  In 
the case of a participant death, a summary of available autopsy findings must be submitted as 
soon as possible to Pfizer Safety.  Any pertinent additional information must be reported on 
the CT SAE Report Form; additional source documents (eg, medical records, eCRF, 
laboratory data) are to be sent to Pfizer Safety ONLY upon request.
As part of ongoing safety reviews conducted by the sponsor, any non-serious 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.
8.1.1. Additional Details on Recording Adverse Events on the Case Report Form (CRF)
All events detailed in the table above will be recorded on the AE page(s) of the eCRF.  It 
should be noted that the CT SAE Report Form for reporting of SAE information is not the 
same as the AE page of the eCRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the eCRF and the CT SAE Report 
Form for reporting of SAE information.
8.1.2. Eliciting Adverse Event Information
The investigator is to record on the eCRF all directly observed AEs and all AEs 
spontaneously reported by the study participant and that are detailed in the table above.  In 
addition, each study participant will be questioned about the occurrence of AEs in a 
non-leading manner.
8.1.3. Withdrawal from the Study Due to Adverse Events (see also the Participant 
Withdrawal section)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted below, and recorded on the eCRF. 
When a participant withdraws from the study because of an SAE, the SAE must be recorded 
on the eCRF and reported, as appropriate, on the CT SAE Report Form, in accordance with 
the Requirements section above.
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8.1.4. Time Period for Collecting AE/SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure), through the duration of the study until their final study or early 
termination visit.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
8.1.4.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form.
Follow-up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
8.1.4.2. Recording Non-serious AEs and SAEs on the eCRF
During the active collection period, both non-serious AEs and SAEs are recorded on the 
eCRF as stated in the table above.
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.
8.1.5. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the investigator must record the causal relationship on the eCRF, 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 standard of care therapy caused or contributed to an AE; generally, the facts 
(evidence) or arguments to suggest a causal relationship should be provided.  If the 
investigator’s final determination of causality is “unknown” and s/he does not identify 
whether standard of care therapy caused the event, then the event must still be reported 
within 24 hours.  If the investigator's causality assessment is “unknown but not related” to 
standard of care therapy, this should be clearly documented on study records and for all AEs 
reported to Safety as per table above on the CT SAE Report Form.
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, and 
report such an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.
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8.1.6. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
8.2. Definitions
8.2.1. Adverse Events
An AE is any untoward medical occurrence in a study participant administered a product or 
medical device; the event need not necessarily have a causal relationship with the treatment 
or usage.  In this study, all participants will remain on their usual respective FIX or FVIII 
replacement therapy and will not be receiving an investigational product. The study 
comprises a screening phase with blood draw to assess nAb status of the participant followed 
by a data collection phase in accordance with routine clinical care.  Based on the study 
design, the sponsor will restrict safety data collection to the following AEs:

Any research related injury arising through blood draw collection as part of screening 
procedures;

FIX/FVIII inhibitor;

Thrombotic event;

FIX/FVIII Hypersensitivity reaction;

Any event leading to participant withdrawal or discontinuation from the study;

Any event necessitating an unscheduled visit to the study site.
Hemophilia events that are likely to occur due to the participant’s hemophilia (for example, 
bleeding and pain, swelling or decreased range of motion as a consequence of the bleed) are 
not reportable as AEs unless the event meets one of the criteria for AE reporting detailed in 
the protocol or meets SAE criteria and therein should be reported as a SAE.  Consideration 
on whether an event is a hemophilia event is based on investigator discretion and bleeding 
events recorded by the participant in their electronic diary will be reviewed by the 
investigator and assessed against reporting obligations for S/AE.
8.2.2. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);
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
Results in congenital anomaly/birth defect.
Or that is considered to be:

An important medical event.  The protocol specified events of special interest: 
FIX/FVIII inhibitor, thrombotic event and FIX/FVIII hypersensitivity reaction are to 
be reported as SAEs.
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event.  An important medical event may not be immediately life-threatening and/or 
result in death or hospitalization.  However, if it is determined that the event may jeopardize 
the participant or may require intervention to prevent one of the other AE outcomes, the 
important medical event should be reported as serious.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; 
or development of drug dependency or drug abuse.
8.2.3. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility, or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit is 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 a persistent pretreatment laboratory abnormality);
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
Social admission (eg, participant 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);

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 participant.
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as SAEs.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an SAE.  For example, an acute 
appendicitis that begins during the reporting period should be reported if the SAE 
requirements are met, and the resulting appendectomy should be recorded as treatment of the 
AE.
8.3. Severity Assessment
If required on the AE page of the CRF, 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 participant’s usual function.
MODERATE
Interferes to some extent with participant’s usual function.
SEVERE
Interferes significantly with participant’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 participant’s usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.4. Special Situations
8.4.1. Protocol Specified Serious Adverse Events
There are no protocol-specified SAEs exempt from reporting in this study.  All SAEs will be 
reported to Pfizer Safety by the investigator as described in previous sections and will be 
handled as SAEs in the safety database. 
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8.4.2. Exposure to Standard of Care Therapy during Pregnancy and Occupational 
Exposure
Exposure to the standard of care therapy during pregnancy and occupational exposure are 
reportable to Pfizer Safety within 24 hours of investigator awareness.
8.4.2.1. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

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 standard of care 
therapy or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the standard of care therapy;

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).

A male has been exposed (eg, because of treatment or environmental exposure) to the 
standard of care therapy prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy. 
If a participant or participant’s partner becomes or is found to be pregnant during the 
participant’s treatment with the standard of care therapy, the investigator must report this 
information to Pfizer Safety on the CT SAE Report Form and an EDP supplemental form, 
regardless of whether an SAE has occurred.  In addition, the investigator must submit 
information regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a 
participant reports that she is pregnant and has been exposed to a cytotoxic product by 
inhalation or spillage) to Pfizer Safety 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 Safety 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 pre-
procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
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liveborn baby, 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 to Pfizer Safety 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 the standard of care therapy.

Additional information regarding the EDP may be requested by the sponsor.  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 participant with the Pregnant Partner Release of 
Information Form to deliver to his partner.  The investigator must document in the 
source documents that the participant was given the Pregnant Partner Release of 
Information Form to provide to his partner.
8.4.2.2. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
standard of care therapy which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a participant enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.4.3. Medication Errors and Lack of Efficacy
Other exposures to the standard of care therapy may occur in clinical trial settings, such as
medication errors and lack of efficacy.
Safety Event
Recorded on the eCRF
Reported on the CT SAE
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
Medication errors
All (regardless of whether 
associated with an AE)
Only if associated with an 
SAE
Lack of efficacy
All (regardless of whether
associated with an AE)
All* (regardless of whether
associated with an AE)
*
LOE serious and non-serious events reportable on the CT SAE form to Pfizer safety.
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8.4.3.1. Medication Errors
Medication errors may result from the administration or consumption of the standard of care 
therapy by the wrong participant, or at the wrong time, or at the wrong dosage strength. 
Medication errors include:

Medication errors involving participant exposure to the standard of care therapy;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the study participant.
Such medication errors occurring to a study participant are to be captured on the medication
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4.3.2. Lack of Efficacy
Reports of lack of efficacy to any of the respective usual FIX or FVIII replacement products 
are reported to Pfizer by the investigator, irrespective of the presence of an associated 
AE/SAE.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment.
All data analyses will be performed separately for each population (hemophilia A and 
hemophilia B).  There will be no joint analysis done that includes both populations together 
outside of the exploratory endpoint of neutralizing antibody positivity rates. 
9.1. Sample Size Determination
Hemophilia B:
The sample size for this hemophilia B cohort is based on the number of evaluable 
participants needed for the subsequent Phase 3 registration study C0371002 (ie, N=80 to be 
enrolled and treated in C0371002; it is anticipated that 60 participants will have at least 
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6 months of follow-up data from this study [C0371004]; for the remaining participants, the 
duration of follow-up data from this study [C0371004] may vary depending on the timing of 
their enrollment into the subsequent treatment protocol [C0371002]).  It is expected that the 
attrition rate between this study and C0371002 will be approximately 20%.  Additionally, it 
is anticipated that approximately 10% of participants in C0371004 will not complete the 
study.  Therefore, it is estimated that 111 participants will need to be enrolled to allow 
approximately 100 participants to complete study C0371004 and be eligible for enrollment 
into C0371002.
Hemophilia A:
The minimum sample size for this hemophilia A cohort is based on the minimum number of 
evaluable participants needed for the primary analysis of the subsequent Phase 3 registration 
study C3731003 (ie, at least N=50 with at least 6 months of follow-up data from this study 
[C0371004] to reach the primary analysis time point in C3731003).  It was initially 
anticipated that approximately 20% of participants in C0371004 would not enter the 
C3731003 study. However, the attrition rate was higher than expected following the 
temporary pause in the subsequent Phase 3 study (C3731003). Therefore, it is now estimated 
that approximately 95 participants will need to be enrolled in this cohort to allow 
approximately 70 participants to be enrolled into C3731003 to provide the minimum sample 
size required for C3731003. A sufficient number of participants will be screened in this study 
[C0371004] in order to enroll approximately 95 participants.
9.2. Efficacy Analysis
All participants that signed the ICD, were subsequently identified as nAb negative (negative 
for circulating IgG antibody to AAV-Spark100, or negative for circulating IgG antibody to 
AAV6) and who participated in the prospective data collection phase as part of their usual 
healthcare setting will be included in the efficacy analysis set.  The cohort of hemophilia B 
and hemophilia A participants will be analyzed separately.
9.2.1. Analysis of the Primary Endpoint
The annualized bleeding rate (ABR) per participant will be calculated as the number of 
bleeds over number of days from baseline visit (Day 1) to end of study x 365.25 days.  ABR 
will be summarized using descriptive statistics (n, mean, standard deviation, median, Q1, Q3, 
minimum, maximum).
9.2.2. Analysis of Secondary Endpoints
The annualized infusion rate (AIR) per participant will be calculated as the number of 
infusions received over number of days from baseline visit (Day 1) to end of study x 
365.25 days.  AIR will be summarized using descriptive statistics (n, mean, standard 
deviation, median, Q1, Q3, minimum, maximum).
The total respective Factor IX or VIII replacement therapy consumption and the 
corresponding dose will be descriptively summarized by the categories of the replacement 
therapy, where appropriate.  Infusion diary (electronic diary) of the respective Factor IX or 
VIII replacement therapy will be listed.
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The number of bleeding episodes will be summed up by spontaneous, traumatic and overall, 
as defined in Appendix 2.
9.3. Analysis of Other Endpoints (Exploratory Endpoint)
9.3.1. nAb Assessment
The individual circulating IgG antibody titer, AAV-Spark100 and AAV6.  nAb status will be 
listed for each participant in the screening phase.  The frequency and percentage by nAb 
status (positive, negative) will be summed for all countries combined and/or regions.  The 
cohort of hemophilia B and hemophilia A participants will be analyzed separately, as well as 
combined.
9.4. Safety Analysis
Safety data will be listed and summarized descriptively for each respective participant 
population (hemophilia B and hemophilia A) separately.  The primary safety analysis will be 
performed on all participants that sign the informed consent document and are subsequently 
identified as nAb negative and are enrolled (complete baseline visit) into the study.  The 
events of special interest (ESI) include, but not limited to, inhibitor against FIX/FVIII, 
thrombotic events, and FIX/FVIII hypersensitivity reactions.  Frequency and percentage of 
these ESI events will be summarized.  In addition, any events leading to discontinuation from 
the study will be described.
Safety data collected from those participants that sign the informed consent document and 
subsequently are discontinued from further participation in the study will be listed and 
presented separately.
9.5. Interim Analysis 
There is currently no plan for a formal interim analysis.  
Prior to the final analysis, there may be periodic reviews of data to support publications, 
regulatory submission, and responses.  Periodic reviews will be conducted to provide an 
assessment of AAV-Spark100 and AAV6 immune status for publication (eg, abstract, 
manuscript).  The review will be planned once the target number of participants have been 
enrolled into the data collection phase, if data permit.  These reviews and summaries will 
include but may not be limited to the frequency of the positive and negative participants to 
the neutralizing antibody against AAV-Spark100 and AAV6, distribution of the population, 
range of neutralizing antibody titers, and other screening data related to hemophilia, such as 
hemophilia history.
9.6. Data Monitoring Committee 
This study will not use a data monitoring committee.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct 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 CRFs are accurate.  The 
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investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the investigator site may be subject to 
review by the institutional review board/ethics committee (IRB/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.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the investigator site for the inspection and will allow Pfizer or its 
agent, whenever feasible, to be present during the inspection.  The investigator site and 
investigator will promptly resolve any discrepancies that are identified between the study 
data and the participant’s medical records.  The investigator will promptly provide copies of 
the inspection findings to Pfizer or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide Pfizer or its agents with an opportunity to review 
and comment on responses to any such findings.
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.
Quality Tolerance Limits (QTLs) are predefined parameters that are monitored during the 
study. Important deviations from the QTLs and any remedial actions taken will be 
summarized in the CSR.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term 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 participant.  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 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 are 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. 
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In most cases, the source documents are the hospital or the physician participant chart.  In 
these cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF may also serve as the source document.  In these cases, a document 
should be available at the investigator site and at Pfizer that clearly identifies those data that 
will be recorded on the CRF, and for which the CRF will stand as the source document.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.
11.2. Record Retention
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, the 
investigator agrees to keep records, including the identity of all participating participants 
(sufficient information to link records, eg, eCRFs and hospital records), all original signed 
informed consent documents, copies of all eCRFs, safety reporting forms, source documents, 
and detailed records of treatment (FIX or FVIII therapy) disposition, and adequate 
documentation of relevant correspondence (eg, letters, meeting minutes, and telephone call 
reports).  The records should be retained by the investigator according to the International 
Council of Harmonization (ICH) guidelines, according to local regulations, or as specified in 
the clinical study agreement (CSA), whichever is longer. 
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 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.
11.3. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic and/or paper
form and will be password protected or secured in a locked room 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 study site will 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 participants with regard to the processing of personal 
data, participants will be assigned a single, participant-specific numerical code. Any 
participant records or data sets that are transferred to the sponsor will contain the numerical 
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code; participant names will not be transferred. All other identifiable data transferred to the 
sponsor will be identified by this single, participant-specific code. The study site will 
maintain a confidential list of participants who participated in the study, linking each 
participant’s numerical code to their actual identity and medical record ID. In case of data 
transfer, the sponsor will protect the confidentiality of participants’ personal data consistent 
with the clinical study agreement and applicable privacy laws.
Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access.
The sponsor maintains SOPs on how to respond in the event of unauthorized access, use, or 
disclosure of sponsor information or systems.
12. ETHICS
12.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:
•
Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines;
•
Applicable ICH GCP guidelines;
•
Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, SRSD(s), and other relevant documents (eg, 
advertisements) must be reviewed and approved by the sponsor, submitted to an IRB/EC by 
the investigator, and reviewed and approved by the IRB/EC before the study is initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard to 
study participants.
The investigator will be responsible for the following:
•
Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures established by 
the IRB/EC;
•
Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;
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•
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH GCP guidelines, the IRB/EC, European regulation 536/2014 
for clinical studies, European Medical Device Regulation 2017/745 for clinical device 
research, and all other applicable local regulations.
12.2. Participant Information and Consent
All parties will ensure protection of participant personal data and will not include participant 
names or other identifiable data in any reports, publications, or other disclosures, except 
where required by law. 
When study data are compiled for transfer to Pfizer and other authorized parties, participant 
names, addresses, and other identifiable data will be replaced by numerical codes based on a 
numbering system provided by Pfizer in order to de-identify study participants.  The 
investigator site will maintain a confidential list of participants who participated in the study, 
linking each participant’s numerical code to his or her actual identity.  In case of data 
transfer, Pfizer will maintain high standards of confidentiality and protection of participants’ 
personal data consistent with applicable privacy laws.
The informed consent document and any participant recruitment materials must be in 
compliance with ICH GCP, local regulatory requirements, and legal requirements, including 
applicable privacy laws.
The ICD will contain a separate section that addresses the use of remaining mandatory 
samples for optional additional research.  The optional additional research does not require 
the collection of any further samples.  The investigator or authorized designee will explain to 
each participant the objectives of the additional research.  Participants will be told that they 
are free to refuse to participate and may withdraw their consent at any time and for any 
reason during the storage period.  A separate signature will be required to document a 
participant's agreement to allow any remaining specimens to be used for additional research.  
Participants who decline to participate in this optional research will not provide this separate 
signature.
The informed consent document used during the informed consent process and any 
participant recruitment materials must be reviewed and approved by Pfizer, approved by the 
IRB/EC before use, and available for inspection. 
The investigator must ensure that each study participant is fully informed about the nature 
and objectives of the study and possible risks associated with participation. 
The investigator, or a person designated by the investigator, will obtain written informed 
consent from each participant before any study-specific activity is performed.  The 
investigator will retain the original of each participant’s signed consent document.
12.3. 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 
regulatory authority in any area of the world, or if the investigator is aware of any new 
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information that might influence the evaluation of the benefits and risks of the study 
intervention, 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 participants 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 TRIAL
13.1. End of Trial in a Member State 
End of trial in a Member State of the European Union is defined as the time at which it is 
deemed that a sufficient number of participants have been recruited and completed the study 
(last participant last visit [LPLV]) as stated in the regulatory application (ie, clinical trial 
application [CTA]) and ethics application in the Member State.  Poor recruitment (recruiting 
less than the anticipated number in the CTA) by a Member State is not a reason for 
premature termination but is considered a normal conclusion to the study in that Member 
State.
13.2. End of Trial in All Other Participating Countries 
End of trial in all other participating countries is defined as LPLV.
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, safety problems, or at the discretion of Pfizer.  In addition, 
Pfizer retains the right to discontinue development of fidanacogene elaparvovec and 
giroctocogene fitelparvovec at any time.
If a study is prematurely terminated, Pfizer will promptly notify the investigator.  After 
notification, the investigator must contact all participating participants and the hospital 
pharmacy (if applicable).  As directed by Pfizer, all study materials must be collected and all 
CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the EudraCT/CTIS, and/or 
www.pfizer.com, and other public registries and websites in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its SOPs.
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
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Pfizer posts clinical trial results on www.clinicaltrials.gov for Pfizer-sponsored interventional 
studies (conducted in patients) that evaluate the safety and/or efficacy of a product, 
regardless of the geographical location in which the study is conducted. These results are 
submitted for posting in accordance with the format and timelines set forth by US law.
EudraCT/CTIS
Pfizer posts clinical trial results on EudraCT/CTIS for Pfizer sponsored interventional studies 
in accordance with the format and timelines set forth by EU requirements.
www.pfizer.com
Pfizer posts CSR synopses and plain-language study results summaries on www.pfizer.com 
for Pfizer-sponsored interventional studies at the same time the corresponding study results 
are posted to www.clinicaltrials.gov. CSR synopses will have personally identifiable 
information anonymized.
Documents within marketing applications
Pfizer complies with applicable local laws/regulations to publish clinical documents included 
in marketing applications. Clinical documents include summary documents and CSRs 
including the protocol and protocol amendments, sample CRFs, and SAPs. Clinical 
documents will have personally identifiable information anonymized.
Data sharing
Pfizer provides researchers secure access to participant-level data or full CSRs for the 
purposes of “bona-fide scientific research” that contributes to the scientific understanding of 
the disease, target, or compound class. Pfizer will make data from these trials available 18 
months after study completion. Participant-level data will be anonymized in accordance with 
applicable privacy laws and regulations. CSRs will have personally identifiable information 
anonymized.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses. Research teams must include a biostatistician. Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.
15.2. Publications by Investigators
For multicenter trials, the primary publication will be a joint publication developed by the 
investigator and Pfizer reporting the primary endpoint(s) of the study covering all study sites. 
The investigator agrees to refer to the primary publication in any subsequent publications. 
Pfizer will not provide any financial compensation for the investigator’s participation in the 
preparation of the primary congress abstract, poster, presentation, or primary manuscript for 
the study.
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Investigators are free to publish individual center results that they deem to be clinically 
meaningful after publication of the overall results of the study or 12 months after primary 
completion date or study completion at all sites, whichever occurs first, subject to the other 
requirements described in this section.
The investigator will provide Pfizer an opportunity to review any proposed publication or 
any other type of disclosure of the study results (collectively, “publication”) before it is 
submitted or otherwise disclosed and will submit all publications to Pfizer 30 days before 
submission. 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 
upon request from Pfizer. This allows Pfizer to protect proprietary information and to provide 
comments, and the investigator will, on request, remove any previously undisclosed 
confidential information before disclosure, except for any study intervention or  Pfizer 
related information necessary for the appropriate scientific presentation or understanding of 
the study results. For joint publications, should there be disagreement regarding 
interpretation and/or presentation of specific analysis results, resolution of, and responsibility 
for, such disagreements will be the collective responsibility of all authors of the publication.
For all publications relating to the study, the investigator and Pfizer will comply with 
recognized ethical standards concerning publications and authorship, including those 
established by the International Committee of Medical Journal Editors. The investigator will 
disclose any relationship with Pfizer and any relevant potential conflicts of interest, including 
any financial or personal relationship with Pfizer, in any publications. All authors will have 
access to the relevant statistical tables, figures, and reports (in their original format) required 
to develop the publication.
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16. REFERENCES
1.
Blanchette, V. S., Key, N. S., Ljung, L. R., Manco-Johnson, M. J., van den Berg, H. M., 
& Srivastava, A. (2014).  Definitions in hemophilia: communication from the SSC of 
the ISTH. J Thromb Haemost, 12(11), 1935-1939. 
2.
Berntorp E, Shapiro AD. Modern haemophilia care. Lancet. 2012 Apr 
14;379(9824):1447-56. doi: 10.1016/S0140-6736(11)61139-2. Epub 2012 Mar 27. 
Review.
3.
WFH guidelines: https://www1.wfh.org/publication/files/pdf-1472.pdf.
4.
Blanchette VS, McCready M, Achonu C, et al. A Survey of Factor Prophylaxis in Boys 
with Haemophilia Followed in North American Haemophilia Treatment Centres. 
Haemophilia 2003;9(Suppl 1):19- 26.
5.
Lillicrap D. Extending half-life in coagulation factors: where do we stand? Thromb Res 
2008;122 Suppl 4: S2-8.
6.
Oldenburg, J., Mahlangu, J. N., Kim, B., Schmitt, C., Callaghan, M. U., Young, G.  
Shima, M. (2017). Emicizumab Prophylaxis in Hemophilia A with Inhibitors. New 
England Journal of Medicine, 377(9), 809-818. (Online supplementary Protocol). 
7.
Turkish Guideline for Observational Drug Studies (13 November 2015).
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Appendix 1. Abbreviations 
This following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
AAV
adeno-associated virus
AAV2/6
adeno-associated virus 2/6
AAV6
adeno-associated virus vector 6
AAV-Spark100
Bioengineered AAV capsid, derived from a naturally 
occurring AAV serotype
AAV-Spark100-hFIX19-Padua
Adeno-associated viral vector comprised of the 
Spark100 AAV capsid encoding hFIX-Padua
ABR
Annualized Bleeding Rate
AIR
Annualized Infusion Rate 
AE
adverse event
AST
Aspartate Transaminase
BDD
B-domain deleted
BU
Bethesda Unit
CAF
Contact Authorization Form
CD4+
Cluster of Differentiation 4 positive
cDNA
Complementary DNA
CFR
Code of Federal Regulations
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
Coronavirus disease 2019
CRF
case report form
CSA
clinical study agreement
CSR
clinical study report
CT
clinical trial
CTA
clinical trial application
EC
ethics committee
EDP
exposure during pregnancy
eCRF
Electronic case report form
ESI
Events of Special Interest
EU
European Union
EudraCT
European Clinical Trials Database
FIX
Factor IX
FIX:C
Factor IX Circulating
FVIIa
Factor VIIa
FVIII
Factor VIII
FVIII:C
Factor VIII Circulating
GCP
Good Clinical Practice
HBc
Hepatitis B Core
HBsAg
Hepatitis B Surface Antigen
HBV-DNA
Hepatitis B Virus – Deoxyribonucleic Acid
HCV
Hepatitis C Virus
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Abbreviation
Term
HCV-RNA
Hepatitis C Virus –Ribonucleic Acid
hFVIII
human FVIII
HIV
human immunodeficiency virus
IA
interim analysis
ICD
Informed Consent Document
ICH
International Council of Harmonization
ID
identification
IgG
Immunoglobulin G
IND
investigational new drug application
IRB
institutional review board
IU
international unit
LOE
Lack of Efficacy
LPLV
last participant last visit 
MAH
marketing authorization holder
MoH
Ministry of Health
N
number
N/A
not applicable
nAb
neutralizing antibody
PACL
protocol administrative change letter
PCD
primary completion date
PI
principal investigator
QTL
quality tolerance limit
rAAV2/6
Recombinant adeno-associated virus 2/6
RBC
Red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
SB-525 (rAAV6-hFVIII-BDD)
Adeno-associated viral vector comprised of AAV6
capsid encoding hFVIII-BDD
SOC
standard of care
SOP
standard operating procedure
SRSD
single reference safety document
SUSAR
suspected unexpected serious adverse reactions
US
United States
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Appendix 2. Bleed and Factor Replacement Regimen Definitions1,2,3
Definition of a Bleed (for analysis purposes)
Treated Bleed: An event necessitating administration of coagulation factor within 72 hours of 
signs or symptoms of bleeding (protocol definition, unless specifically referring to untreated 
bleed).
Untreated Bleed: A bleeding event not necessitating administration of coagulation factor 
within 72 hours of signs or symptoms of bleeding.
New Treated Bleed: A treated bleed occurring >72 hours after stopping treatment from the 
original bleed for which treatment was initiated or a treated bleed occurring at a different site 
from the original bleed regardless of the time from last injection. 
New Untreated Bleed: An untreated bleed occurring >72 hours after the previous untreated 
bleed at the same site or occurring >72 hours after stopping treatment from the original bleed 
for which treatment was initiated, or an untreated bleed occurring at a different site from the 
original bleed regardless of the time from last bleed or last injection.
Definition of a Bleed Location
Target Joint: Defined as a major joint (eg, hip, elbow, wrist, shoulder, knee, and ankle) into 
which repeated bleeds occur (three or more spontaneous bleeds into a single joint within a
consecutive 6-month period).  A target joint is considered resolved when there are ≤2 bleeds 
into the joint within a 12-month period. 
Joint Bleed: A bleeding episode characterized by rapid loss of range of motion as compared 
with baseline that is associated with any combination of the following: pain or an unusual 
sensation in the joint, palpable swelling, and warmth of the skin over the joint. 
Muscle Bleed: An episode of bleeding into a muscle, determined clinically and/or by imaging 
studies, generally associated with pain and/or swelling and functional impairment. 
Definition of Bleed Types
Spontaneous Bleeds: Bleeding for no apparent/known reason particularly into the joints, 
muscles, and soft tissues.
Traumatic Bleeds: Bleeding event occurring for an apparent/known reason.
Note: Bleeds related to a procedure/surgery such as hematomas/bruising resulting from any 
surgeries or invasive procedures (eg, tooth extractions, venipuncture, or subcutaneous drug 
administrations) or invasive diagnostic procedures (eg, lumbar puncture, endoscopy with 
biopsy) would NOT be counted as bleeds.  Bleeds related to procedure/surgery are not 
associated with any trauma except procedure/surgery-induced trauma.
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Definition of Factor Replacement Regimens
Prophylaxis Therapy: The regularly scheduled and regimented administration of factor 
replacement therapy to prevent bleeding.
Preventative Therapy: Infusion of clotting factor that is given in anticipation of a planned 
physical activity that has a high risk of injury (eg, surgery or sporting activity).
On-Demand Therapy: The administration of factor replacement therapy only at the time of an 
acute bleeding event.
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Appendix 3. France Country-Specific Requirement
This appendix applies to study sites located in France.
Per France regulations, a France-specific protocol appendix is to be included in the final 
approved protocol to capture some operational items not included in the mandatory contract 
format for France (ie, French “Contract Unique”), which Pfizer includes in standard contract 
language for other countries.  The following items included do not impact the conduct of the 
trial, the safety or integrity of the participant, or use of their data:
1. GCP Training 
Prior to enrollment of any participants, the investigator and any sub-investigators will 
complete the Pfizer-provided Good Clinical Practice training course (“Pfizer GCP Training”) 
or training deemed equivalent by Pfizer.  Any investigators who later join the study will 
complete the Pfizer GCP Training or equivalent before performing study-related duties.  For 
studies of applicable duration, the investigator and sub-investigators will complete Pfizer 
GCP Training or equivalent every three years during the term of the study, or more often if 
there are significant changes to the ICH GCP guidelines or course materials.
2. SUSARs
Pursuant to a sponsor’s safety reporting obligations under 21 Code of Federal Regulations 
(CFR) 312.32(c)(1), Pfizer will report to the investigator all Serious Unexpected Suspected 
Adverse Reactions (“SUSARs”).  The investigator will receive and review SUSAR reports 
and report SUSARs to the responsible IRB/IEC according to institution’s guidelines.  
Institution will retain SUSAR reports consistent with Section 11.2 of the Protocol. 
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Appendix 4. Turkey Country-Specific Requirement 
Protocol Title
The original C0371004 study (hemophilia B cohort) was approved as an observational study 
in Turkey, as there was no intervention in the SoC factor replacement prophylaxis treatment 
and all the treatment decisions are taken by the investigators. This design is aligned with the 
requirements defined in the local Turkish regulatory “Guideline for Observational Drug 
Studies (13 November 2015).”7  The study title was changed with protocol amendment 3 to 
include hemophilia A cohort and reference to subsequent Phase 3 studies, in order to clarify 
that the two lead-in study cohorts will participate in separate Phase 3 studies.  Subsequently, 
on 11 November 2019, the Turkish MoH requested that the text regarding subsequent 
Phase 3 studies be deleted from the protocol title, as it is out of the scope of the objectives for 
the current study as defined in the regulatory guideline. 
Protocol amendment 4, which reflects protocol changes specific to Turkey, removes the 
following text from the protocol title: “Prior to the Respective Therapeutic Phase 3 Gene 
Therapy Studies.” 
The protocol title for use specific to Turkey will be as follows:

“An open-label, non-investigational product, multi-center, lead-in study to evaluate 
prospective efficacy and selected safety data of current Factor IX (FIX) or Factor 
VIII (FVIII) prophylaxis replacement therapy in the usual care setting of moderately 
severe to severe adult hemophilia B participants (FIX:C≤2%) who are negative for 
neutralizing antibodies to adeno-associated virus vector-Spark100 (BENEGENE-1) 
and moderately severe to severe hemophilia A adult participants (FVIII:C≤1%) who 
are negative for neutralizing antibodies to adeno-associated virus vector 6 (AAV6).”
Comprehensive study documents which apply to all countries, including the clinical study 
report and any protocol amendments, will include a description of the protocol title change 
for Turkey, but these documents will reflect the original study title.  Shorter documents 
which apply to all countries, such as administrative letters, will not reflect the title change for 
Turkey but will reflect the original study title.  Participant facing materials in Turkey will use 
the protocol title specific to Turkey. 
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