A PHASE 1/2, OPEN-LABEL, ADAPTIVE, DOSE-RANGING STUDY TO ASSESS THE SAFETY AND TOLERABILITY OF SB-525 (PF-07055480) (RECOMBINANT AAV2/6 HUMAN FACTOR 8 GENE THERAPY) IN ADULT SUBJECTS WITH SEVERE HEMOPHILIA A
Phase: PHASE2
Conditions: Hemophilia A
Sponsor: Pfizer

SB-525 (PF-07055480) / SB-525-1603 (Pfizer reference: Protocol C3731001)
Final Protocol Amendment 5, 30 March 2023
PFIZER CONFIDENTIAL
Page 1
Title Page
A PHASE 1/2, OPEN-LABEL, ADAPTIVE, DOSE-RANGING STUDY TO ASSESS 
THE SAFETY AND TOLERABILITY OF SB-525 (PF-07055480) (RECOMBINANT 
AAV2/6 HUMAN FACTOR 8 GENE THERAPY) IN ADULT SUBJECTS WITH 
SEVERE HEMOPHILIA A
Compound: SB-525 (Pfizer reference: PF-07055480)
Regulatory Agency Identifier Number(s)
Registry
ID
IND
17250
EudraCT
N/A
Protocol Number: SB-525-1603 (Pfizer reference: C3731001)
Amendment Number: 5
Phase: Phase 1/Phase 2
Short Title: Phase 1/2 Dose-Ranging Study of Recombinant AAV2/6 Human Factor VIII 
Gene Therapy SB-525 (Pfizer reference: PF-07055480) in Subjects with Severe Hemophilia 
A.
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
Version Date
Amendment 5
30-Mar-2023
Amendment 4
05-May-2020
Amendment 3
31-Jul-2018
Amendment 2
11-Oct-2017
Amendment 1
13-Jan-2017
Original Protocol
16-Nov-2016
Document History
This amendment incorporates all revisions to date, including amendments made at the request of country health authorities and
IRBs/ECs and any protocol administrative change letter(s).
Protocol Amendment Summary of Changes Table
Amendment 5 (30 March 2023)
Overall Rationale for the Amendment: change related to an addition of an optional liver biopsy substudy.
Section # and Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial
Section 1.3 Schedule of 
Activities
Section 3. Objectives, 
Estimands, and Endpoints 
Section 8.2.7. Liver Assessment
Addition of an optional liver 
biopsy substudy (and 
recommended related 
assessments).
The objective of this exploratory 
substudy is to assess the vector 
integration in the liver, to examine the 
liver tissue for any alteration and to 
provide a better understanding of the 
mechanism of action of the study drug in 
the liver. 
Substantial
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Section # and Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial
Section 8.2.14. Optional Liver 
Biopsy
Section 9.4.3. Exploratory 
Endpoints Analyses
Section 10.10. Appendix 10
Section 8.1.1 Factor FVIII 
activity
Section 8.1.3. Bleeding episodes 
and FVIII concentrates
As implemented via the PACL 
dated 09Jun2022:
Clarifications on which data 
(bleeds and infusions) have to be 
collected in eDiary in the event a 
participant resumes prophylaxis 
after Month 24 visit.
Clarifications with regards to the 
frequency of FVIII assessments in 
the setting of elevated FVIII 
activity levels >150%.
The revisions on bleeds and FVIII 
infusions collection are to limit 
participants’ burden when they resume 
prophylaxis. 
The revisions on FVIII activity 
assessments are for clarity.
Nonsubstantial
Section 1.3 Schedule of 
Activities
Clarification that assessment of
anti-AAV antibodies to AAV6 
(total and neutralizing) is 
performed yearly which includes 
week 52.  
This revision is to add a missing cross in 
the schedule of activities.
Nonsubstantial
Section 10.1.1 Regulatory and 
Ethical Considerations
Section 10.1.3 Informed 
Consent Process
Section 10.1.4 Data Protection
Clarifications
Updates made for consistency with the 
sponsor’s protocol template.
Nonsubstantial
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Section # and Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial
Section 10.1.5 Dissemination of 
Clinical Study Data
Section 10.1.6 Data Quality 
Assurance
Section 10.1.8 Study and Site 
Start and Closure
Section 10.1.9 Publication 
Policy
This amendment incorporates all revisions to date, including amendments made at the requests of country health authorities and 
IRBs/ECs.
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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................10
LIST OF FIGURES .................................................................................................................10
1. PROTOCOL SUMMARY...................................................................................................11
1.1. Synopsis ..................................................................................................................11
1.2. Schema ....................................................................................................................14
1.3. Schedule of Activities (SoA)...................................................................................15
2. INTRODUCTION ...............................................................................................................19
2.1. Study Rationale .......................................................................................................19
2.2. Background .............................................................................................................19
2.2.1. Hemophilia A..............................................................................................19
2.2.2. SB-525 (PF-07055480) Molecular Design and Construction ....................20
2.2.3. Preclinical Studies ......................................................................................20
2.3. Benefit Risk Assessment.........................................................................................21
3. OBJECTIVES, ESTIMANDS AND ENDPOINTS ............................................................21
4. STUDY DESIGN.................................................................................................................22
4.1. Overall Design.........................................................................................................22
4.1.1. Screening Period.........................................................................................23
4.1.2. Treatment Period ........................................................................................23
4.1.2.1. Dose Escalation Based on Pharmacodynamic Response ..........24
4.1.2.2. Dose Escalation Based on Safety..............................................24
4.1.3. Early Termination.......................................................................................24
4.2. Scientific Rationale for Study Design.....................................................................25
4.2.1. Rationale for Use of rAAV2/6 Serotype Based on Preclinical Studies......25
4.3. Justification for Dose ..............................................................................................25
4.4. End of Study Definition ..........................................................................................26
5. STUDY POPULATION......................................................................................................26
5.1. Inclusion Criteria.....................................................................................................26
5.2. Exclusion Criteria....................................................................................................27
5.3. Lifestyle Considerations..........................................................................................28
5.4. Screen Failures ........................................................................................................28
6. STUDY INTERVENTION..................................................................................................28
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6.1. Study Intervention(s) Administered........................................................................29
6.1.1. Administration............................................................................................29
6.2. Preparation/Handling/Storage/Accountability ........................................................30
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................30
6.4. Study Intervention Compliance...............................................................................31
6.5. Concomitant Therapy..............................................................................................31
6.5.1. Allowed Therapy ........................................................................................31
6.5.2. Disallowed Therapy....................................................................................32
6.6. Dose Modification...................................................................................................32
6.7. Intervention after the End of the Study...................................................................32
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................32
7.1. Discontinuation of Study Intervention ....................................................................32
7.1.1. Temporary Discontinuation........................................................................32
7.1.2. Rechallenge.................................................................................................32
7.2. Participant Discontinuation/Withdrawal from the Study........................................32
7.2.1. Withdrawal of Consent...............................................................................33
7.3. Lost to Follow up ....................................................................................................33
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................34
8.1. Efficacy Assessments..............................................................................................35
8.1.1. Factor VIII activity .....................................................................................35
8.1.2. Health Outcome Questionnaire...................................................................36
8.1.3. Bleeding Episodes and FVIII Concentrates Usage.....................................36
8.2. Safety Assessments .................................................................................................36
8.2.1. Physical Examinations................................................................................37
8.2.2. Vital Signs ..................................................................................................37
8.2.3. Electrocardiograms.....................................................................................37
8.2.4. Clinical Laboratory Tests ...........................................................................37
8.2.5. Chest X-Ray................................................................................................38
8.2.6. Liver Elastography......................................................................................38
8.2.7. Liver Assessment........................................................................................38
8.2.8. Abdominal Examination.............................................................................39
8.2.9. Interim Follow-up Contact .........................................................................39
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8.2.10. Suicidal Ideation and Behavior Risk Monitoring .....................................39
8.2.11. Pregnancy Testing ....................................................................................39
8.2.12. Rater Qualifications..................................................................................39
8.2.13. Immunogenicity Assessments ..................................................................39
8.2.13.1. AAV2/6 Antibodies.................................................................39
8.2.13.2. FVIII Inhibitor Titer................................................................39
8.2.13.3. Interferon-Gamma ELISPOT..................................................40
8.2.14. Optional Liver Biopsy ..............................................................................40
8.3. Adverse Events and Serious Adverse Events..........................................................41
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......42
8.3.1.1. Reporting SAEs to Pfizer..........................................................42
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................42
8.3.2. Method of Detecting AEs and SAEs ..........................................................43
8.3.3. Follow-up of AEs and SAEs.......................................................................43
8.3.4. Regulatory Reporting Requirements for SAEs...........................................43
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................44
8.3.5.1. Exposure During Pregnancy (EDP) ..........................................44
8.3.5.2. Exposure During Breastfeeding ................................................44
8.3.5.3. Occupational Exposure .............................................................44
8.3.6. Cardiovascular and Death Events...............................................................44
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................44
8.3.7.1. Lack of Efficacy........................................................................44
8.3.8. Medication Errors .......................................................................................45
8.4. Treatment of Overdose............................................................................................45
8.5. Pharmacokinetics ....................................................................................................46
8.5.1. AAV2/6 Vector Shedding...........................................................................46
8.6. Pharmacodynamics..................................................................................................46
8.7. Genetics...................................................................................................................46
8.7.1. Specified Genetics ......................................................................................46
8.8. Biomarkers ..............................................................................................................46
8.9. Health Economics ...................................................................................................47
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9. STATISTICAL CONSIDERATIONS ................................................................................47
9.1. Estimands and Statistical Hypotheses.....................................................................47
9.2. Sample Size Determination.....................................................................................47
9.3. Analysis Set.............................................................................................................48
9.4. Statistical Analyses .................................................................................................48
9.4.1. Primary Endpoints Analyses.......................................................................48
9.4.2. Secondary Endpoints Analyses...................................................................48
9.4.3. Exploratory Endpoints Analyses ................................................................49
9.5. Interim Analyses .....................................................................................................49
9.6. Data Monitoring Committee ...................................................................................49
10. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS..........................................................................................................50
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............50
10.1.1. Regulatory and Ethical Considerations ....................................................50
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................50
10.1.2. Financial Disclosure .................................................................................51
10.1.3. Informed Consent Process........................................................................51
10.1.4. Data Protection .........................................................................................52
10.1.5. Dissemination of Clinical Study Data ......................................................52
10.1.6. Data Quality Assurance ............................................................................54
10.1.7. Source Documents....................................................................................55
10.1.8. Study and Site Start and Closure ..............................................................56
10.1.9. Publication Policy.....................................................................................57
10.1.10. Sponsor’s Qualified Medical Personnel .................................................58
10.2. Appendix 2: Clinical Laboratory Tests .................................................................59
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................61
10.3.1. Definition of AE .......................................................................................61
10.3.2. Definition of SAE.....................................................................................62
10.3.3. Recording/Reporting and Follow-Up of AE and/or SAE.........................63
10.3.4. Reporting of SAEs....................................................................................66
10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................................................67
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10.5. Appendix 5: Genetics............................................................................................68
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ........69
10.7. Appendix 7: Safety Monitoring and Mitigation Plan............................................71
10.8. Appendix 8: ECG Findings of Potential Clinical Concern ...................................72
10.9. Appendix 9: Abbreviations ...................................................................................74
10.10. Appendix 10: Instruction for Tissue Sample Collection and Tissue 
Preparation.................................................................................................................77
10.11. Appendix 11: Document History ........................................................................78
10.12. Appendix 12: Protocol Administrative Changes and Clarifications ...................85
11. REFERENCES ..................................................................................................................87
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LIST OF TABLES
Table 1.
Schedule of Activities...............................................................................15
Table 2.
Objectives and Endpoints .........................................................................21
LIST OF FIGURES
Figure 1
C3731001 Study Design...........................................................................14
Figure 2
SB-525 (PF-07055480) cDNA Construct.................................................20
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1. PROTOCOL SUMMARY
1.1. Synopsis
Protocol Title: A PHASE 1/2, OPEN-LABEL, ADAPTIVE, DOSE-RANGING STUDY TO 
ASSESS THE SAFETY AND TOLERABILITY OF SB-525 (PF-07055480) 
(RECOMBINANT AAV2/6 HUMAN FACTOR 8 GENE THERAPY) IN ADULT 
SUBJECTS WITH SEVERE HEMOPHILIA A
Short Title: Phase 1/2 Dose-Ranging Study of Recombinant AAV2/6 Human Factor VIII 
Gene Therapy SB-525 (Pfizer Reference: PF-07055480) in Adult Participants with Severe 
Hemophilia A.
Rationale:
Hemophilia A is an X linked blood coagulation disorder caused by mutations of the Factor 8 
gene (F8), which encodes the Factor VIII (FVIII) clotting protein. Activated FVIII 
associates with activated Factor IXa to form the intrinsic Factor Xase complex, a complex 
that is critical for the intrinsic clotting pathway. Patients with severe hemophilia A have 
FVIII activity of less than 1% of normal (<1 IU/dL; equivalent to 0.01U/mL).
Restoration of production of functional FVIII to >1% of normal levels can reduce or 
eliminate the need for prophylactic treatment with FVIII concentrate, and, if at or above 5% 
of normal activity, can substantially reduce hemorrhage following all but the most severe 
trauma. However, chronic, repeated intravenous (IV) treatment is required for prophylaxis 
against spontaneous hemorrhage. Acute hemarthrosis usually requires access to several 
repeated IV infusions of FVIII until the bleeding stops.
The proposed SB-525 (PF-07055480) clinical study uses a recombinant adeno-associated 
vector 2/6 (AAV2/6) encoding the complementary deoxyribonucleic acid (cDNA) for the B-
domain deleted (BDD) human F8 gene (hF8). The SB-525 (PF-07055480) vector encodes a 
liver-specific promotor module and AAV2/6 exhibits liver tropism, thus providing the 
potential for long-term hepatic production of FVIII in participants with hemophilia A.
Objectives and Endpoints
Objectives
Endpoints
Primary objective
Primary endpoints

To evaluate the safety and tolerability 
of SB-525 (PF-07055480)

Incidence of Adverse Events (AEs) and 
Serious Adverse Events (SAEs) including 
clinically significant changes in physical 
examination, clinical laboratory 
assessments, immune parameters, vital 
signs, ECG, liver imaging
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Objectives
Endpoints

To evaluate the time-course profile of 
FVIII activity after dosing with SB-
525 (PF-07055480).

Changes in circulating FVIII activity
Secondary objectives
Secondary endpoints

To evaluate clinical impact (efficacy 
and quality of life) on hemophilia after 
dosing with SB-525 (PF-07055480).

Change from baseline in use of FVIII 
replacement therapy and frequency and 
severity of bleeding episodes

Change from baseline in the EQ-5D-5L

To evaluate immune response to 
FVIII.

Measurements of FVIII inhibitor levels

To evaluate vector shedding of 
AAV2/6.

Detection of AAV2/6 vector DNA by 
PCR in plasma, saliva, urine, stool and 
semen
Exploratory objectives
Exploratory endpoints

To evaluate the concurrence between 
FVIII levels by ELISA (FVIII antigen) 
and by FVIII activity assays 

Measurements of FVIII antigen levels

To further investigate SB-525
(PF-07055480) mechanism of action 
and the immune response

Measurements of neutralizing activity and 
antibodies to AAV2/6, as well as T-cell 
responses to AAV2/6 and FVIII

Measurements of von Willebrand factor 
(vWF), C-reactive protein (CRP), and IL6 
Optional liver biopsy substudy only:

To evaluate vector integration in the 
liver

To evaluate the histopathology of the 
liver tissue

To assess the expression of protein 
and/or RNA levels of FVIII and other 
biomarkers of interest in the liver

For the integrations analyses (as feasible, 
i.e. depending on the quantity of 
biological material collected): the number 
and location of integration sites, the 
location of the integration sites relative to 
transcription start sites, the nature of the 
inserted sequence, the frequency of 
insertions, and the frequency and 
distribution for each size and type of 
insertion

Other exploratory endpoints (as feasible): 
histopathology assessment (eg. presence 
of fibrosis assessment, presence of 
lymphocytic invasion), protein and/or 
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Objectives
Endpoints
RNA expression of FVIII and selected 
biomarkers (eg. Grp78, Gal3BP)
Overall Design:
SB-525-1603 (C3731001) is a phase 1/2, open-label, single-dose, dose-ranging study. The 
dose selection and number of participants studied at each dose level will be based on safety 
and kinetics of circulating FVIII levels observed in previously dosed participants.  
Number of Participants:
Approximately 20 participants may be enrolled in this study.  The dose selection and number 
of participants studied at each dose level will be based on safety and the cumulative kinetics 
of circulating FVIII levels observed in previously dosed participants.
Intervention Groups and Duration:
The possible clinical dose level range will be from 6 × 1011 vg/kg to 6 × 1013 vg/kg, with a 
starting dose of 9 × 1011 vg/kg, which is expected to yield >5% normal FVIII levels in 57% 
of treated participants.  Several dose levels may need to be studied to identify a safe and 
tolerable therapeutic range. If observed FVIII levels at the starting dose level of 9 × 1011
vg/kg are higher than anticipated, then dose de-escalation to 6 × 1011 vg/kg will be 
considered. The planned dose escalation interval between dose levels is roughly 2-fold (0.33 
log). 
Dose levels considered include: 
Possible Total rAAV Dose (vg/kg)
6 × 1011
9 × 1011
1.2 × 1012
2 × 1012
4 × 1012
6 × 1012
1 × 1013
2 × 1013
3 × 1013
4 × 1013
5 × 1013
6 × 1013
The duration of study participation will be approximately 62 months for each participant, 
divided into approximately 8 weeks (2 months) for screening, and 60 months for treatment 
and study follow-up. Accrual is planned for 20 months.
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Data Monitoring Committee: Yes
Statistical Methods
Analyses will be descriptive and exploratory in nature.
All analyses of safety will be performed on the safety population, and participants will be 
analyzed according to the actual treatment they received.  Efficacy analyses will be 
performed using descriptive methods. No formal statistical analysis of study data is planned.  
1.2. Schema
Figure 1
C3731001 Study Design
Note: From Week 52 to Month 60, protocol defined laboratory assessments (Table 1) will be collected every 6 
months.
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1.3. Schedule of Activities (SoA)
Table 1 provides an overview of the protocol visits and procedures.  Refer to the Study Assessments and Procedures section 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 in Table 1, in order to conduct evaluations or assessments required to 
protect the well-being of the participant.  
Table 1.
Schedule of Activities
Procedure
Screening
Baselinea
Infusion Center
Day 7
(±1 day)
Weeks
2, 4, 6, 8, 10, 
12
(±3 days)
Weeks
16, 20, 24, 28, 32, 
36, 40, 44, 48, 52
(±1 wk)
Months
24, 36, 48, 
60
(±1 M)
Early 
Termination 
Visit
Day 0b
Day 1
Informed consent
X
Neutralizing activity to AAV2/6
Xc
Medical history, inclusion/exclusion 
criteria
X
Chest X-rayd
X
Urinalysis with microscopic 
examination
X
Liver elastographyd,e
X
Hepatitis B panel, HCV antibody, HCV 
RNA viral load, and HIV RNA viral 
load and HIV-1/2 antibody assay
X
FVIII genome sequencingf
X
Circulating alpha fetoprotein levelg
X
X
(wk 12 only)
X
(wks 24 and 52)
X
X
Liver MRId,g
X
X
(wk 12 only)
X
(wks 24 and 52)
X
X
12-lead ECGd
X
X
(wk 52)
X
Physical examination including vital 
signs, height, and weighth
X
X
(weight 
only)
X
X
(wks 4, 8, 
12)
X
(wks 20, 28, 36, 
44, 52)
X
X
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Table 1.
Schedule of Activities
Procedure
Screening
Baselinea
Infusion Center
Day 7
(±1 day)
Weeks
2, 4, 6, 8, 10, 
12
(±3 days)
Weeks
16, 20, 24, 28, 32, 
36, 40, 44, 48, 52
(±1 wk)
Months
24, 36, 48, 
60
(±1 M)
Early 
Termination 
Visit
Day 0b
Day 1
Vital Signsq when not already included 
with physical examination
X
X
Concomitant medication review
X
X
X
X
X
X
X
Xt
X
CBC with differential and platelet count
X
X
X
X
X
(wks 4, 8, 
12)
X
(wks 28, 52)
X
X
Serum chemistry
X
X
X
X
X
X
X
X
Liver paneli
X 
X
X
(2x in first 
wk)
X
(2x/wk)
Xj
(2x/wk, 
wks 13-20)
X
(every 6m 
from Wk52 
to Mth60)
X
Coagulation screen (PT, INR, and 
aPTT)
X
X
X
X
(wks 4, 8, 
12)
X
X
X
Anti-AAV antibodies to AAV2/6 (total 
and neutralizing)
X
X
(wk 4 only)
X 
(wk 52 only)
X
FVIII activityk.m
X
X
X
X 
X
(1x/wk)
X
(1x/wk through 
Wk 20) l
X
(every 6m 
from Wk52 
to Mth60)
X
FVIII antigenv
X
X
X
X
X
(1x/wk)
Xl
X
X
FVIII inhibitor titern
X
X
X
Xl
(wks 4, 8, 
12)
Xl
X
(every 6m 
from Wk52 
to Mth60)
X
EQ-5D-5L
X
X
(wk 12 only)
X
(wks 24, 52)
X
X
sEGFR and Gal3BP
X
vWF and plasma banking
X
X
X
(wks 4, 8, 
12)
X
X
X
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Table 1.
Schedule of Activities
Procedure
Screening
Baselinea
Infusion Center
Day 7
(±1 day)
Weeks
2, 4, 6, 8, 10, 
12
(±3 days)
Weeks
16, 20, 24, 28, 32, 
36, 40, 44, 48, 52
(±1 wk)
Months
24, 36, 48, 
60
(±1 M)
Early 
Termination 
Visit
Day 0b
Day 1
CRP/IL6
X
X
AAV2/6 vector genome in plasma, 
saliva, urine, stool, and semen by PCRo
X
X
(plasma 
only)
X
X
(wks 2, 4, 8, 
12) 
Xp
Xp
X
Assessment of bleeding episodes and
FVIII concentrates usage
This is an ongoing collection and review.
Abdominal examination for 
hepatomegaly
X
X
X
X
X
AE(s) assessment
X
X
X
X
X
X
X
X
X
SB-525 (PF-07055480) infusion
X
Interferon-gamma ELISPOTr
X
X
(wk 6)
Xu
Xu
Interim phone contacts
X
(Months 
30, 42 and 
54)
Optional Liver Biopsyw
X (postinfusion)
a.
Baseline assessments to be performed approximately 1 week prior to SB-525 (PF-07055480) infusion.
b.
Laboratory samples to be collected prior to dosing.
c.
Following informed consent, the screening process starts with assessing the neutralizing activity to AAV2/6. It is recommended to perform the other 
screening tests only if the AAV2/6 neutralizing activity results are acceptable. The neutralizing activity is to be reassessed if the screening period takes 
more than 8 weeks.
d.
If a participant had this procedure conducted within 6 months prior to screening, then it can be used in place of the screening assessment.
e.
Liver elastography (or any equivalent imaging technology) required for any participant with a history of hepatitis C or suspicion of chronic liver disease to 
evaluate for fibrosis. Also see footnote c.
f.
Only for participants with no FVIII gene sequencing previously.
g.
For every participant. However, any participant treated with SB-525 (PF-07055480) who has an elevated alpha fetoprotein and MRI mass greater than 2 
cm or suspicious for HCC will undergo biopsy using surgical doses of Factor VIII replacement, if needed. An MRI of the liver can be replaced by an 
abdomen CT-scan (or any equivalent imaging technology) – with vascular phases specific for a search of a liver mass – in case the participant has a 
contraindication to MRI (for example history of hip replacement). 
h.
Height (cm) will be collected at screening only, and weight (kg) will be collected at screening and baseline only.
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Table 1.
Schedule of Activities
Procedure
Screening
Baselinea
Infusion Center
Day 7
(±1 day)
Weeks
2, 4, 6, 8, 10, 
12
(±3 days)
Weeks
16, 20, 24, 28, 32, 
36, 40, 44, 48, 52
(±1 wk)
Months
24, 36, 48, 
60
(±1 M)
Early 
Termination 
Visit
Day 0b
Day 1
i.
Both local and central LFTs will be performed.  At Screening, liver panel will be performed twice, at least 1 week apart.  Following infusion, LFTs will be 
done twice a week from the first collection approximately 3 to 4 days after Day 0 and continuing until Week 20.  The local laboratory results may be 
utilized for the investigator to react promptly if an ALT elevation occurs.  Note: Local and central LFTs are drawn tandemly twice weekly.
j.
Continue central and local LFT assessments twice per week if participant is receiving steroids. LFT assessments will continue twice weekly until 3 
consecutive results demonstrate stable liver function.  At this time LFT assessment may be decreased to once a week.
k.
If a participant has FVIII administration around the day of a visit when FVIII activity is scheduled, sample collection should be postponed at least 48 or 
72 hours based on the FVIII product used (short half-life or long half-life, respectively). 
l.
If a participant is receiving steroids or if a participant develops an inhibitor, weekly assessments of FVIII activity, FVIII antigen and FVIII inhibitor titer 
will continue.
m. Central and local FVIII activity assessment will be performed.  After Week 52, measurement of FVIII activity will be done every 6 months, and may 
increase if warranted by changes in FVIII activity or presence of inhibitor.  Mobile phlebotomy can be used as needed.
n.
Central FVIII inhibitor titer assessment will be conducted.  After Week 52, measurement of FVIII inhibitor titer may increase if warranted by changes in 
FVIII activity or the presence of inhibitor. 
o.
Vector genomes in plasma, saliva, urine, stool, and semen by PCR (unless three previous consecutive specimens have been negative, see footnote p). On 
Day 0, vector genome titer should be obtained in plasma only at 12 hours from the start of the infusion ± 1 hour. 
p.
Collection will only continue until three consecutive negative samples are obtained on a sample-type basis and every 1 month after Week 52 to Month 60 
[±1 month]). For example, after urine sample results are negative 3 consecutive times, the urine sample will stop being collected while the other samples 
may continue if they are positive.
q.
Vital signs to be collected at various times from pre-dose until discharge as described in Section 8.2.2.
r.
Additional samples will be collected if there is a 50% drop in Factor VIII expression, and/or if possible prior to initiation of a corticosteroid treatment.  
s.
Follow-up phone calls to be conducted every 6 months through Month 60 starting 6 months after Month 24 visit between yearly visits (Months 30, 42 and 
54) to review AEs, bleeding events and concomitant medications.  Telephone contacts are not required if they fall when a participant is due on site for a 
blood draw (Months 36 and 60).
t.
As per concomitant medication reporting requirements as described in Section 6.5.
u.
As clinically warranted.
v.
FVIII antigen testing will be conducted only at central lab for all time points and as clinically necessary.
w.
Participants who consent to participate in this optional substudy will undergo liver biopsy. The biopsy may be performed at any time postinfusion when 
deemed appropriate by the investigator, and according to Section 8.2.14.
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2. INTRODUCTION
SB-525 (PF-07055480) is an AAV2/6 vector encoding the hF8 cDNA that is currently being 
investigated in participants with severe Hemophilia A.  SB-525 is legacy nomenclature 
referring to SB-525 (PF-07055480) and may be utilized interchangeably within this protocol.
2.1. Study Rationale
The purpose of this study is to evaluate the safety and tolerability of SB-525 (PF-07055480)
and the FVIII activity by increasing dose levels.  
2.2. Background
2.2.1. Hemophilia A
Hemophilia A, the most common form of hemophilia, occurs in 1 in 5000 males and makes 
up about 80% of the 20,000 individuals in the United States with hemophilia.1 Hemophilia A 
is an X linked blood coagulation disorder caused by mutations of the F8 gene, which encodes 
the FVIII clotting protein. Activated FVIII associates with activated Factor IXa to form the 
intrinsic Factor Xase complex, a complex that is critical for the intrinsic clotting pathway. 
Patients with severe hemophilia A have FVIII activity of less than 1% of normal (<1 IU/dL; 
equivalent to <0.01 IU/mL). If untreated, they suffer frequent hemorrhage into joints or 
muscles, either spontaneously or in response to mild trauma resulting in crippling arthropathy 
or premature death.
Restoration of production of functional FVIII to >1% of normal levels can reduce or 
eliminate the need for prophylactic treatment with FVIII concentrate, and, if at or above 5% 
of normal activity, can substantially reduce hemorrhage following all but the most severe 
trauma. Chronic, repeated IV treatment is currently required for prophylaxis against 
spontaneous hemorrhage. Acute hemarthrosis usually requires access to several repeated IV 
infusions of FVIII until the bleeding stops. FVIII administered as a protein replacement 
therapy has a short half-life (12 hours) requiring frequent IV injections (approximately 3 
times/week) to maintain hemostatically effective levels. FVIII replacement products with 
longer half-lives have recently been commercialized, but they still require frequent infusions 
due to only modest improvement in half-life (approximately 1.5-fold over standard 
replacement therapy). Furthermore, the development of inhibitors to administered FVIII is a 
complication in 25-30% of severe hemophiliacs; in these inhibitor patients, hemostatic 
bypass agents can be used to treat or prevent bleeding and repeated infusions of FVIII, often 
over many months, can be used to induce immune tolerance and reduce inhibitor levels.
The rationale for the proposed clinical therapy is to reduce or eliminate the need for FVIII 
replacement therapy. This study uses a recombinant AAV2/6 encoding the cDNA for the 
BDD hF8. The secreted FVIII has the same amino acid sequence as approved recombinant 
anti-hemophilic factors (ReFacto AF and Xyntha). The SB-525 (PF-07055480) vector 
encodes a liver-specific promotor module and AAV2/6 exhibits liver tropism, thus providing 
the potential for long-term hepatic production of FVIII in patients with hemophilia A.
Preclinical studies in hemophilia A mice, normal mice and non-human primates (NHP)
treated with SB-525 (PF-07055480) demonstrated clinically relevant levels of circulating 
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human FVIII. Bleeding time was significantly reduced following IV administration of SB-
525 (PF-07055480) to hemophilia A mice. Normal mice and NHPs administered SB-525
(PF-07055480) IV and evaluated over 3 months and 2 months, respectively, showed no 
adverse effects related to treatment. There were no tumors detected or evidence of 
carcinogenicity in either species. SB-525 (PF-07055480) was shown to preferentially target 
the liver compared to other tissue types. The highest dose levels tested in mouse and NHP 
studies were 22-fold and 6.7-fold higher, respectively, than the anticipated clinical starting 
dose of 9 × 1011 vg/kg. 
The constant production of FVIII after a single SB-525 (PF-07055480) administration may 
provide potential benefit in durable protection against bleeding and the complications thereof 
without lifelong repetitive IV factor replacement administration.
2.2.2. SB-525 (PF-07055480) Molecular Design and Construction
Gene therapy approaches in hemophilia A have been historically constrained by the large 
size of the hF8 gene, the high AAV dose required to achieve therapeutic FVIII levels, and the 
low manufacturing yields of AAV hF8. The study intervention SB-525 (PF-07055480), 
however, has a shorter coding sequence for hF8 (the hF8 BDD), an optimized, robust 
liver-specific promoter module to drive hF8 expression, and improved virus yields. 
SB-525 (PF-07055480) is an AAV2/6 vector encoding the hF8 cDNA (Figure 2). The SB-
525 (PF-07055480) hF8 cDNA expression cassette consists of liver-specific regulatory 
elements that drive expression of the hF8 transgene. The hF8 transgene is under the control 
of a liver-specific promoter module that is specifically and highly active in the liver, the 
intended target tissue, but inactive in non-liver cells and tissue types, which prevents the 
expression and activity of FVIII in non-target tissues. The hF8 transgene comprises a codon-
optimized hF8 BDD construct, including the native hF8 signal peptide (SP) and is flanked by 
AAV serotype 2 inverted terminal repeats (ITRs). Importantly, the secreted FVIII has the 
same amino acid sequence as approved recombinant anti-hemophilic factors (ReFacto AF 
and Xyntha). 
Figure 2
SB-525 (PF-07055480) cDNA Construct 
2.2.3. Preclinical Studies
The preclinical studies demonstrated that treatment with PF-07055480 resulted in circulating 
levels of biologically active human FVIII that appear sufficient to have an efficacious impact 
in human subjects. Toxicity studies did not show any adverse findings of concerns for use in 
human patients.
5’ ITR
3’ ITR
Liver-Specific
Promoter Module
polyA
5132 bp
SP
Human Factor 8 
B-Domain Deleted Transgene
SB-525
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Detailed information about preclinical studies with SB-525 (PF-07055480) is provided in the 
Investigator’s Brochure.
2.3. Benefit Risk Assessment
Detailed information about the known and expected benefits and risks and reasonably 
expected AEs of SB-525 (PF-07055480) may be found in the investigator’s brochure, which 
is the single reference safety document (SRSD) for this study.
3. OBJECTIVES, ESTIMANDS AND ENDPOINTS
Table 2.
Objectives and Endpoints
Objectives
Endpoints
Primary objective
Primary endpoints

To evaluate the safety and tolerability 
of SB-525 (PF-07055480).

Incidence of AEs and SAEs including 
clinically significant changes in physical 
examination, clinical laboratory 
assessments, immune parameters, vital 
signs, ECG, liver imaging

To evaluate the time-course profile of 
FVIII activity after dosing with SB-525
(PF-07055480).

Changes in circulating FVIII activity
Secondary objectives
Secondary endpoints

To evaluate clinical impact (efficacy 
and quality of life) on hemophilia after 
dosing with SB-525 (PF-07055480).

Change from baseline in use of FVIII 
replacement therapy and frequency and 
severity of bleeding episodes

Change from baseline in the EQ-5D-5L

To evaluate immune response to FVIII.

Measurements of FVIII inhibitor levels

To evaluate vector shedding of 
AAV2/6.

Detection of AAV2/6 vector DNA by 
PCR in plasma, saliva, urine, stool and 
semen
Exploratory objectives
Exploratory endpoints

To evaluate the concurrence between 
FVIII levels by ELISA (FVIII antigen) 
and by FVIII activity assays.

Measurements of FVIII antigen levels
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Table 2.
Objectives and Endpoints
Objectives
Endpoints
To further investigate SB-525
(PF-07055480) mechanism of action 
and the immune response.

Measurements of neutralizing activity 
and antibodies to AAV2/6, T-cell 
responses to AAV2/6 and FVIII

Measurements of von Willebrand factor 
(vWF), C-reactive protein (CRP), and 
IL6 
Optional liver biopsy substudy only:

To evaluate vector integration in the 
liver

To evaluate the histopathology of the 
liver tissue

To assess the expression of protein 
and/or RNA levels of FVIII and other 
biomarkers of interest in the liver

For the integrations analyses (as feasible, 
i.e, depending on the quantity of 
biological material collected): the 
number and location of integration sites, 
the location of the integration sites 
relative to transcription start sites, the 
nature of the inserted sequence, the 
frequency of insertions, and the 
frequency and distribution for each size 
and type of insertion

Other exploratory endpoints (as feasible): 
histopathology assessment (eg, presence 
of fibrosis assessment, presence of 
lymphocytic invasion), protein and/or 
RNA expression of FVIII and selected 
biomarkers (eg, Grp78, Gal3BP)
4. STUDY DESIGN
4.1. Overall Design
This study is a phase 1/2, open-label, single-dose, dose-ranging study. The dose selection 
and number of participants studied at each dose level will be based on safety and kinetics of 
circulating FVIII levels observed in previously dosed participants.
The adaptive design of this phase 1/2 study assigns participants to SB-525 (PF-07055480) 
dose levels based on the average of FVIII expression in the 2 first participants of a cohort.
For each cohort, the first dosed participant will be followed for 6 weeks before a second 
participant can be dosed. After the second participant in a cohort is followed for 6 weeks, the 
Data Monitoring Committee (DMC) will meet and recommend either a dose escalation, dose 
de-escalation, or cohort expansion (with potential reassessment of participant’s data) based 
on their review of the cumulative data available from the first 2 participants of a cohort.
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The duration of study participation will be approximately 62 months for each participant, 
divided into approximately 8 weeks (2 months) for screening, and 60 months for treatment 
and study follow-up.
4.1.1. Screening Period
In order to facilitate enrollment and decrease unnecessary blood sampling, it is recommended 
to start the screening process with the assessment of the AAV2/6 serological status only 
(Section 8.2.13.1). If the participant qualifies, then the rest of the screening tests (total 
duration approximately 8 weeks) will be performed. 
All screening assessments are listed in the SoA table (Table 1). A participant must meet all 
Inclusion Criteria, and none of the Exclusion Criteria, to participate in this study.
4.1.2. Treatment Period
This study will follow an adaptive, dose escalation and participant enrollment design to 
establish and enroll participants at a dose level that can achieve therapeutically useful FVIII 
levels comparable with emerging gene therapies (in the 10-150% range), with a therapeutic 
goal of FVIII activity of 40-100% of normal. The schema aims to minimize enrollment to 
dose levels that are inactive or results in FVIII levels of >150%.
One (1) participant will initially be enrolled at a given dose level and followed over 6 weeks. 
After review of safety data for the first participant, a second participant will be enrolled at the 
same dose level and also followed for 6 weeks. Then DMC will meet and recommend dose 
escalation, dose de-escalation, or cohort expansion.
The possible clinical dose level range will be from 6 × 1011 vg/kg to 6 × 1013 vg/kg, with a 
starting dose of 9 × 1011 vg/kg, which is expected to yield >5% normal FVIII levels in 57% 
of treated participants.  Several dose levels may need to be studied to identify a safe and 
tolerable therapeutic range. If observed FVIII levels at the starting dose level of 9 × 1011
vg/kg are higher than anticipated, then dose de-escalation to 6 × 1011 vg/kg will be 
considered. The planned dose escalation interval between dose levels is roughly 2-fold (0.33 
log).
Participants will be dosed with one of 12 potential dose levels, as outlined in the table below:
Possible Total rAAV Dose (vg/kg)
6 × 1011
9 × 1011
1.2 × 1012
2 × 1012
4 × 1012
6 × 1012
1 × 1013
2 × 1013
3 × 1013
4 × 1013
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Possible Total rAAV Dose (vg/kg)
5 × 1013
6 × 1013
The starting dose level (9 × 1011 vg/kg) was associated with FVIII activity of 12% of normal 
in a NHP study. Unless more are recommended by the DMC, approximately 20 participants 
are planned to be dosed in this clinical trial.
Based on DMC review of safety and pharmacodynamics (PD) data, additional participants 
may be enrolled at a specific dose level. The dose selected will be a tolerable dose level 
where FVIII activity does not exceed 150% based on observed activity and variability.
4.1.2.1. Dose Escalation Based on Pharmacodynamic Response
The dose escalation plan and participant assignment to dose levels will be according to an 
analysis of FVIII expression response based on weekly longitudinal FVIII activity 
measurements. At the end of the first cohort, safety and expression data will be available for 
2 participants over 12 and 6 weeks, respectively. The DMC will review all the safety data 
and will recommend, based on this review and the expression levels, to move to a different 
dose level, de-escalate or expand the current one.
While these guidelines use mean FVIII activity results within dose levels, the DMC must 
also be consulted if any participant at a given dose level has FVIII peak activity of >150% 
prior to adding further participants.
4.1.2.2. Dose Escalation Based on Safety
Determination of Dose limiting toxicities (DLTs) will be made by the DMC (Section 9.6). 
Further enrollment to a dose level and dose escalation based on PD response per the above 
schema will be modified for reasons of safety based on the guidelines below:

If at any given dose level, >50% participants experience a DLT, additional 
participants can only be enrolled at that dose level in concert with the DMC.

Escalation to a higher dose level can only occur if not more than 40% of participants, 
and at least 2 participants experience a DLT.

An average FVIII expression of 150% or more will be considered as a safety issue 
and the DMC may consider dose de-escalation.
Safety data will take precedence over expression data for dose escalation. If further 
enrollment in a cohort for safety reasons is prevented by insufficient expression data, the 
DMC and sponsor will adjudicate the circumstances for further participant enrollment.
4.1.3. Early Termination
Participants who discontinue from the study prematurely or are withdrawn from the study 
will be asked to return to the study site for an Early Termination Visit (ETV). It is at the 
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discretion of the investigator to waive any procedures if they have been performed as part of 
standard of care within the standard interval of scheduled study visits per protocol. See the 
list of assessments to be performed at the ETV in the SoA (Table 1).
The investigator must make and document every attempt to ensure all participants are 
followed through the end of study (Month 60).
4.2. Scientific Rationale for Study Design
Hemophilia is an attractive target for gene therapy. This is due in part because minute-to-
minute regulation of FVIII/Factor IX clotting protein (FIX) expression is not required (unlike 
proteins such as insulin). In addition, there is a wide therapeutic window for FVIII/FIX 
expression since therapeutic benefit can be achieved in severe hemophiliacs, who have 
FVIII/FIX activity <1%, with only modest improvements in factor expression. Any factor 
activity over 1% results in an improved phenotype (moderate hemophilia 1-5% or mild 
hemophilia 5-40%).
As the study was being planned, 1 adeno-associated virus (AAV)-mediated FVIII cDNA-
and 5 AAV-mediated FIX cDNA-gene-transfer studies have been initiated and have reported 
at least some clinical study data. Details are provided in the Investigator’s Brochure. Of the 
various AAV serotypes tested in the clinic, none have utilized the AAV6 serotype that will 
be tested in this clinical trial. Of the 4 studies where gene therapy was delivered 
intravenously, factor protein expression generally exhibited a dose response, though peak 
expression and durability of effect have been variable. Alanine aminotransferase (ALT) 
elevations due to AAV-associated transaminitis have been observed in at least 1 dose level in 
all studies reported to date using the IV route. AAV-associated transaminitis has been 
reported at vector doses ranging from 5 × 1011 vg/kg to 6 × 1013 vg/kg, with variable amount 
of losses in factor protein expression that may be associated with time to initiation of steroid 
therapy. Additional information on AAV-associated transaminitis is provided in 
Section 10.7.
4.2.1. Rationale for Use of rAAV2/6 Serotype Based on Preclinical Studies
The rAAV2/6 serotype was selected for use in Sangamo gene therapy platforms based on 
previous NHP data showing that AAV2/6 was primarily hepatotrophic, with similar 
biodistribution to AAV2/8 and that AAV2/6 and AAV2/8 vectors yielded similar levels of 
circulating FIX transgene expression (see the Investigator’s Brochure).
4.3. Justification for Dose
The rationale for SB-525 (PF-07055480) dose selection was based on (i) the dose-response 
relationship of circulating levels of human FVIII generated in NHP following a single IV 
dose administration of SB-525 (PF-07055480), (Sangamo Study Number TX16-HMA-008); 
(ii) preclinical dose ranging safety studies (2 × 1011 to 2 × 1013 vg/kg) in mice and NHP 
resulting in no adverse events (AEs), histological changes or tumorigenicity; and (iii) 
recently published clinical trials involving similar cDNA-based strategies (see the 
Investigator’s Brochure). The proposed clinical dose range is 6 × 1011 to 6 × 1013 vg/kg, with 
a starting dose of 9 × 1011 vg/ kg, which was associated with FVIII activity of 12% of normal 
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in an NHP study. The 6 × 1011 dose is an optional de-escalation dose level if FVIII activity 
in humans is much higher than observed in NHPs.
Although the translation of SB-525 (PF-07055480) pharmacodynamics (PD); delivery to 
liver, transduction, and FVIII expression) from NHP to humans is unknown, the dose 
escalation assumes a direct translation between species with starting low dose levels expected 
to result in therapeutic FVIII levels. Subsequent doses will follow an adaptive dose 
escalation or de-escalation plan to mitigate the possibility that the human efficacious dose is 
higher than observed in NHP.
A population kinetic-PD model incorporated the monkey plasma human FVIII data with the 
assumption that the NHP response models human response in terms of plasma FVIII levels. 
With this model, a clinical starting dose of 9 × 1011 vg/kg is expected to yield >5% normal 
FVIII levels in 57% of treated participants. This is a reasonable target for the starting dose. 
Further information of the dose escalation plan is found in Section 4.1.2.
4.4. End of Study Definition
A participant is considered to have completed the study if he has completed all phases of the 
study including the End-of-Study (EOS) visit (Month 60).
The end of the study is defined as the date of the EOS Visit of the last participant in the 
study.
5. STUDY POPULATION
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 nonmedical conditions should be 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1. Signed informed consent.
2. Male ≥18 years of age able to understand the informed consent.
3. Severe hemophilia A (with past evidence of circulating FVIII activity of <1% normal).
4. Treated or exposed to FVIII concentrates or cryoprecipitate for at least 150 exposure 
days.
5. ≥12 bleeding episodes if receiving on-demand therapy over the preceding 12 months.
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6. Sexually active participants must agree to use double barrier contraceptive (one of them 
being a condom) or abstinence, and all participants must refrain from donating their 
sperm until at least 3 consecutive semen samples after SB-525 (PF-07055480) treatment 
are negative for AAV2/6 and for a minimum of 90 days after SB-525 (PF-07055480)
administration.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1. Neutralizing activity to AAV6 capsid.
2. Current inhibitor, or history of FVIII inhibitor (except for transient low titer inhibitor 
detected in childhood).
3. History of hypersensitivity response to FVIII.
4. History of hepatitis B or HIV-1/2 infection.
5. History of hepatitis C, unless viral assays in 2 samples, collected at least 6 months apart, 
are negative.
6. Two (2) or more occurrences of any of the following: hemoglobin <10g/dL, platelets 
<100,000/µL, or white blood cells less than 4,000 cells/µL.
7. Evidence of any bleeding disorder in addition to hemophilia A.
8. History of tuberculosis or systemic fungal disease.
9. Symptomatic cardiovascular disease as a co-morbid condition.
10. Markers of hepatic inflammation or overt or occult cirrhosis as evidenced by 1 or more of 
the following:

Albumin ≤3.5 g/dL;

Total bilirubin >1.5 x ULN and direct bilirubin ≥0.5 mg/dL;

Alkaline phosphatase >2.0 × ULN;

ALT or aspartate aminotransferase (AST) >1.3 × ULN;

International Normalized Ratio (INR) >1.5.
11. History of chronic renal disease or creatinine ≥1.5 mg/dL.
12. Use of systemic (IV or oral) immunomodulatory agent or steroid use within 3 months 
prior to screening (inhaled or topical treatment is allowed, eg, for asthma or eczema).
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13. History of chronic infection or other chronic disorder considered an unacceptable risk.
14. Presence of liver mass on magnetic resonance imaging (MRI) or any equivalent imaging 
technology, or, positive alpha fetoprotein.
15. Presence of >Grade 2 liver fibrosis on elastography (or any equivalent imaging 
technology) for participants with history of treated Hepatitis C or suspicion of chronic 
liver disease.
16. History of malignancy except for successfully treated basal cell carcinoma.
17. History of alcohol or substance abuse.
18. Any contraindication to the use of corticosteroids.
19. Previously received gene therapy product.
20. Participation in prior investigational drug or medical device study within 3 months prior 
to screening.
21. History of therapeutic non-adherence.
22. Any other reason that, in the opinion of the investigator or medical monitor, would render 
the participant unsuitable for participation in the study.
5.3. Lifestyle Considerations
Sexually active patients should use 1 of the acceptable forms of contraceptives described in 
Appendix 4 (Section 10.4).
5.4. 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 SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Rescreened participants are required to sign a new ICF and will be assigned a 
different participant number.
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
For the purposes of this protocol, study intervention refers to SB-525 (PF-07055480).
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6.1. Study Intervention(s) Administered
ARM Name
Single arm study
Intervention 
Name
PF-07055480          
Type 
Gene therapy
Dosage Form
Injectable
Dose Strength
6 × 1011, 9 × 1011, 1.2 × 1012, 2 × 1012, 4 × 1012, 6 × 1012, 1 × 1013, 
2 × 1013, 3 × 1013, 4 × 1013, 5 × 1013, 6 × 1013 vg/kg
Dosage
Single infusion
Several dose levels may need to be studied to identify a safe and 
tolerable therapeutic range.
For a participant with BMI >30 kg/m2, dose will be calculated based 
on an adjusted body weight determination that assumes a maximum 
permissible BMI of 30 kg/ m2, eg, for 187.96 cm (6’2”) height and 
167.8 kg weight (BMI 47.5 kg/m2) dose will be based on 106.1 kg, 
which is the weight associated with a BMI of 30 kg/m2 for a 187.96 
cm (6’2”) tall individual
Route of 
Administration
Intravenous infusion/injection
IMP and NIMP
IMP (investigational medicinal product)
Sourcing
Provided centrally by the sponsor.
Packaging and 
Labeling
Study Intervention will be provided in a 4.7 mL/vial.  Each vial will 
be labeled as required per country requirement.
Current/Former 
Name(s) or 
Alias(es)
PF-07055480
SB-525
Adeno-associated viral vector with human factor VIII gene
6.1.1. Administration
Side effects following SB-525 (PF-07055480) administration may include transient fever, 
chills, and/or nausea.  It is recommended that the participant should be pre-medicated with 
acetaminophen 650 mg by mouth and diphenhydramine hydrochloride (Benadryl) 25-50 mg 
by mouth or IV approximately 1 hour prior to the administration of SB-525 (PF-07055480).  
These medications may be repeated every 3 - 4 hours as needed.  NSAIDs are not 
recommended because of the potential to cause platelet dysfunction but may be used at the 
discretion of the investigator.
It is recommended that the participant also fast for 2 hours after the administration. All 
participants will be switched to an on-demand regimen approximately 2 weeks after infusion 
and subsequently modulate their FVIII replacement use according to their needs.
SB-525 (PF-07055480) will be injected IV using a syringe pump or IV infusion pump (FDA 
approved delivery system as described in the Study Investigational Product [IP] Manual).  
Total volumes will be dependent on participant’s cohort assignment and body weight (kg) at 
baseline.  SB-525 (PF-07055480) will be administered through an IV catheter at a controlled 
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speed while monitoring the participant’s vital signs (heart rate, blood pressure [BP], 
respiratory rate [RR], and temperature).  Detailed instructions for the thaw and administration 
of the investigational product are in the Study IP Manual.
Participants will be admitted to the infusion center facility for SB-525 (PF-07055480)
infusion and will remain in the infusion center for 24 hours after the end of infusion for 
observation and will be discharged when all AEs, concomitant medications, and all vital 
signs (temperature, heart rate [HR], RR, and BP) are stable.
All participants will be asked to return to the study site for a follow-up visit 7 ± 1 days after 
SB-525 (PF-07055480) infusion.  All safety data must be reviewed prior to discharge.
6.2. Preparation/Handling/Storage/Accountability

The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all study intervention received and any 
discrepancies are reported and resolved before use of the study intervention.

Only participants enrolled in the study may receive study intervention and only 
authorized site staff may supply or administer study intervention. All study 
intervention must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with 
access limited to the investigator and authorized site staff.

The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records).

Further guidance and information for the final disposition of unused study 
interventions are provided in the IP Manual.
Ordering the IP and Preparation: Details are provided in the IP Manual and it should be 
reviewed carefully.  Once eligibility has been confirmed, the IP can be ordered noting that it 
will take approximately 3 weeks for product delivery. 
6.3. Measures to Minimize Bias: Randomization and Blinding
Allocation of study 
intervention
This is an open-label study; however, the specific intervention to 
be taken by a participant will be assigned using an IRT system 
(eg, IMPALA). The site will contact the IRT system 
approximately 3 weeks before the start of study intervention 
administration for each participant. The infusion site will record 
the intervention assignment on the applicable case report form, if 
required.
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6.4. Study Intervention Compliance
Study treatment will be infused via infusion pump on Day 0 under supervision by the site 
staff. The vial lot number, total volume, and infusion time (start and stop times) will be 
monitored and recorded by the site staff.  Full compliance with study treatment infusion is 
anticipated. 
Administration: If a participant does not receive a complete infusion for any reason, she or he 
will not be rescreened, but will be followed for safety.
6.5. Concomitant Therapy
All concomitant medications and therapy taken through Month 36 must be captured in the 
CRF.  After Month 36, only concomitant medications and therapy associated with SAEs, 
AEs related to the study drug, or to AEs with an unknown cause will be reported through 
Month 60 or the ETV, if applicable.  See Section 8.3.1 for AE reporting requirements.
The investigator will record all concomitant medications including those given in treatment 
of AEs on the concomitant medication page in the participant’s CRF.  Any medication taken 
by the participant from 30 days prior to screening throughout the course of the study, 
including over-the-counter medicinal products, dietary supplements, and herbal medications, 
should be recorded on this form.  A short course of prednisone may be instituted either as 
prophylaxis or post AAV exposure if an immune reaction to the AAV capsid develops 
(Section 10.7).  Any treatment with prednisone and pre-treatment with acetaminophen and 
diphenhydramine hydrochloride should be recorded on the concomitant medications page.
Participants enrolled in this study who previously received prophylactic FVIII replacement 
regimens will be required to switch to on-demand therapy approximately 2 weeks after 
infusion with SB-525 (PF-07055480), pending data shows it is safe to do so.  The use and 
timing of FVIII replacement will be monitored closely in this study and will influence the 
timing of PD assessments for FVIII activity.  There is no washout period per se, but all 
participants will be switched to an on-demand regimen approximately 2 weeks after infusion 
and subsequently modulate their FVIII replacement use according to their needs.  All 
participants are to carefully record the date and time of each FVIII administration in an 
e-Diary, so that the elapsed time between their last FVIII administration and each FVIII level 
collection can be collected.  For participants using short half-life replacement products, the 
resulting FVIII levels are valid only if elapsed time is more than 48 hours.  For participants 
using extended half-life FVIII replacement products, this time is extended to 72 hours.  Of 
note, 48 and 72 hours are reference values, these times can be modified depending on the 
participant profile (slow versus fast metabolizers) and the prescribing information of each 
product.  The investigator may recommend a different time for his/her study participant after 
discussion with the medical monitor. 
6.5.1. Allowed Therapy
All medications (such as FVIII) with the exception of those that are potentially hepatotoxic 
are permitted.  
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6.5.2. Disallowed Therapy
Hepatotoxic agents such as diclofenac, amiodarone, chlorpromazine, fluconazole, isoniazid, 
rifampin, valproic acid, and high doses of acetaminophen (maximum 4 gm/day) or celecoxib 
(>100 mg/day) are to be avoided.  Participants should be counseled to moderate alcohol 
consumption throughout the trial (not more than 1 drink per week is suggested); especially 
for 3 months following dosing with SB-525 (PF-07055480).
6.6. Dose Modification
Within an individual participant, no dose modifications are possible as this is a single 
administration study.
6.7. Intervention after the End of the Study
No further intervention is planned after the end of the study.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
Since no more than 1 single infusion of SB-525 (PF-07055480) on Day 0 will be 
administered during the study, this section is not applicable. See Section 4.1 for any 
disruption in administration of the infusion.
7.1.1. Temporary Discontinuation
Not applicable for this study.
7.1.2. Rechallenge
Not applicable for this study.
7.2. Participant Discontinuation/Withdrawal from the Study
Participants may withdraw or should be discontinued from study for any of the following 
reasons:

Request by the participant to withdraw.

Request of the sponsor or primary care provider if he or she thinks the study is no longer 
in the best interest of the participant.

Participant judged by the investigator to be at significant risk of failing to comply with 
the provisions of the protocol as to cause harm to self or seriously interfere with the 
validity of the study results.

At the discretion of the Institutional Review Board (IRB), Office for Human Research 
(OHR), Food and Drug Administration (FDA), investigator, or sponsor.
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At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted.  See the SoA (Table 1) for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed.
The early discontinuation visit applies only to participants who are enrolled and then are 
prematurely withdrawn from the study.  Participants should be questioned regarding their 
reason for withdrawal.  
If a participant withdraws from the study, he may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see Section 7.2.1) 
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.
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved.
7.2.1. Withdrawal of Consent
Withdrawal of Consent occurs when a participant specifically withdraws consent for any 
further contact with him or persons previously authorized by the participant to provide this 
information.  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, as to whether the 
withdrawal is from study procedures and/or post-treatment study follow-up, and entered on 
the appropriate CRF page.  In the event that vital status (whether the participant is alive or 
dead) is being measured, publicly available information should be used to determine vital 
status only as appropriately directed in accordance with local law.
7.3. Lost to Follow up
A participant will be considered lost to follow-up if he repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study.

Before a participant is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
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equivalent methods). These contact attempts should be documented in the participant’s 
medical record.

Should the participant continue to be unreachable, he will be considered to have 
withdrawn from the study. 
8. STUDY ASSESSMENTS AND PROCEDURES
Screening evaluation may take approximately 8 weeks and may be performed across several 
visits during the screening period. Screening and Baseline may be approximately 10 weeks 
in duration. Assessments must be completed, and the results reviewed to confirm eligibility. 
Tests to be performed at screening and baseline are described in the SoA (Table 1). 
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures.  ICF and ICD are synonymous 
and used interchangeably in this protocol.
Study procedures and their timing are summarized in the SoA.  Protocol waivers or 
exemptions are not allowed.
Safety issues should be discussed with the sponsor immediately upon occurrence or 
awareness to determine whether the participant should continue or discontinue study 
intervention.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it unfeasible to perform 
the test.  In these cases, the investigator must 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 the missed test and any corrective and preventive 
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible.  The study team must 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.
Procedures for performing each assessment not detailed in this protocol should follow local 
standard of care.
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The actual date should be recorded for all procedures and the investigator should make every 
effort to perform procedures at the scheduled nominal dates.
Planned safety and laboratory assessments may be collected at additional time points 
following conversation between the investigator and medical monitor based on emerging 
clinical events. The change in timing for any planned study assessments must be approved 
and documented by the sponsor, but this will not constitute a protocol amendment. The 
addition of any new study assessments to the protocol required for any ongoing and new 
participants would constitute an amendment.
Demographic/Medical History Assessments
The following demographic parameters will be captured: date of birth, sex, race, and 
ethnicity.
Medical and medication history will be assessed during the screening period as related to the 
eligibility criteria in Sections 5.1 and 5.2 and will include but is not limited to the following:

Extensive medical history;

Medication history (all medications taken within 30 days prior to Screening visit with a 
particular focus on their FVIII replacement regimen) inclusive of all herbal medications, 
over-the-counter medicines, protein/high-energy supplements or drinks, weight-loss 
products, smoking cessation products (inhalers, patches, gum), aspirin (or aspirin-
containing products), non-steroidal anti-inflammatory drugs (NSAIDs; or NSAID-
containing products), and celecoxib

History of drug and alcohol use
If the participant is not normally seen at the study site, medical records should be obtained to 
confirm study eligibility.
8.1. Efficacy Assessments
8.1.1. Factor VIII activity
FVIII activity will be measured as described in the SoA (Table 1).  Weekly assessments,
starting at Week 24 through Week 52, may be required if a participant is receiving steroids or 
develops an inhibitor. After Week 52, measurement of FVIII activity may increase if 
warranted by changes in FVIII activity or the presence of inhibitor. If a participant has a 
FVIII activity level (chromogenic assay) > 150%, FVIII activity measurement will be 
assessed at least every 3 months until activity levels have stabilized below 150%. If a 
participant has FVIII administration around the day of a visit when FVIII activity is 
scheduled, sample collection should be postponed at least 48 or 72 hours based on the FVIII 
product used (short half-life or long half-life respectively).  Measurement of the FVIII 
activity level, post FVIII infusion, only pertains to scheduled time points, ie, Week 2, Week 
4, etc, and not to each time a participant takes FVIII replacement, should FVIII treatment be 
necessary.
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All samples collected from participants for plasma factor FVIII activity levels will be 
analyzed by central and local laboratories.

In the central laboratory, FVIII activity will be assessed both by chromogenic and 
onestage clotting assay.

In local laboratories, FVIII activity will be assessed by chromogenic or one-stage clotting 
assay based on local laboratory’s usual practice.
8.1.2. Health Outcome Questionnaire
An EQ-5D-5L will be conducted as described in the SoA (Table 1) using a tablet device 
provided to each site or the participant’s mobile phone.
Developed by the EuroQoL Group, the EQ-5D-5L (EuroQoL, 5 dimensions, 5 levels) is 
considered the premier measure of health status used in the assessment of the Quality 
Adjusted Life Year.  It measures 5 dimensions of health on a 5-point (5L) scale including 
Mobility, Self-care, Usual activities, Pain/discomfort, and Anxiety/depression.
Also included is a visual analog scale anchored by worst and best imaginable health on a 0 to 
100 scale where participants are asked to indicate where on the scale they rate their current 
health.
8.1.3. Bleeding Episodes and FVIII Concentrates Usage
Bleeding episodes and FVIII concentrate usage will be reviewed as described in the SoA 
(Table 1).  An e-Diary, a handheld device, will be provided to all participants at baseline 
which will be used until the EOS. 
The participants are required to enter any occurrence of hemophilic bleeding episodes 
(including date, time, location and etiology) and any exogenous FVIII replacement 
(including date, time, reason and dose) required to treat the bleeds in the e-Diary throughout 
follow-up regardless of whether or not the participant has resumed prophylactic therapy. If a 
participant has to resume FVIII prophylaxis treatment, prophylaxis FVIII infusion data will 
not have to be reported on the e-Diary after Month 24 but they will be recorded in the eCRF. 
On-demand and preventative infusions will continue to be required to be reported on the e-
Diary throughout follow-up.
Follow-up contacts (eg, phone calls) to review safety, bleeding episodes and FVIII 
concentrates usage should occur every 6 months (±1 month) after the Month 24 visit.
Study sites will review a bleeding e-Diary where the participant records replacement product 
use, bleeding episodes especially in the target joints, and information on timing and duration.  
This information is captured in the dataset.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Table 1).
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8.2.1. Physical Examinations
A complete physical examination will be performed as described in the SoA (Table 1). 
Every physical exam will include the vital signs described below. Genital and rectal 
examination may be excluded if not clinically indicated. Height (cm) will be collected at 
screening only, and weight (kg) will be collected at screening and baseline only.
8.2.2. Vital Signs
Vital sign measurements will include systolic and diastolic blood pressure (SBP and DBP), 
HR, RR, and temperature and will be measured during the complete physical examination 
(Section 8.2.1). Additional measurements will occur on Day 0 and Day 1. Vital signs should 
be performed per standard of care as long as the same position for each participant is used at 
every assessment and after a rest period of at least 1 minute. 
On the infusion day (Day 0) and Day 1, vital signs will be obtained prior to infusion and then 
within 5 minutes of the start of the infusion, every 15 (±5) minutes for the length of the 
infusion, every 15 (±5) minutes until stable (±10 mmHg), then every 30 (±5) minutes until 2 
hours post-infusions, then every 4 hours (±10 min) until discharge.
8.2.3. Electrocardiograms
Standard 12-lead ECGs will be performed as described in the SoA (Table 1).  If a participant
had an ECG conducted within 6 months prior to screening, then it can be used in place of the 
screening assessment.
An ECG will be obtained after the participant has rested for at least 10 (±5) minutes per 
standard of care as long as the same position for each participant is used at every assessment.
ECG values of potential clinical concern are listed in Appendix 8.
8.2.4. Clinical Laboratory Tests
See Appendix 2 (Section 10.2) for the list of clinical safety laboratory tests to be performed 
and the SoA (Table 1) for the timing and frequency.  All protocol-required laboratory 
assessments, as defined in Appendix 2, must be conducted in accordance with the laboratory 
manual and the SoA.  Unscheduled clinical laboratory measurements may be obtained at any 
time during the study to assess any perceived safety issues.
When applicable, laboratory samples are to be collected prior to dosing.  Lab samples 
obtained every 6 months after week 52 do not require a formal visit to the site, except 
Months 24 and 36.
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF.  The 
laboratory reports must be filed with the source documents.  Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant's condition.
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All laboratory tests with values considered clinically significantly abnormal during 
participation in the study should be repeated until the values return to normal or baseline or 
are no longer considered clinically significant by the investigator or medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.
See Appendix 6 for suggested actions and follow-up assessments in the event of potential 
drug-induced liver injury.
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must 
be conducted in accordance with the laboratory manual and the SoA (Table 1).
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the investigator (eg, SAE or AE or dose modification), then the 
results must be recorded in the CRF as an AE, where falling within protocol-specified AE 
reporting criteria (see Section 8.3.1).
8.2.5. Chest X-Ray
An anterior/posterior or posterior/anterior and lateral chest X-ray will be performed at 
screening. If a participant had a chest X-ray conducted within 6 months prior to screening, 
then it can be used in place of the screening assessment.
8.2.6. Liver Elastography
A liver elastography (or any equivalent imaging technology) is required at screening only for 
participants with a history of hepatitis C or suspicion of chronic liver disease to evaluate for 
fibrosis. If a participant had a liver elastography conducted within 6 months prior to 
screening, then it can be used in place of the screening assessment.
8.2.7. Liver Assessment
A liver MRI will be performed for every participant as described in the SoA (Table 1). If a 
participant had a liver MRI conducted within 6 months prior to screening, then it can be used 
in place of the screening assessment.
Circulating alpha fetoprotein level will be determined for every participant as described in 
the SoA (Table 1).  Any participant treated with SB-525 (PF-07055480) who has an elevated 
alpha fetoprotein and MRI mass greater than 2 cm or suspicious for HCC will undergo 
biopsy using surgical doses of factor VIII replacement, if needed. An MRI of the liver can 
be replaced by an abdomen CT-scan (or any equivalent imaging technology) – with vascular 
phases specific for a search of a liver mass – in case the participant has a contraindication to 
MRI (for example history of hip replacement).
Histopathologic examination and genomic analysis will be performed to determine the origin 
and nature of the tumor. Detailed instruction on sample collection and tissue preparation for 
genomic analysis is provided in Appendix 10 (Section 10.10).
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An optional liver biopsy substudy is also proposed to participants (Section 8.2.14).
8.2.8. Abdominal Examination
An abdominal examination for hepatomegaly will be performed as described in the SoA 
(Table 1).
8.2.9. Interim Follow-up Contact
After the completion of Month 24 visit, follow-up contacts (eg, phone calls) every 6 months 
(±1 month) will be placed in between the on-site visits (at Months 30, 42 and 54) to review 
general health status, including safety and bleeding episodes as well as any FVIII concentrate 
usage.  If the initial contact attempt is unsuccessful, a minimum of 3 contact attempts must be 
documented before the interim follow-up can be considered unsuccessful.  AEs and 
concomitant medications should be reviewed and captured as per Sections 8.3 and 6.5, 
respectively.
Telephone contacts are not required if they fall when a participant is due on site for a blood 
draw.
8.2.10. Suicidal Ideation and Behavior Risk Monitoring
Not applicable for this study.
8.2.11. Pregnancy Testing
Not applicable for this study.
8.2.12. Rater Qualifications 
Not applicable for this study.
8.2.13. Immunogenicity Assessments
Blood samples for immunogenicity assessments will be collected as outlined below.  
8.2.13.1. AAV2/6 Antibodies
Samples for neutralizing activity to AAV capsid proteins (neutralizing antibodies) will be 
collected at screening to determine eligibility for the study. It is recommended to perform 
the other screening tests only if the AAV2/6 neutralizing activity results are acceptable. The 
neutralizing activity is to be reassessed if the screening period takes more than 8 weeks.
Samples will also be collected to assess both total and neutralizing antibodies to AAV2/6 
over time, as displayed in the SoA (Table 1).
8.2.13.2. FVIII Inhibitor Titer
FVIII inhibitor levels will be measured as displayed in the SoA (Table 1). Weekly 
assessments (through Week 52) may be required if a participant is receiving steroids or 
develops an inhibitor. After Week 52, measurement of FVIII inhibitor titer may increase if 
warranted by changes in FVIII activity or the presence of inhibitor.
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8.2.13.3. Interferon-Gamma ELISPOT
Samples for Interferon-gamma ELISPOT will be collected to detect a proliferation of 
capsid-specific T cells at baseline and Week 6 (±3 days). Additional samples will be 
collected if there is a 50% drop in Factor VIII expression and/or prior to initiation of a 
corticosteroid treatment if possible.
8.2.14. Optional Liver Biopsy
An optional liver biopsy can be performed (in participants who consent to do so and as per 
investigator’s judgement) during the postinfusion period until year 5 i.e, the end of the study. 
The procedure may be repeated once, later in the study, to assess evolution over time (in 
participants who consent to do so and as per investigator’s judgement). 
This substudy may be proposed to any participant, unless there is a condition that, in the 
opinion of the investigator or a hepatologist or radiologist, would make liver biopsy 
contraindicated. 
The exploratory objectives of the substudy are to evaluate vector integration in the liver, the 
histopathology of the liver tissue and to assess the expression of protein and/or RNA levels 
of FVIII and other biomarkers of interest in the liver (depending on collected material). A 
biopsy will be made upon investigator’s decision; it can be performed at any time
postinfusion to assess liver health, integration and FVIII in the liver, but could also be 
triggered by sustained elevated FVIII activity levels, by a significant FVIII activity decline, 
by a sustained ALT elevation > ULN or to assess the long-term gene therapy effects on the 
liver.
Any participant who consents to the procedure will have a liver biopsy via either transjugular 
or percutaneous (ultrasound-guided) route, according to the standard procedures of the
institution. At least 2 tissue cores will be harvested and additional details for collecting and 
handling the biopsy specimens are provided in the Laboratory Manual.
FVIII activity levels should be assessed within 7 days before the biopsy and on the day of the 
biopsy, prior to the procedure. It is recommended that participants have a FVIII activity level 
of ≥ 50% (or higher, depending on local guidelines and/or investigator discretion) when 
doing the procedure. As needed, participants may be treated with additional exogenous FVIII 
replacement products in order to increase their FVIII activity levels to an appropriate level, 
under the supervision/instruction of the investigator, to ensure the safety of the participant 
during the procedure. 
Participants consenting to the optional liver biopsy are recommended to undergo pre-biopsy 
assessments such as:
At least 28 days before the procedure:
-
Physical examination
-
Central laboratory safety panels (hematology and clinical chemistry, including LFTs) 
and hemostasis parameters
-
Liver ultrasound (fasting recommended at least 8 hours prior to ultrasound)
-
FibroScan or Fibrotest
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At least 7 days before the procedure:
-
Central and local FVIII activity level assessments
-
Pre-biopsy consultation (with hepatologist and/or radiologist)
On the day of the biopsy before the procedure:
-
Participants will be required to observe an 8-hour fasting period before the procedure.
-
Brief physical examination
-
Central and local laboratory safety panels (hematology and clinical chemistry, 
including LFTs) and hemostasis parameters
-
Central and local FVIII activity level assessments
-
As needed, participants may be treated with additional exogenous FVIII replacement 
products to increase their FVIII activity levels to an appropriate level. 
The follow-up care should be done according to the local standard of care. If only a small 
amount of tissue (< 2 cm) is obtained at the time of the biopsy, the participant may be asked 
to consent for a second pass. In this case, the original < 2 cm sample should still be retained 
and handled according to the instructions for handling biopsy specimens in the Laboratory 
Manual. 
Following completion of the biopsy, the participant should remain under observation in the 
hospital according to the local procedure. Overnight post-procedure observation may be done 
at the investigator’s discretion and/or according to local guidelines.
Whenever applicable, any finding related to the optional biopsy should be further assessed 
and followed as clinically appropriate to manage the participant’s medical care. A 
hepatologist and/or other specialist clinicians should be consulted if required. Additional 
liver ultrasound and/or FibroScan may be considered at the discretion of the investigator 
and/or hepatologist.
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant's legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether the 
event meets the criteria for classification as an SAE or caused the participant to discontinue 
the study intervention (see Section 7.1). 
Each participant will be questioned about the occurrence of AEs in a nonleading manner.
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
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8.3.1. Time Period and Frequency for Collecting AE and 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 and/or receiving study intervention), through and including to 
the last visit (completion at 60 months [±1 months]) or at ETV for participants who 
discontinue.
However, from Month 36 through to the end of study (Month 60), only the following AEs 
will be actively collected:

SAEs

Non-serious AEs determined to be related to study intervention by the investigator or 
where causality is unknown.
Follow-up by the investigator continues throughout and after the active collection period and 
until the AE or SAE or its sequelae resolve or stabilize at a level acceptable to the 
investigator and Pfizer concurs with that assessment.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant definitively discontinues or temporarily discontinues study intervention 
because of an AE or SAE, the AE or SAE must be recorded on the CRF and the SAE 
reported using the CT SAE Report Form.
Investigators are not obligated to actively seek AEs or SAEs after the participant has 
concluded study participation.  However, if the investigator learns of any SAE, including a 
death, at any time after a participant has been discharged from the study, and he/she 
considers the event to be reasonably related to the study intervention or study participation, 
the investigator must promptly notify the sponsor.
8.3.1.1. Reporting SAEs to Pfizer
All SAEs, occurring in a participant during the active collection period as described in 
Section 8.3.1 are reported to Pfizer Safety on the CT SAE Report Form immediately upon 
awareness and under no circumstance should this exceed 24 hours, as indicated in 
Appendix 3 (Section 10.3).  The investigator will submit any updated SAE data to the 
sponsor within 24 hours of it being available.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period as 
described in Section 8.3.1 are recorded on the CRF.  AEs and SAEs that begin after obtaining 
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informed consent but before the start of study intervention will be recorded on the Medical 
History/Current Medical Conditions section of the CRF, not the AE section.  AEs and SAEs 
that begin after the start of study intervention are recorded on the AE section of the CRF.
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3
(Section 10.3).
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts.  For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information 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.
Further information on follow-up procedures is given in Appendix 3 (Section 10.3).
8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a 
study intervention under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation.  The 
sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IRBs/ Independent Ethics Committees (IECs), and 
investigators.
Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
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An investigator who receives SUSARs or other specific safety information (eg, summary or 
listing of SAEs) from the sponsor will review and then file it along with the SRSD(s) for the 
study and will notify the IRB/IEC, if appropriate according to local requirements.
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Pregnancies of a partner should be recorded using the Pregnancy Initial Report Form. 
Pregnancies should be followed until final outcome is known. All follow-up for a pregnancy 
should be submitted on a Pregnancy Follow-up Report Form.
8.3.5.1. Exposure During Pregnancy (EDP)

Details of all pregnancies in female partners of male participants will be collected after 
the start of study intervention and until end of study participation.

If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4
(Section 10.4). 

Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs.
8.3.5.2. Exposure During Breastfeeding
Not Applicable for this study.
8.3.5.3. Occupational Exposure
An occupational exposure occurs when a person receives unplanned direct contact with the 
study intervention, which may or may not lead to the occurrence of an AE.  Such persons 
may include healthcare providers, family members, and other roles that are involved in the 
trial participant’s care.
The investigator must report occupational exposure to Pfizer Safety within 24 hours of the 
investigator’s awareness, regardless of whether there is an associated SAE.  The information 
must be reported using the CT SAE Report Form.  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.
8.3.6. Cardiovascular and Death Events
Not applicable for this study.
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
Bleeding episodes as part of the natural history of severe hemophilia are not reported as AEs.
8.3.7.1. Lack of Efficacy
Lack of efficacy is reportable to Pfizer Safety only if associated with an SAE.
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8.3.8. Medication Errors
Medication errors may result from the administration or consumption of the study 
intervention by the wrong participant, or at the wrong time, or at the wrong dosage strength.  
Exposures to the study intervention under study may occur in clinical trial settings, such as 
medication errors.
Safety Event
Recorded on the CRF
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
Medication errors include:

Medication errors involving participant exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating 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. Treatment of Overdose
For this study, any dose of SB-525 (PF-07055480) greater than the intended dose for the 
participant will be considered an overdose.
Sponsor does not recommend specific treatment for an overdose.
In the event of an overdose, the investigator/treating physician should:
1. Contact the medical monitor immediately.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities.
3. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
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4. Overdose is reportable to Safety only when associated with an SAE.
8.5. Pharmacokinetics
8.5.1. AAV2/6 Vector Shedding
AAV2/6 genome in plasma, saliva, urine, stool, and semen by polymerase chain reaction 
(PCR) will be assessed as described in the SoA (Table 1). On Day 0, vector genome titer 
should be obtained in plasma only at 12 hours from the start of the infusion ±1 hour.
After Week 12, collection will only continue until three consecutive negative samples are 
obtained on a sample-type basis (Weeks 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 [±1 week] 
and every 1 month after Week 52 to Month 60 [±1 month]).  For example, after urine sample 
results are negative 3 consecutive times, the urine sample will stop being collected while the 
other samples may continue to be collected if they continue to be positive.
8.6. Pharmacodynamics
Blood samples will be drawn to further explore the study drug mechanism of action and 
immune responses. These may include, but are not limited to, sEGFR, Gal3BP, von 
Willebrand factor (vWF), FVIII antigen levels, IL6 and CRP as specified in the SoA 
(Table 1).
At each visit where vWF is planned, one plasma sample will also be banked to allow for any 
additional exploratory assessments.
In addition, weekly assessments of FVIII antigen may be required if a participant is receiving 
steroids or develops an inhibitor or if warranted by changes in FVIII activity.
Blood samples will be collected and processed according to the instructions provided in the 
laboratory manual.
8.7. Genetics
FVIII gene sequencing will be performed at screening but only for participants with no prior 
FVIII sequencing.
A blood sample for DNA isolation will be collected.  In the event of DNA extraction failure, 
a replacement genetic blood sample may be requested from the participant.
See Appendix 5 for information regarding genetic research.  Details on processes for 
collection and shipment and destruction of these samples can be found in the Laboratory 
Manual.
8.7.1. Specified Genetics
Genetics (specified analyses) are not evaluated in this study.
8.8. Biomarkers
Biomarkers are not evaluated in this study.
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8.9. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
9. STATISTICAL CONSIDERATIONS
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.
9.1. Estimands and Statistical Hypotheses
There are no statistical hypotheses and estimands needed for this study.
9.2. Sample Size Determination
This study will enroll approximately 20 participants. Participants who do not complete at 
least 12 months of the study may be replaced, except participants who experience toxicity 
due to AEs considered related to study drug and discontinue the study for that reason. These 
latter participants will not be replaced. In addition, participants who experience transaminitis 
resulting in loss of efficacy prior to week 4 will not be used to determine dose cohort 
assignment for subsequent participants. As this is an adaptive design study, the number of 
participants to be treated at any given dose level will be determined by the available efficacy 
and safety data in proceeding participants and will not be based on statistical calculations.
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9.3. Analysis Set
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled
All participants who sign the ICF and meet all 
inclusion/exclusion criteria.
Safety
All participants enrolled in this study who receive any 
portion of study drug and have at least one post-baseline 
safety assessment will be included in the safety population. 
All participants who enrolled in the study and received the 
study intervention. 
Evaluable
All participants enrolled in the study and take the full dose 
of study intervention and no significant interruption of 
efficacy measurement.
9.4. Statistical Analyses
All analyses of safety will be performed on the safety population, and participants will be
analyzed according to the actual treatment they received.  Efficacy analyses will be 
performed using descriptive methods.  No formal statistical analysis of study data is planned.
The SAP will be developed and finalized before database lock and will describe the 
participant populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data.  This section is a summary of the planned statistical 
analyses of the primary and secondary endpoints.  
9.4.1. Primary Endpoints Analyses
Safety analyses will be performed on data from all participants in the Safety Population.
The incidence of AEs and SAE will be tabulated by dose and overall across dose groups. The 
rate of occurrence for each adverse event will be summarized by body system, severity, and 
relation to the administration of PF-07055480. All serious adverse events will be summarized 
separately.  
Additional descriptive analyses to support the primary endpoint will include changes from 
baseline in clinical laboratory variables (including FIX inhibitor and laboratory parameters 
for thrombotic potential), vital signs, and vector shedding analysis. 
The time course profile of FVIII activity will be determined by measuring changes in 
circulating FVIII activity.
9.4.2. Secondary Endpoints Analyses
The clinical impact on hemophilia after dosing with SB-525 (PF-07055480) will be 
determined from the summarization of the change from baseline in the use of FVIII 
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replacement therapy and the frequency and severity of bleeding episodes.  Changes from 
baseline in the EQ-5D-5L will also be summarized.
The immune response to SB-525 (PF-07055480) will be evaluated from the summarization 
of FVIII inhibitor levels.  Summarization of vector shedding data will include vector DNA 
detection by PCR in plasma, saliva, urine, stool, and semen. 
9.4.3. Exploratory Endpoints Analyses
The impact of potentially relevant circulating factors on FVIII activity will be assessed by 
summarization of vWF, CRP, IL6, and FVIII antigen.  Immune response will be studied by 
measuring neutralizing activity and antibodies to AAV2/6, as well as Interferon-gamma 
ELISPOT.
Change from the preceding year values may be calculated for selected clinical and laboratory 
parameters.  Shift-tables (change-from-baseline relative to the normal range) may be 
constructed for selected laboratory parameters.  Participants will continue to be followed for 
years 2 through 5 to gain additional data on safety and durability of effect.
Details for additional exploratory endpoint analyses (eg. optional liver biopsy) will be 
provided in the SAP.
9.5. Interim Analyses
An interim analysis of safety and efficacy data will be conducted at 1 year after the last 
enrolled participant receives SB-525 (PF-07055480) infusion.  As this is an open-label study, 
the sponsor may conduct unblinded reviews of the data during the course of the study for the 
purpose of safety assessment, facilitating dose-escalation decisions, facilitating 
pharmacokinetic (PK)/pharmacodynamic (PD) modeling, and/or to support clinical 
development.
9.6. Data Monitoring Committee
This study will use an external data monitoring committee (DMC).  The DMC is independent 
of the study team and includes only external members.  The DMC will convene 
approximately every 6 months until study completion to monitor the safety and efficacy of 
the participants.  Ad-hoc meetings will be organized as needed (eg, to assess events of 
special interest or after receipt of a SUSAR).  
The DMC will be responsible for ongoing monitoring of the efficacy and safety of 
participants in the study according to the charter.  The recommendations made by the DMC 
to alter the conduct of the study will be forwarded to the appropriate Pfizer personnel for 
final decision.  Pfizer will forward such decisions, which may include summaries of 
aggregate analyses of endpoint events and of safety data that are not endpoints, to regulatory
authorities, as appropriate.
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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. 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 Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be reviewed and approved by the sponsor and 
submitted to an IRB/IEC by the investigator and reviewed and approved by the IRB/IEC 
before the study is initiated.
Any amendments to the protocol will require IRB/IEC 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/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC

Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations
10.1.1.1. 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 
information that might influence the evaluation of the benefits and risks of the study 
intervention, Pfizer should be informed immediately.
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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.
10.1.2. Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate 
financial information as requested to allow the sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the study 
and for 1 year after completion of the study.
10.1.3. Informed Consent Process
The investigator or his representative will explain the nature of the study to the participant 
and answer all questions regarding the study.  The participant should be given sufficient time 
and opportunity to ask questions and to decide whether or not to participate in the trial.
Participants must be informed that their participation is voluntary.  Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, privacy and data protection requirements, where 
applicable, and the IRB/EC or study center.
The investigator must ensure that each study participant is fully informed about the nature 
and objectives of the study, the sharing of data related to the study, and possible risks 
associated with participation, including the risks associated with the processing of the 
participant’s personal data. 
The participant must be informed that his personal study related data will be used by the 
sponsor in accordance with local data protection law.  The level of disclosure must also be 
explained to the participant.
The participant must be informed that his medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant is fully informed about his 
right to access and correct his or her personal data and to withdraw consent for the processing 
of his or her personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained.  
The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the IRB/EC-approved ICD(s) 
during their participation in the study as required per local regulation.
A copy of the ICD(s) must be provided to the participant.
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Participants who are rescreened are required to sign a new ICD.
10.1.4. 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 
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 his or her actual identity and medical record identification.  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 standard operating procedures on how to respond in the event of 
unauthorized access, use, or disclosure of sponsor information or systems.
10.1.5. Dissemination of Clinical Study Data
Data or results generated in the performance of the study may be used by sponsor for any 
purpose, including in registration documents for regulatory authorities in the US or abroad, 
or for public dissemination in the form of papers, abstracts, posters, or other informational 
materials to be presented at scientific meetings, or published in professional journals, or as a 
part of an academic thesis. Sponsor shall have the right to first publication of the data or 
results of the study, which is intended to be a joint, multi-center publication of the study 
results made by sponsor in conjunction with the investigators from all appropriate 
investigational sites contributing data, analysis and comments.  Authorship of multi-center 
publications resulting from this study will be based on customary standards for attribution of 
authorship taking into consideration factors such as significance of contribution to the design 
of the study, analysis and interpretation of the data, and critical review of the publication. 
Subsequent to the first publication of the study results by sponsor, the investigator may 
publish the site-specific data or results. If the investigator wishes to publish the 
investigator’s site specific data or results, a copy of such proposed publications, papers, 
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abstracts, or other written materials or an outline of any proposed oral presentations, shall be 
submitted to sponsor for review at least 60 days (or other number of days agreed to in the 
applicable clinical trial agreement governing the conduct of the study at the investigator’s 
site) prior to submission of such written materials for publication, or any proposed oral 
presentation.  Sponsor shall have the right to review and comment on such written material or 
outline, and to confirm the accuracy of the data described therein by comparison with that 
collected during the course of this study. In addition, sponsor may require investigator to, 
and investigator will, remove specifically identified confidential information of sponsor 
(other than the data or results of the study) and/or delay the proposed publication for an 
additional 60 days (or other number of days agreed to in the applicable clinical trial 
agreement governing the conduct of the study at the investigator’s site) to enable sponsor to 
file patent applications.
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 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
Pfizer posts clinical trial US Basic results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in participants) 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 all 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 
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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 patient-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 available data from these trials 
18 months after study completion.  Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations.  CSRs will have personally identifiable information 
redacted.
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.
10.1.6. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF
(eCRF) unless transmitted to the sponsor or designee electronically (eg, laboratory data). 
The investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.
Guidance on completion of CRFs will be provided in the CRF Completion Requirements 
document.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic and/or paper form and are password protected or secured in a locked room to 
prevent access by unauthorized third parties.
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source records and documents. 
This verification may also occur after study completion.  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.
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are provided in the Study 
Monitoring Plan.
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
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Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed during 
the retention period without the written approval of the sponsor.  No records may be 
transferred to another location or party without written notification to the sponsor.  The 
investigator must ensure that the records continue to be stored securely for so long as they are 
maintained.
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.
The investigator(s) will notify sponsor or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with 
sponsor or its agents to prepare the investigator site for the inspection and will allow sponsor 
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 sponsor or its agent.  Before response submission to the regulatory 
authorities, the investigator will provide sponsor or its agents with an opportunity to review 
and comment on responses to any such findings.
10.1.7. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator site.
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained.  The 
investigator may need to request previous medical records or transfer records, depending on 
the study.  Also, current medical records must be available.
Definition of what constitutes a source document can be found in the data review plan.
Description of the use of computerized system is documented in the data management plan.
Study Documentation
The investigator and study staff are responsible for maintaining a comprehensive and 
centralized filing system containing all study-related documentation. These files must be 
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suitable for inspection by the sponsor or the FDA at any time and should consist of the 
following elements:
a) Participant files containing the completed medical records, supporting source 
documentation, eCRFs and the IRB approved Informed Consent signed by 
participants.
b) Study files containing all versions of the IRB approved protocol with all amendments, 
IRB approved informed consent forms, copies of all pre-study documentation, 
Form FDA 1572 and all correspondence to and from the IRB and the sponsor.
c) The investigator should maintain a list of appropriately qualified persons who are 
delegated to perform significant study-related studies. In addition, the investigator 
should maintain a signature sheet to document signatures and initials of all persons 
authorized to make entries and/or corrections on the source documents and electronic 
case report forms.
Record Retention
According to 21 CFR 312.62(c), the investigator shall retain records required to be 
maintained under this part for a period of 2 years following the date a marketing application 
is approved for the drug for the indication for which it is being investigated. If no application 
is to be filed or if the application is not approved for such indication, the investigator shall 
retain these records until 2 years after the investigation is discontinued and the FDA is 
notified. These documents should be retained for a longer period, however, if required by the 
applicable regulatory requirements or by an agreement with sponsor. It is the responsibility 
of sponsor to inform the investigator as to when these documents no longer need to be 
retained.
10.1.8. Study and Site Start and Closure
The study start date is the date of the first participant’s first visit.
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor, including (but not limited to) 
regulatory authority decision, change in opinion of the IRB/EC, or change in benefit-risk 
assessment.  Study sites will be closed upon study completion.  A study site is considered 
closed when all required documents and study supplies have been collected and a study-site 
closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the sponsor 
or designee/CRO if requested to do so by the responsible IRB/EC or if such termination is 
required to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or GCP guidelines;
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
Inadequate recruitment of participants by the investigator;

Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the ECs/IRBs, the regulatory authorities, and any CRO(s) used in the study of 
the reason for termination or suspension, as specified by the applicable regulatory 
requirements.  The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Study termination is also provided for in the clinical study agreement.  If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.
10.1.9. Publication Policy
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.
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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10.1.10. 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 ISF. 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card.  The contact card 
contains, at a minimum, protocol and study intervention identifiers, 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.  For sites other than 
a Pfizer CRU, 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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10.2. Appendix 2: Clinical Laboratory Tests
The following safety and efficacy laboratory tests will be performed at times defined in the 
SoA (Table 1).  
Additional laboratory results may be reported on these samples as a result of the method of 
analysis or the type of analyzer used by the clinical laboratory, or as derived from calculated 
values.  These additional tests would not require additional collection of blood.  Unscheduled 
clinical laboratory measurements may be obtained at any time during the study to assess any 
perceived safety issues.
The tests detailed below will be performed by the Central Laboratory (CL) unless otherwise 
indicated Local Laboratory (LL).
Hematology (CBC with Differential and Platelet Count) - Safety
Platelet Count
RBC Indices:
Automated WBC Differential 
(absolute and percent):
RBC Count
MCV
Neutrophils
WBC Count (absolute) 
MCH
Lymphocytes
Hemoglobin
MCHC
Monocytes
Hematocrit
Eosinophils
Reticulocytes 
Basophils
Clinical Chemistry - Safety 
Serum Chemistry
Liver Function Tests (CL and LL)
Blood Urea Nitrogen
AST (SGOT)
Creatinine
ALT (SGPT)
Glucose 
GGT
Sodium
Alkaline phosphatase
Potassium
Total and direct bilirubin
Chloride
Total CO2
Calcium, Magnesium, 
Phosphate
Uric Acid
Albumin
Total Protein
Lactate dehydrogenase
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Factor VIII activity (CL and LL)
Central FVIII activity assessed by both chromogenic and one-stage assays
Local FVIII activity assessed by chromogenic or one-stage assays
Immunogenicity
Anti-AAV2/6 antibodies (neutralizing and total)
FVIII inhibitor testing
T-cell responses specific to AAV2/6 and FVIII by ELISPOT assay
Vector Shedding
Detection of AAV2/6 vector by PCR in plasma, saliva, urine, stool and semen
Urinalysis - Safety 
Specific gravity
pH, glucose, protein, blood and ketones
Blood or protein if >trace positive
Microscopic exam if macroscopic blood or protein is small (1+), moderate (2+), or large 
(3+)
Exploratory Parameters
Study drug mechanism of action and immune responses: including but not limited to 
IL6, CRP, soluble epidermal growth factor receptor (sEGFR), galectin-3-binding 
protein (Gal3BP), C-reactive protein (CRP)
FVIII antigen
vWF
Other Parameters
HIV RNA viral load and HIV 1/2 antibody assay - screening only
Hepatitis B panel, hepatitis C virus antibody, and HCV RNA viral load – screening only
Coagulation parameters: PT, aPTT, INR
Circulating alpha fetoprotein 
FVIII gene sequencing
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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1. Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered 
related to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator.  Any abnormal laboratory test 
results that meet any of the conditions below must be recorded as an AE:

Is associated with accompanying symptoms.

Requires additional diagnostic testing or medical/surgical intervention.

Leads to a change in study dosing (outside of any protocol-specified dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy.

Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drugdrug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.  Overdose per se will not be reported as an 
AE/SAE unless it is an intentional overdose taken with possible suicidal/selfharming 
intent.  Such overdoses should be reported regardless of sequelae.
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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads 
to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
10.3.2. Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Death
b.
Is life-threatening
An AE in which the participant was at risk of death at the time of the event; it does not 
refer to an event which hypothetically might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
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d.
Results in persistent disability/incapacity
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition.  These events 
should usually be considered serious.

Examples of such events include invasive or malignant cancers, 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.
10.3.3. Recording/Reporting and Follow-Up of AE and/or SAE
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording AEs on the CRF and for 
reporting SAEs on the Clinical Trial (CT) SAE Report Form to Pfizer Safety.  These 
requirements are delineated for 3 types of events: (1) SAEs; (2) non-serious adverse events 
(AEs); and (3) exposure to the study intervention under study during pregnancy or 
breastfeeding, and occupational exposure.  
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 CRF.  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 CRF and the CT SAE Report 
Form for reporting of SAE information.
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Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Sponsor 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Non-serious AE

Until Month 36: All

After Month 36: only 
AEs related to the study 
drug, or AEs with 
an unknown cause 
None
Exposure to the study 
intervention under study 
during pregnancy or 
breastfeeding, and 
occupational exposure
None
All (And EDP supplemental 
form for EDP)  
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostic reports) 
related to the event.
The investigator will then record all relevant AE/SAE information in the CRF.
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to Pfizer Safety in lieu of completion of the CT SAE Report Form/AE/SAE CRF 
page.
There may be instances when copies of medical records for certain cases are requested by 
Pfizer Safety.  In this case, all participant identifiers, with the exception of the participant 
number, will be redacted on the copies of the medical records before submission to Pfizer 
Safety.
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information.  Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
Intensity will be categorized by toxicity grade according to the Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.03.
AEs not listed in the CTCAE version 4.03 will be evaluated by using the following criteria: 

Grade 1, Mild: Symptoms causing no or minimal interference with usual social & 
functional activities;
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
Grade 2, Moderate: Symptoms causing greater than minimal interference with usual 
social & functional activities;

Grade 3, Severe: Symptoms causing inability to perform usual social & functional 
activities;

Grade 4, Potentially Life-threatening: Symptoms causing inability to perform basic self-
care functions OR medical or operative intervention indicated to prevent permanent 
impairment, persistent disability, or death;

Grade 5: For any AE where the outcome is death.
All Grade 3 and 4 clinical laboratory results that represent an increase in severity from 
baseline will be reported as AEs if not associated with a diagnosis already reported on the 
CRF. A Grade 1 or 2 clinical laboratory abnormality should be reported as an AE only if it 
is considered clinically significant by the investigator.
Assessment of Causality
Any AE that does not meet the definition of a suspected AE reaction will be categorized as 
Not Related.

The investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot be 
ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.

The investigator will also consult the Investigator’s Brochure and/or Product 
Information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to sponsor. However, it is very important 
that the investigator always make an assessment of causality for every event before 
the initial transmission of the SAE data to sponsor.
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
The investigator may change his/her opinion of causality in light of follow-up 
information and send a SAE follow-up report with the updated causality assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

If the investigator does not know whether or not the study intervention caused the event, 
then the event will be handled as “related to study intervention” for reporting purposes, 
as defined by the sponsor.  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 CRF, and report such an assessment in the dedicated section 
of the CT SAE Report Form and in accordance with the SAE reporting requirements.
Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.

If a participant dies during participation in the study or during a recognized follow-up 
period, the investigator will provide sponsor with a copy of any postmortem findings 
including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor within 24 hours of 
receipt of the information.
10.3.4. Reporting of SAEs
SAE Reporting CT SAE Report Form

Facsimile transmission of the CT SAE Report Form is the preferred method to transmit 
this information to Pfizer Safety.

In circumstances when the facsimile is not working, notification by telephone is 
acceptable with a copy of the CT SAE Report Form sent by overnight mail or courier 
service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated reporting 
time frames.
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10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information
To avoid the transmission of vector-related material and pregnancy, all sexually active 
participants are required to 1 of the following acceptable forms of contraceptives during the 
study until at least 3 consecutive post-treatment semen samples are negative for AAV2/6 and 
for a minimum of 90 days after SB-525 (PF-07055480) administration:

Double barrier contraceptive including use of a condom plus one other form of 
contraception used by the participant or partner (eg, vasectomy, intrauterine device 
[IUD], birth control pills, and diaphragm with spermicide).

A condom must be used for any form of sexual activity to prevent the transmission of 
vector-related material.

Sexual abstinence.
Pregnancies of a partner should be recorded using the Pregnancy Initial Report Form.  
Pregnancies should be followed until final outcome is known.  All follow-up for a pregnancy 
should be submitted on a Pregnancy Follow-up Report Form.  
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10.5. Appendix 5: Genetics
Use/Analysis of DNA

Genetic variation may impact a participant’s response to study intervention, susceptibility 
to, and severity and progression of disease. Therefore, where local regulations and 
IRB/IEC allow, a blood sample will be collected for DNA analysis.

The results of genetic analyses may be reported in the CSR or in a separate study 
summary, or may be used for internal decision-making without being included in a study 
report.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.
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10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments
Potential Cases of Drug Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors”.  In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome.  These participants fail to adapt and therefore are 
“susceptible” to progressive and serious liver injury, commonly referred to as drug-induced 
liver injury (DILI).  Participants who experience a transaminase elevation above 3 × ULN
should be monitored more frequently to determine if they are an “adaptor” or are 
“susceptible”.
In the majority of DILI cases, elevations in AST and/or ALT precede total bilirubin (TBili) 
elevations (>2 × ULN) by several days or weeks.  The increase in TBili typically occurs 
while AST/ALT is/are still elevated above 3 × ULN (ie, AST/ALT and TBili values will be 
elevated within the same lab sample).  In rare instances, by the time TBili elevations are 
detected, AST/ALT values might have decreased.  This occurrence is still regarded as a 
potential DILI.  Therefore, abnormal elevations in either AST OR ALT in addition to TBili 
that meet the criteria outlined below are considered potential DILI (assessed per Hy’s law 
criteria) cases and should always be considered important medical events, even before all 
other possible causes of liver injury have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions.  Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:

Participants with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value >2 × ULN 
with no evidence of hemolysis and an alkaline phosphatase value <2 × ULN or not 
available;

For participants with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:
a.
Preexisting AST or ALT baseline values above the normal range: AST or ALT values 
>2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is smaller).
b. Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches >3 × ULN 
(whichever is smaller).
Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor. The participant 
should return to the investigator site and be evaluated as soon as possible, preferably within 
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48 hours from awareness of the abnormal results.  This evaluation should include laboratory 
tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT and TBili for suspected cases of 
Hy’s law, additional laboratory tests should include albumin, CK, direct and indirect 
bilirubin, GGT, PT/INR, total bile acids, and alkaline phosphatase.  Consideration should 
also be given to drawing a separate tube of clotted blood and an anticoagulated tube of blood 
for further testing, as needed, for further contemporaneous analyses at the time of the 
recognized initial abnormalities to determine etiology.  A detailed history, including relevant 
information, such as review of ethanol, acetaminophen/paracetamol (either by itself or as a 
coformulated product in prescription or over-the-counter medications), recreational drug, 
supplement (herbal) use and consumption, family history, sexual history, travel history, 
history of contact with a jaundiced person, surgery, blood transfusion, history of liver or 
allergic disease, and potential occupational exposure to chemicals, should be collected.  
Further testing for acute hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary 
tract) and collection of serum samples for acetaminophen/paracetamol drug and/or protein 
adduct levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the LFT abnormalities has yet been found.  Such potential DILI (Hy’s law) 
cases are to be reported as SAEs, irrespective of availability of all the results of the 
investigations performed to determine etiology of the LFT abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.
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10.7. Appendix 7: Safety Monitoring and Mitigation Plan
The liver function (AST, ALT, bilirubin, alkaline phosphatase, and GGT) of study 
participants will be monitored closely throughout the study. 
Based on preclinical evidence, SB-525 (PF-07055480) has the potential to deliver effective 
FVIII activity at low administered AAV doses, thus avoiding the transaminitis observed with 
other gene therapy products at higher AAV doses. For this reason, routine steroid 
prophylaxis is not planned for initial doses or any dose levels. This study, however, will 
closely monitor LFT (at least twice weekly through the second LTF determination during 
Week 20 following dosing) and FVIII activity (at least weekly for through Week 20) after 
dosing to assess for any potential transaminitis and/or effects on FVIII activity. Steroid 
treatment will be initiated (recommended: prednisone 60 mg daily or equivalent) in any 
participant who experiences an ALT increase >1.5 × baseline level after dosing with SB-525 
(PF-07055480). Note that the baseline ALT levels will be determined by the central 
laboratory with subsequent LFTs (ALT and AST at a minimum) performed by the local 
laboratories for safety. Additionally, steroid treatment may not be initiated if medically 
contraindicated.
In the case of ALT elevation requiring steroid, LFTs will continue to be followed twice 
weekly, and steroids will continue to be dosed until the ALT value has stabilized (3
consecutive values under the ULN with no increase of ALT). At that point, if steroids were 
taken for more than 3 weeks, a steroid taper, with close laboratory monitoring, can be 
initiated per the following table:
Week 1
Week 2
Week 3
Week 4
Prednisone
60 mg/day
30 mg/day
15 mg/day
5 mg/day
The steroid taper can be halted and the dosing reverted at any time to a higher prednisone 
dose if the 3 consecutive values of ALT are not decreasing to baseline and/or ALT values are 
above the ULN. If 3 consecutive values are below the ULN but have not fully returned to 
baseline, the taper can continue after discussion with the medical monitor. Refer to SoA
Table (Table 1).
Routine steroid prophylaxis will be considered for all current and future dose levels if ALT 
elevation is observed in 2 participants above 1.5 × ULN, or, above 5 × ULN in 1 participant.
DMC will be contacted or convened appropriately. The regulatory authorities will be 
notified and will review plans if prophylaxis implementation is planned. Note that while 
ALT changes from baseline will guide decisions to initiate steroid therapy within an 
individual, changes above the ULN will guide criteria to convene the DMC or decide future 
prophylactic steroid recommendations. If warranted, the prophylactic steroid regimen would 
be defined by the DMC in concert with the sponsor.
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10.8. Appendix 8: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as Adverse Events

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >280 msec.

New prolongation of QTcF to >480 msec (absolute) or by 60 msec from baseline.

New-onset atrial flutter or fibrillation, with controlled ventricular response rate: ie, 
rate <120 bpm.

New-onset type I second-degree (Wenckebach) AV block of >30 seconds’ 
duration.

Frequent PVCs, triplets, or short intervals (<30 seconds) of consecutive ventricular 
complexes.
ECG Findings That May Qualify as Serious Adverse Events

QTcF prolongation >500 msec.

New ST-T changes suggestive of myocardial ischemia.

New onset left bundle branch block (QRS >120 msec).

New onset right bundle branch block (QRS >120 msec).

Symptomatic bradycardia. 

Asystole:

In awake, symptom free patients in sinus rhythm, with documented periods of 
asystole 3.0 seconds or any escape rate <40 bpm, or with an escape rhythm 
that is below the AV node; 

In awake, symptom free patients with atrial fibrillation and bradycardia with 1 
or more pauses of at least 5 seconds or longer; 

Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm.

Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute).

Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm (heart 
rate <40 bpm), accelerated idioventricular rhythm (HR 40 bpm to <100 bpm), and 
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monomorphic/polymorphic ventricular tachycardia (HR >100 bpm (such as 
torsades de pointes)).

Type II second -degree (Mobitz II) AV block.

Complete (third degree) heart block.
ECG Findings That Qualify as Serious Adverse Events

Change in pattern suggestive of new myocardial infarction. 

Sustained ventricular tachyarrhythmias (>30 seconds’ duration).

Second or third degree AV block requiring pacemaker placement.

Asystolic pauses requiring pacemaker placement.

Atrial flutter or fibrillation with rapid ventricular response requiring cardioversion.

Ventricular fibrillation/flutter.

At the discretion of the investigator, any arrhythmia classified as an adverse 
experience.
The enumerated list of major events of potential clinical concern are recommended as “alerts” or 
notifications from the core ECG laboratory to the investigator and Pfizer study team, and not to be 
considered as all inclusive of what to be reported as AEs/SAEs.
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10.9. Appendix 9: Abbreviations
Abbreviation
Definition
AAV
adeno-associated virus
AAV2/6
adeno-associated vector 2/6
AE
adverse event
ALT
alanine transaminase
aPTT
activated partial thromboplastin time
AST
aspartate transaminase
BDD
B-domain deleted
BP
blood pressure
bpm
beat(s) per minute
CBC
complete blood count
cDNA
complementary deoxyribonucleic acid
CIOMS
Council for International Organizations of Medical Sciences
CL
central laboratory
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
Corona Virus Disease 2019
CRF
case report form
CRO
Contract Research Organization
CRP
C-reactive protein
CRU
clinical research unit
CSR
clinical study report
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DILI
drug-induced liver injury
dL
deciliter
DLT
dose limiting toxicity
DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
ECG
electrocardiogram
eCRF
electronic case report form
EDP
exposure during pregnancy
ELISA
enzyme-linked immunosorbent assay
ELISPOT
enzyme-linked immunospot
EMA
European Medicines Agency
EOS
end of study
EQ-5D-5L
EuroQol, 5 Dimensions, 5 Levels
ETV
Early Termination Visit
EU
European Union
EudraCT
European Clinical Trials Database
F8
Factor 8 gene
FDA
US Food and Drug Administration
FVIII
Factor VIII
FIX
Factor IX clotting protein
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Abbreviation
Definition
Gal3BP
Galectin-3-binding protein
GCP
Good clinical practice
GGT
gamma-glutamyl transferase
HCC
Hepatocellular carcinoma
HCV
hepatitis C virus
hF8
human F8 gene
HIV
human immunodeficiency virus
HR
heart rate
ICD
informed consent document (synonymous with ICF)
ICF
informed consent form
ICH
International Council on Harmonisation
IEC
Independent Ethics Committee
IL
interleukin
IMP
Investigational medicinal product
IND
Investigational New Drug
INR
International Normalized Ratio
IP
investigational product
IRB
Institutional Review Board
IRT
interactive response technology
ISF
investigator site file
ITR
inverted terminal repeat
IU
international units
IUD
intrauterine device
IV
intravenous
IVRS/IWRS
Interactive Voice Response System/Interactive Web Response System
LFT
liver function tests
LL
Local Laboratory
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MRI
magnetic resonance imaging
N/A
Not Applicable
NHP
non-human primates
NIMP
noninvestigational medicinal product
NSAIDs
non-steroidal anti-inflammatory drugs
OHR
Office for Human Research
PACL
Protocol Administrative Change Letter
PCR
polymerase chain reaction
PD
pharmacodynamics(s)
PK
pharmacokinetic(s)
PT
prothrombin time
PVC
Polyvinyl chloride
QTcF
corrected QT (Fridericia method)
rAAV
recombinant adeno-associated viral vector
RBC
red blood cell
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Abbreviation
Definition
RNA
ribonucleic acid
RR
respiratory rate
SAE
serious adverse event
SAP
Statistical Analysis Plan
SBP
systolic blood pressure
sEGFR
soluble epidermal growth factor receptor
SGOT
serum glutamic-oxaloacetic transaminase
SGPT
serum glutamic-pyruvic transaminase
SMC
Safety Monitoring Committee
SoA
schedule of activities
SOP
standard operating procedure
SP
signal peptide
SRSD
single reference safety document
SUSAR
suspected unexpected serious adverse reaction
TBili
total bilirubin
ULN
upper limit of normal
US
the United States
Vg
vector genome
vWF
von Willebrand factor
WBC
white blood cell
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10.10. Appendix 10: Instruction for Tissue Sample Collection and Tissue Preparation
In the event that certain findings occur in the liver or in other tissues (eg,.any participant who 
has an elevated alpha fetoprotein and MRI mass suspicious for HCC or greater than 2 cm),
the investigator may recommend a liver biopsy or tissue collection (using surgical doses of 
Factor VIII replacement, if needed). Local histopathologic examination and central genomic 
analysis (eg, integration site sequencing analysis) will be performed.
For liver biopsy substudy, please refer to section 8.2.14. 
Also refer to the Laboratory manual for liver biopsy collection and processing. 
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10.11. Appendix 11: Document History 
Document
Version 
Date
Summary of Changes and Rationale
Amendment 
4
05-May-
2020
The duration of study was extended to 5 years from a 3-year 
study, requiring 2 additional study visits (Months 48 and 60), 
to ensure appropriate long-term follow-up of participants after 
study intervention in line with the FDA and EMA 
recommendations for duration of long-term follow-up 
observations for AAV vectors. As a result of this extension, 
the protocol was updated to include:
o
Two additional site visits added at Month 48 
and 60.
o
Additional visits (remote or onsite) for 
laboratory assessments of liver panel, FVIII 
activity and FVIII inhibitor titer, every 
6 months from Week 52 to Month 60.
o
A requirement for interim follow-up contacts 
(phone calls), between yearly visits (at Months 
30, 42 and 54), were added in the protocol to 
review general health status, including safety 
and bleeding episodes, as well as any FVIII 
concentrate usage. However, those follow-up 
phone contacts will not be required if they fall 
on the same day as a scheduled site visit.
o
From Month 36 through to the end of study 
(Month 60), only the following Adverse Events 
(AEs) and the associated concomitant 
medications will be actively collected:

Serious Adverse Events (SAEs);

Non-serious AEs determined to be 
related to study intervention by the 
investigator or where causality is 
unknown.
The requirement for an additional separate LTFU study was 
consequently removed from the protocol.
The following sections of the protocol have been modified 
with these changes:

Section 1.1 Synopsis

Section 1.2 Schema

Section 1.3 Schedule of Activities

Section 4.1.3 Early Termination

Section 4.4 End of Study Definition

Section 6.5 Concomitant Therapy
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Document
Version 
Date
Summary of Changes and Rationale

Section 8 Assessments and Procedures
In response to an EMA request to provide data on additional 
subjects at the highest dose defined as the pivotal Phase 3 
study dose, more than five (5) subjects may be enrolled per 
cohort, and more specifically in cohort 4. The following 
section of the protocol has been modified with this change:

Section 4.1.2 Treatment Period
The Sangamo Therapeutics Protocol Amendment 03 
document was transferred into the new Pfizer Protocol 
Template, and mandatory and/or recommended Pfizer 
protocol template language was adopted in all relevant 
sections as appropriate. This is a global change within the 
document. 
The following sections were included as part of the Pfizer 
protocol template:

Section 4.4 End of Study definition

Section 6.2 
Preparation/Handling/Storage/accountability

Section 6.3 Measures to minimize biais: 
Randomization and blinding

Section 6.4 Study Intervention Compliance

Section 6.6 Dose modification

Section 6.7 Intervention after the End of the Study

Section 7.1 Discontinuation of Study Intervention

Section 7.2.1 Withdrawal of consent

Section 7.3 Lost to Follow Up

Section 8.4 Treatment of Overdose

Section 8.9 Health Economics

Appendix 1 Regulatory, Ethical and Study Oversight 
Considerations

Appendix 3 Adverse Event definitions and Procedures 
for Recording, Evaluating, Follow-up, and Reporting

Appendix 5 Genetics

Appendix 6 Liver Safety: Suggested Actions and 
Follow-up Assessments - Potential Cases of Drug 
Induced Liver Injury

Appendix 8 ECG findings of Potential Clinical 
Concerns
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Document
Version 
Date
Summary of Changes and Rationale
As per Pfizer protocol template, the consequences in case of 
Study Discontinuation have been clarified. The following 
section of the protocol has been modified with this change:

Section 7.2 Participant Discontinuation/Withdrawal 
from the Study
The Protocol ID and study intervention nomenclature were 
also updated to reflect both the legacy and the Pfizer 
references as noted below. This is a global change within the 
document.

Protocol ID: SB-525-1603 (Pfizer reference: 
C3731001)

Study intervention reference: SB-525 (Pfizer 
reference: PF-07055480)
To align with the Phase 3 protocol (C3731003), the dosage 
will be calculated according to weight (i.e. vg/kg) except in 
situations where a participant’s BMI is > 30 kg/m2. In 
addition, the study intervention will be provided in 4.7 
ml/vial. The following section of the protocol has been 
modified with this change:

Section 6.1 Study Intervention(s) Administered
Some assessments initially done until W52 only have been 
added on an annual basis: ECG, EQ-5D-5L, vWF 
measurement and study drug antibodies (total and 
neutralizing) testing.
To reduce visits and related blood sampling, the frequency of 
LFT assessments for participants receiving steroids was 
decreased from twice weekly to once a week, if 3 consecutive 
results demonstrate stable liver function. The following 
section of the protocol has been modified with this change:

Section 1.3 Schedule of Activities
The laboratory requirements for FVIII activity were updated 
to clarify that all samples collected from participants for FVIII 
activity levels will be analyzed by central and local 
laboratories. Methodologies for sample analysis for FVIII 
activity levels by the local and central laboratories were also 
included. The following sections of the protocol have been 
modified with these changes:

Section 1.3 Schedule of Activities

Section 8.1.1 Factor FVIII Activity
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Frequency of collection of the biological samples to evaluate 
shedding post-W52 has been clarified; from W52, samples 
will be collected on a monthly basis until 3 negative samples 
are obtained.

Section 1.3 Schedule of Activities

Section 8.5.1 AAV2/6 Vector Shedding
The primary and exploratory endpoints language was updated 
to provide clarity around the endpoints.  No changes were 
made to the study objectives. The following sections of the 
protocol have been modified with this change:

Section 1.1 Synopsis

Section 3 Objectives, Estimands and Endpoints
The Preclinical Studies summary text and the Benefit Risk 
Assessment text was deleted and the Investigators Brochure, 
which has the most up to date summaries, referenced in the 
protocol. The following sections of the protocol have been 
modified with this change:

Section 2.2.3 Preclinical Studies

Section 2.3 Benefit Risk Assessment
More information on the EQ-5D-5L questionnaire and on the 
e-Diary process were added. The following sections of the 
protocol have been modified

Section 8.1.2 Health Outcome Questionnaire

Section 8.1.3 Bleeding Episodes and FVIII 
Concentrates usage

Section 1.3 Schedule of Activities
The AAV2/6 Antibodies section was updated to differentiate 
between the samples collected at screening and samples 
collected after screening. Samples for neutralizing activity to 
AAV capsid proteins (neutralizing antibodies) will be 
collected at screening to determine eligibility for the study. 
Samples will also be collected to assess both total and 
neutralizing antibodies to AAV2/6 over time. The following 
sections of the protocol have been modified with this change:

Section 1.3 Schedule of Activities

Section 8.2.13.1 AAV2/6 Antibodies
All references to the Safety Monitoring Committee were 
updated to external Data Monitoring Committee to align with 
the Pfizer template language.  The following sections of the 
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protocol have been modified with this change and any 
reference to the SMC was replaced by DMC. The following 
section of the protocol has been modified with this change:

Section 9.6 Data Monitoring Committee
Pfizer safety process are followed from the date of the sponsor 
IND transfer in December 2019.  The following sections of 
the protocol have been modified with this change:

Schedule of Activities: AE assessment begins at time 
of signing ICD (ie, from the screening visit)

Section 8.3.4 Regulatory Reporting Requirements for 
SAEs

Section 8.3.5 Exposure During Pregnancy or 
Breastfeeding, and Occupational Exposure

Appendix 3 Adverse Events: Definitions and 
Procedures for Recording, Evaluating, Follow-up, and 
Reporting

Appendix 4 Contraceptive Guidance and Collection of 
Pregnancy Information
In addition, it was clarified that bleeding episodes should not 
be reported as an Adverse Event. The following section of the 
protocol was added:

Section 8.3.7 Disease-related Events and/or Disease-
related outcomes not qualifying as AEs or SAEs
The table of safety and efficacy laboratory tests was updated 
to include a complete list of samples to be collected and 
analyzed. No new laboratory tests were added to the table. 
When applicable, information about methods and frequency 
of these labs were removed from the in-text section and added 
to this table or to the SoA. Guidance on lab results review has 
been added as per Pfizer protocol template. The following 
sections of the protocol have been modified with this change:

Section 8.2.4 Clinical Laboratory Tests

Appendix 2 Clinical Laboratory Tests
The populations for analyses were revised and the Intent-To-
Treat population was removed since this population is the 
same as the safety population.  In addition, details on the 
primary analyses were provided. The following sections of the 
protocol have been modified with these changes:

Section 9.3 Analysis Set

Section 9.4.1 Primary Endpoints Analyses
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Protocol Administrative Changes and Clarifications related to 
the COVID-19 situation issued on 27 March 2020 was 
attached as an Appendix to this protocol amendment. The 
following section of the protocol was added:

Appendix 11: Protocol Administrative Changes and 
Clarifications
Amendment 
3
31-Jul-
2018
Protocol Amendment 3 was modified to add a higher dose of 
SB-525 based on newly available safety data from other 
studies and to provide clarity on inclusion and exclusion 
criteria, and details and timing of study assessments.  Key 
changes were summarized below:

Primary endpoints were updated to include SAEs.

Exploratory endpoints were updated.

Prohibited use of celecoxib was modified to only include 
high doses (>100 mg/day) in Concomitant Medications 
section.

Updated with additional dose levels in Dose and Rational 
for Dose Selection section.

Provided clarification on stopping rules.

Added the Screening and Baseline may be approximately 
10 weeks in duration.

Updated the footnotes in the Schedule of Activities table.
Amendment 
2
11-Oct-
2017
Key changes were summarized below:

Updated exploratory endpoints.

Updated #14 and #15 Exclusion Criteria, to add 
explanation that an MRI of the liver can be replaced by an 
abdomen CT-scan.

Administrative changes in several sections to get an earlier 
input from the Safety Monitoring Committee at every 
steps of the clinical study.

Clarified requirements for various procedures, including 
addition of HCV antibody, liver MRI footnote, Physical 
Exam, Liver Panel footnote, Vital Signs, and added 
procedure/footnote for Interferon-gamma ELISPOT. 
Amendment 
1
13-Jan-
2017
Protocol was updated to address FDA questions/comments.  
Key changes were summarized below:

Deleted “recombinant” in the Study Population section.

Removed predictions on FVIII levels, dose decisioning 
based only on participants’ cumulative data in Study 
Design section.

Dose escalation will not be permitted simultaneously, the 
protocol was revised accordingly in Study Design section.
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
Clarified participants will have different lengths of 
exposure for a given dose level in Dose Escalation Based 
on Safety section.

Details were added in the Sample Size section.
Original 
Protocol
16-Nov-
2016
Not applicable (N/A)
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10.12. Appendix 12: Protocol Administrative Changes and Clarifications
In response to the ongoing global pandemic COVID-19, and the increasing restrictions and 
concerns on public health, the following changes are being incorporated into the SB-525-
1603 (Pfizer reference: C3731001) protocol to clarify alternative solutions to accommodate 
study procedures during the COVID-19 pandemic.

In the event that the in-clinic study visit cannot be conducted, mobile phlebotomy should 
be used for the following assessments at the scheduled or unscheduled visits per the 
protocol Schedule of Event (Table 1):
o
Vital Signs
o
Blood drawing for the following parameters as applicable:

Circulating alpha fetoprotein level

CBC with differential and platelet count

Serum chemistry

Liver panel

Coagulation screen (PT, INR, and aPTT)

FVIII activity

FVIII antigen 

FVIII inhibitor titer

Von Willebrand Factor

Interferon-gamma ELISPOT

Pharmacodynamic/exploratory tests
o
Plasma, saliva, urine, stool and semen samples collection for AAV2/6 vector 
shedding if still required.

The EQ-5D-5L questionnaire can be self-administered by the study participant on his 
mobile phone if the study-recommended device cannot be used.

In addition, every effort should be made to follow-up the safety of study participants by 
phone contact.  Video contact can be used if permitted by local regulations.  During the 
phone (or video) contact, the following assessments should be performed:
o
Review and record any new concomitant medications or changes in concomitant 
medications since last contact;
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o
Review and record any AEs and SAEs since last contact, including but not limited to 
COVID-19 related events.  The AE and SAE reporting process should be followed 
per protocol;
o
Review bleeding episodes and FVIII concentrates usage reported in the e-diary.
Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described in the protocol.  However, it is anticipated that from time to time 
there may be circumstances outside the control of the investigator that may make it 
unfeasible to perform the test.  In these cases, the investigator must 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 the missed test and any corrective 
and preventive actions that he or she has taken to ensure that required processes are adhered 
to as soon as possible.  The study team must be informed of these incidents in a timely 
manner.
If the sponsor determines that the impact of COVID-19 on protocol visits and procedures and 
associated timeframe needs to be reported on a case report form (CRF), this will be 
requested.  In case of participant discontinuation, select the most appropriate status for 
discontinuation in the CRF; if the discontinuation is associated with the current COVID-19 
pandemic, enter “COVID-19” in the “Specify Status” field.
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11. REFERENCES
1.
http://www.hemophilia.org/About-Us/Fast-Facts
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