Phase 3, Open-Label, Single-Arm Study to Evaluate the Efficacy and Safety of PF-07055480 (Recombinant AAV2/6 Human Factor VIII Gene Therapy) in Adult Male Participants With Moderately Severe to Severe Hemophilia A(FVIII:C≤1%)
Phase: PHASE3
Conditions: Hemophilia A
Sponsor: Pfizer

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 1
TITLE PAGE
Protocol Title: Phase 3, Open-Label, Single-Arm Study to Evaluate the Efficacy and 
Safety of PF-07055480 (Recombinant AAV2/6 Human Factor VIII Gene Therapy) in 
Adult Male Participants with Moderately Severe to Severe Hemophilia A 
(FVIII:C≤1%)
Protocol Number: C3731003
Amendment Number: 10
Compound Number: PF-07055480 (formerly SB-525)
Study Phase: Phase 3
Short Title: Not applicable
Acronym: Not applicable
Sponsor Name: Pfizer, Inc.
Legal Registered Address: 66 Hudson Boulevard East, New York, NY 10001
Regulatory Agency Identifier Number(s)
Registry
NCT04370054
IND
BB-IND 17250
EudraCT
2019-004451-37
Approval Date: 28 September 2023
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.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 2
Medical Monitor Name and Contact Information 
Will be provided separately.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 3
Document History
Document 
Version Date
Amendment 10
28 September 2023
Amendment 9
03 February 2023
Amendment 8
21 November 2022
Amendment 7
26 May 2022
Amendment 6
13 January 2022
Amendment 5
13 May 2021
Amendment 4
09 April 2021
Amendment 3
12 Mar 2021
Amendment 2
09 December 2020
Amendment 1
13 May 2020
Original protocol
10 December 2019
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 10 (28 September 2023)
Overall Rationale for the Amendment: Changes in the Primary analysis to allow the 
inclusion of additional data to at least Month 15, according to feedback from regulatory 
agency: 
Description of Change
Brief Rationale
Section # and Name
Substantial Modification(s)
Modification of the main 
analysis for Total ABR to 
include all available data 
from Week 12 through at 
least Month 15 up to the 
primary analysis data cutoff. 
For consistency, the same 
change has been applied to 
the key secondary endpoint 
of ABR and the secondary 
endpoints of AIR, 
Annualized FVIII 
To support a 
comprehensive assessment 
of total ABR and other 
related endpoints, by 
increasing the time frame of 
included data, in line with 
regulatory feedback. There 
is no change to the timepoint 
for the primary analysis for 
the study.
1.1 Synopsis
2.1 Study rationale
3. Objectives, Estimands, 
and Endpoints
4.1 Overall design
9.1.1. Estimands
9.4.1. Efficacy analysis
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 4
Description of Change
Brief Rationale
Section # and Name
consumption, ABR of 
specific type, Total ABR by 
cause and by location and 
Percentage of participants 
without bleeds.
Updated required wash-out 
period for extended half-life 
FVIII product from 96h to 
120h before testing of FVIII 
activity, FVIII inhibitors and 
hemostasis and 
thrombophilia-related 
factors. Similar rules have 
been applied for the 
statistical analysis of FVIII 
activity-related endpoints to 
exclude from the 
assessments any samples 
taken within 72 hours for 
standard half-life products 
and 120 hours for extended 
half-life products (currently 
96 hours regardless of half-
life) after administration of 
exogenous FVIII 
replacement therapy for any 
purpose.
Take into account the 
difference in half-lives 
between FVIII products.
1.3. Scope of Activities
3. Objectives, Estimands, 
and Endpoints
9.1.1. Estimands
Non-substantial Modification(s)
Updated the domain names 
in Haem-A-QoL.
Changes made to reflect the 
latest information on this 
PRO
8.1.4.1 Haemophilia Quality 
of Life Questionnaire for
Adults (Haem-A-QoL)
Clarification that any tissue 
collected in the context of a 
safety investigation as 
further described in this 
section might be assessed 
for integration, as already 
indicated in the ICF.
Text initially erroneously 
described in Section 8.2.4.
moved to a new section 
8.2.5. Samples for Other 
Vector Integration Related 
Testing (if applicable). 
Minor clarification added.
8.2.5. Samples for Other 
Vector Integration Related 
Testing (if applicable).
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 5
Description of Change
Brief Rationale
Section # and Name
Added antifibrinolytics 
(aminocaproic acid and 
tranexamic acid) to the list 
of disallowed therapies for 
this study.
For clarity and consistency 
with the design/purpose of 
the study (there is no change 
to the study eligibility 
/conduct).
6.5.2. Disallowed therapy.
Added to the synopsis 
sections regarding study 
population, statistical 
methods and ethical 
considerations  
To ensure 
consistency/compliance with 
Pfizer’s protocol template
1.1.Synopsis
10.10. Appendix 10. 
Protocol amendment history
Minor changes to the 
statistical wording 
For consistency with SAP
3. Objectives, Estimands, 
and Endpoints
9.1.1. Estimands
9.4. Statistical analysis
Editorial changes, deletion 
of redundant text
For consistency, clarity and 
to ensure compliance with 
Pfizer’s protocol template
3. Objectives, Estimands, 
and Endpoints
9.1.1. Estimands
10.1 Regulatory, Ethical, 
and Study oversight 
consideration
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 6
TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................12
LIST OF FIGURES .................................................................................................................12
1. PROTOCOL SUMMARY...................................................................................................13
1.1. Synopsis ..................................................................................................................13
1.2. Schema ....................................................................................................................20
1.3. Schedule of Activities (SoA)...................................................................................21
2. INTRODUCTION ...............................................................................................................41
2.1. Study Rationale .......................................................................................................41
2.2. Background .............................................................................................................42
2.2.1. Summary of Clinical Experience with PF-07055480.................................42
2.3. Benefit/Risk Assessment.........................................................................................43
2.3.1. Risk Assessment.........................................................................................44
2.3.2. Benefit Assessment.....................................................................................51
2.3.3. Overall Benefit/Risk Conclusion................................................................51
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ...........................................................51
4. STUDY DESIGN.................................................................................................................56
4.1. Overall Design.........................................................................................................56
4.2. Scientific Rationale for Study Design.....................................................................57
4.3. Justification for Dose ..............................................................................................58
4.4. End of Study Definition ..........................................................................................58
5. STUDY POPULATION......................................................................................................59
5.1. Inclusion Criteria.....................................................................................................59
5.2. Exclusion Criteria....................................................................................................60
5.3. Lifestyle Considerations..........................................................................................62
5.4. Screen Failures ........................................................................................................63
6. STUDY INTERVENTION..................................................................................................63
6.1. Study Intervention(s) Administered........................................................................63
6.2. Preparation/Handling/Storage/Accountability ........................................................64
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................64
6.4. Study Intervention Compliance...............................................................................65
6.5. Concomitant Therapy..............................................................................................65
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 7
6.5.1. Allowed Therapy ........................................................................................66
6.5.2. Disallowed Therapy....................................................................................67
6.6. Dose Modification...................................................................................................67
6.7. Intervention After the End of the Study..................................................................67
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................68
7.1. Discontinuation of Study Intervention ....................................................................68
7.2. Participant Discontinuation/Withdrawal from the Study........................................68
7.2.1. Withdrawal of Consent...............................................................................69
7.3. Lost to Follow-up....................................................................................................69
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................69
8.1. Efficacy Assessments..............................................................................................72
8.1.1. Hemophilic Bleeding Episodes and Treatment ..........................................72
8.1.2. Factor VIII activity .....................................................................................73
8.1.2.1. General Information About Planned Assays.............................73
8.1.2.2. Guidance Related to FVIII Infusions, Bleeds and FVIII 
Decreases...........................................................................................73
8.1.2.3. Guidance Related to Elevated FVIII Activities and 
Stopping Rule....................................................................................73
8.1.2.4. Recovery Testing.......................................................................74
8.1.3. Joint Assessments.......................................................................................74
8.1.3.1. Hemophilia Joint Health Score (HJHS) ....................................74
8.1.3.2. Ultrasound to Evaluate Joints....................................................75
8.1.3.3. X-ray Assessments to Evaluate Joints.......................................75
8.1.4. Other PROs.................................................................................................76
8.1.4.1. Haemophilia Quality of Life Questionnaire for Adults 
(Haem-A-QoL)..................................................................................76
8.1.4.2. Hemophilia Activities List (HAL, Version 2)...........................76
8.1.4.3. Hemophilia Life Impacts Questionnaire (HLIQ)......................77
8.1.4.4. EQ-5D-5L..................................................................................77
8.1.4.5. Patient Global Impression of Severity (PGIS) and Patient 
Global Impression of Change (PGIC) ...............................................77
8.1.5. Imaging Assessments..................................................................................78
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 8
8.1.5.1. Management of Incidental Findings..........................................78
8.2. Safety Assessments .................................................................................................78
8.2.1. Physical Examinations................................................................................78
8.2.2. Vital Signs ..................................................................................................78
8.2.3. Cardiac Monitoring.....................................................................................79
8.2.4. Liver Ultrasound.........................................................................................79
8.2.5. Samples for Other Vector Integration Related Testing (if applicable).......79
8.2.6. Clinical Laboratory Assessments ...............................................................79
8.2.7. Immunogenicity..........................................................................................80
8.2.7.1. Analysis of Anti-PF-07055480 Antibodies (ADAs) and 
Neutralizing Anti PF-07055480 Antibodies......................................80
8.2.7.2. Analysis of FVIII Inhibitor .......................................................81
8.2.7.3. Analysis of Cellular Immune Response by ELISPOT..............81
8.2.8. Hemostasis Parameters, Thrombotic Potential Assessment and 
Thrombophilia Parameters...............................................................................82
8.2.9. Optional Liver Biopsy ................................................................................82
8.3. Adverse Events and Serious Adverse Events..........................................................84
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......84
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................85
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................85
8.3.2. Method of Detecting AEs and SAEs ..........................................................85
8.3.3. Follow-up of AEs and SAEs.......................................................................86
8.3.4. Regulatory Reporting Requirements for SAEs...........................................86
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................86
8.3.5.1. Exposure During Pregnancy......................................................87
8.3.5.2. Exposure During Breastfeeding ................................................87
8.3.5.3. Occupational Exposure .............................................................87
8.3.6. Cardiovascular and Death Events...............................................................87
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................87
8.3.8. Adverse Events of Special Interest.............................................................88
8.3.9. Medical Device Deficiencies......................................................................88
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 9
8.3.10. Immunomodulation Optimization (Presumed T-Cell Activation)............88
8.3.11. Infusion Related Hypersensitivity and Allergic Reaction ........................93
8.3.12. Medication Errors .....................................................................................93
8.4. Treatment of Overdose............................................................................................94
8.5. Pharmacokinetics ....................................................................................................94
8.5.1. Vector Shedding and Infectivity.................................................................94
8.6. Pharmacodynamics..................................................................................................95
8.6.1. FVIII Antigen .............................................................................................95
8.6.2. Von Willebrand Factor ...............................................................................95
8.7. Genetics...................................................................................................................95
8.7.1. Specified Genetics ......................................................................................95
8.7.2. Banked Biospecimens for Genetics............................................................95
8.8. Biomarkers ..............................................................................................................95
8.9. Medical Resource Utilization and Health Economics.............................................95
8.10. Additional Study Assessments..............................................................................96
8.10.1. Binding IgG versus IgM ...........................................................................96
8.10.2. Exploratory Cell-Mediated Assays...........................................................96
8.10.3. Archive Plasma Samples ..........................................................................96
8.10.4. Other Exploratory Assays.........................................................................96
9. STATISTICAL CONSIDERATIONS ................................................................................96
9.1. Estimands and Statistical Hypotheses.....................................................................96
9.1.1. Estimands....................................................................................................96
9.2. Sample Size Determination.....................................................................................98
9.3. Populations for Analyses.......................................................................................101
9.4. Statistical Analyses ...............................................................................................101
9.4.1. Efficacy Analyses .....................................................................................102
9.4.2. Safety Analyses ........................................................................................104
9.4.3. Other Analyses..........................................................................................104
9.5. Interim Analyses ...................................................................................................104
9.5.1. Data Monitoring Committee (DMC)........................................................104
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS........................................................................................................106
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 10
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations.............106
10.1.1. Regulatory and Ethical Considerations ..................................................106
10.1.2. Financial Disclosure ...............................................................................107
10.1.3. Informed Consent Process ......................................................................107
10.1.4. Data Protection .......................................................................................108
10.1.5. Committees Structure .............................................................................109
10.1.6. Dissemination of Clinical Study Data ....................................................109
10.1.7. Data Quality Assurance ..........................................................................110
10.1.8. Source Documents..................................................................................112
10.1.9. Study and Site Start and Closure ............................................................112
10.1.10. Publication Policy.................................................................................113
10.1.11. Sponsor’s Qualified Medical Personnel ...............................................113
10.2. Appendix 2: Clinical Laboratory Tests ...............................................................115
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ....................................................................117
10.3.1. Definition of AE .....................................................................................117
10.3.2. Definition of SAE...................................................................................118
10.3.3. Recording and Follow-Up of AE and/or SAE........................................120
10.3.4. Reporting of SAEs..................................................................................123
10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information..............................................................................................................125
10.5. Appendix 5: Genetics..........................................................................................127
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ......128
10.7. Appendix 7: Factor Replacement Regimens and Bleed Definitions...................130
10.8. Appendix 8: Country-Specific Requirements .....................................................131
10.8.1. France Appendix.....................................................................................131
10.8.2. Japan Appendix ......................................................................................132
10.8.2.1. Study Intervention Defects Definitions.................................132
10.8.2.2. Reporting Criteria..................................................................132
10.8.2.3. Reporting Procedures ............................................................132
10.8.2.4. Japan-Specific Protocol Wording..........................................133
10.8.3. Germany Appendix.................................................................................133
10.8.3.1. Section 5.1 Inclusion Criteria................................................133
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 11
10.8.3.2. Section 5.2 Exclusion Criteria...............................................133
10.8.3.3. Section 10.1.3 Informed Consent Process.............................134
10.8.3.4. Section 1.3 Schedule of Activities (SoA)..............................134
10.8.3.5. Section 8.1.3.3 X-ray Assessments to Evaluate Joints..........134
10.8.4. Sweden Appendix...................................................................................134
10.8.4.1. Section 10.1.7. Data Quality Assurance................................134
10.9. Appendix 9: Alternative Measures During Public Emergencies ........................135
10.9.1. Participants Who Test Positive for COVID-19 ......................................135
10.9.2. Telehealth Visits.....................................................................................136
10.9.3. Home Health Visits.................................................................................136
10.9.4. Adverse Events and Serious Adverse Events.........................................136
10.9.5. Guidance for Missed Visits/Assessments and Protocol Deviations .......136
10.9.6. Guidance for COVID-19 Vaccination....................................................137
10.10. Appendix 10: Protocol Amendment History.....................................................139
10.11. Appendix 11: Abbreviations .............................................................................157
11. REFERENCES ................................................................................................................161
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 12
LIST OF TABLES
Table 1.
Recommended Regimen for Oral Corticosteroids....................................90
Table 2.
Recommended Regimen for Combination Intravenous and Oral 
Corticosteroids..........................................................................................92
Table 3.
Estimated Effect of Treated Bleeds and All Bleeds Per Year in 
Emicizumab Studies ...............................................................................100
Table 4.
Protocol-Required Laboratory Assessments...........................................115
LIST OF FIGURES
Figure 1
C3731003: Study Design..........................................................................20
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 13
1. PROTOCOL SUMMARY
1.1. Synopsis
Protocol Title: Phase 3, Open-Label, Single-Arm Study to Evaluate the Efficacy and 
Safety of PF-07055480 (Recombinant AAV2/6 Human Factor VIII Gene Therapy) in 
Adult Male Participants with Moderately Severe to Severe Hemophilia A 
(FVIII:C≤1%)
Short Title: Not applicable
Rationale:
Sangamo Therapeutics has developed SB-525 (hereafter PF-07055480), a recombinant 
adeno‑associated virus 6 (rAAV6) capsid and cDNA encoding for the BDD hFVIII. It 
encodes a liver-specific promoter module and rAAV6 exhibits liver tropism, thus providing 
the potential for sustained hepatic production of FVIII in hemophilia A participants to reduce 
or eliminate the need for FVIII replacement therapy.
PF-07055480 is being evaluated in an open-label, adaptive, dose-ranging Phase 1/2 study 
(SB-525-1603 [hereafter C3731001]) to assess the safety and tolerability in male participants 
≥18 years of age with severe hemophilia A. The preliminary data from the Phase 1/2 study 
indicate that treatment of hemophilia A with PF-07055480 offers clinical advantage over 
routine prophylactic treatment with FVIII. Specifically, these data indicate that treatment of 
hemophilia A with PF-07055480 is well tolerated and demonstrated a dose-dependent 
increase in FVIII levels, achieving clinically relevant increases in FVIII activity in the higher 
dose cohorts and at or near normal FVIII levels in the 3 x 1013 vg/kg highest dose cohort 
(normal range: 50-150%). In the highest dose cohort, participants did not require factor 
replacement therapy (after initial use of prophylactic factor) and experienced no bleeding 
events in the first year post dosing. 
The Phase 3 program includes 2 separate studies: a non-IMP lead-in study (C0371004), 
where data will be prospectively collected in the context of routine prophylaxis with FVIII 
products, and this C3731003 pivotal Phase 3 dosing study.
C3731003 pivotal Phase 3 study will further evaluate the clinical efficacy and safety of 
PF-07055480 in adult male participants with moderately severe to severe hemophilia A 
(FVIII:C≤1%) for 5 years after a single administration of the study intervention at the dose of 
3 x 1013 vg/kg, compared to routine prophylaxis with FVIII products. 
The study will enroll approximately 70 eligible participants from Study C0371004 to achieve 
at least 50 dosed participants who complete at least 15 months of follow-up postinfusion in 
this study (C3731003). These 50 participants will have completed at least 6 months of 
routine prophylaxis follow-up in Study C0371004. The duration of follow-up for subsequent 
participants in the lead-in study (C0371004) may be shorter than 6 months after at least 50 
hemophilia A participants are expected to reach 15 months postinfusion in this study 
(C3731003).
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 14
The primary analysis will be conducted when at least 50 dosed participants have reached at 
least 15 months of follow-up postinfusion (ie, the data cutoff for the primary analysis),
corresponding to at least 12 months of follow-up for these 50 dosed participants after the 
estimated FVIII activity steady state onset. The onset of FVIII activity steady state based on 
the C3731001 study data is expected to be reached at the beginning of Week 9 postinfusion. 
However, as a conservative approach, the beginning of steady state will be considered as 
Week 12 (ie, approximately 3 months) for the primary analysis. 
The primary endpoint in this study (C3731003) will be the Total ABR, including both treated 
and untreated bleeding events, through at least 15 months postinfusion, and it will be 
compared with prior routine prophylaxis. The Total ABR will be assessed from Week 12 
through at least 15 months postinfusion in at least 50 dosed participants.
FVIII activity level >5% at 15 months postinfusion will be a key secondary endpoint. The 
other key secondary endpoint is the ABR (treated bleeding events) from Week 12 through at 
least 15 months postinfusion in at least 50 dosed participants, compared to preinfusion 
prophylaxis.
The final analysis will be conducted when all dosed participants have completed the entire 
study (ie, 5 years of follow-up duration per participant) or discontinued prematurely from the 
study.
Objectives, Estimands, and Endpoints:
Primary Efficacy Objective
Primary Endpoint and Key Secondary 
Endpoints
Evaluate the efficacy of a single infusion 
of PF-07055480 in participants ≥18 and 
<65 years of age with moderately severe 
to severe hemophilia A (FVIII C ≤1%).
Primary Endpoint:

Total ABR (spontaneous and 
traumatic bleedings, treated and 
untreated) from Week 12 through at 
least 15 months following PF-
07055480 infusion versus Total 
ABR on prior FVIII prophylaxis 
replacement regimen.
Key Secondary Endpoints:

FVIII activity level >5% at 
15 months following infusion of 
PF-07055480.

ABR (spontaneous and traumatic 
treated bleedings) from Week 12 
through at least 15 months following 
PF-07055480 infusion versus ABR 
on prior FVIII prophylaxis 
replacement regimen.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 15
Secondary Efficacy Objectives
Secondary Efficacy Endpoints
To demonstrate that the use of 
exogenous FVIII is significantly reduced 
post PF-07055480 infusion.

AIR of exogenous FVIII from Week 12 
through at least 15 months following 
infusion of PF-07055480 versus AIR on 
prior FVIII prophylaxis replacement 
regimen.
To assess additional efficacy parameters 
post PF-07055480 infusion including 
FVIII activity level, use of exogenous 
FVIII, information on bleeding events 
and PROs.

FVIII activity level from Week 12 
through 15 months following infusion of 
PF-07055480.
The following secondary parameters will be 
assessed from Week 12 through at least
15 months after PF-07055480 infusion and 
compared with prior FVIII prophylaxis 
replacement regimen:

Annualized FVIII consumption

ABR of specific type:
o
by cause (spontaneous or traumatic).
o
by location (in joints, in target joints, 
or in soft tissue).

Total ABR by cause and by location.

Percentage of participants without 
bleeds.
The following secondary parameters will be 
assessed by visit after PF-07055480 
infusion:

FVIII activity level 

Change from baseline in joint health as 
measured by the HJHS instrument.

Change from baseline in the following 
PRO endpoints:
o
Haem-A-QoL.
o
HAL.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 16
Estimate the durability of efficacy up to 
5 years after PF-07055480 infusion.
The following parameters will be analyzed 
yearly or by visit as appropriate:

ABR.

FVIII activity level.

AIR of exogenous FVIII.

Annualized FVIII consumption.

ABR of specific type:
o
by cause (spontaneous or traumatic).
o
by location (in joint, in target joints, 
or in soft tissue).

Total ABR.

Total ABR by cause and by location.

Percentage of participants without 
bleeds.

Change from baseline in joint health as 
measured by the HJHS instrument.

Change from baseline in PRO 
endpoints: Haem-A-QoL and HAL.
In addition, ABR, Total ABR, and AIR will 
be analyzed throughout the 5-year study 
period.
Secondary Safety Objectives
Secondary Safety Endpoints
To estimate the safety and tolerability of 
PF-07055480, including 
immunogenicity, for the study duration 
of 5 years after PF-07055480 infusion.

Incidence and severity of AEs.

Events of special interest (such as 
hypersensitivity reactions, clinically 
reported thrombotic events, and 
malignancy).

Immunogenicity:
o
Antibodies against AAV6 capsid 
protein (nAbs and ADAs).
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 17
o
T-cell responses against AAV6 
capsid and against the transgene.
o
FVIII inhibitors.
Overall Design
C3731003 is a pivotal Phase 3 study to evaluate the clinical efficacy and safety of a single IV 
infusion of PF-07055480 in adult male participants with moderately severe or severe 
hemophilia A (FVIII:C≤1%) for the study duration of 5 years. The study will enroll eligible 
participants who were followed on routine prophylaxis with FVIII products in the non-IMP 
lead-in Study C0371004. After this 5-year follow-up period in Study C3731003, participants 
will be invited to enter a separate study to assess the long-term safety and effectiveness of 
PF-07055480 for the treatment of hemophilia A for a total of up to 10 additional years, 
corresponding to up to 15 years post-PF-07055480 infusion.
Disclosure Statement
This is a Single Group Treatment study with 1 Arm that has No masking.
Number of Participants
Approximately 70 participants from the lead-in Study C0371004 will be enrolled to achieve 
at least 50 dosed participants completing at least 15 months of follow-up postinfusion.
Study population
Key inclusion and exclusion criteria are listed below:
Inclusion Criteria 
Participants must meet the following inclusion criteria to be eligible for enrollment into the 
study:
1. Participant must be ≥18 and <65 years of age at the time of signing the informed 
consent.
2. Participants must have been followed on routine FVIII prophylaxis therapy in the 
lead-in study (C0371004) and have ≥150 documented exposure days to a FVIII 
protein product (standard half-life or extended half-life recombinant, plasma derived).
3. Participants who have documented moderately severe to severe hemophilia A defined 
as circulating FVIII activity levels ≤1%.
4. Participants must agree to suspend prophylaxis therapy for hemophilia A after 
administration of the study intervention (see guidance in general notes of SoA). FVIII 
replacement therapy is allowed as needed (see Section 6.5.1).
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 18
5. Acceptable screening central laboratory values as follows:

Hemoglobin ≥11 g/dL

Platelets ≥100,000 cells/µL;

Creatinine ≤2.0 mg/dL. 
Exclusion Criteria 
Participants with any of the following characteristics/conditions will be excluded:
1. Anti-AAV6 nAb titers, above or equal to the established threshold of 1:4, performed 
by a central laboratory during screening.
2. Prior history of FVIII inhibitor (clinical or laboratory-based assessment) defined as a 
titer ≥0.6 BU/mL
3. Known hypersensitivity to FVIII replacement product or intravenous immunoglobulin 
administration.
4. History of chronic infection or other chronic disease that investigator deems an 
unacceptable risk. In addition, any participant with conditions associated with 
increased thromboembolic risk such as inherited or acquired thrombophilia, or a 
history of thrombotic events, including but not limited to stroke, myocardial 
infarction, or venous thromboembolism, is excluded.
5. ALT, AST, ALP >2x ULN, based on central laboratory results.
6. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%), based on central laboratory results.
7. Active hepatitis B or C:

HBcAb, HBsAg, and HBV DNA positivity. Exception: if a participant is 
positive for HBcAb, then HBsAg and HBV DNA must be negative for 
inclusion. 

HCV-RNA positivity.
8. Significant liver disease, defined by pre-existing diagnosis of portal hypertension, 
splenomegaly or hepatic encephalopathy. 
9. Serological evidence of HIV-1 or HIV-2 with either CD4+ cell count ≤200 mm3 or 
viral load >20 copies/mL.
Intervention Groups and Duration
The study treatment, a single infusion of PF-07055480, a gene transfer agent, will be 
administered on Day 1 at a dose of 3 x 1013 vg/kg of body weight. 
The safety and efficacy data will be collected over 5 years as described in the SoA included 
in Section 1.3.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 19
Data Monitoring Committee: Yes
Statistical Methods:
The primary endpoint and the associated hypothesis testing is to demonstrate NI of 
PF-07055480 to routine prophylaxis on the difference in Total ABR (NI margin of 3 
bleeds/year) by comparison of postinfusion of PF-07055480 Total ABR (through at least 15 
months up to data cutoff) versus prestudy intervention infusion Total ABR collected during 
the lead-in study (C0371004) and preinfusion of PF-07055480 in this study (C3731003), in 
male participants ≥18 years of age with moderately severe to severe hemophilia A (FVIII 
activity ≤1%), who have tested negative for nAb, to AAV6 and have no medical history of 
FVIII inhibitor.
A gatekeeping process will be applied to control for multiple endpoint comparisons at the 
primary analysis which is planned after at least 15 months of follow-up postinfusion in at 
least 50 dosed participants who have completed at least 6 months in the lead-in study 
(C0371004). The subsequent hypothesis testing will only be performed after success on the 
previous hypothesis test. The sequence of gatekeeping process and details of statistical 
methodology will be specified in the SAP.  
The safety endpoints of this study include vital signs, AEs, serious AEs (SAEs), physical
examinations, electrocardiograms (ECG), liver ultrasounds, immunogenicity, and laboratory 
tests. Descriptive analyses will be conducted.
Ethical Considerations:
The major benefit of gene therapy is that it may provide persistent treatment of hemophilia 
by continuous endogenous production of functional FVIII, providing therapeutic effect and a 
relief from the medical and lifestyle burden of recurrent on demand or routine prophylactic 
protein replacement therapy. By providing a stable production of serum FVIII levels, 
protection for bleeding episodes may be provided. Although replacement therapy increases 
FVIII levels in the bloodstream, these levels include peaks and troughs that are non 
physiological and lead to less protection before the next infusion. Gene therapy may also 
favourably impact the recognised complications of hemophilia: recurrent hemarthroses and 
the subsequent arthropathy. It is feasible that gene therapy treatment may result in 
expression of FVIII consistent with conversion from a moderate or severe to a mild 
hemophilia or better, persisting for at least a decade. 
Identified and main potential risks associated with PF-07055480 include: Identified risks:

Infusion reactions (including hypersensitivity): PF-07055480 may include infusion-
related reactions (IRRs) which may be due to immune reactions and/or allergic 
reactions/ hypersensitivity and lead to fever, chills, tachycardia, headache, nausea, 
vomiting or hypotension.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 20
Main Potential risks:

Hepatotoxicity: there is a potential risk of liver inflammation for this liver-tropic 
viral vector due to activation of the immune system in the liver. Liver inflammation 
can be detected by elevated blood liver enzymes (transaminases; ALT and/or AST).

Neutralizing antibodies to AAV6 since administration of AAV vectors leads to 
humoral immune response to AAV.

FVIII Inhibitors: antibodies to FVIII that neutralize the clotting activity of FVIII 
after administration of FVIII are a known complication in 25-30% of severe 
hemophilia A patients.

Thromboembolic events: This is related to potential FVIII activity levels >ULN post 
IP infusion. 

Taking into account the measures taken to minimize risk to study participants, the 
potential risks identified in association with PF-07055480 are justified by the 
anticipated benefits that may be afforded to participants with hemophilia A.
1.2. Schema
Figure 1
C3731003: Study Design
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 21
1.3. Schedule of Activities (SoA)
General Notes: 
The screening and baseline period may be extended after consulting with the sponsor’s 
medical monitor. The reason must be recorded in the source documents. Depending on the 
length of extension (of either period), the medical monitor may request to have visit 
procedures repeated.

FVIII prophylaxis recommendations:
o
FVIII prophylaxis is authorized during screening and baseline period, but perform 
FVIII activity, inhibitor and hemostasis assays in the absence of residual infused FVIII 
(recommended washout is 72 h for standard half-life FVIII products and 120 h for 
extended half-life FVIII products).
o
Schedule the FVIII infusions so that a FVIII infusion is performed on Day 1 (before 
study intervention).
o
After study intervention is administered, prophylaxis is recommended for 2 weeks.
Study sites without necessary infusion facilities will complete Visits 1-2 at the study site and 
Visit 3 (Day 1) will be completed at the designated infusion center. 
Unscheduled visits may be necessary for safety monitoring or to repeat any blood sampling 
if required.
Early discontinuation visit should follow the procedures for Week 260 visit. Discuss 
participant management and risks inherent with discontinuation with the sponsor’s 
medical monitor.
Alternative study measures during the COVID-19 Pandemic are described in Appendix 9.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 22
Procedures
Year 1
Screening Period
Baseline Period
Study Intervention
Week 1-12
(±2 days)
Weeks 13-52
(±1 week)
o
# The schedule of assessments should be based on Day 1.
o *Visit 4/Week 1: The participant is not required to appear onsite. 
If onsite visit: perform all procedures as specified in the SoA. If not 
onsite visit: collect only all required laboratory specimens as specified 
in the SoA.
o **Day 1: after end of study intervention infusion, 24 h 
hospitalization is planned.
o Home health/mobile phlebotomy services may be used for pre-
dose LFT blood draw and any time after Study Day 1/Visit 3, as 
needed (for most biological samples collection). 
o Clinical decisions may be based on local or central laboratory 
assessments.
o Refer also to the General Notes at the beginning of the SoA.
Study Visit
1
2
3
4*
5
6
7
8
9
10
11
12
13
Weeks after 
study 
intervention#
Week -6 to 
Week -3
Week -3 to 
Day 1
Day 1**
1
2
4
8
12
18
24
32
42
52
Informed consent
X
Must be obtained before any study-related procedures. Two ICFs may 
be required, one from the study site and the other from the infusion 
center (if applicable).
Assess/confirm 
eligibility 
(inclusion and 
exclusion criteria)
X*
X*
X#
*Review and confirm eligibility criteria (see Section 5.1 and Section 
5.2) before ordering the study intervention at the beginning of the 
baseline period.
#Review and confirm eligibility (see Section 5.1 and Section 5.2) 
before infusion. The infusion center should confirm eligibility with 
study site.
Demographics, 
medical, surgical, 
and hemophilia 
history
X
All ongoing AEs and SAEs, including AEs of special interest, in the 
lead-in study (C0371004) will be collected as medical history for this 
study. Only changes to historical data on medical, surgical and 
hemophilia history will be captured. Any new AEs/SAEs after 
completion of the lead-in study will follow the AE reporting process 
(Section 8.3.1, Appendix 3).
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 23
Procedures
Year 1
Screening Period
Baseline Period
Study Intervention
Week 1-12
(±2 days)
Weeks 13-52
(±1 week)
o
# The schedule of assessments should be based on Day 1.
o *Visit 4/Week 1: The participant is not required to appear onsite. 
If onsite visit: perform all procedures as specified in the SoA. If not 
onsite visit: collect only all required laboratory specimens as specified 
in the SoA.
o **Day 1: after end of study intervention infusion, 24 h 
hospitalization is planned.
o Home health/mobile phlebotomy services may be used for pre-
dose LFT blood draw and any time after Study Day 1/Visit 3, as 
needed (for most biological samples collection). 
o Clinical decisions may be based on local or central laboratory 
assessments.
o Refer also to the General Notes at the beginning of the SoA.
Physical exam, 
height*, weight, 
and vital signs
X*
X
X#
X
X
X
X
X
X
X
X
X
X
Complete a physical exam at all clinic visits. 
*Height is required to be collected at the screening visit only. 
Weight must be obtained at the screening visit to order the correct 
quantity of study intervention and to calculate the dose (Section 
8.2.1).
Vital signs include body temperature (°C), pulse rate, respiratory 
rate, and blood pressure (systolic and diastolic), after at least 5 
mins rest in supine or upright/sitting position.
#On Day 1, vital signs will be obtained:
before study intervention infusion;
within 5 min of start of study intervention infusion;
every 15 [±5] minutes for the length of the study intervention 
infusion, every 15 [±5] minutes until stable (±10 mmHg), 
then every 30 [±5] minutes until 2 hours after infusion 
completion, then every 4 hours [±10 min] until discharge.
Please note:
Study intervention infusion may take several hours. 
Completion of study intervention infusion is defined as study 
intervention infusion and IV line flush. Vital signs will also be 
performed 24 h [±3] h after completion of infusion and before 
hospital discharge.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 24
Procedures
Year 1
Screening Period
Baseline Period
Study Intervention
Week 1-12
(±2 days)
Weeks 13-52
(±1 week)
o
# The schedule of assessments should be based on Day 1.
o *Visit 4/Week 1: The participant is not required to appear onsite. 
If onsite visit: perform all procedures as specified in the SoA. If not 
onsite visit: collect only all required laboratory specimens as specified 
in the SoA.
o **Day 1: after end of study intervention infusion, 24 h 
hospitalization is planned.
o Home health/mobile phlebotomy services may be used for pre-
dose LFT blood draw and any time after Study Day 1/Visit 3, as 
needed (for most biological samples collection). 
o Clinical decisions may be based on local or central laboratory 
assessments.
o Refer also to the General Notes at the beginning of the SoA.
Cardiac 
monitoring: 
Local ECG*
Troponin I (CL)#
X*
X#
X#
(Wk 6 
and 12 
only)
X#
X
*
*ECG:
Local single 12-lead ECG.
Additional single ECGs may be obtained as clinically indicated.
If an ECG cannot be performed at Visit 13, it is recommended that it 
be performed at the next subsequent on-site visit or unplanned 
visit.
#Troponin I:
Troponin I (high sensitivity Troponin I assay) to be assessed at 
baseline and Weeks 6, 12, and 18.
During study: troponin I to be performed whenever an LFT increase 
occurs and is associated with a suspected T-Cell response. 
o
If troponin is elevated (ie, >99th percentile), repeat the assay 
for confirmation.
o
If troponin I elevation is confirmed, then arrange an ECG and 
cardiology consultation.
Target joint 
assessment
X
See for definition of a target joint.
Done as part of hemophilia history.
Joint X-ray*
X#
*Some participants (except in Germany) who consent to participate in 
an optional substudy will undergo X-ray for assessment of joints 
(Section 8.1.3.3). Central reading will be performed (Pettersson 
score).
# If this X-ray cannot be performed during the screening period, it is 
acceptable to postpone this testing no later than Week 4 / Visit 6.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 25
Procedures
Year 1
Screening Period
Baseline Period
Study Intervention
Week 1-12
(±2 days)
Weeks 13-52
(±1 week)
o
# The schedule of assessments should be based on Day 1.
o *Visit 4/Week 1: The participant is not required to appear onsite. 
If onsite visit: perform all procedures as specified in the SoA. If not 
onsite visit: collect only all required laboratory specimens as specified 
in the SoA.
o **Day 1: after end of study intervention infusion, 24 h 
hospitalization is planned.
o Home health/mobile phlebotomy services may be used for pre-
dose LFT blood draw and any time after Study Day 1/Visit 3, as 
needed (for most biological samples collection). 
o Clinical decisions may be based on local or central laboratory 
assessments.
o Refer also to the General Notes at the beginning of the SoA.
Joint ultrasound* 
X#
X
X
*Some participants (n~20) who consent to participate in an optional 
substudy will undergo joint ultrasound (Section 8.1.3.2).
# If this ultrasound cannot be performed during the baseline period, it 
is acceptable to postpone this testing no later than Week 4 / Visit 6.
Hepatitis/HIV 
screening (CL) 
and liver fibrosis 
testing (CL)
X
Hepatitis B and C: HBsAg, HBcAb, HBV-DNA; HCV-RNA 
Quantitative 
HIV: Antibody testing. If positive antibodies, CD4+ count and HIV 
viral load.
Liver fibrosis: FibroScan, or FibroTest/FibroSURE.
FibroScan, if performed, would be performed locally (fasting 
recommended).
-fetoprotein (CL)
X
X
To be tested as biomarker for hepatic carcinoma.
FVIII genetic 
testing (CL)
X*
*To be performed if not performed before and/or result not available 
in medical file.
FVIII inhibitor 
testing (CL, test in 
LL if clinically 
necessary)
X*
X
X
X
X
X
X
X
X
X
Samples should be collected in the absence of residual infused 
FVIII product (recommended washout is 72 h for standard half-life 
FVIII products and120 h for extended half-life FVIII products).
*Positive inhibitor testing as measured by the central laboratory 
≥0.6 BU at Visit 1 would be exclusionary.
Nijmegen Bethesda Inhibitor assay to be done at the central laboratory 
unless testing at a local laboratory is necessary due to a clinical 
concern.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 26
Procedures
Year 1
Screening Period
Baseline Period
Study Intervention
Week 1-12
(±2 days)
Weeks 13-52
(±1 week)
o
# The schedule of assessments should be based on Day 1.
o *Visit 4/Week 1: The participant is not required to appear onsite. 
If onsite visit: perform all procedures as specified in the SoA. If not 
onsite visit: collect only all required laboratory specimens as specified 
in the SoA.
o **Day 1: after end of study intervention infusion, 24 h 
hospitalization is planned.
o Home health/mobile phlebotomy services may be used for pre-
dose LFT blood draw and any time after Study Day 1/Visit 3, as 
needed (for most biological samples collection). 
o Clinical decisions may be based on local or central laboratory 
assessments.
o Refer also to the General Notes at the beginning of the SoA.
Neutralizing 
antibodies to 
AAV6 and other 
AAVs (CL)
X*
X
Collect blood for serum samples preparation.
*Participants with anti-AAV6 nAb titer ≥1:4 are to be excluded from 
the study.
nAb against other AAVs serotypes may be tested on same sample to 
assess cross reactivity.
Anti-drug 
antibody (CL)
X
X
Anti-PF-07055480 antibodies.
Collect blood for serum samples preparation.
Laboratory safety 
panels: 
hematology and 
clinical chemistry 
(CL)
X*
X
X
X
X
X
X
X
X
X
See Appendix 2 for a full list.
*ABO blood group planned at screening only if unknown.
Laboratory safety 
panels: lipid panel 
and urinalysis 
(CL)
X
X
See Appendix 2 for a full list.
At least 8 hours of fasting is required for lipid panel blood collection.
FVIII activity (CL, 
LL), LFT (CL, 
LL) and FVIII 
antigen (CL)
X
X*
Day 1 to Week 12:
FVIII activity and LFT:
at least 2 times every 
week starting from Day 1
FVIII antigen: weekly 
testing starting from Day 
1
Week 13 to 20:
FVIII activity: weekly 
and LFT: 2 times weekly
FVIII antigen: weekly 
Week 22 to 34:
FVIII activity and LFT: 
every 2 weeks (Weeks 
LFT: See Appendix 2 for a full list.
* Collect blood for local and central LFTs prior to dosing (up to 3 
days prior to Day 1/Visit 3 is acceptable). Utilize mobile 
phlebotomy as needed. Local LFTs have to be reviewed before dosing 
and prior to thawing drug. If the investigator has any clinical concerns 
regarding the local LFT results, drug should not be thawed. These 
LFT results may help in the assessment of future LFTs and decisions 
on when to begin corticosteroid treatment, if necessary. FVIII activity 
testing on Day 1 is optional.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 27
Procedures
Year 1
Screening Period
Baseline Period
Study Intervention
Week 1-12
(±2 days)
Weeks 13-52
(±1 week)
o
# The schedule of assessments should be based on Day 1.
o *Visit 4/Week 1: The participant is not required to appear onsite. 
If onsite visit: perform all procedures as specified in the SoA. If not 
onsite visit: collect only all required laboratory specimens as specified 
in the SoA.
o **Day 1: after end of study intervention infusion, 24 h 
hospitalization is planned.
o Home health/mobile phlebotomy services may be used for pre-
dose LFT blood draw and any time after Study Day 1/Visit 3, as 
needed (for most biological samples collection). 
o Clinical decisions may be based on local or central laboratory 
assessments.
o Refer also to the General Notes at the beginning of the SoA.
Home health/mobile 
phlebotomy services 
allowed.
22, 24 (onsite), 26, 28, 30, 
32 (onsite), 34)
FVIII antigen: 
approximately monthly 
(Weeks 24 (onsite), 28, 32 
(onsite), and 34)
Week 38 to 52:
FVIII activity, FVIII 
antigen and LFT:  
approximately monthly
Weeks 38, 42 (onsite), 48, 
52 (onsite)
Home health/mobile 
phlebotomy services are 
allowed.
Any FVIII activity and LFT testing will be conducted at local 
and central lab for all time points and as clinically necessary 
(also applicable to unscheduled or repeated tests). 
LFT and FVIII activity obtained at local labs may be used for 
clinical decisions (as identification of changes suggestive of T-cell 
reactions and initiation of corticosteroids – see also Section 8.3.10). 
FVIII antigen testing will be conducted ONLY at central lab for all 
time points and as clinically necessary. 
FVIII activity should be collected in the absence of residual 
infused FVIII (recommended washout is 72 h for standard half-life 
FVIII products and 120 h for extended half-life FVIII products).
FVIII activity should be measured in the event of an untreated bleed, 
as close to the bleeding event as possible. If the bleed necessitates 
exogenous FVIII, FVIII activity should be assessed post clearance of 
FVIII product. See also Section 8.1.2.
It is recommended to repeat FVIII activity assessment anytime if there 
is a significant decrease (not attributed to standard fluctuation or to 
variability of assays) as assessed by the investigator. The medical 
monitor may be consulted as needed. See also Section 8.1.2.
Frequency of FVIII activity and LFT monitoring:
First 12 weeks: at least 2 times every week due to potential rise in 
hepatic transaminases and/or loss of FVIII transgene expression. 
Week 13 to Week 20: FVIII activity weekly and LFTs 2 times per 
week.
Week 22 to Week 34: every 2 weeks.
Week 38 to Week 52: approximately monthly.
Frequency of FVIII antigen: weekly until Week 20, and then 
monthly.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 28
Procedures
Year 1
Screening Period
Baseline Period
Study Intervention
Week 1-12
(±2 days)
Weeks 13-52
(±1 week)
o
# The schedule of assessments should be based on Day 1.
o *Visit 4/Week 1: The participant is not required to appear onsite. 
If onsite visit: perform all procedures as specified in the SoA. If not 
onsite visit: collect only all required laboratory specimens as specified 
in the SoA.
o **Day 1: after end of study intervention infusion, 24 h 
hospitalization is planned.
o Home health/mobile phlebotomy services may be used for pre-
dose LFT blood draw and any time after Study Day 1/Visit 3, as 
needed (for most biological samples collection). 
o Clinical decisions may be based on local or central laboratory 
assessments.
o Refer also to the General Notes at the beginning of the SoA.
Sponsor recommends collecting specimens Monday through 
Thursday so results are available before the weekend.
It is highly recommended that participants be provided with a 
prednisone prescription before dosing so that it can be filled and 
ready should treatment be needed.  
It is highly recommended that participants who are initiated on 
corticosteroid treatment be treated with a gastric acid reducer, 
preferably a proton pump inhibitor (PPI) (eg, omeprazole), or 
alternatively a histamine type 2 (H2) antagonist (eg, famotidine) for 
the duration of the corticosteroid course.
FVIII recovery may be tested if prophylaxis is resumed and/or if 
prophylaxis is administered prior to a surgical procedure. Refer to 
Section 8.1.2 for more guidance.
Refer to Section 8.3.10 for more guidance about elevated liver 
enzymes and/or optimization of immunomodulation. Note: if 
corticosteroid therapy is started, measurement of LFT and of FVIII 
activity is recommended at least 2 times per week until the end of this 
therapy.
Refer to Sections 8.1.2 and 8.2.7 for more guidance on how to 
manage participants with FVIII activity levels >ULN. See also the 
separate “Management Guide for Elevated Factor VIII Activity 
Levels”. 
Request delivery 
of study 
intervention from 
sponsor
X
Order the study intervention at the beginning of the baseline period 
after confirming eligibility criteria. The study intervention will take 
approximately 3 weeks for delivery. Prior to IP ordering, consider 
Sections 10.9.1 and 10.9.6.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 29
Procedures
Year 1
Screening Period
Baseline Period
Study Intervention
Week 1-12
(±2 days)
Weeks 13-52
(±1 week)
o
# The schedule of assessments should be based on Day 1.
o *Visit 4/Week 1: The participant is not required to appear onsite. 
If onsite visit: perform all procedures as specified in the SoA. If not 
onsite visit: collect only all required laboratory specimens as specified 
in the SoA.
o **Day 1: after end of study intervention infusion, 24 h 
hospitalization is planned.
o Home health/mobile phlebotomy services may be used for pre-
dose LFT blood draw and any time after Study Day 1/Visit 3, as 
needed (for most biological samples collection). 
o Clinical decisions may be based on local or central laboratory 
assessments.
o Refer also to the General Notes at the beginning of the SoA.
Immunology –
ELISPOT 
(PBMC) (CL)
X
Only if corticosteroid treatment is needed for a 
suspected T-cell response.

Collect blood for PBMC preparation and ELISPOT assay at 
baseline and if the corticosteroid treatment is needed for a 
suspected T-cell response.

Collect specimens before initiating the corticosteroid treatment. If 
specimens are not collected before initiation, then collect the 
specimens within 24 hours of administering corticosteroids.

Collect specimens approximately 3 weeks after steroid 
administration and at the end of the weaning time. Additional 
specimens may be recommended by the sponsor, in consultation 
with the investigator, depending on the participant’s response to 
corticosteroid therapy.
Exploratory 
immunology –
other cell 
mediated assays 
(PBMC) (CL)
X
X
X
X
X
X
Collect blood for PBMC preparation for cell-mediated exploratory 
immunology assays.
Exploratory 
immunology: 
binding IgG vs 
IgM antibody 
response (CL)
X
X
X
Collect blood for serum samples preparation.
Von Willebrand 
factor (CL)
X
X
X
X
X
X
X
X
X
Collect blood for plasma sample preparation.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 30
Procedures
Year 1
Screening Period
Baseline Period
Study Intervention
Week 1-12
(±2 days)
Weeks 13-52
(±1 week)
o
# The schedule of assessments should be based on Day 1.
o *Visit 4/Week 1: The participant is not required to appear onsite. 
If onsite visit: perform all procedures as specified in the SoA. If not 
onsite visit: collect only all required laboratory specimens as specified 
in the SoA.
o **Day 1: after end of study intervention infusion, 24 h 
hospitalization is planned.
o Home health/mobile phlebotomy services may be used for pre-
dose LFT blood draw and any time after Study Day 1/Visit 3, as 
needed (for most biological samples collection). 
o Clinical decisions may be based on local or central laboratory 
assessments.
o Refer also to the General Notes at the beginning of the SoA.
Spare plasma 
X
X
X
X
X
X
X
X
X
X
X
X
X
Draw approximately 5 mL of blood to prepare approximately 2 mL of 
plasma at each timepoint (when central analyses are done and at least, 
at each mandatory onsite visit and at each laboratory visit for ALT / 
FVIII assessment from Week 32 and until the End of Study Visit). 
The pre-dose 5 mL blood sample to be collected on Day 1* (or -3 
Days before Day 1) will be used to prepare approximately 2 mL of 
serum. Plasma/serum will be stored for repeat or additional testing 
(including exploratory biomarkers to assess immune response and 
study intervention mechanism of action) (Section 8.10.3 and Section 
8.10.4). 
Liver ultrasound
X
X
*
Refer to Section 8.2.4 and to the liver ultrasound scanning guidance.
*If an ultrasound cannot be performed at Visit 13, it is recommended 
that it be performed at the next subsequent on-site visit or unplanned 
visit.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 31
Procedures
Year 1
Screening Period
Baseline Period
Study Intervention
Week 1-12
(±2 days)
Weeks 13-52
(±1 week)
o
# The schedule of assessments should be based on Day 1.
o *Visit 4/Week 1: The participant is not required to appear onsite. 
If onsite visit: perform all procedures as specified in the SoA. If not 
onsite visit: collect only all required laboratory specimens as specified 
in the SoA.
o **Day 1: after end of study intervention infusion, 24 h 
hospitalization is planned.
o Home health/mobile phlebotomy services may be used for pre-
dose LFT blood draw and any time after Study Day 1/Visit 3, as 
needed (for most biological samples collection). 
o Clinical decisions may be based on local or central laboratory 
assessments.
o Refer also to the General Notes at the beginning of the SoA.
Global hemostasis 
and 
thrombophilia-
related markers 
(CL)
X*
X
X
See Appendix 2 for a full list of possible markers and Section 8.2.8
for more information.
These samples should be collected in the absence of residual infused 
FVIII product (recommended washout is 72 h for standard half-life 
FVIII products and 120 h for extended half-life FVIII products).
On Day 1, blood samples for TAT will be used to establish baseline 
value (before FVIII product infusion).
Hemostasis markers should be assessed as clinically indicated 
throughout the study and are recommended if vector-derived 
FVIII:C >150% of normal are achieved (Section 8.2.8).
*Defined thrombophilia-related markers are assessed during 
screening as part of eligibility confirmation and some parameters 
can be repeated as clinically indicated (not repeated on Day 1 and 
Week 52). These markers should be assessed at least once in each 
participant. 
Issue the eDiary
X
Provide eDiary and training to operate it, including timing and 
information to be entered (Section 8.1.1) starting at Visit 1. 
Participants will enter information as soon as eDiary has been issued.
Review the eDiary
Ongoing (including unscheduled visits)#
Review the eDiary at each onsite visit and ensure appropriate entries 
during unscheduled and scheduled visits.
See definitions of Bleeds and Replacement Factor Regimens in 
Appendix 7.
#Not applicable for Visit 3 if done at infusion center.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 32
Procedures
Year 1
Screening Period
Baseline Period
Study Intervention
Week 1-12
(±2 days)
Weeks 13-52
(±1 week)
o
# The schedule of assessments should be based on Day 1.
o *Visit 4/Week 1: The participant is not required to appear onsite. 
If onsite visit: perform all procedures as specified in the SoA. If not 
onsite visit: collect only all required laboratory specimens as specified 
in the SoA.
o **Day 1: after end of study intervention infusion, 24 h 
hospitalization is planned.
o Home health/mobile phlebotomy services may be used for pre-
dose LFT blood draw and any time after Study Day 1/Visit 3, as 
needed (for most biological samples collection). 
o Clinical decisions may be based on local or central laboratory 
assessments.
o Refer also to the General Notes at the beginning of the SoA.
FVIII infusion, 
accountability 
X
Prior to dosing, consider Sections 10.9.1 and 10.9.6. On Day 1 a 
single prophylactic IV infusion of a FVIII product will be 
administered under medical supervision over a period of 
approximately 10 minutes at the standard prophylaxis dose for 
standard half-life products and for extended half-life products (within 
reasonable margin of error of approximately ±20%). If there is 
evidence that this dose may place the participant at supratherapeutic 
FVIII levels, the dose can be adjusted.
Participants are expected to bring their current FVIII replacement 
therapy with them.
Study intervention 
infusion, 
accountability
X
After completing the prophylactic FVIII product infusion, participants 
will receive a single IV infusion of the study intervention by means of
an infusion pump. The length of the infusion will depend on the 
volume received and may last several hours. Please also refer to the IP 
manual. 
Refer to the Infusion Reaction Management Guide for 
recommendations about clinical management before, during, and after 
infusion.
Do not thaw the study intervention before confirming participant 
eligibility and that the participant is physically present at the site or 
infusion center. 
Flush the IV line at the conclusion of the study intervention infusion.
HJHS
X
X
*
X
*
To be completed by investigator or the designee (Section 8.1.3.1).
*If the HJHS cannot be performed at Visit 10 and/or 13, it is 
recommended that it be performed at the next subsequent on-site visit 
or unplanned visit.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 33
Procedures
Year 1
Screening Period
Baseline Period
Study Intervention
Week 1-12
(±2 days)
Weeks 13-52
(±1 week)
o
# The schedule of assessments should be based on Day 1.
o *Visit 4/Week 1: The participant is not required to appear onsite. 
If onsite visit: perform all procedures as specified in the SoA. If not 
onsite visit: collect only all required laboratory specimens as specified 
in the SoA.
o **Day 1: after end of study intervention infusion, 24 h 
hospitalization is planned.
o Home health/mobile phlebotomy services may be used for pre-
dose LFT blood draw and any time after Study Day 1/Visit 3, as 
needed (for most biological samples collection). 
o Clinical decisions may be based on local or central laboratory 
assessments.
o Refer also to the General Notes at the beginning of the SoA.
PROs
X*
X
X
X
Participants will complete 6 instruments at the site using an electronic 
tablet: Haem-A-QoL, HAL (v2), HLIQ, EQ-5D-5L, PGIS (n=3), 
PGIC (n=3). Administer the questionnaires before dosing, treatment, 
or conversation between the healthcare team and participants about 
their health condition. See Section 8.1.4 for additional considerations.
*PGIC items are not completed at baseline visit
Every effort should be made to conduct the PROs according to the 
protocol specified timepoints; however if not feasible, baseline PROs 
have to be conducted any time prior to start of infusion on Day 1, 
postinfusion PROs at the next subsequent on-site visit or unplanned 
visit.
Vector shedding 
analysis by PCR 
and infectivity 
(CL)
X
X*
Weekly, as needed #
Or every 2 weeks past Week 20
Home health/mobile phlebotomy services allowed
From Week 34, monthly collection is allowed in the 
absence of home health/mobile phlebotomy services at 
a site or country
#Collect plasma, PBMC, saliva, semen, and urine specimens at 
baseline and every week after study intervention until 3 consecutive 
specimens test negative for the given specimen type.
#Collection of blood to prepare PBMCs and assess shedding 
postinfusion will start from Week 20.
Semen samples may be collected at home the night before a clinic or 
home health/mobile phlebotomy services visit and stored in the 
participant’s freezer until the clinic or home health/mobile 
phlebotomy services visit.
*Optional vector shedding sub-study (12 participants): additional 
samples (plasma, PBMC, saliva, semen and urine) will be collected, 
onsite only, 2 h [±30 min], 24 h [±3 h], and 72 h [±4 h] after 
completion of the study intervention infusion/IV line flush.
Infectivity will be performed as applicable. Refer to Section 8.5.1 for 
additional details. 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 34
Procedures
Year 1
Screening Period
Baseline Period
Study Intervention
Week 1-12
(±2 days)
Weeks 13-52
(±1 week)
o
# The schedule of assessments should be based on Day 1.
o *Visit 4/Week 1: The participant is not required to appear onsite. 
If onsite visit: perform all procedures as specified in the SoA. If not 
onsite visit: collect only all required laboratory specimens as specified 
in the SoA.
o **Day 1: after end of study intervention infusion, 24 h 
hospitalization is planned.
o Home health/mobile phlebotomy services may be used for pre-
dose LFT blood draw and any time after Study Day 1/Visit 3, as 
needed (for most biological samples collection). 
o Clinical decisions may be based on local or central laboratory 
assessments.
o Refer also to the General Notes at the beginning of the SoA.
Any additional 
safety tests
Ongoing (as needed)
Additional laboratory testing or procedures may be conducted as 
deemed clinically necessary by the investigator to ensure the safety of 
participants.
Adverse events
Ongoing (including unscheduled visits)
During the short-term monitoring period (up to and including 104 
weeks postinfusion) all SAEs and AEs will be collected (Section 8.3.1
and Appendix 3).
Concomitant 
medications, 
surgeries, and
procedures
Ongoing (including unscheduled visits)
All concomitant therapy will be collected from up to 30 days before 
screening until the end of the short-term safety monitoring period 
(104 weeks) (from the lead-in study, when applicable) (see Section 
6.5).
All procedures and surgeries (including elective surgeries) are to be 
recorded (see Section 6.5).
Note: FVIII product infusions will be recorded in the eDiary.
Optional Liver 
Biopsy
X (postinfusion)
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 8.2.8.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 35
Procedures
Year 2 to Year 5
Week 53-
104
(± 2 
weeks)
Week 
105-208-
(± 3 weeks)
EOS or Early 
Discontinuation
Week 260
(± 3 weeks)
o
Home health/mobile phlebotomy services may be used as needed (for most 
biological samples collection only).
o
Clinical decisions may be based on local or central laboratory assessments.
Study Visit
14
15
16
17
18
Weeks after study 
intervention
78
104
156
208
260
Physical exam, weight, 
and vital signs
X
X
X
X
X
Complete the physical exam at all visits.
Vital signs include blood pressure, pulse rate, respiratory rate, body temperature 
(°C) after at least 5 mins rest in supine or upright/sitting position.
Cardiac monitoring:
Local ECG*
Troponin I (CL)#
X
X
X
X
*ECG:
Local single 12-lead ECG. 
Additional single ECGs as clinically indicated. 
Authorized time window for ECG assessment during the long term follow-up 
period: ±1 month at W104 and ±2 months at W156 and W208.
If the ECG cannot be performed at a visit, it is recommended that it be 
performed at the next subsequent on-site visit or unplanned visit.
#Troponin I:
Troponin I to be performed whenever an LFT increase occurs and is associated 
with a suspected T-Cell response. 
o
If troponin elevated (ie, >99th percentile), repeat the assay for confirmation. 
o
If troponin I elevation confirmed, then arrange an ECG and cardiology 
consultation.
Joint X-ray*
X#
X
*Some participants (except in Germany) who consent to participate in an optional 
substudy will undergo X-ray for assessment of joints (Section 8.1.3.3). Central 
reading to be performed (Pettersson score).
#Authorized time window to complete the X-ray at W156 is ±2 months 
-fetoprotein (CL)
X
X
X
X
X
To be tested as biomarker for hepatic carcinoma.
FVIII inhibitor testing 
(CL, test in LL if 
clinically necessary)
X
X
X
X
X
Samples should be collected in the absence of residual infused FVIII product 
(recommended washout is 72 h for standard half-life FVIII products and 120 h for 
standard and extended half-life FVIII products).
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 36
Procedures
Year 2 to Year 5
Week 53-
104
(± 2 
weeks)
Week 
105-208-
(± 3 weeks)
EOS or Early 
Discontinuation
Week 260
(± 3 weeks)
o
Home health/mobile phlebotomy services may be used as needed (for most 
biological samples collection only).
o
Clinical decisions may be based on local or central laboratory assessments.
Study Visit
14
15
16
17
18
Weeks after study 
intervention
78
104
156
208
260
Nijmegen Bethesda Inhibitor Assay: to be done at the central laboratory unless 
testing at a local laboratory is necessary due to a clinical concern.
Neutralizing antibodies 
to AAV6 and other 
AAVs (CL)
X
X
X
X
Collect blood for serum preparation.
nAb against other AAVs serotypes may be tested on same sample to assess cross 
reactivity.
Anti-drug antibody (CL)
X
X
X
X
Anti-PF-07055480 antibodies.
Collect blood for serum preparation.
Laboratory safety 
panels: hematology and 
clinical chemistry (CL)
X
X
X
X
X
See Appendix 2 for a full list.
FVIII activity (CL, LL), 
LFT (CL, LL) and FVIII 
antigen (CL)
Starting at 
Week 53 and until 
week 156 
(ie, during Year 2 
and Year 3), 
monitor once 
every 3 months#:
Weeks 65, 78
(Visit 14), 91, 104 
(Visit 15), 117, 
130, 143, 156 
(Visit 16)
From 
Week 157, every 
6 months #: 
Weeks 182, 208 
(Visit 17), and 
234
X#
LFT: See Appendix 2 for a full list.
FVIII activity and LFT testing will be conducted at local and central 
laboratories. 
Any unscheduled or repeated blood testing for LFTs and/or FVIII activity 
must be conducted at local AND central labs.
FVIII activity should be collected in the absence of residual infused FVIII 
product (recommended wash-out is 72 h for standard half-life FVIII products and 
120 h for extended half-life FVIII products).
FVIII activity should be measured in the event of an untreated bleed, as close to 
the bleeding event as possible. If the bleed necessitates exogenous FVIII, FVIII 
activity should be assessed post clearance of FVIII product. See also 
Section 8.1.2.
It is recommended to repeat FVIII activity assessment anytime if there is a 
significant decrease (not attributed to standard fluctuation or to variability of 
assays) as assessed by the investigator. The medical monitor may be consulted as 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 37
Procedures
Year 2 to Year 5
Week 53-
104
(± 2 
weeks)
Week 
105-208-
(± 3 weeks)
EOS or Early 
Discontinuation
Week 260
(± 3 weeks)
o
Home health/mobile phlebotomy services may be used as needed (for most 
biological samples collection only).
o
Clinical decisions may be based on local or central laboratory assessments.
Study Visit
14
15
16
17
18
Weeks after study 
intervention
78
104
156
208
260
needed. See also Section 8.1.2. Sponsor recommends collecting specimens on 
Monday through Thursday so results are available before the weekend.
FVIII antigen testing will be conducted ONLY at central lab. 
Clinical decisions may be based on local and/or central lab results.
#Samples should be taken at Weeks 65, 78 (Visit 14), 91, 104 (Visit 15), 117, 
130, 143, 156 (Visit 16), 182, 208 (Visit 17), 234, 260 (Visit 18).
Use home health/mobile phlebotomy services as needed.
Refer to Section 8.3.10 for more guidance about elevated liver enzymes and/or 
optimization of immunomodulation.Note: if corticosteroid therapy is started, 
measurement of LFTs and of FVIII activity is recommended at least 2 times per 
week until the end of this therapy.
It is highly recommended that participants who are initiated on corticosteroid 
treatment be treated with a gastric acid reducer, preferably a proton pump 
inhibitor (PPI) (eg, omeprazole), or alternatively a histamine type 2 (H2) 
antagonist (eg, famotidine) for the duration of the corticosteroid course.
FVIII recovery may be tested if prophylaxis is resumed and/or if prophylaxis is 
administered prior to a surgical procedure. Refer to Section 8.1.2 for more 
guidance.
Immunology/ELISPOT 
(PBMC) (CL)
Only if corticosteroid treatment is needed for a suspected T-
cell response.
Home health/mobile phlebotomy services allowed.
Collect specimens for PBMC preparation and ELISPOT if the corticosteroid 
treatment is needed for a suspected T-cell response.
Collect specimens before initiating the corticosteroid treatment. If specimens are 
not collected before initiation, then collect specimens within 24 hours of 
administering corticosteroids.
Collect specimens approximately 3 weeks after steroid administration and at the 
end of the weaning time. Additional specimens may be recommended by the 
sponsor, in consultation with the investigator, depending on the participant’s 
response to corticosteroid therapy.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 38
Procedures
Year 2 to Year 5
Week 53-
104
(± 2 
weeks)
Week 
105-208-
(± 3 weeks)
EOS or Early 
Discontinuation
Week 260
(± 3 weeks)
o
Home health/mobile phlebotomy services may be used as needed (for most 
biological samples collection only).
o
Clinical decisions may be based on local or central laboratory assessments.
Study Visit
14
15
16
17
18
Weeks after study 
intervention
78
104
156
208
260
Spare plasma
X
X
X
X
X
Draw approximately 5 mL of blood to prepare approximately 2 mL of plasma at 
each timepoint (when central analyses are done and at least, at each mandatory 
onsite visit and at each laboratory visit for ALT / FVIII assessment from Week 32 
and until the End of Study Visit). Plasma will be stored for repeat or additional 
testing (including exploratory biomarkers to assess immune response and study 
intervention mechanism of action) (Section 8.10.3 and Section 8.10.4).
Liver ultrasound
X
X
X 
X
All participants will undergo liver ultrasounds yearly, at a minimum, with more 
frequent ultrasounds allowed per investigator discretion (eg, participants with risk 
factors for HCC) or if necessitated to align with participant’s standard of care. Refer 
to Section 8.2.4 and to the liver ultrasound scanning guidance.
Authorized time window for liver ultrasound during the long-term follow-up 
period: ±1 month at W104 and ±2 months at W156 and W208.
If the ultrasound cannot be performed at a visit, it is recommended that it be 
performed at the next subsequent on-site visit or unplanned visit.
Global hemostasis 
markers and 
thrombophilia related 
markers (CL)
X*
X*
X*
X*
See Appendix 2 for a full list of possible markers and Section 8.2.8for more 
information.
These samples should be collected in the absence of residual infused FVIII 
product (recommended washout is 72 h for standard half-life FVIII products 
and 120 h for extended half-life FVIII products).
*Defined thrombophilia-related markers should be assessed at least once in each 
participant (if not initially assessed as part of eligibility confirmation) and some 
parameters can be repeated as clinically indicated, but are not repeated at each visit.
Hemostasis markers should be assessed as clinically indicated throughout the 
study and are recommended to be tested if vector-derived FVIII:C >150% of 
normal are achieved . 
HJHS
X
X
X
X
To be completed by the investigator or the designee (Section 8.1.3.1).
Authorized time window: ±1 month at W104 and ±2 months at W156 and W208.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 39
Procedures
Year 2 to Year 5
Week 53-
104
(± 2 
weeks)
Week 
105-208-
(± 3 weeks)
EOS or Early 
Discontinuation
Week 260
(± 3 weeks)
o
Home health/mobile phlebotomy services may be used as needed (for most 
biological samples collection only).
o
Clinical decisions may be based on local or central laboratory assessments.
Study Visit
14
15
16
17
18
Weeks after study 
intervention
78
104
156
208
260
If the HJHS cannot be performed at a visit, it is recommended that it be performed 
at the next subsequent on-site visit or unplanned visit.
PROs
X
X
X
X
Participants will complete 6 instruments at the study site using an electronic tablet: 
Haem-A-QoL, HAL (v2), HLIQ, EQ-5D-5L, PGIS (n=3), PGIC (n=3). Administer 
the questionnaires before dosing, treatment, or conversation between the health care 
team and participants about their health condition. See Section 8.1.4 for additional 
considerations.
If PROs cannot be performed at a visit, it is recommended that it be performed at 
the next subsequent on-site visit or unplanned visit.
Phone call
Ongoing
After Week 156, phone calls every 6 months (ie, Weeks 182 and 234) in addition to 
the annual visits. Inquire about AEs and concomitant treatments (including 
surgeries).
Vector shedding 
analysis by PCR and 
infectivity (CL)
Every 2 weeks #
Home health/mobile phlebotomy services allowed.
From Week 34, monthly collection is allowed in the absence 
of home health/mobile phlebotomy services at a site or 
country
#Collect plasma, PBMC, saliva, semen, and urine specimens every 2 weeks  until 
3 consecutive negative test results for the given specimen type.
Semen samples can be collected at home the night before a clinic or home 
health/mobile phlebotomy services visit and stored in the participant’s freezer 
until the clinic or home health/mobile phlebotomy services visit.
Infectivity will be performed as applicable. Refer to Section 8.5.1 for additional 
details.
Any additional safety 
tests
Ongoing
Additional laboratory testing or procedures may be conducted as deemed clinically 
necessary by the investigator to ensure safety of participants.
Adverse events
Ongoing (including unscheduled visits)
During the short-term monitoring period (up to and including 104 weeks 
postinfusion) all SAEs and AEs will be collected (Section 8.3.1 and Appendix 3).
During the long-term monitoring period (Week 105 postinfusion to EOS) the 
following adverse events will be collected:
SAEs (including medically important events, Appendix 3).
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 40
Procedures
Year 2 to Year 5
Week 53-
104
(± 2 
weeks)
Week 
105-208-
(± 3 weeks)
EOS or Early 
Discontinuation
Week 260
(± 3 weeks)
o
Home health/mobile phlebotomy services may be used as needed (for most 
biological samples collection only).
o
Clinical decisions may be based on local or central laboratory assessments.
Study Visit
14
15
16
17
18
Weeks after study 
intervention
78
104
156
208
260
Nonserious AEs determined to be related to study intervention by the 
investigator or where causality is unknown.
Particular attention will be given to renal disease, autoimmune, neurological and 
hematological changes.
Concomitant 
medications and 
procedures
Ongoing (including unscheduled visits)
Record concomitant therapy (related to reportable events) through the EOS (see 
Section 6.5).
All procedures and surgeries (including elective surgeries) will be recorded.
Note: FVIII product infusions will be recorded in the eDiary.
Review of the eDiary
Ongoing (including unscheduled visits)
Review the eDiary and ensure appropriate entries during unscheduled and 
scheduled visits.
Return eDiary
X
The eDiary will be returned during the Week 260 visit.
Optional Liver Biopsy
X
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 8.2.8.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 41
2. INTRODUCTION
2.1. Study Rationale
Sangamo Therapeutics has developed SB-525 (hereafter PF-07055480), an rAAV6 capsid 
and cDNA encoding for the BDD hFVIII. It encodes a liver-specific promoter module and 
rAAV6 exhibits liver tropism, thus providing the potential for sustained hepatic production 
of FVIII in hemophilia A participants to reduce or eliminate the need for FVIII replacement 
therapy.
PF-07055480 is being evaluated in an open-label, adaptive, dose-ranging Phase 1/2 study 
(SB-525-1603 [hereafter C3731001]) to assess the safety and tolerability in male participants 
≥18 years of age with severe hemophilia A. The preliminary data from the Phase 1/2 study 
indicate that treatment of hemophilia A with PF-07055480 offers clinical advantage over 
routine prophylactic treatment with FVIII. Specifically, these data indicate that treatment of 
hemophilia A with PF-07055480 is well tolerated and demonstrated a dose-dependent 
increase in FVIII levels, achieving clinically relevant increases in FVIII activity in the higher 
dose cohorts and at or near normal FVIII levels in the 3 x 1013 vg/kg highest dose cohort 
(normal range: 50-150%). In the highest dose cohort, participants did not require factor 
replacement therapy (after initial use of prophylactic factor) and experienced no bleeding 
events in the first year post dosing. 
The Phase 3 program includes 2 separate studies: a non-IMP lead-in study (C0371004), 
where data will be prospectively collected in the context of routine prophylaxis with FVIII 
products, and this C3731003 pivotal Phase 3 dosing study.
C3731003 pivotal Phase 3 study will further evaluate the clinical efficacy and safety of 
PF-07055480 in adult male participants with moderately severe to severe hemophilia A 
(FVIII:C≤1%) for 5 years after a single administration of the study intervention at the dose of 
3 x 1013 vg/kg, compared to routine prophylaxis with FVIII products. 
The study will enroll approximately 70 eligible participants from Study C0371004 to achieve 
at least 50 dosed participants who complete at least 15 months of follow-up postinfusion in 
this study (C3731003). These 50 participants will have completed at least 6 months of 
routine prophylaxis follow-up in Study C0371004. The duration of follow-up for subsequent 
participants in the lead-in study (C0371004) may be shorter than 6 months after at least 50 
hemophilia A participants are expected to reach 15 months postinfusion in this study 
(C3731003). 
The primary analysis will be conducted when at least 50 dosed participants with 6 months of 
follow up in the Lead_In study (C0371004) have reached at least 15 months of follow-up 
postinfusion (ie, data cutoff for primary analysis), corresponding to at least 12 months of 
follow-up for these 50 dosed participants after the estimated FVIII activity steady state onset. 
The onset of FVIII activity steady state based on the C3731001 study data is expected to be 
reached at the beginning of Week 9 postinfusion. However, as a conservative approach, the 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 42
beginning of steady state will be considered as Week 12 (ie, approximately 3 months) for the 
primary analysis. 
The primary endpoint in this study (C3731003) will be the Total ABR, including both treated 
and untreated bleeding events, and it will be compared with prior routine prophylaxis. The 
Total ABR will be assessed from Week 12 through at least 15 months postinfusion up to data 
cutoff. 
FVIII activity level >5% at 15 months postinfusion will be a key secondary endpoint. 
The other key secondary endpoint is the ABR (treated bleeding events) from Week 12 
through at least 15 months postinfusion up to data cutoff, compared to preinfusion 
prophylaxis.
The final analysis will be conducted when all dosed participants have completed the entire 
study (ie, 5 years of follow-up duration per participant) or discontinued prematurely from the 
study.
2.2. Background
PF-07055480 (SB-525) 
Gene therapy approaches in hemophilia A have been historically constrained by the large 
size of hFVIII gene, the high AAV dose required to achieve therapeutic FVIII levels, and the 
low manufacturing yields of AAV hFVIII. PF-07055480 has a shorter coding sequence for 
hFVIII BDD, an optimized, robust liver-specific promoter module to drive hFVIII 
expression, and improved virus yields. PF-07055480 is designed to require only a single 
administration into hemophilia A individuals, eliminating the disease burden associated with 
the condition and its treatment.
2.2.1. Summary of Clinical Experience with PF-07055480
Eleven (11) participants have been treated across 4 escalating dosage cohorts in the Phase 1/2 
study with 2 participants each in Cohorts 1 to 3 (9 x 1011 vg/kg, 2 x 1012 vg/kg, and 1 x 1013
vg/kg, respectively) and 5 participants in Cohort 4 at the Phase 3 dose of 3 x 1013 vg/kg.
Participants demonstrated a nonlinear dose-related increase in FVIII activity levels, 
achieving clinically relevant increases in FVIII activity in the higher dosage cohorts and at or 
near normal FVIII levels in the 3 x 1013 vg/kg dose cohort (normal range: 50 -150%) by the 
chromogenic substrate assay. 
In the highest dose cohort, participants did not require factor replacement therapy (after 
initial use of prophylactic factor) and experienced no bleeding events in the first year post 
dosing.
The most common treatment-related AEs in Cohort 4 were ALT and AST elevation, fever, 
and tachycardia. The respective episodes of fever (3 participants in Cohort 4) and the 
respective episodes of tachycardia (2 participants in Cohort 4) were Grade 1 or 2 in severity; 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 43
all episodes occurred within a day of dosing of PF-07055480. ALT and AST elevations were 
all of Grade 1 (3/4 participants) or 2 (1/4 participant) in intensity. Onset of ALT elevations 
occurred between 4 to 12 weeks after dosing and all resolved following tapering courses of 
corticosteroids. In all instances, corticosteroid taper was initiated within 12 weeks of 
corticosteroid implementation.
A treatment-related serious adverse event was reported in 1 participant at the 3 x 1013 vg/kg 
dose level (Cohort 4) and consisted of severe hypotension (Grade 3) and fever (Grade 2), 
with an onset 6 hours after completion of PF-07055480 infusion. The participant was treated
with 
 
 and was discharged 24 hours after the end of 
the PF-07055480 infusion, with no clinical signs remaining. Four other participants have 
subsequently been dosed at the 3 x 1013 vg/kg dose level and overall treatment was well 
tolerated with no other occurrence of Grade 3 or higher treatment related AEs. Allergic 
reactions, which may include hypotension and fever, were previously identified as potential 
risks of treatment with PF-07055480 and an Infusion Reaction Management Guide (with 
premedications and follow-up recommendations) will be implemented in this Phase 3 study. 
No participants experienced AEs leading to discontinuation of study participation and there 
was no emergence of confirmed FVIII inhibitors.
2.3. Benefit/Risk Assessment
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of PF-07055480 may be found in the Investigator’s Brochure, which 
is the single reference safety document for this study. 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)
PPD

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 44
2.3.1. Risk Assessment
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Identified Risks Associated with the Study Intervention
Infusion reactions (including 
hypersensitivity)
PF-07055480 may induce infusion-related reactions (IRRs) during 
or following administration. These reactions may be due to immune 
reactions and/or allergic reactions/hypersensitivity and lead to fever, 
chills, tachycardia, headache, nausea, vomiting or hypotension.
Several complex processes contribute to generating an immune 
response against an offending pathogen. Because AAV vectors lack 
any coding viral sequence, the main sources of foreign antigens 
brought in during gene transfer, aside from contaminant carryovers 
from the production and purification process, include the viral 
capsid.1 Innate immunity mounts rapidly, is non-specific, and does 
not result in immunological memory.
In the C3731001 Phase 1/2 study, IRR symptoms that occurred 
within a day of infusion included fever, tachycardia and 
hypotension. A case of severe hypotension occurred in one 
participant treated at the 3 x 1013 vg/kg dose which is being studied 
in this study, 6 hours after the end of the infusion and was 
successfully treated with 
 with discharge 
within 24 hours after the end of the study drug infusion.
To minimize and manage a potential adverse 
immune response to PF-07055480 or its excipients, 
premedication with acetaminophen and/or 
diphenhydramine hydrochloride is recommended 
before initiating dosing and during infusion.
In addition, IV infusion will occur while the 
participant is in the hospital or acute care facility, 
where he will remain for observation for a 
sufficient period of time postinfusion (at least 
24 hours), to monitor for an acute reaction and 
ensure the participant is in stable condition prior to 
discharge.
An IRR management guide which provides 
recommendations (summarized in the IB Section 
7.4.1 [Infusion Reactions [Including 
Hypersensitivity]]) on the infusion practice and 
clinical management of the study participants 
before, during and after PF-07055480 infusion 
(until discharge) will be distributed to the clinical 
sites.
Potential Risks Associated with the Study Intervention
Hepatotoxicity
The potential risk of liver inflammation for this liver-tropic viral 
vector is due to the activation of the immune system in the liver. All 
mechanisms are not elucidated but the T-cell mediated immune 
response activation may play a key role.2 The vector capsid remains 
behind in the cytosol of the transduced hepatocyte and undergoes 
proteasomal processing. Capsid-derived peptides are then 
transported to the endoplasmic reticulum and loaded onto MHC I 
molecules. CD8+ T-cells may recognize the viral vector capsid 
proteins which are presented as peptides on the surface of 
transfected hepatocytes that take up the rAAV. This may lead to 
transduced liver cells being killed by cytotoxic T lymphocytes and 
ultimately, to FVIII activity decrease. Activation of CD8+ T-cells 
Participants with markers of hepatic inflammation, 
cirrhosis, or fibrosis beyond limits specified in the 
protocol will be excluded from participation in this 
study, and hepatotoxic concomitant medications 
should be avoided.
Routine corticosteroid prophylaxis is not planned. 
However, due to a lack of clear predictability of a 
liver response based on NHP studies and the
possibility of decreased gene expression when 
corticosteroid initiation is delayed, both liver 
function tests and FVIII activity levels will be 
closely followed during the study (with frequent 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)
PPD

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 45
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
and presentation of capsid-derived peptides must occur in a similar 
time course to result in a clinically detectable event. Liver 
inflammation can be detected by elevated blood liver enzymes 
(transaminases; ALT and/or AST).
No published preclinical study in non-human primates (NHP) of any 
of AAV vectors showed a predictable liver response.3,4,5,6 All 
clinical studies reported thus far using AAV in hemophilia have 
shown a similar pattern where liver effects are seen approximately 3 
to 10 weeks (depending on the serotype and possibly on vector dose) 
after administration. ALT elevations are often accompanied by a 
decrease in transgene expression. ALT usually normalizes within a 
few weeks of initiating corticosteroids; however, a loss of transgene 
expression, when observed, did not typically recover.
In the ongoing Phase 1/2 (C3731001), all transitory elevations of 
liver function tests (LFTs) have been successfully treated with 
corticosteroid.
measurements as specified in the Schedule of 
Activities [Section 1.3]) and corticosteroids will be 
administered at the first sign of liver inflammation.
If there is evidence of transaminitis, the dose of 
prednisone or equivalent corticosteroid will be 
initiated as specified in Section 8.3.10
(Immunomodulation Optimization [Presumed 
T-Cell Activation]) of this study protocol. At this 
point, liver function and FVIII activity will be 
assessed twice a week until normalization of liver 
enzymes, and then per protocol thereafter. In 
addition, T-cell response will be assessed by a 
specific assay (ELISPOT) until normalization.
Neutralizing antibodies to AAV6
Administration of AAV vectors leads to the production of a humoral 
immune response to AAV. In clinical trials to date, anti-AAV 
neutralizing antibodies have been detected in all participants after 
vector infusion.1 The presence of neutralizing antibodies to AAV 
prior to PF-07055480 administration can affect transduction by 
forming immune complexes with the infused vector, and thereby 
prevent hepatocyte transduction.
Prior to the administration of PF-07055480, 
participants will be screened for neutralizing 
antibodies to AAV6 and those testing positive at 
the pre-specified threshold will not be administered 
PF-07055480.
In general, antibodies against PF-07055480 (total 
and neutralizing) will be continuously assessed 
throughout this study.
FVIII inhibitors
Factor VIII inhibitors are antibodies to FVIII that neutralize the 
clotting activity of FVIII. Development of inhibitors to administered 
FVIII is a known complication in 25-30% of severe hemophilia 
A patients. Influences for developing inhibitors include FVIII 
mutations, human leukocyte antigen (HLA) associations, and type of 
factor treatment (plasma derived factor concentrates or 
recombinant).7 Potential risk factors are early intensive replacement 
therapy and source of FVIII (human plasma or recombinant).8,9
In theory, there is a possibility that inhibitors to FVIII transgene can 
also develop. However, in the context of AAV trials, anti-transgene 
immune responses have been documented in only a few instances, 
mostly in the context of intramuscular delivery of AAV vectors. 
Participants with prior history of FVIII inhibitor 
(clinical or laboratory-based assessment) will be 
excluded from this study. Participants will also be 
required to have at least 150 documented EDs to a 
FVIII protein product (standard half-life or 
extended half-life recombinant, plasma derived) to 
be eligible for the study. This reduces the risk of 
inhibitor development as nearly all inhibitors occur 
prior to 50 EDs.
Study participants will also be assessed for the 
development of FVIII inhibitors at routine intervals 
post-PF-07055480 infusion, as described in the 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 46
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Indeed, one key factor determining the level of antitransgene 
immune responses is the target organ for gene transfer, which is 
determined by the combination of the AAV capsid, the vector 
delivery route, and the tissue specificity of the promoter driving 
gene expression. In particular, systemic and intramuscular vector 
administration, with either ubiquitous or muscle-specific promoters, 
have been shown to be more immunogenic than gene transfer to 
immune privileged organs as liver, as well as systemic 
administration with liver-specific promoters.1
In addition, high titer inhibitors generally do not occur after 150 
exposure days10 but may encounter a second peak in participants 
older than 60.11 Current AAV clinical trials in previously treated 
participants include participants with >150 exposure days (EDs) and 
no evidence of an inhibitor prior to entering a trial for a novel FVIII 
investigational product.6
To date, none of the participants enrolled in the AAV hemophilia 
trials have developed  inhibitors.12 In addition, none of the 11 
participants dosed with PF-07055480 in the ongoing Phase 1/2 
Study C3731001 have developed confirmed FVIII inhibitors.
protocol. There are existing protocols of treatment 
for patients with inhibitors such as use of the 
hemostatic bypass to treat or prevent bleeding and 
repeated infusions of FVIII to induce immune 
tolerance and reduce inhibitor levels.13
This study may be paused in the event of a 
confirmed inhibitor level for a participant; no 
additional participant will be treated until the 
circumstances for such an event are assessed and 
regulatory agencies are notified, if required.
Thromboembolic events
Some participants in the Phase 1/2 Study C3731001 and in this 
Phase 3 study experienced FVIII activity levels >ULN.
To date, no events of thrombosis or evidence of excessive 
coagulation have been reported in the ongoing Phase 1/2 Study 
C3731001. One event of thrombosis was reported to date (DVT) in 
this ongoing Phase 3 Study C3731003; it occurred in a participant 
who had multiple risk factors, 
 
 
Hemostasis parameters including, but not limited 
to, D-Dimer and thrombin-antithrombin levels as 
thrombotic potential will be measured on a regular 
basis and if vector-derived FVIII:C activity levels 
are >ULN in any participant during this study. In 
addition to activity levels, expression of FVIII 
antigen and of von Willebrand factor will also be 
regularly monitored. Participants will be monitored 
for any signs of adverse events.
Investigators will be provided with a guidance to 
manage participants with FVIII activity levels 
>ULN (“Management Guide for Elevated Factor 
VIII Activity Levels”), summarized in Section 
8.1.2 (Factor VIII activity) and in Section 8.2.7
(Hemostasis Parameters and Thrombotic Potential 
Assessment).
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)
PPD

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 47
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Participants with conditions associated with 
increased thromboembolic risk such as inherited or 
acquired thrombophilia, or a history of thrombotic 
events, including but not limited to stroke, 
myocardial infarction, or venous 
thromboembolism, are excluded.
This study will be paused in the case of an initial 
thrombotic event suspected to be related to >ULN 
FVIII activity levels for a participant; no additional 
participant will be treated until the circumstances 
for such an event are assessed and regulatory 
agencies are notified, if required. In the case of 
recurrence of a thrombotic event in a participant, 
the DMC will be convened urgently to assess the 
event. DMC recommendations will be taken into 
account in the decision to pause the study.
Off target effects
Transgene expression is driven by an expression cassette that 
contains a human liver-specific promoter. This restricts hF8 
expression to the liver as confirmed both in mice and NHPs where 
FVIII messenger ribonucleic acid (mRNA) expression was not 
detected in heart tissue. Recombinant AAV6 hFVIII vector genomes 
were detectable in other tissues (eg, heart), at levels several orders of 
magnitude lower than found in the liver and are not anticipated to 
present a clinical risk. However, there is the potential for capsid 
antigen presentation in the heart, should a cardiomyocyte be 
transduced by PF-07055480, and consequently the potential for a T 
cell response to occur.
To confirm that rAAV6 vector genomes produce no damage to heart 
muscle, electrocardiograms (ECGs) were performed at baseline and 
yearly postinfusion in the ongoing Phase 1/2 Study C3731001. To 
date, no clinically significant ECG abnormalities have been 
detected.
In this study, to monitor for such an event, baseline 
Troponin I will be measured at several time points 
in the first 18 weeks post-dosing, and in addition, if 
elevations in transaminases are observed that could 
signal a potential T-cell response to capsid antigen, 
then Troponin I will also be evaluated. If a 
confirmed elevation in Troponin I is observed 
greater than 99th percentile for upper limit of 
normal (ULN) confidence interval (CI), an ECG 
will be performed, and a cardiologist consulted. In 
addition, ECGs will be performed at baseline and 
annually.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 48
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Insertional mutagenesis
Following cellular transduction by AAV, most transgenes remain 
extrachromosomal as an episome; however, a small proportion have 
been found to integrate into the genome of transduced cells.14,15,16,17
Data from mice, dogs, NHPs and humans suggest that the 
integration of AAV vectors is a rare event, with most of the vector 
assimilating into concatemeric episomes.18,19,20 Unlike retroviral 
vectors, which encode viral proteins to create double-stranded 
breaks, when AAV integration does occur, it does so at preexisting 
chromosomal breaks.19,21 The results of integration are deletions in 
the AAV inverted terminal repeats (ITRs) and duplications of host 
sequences. Given the tissue tropism of AAV6 and the results of non-
clinical and clinical studies, the greatest potential for integration is 
within hepatocytes and to a much lesser extent in skeletal and 
cardiac myocytes (recombinant AAV2/6 hF8 vector genomes were 
detectable in other tissues (eg heart), but levels were several orders 
of magnitude lower than found in the liver).
The mouse and monkey studies performed with PF-07055480 
showed no findings of tumors by gross and histopathologic 
examination.16 Although there is no adequate animal model to 
address the tumorigenic potential, the available data from toxicology 
studies did not show any tumor formation.
In the ongoing Phase 1/2 Study C3731001, no neoplastic events, 
abnormal alpha-fetoprotein (AFP) and/or liver masses have been 
observed to date.
The choice of AAV as the basis for PF07055480 
already lowers the risk significantly. Participants in 
this study will be observed for at least 5 years post-
dosing.
In this study, for evaluation of liver 
carcinogenicity, hepato-cellular carcinoma (HCC) 
screening and monitoring will be conducted, which 
includes liver ultrasound and blood AFP 
measurements (blood marker of hepatocarcinoma) 
performed at least on an annual basis during the 5-
year study duration. Liver biopsy is recommended 
if there is an abnormal AFP and a >2 cm mass in 
the liver.22
Vector integration will be assessed on all available 
liver samples (collected to further assess 
abnormalities and/or via the optional liver biopsy 
substudy).
Germ line transmission from treated 
patients to the general population via 
transduction of germ cells or 
transmission of vector in sperm
Non-clinical studies in rabbits and human clinical studies indicate 
that AAV2 and AAV8 vectors shed to body fluids, including semen. 
In rabbits, the duration of detection of vector genomes in the semen 
is dose-dependent and time-dependent, with AAV infectious 
particles present up to Day 4 post-injection and undetectable 
thereafter.23 The virus present in these samples are in the seminal 
fluid, but transduction of sperm cells does not occur even at doses of 
AAV that are orders of magnitude above what is found in seminal 
fluid.24 This is consistent with the findings of several studies in 
rabbit and mouse suggesting that the risk of inadvertent germline 
transmission in males following IV administration of AAV vectors 
This study will enroll male participants only.
Participants in this study will be required to refrain 
from donating sperm, be abstinent (and agree to 
remain abstinent) or wear condoms during sexual 
activities until the vector can no longer be detected 
3 consecutive times in a row in semen.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 49
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
is negligible. Transduction of spermatocytes or sperm cells has not 
been observed yet.23,24,25,26,27,28
No data are available suggesting transmission of the AAV vector to 
the offspring of an exposed male participant.
Spread of vector from treated patients to 
other humans/organisms/environment
PF-07055480 theoretically may be transmitted to persons other than 
a participant in this study. The recombinant vector is replication-
incompetent and is not expected to survive, multiply or disperse if it 
were to be eliminated intact from a treated patient.
Recombinant AAV vectors have been substantially modified 
compared to wildtype AAV. PF-07055480 is replication defective 
due to removal of all the viral gene coding sequences, including the 
rep and cap genes, required for replication. As a consequence, PF-
07055480 is replication defective even in a cell co-infected with 
known AAV helper viruses (adenovirus, herpesvirus).
Following injection into the patient, PF-07055480 replication could 
only occur in the extremely unlikely event of a host cell being 
coinfected by three separate entities (PF-07055480, wild-type AAV 
and a helper virus such as human adenovirus or herpes simplex 
virus).
In the ongoing Phase 1/2 Study C3731001, vector shedding has been 
assessed using quantitative real-time PCR (qPCR) analysis of saliva, 
urine, semen, stool, and plasma. Data suggested that that the levels 
of shedding vector were generally highest during the first couple of 
weeks after vector infusion, and gradually declined in all types of 
specimens.
Vector shedding will be monitored and will be 
measured by quantitative PCR in plasma, 
peripheral blood mononuclear cells (PBMC), 
saliva, semen and urine of participants following 
administration of PF-07055480 until 3 consecutive 
samples, for each matrix tested, demonstrate a 
qPCR signal at or below the limit of assay 
detection.
Should intact vector particles be shed into the 
environment, these particles will still be 
non-replicative and nonpathogenic. Vector particles 
would be degraded quickly in the environment. 
Hence, the chance of harm being caused by spread 
of the vector in the environment is negligible.
Participants in this study will be required to refrain 
from donating sperm, be abstinent (and agree to 
remain abstinent) or wear condoms during sexual 
activities until the vector can no longer be detected 
3 consecutive times in a row in semen.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 50
Potential Risk of Clinical Significance
Summary of Data/Rationale for Risk
Mitigation Strategy
Risk Associated With the Study Procedures
Placement/Removal of an IV catheter
The placement of an IV catheter and bleeding after removal of the 
catheter are both considered low risk.
With any parenteral injection, a risk of local or systemic infection 
also exists.
In this study, bleeding risk will be lowered by the 
application of local pressure according to the 
standard procedure following IV infusions. In 
addition, it is recommended that participants 
receive an infusion of FVIII replacement therapy 
within 24 hours prior to the PF-07055480 infusion, 
as indicated in the protocol, and will have 
appropriate factor coverage for approximately 2 
weeks post PF-07055480 infusion.
In order to minimize the risk of infection, 
PF-07055480 will also be administered using 
standard sterile techniques.
Optional liver biopsy
The procedure of percutaneous liver biopsy and inserted needle can 
lead to bleeding and perforation to nearby organs (with serious 
complications occurring less than once in every 10,000 procedures). 
A risk of local or systemic infection also exists.
To reduce these risks, a robust pre- and post-
biopsy surveillance plan according to the local 
procedures and as suggested in Section 8.2.8 is 
recommended. 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. In order to 
minimize the risk of infection, standard sterile 
techniques will be used.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 51
2.3.2. Benefit Assessment
The major benefit of gene therapy is that it may provide persistent treatment of hemophilia 
by continuous endogenous production of functional FVIII, providing therapeutic effect and a 
relief from the medical and lifestyle burden of recurrent on demand or routine prophylactic 
protein replacement therapy. By providing a stable production of serum FVIII levels, 
protection for bleeding episodes may be provided. Although replacement therapy increases 
FVIII levels in the bloodstream, these levels include peaks and troughs that are non 
physiological and lead to less protection before the next infusion. Gene therapy may also 
favourably impact the recognised complications of hemophilia: recurrent hemarthroses and 
the subsequent arthropathy. It is feasible that gene therapy treatment may result in 
expression of FVIII consistent with conversion from a moderate or severe to a mild 
hemophilia or better, persisting for at least a decade.19,29 Under such circumstances, 
treatment could offer a major contribution to patient care whereby sufferers of hemophilia A 
could be considered largely relieved of disease symptoms and the burden of treatment. Gene 
therapy may also be especially beneficial to individuals that have difficulty maintaining 
adequate adherence to the regular prophylaxis treatment whether due to lack of compliance, 
the burden of care imposed by prophylactic treatment regimens or other considerations such 
as lack of sufficient venous access.
Phase 1/2 study provided preliminary evidence of PF-07055480 efficacy in terms of FVIII 
activity with associated decreases in bleeding episodes, FVIII consumption and replacement 
infusions. The aim of this Phase 3 study is to further assess these potential clinical benefits 
after infusion of study intervention. Additional benefits of study participation include close 
medical monitoring during the study including where appropriate, but not limited to physical 
exams, ECGs and liver ultrasounds.
2.3.3. Overall Benefit/Risk Conclusion
Taking into account the measures taken to minimize risk to study participants, the potential 
risks identified in association with PF-07055480 are justified by the anticipated benefits that 
may be afforded to participants with hemophilia A.
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS
Objectives
Endpoints
Primary Efficacy Objective
Primary Endpoint and Key Secondary 
Endpoints

Evaluate the efficacy of a single infusion of 
PF-07055480 in participants ≥18 and 
<65 years of age with moderately severe to 
severe hemophilia A (FVIII C ≤1%).
Primary Endpoint:

Total ABR (spontaneous and traumatic 
bleedings, treated and untreated) from 
Week 12 through at least 15 months 
following PF-07055480 infusion versus 
Total ABR on prior FVIII prophylaxis 
replacement regimen.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 52
Objectives
Endpoints
Key Secondary Endpoints:

FVIII activity level >5% at 15 months 
following infusion of PF-07055480.

ABR (spontaneous and traumatic treated 
bleedings) from Week 12 through at least 
15 months following PF-07055480 infusion 
versus ABR on prior FVIII prophylaxis 
replacement regimen.
Secondary Efficacy Objectives
Secondary Efficacy Endpoints

To demonstrate that the use of exogenous 
FVIII is significantly reduced post 
PF-07055480 infusion.

AIR of exogenous FVIII from Week 12 
through at least 15 months following 
infusion of PF-07055480 versus AIR on 
prior FVIII prophylaxis replacement 
regimen.

To assess additional efficacy parameters post 
PF-07055480 infusion including FVIII 
activity level, use of exogenous FVIII, 
information on bleeding events and PROs.

FVIII activity level from Week 12 through 
15 months following infusion of 
PF-07055480.
The following secondary parameters will be 
assessed from Week 12 through at least 15 
months after PF-07055480 infusion and 
compared with prior FVIII prophylaxis 
replacement regimen:

Annualized FVIII consumption.

ABR of specific type:
o
by cause (spontaneous or traumatic)
o
by location (in joints, in target joints, or 
in soft tissue).

Total ABR by cause and by location.

Percentage of participants without bleeds.
The following secondary parameters will be 
assessed by visit after PF-07055480 infusion:

FVIII activity level 

Change from baseline in joint health as 
measured by the HJHS instrument.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 53
Objectives
Endpoints

Change from baseline in the following 
PRO endpoints:

Haem-A-QoL

HAL.

Estimate the durability of efficacy up to 
5 years after PF-07055480 infusion.
The following parameters will be analyzed 
yearly or by visit as appropriate:

ABR.

FVIII activity level.

AIR of exogenous FVIII.

Annualized FVIII consumption.

ABR of specific type:
o
by cause (spontaneous or traumatic).
o
by location (in joint, in target joints, or 
in soft tissue).

Total ABR.

Total ABR by cause and by location.

Percentage of participants without bleeds.

Change from baseline in joint health as 
measured by the HJHS instrument.

Change from baseline in PRO endpoints: 
Haem-A-QoL and HAL.
In addition, ABR, Total ABR, and AIR will be 
analyzed throughout the 5-year study period.
Secondary Safety Objective
Secondary Safety Endpoints

To estimate the safety and tolerability of 
PF-07055480, including immunogenicity, 
for the study duration of 5 years after 
PF-07055480 infusion.

Incidence and severity of AEs.

Events of special interest (such as 
hypersensitivity reactions, clinically 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 54
Objectives
Endpoints
reported thrombotic events, and 
malignancy).

Immunogenicity:
o
Antibodies against AAV6 capsid 
protein (nAbs and ADAs).
o
T-cell responses against AAV6 capsid 
and against the transgene.
o
FVIII inhibitors.
Tertiary/Exploratory

To evaluate vector shedding and infectivity 
in body fluids.

Vector shedding and infectivity of 
PF-07055480 in plasma, saliva, PBMC, 
urine, and semen until negative on 
3 consecutive occasions for each specimen 
type.

To evaluate exploratory pharmacodynamic 
biomarkers.

FVIII antigen levels.

Von Willebrand factor.

To compare joint health post PF-07055480 
infusion to baseline and evaluate long-term 
joint outcomes.

Number of target joints.

Joint status as assessed by X-ray.

Joint status as assessed by ultrasound.

To evaluate for any effects on coagulation.

Coagulation activation tests: aPTT, INR, 
D-dimer, TGA, and TAT.

Comparison of FVIII activity between one 
stage assay and chromogenic assay.

Recovery of FVIII products post gene 
therapy

To further compare PF-07055480 on PROs 
addressing health-related quality of life, 
activities of daily living and general health 
status.
The following PRO instruments will be 
compared with FVIII replacement regimen, 
using comparisons pre and postinfusion of 
PF-07055480 through 12 months and annually 
during the follow-up period:

HLIQ
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 55
Objectives
Endpoints

EQ-5D-5L

To further evaluate PF-07055480 
mechanism of action and immune 
responses.

Cellular immunity by cell-mediated assays.

Binding IgG versus IgM assay.

Other biomarkers as inflammatory 
cytokines.

To evaluate the cross reactivity between 
AAV serotypes.

nAbs against other AAV serotypes.
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): 
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)
The primary estimand is the treatment effect of PF-07055480 with respect to Total ABR 
(including both treated and untreated bleeding events) after the estimated FVIII activity 
steady state onset, ie, from Week 12 through at least 15 months postinfusion or until 
resumption of FVIII prophylaxis regimen (if necessary). Total ABR will be analyzed using 
comparisons of postinfusion PF-07055480 Total ABR versus preinfusion Total ABR 
collected during the lead-in study (C0371004) and prior to dosing in this study (C3731003) 
using a repeated measures negative binomial regression model. Data before Week 12
postinfusion are excluded to account for the potential differences in participants’ 
pharmacokinetics post infusion. Data following resumption of the prophylaxis FVIII regimen 
(if necessary) will be excluded. Because no more than a single dose of study intervention will 
be administered during the study, there should be no treatment discontinuations. 
The secondary estimands are the treatment effect of PF-07055480 with respect to FVIII 
activity level >5% at 15 months postinfusion and the ABR (treated bleeding events) from 
Week 12 through at least 15 months postinfusion. 
Any sample taken within 72  hours  of standard half-life exogenous FVIII replacement 
therapy or 120 hours of extended half-life exogenous FVIII replacement therapy 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 56
administered for any purpose (including treatment of bleeding or prevention purposes) will 
be excluded from the assessment of FVIII activity level at 15 months. Additionally, any 
FVIII activity levels after the resumption of FVIII prophylaxis regimen before 15 months 
will be replaced with 0.9% for analysis purposes, and therefore considered as having FVIII 
activity ≤ 5%.  Because no more than a single dose of study intervention will be administered 
during the study, there should be no treatment discontinuations. Missing data are anticipated 
to be rare; thus, there will be no imputations for missing data. 
ABR will be analyzed using the same analysis method as described for Total ABR.
4. STUDY DESIGN
     
4.1. Overall Design
Study C3731003 is a Phase 3, open-label, multicenter, single arm study to evaluate the 
efficacy and safety of a single infusion of PF-07055480 in adult male participants with 
moderately severe to severe hemophilia A (FVIII:C ≤1%).
Eligible study participants will be followed while on routine FVIII prophylaxis therapy in the 
lead-in Study C0371004 in order to collect pretreatment (established usual care) data for 
efficacy and selected safety parameters. 
This study will include a 6-week screening and baseline period followed by the dosing day 
(Day 1), a 2-year efficacy and safety observation period (short term follow-up), and a 3-year 
long-term follow-up period. After this 5-year follow-up period in Study C3731003, 
participants will be invited to enter a separate study to assess the long-term safety and 
effectiveness of PF-07055480 for the treatment of hemophilia A and to allow follow-up for a 
total of up to 10 additional years post-study, corresponding to up to 15 years 
post-PF-07055480 infusion. This long-term follow-up study is planned to assess the 
durability of efficacy demonstrated through main efficacy endpoints of FVIII activity levels, 
the occurrence of bleed events (eg, ABR) and FVIII product use. The safety follow-up is 
planned to include the collection of SAEs, AEs of special interest (eg, hypersensitivity 
reactions, thromboembolic events, liver abnormalities, FVIII inhibitor, malignancy, 
cardiovascular events) and all-cause mortality. Visits are planned to occur as per standard 
practice for each site to include at least 1 annual visit.
Approximately 70 participants from the lead-in Study C0371004 will be enrolled and eligible 
participants will be assigned to study intervention to achieve a desired sample size of at least 
50 dosed participants completing at least 15 months of follow-up postinfusion. These 50 
participants will have completed at least 6 months of routine prophylaxis follow-up in Study 
C0371004. 
The primary analysis will be conducted when at least 50 dosed participants with 6 months of 
follow up in the Lead In study (C0371004) have reached at least 15 months of follow-up 
postinfusion (ie, data cutoff for primary analysis), corresponding to at least 12 months of 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 57
follow-up for these 50 dosed participants after the estimated FVIII activity steady state onset. 
The onset of FVIII activity steady state based on the C3731001 study data is expected to be 
reached at the beginning of Week 9 postinfusion. However, as a conservative approach, the 
beginning of steady state will be considered as Week 12 (ie, approximately 3 months) for the
primary analysis. 
The primary analysis will assess the Total ABR, including both treated and untreated 
bleeding events, and it will be compared with prior routine prophylaxis.  The Total ABR will 
be assessed from Week 12 through at least 15 months postinfusion up to data cutoff in at 
least 50 dosed participants (Figure 1), compared to preinfusion prophylaxis.
FVIII activity level >5% at 15 months postinfusion will be a key secondary endpoint. The 
other key secondary endpoint is the ABR (treated bleeding events) from Week 12 through at 
least 15 months postinfusion up to data cutoff in at least 50 dosed participants, compared to 
preinfusion prophylaxis.
The final analysis will be conducted when all dosed participants have completed the entire 
study (ie, 5 years of follow-up duration per participant) or discontinued prematurely from the 
study.
The study may be paused in the event of a confirmed inhibitor level or a thrombotic event 
suspected to be related to >ULN FVIII activity levels for a participant as further described in 
Section 8.2.7.2 and in Section 8.1.2.3.
If the decision to pause the study is made, no additional participant will be treated until the 
circumstances for such an event are assessed and regulatory agencies are notified, if required. 
If paused, the trial re-start will only be possible after Regulatory Authority approval via 
substantial amendment, where applicable, based on local/regional regulatory requirements.
4.2. Scientific Rationale for Study Design
Collecting prospective data in the lead-in study and collecting data after a single 
PF-07055480 infusion allows for comparison analyses and a relatively low number of 
participants for a statistically robust study. During this lead-in study, eligible adult 
participants would have received prophylaxis with FVIII replacement product as part of SOC 
along with on-demand infusions as necessary for bleeding events.  
The planned study duration of 5 years for each participant takes into consideration the EMA 
and FDA Guidances for gene therapy30,31,32,33 and includes 2 years of initial efficacy and 
safety observations (short-term follow-up) followed by a 3-year efficacy and safety 
long-term follow-up period. The short-term follow-up period focuses on efficacy and safety 
concerns expected within the first 2 years and will include frequent visits and laboratory 
assessments with special emphasis placed on liver, cardiac toxicity, inhibitors and FVIII 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 58
activity. During this period, all AEs and SAEs will be collected. Monitoring of liver function 
and FVIII activity will continue during the next 3 years of follow-up. In addition, other 
potential systemic complications (such as renal disease, autoimmune, neurological, or 
hematologic changes), medically important events, and events related to study intervention 
(or when causality is unknown) will be monitored.
The primary efficacy endpoint will be the Total ABR (including both treated and untreated 
bleeds) from Week 12 through at least 15 months following infusion of PF-07055480 in at 
least 50 dosed participants. The ABR (treated bleeds) from Week 12 through at least 15 
months postinfusion will be a key secondary endpoint. Analyses will be based on 
comparisons of Total ABR and ABR before treatment with PF-07055480 (lead-in C0371004 
study and preinfusion of PF-07055480 in this study [C3731003]) and following treatment 
with PF-07055480.
Annualized bleeding rate is an endpoint demonstrating meaningful clinical benefit that has 
been used as the primary endpoint in prelicensure studies of new FVIII and FIX products and 
is strongly associated with long‐term joint function.34
FVIII activity level >5% at 15 months postinfusion will be another key secondary endpoint. 
Factor VIII levels determine the severity of the disease and correlate with the risk of bleeding 
episodes.35 In studies of prophylaxis in hemophilia A and in hemophilia B participants, 
higher doses of the respective clotting factor products administered at the same frequency as 
lower doses resulted in a lower incidence of bleeding episodes into joints and bleeding 
episodes, respectively.36,37 The increase in FVIII activity reduces the ABR, and this reduction 
in the ABR (ie, treated bleeding episodes) has been used as the endpoint for assessing 
efficacy of FVIII prophylaxis treatment regimens. As FVIII gene therapy assures consistent 
expression of FVIII activity, clotting factor activity is also an accurate and objective endpoint 
to evaluate efficacy.38
FVIII activity at 15 months will be compared to a fixed threshold of 5% activity to determine 
the percentage of participants reaching this threshold. The therapeutic range of FVIII is wide 
and levels above 5% reflect a range of FVIII activity that is clinically meaningful based on 
reducing the frequency of bleeding episodes in general and the frequency of episodes of 
hemarthrosis, a major risk of hemophilic arthropathy.      
4.3. Justification for Dose
The data from the Phase 1/2 study indicate that the single dose of 3×1013 vg/kg of body 
weight has an acceptable safety profile and is efficacious in all 5 participants with severe 
hemophilia A (<1%) treated at this dose (Section 2.2). All participants at this dose have had 
increases in FVIII activity and at or near FVIII levels within the normal range, with no 
bleeding episodes and FVIII product infusions reported in the first year post dosing.
4.4. End of Study Definition
A participant is considered to have completed the study if he has completed the entire study 
including EOS visit (Week 260).
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 59
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:
Age:
1. Participant must be ≥18 and <65 years of age at the time of signing the informed 
consent.
Type of Participant and Disease Characteristics
2. Participants must have been followed on routine FVIII prophylaxis therapy in the 
lead-in study (C0371004) and have ≥150 documented exposure days to a FVIII 
protein product (standard half-life or extended half-life recombinant, plasma 
derived).
3. Participants who have documented moderately severe to severe hemophilia A 
defined as circulating FVIII activity levels ≤1%.
4. Participants must agree to suspend prophylaxis therapy for hemophilia A after 
administration of the study intervention (see guidance in general notes of SoA). 
FVIII replacement therapy is allowed as needed (see Section 6.5.1).
5. Acceptable screening central laboratory values as follows:

Hemoglobin ≥11 g/dL

Platelets ≥100,000 cells/µL;

Creatinine ≤2.0 mg/dL. 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 60
Sex
6. Male
Contraceptive use by men should be consistent with local regulations regarding the methods 
of contraception for those participating in clinical studies.
a.
Male Participants:
Male participants are eligible to participate if they agree to the following during the 
intervention period and for at least the time required for 3 consecutive ejaculate samples to 
test negative for vector shedding:

Refrain from donating sperm.
PLUS, either:

Be abstinent from heterosexual or homosexual intercourse as their preferred and 
usual lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent. 
OR

Must agree to use contraception/barrier as detailed below. 
o
Agree to use male condom when engaging in any activity that allows 
for passage of ejaculate to another person.
Informed Consent
7. Capable of giving signed informed consent as described in Appendix 1 which 
includes compliance with the requirements and restrictions listed in the ICF and in 
this protocol.
For German sites, please refer to Country-Specific Appendix (Section 10.8.3).
5.2. Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. Anti-AAV6 nAb titers, above or equal to the established threshold of 1:4, performed 
by a central laboratory during screening.
2. Prior history of FVIII inhibitor (clinical or laboratory-based assessment) defined as a 
titer ≥0.6 BU/mL, regardless of the laboratory normal range, or any measured 
Bethesda inhibitor titer greater than the ULN for the laboratory performing the assay. 
Clinically, no signs or symptoms of decreased response to FVIII administration.
3. Known hypersensitivity to FVIII replacement product or intravenous immunoglobulin 
administration.
4. History of chronic infection or other chronic disease that investigator deems an 
unacceptable risk. In addition, any participant with conditions associated with 
increased thromboembolic risk such as inherited or acquired thrombophilia, or a 
history of thrombotic events, including but not limited to stroke, myocardial 
infarction, or venous thromboembolism, is excluded.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 61
5. Any concurrent clinically significant major disease or condition  or other acute or 
chronic medical or psychiatric condition including recent (within the past year) or 
active suicidal ideation or behavior (including alcoholism) or laboratory abnormality 
that may increase the risk associated with study participation or may interfere with 
the interpretation of study results and, in the judgment of the investigator, would 
make the participant inappropriate for entry into this study. In addition, any 
participant with a history of a neoplasm (including hepatic malignancy) that required 
treatment (eg, chemotherapy, radiotherapy, immunotherapy), is excluded, except for 
adequately treated basal or squamous cell carcinoma of the skin or a surgically 
removed benign neoplasm not requiring chemotherapy, radiotherapy and/or 
immunotherapy. Any other neoplasm that has been cured by resection should be 
discussed between the investigator and sponsor.
6. ALT, AST, ALP >2x ULN, based on central laboratory results.
7. Bilirubin >1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is 
fractionated and direct bilirubin <35%), based on central laboratory results.
8. Current unstable liver or biliary disease per investigator assessment defined by the 
presence of ascites, hepatic encephalopathy, coagulopathy, hypoalbuminemia, 
esophageal or gastric varices, persistent jaundice, or cirrhosis. Note: Stable chronic 
liver disease (including Gilbert's syndrome, asymptomatic gallstones), is acceptable if 
the participant otherwise meets entry criteria.
Note: Participants who have a central laboratory test value that is outside the range 
specified by the exclusion criteria may have the test repeated, by the central laboratory, to 
determine eligibility; however, the result must be available prior to Baseline Visit/Visit 2.
Prior/Concomitant Therapy:
9. Currently on antiviral therapy for hepatitis B or C.
10. Any participant with a planned surgical procedure requiring FVIII surgical 
prophylactic factor treatment in the next 12 months.
11. Participants using therapies that are restricted. See Section 6.5.2 for therapies not 
allowed during study participation.
12. Participants who previously received PF-07055480 or any other gene therapy.
Prior/Concurrent Clinical Study Experience:
13. Previously dosed in a gene therapy research trial at any time or an interventional 
clinical study within the last 12 weeks, excluding participation in Study C0371004.
Diagnostic Assessments:
14. Active hepatitis B or C:

HBcAb, HBsAg, and HBV DNA positivity. Exception: if a participant is 
positive for HBcAb, then HBsAg and HBV DNA must be negative for 
inclusion. 

HCV-RNA positivity.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 62
15. Significant liver disease, defined by pre-existing diagnosis of portal hypertension, 
splenomegaly or hepatic encephalopathy. Additionally, during screening, a serum 
albumin level below normal limits and/or significant liver fibrosis by any of the 
following diagnostic modalities (Please note that only 1 test is needed for screening 
purposes): FibroScan score >8 kPa units, Fibro Test/FibroSURE >0.48. If there is 
concern regarding the FibroTest or the FibroScan results due to a confounding 
medical history (eg, proteinuria can impact FibroTest result), or in the event of 
conflicting results between the modalities, the investigator should contact the sponsor 
for further guidance.
Note: if a participant has a known history of Gilbert's syndrome, a FibroTest cannot 
be used for fibrosis testing.
16. Serological evidence of HIV-1 or HIV-2 with either CD4+ cell count ≤200 mm3 or 
viral load >20 copies/mL.
Other Exclusions:
17. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 
participants who are Pfizer employees, including their family members, directly 
involved in the conduct of the study. 
For German sites, please refer to Country-Specific Appendix (Section 10.8.3). 
18. Unable to comply with scheduled visits, infusion of PF-07055480 in the 
investigator’s judgement. 
For German sites, please refer to Country-Specific Appendix (Section 10.8.3). 
19. Unable or unwilling to comply with the protocol.
20. Sensitivity to heparin or heparin-induced thrombocytopenia.
21. Sensitivity to any of the study interventions, or components thereof, or drug or other 
allergy that, in the opinion of the investigator or the sponsor’s Medical Monitor, 
contraindicates participation in the study.
5.3. Lifestyle Considerations
1. Participants are expected to remain compliant with inclusion criterion 6 at least until 
3 consecutive ejaculate samples test negative for vector shedding.
2. Participants should report increased alcohol consumption (compared to usual/baseline 
consumption).
3. Participants should be informed that alcohol consumption could contribute to 
abnormally elevated LFT results and thereby delay the infusion of the study drug. 
In addition, participants who report increased alcohol consumption (which is any 
amount of alcohol consumption greater than the baseline amount for that participant) 
at any time throughout the study, should have at a minimum local LFTs and FVIII 
activity monitored.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 63
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. Some procedures may need to be repeated based on the 
rescreening date, the protocol’s screening/baseline authorized time windows and after 
consulting with the sponsor’s medical monitor.
Participants who have a central laboratory test value that is outside the range specified by the 
exclusion criteria may have the test repeated, by the central laboratory, to determine 
eligibility; however, the result must be available prior to Baseline Visit/Visit 2.
6. STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, medical device(s), or study procedure(s) intended to be administered to a study 
participant according to the study protocol.
6.1. Study Intervention(s) Administered
ARM Name
Single arm study
Intervention 
Name
PF-07055480   
Type 
Gene therapy
Dosage Form
Injectable
Dose Strength
1.0×1013 vg/mL
This nominal strength will be used for dosage calculation
Dosage
Single infusion: 3×1013 vector genomes/kg body weight.
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 
Sourcing
Provided centrally by the sponsor.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 64
Packaging and 
Labeling
Study intervention may be provided in 4.7 mL/vial or 6 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
For Japanese sites and Japanese investigators, please refer to Section 10.8.2 for the reporting 
of study intervention defects.
6.2. Preparation/Handling/Storage/Accountability
1. 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.
2. 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.
3. 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 study intervention may be 
ordered noting that it will take approximately 3 weeks for study intervention delivery. Prior 
to IP ordering, consider Sections 10.9.1 and 10.9.6.
No participants or third-party payers will be charged for study intervention.
6.3. Measures to Minimize Bias: Randomization and Blinding
Open-label using 
central 
randomization via 
(IVRS/IWRS)
This is an open-label study; however, the specific intervention to be 
taken by a participant will be assigned using an IVRS/IWRS 
(eg, IMPALA). The site will contact the IVRS/IWRS 
approximately 3 weeks before the start of study intervention 
administration for each participant (during baseline period). The 
infusion site will record the intervention assignment on the 
applicable case report form, if required.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 65
6.4. Study Intervention Compliance
Study treatment will be infused via infusion pump on Day 1 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. Prior to dosing, consider Sections 10.9.1 and 10.9.6. For Japanese sites, please 
refer to Japan Appendix (Section 10.8.2).
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
Any concomitant therapy such as procedures, medication, or vaccine use (including: 
prescription and non-prescription medications, including over-the-counter and alternative 
preparations such as herbal remedies, vitamins, and health food supplements) in the 30 days 
before screening and during screening must be recorded at baseline on the participant’s 
eCRF, according to instructions for eCRF completion. With the exception of FVIII 
replacement therapy, concomitant therapy throughout the study must be recorded on the 
eCRF as follows:

All concomitant therapy (including any COVID-19 vaccinations – see Section 10.9.6) 
during the short-term monitoring period (up to and including 104 weeks 
postinfusion).

The concomitant therapy associated with AEs reported during the long-term 
monitoring period (Week 105 postinfusion until EOS). See Section 8.3.1 for AE 
recording requirements.

All surgical procedures, including elective surgeries, will be recorded throughout the 
entire study. Additional information regarding surgeries (eg, blood loss and/or 
transfusion information) will be collected on relevant CRF(s).
The reasons for concomitant therapy will include:

Reason for use.

Dates of administration including start and end dates.

Dosage information including dose and frequency.
The sponsor’s Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
Participants taking medication for a preexisting condition should be on a regimen for at least 
3 weeks. Ideally, dosage should not be changed during the first year after PF-07055480 
infusion.
Recommended premedications and procedures related to PF-07055480 infusion and to the 
clinical management of infusion reaction are indicated in the Infusion Reaction Management 
Guide. 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 66
6.5.1. Allowed Therapy
In the event of lack of efficacy, participants may resume their previous treatment plan 
(ie, treatment before gene therapy administration). Otherwise, FVIII product may be 
administered when clinically indicated (ie, surgical prophylaxis, traumatic bleed). 
During the study, participants will be requested to suspend their FVIII prophylaxis regimen 
approximately 2 weeks after infusion of PF-07055480, but FVIII replacement therapy is 
allowed, as needed. The infusion data (specific product, date, time, dosage, reason) is to be 
recorded in the eDiary.

For a bleeding event, the investigator/study staff will recommend the appropriate 
dose of FVIII product to treat the bleed, taking into consideration the most recent 
and highest PF-07055480-induced FVIII activity levels (by one-stage or 
chromogenic assays, either from the local or central laboratory) to avoid 
overdosing. Corrections that increase total FVIII activity levels to >150% may 
result in an increased risk of potential thrombotic events. World Federation of 
Hemophilia guidelines for target FVIII levels based on bleed type should be 
followed.39
A participant may resume prophylaxis if the PF-07055480 treatment is not efficacious, 
defined for this study as:

FVIII activity after 12 weeks of ≤1% (in the absence of a confirmed FVIII 
inhibitor) as determined by the central laboratory on 2 consecutive samples 
collected within a 2-week period and/or over a 4-week period (in the absence of a 
confirmed FVIII inhibitor);

2 or more spontaneous bleeds into a major joint and/or target joint, or

3 or more spontaneous bleeds (consisting of joint bleeds and/or significant soft 
tissue/muscle or other site bleeds). Significant spontaneous bleeds are defined as 
those that lead to a transient or persistent loss of function.
The investigator is to inform the sponsor's medical monitor before resuming prophylaxis or if 
prophylaxis has been resumed. Dosing of prophylaxis will be based on the current steady-
state FVIII activity level. A participant who resumes prophylaxis may choose to discontinue 
it; however, before discontinuation, the investigator is to discuss with the Sponsor's medical 
monitor.
Additional allowed therapies include the following:

COX-2 inhibitors and topical NSAIDs

HIV therapy

Prophylactic anticoagulation therapy in the setting of FVIII activity increases >ULN 
(please also refer to the “Management Guide for Elevated Factor VIII Activity 
Levels”)
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 67
For guidance about COVID-19 vaccination, refer to Appendix 9 (Section 10.9.6). 
Hepatitis B and hepatitis C therapies: For all participants, any use of therapy for hepatitis B 
and/or hepatitis C, regardless of the time period when taken or association with a reported 
adverse event, is to be collected and recorded on the CRF (for pre-study therapies, only if 
known).
HIV therapies: The ongoing therapies taken by the participants with stable HIV at inclusion 
will be collected as part of the concomitant therapies. If there is a change in HIV therapies 
during study or if a participant gets infected by HIV while on study, any use of HIV therapy, 
regardless of the time period when taken or association with a reported adverse event, is to be 
collected and recorded on the CRF.
6.5.2. Disallowed Therapy
The following concomitant medications are not permitted during the study:

Blood products such as RBCs, platelets, and fresh frozen plasma, except as 
required during a surgery or as clinically indicated in the setting of an emergency.

Medications that may increase the risk of bleeding such as anti-platelet agents (eg, 
aspirin, clopidogrel); NSAIDs (eg, ibuprofen, naproxen); anticoagulants (eg, 
warfarin, apixaban), except for the management of FVIII activity increases >ULN 
(please also refer to Section 6.5.1 and the “Management Guide for Elevated 
Factor VIII Activity Levels”). Low dose aspirin (<100 mg/day) and PRN use of 
NSAIDs are allowed where medically necessary. Please contact the sponsor’s 
medical monitor if there are any questions regarding the use of medications that 
may prolong bleeding.

Where possible, medications with known hepatoxicity should be avoided. The 
investigator should inform the sponsor’s medical monitor of any plan to 
administer a medication with known hepatotoxicity.

Concomitant use of another investigational therapy (for guidance about 
COVID-19 vaccination, refer to Appendix 9 [Section 10.9.6]); concurrent 
participation in another interventional clinical study is not allowed.

Bypassing agents (eg, factor VIIa, activated prothrombin complex concentrate) 
and nonfactor treatment (eg, emicizumab), except in situations where it is 
medically necessitated. Antifibrinolytics (aminocaproic acid or tranexamic acid)
are also disallowed.
6.6. Dose Modification
No more than a single dose of the study intervention on Day 1 will be administered during 
this study.
6.7. Intervention After the End of the Study
No further intervention is planned after the end of the study.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 68
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
     
7.1. Discontinuation of Study Intervention
Because no more than 1 single infusion of PF-07055480 on Day 1 will be administered 
during the study, this section is not applicable. Refer to the IP Manual for information 
regarding any disruption in administration of the infusion.
7.2. Participant Discontinuation/Withdrawal from the Study
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, 
or administrative reasons. Reasons for discontinuation from the study include the following:
Refused further follow-up;
Lost to follow-up;
Death;
Study terminated by sponsor.
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted, as shown in the SoA. See the SoA 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/randomized 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/she 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 a withdrawal of consent.
When a participant withdraws from the study because of an SAE, the SAE must be recorded 
on the CRF and reported on the CT SAE Report.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 69
7.2.1. Withdrawal of Consent
When a participant specifically withdraws consent for any further contact with him or her or 
persons previously authorized by the participant to provide this information, the participant 
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 posttreatment 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 or she 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 equivalent methods). These contact attempts should be documented 
in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
8. STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed; hence, participants should follow the procedures as 
described in the study protocol.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness.

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.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 70

Procedures conducted as part of the participant’s routine clinical management (eg, 
blood count) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and 
were performed within the time frame defined in the SoA.
The investigational sites for this study may be categorized as follows:

Study Site: Will screen and follow study participant postinfusion of PF-07055480 
for the duration of the study. Some study sites may be approved to carry out 
infusions within their institution.

Infusion Center: a site, external from the study site, approved for the administration 
of PF-07055480.
PF-07055480 is an investigational product, and there is a possible risk of anaphylaxis: 
Emergency medical equipment will be available at both locations in case the participant has 
an allergic response, severe hypotensive crisis, or any other reaction to the administration. In 
the unlikely event that the participant develops sepsis or systemic bacteremia, appropriate 
cultures and medical management should be initiated.
Screening Period
Screening procedures will be conducted according to the SoA (Section 1.3). The screening 
period will end and the baseline period will begin when a participant is determined to be 
eligible for the study.
Baseline Period and Scheduling the PF-07055480 Infusion
Baseline procedures will be conducted according to the SoA. PF-07055480 is to be ordered 
at the beginning of the baseline period after confirming eligibility. Prior to IP ordering, 
consider Sections 10.9.1 and 10.9.6. The study intervention will require approximately 3 
weeks for shipment. Also, the timing of the participant’s next FVIII prophylaxis dose is to be 
planned to occur on the same day of PF-07055480 infusion (Day 1). 
The screening and baseline period may be extended after consulting with the Sponsor’s 
medical monitor. The reason must be recorded in the source documents.
Study sites without necessary infusion facilities will complete Visit 2 at the study site and 
Visit 3 (Day 1) at the designated infusion center.
Day 1 (at Study Site or at approved Infusion Center)
Day 1 procedures will be conducted according to the SoA. Participants will be hospitalized 
for 24 hours.
Blood for local and central LFTs has to be collected prior to dosing (up to 3 days prior to 
Day 1/Visit 3 is acceptable). Mobile phlebotomy can be used as needed. Local LFTs have to 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 71
be reviewed before dosing and prior to thawing drug. If the investigator has any clinical 
concerns regarding the local LFT results, drug should not be thawed. These LFT results may 
help in the assessment of future LFTs and decisions on when to begin corticosteroid 
treatment, if necessary.
Note: Participants should be informed that increased alcohol consumption could contribute to 
abnormally elevated LFT results and thereby delay the infusion of the study drug.
The site staff (or infusion center staff) will confirm that the participant is eligible (see 
Section 5.1 and Section 5.2) to receive PF-07055480 infusion. Prior to dosing, consider 
Sections 10.9.1 and 10.9.6. The study intervention should not be thawed and prepared until 
eligibility criteria are reconfirmed and the participant is physically present at the clinical site 
(or infusion center).
Participants are expected to bring their current FVIII replacement therapy with them.
If the infusion of PF-07055480 is started for a participant and cannot be completed (receives 
less than the prescribed dose) for any reason, the protocol does not allow for the participant 
to be rescreened. The participant will be followed for safety; the data obtained from such 
participant will not be included in efficacy analyses.
For Japanese sites please refer to Japan appendix (Section 10.8.2).
Study Site Visits (at Study Sites)
Participants should adhere to the visit schedule and procedures in the SoA.
If a participant discontinues or withdraws from the study before Week 260, the early 
discontinuation visit will follow the same procedures as the Week 260 (EOS) in accordance 
with the SoA.
Every effort should be made to ensure that 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 (also see Appendix 9). 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.
In the event that any of the safety and/or efficacy related postinfusion procedures listed 
below cannot be performed according to the timepoints specified in the study protocol, due to 
COVID-19 restrictions or otherwise, it is recommended that they be performed at the next 
subsequent on-site visit or unplanned visit. Even though the procedures may have been 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 72
performed at a subsequent visit, any procedures not performed according to the timepoints 
specified in the study protocol are still considered protocol violations.

ECG

Liver ultrasound

HJHS

PROs
8.1. Efficacy Assessments
8.1.1. Hemophilic Bleeding Episodes and Treatment
An eDiary, a handheld device, will be provided to all participants on Visit 1. 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 eDiary.
If bleeding episodes or treatments are not entered during the appropriate time window in the 
eDiary, participants should communicate all bleeds and all relevant infusion data not entered 
into the eDiary to the investigator (or appropriate site staff member), and data should be 
entered by the investigator (or appropriate site staff member) according to the process in 
place with appropriate source documentation in the participant’s medical record. Non-FVIII 
treatments or procedures to treat bleeds, will be entered by the investigator (or appropriate 
site staff member) according to the process in place.
The site staff should counsel participants regarding late eDiary entries and emphasize the 
importance of being compliant with expected eDiary entries (eg, it helps monitor the 
participant’s condition throughout the study) and of reporting all bleeds and all relevant 
infusion data to the site staff on a contemporaneous basis. 
During the site visits, the investigator (or qualified designee) will review the eDiary with 
participants. Bleeding episodes and any related treatments will be reviewed to ensure 
consistency between the medical record and/or eDiary (and/or CRF).
In the event that a participant may have to resume FVIII prophylaxis treatment, prophylaxis 
FVIII infusion data will not have to be reported on the eDiary (or conveyed to the study site 
staff on a contemporaneous basis) after Week 78 (Visit 14). Bleeds and non-prophylactic 
infusions (eg, on-demand and preventative) should continue to be reported throughout the 
course of the study. Prescribed FVIII product information will continue to be captured (eg, 
change in regimen), by the site staff, according to the process in place.
Bleeding episodes requiring treatment with FVIII product (as recommended in the World 
Federation of Hemophilia guidelines)39 will count toward the determination of bleeding 
episode frequency and the eDiary and/or medical record will serve as the source document 
for bleeding episodes. Definitions of bleeds are in Appendix 7.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 73
8.1.2. Factor VIII activity
8.1.2.1. General Information About Planned Assays
All samples collected from participants for plasma factor VIII activity levels will be analyzed 
by central and local laboratories.

In the central laboratory, FVIII activity will be assessed both by chromogenic and one-
stage clotting assay. 

In local laboratories, FVIII activity will be assessed by chromogenic or one-stage clotting 
assay based on standard practice. 
Primary and secondary objectives are based on the chromogenic assay and results will be 
used to determine steady-state vector-derived circulating FVIII activity levels. As an 
exploratory objective, both assays performed in central laboratories will be compared.
8.1.2.2. Guidance Related to FVIII Infusions, Bleeds and FVIII Decreases
Measurement of the vector-derived FVIII:C activity levels may be confounded by exogenous 
factor replacement because participants are allowed to use factor protein products to treat any 
bleeding events during the study. Thus, calculation of the vector-derived FVIII:C activity 
levels will take into consideration data entered in the eDiary. As FVIII inhibitors or T-cell 
mediated immune response may impact the FVIII activity levels, this information will also be 
taken into account while deriving FVIII:C activity levels.
Refer to guidance related to FVIII activity level measurements and suspected T-Cell 
activation in Section 8.3.10.
In addition, FVIII activity level should be measured in the below events:

In the event of an untreated bleed, the measurement should be taken as close to the 
bleeding event as possible. If the bleed necessitates treatment with exogenous FVIII, the 
FVIII activity should be assessed post clearance of FVIII product.

It is recommended to repeat FVIII activity assessment anytime if there is a significant 
decrease (not attributed to standard fluctuation or to variability of assays) as assessed by 
the investigator. The medical monitor may be consulted if there are any questions 
regarding whether a decline in FVIII activity warrants a repeat of FVIII activity level.
8.1.2.3. Guidance Related to Elevated FVIII Activities and Stopping Rule
Participants with FVIII activity levels >ULN should be managed according to the 
recommendations provided in the “Management Guide for Elevated Factor VIII Activity 
Levels.”
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 74
The guide includes recommendations based on thresholds of FVIII activity levels with 
2 main situations described:
(1) participants with elevated FVIII activity levels from 150% to 230% via central or local 
chromogenic assay or from 230% to 400% via local one-stage assay, and;
(2) participants with elevated FVIII Levels ≥230% via local or central chromogenic assay or 
≥400% via local one-stage assay.
According to these levels and after the review of participant’s current condition, underlying 
disease, medical history and risk factors including but not limited to smoking, BMI, prior 
history of thrombotic event, malignancy, family history, lifestyle, as well as thrombophilia 
and cardiovascular risk factors, initiation of prophylactic/preventative dose anticoagulation in 
participants should be considered. Additional laboratory parameters can be recommended 
(also refer to Section 8.2.7).
FVIII activity may be impacted by corticosteroid treatment. This should be taken into 
consideration for corticosteroid dosing and weaning.
In the case of an initial thrombotic event suspected to be related to >ULN FVIII activity 
levels for a participant, the study will be paused and no additional participant will be treated 
until the circumstances for such an event are assessed and regulatory agencies are notified, if 
required. In the event of recurrence of a thrombotic event in a participant, the DMC will be 
convened urgently to assess the event. DMC recommendations will be taken into account in 
the decision to pause the study. 
Should the study be paused, the trial re-start will only be possible after Regulatory Authority 
approval via substantial amendment, where applicable, based on local/regional regulatory 
requirements.
8.1.2.4. Recovery Testing
As part of the exploratory assessments of coagulation, recovery of FVIII activity levels may 
be assessed if prophylaxis is resumed and/or there is a need for prophylaxis to be 
administered prior to a surgical procedure. The FVIII activity levels measurements can be 
performed locally or centrally, with repeated samples collected pre-infusion and at 
30 minutes post FVIII product infusion. 
8.1.3. Joint Assessments
See Appendix 7 for definition of target joints. The investigator will assess the health of the 
target joint(s), identified at screening, as specified in the SoA. A target joint is considered 
resolved when there are ≤2 bleeds into the joint within a 12-month period.
8.1.3.1. Hemophilia Joint Health Score (HJHS)
Swelling, on motion Joint assessments will be performed using the HJHS40 version 2.1 to 
evaluate joint total (swelling, duration of swelling, muscle atrophy, crepitus on motion, 
flexion loss, extension loss, joint pain, and strength) and global gait scores. The HJHS is 
designed for use by physiotherapists. In order to maintain precision and validity of the tool 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 75
(score), the developers strongly recommend that the tool be used by 
physiotherapists/healthcare professionals who have hemophilia-related expertise/experience 
and have been trained in the use of clinical measures, musculoskeletal assessments and 
specifically administration of the HJHS. Training on use of the HJHS assessment tools will 
be provided, by the sponsor, and must be completed by the investigator or designee(s) 
performing these assessments.
Study participants with prosthetic joints should still have the joints evaluated. The replaced 
joint should be scored on all items that are possible. Any item that is not tested, for whatever 
reason, will need to be scored as NE (non-evaluable). This might pertain particularly to the 
gait skills of running and hopping on 1 leg if the participant is unable to perform the skill or 
the assessor perceives risk (eg, of bleeding or injury) to the participant if he does perform 
these skills.
If the HJHS cannot be performed at Visit 10 and/or 13, it is recommended that it be 
performed at the next subsequent on-site visit or unplanned visit.
8.1.3.2. Ultrasound to Evaluate Joints
A subset of participants (n~20) will undergo ultrasound exams to assess damage within joints 
by evaluating soft-tissue changes and osteochondral changes. These participants will be 
chosen based on the expertise of the site, availability of ultrasound at the site, and participant 
consent to undergo the procedure. The ultrasound scanning protocol will include acquisition 
of knees, elbows and ankles.
Ultrasound scans will be acquired locally according to the SoA. All details of the ultrasound 
acquisition including the system will be captured in a separate guide. At a minimum, joint 
images will be reviewed following the extended ultrasound scale with a final score 
combining soft-tissue and osteochondral subscores. 
If the ultrasound cannot be performed during the baseline period, it is acceptable to postpone 
this testing no later than Week 4 / Visit 6. If the baseline ultrasound as part of a sub-study 
could not be performed before or at Week 4 / Visit 6, the study participant does not need to 
do the post-dosing ultrasounds.
8.1.3.3. X-ray Assessments to Evaluate Joints
Some participants who consent to participate in an optional substudy, except for those 
participating in Germany, will undergo X-ray assessment of knees, elbows and ankles to 
assess damage within joints as detectable at a radiologic level. X-rays will be acquired 
according to the SoA. All details of the X-ray acquisition will be captured in a separate 
scanning guide. At a minimum, joint images will be reviewed following the Pettersson 
scale.41 Central reading of X-ray images will be performed.
If the X-ray cannot be performed during the screening period, it is acceptable to postpone this 
testing no later than the Week 4 / Visit 6. If the baseline X-ray could not be performed before 
or at the Week 4 / Visit 6, the study participant does not need to do the 2 post-dosing 
assessments.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 76
8.1.4. Other PROs
Patient-reported outcomes implemented in this study are the Haem-A-QoL, the HAL, the 
HLIQ, and the EQ-5D-5L.42 Additionally, 6 anchor items have been developed to assess 
change over time on the Haem-A-QoL, the HAL, and the HLIQ: three global impression of 
severity items (PGIS) and 3 global impression of change items (PGIC). The 3 PGIS single 
item assessments will be completed at each clinic visit when the Haem-A-QoL, HAL and 
HLIQ are assessed. The 3 PGIC single item assessments will be also completed at each clinic 
visit when the Haem-A-QoL, HAL and HLIQ are assessed, but not at the baseline visit.
The PRO questionnaires should be administered in the following order: Haem-A-QoL, HAL 
(v2), HLIQ, EQ-5D-5L, PGIS (n=3), and PGIC (n=3).
The PRO questionnaires should be completed in accordance with the SoA during the 
scheduled site visits using a tablet device that will be provided to each site. Baseline PRO 
assessments need to be done prior to start of infusion on Day 1 if not done at baseline visit. If 
the postinfusion PROs cannot be performed at a particular visit, they should be performed at 
the next subsequent visit or unplanned visit. At each relevant visit, the assessment 
questionnaires should be administered before dosing, treatment, or conversation between 
health care team and participants about their health condition. Participants should complete 
the questionnaires in a quiet area within the clinic (ie, cannot be taken home) and without 
help or interaction from family members or other caregivers. Spouses, family members, 
visitors, or health care team members should not assist the participant in answering 
questionnaires.
8.1.4.1. Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL)
The Haem-A-QoL43 is a disease specific measure of health-related quality of life in 
participants with hemophilia. Intended for adults, the instrument uses a 4-week recall period 
to assess health across 10 domains consisting of 46 items. The 10 domains and the number of 
items within each domain of the adult version are the following: Physical Health (5 items); 
Feelings (4 items); View of Self (5 items); Sport and Leisure (5 items); Work and school 
(4 items); Dealing with Haemophilia (3 items); Treatment (8 items); Future (5 items); Family 
Planning (4 items); and Partnerships and Sexuality (3 items).  Scores are calculated by 
domain and a single total score.
8.1.4.2. Hemophilia Activities List (HAL, Version 2)
The Hemophilia Activities List44,45 (version 2) is a multiple domain measure of the impact of 
hemophilia on functional abilities in adults. The 7 domains of this instrument contain 
42 items in total, as follows: Lying/sitting/kneeling/standing (8 items); lower (leg) 
functioning (9 items); upper (arm) functioning (4 items); Transportation (3 items); Self-care 
(5 items); Household tasks (6 items); and Sports/Leisure (7 items). Scoring can be done by 
domain, components (Activities involving the Upper Extremities, Basic activities involving 
the Lower Extremities, and Complex activities involving the Lower Extremities) or a 
standardized total score.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 77
8.1.4.3. Hemophilia Life Impacts Questionnaire (HLIQ)
The HLIQ is a 9-item assessment of life impacts associated with living with and treating 
hemophilia. The HLIQ employs a ‘past week’ recall period. Four items are assessed on a 
5-point, ordinal, verbal rating scale scored from 0 to 4, while 4 items are gated such that 
responding ‘yes’ branches to a 5-point, ordinal verbal rating scale and responding ‘no’ 
branches to a reason for not participating in the activity (ie, due to hemophilia or due to other 
reasons). One item is assessed on a 4-point, ordinal, verbal rating scale scored from 0 to 3. 
Higher scores on the verbal rating scales indicate greater impact due to living with or treating 
hemophilia.
8.1.4.4. EQ-5D-5L
Developed by the EuroQoL Group, the EQ-5D-5L (EuroQol, 5 dimensions, 5 levels)42 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.
8.1.4.5. Patient Global Impression of Severity (PGIS) and Patient Global Impression of 
Change (PGIC)
The PGIS-PH is a single item assessment of the participant’s overall impression of severity 
of physical health over the past 7 days. The response scale is a 4-point categorical rating 
scale ranging from “none” to “severe”.
The PGIS-PF is a single item assessment of the participant’s overall impression of severity of 
physical functioning over the past 7 days. The response scale is a 4-point categorical rating 
scale ranging from “none” to “severe”.
The PGIS-H is a single item assessment of the participant’s overall impression of severity of 
life interference with hemophilia over the past 7 days. The response scale is a 4-point 
categorical rating scale ranging from “none” to “severe”.
The PGIC-PH is a single item assessment of the participant’s overall impression of change in 
their physical health since receiving gene therapy. The response scale is a 5-point categorical 
rating centered around “no change” with 2 grades of improvement and 2 grades of 
worsening.
The PGIC-PF is a single item assessment of the participant’s overall impression of change in 
their physical functioning since receiving gene therapy. The response scale is a 5-point 
categorical rating centered around “no change” with 2 grades of improvement and 2 grades 
of worsening.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 78
The PGIC-H is a single item assessment of the participant’s overall impression of change in 
their life with hemophilia since being enrolled in the study. The response scale is a 5-point 
categorical response scale centered around ‘no change’ with 2 grades of improvement and 2 
grades of worsening. 
8.1.5. Imaging Assessments 
Please refer to Section 8.1.3.2 and Section 8.1.3.3.
8.1.5.1. Management of Incidental Findings
An incidental finding is one unknown to the participant that has potential health or 
reproductive importance, which is discovered unexpectedly in the course of a research study 
but is unrelated to the purpose and beyond the aims of the study.
X-ray images will be reviewed by a central review facility. Central image review is not a 
complete medical review of the participant. If during the central review process, an 
unexpected observation is identified and this finding could, in the opinion of the central 
reviewer, have a significant health or reproductive consequence, this finding may be shared 
with the study sponsor for disclosure to the principal investigator. All follow-up testing and 
final diagnosis will be left to the discretion of the medical professionals at the site or those 
with an existing physician-participant relationship. The principal investigator will be 
responsible for reporting any adverse events identified from incidental findings as described 
in the Adverse Event Reporting section. Identification of such incidental findings during the 
central review process should not be expected, and the site maintains responsibility for 
performing a general safety review of all images in accordance with site protocols.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
Unscheduled clinical laboratory measurements may be obtained at any time during the study 
to assess any perceived safety issues.
8.2.1. Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, and neurological systems. Height and 
weight will also be measured and recorded.

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
8.2.2. Vital Signs

Body temperature (°C), pulse rate, respiratory rate, and blood pressure (systolic and 
diastolic) will be assessed after at least 5 minutes rest in supine or upright/sitting 
position.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 79
Obtaining oral temperature is preferred, however, if unable to obtain oral 
temperature, other methods of body temperature assessment such as: tympanic, 
rectal, axillary, skin, and temporal artery are allowed.
8.2.3. Cardiac Monitoring

Local single 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) 
using an ECG machine that automatically calculates the heart rate and measures PR, 
QRS and corrected QT intervals (QTc).

Troponin I will be assessed as described in the SoA.

A cardiology consultation may be arranged as needed. Refer to SoA for details.
8.2.4. Liver Ultrasound
Local liver surveillance by ultrasound (including HCC detection) is planned as detailed in the 
SoA. A liver ultrasound scanning guidance will be provided to the sites. Ultrasound images 
will be acquired locally by an appropriately trained individual. After the first year, all 
participants will undergo liver ultrasounds yearly, at a minimum, and more frequent 
ultrasounds may be performed per investigator discretion (eg, participants with risk factors 
for HCC) or if necessitated to align with participant’s standard of care.
This type of hepatic testing will help assess liver structure, and may detect abnormal 
architecture, tumors, as well as, liver fibrosis. In combination with blood tests, liver testing 
may help direct the investigative team to early diagnoses of hepatic disease.
8.2.5. Samples for Other Vector Integration Related Testing (if applicable)
In the event that certain findings occur (for example, new abnormalities), further testing may 
be done as standard of care; for example, repeat testing over time may be ordered. To 
investigate an abnormal finding, an investigator may recommend a biopsy or tissue collection 
(liver or other location). In this event, tissue obtained may be requested by the sponsor for 
further analyses. Tissue analyses may be helpful in establishing (or refuting) a relationship 
between the adverse event and the gene transfer vector. Analyses would include a vector 
integration analysis, and possibly quantitation of vector transgene expression, depending on 
tissue integrity and viability. The consent includes tissue collection; surgical and procedural 
consents generally cover obtaining samples of tissue for analyses. Likewise, if autopsy 
material became available for analysis of attribution of vector to an adverse event, tissue 
would be requested by the sponsor to assess this possibility.
Refer to Section 8.1.5.1 for the management of incidental findings.
8.2.6. Clinical Laboratory Assessments

See Appendix 2 for the list of clinical laboratory tests to be performed and to the 
SoA for the timing and frequency.

The investigator must review the laboratory report, document this review, and 
record any clinically relevant changes occurring during the study in the AE section 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 80
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.

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.
o
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.
o
All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.
o
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).
8.2.7. Immunogenicity
All samples collected will be analyzed using a validated analytical method in compliance 
with standard operating procedures. The samples must be processed and shipped as indicated 
in the instructions provided to the investigator site to maintain sample integrity. Any 
deviations from the sample handling procedure (eg, sample collection and processing steps, 
interim storage or shipping conditions), including any actions taken, must be documented and 
reported to the sponsor. On a case-by-case basis, the sponsor may make a determination as to 
whether sample integrity has been compromised. 
8.2.7.1. Analysis of Anti-PF-07055480 Antibodies (ADAs) and Neutralizing Anti 
PF-07055480 Antibodies
Whole blood specimens of approximately 5 mL to provide a minimum of 2 mL of serum will 
be collected for determination of total anti-PF-07055480 antibodies (ADAs) and 
approximately 4 mL of whole blood to provide a minimum of 2 mL of serum will be 
collected for determination of nAbs to PF-07055480 (anti-AAV6 nAbs and, as part of 
exploratory endpoints, other nAbs against other AAV serotypes may be assessed) as 
specified in the SoA (Section 1.3) of the protocol. Instructions for collection and handling of 
biological samples will be provided by the sponsor.
Those samples may also be used for additional characterization of the immune system and/or 
evaluation of the bioanalytical methods. Storage will be done in a facility selected by the 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 81
sponsor for a maximum of 10 years (or according to local regulations) following the last 
participant's last visit for the study.
8.2.7.2. Analysis of FVIII Inhibitor
During all study periods, blood samples will be collected for measurement of inhibitory 
antibodies against FVIII (inhibitors) as specified in the SoA section of the protocol.
The Bethesda-Nijmegen assay will be used. One BU is defined as the amount of inhibitor 
that results in 50% residual FVIII:C activity.
Both de novo inhibitors and clinically significant de novo inhibitors will be assessed and are 
defined based on the following criteria.  

A de novo FVIII inhibitor is defined as a positive central laboratory inhibitor result 
(inhibitor assay result > 0.6 BU) by the Nijmegen method of the Bethesda assay, in an 
individual with no prior history of FVIII inhibitors, that is confirmed in a second 
separately drawn specimen, at least 6 weeks later, that is also assayed at the central 
laboratory. A local laboratory result indicating possible presence of an inhibitor will 
prompt an unplanned inhibitor assessment at the central laboratory.  

A de novo inhibitor will be deemed clinically relevant if the occurrence is associated 
with either complete loss of previously attained FVIII transgene expression (return to 
baseline FVIII activity level) or the need for the participant to administer non-FVIII 
coagulation factor products (by-pass agents) in order to achieve efficacy when 
treating breakthrough bleeding episodes.
In the event of a confirmed inhibitor level for a participant, the study will be paused (no 
additional participant will be treated) until the circumstances for occurrence of the event are 
assessed and until notification of regulatory agencies if required. The trial re-start will only 
be possible after Regulatory Authority approval via substantial amendment, where applicable 
based on local/regional regulatory requirements.
8.2.7.3. Analysis of Cellular Immune Response by ELISPOT
The ELISPOT assay is a highly sensitive quantitative immunoassay for measuring relevant 
parameters of T cell activation (the frequency of cytokine-secreting cells at the single-cell 
level) on PBMC.
Whole blood specimens (approximately 30 mL) will be collected in dedicated tubes to 
prepare centrally PBMC. Detailed collection, processing, storage, and shipment instructions 
are provided in the central laboratory manual.
T-cell responses to AAV capsid and transgene product will be evaluated as specified in the 
SoA.
The specimen is to be collected at baseline, and before beginning the corticosteroid treatment 
when a T-cell response is suspected. If not collected before starting corticosteroid treatment, 
it must be collected within 24 hours of administering corticosteroids. Analysis should also be 
repeated approximately 3 weeks after corticosteroid administration and at the end of the 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 82
weaning time. Additional specimens may be recommended by the sponsor, in consultation 
with the investigator, depending on the participant’s response to corticosteroid therapy.
As part of understanding of the immunogenicity of the study drug, samples may be used for 
further characterization and/or evaluation of the bioanalytical method. These data will be 
used for internal exploratory purposes and will not be included in the clinical report. Samples 
collected for this purpose will be retained in accordance to local regulations and if not used 
within this timeframe, will be destroyed.
8.2.8. Hemostasis Parameters, Thrombotic Potential Assessment and Thrombophilia 
Parameters
Hemostasis parameters can include aPTT, INR, TAT, TGA, Fibrinogen (activity and antigen) 
and D-Dimer. 
Blood samples to assess aPTT, INR, TAT, TGA and D-Dimer will be collected as defined in 
the SoA and as specified in the Laboratory Manual. 
In addition, all or selected hemostasis parameters listed should also be assessed as clinically 
needed, and if vector-derived FVIII activity levels >150% of normal are achieved, based on 
local or central chromogenic assay. Any hemostasis parameter can also be assessed locally. 
The one-stage assay can lead to higher activity levels, therefore this threshold might be 
higher and prior measurements / evaluation should be considered. Blood samples for TAT 
obtained on Day 1 will be used to establish baseline value. 
Some parameters related to hereditary or acquired thrombophilia will be assessed for 
eligibility confirmation, to rule out the presence of AT deficiency, Protein S deficiency, 
Protein C deficiency, FV Leiden thrombophilia and of the Factor II / Prothrombin gene 
mutation (G20210A).
Laboratory parameters to be conducted centrally to confirm eligibility include AT activity, 
Protein C activity, Protein S activity, FV Leiden mutation and the prothrombin G20210A 
gene mutation. Protein S, protein C and AT antigen levels will be performed as needed.In the 
setting of FVIII activity levels >ULN and as described in the “Management Guide for 
Elevated Factor VIII Activity Levels”, these assessments (AT, Protein C and Protein S 
activities and/or antigens) can be repeated centrally and locally as clinically indicated.
8.2.9. Optional Liver Biopsy
One optional liver biopsy can be performed (in participants who consent to do so and as per 
investigator’s judgement) during Year 1 postinfusion and/or subsequently during Years 2-5 
postinfusion. 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 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 83
biopsy will be made upon investigator’s decision; it can be performed at any time 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 subject 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
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. 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 84
Following completion of the biopsy, the subject 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 and an 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 it 
meets the criteria for classification as an SAE, or caused the participant to discontinue the 
study intervention (see Section 7).
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. 
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
All ongoing AEs and SAEs in the lead-in study (C0371004), including events of special 
interest, as defined in the lead-in study (C0371004), will be collected as medical history for 
this study. Historical data on Medical, Surgical and Hemophilia History will be captured 
from the lead-in study. Any new AEs/SAEs after completion of the lead-in study will follow 
the AE reporting process (Appendix 3).
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 a 
minimum of 5 years after the last administration of the study intervention, or at EOS for 
participants who discontinue. The active collecting period for this study is categorized into 
short-term or long-term monitoring period and is defined later in this section.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 85
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.
During the short-term monitoring period (up to and including 104 weeks postinfusion) all 
SAEs (including medically important events, Appendix 3) and AEs will be collected.
During the long-term monitoring period (Week 105 postinfusion to EOS) the following AEs 
will be collected:

SAEs (including medically important events, Appendix 3)

Nonserious AEs determined to be related to study intervention by the investigator 
or where causality is unknown.
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the 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 Safety 
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. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available.
SAEs occurring in a participant after the active collection period has ended are reported to 
Pfizer Safety if the investigator becomes aware of them; at a minimum, all SAEs that the 
investigator believes have at least a reasonable possibility of being related to investigational 
product must be reported to Pfizer Safety.
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, 
which begins after obtaining informed consent as described in Section 8.3.1, will be 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 AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 86
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.
8.3.4. Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of a 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, IRB/IECs, and 
investigators.

Investigator safety reports must be prepared for SUSAR according to local 
regulatory requirements and sponsor policy and forwarded to investigators as 
necessary.

An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements.

For French sites please refer to France appendix (Section 10.8.1).

For Japanese sites please refer to Japan appendix (Section 10.8.2).
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the study intervention under study during pregnancy and occupational exposure 
are reportable to Pfizer Safety within 24 hours of investigator awareness.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 87
8.3.5.1. Exposure During Pregnancy

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.

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, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
study intervention, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE. Since the information does not pertain to a participant enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.3.6. Cardiovascular and Death Events
Not applicable
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
The DREs for this study include episodes of bleeding related to hemophilia A. The bleeding 
episode itself is not reported as an AE, unless the bleeding episode meets the criteria outlined 
below.
Consideration on whether the bleeding event is a DRE is based on investigator determination 
and bleeding events recorded by the participant in their electronic diary will be reviewed by 
the investigator and assessed against reporting obligations for AE/SAE.
Bleeding, not due to the participant's hemophilia, will be recorded as an AE, and not a DRE. 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 88
In addition, if any of the following conditions apply, then the event must be recorded and 
reported as an AE or SAE (instead of a DRE):

Bleeding events that require hospitalization or meet other SAE criteria (see 
Appendix 3) should be reported as SAEs. When bleeding episodes that meet the SAE 
criteria are recorded on the AE CRF, the location (site) of the bleed and the etiologic 
classification as spontaneous or traumatic should be included (as described in 
Section 8.1.1 and Appendix 2).

The bleeding event is, in the investigator's opinion, of greater intensity, frequency, or 
duration than expected for the individual participant.
OR

The investigator considers that there is a reasonable possibility that the bleeding event 
was related to study intervention.
8.3.8. Adverse Events of Special Interest
Adverse events of special interest (AESIs) are examined as part of routine safety data review 
procedures throughout the clinical trial and as part of signal detection processes.
All AESIs must be reported as an AE or SAE following procedures described 
in Sections 8.3.1 through 8.3.4. An AESI is to be recorded as an AE or SAE on the CRF. In 
addition, an AESI that is also an SAE must be reported using the CT SAE Report Form.
Adverse events of special interest include: all medically important events (see Appendix 3) 
that are to be reported as an SAE, and any clinical thrombotic event or 
hypersensitivity/infusion-related reactions events assessed as non-serious AEs. 
8.3.9. Medical Device Deficiencies
Not applicable
8.3.10. Immunomodulation Optimization (Presumed T-Cell Activation)
A tapering course of oral corticosteroids (eg, prednisone/prednisolone) will be the first 
consideration for suppression of apparent immune hepatitis. The rationale for this approach is 
that corticosteroids are effective in severe autoimmune hepatitis, a disease in which 
hepatocytes are attacked by epitope-specific cytotoxic T-Lymphocyte. The mechanism for 
this immune reactivity is not clear. It is possible that an elevation in liver transaminases is not 
due to immune responses.
It is highly recommended that participants be provided with a prednisone prescription before 
dosing so that it can be filled and ready should treatment be needed. 
It is highly recommended that participants who are initiated on corticosteroid treatment be
treated with a gastric acid reducer, preferably a proton pump inhibitor (PPI) (eg, omeprazole), 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 89
or alternatively a histamine type 2 (H2) antagonist (eg, famotidine) for the duration of the 
corticosteroid course. 
Ultimate decision to initiate corticosteroid therapy is at the discretion of the Investigator.
Due to the importance of timely intervention of corticosteroids, decisions to begin treatment 
will be based on local laboratory values. Based on gained experience and on guidelines 
published by the American Association for the Study of Liver Diseases46, hemophilia B gene 
therapy study data of the St. Jude Children’s Research Hospital and University College London 
group,6,47 data from the Phase 1/2a study, treatment with corticosteroids for vector-induced 
hepatitis should be considered to be instituted as follows:
(1) Transaminase increase:

Between Day 1 and Day 14 postinfusion, oral corticosteroids should be considered in 
the following scenarios, in the absence of alternative etiologies:
o
in the presence of ALT above the normal range 
o
in the presence of ALT increase ≥ 1.5 fold the lowest baseline value (since 
screening into the study and prior to infusion) and declining FVIII activity 
level (not resulting from residual exogenous FVIII). 

From Day 15 to Day 120 postinfusion, oral corticosteroids should be considered in 
the following scenarios, in the absence of alternative etiologies:
o
in the presence of ALT increase ≥1.5-fold of the lowest baseline value and 
with FVIII activity level below the normal range or declining.
o
in the presence of ALT above the normal range and if the FVIII activity level 
is in the normal range (or above).
Following the trend of ALT values is especially important as it is possible that levels 
seen postinfusion may be below those seen during screening/baseline. Whenever 
possible, consider a confirmatory lab draw for ALT , along with FVIII activity, prior to 
initiating oral corticosteroids. This should not delay the initiation of corticosteroids if 
clinically indicated. 

Beyond 120 days post-infusion:
As AAV-specific cellular immune responses are expected to mainly occur within the 
first months post infusion, if transaminase increase is occurring beyond 120 days 
postinfusion, the investigator should contact the sponsor’s Medical Monitor to discuss 
prior to initiating corticosteroids unless otherwise clinically indicated. 
Stable FVIII activity levels and/or >ULN levels might not be suggestive of 
hepatocytes attacked by epitope-specific cytotoxic T-Lymphocytes.
Corticosteroids should be considered if ALT increase is above normal ranges, AND 
with FVIII activity level declining.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 90
(2) FVIII activity level decrease:
FVIII activity levels should always be taken into account in the decision to initiate 
corticosteroid treatment.

During the first 120 days post-infusion and in the absence of ALT elevations: 
corticosteroid initiation should be considered if FVIII activity level is below the 
normal range and is showing consecutive significant decreases (a decline in FVIII 
activity levels on at least 2 consecutive blood tests independent of transaminase 
values).

Beyond 120 days postinfusion, the investigator should contact the sponsor’s Medical 
Monitor to discuss prior to initiating corticosteroids unless otherwise clinically 
indicated. 
Any question about corticosteroid treatment initiation, or any delay or deviation in the 
initiation of treatment based on the above listed recommendations, should be discussed with 
the sponsor’s medical monitor in the context of the overall clinical management plan of each 
participant. Ultimate decision to initiate corticosteroid therapy is at the discretion of the 
Investigator.
The recommended starting dose of oral corticosteroids for the first week is 60 mg or 1 mg/kg 
(whichever is higher), once daily unless the investigator believes a different regimen should 
be implemented based on the participant’s medical history.
The subsequent prednisolone/prednisone taper should not be started until:

Transaminases have declined at least 2 consecutive laboratory draws, or have 
returned to approximately baseline (lowest transaminase value preadministration) 
levels,
And

Any decline in FVIII activity has plateaued.
If FVIII activity decreases or transaminases increase following dose reduction, 
corticosteroids dose should re-start using the Week 1 dose and taper should not be initiated 
until the above requirements are met again.
Table 1.
Recommended Regimen for Oral Corticosteroids
Schedule
(oral corticosteroid treatment regimen)
Prednisolone/Prednisone (mg/day)
Week 1
60 mg or 1 mg/kg (whichever is higher) 
Week 2
60 mg or 1 mg/kg (whichever is higher) *
Week 3
40 **
Week 4
30
Week 5
30
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 91
Table 1.
Recommended Regimen for Oral Corticosteroids
Schedule
(oral corticosteroid treatment regimen)
Prednisolone/Prednisone (mg/day)
Week 6
20 ***
Week 7
15
Week 8
10
* Based on the judgment of the investigator, administration of 60 mg or 1 mg/kg once daily oral 
corticosteroids can be extended to week 3 if the participant has no adverse effect. 
** If participant’s weight is more than 60 kg, then, decrease week 2 dose in 20 mg/day until 60 mg is reached 
and continue following above table schedule from week 3 (Example if participant’s weight is 90 kg; W1: 
90 mg/day , W2: 90 mg/day, W3: 70 mg/day, W4: 60 mg/day, W5: 40 mg/day, W6: 30 mg/day, W7: 30 
mg/day, W8: 20 mg/day, W9: 15 mg/day, W10: 10 mg/day).
*** Maintain at 20 mg/day until transaminases return to baseline, then reduce by 5 mg/day until 10 mg/day 
are achieved then reduce by 2.5 mg/week up to 5 mg daily.
Note: If available, ELISPOT results will be monitored during tapering.
The sponsor’s medical monitor can be consulted at any time to discuss either the decision to 
initiate corticosteroids, escalate immunosuppressive treatment, or taper corticosteroid 
treatment.
If the tapering criteria are not met after approximately 4 weeks on the increased dose, then 
the investigator and the sponsor’s medical monitor should discuss further management. In 
some situations, further escalation may be warranted (eg, consideration of more intensive 
immunomodulatory regimens of combined oral and intravenous corticosteroids or a different 
immunosuppressant therapy) and in other situations a wean may be initiated (ie, stable but 
elevated liver function tests without loss of FVIII activity during the treatment period).
Any modification of this approach should be discussed with the sponsor medical monitor.
If corticosteroid therapy is started, measurement of LFTs and of FVIII activity is 
recommended at least 2 times per week until the end of this therapy.
The following schedule of combined oral corticosteroids and intravenous corticosteroids 
(methylprednisolone) is recommended if there is no evidence of resolution of transaminase 
elevation or persistent loss of FVIII activity while on oral corticosteroids treatment alone 
(Table 2).
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 92
Table 2.
Recommended Regimen for Combination Intravenous and Oral 
Corticosteroids
Schedule
(corticosteroid treatment 
regimen)
Oral Prednisolone/Prednisone 
(mg/day)
Intravenous 
Methylprednisolone (g/day)
Days 1 to 3
n/a
1
Days 4 to 7
20
n/a
Week 2
60
n/a
Week 3
60
n/a
Week 4
40
n/a
Week 5
30
n/a
Week 6
30
n/a
Week 7
20
n/a
Week 8
10
n/a
Week 9
5
n/a
The investigator will have flexibility in implementing the immunomodulatory regimen 
because the exact regimen and course will depend on clinical circumstances. If the 
investigator chooses an immunosuppressive regimen that differs from that suggested above,
the investigator should discuss the plan with the Sponsor’s medical monitor; this discussion 
should not delay initiation of immunosuppression. 
The long-term side effects of the immunomodulatory drugs to be considered in this study are 
well characterized. Participants who develop immune hepatitis will be monitored closely to 
minimize the risk of the side effects. To use the lowest effective dose and to shorten the 
duration of the immunosuppressive therapies, tapering of the regimen will start as soon as 
there is evidence of resolution of hepatic transaminases elevation and FVIII activity has 
plateaued. If available, ELISPOT results will be monitored during tapering. While on 
immunomodulatory regimens, participants will also be monitored for side effects, such as 
opportunistic infections. Antibiotics or other medications to minimize the risk of 
opportunistic infection may be prescribed at the discretion of the investigator. All events 
related to the use of immunomodulatory drugs (eg, hyperglycemia, weight gain, infections) 
will be recorded as AEs connected to their use.

If 2 or more participants are nonresponsive to immunomodulatory regimens, or if the 
value of the transaminases continues to rise, the Sponsor’s medical monitor and 
investigator will discuss more intensive immunomodulatory regimens. The Sponsor 
will convey the information to the eDMC.
While on immunomodulatory regimens, participants will also be monitored for adverse 
events, including infections. Antibiotics or other medications to minimize the risk of 
opportunistic infection may be prescribed at the discretion of the investigator. All events 
related to the use of immunomodulatory drugs (eg, hyperglycemia, weight gain, infections) 
will be recorded as AEs.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 93
For participants with positive HBcAb at screening: HBV surface antigen and HBV DNA will 
be tested at the end of the tapering course of corticosteroids. If HBV reactivation is noted, 
management will be based pending a thorough assessment of the participant’s clinical status.
8.3.11. Infusion Related Hypersensitivity and Allergic Reaction
In the dose ranging Phase 1/2 study (SB-525-1603), one participant experienced an SAE of 
severe hypotension and fever, with onset 6 hours after completion of PF-07055480 infusion, 
treated with
 
. The participant was discharged 24 hours after 
the end of the PF-07055480 infusion, with no clinical signs remaining. 
Hypersensitivity and allergic reactions were previously identified as potential risks of 
treatment with PF-07055480. An Infusion Reaction Management Guide describes clinical 
protective measures recommended before, during and after infusion (until hospital 
discharge). This guide also gives recommendation on the management of such cases.
8.3.12. 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 study intervention;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating participant;

Not performing a flush of the IV line at the conclusion of the study intervention 
infusion.
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 within 24 hours.
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 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)
PPD

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 94
applicable, any associated AE(s), serious and nonserious, 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 PF-07055480 greater than 3 x 1013 vg/kg of body weight 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 within 24 hours.
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.
4. Overdose is reportable to Safety only when associated with a SAE.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant.
8.5. Pharmacokinetics
8.5.1. Vector Shedding and Infectivity
Shedding will be assessed by quantitative real time PCR. Samples of plasma, saliva, PBMC, 
urine, and semen will be collected as specified in the SoA for analysis of vector shedding and 
infectivity. These samples will be collected as per the instructions provided to the sites to 
maintain sample integrity for each sample type. Any deviations from that sample handling 
procedure must be documented and reported to the sponsor.
In the event that a participant is unable to provide any semen for vector shedding over the 
course of 1 month postinfusion, future attempts to provide semen samples can be stopped 
provided that 3 consecutive negative PBMC samples are obtained, before no longer being 
required to follow the restriction within inclusion criteria #6 in Section 5.1.
In the event that samples of plasma, saliva, PBMC, urine, and semen have not yet cleared 
20 weeks post infusion, collection can be reduced to every 2 weeks.
Based on preliminary vector shedding data obtained on PBMCs assessed in the ongoing 
C3731003 study and to limit burden to the participants and collected blood volume, 
collection of blood to prepare PBMCs and assess shedding post infusion will start from 
Week 20.
In the event that plasma, saliva, PBMC, urine, and semen have not yet cleared 34 Weeks 
post infusion, and if home health care service is not available in a country or at a site, 
collection can be reduced to approximately monthly.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 95
Some participants (n=12), who consent to participate in an optional substudy, are expected to 
provide additional samples at early timepoints following study intervention (2 h [± 30 
minutes], 24 h [± 3 h], 72 h [± 4 h] after completion of study intervention infusion and IV 
line flush). This subset of samples will also be used for DNase treatment for additional 
characterization.
If further characterization is needed (eg, unusual shedding result), a functional assay may be 
done to evaluate the infectivity of the virus. This assay will involve in vitro culture of shed 
material with a permissive cell line.
8.6. Pharmacodynamics
8.6.1. FVIII Antigen
Blood samples will be collected as specified in the SoA and as specified in the Laboratory 
Manual to measure FVIII antigen levels.
8.6.2. Von Willebrand Factor
Von Willebrand factor levels will be measured. This factor is the transport protein for FVIII 
and its levels may influence FVIII levels and activity.
Blood samples will be collected, prepared and stored as specified in the SoA and in the 
Laboratory Manual. 
8.7. Genetics
8.7.1. Specified Genetics
FVIII gene sequencing will be performed where acceptable in accordance with local 
regulations for the participants who do not have it at baseline (if not previously done and/or 
not available in the medical file). 
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.
8.7.2. Banked Biospecimens for Genetics 
Banked biospecimens for genetics are not included in this study.
8.8. Biomarkers
Biomarkers are not evaluated in this study.
8.9. Medical Resource Utilization and Health Economics
No medical resource utilization and health economics are used in this study.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 96
8.10. Additional Study Assessments
8.10.1. Binding IgG versus IgM
Binding of IgG versus IgM will be measured as specified in the SoA on early timepoints to 
assess a potential immunoglobulin class switching, which can occur in the first weeks of 
immune response. 
Blood samples will be collected, prepared and stored as described in the SoA and as specified 
in the Laboratory Manual. 
8.10.2. Exploratory Cell-Mediated Assays
Cellular responses overtime will be assessed with cell-mediated exploratory assays on 
PBMCs prepared from whole blood (approximately 48 mL) at timepoints defined in the SoA. 
Detailed collection, processing, storage, and shipment instructions are provided in the
Laboratory Manual.
8.10.3. Archive Plasma Samples 
Spare plasma samples (or pre-dose serum on Day 1/Visit 3) for each participant as specified 
in the SoA. These samples will be archived to repeat testing (if required), for clarification of 
any clinical or laboratory AE, and for additional exploratory biomarkers (see Section 8.10.4).  
8.10.4. Other Exploratory Assays
Remaining serum, plasma and/or PBMC samples may be used to further evaluate the 
immune responses and study drug mechanism including, but not limited to, the expression of 
inflammatory markers (eg, IL6 and CRP), markers involved in AAV transduction (eg, 
EGFR) or any other mechanism-based biomarkers that may be identified in the other ongoing 
clinical studies with the study drug or other AAV-based gene therapies. Remaining samples 
may also be used for further development of the study-required laboratory assays.
No samples will be used for genetic analyses. The samples will be destroyed no later than the 
completion of the clinical study report.
9. STATISTICAL CONSIDERATIONS
9.1. Estimands and Statistical Hypotheses
A gatekeeping process will be applied to control for multiple endpoint comparisons at the 
primary analysis which is planned after at least 15 months of follow-up postinfusion in at least 50 
dosed participants who have completed at least 6 months in the lead-in study (C0371004). The
subsequent hypothesis testing will only be performed after success on the previous hypothesis 
test. The sequence of gatekeeping process and details of statistical methodology will be 
specified in the SAP.  
9.1.1. Estimands
The primary endpoint and the associated hypothesis testing is to demonstrate NI of 
PF-07055480 to routine prophylaxis on the difference in Total ABR (NI margin of 3 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 97
bleeds/year) by comparison of postinfusion of PF-07055480 Total ABR (through at least 15 
months up to data cutoff) versus prestudy intervention infusion Total ABR collected during 
the lead-in study (C0371004) and preinfusion of PF-07055480 in this study (C3731003), in 
male participants ≥18 years of age with moderately severe to severe hemophilia A (FVIII 
activity ≤1%), who have tested negative for nAb, and have no medical history of FVIII 
inhibitor.
The corresponding 4 estimand attributes are provided below: 
Estimand
Attribute
Description 
Population
Male participants ≥18 years of age with moderately severe to severe hemophilia A 
(FVIII:C ≤1%), who have tested negative for nAb, have no medical history of FVIII 
inhibitor. 
Variable
Total ABR (treated and untreated bleedings) from Week 12 through at least 15 months (up 
to data cutoff) post PF-07055480 infusion.
Intercurrent 
Event

Any data after the resumption of FVIII prophylaxis regimen (if necessary) will be 
excluded.

Data after study discontinuation will not be imputed.
Population-
Level 
Summary
Total ABR post PF-07055480 infusion will be compared to participants’ Total ABR on 
prior FVIII prophylaxis regimen using a repeated measure negative binomial regression 
model. Model-based estimated difference in mean Total ABR and the 95% CI will be 
reported.
In addition, percent reduction in mean Total ABR and the corresponding 95% CI will be 
estimated.
Secondary estimands:
The two secondary estimands are:
- the treatment effect of PF-07055480 with respect to FVIII activity levels >5% at 15 months 
postinfusion or resumption of FVIII prophylaxis regimen (if necessary). 
Estimand
Attribute
Description
Population
Male participants ≥18 years of age with moderately severe to severe hemophilia A 
(FVIII:C ≤1%), who have tested negative for nAb, have no medical history of FVIII 
inhibitor.
Variable
FVIII activity level >5% at 15 months (65 weeks) post IP infusion.
Intercurrent 
Event

Any sample taken within 72 hours for standard half-life products  and 120 hours for 
extended half-life products after administering exogenous FVIII replacement therapy 
for any purpose (including treatment of bleeding or prevention purposes) will be 
excluded from the assessment of FVIII activity post PF-07055480 infusion.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 98
Estimand
Attribute
Description

Any FVIII activity levels after the resumption of FVIII prophylaxis regimen (if 
necessary) will be imputed with 0.9%. Participants who resume prophylaxis regimen 
prior to Month 15 post PF-07055480 infusion will be considered as having FVIII 
activity level ≤5%.

Participants who discontinue from the study will be considered as having FVIII 
activity level ≤5%. 
Population-
Level 
Summary
The percentage of participants with FVIII activity level >5% will be calculated and 
compared to a null hypothesis of percentage ≤68% using an exact binomial test at one-
sided alpha = 0.025. 
- the ABR:
Estimand
Attribute
Description 
Population
Male participants ≥18 years of age with moderately severe to severe hemophilia A (FVIII 
activity ≤1%), who have tested negative for nAb, have no medical history of FVIII 
inhibitor.
Variable
ABR (treated bleedings) from Week 12 through at least 15 months (up to data cutoff) post 
PF-07055480 infusion.
Intercurrent 
Event

Any data after the resumption of FVIII prophylaxis regimen (if necessary) will be 
excluded.

Data after study discontinuation will not be imputed.
Population-
Level 
Summary
ABR post PF-07055480 infusion will be compared to participants’ ABR on prior FVIII 
prophylaxis regimen using a repeated measure negative binomial regression model. Model-
based estimated difference in mean ABR and the 95% CI will be reported.
In addition, percent reduction in mean ABR and the corresponding 95% CI will be 
estimated.
9.2. Sample Size Determination
Approximately 70 participants from the lead-in Study C0371004 will be enrolled and eligible 
participants will be assigned to study intervention to achieve a desired sample size of at least 
50 dosed participants completing at least 15 months of follow-up postinfusion. All 
participants are expected to be dosed in this single armed study. The number of participants 
may exceed 50, because all C0371004 participants who meet the eligibility criteria will be 
allowed to participate in this study.
Sample size for the primary analysis based on treated ABR assumptions: A sample size of at 
least 50 dosed participants who have completed at least 15 months post PF-07055480 
infusion will provide at least 95% power (one-sided test with alpha=0.025) to demonstrate 
noninferiority of gene therapy compared to prophylaxis treatment on the difference in ABR 
with an NI margin of 3.0 bleeds/year. The sample size and power determination were 
performed using simulations (5000 samples) with a negative binomial distribution of ABR 
for FVIII prophylaxis regimen. This sample size is based on an assumed 4.0 bleeds/year in 
the ABR of prophylaxis regimen and 1.0 bleed/year in the ABR through 15 months post 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 99
PF-07055480 infusion. The correlation between PF-07055480 and FVIII prophylaxis 
treatment was assumed to be 0.2 in simulations based on prior internal data with BeneFIX 
(Study B1821002).48
The choice of the NI margin is based on the FDA guideline49 of selecting a margin based on 
historical data and EMA guideline50 and ICH guidelines51,52,53, on the choice of NI margin, 
taking into consideration the constancy assumption, and using the “95%-95%” method.
The NI margin is based on the effect of prophylaxis treatment over on-demand treatment (as 
the reference treatment and the active control), which is expressed by a mean difference in 
ABR in a single arm trial with a switch from on-demand to prophylaxis using a paired 
comparison (see Appendix 7 for definitions of factor replacement regimens). Historical data 
were investigated among prior Pfizer hemophilia studies. This enabled selection of individual 
participant level data that would closely match the inclusion/exclusion criteria. Studies 
having both prophylaxis and on-demand treatment were selected to provide a within-study 
treatment difference estimate. The following 3 studies satisfied these criteria: B1821010 
(BeneFIX),54 B1821002 (BeneFIX),48 and B1831004 (Xyntha/ReFacto).55 Both Hemophilia 
A and Hemophilia B data were considered due to similarity in the benefit of prophylaxis 
versus on-demand treatment seen in ABR with respective factor replacement therapies. The 
mean ABR difference between prophylaxis and on-demand treatment was estimated using an 
additive negative binomial model. Based on the lower bound of the confidence interval of 
this estimate, the on-demand ABR is assumed to be higher by at least 16.8, which will be 
considered as M1 in the noninferiority test setting. 
Given the large effect size of prophylaxis treatment (over on-demand therapy), an 
appropriate value for M2 was selected in order to preserve a sufficiently large proportion of 
this effect. Preservation levels of 75, 80, and 85% of M1 correspond to noninferiority margin 
values of 4.2, 3.4, and 2.5 bleeding events/year, on an absolute scale, respectively. A value of 
3.0 for M2 (approximately 82% of the M1 effect preserved) is both clinically meaningful and 
yielding a reasonable sample size for establishing efficacy.
Clinical justification of the noninferiority margin is further supported from a review of 
observed ABR from real world studies and clinical studies. The Sponsor has compared 
prophylaxis efficacy results for the FVIII product moroctocog alfa (AF-CC) in the real-world 
setting (Study 3082B2-4432)56 and in the clinical trial setting (Study 3082B2-310)57. 
Study 3082B2-4432 was a postauthorization study in which 154 participants with FVIII:C 
<1% received an investigator-prescribed regimen of prophylaxis treatment. Study 
3082B2-310 was a preauthorization clinical trial in which 94 participants with FVIII:C ≤2% 
(including 87 participants with FVIII:C ≤1%) received a protocol-specified prophylaxis 
treatment regimen. The ABR was 8.43 during the during prophylaxis treatment in 
Study 3082B-4432, whereas in Study 3082B2-310 the mean ABR observed during 
prophylaxis was 3.9. In the recently published lead-in study of emicizumab in noninhibitor 
hemophilia A participants (≥12 years of age) the on-demand ABR was 36.1 and the FVIII 
prophylaxis regimen ABR was 5.0 for treated bleeds58. The results of prophylaxis treatment 
from the Pfizer clinical studies are within the range of results observed in other studies and 
therefore indicate that they are representative of hemophilia A prophylaxis results. Given the 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 100
range of mean ABR observed in various clinical trials and real-world data (0 - 8.9), a value 
of 3.0 represents a reasonably conservative margin of NI.
Adjustments Based on Total ABR as The Primary Endpoint 
In the absence of internal historical data for total bleeds, the results of emicizumab 
publications of HAVEN1 and HAVEN3 studies were used as a reference.59,60  A treatment 
difference (in terms of mean number of bleeds) between the on-demand treatment (no 
prophylaxis) versus the prophylaxis (emicizumab) treatment and the ratio of treatment 
difference in total bleeds over that in treated bleeds were calculated from the two referenced 
studies.  It is then assumed that the treatment difference ratio of the on-demand treatment (no 
prophylaxis) compared to the prophylaxis (emicizumab) treatment will be similar to the ratio 
in comparison of the prophylaxis treatment to the gene therapy. Table 3 shows that the 
difference in mean Total ABR is 12% to 23% higher than the difference in mean treated 
ABR, resulting in a geometric mean increase of 17% for Total ABR versus treated ABR.  
Table 3.
Estimated Effect of Treated Bleeds and All Bleeds Per Year in 
Emicizumab Studies
HAVEN1 (Inhibitors)
HAVEN3 (No inhibitors)
Prophylaxis
On 
demand 
Treatment 
difference
Prophylaxis
On 
demand
Treatment 
difference*
Treated ABR
2.9
23.3
20.4
1.5
38.2
36.7
Total ABR
5.5
28.3
22.8
2.5
47.6
45.1
Ratio 
(Total/Treated)
1.90
1.12
1.67
1.23
*Difference between the on-demand treatment and the emicizumab prophylaxis in the once weekly 
group.
Adjustment of M1 and M2 :
M1 of 16.8 (difference in mean treated ABR between FVIII product prophylaxis and on-
demand treatment based on internal studies listed above) is expected to be equivalent to 
19.66 (ie, 16.8*1.17) when considering mean Total ABR. Preservation levels of 75%, 80%, 
and 85% of M1 will correspond to noninferiority margin values of 4.9, 3.9, and 2.9 bleeding 
events/year, on an absolute scale, respectively. A value of 3.0 for M2 (approximately 84.7% 
of the M1 effect preserved) is both clinically meaningful and yielding a reasonable sample 
size for establishing efficacy based on Total ABR.
Adjustment of assumptions:
According to Table 3, the ratio of Total ABR over treated ABR in the emicizumab 
prophylaxis treatment group was 1.90 in the HAVEN1 study and 1.67 in the HAVEN3 study.  
It is assumed that the relationship between Total ABR and treated ABR with gene therapy is 
similar to that with emicizumab prophylaxis therapy.  
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 101
Study C3731003 assumes the treated ABR under the standard FVIII prophylaxis regimen is 4 
bleeds/year based on related data in 3 internal studies and 1 bleed/year (a 75% reduction 
from 4 bleeds/year) with the gene therapy.   Based on the ratio of 1.90 for Total ABR over 
treated ABR from HAVEN1 (ie, the higher ratio of Total/Treated observed), it is assumed the 
Total ABR will be 2 bleeds/year after the gene therapy (ie, 1*1.90 approximately equal to 2).  
In addition, the lowest mean treated ABR reported among the 3 internal FVIII product 
studies was 2.6; as a conservative approach, Total ABR will be assumed to correspond to 5 
bleeds/year (ie, 2.6*1.90 approximately equal to 5) for prior prophylaxis treatment.  This 
assumption is equivalent to a 60% reduction in mean Total ABR after gene therapy compared 
to prophylaxis treatment.
Based on the simulations described above, the sample size for the primary analysis based on 
Total ABR remains unchanged. A sample size of at least 50 dosed participants who have 
completed at least 15 months of follow-up post PF-07055480 infusion will provide at least 
95% power (1-sided test with alpha=0.025) to demonstrate noninferiority of gene therapy 
compared to prophylaxis treatment based on a difference in mean Total ABR with an NI 
margin of 3.0 bleeds/year.  
9.3. Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All participants who sign the ICF and meet all inclusion/exclusion criteria.
Dosed/Safety
All participants enrolled in the study and who receive the study 
intervention.
Evaluable
All participants enrolled in the study and who receive the study 
intervention and have no significant interruption of efficacy measurement 
and no major protocol deviation.
Efficacy
All participants in the “Dosed” population who have completed at least 6 
months in the lead-in study and at least 15 months of follow-up or 
discontinued from the study C3731003 prior to the data cutoff for 
reporting. 
9.4. Statistical Analyses
The primary analysis will be conducted when at least 50 dosed participants with 6 months of 
follow up in the Lead_In study (C0371004) have reached at least 15 months of follow-up 
postinfusion (ie, data cutoff for primary analysis).
The statistical analysis plan 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. The overall probability of Type 1 error for 
primary statistical tests, and other tests included in the multiple testing procedure, is 
controlled at .05 (or one-sided .025). For the primary analysis, the Type I error will be 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 102
controlled using a hierarchical testing approach whereby the primary hypothesis of NI of 
Total ABR from Week 12 through at least 15 months (up to data cutoff) post PF-07055480 
infusion compared to the Total ABR pre-PF-07055480 infusion will be tested first followed 
by a comparison of the percentage of participants with FVIII activity level >5% at 15 months 
to a null hypothesis of percentage ≤68% using an exact binomial test at one-sided alpha = 
0.025, and then a NI test on the ABR from Week 12 through at least 15 months (up to data 
cutoff) postinfusion compared to the ABR pre-PF-07055480 infusion. Subsequently a test for 
superiority of AIR, annualized FVIII consumption, Total ABR, and ABR will be performed. 
Additional secondary endpoints including PROs may also be tested following the test for 
superiority of ABR using the same gatekeeping approach. More information about 
gatekeeping approach is included in the SAP.
Central chromogenic assay results will be used as the primary FVIII activity measurement as 
this approach is considered the most conservative because it resulted in the lowest activity 
levels in the Phase 1/2 study (C3731001).
Any minor changes to the statistical methodology stated in the protocol will be described in 
the SAP. This section is a summary of the planned statistical analyses of the primary and 
secondary endpoints.
9.4.1. Efficacy Analyses
The primary analysis is planned after at least 15 months of follow-up postinfusion in at least 
50 dosed participants, with endpoints in the table below. The planned endpoints after the 
primary analysis, so called final analysis, are focused on extended efficacy and longer-term 
safety. 
Category of 
Endpoint
Primary Analysis
Statistical Analysis Methods
Primary

Total ABR (treated and untreated bleedings) from Week 12 through at least 15 
months (up to data cutoff)  postinfusion of PF-07055480 will be compared to 
preinfusion of PF-07055480 (under SOC FVIII prophylaxis replacement regimen). A 
repeated measure negative binomial regression model will be used to test NI with NI 
margin = 3 bleeds/year at one-sided alpha level = 0.025. If the noninferiority on Total 
ABR is established, subsequently testing for superiority will be conducted.
Key secondary

FVIII activity level >5%  at 15 months postinfusion of PF-07055480. The percentage 
of participants will be compared to a null hypothesis of percentage ≤68% using an 
exact binomial test at the one-sided alpha level = 0.025. Based on the interim data of 
the Phase 1/2 Study, 80% of participants in Cohort 4 (Phase 3 study dose) had a 
FVIII activity level greater than 5% at 18 months postinfusion. The null hypothesis of 
percentage ≤ 68% is determined so it could be rejected when the observed percentage 
is greater than 80%.

ABR from Week 12 through at least 15 months (up to data cutoff)  postinfusion of 
PF-07055480 will be compared to preinfusion of PF-07055480 (under SOC FVIII 
prophylaxis replacement regimen) and analyzed separately using the same method 
applied to Total ABR.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 103
Category of 
Endpoint
Primary Analysis
Statistical Analysis Methods
Secondary
The following secondary endpoints will be analyzed with one-sided test at the alpha level 
= 0.025 (except for the paired t-test with 2-sided alpha = 0.05) or summarized.

FVIII Activity from Week 12 through 15 months postinfusion of PF-07055480 will 
be summarized with descriptive statistics. 

FVIII activity level will be summarized by visit with descriptive statistics. In 
addition, the percentage of participants with FVIII activity thresholds (e.g., <1%, 1-
5%, >5-<15%, 15-<40%, 40-≤150%, >150%) at selected visits postinfusion will be 
reported.

AIR from Week 12 through at least 15 months (up to data cutoff) postinfusion of PF-
07055480 will be compared to preinfusion (under SOC FVIII prophylaxis 
replacement regimen) and analyzed using a paired t-test. 

Annualized FVIII consumption, from Week 12 through at least 15 months (up to data 
cutoff) postinfusion of PF-07055480, will be analyzed using the same method applied 
to AIR. 

ABR of specific type (spontaneous and traumatic) from Week 12 through at least 15 
months (up to data cutoff) postinfusion of PF-07055480 will be analyzed separately 
using the same method applied to Total ABR.

ABR by location (in joints, in target joints, or in soft tissue) from Week 12 through at 
least 15 months (up to data cutoff) postinfusion of PF-07055480 will be analyzed 
using the same method as Total ABR.

Total ABR (treated and untreated) by location from Week 12 through at least 15 
months (up to data cutoff) postinfusion of PF-07055480 will be analyzed using the 
same method as Total  ABR.

The percentage of participants (from Week 12 through at least 15 months (up to data 
cutoff) postinfustion of PF-07055480) without bleeds will be summarized. 

HJHS by visit postinfusion of PF-07055480 will be compared to baseline using a 
paired t-test.

PRO endpoints (Haem-A-Qol, HAL) by visit postinfusion of PF-07055480 will be 
summarized and compared to baseline to assess the improvement from baseline if 
baseline is available.
Exploratory
Will be described in SAP finalized before database lock.
Category of 
Endpoint
Final analysis
Statistical Analysis Methods
Secondary (all 
final analysis 
endpoints are 
considered 
secondary in 
this study)
Analyses will be performed at the following intervals (Month 15, Years 2 through 5). 
Details will be described in the SAP finalized before database lock.
Exploratory
Comparison of FVIII activity assays and other exploratory analyses will be described in 
the SAP finalized before database lock.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 104
Category of 
Endpoint
Primary Analysis
Statistical Analysis Methods
Category of 
Endpoint
Ultrasound Substudy
Exploratory
Joint images will be reviewed following the extended ultrasound scale with a final score 
combining soft tissue and osteochondral subscores, and compared to screening (at 
Week 24 and Week 52 (or EOSV).
Category of 
Endpoint
Vector Shedding Substudy
Exploratory
A subset of participants (N=12) will have more extensive vector shedding analysis 
performed to further characterize the kinetics of vector shedding.
Category of 
Endpoint
Joint X-Ray Substudy
Exploratory
X-ray assessments will be performed to assess damage within joints as detectable at a 
radiologic level.  X-rays will be acquired at Screening or not later than Week 4/Visit 6, 
Week 156, and Week 260 or Early Discontinuation Visit.  
9.4.2. Safety Analyses
All safety analyses will be performed on the Safety Population.
Endpoint
Statistical Analysis Methods
Primary
No primary safety endpoint.
Secondary
Descriptive analyses of SAE, AE of special interests, lab abnormality, etc. will be 
conducted.
Exploratory
Will be described in the SAP finalized before database lock.
9.4.3. Other Analyses 
Pharmacodynamics (as FVIII antigen levels), and other exploratory analyses will be 
described in the SAP finalized before database lock. 
9.5. Interim Analyses
No interim analysis is planned. As this is an open-label study, the sponsor may conduct 
reviews of the data during the course of the study for the purpose of safety assessment. 
9.5.1. Data Monitoring Committee (DMC)
This study will use an eDMC. The eDMC is independent of the study team and includes only 
external members. The eDMC 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 
eDMC charter describes the role of the eDMC in more detail.
The recommendations made by the eDMC will be forwarded to the appropriate authorized 
Pfizer personnel for review and final decision. Pfizer will communicate such decisions, 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 105
which may include summaries of aggregate analyses of study endpoints and of safety data, to 
regulatory authorities and investigators, as appropriate.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 106
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 International Ethical Guidelines;

Applicable ICH 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 Regulatory Authority 
approval before implementation, where applicable based on local/regional regulatory 
requirements, 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
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 investigational 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 107
product, Pfizer should be informed immediately. For Japanese sites please refer to Japan 
Appendix, Section 10.8.2.4.
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/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions 
regarding the study. The participant [or their legally authorized representative] 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 or 
their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, ICH 
guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/EC or study center.

The investigator must ensure that each study participant or his or her legally 
authorized representative 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/her 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/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.

The investigator further must ensure that each study participant or his or her legally 
authorized representative is fully informed about his or her right to access and 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 108
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 ICF.

Participants must be re-consented to the most current version of the IRB/EC-
approved ICF(s) during their participation in the study as required per local 
regulations

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.

For German sites please refer to Country-Specific Appendix (Section 10.8.3.3).

For Japanese sites please refer to Country-Specific Appendix (Section 10.8.2.4).
Participants who are rescreened are required to sign a new ICF.
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research. The investigator or authorized designee will 
explain to each participant the objectives of the exploratory research. Participants will be told 
that they are free to refuse to participate and may withdraw their consent at any time and for 
any reason during the storage period. A separate signature will be required to document a 
participant's agreement to allow any remaining specimens to be used for exploratory 
research. Participants who decline to participate in this optional research will not provide this 
separate signature.
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 shall be responsible for determining whether a personal data 
breach has in fact occurred and, if so, providing breach notifications as required by 
law.

To protect the rights and freedoms of natural persons with regard to the processing 
of personal data, participants will be assigned a single, participant-specific 
numerical code. Any participant records or datasets that are transferred to the 
sponsor will contain the numerical code; participant names will not be transferred. 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 109
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. 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. Committees Structure
Refer to Section 9.5.1 for information on the DMC.
10.1.6. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the  EudraCT/CTIS, and/or 
www.pfizer.com, and other public registries in accordance with applicable local 
laws/regulations. In addition, Pfizer reports study results outside of the requirements of local 
laws/regulations pursuant to its standard operating procedures.
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 that are in scope of EU requirements. 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 110
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 authorization packages/submissions
Pfizer complies with applicable local laws/regulations to publish clinical documents included 
in marketing applications. Clinical documents include summary documents and CSRs 
including the protocol and protocol amendments, sample CRFs, and SAPs. Clinical 
documents will have personally identifiable information anonymized.
Data Sharing
Pfizer provides researchers secure access to participant-level data or full CSRs for the 
purposes of “bona-fide scientific research” that contribute to the scientific understanding of 
the disease, target, or compound class. Pfizer will make available data from these trials 
24 months after study completion. Participant-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.
10.1.7. Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic 
CRF 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 data documents. 
This verification may also occur after study completion. It is important that the 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 111
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.

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. For Swedish sites, 
please refer to Country-Specific Appendix (Section 10.8.4).

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.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 112
10.1.8. 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’s 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 source data can be found in the Study Data 
Monitoring Plan.
10.1.9. Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment is the date of the first participant’s first visit and will be the study 
start date.
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 Contract 
Research Organization if requested to do so by the responsible IRB/IEC 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/IEC or local health authorities, the sponsor's procedures, or GCP guidelines

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 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 113
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.
10.1.10. 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.
10.1.11. 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. 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 114
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 investigational product 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.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 115
10.2. Appendix 2: Clinical Laboratory Tests
The tests detailed in Table 3 will be performed by the CL unless otherwise indicated in 
Table 4.

Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5 of the protocol.

Additional tests may be performed at any time during the study as determined 
necessary by the investigator or required by local regulations.
Table 4.
Protocol-Required Laboratory Assessments
Laboratory Assessments
Parameters
Hematology
Platelet Count
RBC Count
Hemoglobin
Hematocrit
RBC Indices: MCV, MCHC, MCH 
ABO: only if unknown at screening
WBC count with 
Differential:
Neutrophils
Lymphocytes
Monocytes
Eosinophils
Basophils
Clinical chemistry
Blood urea nitrogen
Serum creatinine
Potassium
Sodium
Chloride
Bicarbonate
Glucose
Phosphate
Lipid panel 
(8 h of fasting)
LDL
VLDL
HDL
Triglycerides
Total cholesterol
Routine urinalysis
Specific gravity
pH, glucose, protein, blood, ketones
Cardiac monitoring
Troponin I
Liver function tests (CL and LL)
Albumin 
Total bilirubin
Direct bilirubin
Indirect bilirubin
ALP
AST
ALT
Total protein
GGT
LDH
FVIII activity (CL and LL)
Central laboratory: Chromogenic and one stage clotting assays 
Local laboratory: routine assay
Coagulation
Global hemostasis markers

Main group: aPTT (in ratio), INR, TAT, TGA, D-dimer

As needed: Fibrinogen (activity and antigen)
Thrombophilia related parameters

AT, Protein C, Protein S activities and antigens (free and total)
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 116
Table 4.
Protocol-Required Laboratory Assessments
Laboratory Assessments
Parameters

Genetic analyses: FV Leiden thrombophilia mutation and FII / 
Prothrombin gene mutation (G20210A) 
FVIII inhibitor
FVIII inhibitor testing (Nijmegen Bethesda),
(LL only if clinically indicated)
AAV neutralizing antibody
Anti-AAV6 neutralizing antibodies
nAbs against other AAV serotypes (for cross reactivity)
ADA
Anti-PF-07055480 antibodies
Immunology
PBMC preparation for ELISPOT assays (specific to AAV6 and to the 
transgene) and for other exploratory cell-mediated assays
Binding IgG versus IgM antibody response
Exploratory pharmacodynamics 
markers 
Von Willebrand Factor 
FVIII Antigen levels
Vector shedding and infectivity
Vector shedding will be detected in plasma, urine, saliva, semen, and in 
PBMC
Infectivity will be performed if applicable
Hepatitis B and hepatitis C
Hepatitis B surface antigen (HBsAg)
Hepatitis B core total antibodies (HBcAb)
HBV DNA
Hepatitis C virus AB
HCV RNA Quantitative
Liver fibrosis

FibroTest/FibroSURE (including 2-macroglobulin, 
apolipoprotein A1 and haptoglobin)
Biomarker for hepatic carcinoma 
-Fetoprotein 
HIV
HIV-1/HIV-2 antibody screen
HIV-1 RNA (qualitative) and CD4+ count if positive antibodies
Spare plasma
Plasma (or pre-dose serum on Day 1/Visit 3) will be stored for repeat 
and/or the testing of additional exploratory biomarkers of the immune 
response and study intervention mechanism of action
FVIII genetic testing
Mutation in FVIII gene
If not available in the source documents only
Investigators must document their review of each laboratory safety report.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 117
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 signs measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease). 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 pre-existing 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 drug-drug 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/self-
harming intent. Such overdoses should be reported regardless of sequelae.

“Lack of efficacy” or “failure of expected pharmacological action” per se will not 
be reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 118
lack of efficacy will be reported as AE or SAE if they fulfil the definition of an AE 
or SAE.
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).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event 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.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 119
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
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.

Suspected transmission via a Pfizer product of an infectious agent, pathogenic or 
non-pathogenic, is considered serious. The event may be suspected from clinical 
symptoms or laboratory findings indicating an infection in a participant exposed to 
a Pfizer product. The terms “suspected transmission” and “transmission” are 
considered synonymous. These cases are considered unexpected and handled as 
serious expedited cases by pharmacovigilance personnel. Such cases are also 
considered for reporting as product defects, if appropriate.

In this study, the following events that occur poststudy treatment infusion are 
considered medically important events and should be reported as SAEs:
1. Any participant develops clinical thrombotic event (with the exception of IV 
infusion-site thrombophlebitis). 
2. Any participant develops a confirmed FVIII inhibitor. 
3. Any participant develops clinically significant hypersensitivity reaction (eg, 
bronchospasm and anaphylaxis). Infusion related reactions should be reported 
as serious only if they meet serious criteria.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 120
4. Any participant develops a hepatic malignancy. 
5. Any participant develops drug-related elevated hepatic transaminases that fail 
to improve or resolve through treatment with immunosuppressive regimens.
6. Any occurrence of a malignancy assessed as having reasonable possibility 
relatedness to study drug.
10.3.3. Recording and Follow-Up of AE and/or SAE
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF 
and for reporting serious adverse events on the 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 investigational product under study during 
pregnancy 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.
During the Short Term Monitoring Period (up to and including 104 weeks postinfusion)
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE (including the 
medically important 
events – as defined in 
Section 10.3.2)
All
All
Non-serious AE
All
None
Exposure to the study 
intervention under study 
during pregnancy and 
occupational exposure
All AEs/SAEs associated 
with exposure during 
pregnancy.
Occupational exposure is not 
recorded.
All (and EDP supplemental 
form for EDP)
Note: Include all SAEs 
associated with exposure 
during pregnancy. Include 
all AEs/SAEs associated 
with occupational exposure.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 121
During the Long Term Monitoring Period (Week 105 until EOS Visit)
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE (including the 
medically important 
events – as defined in 
Section 10.3.2)
All
All
Non-serious AE 
determined to be related 
to the study intervention 
by the investigator; 
and/or where causality is 
unknown.
All
None
Exposure to the study 
intervention under study 
during pregnancy and 
occupational exposure
All AEs/SAEs associated 
with exposure during 
pregnancy.
Occupational exposure is not 
recorded.
All (and EDP supplemental 
form for EDP)
Note: Include all SAEs 
associated with exposure 
during pregnancy. Include 
all AEs/SAEs associated 
with occupational exposure.

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics 
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.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 122
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 

Mild: An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities.

Moderate: An event that causes sufficient discomfort and interferes with normal 
everyday activities.

Severe: An event that prevents normal everyday activities. An AE that is assessed 
as severe should not be confused with a SAE. Severe is a category utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as severe.
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes 
as described in the definition of an SAE, NOT when it is rated as severe.
Assessment of Causality

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 the 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 the sponsor.

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 investigational product caused 
the event, then the event will be handled as “related to investigational product” for 
reporting purposes, as defined by the sponsor" and "In addition, if the investigator 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 123
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 the 
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 Pfizer Safety 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 to Pfizer Safety via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as it becomes 
available.

After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to the Pfizer Safety by telephone.

Contacts for SAE reporting can be found in the ISF.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 124
SAE Reporting to Pfizer Safety via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to Pfizer Safety.

In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE data collection tool sent by 
overnight mail or courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE CRF pages within the designated reporting time frames.

Contacts for SAE reporting can be found in the ISF.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 125
10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information
Contraception Guidance:
Contraception guidance for the male participants until at least 3 consecutive ejaculate 
samples test negative for vector shedding as follows:

Refrain from donating sperm
PLUS either:

Be abstinent from heterosexual or homosexual intercourse as their preferred and 
usual lifestyle (abstinent on a long term and persistent basis) and agree to remain 
abstinent. 
OR

Must agree to use contraception/barrier as detailed below. 
o
Agree to use male condom when engaging in any activity that allows for 
passage of ejaculate to another person.
Collection of Pregnancy Information:
For both unapproved/unlicensed products and for marketed products, an EDP occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;

An example of environmental exposure would be a case involving direct 
contact with a Pfizer product in a pregnant woman (eg, a nurse reports that she 
is pregnant and has been exposed to chemotherapeutic products).

A male has been exposed (eg, because of treatment or environmental exposure) to 
the investigational product prior to or around the time of conception and/or is 
exposed during his partner’s pregnancy. 
If a participant or participant’s partner becomes or is found to be pregnant during the 
participant’s treatment with the investigational product, the investigator must report this 
information to Pfizer Safety on the CT SAE Report Form and an EDP supplemental form, 
regardless of whether an SAE has occurred. In addition, the investigator must submit 
information regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a 
participant reports that she is pregnant and has been exposed to a cytotoxic product by 
inhalation or spillage) to Pfizer Safety using the EDP supplemental form. This must be done 
irrespective of whether an AE has occurred and within 24 hours of awareness of the 
exposure. The information submitted should include the anticipated date of delivery (see 
below for information related to termination of pregnancy).
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 126
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome. The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form. In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth. In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless pre-
procedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.
Additional information regarding the EDP may be requested by the sponsor. Further follow-
up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on preterm 
infants to identify developmental delays). In the case of paternal exposure, the investigator 
will provide the participant with the Pregnant Partner Release of Information Form to deliver 
to his partner. The investigator must document in the source documents that the participant 
was given the Pregnant Partner Release of Information Form to provide to his partner.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 127
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 clinical study report 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.

The samples will be retained as indicated:

Samples for specified genetic analysis (see Section 8.7) will be stored for up to 
5 years or other period as per local requirements or will not be stored beyond the 
completion of this study (eg, clinical study report finalization).
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 128
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments 
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 DILI. 
Participants who experience a transaminase elevation above 3 times the upper limit of normal 
(× 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 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:
o
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).
o
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 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 129
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, creatine kinase, direct and 
indirect bilirubin, GGT, PT/INR, total bile acids, and ALP. 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 (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 sample 
for acetaminophen 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.
Unique to PF-07055480 is the potential for T-cell induced hepatocyte destruction. In some 
cases, presentation of AAV capsid protein by MHC to the surface of a hepatocyte can trigger 
CD8 cell mediated targeting of hepatocytes. This presents asymptomatically with a rise in 
LFTs and/or a decline in FVIII activity levels. This effect is not due to direct hepatocyte 
toxicity rather it is an immunologic response. This immunologic reaction has been shown in 
prior studies and more particularly in 2 participants in the Phase 1/2a dose escalation study 
who have both responded to a short course of corticosteroids. 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 130
10.7. Appendix 7: Factor Replacement Regimens and Bleed Definitions
Definition of Factor Replacement Regimens
Prophylaxis Therapy: The regularly scheduled and regimented administration of factor 
replacement therapy to prevent bleeding.
Preventative Therapy: Infusion of clotting factor that is given in anticipation of a planned 
physical activity that has a high risk of injury (eg, surgery or sporting activity).
On-Demand Therapy: The administration of factor replacement therapy only at the time of an 
acute bleeding event.
Definition of a Bleed
Treated Bleed: An event necessitating administration of coagulation factor within 72 hours of 
signs or symptoms of bleeding (protocol definition, unless specifically referring to untreated 
bleed).
Untreated Bleed: A bleeding event not necessitating administration of coagulation factor 
within 72 hours of signs and symptoms of bleeding.
New Bleed: A bleed occurring >72 hours after stopping treatment from the original bleed for 
which treatment was initiated or a bleed occurring at a different site from the original bleed 
regardless of the time from last injection.
Definition of a Bleed Location
Target Joint: Defined as a major joint (eg, hip, elbow, wrist, shoulder, knee, and ankle) into 
which repeated bleeds occur (3 or more spontaneous bleeds into a single joint within a 
consecutive 6-month period). A target joint is considered resolved when there are ≤2 bleeds 
into the joint within a 12-month period.
Joint Bleed: A bleeding episode characterized by rapid loss of range of motion as compared 
with baseline that is associated with any combination of the following: pain or an unusual 
sensation in the joint, palpable swelling, and warmth of the skin over the joint.
Muscle Bleed: An episode of bleeding into a muscle, determined clinically and/or by imaging 
studies, generally associated with pain and/or swelling and functional impairment.
Definition of Bleed Types
Spontaneous Bleeds: Bleeding for no apparent/known reason particularly into the joints, 
muscles, and soft tissues.
Traumatic Bleeds: Bleeding event occurring for an apparent/known reason.
Note: Bleeds related to a procedure/surgery such as hematomas/bruising resulting from any 
surgeries or invasive procedures (eg, tooth extractions, venipuncture, or subcutaneous drug 
administrations) or invasive diagnostic procedures (eg, lumbar puncture, endoscopy with 
biopsy) would NOT be counted as bleeds. Bleeds related to procedure/surgery are not 
associated with any trauma except procedure/surgery-induced trauma.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 131
10.8. Appendix 8: Country-Specific Requirements
10.8.1. France Appendix
This appendix applies to study sites located in France.
Per France regulations, a France-specific protocol appendix is to be included in the final 
approved protocol to capture some operational items not included in the mandatory contract 
format for France (ie, French “Contract Unique”), which Pfizer includes in standard contract 
language for other countries. The following items included do not impact the conduct of the 
trial, the safety or integrity of the participant, or use of their data:
1.
GCP Training
Prior to enrollment of any participants, the investigator and any sub-investigators will 
complete the Pfizer-provided GCP training course (“Pfizer GCP Training”) or training 
deemed equivalent by Pfizer. Any investigators who later join the study will complete the 
Pfizer GCP Training or equivalent before performing study-related duties. For studies of 
applicable duration, the investigator and sub-investigators will complete Pfizer GCP Training 
or equivalent every three years during the term of the study, or more often if there are 
significant changes to the ICH GCP guidelines or course materials.
2.
Study Intervention
No participants or third-party payers will be charged for study intervention.
3.
Record Retention
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified. The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations. The 
investigator must obtain Pfizer’s written permission before disposing of any records, even if 
retention requirements have been met.
4.
SUSARs
Pursuant to a sponsor’s safety reporting obligations under 21 CFR 312.32(c)(1), Pfizer will 
report to the investigator all Serious Unexpected Suspected Adverse Reactions (“SUSARs”). 
Investigator will receive and review SUSAR reports and report SUSARs to the responsible 
IRB/IEC according to institution’s guidelines. Institution will retain SUSAR reports 
consistent with the above paragraph (Record Retention) and Appendix 1. 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 132
10.8.2. Japan Appendix
This appendix is only for investigators at Japanese sites.
10.8.2.1. Study Intervention Defects Definitions
Defect: Refers to lack of function of the study intervention (see Section 6.1), causing 
generally poor conditions where the cells cause adverse reactions that affect the human body, 
irrespective of what stage of manufacture, delivery, storage or use the defect occurs.
10.8.2.2. Reporting Criteria
All study intervention defects are to be reported to the sponsor within 24 hours of 
investigator awareness (see Section 10.8.2.3) if any of the points listed below apply. Note: 
The reporting of study intervention defects will not result in any change to the reporting of 
AEs as described in Section 10.3 (Appendix 3: Adverse Events: Definitions and Procedures 
for Recording, Evaluating, Follow-up, and Reporting). 

Occurrence of study intervention defects directly or indirectly leads to SAEs (see
Section 10.3.2) of a participant/user/other person. 

OR

Study intervention defects have not actually led to SAEs but may possibly lead to SAEs 
of a participant/user/other person. 
For product complaints that do not meet the reporting criteria above, refer to the 
Investigational Product Complaints section of the study Investigational Product (IP) Manual 
for detailed reporting procedures.
10.8.2.3. Reporting Procedures
The following procedures are to be followed in order to report the Study Intervention 
Defect(s) to the sponsor: 
1. Study intervention defects information should be recorded, as completely as possible, on 
the Investigational Drug Product (Regenerative medicine products) Complaint 
Submission Form located in the Investigator Site File (ISF). 
2. The form should be submitted electronically to sponsor within 24 hours of being aware of 
an intervention defect. 
3. After the complaint is received by the sponsor, a close out memo will be generated. This 
close out memo will be provided to the study site.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 133
10.8.2.4. Japan-Specific Protocol Wording
10.8.2.4.1. Section 6.4 Study Intervention Compliance
The study drug will NOT be administered to multiple Japanese participants on the same day 
of the administration to the first Japanese participant.
10.8.2.4.2. Section 8.3.4 Regulatory Reporting Requirements for SAEs
The sponsor will report SAEs that impact study status to the Japan sites approximately 
24 hours of Pfizer Japan receipt of the report.
10.8.2.4.3. Section 10.1.1 Regulatory and Ethical Considerations
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 investigational 
product, Pfizer should be informed immediately. This information should be shared with 
Japan sites approximately 24 hours after Pfizer Japan is aware of this information.
10.8.2.4.4. Section 10.1.3 Informed Consent Process
When a minor participant (defined as less than 20 years old) is included in this study in 
Japan, written informed consents will be obtained from both the participant and his legally 
acceptable representative.
10.8.3. Germany Appendix
This appendix is only for investigators at German sites.
10.8.3.1. Section 5.1 Inclusion Criteria
7.
Capable of giving signed informed consent as described in Appendix 1 which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol. German adult participants need to be of age AND be able to 
consent themselves in writing to be eligible to participate in the study.
10.8.3.2. Section 5.2 Exclusion Criteria
17. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 
participants who are Pfizer employees, including their family members, directly 
involved in the conduct of the study. In Germany, employees of the sponsor, CRO, or 
study site are not eligible to participate in the study even if they are not involved directly 
with the conduct of the study.
18. Unable to comply with scheduled visits, treatment plan, laboratory tests and other study 
procedures for up to 6 years post study drug infusion in the investigator’s judgement. In 
Germany, participants committed to an institution by virtue of an order issues either by 
the judicial or the administration authorities are not eligible to participate in the study.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 134
10.8.3.3. Section 10.1.3 Informed Consent Process
German adult participants need to be of age AND be able to consent themselves in writing to 
be eligible to participate in the study.
10.8.3.4. Section 1.3 Schedule of Activities (SoA)
Participants seen at German sites will not be permitted to undergo X-ray testing for this 
study.
10.8.3.5. Section 8.1.3.3 X-ray Assessments to Evaluate Joints
Participants seen at German sites will not be permitted to undergo X-ray testing for this 
study.
10.8.4. Sweden Appendix
This appendix is only for investigators at Swedish sites.
10.8.4.1. Section 10.1.7. Data Quality Assurance
Records and documents, including signed ICFs, pertaining to the conduct of this 
study must be retained by the investigator for 30 years after study completion. 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. 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 135
10.9. Appendix 9: Alternative Measures During Public Emergencies
The alternative study measures described in this section are to be followed during public 
emergencies, including the COVID-19 pandemic. This appendix applies for the duration of 
the COVID-19 pandemic globally and will become effective for other public emergencies 
only upon written notification from Pfizer.
Use of these alternative study measures are expected to cease upon the return of business as 
usual circumstances (including the lifting of any quarantines and travel bans/advisories).
10.9.1. Participants Who Test Positive for COVID-19
While SARS-CoV2 testing is not mandated for this study, local clinical practice standards for 
testing should be followed.
If a participant tests positive for COVID-19, the study site staff should continue to follow 
their routine practice guidelines for COVID-19, for example: the participant may receive 
study intervention when he has no COVID-19 symptoms for 10 days and:

tests negative for COVID-19

Or

continues to test positive for COVID-19, but at least 21 days since the first positive 
COVID-19 test. 
Prior to dosing:

sites should continue to follow their routine practice guidelines for COVID-19 (for 
example, ruling out an underlying pneumonia by performing O2 saturation [via pulse 
oximetry device] and/or a chest x-ray, check D-dimer, or other relevant assessment, if 
applicable).

And

consult with the sponsor.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 136
10.9.2. Telehealth Visits
In the event that in-clinic study visits cannot be conducted, every effort should be made to 
follow-up on the safety of study participants at scheduled visits per the Schedule of 
Activities or unscheduled visits. Telehealth visits may be used to continue to assess 
participant safety and collect data points. Telehealth includes the exchange of healthcare 
information and services via telecommunication technologies (eg, audio, video, video-
conferencing software) remotely, allowing the participant and the investigator to 
communicate on aspects of clinical care, including medical advice, reminders, education, and 
safety monitoring. The following assessments must be performed during a telehealth visit:

Review and record any AEs and SAEs since the last contact. Refer to Section 8.3.

Review and record any new concomitant medications or changes in concomitant 
medications since the last contact.

Review and record contraceptive method. Confirm that the participant is adhering to the 
contraception method(s) required in the protocol.

Review bleeding episodes and FVIII infusions reported in the eDiary.
Study participants must be reminded to promptly notify site staff about any change in their 
health status.
10.9.3. Home Health Visits
The home health care service (3rd party provider contracted to Pfizer or its designee) 
will be utilized to facilitate scheduled visits per the Schedule of Activities. Home health 
visits include a healthcare provider conducting an in-person study visit at the participant’s 
location, rather than an in-person study visit at the site. Biological samples may be collected 
during a home health visit in order to perform: standard safety tests (hematology and clinical 
chemistry including liver function tests), hemostasis/coagulation parameters, lipid panel, 
troponin I, α-fetoprotein, FVIII activity, FVIII antigen, FVIII inhibitors, total and 
neutralizing anti-AAV antibodies, Elispots, exploratory cell mediated assays, IgG/IgM class 
switching assay, von Willebrand factor, vector shedding, spare plasma. Additionally, vital 
signs and PROs may be collected during a home health visit by the same health care service.
10.9.4. Adverse Events and Serious Adverse Events
If a participant has COVID-19 during the study, this should be reported as an adverse event 
(AE) or serious adverse event (SAE) and appropriate medical intervention provided.
It is recommended that the investigator discuss temporary or permanent discontinuation of 
concomitant medications with immunosuppressive activity with the study medical monitor.
10.9.5. Guidance for Missed Visits/Assessments and Protocol Deviations
Every effort should be made to ensure that protocol required tests and procedures are 
completed as described. However, it is anticipated that from time to time, there may be 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 137
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 
wellbeing 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 safety of a trial participant is at risk because they cannot complete required evaluations 
or adhere to critical mitigation steps, then discontinuing that participant from study must be 
considered. For participant discontinuation reporting in the CRF: select the most appropriate 
status for discontinuation; if the discontinuation is associated with the current COVID-19 
pandemic, enter “COVID-19” in the “Specify Status” field.
In the event that any of the safety and/or efficacy related postinfusion procedures listed 
below cannot be performed according to the timepoints specified in the study protocol, due to 
COVID-19 restrictions or otherwise, it is recommended that they be performed at the next 
subsequent on-site visit or unplanned visit. Even though the procedures may have been 
performed at a subsequent visit, any procedures not performed according to the timepoints 
specified in the study protocol are still considered protocol violations.

ECG

Liver ultrasound

HJHS

PROs
10.9.6. Guidance for COVID-19 Vaccination
Vaccination against COVID-19 is not contraindicated as a part of this study. However, key 
considerations for trial participants receiving COVID-19 vaccinations are:
a.
Potential for a reduced response to vaccine if administered while participant is 
receiving corticosteroids
b. Potential infusion related reactions to gene therapy or vaccine occurring 
simultaneously.
As such, the following recommendations are provided: 
1. For participants receiving COVID-19 vaccination prior to administration of the study 
drug, it is recommended that the infusion of the study drug should not occur until at 
least 4 weeks after last injection with the vaccination (some vaccines may require 
more than 1 injection). For participants who have already received the study drug, the 
COVID-19 vaccine may be administered once the participant has reached at least 
12 weeks of follow-up post-study drug infusion if the participant is not currently on 
corticosteroids. If the participant is on corticosteroids at 12 weeks postinfusion, it is 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 138
recommended vaccination is delayed until the participant has been weaned off of 
corticosteroids.  
2. It is recommended to follow WFH guidelines on how to administer the vaccine (see 
https://www.hemophilia.org/News/COVID-19 Vaccination Guidance from NHF, 
WFH, EAHAD, and EHC for the Bleeding Disorders Community). Specifically:
a.
Intramuscular injection
b. Ensure exogenous factor is available in the event of a bleeding event
c.
Consider an infusion of exogenous factor prior to vaccine administration if in the 
investigator’s opinion the last factor activity level places participant at risk of 
developing a bleeding event associated with the administration of the vaccine. 
3. Please contact the Pfizer medical monitor if you have any questions concerning 
COVID-19 vaccination in study participants.
4. COVID-19 vaccinations should be reported to the study investigator and reported as a 
concomitant medication on the CRF.
Ultimate decision-making regarding administration of the COVID-19 vaccine will be 
between the investigator and the study participant. 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 139
10.10. Appendix 10: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the table of contents (TOC). The protocol amendment summary of changes 
tables for past amendment(s) can be found below:
Amendment 9 (03 February 2023)
Overall Rationale for the Amendment: change related to dose calculation, implemented in 
response to FDA, and 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 2.3.1. Risk 
Assessment
Section 3. 
Objectives, 
Estimands, and 
Endpoints 
Section 8.2.8. 
Optional Liver 
Biopsy
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
Section 6.1
Study 
Intervention(s) 
Administered
Participants will now 
have their dose 
(3x1013 vg/kg) 
calculated based on the 
use of the IMP nominal 
concentration of 
1.0x1013 vg/mL.
This change is being made 
to facilitate dosing 
calculation at the sites and 
is not secondary to a safety 
concern.
Substantial
Section 2.3.1 Risk 
Assessment
Update to the list of 
important risks 
(including terminology).
Changes made for 
consistency with latest IB 
update to align with recent 
EMA feedback on the list 
of important risks for other 
AAV-based gene therapy 
programs in hemophilia. 
No change per se to the 
risk profile of 
giroctocogene 
fitelparvovec.
Substantial
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 140
Section # and 
Name
Description of 
Change
Brief Rationale
Substantial or 
Nonsubstantial
Section 1.1 Synopsis
Section 2.1 Study 
Rationale
4.1 Overall Design
9.2 Sample Size 
Determination
Update to the sample 
size from 63 eligible 
participants to 70 
eligible participants.
Changes made to account 
for potential attrition 
(following the study 
temporary pause). 
Substantial
Section 8.3.10 
Immunomodulation 
Optimization 
(Presumed T-Cell 
Activation)
As implemented via the 
PACL dated 12 
September 2022:
consolidation and 
further refinement of the 
guidance for initiation 
of corticosteroid  
treatment to more 
clearly incorporate 
considerations about 
ALT levels, FVIII 
activity levels along 
with time from 
giroctocogene 
fitelparvovec infusion.
The revisions are for 
clarity and completeness, 
to further assist 
investigators in their 
decision making. All 
considerations included in 
protocol Section 8.3.10 
continue to be for guidance 
only as the decision on 
whether and when to 
initiate corticosteroid 
treatment in a study 
participant remains with 
the investigator, based on 
clinical judgement.
Nonsubstantial
Section 1.3 Schedule 
of Activities
Section 8.5.1 Vector 
shedding and 
infectivity
As implemented via the 
PACL dated 12 
December 2022: Blood 
collection to prepare 
PBMCs and assess 
shedding in this matrix 
will start from Week 20. 
Update made based on 
preliminary data from the 
already dosed participants 
and the observed 
prolonged clearance time 
in PBMCs, to limit burden 
to the participants and 
collected blood volume. 
This change will have no 
impact on the assessment 
of clearance time in 
PBMCs. Available data for 
the already dosed 
participants will allow 
assessment of early 
shedding kinetics and peak 
related data. 
Nonsubstantial
Section 9.3 
Populations for 
Analyses
Minor 
clarifications/corrections
Updates made for 
consistency with SAP
Nonsubstantial
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 141
Section # and 
Name
Description of 
Change
Brief Rationale
Substantial or 
Nonsubstantial
Section 9.4.1 
Efficacy Analyses
Section 9.5.1 Data 
Monitoring 
Committee (DMC)
Section 10.1.1 
Regulatory and 
Ethical 
Considerations
Section 10.1.4 Data 
Protection
Section 10.1.6 
Dissemination of 
Clinical Study Data
Section 10.1.7 Data 
Quality Assurance
Section 10.1.9 Study 
and Site Start and 
Closure
Section 10.1.10 
Publication Policy
Clarifications
Updates made for 
consistency with the 
sponsor’s protocol 
template regularly updated 
to ensure regulatory 
compliance.
Nonsubstantial
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).
Editorial, grammatical, formatting, and administrative changes were made throughout the document.
Amendment 8 (21 November 2022)
Overall Rationale for the Amendment: change related to dose calculation, implemented in response 
to FDA.
Section # and Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial
Section 6.1
Study 
Intervention(s) 
Administered
Country specific change 
for Brazil, Canada, Saudi 
Arabia, Taiwan and 
Turkey: participants will 
now have their dose 
(3x1013 vg/kg) calculated 
based on the use of the 
This change is being made to 
facilitate dosing calculation at 
the sites and is not secondary 
to a safety concern.
Substantial
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 142
Section # and Name
Description of Change
Brief Rationale
Substantial or 
Nonsubstantial
nominal concentration of 
1.0x1013 vg/mL.
Section 8.3.10 
Immunomodulation 
Optimization 
(Presumed T-Cell 
Activation)
As implemented via the 
PACL dated 12 
September 2022:
consolidation and further 
refinement of the 
guidance for initiation of 
corticosteroid  treatment 
to more clearly 
incorporate 
considerations about 
ALT levels, FVIII 
activity levels along with 
time from giroctocogene 
fitelparvovec infusion.
The revisions are for clarity 
and completeness, to further 
assist investigators in their 
decision making. All 
considerations included in 
protocol Section 8.3.10 
continue to be for guidance 
only as the decision on 
whether and when to initiate 
corticosteroid treatment in a 
study participant remains with 
the investigator, based on 
clinical judgement.
Nonsubstantial
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).
DOCUMENT HISTORY
Document
Version Date
Summary and Rationale for Changes
Amendment 7
26 May 2022
1. Safety Updates Following Occurrence of a Thrombotic Event:
- ‘conditions associated with increased thromboembolic risk such as
inherited or acquired thrombophilia’ is added within the exclusion 
criterion # 4 listing the history of chronic diseases and of conditions 
excluding participants (Section 5.2. Exclusion Criteria).
- Measurement of laboratory parameters to assess the presence of 
inherited or acquired thrombophilia (protein S deficiency, protein C 
deficiency, antithrombin deficiency, FV Leiden thrombophilia and 
G20210A prothrombin (FII) mutation) will be performed centrally. 
These assessments are added in the Schedule of Activities (Year 1 and 
Years 2 to 5 [Section 1.3]), in Section 8.2.7 (Hemostasis Parameters, 
Thrombotic Potential Assessment and Thrombophilia Parameters) and 
in Appendix 2. These laboratory parameters were previously 
recommended to be conducted locally in the event of elevated FVIII 
levels as described in the protocol Section 8.2.7 and in the 
“Management Guide for Elevated Factor VIII Activity Levels”. 
- Addition of Fibrinogen (activity and antigen) as part of the global 
hemostasis parameters in Section 8.2.7 (Hemostasis Parameters, 
Thrombotic Potential Assessment and Thrombophilia Parameters) and 
in Appendix 2.
- The risk section is updated to include a deep vein thrombotic (DVT) 
event reported in a C3731003 participant with prior history of 
 (Section 2.3.1. Risk Assessment). Additional mitigations 
described above are also added.
- The protocol stopping rule related to the occurrence of thrombotic 
events was amended; in case of an initial thrombotic event in a 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)
PPD

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 143
DOCUMENT HISTORY
Document
Version Date
Summary and Rationale for Changes
participant, the study will be paused as initially defined, whereas the 
DMC will be urgently convened in case of the recurrence of a 
thrombotic event in a participant before making a decision about study 
continuation or pause. 
(Section 2.3.1 [Risk Assessment], Section 4.1 [Overall Design] and 
Section 8.1.2.3 [Guidance Related to Elevated FVIII Activities and 
Stopping Rule]). 
2. Revisions in Response to US FDA Comments on Study 
Endpoints:
- The ABR primary efficacy endpoint has been revised to be total 
ABR (including treated and untreated bleeds). The ABR (treated 
bleeds) is now part of the key secondary endpoints.
- The assessment of all endpoints related to bleeds and infusions 
(including Total ABR, ABR and AIR) will start from 12 weeks post 
study drug infusion (instead of 4 weeks), corresponding to the 
estimated FVIII activity level steady state onset.
Synopsis (Section 1.1), Schema (Section 1.2), Study Rationale 
(Section 2.1), Objectives, Estimands, and Endpoints (Section 3), 
Overall Design (Section 4.1), Scientific Rationale for Study Design 
(Section 4.2), Section 9.1.1 (Estimands), Section 9.2 (Sample Size 
Determination), Section 9.3 (Populations for Analyses), Section 9.4 
(Statistical Analyses), and Section 9.4.1 (Efficacy Analyses).
- The justifications for the population size and NI margin are updated 
based on the use of Total ABR instead of ABR as the primary 
endpoint.
Section 9.3 (Populations for Analyses) and references.
- The percentage of participants with FVIII activity levels ≥40% at 
each visit will be provided within FVIII activity analyses (Section 
9.4.1 (Efficacy Analyses)).
Section 9.4.1 (Efficacy Analyses).
3. Clarification of the Recommendations for Immunomodulation 
Optimization:
Section 8.3.10 (Immunomodulation Optimization) is updated to clarify 
guidance to start corticosteroid treatments based on gained experience 
from the management of the already dosed participants in the Phase 3 
study, including the confirmation of the absence of any other 
etiologies before starting treatment and guidance about late initiation 
of corticosteroids
4. Clarification on eDiary Completion Requirements: 
Section 8.1.1 (Hemophilic Bleeding Episodes and Treatment) is 
updated to clarify (1) guidance for participants non-compliant with 
eDiary requirements and (2) bleed and infusion entry requirements 
after prophylaxis resumption (and from Week 78), to limit the burden 
to participants.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 144
DOCUMENT HISTORY
Document
Version Date
Summary and Rationale for Changes
5. Clarification on the Planned Long Term Follow-Up Study 
(After the End of this Phase 3 Study):
Synopsis and Section 4.1 (Overall Design).
6. Clarification on the Exclusion Criterion #5:
Clarification about the history of malignancies in participants; except 
for adequately treated basal or squamous cell carcinoma of the skin or 
a surgically removed benign neoplasm not requiring chemotherapy 
and/or radiotherapy, participants with any history of a neoplasm 
(including hepatic malignancy) that required treatment (eg. 
chemotherapy, radiotherapy, immunotherapy), are excluded. Any 
other neoplasm that has been cured by resection should be discussed 
between the investigator and the sponsor.
Section 5.2 (Exclusion Criteria).
7. Minor clarification on the duration of Lead-In Study:
Synopsis and Section 4.1 (Overall Design).
8. Added clarification on the gatekeeping process:
Section 9.1 (Estimands and Statistical Hypotheses).
9. Inclusion of Protocol Administrative Change Letter (PACL) 
and Country-Specific Amendment:
Added clarification to Section 8.5.1 (Vector Shedding and Infectivity) 
and in the Schedule of Activities (Year 1 and Years 2 to 5 
[Section 1.3]) to allow for decreased frequency of sample collection 
for shedding assessment after 34 weeks in the study in the event that 
samples have not yet cleared at this time and if home-health care is not 
available at a site or country.
Editorial, grammatical, formatting, and administrative changes 
were made throughout the document.
Amendment 6
13 January 2022
1. Revisions in Response to US FDA Comments:

Primary analysis moved from 12 months postinfusion to 
15 months postinfusion, corresponding to 12 months of 
follow-up after Week 12.

Change of the key secondary FVIII activity endpoint initially 
based on the geometric mean FVIII activity level (from onset 
of steady state to 12 months postinfusion) to the proportion of 
participants having more than 5% FVIII activity level at 
15 months postinfusion. The geometric mean FVIII activity 
level (from onset of steady state to 15 months postinfusion) 
has been retained as a secondary endpoint.

Total ABR added as another key secondary endpoint. The 
study will therefore include 2 key secondary endpoints.

Removal of the interim analysis initially planned at 
12 months postinfusion on 20 participants.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 145
DOCUMENT HISTORY
Document
Version Date
Summary and Rationale for Changes
Synopsis (Section 1.1), Schema (Section 1.2), Study Rationale 
(Section 2.1), Objectives, Estimands, and Endpoints (Section 3), 
Overall Design (Section 4.1), Scientific Rationale for Study Design 
(Section 4.2), Section 9.1.1 (Estimands), Section 9.2 (Sample Size 
Determination), Section 9.3 (Populations for Analyses), Section 9.4 
(Statistical Analyses), and Section 9.4.1 (Efficacy Analyses).
2. Safety Updates:

To support a consistent approach to manage participants with 
FVIII activity >ULN postinfusion, a guide including 
recommendations for Investigators has been developed and 
endorsed by the eDMC (“Management Guide for Elevated 
Factor VIII Activity Levels”). Key recommendations 
included in this guide are summarized in Factor VIII activity 
(Section 8.1.2) and Hemostasis Parameters and Thrombotic 
Potential Assessment (Section 8.2.7). The guide is referenced 
in Schedule of Activities (Section 1.3), Risk Assessment 
(Section 2.3.1), Allowed Therapy (Section 6.5.1), and 
Disallowed Therapy (Section 6.5.2).

Addition of a stopping rule in case of a thrombotic event 
suspected to be related to >ULN FVIII activity levels 
(Overall Design [Section 4.1] and Factor VIII activity 
[Section 8.1.2]).

The risk of “Overexpression of transgene and activity of 
transgene in treated patients/thrombotic events” in the 
risks/mitigations table has been updated to refer to the cases 
of participants with >ULN FVIII activity levels, to the 
implemented recommendations to manage these participants, 
and to the added stopping rule (Risk Assessment [Section 
2.3.1]).

Minor update of exclusion criterion #4 to further clarify that 
participants with a history of thrombotic events should be 
excluded and that this is not open to investigator discretion 
(Exclusion Criteria [Section 5.2]).
3. Inclusion of Protocol Administrative Change Letter (PACL) 
and Country-Specific Amendment:

Inclusion of PACL#3 changes:

Clarified the preparation of the spare sample collected before 
dosing (on Day 1 or 3 days before Day 1); serum samples, 
instead of plasma should now be stored on that day (Schedule 
of Activities, Year 1 [Section 1.3], Archive Plasma Samples 
[Section 8.10.3], and Table 3 Protocol-Required Laboratory 
Assessments [Section 10.2]).

Provided additional recommendations for liver ultrasounds 
(Schedule of Activities, Years 2 to 5 [Section 1.3] and Liver 
Ultrasound [Section 8.2.4]).
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 146
DOCUMENT HISTORY
Document
Version Date
Summary and Rationale for Changes

Provided additional recommendations while the participant is 
treated with corticosteroids, including the duration that a 
participant may be on an increased corticosteroid dose and 
clarification addressing opportunistic infections 
(Immunomodulation Optimization [Presumed T-Cell 
Activation] [Section 8.3.10]).

Provided clarifications of the procedures to be repeated for 
screen-failed participants being rescreened (Screen Failures 
[Section 5.4]).

Provided clarifications for the collection of therapies for HIV, 
hepatitis B and hepatitis C to be recorded on the CRF 
(Allowed Therapy [Section 6.5.1]).

Provided clarifications for the assessment of Troponin I 
(Schedule of Activities, Year 1 and Years 2 to 5 
[Section 1.3]).

Provided clarification about the schedule of ELISPOT testing 
after the initiation of corticosteroid treatment (Schedule of 
Activities, Year 1 and Years 2 to 5 [Section 1.3]).

Inclusion of changes made upon German Regulatory 
Authority request and initially implemented in Germany only 
via Amendment 5.
4. Minor clarifications and administrative changes

Clarification on the schedule of spare plasma (Schedule of 
Activities, Year 1 and Years 2 to 5 [Section 1.3]).

Re-addition of an asterisk which had been deleted by mistake 
in the Schedule of Activities, Day 1, FVIII activity (CL, LL), 
LFT (CL, LL) and FVIII antigen (CL) (Section 1.3, Year 1). 
Added clarification to specify that FVIII activity assessment 
on Day 1 is optional.

Added clarification for Phase 1/2 data to specify that no 
“confirmed” inhibitor has been observed (Summary of 
Clinical Experience with PF-07055480 [Section 2.2.1] and 
Risk Assessment [Section 2.3.1]) for consistency with 
Phase 3 definitions.

Added clarification to specify FVIII inhibitor must be 
confirmed to be reported as a medically important event as 
already specified in Section 8.2.6.2, and deleted information 
about laboratory test as a confirmed inhibitor refers to the 
protocol definition including both laboratory and clinical 
aspects (Section 10.3.2).

Added clarification to Section 8.5.1 (Vector Shedding and 
Infectivity) and in the Schedule of Activities (Year 1 and 
Years 2 to 5 [Section 1.3]) to allow for decreased frequency 
of sample collection for shedding assessment after 20 weeks 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 147
DOCUMENT HISTORY
Document
Version Date
Summary and Rationale for Changes
in the study in the event that samples have not yet cleared at 
this time.

Added clarification to Section 8.10.4 (Other Exploratory 
Assays) to specify that remaining study samples may also be 
used for needed additional validations of study-required 
laboratory assays.
5. Editorial, grammatical, formatting, and administrative changes 
were made throughout the document.
Amendment 5
13 May 2021
Changes implemented in response to German Regulatory 
Authority (PEI)’s comments, applicable to Germany only:
Synopsis - Overall Design (Section 1.1) and Overall Design 
(Section 4.1):
-
Added text about the planned long-term follow-up after the 5-year 
period in this study to clarify that all participants will be invited to 
enter a separate multi-country, non-interventional, registry-based 
study to allow for at least 10 years of follow-up post-gene therapy 
infusion.
Amendment 4
09 April 2021
1. Revisions in response to US FDA Comments:

Description of changes:
-
Revised Interim Analysis to occur at 12 months postinfusion 
instead of 6 months post steady state with the same endpoints as 
for the Primary Analysis (ABR as primary, FVIII activity level as 
key secondary, AIR as secondary).
o
Changes in Synopsis (Section 1.1), Schema (Section 1.2), 
Study Rationale (Section 2.1), Objectives, Estimands, and 
Endpoints (Section 3), Overall Design ( Section 4.1), 
Scientific Rationale for Study Design (Section 4.2), Section 
9.1.1 (Estimands), Section 9.2 (Sample Size Determination), 
Section 9.4 (Statistical Analyses), Section 9.4.1 (Efficacy 
Analyses) and Section 9.5 (Interim Analyses).
-
Added Hypothesis testing for the Interim Analysis.
o
Changes in Section 9.1.1 (Estimands), Section 9.4 (Statistical 
Analyses), Section 9.4.1 (Efficacy Analyses) and Section 9.5 
(Interim Analyses).
-
Added text to specify that the onset of FVIII activity steady state 
is expected to be reached at the beginning of Week 9 postinfusion 
(based on Phase 1/2 Study C3731001 data).
o
Changes in Synopsis (Section 1.1), Study Rationale 
(Section 2.1), Objectives, Estimands, and Endpoints (Section 
3), Overall Design ( Section 4.1), Scientific Rationale for 
Study Design (Section 4.2), Section 9.1.1 (Estimands), 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 148
DOCUMENT HISTORY
Document
Version Date
Summary and Rationale for Changes
Section 9.4 (Statistical Analyses), and Section 9.4.1 (Efficacy 
Analyses).
-
Updates to the study sample size justification at the Primary 
Analysis with addition of more information on the simulations 
made and correlation assumed to define the study sample size.
o
Changes in Section 9.2 (Sample Size Determination).
-
Deleted justifications of the sample size of the population at the 
Interim Analysis as hypothesis testing is now included. The study 
sample size is based on the Primary Analysis. The sample size 
n=20 for the Interim Analysis is based on treatment effect 
observed using historical data and is sufficient to demonstrate 
statistical significance.
o
Changes in Section 9.2 (Sample Size Determination).
2. Alignment with recent updates in C0371004 Lead-In study: 
Clarification of the duration of follow-up on routine FVIII prophylaxis 
therapy in C0371004 required prior to enrollment into C3731003 to 
align with changes made to the duration of follow-up in the C0371004 
protocol.
In the C0371004 protocol, the exact duration of follow-up for each 
individual participant may be:
(1) 6 months or longer as dictated by enrollment into the subsequent 
dosing study (eg. for site activation delay, participant availability);
(2) shorter than 6 months after at least 50 participants are followed for 
at least 12 months in this study (C3731003).
-
Changes in Synopsis (Section 1.1), Study Rationale (Section 2.1), 
Overall Design (Section 4.1), Scientific Rationale of the Study 
(Section 4.2), Inclusion Criteria #2 (Section 5.1) and in Figure 1.
3. Addition of secondary endpoints to assess FVIII activity level by 
visit, in addition to the geometric mean from steady state to W52:

Added in Synopsis (Section 1.1) and in Objectives, 
Estimands and Endpoints (Section 3).
4. Readjustment to the frequency of the FVIII antigen, FVIII activity 
levels and LFTs assessments with additional timepoints added closer 
to Week 52 (IA and PA) whilst some assessments at earlier timepoints 
were removed to avoid additional burden on participants: (1) decrease 
of the frequency from weekly to monthly (from W20) for FVIII 
antigen, (2) decrease from twice a week to weekly from W13 to W20 
for FVIII activity, (3) decrease from weekly to every 2 weeks from 
W22 to W34 for FVIII activity and LFTs (4) addition of 2 laboratory 
visits to allow an approximate monthly assessment of FVIII activity 
and LFTs in the second half of year 1, (5) added general guidance 
about FVIII activity measurements in case of a significant decrease or 
in case of bleed:

Changes in Schedule of Activities (Section 1.3).
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 149
DOCUMENT HISTORY
Document
Version Date
Summary and Rationale for Changes
5. Addition of an exploratory endpoint to further assess 
coagulation and more specifically FVIII recovery post 
administration of FVIII product during the study (post gene 
therapy). This may be done at the time of a planned surgery or if a 
participant resumed prophylaxis.

Added in Objectives, Estimands and Endpoints (Section 3) 
and in Factor VIII Activity (Section 8.1.2).
6. Clarification of inclusion criterion #2 (Section 5.1): to allow 
participants to have their eligibility confirmed earlier, participants can 
start the Study C3731003 screening visit (V1) while still in the non-
IMP Lead-In Study C0371004.
7. Minor statistical clarifications:

Clarification of the population for the primary analysis: 
“50 evaluable” replaced by “50 dosed completing 12 months,” to 
avoid confusion with the evaluable population as defined in the 
table in Section 9.3 as “all participants enrolled in the study and 
who receive the study intervention and have no significant 
interruption of efficacy measurement”.

Changes in Synopsis (Section 1.1), Study Rationale 
(Section 2.1), Overall Design (Section 4.1) and Sample Size 
Determination (Section 9.2).

Clarification for consistency across the document: for the 
planned efficacy analyses comparing PF-07055480 to prior FVIII 
prophylaxis, all preinfusion data will be considered as prior 
routine FVIII prophylaxis, including both the C0371004 Study 
and the PF-07055480 preinfusion period of this study 
(C3731003).

Clarification of the period to assess ABR, AIR and associated 
endpoints: the analyses will exclude the first 3 weeks of 
prophylaxis (approximately 2 weeks is recommended to 
participants), and therefore will start from Week 4 (Day 22). 
There is no change to analyses initially planned.

Addition of the efficacy population definition for consistency 
with SAP in Populations for Analyses (Section 9.3).
8. Added guidance to the sites or clarifications:

For clarity, addition of an introductory sentence to present 
the Phase 3 program, including the C0371004 Lead-In study and 
the C3731003 Phase 3 study (Section 1.1 and Section 2).

Updates to the Phase 1/2 C3731001 study data:

Changes in Synopsis (Section 1.1), Study Rationale 
(Section 2.1), Summary of Clinical Experience (Section 
2.2.1) and Justification for Dose (Section 4.3)

Minor clarification for HIV testing in case of serological 
evidence of HIV, both CD4+ count and viral load should be 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 150
DOCUMENT HISTORY
Document
Version Date
Summary and Rationale for Changes
assessed to confirm acceptable CD4+ count and undetectable viral 
load:

Changes in Schedule of Activities (Section 1.3), Exclusion 
Criteria #16 and Table 3 (Appendix 2 – Clinical Laboratory 
Tests)

Deletion of the collection of tuberculosis vaccination history in 
Schedule of Activities (Section 1.3): this will be reviewed and 
discussed by the investigator if corticosteroid treatment is started,
as part of all other practical recommendations for the monitoring, 
prevention and management of systemic corticosteroid-induced 
adverse events.

Revision of exclusion criterion #15: added clarification about 
liver fibrosis assessment to specify that in case of inconsistent 
results between modalities, Pfizer should be contacted (Section 
5.2).

Added recommendations for immunomodulation treatments:
in Immunomodulation Optimization (Presumed T-Cell 
Activation) (Section 8.3.10), it is now specified that (1) 
participants should be provided with a prednisone prescription 
before dosing and (2) addition of guidance if the selected 
immunosuppressive regimen differs from what is proposed in the 
protocol.

Added guidance for liver ultrasound, more specifically in case 
of abnormal findings (Section 8.2.4).

Added guidance in case FVIII activity levels are superior to 
150% including local/central parameters to be tested and assay 
considerations in Hemostasis Parameters and Thrombotic 
Potential Assessment (Section 8.2.7).

Added guidance for the selection of the appropriate dose of 
FVIII product in case of a bleeding event occurring during the 
study (post gene therapy infusion) (Section 6.5.1). This guidance 
is based on the most recent and highest available FVIII activity in 
an effort to avoid achieving levels that are supratherapeutic 
(>150%).

Added clarifications on hypersensitivity and infusion-related 
reactions in Adverse Events of Special Interest and in Definition 
of SAE (Sections 8.3.8 and 10.3.2).
9. Inclusion of Protocol Administrative Change Letters (PACLs) 
and country-specific amendments:

Inclusion of PACL#1 changes:

Implementation of COVID-19 measures added into Appendix 
9. Related changes for added flexibility of some assessments 
(ECG, liver ultrasound, joint X-rays, joint ultrasound, HJHS, 
PROs), when not impacting the scientific integrity and the 
quality of the data have been added to the Schedule of 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 151
DOCUMENT HISTORY
Document
Version Date
Summary and Rationale for Changes
Activities (Section 1.3). Sections 8, 8.1.3.2, 8.1.3.3 and 8.1.4 
have also been updated accordingly.

Joint X-Rays are now optional for participants as specified in 
the Schedule of Activities (Section 1.3) and in Section 
8.1.3.3.

Update of joint ultrasounds timepoints in the Schedule of 
Activities (Section 1.3): addition of an earlier assessment 
(6-month postinfusion) to focus on early changes, with the 
deletion of the 5-year ultrasound and the total number of 
assessments remaining 3.

Added recommendation for participants who are initiated on 
corticosteroid treatment, to be treated with a gastric acid 
reducer for the duration of the corticosteroid course to 
prevent any gastrointestinal event (Schedule of Activities 
(Section 1.3) and Section 8.3.10).

Clarifications about adverse events of special interest and 
added definition (Sections 8.3.8 and 10.3.2).

Clarification of the definition for intercurrent event related to 
the FVIII activity level variable (Sections 3 and 9.1.1). A 
conservative approach was selected and all samples taken 
within 96 hours of exogenous FVIII replacement therapy 
with no distinction between standard and extended half-life 
will be excluded from the assessment of steady state FVIII 
post vector infusion.

Minor correction: deletion of MPV parameter from the list of 
Hematology/RBC Indices parameters (Section 10.2). This 
parameter cannot be assessed centrally due to low stability of 
this parameter and is not compatible with shipment time. This 
deletion has no impact on the safety monitoring of 
participants and will be assessed locally whenever needed.

Inclusion of PACL#2 changes:

Guidance for participants who test positive for COVID-19 
(Section 10.9.1) and for COVID-19 Vaccination (Section 
10.9.6) added within the COVID-19 Appendix. 

Reference to COVID-19 Appendix added as applicable in 
Schedule of Activities, 6.2 
(Preparation/Handling/Storage/Accountability), 6.4 (Study 
Intervention Compliance), 6.5 (Concomitant Therapy), 6.5.1 
(Allowed Therapy), 6.5.2 (Disallowed Therapy) and Section 
8 (Study Assessments).

Addition of more guidance for missed ECGs, HJHS, PROs 
and liver ultrasounds if assessments missed for COVID-19, in 
Section 8 (Study Assessments and Procedures) and in Section 
10.9.5 (Guidance for Missed Visits/Assessments and Protocol 
Deviations). 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 152
DOCUMENT HISTORY
Document
Version Date
Summary and Rationale for Changes

Inclusion of changes made upon Sweden Regulatory 
Authority request and initially implemented in Sweden only 
via Amendment 3 listed below.

Inclusion of Japan-specific PACL changes (v10Dec20):

Clarification of the informed consent process in terms of the 
age criteria and definition of minor participants in Sections 
10.1.3 and 10.8.2.4.

Inclusion of changes made upon UK Regulatory Authority 
request and initially implemented in the UK only via 
Amendment 2 listed below.
10. Editorial, grammatical, formatting, and administrative 
changes were made throughout the document.
Amendment 3
12 March 2021
Changes upon Sweden Regulatory Authority request, applicable 
to Sweden:
Benefit/Risk Assessment (Section 2.3):

Added a more detailed benefit/risk assessment so that the 
investigator can easily form his/her own opinion of the 
benefit/risks for a particular participant to be included in the 
current clinical trial.
Data Quality Assurance (Section 10.1.7) and Sweden Appendix 
(10.8.4):

Amended Data Quality Assurance section and created new 
appendix to specify, according to current Swedish 
regulations, essential documents in an ATMP trial must be 
retained for at least 30 years.
Regulatory and Ethical Considerations (Section 10.1.1):

Amended to address the procedure for amendments to the 
protocol.
Amendment 2
09 December 
2020
Changes upon UK Regulatory Authority (MHRA)’s request, 
applicable to the UK:
Exclusion Criteria (Section 5.2):

At Regulatory Authority’s request, clarification of the 
exclusion criterion #5 to specify malignancies and more 
specifically hepatic malignancies, as part of 
the concurrent clinically significant major diseases or 
conditions for exclusion.
Participant Discontinuation/Withdrawal from the Study 
(Section 7.2):
At Regulatory Authority’s request, deletion of a sentence about 
protocol deviations management.
Analysis of FVIII Inhibitor (Section 8.2.6.2):

At Regulatory Authority’s request, added clarification to 
confirm that in case of study pause following confirmed 
inhibitory antibodies against FVIII for a participant, the trial 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 153
DOCUMENT HISTORY
Document
Version Date
Summary and Rationale for Changes
re-start will only be possible after Regulatory Authority 
approval via substantial amendment.
Regulatory and Ethical Considerations (Section 10.1.1):
At Regulatory Authority’s request, added clarification to specify that 
any substantial amendment to the protocol will require 
Regulatory Authority approval before implementation.
Amendment 1
13 May 2020
As per FDA request, update of the endpoint to support the early 
approval pathway: for the first interim analysis planned in 
20 participants, FVIII activity level will be monitored during 6 months 
after FVIII activity level steady state is reached, instead of 6 months 
post study drug infusion. Additional visits for laboratory assessments 
(using home health/mobile phlebotomy services as applicable) have 
been added as described in the schedule of activities to allow 
comprehensive FVIII monitoring (activity and expression). Liver 
function tests will also be performed.
Related updates were made in:
-
Synopsis, including Figure 1 (Section 1.1 and 
Section 1.2)
-
Schedule of Activities (Section 1.3)
-
Study Rationale (Section 2.1)
-
Objectives, Estimands, and Endpoints (Section 3)
-
Study Design (Section 4)
-
Statistical Considerations (Section 9.2, Section 9.4.1 and
Section 9.5)
Objectives, Estimands, and Endpoints (Section 3):

Revision of text to clarify the primary endpoints for interim 
and primary analyses. As per FDA request, the primary 
endpoint to support the early approval pathway has been 
updated: for the first interim analysis planned in 
20 participants, FVIII activity level will be monitored during 
6 months after FVIII activity level steady state is reached, 
instead of 6 months post study drug infusion. In addition, 
wording for other endpoints and estimands have been revised 
for clarity (Section 3).

For clarity and consistency with the statistical analyses 
planned, the secondary endpoint of the interim analysis has 
been deleted from Section 3, and is now only displayed 
within Section 9.5 (Interim Analyses).

Immunogenicity: reference to the ELISPOT method deleted 
from the endpoint.

Deletion of wording within the list of endpoints related to the 
joint health objective as analyses are detailed in SAP.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 154
DOCUMENT HISTORY
Document
Version Date
Summary and Rationale for Changes
Minor Clarifications in Inclusion/Exclusion Criteria (Section 5.1 
and Section 5.2):

Inclusion Criteria #4 and 5 were revised for clarity.  

Inclusion Criterion #7 was revised to meet German Ethics 
Committee requirements in Section 5.1.

Exclusion Criteria #6, 7, 8, and 13 were revised for clarity.

Exclusion Criterion #8 was revised to clarify specifics of 
repeat testing and that “hepatic” encephalopathy is 
exclusionary, in relationship with unstable liver disease.

Exclusion Criterion #15 was revised to clarify specifics of 
liver fibrosis testing.

Exclusion Criteria #17 and #18 were revised to meet German 
Ethics Committee requirements in Section 5.2.
Lifestyle Considerations Clarification (Section 5.3):

It was added that participants should be informed that alcohol 
consumption could contribute to abnormally elevated liver 
function test (LFT) results and delay infusion of the 
investigational product (IP) infusion, and increased alcohol 
consumption was defined.
Screen Failures (Section 5.4):

Text was updated and revised for consistency with updates in 
Exclusion Criterion #8.
Study Intervention(s) Administered (Section 6.1):

Updated for clarity and consistency, and wording was added 
to refer to new country-specific language in Section 10.8.
Preparation/Handling/Storage/Accountability (Section 6.2):

Text added to confirm the absence of charge for participants 
and payers related to study intervention.
Study Intervention Compliance (Section 6.4):

Wording was added to refer to new country-specific language 
in Section 10.8.
Concomitant Therapy (Section 6.5):

Clarified that all surgical procedures, including elective 
surgeries, will be recorded throughout the entire study. 
Added note in SoA.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 155
DOCUMENT HISTORY
Document
Version Date
Summary and Rationale for Changes

Minor clarifications in disallowed therapies.
Study Assessments and Procedures (Section 8), Schedule of 
Activities (Section 1.3):

Vital signs were revised from oral temperature to body
temperature to permit flexibility with methods utilized by the 
sites (Section 1.3 and Section 8.2.2). 

Vital signs were revised from upright position to 
upright/sitting position for clarity (Section 1.3 and 
Section 8.2.2).

When applicable, fasting is recommended for Fibroscan 
(Section 1.3).

Local LFTs results have to be reviewed prior to study drug 
infusion. An up to 3 days time window is therefore allowed 
to collect blood for local and central LFTs (Section 1.3 and 
Section 8).

A reasonable margin of error and guidelines have been added 
in SoA for FVIII product infusion on Day 1 (prior to study 
drug) (Section 1.3).

eDiary: clarification of data collection process 
(Section 8.1.1).

HJHS: clarification added for participants with prosthetic 
joints (Section 8.1.3).

Section 8.2.7.1 and Section 8.2.7.3: blood volumes updated 
or clarified.
Statistical Considerations (Section 9):

The reference to the ITT population has been deleted 
(Section 9.3) as it is not applicable for the study.

As specified for Section 3, the secondary endpoint of the 
interim analysis has been deleted from Section 3, and is now 
only displayed within Section 9.5 (Interim Analyses). 
Wording in Section 9.5 has been revised for clarity.

Estimands and endpoints wording revised for clarity. 
Whenever applicable, the “within-participant” wording has 
been deleted to avoid confusion, as the comparison of lead-in 
and Phase 3 data will be made using analysis models and not 
using participant-level difference.
Adverse Events and Serious Adverse Events:

Section 8.3.10: Wording was revised regarding 
immunomodulation optimization (for participants who 
develop hepatitis transaminitis) to more clearly describe 
elevations in liver transaminases and to eliminate any 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 156
DOCUMENT HISTORY
Document
Version Date
Summary and Rationale for Changes
potential delays in initiating corticosteroid treatment. Specific 
examples were added.
Efficacy - FVIII:

For clarity and flexibility, it was added that as FVIII 
inhibitors or T-cell mediated immune response may impact 
the FVIII activity levels, this information will also be taken 
into account while deriving FVIII:C activity levels.
Appendices:

Clinical Laboratory Tests table was revised for consistency 
and minor corrections were made (Section 10.2).

A country-specific requirements appendix was added for 
France as per France RA and ethical requirements 
(Section 10.8.1). 

A country-specific requirements appendix was added for 
Japan as per Japanese RA requirement (see Section 10.8.2). 
Corresponding cross references were added to appropriate 
sections.

A country-specific requirements appendix was added for 
Germany as per German regulations and RA requirements
(see Section 10.8.3). Corresponding cross references were 
added to appropriate sections.
Editorial, grammatical, formatting, and administrative changes 
were made throughout the document, including changes to the 
List of Abbreviations and changes to comply with protocol 
template format (eg, added wording for clarification within study 
population, participant discontinuation, and safety sections).
Original 
protocol
10 December
2019
N/A
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 157
10.11. Appendix 11: Abbreviations
Abbreviation
Definition
-fetoprotein
alpha-fetoprotein
AAV
adeno-associated virus
AAV2/6
adeno-associated virus vector 2/6
ABR
annualized bleeding rate
ADA
anti-drug antibody
AE
adverse event
AESI
adverse event of special interest
AF-CC
albumin-free cell culture
AFP
alpha-fetoprotein
AIR
annualized (FVIII) infusion rate
ALP
alkaline phosphatase
ALT
alanine transaminase
aPTT
activated partial thromboplastin time
AST
aspartate transaminase
AT
antithrombin
ATMP
Advanced Therapy Medicinal Products
BDD
B-domain deleted
BMI
body mass index
BU
Bethesda Units
CD4+
cluster of differentiation 4
CD8+
cluster of differentiation 8
CFR
Code of Federal Regulations
CI
confidence interval
CL
central laboratory
CONSORT
Consolidated Standards of Reporting Trials
COVID-19
coronavirus disease 2019
COX-2
cyclooxygenase-2
CRF
case report form
CRO
contract research organization
CRP
C-reactive protein
CRU
clinical research unit
CSR
clinical study report
CT SAE
clinical trial serious adverse event
DILI
drug-induced liver injury
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DNase
deoxyribonuclease
DRE
disease related event
DVT
deep vein thrombosis
EAHAD
European Association for Haemophilia and Allied Disorders
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 158
Abbreviation
Definition
ECG
electrocardiogram
EC
Ethics Committee
eCRF
electronic case report form
ED
exposure days
eDiary
electronic diary
eDMC
external Data Monitoring Committee
EDP
exposure during pregnancy
EGFR
epidermal growth factor receptor
EHC
European Haemophilia Consortium
ELISPOT
Enzyme-Linked Immune-Spot
EMA
European Medicines Agency
EOS
end of study
EQ-5D-5L
EuroQol, 5 dimensions, 5 levels
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials 
(European Clinical Trials Database)
FA
final analysis
FDA
U.S. Food and Drug Administration
FIX
coagulation factor IX
FII
coagulation factor II (or prothrombin)
FV
coagulation factor V
FVIII
coagulation factor VIII
FVIII:C
factor VIII: circulating
Gal3BP
Galectin-3 Binding Protein
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
Grp78
78-kDa glucose-regulated protein
H2
histamine type 2
Haem-A-QoL
Haemophilia Quality of Life Questionnaire for Adults
HAL
Haemophilia Activities List
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCC
hepatocellular carcinoma
HCV
hepatitis C virus
HDL
high-density lipoprotein
hFVIII
human factor VIII
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HJHS
Hemophilia Joint Health Score
HLA
human leukocyte antigen
HLIQ
Hemophilia Life Impacts Questionnaire
IA
interim analysis
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 159
Abbreviation
Definition
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use
IEC
institutional ethics committee
IgG
immunoglobulin G
IgM
immunoglobulin M
IL-6
interleukin-6
IMP
investigational medicinal product
IND
Investigational New Drug
INR
international normalized ratio
IP
investigational product
IRB
institutional review board
IRR
infusion-related reaction
ISF
investigator site file
ITR
inverted terminal repeat
IV
intravenous
IVRS/IWRS
Interactive Voice Response System/Interactive Web Response 
System
LDH
lactic acid dehydrogenase
LDL
low-density lipoprotein
LFT
liver function tests
LL
local laboratory
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MHC
major histocompatibility complex
mRNA
messenger ribonucleic acid
nAb
neutralizing antibodies
NE
non-evaluable
NHF
National Hemophilia Foundation
NHP
non-human primate
NI
noninferiority
NIMP
noninvestigational medicinal product
NSAIDs
nonsteroidal anti-inflammatory drugs
PA
primary analysis
PACL
protocol administrative change letter
PBMC
peripheral blood mononuclear cells
PCD
primary completion date
PCR
polymerase chain reaction
PGIC
Patient Global Impression of Change
PGIC-H
Patient Global Impression of Change - Hemophilia
PGIC-PF
Patient Global Impression of Change – Physical Functioning 
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 160
Abbreviation
Definition
PGIC-PH
Patient Global Impression of Change – Physical Health 
PGIS
Patient Global Impression of Severity
PGIS-H
Patient Global Impression of Severity – Haemophilia (PGIS-H
PGIS-PF
Patient Global Impression of Severity – Physical Functioning 
PGIS-PH
Patient Global Impression of Severity – Physical Health
PK
pharmacokinetic
PPI
proton pump inhibitor
PRN
as needed
PROs
patient-reported outcomes
PT
prothombin
qPCR
quantitative real-time polymerase chain reaction
QTc
corrected QTc interval
rAAV
recombinant adeno-associated virus
rAAV6
recombinant adeno-associated virus serotype 2/6
RBC
red blood cell
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV2
severe acute respiratory syndrome coronavirus 2
SoA
schedule of activities
SOC
standard of care
SUSAR
suspected unexpected serious adverse reactions
TAT
thrombin-antithrombin level
TBili
total bilirubin
TGA
thrombin generation assay
ULN
upper limit of normal
US
United States
vg/kg
vector genome per kilogram
VLDL
very-low-density lipoprotein
WBC
white blood cell
WFH
World Federation of Hemophilia
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 161
11. REFERENCES
1
Verdera HC, Kuranda K, Mingozzi F. AAV vector immunogenicity in humans: A long 
journey to successful gene transfer. Mol Ther. 2020;28(3):723-46.
2
Mingozzi F, High KA. Therapeutic in vivo gene transfer for genetic disease using AAV: 
progress and challenges. Nat Rev Genet. 2011;12:341-55.
3
BioMarin R&D Day, Investor’s Meeting 2016.
4
Nijmeijer B, Petry H, Spronck L, et al. Safety and efficacy of an adeno associated 
virus-based vector carrying the human clotting factor IX gene (AAV5-hFIX) as studied 
in nonhuman primates. Blood. 2014;124(21):4800.
5
Jiang H, Lillicrap D, Patarroyo-White S, et al. Multiyear therapeutic benefit of AAV 
serotypes 2, 6, and 8 delivering factor VIII to hemophilia A mice and dogs. Blood. 
2006;108:107-15.
6
Nathwani, AC, Reiss, UM, Tuddenham, EG, et al. Long-term safety and efficacy of 
factor IX gene therapy in hemophilia B. N Engl J Med. 2014;371(21):1994-2004.
7
Carcao M and Goudemand J. Inhibitors in hemophilia: A primer. World Federation of 
Hemophilia, Treatment of Hemophilia. 2018;7:1-19.
8
Chalmers EA, Brown SA, Keeling D, et al. Early factor VIII exposure and subsequent 
inhibitor development in children with severe haemophilia A. Haemophilia. 
2007;13(2):149-55.
9
Peyvandi F, Mannucci PM, Garagiola I, et al. A randomized trial of factor VIII and 
neutralizing antibodies in hemophilia A. N Engl J Med. 2016;374:2054-64.
10
Miller CH, Rice AS, Boylan B, et al. Characteristics of hemophilia patients with factor 
VIII inhibitors detected by prospective screening. Am J Hematol. 2015;90(10):871-6.
11
Hay CRM, Dichele DM. The principal results of the international immune tolerance 
study: a randomized dose comparison. Blood. 2012;119(6):1335-44.
12
Colella P, Ronzitti G, Mingozzi F. Emerging issues in AAV-mediated in vivo gene 
therapy. Mol Ther Methods Clin Dev. 2018;8:87-104.
13
DiMichele DM, Hoots WK, Pipe SW, et al. International workshop on immune 
tolerance induction: consensus recommendations. Haemophilia. 2007;13(suppl 1):1-22.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 162
14
Miao CH, Ohashi K, Patijn GA, et al. Inclusion of the hepatic locus control region, an 
intron, and untranslated region increases and stabilizes hepatic factor IX gene expression 
in vivo but not in vitro. Mol Ther. 2000;1:522-32.
15
Miao CH, Snyder RO, Schowalter DB, et al. The kinetics of rAAV integration in the 
liver. Nat Genet. 1998;19:13-5.
16
Nakai H, Yant SR, Storm TA, et al. Extrachromosomal recombinant adeno-associated 
virus vector genomes are primarily responsible for stable liver transduction in vivo. J 
Virol. 2001;75:6969-76.
17
Ruthledge EA, Russell DW. Adeno-associated virus vector integration junctions. J 
Virol. 1997;71(11):8429-36.
18
Kaeppel C, Beattie SG, Fronza R, et al. A largely random AAV integration profile after 
LPLD gene therapy. Nat Med. 2013;19(7):889-91.
19
Niemeyer GP, Herzog RW, Mount J, et al. Long-term correction of inhibitor-prone 
hemophilia B dogs treated with liver-directed AAV2-mediated factor IX gene therapy. 
Blood. 2009;113(4):797-806.
20
Nowrouzi A, Penaud-Budloo M, Kaeppel C, et al. Integration frequency and 
intermolecular recombination of rAAV vectors in non-human primate skeletal muscle 
and liver. Mol Ther. 2012;20(6):1177-86.
21
Miller DG, Petek LM, Russell DW. Adeno-associated virus vectors integrate at 
chromosome breakage sites. Nat Genet. 2004;36(7):767-73.
22
El-Serag HB, Davila JA. Surveillance for hepatocellular carcinoma: in whom and how? 
Therap Adv Gastroenterol. 2011;4(1):5-10.
23
Schuettrumpf J, Liu JH, Couto LB, et al. Inadvertent germline transmission of AAV2 
vector: findings in a rabbit model correlate with those in a human clinical trial. Mol 
Ther. 2006;13(6):1064-73.
24
Arruda VR, Fields PA, Milner R, et al. Lack of germline transmission of vector 
sequences following systemic administration of recombinant AAV-2 vector in males. 
Mol Ther. 2001; 4(6):586-92.
25
Couto LB, Pierce GF. AAV-mediated gene therapy for hemophilia. Curr Opin Mol 
Ther. 2003;5:517-23.
26
Favaro P, Downey HD, Zhou JS, et al. Host and vector-dependent effects on the risk of 
germline transmission of AAV vectors. Mol Ther. 2009;17(6):1022-30.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 163
27
Manno CS, Pierce GF, Arruda VR, et al. Successful transduction of liver in hemophilia 
by AAV-Factor IX and limitations imposed by the host immune response. Nat Med. 
2006;12(3):342-7.
28
Couto L, Parker A, Gordon JW. Direct exposure of mouse spermatozoa to very high 
concentrations of a serotype-2 adeno-associated virus gene therapy vector fails to lead to 
germ cell transduction. Hum Gene Ther. 2004;15(3):287-91.
29
Nathwani AC, Davidoff AM, Tuddenham EGD. Gene Therapy for Hemophilia. 
Hematol Oncol Clin North Am. 2017;31(5):853-68.
30
Committee for Advanced Therapies (CAT). Guideline on the quality, non-clinical and 
clinical aspects of gene therapy medicinal products Published 22 March 2018 
[Accessed: 09 Oct 2019]. Available from: 
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-quality-non-
clinical-clinical-aspects-gene-therapy-medicinal-products_en.pdf.
31
EMA/CHMP. Guideline on follow-up of patients administered with gene therapy 
medicinal products Published: 22 Oct 2009 [Accessed: 09 Oct 2019]. Available from: 
https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-follow-patients-
administered-gene-therapy-medicinal-products_en.pdf
32
EMA/CHMP. Guideline on safety and efficacy follow-up risk management of advanced 
therapy medicinal products Published: 31 December 2008 [Accessed: 09 Oct 2019]. 
Available from: https://www.ema.europa.eu/en/documents/scientific-
guideline/guideline-safety-efficacy-follow-risk-management-advanced-therapy-
medicinal-products_en.pdf.
33
US Food and Drug Administration. Guidance for industry: human gene therapy for 
hemophilia. In: Research CfBEa, editor. Rockville, MD. July 2018.
34
Konkle, BA, Skinner, M, Iorio, A. Hemophilia trials in the twenty-first century: 
Defining patient important outcomes. Res Pract Thromb Haemost. 2019;3(2):184-92.
35
Blanchette, VS, Key, NS, Ljung, LR, et al. Definitions in hemophilia: communication 
from the SSC of the ISTH. J Thromb Haemost. 2014;12(11):1935-9.
36
van den Berg, HM, Fischer, K, Mauser-Bunschoten, EP, et al. Long-term outcome of 
individualized prophylactic treatment of children with severe haemophilia. Br J 
Haematol. 2001;112(3):561-5.
37
Collins, PW, Young, G, Knobe, K, et al. Recombinant long-acting glycoPEGylated 
factor IX in hemophilia B: a multinational randomized phase 3 trial. Blood. 
2014;124(26):3880-6.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 164
38
Pierce, GF, Ragni, MV, van den Berg, HM, et al. Establishing the appropriate primary 
endpoint in haemophilia gene therapy pivotal studies. Haemophilia. 2017;23(5):643-4.
39
Srivastava, A, Brewer, AK, Mauser-Bunschoten, EP, et al. Guidelines for the 
management of hemophilia. Haemophilia. 2013;19(1):e1-47.
40
Feldman, BM, Funk, SM, Bergstrom, BM, et al. Validation of a new pediatric joint 
scoring system from the International Hemophilia Prophylaxis Study Group: validity of 
the hemophilia joint health score. Arthritis Care Res (Hoboken). 2011;63(2):223-30.
41
Pettersson, H, Ahlberg, A, Nilsson, IM. A radiologic classification of hemophilic 
arthropathy. Clin Orthop Relat Res. 1980(149):153-9.
42
EuroQol, G. EuroQol--a new facility for the measurement of health-related quality of 
life. Health Policy. 1990;16(3):199-208.
43
von Mackensen, S, Eldar-Lissai, A, Auguste, P, et al. Measurement properties of the 
Haem-A-QoL in haemophilia clinical trials. Haemophilia. 2017;23(3):383-91.
44
van Genderen, FR, van Meeteren, NL, van der Bom, JG, et al. Functional consequences 
of haemophilia in adults: the development of the Haemophilia Activities List. 
Haemophilia. 2004;10(5):565-71.
45
van Genderen, FR, Westers, P, Heijnen, L, et al. Measuring patients' perceptions on their 
functional abilities: validation of the Haemophilia Activities List. Haemophilia. 
2006;12(1):36-46.
46
Chalasani, N, Younossi, Z, Lavine, JE, et al. The diagnosis and management of 
nonalcoholic fatty liver disease: practice guidance from the American Association for 
the Study of Liver Diseases. 2018;67(1):328-57.
47
Nathwani, AC, Tuddenham, EG, Rangarajan, S, et al. Adenovirus-associated virus 
vector-mediated gene transfer in hemophilia B. N Engl J Med. 2011;365(25):2357-65.
48
Rendo P, Smith L, Lee HY, et al. Nonacog alfa: an analysis of safety data from six 
prospective clinical studies in different patient populations with haemophilia B treated 
with different therapeutic modalities. Blood Coagul Fibrinolysis. 2015;26(8):912-8.
49
US Food and Drug Administration. Guidance for industry: non-inferiority clinical trials 
to establish effectiveness. November 2016.
50
EMA. Guideline on the choice of the non-inferiority margin. January 2006 [Accessed: 
09 Oct 2019]. Available from: https://www.ema.europa.eu/en/documents/scientific-
guideline/guideline-choice-non-inferiority-margin_en.pdf.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)

PF-07055480
C3731003
Final Protocol Amendment 10, 28 September 2023
PFIZER CONFIDENTIAL
Page 165
51
EMEA. ICH Topic E9. Note for guidance on statistical principles for clinical trials. In: 
The European Agency for the Evaluation of Medicinal Products, Human Medicines 
Evaluation Unit. CPMP/ICH363/96. London; 18 Mar 1998: 38 pages.
52
Anonymous. Points to consider on switching between superiority and non-inferiority. In: 
The European Agency for the Evaluation of Medicinal Products. Evaluation of 
Medicines for Human Use. Committee for Proprietary Medicinal Products. 
CPMP/EWP/482/99. 27 Jul 2000; London: 11 pages.
53
US Food and Drug Administration. ICH E10: Choice of control group and related issues 
in clinical trials. 2000.
54
Valentino LA, Rusen L, Elezovic I, et al. Multicentre, randomized, open-label study of 
on-demand treatment with two prophylaxis regimens of recombinant coagulation factor 
IX in haemophilia B subjects. Haemophilia. 2014;20(3):398-406.
55
Lopez RP, Nemes L, Jimenez-Yuste V, et al. Prospective surveillance study of 
haemophilia A patients switching from moroctocog alfa or other factor VIII products to 
moroctocog alfa albumin-free cell culture (AF-CC) in usual care settings. Thromb 
Haemost. 2015;114(4):676-84.
56
Lopez R, Jiminez-Yuste V, Rusen L et al. Prospective surveillance study of haemophilia 
A patients switching from moroctocog alfa or other factor VIII products to moroctocog 
alfa albumin-free cell culture (AF-CC) in usual care set. Thromb Haemost 
2015;114(4):676-84.
57
Recht M, Nemes L, Matysiak M et al. Clinical evaluation of moroctocog alfa (AF-CC), 
a new generation of B-domain deleted recombinant factor VIII (BDDrFVIII) for 
treatment of haemophilia A: demonstration of safety, efficacy, and pharmacokinetic 
equivalence to full-length recombinant FVIII. Haemophilia 2009;15:869-880.
58
Kruse‐Jarres R, Oldenburg J, Santagostino E et al. Bleeding and safety outcomes in 
persons with haemophilia A without inhibitors: Results from a prospective non‐
interventional study in a real‐world setting. Haemophilia 2019;25(2):213-20.
59
Oldenburg J, Mahlangu JN, Kim B, et al. Emicizumab prophylaxis in hemophilia A with 
inhibitors. N Engl J Med 2017;377(9):809-18.
60
Mahlangu J, Oldenburg J, Paz-Priel I, et al. Emicizumab prophylaxis in patients who 
have hemophilia A without inhibitors. N Engl J Med 2018;379(9):811-22.
090177e19f2be8a6\Approved\Approved On: 15-Nov-2023 01:07 (GMT)