Phase 3, Open-label, Single-arm Study to Evaluate Efficacy and Safety of FIX Gene Transfer With PF-06838435 (rAAV-Spark100-hFIX-R338L) in Adult Male Participants With Moderately Severe to Severe Hemophilia B (FIX:C ≤2%) (BeneGene-2)
Phase: PHASE3
Conditions: Hemophilia B
Sponsor: Pfizer

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TITLE PAGE
Protocol Title: Phase 3, open label, single arm study to evaluate efficacy and safety of 
FIX gene transfer with PF-06838435 (rAAV-Spark100-hFIX-Padua) in adult male 
participants with moderately severe to severe hemophilia B (FIX:C ≤2%) (BeneGene-2)  
Protocol Number: C0371002
Amendment Number: 3
Compound Number: PF-06838435
Study Phase: Phase 3
Short Title: BeneGene-2
Acronym: Not applicable
Sponsor Name: Pfizer, Inc.
Legal Registered Address: 235 East 42nd Street, New York, NY 10017-5755, USA. 
Regulatory Agency Identifier Number(s)
Registry
ID
IND
016437
EudraCT
2018-003086-33
Approval Date: 29 June 2022
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by applicable law) or 
use it for unauthorized purposes.  In the event of any actual or suspected breach of this obligation, Pfizer 
must be promptly notified.

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Protocol Amendment Summary of Changes Table
DOCUMENT HISTORY
Document
Date
Summary and Rationale for Changes
Amendment 3
29 June 2022
Pfizer has adjusted the position and ordering of endpoints 
to align with FDA recommendations (received 28 Mar 
2022) which are in line with the changing landscape of 
gene therapy for hemophilia.  The following revisions were 
made (Sections 1.1, 1.2, 2.2.2, 3, 4.2, 9.1, 9.4.1):

The primary endpoint was revised to ABR for 
total bleeds (treated and untreated).  ABR for 
treated bleeds is now part of the key secondary 
endpoints. 

Moved, “Vector-derived FIX:C level at steady-
state (from Week 12 to 15 months) demonstrated 
to be greater than 5%,” to key secondary endpoint 
and added, “FIX:C will also be summarized 
descriptively by study visit.”

The assessment of all endpoints related to bleeds 
and infusions (including ABR for total bleeds, 
ABR for treated bleeds, AIR, FIX consumption, 
and annualized number of bleeding events of 
specific type) will start from Week 12 post-PF-
06838435 infusion (instead of Day 1), 
corresponding to the estimated FIX:C steady state 
onset.

Re-ordered the sequence of secondary endpoints 
and added “Vector-derived FIX:C level by study 
visit and the geometric mean at each yearly 
interval” to secondary endpoints.
Incorporated clarifications previously communicated by 
PACL #8 (Section 8.1.1):

What steps should be taken in the event of eDiary 
non-compliance.

What factor IX (FIX) treatment is required to be 
reported after Week 78 (Visit 14) for those 
participants who may have to resume FIX 
prophylaxis treatment.
Updated sample size justification for ABRtotal:

Section 9.2 Sample Size Determination
Clarified that the definition of bleed refers to treated bleed:

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DOCUMENT HISTORY
Document
Date
Summary and Rationale for Changes

Section 10.7 Appendix 7: Bleed and Factor 
Replacement Regimen Definitions
Updated rationale for NI margin selection for ABRtotal:

Section 10.10 Appendix 10: Non-Inferiority 
Margin Selection
Editorial, grammatical, formatting, and administrative 
changes were made throughout the document, including 
changes to the List of Abbreviations.
Editorial, grammatical, formatting, and administrative changes were made throughout the document.
This amendment incorporates all revisions to date, including amendments made at the 
request of country health authorities and institutional review boards (IRBs)/independent 
ethics committees (IECs).

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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................9
LIST OF FIGURES ...................................................................................................................9
1. PROTOCOL SUMMARY...................................................................................................10
1.1. Synopsis ..................................................................................................................10
1.2. Schema ....................................................................................................................12
1.3. Schedule of Activities (SoA)...................................................................................13
2. INTRODUCTION ...............................................................................................................29
2.1. Study Rationale .......................................................................................................31
2.2. Background .............................................................................................................31
2.2.1. PF–06838435, Composition of the Vector.................................................31
2.2.2. Summary of Clinical Experience with PF–06838435 ................................32
2.3. Benefit/Risk Assessment.........................................................................................33
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ...........................................................33
4. STUDY DESIGN.................................................................................................................35
4.1. Overall Design.........................................................................................................35
4.2. Scientific Rationale for Study Design.....................................................................36
4.3. Justification for Dose ..............................................................................................36
4.4. End of Study Definition ..........................................................................................36
5. STUDY POPULATION......................................................................................................37
5.1. Inclusion Criteria.....................................................................................................37
5.2. Exclusion Criteria....................................................................................................38
5.3. Lifestyle Considerations..........................................................................................40
5.4. Screen Failures ........................................................................................................41
6. STUDY INTERVENTION..................................................................................................41
6.1. Study Intervention(s) Administered........................................................................41
6.2. Preparation/Handling/Storage/Accountability ........................................................42
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................42
6.4. Study Intervention Compliance...............................................................................42
6.5. Concomitant Therapy..............................................................................................43
6.5.1. Allowed Therapy ........................................................................................44
6.5.2. Disallowed Therapy....................................................................................45

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6.6. Dose Modification...................................................................................................45
6.7. Intervention after the End of the Study...................................................................45
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL...........................................................................45
7.1. Discontinuation of Study Intervention ....................................................................45
7.2. Participant Discontinuation/Withdrawal from the Study........................................46
7.2.1. Withdrawal of Consent...............................................................................46
7.3. Lost to Follow up ....................................................................................................47
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................47
8.1. Efficacy Assessments..............................................................................................50
8.1.1. Hemophilic Bleeding Episodes and Treatment ..........................................50
8.1.2. Joint Assessments.......................................................................................51
8.1.2.1. Hemophilia Joint Health Score (HJHS) ....................................51
8.1.2.2. Magnetic Resonance Imaging (MRI) to Evaluate Joints...........51
8.1.2.3. X–ray Assessments to Evaluate Joints......................................52
8.1.3. Patient–Reported Outcomes (PROs) ..........................................................52
8.1.3.1. Haemophilia Quality of Life Questionnaire for Adults 
(Haem–A–QoL).................................................................................53
8.1.3.2. Hemophilia Activities List (HAL, Version 2)...........................53
8.1.3.3. Patient Global Impression of Change – Hemophilia 
(PGIC–H) ..........................................................................................53
8.1.3.4. Hemophilia Life Impacts Questionnaire (HLIQ)......................53
8.1.3.5. EQ–5D–5L ................................................................................54
8.2. Safety Assessments .................................................................................................54
8.2.1. Physical Examinations................................................................................54
8.2.2. Vital Signs ..................................................................................................54
8.2.3. Electrocardiograms.....................................................................................54
8.2.4. Clinical Laboratory Assessments ...............................................................54
8.2.5. Liver Ultrasound.........................................................................................55
8.3. Adverse Events and Serious Adverse Events..........................................................55
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......56
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................57
8.3.1.2. Recording Non-serious AEs and SAEs on the CRF .................57

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8.3.2. Method of Detecting AEs and SAEs ..........................................................57
8.3.3. Follow–up of AEs and SAEs......................................................................57
8.3.4. Regulatory Reporting Requirements for SAEs...........................................58
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................58
8.3.5.1. Exposure During Pregnancy......................................................58
8.3.5.2. Exposure During Breastfeeding ................................................60
8.3.5.3. Occupational Exposure .............................................................60
8.3.6. Immunogenicity..........................................................................................60
8.3.6.1. Analysis of Anti– PF–06838435 Antibodies and 
Neutralizing Anti PF–06838435 Antibodies.....................................60
8.3.6.2. Analysis of FIX Inhibitor ..........................................................61
8.3.6.3. Analysis of Cellular Immune Response by ELISPOT 
(enzyme–linked immuno–spot).........................................................61
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs..............................................................................62
8.3.8. Immunomodulation Optimization (Presumed T-Cell Activation)..............62
8.3.9. Adverse Events of Special Interest.............................................................66
8.3.9.1. Lack of Efficacy........................................................................66
8.3.10. Thrombotic Potential Assessments (ONLY for participants who 
reach vector-derived FIX:C Activity Levels >150% After the Infusion 
of PF–06838435) .............................................................................................66
8.3.11. Medication Errors.....................................................................................66
8.4. Treatment of Overdose............................................................................................67
8.5. Pharmacokinetics ....................................................................................................67
8.5.1. Samples for Vector Shedding Assays.........................................................68
8.6. Pharmacodynamics..................................................................................................68
8.6.1. Samples for FIX Antigen Levels................................................................69
8.6.2. Samples for Thrombin Generation .............................................................69
8.6.3. Samples for D-dimer...................................................................................69
8.6.4. Shipment of Pharmacodynamic Samples ...................................................69
8.7. Genetics...................................................................................................................69
8.7.1. Specified Genetics ......................................................................................69
8.7.2. Banked Biospecimens for Genetics............................................................70

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8.8. Biomarkers ..............................................................................................................70
8.9. Health Economics ...................................................................................................70
9. STATISTICAL CONSIDERATIONS ................................................................................70
9.1. Estimands and Statistical Hypotheses.....................................................................70
9.1.1. Estimands....................................................................................................70
9.2. Sample Size Determination.....................................................................................71
9.3. Populations for Analyses.........................................................................................71
9.4. Statistical Analyses .................................................................................................71
9.4.1. Efficacy Analyses .......................................................................................72
9.4.2. Safety Analyses ..........................................................................................74
9.4.3. Other Analyses............................................................................................74
9.5. Interim Analyses .....................................................................................................74
9.5.1. External Data Monitoring Committee (eDMC)..........................................74
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................75
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............75
10.1.1. Regulatory and Ethical Considerations ....................................................75
10.1.2. Financial Disclosure .................................................................................76
10.1.3. Informed Consent Process ........................................................................76
10.1.4. Data Protection .........................................................................................77
10.1.5. Committees Structure ...............................................................................78
10.1.6. Dissemination of Clinical Study Data ......................................................78
10.1.7. Data Quality Assurance ............................................................................79
10.1.8. Source Documents....................................................................................81
10.1.9. Study and Site Closure..............................................................................81
10.1.10. Publication Policy...................................................................................81
10.1.11. Sponsor’s Qualified Medical Personnel .................................................82
10.2. Appendix 2: Clinical Laboratory Tests .................................................................83
10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow–up, and Reporting......................................................................85
10.3.1. Definition of AE .......................................................................................85
10.3.2. Definition of SAE.....................................................................................86
10.3.3. Recording and Follow–Up of AE and/or SAE .........................................89

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10.3.4. Reporting of SAEs....................................................................................92
10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................................................94
10.5. Appendix 5: Genetics............................................................................................95
10.6. Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments ........96
10.7. Appendix 7: Bleed and Factor Replacement Regimen Definitions ......................98
10.8. Appendix 8: Guidelines for Target Factor IX Levels Based on Bleed Type ......100
10.9. Appendix 9: Instruments for Patient-Reported Outcomes (PROs) .....................101
10.9.1. Haemophilia Quality of Life Questionnaire for Adults 
(Haem-A-QoL) ..............................................................................................101
10.9.2. Hemophilia Activities List (HAL)..........................................................108
10.9.3. Patient Global Impression of Change - Hemophilia (PGIC-H)..............116
10.9.4. Hemophilia Life Impacts Questionnaire (HLIQ) ...................................117
10.9.5. EQ-5D-5L Questionnaire........................................................................121
10.10. Appendix 10: Non-Inferiority Margin Selection...............................................124
10.11. Appendix 11: Country-specific Requirements..................................................126
10.11.1. Japan Appendix ....................................................................................126
10.11.1.1. Study Intervention Defects Definitions (per Japanese 
regulations)......................................................................................126
10.11.1.2. Reporting Criteria................................................................126
10.11.1.3. Reporting Procedures ..........................................................126
10.11.1.4. Japan Specific Protocol Wording........................................127
10.11.2. Germany Appendix...............................................................................127
10.11.2.1. Section 5.1 Inclusion Criteria..............................................128
10.11.2.2. Section 5.2 Exclusion Criteria.............................................128
10.11.2.3. Section 10.1.3. Informed Consent Process..........................128
10.11.2.4. Section 1.3. Schedule of Activities (SoA)...........................128
10.11.2.5. Section 8.1.2.3. X-ray Assessments to Evaluate Joints.......128
10.12. Appendix 12: Hemophilia Joint Health Score...................................................129
10.13. Appendix 13: Alternative Measures During Public Emergencies.....................131
10.13.1. Alternative Study Procedures During COVID-19 Pandemic ...............131
10.13.1.1. Home Health Visits .............................................................131
10.13.1.2. Telehealth Visits..................................................................131

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10.13.1.3. Guidelines for Capturing Post-Infusion Procedures............132
10.13.2. Alternative Study Procedures For Extenuating Circumstances............132
10.13.3. Participants Who Test Positive for COVID-19 ....................................132
10.13.4. COVID-19 Vaccination Guidelines......................................................133
10.14. Appendix 14: Protocol Amendment History.....................................................134
10.15. Appendix 15: Abbreviations .............................................................................145
11. REFERENCE...................................................................................................................149
LIST OF TABLES
Table 1.
Recommended Regimen for Oral Corticosteroids....................................64
Table 2.
Recommended Regimen for Combination Intravenous and Oral 
Corticosteroids..........................................................................................65
LIST OF FIGURES
Figure 1.
C0371002: Study Schematic.....................................................................12
Figure 2.
Schematic of PF-06838435 Vector Genome ............................................32

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1. PROTOCOL SUMMARY
1.1. Synopsis
Protocol Title: Phase 3, open label, single arm study to evaluate efficacy and safety of 
FIX gene transfer with PF-06838435 (rAAV-Spark100-hFIX-Padua) in adult male 
participants with moderately severe to severe hemophilia B (FIX:C ≤2%) (BeneGene-2)
Short Title: BeneGene-2
Rationale:
The published data from the Phase 1/2a study for PF-06838435 (SPK-9001-101) indicate that 
treatment of hemophilia B with PF-06838435 offers considerable clinical advantage over 
routine prophylactic treatment with factor IX (FIX) product.  A single infusion of 
PF-06838435 results in sustained FIX activity levels in the mild to normal range with 
associated low bleeding rates and a marked reduction in the number of infusions of FIX 
product (see Section 2.2.2).  This Phase 3 confirmatory study will compare the efficacy of 
PF-06838435 treatment with routine prophylaxis with the objective to establish 
non-inferiority and possibly superiority.
Objectives, Estimands and Endpoints
The primary objective is addressed via the primary endpoint of annualized bleeding rate 
(ABR) for total bleeds (treated and untreated) (referred to as ABRtotal thereafter in this 
document).  Efficacy by ABRtotal is summarized by the difference between pre- and 
post-treatment with PF-06838435; pre-treatment data will be obtained from the lead-in study 
(C0371004) as well as during the period prior to study drug infusion in Study C0371002 
(referred to as “Pre-Infusion Period” thereafter in this document).  Steady-state circulating 
FIX (FIX:C) is a key secondary endpoint and the efficacy by FIX:C is summarized by the 
steady-state population mean post-treatment compared to a fixed threshold of 5%.  Since no 
more than the single dose of study treatment on Day 1 will be administered during the study, 
there should be no treatment discontinuations.  Resumption of FIX prophylaxis regimen is 
allowed as detailed in Section 6.5.1and is assessed directly via secondary endpoints 
(annualized (FIX) infusion rate [AIR] and FIX consumption).  Data following resumption of 
FIX prophylaxis regimen will not be included in the primary analysis of ABRtotal.  There may 
be missing data from participants lost to follow-up, but it is anticipated to be rare.  The 
primary endpoint, ABRtotal, will utilize all applicable data to define the endpoint.  Any 
missing data will not be imputed for the primary endpoint.  The method to handle missing 
data of other endpoints will be discussed in the Statistical Analysis Plan (SAP).  Baseline for 
change from baseline analyses will be defined based on the data collection method of each 
endpoint, but will reflect data before PF-06838435 (also referred to as IP) infusion. 

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Primary Objectives
Primary Endpoints
To demonstrate the efficacy of a single infusion of 
PF-06838435 in male participants ≥18 years of age 
with moderately severe to severe hemophilia B 
(FIX:C ≤2%).
Primary endpoint: 

Non-inferiority on annualized bleeding rate 
(ABR) for total bleeds (treated and untreated) 
from Week 12 to Month 15 versus standard of 
care (SOC) FIX prophylaxis replacement 
regimen, comparing pre-and post-IP infusion.
Secondary Objectives
Secondary Endpoints
Key secondary objectives: To demonstrate the 
efficacy of PF-06838435 in terms of the use of 
exogenous FIX, the treated bleeds, and FIX:C.  

Key secondary endpoints:
o
Non-inferiority on ABR for treated bleeds 
from Week 12 to Month 15 versus SOC FIX 
prophylaxis replacement regimen, comparing 
pre- and post-IP infusion. 
o
Annualized infusion rate (AIR) of exogenous 
FIX from Week 12 to Month 15 versus AIR 
of FIX with SOC FIX replacement regimen 
pre-IP infusion.
o
Vector-derived FIX:C level at steady state 
(from Week 12 to 15 months) demonstrated 
to be greater than 5%.  FIX:C will also be 
summarized descriptively by study visit.
Overall Design:
This Phase 3, open-label, single arm, multi-site study will compare the efficacy of a single 
intravenous (IV) infusion of PF-06838435 with routine FIX prophylaxis, in adult male 
participants from the lead-in study (C0371004) with severe to moderately severe 
hemophilia B (≤2%).  Eligible study participants will have completed a minimum 6 months 
of routine FIX prophylaxis therapy during the lead-in study (C0371004).  The study duration 
for each participant in this study will be 312 weeks (see Section 1.3 for SoA).  At least 
50 participants will be screened to dose at least 40 participants with PF-06838435, and all 
40 participants are expected to be evaluable.
Disclosure Statement: 
This is a Single Group Treatment study with 1 Arm that has No masking.
Number of Participants:
Approximately 50 participants will be screened to achieve 40 participants assigned to study 
intervention for an estimated total of 40 evaluable participants.
Intervention Groups and Duration:
The study treatment, a single infusion of PF-06838435, a gene transfer agent, will be 
administered on Day 1 at a dose of 5 × 1011 vector genomes/kg of body weight.  The safety 
and efficacy data will be collected over 6 years as per the SoA included in Section 1.3.

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Data Monitoring Committee: Yes
1.2. Schema
Figure 1.
C0371002: Study Schematic

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1.3. Schedule of Activities (SoA)
Alternative study measures during the COVID-19 Pandemic and for Extenuating Circumstances is described in Appendix 13.
Procedures
Year 1
Screening Period
Baseline Period
IP Infusion
Week 1-12
(± 2 days)
Week 13-52
(±1 week)
The following Screening labs should be collected in the absence of residual infused FIX
(FIX trough): FIX activity, hemostasis markers, inhibitor testing. 
The Screening and Baseline period may be extended, upon consultation with the sponsor’s 
medical monitor.  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.
After determination of eligibility, FIX replacement therapy and IP Infusion will be planned at a 
time when a routine FIX infusion will occur during the study visit on Day 1.
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.  
Day 1: All eligible participants will be dosed on Day 1 and are required to return to the infusion 
center or study site 24 hours after being dosed (on Day 2) to have their vital signs assessed.
Visit 4: The participant is not required to appear in person at this visit.  Visit 4 study procedures 
are not required to be performed if the participant does not appear in person with the exception 
of all required laboratory specimens (eg, Immunology – Exploratory [IgG vs IgM antibody 
response], Vector Shedding Analysis by PCR, FIX Activity, Antigen and LFT) which can be 
obtained via mobile phlebotomy home health services.  If participants physically attend this visit, 
all procedures are to be performed per SOA.  
Unscheduled visits may be necessary during the study for safety monitoring or to repeat any 
blood sampling if required.
Mobile phlebotomy/home health services may be utilized for Pre-Dose LFT blood draws and 
most blood collections after Study Day 1/Visit 3 infusion, as needed. Additionally, mobile 
phlebotomy/home health service may be utilized, prior to Visit 3, upon sponsor approval, except 
for pre-dose LFT blood draws which do not require sponsor approval. 
Early discontinuation visit should follow the procedures for Week 312 visit.  The management of 
the participant and the risks inherent with discontinuation from the study should be discussed 
with the sponsor’s medical monitor.
Study Visit
1
2
3
4*
5
6
7
8
9 10 11 12 13
Weeks after IP 
administration
The schedule of 
assessments should be 
based on Day 1
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 from participants prior to 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
X*
X#
* Review and confirm eligibility criteria (see Sections 5.1 & 5.2).  This needs to be completed 
prior to ordering IP at the beginning of the Baseline Period. 
# Review and confirm eligibility (see Sections 5.1 & 5.2) prior to infusion (Infusion Center should 
confirm eligibility with study site).
Demographics,Medical,
Surgical, and Hemophilia
History (including 
vaccination history)
X
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.  
Only changes to historical data on Demographics, 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).

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Procedures
Year 1
Screening Period
Baseline Period
IP Infusion
Week 1-12
(± 2 days)
Week 13-52
(±1 week)
The following Screening labs should be collected in the absence of residual infused FIX
(FIX trough): FIX activity, hemostasis markers, inhibitor testing. 
The Screening and Baseline period may be extended, upon consultation with the sponsor’s 
medical monitor.  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.
After determination of eligibility, FIX replacement therapy and IP Infusion will be planned at a 
time when a routine FIX infusion will occur during the study visit on Day 1.
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.  
Day 1: All eligible participants will be dosed on Day 1 and are required to return to the infusion 
center or study site 24 hours after being dosed (on Day 2) to have their vital signs assessed.
Visit 4: The participant is not required to appear in person at this visit.  Visit 4 study procedures 
are not required to be performed if the participant does not appear in person with the exception 
of all required laboratory specimens (eg, Immunology – Exploratory [IgG vs IgM antibody 
response], Vector Shedding Analysis by PCR, FIX Activity, Antigen and LFT) which can be 
obtained via mobile phlebotomy home health services.  If participants physically attend this visit, 
all procedures are to be performed per SOA.  
Unscheduled visits may be necessary during the study for safety monitoring or to repeat any 
blood sampling if required.
Mobile phlebotomy/home health services may be utilized for Pre-Dose LFT blood draws and 
most blood collections after Study Day 1/Visit 3 infusion, as needed. Additionally, mobile 
phlebotomy/home health service may be utilized, prior to Visit 3, upon sponsor approval, except 
for pre-dose LFT blood draws which do not require sponsor approval. 
Early discontinuation visit should follow the procedures for Week 312 visit.  The management of 
the participant and the risks inherent with discontinuation from the study should be discussed 
with the sponsor’s medical monitor.
Study Visit
1
2
3
4*
5
6
7
8
9 10 11 12 13
Weeks after IP 
administration
The schedule of 
assessments should be 
based on Day 1
Week -6 to Week -3
Week -3 to Day 1
Day 1
1
2
4
8
12 18 24 32 42 52
Physical Exam, Weight,
and Vital Signs
X
X
X X
X
X
X
X
X X
X
X
X Complete Physical Exam at all clinic visits (Height is required to be collected at Screening Visit).  
Weight must be obtained at Screening Visit to order the correct quantity of IP.  Weight at 
Screening Visit (Visit 1) will be used to calculate the dose (Section 8.2.1).
Vital signs include: body temperature (°C) (see Section 8.2.2), BP, pulse rate, respiratory rate, 
after at least 5 mins rest in supine or upright/sitting position.
Vital signs are to be measured as specified below.
Vital signs (at Day 1) will be obtained: 

prior to FIX infusion;

30±2 mins after the start of IP infusion (taken during infusion);

approximately 2 mins, 2 hrs ±10 mins, 6 hrs ±10 mins, and 24 (±3) hrs after 
completion of IP infusion and IV line flush.
Electrocardiogram
X
X 12-lead ECG will be obtained for the study.  Additional ECGs may be obtained as clinically 
indicated. 
Target Joint Assessment
X
See Appendix 7 for definition of a target joint.
Done as part of hemophilia history.

PF-06838435 (fidanacogene elaparvovec)
C0371002
Final Protocol Amendment 3, 29 June 2022
PFIZER CONFIDENTIAL
Page 15
Procedures
Year 1
Screening Period
Baseline Period
IP Infusion
Week 1-12
(± 2 days)
Week 13-52
(±1 week)
The following Screening labs should be collected in the absence of residual infused FIX
(FIX trough): FIX activity, hemostasis markers, inhibitor testing. 
The Screening and Baseline period may be extended, upon consultation with the sponsor’s 
medical monitor.  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.
After determination of eligibility, FIX replacement therapy and IP Infusion will be planned at a 
time when a routine FIX infusion will occur during the study visit on Day 1.
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.  
Day 1: All eligible participants will be dosed on Day 1 and are required to return to the infusion 
center or study site 24 hours after being dosed (on Day 2) to have their vital signs assessed.
Visit 4: The participant is not required to appear in person at this visit.  Visit 4 study procedures 
are not required to be performed if the participant does not appear in person with the exception 
of all required laboratory specimens (eg, Immunology – Exploratory [IgG vs IgM antibody 
response], Vector Shedding Analysis by PCR, FIX Activity, Antigen and LFT) which can be 
obtained via mobile phlebotomy home health services.  If participants physically attend this visit, 
all procedures are to be performed per SOA.  
Unscheduled visits may be necessary during the study for safety monitoring or to repeat any 
blood sampling if required.
Mobile phlebotomy/home health services may be utilized for Pre-Dose LFT blood draws and 
most blood collections after Study Day 1/Visit 3 infusion, as needed. Additionally, mobile 
phlebotomy/home health service may be utilized, prior to Visit 3, upon sponsor approval, except 
for pre-dose LFT blood draws which do not require sponsor approval. 
Early discontinuation visit should follow the procedures for Week 312 visit.  The management of 
the participant and the risks inherent with discontinuation from the study should be discussed 
with the sponsor’s medical monitor.
Study Visit
1
2
3
4*
5
6
7
8
9 10 11 12 13
Weeks after IP 
administration
The schedule of 
assessments should be 
based on Day 1
Week -6 to Week -3
Week -3 to Day 1
Day 1
1
2
4
8
12 18 24 32 42 52
Joint X-ray
X*#
*Some participants (n~40), who consent to participate in an optional sub-study, will undergo 
X-ray for assessment of joints (Section 8.1.2.3). For German sites please refer to Germany 
Appendix (Section 10.11.2.4).
# If this X-ray can’t be performed during the baseline period, it is acceptable to postpone this 
testing no later than Week 4/ Visit 6.
Joint MRI
X*#
*Some participants (n~20), who consent to participate in an optional sub-study, will undergo joint 
MRIs (Section 8.1.2.2).
# If this MRI can’t be performed during the baseline period, it is acceptable to postpone this 
testing no later than Week 4/ Visit 6.
HBcAB, HCV, CD4,
human immunodeficiency 
virus (HIV) Serology, Liver 
fibrosis testing &
Urinalysis (CL*)
X
Hepatitis: HBsAg, HBcAb, HBV-deoxyribonucleic acid (DNA); HCV-RNA Quantitative
Liver fibrosis: FibroScan, FibroTest/FibroSURE, or AST to platelet ratio index (APRI).
* FibroScan, if performed, would be performed locally.
HIV: Antibody testing, and CD4 count/HIV viral load (if antibody positive).
Urinalysis: pH, specific gravity, protein, blood, ketones, glucose.
-Fetoprotein (CL)
X
X To be tested as biomarker for hepatic carcinoma.
FIX genetic testing (CL)
X*
*Test to be performed if results are not available in the source documents.

PF-06838435 (fidanacogene elaparvovec)
C0371002
Final Protocol Amendment 3, 29 June 2022
PFIZER CONFIDENTIAL
Page 16
Procedures
Year 1
Screening Period
Baseline Period
IP Infusion
Week 1-12
(± 2 days)
Week 13-52
(±1 week)
The following Screening labs should be collected in the absence of residual infused FIX
(FIX trough): FIX activity, hemostasis markers, inhibitor testing. 
The Screening and Baseline period may be extended, upon consultation with the sponsor’s 
medical monitor.  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.
After determination of eligibility, FIX replacement therapy and IP Infusion will be planned at a 
time when a routine FIX infusion will occur during the study visit on Day 1.
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.  
Day 1: All eligible participants will be dosed on Day 1 and are required to return to the infusion 
center or study site 24 hours after being dosed (on Day 2) to have their vital signs assessed.
Visit 4: The participant is not required to appear in person at this visit.  Visit 4 study procedures 
are not required to be performed if the participant does not appear in person with the exception 
of all required laboratory specimens (eg, Immunology – Exploratory [IgG vs IgM antibody 
response], Vector Shedding Analysis by PCR, FIX Activity, Antigen and LFT) which can be 
obtained via mobile phlebotomy home health services.  If participants physically attend this visit, 
all procedures are to be performed per SOA.  
Unscheduled visits may be necessary during the study for safety monitoring or to repeat any 
blood sampling if required.
Mobile phlebotomy/home health services may be utilized for Pre-Dose LFT blood draws and 
most blood collections after Study Day 1/Visit 3 infusion, as needed. Additionally, mobile 
phlebotomy/home health service may be utilized, prior to Visit 3, upon sponsor approval, except 
for pre-dose LFT blood draws which do not require sponsor approval. 
Early discontinuation visit should follow the procedures for Week 312 visit.  The management of 
the participant and the risks inherent with discontinuation from the study should be discussed 
with the sponsor’s medical monitor.
Study Visit
1
2
3
4*
5
6
7
8
9 10 11 12 13
Weeks after IP 
administration
The schedule of 
assessments should be 
based on Day 1
Week -6 to Week -3
Week -3 to Day 1
Day 1
1
2
4
8
12 18 24 32 42 52
FIX Inhibitor testing (CL, 
test in LL if clinically 
necessary)
X*
X
X
X
X
X
X
X
X
X These specimens should be collected in the absence of residual infused FIX.
*Positive inhibitor testing as measured by the central laboratory ≥0.6 Bethesda Units (BU) at Visit 
1 would be exclusionary.
Nijmegen Bethesda Inhibitor assay at the central lab unless testing at a local lab is necessary due 
to a clinical concern.
nAb Assay to adeno-
associated virus 
(AAV)-Spark 100 (CL)
X*
X *Participants with Anti-AAV-Spark100 neutralizing antibodies (nAb) titer ≥ 1:1 (ie, positive for 
nAb) are to be excluded from the study.
Anti-Drug Antibody/ADA 
(CL)
X
X Anti-PF-06838435 antibodies (ADA) from human serum.
Laboratory Safety Panels 
(Hematology and Clinical 
Chemistry) (CL)
X
X
X
X
X
X X
X
X
X Hematology: WBC and differential, RBC, hemoglobin, hematocrit, and platelet count.
ABO blood group (CL) (at Screening if unknown).
Chemistry: Na, K, Cl, phosphate, bicarbonate, glucose, BUN, serum creatinine.
Laboratory Safety Panels 
(Lipid Panel) (CL)
X
X These specimens are to be drawn after at least 8 hours of fasting (Appendix 2).

PF-06838435 (fidanacogene elaparvovec)
C0371002
Final Protocol Amendment 3, 29 June 2022
PFIZER CONFIDENTIAL
Page 17
Procedures
Year 1
Screening Period
Baseline Period
IP Infusion
Week 1-12
(± 2 days)
Week 13-52
(±1 week)
The following Screening labs should be collected in the absence of residual infused FIX
(FIX trough): FIX activity, hemostasis markers, inhibitor testing. 
The Screening and Baseline period may be extended, upon consultation with the sponsor’s 
medical monitor.  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.
After determination of eligibility, FIX replacement therapy and IP Infusion will be planned at a 
time when a routine FIX infusion will occur during the study visit on Day 1.
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.  
Day 1: All eligible participants will be dosed on Day 1 and are required to return to the infusion 
center or study site 24 hours after being dosed (on Day 2) to have their vital signs assessed.
Visit 4: The participant is not required to appear in person at this visit.  Visit 4 study procedures 
are not required to be performed if the participant does not appear in person with the exception 
of all required laboratory specimens (eg, Immunology – Exploratory [IgG vs IgM antibody 
response], Vector Shedding Analysis by PCR, FIX Activity, Antigen and LFT) which can be 
obtained via mobile phlebotomy home health services.  If participants physically attend this visit, 
all procedures are to be performed per SOA.  
Unscheduled visits may be necessary during the study for safety monitoring or to repeat any 
blood sampling if required.
Mobile phlebotomy/home health services may be utilized for Pre-Dose LFT blood draws and 
most blood collections after Study Day 1/Visit 3 infusion, as needed. Additionally, mobile 
phlebotomy/home health service may be utilized, prior to Visit 3, upon sponsor approval, except 
for pre-dose LFT blood draws which do not require sponsor approval. 
Early discontinuation visit should follow the procedures for Week 312 visit.  The management of 
the participant and the risks inherent with discontinuation from the study should be discussed 
with the sponsor’s medical monitor.
Study Visit
1
2
3
4*
5
6
7
8
9 10 11 12 13
Weeks after IP 
administration
The schedule of 
assessments should be 
based on Day 1
Week -6 to Week -3
Week -3 to Day 1
Day 1
1
2
4
8
12 18 24 32 42 52
FIX Activity, LFT (CL, 
LL) and 
FIX Antigen (CL)*
X
Collect 2-3 times 
every week 
starting from 
Day 1.  
Utilize mobile 
phlebotomy/ 
home health 
services as 
needed. 
Week 13 to 
Week 18: Collect 
once every week. 
Utilize mobile 
phlebotomy/ 
home health 
services as 
needed.
Week 19 to 
Week 52: Collect 
at site visits.
LFT: albumin, total bilirubin, direct bilirubin, indirect bilirubin (if available), ALP, AST, ALT, 
total protein, GGT, LDH.
FIX:C, FIX Ag.
FIX Activity should be collected in the absence of residual infused FIX.  
For first 12 weeks, 2 or 3 times every week monitoring will be conducted due to potential rise in 
hepatic transaminases and/or loss of FIX transgene expression.  
Sponsor recommends collecting specimens on Mondays through Thursdays so that the results are 
available prior to the weekend. 
* FIX Activity and LFT testing will be conducted at local AND central lab for all time 
points and as clinically necessary (including samples drawn at the clinic and any mobile 
phlebotomy/ home health service visits).  FIX Antigen testing will be conducted ONLY at 
central lab for all time points and as clinically necessary.  Clinical decisions may be based on 
local and/ or central lab results.
Order the IP
X
IP is to be ordered at the beginning of the Baseline Period after confirming eligibility criteria.  The 
IP will take approximately 3 weeks for delivery.  Prior to ordering IP, Sections 10.13.3 and 
10.13.4 should be considered.

PF-06838435 (fidanacogene elaparvovec)
C0371002
Final Protocol Amendment 3, 29 June 2022
PFIZER CONFIDENTIAL
Page 18
Procedures
Year 1
Screening Period
Baseline Period
IP Infusion
Week 1-12
(± 2 days)
Week 13-52
(±1 week)
The following Screening labs should be collected in the absence of residual infused FIX
(FIX trough): FIX activity, hemostasis markers, inhibitor testing. 
The Screening and Baseline period may be extended, upon consultation with the sponsor’s 
medical monitor.  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.
After determination of eligibility, FIX replacement therapy and IP Infusion will be planned at a 
time when a routine FIX infusion will occur during the study visit on Day 1.
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.  
Day 1: All eligible participants will be dosed on Day 1 and are required to return to the infusion 
center or study site 24 hours after being dosed (on Day 2) to have their vital signs assessed.
Visit 4: The participant is not required to appear in person at this visit.  Visit 4 study procedures 
are not required to be performed if the participant does not appear in person with the exception 
of all required laboratory specimens (eg, Immunology – Exploratory [IgG vs IgM antibody 
response], Vector Shedding Analysis by PCR, FIX Activity, Antigen and LFT) which can be 
obtained via mobile phlebotomy home health services.  If participants physically attend this visit, 
all procedures are to be performed per SOA.  
Unscheduled visits may be necessary during the study for safety monitoring or to repeat any 
blood sampling if required.
Mobile phlebotomy/home health services may be utilized for Pre-Dose LFT blood draws and 
most blood collections after Study Day 1/Visit 3 infusion, as needed. Additionally, mobile 
phlebotomy/home health service may be utilized, prior to Visit 3, upon sponsor approval, except 
for pre-dose LFT blood draws which do not require sponsor approval. 
Early discontinuation visit should follow the procedures for Week 312 visit.  The management of 
the participant and the risks inherent with discontinuation from the study should be discussed 
with the sponsor’s medical monitor.
Study Visit
1
2
3
4*
5
6
7
8
9 10 11 12 13
Weeks after IP 
administration
The schedule of 
assessments should be 
based on Day 1
Week -6 to Week -3
Week -3 to Day 1
Day 1
1
2
4
8
12 18 24 32 42 52
Immunology (PBMC) 
(CL)
X
Only if corticosteroid treatment is 
needed for a suspected T-cell 
response. 
Utilize mobile phlebotomy/ home 
health services as needed and if 
possible.
Specimens for PBMC by ELISPOT are to be collected at Baseline and if the corticosteroid 
treatment is needed for a suspected T-cell response.
Specimens are to be collected prior to initiating the corticosteroid treatment.  If not collected 
prior to initiation, specimens must be collected within 24 hours of administering corticosteroids.
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, ranitidine) for the duration of the 
corticosteroid course. 
Specimens are to be collected approximately 3 weeks after steroid administration.  Additional 
specimens may be necessary if ELISPOT has not normalized at 3 weeks and/or based on medical 
judgement.
Immunology Exploratory 
(PBMC) (CL)
X
X
X
X
X
X Utilize mobile phlebotomy/ home health services, as needed and if possible.
Collect blood for PBMC preparation for cell-mediated exploratory immunology assays. 

PF-06838435 (fidanacogene elaparvovec)
C0371002
Final Protocol Amendment 3, 29 June 2022
PFIZER CONFIDENTIAL
Page 19
Procedures
Year 1
Screening Period
Baseline Period
IP Infusion
Week 1-12
(± 2 days)
Week 13-52
(±1 week)
The following Screening labs should be collected in the absence of residual infused FIX
(FIX trough): FIX activity, hemostasis markers, inhibitor testing. 
The Screening and Baseline period may be extended, upon consultation with the sponsor’s 
medical monitor.  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.
After determination of eligibility, FIX replacement therapy and IP Infusion will be planned at a 
time when a routine FIX infusion will occur during the study visit on Day 1.
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.  
Day 1: All eligible participants will be dosed on Day 1 and are required to return to the infusion 
center or study site 24 hours after being dosed (on Day 2) to have their vital signs assessed.
Visit 4: The participant is not required to appear in person at this visit.  Visit 4 study procedures 
are not required to be performed if the participant does not appear in person with the exception 
of all required laboratory specimens (eg, Immunology – Exploratory [IgG vs IgM antibody 
response], Vector Shedding Analysis by PCR, FIX Activity, Antigen and LFT) which can be 
obtained via mobile phlebotomy home health services.  If participants physically attend this visit, 
all procedures are to be performed per SOA.  
Unscheduled visits may be necessary during the study for safety monitoring or to repeat any 
blood sampling if required.
Mobile phlebotomy/home health services may be utilized for Pre-Dose LFT blood draws and 
most blood collections after Study Day 1/Visit 3 infusion, as needed. Additionally, mobile 
phlebotomy/home health service may be utilized, prior to Visit 3, upon sponsor approval, except 
for pre-dose LFT blood draws which do not require sponsor approval. 
Early discontinuation visit should follow the procedures for Week 312 visit.  The management of 
the participant and the risks inherent with discontinuation from the study should be discussed 
with the sponsor’s medical monitor.
Study Visit
1
2
3
4*
5
6
7
8
9 10 11 12 13
Weeks after IP 
administration
The schedule of 
assessments should be 
based on Day 1
Week -6 to Week -3
Week -3 to Day 1
Day 1
1
2
4
8
12 18 24 32 42 52
Immunology - Exploratory 
(binding IgG vs IgM 
antibody response) (CL)
X
X* X
Serum samples will be used for these tests. 
Post-dose samples will be collected on Week 1 and Week 2. 
*Specimen is required at Visit 4 and can be obtained via mobile phlebotomy/ home health service. 
Spare Plasma
X
X
X X
X
X
X
X
X X
X
X
X Approximately 5 mL of blood will be drawn to provide approximately 2 mL of plasma, each time 
blood is collected for central laboratory samples. The plasma will be stored for repeat or 
additional testing.  These samples will be destroyed at the end of the study. 
Liver Ultrasound
X
X All participants will undergo liver ultrasound. Imaging will be performed locally (Section 8.2.5).
Global Hemostasis
Markers (CL)
X
X aPTT (in seconds), INR, TAT, TGA, and D-dimer, 
These specimens should be collected in the absence of residual infused FIX.
The tests may be conducted as clinically indicated throughout the study.
Issue the eDiary
X
Provide eDiary and training to operate it, including timing and information to be entered starting 
at Visit 1 (see Section 8.1.1).
Review the eDiary
Ongoing (including unscheduled visits)#
Review the eDiary data (see Section 8.1.1), ensure appropriate entries, during unscheduled and 
scheduled visits.
# Infusion centers are not required to perform this activity on Visit 3; however, the study site is 
required to perform this review.

PF-06838435 (fidanacogene elaparvovec)
C0371002
Final Protocol Amendment 3, 29 June 2022
PFIZER CONFIDENTIAL
Page 20
Procedures
Year 1
Screening Period
Baseline Period
IP Infusion
Week 1-12
(± 2 days)
Week 13-52
(±1 week)
The following Screening labs should be collected in the absence of residual infused FIX
(FIX trough): FIX activity, hemostasis markers, inhibitor testing. 
The Screening and Baseline period may be extended, upon consultation with the sponsor’s 
medical monitor.  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.
After determination of eligibility, FIX replacement therapy and IP Infusion will be planned at a 
time when a routine FIX infusion will occur during the study visit on Day 1.
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.  
Day 1: All eligible participants will be dosed on Day 1 and are required to return to the infusion 
center or study site 24 hours after being dosed (on Day 2) to have their vital signs assessed.
Visit 4: The participant is not required to appear in person at this visit.  Visit 4 study procedures 
are not required to be performed if the participant does not appear in person with the exception 
of all required laboratory specimens (eg, Immunology – Exploratory [IgG vs IgM antibody 
response], Vector Shedding Analysis by PCR, FIX Activity, Antigen and LFT) which can be 
obtained via mobile phlebotomy home health services.  If participants physically attend this visit, 
all procedures are to be performed per SOA.  
Unscheduled visits may be necessary during the study for safety monitoring or to repeat any 
blood sampling if required.
Mobile phlebotomy/home health services may be utilized for Pre-Dose LFT blood draws and 
most blood collections after Study Day 1/Visit 3 infusion, as needed. Additionally, mobile 
phlebotomy/home health service may be utilized, prior to Visit 3, upon sponsor approval, except 
for pre-dose LFT blood draws which do not require sponsor approval. 
Early discontinuation visit should follow the procedures for Week 312 visit.  The management of 
the participant and the risks inherent with discontinuation from the study should be discussed 
with the sponsor’s medical monitor.
Study Visit
1
2
3
4*
5
6
7
8
9 10 11 12 13
Weeks after IP 
administration
The schedule of 
assessments should be 
based on Day 1
Week -6 to Week -3
Week -3 to Day 1
Day 1
1
2
4
8
12 18 24 32 42 52
Pre-Dosing LFTs
X
Blood for LFTs are to be drawn and tested locally and centrally prior to dosing participants (up to 
3 days prior to Day 1/ Visit 3 is acceptable). Utilize mobile phlebotomy/ home health services as 
needed, and if possible. 
Local LFTs are required to be reviewed 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. These LFT results should be entered into the CRF as an unplanned visit.
FIX Infusion, 
Accountability 
X
On Day 1 a single prophylactic IV infusion of a FIX product will be administered under medical 
supervision, over a period of approximately 10 minutes at a dose of 100 IU/kg for standard 
half-life products and 50 IU/kg for extended half-life products, within reasonable margin of 
error (approximately ±20%). If there is evidence to show that these doses may place the 
participant at supratherapeutic FIX levels, the dose can be adjusted.
Participants are expected to bring their current Factor IX replacement therapy with them.

PF-06838435 (fidanacogene elaparvovec)
C0371002
Final Protocol Amendment 3, 29 June 2022
PFIZER CONFIDENTIAL
Page 21
Procedures
Year 1
Screening Period
Baseline Period
IP Infusion
Week 1-12
(± 2 days)
Week 13-52
(±1 week)
The following Screening labs should be collected in the absence of residual infused FIX
(FIX trough): FIX activity, hemostasis markers, inhibitor testing. 
The Screening and Baseline period may be extended, upon consultation with the sponsor’s 
medical monitor.  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.
After determination of eligibility, FIX replacement therapy and IP Infusion will be planned at a 
time when a routine FIX infusion will occur during the study visit on Day 1.
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.  
Day 1: All eligible participants will be dosed on Day 1 and are required to return to the infusion 
center or study site 24 hours after being dosed (on Day 2) to have their vital signs assessed.
Visit 4: The participant is not required to appear in person at this visit.  Visit 4 study procedures 
are not required to be performed if the participant does not appear in person with the exception 
of all required laboratory specimens (eg, Immunology – Exploratory [IgG vs IgM antibody 
response], Vector Shedding Analysis by PCR, FIX Activity, Antigen and LFT) which can be 
obtained via mobile phlebotomy home health services.  If participants physically attend this visit, 
all procedures are to be performed per SOA.  
Unscheduled visits may be necessary during the study for safety monitoring or to repeat any 
blood sampling if required.
Mobile phlebotomy/home health services may be utilized for Pre-Dose LFT blood draws and 
most blood collections after Study Day 1/Visit 3 infusion, as needed. Additionally, mobile 
phlebotomy/home health service may be utilized, prior to Visit 3, upon sponsor approval, except 
for pre-dose LFT blood draws which do not require sponsor approval. 
Early discontinuation visit should follow the procedures for Week 312 visit.  The management of 
the participant and the risks inherent with discontinuation from the study should be discussed 
with the sponsor’s medical monitor.
Study Visit
1
2
3
4*
5
6
7
8
9 10 11 12 13
Weeks after IP 
administration
The schedule of 
assessments should be 
based on Day 1
Week -6 to Week -3
Week -3 to Day 1
Day 1
1
2
4
8
12 18 24 32 42 52
IP   Infusion, Accountability 
X
Prior to dosing, Section 10.13.3 and 10.13.4 should be considered.
After the completion of FIX product infuion, participants will receive a single IV infusion of the 
IP over approximately 60 minutes via infusion pump.  IP should NOT be thawed without: 
confirmation of eligibility, Pre-Dosing LFT results, AND affirming that the participant is 
physically present at the study site (or infusion center).  
The IV line should be flushed at the conclusion of the IP infusion. 
HJHS
X
X
X
To be completed by investigator or the designee (Section 8.1.2.1).
Patient-Reported 
Outcomes (PROs)
X*
X
X
X Participants will complete 5 instruments at the site using an electronic tablet: Haem-A-QoL, 
Haemophilia Activities List [HAL (v2)], PGIC-H, HLIQ, and EQ-5D-5L.  The questionnaires 
should be administered before dosing, treatment, or conversation between health care team and 
participants about their health condition.  See Section 8.1.3 for additional considerations.
* PGIC-H is not completed at baseline visit.
Every effort should be made to conduct the PROs according to the protocol specified timepoints, 
especially the baseline visit. Baseline PRO assessments need to be done prior to start of infusion 
on Day 1 if not done at baseline visit. If the post-infusion PROs can’t be performed at a particular 
visit, they should be performed at the next visit.

PF-06838435 (fidanacogene elaparvovec)
C0371002
Final Protocol Amendment 3, 29 June 2022
PFIZER CONFIDENTIAL
Page 22
Procedures
Year 1
Screening Period
Baseline Period
IP Infusion
Week 1-12
(± 2 days)
Week 13-52
(±1 week)
The following Screening labs should be collected in the absence of residual infused FIX
(FIX trough): FIX activity, hemostasis markers, inhibitor testing. 
The Screening and Baseline period may be extended, upon consultation with the sponsor’s 
medical monitor.  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.
After determination of eligibility, FIX replacement therapy and IP Infusion will be planned at a 
time when a routine FIX infusion will occur during the study visit on Day 1.
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.  
Day 1: All eligible participants will be dosed on Day 1 and are required to return to the infusion 
center or study site 24 hours after being dosed (on Day 2) to have their vital signs assessed.
Visit 4: The participant is not required to appear in person at this visit.  Visit 4 study procedures 
are not required to be performed if the participant does not appear in person with the exception 
of all required laboratory specimens (eg, Immunology – Exploratory [IgG vs IgM antibody 
response], Vector Shedding Analysis by PCR, FIX Activity, Antigen and LFT) which can be 
obtained via mobile phlebotomy home health services.  If participants physically attend this visit, 
all procedures are to be performed per SOA.  
Unscheduled visits may be necessary during the study for safety monitoring or to repeat any 
blood sampling if required.
Mobile phlebotomy/home health services may be utilized for Pre-Dose LFT blood draws and 
most blood collections after Study Day 1/Visit 3 infusion, as needed. Additionally, mobile 
phlebotomy/home health service may be utilized, prior to Visit 3, upon sponsor approval, except 
for pre-dose LFT blood draws which do not require sponsor approval. 
Early discontinuation visit should follow the procedures for Week 312 visit.  The management of 
the participant and the risks inherent with discontinuation from the study should be discussed 
with the sponsor’s medical monitor.
Study Visit
1
2
3
4*
5
6
7
8
9 10 11 12 13
Weeks after IP 
administration
The schedule of 
assessments should be 
based on Day 1
Week -6 to Week -3
Week -3 to Day 1
Day 1
1
2
4
8
12 18 24 32 42 52
Vector Shedding Analysis 
by PCR (CL)
X X*
Weekly, as needed# 
Utilize mobile phlebotomy / home 
health services, as needed
# Plasma, PBMC, saliva, semen, and urine specimens will be collected at baseline and every 
week after IP administration until 3 consecutive specimens test negative for the given specimen 
type. 
Semen samples can be collected at home the night before a clinic or mobile phlebotomy/ home 
health service visit and stored in the participant’s freezer until the clinic or mobile phlebotomy/  
home health service visit, with the exception of semen samples collected as part of the optional 
vector shedding sub-study (see bullet point below)
*Optional Vector Shedding Sub-study: Additional (2 hrs (±30 minutes), 24 hrs (±3 hrs), 72 hrs 
(±4 hrs) after completion of IP infusion and IV line flush on Day 1) samples (plasma, PBMC, 
saliva, semen, and urine) will be collected from some participants (n=12) who consent to 
participate in an optional sub-study. Utilize mobile phlebotomy/ home health services as needed. 
Any Additional Safety 
Tests
Ongoing (as needed)
Additional laboratory testing 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 52 weeks post-infusion) all SAEs 
and AEs (including medically important events) will be collected (Appendix 3).

PF-06838435 (fidanacogene elaparvovec)
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Procedures
Year 1
Screening Period
Baseline Period
IP Infusion
Week 1-12
(± 2 days)
Week 13-52
(±1 week)
The following Screening labs should be collected in the absence of residual infused FIX
(FIX trough): FIX activity, hemostasis markers, inhibitor testing. 
The Screening and Baseline period may be extended, upon consultation with the sponsor’s 
medical monitor.  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.
After determination of eligibility, FIX replacement therapy and IP Infusion will be planned at a 
time when a routine FIX infusion will occur during the study visit on Day 1.
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.  
Day 1: All eligible participants will be dosed on Day 1 and are required to return to the infusion 
center or study site 24 hours after being dosed (on Day 2) to have their vital signs assessed.
Visit 4: The participant is not required to appear in person at this visit.  Visit 4 study procedures 
are not required to be performed if the participant does not appear in person with the exception 
of all required laboratory specimens (eg, Immunology – Exploratory [IgG vs IgM antibody 
response], Vector Shedding Analysis by PCR, FIX Activity, Antigen and LFT) which can be 
obtained via mobile phlebotomy home health services.  If participants physically attend this visit, 
all procedures are to be performed per SOA.  
Unscheduled visits may be necessary during the study for safety monitoring or to repeat any 
blood sampling if required.
Mobile phlebotomy/home health services may be utilized for Pre-Dose LFT blood draws and 
most blood collections after Study Day 1/Visit 3 infusion, as needed. Additionally, mobile 
phlebotomy/home health service may be utilized, prior to Visit 3, upon sponsor approval, except 
for pre-dose LFT blood draws which do not require sponsor approval. 
Early discontinuation visit should follow the procedures for Week 312 visit.  The management of 
the participant and the risks inherent with discontinuation from the study should be discussed 
with the sponsor’s medical monitor.
Study Visit
1
2
3
4*
5
6
7
8
9 10 11 12 13
Weeks after IP 
administration
The schedule of 
assessments should be 
based on Day 1
Week -6 to Week -3
Week -3 to Day 1
Day 1
1
2
4
8
12 18 24 32 42 52
Concomitant Medications, 
Surgeries, and Procedures
Ongoing (including unscheduled visits)
All concomitant therapy 30 days prior to Screening, during Screening and Short-Term Monitoring 
Period will be recorded up to and including 52 weeks post-infusion as per Section 6.5.
All procedures and surgeries (including elective surgeries) during the Screening and Short-Term 
Monitoring Period are to be recorded.
Note: Study Site: Will screen and follow study participants post-infusion of PF-06838435 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-06838435.
AAV: adeno-associated virus; ADA: Anti-drug antibody; AE: adverse event; ALP: alkaline phosphatase; ALT: alanine transaminase; APRI: AST to Platelet Ratio Index; aPTT: 
activated partial thromboplastin time, AST: aspartate transaminase; BUN: blood urea nitrogen; CBC: complete blood count; CD4: cluster of differentiation or classification 
determinant; CL: central laboratory; CPT: cell preparation tube; Cr: creatinine; DNA: deoxyribonucleic acid; ECG: electrocardiogram; ELISPOT: Enzyme-Linked ImmunoSpot 
assay; EOS: End of Study; EQ-5D-5L: EuroQol, 5 dimensions, 5 levels; FIX: coagulation factor IX; FIX Ag: factor IX antigen; FIX:C: circulating FIX; HBcAb: Hepatitis B core 
antibody; GGT: gamma-glutamyl transferase; 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; HCV: hepatitis C virus; HIV: human immunodeficiency virus; HJHS: hemophilia joint health score; HLIQ: 
Hemophilia Life Impacts Questionnaire; ICF: Informed Consent Form; IgG: immunoglobulin G; IgM: immunoglobulin M; INR: international normalized ratio; IP: investigational 
product; IU: international units; K: potassium; LDH: lactic acid dehydrogenase; LFT: liver function tests; LL: local laboratory; mins: minutes; MRI: magnetic resonance imaging; 
n: number; Na: sodium; nAb: neutralizing antibodies; PBMC: peripheral blood mononuclear cells; PCR: polymerase chain reaction; PGIC-H: Patient Global Impression of 

PF-06838435 (fidanacogene elaparvovec)
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PFIZER CONFIDENTIAL
Page 24
Procedures
Year 1
Screening Period
Baseline Period
IP Infusion
Week 1-12
(± 2 days)
Week 13-52
(±1 week)
The following Screening labs should be collected in the absence of residual infused FIX
(FIX trough): FIX activity, hemostasis markers, inhibitor testing. 
The Screening and Baseline period may be extended, upon consultation with the sponsor’s 
medical monitor.  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.
After determination of eligibility, FIX replacement therapy and IP Infusion will be planned at a 
time when a routine FIX infusion will occur during the study visit on Day 1.
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.  
Day 1: All eligible participants will be dosed on Day 1 and are required to return to the infusion 
center or study site 24 hours after being dosed (on Day 2) to have their vital signs assessed.
Visit 4: The participant is not required to appear in person at this visit.  Visit 4 study procedures 
are not required to be performed if the participant does not appear in person with the exception 
of all required laboratory specimens (eg, Immunology – Exploratory [IgG vs IgM antibody 
response], Vector Shedding Analysis by PCR, FIX Activity, Antigen and LFT) which can be 
obtained via mobile phlebotomy home health services.  If participants physically attend this visit, 
all procedures are to be performed per SOA.  
Unscheduled visits may be necessary during the study for safety monitoring or to repeat any 
blood sampling if required.
Mobile phlebotomy/home health services may be utilized for Pre-Dose LFT blood draws and 
most blood collections after Study Day 1/Visit 3 infusion, as needed. Additionally, mobile 
phlebotomy/home health service may be utilized, prior to Visit 3, upon sponsor approval, except 
for pre-dose LFT blood draws which do not require sponsor approval. 
Early discontinuation visit should follow the procedures for Week 312 visit.  The management of 
the participant and the risks inherent with discontinuation from the study should be discussed 
with the sponsor’s medical monitor.
Study Visit
1
2
3
4*
5
6
7
8
9 10 11 12 13
Weeks after IP 
administration
The schedule of 
assessments should be 
based on Day 1
Week -6 to Week -3
Week -3 to Day 1
Day 1
1
2
4
8
12 18 24 32 42 52
Change- Hemophilia; PROs: patient-reported outcomes; RNA: ribonucleic acid; SAE: serious adverse event; TAT: thrombin-antithrombin level; TGA: Thrombin generation 
assay; vg: vector genome; WBC: white blood cell. 

PF-06838435 (fidanacogene elaparvovec)
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Final Protocol Amendment 3, 29 June 2022
PFIZER CONFIDENTIAL
Page 25
Alternative study measures during the COVID-19 Pandemic and for Extenuating Circumstances is described in Appendix 13.
Procedures
Year 2 to Year 6
Week 53-156
(±2 weeks)
Week
157-260
(±3 weeks)
EOS
Week 312 
(±3 weeks)
Unscheduled visits may be necessary during the study.  Tests being performed are for safety 
monitoring purposes, for repeat safety assessments, or to repeat any blood sampling if required. 
During Long-Term Monitoring Period (Weeks 53 to 312), mobile phlebotomy/ home health services 
may be utilized as needed, when site visits are not scheduled. 
Early discontinuation visit should follow the procedures for Week 312 visit.  The management of the 
participant and the risks inherent with discontinuation from the study should be discussed with the 
sponsor’s medical monitor.
Study Visit
14
15
16
17
18
19
20
Weeks after IP 
administration
78 104 130 156
208
26
0
312
Physical Exam, Weight,
and Vital Signs
X
X
X
X
X
X
X
Complete Physical Exam at all visits. 
Vital signs include: body temperature (°C) (see Section 8.2.2), BP, pulse rate, respiratory rate, after at 
least 5 mins rest in supine or upright/sitting position.
Electrocardiogram
As needed
12-lead ECG will be obtained for the study.  Additional ECGs may be obtained as clinically indicated. 
Joint X-ray
X*,#
X*,#
*Some participants (n~40), who consent to participate in an optional sub-study, will undergo X-ray for 
assessment of joints (Section 8.1.2.3). For German sites please refer to Germany Appendix 
(Section 10.11.2.4).
# If the baseline X-ray could not be performed ≤ Week 4/ Visit 6, the study participant does not need to 
do the 3 (Visit 17) and 6 year (Visit 20) follow-up X-rays.
Joint MRI
X*,#
X*,#
*Some participants (n~20), who consent to participate in an optional sub-study, will undergo joint MRIs 
(Section 8.1.2.2).
# If the baseline MRI could not be performed ≤ Week 4/ Visit 6, the study participant does not need to 
do the 3 (Visit 17) and 6 (Visit 20) year follow-up MRIs.
-Fetoprotein (CL)
X
X
X
X
X
X
X
To be tested as biomarker for hepatic carcinoma.
FIX Inhibitor Testing (CL, 
test in LL if clinically 
necessary)
X
X
X
X
X
X
X
Nijmegen Bethesda Inhibitor Assay: At central laboratory; local laboratory allowed if required for 
clinical reasons.
These specimens should be collected in the absence of residual infused FIX.
nAb Assay to AAV Spark 
100 (CL)
X
X
X
X
X
Anti-Drug Antibody/ADA 
(CL)
X
X
Whole blood will be collected for determination of anti-PF-06838435 antibodies (ADA) from human 
serum.
Laboratory Safety Panels 
(Hematology and Clinical 
Chemistry) (CL)
X
X
X
X
X
X
X

Hematology: WBC and differential, RBC, hemoglobin, hematocrit, and platelet count

Chemistry: Na, K, Cl, phosphate, bicarbonate, glucose, BUN, serum creatinine. 

PF-06838435 (fidanacogene elaparvovec)
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Final Protocol Amendment 3, 29 June 2022
PFIZER CONFIDENTIAL
Page 26
Procedures
Year 2 to Year 6
Week 53-156
(±2 weeks)
Week
157-260
(±3 weeks)
EOS
Week 312 
(±3 weeks)
Unscheduled visits may be necessary during the study.  Tests being performed are for safety 
monitoring purposes, for repeat safety assessments, or to repeat any blood sampling if required. 
During Long-Term Monitoring Period (Weeks 53 to 312), mobile phlebotomy/ home health services 
may be utilized as needed, when site visits are not scheduled. 
Early discontinuation visit should follow the procedures for Week 312 visit.  The management of the 
participant and the risks inherent with discontinuation from the study should be discussed with the 
sponsor’s medical monitor.
Study Visit
14
15
16
17
18
19
20
Weeks after IP 
administration
78 104 130 156
208
26
0
312
FIX Activity, LFT (CL, LL) 
and 
FIX Antigen (CL)*
Starting at 
Week 53, monitor 
once every 
3 months$
Starting at 
Week 157, 
monitor 
once every 
6 months#
X
LFT: albumin, total bilirubin, direct bilirubin, indirect bilirubin (if available), ALP, AST, ALT, total 
protein, GGT, LDH.
FIX:C, FIX Ag.
FIX Activity should be collected in the absence of residual infused FIX
Sponsor recommends collecting specimens on Mondays through Thursdays so that the results are 
available prior to the weekend.
* FIX Activity and LFT testing will be conducted at local AND central lab for all time points and 
as clinically necessary (including samples drawn at the clinic and any mobile phlebotomy/ home 
health service visits).  FIX Antigen testing will be conducted ONLY at central lab for all time points 
and as clinically necessary.  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 (Visit 16), 143, 156 
(Visit 17).
# Samples should be taken at weeks: 182, 208 (Visit 18), 234, 260 (Visit 19) and 286.
Utilize mobile phlebotomy/ home health services as needed.
Immunology (PBMC) 
(CL)
Only if corticosteroid treatment 
is needed for a suspected T-cell 
response.
Utilize mobile phlebotomy/ 
home health services, as 
needed and if possible.
X
Specimens for PBMC by ELISPOT are to be collected at End of Study and if the corticosteroid 
treatment is needed for a suspected T-cell response.
Specimens are to be collected prior to initiating the corticosteroid treatment.  If not collected prior to 
initiation, specimens must be collected within 24 hours of administering corticosteroids.
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, ranitidine) for the duration of the corticosteroid course.
Specimens are to be collected approximately 3 weeks after steroid administration.  Additional 
specimens may be necessary if ELISPOT has not normalized at 3 weeks and/or based on medical 
judgement.
Spare Plasma
X
X
X
X
X
X
X
Approximately 5 mL of blood will be drawn to provide approximately 2 mL of plasma, each time blood 
is collected for central laboratory samples. The plasma will be stored for repeat or additional testing.  
These samples will be destroyed at the end of the study.
Liver Ultrasound
X
X
X
X
X
All participants will undergo liver ultrasound. Imaging will be performed locally (Section 8.2.5).
Global Hemostasis
Markers (CL)
X
X
X
X
X
aPTT (in seconds), INR, TAT, TGA, and D-dimer. 
These specimens should be collected in the absence of residual infused FIX.
The tests may be conducted as clinically indicated throughout the study.
HJHS
X
X
X
X
X
To be completed by the investigator or the designee (Section 8.1.2.1).

PF-06838435 (fidanacogene elaparvovec)
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Final Protocol Amendment 3, 29 June 2022
PFIZER CONFIDENTIAL
Page 27
Procedures
Year 2 to Year 6
Week 53-156
(±2 weeks)
Week
157-260
(±3 weeks)
EOS
Week 312 
(±3 weeks)
Unscheduled visits may be necessary during the study.  Tests being performed are for safety 
monitoring purposes, for repeat safety assessments, or to repeat any blood sampling if required. 
During Long-Term Monitoring Period (Weeks 53 to 312), mobile phlebotomy/ home health services 
may be utilized as needed, when site visits are not scheduled. 
Early discontinuation visit should follow the procedures for Week 312 visit.  The management of the 
participant and the risks inherent with discontinuation from the study should be discussed with the 
sponsor’s medical monitor.
Study Visit
14
15
16
17
18
19
20
Weeks after IP 
administration
78 104 130 156
208
26
0
312
Patient-Reported 
Outcomes (PROs)
X
X
X
X
X
Participants will complete 5 instruments at the study site using an electronic tablet: Haem-A-QoL, HAL 
(v2), PGIC-H, HLIQ, and EQ-5D-5L.  The questionnaires should be administered before dosing, 
treatment, or conversation between health care team and participants about their health condition.  See 
Section 8.1.3 for additional considerations.
Every effort should be made to conduct the PROs according to the protocol specified timepoints. If the 
post-infusion PROs can’t be performed at a particular visit, they should be performed at the next visit.
Phone call
Ongoing
After Week 156, phone calls every 6 months (ie, weeks: 182, 234, 286) in addition to the annual visits.  
Inquire about AEs and concomitant treatments (including surgeries and procedures).
Vector Shedding Analysis 
by PCR (CL)
Weekly, as needed# 
Utilize mobile phlebotomy/ home health 
services as needed
# Plasma, PBMC, saliva, semen, and urine: Specimens will be collected at baseline and every week 
after IP administration until 3 consecutive specimen test negative for the given specimen type. 
Semen samples can be collected at home the night before a clinic or mobile phlebotomy/ home health  
service visit and stored in the participant’s freezer until the clinic or mobile phlebotomy/ home health 
service visit.
Any Additional Safety 
Tests
Ongoing
Additional laboratory testing may be conducted as deemed clinically necessary by the investigator to 
ensure safety of participants.
Adverse Events 
Ongoing (including unscheduled visits)
During the Long-Term Monitoring Period (Week 53 post-infusion to EOS) the following adverse events 
will be collected:
SAEs (including medically important events, Appendix 3).
Non-serious AEs determined to be related to IP by the investigator or where causality is unknown.
Concomitant Medications, 
Surgeries, and Procedures
Ongoing (including unscheduled visits)
During the Long-Term Monitoring Period (Week 53 post-infusion to EOS) the concomitant therapy 
associated with:
SAEs (including medically important events, Appendix 3) 
Non-serious AEs determined to be related to IP by the investigator or where causality is unknown. 
All procedures and surgeries (including elective surgeries) during the Long-Term Monitoring Period are 
to be recorded.
Review of the eDiary
Ongoing (including unscheduled visits)
Review the eDiary; ensure appropriate entries, during unscheduled and scheduled visits.
Return eDiary
X
The eDiary will be returned during the Week 312 visit.
Study Site: Site that will screen and follow participant post-infusion of PF-06838435 for the duration of the study.
AAV: adeno-associated virus; ADA: Anti-drug antibody; AE: adverse event; ALP: alkaline phosphatase; ALT: alanine transaminase; APRI: AST to Platelet Ratio Index; aPTT: 
activated partial thromboplastin time, AST: aspartate transaminase; BUN: blood urea nitrogen; CBC: complete blood count; CL: central laboratory; CPT: cell preparation tube; Cr: 
creatinine; DNA: deoxyribonucleic acid; ELISPOT: Enzyme-Linked ImmunoSpot assay; EOS: End of Study; EQ-5D-5L: EuroQol, 5 dimensions, 3 levels; FIX: coagulation factor 
IX; FIX Ag: factor IX antigen; HBcAb: Hepatitis B core antibody; GGT: gamma-glutamyl transferase; Haem-A-QoL: Haemophilia Quality of Life Questionnaire for Adults; 
HAL: Haemophilia Activities List; HBsAg: hepatitis B surface antigen; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; HJHS: hemophilia 
joint health score; HLIQ: Hemophilia Life Impacts Questionnaire; ICF: Informed Consent Form; INR: international normalized ratio; IP: investigational product; IU: international 

PF-06838435 (fidanacogene elaparvovec)
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Final Protocol Amendment 3, 29 June 2022
PFIZER CONFIDENTIAL
Page 28
Procedures
Year 2 to Year 6
Week 53-156
(±2 weeks)
Week
157-260
(±3 weeks)
EOS
Week 312 
(±3 weeks)
Unscheduled visits may be necessary during the study.  Tests being performed are for safety 
monitoring purposes, for repeat safety assessments, or to repeat any blood sampling if required. 
During Long-Term Monitoring Period (Weeks 53 to 312), mobile phlebotomy/ home health services 
may be utilized as needed, when site visits are not scheduled. 
Early discontinuation visit should follow the procedures for Week 312 visit.  The management of the 
participant and the risks inherent with discontinuation from the study should be discussed with the 
sponsor’s medical monitor.
Study Visit
14
15
16
17
18
19
20
Weeks after IP 
administration
78 104 130 156
208
26
0
312
units; LDH: lactic acid dehydrogenase; LFT: liver function tests; LL: local laboratory; mins: minutes; MRI: magnetic resonance imaging; nAb: neutralizing antibodies; 
PBMC: peripheral blood mononuclear cells; PGIC-H: Patient Global Impression of Change- Hemophilia; PROs: patient-reported outcomes; RNA: ribonucleic acid; SAE: serious 
adverse event; TAT: thrombin-antithrombin level; TGA: Thrombin generation assay; vg: vector genome; WBC: white blood cell.

PF-06838435 (fidanacogene elaparvovec)
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Final Protocol Amendment 3, 29 June 2022
PFIZER CONFIDENTIAL
Page 29
2. INTRODUCTION
PF-06838435 (generic name: fidanacogene elaparvovec; formerly known as SPK-9001 or 
rAAV Spark100-hFIX-Padua) is an adeno-associated viral (AAV) vector designed to drive 
expression of the human factor IX-Padua (hFIX-Padua) transgene and raise the circulating 
levels of FIX (FIX:C). 
C0371002 is a pivotal Phase 3 study designed to evaluate clinical efficacy and safety of 
PF-06838435 in adult male participants with moderately severe or severe hemophilia B 
(FIX:C ≤2% or ≤2 IU/deciliter [dL]) for the study duration of 6 years after a single 
administration of the study treatment.  The study will enroll eligible participants who have 
completed at least 6 months of routine prophylaxis in the C0371004 study.  The data for 
ABRtotal from the Pre-Infusion Period will serve as historical control to test the Study 
C0371002 primary endpoint for non-inferiority.  If non-inferiority of ABRtotal with 
PF-06838435 treatment over routine prophylaxis is demonstrated, superiority will be tested 
on the ABRtotal. 
The guidance document by the Food and Drug Administration (FDA) were considered while 
developing this protocol.2,3
Overview of Hemophilia B
Hemophilia B, or Christmas disease, results from a deficiency of blood coagulation Factor IX 
(FIX).  The gene for FIX is located on the X-chromosome and inherited in a classic x-linked 
pattern.  Mutations may cause the gene to be ineffective leading to reduced FIX expression in 
males with a defective gene. Female carriers may have modest reductions in the FIX level.4,5
Factor IX, a serine protease, and factor VIII, a co-factor for FIX, work in concert to activate 
factor X, a central step in the coagulation cascade.  The plasma factors are activated in the 
form of a cascade or “waterfall” (Macfarlane 1964; Davie and Ratnoff 1964) one after the 
other until the soluble plasma protein, fibrinogen, is transformed into a fibrinous clot.  An 
effective clot cannot be formed without adequate levels of procoagulant factors.  The level of 
coagulation factors in the plasma of normal individuals range from 50 to 150% (or 
50-150 IU/dL) of the level in normal pooled plasma.  Therefore, severity of the disease is 
determined by clinical features and factor coagulant activity. 
Individuals with severe to moderately severe hemophilia B (circulating FIX level ≤2% or 
≤2 IU/dL) frequently experience bleeding and recurrent spontaneous bleeding events into 
muscle, soft tissue, and joints (hemarthroses) starting from infancy and throughout 
adulthood.  Examples of bleeding events include intracranial hemorrhage, deep muscle and 
joint hemorrhage, hematomas, retroperitoneal hemorrhage, bleeding following tooth 
extraction, post-surgical bleeding, easy bruising, and mucosal bleeding.  Musculoskeletal 
hemorrhages can lead to recurrent hemarthroses and the development of target joints (a 
minimum of three bleeds into a single joint within a consecutive six-month period).6 Such 
bleeding events inevitably result in progressive joint damage, leading to disabling arthritis 
with decreased physical and psychosocial quality of life (QoL) and socio-economic 
parameters.  Intracranial hemorrhage is a leading cause of death among individuals with 

PF-06838435 (fidanacogene elaparvovec)
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Final Protocol Amendment 3, 29 June 2022
PFIZER CONFIDENTIAL
Page 30
hemophilia, with a mortality rate of up to 50% in adults as well as in children.  Intracranial 
hemorrhage can occur after trauma, but as many as 50% of cases occur spontaneously.7
Development of inhibitory antibodies (ie, inhibitors) is the main complication of any factor 
replacement therapy, including FIX treatment.8,9,10  Inhibitory antibodies develop in 
approximately 3-5% of patients with hemophilia B following exposure to factor replacement 
therapy.  Hemophilia B inhibitors may present with anaphylactic responses to infusion of 
FIX products and in the presence of inhibitory antibodies, factor replacement is less 
effective.  Therefore, acute management of bleeding requires agents that bypass FIX activity.  
Also, eradication of inhibitor through immune tolerance, typically implemented for long-term 
management of inhibitors in hemophilia A, is problematic and less effective in hemophilia B, 
especially in association with anaphylaxis.  Thus, development of inhibitors significantly 
adds to the disease burden of hemophilia B patients. 
Current Therapies for Hemophilia B
There is no available cure for hemophilia B.  Treatment has focused on the replacement of 
FIX with intravenous (IV) administration of FIX concentrates to promote clotting.  Current 
treatment is based on venipuncture and IV administration of either plasma-derived or 
recombinant FIX protein replacement therapy to raise the circulating FIX (FIX:C) activity 
level to the lowest effective level to achieve either resolution of bleeding (on-demand 
treatment) or prevention of bleeding (prophylaxis treatment).4,11,12  The frequency of 
administration of FIX products varies and is tailored to the individual’s clinical status, taking 
into consideration the type and frequency of bleed, and the goal of treatment.  Both U.S. 
National Hemophilia Foundation and the World Federation of Hemophilia have established 
recommendations of plasma factor levels and duration of administration for different types of 
bleeds based on observational studies.12,13  Improvements in FIX replacement therapy have 
vastly increased the QoL and life expectancy of individuals with hemophilia B.4  Modified 
FIX agents with extended half-life provide more convenient dosing options and in some 
cases result in trough levels of FIX >12% of normal, a level that nearly eliminates 
spontaneous joint bleeds, can be maintained with weekly prophylactic dosing.14,15,16,17,18
Prophylaxis aims to convert a severe to a moderate phenotype through regular infusions of 
clotting factor.  With full adherence in dosing regimen, prophylaxis is more effective than 
on-demand treatment for preserving joint health and has enabled affected individuals to 
participate more extensively in physical activity.19,20,21,22  Utilization of prophylactic therapy 
for hemophilia has gradually increased among the adult population in the United States of 
America (USA), but is still not universally practiced.  In the USA, as of 2014, an estimated 
85% of children and 63% of adults with hemophilia were on prophylactic regimens.23  
Recent results from a multi-site study assessing adherence to prophylaxis and clinical 
outcomes in the Netherlands revealed only 43% of the patients adhered to the prophylactic 
regimen.24  

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Gene Transfer Therapy in Hemophilia
Gene transfer may manage hemophilia better and also remove the burden of frequent 
injections.  Gene therapy for hemophilia works by packaging a corrected form of the FIX 
gene into a virus, most commonly an AAV.  Using hepatotropic AAV serotypes allows the 
transgene to be delivered to hepatocytes in a highly efficient manner.  Once delivered to 
hepatocytes, the gene is expressed and FIX enters to the circulation to contribute to the 
hemostatic process. 
Hemophilia is an ideal candidate for gene transfer therapy because precise regulation of 
transgene expression of FIX is not required.  The therapeutic range of FIX is remarkably 
wide, >1% to 150% of normal.  Even attaining low level FIX activity between 1 and 5% of 
normal provides protection against chronic arthropathy and CNS bleeding.  Patients with 
levels above 5% have much milder disease and only rarely experience spontaneous bleeding 
episodes, although they exhibit abnormal bleeding in response to hemostatic challenges such 
as surgery or trauma.  Information about PF-06838435, including clinical experience, is 
provided in Section 2.2.  Proof of concept of gene therapy was recently shown in a clinical 
study utilizing AAV8 gene transfer to patients with severe hemophilia B, sponsored by 
St. Jude Children’s Research Hospital and University College London (SJ-UCL).  In this 
study, levels of circulating FIX were achieved that effectively improved the phenotype of the 
patients with hemophilia B. 
Spark Therapeutics has developed a customized AAV vector with enhanced liver tropism 
with which to deliver the highly active Padua variant of FIX.  Using this approach in a 
Phase 1/2a trial of PF-06838435, Spark was able to achieve stable expression of FIX with all 
patients achieving mild status.1
2.1. Study Rationale
The published data from the Phase 1/2a study for PF-06838435 (SPK-9001-101) indicate that 
treatment of hemophilia B with PF-06838435 offers considerable clinical advantage over 
routine prophylactic treatment with FIX.  A single infusion of PF-06838435 results in 
sustained FIX activity levels in the mild to normal range with associated low bleeding rates 
and a marked reduction in the number of infusions of FIX product (see Section 2.2.2).1  This 
Phase 3 confirmatory study will compare efficacy of PF-06838435 treatment with routine 
prophylaxis with the objective to establish non-inferiority and possibly superiority. 
2.2. Background
2.2.1. PF–06838435, Composition of the Vector
PF-06838435 is designed to require only a single administration into hemophilia B
individuals, eliminating the disease burden associated with the condition and its treatment.  It 
is a recombinant adeno-associated viral (rAAV) vector comprised of AAV-Spark100 
(a bio-engineered hepatotropic AAV capsid) and hFIX39-Padua (a codon-optimized 
expression cassette encoding a naturally occurring FIX variant, FIX-Padua), under the 
regulatory control of the liver-specific modified hAAT promoter and portions of the 
apolipoprotein E hepatic locus control region [ApoE HCR-1] (Figure 2).

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Figure 2.
Schematic of PF-06838435 Vector Genome
A number of measures have been taken to improve both the performance and safety of the 
earlier AAV vectors; PF-06838435 differs from the earlier vectors in two main ways:
1. Capsid:

Utilizes a different AAV capsid, called AAV-Spark100.  This a novel capsid 
engineered from a naturally-occurring AAV serotype, which shows a strong 
hepatotropic profile in mice and nonhuman primates (NHPs), comparable to 
AAV8; and

Increases resistance to circulating neutralizing antibodies (nAbs) to AAV in 
humans while maintaining good transduction efficiency in large animal models.
2. Cassette:

Encodes a naturally occurring FIX variant (ie, FIX-Padua), which has 
approximately 5-8 fold higher specific activity than wild-type FIX due to the 
substitution of an arginine for a leucine at amino acid position 338 (R338L).25  
Use of a FIX variant that has a higher specific activity than the wild-type protein 
may result in improved FIX:C activity levels. 
2.2.2. Summary of Clinical Experience with PF–06838435
The Phase 1/2 Study (C0371005; formerly known as SPK-9001-101), in which 
10 participants with FIX coagulant activity of ≤2% received a single infusion of 
PF-06838435 at 5 × 1011 vg/kg, reported no serious adverse events (SAEs), including no 
emergence of FIX inhibitors or thrombosis after a cumulative follow-up of 492 weeks.  
Asymptomatic increase in liver enzymes, suspected to be AAV capsid-specific immune 
response, was reported in two patients and resolved with short term prednisone treatment.  
Steady-state FIX coagulant activity was observed to be 33.7±18.5% (range, 14 to 81).  After 
administration of PF-06838435, on cumulative follow-up of 492 weeks (range of follow-up 
in individual patients, 28 to 78 weeks), the mean ABR for treated bleeds was reduced from 
11.1 events per year prior to administration (range, 0 to 48) to 0.4 events per year (range, 0 to 
4) after administration (P = 0.02).  Use of exogenous FIX was reduced as well (mean dose, 
2908 IU/kg to [range, 0 to 8090] to 49.3 IU/kg [range, 0 to 376]; P = 0.004).  A total of 8 of 

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10 participants did not use any factor and 9 of 10 did not have any bleeds after PF-06838435 
administration.1,26
2.3. Benefit/Risk Assessment
The Phase 1/2 data has indicated that a single infusion of PF-06838435 would potentially 
allow patients to realize the benefit of FIX replacement without the need for frequent 
intravenous infusions, with an acceptable safety profile.
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of PF-06838435 may be found in the PF-06838435 Investigator’s 
Brochure, which is the single reference safety document (SRSD) for this study.26  
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS
Objectives
Endpoints
Primary
Primary

To demonstrate the efficacy of a single infusion 
of PF-06838435 in male participants ≥18 years 
of age with moderately severe to severe 
hemophilia B (FIX:C ≤2%).
Primary endpoint: 

Non-inferiority on annualized bleeding rate 
(ABR) for total bleeds (treated and untreated) 
from Week 12 to Month 15 versus standard of 
care (SOC) FIX prophylaxis replacement 
regimen, comparing pre- and post-IP infusion.
Secondary
Secondary

Key secondary objectives: To demonstrate the 
efficacy of PF-06838435 in terms of the use of 
exogenous FIX, the treated bleeds, and FIX:C.   

Key secondary endpoints:
o
Non-inferiority on ABR for treated bleeds 
from Week 12 to Month 15 versus SOC FIX 
prophylaxis replacement regimen, comparing 
pre- and post-IP infusion. 
o
Annualized infusion rate (AIR) of exogenous 
FIX from Week 12 to Month 15 versus AIR 
of FIX with SOC FIX replacement regimen 
pre-IP infusion.
o
Vector-derived FIX:C level at steady state 
(from Week 12 to 15 months) demonstrated 
to be greater than 5%.  FIX:C will also be 
summarized descriptively by study visit.

To compare additional efficacy parameters post-
PF-06838435 infusion to baseline in order to 
further characterize PF-06838435 treatment, 
including use of exogenous FIX, information on 
bleeding events, and patient reported outcomes 
addressing health related quality of life, 
activities of daily living and general health 
status.
The following parameters will be compared with 
SOC FIX replacement regimen, comparing pre- and 
post-IP infusion from Week 12 to Month 15:

Annualized FIX consumption. 

Annualized number of bleeding events of 
specific type: spontaneous and traumatic, and 
untreated. 

Frequency of target joint bleeds.

Percentage of the participants without bleeds.
The following parameters will be compared with 
SOC FIX replacement regimen, comparing pre- and 
post-IP infusion at 12 months:

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Objectives
Endpoints

Change in joint health as measured by the 
Hemophilia Joint Health Score (HJHS) 
instrument.

PRO instruments:

Haem-A-QoL Physical Health domain;

HAL Complex Lower Extremity Activities 
Component Score.

Safety and tolerability of PF-06838435, 
including immunogenicity, for the study 
duration of 6 years after PF-06838435 infusion

Incidence and severity of adverse events 
collected during the study, as per details 
provided in Section 10.3.3.

Adverse Events of special interest: 

Hypersensitivity reactions;

Clinical thrombotic events;

FIX inhibitors, 

Hepatic malignancies.

Drug related elevated hepatic transaminases 
that fail to improve or resolve

Malignancy assessed as having reasonable 
possibility of being related to study drug

Other immunogenicity-based laboratory data 
including: neutralizing antibody (nAb) to AAV 
capsid, immune response (presumed T-cell 
activation) to AAV capsid protein and/or FIX 
transgene

Assess durability of efficacy up to 6 years.
The following parameters will be assessed 
throughout the 6-year study period according to the 
SoA.  Summaries will be provided for the overall 
follow-up period, as well as by yearly intervals:

Annualized Bleeding Rate for total bleeds 
(treated and untreated). 

ABR for treated bleeds. 

AIR of exogenous FIX. 

Vector-derived FIX:C level by study visit and 
the geometric mean at each yearly interval.

Annualized FIX consumption. 

Annualized number of bleeding events of 
specific type: spontaneous and traumatic, and 
untreated.

HJHS total score.

Frequency of target joint bleeds.

PROs instruments.

Haem-A-QoL Physical Health domain.

HAL Complex Lower Extremity Activities 
Component Score. 

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Objectives
Endpoints
Tertiary/Exploratory
Tertiary/Exploratory

Pharmacodynamics of PF-06838435.

Vector shedding of PF-06838435 as measured 
by PCR in plasma, saliva, PMBC, urine, and 
semen until 3 consecutive specimens test 
negative for the given specimen type.

FIX antigen levels.

To compare joint health post-PF-06838435 
infusion to baseline. 

Number of target joints.

Joint status as assessed by X-ray in some 
participants who consent to participate in an 
optional sub-study.

Joint status as assessed by MRI in some 
participants who consent to participate in an 
optional sub-study.

Impact on coagulation.

Coagulation activation tests: activated partial 
thromboplastin time (aPTT), INR, D-dimer, 
thrombin generation assay (TGA), and 
thrombin-antithrombin level (TAT). 

Correlation of FIX activity between one stage 
assay and chromogenic straight assay.

To compare additional efficacy parameters post-
PF-06838435 infusion in order to further 
characterize PF-06838435 treatment in terms of 
patient-reported outcomes assessing hemophilia 
life impacts and global health status.

PRO instruments: Haem-A-QoL (domains not 
previously specified), HAL (scores not 
previously specified), HLIQ, and EQ-5D-5L, in 
the first 12 months and annually in the 
follow-up period, years 2-6.
Estimands: The primary objective is addressed via the primary endpoint of ABRtotal.  
Efficacy by ABRtotal is summarized by the difference between pre- and post-treatment with 
PF-06838435; pre-treatment data will be obtained from the Pre-Infusion Period, including the 
lead-in Study C0371004. Steady-state FIX:C is a key secondary endpoint and the efficacy by 
FIX:C is summarized by the steady-state population mean post-treatment compared to a fixed 
threshold of 5%.  Since no more than the single dose of study treatment on Day 1 will be 
administered during the study, there should be no treatment discontinuations.  Resumption of 
FIX prophylaxis regimen is allowed as detailed in Section 6.5.1 and is assessed directly via 
secondary endpoints (AIR and FIX consumption).  Data following resumption of FIX 
prophylaxis regimen will not be included in the analysis of ABRtotal.  There may be missing 
data from participants lost to follow-up, but it is anticipated to be rare.  The primary 
endpoint, ABRtotal, will utilize all applicable data to define the endpoints.  Any missing data 
will not be imputed for the primary endpoint.  The method to handle missing data of other 
endpoints will be discussed in the Statistical Analysis Plan (SAP).  Baseline for 
change-from-baseline analyses will be defined based on the data collection method of each 
endpoint, but will reflect data before PF-06838435 (also referred to as IP) infusion.
4. STUDY DESIGN
4.1. Overall Design
This Phase 3, open-label, single-arm, multi-site study will compare the efficacy of a single 
intravenous (IV) infusion of PF-06838435 with routine FIX prophylaxis, in adult male 

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participants from the lead-in study (C0371004) with severe to moderately severe 
hemophilia B (≤2%).  Eligible study participants will have completed a minimum 6 months 
of routine FIX prophylaxis therapy during the lead-in study (C0371004).  The study duration 
for each participant in this study will be 312 weeks (see Section 1.3 for SoA).  At least 
50 participants will be screened to dose at least 40 participants with PF-06838435, and all 
40 participants are expected to be evaluable.
4.2. Scientific Rationale for Study Design
Collecting prospective data in the Pre-Infusion Period and collecting data after PF-06838435 
infusion allows for within-subject comparison analysis and a relatively low number of 
participants for a statistically robust study in hemophilia B, a rare disease.  During the lead-in 
study, the eligible adult participants would have received prophylaxis with FIX replacement 
product as part of standard of care (SOC) along with on-demand infusions as necessary for 
bleeding events, for at least 6 months. 
The planned study duration of 312 weeks for each participant takes into consideration the 
FDA Guidance for gene therapy39 and includes 52 weeks of initial safety observation 
(Short-Term Monitoring Period) followed by 260 weeks of safety and durability follow-up 
(Long-Term Monitoring Period). 
Based on non-clinical studies in NHPs, and the study NCT01687608 using hFIX-Padua and 
the Phase 1/2a study, it is not predicted that vector-derived FIX:C activity levels >150% of 
normal will be achieved in this study.  However, thrombin-antithrombin levels (TAT) as 
thrombotic potential will be measured if vector-derived FIX:C activity levels >150% of 
normal are achieved in any participant during the study.  Blood specimens for TAT during 
screening (prior to PF-06838435 infusion) will be used to establish baseline value.  Also, 
global hemostasis markers will be measured at the end of Year 1. 
Based on observation and experience from earlier clinical studies of liver-directed AAV gene 
transfer, including the SJ-UCL trial, additional earlier clinical studies, the Baxter trial 
(NCT#01687608), and the on-going Phase 1/2a study, participants may develop an apparent 
immune response to the vector capsid, as evidenced by a transient rise in transaminases 
(aspartate transaminase [AST] and/or alanine transaminase [ALT]) and an increase in AAV 
capsid-specific T cells in the peripheral blood.  Immunomodulation will be instituted for 
these participants in an effort to limit the immunologic response in the liver and maintain 
endogenous FIX expression (Section 8.3.8).
4.3. Justification for Dose
The data from the Phase 1/2 study indicate that the single dose of 5 × 1011 vector genomes 
per kg (vg/kg) of body weight is safe and efficacious in patients with severe to moderately 
severe hemophilia B (≤2%) (see Section 2.2.2).1
4.4. End of Study Definition
A participant is considered to have completed the study if he has completed the entire study 
including the End of Study (EOS) visit (Week 312).

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The end of the study is defined as the date of the EOS Visit of the last participant in the 
study.
5. STUDY POPULATION
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:
Type of Participant and Disease Characteristics
1. Participants must have completed at least 6 months of routine FIX prophylaxis 
therapy during the lead-in study (C0371004) prior to providing consent at the 
screening visit for this study.
2. Participants who have documented moderately severe to severe hemophilia B, 
defined as FIX:C ≤2%.
3. Participants must agree to suspend prophylaxis therapy for hemophilia B after 
administration of the IP.  FIX replacement therapy is allowed as needed (see 
Section 6.5.1).
4. Acceptable screening laboratory values as follows:

Hemoglobin ≥11 g/dL;

Platelets ≥100,000 cells/µL;

Creatinine ≤2.0 mg/dL.
Sex
5. Male.
Contraceptive use by men should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
Male participants are eligible to participate if they agree to the following for at least 
time required for 3 consecutive ejaculate samples to test negative for vector shedding:

Refrain from donating sperm.

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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: 

Agree to use male condom when engaging in any activity that allows for 
passage of ejaculate to another person
Informed Consent
6. 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.

For German sites please refer to Germany Appendix (Section 10.11.2.1). 
5.2. Exclusion Criteria 
Participants are excluded from the study (ie, not eligible) if any of the following criteria 
apply:
Medical Conditions
1. Anti-AAV-Spark100 neutralizing antibodies (nAb) titer ≥1:1 (ie, positive for nAb), 
performed by a central laboratory during screening.
2. Prior history of inhibitor to FIX or positive inhibitor testing as measured by the 
central laboratory ≥0.6 Bethesda Units (BU) during screening.  Clinical signs or 
symptoms of decreased response to FIX.
3. Known hypersensitivity to FIX replacement product or intravenous immunoglobulin 
administration.
4. History of chronic infection or other chronic disease that investigator deems as an 
unacceptable risk. 
5. Any concurrent clinically significant major disease or condition that the investigator 
deems unsuitable for participation or other acute or chronic medical or psychiatric 
condition including recent (within the past year) or active suicidal ideation or 
behavior (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.

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6. Alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase 
(ALP) >2 × upper limit of normal (ULN), based on central laboratory results.
7. Bilirubin >1.5 × ULN (isolated bilirubin >1.5 × ULN 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 FIX surgical prophylactic 
factor treatment in the next 15 months.
11. Participants using therapies that are restricted.  See Section 6.5.2 for therapies not 
allowed during study participation.
Prior/Concurrent Clinical Study Experience
12. Previously dosed in a gene therapy research trial at any time or in an interventional 
clinical study within the last 12 weeks, excluding participation in Study C0371004.
Diagnostic Assessments
13. Active hepatitis B or C; HBsAg, HBV-DNA positivity, or HCV-RNA positivity.
14. Significant liver disease, as 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: FibroScan score >8 kPa units, Fibro 
Test/FibroSURE >0.48* or AST-to-Platelet Ratio Index (APRI) >1.  In the 
investigator’s opinion, if there is concern regarding the FibroTest results due to a 
confounding medical history (eg, proteinuria can impact FibroTest result), the 
investigator can perform a different assessment of liver fibrosis (eg, FibroScan or 
APRI) during the screening period.  

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*Please note: if a participant has a known history of Gilbert's syndrome, a FibroTest 
cannot be used for fibrosis testing.  However, the participant could be tested using 
FibroScan or APRI.
15. Serological evidence of HIV-1 or HIV-2 infection with either CD4+ cell count 
≤200 mm3 or viral load >20 copies/mL.
Other Exclusions
16. 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 Germany Appendix (Section 10.11.2.2).
17. Unable to comply with scheduled visits, treatment plan, laboratory tests and other 
study procedures for up to six years post-infusion of PF-06838435 in the 
investigator’s judgement.

For German sites please refer to Germany Appendix (Section 10.11.2.2).
18. Sensitivity to heparin or heparin induced thrombocytopenia.
19. 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. 

For Japanese sites please refer to Japan appendix (Section 10.11.2.2).
5.3. Lifestyle Considerations
Participants are expected to remain compliant with inclusion criterion 5 at least until 
3 consecutive ejaculate samples test negative for vector shedding (see Section 8.5.1).
One participant was noted to have increased LFTs in the setting of 
 
 in the long-term follow-up period.  Upon discontinuation of 
, his LFTs 
normalized but was later noted to have a decline in his steady-state FIX activity level.  While 
this was a single episode and a definitive conclusion cannot be drawn, it supports monitoring 
of 
 during the study.  Participants should be informed that 
 
 could contribute to abnormally elevated LFT results and thereby delay the 
infusion of the study drug. In addition, participants who report increased 
 
 (which is any amount of 
 greater than the baseline amount 
for that participant) at any time throughout the study, should have at a minimum local LFTs 
and FIX activity monitored. 
PPD
PPD
PPD
PPD
PPD
PPD

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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 serious adverse event (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.
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, or medical device(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-06838435 
Type 
Gene therapy
Dosage Form
Injectable
Strength
1.00 × 1013 vg/mL.
This is the nominal strength.  The actual strength for each lot will be 
provided for dosage calculation. 
Dosage
5 × 1011 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 cms (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 cms (6’2”) tall individual.
Route of Administration
Intravenous infusion/injection.*
IMP and NIMP
IMP (investigational medicinal product).
Sourcing
Provided centrally by the sponsor.
Packaging and Labeling
Study Intervention will be provided in a 2 mL vial.  Each vial will be 
labeled as required per country requirement.
Current/Former Name(s) or 
Alias(es)
PF-06838435, 
SPK-9001, 
AAV-Spark100-hFIX39- Padua,
Adeno-associated viral vector with human factor IX Padua gene.
* The Study Intervention/ IP will be administered using a prepared dosing solution (
 
 for Injection 
). The 
 
 will be provided by the site (or infusion center). Further information is provided in the IP 
Manual.
CCI
CCI
CCI

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For sites and Japan please refer to Section 10.11.1.3 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.  Note that this bullet is also 
applicable to authorized staff at Infusion Centers. 
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).
4. 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 Investigational Product (IP) 
Manual and it should be reviewed carefully.  Once eligibility has been confirmed, the IP can 
be ordered noting that it will take approximately 3 weeks for product delivery.  Prior to 
ordering IP, Sections 10.13.3 and 10.13.4 should be considered.
Wording in this paragraph is only required for study sites in France and is applicable 
to all sites participating in the study: No participants or third-party payers will be charged 
for investigational product.
6.3. Measures to Minimize Bias: Randomization and Blinding
Open label using 
central randomization 
via Interactive Voice 
Response 
System/Interactive 
Web Response System 
(IVRS/IWRS)
This is an open label nonrandomized 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 prior to the start of 
study intervention administration for each participant.  The infusion site will 
record the intervention assignment on the applicable case report form (CRF), if 
required. 
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, Sections 10.13.3 and 10.13.4 should be considered.  For 
Japanese sites please refer to Japan appendix, Section 10.11.1.4.

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Administration: If a participant does not receive a complete infusion for any reason, 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 nonprescription medications, including over-the-counter and alternative 
preparations such as herbal remedies, vitamins, and health food supplements) in the 30 days 
prior to screening and during screening must be recorded at Baseline on the participant’s 
eCRF, according to instructions for eCRF completion.  With the exception of FIX 
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 10.13.4) during the Short-term Monitoring Period (up to and including 
52 weeks post-infusion).

The concomitant therapy associated with adverse events (AEs) reported during 
the Long-term Monitoring Period (Week 53 post-infusion to EOS).  See 
Section 8.3.1 for AE recording requirements. 

All surgical procedures, including elective surgeries, will be recorded throughout 
the study.  Additional information regarding surgeries (eg, blood loss and/or 
transfusion amounts) will be collected on relevant CRF(s).
The records 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 routinely for a pre-existing condition should be on a regimen, 
which has been stable for at least 3 weeks, and ideally dosage should not be changed during 
the first year after PF-06838435 infusion. 

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6.5.1. Allowed Therapy
During the study participants are requested to suspend their FIX prophylaxis regimen after 
infusion of PF-06838435, but may take:

FIX 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 FIX to treat the bleed because the dose of factor concentrate should include 
the recent steady-state PF-06838435 induced FIX activity levels to avoid overdosing 
resulting in a potential thrombotic event.  The table in Appendix 8 provides 
guidelines for target FIX levels based on bleed type.

A participant may resume prophylaxis if the PF-06838435 treatment is not 
efficacious, defined for this study as:

FIX activity after 12 weeks of ≤2% (in the absence of a confirmed FIX 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 FIX 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 discuss the case with the sponsor's medical monitor prior to resumption 
of prophylaxis.  Dosing of prophylaxis will take into account the current steady-state FIX 
activity level.  A participant who resumes prophylaxis may choose to discontinue it; 
however, prior to discontinuation, the investigator is to discuss with the sponsor's medical 
monitor. 
Additional allowed therapies include the following:

COX-2 inhibitors and topical NSAIDs, where medically necessary

HIV therapy

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6.5.2. Disallowed Therapy
The following concomitant medications are not permitted during the study:

Blood products such as red blood cells (RBC), platelets, and fresh frozen plasma, 
except 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), anticoagulants (eg, warfarin, apixaban), regular 
long-term use of NSAIDs (eg, ibuprofen, naproxen). However, low dose aspirin 
(<100 mg/day) and PRN/short-term use of NSAIDs may be used where medically 
necessary. Please contact the sponsor’s medical monitor if there are any questions 
regarding the use of medications that may prolong bleeding.

Concomitant use of another investigational therapy; concurrent participation in 
another interventional clinical study is not allowed.

Bypassing agents (eg, factor VIIA/ rFVIIA, activated prothrombin complex 
concentrate), except in situations where it is medically necessitated (ie, medical 
emergencies).
For COVID-19 vaccinations please refer to Section 10.13.4.
6.6. Dose Modification
No more than a single dose of the study treatment, on Day 1, will be administered during this 
study. 
The dose of 5 × 1011 vector genomes/kg body weight will be modified for a participant with 
BMI >30 kg/m2 (See the table in Section 6.1). 
6.7. Intervention after the End of the Study
No further intervention is planned after the end of the study.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Study Intervention
Since no more than the single infusion of PF-06838435 on Day 1 will be administered during 
the study, this section is not applicable.  See Section 6.4 for any disruption in administration 
of the infusion.

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7.2. Participant Discontinuation/Withdrawal from the Study
A participant may withdraw from the study at any time at his own request.  Reasons for 
discontinuation from the study include the following:

Refused further follow-up;

Lost to follow-up;

Death;

Study terminated by sponsor;

At the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons.
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted, as shown in the SoA.  See SoA for any assessments to be collected at the time 
of study discontinuation and follow-up 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 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.
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved.
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.
7.2.1. Withdrawal of Consent
When a participant specifically withdraws consent for any further contact with him 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 

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available information should be used to determine vital status only as appropriately directed 
in accordance with local law.
7.3. Lost to Follow up
A participant will be considered lost to follow-up if he repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study.

Before a participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods).  These contact attempts should be documented 
in the participant’s medical record.

Should the participant continue to be unreachable, he will be considered lost to 
follow-up. 

Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix 1.
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.

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, where indicated in the SoA, provided the procedures 

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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 post-infusion of PF-06838435 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-06838435.
Screening Period 
Screening procedures will be conducted according to the SoA (Section 1.3).  The Screening 
Period will end and Baseline Period will commence when a participant is determined to be 
eligible for the study. 
Baseline Period and Scheduling the PF-06838435 Infusion 
Baseline procedures will be conducted according to the SoA (Section 1.3).  PF-06838435 is 
to be ordered at the beginning of the Baseline Period after confirming eligibility.  Prior to 
ordering IP, Sections 10.13.3 and 10.13.4 should be considered.  The IP will require 
approximately 3 weeks for shipment.  Also, the timing of the participant’s next FIX 
prophylaxis dose is to be planned to occur on the same day of PF-06838435 infusion (Day 1).
The Screening and Baseline period may be extended, upon consultation with the sponsor’s 
medical monitor.  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) will be conducted 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 (Section 1.3).
Blood for LFTs are to be drawn and tested locally and centrally prior to dosing participants 
(up to 3 days prior to Day 1/ Visit 3 is acceptable).  Utilize mobile phlebotomy/ home health 
services as needed, and if possible.  Local LFTs are required to be reviewed 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.  These LFT results should 
be entered into the CRF as an unplanned visit.
Note: Participants should be informed that alcohol consumption could contribute to 
abnormally elevated LFT results and thereby delay the infusion of the study drug. 

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The site staff (or Infusion Center staff) will confirm that the participant is eligible (see 
Section 5.1and 5.2) to receive PF-06838435 infusion.  Prior to dosing, Sections 10.13.3 and 
10.13.4 should be considered.  The IP should NOT be thawed and prepared without this 
eligibility confirmation AND affirming that the participant is physically present at the clinic 
(or infusion center). 
Participants are expected to bring their current Factor IX replacement therapy with them.
If the infusion of PF-06838435 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 towards efficacy assessment.
For Japanese sites please refer to Japan appendix, Section 10.11.1.4.
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 prior to Week 312, the early 
discontinuation visit will follow the same procedures as the Week 312 visit (End of Study), 
per 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.  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 post-infusion 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 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 deviations.

ECG

Liver ultrasound

HJHS

Global Hemostasis Markers

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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 FIX replacement (including date, time, 
reason, and dose) required to treat the bleeds in the eDiary (see Appendix 7). If bleeding 
episodes or treatments are not entered in the eDiary during the appropriate time window, 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. 
The bleeding episodes and exogenous FIX replacement data mentioned above will be 
referred to as “eDiary data” regardless of how it is collected (ie, via the handheld device or 
according to the process in place). 
As part of the process in place, participants should communicate all bleeds and all relevant 
infusion data that was not entered into the eDiary within the appropriate time window (ie, 
“late eDiary entries”) to the investigator (or appropriate site staff member).  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).  In the event of continued late eDiary entries or non-use of the eDiary 
device (ie, non-compliances), the site staff should remind the participant that he will be 
expected to report all bleeds and all relevant infusion data to the site staff on a 
contemporaneous basis and that he may be expected to surrender his eDiary.  The site staff 
will be expected to enter the information, provided by the participant, into the CRFs with 
appropriate source documentation in the participant’s medical record for the remainder of the 
study. 
In the event that a participant may have to resume FIX prophylaxis treatment at some point 
after IP infusion, prophylaxis FIX infusion data will not have to be reported on the eDiary (or 
conveyed to the study site staff on contemporaneous basis) after Week 78 (Visit 14).  
However, bleeds and non-prophylactic infusions (eg, On-demand and Preventative) would 
continue to be reported for these participants throughout the course of the study.  Prescribed 
FIX prophylaxis replacement therapy will continue to be captured (eg, particularly any 
change in regimen), by the site staff, using the “FIX Replacement (Prescribed Dose)” CRF.
During the site visits, the investigator (or qualified designee) will review eDiary data with the 
participants. Bleeding episodes and any exogenous FIX treatments will be reviewed to ensure 
consistency between the medical record and/or eDiary and the CRFs.
Bleeding episodes requiring treatment with FIX product 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.

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8.1.2. Joint Assessments
See Appendix 7 for definition of target joints.  Investigator will assess the health of the target 
joint(s), identified at screening, as per the SoA.  A target joint is considered resolved when 
there are ≤2 bleeds into the joint within a 12-month period.
8.1.2.1. Hemophilia Joint Health Score (HJHS)
Swelling, on motion Joint assessments will be performed using the Hemophilia Joint Health 
Score (HJHS) version 2.1 (Appendix 12) 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 (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.
8.1.2.2. Magnetic Resonance Imaging (MRI) to Evaluate Joints
Some participants (n~20), who consent to participate in an optional sub-study, will undergo 
MRI exams to assess damage within joints by evaluating soft-tissue changes and 
osteochondral changes.  These participants will be chosen based on the availability of MRI at 
the site and participant willingness to undergo the procedure.  The MRI scanning protocol 
will include acquisition of knees, elbows, and ankles.  MRI scans will be acquired according 
to the SoA.  If the MRI can’t be performed during the baseline period, it is acceptable to 
postpone this testing no later than Week 4/ Visit 6.  If the baseline MRI 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 3 (Visit 17) and 6 (Visit 20) year follow-up MRIs.  All details of the MRI acquisition will 
be captured in a separate scanning guide.  At a minimum, joint images will be reviewed 
following the extended MRI scale with a final score combining soft-tissue and osteochondral 
sub-scores.  All details of the independent review will be captured in a separate Imaging 
Charter. 
8.1.2.2.1. 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.

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MRI images will be reviewed by a central review facility.  The purpose of this review is to 
evaluate images for soft tissue and osteochondral changes.  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 as per site protocols. 
MRI images will not be evaluated using a real-time reading paradigm and therefore there 
may be a significant delay between image submission and realization of an incidental 
finding. 
8.1.2.3. X–ray Assessments to Evaluate Joints 
Some participants (n~40), who consent to participate in an optional sub-study, will undergo 
X-ray assessment of knees, elbows, and ankles to assess damage within joints as detectable at 
a radiologic level. For German sites please refer to Germany Appendix (Section 10.11.2.5). 
X-rays will be acquired according to the SoA.  If the X-ray can’t be performed during the 
baseline 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 3 (Visit 17) and 6 year (Visit 20) follow-up X-rays.  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.27  All details of the independent 
review will be captured in a separate Imaging Charter. 
8.1.3. Patient–Reported Outcomes (PROs)
Patient-reported outcomes (PROs) implemented in this study are the Haemophilia Quality of 
Life Questionnaire for Adults (Haem-A-QoL), the Hemophilia Activities List (HAL), the 
Hemophilia Life Impacts Questionnaire (HLIQ), and the EQ-5D-5L Additionally, the Patient 
Global Impression of Change (PGIC-H), a single item assessment of the participant’s overall 
impression of change in their life with hemophilia since being enrolled in the study and 
infused with PF-06838435 will also be administered.
The PRO questionnaires should be administered in the following order: Haem-A-QoL, HAL 
(v2), PGIC-H, HLIQ, and EQ-5D-5L.
They should be completed as per the SoA during the scheduled site visits, especially the 
baseline visit, using a tablet device that will be provided to each site.  Baseline PRO 
assessments need to be done prior to start of infusion if not done at baseline visit. If the post-
infusion PROs can’t be performed at a particular visit, they should be performed at the next 
visit. At each relevant visit, the assessment questionnaires should be administered before 

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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.
8.1.3.1. Haemophilia Quality of Life Questionnaire for Adults (Haem–A–QoL)
The Haem-A-QoL 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); 
Feelings (4); View of Self (5); Sport/Leisure (5); Work/school (4); Dealing with Haemophilia 
(3); Treatment (8); Future (5); Family Planning (4); and Partnership and Sexuality (3).  
Scores are calculated by domain and a single total score.  Physical health domain is 
considered as the primary domain in this questionnaire and will be further assessed using the 
anchor-based method for each yearly visit.  See Section 10.9.1 for the instrument.
8.1.3.2. Hemophilia Activities List (HAL, Version 2)
The Hemophilia Activities List (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); Lower (leg) functioning (9); 
Upper (arm) functioning (4); Transportation (3); Self-care (5); Household tasks (6); and 
Sports/Leisure (7).  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.  The component score of 
“complex lower extremity activities” is considered the most important in this questionnaire 
and will be assessed using the anchor-based method for each yearly visit.  See Section 10.9.2
for the instrument.
8.1.3.3. Patient Global Impression of Change – Hemophilia (PGIC–H)
The Patient Global Impression of Change – Hemophilia (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 and infused with PF-06838435.  The recall period for the 
PGIC-H is “since the start of the study”.  The response scale is a 7-point categorical response 
scale centered around ‘no change’ with 3 grades of improvement and 3 grades of worsening.  
See Section 10.9.3 to view the item.
8.1.3.4. Hemophilia Life Impacts Questionnaire (HLIQ)
The Hemophilia Life Impacts Questionnaire (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 (VRS) scored from 
0 to 4, while 4 items are gated such that responding ‘yes’ branches to a 5-point, ordinal VRS 
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 

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scale (VRS) scored from 0 to 3.  Higher scores on the VRSs indicate greater impact due to 
living with or treating hemophilia.  See Section 10.9.4 for the HLIQ instrument.
8.1.3.5. EQ–5D–5L
Developed by the EuroQoL Group, the EQ-5D-5L (EuroQol, 5 dimensions, 5 levels) is 
considered the premier measure of health status used in the assessment of the Quality 
Adjusted Life Year (QALY).  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 (VAS) 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.  See Section 10.9.5 for the instrument.
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
8.2.1. Physical Examinations

Only complete physical examinations will be conducted during this trial.  A complete 
physical examination will include, at minimum, assessments of the cardiovascular, 
respiratory, gastrointestinal, and neurological systems.  Height (required at screening) 
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.

*Note: 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. Electrocardiograms

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, QT, 
and corrected QT intervals (QTc).
8.2.4. 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 of the 

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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.

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.

All protocol-required laboratory assessments, as defined in Appendix 2, must be 
conducted in accordance with the laboratory manual and the SoA.

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 Time Period and Frequency for Collecting AE and SAE 
Information).
8.2.5. Liver Ultrasound
All participants will undergo ultrasound imaging of the liver at times specified in the SoA.  
Details of the ultrasound acquisition will be provided in a separate scanning guide.  
Ultrasound images will be acquired locally by an appropriately trained individual.
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 3.
The definition of adverse events of special interest can also be found in Section 8.3.9.
AE 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 that caused the participant to discontinue 
the study (see Section 7).

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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 Demographics, 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 investigational product), through and including 
6 years after the last administration of the investigational product, or at EOS for participants 
who discontinue.  The active collecting period for this study is categorized into Short-Term 
and Long-Term Monitoring Period as defined later in this section.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
Follow up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
If the participant withdraws from the study and also withdraws consent for the collection of 
future information, the active collection period ends when consent is withdrawn.
If a participant discontinues study intervention because of an AE or SAE, the AE or SAE 
must be recorded on the CRF and the SAE reported using the CT SAE Report Form.
During the Short-Term Monitoring Period (up to and including 52 weeks post-infusion) all 
SAEs (including medically important events, see Appendix 3) and AEs will be collected. 
During the Long-Term Monitoring Period (Week 53 post-infusion to EOS) the following 
AEs will be collected:

SAEs (including medically important events, Appendix 3).

Non-serious AEs determined to be related to IP by the investigator or where causality 
is unknown.
Investigators are not obligated to actively seek AE or SAE 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 

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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 are reported to Pfizer 
Safety on the CT SAE Report Form immediately 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 Non-serious 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 directly observed and spontaneously reported AEs 
and SAEs during the Short-Term and Long-Term Monitoring Periods per details provided in 
Section 10.3.3.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
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.

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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, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.

Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (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.

Wording in this paragraph is applicable to study sites in France only: Pursuant to 
a sponsor’s safety reporting obligations under 21 Code of Federal Regulations (CFR) 
312.32(c)(1), Pfizer will report to the investigator all Serious Unexpected Suspected 
Adverse Reactions (“SUSARs”).  Investigator will receive and review SUSAR 
reports and report SUSARs to the responsible IRB/IEC according to institution’s 
guidelines.  Institution will retain SUSAR reports consistent with Section 8.3.4 of the 
protocol.

For Japanese sites please refer to Japan appendix, Section 10.11.1.4.
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the investigational product under study during pregnancy and occupational 
exposure are reportable to Pfizer Safety within 24 hours of investigator awareness.
8.3.5.1. Exposure During Pregnancy
An exposure during pregnancy (EDP) occurs if: 

A male participant who received study intervention exposes a female partner prior to 
or around the time of conception. 

A female is found to be pregnant while being exposed or having been exposed to 
study intervention due to environmental exposure.  Below are examples of 
environmental exposure during pregnancy:  

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
A female family member or healthcare provider reports that she is pregnant 
after having been exposed to the study intervention by the vascular system.

A male family member or healthcare provider who has been exposed to the 
study intervention by the vascular system then exposes his female partner 
prior to or around the time of conception. 
The investigator must report EDP to Pfizer Safety within 24 hours of the investigator’s 
awareness, irrespective of whether an SAE has occurred. The initial information submitted 
should include the anticipated date of delivery (see below for information related to 
termination of pregnancy). 

If EDP occurs in a participant’s partner, 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.  Details of the pregnancy will be 
collected after the start of study intervention and until the end of study participation. 

If EDP occurs in the setting of environmental exposure, the investigator must report 
information to Pfizer Safety using the CT SAE Report Form and EDP Supplemental 
Form.  Since the exposure information does not pertain to the 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.
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).
Abnormal pregnancy outcomes are considered SAEs.  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 including 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 study intervention. 

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Additional information regarding the EDP may be requested by the sponsor.  Further follow 
up of birth outcomes will be handled on a case-by-case basis (eg, follow up on preterm 
infants to identify developmental delays).  In the case of paternal exposure, the investigator 
will provide the participant with the Pregnant Partner Release of Information Form to deliver 
to his partner.  The investigator must document in the source documents that the participant 
was given the Pregnant Partner Release of Information Form to provide to his partner.
8.3.5.2. Exposure During Breastfeeding
Not applicable.
8.3.5.3. Occupational Exposure 
An occupational exposure occurs when a person receives unplanned direct contact with the 
study intervention, which may or may not lead to the occurrence of an AE. Such persons may 
include healthcare providers, family members, and other roles that are involved in the trial 
participant’s care.
The investigator must report occupational exposure to Pfizer Safety within 24 hours of the 
investigator’s awareness, regardless of whether there is an associated SAE.  The information 
must be reported using the CT SAE Report Form.  Since the information does not pertain to a 
participant enrolled in the study, the information is not recorded on a CRF; however, a copy 
of the completed CT SAE Report Form is maintained in the investigator site file.
8.3.6. Immunogenicity
8.3.6.1. Analysis of Anti– PF–06838435 Antibodies and Neutralizing Anti PF–06838435 
Antibodies 
Whole blood specimens of approximately 4-5 mL to provide a minimum of 2 mL of serum 
will be collected for determination of anti-AAV capsid protein antibodies (ADA) and 
approximately 4 mL of whole blood will be collected to provide a minimum of 2 mL of 
serum for determination of neutralizing antibodies (Nab) to PF-06838435 (specifically to the 
SPK-100 AAV capsid) as specified in the SoA (Section 1.3) of the protocol.  Instructions for 
the collection and handling of biological samples will be provided in the laboratory manual 
or by the sponsor.  The actual date and time (24-hour clock time) of each sample will be 
recorded.
Samples collected for determination of anti-PF-06838435 antibodies and neutralizing 
anti-PF-06838435 antibodies may also be used for additional characterization of the immune 
response and/or evaluation of the bioanalytical method, or for other internal exploratory 
purposes.  These data will be used for internal exploratory purposes.  The neutralizing anti-
PF-06838435 antibodies may be stored at a facility selected by the sponsor for a maximum of 
10 years (or according to local regulations) following the last participant’s last visit for the 
study.
Samples will be analyzed using a validated analytical method in compliance with applicable 
SOPs.  Samples determined to be positive for ADA may be further characterized for NAb.

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The immunogenicity samples must be processed and shipped as indicated in the instructions 
provided to the investigator site to maintain sample integrity.  Any deviations from the 
immunogenicity 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.
8.3.6.1.1. Immunology Exploratory (PBMC and binding IgG vs IgM antibody response)
The exploratory immunology samples (peripheral blood mononuclear cells [PBMC] and 
serum for IgG and IgM antibody response) are being collected to characterize the cell and 
humoral immune response to the vector capsid protein.
These samples will be destroyed upon or before  completion of the last clinical study report 
for the study.
8.3.6.2. Analysis of FIX Inhibitor
During all study periods, blood samples will be collected for measurement of FIX inhibitor 
as specified in the SoA section of the protocol. 

Samples collected will be analyzed using a validated analytical method in compliance 
with standard operating procedures (SOPs).  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 central laboratory may make a determination as to whether sample 
integrity has been compromised.  Any deviation from the specified sample handling 
procedure resulting in compromised sample integrity will be considered a protocol 
deviation.  These data will not be included in the clinical study report (CSR).
8.3.6.3. Analysis of Cellular Immune Response by ELISPOT (enzyme–linked immuno–
spot)
This is a quantitative method for measuring relevant parameters of T cell activation.  The 
sensitivity of ELISPOT allows the detection of low-frequency antigen-specific T cells that 
secrete cytokines and effector molecules.  Specimen for PBMC by ELISPOT will be 
collected at times specified in the SoA. 
Specimen is to be collected prior to initiating the corticosteroid treatment.  If not collected 
prior to initiation, it must be collected within 24 hours of administering corticosteroids. 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, ranitidine) for the duration of the 
corticosteroid course.

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Whole blood specimens (approximately 48 mL) will be collected in sodium heparin 
vacutainer tubes to provide PBMC to monitor T cell responses to AAV capsid and transgene 
products at times specified in the SoA of the protocol. 
Detailed collection, processing, storage, and shipment instructions are provided in the central 
laboratory manual. 
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.
8.3.7. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as AEs 
or SAEs
The disease related events (DREs) for this study include episodes of bleeding related to 
hemophilia B.  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 S/AE.
Bleeding, not due to the participant's hemophilia, will be recorded as an AE, and not a DRE.  
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. Immunomodulation Optimization (Presumed T-Cell Activation) 
A tapering course of oral corticosteroids (ie, 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 

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this immune reactivity is not clear, but viruses may be causal. It is also possible that an 
elevation in liver transaminases is not due to immune responses.
While not all elevations in liver transaminases may be immunologically mediated, the 
decision to treat will not be delayed while attempting to decipher the etiology. 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, ranitidine) for the duration of the 
corticosteroid course. Due to the importance of timely intervention of corticosteroids, 
decisions to begin treatment will be based on local laboratory values.  Based on guidelines 
published by the American Association for the Study of Liver Diseases and in the absence of 
alternative etiology, and from the study data of the SJ-UCL group along with the Phase 1/2a 
study, treatment with corticosteroids for vector-induced hepatitis would be highly 
recommended if any  of the  criteria are met:

Transaminase increase, per local lab results:

Single increase ≥1.5 fold of the lowest transaminase value, since screening into 
the study and prior to infusion.

For example, a participant may have an ALT of 35 U/L prior to infusion, but 
at week 5 the value increases to 53 U/L.  This increase would be enough to 
initiate treatment even though the values are within normal range.

Consecutive increases (an increase in transaminases on two subsequent blood 
tests independent of FIX:C values).  Following the trend is especially important as 
it is possible that LFTs seen post-infusion may be below that seen during 
screening/baseline.  In these situations, following for consecutive increases/ 
trends is particularly important.

For example, a participant may have an ALT of 18 U/L.  Then on the next two 
lab draws (obtained during a study visit or unplanned visit) the values increase to 
22 U/L and then 26 U/L, this increase would be enough to initiate treatment even 
though the values are within normal range.

For example, a participant may have an ALT of 38 U/L as the baseline 
value. Post-infusion, the ALT values are lower than that seen during screening 
and range from 18-22 U/L over the first few weeks.  Then on the next 
2 laboratory draws (obtained during a study visit or unplanned visit), the values 
increase to 29 U/L and then 37 U/L. This increase would be enough to initiate 
treatment even though the values are both below baseline and within normal 
range. 

Note: Any delay or deviation in the initiation of corticosteroid treatment, based 
on the transaminase increase points above, must be discussed with the sponsor’s 

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medical monitor in the context of the overall clinical management plan to ensure 
participant safety.

FIX:C decrease, per local lab results:

Single significant decrease, not associated with a recent infusion of external FIX 
product. 

For example, a participant may have a FIX:C of 51 IU/mL at Week 4, but at 
Week 5 the value decreases to 28 IU/mL.  This decrease would be enough to 
initiate treatment.

Consecutive decreases (a decline in FIX activity on two consecutive blood tests 
independent of transaminase values) if occurring during the first 120 days post-
infusion.  

For example, a participant may have a FIX:C value of 34 IU/mL at Week 4.  
Then on the next two lab draws (obtained during a study visit or unplanned visit) 
the values decrease to 27 IU/mL and then 24 IU/mL, this decrease would be 
enough to initiate treatment.
If occurring beyond 120 days post-infusion, the investigator should contact the 
sponsor’s medical monitor to discuss prior to initiating corticosteroids unless 
otherwise clinically indicated (eg, a decline in FIX:C level thought to be beyond 
the margin of error for FIX:C assay or biological fluctuation).

Note: Any delay or deviation in the initiation of corticosteroid treatment, based 
on the FIX:C decrease points above, must be discussed with the sponsor’s 
medical monitor in the context of the overall clinical management plan to ensure 
participant safety.
Table 1.
Recommended Regimen for Oral Corticosteroids
Schedule 
(oral corticosteroid 
treatment regimen)
Prednisolone/Prednisone (mg/day)
Week 1
~60 – 100*
Week 2
60**
Week 3
40
Week 4
30
Week 5
30
Week 6
20***
Week 7
15
Week 8
10
*
Mainly based on body weight.
**
See the paragraph below this table.
*** 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.  If available, ELISPOT results will be 
monitored during tapering.

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Approximately 60-100 mg/PO (orally) qd (once a day) of oral corticosteroids for the first 
week is recommended as the starting dose unless the investigator believes a different regimen 
should be implemented based on the participant’s medical history.  Per the judgment of the 
investigator, the first week dose can be extended to another week if the participant has no 
adverse effect.  The subsequent prednisolone/prednisone taper should not be started until the 
ALT and/or AST have declined at least two consecutive lab draws, or have returned to 
approximately baseline (pre-administration) levels and any decline in FIX:C activity has 
plateaued.  See Table 1 above.
The following schedule of combined oral corticosteroids and intravenous corticosteroids 
(methylprednisolone) is recommended if there is no evidence of resolution of transaminase 
elevation while on oral corticosteroids treatment alone.
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 since 
the exact regimen and course will depend on clinical circumstances.  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 FIX:C 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 
adverse events connected to their use. 

If 2 or more participants are non-responsive to immunomodulatory regimens, or if the 
value of the transaminases continues to rise, consideration of more intensive 
immunomodulatory regimens will be entertained per discussion between the sponsor 

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medical monitor and the investigator.  The sponsor will convey the information to the
External Data Monitoring Committee (eDMC).
8.3.9. Adverse Events of Special Interest
All AESIs must be reported as an AE or SAE following procedures described in
Section 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 
events assessed as non-serious AEs. 
8.3.9.1. Lack of Efficacy
Not applicable
8.3.10. Thrombotic Potential Assessments (ONLY for participants who reach 
vector-derived FIX:C Activity Levels >150% After the Infusion of PF–06838435)
Based on non-clinical studies in NHPs, the prior Baxter study using hFIX-Padua, and the 
Phase 1/2a study, it is not predicted that vector-derived FIX:C activity levels >150% of 
normal will be achieved in this study.  However, thrombin-antithrombin levels (TAT) as 
thrombotic potential will be measured if vector-derived FIX:C activity levels >150% of 
normal are achieved in any participant during the study.  Blood samples for TAT obtained 
during screening will be used to establish baseline value.  Additional testing can be 
performed upon discussion with the medical monitor including by not limited to D-dimer, 
TGA, and/or prothrombin fragments 1+2.
8.3.11. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong participant, or at the wrong time, or at the wrong dosage strength. 
Exposures to the investigational product under study may occur in clinical trial settings, such 
as medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 
24 Hours of Awareness
Medication errors 
All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:

Medication errors involving participant exposure to the investigational product;

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
Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participant;

Not performing a flush of the IV line at the conclusion of the IP 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 
applicable, any associated AE(s), serious and non-serious, are recorded on an AE page of the 
CRF. 
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4. Treatment of Overdose
For this study, any dose of PF-06838435 greater than 5 × 1011 vg/kg of the 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:

Contact the sponsor’s medical monitor within 24 hours.

Closely monitor the participant for any AE/SAE and laboratory abnormalities. 

Document the quantity of the excess dose as well as the duration of the overdose in 
the Medication Error CRF.

Overdose is reportable to Safety only when associated with a SAE.
8.5. Pharmacokinetics
All samples collected from participants for plasma factor IX activity levels as per the SoA
will be analyzed at a certified clinical laboratory by two different one stage assays along with 
analysis by chromogenic assay.  Results will be used to determine vector-derived FIX:C 
activity level at steady-state (Week 12 and after). 
Measurement of the vector-derived FIX: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 FIX:C activity 
levels will take into consideration data entered in the eDiary. As FIX inhibitors or T-cell 

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mediated immune response may impact the FIX activity levels, this information will also be 
taken into account while deriving FIX:C activity levels.

During all study periods, blood samples will be collected for measurement of 
vector-derived FIX:C as specified in the SoA section of the protocol. 

Samples collected will be analyzed using a validated analytical method in compliance 
with standard operating procedures (SOPs).  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.  Any deviation from the specified sample handling procedure 
resulting in compromised sample integrity will be considered a protocol deviation.  
These data will not be included in the CSR. 
8.5.1. Samples for Vector Shedding Assays
Samples of plasma, saliva, PBMC, urine, and semen will be collected as specified in the SoA
for analysis of vector shedding. 
In the event that a participant is unable to provide any semen for vector shedding over the 
course of 1 month post-IP infusion, future attempts to provide semen samples can be stopped 
provided that the participant provides 3 consecutive negative PBMC samples before no 
longer being required to follow the restrictions within inclusion criteria #5 in Section 5.1.
Some participants (n = 12), who consent to participate in an optional sub-study, are expected 
to provide additional (2 hours ±30 minutes, 24 hours ±3 hours, 72 hours ±4 hours after 
completion of IP infusion and IV line flush on Day 1) samples (plasma, PBMC, saliva, 
semen, and urine).
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.
8.6. Pharmacodynamics
Pharmacodynamic markers such as thrombin generation assay (TGA) will be measured for 
all participants.  Global hemostasis markers will also be collected (Appendix 2).
The samples will be collected as per the SoA and detailed in the Laboratory Manual. 
The PD samples must be processed and shipped as indicated in the instructions provided to 
the investigator site to maintain sample integrity.  Any deviations from the PD 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 

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integrity has been compromised.  Any sample deemed outside of established stability, or of 
questionable integrity, will be considered a protocol deviation.
As part of understanding the PD of the investigational product, samples may be used for 
evaluation of the bioanalytical method, as well as for other internal exploratory purposes.  
These data will not be included in the CSR.
Samples will be analyzed using a validated analytical method in compliance with applicable 
SOPs.  These data will be used for internal exploratory purposes and will not be included in 
the CSR.
8.6.1. Samples for FIX Antigen Levels
Blood samples will be collected per the SoA and as specified in the Laboratory Manual to 
measure FIX antigen levels. 
8.6.2. Samples for Thrombin Generation
During all study periods, blood samples (3.5 mL) to provide approximately 600 µL plasma 
for TGA analysis will be collected into appropriately labeled tubes containing sodium citrate 
at times specified in the SoA. 
Details regarding the collection, processing, storage, and shipping of the blood samples will 
be provided in the central lab manual.
8.6.3. Samples for D-dimer
Blood samples will be collected per the SoA and as specified in the Laboratory Manual to 
measure D-dimer. 
8.6.4. Shipment of Pharmacodynamic Samples
The shipment address and analytical laboratory contact information will be provided to the 
investigator site prior to initiation of the study.
8.7. Genetics
8.7.1. Specified Genetics
A blood sample for DNA isolation will be collected as specified in the Laboratory Manual, 
only if a participant has not undergone FIX genetic testing in the past or the results of such 
testing are not available it the source documents.  DNA samples will be analyzed for the 
purpose of determining the underlying FIX gene mutation.
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.

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8.7.2. Banked Biospecimens for Genetics
Banked Biospecimen collection is not required for this study. 
8.8. Biomarkers
Not applicable.
8.9. Health Economics
Not applicable.
9. STATISTICAL CONSIDERATIONS
9.1. Estimands and Statistical Hypotheses
The details of statistical methodology will be specified in the Statistical Analysis Plan (SAP). 
The hypothesis testing of the primary endpoint is listed below.  

To demonstrate non-inferiority (NI) of PF-06838435 to routine prophylaxis on 
difference in ABRtotal (NI margin of 3 bleeds/year) by comparison of post-infusion of 
PF-06838435 ABRtotal from Week 12 to Month 15 versus pre-IP infusion ABRtotal
collected during Pre-Infusion Period, in participants ≥18 years of age with moderately 
severe to severe hemophilia B (FIX:C ≤2%), who have tested negative for nAb and 
have no medical history of FIX inhibitor.  The primary objective for ABRtotal will be 
considered to have been met if non-inferiority is demonstrated.  Additionally, if 
non-inferiority is demonstrated on ABRtotal, subsequent testing for superiority will be 
conducted on the endpoint. Superiority of ABRtotal is considered a secondary analysis.
9.1.1. Estimands
The primary objective is addressed via the primary endpoint of ABRtotal.  Efficacy by 
ABRtotal is summarized by the difference between pre- and post-treatment with PF-06838435; 
pre-treatment data will be obtained from the Pre-Infusion Period, including the lead-in Study 
C0371004. Steady-state FIX:C is a key secondary endpoint and the efficacy by FIX:C is 
summarized by the steady-state population mean post-treatment compared to a fixed 
threshold of 5%.  Since no more than the single dose of study treatment on Day 1 will be 
administered during the study, there should be no treatment discontinuations.  Resumption of 
FIX prophylaxis regimen is allowed as detailed in Section 6.5.1 and is assessed directly via 
secondary endpoints (AIR and FIX consumption).  Data following resumption of FIX 
prophylaxis regimen will be excluded from the analysis of ABRtotal.  There may be missing 
data from participants lost to follow-up, but it is anticipated to be rare.  The primary 
endpoint, ABRtotal will utilize all applicable data to define the endpoints.  A description of the 
data which are not applicable for ABRtotal (eg, data following the resumption of prior 
prophylaxis therapy) will be discussed in detail in the Statistical Analysis Plan (SAP).  Any 
missing data will not be imputed for the primary endpoint.  The method to handle missing 
data of other endpoints will be discussed in SAP.  Baseline for change from baseline analyses 
will be defined based on the data collection method of each endpoint, but will reflect data 
before IP infusion.

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9.2. Sample Size Determination
Participants who complete the lead-in protocol C0371004 will be screened to achieve desired 
sample size of 40 participants, and eligible participants will be assigned to study intervention.  
All 40 participants are expected to be evaluable in this one-armed study.
When all 40 participants have completed at least 15 months of follow-up post-infusion of PF-
06838435, the ABRtotal data will provide at least 90% power (one-sided test with =0.025) to 
demonstrate non-inferiority of gene therapy compared to prophylaxis treatment on the 
difference in ABRtotal, using a repeated measure negative binomial regression, with a non-
inferiority margin of 3.0 bleeds/year.  The assumed background rate of annualized bleeding 
is a conservative 5.0 and the assumed annualized bleeding rate post-PF-06838435 is 1.5.  The 
details of non-inferiority margin selection are included in Appendix 10. 
The number of participants may exceed 40, because all participants who complete the lead-in 
study (C0371004) and meet other eligibility criteria will be allowed to participate in this 
study. 
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.
Dosed1
All participants enrolled in the study and received IP.
Safety
All participants enrolled in the study and received IP, which is the same as dosed 
population. 
Intent To Treat (ITT)
ITT population is not defined for this study since it is not a randomized study.
Evaluable
All participants are enrolled in the study and take study medication and no 
significant interruption of efficacy measurement.2
1.
Dosed population is the primary analysis population for efficacy endpoint analysis, while evaluable 
population is the analysis population for sensitivity analysis.
2.
Significant interruption will be assessed after discussion between the investigator and the medical 
monitor, eg, if a participant requires a major surgery, this will be a significant interruption of 
measurement.
9.4. Statistical Analyses
The SAP will be developed and finalized before database lock and will describe the 
participant populations to be included in the analyses, any multiple testing procedures (to 
control the overall type I error of primary, secondary hypothesis test), and procedures for 
accounting for missing, unused, and spurious data.  The overall probability of Type 1 error 
alpha for primary statistical tests, and other tests included in the multiple testing procedure, is 
controlled at .05 (or one-sided .025).  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.

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9.4.1. Efficacy Analyses
The primary analysis is focused on 15 months follow-up after infusion of PF-06838435, with 
endpoints in below table.  The planned endpoints after the primary analysis, so called final 
analysis, are focused on extended efficacy and longer-term safety.
Since there is only one primary endpoint, no multiplicity correction is needed.  A 
gatekeeping process will be applied to control multiplicity of testing multiple secondary 
endpoints.  The subsequent hypothesis testing will only be applied after success on a 
previous hypothesis test.  The analyses cease when a failure occurs. The sequence of the 
gatekeeping process will be further detailed in SAP.
Endpoint
Primary analysis
Statistical Analysis Methods
Primary

ABR for total bleeds (treated and untreated bleeds from Week 12 to Month 15) will 
be compared to pre-infusion of PF-06838435 (under SOC FIX prophylaxis 
replacement regimen).  A repeated measure negative binomial regression model will 
be used to do the hypothesis test on non-inferiority with one-sided test with the 
specified α.  If the non-inferiority on ABRtotal is established, subsequently testing for 
superiority will be conducted.
Secondary

ABR for treated bleeds from Week 12 to Month 15 will be compared to pre-infusion 
of PF-06838435 (under SOC FIX prophylaxis replacement regimen) using a repeated 
measure negative binomial regression, with a non-inferiority margin of 3.0 
bleeds/year. 

AIR for FIX from Week 12 to Month 15 versus AIR during SOC FIX replacement 
regimen will be tested for superiority.  Paired T-test will be used to do this hypothesis 
testing.

Vector-derived steady state FIX:C (Week 12 to Month 15) will be compared to a 
threshold of 5% using a one-sided, one sample T-test. FIX:C will be descriptively 
summarized by study visit.

FIX consumption, from Week 12 to Month 15, similar method as applied to AIR will
be used to do hypothesis testing on this endpoint. 

Number of bleeding events of specific type from Week 12 to Month 15: spontaneous 
and traumatic, and untreated.  Similar method applied to ABRtotal will be used to test 
these endpoints. 

Frequency of target joint bleeds from Week 12 to Month 15 will be summarized.  The 
number of target joints bleeds will be compared to baseline.  Similar method applied 
to ABRtotal will be used to test these endpoints.

Percentage of participants without bleeds (total bleeds and treated bleeds) will be 
summarized by type from Week 12 to Month 15.

HJHS for first 12 months post-infusion of PF-06838435 will be compared to baseline 
using 2-sided paired T-test. 

PRO endpoints (Haem-A-QoL Physical Health domain, HAL Complex Lower 
Extremity Activities Component Score) 12 months post-infusion of PF-06838435 

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Endpoint
Primary analysis
Statistical Analysis Methods
will be summarized and compared to baseline to assess the improvement from 
baseline if baseline is available. 
Exploratory

Will be described in the statistical analysis plan.
Final analysis
Secondary

Annualized Bleeding Rate for total bleeds (treated and untreated bleeds from Month 
15 to Month 24, by yearly intervals after 24 months, and across 6 years of follow-up) 
will be analyzed. 

Vector-derived steady state FIX:C (from Month 15 to Month 24, by yearly intervals 
after 24 months, and across 6 years of follow-up) will be analyzed.  FIX:C will be 
descriptively summarized by study visit.

Annualized FIX Infusion Rate (on-demand and Prophylaxis, AIR from Month 15 to 
Month 24, by yearly intervals after 24 months, and across 6 years of follow-up) will 
be tested for superiority by comparing pre- and post-infusion of PF-06838435.

Annualized Bleeding Rate for treated bleeds (from Month 15 to Month 24, by yearly 
intervals after 24 months, and across 6 years of follow-up) will be analyzed.

FIX consumption from Month 15 to Month 24, by yearly intervals after 24 months, 
and across 6 years of follow-up.

Number of bleeding events of specific type from Month 15 to Month 24, by yearly 
intervals after 24 months, and across 6 years of follow-up: spontaneous and 
traumatic, and untreated. 

HJHS yearly after first 12 months and 6 years of follow-up will be compared to 
baseline to assess the improvement from baseline.

Frequency of target joint bleeds from Month 15 to Month 24, by yearly intervals after 
24 months, and across 6 years of follow-up will be summarized.  The number of 
target joints bleeds will be compared to baseline.

PRO endpoints (Haem-A-QoL Physical Health domain, HAL Complex Lower 
Extremity Activities Component Score) yearly after first 12 months and 6 years of 
follow-up will be compared to baseline to assess the improvement from baseline.
Exploratory

Will be described in the statistical analysis plan.
MRI Sub-Study
Exploratory

Joint images will be reviewed following the extended MRI scale with a final score 
combining soft-tissue and osteochondral sub-scores, and compared to baseline (at 
year 3 and after 6 years of follow-up). 
Vector Shedding Sub-Study
Exploratory

A subset of participants (N=12) will have more extensive vector shedding analysis 
performed in an effort to further characterize the kinetics of vector shedding.

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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 statistical analysis plan finalized before database lock.
9.4.3. Other Analyses 
FIX:C antigens, pharmacodynamic, and biomarker exploratory analyses will be described in 
the SAP. 
9.5. Interim Analyses 
There is currently no plan for a formal interim analysis.  As this study is a single arm 
open-label study, the sponsor may conduct unblinded reviews of the data during the course of 
the study for the purpose of safety assessment.
9.5.1. External Data Monitoring Committee (eDMC)
This study will use an external data monitoring committee (eDMC).  The eDMC is 
independent of the study team and includes external members with expertise applicable to the 
study.  The eDMC will convene approximately every 6 months until study completion.  The 
eDMC charter describes the role of the eDMC in more detail. 

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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines.

Applicable ICH Good Clinical Practice (GCP) Guidelines.

Wording in this paragraph is applicable to study sites in France only: Prior to 
enrollment of any participants, the investigator and any sub-investigators will 
complete the Pfizer-provided Good Clinical Practice training course (“Pfizer GCP 
Training”) or training deemed equivalent by Pfizer.  Any investigators who later 
join the study will complete the Pfizer GCP Training or equivalent before 
performing study-related duties.  For studies of applicable duration, the 
investigator and sub-investigators will complete Pfizer GCP Training or 
equivalent every three years during the term of the study, or more often if there 
are significant changes to the ICH GCP guidelines or course materials.

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.

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.

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
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. For sites in Japan 
please refer to Japan Appendix, Section 10.11.1.4.

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 
course of the study and for 1 year after completion of the study.
10.1.3. Informed Consent Process

The investigator or his representative will explain the nature of the study to the 
participant or his legally authorized representative and answer all questions regarding 
the study.

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/IEC or study center.

The investigator must ensure that each study participant or his 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 personal study-related data will be used by 
the sponsor in accordance with local data protection law.  The level of disclosure 
must also be explained to the participant.

The participant must be informed that his medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.

The investigator further must ensure that each study participant or his legally 
authorized representative is fully informed about his right to access and correct his 
personal data and to withdraw consent for the processing of his personal data.

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
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 ICF(s) during 
their participation in the study.

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 Germany Appendix (Section 10.11.2.3).
Participants who are rescreened are required to sign a new ICF. 
Two ICFs may be required, one from the Study Site and the other from the Infusion Center 
(if applicable).
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.  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 

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participants who participated in the study, linking each participant’s numerical code 
to his 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.
10.1.5. Committees Structure
External Data Monitoring Committee (eDMC)
The eDMC is independent of the study team and includes external members with expertise 
applicable to the study.  Further details are provided in the chapter of the eDMC. 
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 European Clinical Trials 
Database (EudraCT), 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 (SOPs).
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in participants) that evaluate the safety and/or efficacy of a 
product, regardless of the geographical location in which the study is conducted.  These 
results are submitted for posting in accordance with the format and timelines set forth by US 
law.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies in accordance with the format and timelines set forth by EU 
requirements.
www.pfizer.com
Pfizer posts public disclosure synopses (CSR synopses in which any data that could be used 
to identify individual participants have been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.

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Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the European Medicines Agency (EMA) website.  Clinical data, under Phase 1 of this 
policy, includes clinical overviews, clinical summaries, CSRs, and appendices containing the 
protocol and protocol amendments, sample CRFs, and statistical methods.  Clinical data, 
under Phase 2 of this policy, includes the publishing of individual participant data.  Policy 
0070 applies to new marketing authorization applications submitted via the centralized 
procedure since 01 January 2015 and applications for line extensions and for new indications 
submitted via the centralized procedure since 01 July 2015.
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.

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 
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 

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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, according to the ICH guidelines, for a 
minimum of 15 years after study completion unless, clinical study agreement (CSA), 
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.

Wording in this paragraph is applicable to study sites in France only: 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.

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.

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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 Section 10.1.7.
10.1.9. Study and Site Closure
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.  Study sites will be closed upon 
study completion.  A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the 
sponsor/contract research organization (CRO) 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.
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

The results of this study may be published or presented at scientific meetings by the 
investigator after publication of the overall study results or one year after end of the 
study (or study termination), whichever comes first. 

The investigator agrees to refer to the primary publication in any subsequent 
publications such as secondary manuscripts, and submit all manuscripts or abstracts 
to the sponsor 30 days before submission.  This allows the sponsor to protect 
proprietary information and to provide comments and the investigator will, on 
request, remove any previously undisclosed confidential information before 

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disclosure, except for any study- or Pfizer intervention-related information necessary 
to the appropriate scientific presentation or understanding of the study results.

For all publications relating to the study, the investigator will comply with recognized 
ethical standards concerning publications and authorship, including those established 
by the International Committee of Medical Journal Editors.

The sponsor will comply with the requirements for publication of the overall study 
results covering all investigator sites.  In accordance with standard editorial and
ethical practice, the sponsor will support publication of multicenter studies only in 
their entirety and not as individual site data.  In this case, a coordinating investigator 
will be designated by mutual agreement.

Authorship of publications for the overall study results will be determined by mutual 
agreement and in line with International Committee of Medical Journal Editors 
authorship requirements.

If publication is addressed in the clinical study agreement, the publication policy set 
out in this section will not apply.
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 investigator site file (ISF). 
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card.  The contact card 
contains, at a minimum, protocol and 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 will be directed back to the investigator site.

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10.2. Appendix 2: Clinical Laboratory Tests

The tests detailed in following table will be performed by the central laboratory 
unless otherwise indicated in the Table (LL = local lab).

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. 
Protocol-Required Laboratory Assessments
Assessment
Description
Hematology 
WBC with Differential:

Neutrophils

Lymphocytes

Monocytes

Eosinophils

Basophils
RBC

Hemoglobin

Hematocrit

Platelet count
Clinical Chemistry

Sodium

Potassium

Chloride

Bicarbonate

Glucose

Phosphate

Serum 
creatinine

BUN
Lipid Panel

LDL

VLDL

HDL

Triglycerides

Total 
Cholesterol
ABO 

ABO group (at Screening if unknown)
Urinalysis 

pH

Specific Gravity

Protein

Blood 

Ketones

Glucose
Liver Function Tests 
(CL & LL)

Albumin 

Total bilirubin

Direct bilirubin

Indirect bilirubin (if 
available)

ALP

AST

ALT 

Total Protein

GGT

LDH
Coagulation 

FIX activity (FIX:C), FIX antigen (FIX Ag) 
Global hemostasis markers

aPTT (in seconds), INR, TAT, TGA, D-dimer

FIX inhibitor testing (Nijmegen Bethesda), 
(LL if clinically indicated)
AAV Neutralizing 
Antibody

nAb Assay to AAV-Spark 100
ADA

Anti-PF-06838435 antibodies (ADA) 
Immunology

PBMC for ELISPOT

Binding IgG versus IgM antibody response (exploratory)

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Assessment
Description
Vector Shedding

Plasma

Urine

Saliva

Semen

PBMC
Hepatitis B and
Hepatitis C

Hepatitis B Surface Antigen

Hepatitis B Core AB Total

HBV DNA

Hepatitis C Virus AB 

HCV RNA
Liver fibrosis

FibroScan, FibroTest/FibroSURE (including 2-macroglobulin, 
apolipoprotein A1 and haptoglobin)

APRI
α-Fetoprotein 

Biomarker for hepatic carcinoma
HIV Serology 

HIV-1/HIV-2 Antibody Screen
Viral load and CD4 

HIV-1 Qualitative, RNA
Spare Plasma (CL) 

Plasma will be stored for repeat or additional testing.  These samples will be 
destroyed at the end of the study
Factor IX genetic 
testing)

Test to be performed if results are not available in the source documents 
Investigators must document their review of each laboratory safety report.

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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow–up, and Reporting
10.3.1. Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of study intervention, whether or not 
considered related to the study intervention.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study intervention.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital 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).

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 lack of efficacy will be reported as AE or SAE if they fulfil the definition of 
an AE or SAE, as per Section 8.3.

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Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) 
present or detected at the start of the study that do not worsen.
10.3.2. Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).
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.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.

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A SAE is defined as any untoward medical occurrence that, at any dose:
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 post-study 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 FIX inhibitor as assessed by Nijmegen assay 
(≥0.6 Bu/mL, central laboratory). 

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A SAE is defined as any untoward medical occurrence that, at any dose:
3. Any participant develops hypersensitivity reaction (eg, bronchospasm and 
anaphylaxis).  Infusion site reactions should be reported as serious only if they 
meet serious criteria.
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 of 
being related to study drug.

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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 Clinical Trial (CT) Serious Adverse Event 
(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 52 weeks post-
infusion)
Safety Event
Recorded on the 
CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE (including a medically 
important event – see 
Section 10.3.2 Definition of SAE, 
Other Situations)
All
All
Non-serious AE
All
None
Exposure to the investigational 
product under study during 
pregnancy, and occupational 
exposure
None
All (And EDP supplemental 
form for EDP)  
Note:  Include all SAEs 
associated with exposure 
during pregnancy. Include 
all AEs/SAEs associated 
with occupational exposure.
During the Long-Term Monitoring Period (Week 53 post-infusion to EOS)
Safety Event
Recorded on the 
CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE (including a medically 
important event – see 
Section 10.3.2 Definition of SAE, 
Other Situations)
All
All

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Non-serious AE

determined to be related to the 
investigational product by the 
investigator;

where causality is unknown.
All
None
Exposure to the investigational 
product under study during 
pregnancy, and occupational 
exposure
None
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 sponsor in lieu of completion of the sponsor/AE/SAE CRF 
page.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer.  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.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
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.

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
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 (IB) 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 Pfizer.  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 Pfizer.

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".  In addition, if the investigator 
determines that an SAE is associated with study procedures, the investigator must 
record this causal relationship in the source documents and CRF, and report such 

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Assessment of Causality
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 Pfizer 
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 with a copy of any 
post-mortem 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 via Paper CRF

Facsimile transmission of the SAE paper CRF is the preferred method to transmit 
this information to the sponsor. 

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.
SAE Reporting to Pfizer via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to Pfizer 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.

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SAE Reporting to Pfizer via an Electronic Data Collection Tool

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 sponsor by telephone. 

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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 is 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: 

Agree to use male condom when engaging in any activity that allows for passage 
of ejaculate to another person.

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10.5. Appendix 5: Genetics
Use/Analysis of DNA

Genetic variation may impact a participant’s response to study intervention, 
susceptibility to, and severity and progression of disease.  Therefore, where local 
regulations and IRB/IEC allow, a blood sample will be collected for DNA analysis.

The results of genetic analyses may be reported in the clinical study report (CSR) or 
in a separate study summary, or may be used for internal decision-making without 
being included in a study report.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.

The samples will be retained as indicated:

Samples for specified genetic analysis (see Section 8.7) will be stored for up to 
6 years or other period as per local requirements or will not be stored beyond the 
completion of this study (eg, Clinical Study Report finalization).

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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 drug-induced 
liver injury (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 aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks. The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same lab sample).  
In rare instances, by the time TBili elevations are detected, AST/ALT values might have 
decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions.  Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:

Participants with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available.

For participants with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

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).

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 

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should return to the investigator site and be evaluated as soon as possible, preferably within 
48 hours from awareness of the abnormal results.  This evaluation should include laboratory 
tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT and TBili for suspected cases of 
Hy’s Law, additional laboratory tests should include albumin, creatine kinase (CK), direct 
and indirect bilirubin, gamma-glutamyl transferase (GGT), prothrombin time 
(PT)/international normalized ratio (INR), total bile acids, and alkaline phosphatase.  
Consideration should also be given to drawing a separate tube of clotted blood and an 
anticoagulated tube of blood for further testing, as needed, for further contemporaneous 
analyses at the time of the recognized initial abnormalities to determine etiology.  A detailed 
history, including relevant information, such as review of ethanol, acetaminophen (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-06838435 is the potential for T-cell induced hepatocyte destruction.  In a 
subset of participants, presentation of 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 FIX 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 the Phase 1/2a study to respond to intervention with 
corticosteroids. 

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10.7. Appendix 7: Bleed and Factor Replacement Regimen Definitions
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 or 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 (three or more spontaneous bleeds into a single joint within a
consecutive 6-month period).  A target joint is considered resolved when there are ≤2 bleeds
into the joint within a 12-month period.
Joint Bleed: A bleeding episode characterized by rapid loss of range of motion as compared
with baseline that is associated with any combination of the following: pain or an unusual
sensation in the joint, palpable swelling, and warmth of the skin over the joint.
Muscle Bleed: An episode of bleeding into a muscle, determined clinically and/or by imaging
studies, generally associated with pain and/or swelling and functional impairment.
Definition of Bleed Types
Spontaneous Bleeds: Bleeding for no apparent/known reason particularly into the joints,
muscles, and soft tissues.
Traumatic Bleeds: Bleeding event occurring for an apparent/known reason.
Note: Bleeds related to a procedure/surgery such as hematomas/bruising resulting from any
surgeries or invasive procedures (eg, tooth extractions, venipuncture, or subcutaneous drug
administrations) or invasive diagnostic procedures (eg, lumbar puncture, endoscopy with 
biopsy) would NOT be counted as bleeds.  Bleeds related to procedure/surgery are not 
associated with any trauma except procedure/surgery-induced trauma.
Definition of Factor Replacement Regimens:
Prophylaxis Therapy: The regularly scheduled and regimented administration of factor 
replacement therapy to prevent bleeding.

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Preventative Therapy: Infusion of clotting factor that is given in anticipation of a planned 
physical activity that has a high risk of injury (eg, surgery or sporting activity).
On-Demand Therapy: The administration of factor replacement therapy only at the time of 
an acute bleeding event.

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10.8. Appendix 8: Guidelines for Target Factor IX Levels Based on Bleed Type

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10.9. Appendix 9: Instruments for Patient-Reported Outcomes (PROs)
10.9.1. Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL) 

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10.9.2. Hemophilia Activities List (HAL) 
emophilia
ctivities
ist
Version 2.0 2015
USA/Canadian Version
© Van Creveldkliniek 
University Medical Centre Utrecht
Date
: ........................................
Patient ID : ........................................

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© Van Genderen et al., 2005, UMC Utrecht
Contact: vck-secretariaat@umcutrecht.nl
All rights reserved. No part of this document may be reproduced, stored in a retrieval system, or transmitted in 
any form or by any means, without the prior permission of the author.
When using this questionnaire, please use the following references:
Van Genderen FR, Van Meeteren NLU, Van der Bom JG, Heijnen L, De Kleijn P, Van den Berg HM, Helders 
PJM. Functional consequences of haemophilia in adults: the development of the Haemophilia Activities List. 
Haemophilia 2004; 10: 565-71.
Van Genderen FR, Westers P, Heijnen L, De Kleijn P, Van den Berg HM, Helders PJM, Van Meeteren NLU. 
Measuring patients' perceptions on their functional abilities: validation of the Haemophilia Activities List 
(HAL). Haemophilia 2006; 12: 36-46.

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Hemophilia Activities List
Introduction
This is the Hemophilia Activities List, or HAL.  In this questionnaire several activities are 
listed that could be difficult for adults who have hemophilia.  The aim of this questionnaire is 
to see how easy it is for you to do these activities. 
General comments
When answering the questions, it is only your own experience that counts.  For every 
activity, you are asked whether you had any difficulty in performing that activity due to 
hemophilia.  There are seven different response options. Answer each question by placing an 
“X” in the box that describes your situation.
Example:
In the past month, did you have any difficulty due to hemophilia with: 
n/a
Impossible
Always 
a problem
Mostly 
a problem
Sometimes 
a problem
Rarely 
a problem
Never 
a 
problem
Using public transportation 
(bus, train, subway, streetcar)
 8
 1
 2
 3
 4
 5
 6
Please choose only one box per question.  The “N/A” response option (“not applicable”) can 
be used if you never (had to) perform that specific activity.  The “N/A” option is only 
available for some activities.  The difference between the “Impossible” and “Always” 
response option, is that with “Always” you were in fact able to perform that activity, but with 
problems and with “Impossible” you are unable to perform that activity. 
It is very important that you answer all questions.  Even when a question seems irrelevant to 
you, or when you have no opinion relating to the question, please mark the box that describes 
your situation most closely. 
It will take 5-10 minutes to finish this questionnaire.
V2.0, 2015 – USA/Canadian
Van Creveldkliniek

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Hemophilia Activities List
Lying down/sitting/kneeling/standing
In the previous month, did you have any difficulty, due to hemophilia, with:
Impossible 
Always 
a problem
Mostly 
a problem
Sometimes 
a problem
Rarely
a problem
Never 
a problem
Sitting down
(e.g. on a chair or couch)
   1
   2
   3
   4
   5
   6
Standing up from a chair that has
armrests
   1
   2
   3
   4
   5
   6
Standing up from a chair that does 
not have armrests
   1
   2
   3
   4
   5
   6
Kneeling/squatting 
  1
  2
  3
  4
  5
  6
Bending forward 
  1
  2
  3
  4
  5
  6
Kneeling for long periods of time
  1
  2
  3
  4
  5
  6
Squatting for long periods of time
  1
  2
  3
  4
  5
  6
Standing for long periods of time
  1
  2
  3
  4
  5
  6
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Hemophilia Activities List
Legs
In the previous month, did you have any difficulty, due to hemophilia, with: 
Impossible 
Always 
a problem
Mostly 
a problem
Sometimes 
a problem
Rarely
a problem
Never 
a problem
Walking short distances
(less than 0.6 miles/less than 
15 minutes) 
   1
   2
   3
   4
   5
   6
Walking long distances
(more than 0.6 miles/more than 
15 minutes)
   1
   2
   3
   4
   5
   6
Walking on a soft surface 
(e.g. on the beach)
   1
   2
   3
   4
   5
   6
Walking on an uneven surface 
(e.g. cobblestones, high sidewalks)
   1
   2
   3
   4
   5
   6
Strolling/(window-)shopping
  1
  2
  3
  4
  5
  6
Walking up a flight of stairs 
(a flight of stairs is approximately 
14 steps)
   1
   2
   3
   4
   5
   6
Climbing down a flight of stairs
  1
  2
  3
  4
  5
  6
Running 
(e.g. in order to catch the bus)
   1
   2
   3
   4
   5
   6
Jumping
  1
  2
  3
  4
  5
  6
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Hemophilia Activities List
Arms
In the previous month, did you have any difficulty, due to hemophilia, with:
Impossible 
Always 
a problem
Mostly 
a problem
Sometimes 
a problem
Rarely
a problem
Never 
a problem
Lifting heavy objects
  1
  2
  3
  4
  5
  6
Carrying heavy objects in the arms 
  1
  2
  3
  4
  5
  6
Fine hand movements 
(e.g. doing up buttons) 
   1
   2
   3
   4
   5
   6
Reaching above your head 
(to pick something up from a high 
shelf)
   1
   2
   3
   4
   5
   6
Use of transportation
In the previous month, did you have any difficulty due to hemophilia, with:
n/a
Impossible 
Always 
a problem
Mostly 
a problem
Sometimes 
a problem
Rarely
a problem
Never 
a problem
Riding a bicycle
 8   1
  2
  3
  4
  5
  6
Getting in and out of a car
 8   1
  2
  3
  4
  5
  6
Using public transportation 
(bus, train, subway)
 8    1
   2
   3
   4
   5
   6
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Hemophilia Activities List
Self care
In the previous month, did you have any difficulty due to hemophilia, with:
Impossible 
Always 
a problem
Mostly 
a problem
Sometimes 
a problem
Rarely
a problem
Never 
a problem
Drying your whole body
  1
  2
  3
  4
  5
  6
Putting on a shirt, sweater etc. 
  1
  2
  3
  4
  5
  6
Putting on socks and shoes
  1
  2
  3
  4
  5
  6
Putting on a tie or closing the top 
button of a shirt
   1
   2
   3
   4
   5
   6
Going to the toilet
  1
  2
  3
  4
  5
  6
Household tasks
In the previous month, did you have any difficulty, due to hemophilia, with: 
n/a
Impossible
Always
a problem
Mostly
a problem
Sometimes
a problem
Rarely
a problem
Never
a problem
Going out shopping 
(for food, drink etc.)
 8
   1
   2
   3
   4
   5
   6
Washing the dishes, cleaning the sink  8
  1
  2
  3
  4
  5
  6
Cleaning the house
 8
  1
  2
  3
  4
  5
  6
Other household tasks 
(ironing, making the beds)
 8
   1
   2
   3
   4
   5
   6
Doing odd jobs 
(both in and around the house) 
 8
   1
   2
   3
   4
   5
   6
Gardening
 8
  1
  2
  3
  4
  5
  6
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Hemophilia Activities List
Leisure activities and sports
In the previous month, did you have any difficulty due to hemophilia with:
n/a
Impossible 
Always 
a problem
Mostly 
a problem
Sometimes 
a problem
Rarely
a problem
Never 
a problem
Playing games (outdoors, e.g. with 
your children)
 8
   1
   2
   3
   4
   5
   6
Sports
 8
  1
  2
  3
  4
  5
  6
Going out 
(theatre/museum/
movie theatre/bar)
 8
   1
   2
   3
   4
   5
   6
Hobbies 
 8
  1
  2
  3
  4
  5
  6
Dancing
 8
  1
  2
  3
  4
  5
  6
Going on a vacation (active)
 8
  1
  2
  3
  4
  5
  6
Going on a vacation (“passive”; 
beach-/hotel holiday)
 8
   1
   2
   3
   4
   5
   6
V2.0, 2015 – USA/Canadian
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10.9.3. Patient Global Impression of Change - Hemophilia (PGIC-H)
Instructions: For the question below, please select the response that best describes your 
impression since the start of the study. 
Since the start of the study, my life with hemophilia has:
Greatly improved
Moderately improved
Slightly improved
Not changed
Slightly worsened
Moderately worsened
Greatly worsened

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10.9.4. Hemophilia Life Impacts Questionnaire (HLIQ) 
OVERALL INSTRUCTIONS: 
The following questions ask about the ways that living with AND treating hemophilia has 
affected your life during the past week.  There are no right or wrong answers.  Please select 
the response that best represents your experience. 
ITEMS 1-7 INSTRUCTIONS:
Please answer these first 7 questions thinking specifically about your experience living with 
and treating your hemophilia. 
1. During the past week, how much was your hemophilia on your mind?
Not at all
A little
Somewhat
Quite a bit
Constantly
2. During the past week, 
a.
Did you take any precautions because of your hemophilia? (Gate Question)
 Yes (Go to 2b)
 No (Stop)
b. If 2a = Yes 
During the past week, how much precaution did you take because of your hemophilia?
A little
Some
Quite a bit
A lot
3. During the past week, how much did having hemophilia interfere with your ability to 
perform day-to-day activities (eg, at home, work or school)?
Not at all
A little
Somewhat
Quite a bit
Extremely


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4. During the past week, how much did having hemophilia limit your ability to live the life 
you want to live?
Not at all
A little
Somewhat
Quite a bit
Extremely
5. During the past week, 
a.
Did you participate in any social activities (eg, with friends and/or family)? 
(Gate Question)
 Yes (Go to 5c)
 No (Go to 5b)
b. If 5a = No
You answered that you did not participate in any social activities, was this:
 Due to having hemophilia (Stop)
 Due to other reasons (Stop)
c.
If 5a = Yes 
During the past week, how much did having hemophilia interfere with your ability to 
participate in social activities (eg, with friends and/or family)?
Not at all
A little
Somewhat
Quite a bit
Extremely
6. During the past week, 
a.
Did you participate in any hobbies or leisure activities? (Gate Question)
 Yes (Go to 6c)
 No (Go to 6b)

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b. If 6a = No
You answered that you did not participate in any hobbies or leisure activities, was 
this:
 Due to having hemophilia (Stop)
 Due to other reasons (Stop)
c.
If 6a = Yes 
During the past week, how much did having hemophilia interfere with your ability to 
participate in hobbies or leisure activities?
Not at all
A little
Somewhat
Quite a bit
Completely
7. During the past week, 
a.
Did you participate in any physical activities (eg, exercise or sports)? 
(Gate Question)
 Yes (Go to 7c)
 No (Go to 7b)
b. If 7a = No
You answered that you did not participate in any physical activities (eg, exercise or 
sports), was this:
 Due to having hemophilia (Stop)
 Due to other reasons (Stop)
c.
If 7a = Yes 
During the past week, how much did having hemophilia interfere with your ability to 
participate in physical activities (eg, exercise or sports)?
Not at all
A little
Somewhat
Quite a bit
Completely


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ITEMS 8 & 9 INSTRUCTIONS:
Please answer these last 2 questions thinking specifically about your experience with 
treating your hemophilia. 
8. During the past week, how difficult was it to fit hemophilia treatment into your life?
Not at all
A little
Somewhat
Quite a bit
Extremely
9. During the past week, how much did treating your hemophilia interfere with your 
ability to enjoy life?
Not at all
A little
Somewhat
Quite a bit
Extremely


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10.9.5. EQ-5D-5L Questionnaire
Health Questionnaire
English version for the USA
USA (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group

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Under each heading, please check the ONE box that best describes your health TODAY.
MOBILITY
I have no problems walking
I have slight problems walking
I have moderate problems walking
I have severe problems walking
I am unable to walk
SELF-CARE
I have no problems washing or dressing myself
I have slight problems washing or dressing myself
I have moderate problems washing or dressing myself
I have severe problems washing or dressing myself
I am unable to wash or dress myself
USUAL ACTIVITIES (eg, work, study, housework, family or leisure 
activities)
I have no problems doing my usual activities
I have slight problems doing my usual activities
I have moderate problems doing my usual activities
I have severe problems doing my usual activities
I am unable to do my usual activities
PAIN/DISCOMFORT
I have no pain or discomfort
I have slight pain or discomfort
I have moderate pain or discomfort
I have severe pain or discomfort
I have extreme pain or discomfort
ANXIETY/DEPRESSION
I am not anxious or depressed
I am slightly anxious or depressed
I am moderately anxious or depressed
I am severely anxious or depressed
I am extremely anxious or depressed
USA (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group

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The worst health 
you can imagine

We would like to know how good or bad your health is TODAY.

This scale is numbered from 0 to 100.

100 means the best health you can imagine.
0 means the worst health you can imagine.

Mark an X on the scale to indicate how your health is TODAY.

Now, please write the number you marked on the scale in the 
box below.
USA (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group
The best health 
you can imagine
10
0
20
30
40
50
60
80
70
90
100
5
15
25
35
45
55
75
65
85
95
YOUR HEALTH TODAY =

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10.10. Appendix 10: Non-Inferiority Margin Selection
The choice of the non-inferiority margin is based on the consideration of the following 
guidelines.  The constancy assumption was taken into consideration and the “95%-95%” 
method is used.

FDA guideline for selecting a margin based on historical data.28

EMA guidelines on the choice of non-inferiority margin.29

International Conference on Harmonization (ICH) Note for Guidance E9 (Statistical 
Principles for Clinical Trials).30

ICH Note for Guidance E10 (Choice of Control Group).31

CPMP Points to Consider on Switching Between Superiority and Non-Inferiority.32
The non-inferiority margin will be based on the effect of prophylaxis treatment over on-
demand treatment (as the reference treatment).  This will be expressed via a mean difference 
in ABR in a single arm trial with a switch from on-demand to prophylaxis using a paired 
comparison.  This design reflects the Committee for Medicinal Products for Human (CHMP) 
guidance for the design of prophylaxis clinical trials.  Based on the lower bound of the 
confidence interval of an estimate for the ABR for treated bleeds (referred to as ABRtreat) in 
on-demand participants, the ABRtreat is assumed to be higher by at least 
, which will be
considered as M1 in the non-inferiority test setting for the ABRtreat.  It is assumed that the 
treatment difference (on-demand – prophylaxis) in ABRtotal is proportional to that in ABRtreat.  
The ratio of the treatment difference (ABRtotal over ABRtreat) is estimated to be 
.33,34  
Thus M1 for ABRtotal is estimated to be 
.
Given the large effect size of prophylaxis treatment (over on-demand therapy), an 
appropriate value for M2 will be considered in order to preserve a sufficiently large 
proportion of this effect.  Simulations have been conducted to assess preservation levels of 
 of M1.  These percentages correspond to non-inferiority margin values of 
 bleeding events/year respectively, on an absolute scale.  A value of 3.0 for 
M2 (approximately 
 of the M1 effect preserved) is proposed as both clinically 
meaningful and yielding a reasonable sample size for establishing efficacy.
“The choice of delta must always be justified on both clinical and statistical grounds.  It 
always needs to be tailored specifically to the particular clinical context and no rule can be 
provided that covers all clinical situations”.29  In the sponsor’s BeneFix study 3090A1-400, 
which included 50 adult hemophilia B patients to compare prophylaxis efficacy results for 
this FIX product on different regimen in the clinical trial setting, ABRtreat was estimated to 
range from 
.  “A separate study compared recombinant factor IX Fc fusion protein 
(rFIXFc, Alprolix; Biogen Inc.  Cambridge, MA USA).  The ABRtreat of the prophylaxis 
regimen are 3.0 and 1.4”.35  In a “European retrospective study of real-life haemophilia 
treatment”, the mean ABRtreat observed of prophylaxis regimen in different European 
countries range from 1.7 to 6 for haemophilia B severe patients.36  From the experience with 
CCI
CCI
CCI
CCI
CCI
CCI
CCI

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Hemlibra (emicizumab-kxwh; Genentech, Inc. South San Francisco CA), the ABRtotal ranged 
from 2.5 (HAVEN-1 study) to 5.5 (HAVEN-3 study).  The HOPE-B trial result for AMT-
061 showed an ABRtotal of 1.51 (EAHAD 2022).37  Given a difference of 
 between the 
prospectively assessed ABRtreat in the real world setting and in the clinical trial setting, and a 
difference of
in ABRtotal, and allowing for modest differences in the respective study 
populations, the sponsor feels a value of 3.0 represents a reasonably conservative margin of 
non-inferiority.  
CCI
CCI

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10.11. Appendix 11: Country-specific Requirements
10.11.1. Japan Appendix
This appendix is only for Japanese investigators at Japanese sites.
10.11.1.1. Study Intervention Defects Definitions (per Japanese regulations)

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.
10.11.1.2. Reporting Criteria
All study intervention defects are to be reported to the sponsor within 24 hours of 
investigator awareness (see Section 10.11.1.3) 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.
10.11.1.3. 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.

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10.11.1.4. Japan Specific Protocol Wording
Protocol Section 5.2. Exclusion Criteria
Other Exclusions
The text with underline was added.
19. Sensitivity to any of the study interventions, or components thereof, or bovine-derived 
component, or drug or other allergy that, in the opinion of the investigator or the 
sponsor’s medical monitor, contraindicates participation in the study.
Protocol Section 6.4. Study Intervention Compliance
The text with underline was added.
The study drug will NOT be administered to multiple Japanese participants on the same day 
of the administration to the first Japanese participant.
Protocol Section 8. STUDY ASSESSMENTS AND PROCEDURES
Day 1 (at Study Site or at approved Infusion Center)
The text with underline was added after the last paragraph
Japanese participants enrolled at Japanese sites must be hospitalized on IP infusion day and 
their condition must be closely monitored at the study site through next day after the IP 
administration for ensuring the participant safety. The necessity of hospitalization thereafter 
should be determined by the principal investigator according to the participant’s condition.
Protocol Section 8.3.4. Regulatory Reporting Requirements for SAEs
The text with underline was added.
The sponsor will report SAEs that impact study status to the Japan sites approximately 
24 hours of Pfizer Japan receipt of the report.
Protocol Section 10.1.1. Regulatory and Ethical Considerations
The text with underline was added.
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. 
10.11.2. Germany Appendix
This appendix is only for sites in Germany.

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10.11.2.1. Section 5.1 Inclusion Criteria
6. 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.
10.11.2.2. Section 5.2 Exclusion Criteria
16. 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.
17. Unable to comply with scheduled visits, treatment plan, laboratory tests and other study 
procedures for up to six years post-infusion of PF-06838435 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.
10.11.2.3. 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.
10.11.2.4. Section 1.3. Schedule of Activities (SoA)
Participants seen at German sites will not be permitted to undergo x-ray testing for this study.
10.11.2.5. Section 8.1.2.3. X-ray Assessments to Evaluate Joints
Participants seen at German sites will not be permitted to undergo x-ray testing for this study.

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10.12. Appendix 12: Hemophilia Joint Health Score
The Hemophilia Joint Health Score 2.1 worksheet can be found in Feldman et al (2011).38

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10.13. Appendix 13: 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).
10.13.1. Alternative Study Procedures During COVID-19 Pandemic
10.13.1.1. Home Health Visits
A home health care service may be utilized to facilitate scheduled visits per the Schedule of 
Activities.  In the event that an on-site clinic visit or unscheduled on-site clinic visit cannot 
be conducted after Day 1, study sites are permitted to defer the conduct of the 
procedures, listed below, to the mobile phlebotomy/ home health services, provided that local 
regulations permit:

All protocol required lab draws

Weight and vital signs (eg, body temperature, BP, pulse rate, respiratory rate)

Patient-Reported Outcomes (PROs)
In the event that an on-site clinic visit cannot be completed, it is understood that the 
procedures, like the ones listed below, may not be able to be performed. In such cases, you 
should document the reason for the missed test (eg, on-site clinic  visit missed due to 
COVID-19 restrictions).

Physical exam

Electrocardiogram

Target Joint Assessment

Liver Ultrasounds

Hemophilia Joint Health Score (HJHS)

Joint X-ray (Optional)

Joint MRI (Optional)
10.13.1.2. 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 by phone contact. Video contact can be used if permitted by local 
regulations. During the phone (or video) contact, the following assessments should be 
performed:

Review and record any new concomitant medications or changes in concomitant 
medications since last contact;

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
Review and record any AEs and SAEs since last contact, including but not limited 
to COVID-19 related events. The AE and SAE reporting process should be 
followed per protocol (Section 10.3, Appendix 3);

Review bleeding episodes and FIX infusions reported in the eDiary.
Study participants must be reminded to promptly notify site staff about any change in their 
health status.
10.13.1.3. Guidelines for Capturing Post-Infusion Procedures
In the event that any of the post-infusion 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 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 deviations.

ECG

Liver ultrasound

HJHS

Global Hemostasis Markers
10.13.2. Alternative Study Procedures For Extenuating Circumstances
In the event of extenuating circumstances, the same mitigations that were put in place for the 
COVID-19 pandemic, see Section 10.13.1, will be used for the duration of the trial.
10.13.3. Participants Who Test Positive for COVID-19
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 medication when he has no COVID-19 symptoms for 10 days and:

tests negative for COVID-19
Or

continue to test positive for COVID-19, but at least 21 days after the earliest 
COVID-19 positive test.
Prior to dosing:
o
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 etc., if applicable)

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And
o
consult with the sponsor.
10.13.4. COVID-19 Vaccination Guidelines
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 
investigational product, it is recommended that the infusion of the investigational 
product 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 investigational product, the COVID-19 vaccine may be 
administered once the patient has reached at least 12 weeks of follow-up post-
investigational product infusion if the participant is not currently on corticosteroids.  
If the participant is on corticosteroids at 12 weeks post-infusion, it is recommended to 
delay vaccination until the participant has been weaned off corticosteroids.
2. It is recommended that WFH guidelines be followed 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 for any questions concerning COVID-19 
vaccination and study participants.
4. COVID-19 vaccinations should be reported as a concomitant medication on the case 
report form (CRF).
Ultimate decision-making regarding administration of the COVID-19 vaccine will be 
between the investigator and the study participant.

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10.14. Appendix 14: 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 2
12 October 2021
The primary reason for Amendment 2 is to change the 
analysis period for the co-primary endpoints and the key 
secondary endpoints based on FDA feedback that analysis 
be performed 12 months post-steady state versus 12 months 
post-infusion.

For co-primary endpoints and key secondary 
endpoints, 12 months updated to 15 months in 
Synopsis (Section 1.1), Schema (Section 1.2), 
Objectives, Estimands and Endpoints (Section 3), 
Estimands and Statistical Hypotheses (Section 9.1), 
Sample Size Determination (Section 9.2), and Efficacy 
Analyses (Section 9.4.1). Additionally, all bleeding 
related secondary efficacy endpoints were updated 
from 12 months to 15 months in Objectives, Estimands 
and Endpoints (Section 3) and Efficacy Analyses 
(Section 9.4.1).

Extended the time period for any participant with a 
planned surgical procedure requiring FIX surgical 
prophylactic factor treatment from 12 to 15 months in 
Exclusion Criterion #10 (Section 5.2).
Removal of planned interim analysis (Sections 9.4, 9.4.1, 
and 9.5), clarified primary endpoint of ABR is for treated 
bleeds (Sections 1.1, 3, 9.1.1, and 9.4.1), added ABR for 
total bleeds (treated and untreated) as a key secondary 
objective and endpoint (Sections 1.1, 1.2, 3, 9.1.1, and 
9.4.1), and clarified the efficacy of PF-06838435 in terms 
of the use of exogenous FIX in the key secondary 
endpoints (Sections 1.1 and 3) based on evolving 
regulatory expectations.
Added allowed therapies including COX-2 inhibitors and 
topical NSAIDs, where medically necessary, and HIV 
therapy (Section 6.5.1), and clarified low dose aspirin and 
PRN/short-term use of NSAIDs may be used where 
medically necessary (Section 6.5.2).
Added guidance in the event that a participant is unable to 
provide any semen for vector shedding over the course of 
1 month post IP infusion in Samples for Vector Shedding 
Assays (Section 8.5.1).
Incorporated clarifications previously communicated by 
PACL #7:

Guidance regarding the inclusion of participants who 
test positive for COVID-19 was added within the 

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Amendment 2
12 October 2021
The primary reason for Amendment 2 is to change the 
analysis period for the co-primary endpoints and the key 
secondary endpoints based on FDA feedback that analysis 
be performed 12 months post-steady state versus 12 months 
post-infusion.
Alternative Measures During Public Emergencies 
Appendix (Section 10.13) and references to this 
guidance were added in Schedule of Activities 
(Section 1.3), 
Preparation/Handling/Storage/Accountability 
(Section 6.2), Study Intervention Compliance 
(Section 6.4), and Study Assessments and Procedures 
(Section 8).

Guidance regarding COVID-19 vaccination was added 
within the Alternative Measures During Public 
Emergencies Appendix (Section 10.13) and references 
to this guidance were added in Schedule of Activities 
(Section 1.3), 
Preparation/Handling/Storage/Accountability 
(Section 6.2), Study Intervention Compliance 
(Section 6.4), Concomitant Therapy (Section 6.5), 
Disallowed Therapy (Section 6.5.2), and Study 
Assessments and Procedures (Section 8).

Addition of language regarding missed assessments to 
Study Assessments and Procedures (Section 8) and 
Alternative Measures During Public Emergencies 
Appendix (Section 10.13).

Minor typographical correction to HIV Exclusion 
Criterion #15 (Section 5.2).

Language regarding use of mobile phlebotomy/home 
health services and pre-dose LFT blood clarified in 
Schedule of Activities (Section 1.3).

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Amendment 1
23 June 2020
The main reason for Amendment 1 is to incorporate 
changes requested by German Ethics Committee and 
incorporate clarifications previously communicated by 
protocol administrative change letters (PACLs).
Revisions and additions were made per Germany, Japan 
and France Ethics Committee and/or regulatory authority 
(RA) requirements. The following sections were affected:

Objectives, Estimands and Endpoints

Estimands wording was revised for clarity per 
German Ethics Committee.

Inclusion/Exclusion Criteria

Inclusion Criterion #6 was revised to meet 
German Ethics Committee required language 
in Section 10.11.2.1.  

Exclusion Criteria #16 and #17 were revised 
to meet German Ethics Committee  required 
language in Section 10.11.2.2.

Exclusion Criterion #19 was revised to meet 
Japan required language in Section 10.11.1.4.

Preparation/Handling/Storage/Accountability

Regulatory and Ethical Considerations was 
revised with language applicable to study 
sites in France. 

Study Intervention(s) Administered

Reference was added to new country-specific 
language in Section 10.11.

Study Assessments and Procedures

References to new country-specific language 
in Section 10.11 were added.

Adverse Events and Serious Adverse Events

References to new country-specific language 
in Section 10.11 were added.

Pharmacokinetics

For clarity and flexibility and as a country-
level request (Germany), it was added that as 
FIX inhibitors or T-cell mediated immune 
response may impact the FIX activity levels, 

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Amendment 1
23 June 2020
The main reason for Amendment 1 is to incorporate 
changes requested by German Ethics Committee and 
incorporate clarifications previously communicated by 
protocol administrative change letters (PACLs).
this information will also be taken into 
account while deriving FIX:C activity levels.

Statistical Considerations

Clarifications were made in the text 
describing hypothesis testing as a country-
level request (Germany).

Revisions and updates were made to provide 
clarification in estimands and statistical 
hypotheses, populations for analyses, efficacy 
analyses and interim analyses according to 
German Ethics Committee required language.

Appendices

Regulatory and Ethical Considerations was 
revised with language applicable to study 
sites in France.

Cross references were added to appropriate 
sections for new German-specific and Japan-
specific language.

A country-specific requirements appendix 
was added for Japan as Section 10.11.1 as per 
Japanese RA requirement.

A country-specific requirements appendix 
was added for Germany as Section 10.11.2 as 
per German regulations and RA requirements. 
PGIC-H was removed from endpoints. This was a 
correction as PGIC-H is not an endpoint but is an anchor 
measure used to assist with the interpretation of the PRO 
endpoints. The following sections were affected:

Objectives, Estimands and Endpoints

PGIC-H was removed from Objectives and 
Endpoints table.

Statistical Considerations

PGIC-H was removed from secondary 
efficacy analysis endpoints.

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Amendment 1
23 June 2020
The main reason for Amendment 1 is to incorporate 
changes requested by German Ethics Committee and 
incorporate clarifications previously communicated by 
protocol administrative change letters (PACLs).
Blood for LFTs is now required (rather than recommended) 
to be drawn and tested locally and centrally up to 3 days 
prior to Day 1 dosing, and reviewed prior to thawing drug, 
as these LFT results may help in the assessment of future 
LFTs and decisions on when to begin corticosteroid 
treatment, if necessary. The following sections were 
affected:

Schedule of Activities for Year 1

Table headers and notations were revised

Study Assessments and Procedures
To align with data capture guidance and SAE process, AEs 
and SAEs that begin after obtaining informed consent but 
before the start of study intervention must now be recorded 
on the AE section of the CRF, not the Medical 
History/Current Medical Conditions section. The following 
sections were affected:

Time Period and Frequency for Collecting AE and 
SAE Information

Text was removed stating that medical 
occurrences that begin before the start of 
study intervention but after obtaining 
informed consent will be recorded on the 
Medical History/Current Medical Conditions 
section of the case report form (CRF) not the 
AE section.

Text was added describing AE/SAE 
collection details in case of participant 
discontinuation.Text was added that all 
nonserious AEs and SAEs occurring in a 
participant during the active collection period, 
which begins after obtaining informed 
consent, will be recorded on the AE section of 
the CRF. 

A statement was added that the investigator is 
to record on the CRF directly observed and 
spontaneously reported AEs and SAEs per 
details provided in Section 10.3.3.
It was recommended that participants who are initiated on 
corticosteroid treatment be treated with an acid reducer for 

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Amendment 1
23 June 2020
The main reason for Amendment 1 is to incorporate 
changes requested by German Ethics Committee and 
incorporate clarifications previously communicated by 
protocol administrative change letters (PACLs).
the duration of the corticosteroid course. The following 
sections were affected:

Schedules of Activities for Year 1 and Year 2 to 
Year 6

Study Assessments and Procedures

Adverse Events and Serious Adverse Events

Analysis of Cellular Immune Response by 
ELISPOT (enzyme linked immune-spot)

Immunomodulation Optimization (Presumed 
T-Cell Activation) 
Corrections, clarifications and revisions for consistency 
were made. The following sections were affected:

Schedules of Activities for Year 1 and Year 2 to 6

Table headers and notations were revised, 
added and removed as appropriate for clarity, 
consistency, as corrections and for flexibility.

Introduction

Correction regarding female carriers was 
made in the Overview of Hemophilia B.

Correction was made to target joint definition.

Clarifications were made in the Gene Transfer 
Therapy in Hemophilia sub-section.

Objectives, Estimands and Endpoints

Wording within primary and secondary 
endpoint and additional tertiary objective and 
endpoint sections were corrected and revised 
for clarity. 

Inclusion/Exclusion Criteria

Inclusion Criterion #1 was revised as 
participants would have met these 
requirements in C0371004 before entering 
C0371002, and to add clarity regarding when 

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Amendment 1
23 June 2020
The main reason for Amendment 1 is to incorporate 
changes requested by German Ethics Committee and 
incorporate clarifications previously communicated by 
protocol administrative change letters (PACLs).
the 6 months of routine FIX prophylaxis 
should be completed. 

Inclusion Criterion #2 was corrected to 
specify that participants should have 
documented moderately severe to severe 
hemophilia B, defined as FIX:C ≤2%.

Exclusion Criteria #1, 6, 7 and 8 were revised 
for clarity.

Inclusion Criterion #4 was corrected as 
creatinine ≤2.0 mg/dL.  

Exclusion Criterion #8 was revised to clarify 
specifics of repeat testing.

Exclusion Criterion #12 was corrected to 
specify that participants previously dosed in a 
gene therapy research trial would be 
excluded.

Lifestyle Considerations

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

Text was updated and revised for consistency 
with updates in Exclusion Criterion #8.

Study Intervention(s) Administered

Updated for clarity and consistency.

Concomitant Therapy

Clarified that information regarding surgeries 
(eg, blood loss and/or transfusion amounts) 
will be collected on relevant CRF(s) 
throughout the study.

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Amendment 1
23 June 2020
The main reason for Amendment 1 is to incorporate 
changes requested by German Ethics Committee and 
incorporate clarifications previously communicated by 
protocol administrative change letters (PACLs).

Disallowed therapies were clarified.

Participant Discontinuation/Withdrawal from the 
Study

Clarified language to the Participant 
Discontinuation/Withdrawal from Study 
section and added Section 7.2.1 to clarify 
instructions to be followed when a participant 
withdraws consent.

Study Assessments and Procedures

Text was updated and revised for consistency 
with updates in the Schedules of Activities.

Efficacy Assessments

Text was added to clarify process to follow if 
bleeding episodes or treatments are not 
entered in the eDiary during the appropriate 
time window.

The title of the Haemophilia Quality of Life 
Questionnaire for Adults (Haem-A-QoL) was 
corrected as needed in this section and 
throughout the document. Domain names for 
the Haem-A-QoL were updated to be 
consistent with the development publication.

Statements were added for consistency with 
the SoAs in the MRI to Evaluate Joints and 
X-Ray Assessments to Evaluate Joints 
sub-sections.

Safety Assessments

Vital signs were revised from “oral 
temperature” to “body temperature” to permit 
flexibility with methods utilized by the sites. 

Vital signs were revised from upright
position to upright/sitting position for 
clarity. 

Clinical laboratory assessments language was 
revised to remove redundancy and for clarity.

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Amendment 1
23 June 2020
The main reason for Amendment 1 is to incorporate 
changes requested by German Ethics Committee and 
incorporate clarifications previously communicated by 
protocol administrative change letters (PACLs).

Section 8.2.5 Liver Ultrasound was added to 
clarify that all participants will undergo liver 
ultrasound imaging and details of the 
ultrasound acquisition will be provided in a 
separate scanning guide.

Adverse Events and Serious Adverse Events

Events of special interest was replaced with 
adverse events of special interest. 

Correction was made to specify that central 
laboratory, rather than the sponsor, may make 
a determination as to whether any FIX 
Inhibitor samples have been compromised.

Text was revised to clarify and more clearly 
describe exposure during pregnancy, 
breastfeeding and occupational exposure and 
reporting requirements.

Text was revised to clarify volume required 
for analysis of anti-PF-06838435 antibodies 
and neutralizing anti-PF-06838435 
antibodies. 

Section 8.3.6.1.1 was added to describe 
Immunology Exploratory sampling. 

Wording was revised regarding 
immunomodulation optimization (for 
participants who develop hepatitis 
transaminitis) to more clearly describe 
elevations in liver transaminases and to 
eliminate any potential delays in initiating 
corticosteroid treatment.

Not performing a flush of the IV line at 
conclusion of the IP infusion was added to list 
of medication errors.

It was clarified that the sponsor must be 
notified within 24 hours when there is 
medication dosing error.

New subsection, Adverse Events of Special 
Interest, was added, AESIs were defined, and 
AESIs replaced events of special interest.

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Amendment 1
23 June 2020
The main reason for Amendment 1 is to incorporate 
changes requested by German Ethics Committee and 
incorporate clarifications previously communicated by 
protocol administrative change letters (PACLs).

Pharmacokinetics

Time allowance windows were added for 
samples for vector shedding assays for clarity, 
and the specific volume of samples was 
removed. The specific amounts to be 
collected are included in one place (ie, the 
laboratory manual).

Appendices

Text describing results posted to 
www.clinicaltrials.gov and EudraCT was 
revised for clarity and flexibility.

Clinical Laboratory Tests table was revised 
for consistency and minor corrections were 
made.

Definition of AE was revised for consistency 
with revisions in protocol body, to include 
medically important events in the definition 
of SAE.

Definition of SAEs added guidance that a 
suspected transmission via a Pfizer product of 
an infectious agent, pathogenic or 
nonpathogenic is considered serious.

Text describing events of special interest were 
removed from Definition of SAE.

Additional clarity was added to 
Recording/Reporting and Follow up of AEs 
and/or SAEs during the Short-Term and 
Long-Term Monitoring Periods in 
Section 10.3.3.

Appendix 4 text regarding exposure during 
pregnancy was removed as this is now 
included in Section 8.3.5.1.

Appendix 7 heading was revised to Bleed and 
Factor Replacement Regimen Definitions and 
text was clarified in the appendix. Definitions 
of Factor Replacement Regimens, 
Prophylaxis Therapy, Preventative Therapy 
and On-Demand Therapy were added for 
clarity.

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Amendment 1
23 June 2020
The main reason for Amendment 1 is to incorporate 
changes requested by German Ethics Committee and 
incorporate clarifications previously communicated by 
protocol administrative change letters (PACLs).

References

Reference #6 and 26 were corrected, and #23 
was moved up to #13 per the citation, and 
references were re-numbered accordingly.
Text was added per current COVID-19 guidelines. The 
following sections were affected:

Schedules of Activities for Year 1 and Year 2 to 
Year 6

A statement was added above each table 
referring to a new appendix with guidance for 
alternative study visit information.

Study Assessments and Procedures

Investigators were provided with steps to take 
when circumstances outside their control may 
make it unfeasible to perform protocol-
specified tests and procedures.

Section 10.13, Appendix 13

New appendix was added describing 
alternative study procedures during 
COVID-19 pandemic.
The Protocol Summary was revised as appropriate for 
consistency with changes in the body of the document.
Editorial, grammatical, formatting and administrative changes were made throughout the document, 
including changes to the List of Abbreviations.
Original Protocol
13 December 2018
Not applicable

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10.15. Appendix 15: Abbreviations
AAV
adeno-associated virus
ABR
annualized bleeding rate
ABRtotal
annualized bleeding rate for total bleeds (treated and untreated)
ABRtreat
annualized bleeding rate for treated bleeds
ADA
anti-drug antibody
AE
adverse event
AIR
annualized (FIX) infusion rate
ALP
alkaline phosphatase
ALT
alanine transaminase
APRI
AST to platelet ratio index
aPTT
activated partial thromboplastin time
AST
aspartate transaminase
BP
blood pressure
BU
Bethesda Units
BUN
blood urea nitrogen
CBC
complete blood count
CD
cluster of differentiation or classification determinant
CFR
Code of Federal Regulations
CL
central laboratory
COVID-19
coronavirus disease of 2019
COX-2
cyclooxygenase-2
CPT
cell preparation tube
Cr
creatinine
CRF
case report form
CRO
Contract Research Organization
CSA
clinical study agreement
CT
clinical trial
CTA
Clinical Trials Agreement
DILI
drug-induced liver injury
dL
deciliter

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DMC
Data Monitoring Committee
DNA
deoxyribonucleic acid
eDMC
external data monitoring committee
DRE
disease related event
EAHAD
European Association for Haemophilia and Allied Disorders
ECG
electrocardiogram
EDP
exposure during pregnancy
EHC
European Haemophilia Consortium
EMA
European Medicines Agency
EOS
end of study
EQ-5D-5L
EuroQol, 5 dimensions, 5 levels
EU
European Union
FDA
U.S. Food and Drug Administration
FIX
coagulation factor IX
FIX Ag
coagulation factor IX antigen
FIX:C
factor IX: circulating
GCP
Good clinical practice
GGT
gamma-glutamyl transferase
H2
histamine type 2
Haem-A-QoL
Haemophilia Quality of Life Questionnaire for Adults
HAL
Haemophilia Activities List
HBV
hepatitis B virus
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HJHS
Hemophilia Joint Health Score
HLIQ
Hemophilia Life Impacts Questionnaire
hr
hour/s
HRT
hormonal replacement therapy

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ICF
informed consent form
ICH
International Conference on Harmonization
IEC
Institutional Ethics Committee
IgG
immunoglobulin G
IgM
immunoglobulin M
IND
Investigational New Drug
INR
international normalized ratio
IMP
investigational medicinal product
IP
investigational product
IRB
Institutional Review Board
ISF
investigator site file
ITT
Intent to Treat
IU
international units
IV
intravenous
IVRS/IWRS
Interactive Voice Response System/Interactive Web Response System
LDH
lactic acid dehydrogenase
LFT
liver function tests
LL
local laboratory
min
minute/s
MRI
magnetic resonance imaging
nAb
neutralizing antibodies
NE
non-evaluable
NHF
National Hemophilia Foundation
NI
non-inferiority
NIMP
non-investigational product
NSAIDs
non-steroidal anti-inflammatory drugs
PACL
protocol administrative change letter
PBMC
peripheral blood mononuclear cells
PCD
primary completion date
PGIC-H
Patient Global Impression of Change - Hemophilia
PPI
proton pump inhibitor

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PRN
pro re nata
PROs
Patient-Reported Outcomes
NHP
nonhuman primate/s
QALY
Quality Adjusted Life Year
QTc
corrected QTc interval
rAAV
recombinant adeno-associated viral vector
RA
regulatory authority
RBC
red blood cell
rFIXFc
recombinant factor IX Fc fusion protein
RNA
ribonucleic acid
SAE
serious adverse event
SAP
Statistical Analysis Plan
SJ-UCL
St. Jude Children’s Research Hospital and University College London
SoA
schedule of activities
SOC
standard of care
SOP
standard operating procedure
SRSD
single reference safety document
SUSAR
suspected unexpected serious adverse reactions
TAT
thrombin-antithrombin level
TBili
total bilirubin
TGA
thrombin generation assay
ULN
upper limit of normal
VAS
visual analog scale
VRS
verbal rating scale
Vg
vector genome
WBC
white blood cell
WFH
World Federation of Hemophilia
WOCBP
woman of childbearing potential

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11. REFERENCE
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13.
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38.
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