Phase IIb, Open-label, Single-dose, Single-arm, Multi-center Trial to Confirm the Factor IX Activity Level of the Serotype 5 Adeno-associated Viral Vector Containing the Padua Variant of a Codon-optimized Human Factor IX Gene (AAV5-hFIXco-Padua, AMT-061) Administered to Adult Subjects With Severe or Moderately Severe Hemophilia B
Phase: PHASE2
Conditions: Hemophilia B
Sponsor: CSL Behring

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
Page 1 of 112 
CLINICAL TRIAL PROTOCOL 
Trial Title: 
Phase IIb, open-label, single-dose, single-arm, multi-center trial to confirm 
the Factor IX activity level of the serotype 5 adeno-associated viral vector 
containing the Padua variant of a codon-optimized human factor IX gene 
(AAV5-hFIXco-Padua, AMT-061) administered to adult subjects with 
severe or moderately severe hemophilia B 
Short Title: 
Dose confirmation trial of AAV5-hFIXco-Padua. 
Protocol Identification: 
CT-AMT-061-01 
Name of Investigational Product: 
AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
IND No.: 
 
Indication Studied: 
Hemophilia B 
Developmental Phase of Trial: 
IIb 
Name of the Sponsor/Company: 
CSL Behring LLC 
1020 First Avenue 
King of Prussia 
Pennsylvania 19406, USA 
Name of Monitoring CRO: 
Medpace (with oversight by uniQure biopharma B.V.) 
Coordinating Investigator: 
 
Protocol Version and Date: 
Version 4.0 (Amendment 3.0) 08 Feb 2022 
 
Version 3.0 (Amendment 2.0) 10 Feb 2021 
 
Version 2.0 (Amendment 1.0) 21 May 2019 
 
Version 1.0 (Original) 30 Nov 2017 
 
This trial, including the archiving, will be conducted in compliance with Good Clinical Practice (GCP) according 
to the International Council for Harmonisation (ICH) Harmonised Tripartite Guideline (CPMP/ICH/135/95) 
 
Confidentiality statement 
This CSL Behring document is confidential. The information within this document may not be reproduced or 
otherwise disseminated without approval of CSL Behring. 
CSL Behring 
PPD
CCI

AMT-061 (AA VS-bFIXco-Padua; etranacogcne dezaparvovec) 
Protocol ID: CT-AMT-061-01 
CLINICAL TRIAL PROTOCOL SIGNATURE PAGE 
Sponsor's Approval 
Signature: 
, Clinical Development 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Page 2 of 112 
Date: 
CSL Behring 
Date: 08 Feb 2022 
PPD
PPD
PPD

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
Page 3 of 112 
INVESTIGATOR’S ACKNOWLEDGEMENT 
I have read this  
Protocol ID: CT-AMT-061-01 
Title: Phase IIb, open-label, single-dose, single-arm, multi-center trial to confirm the Factor IX 
activity level of the serotype 5 adeno-associated viral vector containing the Padua variant of a 
codon-optimized human factor IX gene (AAV5-hFIXco-Padua, hereafter referred to as 
AMT-061) administered to adult subjects with severe or moderately severe hemophilia B. 
I have fully discussed the objectives of this trial and the contents of this protocol with the 
Sponsor’s representative. 
I understand that the information in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the trial, 
without written authorization from the Sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this trial according to this protocol and any trial specific manuals, to comply 
with its requirements, to subject to ethical and safety considerations and guidelines, and to 
conduct the trial in accordance with International Council for Harmonisation guidelines on Good 
Clinical Practice and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to my 
participation as an Investigator for this trial to be terminated. 
I understand that the Sponsor may decide to suspend or prematurely terminate the trial at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the trial, I will communicate my intention 
immediately in writing to the Sponsor. 
Investigator Name, Address, and 
Telephone Number: 
(please handwrite, print or type) 
 
 
 
 
 
 
Signature: 
 
 
 
Date: 
 
 
CSL Behring 

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
Page 4 of 112 
SUMMARY OF CHANGES 
Current Protocol Amendment 
Summary of Change(s) Since Last Version of Approved Protocol: See Section 13.2 
Amendment Number: 
3.0 (Version 4.0) 
Amendment Date: 
08 Feb 2022 
Global/Country/Site-Specific:  
Global 
 
List of All Previous Amendments 
Summary of Change(s) for Previous Amendments: Not Applicable 
Amendment Number 
Date of Amendment 
Global/Country/Site-Specific 
2.0 (Version 3.0) 
10 Feb 2021 
Global 
1.0 (Version 2.0) 
21 May 2019 
Global 
0.0 (Version 1.0) 
30 Nov 2017 
Global 
 
CSL Behring 

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
Page 5 of 112 
EMERGENCY CONTACT INFORMATION 
In the event of a serious adverse event (SAE) or an adverse event (AE) qualifying for special 
notification, the Investigator must complete the Clinical Trial Serious Adverse Events Form in 
the electronic Case Report Form (eCRF) within 24 hours of becoming aware of the event. In case 
the eCRF is temporarily unavailable, the back-up paper SAE form should be completed and 
submitted to CSL Behring within 24 hours of becoming aware of the event. 
CSL Global Clinical Safety & Pharmacovigilance: 
Email: 
Fax: 
USA: 
AUS: 
GER: 
For protocol- or medical-related issues during normal business hours as well as outside of normal 
business hours, the Investigator must contact both the Medpace and uniQure 
: 
Medpace 
: 
uniQure 
: 
CSL Behring 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
Page 6 of 112 
TABLE OF CONTENTS 
1 
INTRODUCTION ................................................................................................................................ 27
1.1 
Condition Background and Current Treatment ................................................................................... 27 
1.2 
Gene Therapy Therapeutic Concept ................................................................................................... 28 
1.3 
Investigational Product Background .................................................................................................. 28 
1.3.1 
Preclinical Information ................................................................................................................ 28 
1.3.2 
Clinical Information for AMT-060 and Preliminary Information for AMT-061 ............................. 30 
1.3.2.1 
Preliminary Clinical Evidence for Efficacy and Safety of Components of AMT-060 ............. 30 
1.3.2.2 
Results of Clinical Trial-AMT-060-01 .................................................................................. 34 
1.4 
Rationale for the Trial ....................................................................................................................... 37 
1.5 
Risk/Benefit Considerations .............................................................................................................. 39 
1.5.1 
Risk of Infusion-related Toxicity ................................................................................................. 39 
1.5.2 
Risk of Immune Mediated Neutralization of the AAV5 Gene Therapeutic Vector ......................... 39 
1.5.3 
Risk of Immune Mediated Liver Toxicity ..................................................................................... 40 
1.5.4 
Risks to Third Parties and the Environment Related to Shedding via Body Fluids ......................... 41 
1.5.5 
Risk of Vector DNA Integration into the Host Genome ................................................................ 41 
1.5.6 
Risk of Germ-line Transmission of Vector DNA .......................................................................... 41 
1.5.7 
Risk of Off-target Expression of the Transgene ............................................................................ 42 
1.5.8 
Risk of Inhibitor Formation to Protein Expressed from the Transgene ........................................... 42 
1.5.9 
Risk of Breakthrough Bleeding .................................................................................................... 42 
1.6 
Accommodations Due to the COVID-19 Pandemic............................................................................ 43 
2 
TRIAL OBJECTIVES ......................................................................................................................... 44
2.1 
Primary Objective ............................................................................................................................. 44 
2.3 
Safety Objectives .............................................................................................................................. 45 
3 
TRIAL DESIGN ................................................................................................................................... 46
3.1 
Overall Trial Design ......................................................................................................................... 46 
3.1.1 
Considerations Due to the COVID-19 Pandemic .......................................................................... 46 
3.2 
Trial Design Rationale ...................................................................................................................... 47 
3.3 
Trial Endpoints ................................................................................................................................. 48 
3.3.1 
Primary Endpoint ........................................................................................................................ 48 
3.3.2 
Secondary Endpoints ................................................................................................................... 48 
3.4 
Sample Size ...................................................................................................................................... 49 
3.5 
Sites and Regions .............................................................................................................................. 49 
4 
TRIAL POPULATION ........................................................................................................................ 50
4.1 
Inclusion Criteria .............................................................................................................................. 50 
4.2 
Exclusion Criteria ............................................................................................................................. 50 
4.3 
Reproductive Potential ...................................................................................................................... 51 
4.4 
Restrictions ....................................................................................................................................... 52 
4.5 
Withdrawal of Subject from Therapy or Assessment .......................................................................... 52 
4.5.1 
Reasons for Discontinuation ........................................................................................................ 52 
4.5.2 
Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit ........................................................... 53 
5 
TRIAL TREATMENT ......................................................................................................................... 54
5.1 
Treatment(s) Administered ................................................................................................................ 54 
5.3 
Dosing and Administration................................................................................................................ 54 
5.4 
Randomization and Blinding ............................................................................................................. 55 
5.5 
Labeling, Packaging, Storage, and Handling ...................................................................................... 55 
5.6 
Prior and Concomitant Medication/Therapy ...................................................................................... 55 
5.6.1 
Prior Medication/Therapy ............................................................................................................ 55 
5.6.2 
Concomitant Medication/Therapy ................................................................................................ 55 
5.6.3 
Guidelines for Use of Factor IX for Subjects Undergoing Major Surgery ...................................... 56 
5.6.4 
Guidelines for Transaminase Elevations ....................................................................................... 57 
5.7 
Treatment Compliance and Drug Accountability ............................................................................... 58 
6 
TRIAL SCHEDULE AND ASSESSMENTS ....................................................................................... 59
CSL Behring 
CCI
CCI

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
Page 7 of 112 
6.1 
Trial Schedule ................................................................................................................................... 59 
6.1.1 
Screening (Week -6 to Day 0) ...................................................................................................... 59 
6.1.2 
IMP Administration ..................................................................................................................... 60 
6.1.2.1 
Baseline - Day 0 pre IMP ..................................................................................................... 60 
6.1.2.2 
IMP Administration and Post IMP ........................................................................................ 61 
6.1.3 
Post-Treatment Follow-up ........................................................................................................... 61 
6.1.3.1 
Final Visit or Early Discontinuation...................................................................................... 62 
6.1.4 
Long-term Follow-up................................................................................................................... 62 
6.1.5 
Additional Visits ......................................................................................................................... 63 
6.1.6 
Additional Care of Subjects after the Trial.................................................................................... 63 
6.2 
Trial Evaluations ............................................................................................................................... 63 
6.2.1 
Demographic and Other Baseline Characteristics ......................................................................... 63 
6.2.1.1 
Demographics ...................................................................................................................... 63 
6.2.1.2 
Medical History and Concomitant Illnesses .......................................................................... 63 
6.2.1.3 
Prior and Concomitant Medication/Therapy .......................................................................... 64 
6.2.1.4 
Hemophilia B Status and History .......................................................................................... 64 
6.2.1.5 
History of Bleeding and Factor IX Use ................................................................................. 65 
6.2.1.6 
Factor IX Gene Sequencing .................................................................................................. 65 
6.2.2 
Efficacy Evaluations .................................................................................................................... 66 
6.2.2.1 
Factor IX Replacement Therapy ........................................................................................... 66 
6.2.2.2 
Bleeding Episodes ................................................................................................................ 67 
6.2.2.3 
Factor IX Activity Levels and Factor IX Protein Concentration ............................................. 68 
6.2.3 
Safety Evaluations ....................................................................................................................... 70 
6.2.3.1 
Adverse Events .................................................................................................................... 70 
6.2.3.2 
Vital Signs ........................................................................................................................... 70 
6.2.3.3 
Physical Examination (Including Height and Weight) ........................................................... 71 
6.2.3.4 
Abdominal Ultrasound ......................................................................................................... 71 
6.2.3.5 
Anti-factor IX Antibodies ..................................................................................................... 72 
6.2.3.6 
Factor IX Inhibitors .............................................................................................................. 72 
6.2.3.7 
Factor IX Recovery .............................................................................................................. 72 
6.2.3.8 
Total (IgG and IgM) and Neutralizing Antibodies to AAV5 .................................................. 73 
6.2.3.9 
AAV5 Capsid-specific T cells .............................................................................................. 73 
6.2.3.10 
Vector Genome Detection .................................................................................................... 73 
6.2.3.11 
Inflammatory Markers .......................................................................................................... 74 
6.2.3.12 
Other Safety Laboratory Evaluations .................................................................................... 74 
6.2.4 
Others ......................................................................................................................................... 75 
6.2.4.1 
Blood Sample for Future Research ....................................................................................... 75 
6.2.4.2 
Liver Sample for Future Research ........................................................................................ 75 
6.2.5 
General Information Regarding Laboratory Sampling and Results ................................................ 75 
6.2.6 
Volume of Blood to be Drawn From Each Subject ....................................................................... 76 
7 
SAFETY DEFINITIONS, REPORTING AND FOLLOW-UP ........................................................... 77
7.1 
Adverse Event Definitions ................................................................................................................. 77 
7.2 
Adverse Events Qualifying for Special Notification ........................................................................... 78 
7.3 
Adverse Event Assessment Definitions .............................................................................................. 78 
7.3.1 
Severity ....................................................................................................................................... 78 
7.3.2 
Relationship to IMP ..................................................................................................................... 79 
7.4 
Reporting of Adverse Events ............................................................................................................. 79 
7.5 
Prompt Reporting of SAEs and Other Events to CSL Behring ............................................................ 80 
7.6 
Regulatory Reporting Requirements for SAEs and Other Events ........................................................ 81 
7.7 
Reporting of Pregnancies .................................................................................................................. 81 
7.8 
Reporting of Occupational Exposure ................................................................................................. 82 
7.9 
Follow-up on Adverse Events ............................................................................................................ 82 
8 
DATA MANAGEMENT ...................................................................................................................... 83
8.1 
Data Collection ................................................................................................................................. 83 
CSL Behring 
CCI
CCI

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
Page 8 of 112 
8.2 
Clinical Data Management ................................................................................................................ 83 
8.3 
Study Data ........................................................................................................................................ 83 
8.3.1 
Clinical Data – CDISC Study Data Tabulation Model (SDTM) .................................................... 84 
8.3.2 
Analysis Data – CDISC Analysis Data Model (ADaM) ................................................................ 84 
9 
STATISTICAL METHODS ................................................................................................................ 85
9.1 
Statistical Analysis ............................................................................................................................ 85 
9.2 
Planned Interim Analysis .................................................................................................................. 85 
9.3 
Full Analyses .................................................................................................................................... 85 
9.4 
Selection of Subjects to be Included in the Analyses .......................................................................... 86 
9.5 
Subject Disposition ........................................................................................................................... 86 
9.6 
Demographic and Baseline Characteristics ........................................................................................ 86 
9.7 
Investigational Product Exposure ...................................................................................................... 86 
9.8 
Prior and Concomitant Medication .................................................................................................... 86 
9.9 
Efficacy Analyses ............................................................................................................................. 86 
9.9.1 
Primary Efficacy Endpoint ........................................................................................................... 87 
9.9.2 
Secondary Efficacy Endpoints ..................................................................................................... 87 
9.10 
Safety Analyses ................................................................................................................................ 87 
9.11 
Sample Size Justification................................................................................................................... 88 
9.12 
Data Monitoring Committee .............................................................................................................. 89 
10 
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES ......................................................... 90
10.1 
Sponsor’s Responsibilities................................................................................................................. 90 
10.1.1 
Good Clinical Practice Compliance .............................................................................................. 90 
10.1.2 
Indemnity/Liability and Insurance ................................................................................................ 90 
10.1.3 
Public Posting of Trial Information .............................................................................................. 90 
10.1.4 
Submission of Summary of Clinical Trial Report to Competent Authorities of Member States 
Concerned and Independent Ethics Committees ........................................................................... 91 
10.1.5 
Trial Suspension, Termination, and Completion ........................................................................... 91 
10.2 
Investigator’s Responsibilities ........................................................................................................... 91 
10.2.1 
Good Clinical Practice Compliance .............................................................................................. 91 
10.2.2 
Protocol Adherence and Investigator Agreement .......................................................................... 92 
10.2.3 
Documentation and Retention of Records..................................................................................... 92 
10.2.3.1 
Electronic Case Report Forms .............................................................................................. 92 
 .................................................................................................. 93 
10.2.3.3 
Recording, Access, and Retention of Source Data and Trial Documents ................................ 93 
10.2.3.4 
Audit/Inspection................................................................................................................... 93 
10.2.3.5 
Financial Disclosure ............................................................................................................. 94 
10.2.4 
Compliance to all Regional, Local, State, and National Controlled-substance, Biohazard and 
Infectious Disease Regulations and Legislation ............................................................................ 94 
10.3 
Ethical Considerations ...................................................................................................................... 94 
10.3.1 
Informed Consent ........................................................................................................................ 94 
10.3.2 
Institutional Review Board or Independent Ethics Committee ...................................................... 95 
10.3.3 
Subject Treatment Cards .............................................................................................................. 96 
10.4 
Privacy and Confidentiality ............................................................................................................... 96 
10.5 
Publication Policy ............................................................................................................................. 97 
11 
ADMINISTRATIVE ASPECTS .......................................................................................................... 98
11.1 
Investigator(s) ................................................................................................................................... 98 
11.2 
International Coordinating Investigator ............................................................................................. 98 
11.3 
Clinical Trial Sites ............................................................................................................................ 98 
11.4 
Vendors ............................................................................................................................................ 98 
12 
REFERENCE LIST ........................................................................................................................... 100
13 
APPENDICES .................................................................................................................................... 104
13.1 
Laboratory Information ................................................................................................................... 104 
13.2 
Summary of Changes in Current Amendment .................................................................................. 105 
13.3 
Previous Amendments .................................................................................................................... 106 
CSL Behring 
CCI
CCI

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
Page 9 of 112 
List of In-Text Tables 
Table 1 
Flow Chart for Efficacy and Safety Evaluation, for Screening, IMP Administration + Post-
Treatment Follow-up (Week -6 to Week 52) .................................................................................... 19 
Table 2 
Flow Chart for Laboratory Parameters, for Screening, IMP Administration + Post-Treatment 
Follow-up (Week -6 to Week 52) ..................................................................................................... 21 
Table 3 
Flow Chart for Efficacy and Safety Evaluation, for Long-Term Follow-up (up to Month 60) ............ 24 
Table 4 
Flow Chart for Laboratory Parameters, for Long-Term Follow-up (up to Month 60) ......................... 25 
Table 5 
Summary of Published Clinical Experience with Components of AMT-060 ..................................... 31 
Table 6 
Components of AMT-061 Drug Product .......................................................................................... 54 
Table 7 
Use of Prednisolone for the Treatment of Transaminase Elevation.................................................... 58 
Table 8 
Safety Laboratory Parameters Assessed at the Central and/or Local Laboratory ................................ 74 
Table 9 
Timing of Reporting and Follow-up for (Serious) Adverse Events, Adverse Events for Special 
Notification, Pregnancies and Occupational Exposure ...................................................................... 80 
CSL Behring 

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
Page 10 of 112 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
List of Abbreviations 
AAV 
adeno-associated virus 
AAV2 
adeno-associated viral vector serotype 2 
AAV5 
adeno-associated viral vector serotype 5 
AAV5-hFIXco 
recombinant adeno-associated viral vector serotype 5 containing the 
wild-type human factor IX gene, codon-optimized for optimal expression 
in humans, under control of a liver-specific promoter (AMT-060) 
AAV5-hFIXco-
Padua 
recombinant adeno-associated viral vector serotype 5 containing a 
codon-optimized Padua derivative of human coagulation factor IX 
cDNA (AMT-061) 
AAV8 
adeno-associated viral vector serotype 8 
ADR 
adverse drug reaction 
AE 
adverse event 
AFP 
Alpha-fetoprotein 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
APOE 
Apolipoprotein E 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
ATMP 
advanced therapy medicinal product 
BDD-FVIII 
B-domain deleted factor VIII 
 
 
cDNA 
complementary deoxyribonucleic acid 
CHMP 
Committee for Medicinal Products for Human Use 
Cmax 
Maximum concentration 
CMV 
Cytomegalovirus 
COVID-19 
Coronavirus Disease 2019 
CRA 
clinical research associate 
CRO 
Contract Research Organization 
CRP 
c-reactive protein 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
eCRF 
electronic case report form 
ELISA 
enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 
EU 
European Union 
 
 
 
FDA 
Food and Drug Administration 
FVIII 
factor VIII 
FIX 
coagulation factor IX 
GFP 
green fluorescent protein 
ɣGT 
gamma-glutamyl transferase 
gc 
genome copies 
CSL Behring 
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CCI
CCI

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
Page 11 of 112 
GCP 
Good Clinical Practice 
GTWP 
Gene Therapy Working Party 
h 
hour 
hAAT 
human α1-antitrypsin 
HBeAg 
hepatitis B extracellular antigen 
HBsAg 
hepatitis B surface antigen  
HBV 
hepatitis B virus 
HCV 
hepatitis C virus  
hFIX 
human coagulation factor IX 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use (previously International Conference on 
Harmonisation) 
ICF 
Informed Consent Form 
iCSR 
interim Clinical Study Report 
IEC 
Independent Ethics Committee 
IFNγ 
interferon gamma 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
IL-1β 
interleukin-1beta 
IL-2 
interleukin-2 
IL-6 
interleukin-6 
IMP 
investigational medicinal product 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
IU 
international unit 
IV 
intravenous 
LTR 
Long terminal repeat 
MCP-1 
monocyte chemotactic protein-1 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHRA 
Medicines and Healthcare Products Regulatory Agency (UK) 
NAb 
Neutralizing antibody 
NHP 
non-human primate 
PBGD 
porphobilinogen deaminase 
PCR 
polymerase chain reaction 
qPCR 
quantitative (real-time) polymerase chain reaction 
RNA 
ribonucleic acid 
CSL Behring 
CCI
CCI
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CCI
CCI
CCI
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CCI
CCI

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
Page 12 of 112 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SOC 
System Organ Class 
SUSAR 
suspected unexpected serious adverse reactions 
TEAE 
treatment emergent adverse event 
UK 
United Kingdom 
ULN 
Upper limit of normal 
US 
United States 
VAS 
Visual Analogue Scale 
w 
week 
WFH 
World Federation of Hemophilia 
 
Definitions of Terms 
Baseline 
Baseline is defined as Day 0 prior to investigational medicinal product 
(IMP) administration (pre IMP) 
Continuous 
routine 
prophylaxis 
Continuous routine prophylaxis is defined as the intent of treating with an 
a priori defined frequency of infusions (e.g., twice weekly, once every two 
weeks, etc.) as documented in the medical records. 
CSL Behring 

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
Page 13 of 112 
CLINICAL TRIAL PROTOCOL SYNOPSIS 
Protocol Number:  
CT-AMT-061-01 
Investigational Medicinal Product: AMT-061 (AAV5-hFIXco-Padua; 
etranacogene dezaparvovec) 
Title of the Trial: Phase IIb, open-label, single-dose, single-arm, multi-center trial to confirm the Factor IX activity 
level of the serotype 5 adeno-associated viral vector containing the Padua variant of a codon-optimized human 
factor IX gene (AAV5-hFIXco-Padua, AMT-061) administered to adult subjects with severe or moderately severe 
hemophilia B. 
Planned Number of Subjects:  
Three subjects are planned to be treated. 
Planned Number of Sites and Site Location(s):  
It is planned to conduct this trial in approximately three sites in the United States (US) and European Union (EU). 
Coordinating Investigator 
 
Trial Period (Planned): 
First Subject Screening: Q2 2018 
Last Subject Last Visit: Q3 2023  
Clinical Phase: 
IIb 
Indication/Trial Population: 
Male subjects with severe or moderately severe hemophilia B. 
Objectives: 
Primary: To confirm that a single dose of 2 x 1013 genome copies (gc)/kg AMT-061 will result in factor IX (FIX) 
activity levels of ≥5% at six weeks after dosing 
Secondary: To assess further efficacy and safety of 2 x 1013 gc/kg AMT-061. 
Rationale: 
Somatic gene therapy for hemophilia B offers the potential for shift of the disease severity from severe to a moderate 
or mild hemophilic phenotype or complete amelioration through continuous endogenous production of factor IX 
protein after a single administration of adeno-associated viral vector particles. Even a small rise in constantly 
circulating factor IX protein can substantially ameliorate the bleeding phenotype.  
Robust preliminary efficacy and safety results have been obtained with AMT-060 in an ongoing Phase 1/2 trial 
(CT-AMT-060-01) in 10 subjects with hemophilia B. No screening failures due to high titers of pre-existing 
neutralizing antibodies against adeno-associated viral vector serotype 5 (AAV5) were encountered. An increased 
level of factor IX activity was observed after subjects in the low dose cohort and high dose cohort were treated with 
the AMT-060 at 5 x 1012 gc/kg and 2 x 1013 gc/kg, respectively. Clinically relevant endogenous factor IX activity 
(≥2% of normal circulating factor IX) was established in nine out of 10 subjects across both cohorts (five out of 
five in the high dose cohort). Continuous, regular prophylaxis was discontinued in eight out of nine subjects 
previously dependent on prophylaxis (four out of four in the high dose cohort). As of writing, factor IX expression 
levels remain stable and durable for up to 1.5 years without indications of loss of expression. A shift to mild 
hemophilia B phenotype (>5% of normal circulating factor IX) was achieved in two out of five subjects in the low 
dose and in four out of five subjects in the high dose cohort. A reduction/elimination in the use of factor IX 
replacement therapy and a lowering in the risk of bleeding events over time were demonstrated in both cohorts. 
The single intravenous (IV) infusion of AMT-060 was safe and well-tolerated in both the low- and high-dose 
cohorts. The most frequent adverse event (AE) related to gene therapy targeting the liver is alanine aminotransferase 
(ALT) elevation. One subject in the lower dose cohort and two subjects in the higher dose cohort had mild, 
asymptomatic, transient elevations of ALT. No change in factor IX activity and no T-cell response were seen in the 
subjects with ALT elevations. No subjects developed inhibitory antibodies against factor IX. 
The clinical benefit of AMT-060 was achieved with a factor IX protein-to-activity ratio of approximately 1. 
Modifying AMT-060 with the implementation of the naturally occurring PADUA variant (2 nucleotide change in 
the wild-type human factor IX - hereafter referred to as AMT-061) is expected to result in a factor IX protein-to-
activity ratio of approximately six. Although AMT-061 has yet to be studied in humans this design modification is 
anticipated to lead to a higher level of circulating factor IX activity at comparable levels of factor IX protein and 
thereby increase the likelihood of alleviating the need for exogenous therapy, including the need for on-demand 
CSL Behring 
I 
PPD

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
Page 14 of 112 
treatment of traumatic bleeds and selective prevention of a bleed (e.g., because of upcoming physical activity, 
sports, etc.). 
This isolated modification is a prospectively defined product improvement that will not influence other established 
safety characteristics of AAV5 at 2 x 1013 gc/kg such as the level of factor IX protein expressed with 2 x 1013gc/kg 
AMT-061, immune response against AAV5, the occurrence of manageable ALT elevations or risk of T-cell 
responses against transduced cells with potential concurrent loss of efficacy. 
In addition to the above, the continuous accumulation of clinical data from the use of AAV5 in hemophilia subjects 
suggests that AAV5 is associated with a very low risk of inducing immune responses that may lead to loss of the 
newly induced endogenous factor IX protein expression. Furthermore, low titers of pre-existing antibodies against 
AAV5 (using a highly sensitive assay), which may demonstrate neutralization of AAV5 transduction in in-vitro 
assays, have no apparent inhibitory effect in human studies at currently administered dose levels. As a consequence, 
future trials with AMT-061 (including this trial) will allow enrolment of subjects even in the presence of anti-
AAV5 antibodies.  
The strong efficacy (protein expression) and safety results obtained during the Phase 1/2 trial with AMT-060 
demonstrate 2 x 1013 gc/kg to be the optimal dose for use in future trials in terms of safety and efficacy. In addition, 
accumulated clinical and non-clinical data support the implementation of the prospectively defined product 
enhancement of AMT-061 at 2 x 1013 gc/kg for the pivotal trial. The primary aim of this trial is to confirm that a 
single dose of 2 x 1013 gc/kg AMT-061 will result in factor IX activity levels of ≥5%. An objective of the trial is to 
assess whether observed factor IX activity levels are within an expected range, to determine if 2 x 1013 gc/kg 
AMT-061 is suitable from efficacy point of view for administration in the pivotal Phase 3 trial. In addition, the 
safety profile of AMT-061 will be demonstrated. 
Investigational Medicinal Product, Dose, and Mode of Administration: 
The investigational medicinal product (IMP) is identified as AAV5-hFIXco-Padua (AMT-061; etranacogene 
dezaparvovec). AMT-061 is a recombinant AAV5 containing the Padua variant of a codon-optimized human 
factor IX complementary deoxyribonucleic acid (cDNA) under the control of a liver-specific promoter. The 
pharmaceutical form of AMT-061 is a solution for IV infusion.  
The single administered dose of AMT-061 is 2 x 1013 gc/kg. The subjects will be monitored for tolerance to the 
IMP and detection of immediate AEs for 24 hours (overnight stay) after dosing. The dosing of the subjects must be 
separated by a minimum of 14 calendar days to allow for subject safety monitoring and to ensure appropriate action 
can be taken in case any acute reactions are observed. 
Trial Design/Methodology: 
This is an open-label, single-dose, single-arm, multi-center trial, with a screening, a treatment + post-treatment 
follow-up phase, and a long-term follow-up phase. 
Screening 
Maximal six weeks prior to baseline subjects are screened for eligibility, and historical bleeding and factor IX use 
data will be collected. The subjects receive their electronic diary, and the Investigator/study nurse will train them 
in recording of the bleeding episodes and use of factor IX replacement therapy. From screening onwards, subjects 
will record their use of factor IX replacement therapy and bleeding episodes in this dedicated e-diary. Diary data 
will be reviewed on a continuous basis by the Investigator/study nurse. The period from screening up to baseline is 
considered a training period, after which the Investigator/study nurse will review and evaluate any problems with 
recording of e-diary data with the subject. The e-diary training can be repeated at any time during the trial as 
considered necessary by Investigator/study nurse. Baseline is defined as Day 0 prior to IMP administration 
(pre IMP).  
The screening period might be prolonged in consultation with the sponsor in case IMP administration needs to be 
delayed because of subjects experiencing a bleeding episode, surgery, or other event after screening which warrants 
this delay. 
IMP administration + Post-treatment follow-up phase 
At baseline (i.e., Day 0 pre IMP), eligibility will be confirmed. It is recommended that subjects complete the Patient 
Reported Outcomes (PROs) prior to other assessments. Baseline samples will be taken for safety and efficacy 
assessments, physical examination will be performed and 
 will be assessed. 
CSL Behring 
CCI

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
Page 15 of 112 
Once all baseline assessments have been performed and eligibility is confirmed, subjects will receive a single 
infusion of AMT-061. After IMP administration (post IMP), subjects will be monitored for tolerance to the IMP 
and detection of potential immediate AEs at the clinical trial site for 24 hours (overnight stay).  
At baseline, subjects will be administered a challenge dose of short-acting factor IX (40 IU/kg) for the factor IX 
recovery assessment. This challenge dose should provide subjects sufficient factor IX coverage for the initial two 
to three days post treatment. Three days after IMP administration, the subjects should visit the clinic for endogenous 
factor IX activity assessment. If the factor IX activity result is ≥5%, further factor IX prophylaxis will not be given. 
If the factor IX activity result is <5%, another dose of short-acting factor IX will be administered to the subject and 
endogenous factor IX activity assessment will be performed again at the Week 1 routine visit. In a previous trial 
with AMT-060, therapeutic levels of factor IX protein and resultant factor IX activity levels were seen as early as 
one week after treatment. 
Additional on-demand factor IX may be given after treatment with AMT-061, if considered necessary. If the 
endogenous factor IX activity ≥5%, factor IX prophylaxis will not be given and further management will be based 
on Investigator’s clinical judgement and subject preference. Re-initiation of factor IX continuous routine 
prophylaxis may be considered if the endogenous factor IX activity is between 2% and 5% in at least two 
consecutive laboratory measurements, based on the Investigator’s clinical judgment and subject preference. If 
endogenous factor IX activity is below 2% in at least two consecutive central lab measurements, continuous routine 
factor IX prophylaxis may be restarted.  
From baseline until Week 52, subjects continue recording their use of factor IX replacement therapy and bleeding 
episodes in the e-diary. Diary data will be reviewed on a continuous basis by the Investigator/study nurse. In 
addition to the subjects’ reporting of presumed bleeding episodes in the e-diary, the Investigator or designee will 
assess each bleeding episode, by describing the circumstances as well as the nature of the reported bleed in a bleed 
specific narrative as soon as possible but at least within 72 hours after it has been reported by the subject. In case 
the information provided in the e-diary is not sufficient to assess the presumed bleeding and describe it in a 
narrative, the subject needs to be called and/or visit the site. Further samples are taken for safety and efficacy 
laboratory parameters, physical examination will be performed, 
 will be assessed and subjects 
will complete the 
. Use of concomitant medication and occurrence of AEs will be continuously 
monitored. 
For ALT level increments of at least 2-fold baseline (i.e., pre-IMP), and/or greater than the upper limit of normal 
(ULN), by local or central laboratory, the Investigator should contact the Medpace and uniQure Medical Directors 
to discuss a clinical management plan on a case-by-case basis, including potential re-tests and/or initiation of 
corticosteroid treatment. In case of aspartate aminotransaminase (AST) level increments > ULN, the Investigator 
should contact the Medpace and uniQure Medical Directors and a similar discussion should take place. 
Subjects are followed for a total duration of 52 weeks, with weekly visits for the first 12 weeks, every 2nd week 
from Week 12 to Week 26, and every month from Week 26 to Week 52.  
One interim analysis will be performed after six weeks post-dose to determine the efficacy of AMT-061 in terms 
of factor IX activity. After 52 weeks post-dose and 2.5 years post-dose, the complete efficacy and safety data will 
be collected, locked, analyzed and reported in a Clinical Study Report (CSR) and a CSR addendum, respectively. 
At the end of the trial, all safety and efficacy data will be reported in a CSR addendum (5-year analysis). 
Long-term follow-up phase 
After post-treatment follow-up, subjects will enter a long-term follow-up phase for an additional four years to assess 
sustainability of efficacy and long-term safety. During this phase, subjects do not have to record e-diary data, but 
are expected to document factor IX usage and bleeding episode information in study-specific paper diaries. Subjects 
are expected to bring their long-term follow-up bleed diaries and long-term follow-up factor IX use diaries to every 
study visit during the long-term follow-up phase, and site staff will collect the new information at each visit. In 
between study visits, subjects should contact the site staff immediately in case of an experienced bleed and/or factor 
IX use in addition to completing the questions/information requested on the paper diaries to capture all information. 
Subjects will visit the clinic every half year for evaluation of efficacy parameters and safety. Beginning at the 
Month 30 visit, and at every visit thereafter (occurring every 6 months) until study completion, an abdominal 
ultrasound will be performed. Occurrence of AEs will be continuously monitored, with at least quarterly contact 
moments between site staff and subject to discuss. Adjustments to the visit location or schedule may be made to 
CSL Behring 
CCI
CCI

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
Page 16 of 112 
accommodate safety concerns and restrictions due to the Coronavirus Disease 2019 (COVID-19) pandemic. In all 
cases, subjects will be kept informed, via the site staff, as much as possible of changes to the study and monitoring 
plans that could impact them. 
Please refer to Table 1 through Table 4 for an overview of the assessments and testing performed throughout these 
different trial phases. 
Trial Assessments: 
Efficacy assessments include the e-diary for recording of bleedings and factor IX use, several laboratory parameters 
(including factor IX protein and activity levels), assessment of 
, and the 
 on general 
and disease specific 
. 
Safety is assessed by AEs, physical examination, and laboratory parameters. 
Inclusion and Exclusion Criteria: 
Inclusion Criteria:  
1. Male 
2. Age ≥18 years 
3. Subjects with congenital hemophilia B classified as one of the following: 
a. 
Known severe factor IX deficiency (<1% of normal circulating factor IX) for which the subject is either 
on continuous routine factor IX prophylaxis* or using on-demand factor IX replacement therapy 
b. Known moderately severe factor IX deficiency (1-2% of normal circulating factor IX, inclusive) and a 
severe bleeding phenotype as defined by at least one of the following: 
i. On continuous routine factor IX prophylaxis* for a history of bleeding 
ii. On demand factor IX replacement therapy with a history of frequent bleeding (4 or more bleeding 
episodes in the last 12 months) or chronic hemophilic arthropathy (pain, joint destruction, and loss 
of range of motion) in one or more joints 
4. >20 previous exposure days of treatment with factor IX protein 
5. Acceptance to use a condom during sexual intercourse in the period from IMP administration until AAV5 
has been cleared from semen, as evidenced by the central laboratory from negative analysis results for at 
least three consecutively collected semen samples (this criterion is applicable also for subjects who are 
surgically sterilized) 
6. Able to provide informed consent following receipt of verbal and written information about the trial. 
* Continuous routine prophylaxis is defined as the intent of treating with an a priori defined frequency of infusions (e.g., twice 
weekly, once every two weeks, etc.) as documented in the medical records  
 
Exclusion Criteria: 
1. History of factor IX inhibitors 
2. Positive factor IX inhibitor test at screening 
3. Screening laboratory values: 
a. 
ALT >2 times ULN 
b. AST >2 times ULN 
c. 
Total bilirubin >2 times ULN 
d. Alkaline phosphatase (ALP) >2 times ULN 
e. 
Creatinine >2 times ULN 
4. Positive human immunodeficiency virus (HIV) serological test at screening, not controlled with anti-viral 
therapy as shown by CD4+ counts ≤200/μL or by a viral load of >200 copies/mL 
5. Active infection with hepatitis B or C virus as reflected by hepatitis B surface antigen (HBsAg), hepatitis B 
extracellular antigen (HBeAg), hepatitis B virus deoxyribonucleic acid (HBV DNA) or hepatitis C virus 
ribonucleic acid (HCV RNA) positivity, respectively, at screening 
6. History of hepatitis B or C exposure, currently controlled by antiviral therapy 
CSL Behring 
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CCI

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
Page 17 of 112 
7. Known coagulation disorder other than hemophilia B 
8. Thrombocytopenia, defined as a platelet count below 50 × 109/L, at screening 
9. Known severe infection or any other significant concurrent, uncontrolled medical condition including, but 
not limited to, renal, hepatic, cardiovascular, hematological, gastrointestinal, endocrine, pulmonary, 
neurological, cerebral or psychiatric disease, alcoholism, drug dependency or any other psychological 
disorder evaluated by the Investigator to interfere with adherence to the protocol procedures or with the 
degree of tolerance to the IMP 
10. Known significant medical condition that may significantly impact the intended transduction of the vector 
and/or expression and activity of the protein, such as disseminated intravascular coagulation, accelerated 
fibrinolysis, and profound liver fibrosis 
11. Known history of an allergic reaction or anaphylaxis to factor IX products 
12. Known uncontrolled allergic conditions or allergy/hypersensitivity to any component of the IMP excipients 
13. Known medical condition that would require chronic administration of steroids 
14. Previous gene therapy treatment 
15. Receipt of an experimental agent within 60 days prior to screening 
16. Current participation or anticipated participation within one year after IMP administration in this trial in any 
other interventional clinical trial involving drugs or devices 
Maximum Duration of Subject Involvement in the Trial: 
 
Planned duration of screening period: maximal six weeks 
 
Planned duration of treatment: 1 day (single dose) 
 
Planned duration of follow-up: 52 weeks, plus long-term safety follow-up until Month 60 
Endpoints:  
The primary aim of the trial is to demonstrate that AMT-061 will provide a minimal therapeutic response of ≥5% 
factor IX activity using a dose of 2 x 1013 gc/kg. This is the proposed dose to be used in a further pivotal Phase 3 
trial. The primary efficacy parameter is factor IX activity level at six weeks after dosing (at Week 6 post AMT-061 
dose). 
Secondary efficacy endpoints comprise of endogenous factor IX activity level at Week 6 and Week 52 post 
AMT-061 dose, remaining free of previous continuous routine prophylaxis during 52 weeks following AMT-061 
dosing, total usage of factor IX replacement therapy until 52 weeks following AMT-061 dosing (excluding ad hoc 
prophylaxis for invasive procedures), and annualized bleeding rate after 52 weeks of AMT-061 dosing (including 
a further break down of the frequency and percentage of spontaneous, traumatic, and joint bleeding events). 
 
 
Secondary safety endpoints include AEs, hematology and serum chemistry parameters, ALT/AST levels and 
corticosteroid use for ALT/AST elevations, parameters on antibody formation to AAV5 and human factor IX, 
AAV5 capsid-specific T cell response, inflammatory markers, vector DNA in semen and blood, and alpha-
fetoprotein (AFP). Safety endpoints are observed over the 52-week post-treatment follow-up phase and for an 
additional four years in the long-term follow-up phase. 
Statistical Analysis: 
There is no formal sample size calculation performed for this trial. From a clinical perspective, N=3 subjects is 
considered sufficient to provide a reliable impression on the factor IX activity levels that will be demonstrated with 
a single dose of 2 x 1013 gc/kg AMT-061 at six weeks after dosing.  
Considering the small sample size used in this trial, all presentations will be descriptive in nature. Plots, tabular 
displays, and listings will be created, visualizing individual effects for selected efficacy and safety measures. If 
applicable, continuous variables will be summarized with descriptive statistics including: the number of non-
missing values, mean, standard deviation, median, minimum, and maximum. In some cases, the standard error of 
the mean and/or confidence intervals may be provided as well. Categorical variables will be summarized by 
CSL Behring 
CCI

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
Page 18 of 112 
number, percent of subjects, and if applicable, the number of events. No formal inferential statistical analyses will 
be performed, and no analysis population will be defined. All available data will be used in the presentations. 
Analyses will be based on central laboratory measurements if results are available from both local and central 
laboratories. 
After six weeks post-dose, an interim analysis for efficacy will be done using the available data on factor IX activity 
and safety data will be evaluated. The results will be reported in an interim CSR. The rationale for the six weeks 
cut-off is based on data from the Phase 1/2 trial that demonstrated a very fast initial transduction of AAV5 and 
expression of the endogenous factor IX protein within the first week that reached a relatively stable peak level 
within the first six weeks of follow-up.  
After 52 weeks post-dose and 2.5 years post-dose, efficacy and safety data will be collected on all subjects. Those 
data will be locked, analyzed, and reported in a CSR (52-week analysis) and CSR addendum (2.5-year analysis). 
At the end of the 4-year long-term follow-up period (60 months/5 years post-dose), efficacy and safety data will be 
collected on all subjects. The data will be locked, analyzed, and reported in a CSR addendum (5-year analysis). 
CSL Behring 

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
Page 19 of 112 
Trial Schedules 
Table 1 Flow Chart for Efficacy and Safety Evaluation, for Screening, IMP Administration + Post-Treatment Follow-up (Week -6 to Week 52) 
Trial Period 
Screening 
IMP 
Administration 
Post-treatment Follow-up 
Additional 
Visits a 
Weeks/Day 
W-6  
D0  
pre IMP b  
D0  
0h 
D0 
post IMP 
D1 
D3 
W1 to 12 b, c  
(1 visit/W) 
W14 to 26 b, c 
(every 2nd W) 
W31 to 48 b, c 
(1 visit/month)  
W52 b, c 
 
Visit Window (Days) 
0 
0 
0 
0 
0 
±1 
±2  
±3 
±5 
±5 
 
Informed consent 
x 
 
 
 
 
 
 
 
 
 
 
In-/exclusion criteria 
x 
x 
 
 
 
 
 
 
 
 
 
Medical history 
x 
x 
 
 
 
 
 
 
 
 
 
Collection of historical 
bleeding and factor IX use 
data 
x 
 
 
 
 
 
 
 
 
 
 
24-hr stay at clinic 
 
x-----------------------------------------x 
 
 
 
 
 
 
Administration of IMP 
 
 
x 
 
 
 
 
 
 
 
 
Discharge and hand-out of 
subject treatment card d 
 
 
 
 
x 
 
 
 
 
 
 
Concomitant medication 
Continuous 
(x) a 
Vital signs (blood 
pressure, pulse, body 
temperature) 
x 
x 
 
x h 
x h 
 
 
 
 
 
(x) a 
Physical examination 
x 
x 
 
 
 
 
x 
x 
x 
x 
(x) a 
Height 
x 
 
 
 
 
 
 
 
 
 
 
Body weight 
x 
 
 
 
 
 
 
 
 
 
(x) a 
Blood & semen sampling 
(see Table 2) 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 
(x) a 
Subject hand-out e-diary 
device and e-diary 
instruction e 
x 
 
 
 
 
 
 
 
 
 
 
Recording of e-diary data 
by subject 
(bleeding episodes, 
factor IX replacement 
therapy) 
Continuous 
 
Review of e-diary data by 
Investigator/study nurse  
Continuous 
(x) a 
CSL Behring 

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
Page 20 of 112 
Trial Period 
Screening 
IMP 
Administration 
Post-treatment Follow-up 
Additional 
Visits a 
Weeks/Day 
W-6
D0 
pre IMP b 
D0 
0h 
D0 
post IMP 
D1 
D3 
W1 to 12 b, c 
(1 visit/W) 
W14 to 26 b, c 
(every 2nd W) 
W31 to 48 b, c 
(1 visit/month) 
W52 b, c 
Visit Window (Days) 
0 
0 
0 
0 
0 
±1 
±2 
±3 
±5 
±5 
Collection of e-diary 
device 
x 
Subjects provided with 
paper diaries and paper 
diary instruction for Long- 
term Follow-up Phase 
x 
Adjudication of bleeding 
episode(s) by Investigatorf 
Continuous 
(x) a
x 
x (w26) 
x 
x 
x (w26) 
x 
x 
x (w26) 
x 
x 
x (w26) 
x 
x 
x (w26) 
x 
x 
x 
Adverse events 
Continuous 
(x) a
 IMP: investigational medicinal product; 
; W: week. 
a.
An additional visit can be performed at any time for the purpose of conduct of one or more procedures listed in the column “Additional Visits” according to the choice of the
Investigator. Hence, “(x)” refers to a procedure that can be performed, if judged relevant by the Investigator.
b.
For subjects on routine prophylactic factor IX replacement therapy, these visits should take place on the day that routine prophylactic factor IX replacement treatment is
planned to be administered. At these visits, blood sampling will then take place prior to administration of prophylactic factor IX replacement therapy. If a subject uses
additional on-demand factor IX replacement treatment, his upcoming study visit may need to be re-scheduled (to the extent the visit window allows) so that the visit takes
place at the time the subject resumes his routine prophylaxis schedule. For subjects only using on-demand factor IX replacement therapy (only applicable after AMT-061
administration), his upcoming study visit may need to be re-scheduled (to the extent the visit window allows) so that the visit does not take place within 10 days of any on-
demand factor IX product use.
c.
Each visit is scheduled in relation to date of IMP administration, not in relation to the date of its previous visit.
d.
When all assessments at 24 hours after IMP administration are performed, the subject treatment card will be handed out and the subject may leave the clinic.
e.
Instruction can be repeated at any visit as deemed necessary by the Investigator or study nurse.
f.
The Investigator or designee will assess each bleeding episode, by describing the circumstances as well as the nature of the reported bleed in a bleed specific narrative as soon
as possible but at least within 72 hours after it has been reported by the subject.
g.
It is recommended that the 
 (
) are completed by the subject, before he is seen by the
Investigator and/or study nurse for interview and before other (trial specific) assessments are performed, as well as before the administration of IMP, in order for the answers
not to be influenced by the information given by the physician, by the administration of IMP, or by early side-effects of the IMP or (trial related) assessments. At each visit,
the questionnaires are to be completed in the same order every time, following the order presented in the protocol.
h.
Vital signs (blood pressure, pulse, body temperature) will be measured at t=0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours after the IMP infusion has been completed.
CSL Behring 
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CCI

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
Page 21 of 112 
Table 2 Flow Chart for Laboratory Parameters, for Screening, IMP Administration + Post-Treatment Follow-up (Week -6 to Week 52) 
Trial Period 
Screening 
IMP 
Administration 
Post-treatment Follow-up 
Additional 
Visits a 
Weeks/Day 
W-6  
D0 
pre IMP b 
D0 
post IMP 
D1 
D3 
W1 to 12 b, c 
(1 visit/W)  
W14 to 26 b, c 
(every 2nd W)  
W31 to 48 b, c 
(1 visit/month)  
W52 
b, c 
 
Hours After IMP 
Infusion Completed 
 
 
1h 
2h 
3h 
24h 
 
 
 
 
 
 
Visit Window (Days) 
 
 
±15 minutes 
±15 
minutes 
±1 
±2 
±3 
±5 
±5 
 
Local Laboratory 
 
 
 
 
 
 
 
 
 
 
 
Factor IX: one-stage 
aPTT for factor IX 
activity for local 
monitoring  
 
x 
 
 
 
 
x 
x 
x 
x 
x 
(x) a 
Factor IX inhibitors 
(Bethesda assay or 
Nijmegen modified 
Bethesda assay) for local 
monitoring and eligibility 
check d 
x 
x 
 
 
 
 
 
x: W6, 12 
x: W26 
 
x 
(x) a 
Transaminases (AST/ 
ALT) for local 
monitoring e 
x 
x 
 
 
 
 
 
x 
x 
x 
x 
(x) a 
Central Laboratory 
 
 
 
 
 
 
 
 
 
 
 
One-stage aPTT for 
factor IX activity  
 
x 
 
 
 
 
 
x 
x 
x 
x 
(x) a 
Chromogenic assay for 
factor IX activity f 
 
x 
 
 
 
 
 
x 
x 
x 
x 
(x) a 
Factor IX protein 
concentration 
 
x 
 
 
 
 
 
x 
x 
x 
x 
(x) a 
Anti-factor IX antibodies 
 
x 
 
 
 
 
 
x: W6, 12 
x: W26 
 
x 
(x) a 
Factor IX inhibitors  
(Nijmegen modified 
Bethesda assay) d 
x 
x 
 
 
 
 
 
x: W6, 12 
x: W26 
 
x 
(x) a 
Factor IX Recovery g 
 
x 
 
 
 
 
 
 
 
 
 
(x) a 
Total (IgM and IgG) 
antibodies to AAV5 
x 
x 
 
 
 
 
 
x: W1, 2, 3, 
4, 5, 6, 12 
x: W26 
 
x 
(x) a 
Neutralizing antibodies 
to AAV5 
x 
x 
 
 
 
 
 
x: W1, 2, 3, 
4, 5, 6, 12 
x: W26 
 
x 
(x) a 
AAV5 capsid-specific 
T cells  
 
x 
 
 
 
 
 
x 
x 
x 
x 
(x) a 
CSL Behring 
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AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
Page 22 of 112 
Trial Period 
Screening 
IMP 
Administration 
Post-treatment Follow-up 
Additional 
Visits a 
Weeks/Day 
W-6
D0 
pre IMP b 
D0 
post IMP 
D1 
D3 
W1 to 12 b, c 
(1 visit/W)  
W14 to 26 b, c 
(every 2nd W) 
W31 to 48 b, c 
(1 visit/month) 
W52 
b, c 
Hours After IMP 
Infusion Completed 
1h 
2h 
3h 
24h 
Visit Window (Days) 
±15 minutes 
±15 
minutes 
±1 
±2 
±3 
±5 
±5 
Sampling for vector 
genome detection: 
-
Blood h
x 
x 
x 
x 
x 
x 
x 
x 
x 
(x) a
-
Semen h
x 
x:W6, 12 
x:W16, 26 
x 
(x) a
Inflammatory markers 
IL-1β, IL-2, IL-6, IFNγ, 
MCP-1 
x 
x 
x 
x 
x 
(x) a
Alpha-fetoprotein 
x 
(x) a
Hematology and 
coagulation parameters i 
x 
x 
x 
x 
x 
x 
(x) a
Serum chemistry 
parameters j 
x 
x 
x (only 
CRP) 
x 
x 
x 
x 
(x) a
HIV, viral load, CD4+ 
x 
HBsAg, HBeAg, HBV 
DNA and HCV RNA 
x 
Factor IX gene 
sequencing k 
x 
Blood sample for future 
research l 
x 
x 
x: W12 
x 
AAV5: adeno-associated viral vector serotype 5; ALT: alanine aminotransferase; aPTT: activated partial thromboplastin time; AST: aspartate aminotransferase; CRP: C-Reactive 
Protein; DNA: deoxyribonucleic acid; h: hour; HBeAg: hepatitis B extracellular antigen; HBsAg: hepatitis B surface antigen; HBV: hepatitis B virus; HCV RNA: hepatitis C virus 
ribonucleic acid; HIV: human immunodeficiency virus; IFNγ: interferon gamma; IgG: immunoglobulin G; IgM: immunoglobulin M; IL: interleukin: IMP: investigational 
medicinal product; MCP-1: monocyte chemotactic protein-1. 
a.
An additional visit can be performed at any time for the purpose of conduct of one or more procedures listed in the column “Additional Visits” according to the choice of the
Investigator. Hence, “(x)” refers to a procedure that can be performed, if judged relevant by the Investigator.
b.
For subjects on routine prophylactic factor IX replacement therapy, these visits should take place on the day that routine prophylactic factor IX replacement treatment is
planned to be administered. At these visits, blood sampling will then take place prior to administration of prophylactic factor IX replacement therapy. If a subject uses
additional on-demand factor IX replacement treatment, his upcoming study visit may need to be re-scheduled (to the extent the visit window allows) so that the visit takes
place at the time the subject resumes his routine prophylaxis schedule. For subjects only using on-demand factor IX replacement therapy (only applicable after AMT-061
administration), his upcoming study visit may need to be re-scheduled (to the extent the visit window allows) so that the visit does not take place within 10 days of any on-
demand factor IX product use.
c.
Each visit and time point is scheduled in relation to date of IMP administration, not in relation to the date of its previous visit or time point.
d.
In case of a positive test for factor IX inhibitors, a re-test should be performed with two weeks to confirm the positive test. The subject should be called in for an additional
visit in case no routine visit is scheduled within this two-week timeframe.
CSL Behring 
I 
I 

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
Page 23 of 112 
e.
For ALT level increments of at least 2-fold baseline (i.e., pre-IMP) and/or > upper limit of normal (ULN), by local or central laboratory, the Investigator should contact the
Medpace and uniQure Medical Directors to discuss a clinical management plan, on a case-by-case basis, including potential re-tests and/or initiation of corticosteroid
treatment. In case of AST level increments > ULN, the Investigator should contact the Medpace and uniQure Medical Directors and a similar discussion should take place.
f.
No additional blood will be drawn for the chromogenic assay; the test will be performed on backup samples.
g.
At suspicion of factor IX inhibitor, the factor IX recovery assessment should be repeated. Blood samples for factor IX recovery assessment should be drawn just prior to
administering the factor IX challenge dose (40 U/kg) and at 30 minutes after the factor IX challenge dose is administered.
h.
Sampling for the individual subject and for a specific matrix (i.e., blood or semen) is only to be continued until 3 consecutive negative samples have been detected for the
subject for that particular type of matrix. The sampling schedule (frequency) may be increased as agreed between the Investigator and subject following the notification of a
first negative result on blood and/or semen, expediting the opportunity to reach three consecutive negative samples on the specific matrix. Based on the wish of the subject,
semen samples can be collected at home prior to attending the visit (at the visit day or at the day before the visit day). Also, the frequency of semen sampling may be reduced
(to be agreed between Investigator and subject) as long as the subject uses a condom during sexual intercourse until 3 consecutive negative samples have been detected.
i.
For hematology: Hemoglobin, hematocrit, platelet count, red blood cells, white blood cells with differential count (all expressed in % as well as in absolute numbers); for
coagulation: aPTT and prothrombin time (or INR [International Normalized Ratio])).
j.
Serum electrolytes (sodium, potassium), creatinine, creatine kinase, gamma-glutamyltransferase (ɣGT), AST, ALT, alkaline phosphatase (ALP), CRP, albumin, total
bilirubin, glucose (non-fasting).
k.
Only if factor IX gene mutation information is not available and if separate informed consent for factor IX gene sequencing analysis is given by the subject. Preferably at the
screening visit, but otherwise at a later time point during the subject’s trial participation.
l.
Only if separate informed consent is given by the subject.
CSL Behring 

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
Page 24 of 112 
Table 3 Flow Chart for Efficacy and Safety Evaluation, for Long-Term Follow-up (up to Month 60) 
Trial Period 
Long-Term Follow-up 
Additional 
Visits a 
Months 
18 b, c 
24 b, c 
30 b, c 
36 b, c 
42 b, c 
48 b, c 
54 b, c 
60 b, c 
Visit Window (Weeks) 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
Concomitant medication 
Continuous 
(x) a
Collection of bleeding and factor IX 
use data d 
x 
x 
x 
x 
x 
x 
x 
x 
(x) a
Physical examination 
x 
x 
x 
x 
x 
x 
x 
x 
(x) a
Blood & semen sampling (see Table 4) 
x 
x 
x 
x 
x 
x 
x 
x 
(x) a
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Abdominal ultrasound f 
x 
x 
x 
x 
x 
x 
(x) a
Adverse events g 
Continuous 
; IMP: investigational 
medicinal product; 
a.
An additional visit can be performed at any time for the purpose of conduct of one or more procedures listed in the column “Additional Visits” according to the choice of the 
Investigator. Hence, “(x)” refers to a procedure that can be performed, if judged relevant by the Investigator.
b.
Each visit and time point is scheduled in relation to date of IMP administration, not in relation to the date of its previous visit or time point.
c.
For subjects on routine prophylactic factor IX replacement therapy, these visits should take place on the day that routine prophylactic factor IX replacement treatment is planned to be 
administered. At these visits, blood sampling will then take place prior to administration of prophylactic factor IX replacement therapy. If a subject uses additional on-demand factor IX
replacement treatment, his upcoming study visit may need to be re-scheduled (to the extent the visit window allows) so that the visit takes place at the time the subject resumes his
routine prophylaxis schedule. For subjects only using on-demand factor IX replacement therapy (only applicable after AMT-061 administration), his upcoming study visit may need to 
be re-scheduled (to the extent the visit window allows) so that the visit does not take place within 10 days of any on-demand factor IX product use.
d.
Subjects will record bleeding episodes and factor IX replacement therapy use in their study-specific paper long-term follow-up bleed diary and paper long-term follow-up factor IX use 
diary, which they will bring to every study visit. Site staff will collect the information that is new since the previous visit in the paper diaries. In between study visits, subjects should
contact the site staff immediately in case of an experienced bleed and/or factor IX use in addition to completing the questions/information requested on the paper diaries.
e.
It is recommended that the 
 (
) are completed by the subject before he is seen by the physician for 
interview and before other (trial specific) assessments are performed, as well as before the administration of IMP, in order for the answers not to be influenced by the information given 
by the physician, by the administration of IMP, or by early side-effects of the IMP or (trial related) assessments. During the screening visit, the 
 are completed after 
ICF signature, but before other (trial specific) assessments are performed. At each visit, the questionnaires are to be completed in the same order every time, following the order 
presented in the protocol. The questionnaires are to be completed under site supervision at the site. For those subjects where the Month 24, Month 36, Month 48, and/or Month 60 visits 
are impacted by COVID-19, the questionnaires may be conducted at the site within the following window: up to -1 month prior to the target visit, up to +2 months after the target visit, 
and at least 4 months after the last assessment. Adjustments to the visit timing within this window are to be documented. 
f.
For those subjects where Month 30, Month 36, Month 42, Month 48, Month 54, and/or Month 60 visits are impacted by COVID-19, abdominal ultrasounds may be conducted within the 
following window: up to -1 month prior to the target visit and up to +1 month after the target visit. Adjustments to the visit timing within this window are to be documented.
g.
After week 52, the visit frequency is every 26 weeks (6 months). In this long-term follow-up phase there should be at least quarterly contact between the site staff and subject to monitor
the occurrence of adverse events.
CSL Behring 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
Page 25 of 112 
Table 4 Flow Chart for Laboratory Parameters, for Long-Term Follow-up (up to Month 60) 
Trial Period 
Long-Term Follow-up 
Additional 
Visits a 
Months  
18 b, c 
24 b, c 
30 b, c 
36 b, c 
42 b, c 
48 bb, c 
54 b, c 
60 b, c 
 
Visit Window (Weeks) 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
±2 
 
Local Laboratory 
 
 
 
 
 
 
 
 
 
Factor IX: one-stage aPTT for factor IX 
activity for local monitoring  
 
 
x 
x 
x 
x 
x 
x 
(x) a 
Transaminases (AST/ ALT) for local 
monitoring d 
 
 
x 
x 
x 
x 
x 
x 
(x) a 
Central Laboratory 
 
 
 
 
 
 
 
 
 
One-stage aPTT for factor IX activity 
x 
x 
x 
x 
x 
x 
x 
x 
(x) a 
Chromogenic assay for factor IX 
activity e 
x 
x 
x 
x 
x 
x 
x 
x 
(x) a 
Factor IX protein concentration 
x 
x 
x 
x 
x 
x 
x 
x 
(x) a 
Anti-factor IX antibodies  
 
x 
 
x 
 
x 
 
x 
(x) a 
Factor IX inhibitors  
(Nijmegen modified Bethesda assay) f 
 
x 
 
x 
 
x 
 
x 
(x) a 
factor IX Recovery g 
 
 
 
 
 
 
 
 
(x) a 
Total (IgM and IgG) antibodies to 
AAV5 
 
x 
 
x 
 
x 
 
x 
(x) a 
Neutralizing antibodies to AAV5 
 
x 
 
x 
 
x 
 
x 
(x) a 
Sampling for vector genome detection: 
 
 
 
 
 
 
 
 
 
- Blood h 
x 
x 
x 
x 
x 
x 
x 
x 
(x) a 
- Semen h 
x 
x 
x 
x 
x 
x 
x 
x 
(x) a 
Alpha-fetoprotein 
x 
x 
x 
x 
x 
x 
x 
x 
(x) a 
Hematology and coagulation 
parameters i 
x 
x 
x 
x 
x 
x 
x 
x 
(x) a 
Serum chemistry parameters j 
x 
x 
x 
x 
x 
x 
x 
x 
(x) a 
AAV5: adeno-associated viral vector serotype 5; ALT: alanine aminotransferase; aPTT: activated partial thromboplastin time; AST: aspartate aminotransferase; IgG: 
immunoglobulin G; IgM: immunoglobulin M; IMP: investigational medicinal product. 
a. 
An additional visit can be performed at any time for the purpose of conduct of one or more procedures listed in the column “Additional Visits” according to the choice of the 
Investigator. Hence, “(x)” refers to a procedure that can be performed, if judged relevant by the Investigator. 
b. 
Each visit and time point is scheduled in relation to date of IMP administration, not in relation to the date of its previous visit or time point. 
c. 
For subjects on routine prophylactic factor IX replacement therapy, these visits should take place on the day that routine prophylactic factor IX replacement treatment is 
planned to be administered. At these visits, blood sampling will then take place prior to administration of prophylactic factor IX replacement therapy. If a subject uses 
additional on-demand factor IX replacement treatment, his upcoming study visit may need to be re-scheduled (to the extent the visit window allows) so that the visit takes 
place at the time the subject resumes his routine prophylaxis schedule. For subjects only using on-demand factor IX replacement therapy (only applicable after AMT-061 
CSL Behring 

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
Page 26 of 112 
administration), his upcoming study visit may need to be re-scheduled (to the extent the visit window allows) so that the visit does not take place within 10 days of any on-
demand factor IX product use. 
d. 
For ALT level increments of at least 2-fold baseline (i.e., pre-IMP) and/or > upper limit of normal (ULN), by local or central laboratory, the Investigator should contact the 
Medpace and uniQure Medical Directors to discuss a clinical management plan, on a case-by-case basis, including potential re-tests and/or initiation of corticosteroid 
treatment. In case of AST level increments > ULN, the Investigator should contact the Medpace and uniQure Medical Directors and a similar discussion should take place. 
e. 
No additional blood will be drawn for the chromogenic assay; the test will be performed on backup samples. 
f. 
In case of a positive test for factor IX inhibitors, a re-test should be performed with two weeks to confirm the positive test. The subject should be called in for an additional 
visit in case no routine visit is scheduled within this two-week timeframe. 
g. 
At suspicion of factor IX inhibitor, the factor IX recovery assessment should be repeated. Blood samples for factor IX recovery assessment should be drawn just prior to 
administering the factor IX challenge dose (40 U/kg) and at 30 minutes after the factor IX challenge dose is administered. 
h. 
Sampling for the individual subject and for a specific matrix (i.e., blood or semen) is only to be continued until 3 consecutive negative samples have been detected for the 
subject for that particular type of matrix. The sampling schedule (frequency) may be increased as agreed between the Investigator and subject following the notification of a 
first negative result on blood and/or semen, expediting the opportunity to reach three consecutive negative samples on the specific matrix. Based on the wish of the subject, 
semen samples can be collected at home prior to attending the visit (at the visit day or at the day before the visit day). Also, the frequency of semen sampling may be reduced 
(to be agreed between Investigator and subject) as long as the subject uses a condom during sexual intercourse until 3 consecutive negative samples have been detected. 
Semen samples are only to be collected as applicable.  
i. 
For hematology: hemoglobin, hematocrit, platelet count, red blood cells, white blood cells with differential count (all expressed in % as well as in absolute numbers); for 
coagulation: aPTT and prothrombin time (or INR [International Normalized Ratio]). 
j. 
Serum electrolytes (sodium, potassium), creatinine, creatine kinase, gamma-glutamyltransferase (ɣGT), aspartate aminotransferase (AST), alanine transaminase (ALT), 
alkaline phosphatase (ALP), C-Reactive Protein (CRP), albumin, total bilirubin, glucose (non-fasting). 
CSL Behring 

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
Page 27 of 112 
1 INTRODUCTION 
1.1 Condition Background and Current Treatment 
Congenital hemophilia B is an inherited bleeding disorder characterized by an increased bleeding 
tendency due to either a partial or complete deficiency of the essential blood coagulation 
factor IX (FIX). The deficiency is the result of mutations of the respective clotting factor genes. 
Hemophilia B is an X-linked, recessive condition, since it occurs almost exclusively in males. 
Females typically are asymptomatic carriers. The number of people with hemophilia B 
worldwide is approximately 30,000 and in the United States (US) alone is approximately 4,000 
(World Federation of Haemophilia [WFH], 2017). Approximately 1 in 20,000 - 50,000 live male 
newborns has hemophilia B.  
The severity of symptoms can vary and the severe forms become apparent early in life. About 
one-third of individuals with hemophilia B have a severe disorder characterized by functional 
factor IX levels that are less than 1% of normal (Kessler & Mariani, 2006). Moderate and mild 
hemophilia B, with 1 - 5% or 5 - <40% of normal factor IX level, respectively, are each observed 
in about one-third of patients (Kessler & Mariani, 2006).  
Bleeding is the main symptom of the disease and usually increases when the infant becomes 
mobile. Mild cases may go unnoticed until later in life, when they occur in response to surgery or 
trauma. In severe or moderate hemophilia internal bleeding may occur anywhere, but bleeding 
into joints is most common (National Heart, Lung, and Blood Institute, 2013). Severe recurrent 
bleedings may lead to severe arthropathy, joint contractures and pseudotumors, resulting in 
chronic pain, disability and reduced 
 (Bolton-Maggs et al., 2003). As few as 
one to two bleeds can trigger progressive, irreversible joint disease (Gater et al., 2011).  
The overall life expectancy in severe hemophilia is 63 years, which is about 15 years lower than 
general male population (Darby et al., 2007). Life expectancy in patients without liver 
complications (e.g., human immunodeficiency virus [HIV] or hepatitis C) can approach that of 
the general male population (Plug et al, 2006; Osooli et al 2017).  
There is no cure for hemophilia B. The primary goals of hemophilia B therapy are the prevention 
of bleeding episodes, rapid and definitive treatment of bleeding episodes (breakthrough bleeds) 
that occur even while on a regular prophylactic regimen and provision of adequate hemostasis 
during surgery and emergencies. Currently, these goals are essentially met for hemophilia B 
subjects by intravenous (IV) injections of commercially available recombinant- or 
plasma-derived factor IX products, either at the time of a bleed (on-demand) or by regular 
infusions up to several times a week (prophylactically). The recent approvals of extended half-
life factor IX products allow for reduced frequency of factor administration (once every 7 to 21 
days) and maintaining a higher factor IX trough level (Taylor and Kruse-Jarres, 2016). 
CSL Behring 
CCI

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
Page 28 of 112 
1.2 Gene Therapy Therapeutic Concept 
Somatic gene therapy offers the potential for a shift of the disease severity phenotype from 
severe to a moderate or mild hemophilia phenotype or complete amelioration through continuous 
production of stable factor IX levels after a single administration of vector, especially since a 
small rise in circulating factor IX to at least 1% of normal levels can substantially ameliorate the 
bleeding phenotype and thus improve the 
 for patients. 
1.3 Investigational Product Background 
The company has developed AMT-060, a recombinant adeno-associated viral vector serotype 5 
(AAV5) containing the wild-type human factor IX (hFIX) gene, codon-optimized for optimal 
expression in humans, under control of a liver-specific promoter (AAV5-hFIXco or AMT-060). 
AMT-060 has been studied in a Phase 1/2 clinical trial. The investigational medicinal product 
(IMP) that will be used in the current protocol is a derivative of AMT-060: the same recombinant 
AAV5 containing the codon-optimized wild-type human factor IX gene, incorporating a two-
nucleotide change in order to express the naturally occurring Padua variant of human coagulation 
factor IX complementary DNA (cDNA), i.e., AMT-061 or AAV5-hFIXco-Padua. The FIX-
Padua protein differs from the ‘wild-type’ human factor IX protein by a single amino acid and 
possesses a specific activity approximately 6-fold higher than wild-type.  
This is a first-in-human clinical trial for AMT-061. Both AMT-060 and AMT-061 employ the 
same AAV5 capsid as vector and liver-specific promoter, conferring similar safety and 
expression profiles. Section 1.3.1 provides a summary of the preclinical information for 
AMT-060 and AMT-061. Clinical information for AMT-060 is summarized in Section 1.3.2. For 
the most comprehensive information regarding AMT-060 and AMT-061 refer to the most recent 
Investigator’s Brochure. 
1.3.1 Preclinical Information 
Information for AMT-060 
A range of in vivo studies in wild-type and hemophilia B mice and in non-human primates 
(NHPs) have been performed to characterize the safety and pharmacology of AMT-060.  
Pharmacology studies in mice and NHPs showed out that infusion of AMT-060 resulted in 
vector dose-dependent circulating levels of (human) factor IX protein.  
To verify that AMT-060 mediates expression of biologically active human factor IX, and to 
confirm that the human factor IX produced and secreted into the circulation can ameliorate the 
clotting defect inherent to factor IX deficiency, a dose-range study was performed in a murine 
model of hemophilia B (Study NR-060-13-007). Results of this study indicated direct correlation 
in vivo between circulating human factor IX protein levels and human factor IX activity. 
CSL Behring 
CCI

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
Page 29 of 112 
In both Rhesus and Cynomolgus macaques injected with various doses of AMT-060, the 
resulting human factor IX expression correlated with the dose and was sustained for the duration 
of the 6 months follow-up (Cynomolgus macaque; Study 522156 and NR-060-14-006) and 90 
days follow-up (Rhesus monkey; Study 520665 and NR-060-11-009). 
None of the animals presented elevated liver enzymes levels or other signs of toxicity during the 
whole observation period, and after sacrifice no abnormalities were observed in the liver.  
These non-clinical data suggest that IV administration of AMT-060 is able to mediate sustained 
levels of factor IX, and that such administration is not associated with any significant safety 
concerns.  
Information for AMT-061 
The AMT-060 and AMT-061 based gene therapy vectors are identical with the exception of a 
two-nucleotide substitution resulting in a single codon change (AGG to CTG) in the coding 
sequence for factor IX, corresponding to an Arginine to Leucine substitution in the transgenic 
protein.  
The R338L substitution, FIX-Padua, represents a naturally occurring variant of factor IX 
showing a gain-of-function, which results in higher factor IX activity with similar factor IX 
protein expression (Simioni et al., 2009). This augmentation is thought to be largely caused by 
increased affinity of the activated protein to activated clotting factor VIII (FVIIIa; Kao et al., 
2013). Both AMT-060 and AMT-061 employ the same vector AAV5 without any changes and it 
is therefore expected that AMT-061 will present a similar safety profile. 
A NHP study (NR-061-17-001) was performed to assess 4 different dose levels of AMT-061 in 
direct comparison with AMT-060 with respect to liver transduction, circulating factor IX protein 
levels, circulating factor IX activity levels and toxicity, after a single IV dose with 13 or 26-week 
observation period. The study comprised of measurements of circulating human factor IX protein 
levels, total circulating factor IX activity levels, assessment of vector deoxyribonucleic acid 
(DNA) in plasma, biodistribution including more than 25 different organs/tissues, complete 
safety panel routinely performed in GLP-toxicity studies and monitoring of six different liver 
enzymes and additional coagulation markers throughout the study. The study revealed dose 
dependent plasma vector DNA levels, human factor IX protein levels and factor IX activity for 
AMT-061. Clinical signs were unaffected by treatment as well as clinical chemistry and 
hematology. Coagulation investigations up to 26 weeks revealed a shortening of the activated 
partial thromboplastin time (aPTT) and longer prothrombin time (PT) clotting times at the 
highest dose (9.0 x 1013 genome copies [gc]/kg) of AMT-061 only, with unaffected plasma 
D-dimer and thrombin-antithrombin levels, indicating some effect on the clotting cascade within 
physiological compensating boundaries and without an increase of thrombin utilization. The 
study clearly showed that at a dose of 5 x 1012 gc/kg, plasma exposure, liver distribution, liver 
cell transduction and transgene expression are similar for both AMT-060 and AMT-061 and that 
CSL Behring 

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
Page 30 of 112 
transgene activity is approximately 6 times higher per unit protein for AMT-061 as compared to 
AMT-060. Although the study design only included a direct comparison at 5 x 1012 gc/kg, it can 
be expected that plasma exposure, liver distribution, liver cell transduction and transgene 
expression behave similarly at each dose level with a range. As expected, the study demonstrated 
that for the same dose, the mean factor IX protein of AMT-060 (average of 4.89, ranging from 
3.17 to 7.61 %) and AMT-061 (average of 4.85, ranging from 2.92 to 6.17 %) was comparable. 
The confirmation of transgene activity being approximately six times higher per unit protein 
(average of 6.10, ranging from 5.41 to 7.47 %) can similarly be expected to result in multiple of 
the already demonstrated activity levels of AMT-060 within a range. These results are 
comparable to the increase in gain-of-function reported for the Padua factor IX protein compared 
with “wild-type” factor IX protein in animal models (Crudele et al., 2015; Monahan et al., 2015). 
The observed translation of the NHP for AMT-060 to the clinical Phase 1/2 for AMT-060 
supports the translation of the NHP study for AMT-061 (NR-061-17-001, Study No. NC1615) to 
further inform the dose rationale for the proposed dose confirmation trial with 2 × 1013 gc/kg 
AMT-061. At 2 x 1013gc/kg, AMT-061 is predicted to result in mean factor IX activity ranges of 
40% of normal, with acceptable ranges (between approximately 18-76%) within the expected 
safety for factor IX replacement with an upper range well below the cut off of 129%. 
1.3.2 Clinical Information for AMT-060 and Preliminary Information for AMT-061 
The combination of an AAV5 vector and the human factor IX gene (AAV5-hFIX) had not been 
evaluated in human trials prior to the initiation of the Sponsor’s Phase 1/2 clinical trial 
CT-AMT-060-01. The AAV5 capsid and the human factor IX gene cassette, as well as the hFIX-
Padua cassette, have been tested individually in other Phase 1/2 clinical trials. The results from 
these trials providing preliminary clinical evidence for efficacy and safety of AMT-061 are 
summarized in Section 1.3.2.1, and the results of the first in human trial (CT-AMT-060-01) are 
summarized in Section 1.3.2.2. 
1.3.2.1 Preliminary Clinical Evidence for Efficacy and Safety of Components of AMT-060 
In Table 5 the most relevant published data and studies conducted with adeno-associated viral 
vector (AAV) capsids and human factor IX that were identified through searches of PubMed and 
clinicaltrials.gov databases are presented. The data outlined below support that administration of 
AMT-061 will be safe, well-tolerated, and able to generate sustained endogenous production of 
factor IX at clinically meaningful activity levels. 
CSL Behring 

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
Page 31 of 112 
Table 5 Summary of Published Clinical Experience with Components of AMT-060 
Reference 
Capsid 
Gene 
Promotor 
Target Tissue 
Key Findings 
D’Avola, 2016 
AAV5 
PBGD 
-- 
Liver 
- 
No adverse events associated 
with capsid 
- 
Capable of transducing 
hepatocytes in vivo  
Pasi, 2016  
AAV5 
BDD-
FVIII 
-- 
Liver 
- 
Mild asymptomatic 
transaminase elevations in 
4 subjects 
- 
Capable of delivery that results 
in clinically relevant transgene 
expression 
Lu et al, 1993 
Retro-viral 
hFIX 
LTR 
N2CMV 
Autologous skin 
fibroblasts 
- 
Increase in factor IX activity 
and improved symptoms in 
1 subject 
- 
No safety or toxicity concerns 
Kay, 2000 
AAV2 
hFIX 
CMV 
Muscle 
- 
Expression of biologically 
active human factor IX 
- 
No inhibitors to factor IX 
Manno, 2003 
AAV2 
hFIX 
CMV 
Muscle 
- 
Safe incorporation of human 
factor IX into muscle cells 
- 
Persistence of vector genome 
and protein expression to 
10 months 
- 
No inhibitors to factor IX 
Jiang, 2006 
AAV2 
hFIX 
CMV 
Muscle 
- 
Persistence of vector genome 
and local protein expression at 
3.7 years post treatment 
- 
No inhibitors to factor IX 
Manno, 2006 
AAV2 
hFIX 
hAAT-
APOE 
Liver 
- 
Transient expression of factor 
IX at clinically relevant doses 
by transduced hepatocytes  
- 
Loss of factor IX expression 
with ALT elevation 
- 
No inhibitors to factor IX or T-
cell response to the capsid 
Nathwani, 2011 
AAV8 
hFIXcoa 
LP1a 
Liver 
- 
Successful transduction of 
hepatocytes resulting in 
clinically relevant increases in 
serum factor IX activity  
- 
Elevated transaminases in 
4 subjects; factor IX 
expression retained in 2 with 
corticosteroid treatment 
- 
No inhibitors to factor IX 
Nathwani, 2014 
AAV8 
hFIXcoa 
LP1a 
Liver 
- 
Clinically relevant increases in 
FIX activity sustained up to 
approximately 4.5 years 
- 
No inhibitors to factor IX 
- 
No late toxicity 
CSL Behring 

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
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Date: 08 Feb 2022 
 
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Reference 
Capsid 
Gene 
Promotor 
Target Tissue 
Key Findings 
George, 2017 
Undisclosed 
hFIX-
Padua 
Undisclosed 
Liver 
- 
Clinically relevant increases in 
factor IX activity 
- 
Elevated transaminases in 2 
subjects; partial to full factor 
IX activity retained with 
corticosteroid treatment 
- 
No inhibitors to factor IX 
AAV5/AAV2/AAV8: adeno-associated viral vector of serotype 5 (or 2 or 8); ALT: alanine aminotransferase; APOE: 
apolipoprotein E; BDD-FVIII: B-domain deleted factor VIII; CMV: Cytomegalovirus; hAAT: human α1-antitrypsin; LTR: long 
terminal repeat; PBGD: porphobilinogen deaminase. 
a Same transgene expression cassette as is used for AMT-060 
 
AAV5 Capsid 
Two studies of the AAV5 capsid in humans were identified.  
D’Avola et al. (2016) studied the AAV5 vector comprising the capsid shell of AMT-060 and 
containing a functional porphobilinogen deaminase (PBGD) gene tested at varying doses 
(5 x 1011 to 1.8 x 1013 gc/kg; single IV infusion) in eight adult subjects with intermittent acute 
porphyria. One subject failed screening due to pre-existing AAV5 neutralizing antibodies. All 
eight subjects who received AAV5-PBGD were followed for one year. No treatment-related 
adverse events (AEs) were observed during the infusion or the follow-up period. One subject 
who received the highest dose experienced a mild elevation (<3x upper limit of normal [ULN]) 
of liver transaminase levels one week after receiving AAV5-PBGD, coincident with an acute 
porphyria attack. Levels normalized once the attack resolved. As expected, all subjects 
developed antibody titers against AAV5; no subjects developed antibodies against the transgene 
product. The AAV5 vector was cleared from all bodily secretions by 30 days post-
administration. Together, these findings support good safety and tolerability for the AAV5 
capsid. Evaluation of liver biopsies at one year post-treatment showed persistence of vector 
genomes and transgene messenger ribonucleic acid (RNA) in all six subjects evaluated, 
suggesting that the AAV5 capsid is able to effectively deliver genetic material to the nuclei of 
liver cells.  
Preliminary results up to 34 weeks post-treatment have also reported by Pasi et al. (2016) from a 
Phase 1/2 trial of an AAV5-B-domain-deleted factor VIII (FVIII) construct in 9 adults with 
hemophilia A. In this trial, subjects received doses ranging from 6 x 1011 to 6 x 1013 gc/kg via 
single IV infusion. No serious adverse events (SAEs) were observed. The first subject receiving 
the highest dose experienced a mild increase in transaminase levels, which resolved with a short 
course of corticosteroids; subsequent subjects received prophylactic steroid treatment, of whom 
three experienced mild transient increases in their transaminase levels. All subjects demonstrated 
increased FVIII activity with no decreases during these events. 
CSL Behring 

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
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CONFIDENTIAL 
Date: 08 Feb 2022 
 
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Together, these findings support a strong expected safety profile of the AAV5 capsid in humans, 
with no serious safety concerns emerging. Mild, asymptomatic liver transaminase elevations are 
the most common event, consistent with reports from other liver-targeted AAV serotypes. 
Together, these studies provide evidence that the AAV5 capsid is capable of transducing human 
hepatocytes in vivo, resulting in detectable, sustained transgene expression. 
Gene Cassette 
Gene transfer of the human wild-type factor IX gene has been evaluated in three key studies in 
adult subjects with hemophilia B. The most recent reports demonstrate that this construct is 
capable of inducing sustained, clinically relevant increases in factor IX activity without 
associated safety concerns.  
In three subjects receiving transfer of the wild-type human factor IX gene under control of a 
cytomegalovirus (CMV) promotor/enhancer (2 x 1011 gc/kg) into the muscle via AAV2, 
evidence of factor IX protein expression was seen both in the circulation and through histological 
examination of muscle biopsies (Kay et al., 2000). Factor IX consumption was reduced in two 
subjects, providing evidence of biological activity of the secreted protein. Five additional 
subjects were then dosed up to 1.8 x 1012 gc/kg. Presence and expression of the transgene was 
demonstrated via polymerase chain reaction (PCR) and Southern blot in muscle biopsies up to 
month 10 post-injection. No muscle tissue abnormalities were noted, suggesting the cells were 
not damaged by incorporation of the vector genome (Manno et al., 2003). Follow-up of one 
subject 3.7 years after injection showed persistence of the vector genome and protein expression 
locally in the muscle (Jiang et al., 2006). 
A subsequent trial examined the effects of the wild-type human factor IX under control of a 
liver-specific human ɑ1-antitrypsin (hAAT) promotor coupled with the apolipoprotein E (APOE) 
enhancer and hepatic control region, packaged into AAV2 vectors and administered via hepatic 
vein infusion to seven subjects at doses up to 2 x 1012 gc/kg (Manno et al., 2006). No evidence of 
increased circulating factor IX activity was obtained at 8 x 1010 or 4 x 1011 gc/kg. At the highest 
dose, both subjects showed transient increases in circulating factor IX activity (approximately 
12% and 3% of normal) which gradually returned to baseline. The high-responding subject 
demonstrated asymptomatic increases in serum transaminase levels coincident with the decline 
in factor IX activity that subsequently normalized. A second subject who received the middle 
dose also experienced an asymptomatic elevation of serum transaminase levels that normalized 
without intervention. Testing in this subject indicated that no T-cell response developed to the 
factor IX protein. 
The cassette identical to that incorporated in AMT-060, and forming the basis for the modified 
version, AMT-061, has been examined in 10 subjects in a trial sponsored by St Jude’s and 
University College of London (Nathwani et al., 2011; Nathwani et al., 2014). Subjects received 
increasing doses (2 x 1011 to 2 x 1012 gc/kg; single IV infusion) of the LP1-hFIXco construct 
CSL Behring 

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
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CONFIDENTIAL 
Date: 08 Feb 2022 
 
Page 34 of 112 
delivered via AAV8, resulting in a steady state of 1-6% normal factor IX activity that remained 
stable at last reported follow-up (1.5-4.3 years after administration). Use of exogenous factor IX 
replacement was reduced by 92% following treatment. Bleeding episodes in the year after gene 
transfer decreased to a median of 1.5, compared with 15.5 in the year preceding treatment. Four 
of the six subjects who received the highest dose experienced increases in serum transaminase 
levels 7-10 weeks after administration and were treated with prednisolone, of whom three 
experienced an associated loss of factor IX activity. No subjects developed inhibitors to factor IX 
protein. All subjects demonstrated evidence of endogenous synthesis of factor IX from the 
transgene cassette. No evidence of late toxicity has emerged even at approximately 4.5 years post 
treatment. 
Recently, preliminary results have been presented from a single study showing sustained 
factor IX expression driven by a gene cassette encoding a Padua variant FIX (George et al., 
2017). Ten subjects received a single IV dose of 5 x 1011 gc/kg, resulting in mean steady state 
factor IX expression of approximately 29% in those followed for ≥ 12 weeks at time of the 
report. Two subjects experienced elevations of liver transaminases and were treated with 
prednisolone, of whom one experienced a partial loss of factor IX activity. No subjects 
developed inhibitors. 
Across all three studies, no subjects who had received gene transfer (total N=25) developed 
inhibitors to the transgenic human factor IX protein (Manno et al., 2003; Manno et al., 2006; 
Nathwani et al., 2014; George et al., 2017). 
1.3.2.2 Results of Clinical Trial-AMT-060-01 
Enrollment and dosing in a first-in-human trial with AMT-060 (CT-AMT-060-01) has been 
completed. Seventy-eight weeks follow-up from all five subjects in the low dose (5 x 1012 cg/kg) 
cohort and 52 weeks follow-up from all five subjects in the high dose (2 x 1013 cg/kg) cohort are 
currently available. The durability of factor IX protein expression encoded by the codon 
optimized human coagulation factor IX cDNA obtained at this point in time is robust and 
sustainable.  
Adverse Events 
A total of 10 subjects have experienced 84 AEs; five subjects with 46 AEs in the low dose cohort 
and five subjects with 38 AEs in the high dose cohort. There have been no deaths and no AEs 
that have resulted in discontinuation from the trial. The majority of AEs were mild in 
severity/intensity (85%); only one AE has been categorized as severe, a myelopathy resulting in 
lower back pain in subject 
. The majority of treatment emergent AEs (TEAEs) (70 of 84) 
were considered to be unlikely related to trial treatment. There were a total of four SAEs 
reported. In the low dose cohort, there were two SAEs: one SAE of mild elevation of alanine 
aminotransferase (ALT; assessed as serious based on criteria of medical significance) and the 
second SAE of short febrile episode (assessed as serious due to extension of hospital stay for one 
CSL Behring 
PPD

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
Page 35 of 112 
day). Both SAEs were assessed as related to the drug product by the Investigator. In the high 
dose cohort, there were also two SAEs: one SAE of mild elevation of ALT, assessed as related to 
the drug product (SAE criterion of medical significance) and one SAE of myelopathy following 
surgery (SAE criterion was hospitalization), which was assessed as unlikely related. The 
outcomes of all SAEs were considered as recovered/resolved. 
The most frequently experienced AEs were in the System Organ Class (SOC) Musculoskeletal 
and Connective Tissue Disorders (20 events: 16 events in Cohort 1 and 4 events in Cohort 2), 
followed by SOC Infections and Infestations (16 events: 7 events in Cohort 1 and 9 events in 
Cohort 2), SOC Nervous system disorders (8 events: 3 events in Cohort 1 and 5 events in Cohort 
2), SOC General Disorders (7 events: 4 events in Cohort 1 and 3 events in Cohort 2), SOC 
Injury, poisoning and procedural complications (6 events: 2 events in Cohort 1 and 4 events in 
Cohort 2), SOC Investigations (5 events: 2 events in Cohort 1 and 3 events in Cohort 2), SOC 
Psychiatric disorders (5 events: 3 events in Cohort 2 and 2 events in Cohort 2). 
ALT Elevations 
Three subjects (one subject in the low dose cohort and two subjects in the high dose cohort) had 
mild, asymptomatic elevation of ALT and received tapering courses of prednisolone. This is a 
not an unexpected finding, as elevations of transaminases have been observed in clinical trials of 
gene therapy targeting the liver. It is important to note that in all three subjects none of the 
observed ALT elevations were associated with any concurrent loss of endogenous factor IX 
activity.  
T-cell Activation 
There were no sustained T-cell responses to the AAV5 capsid observed in either cohort. One 
subject in the low dose cohort had an isolated, low positive ELISpot measurement at Week 9 that 
was not associated with any clinical symptoms, elevation in liver enzymes, or change in 
factor IX activity. The general lack of ELISpot levels above threshold with no repeat elevations 
in any subjects and no clinical findings suggests that this one measurement is not clinically 
relevant. 
Factor IX inhibitors 
No subjects developed inhibitory antibodies to factor IX during the course of the trial. 
Endogenous Factor IX Activity Levels 
Following AMT-060, the mean of all endogenous factor IX activity values measured in the low 
dose cohort (Cohort 1) was 4.6% of normal (range of subject means: 1.3 - 6.8%), and remained 
stable during 78 to 91 weeks of follow-up. In the high dose cohort (Cohort 2), the mean of all 
factor IX activity levels was 7.1% (range of subject means: 3.1 - 12.7%) during 52 weeks of 
follow-up. 
CSL Behring 

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
Page 36 of 112 
Two of the five subjects in the low dose and four of the five subjects in the high dose cohort have 
a mean factor IX activity of >5% of normal after treatment with AMT-060, which shifted them 
from severe or moderately-severe to a mild hemophilia phenotype, where spontaneous bleeding 
is rare. Four subjects, three in Cohort 1 and one in Cohort 2, shifted from a severe to moderate 
phenotype, where spontaneous bleeding occurs only occasionally. One subject in Cohort 1 
shifted from a severe to moderately-severe phenotype, with endogenous FIX levels ranging from 
1.1 to 1.4%. 
Annualized Factor IX Replacement Therapy 
Eight of the nine subjects who had been on factor IX prophylaxis at the time of trial entry no 
longer require factor IX prophylaxis after treatment with AMT-060. One subject in the low dose 
cohort remained on factor IX prophylaxis with factor IX expression <2%. Following successful 
(N=4) or attempted (N=1) cessation of prophylaxis after AMT-060, annualized exogenous 
factor IX use was reduced by 50 to 100% in the low dose cohort. The annualized relative 
reduction in factor IX replacement use ranged from 66 to 100% for four subjects after cessation 
of prophylaxis in the high dose cohort. For the subject who used factor IX replacement on-
demand before and during the trial an 135% increase in the annualized factor IX use was 
observed, which was however mainly due to use for surgery. 
Annualized Bleeding Rates 
The modest increases in endogenous factor IX activity, leading to discontinuation of factor IX 
prophylaxis and large reductions in exogenous factor IX use, are paired with 58% and 84% 
reductions of annualized spontaneous bleeding rate in the low and high dose cohorts, 
respectively. All bleedings were considered of mild/moderate severity. Rates of traumatic 
bleeding were low and largely unaffected (11% decrease in the low dose cohort and no change in 
the high dose cohort). 
Summary of the Preliminary Results: 
Safety: 
- 
The single IV infusion of AMT-060 was safe and well-tolerated in both the low- and 
high-dose cohorts 
- 
The following SAEs were reported 
o two elevations of ALT 
o one short febrile episode that prolonged hospital stay (<24 hours) 
o myelopathy that required hospitalization 
- 
No subjects developed inhibitory antibodies against factor IX 
- 
No sustained capsid-specific T-cell responses were observed across both cohorts 
CSL Behring 

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
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- 
Three out of 10 subjects (2 out of 5 subjects in the high dose cohort) experienced mild, 
asymptomatic elevations of ALT, which were treated with a tapering course of 
corticosteroids. 
- 
ALT elevations were not associated with a detectable activation of capsid-specific T-cell 
response and not correlated with a loss of endogenous factor IX activity 
 
Efficacy: 
- 
Clinically relevant endogenous factor IX activity (≥3%) was established in 9 out of 10 
subjects across both cohorts (5 out of 5 in the high dose cohort) 
- 
Continuous, regular prophylaxis was discontinued in 8 out of 9 subjects previously 
dependent on prophylaxis (4 out of 4 in the high dose cohort) 
- 
Factor IX expression levels remain stable and durable for up to 1.5 years in the low dose 
and up to 1 year in the high dose cohort without indications of loss of expression 
- 
Shift to mild hemophilia B phenotype (>5%) was achieved in  
o Two out of five subjects in the low dose  
o Four out of five subjects in the high dose cohort  
- 
A reduction/elimination in the use of factor IX replacement therapy and a lowering of the 
annualized bleeding rate was demonstrated in both cohorts 
1.4 Rationale for the Trial 
The current treatment options for hemophilia B have several limitations. Treatment with 
prophylactic regular IV injections of factor IX is not curative and very demanding due to the 
need for frequent IV infusions and concomitant risk for infection and thromboses related to the 
placement of indwelling catheters. Periodic or regular factor IX infusion results in peaks and 
troughs in plasma factor levels allowing for breakthrough bleeding episodes. Due to these 
factors, poor adherence to treatment is a concern and a major contributing factor to failure of 
prophylaxis, associated with increased risk of bleeding and subsequent joint damage, thereby 
adding to the all-cause mortality rate. Despite the exogenous factor replacement, subjects may 
still experience breakthrough bleedings. There is also a risk of developing neutralizing antibodies 
against the administered factor IX. The burden of the disease is high, both for the individual 
subject and their families, and for society. Due to (long-term) impairments in mobility and 
functional status, subjects may not be able to fully participate in social activities, such as sports, 
school or work. Living with hemophilia can have a substantial effect on mental wellbeing, 
particularly among young people and signs of major depressive disorder are not uncommon. The 
economic burden for the society is significant. The cost of severe hemophilia, including indirect 
costs, is estimated at EUR 199,541 per subject in Europe, ranging from EUR 129,365 to 319,024 
(O’Hara et al., 2017). Hemophilia subjects are accredited with requiring 2-3 times the health care 
resources per inhabitant in developed countries (Schramm & Berger, 2003). Hemophilia B 
thereby directly impacts the health-related 
 (Witkop et al., 2017). 
CSL Behring 
CCI

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
Page 38 of 112 
Somatic gene therapy for hemophilia B offers the potential for shift of the disease severity from 
severe to a moderate or mild hemophilic phenotype or complete amelioration through continuous 
endogenous production of factor IX protein after a single administration of AAV vector particles. 
Even a small rise in constantly circulating factor IX protein can substantially ameliorate the 
bleeding phenotype. 
Robust preliminary efficacy and safety results have been obtained with AMT-060 in an ongoing 
Phase 1/2 trial (CT-AMT-060-01) in 10 subjects with hemophilia B. No screening failures due to 
high titers of pre-existing neutralizing antibodies against AAV5 were encountered. An increased 
level of factor IX activity was observed after subjects in the low dose cohort and high dose 
cohort were treated with the AMT-060 at 5 x 1012 gc/kg and 2 x 1013 gc/kg, respectively. 
Clinically relevant endogenous factor IX activity (≥2%) was established in nine out of 
10 subjects across both cohorts (five out of five in the high dose cohort), with two out of five and 
four out of five subjects achieving a shift to mild phenotype (>5%) in the low and high dose 
cohorts, respectively. Continuous, regular prophylaxis was discontinued in eight out of nine 
subjects previously dependent on prophylaxis (four out of four in the high dose cohort). As of 
writing, factor IX expression levels remain stable and durable for 1.5 years without indications of 
loss of expression. A reduction/elimination in the use of factor IX replacement therapy and a 
lowering in the risk of bleeding events over time were demonstrated in both cohorts. The single 
IV infusion of AMT-060 was safe and well-tolerated in both the low- and high-dose cohorts. The 
most frequent AE related to gene therapy targeting the liver is ALT elevation. One subject in the 
lower dose cohort and two subjects in the higher dose cohort had mild, asymptomatic, transient 
elevations of ALT. No change in factor IX activity and no T-cell response were seen in the 
subjects with ALT elevations. No subjects developed inhibitory antibodies against factor IX. 
The clinical benefit of AMT-060 was achieved with a factor IX protein-to-activity ratio of 
approximately 1. Modifying AMT-060 with the implementation of the naturally occurring Padua 
variant is expected to result in a factor IX protein-to-activity ratio of approximately six. 
Although AMT-061 has yet to be studied in humans this design modification is anticipated to 
lead to a higher level of circulating factor IX activity at comparable levels of factor IX protein 
and thereby increase the likelihood of alleviating the need for exogenous therapy, including the 
need for on-demand treatment of traumatic bleeds and selective prevention of a bleed (e.g., 
because of upcoming physical activity, sports, etc.). 
This isolated modification is a prospectively defined product improvement that will not influence 
other established safety characteristics of AAV5 at 2 x 1013 gc/kg such as the level of factor IX 
protein expressed with 2 x 1013 gc/kg AMT-061, immune response against AAV5, the 
occurrence of manageable ALT/AST (aspartate aminotransferase) elevations or risk of T-cell 
responses against transduced cells with potential concurrent loss of efficacy.  
In addition to the above, the continuous accumulation of clinical data from the use of AAV5 in 
hemophilia subjects suggests that AAV5 is associated with a very low risk of inducing immune 
CSL Behring 

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
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CONFIDENTIAL 
Date: 08 Feb 2022 
 
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responses that may lead to loss of the newly induced endogenous factor IX protein expression. 
Furthermore, low titers of pre-existing antibodies against AAV5 (using a highly sensitive assay), 
which may demonstrate neutralization of AAV5 transduction in in-vitro assays, have no apparent 
inhibitory effect in human studies at currently administered dose levels. As a consequence, future 
trials with AMT-061 (including this trial) will allow enrolment of subjects even in the presence 
of anti-AAV5 antibodies.  
The efficacy (protein expression) and safety results obtained during the Phase 1/2 trial with 
AMT-060 demonstrate 2 x 1013 gc/kg to be the optimal dose for use in future trials in terms of 
safety and efficacy. In addition, accumulated clinical and non-clinical data support the 
implementation of the prospectively defined product enhancement of AMT-061 at 2 x 1013 gc/kg 
for the pivotal trial. The primary aim of this trial is to confirm that a single dose of 2 x 1013 gc/kg 
AMT-061 will result in factor IX activity levels of ≥5%. In addition, the safety profile of 
AMT-061 will be demonstrated. 
1.5 Risk/Benefit Considerations 
Somatic gene therapy for hemophilia B offers the potential benefit of a shift of the disease 
severity from severe to a mild hemophilia phenotype or complete amelioration through 
continuous endogenous production of factor IX after a single administration of vector. 
The identified risks are considered low and manageable and to not affect the risk/benefit balance 
in an unfavorable way. The optimized AAV approach has the potential to further limit the risks 
currently associated with AAV gene therapy approaches.  
The risks as described in the following sections have to be considered: 
1.5.1 Risk of Infusion-related Toxicity 
To date no infusion-related toxicities have been observed in previous clinical trials of liver-
directed gene transfer, including the CT-AMT-060-01 trial. Nonetheless, as a precaution subjects 
in this trial will be monitored for tolerance to the IMP and detection of potential immediate AEs 
at the clinical trial site for 24 hours following infusion. 
1.5.2 Risk of Immune Mediated Neutralization of the AAV5 Gene Therapeutic Vector 
Pre-existence of antibodies that recognize a gene therapeutic vector can potentially reduce its 
bioavailability and hence its activity. For this reason, the eligibility criteria for CT-AMT-060-01 
included the absence of detectable levels of circulating AAV5-neutralizing antibodies. Screening 
for AAV5 neutralizing antibodies was performed using a bio-assay based on a green fluorescent 
protein (GFP) reporter gene. In line with previously reported low prevalence for AAV5 
neutralizing antibodies (Boutin et al., 2010), no antibodies were detected and all subjects passed 
screening.  
CSL Behring 

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
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CONFIDENTIAL 
Date: 08 Feb 2022 
 
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Recent availability of a more sensitive bio-assay, based on a luciferase reporter gene prompted 
retrospective analysis of the screening samples from the CT-AMT-060-01 trial and pre-treatment 
samples of some of the nonclinical NHP studies. Retrospective analysis using this more sensitive 
assay revealed the presence of detectable levels of AAV5 neutralizing antibodies in three out of 
10 CT-AMT-060-01 trial subjects and in all tested animals. However, judging by circulating 
factor IX activity levels or safety outcomes, these pre-existing AAV5 neutralizing antibody 
levels held no predictive value: the CT-AMT-060-01 trial subject showing the highest titer of 
1/340 also showed highest circulating factor IX activity levels of this cohort, and in the NHPs no 
impact on efficacy was evident at titers up to 1/1000, at dose levels down to one-tenth of the low 
dose level in the CT-AMT-060-01 trial (i.e., 5 x 1011 gc/kg versus 5 x 1012 gc/kg).  
These studies suggested that although AAV5 neutralizing antibodies are prevalent in humans and 
NHPs, the absolute levels at which they are present may not suffice to impact AMT-060 at the 
infused dose. In all subjects who were shown to have AAV5 neutralizing antibodies prior to 
treatment, factor IX activity remained stable, and none of the subjects showed evidence of liver 
toxicity or activation of T-cell responses against the capsid. As pre-existing antibody levels did 
not seem to preclude efficacy, and were not associated with any immune-mediated adverse 
effect, the proposed trial will allow enrolment of subjects regardless of antibody levels. 
Nonetheless, AAV5 neutralizing antibody levels will be measured in all subjects both before and 
after dosing, in order to allow a retrospective analysis to confirm the suggested lack of impact of 
prevalent titers on the efficacy of AMT-061. For this, the more sensitive luciferase-based assay 
will be used. 
It is of note that after dosing of AMT-061 all subjects will develop antibodies against the capsid 
proteins and these antibodies are likely to persist. As liver transduction will have taken place 
before these responses are fully mounted, these responses are unlikely to impact factor IX 
expression. However, they may impact the efficacy of any future administration (i.e., a second 
dose) of the same vector, since post-dosing antibody levels may exceed prevalent pre-existing 
levels by several orders of magnitude. 
1.5.3 Risk of Immune Mediated Liver Toxicity 
Intravenous administration of a liver-directed AAV vector might lead to transaminase increase. 
Previous clinical trials have shown that increases in liver enzymes respond promptly and 
normalize after administration of glucocorticoids. Subjects in the trial will be monitored weekly 
during the first 12 weeks after infusion of AMT-061 for the occurrence of transaminase 
increases, which, in the absence of an alternative etiology for the ALT increase, may warrant the 
initiation of a corticosteroid treatment (see Section 5.6.4).  
In the CT-AMT-060-01 trial, three subjects (one subject in the low dose cohort and two subjects 
in the high dose cohort) had mild, asymptomatic increase of ALT. This is not an unexpected 
finding, as increases of transaminases have been observed in trials associated with gene therapy 
CSL Behring 

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targeting the liver. It is important to note that in all three subjects none of the observed ALT 
increases was associated with any concurrent loss of endogenous factor IX activity. No evidence 
of immune reaction (e.g., capsid-specific T-cell response) was associated with this increase.  
1.5.4 Risks to Third Parties and the Environment Related to Shedding via Body Fluids 
The AAV vector will distribute systemically and small amounts of vector DNA have been 
observed in previous non-clinical and clinical studies in blood, urine, saliva, nasal secretion, 
faeces and semen. In trial CT-AMT-060-01, vector DNA was detected at 78 weeks and later in 
semen and blood in some subjects. 
Vector DNA measured in these bodily fluids is unlikely to represent infectious particles. In 
addition, the vector is non-pathogenic and cannot replicate. Therefore, the risk for third parties 
such as family and health care personnel is considered marginal. Due to the incapacity of 
replication, the non-infectious nature of the shed DNA and the negligible amounts shed, the risk 
to the environment can be considered negligible. No specific containment or protection measures 
are deemed necessary. 
1.5.5 Risk of Vector DNA Integration into the Host Genome 
Reaction (nr LAM PCR) and subsequent high throughput sequencing on DNA was extracted 
from the livers of both mouse and Cynomolgus macaques after administration of AMT-060 at 
various doses. There was no preferred integration in genes known to mediate malignant 
transformation or clonal dominance. Both episomal (concatemeric) and integrated forms of 
AMT-060 were retrieved, but the sequences were present almost exclusively as non-integrated 
episomal forms. The retrieved integrants were randomly distributed throughout the host genome. 
No specific clustering was seen in Cynomolgus macaque genome, while some level of clustering 
around active genes was seen in the mouse. There were no signs of in vivo clone selection in the 
animals.  
1.5.6 Risk of Germ-line Transmission of Vector DNA 
The risk of germ line transmission is considered negligible for AAV-based vectors due to the 
marginal integration level of the vector DNA into the host genome. Any potential risk is 
addressed by requiring the use of a condom during the trial in the period from administration of 
the investigational drug until the AAV5 vector has been cleared from semen, as evidenced by 
negative analysis results for AAV5 vector for at least 3 consecutively collected semen samples. 
Additionally, subjects are asked to inform their partner of their participation in this trial, as well 
as the importance of contraception use to limit the reproductive potential in the period from IMP 
administration until AAV5 has been cleared from the semen. 
CSL Behring 

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
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1.5.7 Risk of Off-target Expression of the Transgene 
The vector will distribute systemically to all tissues thereby potentially infecting other cells than 
liver cells resulting in off-target gene expression. This risk is addressed by the use of a liver-
specific promoter in the gene cassette. In other clinical trials using similar vector approaches, no 
AEs have been reported that could be related to potential off-target expression. 
1.5.8 Risk of Inhibitor Formation to Protein Expressed from the Transgene 
There is a risk of inhibitor/antibodies development against the expressed factor IX protein. No 
factor IX inhibitor formation was seen in any of the previous clinical trials reported in literature 
where subjects were exposed to human factor IX gene transfer and where the expressed levels of 
factor IX were measurable (Manno et al., 2003; Manno et al., 2006; Nathwani et al., 2011; 
Nathwani et al., 2014) or in CT-AMT-060-01. In-silico studies indicate no higher risk of 
potential immunogenicity for factor IX protein expressed from AMT-061 following 
incorporation of the single amino acid change as compared to the “wild-type” factor IX protein 
expressed from AMT-060. Expression of a Padua transgene product did not result in inhibitors in 
studies conducted in murine and inhibitor-prone canine models (Cantore et al 2012; Monahan, 
2014; Crudele et al 2015).  
To assist with minimizing this risk, subjects will be selected on the basis of a low risk of 
factor IX inhibitor development by choosing subjects with more than 20 exposure days to a 
factor IX product as well as omitting subjects with a previous factor IX inhibitor. Subjects will 
be regularly monitored for factor IX inhibitor development. 
1.5.9 Risk of Breakthrough Bleeding 
The scope of the liver-directed AAV gene therapy approach is to establish a stable and durable 
expression of factor IX and to convert to mild or completely ameliorate the severe hemophilia 
phenotype. Previous clinical trials with similar AAV vectors and the wild-type gene cassette 
have shown that stable and years long factor IX expression can be achieved (Nathwani et al., 
2014). Nonetheless, there is a risk that breakthrough bleeding may occur, particularly if 
demanding physical activity is undertaken. This risk will be managed by the use of factor IX 
replacement as needed throughout the trial. Every effort will be made to avoid routine use of 
prophylactic factor IX replacement therapy during the trial. 
In a previous trial with AMT-060, therapeutic levels of factor IX protein and resultant factor IX 
activity levels were seen as early as one week after treatment.  
At baseline, subjects will be administered a challenge dose of short-acting factor IX (40 IU/kg) 
for the factor IX recovery assessment. This challenge dose should provide subjects sufficient 
factor IX coverage for the initial two to three days post treatment. Three days after IMP 
administration, the subjects should visit the clinic for endogenous factor IX activity assessment 
(by local laboratory). If the factor IX activity result is ≥5%, further factor IX prophylaxis will not 
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AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
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be given. If the factor IX activity result is <5%, another dose of short-acting factor IX will be 
administered to the subject and endogenous factor IX activity assessment will be performed 
again at the week 1 routine visit.  
Additional on-demand factor IX may be given after treatment with AMT-061, if considered 
necessary. Furthermore, subjects are monitored closely for five years after administration of IMP 
and the need for renewed prophylactic therapy will be clinically assessed by the treating 
physician according to the local standard of care for hemophilia subjects. 
1.6 Accommodations Due to the COVID-19 Pandemic 
In the first quarter of 2020, a pandemic was announced for Coronavirus Disease 2019 
(COVID-19), which is caused by the virus severe acute respiratory syndrome coronavirus 2 
(SARS-CoV-2). The pandemic impacted the conduct of clinical trials due to quarantines, site 
closures, travel limitations, diversion of resources, and general interruptions in study related 
procedures, leading to protocol deviations. This study protocol includes contingency measures to 
manage disruptions due to COVID-19 illness and/or public health control measures; see 
Section 3.1.1 for details on measures related to adjustments to visit location/method and 
schedule, as well as Section 6.2.2.4 and Section 6.2.3.4 for details on the new visit windows for 
 questionnaires and abdominal ultrasound assessments, respectively. The impacts of these 
implemented contingency measures on the outcomes of this study, including any protocol 
deviations that ultimately result from COVID-19 illness and/or COVID-19 control measures will 
be discussed in the Clinical Study Report (CSR). 
The decision to test a subject in the study for COVID-19 should be based on the site’s current 
guidelines and at the discretion of the Investigator. If a subject participating in the study is 
identified as a person under investigation for possible COVID-19 infection, it is mandatory to 
immediately notify appropriate authorities as per site’s regulations and to notify Medpace and 
uniQure’s Medical Directors. As co-infections can occur, all subjects should be considered for 
COVID-19 virus testing regardless of whether another respiratory pathogen is found.  
If a subject is confirmed positive for COVID-19 at any time during the trial, the medical care, 
isolation, and management, should be according to national, local, institutional, and public health 
guidelines. 
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AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
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2 TRIAL OBJECTIVES 
2.1 Primary Objective 
To confirm that a single dose of 2 x 1013 gc/kg AMT-061 will result in factor IX activity levels of 
≥5% at six weeks after dosing 
2.2 Secondary and 
 
Secondary Efficacy Objectives are focused on investigating the effect of 2 x 1013 gc/kg 
AMT-061 on endogenous factor IX activity at 52 weeks, discontinuation of previous continuous 
prophylaxis, total usage of factor IX replacement therapy, the annualized bleeding rate, and 
specific types of bleeding events (e.g., spontaneous bleeds, joint bleeds, traumatic bleeds). 
Specifically, the secondary objectives are the following: 
- To assess effect of 2 x 1013 gc/kg AMT-061 on endogenous factor IX activity at 52 
weeks 
- To assess effect of 2 x 1013 gc/kg AMT-061 on discontinuation of previous 
continuous prophylaxis 
- To assess effect of 2 x 1013 gc/kg AMT-061 on total usage of factor IX replacement 
therapy 
- To assess effect of 2 x 1013 gc/kg AMT-061 on the annualized bleeding rate 
- To assess effect of 2 x 1013 gc/kg AMT-061 on specific types of bleeding events (e.g., 
spontaneous bleeds, joint bleeds, and traumatic bleeds) 
 
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2.3 Safety Objectives 
The Safety Objectives include monitoring of AEs, formation of anti-AAV5 antibodies (total 
immunoglobulin M and immunoglobulin G [IgM and IgG], neutralizing antibodies), AAV5 
capsid-specific T cell response, formation of anti-factor IX antibodies, formation of factor IX 
inhibitors, hematology and serum chemistry, shedding of vector DNA in blood and semen, 
inflammatory markers, AST/ALT elevations, use of corticosteroids required to preserve 
factor IX activity in the context of AST/ALT elevations, abdominal ultrasound, and alpha-
fetoprotein (AFP). 
CSL Behring 
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AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
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3 TRIAL DESIGN 
3.1 Overall Trial Design 
This is a Phase IIb, open-label, single-dose, single-arm, multi-center trial consisting of a 
screening, a treatment plus post-treatment follow-up, and a long-term follow-up phase.  
After a screening period of maximal six weeks, eligible subjects will receive a single IV dose of 
2 x 1013 gc/kg AMT-061 and will thereafter be followed for a total of five years (60 months). 
Post-treatment follow-up visits are planned as follows: 
- 
Weekly up to Week 12 
- 
Every 2nd week from Week 12 to Week 26 
- 
Every month from Week 26 to Week 52 
All subjects will continue to be followed every half year from Week 52 to 60 months (4 years 
long-term follow-up). 
The subjects will be monitored for tolerance to the IMP and detection of immediate AEs for 24 
hours (overnight stay) after dosing. The dosing of the subjects must be separated by a minimum 
of 14 calendar days to allow for subject safety monitoring and to ensure appropriate action can 
be taken in case any acute reactions are observed. 
One interim analysis will be performed after six weeks post-dose to determine the efficacy of 
AMT-061 in terms of factor IX activity.  
After 52 weeks post-dose and 2.5 years post-dose, efficacy and safety data will be collected on 
all subjects. These data will be locked, analyzed, and reported in a CSR (52-week analysis) and 
CSR addendum (2.5-year analysis). Data from that point will be considered locked and will not 
be changed. At the end of the 4-year long-term follow-up period (60 months/5 years post-dose), 
all safety and efficacy data will be reported in a CSR addendum covering the entire study period 
including the final 2.5 years post-dose follow-up period (5-year analysis). 
The end of the clinical trial is defined as the point in time when the last subject has completed 
the overall follow-up observation period of 5 years after administration of the IMP. 
3.1.1 Considerations Due to the COVID-19 Pandemic 
Due to the COVID-19 pandemic, adjustments to the visit location/method or schedule may be 
made during the long-term follow-up to accommodate safety concerns and restrictions 
experienced by individual subjects and sites. In all cases, subjects will be kept informed, via site 
staff, as much as possible, of changes to the study and monitoring plans that could impact them. 
Discontinuation of subjects from the study post-treatment with AMT-061 is not considered to be 
in the best interest of the subject, due to the irreversible nature of the IMP. Wherever possible, 
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every effort is to be made to have the subject visit the clinic for the study visits according to 
schedule. Should a clinic visit not be possible, options that may be considered include site nurses 
travelling to a subject’s home, local laboratory use, or home nursing services (for certain visits, if 
pre-approved by the Investigator and Sponsor). These options, if used, will be supplemented with 
a phone call or telemedicine/telehealth safety follow-up call. A (temporary) transfer of a subject 
to an alternate clinical trial site may also be considered in order to continue on-site visits, only if 
this does not pose undue burden to the subject and/or "new" site. 
In some instances, it may not be possible to conduct any type of visit at all. Where none of the 
above options are feasible, subject visits may be moved beyond the maximum visit window 
permitted. Such delays will be assessed on a case by case basis. Until visits are rescheduled, 
supplemental phone calls or telemedicine/telehealth contact between Investigator/study staff and 
subject are to be arranged. 
Supplemental phone calls or telemedicine/telehealth safety follow-up calls will be used to 
confirm the subject’s status and wellbeing. At these calls, safety information should be gathered 
(i.e., AEs, concomitant medication use), subjects should be asked about any new unreported 
bleeds or factor IX consumption and confirm their use of the paper diaries (as applicable), and 
there should be continued discussions with the subject on the importance of a healthy liver. 
These discussions will be documented in the source documents. 
All deviations from the study protocol are to be documented, with rationale. If a protocol 
deviation is due to the COVID-19 pandemic, this will be noted. 
3.2 Trial Design Rationale 
In gene therapy it is common practice to provide a single dose of vector via IV infusion. This 
infusion in a previous trial with AMT-060 was proven to be safe and effective resulting in 
identification of a clincial dose for AMT-060 to proceed to further clinical studies. Although this 
resulted in successful conversion of clinical phenotype to mild in most subjects, the desired goal 
is to achieve higher levels of factor IX activity to allow for a more consistent and meaningful 
clinical response. This trial will investigate AMT-061 at the identified dose for AMT-060 
(2 x 1013 gc/kg). 
This is the first trial with the gene product AMT-061 in humans. As AMT-061 is an isolated 
modification of the wild-type human factor IX in AMT-060, it is expected that the safety of this 
product improvement will be similar as the safety characteristics that have been described for 
AMT-060 at a dose of 2 x 1013 gc/kg. Also, clinical benefit of AMT-060 was achieved at this 
dose (refer also to Section 1.4 for a description of the Phase 1/2 trial). Therefore, a similar dose 
of AMT-061 will be used in this trial. Based on NHP studies with AMT-061, as well as data 
from patients with the natural Padua mutation, it is expected that the modified product AMT-061 
will lead to a higher level of circulating factor IX activity at comparable levels of factor IX 
protein and thereby increase the likelihood of alleviating the need for exogenous therapy, 
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including the need for on-demand treatment of traumatic bleeds and selective prevention of a 
bleed (e.g., because of upcoming physical activity, sports, etc.). At 2 x 1013gc/kg, AMT-061 is 
expected to result in mean factor IX activity ranges of 40% of normal, ranging between 
approximately 18-76%. 
This trial is conducted at multiple centers as the prevalence of severe and moderately severe 
hemophilia B subjects is low. 
Due to the nature of the disease in question it is not ethical to perform a placebo-controlled trial 
and no relevant active comparators exist. Based on this the trial is designed as an open-label and 
uncontrolled trial.  
3.3 Trial Endpoints 
3.3.1 Primary Endpoint 
The primary aim of the trial is to demonstrate that AMT-061 will provide a minimal therapeutic 
response of ≥5% factor IX activity using a dose of 2 x 1013 gc/kg. This is the proposed dose to be 
used in a further pivotal Phase 3 trial. The primary efficacy parameter is factor IX activity level 
at six weeks after dosing (at Week 6 post AMT-061 dose). 
3.3.2 Secondary Endpoints 
Secondary efficacy endpoints: 
- Endogenous factor IX activity at Week 6 and Week 52 post AMT-061 dosing 
- Remaining free of previous continuous prophylaxis during 52 weeks following AMT-
061 dosing 
- Total usage of factor IX replacement therapy until 52 weeks following AMT-061 
dosing, excluding ad hoc prophylaxis for invasive procedures 
- Annualized bleeding rate after 52 weeks of AMT-061 dosing (including a further 
break down of the frequency and percentage of spontaneous, traumatic, and joint 
bleeding events) 
 
Secondary safety endpoints  
- AEs 
- Hematology and serum chemistry parameters 
- ALT/AST levels and corticosteroid use for ALT/AST elevations 
- Parameters on antibody formation to AAV5 and human factor IX 
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- AAV5 capsid-specific T cell response 
- Inflammatory markers 
- Vector DNA in semen and blood 
- AFP 
Safety endpoints are observed over the 52-week post-treatment follow-up phase and for an 
additional four years in the long-term follow-up phase. An additional endpoint in the long-term 
follow-up is abnormal findings on the abdominal ultrasound. 
3.4 Sample Size 
A minimum of three subjects will be enrolled in the trial (see also Section 9.11). To account for 
drop-outs additional subjects may be recruited. 
3.5 Sites and Regions 
It is planned to conduct this trial in approximately three sites in the United States (US) and the 
European Union (EU). 
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4 TRIAL POPULATION 
Subjects will be adult males with severe or moderately severe hemophilia B.  
4.1 Inclusion Criteria 
The subject cannot be enrolled in the trial before all of the following inclusion criteria (including 
test results) are met: 
 Male 
 Age ≥18 years 
 Subjects with congenital hemophilia B classified as one of the following: 
a. Known severe factor IX deficiency (<1% of normal circulation factor IX) for which 
the subject is either on continuous routine factor IX prophylaxis* or using on-demand 
factor IX replacement therapy 
b. Known moderately severe factor IX deficiency (1-2% of normal circulating factor IX, 
inclusive) and a severe bleeding phenotype as defined by at least one of the 
following: 
i. On continuous routine factor IX prophylaxis* for a history of bleeding 
ii. On demand factor IX replacement therapy with a history of frequent bleeding (4 
or more bleeding episodes in the last 12 months) or chronic hemophilic 
arthropathy (pain, joint destruction, and loss of range of motion) in one or more 
joints 
 >20 previous exposure days of treatment with factor IX protein  
 Acceptance to use a condom during sexual intercourse in the period from IMP 
administration until AAV5 has been cleared from semen, as evidenced by the central 
laboratory from negative analysis results for at least three consecutively collected semen 
samples (this criterion is applicable also for subjects who are surgically sterilized) 
 Able to provide informed consent following receipt of verbal and written information 
about the trial 
* Continuous routine prophylaxis is defined as the intent of treating with an a priori defined 
frequency of infusions (e.g., twice weekly, once every two weeks, etc.) as documented in the 
medical records. 
4.2 Exclusion Criteria 
Subjects are excluded from the trial if any of the following exclusion criteria are met:  
 History of factor IX inhibitors 
 Positive factor IX inhibitor test at screening  
 Screening laboratory values: 
a. ALT >2 times ULN 
b. AST >2 times ULN 
1. 
2. 
3. 
4. 
5. 
6. 
1. 
2. 
3. 
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c. Total bilirubin >2 times ULN 
d. Alkaline phosphatase (ALP) >2 times ULN 
e. Creatinine >2 times ULN 
 Positive HIV serological test at screening, not controlled with anti-viral therapy as shown 
by CD4+ counts ≤200/μL or by a viral load of >200 copies/mL  
 Active infection with Hepatitis B or C virus as reflected by hepatitis B surface antigen 
(HBsAg), hepatitis B extracellular antigen (HBeAg), hepatitis B virus deoxyribonucleic 
acid (HBV DNA) or hepatitis C virus RNA (HCV RNA) positivity, respectively, at 
screening 
 History of hepatitis B or C exposure, currently controlled by antiviral therapy 
 Known coagulation disorder other than hemophilia B 
 Thrombocytopenia, defined as a platelet count below 50 × 109/L, at screening  
 Known severe infection or any other significant concurrent, uncontrolled medical 
condition including, but not limited to, renal, hepatic, cardiovascular, hematological, 
gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease, 
alcoholism, drug dependency or any other psychological disorder evaluated by the 
Investigator to interfere with adherence to the protocol procedures or with the degree of 
tolerance to the IMP 
 Known significant medical condition that may significantly impact the intended 
transduction of the vector and/or expression and activity of the protein, such as 
disseminated intravascular coagulation, accelerated fibrinolysis, and profound liver 
fibrosis 
 Known history of an allergic reaction or anaphylaxis to factor IX products 
 Known uncontrolled allergic conditions or allergy/hypersensitivity to any component of 
the IMP excipients 
 Known medical condition that would require chronic administration of steroids 
 Previous gene therapy treatment 
 Receipt of an experimental agent within 60 days prior to screening 
 Current participation or anticipated participation within one year after IMP administration 
in this trial in any other interventional clinical trial involving drugs or devices 
4.3 Reproductive Potential 
Male subjects who participate in this trial accept to use a condom during sexual intercourse in the 
period from IMP administration until AAV5 has been cleared from semen, as evidenced by the 
central laboratory from negative analysis results for at least three consecutively collected semen 
samples (this criterion is applicable also for subjects who are surgically sterilized). 
Subjects are being asked to inform their partner of their participation in this trial, as well as the 
importance of contraception use to limit the reproductive potential in the period from IMP 
administration until AAV5 has been cleared from the semen. 
4. 
5. 
6. 
7. 
8. 
9. 
10. 
11. 
12. 
13. 
14. 
15. 
16. 
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4.4 Restrictions 
There is one restriction associated with participation in this trial, which is related to reproduction 
and described in Section 4.3. 
4.5 Withdrawal of Subject from Therapy or Assessment 
A subject may withdraw from the trial at any time, for any reason, without prejudice to their 
future medical care by his/her physician or at the institution. The Investigator or Sponsor may 
withdraw the subject at any time if it is not in the best interest of the subject to continue 
participation. Since this is a gene therapy trial in which the IMP is administered to human 
subjects as a one-time only dose, the Investigator should make all reasonable attempts to 
maintain the subjects in the trial after IMP administration to allow long-term follow-up on safety. 
Where a subject is withdrawn from the trial at his own request or based on a decision of the 
Investigator, the safety follow-up should be maintained, conditional to the consent of the subject. 
The safety follow-up will include periodic review (approximately every 6 months) of medical 
records to gather information obtained during routine visits from the subject with his treating 
physician for the time until 5 years post IMP administration. Information on AEs, SAEs, 
concomitant medication use, and laboratory assessments will be collected as available. If a 
subject is to withdraw from the trial, the Investigator should make all reasonable attempts to have 
the subject sign the separate informed consent form (ICF) in order to maintain the long-term 
safety follow-up.  
Subjects withdrawing from the trial will be requested to complete the same final evaluations (see 
Section 4.1) as subjects completing the trial according to the protocol, particularly safety 
evaluations in the subject’s interest so that data can be recorded in the same way as for subjects 
who completed the trial. Comments (spontaneous or elicited) or complaints made by the subject 
must be recorded in the source documents. The reason for (if given) and date of withdrawal, 
must be recorded on the electronic case report form (eCRF) and source documents. 
Subjects who withdraw prior to IMP administration or within the first six weeks after IMP 
administration will be replaced. Subjects who discontinue after six weeks post IMP 
administration will not be replaced.  
4.5.1 Reasons for Discontinuation 
The reasons for discontinuation from this gene therapy trial include: 
 
AE 
 
Withdrawal by principal Investigator 
 
Withdrawal by subject 
 
Lost to follow-up 
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4.5.2 Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit 
At least three documented attempts must be made to contact any subject lost to follow-up at any 
time point prior to the last scheduled contact (office visit or telephone contact). One of these 
documented attempts must include a written communication sent to the subject’s last known 
address via courier or mail (with an acknowledgement of receipt request) asking that they return 
the e-diary device (if applicable) and return to the site for final safety evaluations. 
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5 TRIAL TREATMENT 
5.1 Treatment(s) Administered 
The IMP is identified as AAV5-hFIXco-Padua (hereafter referred as AMT-061; etranacogene 
dezaparvovec). AMT-061 is a recombinant adeno-associated viral vector of serotype 5 (AAV5) 
containing the Padua variant of a codon-optimized human factor IX cDNA under the control of a 
liver-specific promoter. The pharmaceutical form of AMT-061 is a solution for IV infusion.  
Subjects will receive a single IV infusion of 2 x 1013 gc/kg AMT-061. 
 
 
 
5.3 Dosing and Administration 
AMT-061 will be administered at a dose of 2 × 1013 gc/kg as a one-time infusion in a peripheral 
vein. The subjects will be monitored for tolerance to the IMP and detection of immediate AEs 
for 24 hours (overnight stay) after dosing. 
The dosing of the subjects must be separated by a minimum of 14 calendar days to allow for 
subject safety monitoring and to ensure appropriate action can be taken in case any acute 
reactions are observed. 
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Detailed instructions for IMP handling e.g., receipt, storage, preparation, administration, 
cleaning, destruction and the recording of these critical activities will be described in the IMP 
Handling Manual. 
5.4 Randomization and Blinding 
Not applicable, as this is an open-label trial with one treatment arm. 
5.5 Labeling, Packaging, Storage, and Handling 
All medication used in this trial will be prepared and labeled according to the rules of Good 
Manufacturing Practice, International Council for Harmonisation (ICH)-Good Clinical Practice 
(GCP) (E6[R2]) and local regulatory requirements. Further details on IMP labeling, packaging 
and handling, e.g., receipt, storage, preparation, administration, cleaning, destruction, 
documentation etc., will be described in the IMP Handling Manual. 
5.6 Prior and Concomitant Medication/Therapy 
5.6.1 Prior Medication/Therapy 
Prior medication/therapy includes medication/therapy (including herbal treatments, vitamins, 
non-pharmacological treatment such as psychotherapy as appropriate) received within 30 days of 
and discontinued prior to the date of screening. Prior medication/therapy information must be 
recorded on the appropriate eCRF page. 
For this trial, it is not allowed to have received an experimental agent within 60 days prior to 
screening. In addition, use of previous gene therapy is not allowed. 
5.6.2 Concomitant Medication/Therapy  
Concomitant medication/therapy is defined as any medication/therapy being continued by the 
subject at the date of screening, and any new medication/therapy received during the trial. 
Concomitant medication/therapy must be recorded on the appropriate eCRF page. 
The following treatments will not be allowed during trial participation: 
- 
Continuous routine factor IX prophylaxis post-dose if a subject’s endogenous factor 
IX activity result is above 5% 
- 
Treatment in another interventional clinical trial involving drugs or devices within 
one year from IMP administration in this trial 
- 
Another gene therapy treatment 
- 
Chronic administration of steroids (oral and/or inhaled)  
Apart from the above listed treatments, no protocol restrictions will apply with respect to 
concomitant treatment. 
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At baseline, subjects will be administered a challenge dose of short-acting factor IX (40 IU/kg) 
for the factor IX recovery assessment. This challenge dose should provide subjects sufficient 
factor IX coverage for the initial two to three days post treatment. Three days after IMP 
administration, the subjects should visit the clinic for endogenous factor IX activity assessment. 
If the factor IX activity result is ≥5%, further factor IX prophylaxis will not be given. If the 
factor IX activity result is <5%, another dose of short-acting factor IX will be administered to the 
subject and endogenous factor IX activity assessment will be performed again at the Week 1 
routine visit.  
Additional on-demand factor IX may be given after treatment with AMT-061, if considered 
necessary. If the endogenous factor IX activity result is ≥5%, management will be based on the 
Investigator’s clinical judgement and subject preference. Re-initiation of factor IX continuous 
routine prophylaxis may be considered if the endogenous factor IX activity is between 2 and 5% 
in at least two consecutive laboratory measurements, based on the Investigator’s clinical 
judgment and subject preference. If the endogenous factor IX activity is below 2% in at least two 
consecutive central lab measurements, continuous routine factor IX prophylaxis may be 
restarted.  
Factor IX infusions are not recommended for subjects with factor IX activity in the 
non-hemophilic (≥40% of normal) range especially in subjects with a confirmed COVID-19 
infection, as increased thrombogenic risk is a known complication of COVID-19. Subjects with 
factor IX activity in the non-hemophilic range post-treatment with AMT-061 and infected with 
COVID-19 may potentially be at the same risk of thrombosis as subjects without hemophilia; 
antithrombotic therapy for these subjects should be considered under the same guidelines 
recommended for those without hemophilia. 
5.6.3 Guidelines for Use of Factor IX for Subjects Undergoing Major Surgery 
Replacement of factor IX for subjects undergoing major surgery in this trial will be according to 
established guideline (Srivastava et al., 2013) in terms of factor IX activity level pre and post-
surgical procedure. The target factor IX activity level pre and post-major surgery regardless of 
whether the regular or extended half-life replacement is administered as per World Federation of 
Hemophilia is as follows: 
 
Factor IX Activity Level 
Pre-operative: 
60-80% 
Post-operative: 
40-60% Day 1-3 
 
30-50% Day 4-6 
 
20-40% Day 7-14 
 
For minor surgery, use of factor IX is up to the Investigator but should be discussed with the 
medical monitor.  
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Factor IX infusions are not recommended for subjects with factor IX activity in the 
non-hemophilic (≥40% of normal) range especially in subjects with a confirmed COVID-19 
infection, as increased thrombogenic risk is a known complication of COVID-19. Subjects with 
factor IX activity in the non-hemophilic range post-treatment with AMT-061 and infected with 
COVID-19 may potentially be at the same risk of thrombosis as subjects without hemophilia; 
antithrombotic therapy for these subjects should be considered under the same guidelines 
recommended for those without hemophilia. 
5.6.4 Guidelines for Transaminase Elevations 
Transaminase levels will be monitored based on the site’s local laboratory results and central 
laboratory results, with local laboratory analysis results arranged, if possible, to be provided on 
the same day or the day after blood sampling has occurred to allow for rapid detection of any 
elevations in transaminase levels. 
For ALT level increments of at least 2-fold baseline (i.e., pre-IMP) and/or > ULN, by local or 
central laboratories, the Investigator should contact the Medpace and uniQure Medical Directors 
to discuss a clinical management plan on a case-by-case basis, including potential re-tests and/or 
initiation of corticosteroid treatment. In case of AST level increments > ULN, the Investigator 
should contact the Medpace and uniQure Medical Directors and a similar discussion should take 
place.  
Investigators should assess potential causes of a transaminase elevation, to rule out if the 
elevation is due to intense exercise, alcohol consumption, or use of concomitant medications. 
Additional laboratory assessments including creatine kinase assessment and a viral panel are 
recommended as needed. 
See Table 7 for a recommended approach to prednisolone treatment. Medications equivalent to 
prednisolone may also be used. A combined immunosuppressant regimen or the use of other 
products can also be considered in case of prednisolone treatment failure or contraindication. 
Corticosteroid tapering should be discussed among the Investigator and Medpace and uniQure 
Medical Directors based on changes in and normalization of transaminase levels. 
Investigators should monitor subjects for corticosteroid-related AEs. If use of high dose 
prednisolone/prednisone is prolonged, blood pressure and glucose levels should be monitored at 
each clinic visit, or more frequently if needed, and Investigators should consider starting subjects 
on vitamin D, a proton pump inhibitor, and/or Pneumocystis jiroveci prophylaxis therapy. 
Subjects who have been placed on corticosteroid treatment should be closely monitored for 
potential COVID-19 infection. Where possible and as per site guidelines and at the discretion of 
the Investigator, subjects should be tested for COVID-19 at the time of initiating corticosteroid 
treatment. Those on corticosteroid treatment who are positive for COVID-19 might be 
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considered for more rapid tapering than outlined in Table 7; corticosteroid tapering should be 
discussed among the Investigator and Medpace and uniQure Medical Directors. 
Table 7 Use of Prednisolone for the Treatment of Transaminase Elevation 
Timeline 
Prednisolone dose (mg/day) 
Week 1 
60 
Week 2 
40 
Week 3 
30 
Week 4 
30 
Maintenance until transaminase returns to baseline level (Day 0, 
pre IMP) 
20 
After pre IMP level has been reached 
Reduce daily dose with 5 mg/week 
 
5.7 Treatment Compliance and Drug Accountability 
Investigators will be provided with a subject pack containing sufficient vials of the IMP to 
prepare and administer the required dose for each subject. The Investigator or designee will 
acknowledge receipt of the subject pack by documenting date of receipt, shipment content and 
condition. Accurate records of all IMP prepared, administered, returned, and/or destroyed must 
be maintained as detailed further in this section as well as in the IMP Handling Manual. 
Investigators will be responsible for implementing a system for subject and product traceability 
at the clinical site. That system should contain sufficient detail to allow linking of each vial 
delivered to the Investigator to the subject receiving it and vice versa.  
The Investigator has overall responsibility for preparing and administering the IMP. Where 
permissible, tasks may be delegated to a qualified designee (e.g., a pharmacist) who is 
adequately trained in the protocol and procedures as described in the IMP Handling Manual and 
who works under the supervision of the Investigator. This delegation must be documented in the 
applicable trial delegation of authority form. 
The Investigator or his/her designee (as documented by the Investigator in the applicable trial 
delegation of authority form) will administer the IMP only to subjects included in this trial, for 
whom it is confirmed that they are eligible for dosing, following the procedures set out in the 
trial protocol and the IMP Handling Manual. Each subject will be given only the IMP carrying 
his treatment assignment. All dispensing will be documented on the eCRFs and/or other IMP 
record. 
The Sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records. 
Based on entries in the site drug accountability forms, it must be possible to reconcile IMPs 
delivered with those used and destroyed if unused. All IMPs must be accounted for and all 
discrepancies must be investigated and documented to the Sponsor’s satisfaction. 
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6 TRIAL SCHEDULE AND ASSESSMENTS 
6.1 Trial Schedule 
For details on the timing and frequency of the assessments and testing during Week -6 to 52 refer 
to the flow charts in Table 1 and Table 2, and for the period of 12 to 60 months refer to Table 3 
and Table 4. 
6.1.1 Screening (Week -6 to Day 0) 
Informed consent must be obtained from each subject prior to any of the trial procedures are 
performed (see also Section 10.3.1).  
Maximal six weeks prior to baseline, subjects are screened for eligibility, and historical bleeding 
and factor IX use data will be collected. Baseline is defined as Day 0 prior to IMP administration 
(Day 0 pre IMP). The screening period might be prolonged in consultation with the sponsor in 
case IMP administration needs to be delayed because of subjects experiencing a bleeding 
episode, surgery, or other event after screening which warrants this delay.  
The electronic diary (e-diary) will be handed over to the subjects, and the Investigator/study 
nurse will train them in recording of the bleeding episodes and use of factor IX replacement 
therapy. From screening onwards, subjects will record their use of factor IX replacement therapy 
and bleeding episodes in the dedicated e-diary. e-Diary data will be reviewed on a continuous 
basis by the Investigator/study nurse. The period from screening up to baseline is considered a 
training period, after which the Investigator/study nurse will review and evaluate any problems 
with recording of e-diary data with the subject. The e-diary training can be repeated at any time 
during the trial as considered necessary by Investigator/study nurse. 
Eligibility according to the trial in- and exclusion criteria will be evaluated at Screening and 
during the period up to baseline (i.e., Day 0 pre IMP). For a description of the in- and exclusion 
criteria please refer to Section 4.1 and Section 4.2. 
The overall eligibility will be determined once all screening values and results of other required 
procedures are available. Subjects who fail to meet inclusion criteria and/or meet at least one of 
the exclusion criteria and did not receive AMT-061 are defined as a screen failure. Subjects 
qualifying as screen failures may be re-evaluated once for participation in the trial in consultation 
with the Sponsor. 
Separate informed consents are to be taken for a blood sample for future research, and for 
factor IX gene sequencing analyses to be performed only if factor IX gene mutation information 
is not available. If the subject provides consent for one or both ICFs, the respective blood 
samples will be taken during the screening visit.  
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The use of concomitant medication and occurrence of AEs will be monitored throughout the trial 
on an ongoing basis. 
6.1.2 IMP Administration 
The day of IMP administration should be planned to take place as an overnight stay at the clinic 
and should take place within a maximum of six weeks after the Screening visit (unless sponsor 
approved a prolonged screening period as described in Section 6.1.1). 
The baseline visit should also be planned as such that the baseline blood sample for factor IX 
activity and factor IX protein concentration assessment will be drawn at the point in time where 
factor IX activity and factor IX protein concentration is expected to be closest to trough levels 
(i.e., the baseline visit should be scheduled on days when routine factor IX prophylaxis is due to 
be administered). In case of on-demand factor IX replacement therapy use in proximity to the 
scheduled visit, the exogenous factor IX is to be washed out and the visit is to be rescheduled to 
the extent the visit window allows. The wash out period will be minimal 10 days for short-acting 
factor IX or more for long-acting factor IX (depending on half-life). 
6.1.2.1 Baseline - Day 0 pre IMP 
Subjects will be admitted to the hospital for an overnight stay. 
It is recommended that each subject should complete the 
 
, prior to the interview by the Investigator and/or study nurse and any other trial 
related procedures.  
Prior to administration of AMT-061, the Investigator should ensure subject’s eligibility (see 
Section 4.1 and Section 4.2). If a subject, who was previously considered eligible, no longer 
meets the trial inclusion criteria, the subject can be re-evaluated once, as described in 
Section 6.1.1. 
The medical history will be evaluated, vital sign measurement, a physical examination and 
 
 will be performed. Furthermore, baseline samples are taken for efficacy 
and safety laboratory parameters, serum chemistry and hematology. Also, for subjects who 
signed the optional ICF, the sample for future research is taken.  
If not taken at screening, the optional blood sample for factor IX gene sequencing will be taken 
(if the subject has signed the separate ICF and only if information on factor IX gene mutation is 
not available).  
From baseline until week 52, subjects continue with recording their use of factor IX replacement 
therapy and bleeding episodes in the e-diary. Diary data will be reviewed on a continuous basis 
by the Investigator/study nurse. In addition to the subjects’ reporting of presumed bleeding 
episodes in the e-diary, the Investigator or designee will assess each bleeding episode, by 
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describing the circumstances as well as the nature of the reported bleed in a bleed specific 
narrative as soon as possible but at least within 72 hours after it has been reported by the subject. 
In case the information provided in the e-diary is not sufficient to assess the presumed bleeding 
and describe it in a narrative, the subject needs to be called and/or visit the site. e-Diary training 
should be repeated at any time during the trial as considered necessary by Investigator/study 
nurse. 
6.1.2.2 IMP Administration and Post IMP 
Subjects will receive a single infusion of AMT-061 according to the procedures described in 
Section 5.3 and in the IMP Handling Manual. After IMP administration (post IMP), subjects will 
be monitored for tolerance to the IMP and detection of potential immediate AEs at the clinical 
trial site for 24 hours (overnight stay).  
After completion of the IMP infusion: 
- Vital signs are measured at 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hours  
- Blood samples are taken for vector genome detection at 1, 2, 3 and 24 hours 
- A blood sample is taken for c-reactive protein (CRP) measurement at 3 hours 
 
The subject may leave the clinic after all assessments at 24 hours after AMT-061 administration 
have been performed, and the subject received his subject treatment card. 
6.1.3 Post-Treatment Follow-up 
During the first year of follow-up, the recording of e-diary data by the subject will be continued 
as well as continuous review of these data, and adjudication of the reported bleeding episodes, by 
the Investigator/study nurse, as described in Section 6.1.2.1. In addition, use of concomitant 
medication and occurrence of AEs will be continuously monitored. 
A physical examination and samples for efficacy and safety laboratory parameters, hematology 
and serum chemistry, are taken at each visit, except for the samples for factor IX antibodies and 
factor IX inhibitors (taken at Week 6, 12, 26 and 52), samples for Total and Neutralizing 
antibodies to AAV5 (taken at Week 1, 2, 3, 4, 5, 6, 12, 26 and 52), semen sampling for shedding 
(taken at Week 6, 12, 16, 26 and 52), and the blood sample taken for future research (taken at 
Week 12 and 52) (see also Table 2).  
At Week 26 and 52, it is recommended that each subject should complete the 
 
 prior to the interview by the Investigator and/or study nurse and any other trial 
related procedures.  
The 
 is evaluated at Week 52. 
At six weeks after IMP administration, the factor IX activity data will be collected for interim 
analysis and reporting of this primary efficacy parameter.  
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At the Week 52 visit, the e-diary data devices are collected, and the paper diaries for the long-
term follow-up are handed out. After the 52 week post-dose visit, the complete set of efficacy 
and safety data are collected. These data will be locked, analyzed, and reported in a CSR. Data 
from that point will be considered locked and will not be changed. 
After the 2.5-year post-dose visit, the complete set of efficacy and safety data since the 52-week 
lock will be collected. These data will be locked, analyzed, and reported in a CSR addendum. 
Data from that point will be considered locked and will not be changed. 
6.1.3.1 Final Visit or Early Discontinuation 
The procedures listed for the final visit, with the exception of the distribution of the 
study-specific paper diaries, must also be performed at early discontinuation (refer also to 
Section 4.5). If a subject discontinues prior to Week 52 he must complete all Week 52 
assessments/procedures. In case a subject discontinues after Week 52 but prior to Month 60 he 
must complete the Month 60 assessments/procedures.  
6.1.4 Long-term Follow-up 
Subjects will visit the clinic every 26 weeks (6 months ± 2 weeks). During these visits, it is 
recommended that the subject completes the 
 (only at Month 24, 36, 48, and 
60), prior to any other trial procedure is performed. Further, a physical examination, evaluation 
of the 
 (only at Month 24, 36, 48, and 60), sampling for efficacy and safety laboratory 
parameters, and review of AEs and concomitant medications will be performed. An abdominal 
ultrasound will be performed at the Month 30, 36, 42, 48, 54, and 60 visits. In addition to AE 
review during these visits, there should be an additional contact moment between site staff and 
subject in between these routine visits to facilitate at least quarterly monitoring of occurrence of 
AEs. Options for how visits may occur to accommodate safety concerns and restrictions due to 
COVID-19 are described in Section 3.1.1. 
In the long-term follow-up phase, subjects will document their use of factor IX replacement 
therapy and bleeding episodes in study-specific paper diaries. Subjects are expected to bring their 
long-term follow-up bleed diaries and long-term follow-up factor IX use diaries to every study 
visit during the long-term follow-up phase. At each visit, site staff will collect the information 
that is new since the previous visit in the paper diaries. In between study visits, subjects should 
contact the site staff immediately in case of an experienced bleed and/or factor IX use in addition 
to completing the questions/information requested on the paper diaries to capture all information. 
In total, each subject will be followed for five years after administration of AMT-061. This is in 
line with the European Medicines Agency (EMA) guideline on follow-up of subjects 
administered with a gene therapy medicinal product (EMA/CHMP/GTWP/60436/2007) and the 
Food and Drug Administration (FDA) guidance on long-term follow-up after administration of 
human gene therapy products.  
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At the end of the long-term follow-up all end-of-trial procedures, i.e., the Month 60 procedures, 
as detailed in Table 3 and Table 4, should be taken. At the end of the trial, all safety and efficacy 
data will be reported in a CSR addendum (5-year analysis). 
6.1.5 Additional Visits 
The subject may be called in for additional visits, at the discretion of the Investigator. The 
subject may also contact the clinical trial site for an additional visit. 
An additional visit may include additional assessments, as deemed necessary by the Investigator, 
such as (but not limited to) physical examination, AE assessment, bleeding adjudication and/or 
repetition of instructions to the subject regarding subject e-diaries (Section 6.1.1), additional 
blood and/or semen sampling, repetition of blood sampling due to erroneous results 
(Section 6.2.4.2), or conduct of measurements that were missed at the previous visit. 
6.1.6 Additional Care of Subjects after the Trial 
No after care (i.e., after the long-term follow-up) is planned for this trial. 
6.2 Trial Evaluations 
6.2.1 Demographic and Other Baseline Characteristics 
6.2.1.1 Demographics 
Demographics collected at Screening include date of birth (i.e., age at screening visit), race, 
ethnic group and gender according to local regulations. 
6.2.1.2 Medical History and Concomitant Illnesses 
Medical history is any previous medical condition or surgical event, i.e., a condition/event that 
started prior to the screening visit, but is not ongoing at the screening visit. A concomitant illness 
is a medical condition that is ongoing at the screening visit.  
Collection of historical medical information regarding hemophilia B is described in 
Section 6.2.1.4.  
At Screening, information on relevant medical history will be obtained and recorded. The 
following conditions and events will be considered relevant (bleeding events excluded): 
- Any surgical event or any chronic or ongoing medical condition, regardless if it 
requires/required therapy or not 
- Any medical condition or surgical event that has resulted in sequelae 
- Any isolated or one-off medical condition or surgical event that has occurred within 
1 year prior to Screening irrespective of the outcome of the event. 
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- Any isolated or one-off medical condition or surgical event that has resolved without 
sequelae and occurred more than 1 year prior to Screening if judged relevant by the 
Investigator (for example conditions that the Investigator evaluates could re-emerge over 
time, e.g., cancers). 
6.2.1.3 Prior and Concomitant Medication/Therapy 
For the definition of prior medication/therapy, refer to Section 5.6.1. For the definition of 
concomitant medication/therapy, refer to Section 5.6.2. At every visit, the Investigator or a 
qualified designee will ask the subject about concomitant medication. The Investigator should 
record the use of all medication (including over the counter medication, vitamin and/or mineral 
supplements, homeopathic remedies and herbal preparations) used and changes in the use of 
medication. Refer to Section 6.2.2.1 for instructions on recording of factor IX replacement 
therapy. The Investigator should also record other concomitant treatments/therapy, e.g., 
physiotherapy.  
The following information will be recorded on concomitant medication/therapy: 
- Drug/therapy name (generic name preferred) 
- Indication 
- Dosing regimen (dose, unit, frequency, route) 
- Start date (if started ≥3 months prior to Screening, then this can be stated instead of 
recording the specific start date) 
- Stop date (or ongoing, if ongoing at end trial participation). 
6.2.1.4 Hemophilia B Status and History 
At Screening, the following medical history data related to hemophilia B will be recorded: 
- Date of initial diagnosis 
- Endogenous factor IX activity level at diagnosis (if available) 
- Date and value of most recent endogenous factor IX activity assessment (if available) 
- Severity of Hemophilia B 
- Family members with a history of factor IX inhibitors 
- Arthropathy 
- 
 as measured with 
 version 2.1 (see Section 6.2.2.5) 
- Number and location of target joints (defined as three or more spontaneous bleeds into a 
single joint within a consecutive six-month period. Where there have been ≤2 bleeds into 
the joint within a consecutive 12-month period the joint is no longer considered a target 
joint) 
- Registered name and dosage regimen of current continuous routine prophylactic factor IX 
replacement therapy (if applicable) 
- Hemophilia B related Surgical History 
o Date of surgery 
o Surgical event 
o Preventive treatment during surgery: recombinant or plasma product 
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6.2.1.5 History of Bleeding and Factor IX Use 
At Screening the following historical information regarding bleeding and factor IX use will be 
collected and recorded in a specific module of the eCRF: 
For the overall period prior to screening: 
- Number of exposure days prior to trial entry. An exposure day is a day where the 
subject received one or more infusion(s) of factor IX replacement therapy. Additional 
information will be recorded for factor IX replacement therapy administered during 
the last 30 days prior to trial entry (trade name of factor IX medication, date & time 
of administration, units per administration). 
Factor IX use data from one year prior to screening: 
- Number of months on factor IX replacement therapy  
- Dose and frequency of dosing; in case the subject is on intermittent prophylactic 
factor IX replacement therapy, each regimen followed in the last 52 weeks should be 
reported 
- Recombinant or plasma factor IX product 
- Number of treatment requiring bleeding episodes during each specific factor IX 
regimen 
- Average number of units to treat a bleed during each specific factor IX regimen  
- Number of bleeding episodes prior to initiation of prophylactic factor IX replacement 
therapy. 
Bleeding data from one year prior to screening: 
- Date of the bleed 
- Type of bleed (spontaneous, traumatic, instrumented, unknown) 
- If factor IX replacement therapy is provided, the name and total dose of the therapy 
Information on invasive procedures requiring factor IX use in the year prior to screening: 
- Date of procedure 
- Type of procedure  
- Factor IX product used (Registered drug name)  
- Total factor IX dose (in IU) used for each procedure 
6.2.1.6 Factor IX Gene Sequencing 
Available information on factor IX gene mutation will be collected at Screening and recorded.  
For those subjects who have given their consent, a blood sample for the purpose of factor IX 
gene sequencing analysis will be collected (preferably at Screening, but otherwise at a later time 
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point during the subject’s trial participation), but only if information of factor IX gene mutation 
is not available and if separate informed consent is given by the subject. 
Subjects who do not wish to participate in the factor IX gene sequencing analysis may still 
participate in the trial and will not be required to withdraw from the trial if they withdraw 
consent for the factor IX gene sequencing analysis.  
Gene sequencing analysis will be performed at a central laboratory.  
6.2.2 Efficacy Evaluations 
For details on the timing and frequency of the assessments refer to the flow charts in Table 1 
through Table 4. 
The name and address of each laboratory used in this trial will be maintained in the 
Investigator’s files at each site. 
Details for the laboratory processing instruction will be provided in the laboratory manual. 
6.2.2.1 Factor IX Replacement Therapy 
From Screening until Week 52, subjects will be asked to record the all use of prophylactic and 
on-demand factor IX replacement therapy in an e-diary. The subject e-diary will include 
questions with respect to: 
- Reason for factor IX use (i.e., continuous routine prophylaxis, selective prevention of 
a bleed [e.g., because of upcoming physical activity, sports, etc.], prophylaxis for 
invasive procedures, or other). 
- Date and time of factor IX infusion 
- Factor IX product used (Registered drug name)  
- Total factor IX dose in International Units (IU) 
The Investigator/study nurse will review the e-diary entries for completeness and accuracy 
against the subject’s medical/hospital records. 
Information on actual factor IX replacement therapy used will be recorded by the subject in the 
e-diary. In addition, the prescribed factor IX replacement therapy regimen will be recorded in the 
eCRF.  
During the long-term follow-up phase, subjects will be expected to continue documenting factor 
IX replacement therapy in their study-specific paper long-term follow-up factor IX use diary, 
which they will bring with them to all study visits. 
Factor IX infusions are not recommended for subjects with factor IX activity in the 
non-hemophilic (≥40% of normal) range especially in subjects with a confirmed COVID-19 
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infection, as increased thrombogenic risk is a known complication of COVID-19. Subjects with 
factor IX activity in the non-hemophilic range post-treatment with AMT-061 and infected with 
COVID-19 may potentially be at the same risk of thrombosis as subjects without hemophilia; 
antithrombotic therapy for these subjects should be considered under the same guidelines 
recommended for those without hemophilia. 
6.2.2.2 Bleeding Episodes 
From Screening until Week 52, subjects will record information of bleeding episodes in an e-
diary. The subject e-diary will include questions regarding each bleeding episode with respect to:  
- Date and time of onset of bleed (start and stop) 
- Location of bleed 
- Circumstances of bleed: spontaneous, traumatic, medical/dental/other procedure, 
unknown cause 
- Location and type of bleed 
- Symptoms associated with the bleed 
- Tests performed 
- Treatment of bleed with factor IX, and response to this treatment  
- Treatment other than factor IX (e.g., compression, ice, pain medication, rest) 
During the long-term follow-up phase, subjects will be expected to continue documenting 
bleeding episodes in their study-specific paper long-term follow-up bleed diary which they will 
bring with them to all study visits. 
In case of the occurrence of a presumed bleeding as reported by the subject in the e-diary, the 
Investigator or designee needs to assess the bleeding as soon as possible but at least within 72 
hours after it has been reported by the subject. In case the information entered in the e-diary is 
not sufficient to assess the bleeding, the subject needs to be called and/or visit the site. 
The Investigator will assess the bleed according to local standard of care (including potential 
imaging). The bleeding data and outcome should be recorded in source documents. 
Recurrent bleed: A bleed is defined as a recurrent bleed when, after no or minimal response to 
treatment, the bleed is occurring within 72 hours after stopping treatment for the original bleed 
for which treatment was initiated. 
Persistent bleed: A bleed is defined as a persistent bleed when the same bleed continues for more 
than 72 hours in the same location, without stopping treatment for the original bleed for which 
treatment was initiated. 
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6.2.2.3 Factor IX Activity Levels and Factor IX Protein Concentration 
Blood samples for determination of endogenous factor IX activity and factor IX protein will be 
collected and assessed at the central and/or local laboratory as indicated in the flow chart 
(Table 2). Central laboratory results for factor IX activity will be used in the analyses and local 
laboratory results for factor IX activity will be used for local monitoring of subjects.  
Throughout the study, it will be the aim to draw blood samples at those time points when the 
subject’s factor IX activity is expected to be at its trough.  
For subjects on routine prophylactic factor IX replacement therapy: 
 
The Investigator and/or study nurse will collaborate with the subject to schedule study 
visits to take place on days when continuous routine prophylactic factor IX replacement 
treatment is due to be administered. At these visits, blood sampling will then take place 
just prior to administration of prophylactic factor IX replacement therapy at the clinic. 
 
If a subject uses additional on-demand factor IX replacement treatment, his upcoming 
study visit may need to be re-scheduled (to the extent the visit window allows) so that the 
visit takes place at the time the subject resumes his routine prophylaxis schedule.  
For subjects only using on-demand factor IX replacement therapy (only applicable after 
AMT-061 administration):  
 
If a subject uses on-demand factor IX replacement treatment, his upcoming study visit 
may need to be re-scheduled (to the extent the visit window allows) so that the visit does 
not take place within 10 days of any on-demand factor IX product use. 
Factor IX activity will be assessed by using the one-stage aPTT assay and a chromogenic assay 
(central laboratory). No additional blood will be drawn for chromogenic assays of factor IX 
activity; the test will be performed on back-up samples. 
 
 
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Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
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6.2.3 Safety Evaluations 
6.2.3.1 Adverse Events  
All AEs will be collected from signing of the informed consent form until the end of the five-
year follow-up. 
At each trial visit, subjects will be questioned in a general way to ascertain if AEs have occurred 
since the previous visit (e.g., “Have you had any health problems since your last visit?”). During 
the long-term follow-up, AEs should be assessed at least quarterly by means of an additional 
contact moment between site staff and subject in between the scheduled visits. AEs are collected 
from the time informed consent is signed. 
For definitions of (S)AEs, and procedures regarding reporting of (S)AEs refer to Section 7. 
6.2.3.2 Vital Signs 
Vital signs (blood pressure, pulse and body temperature) will be measured before and at specific 
time points after IMP administration on Day 0 (see Table 1). Before measurement of blood 
pressure and pulse the subject should rest for at least 5 minutes. For the individual subject, all 
measurements should be performed while the subject is in the same position (i.e., sitting or lying) 
throughout the trial. 
Body temperature should be measured using the same method (e.g., an ear thermometer) for the 
individual subject throughout the trial.  
CSL Behring 
CCI
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AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
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Abnormalities (e.g., high blood pressure) identified at the Screening will be documented in the 
subject’s source documents and on the medical history eCRF. Changes after the Screening Visit 
will be captured as AEs on the AE eCRF page, as deemed clinically significant in the opinion of 
the Investigator. These abnormalities are to be followed until they reached “final outcome” (refer 
to Section 7.9). 
6.2.3.3 Physical Examination (Including Height and Weight) 
A physical examination will be performed at all visits, except for height and weight, which will 
only be measured at screening. 
Height (without shoes) will be measured and recorded, rounded to the nearest centimeter. Body 
weight (without overcoat and shoes) will be measured and recorded, rounded to the nearest 
kilogram.  
At Day 0, the physical examination will be performed prior to IMP administration.  
The physical examination will include general appearance and bedside examination of the 
following body systems: Lymph nodes, eyes and ears, mouth and throat, lungs, abdomen, 
extremities, musculoskeletal system, neurological system, cardiovascular system, and skin. 
The evaluation of each body system will be recorded as “normal” or “abnormal”. Abnormalities 
will need to be specified and recorded. 
Abnormalities (e.g., scar at the left side at knee following total knee replacement, or arthropathy 
of left ankle due to hemophilia B) identified at the Screening will be documented in the subject’s 
source documents and on the medical history eCRF. Changes after the Screening Visit will be 
captured as AEs on the AE eCRF page, as deemed clinically significant in the opinion of the 
Investigator. These abnormalities are to be followed until they reached “final outcome” (refer to 
Section 7.9). 
6.2.3.4 Abdominal Ultrasound 
To monitor subjects for liver fibrosis and potential occurrences of liver malignancies, abdominal 
ultrasounds will be performed. These ultrasounds will occur starting at visit Month 30 and then 
at each visit thereafter as specified in Table 3. 
For those subjects where a long-term follow-up visit is impacted by COVID-19, abdominal 
ultrasounds may be conducted within the following window: 
- 
Up to -1 month prior to the target visit 
- 
Up to +1 month after the target visit 
Adjustments to this visit schedule will be documented. 
Ultrasounds will be evaluated by qualified personnel at each site for fibrosis and malignancy. 
CSL Behring 

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
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Identified abnormalities will be captured as AEs on the AE eCRF page, as deemed clinically 
significant in the opinion of the Investigator. These abnormalities are to be followed until they 
reached “final outcome” (refer to Section 7.9). 
6.2.3.5 Anti-factor IX Antibodies 
Anti-factor IX antibodies will be measured at the central laboratory, at baseline and at specific 
time points after IMP administration as specified in Table 2 and Table 4. 
6.2.3.6 Factor IX Inhibitors 
Factor IX inhibitors will be measured at the central laboratory with the Nijmegen modified 
Bethesda assay, and at the local laboratory with the Bethesda assay or Nijmegen modified 
Bethesda assay as specified in Table 2 and Table 4. Preferably, the same type of assay is applied 
consistently for the individual subject throughout the entire trial period. 
The Investigator should arrange with the local laboratory that analysis results are provided on the 
same day, or the day after, blood sampling has taken place. 
The Investigator (or designee) should enter analysis results, as well as related reference ranges 
and analysis method applied (if applicable) in the eCRF. In addition, the local laboratory result 
reports should be kept in the subject’s medical record. 
A subject is said to suffer from factor IX inhibitors if tested positive for factor IX inhibitors at 
two consecutive tests (as measured by the central laboratory), performed preferably within two 
weeks.  
If a subject is tested positive for factor IX inhibitors, a re-test should be performed preferably 
within two weeks to confirm the positive test. The subject should be called in for an additional 
visit in case no routine visit is scheduled within this two week timeframe. The subject should 
remain in the trial as per the clinical judgement of the Investigator. 
If a subject has confirmed factor IX inhibitors and continues with no change to treatment type for 
six weeks and the factor IX inhibitor test is negative after that time, the factor IX inhibitor is 
classified as transient.  
6.2.3.7 Factor IX Recovery 
Measurement of factor IX recovery (maximum concentration [Cmax]) and incremental recovery 
measured as increase in activity per unit infused (IU/ml per U/kg) at 30 min after infusion of a 
dose of factor IX will be performed at baseline (Day 0 pre IMP). Additionally, measurement of 
factor IX recovery and incremental recovery should be done at suspicion of factor IX inhibitor 
(see also Section 6.2.3.6) as judged by the Investigator.  
At each occasion, a factor IX challenge dose of 40 U/kg should be administered while at the 
clinical trial site. A blood sample should be drawn just prior to administering the factor IX 
CSL Behring 

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
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challenge dose and at 30 minutes after the factor IX challenge dose was administered. The blood 
sample should preferably be drawn from a vein different from the vein used for factor IX 
infusion. 
Date of sampling, times of blood sampling (pre and post factor IX administration), time of 
factor IX challenge dose administration will be recorded.  
Factor IX activity for factor IX recovery assessment will be measured at a central laboratory 
using the one-stage aPTT assay.  
6.2.3.8 Total (IgG and IgM) and Neutralizing Antibodies to AAV5 
Sampling for total (IgG and IgM) and neutralizing antibodies to AAV5 will be performed at 
Screening, baseline and at specific time points after IMP administration as specified in Table 2 
and Table 4. Total IgG and IgM antibodies will be assessed using an enzyme-linked 
immunosorbent assay (ELISA) and a luciferase-based assay will be used for neutralizing 
antibodies to AAV5. The measurements will be performed at the central laboratory. Further 
details of the assays will be provided in the laboratory manual. 
6.2.3.9 AAV5 Capsid-specific T cells 
Sampling for AAV5 capsid-specific T cells will be performed at all visits up to Week 52.  
AAV5 capsid-specific T cells will be measured at the central laboratory.  
6.2.3.10 Vector Genome Detection 
Sampling of blood and semen to determine vector DNA levels will be performed at baseline and 
at specific time points post-baseline, as specified in Table 2 and Table 4 by means of quantitative 
(real-time) polymerase chain reaction (qPCR). Sampling should continue for the individual 
subject and for a specific matrix until three consecutive negative samples have been detected for 
the subject for that particular type of matrix. The sampling schedule may be increased (in 
frequency) as agreed between the Investigator and subject following the notification of a first 
negative result on blood and/or semen, expediting the opportunity to reach three consecutive 
negative samples on the specific matrix. 
Based on the wish of the subject semen samples can be collected at home prior to attending the 
visit (at the visit day or at the day before the visit day). Also, the frequency of semen sampling 
may be reduced (to be agreed between Investigator and subject) as long as the subject uses a 
condom during sexual intercourse until three consecutive negative samples have been detected. 
In case a subject is not able to provide semen samples due to a medical condition, this should be 
recorded by the Investigator in the subjects’ medical record.  
CSL Behring 

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
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6.2.3.11 Inflammatory Markers 
Blood samples will be taken at all visits up to Week 52 to assess IL-1β, IL-2, IL-6, IFNγ, and 
MCP-1 using ELISA. All assessments will be performed at the central laboratory. 
6.2.3.12 Other Safety Laboratory Evaluations 
All clinical laboratory assays will be performed according to the laboratory’s normal procedures. 
Reference ranges are supplied by the laboratory and used to assess the clinical laboratory data for 
clinical significance and out-of-range pathological changes. The Investigator should assess out-
of-range clinical laboratory values for clinical significance, indicating if the value(s) is/are not 
clinically significant or clinically significant. Abnormal clinical laboratory values, which are 
unexpected or not explained by the subject’s clinical condition may be, at the discretion of the 
Investigator or Sponsor, repeated until confirmed, explained, or resolved as soon as possible. 
The safety laboratory assessments that will be performed at the central and/or local laboratory 
are specified in Table 8, and as indicated in the schedule of events (Table 2 and Table 4). 
Table 8 Safety Laboratory Parameters Assessed at the Central and/or Local Laboratory 
Central Laboratory 
 
Serum Chemistry 
Serum electrolytes (sodium, potassium), creatinine, creatine kinase, gamma-
glutamyltransferase, AST, ALT, ALP, CRP, albumin, total bilirubin, glucose (non-
fasting) 
Hematology 
Hemoglobin, hematocrit, platelet count, red blood cells, white blood cells with 
differential count, CD4+ count (all expressed in % as well as in absolute numbers) 
Coagulation 
aPTT, PT (or INR [International Normalized Ratio]) 
Serology 
HIV viral load, HBsAg, HBeAg, HBV DNA and HCV RNA 
Alpha-fetoprotein 
AFP 
Local Laboratory 
AST and ALT 
Abbreviations: AFP: alpha-fetoprotein; ALP: alkaline phosphatase; ALT: alanine aminotransferase; aPTT: activated partial 
thromboplastin time; AST: aspartate aminotransferase; CRP: c-reactive protein; DNA: deoxyribonucleic acid; 
HbeAg: hepatitis B extracellular antigen; HBsAg: hepatitis B surface antigen; HBV: hepatitis B virus; HCB: hepatitis C virus; 
HIV: human immunodeficiency virus; RNA: ribonucleic acid. 
 
The Investigator should attempt to arrange with the local laboratory that analysis results are 
provided on the same day, or the day after, blood sampling has taken place. Local laboratory 
results should be provided as soon as possible to the Investigator. 
The Investigator should enter analysis results, as well as related reference ranges and analysis 
method applied (if applicable) in the eCRF. In addition, the local laboratory result reports should 
be kept in the subject’s medical record. 
Abnormalities identified at the Screening will be documented in the subject’s source documents 
and on the medical history eCRF. Changes after the Screening will be captured as AEs on the AE 
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AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
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eCRF page, as deemed clinically significant in the opinion of the Investigator. These 
abnormalities are to be followed until they reached “final outcome” (refer to Section 7.9). 
6.2.4 Others 
6.2.4.1 Blood Sample for Future Research 
Four additional blood samples for the purpose of potential future research in the hemophilia B 
disease area (including development and validation of assays to support efficacy assessments) 
will be drawn (at screening, baseline [Day 0 pre IMP], Week 12, and Week 52). 
These additional blood samples will only be drawn if separate informed consent is given by the 
subject. Subjects who do not wish to donate blood samples for the purpose of potential future 
research may still participate in the trial and will not be required to withdraw from the trial if 
they withdraw consent for the potential future research.  
The procedures for the collection, processing, storage and shipment of these blood samples are 
described in the Laboratory Manual. 
6.2.4.2 Liver Sample for Future Research 
The Sponsor will also provide an optional consent to ask subjects to agree with providing a tissue 
sample from their liver in case of death, or if the liver becomes available for any other reason 
(e.g., liver transplantation or resection) during the long-term follow-up phase of this study. Liver 
samples will be analyzed to investigate how the gene therapy sequences are maintained within 
the cells of the liver over time, tolerance and/or stress within the cells of the liver, and/or how the 
gene therapy is expressed in different parts of the liver and across the liver cells. This is entirely 
voluntary, and subjects may still participate in the study if they do not wish to agree to donate a 
liver tissue sample. 
6.2.5 General Information Regarding Laboratory Sampling and Results 
All laboratory assessments will be conducted at a central laboratory, except the factor IX activity 
assay for local monitoring of subjects (Section 6.2.2.3), factor IX inhibitor assay for local 
monitoring of subjects and eligibility check (Section 6.2.3.6), and local monitoring of liver 
enzymes (AST and ALT) (Section 6.2.3.12; also see the schedule of events [Table 2 and 
Table 4]). 
Dates and times of sampling will be recorded. 
Detailed procedures for the collection, processing, storage and shipment of central laboratory 
samples are described in the Laboratory Manual. This manual as well as all material such as test 
tubes and labels will be provided by the coordinating central laboratory. 
CSL Behring 

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
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After the laboratory samples have been analyzed, they will remain stored for potential re-analysis 
at any time during the trial to a maximum of up to one year after the trial has been completed, 
before being destroyed. Where allowed by local regulations, left over material of these samples 
may be used throughout the study to support studies in hemophilia B and/or gene therapy 
research, as well as related assay development to support such research. At maximum 1 year 
after the study has been completed, all sample material will be destroyed. Exceptions are the 
future research blood samples, which will be stored and used for medical research until there is 
no sample remaining. 
The Investigator will be provided with laboratory results at regular intervals for review and sign-
off. Any abnormality, judged by the Investigator as a clinically relevant worsening since the first 
measurement, i.e., at Visit 1 or Visit 2, should be reported as an AE, unless the laboratory 
abnormality is associated with an already reported AE. 
Any report of erroneous results from Week 52 and onwards should prompt that the subject is 
called in for an Additional Visit to have blood sample(s) drawn for the purpose of re-
measurement. The Additional Visit should preferably take place within 1 week after the report of 
the erroneous result(s). 
6.2.6 Volume of Blood to be Drawn From Each Subject 
Overall, a total of approximately 2425 mL blood will be drawn from each subject during this 
trial (excluding additional visits). A maximum of 110 mL will be taken per visit. A maximum 
amount of 100 mL will be drawn per additional visit.  
Approximately 2050 mL blood will be drawn as of screening and up till Week 52. During the 
long-term follow-up, approximately 375 mL blood will be drawn.  
The amount of blood to be taken for each assessment may vary according to the instructions 
given in the laboratory manual. The overall total amount of blood that will be drawn from each 
subject may vary according to the amount of additional visits needed for the individual subject. 
When multiple assessments need to be done at the same time point/visit, and they require the 
same type of tube, the assessments may be combined.  
CSL Behring 

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
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7 SAFETY DEFINITIONS, REPORTING AND FOLLOW-UP 
7.1 Adverse Event Definitions 
An AE, an adverse drug reaction (ADR), and a SAE are defined according to ICH Guideline 
E2A. 
An AE is any untoward medical occurrence in a subject administered the IMP and which does 
not necessarily have a causal relationship with this IMP or the IMP administration procedure. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of the IMP including the IMP 
administration procedure. The definition also covers medication errors and uses outside what is 
foreseen in the protocol, including misuse and abuse of the product. 
An ADR is an untoward and unintended response to the IMP related to any dose administered. A 
causal relationship between the IMP and the AE is at least a reasonable possibility. 
An SAE is any untoward medical occurrence that at any dose: 
 
Results in death 
 
Is life-threatening (this refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused 
death if it was more severe) 
 
Requires in-subject hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability or incapacity 
 
Is a congenital anomaly or birth defect 
 
Is judged medically important by the Investigator (this refers to an event, not resulting in 
any of the outcomes listed above, but may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed) 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is an unexpected adverse reaction 
that at any dose results in death, is life-threatening, requires hospitalization or prolongation of 
existing hospitalization, results in persistent or significant disability or incapacity, or is a 
congenital anomaly or birth defect. 
In the following situations events are not defined as an AE: 
 
Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads 
to the procedure is an AE 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the trial that do not worsen 
 
Condition(s) for which pre-planned procedure(s) have been recorded at Screening, 
including hospitalization(s), unless the condition(s) for which the procedure and/or 
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AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
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hospitalization was planned has worsened from the first trial related activity after the 
subject has signed the informed consent form 
 
Concomitant illness identified during the screening procedures will be recorded as 
medical history. However, whenever symptoms for these condition(s) worsen and/or 
become serious, then these events must be reported as an AE or SAE, as applicable. 
7.2 Adverse Events Qualifying for Special Notification 
In addition, the following (S)AEs qualify for special notification as they are seen as safety issues 
of particular concern for Advanced Therapy Medicinal Product (ATMP) (ENTR/F/2/SF/dn 
D(2009) 35810. Brussels, 03/12/2009) and gene therapy medicinal products 
(EMA/CHMP/GTWP/60436/2007): 
 
AEs related to the IMP administration procedure  
 
Suspected or confirmed cases of opportunistic or serious infections that in the 
Investigator’s opinion might be related to the IMP 
 
Unexpected reactions (e.g., hypersensitivity, immunological, toxic or other as 
consequence of a change in the construction or function of the viral vector [e.g., 
generation of replication competent virus]) 
 
AEs related to product failure (including lack of efficacy) 
 
AEs related to mandatory concomitant medication (e.g., immunosuppression) 
 
AEs related to medical devices which form part of the product or are used for application 
of the product 
 
Development of any new/recurrent cancer. 
These AEs should be reported and followed in the same manner as SAEs. Note that the AEs may 
be serious or non-serious by definition (see Section 7.1). 
7.3 Adverse Event Assessment Definitions 
7.3.1 Severity 
The Investigator should assess the severity of all AEs according to the following definitions: 
 
Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living.  
 
Moderate: A type of AE that is usually alleviated with specific therapeutic intervention. 
The event interferes with usual activities of daily living, causing discomfort but poses no 
significant or permanent risk of harm to the research subject. 
 
Severe: A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. 
CSL Behring 

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
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For reporting of S(AE) related laboratory abnormalities, the severity (intensity) needs to be 
evaluated in accordance with the defined criteria for assessment of laboratory value 
abnormalities. 
Note the distinction between seriousness and severity: The term severe is used to describe the 
intensity of the event and a severe event is not necessarily serious (e.g., a severe headache would 
probably not constitute an SAE; however, a mild myocardial infarction could constitute an SAE). 
The seriousness criteria serve as a guide for defining regulatory reporting obligations. 
If an AE changes severity over time, the severity of maximum intensity should be reported. 
7.3.2 Relationship to IMP 
The Investigator must assess the causal relationship of the IMP for each (S)AE. The Investigator 
should decide whether, in his or her medical judgment, there is a reasonable possibility that the 
event may have been caused by the IMP according to the following guidelines and must 
document the causality assessment in the source document. 
Term 
Relationship 
Definition 
Related 
Yes 
The temporal relationship between the event and the administration of the 
IMP is compelling and follows a known or suspected response pattern to 
that product; the response disappears or decreases on cessation or 
reduction of the IMP dose and/or it reappears or worsens when the IMP is 
administered. 
Possibly Related 
Yes 
The temporal relationship between the event and the administration of the 
IMP is compelling and/or follows a known or suspected response pattern to 
that product, but the event could reasonably be explained by the subject’s 
medical condition, other therapies, or accident. 
Unlikely Related 
No 
The temporal relationship between the event and the administration of the 
IMP is less compelling and/or does not follow a known or suspected 
response pattern to that product; the event could plausibly be explained by 
the subject’s medical condition, other therapies, or accident.  
Not Related 
No 
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident and no 
plausible temporal or biologic relationship exists between the IMP and the 
event. In addition, this assessment can be used in cases where the subject 
did not receive any treatment with IMP. 
 
7.4 Reporting of Adverse Events 
All events meeting the definition of an AE must be reported in the period starting at the first visit 
during which any trial related activity takes place until the end-of-trial participation. Only 
medically qualified personnel (Investigators) must assess AEs. 
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AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
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CONFIDENTIAL 
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AEs must be reported in the source data and the eCRF. The diagnosis will be recorded, if 
available and applicable. If no diagnosis is available, each sign and symptom will be recorded as 
individual AEs. 
Recurring AEs should be reported separately, i.e., with separate start date and time and stop date 
and time.  
7.5 Prompt Reporting of SAEs and Other Events to CSL Behring 
SAEs, AEs qualifying for special notification, pregnancies and occupational exposure must be 
reported as described in Table 9 (once the Investigator determines that the event meets the 
protocol definition for that event). 
Table 9 Timing of Reporting and Follow-up for (Serious) Adverse Events, Adverse Events for Special 
Notification, Pregnancies and Occupational Exposure 
 
Initial Reports 
Follow-up Information on a Previous Report 
Type of Event 
Time Frame 
Documents 
Time Frame 
Documents 
All SAEs 
24 hours 
SAE form 
72 hours a 
SAE form 
All AEs qualifying for 
special notification as 
defined in Section 7.2 
24 hours 
SAE form 
72 hours a 
SAE form 
All pregnancies 
24 hours 
Pregnancy 
reporting form 
Once separate informed consent 
is given by the subject and 
pregnant partner, within 72 
hours a 
Pregnancy 
reporting form 
All occupational exposure 
(with or without AE) 
24 hours 
Occupational 
exposure form 
72 hours 
Occupational 
exposure form 
a. 
If however, in the opinion of the Investigator, the follow-up information may have implications for the safety of 
other subjects, the follow-up information is to be reported immediately (i.e., within 24 hours after initial report). 
 
The information will be reported on the respective form and will include assessment of 
seriousness, severity, causal relationship to the IMP or trial procedures, outcome, and a narrative 
description of the course of the event, as applicable. Additional information may be subsequently 
provided. 
The reporting form and all other relevant documents supporting the reported SAE, AE qualifying 
for special notification, pregnancy or occupational exposure (e.g., diagnostic procedures, hospital 
records, and autopsy reports) must be reported to CSL Behring. 
The Independent Ethics Committees/Institutional Review Boards (IECs/IRBs) and regulatory 
authorities will be notified of (S)AEs according to current regulation and local requirements. 
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SAEs occurring to a subject after the subject has completed the clinical trial and for which a 
reasonable possibility of a causal relationship is assessed by the Investigator, should be reported 
by the Investigator to the sponsor if the Investigator becomes aware of them regardless of the 
time that has elapsed (post-trial events). 
7.6 Regulatory Reporting Requirements for SAEs and Other Events 
Prompt notification by the Investigator to CSL Behring of SAEs and AEs qualifying for special 
notification, pregnancy and occupational exposure is essential, so that legal obligations and 
ethical responsibilities towards the safety of subjects are met. 
CSL Behring has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation. CSL Behring will 
comply with ICH/FDA/EMA and country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IECs/IRBs, and Investigators. 
An Investigator who receives a SUSAR describing (an) SAE(s) or other specific safety 
information (e.g., summary or listing of SAEs) from CSL Behring will acknowledge, review, and 
file it in the appropriate section of the ISF and will notify the IECs/IRBs, if appropriate, 
according to local requirements (this information will also be filed in the appropriate ISF section 
by the Investigator). 
In addition to submission of SAEs, an annual development safety update report will be prepared 
and submitted to the EMA, FDA, and locally if applicable, according to the development 
international birth date. 
7.7 Reporting of Pregnancies 
Should a pregnancy occur in a female partner of male subject, it will be recorded separately from 
AEs, but will be reported in a manner identical to the reporting of SAEs, however via the use of 
a pregnancy reporting form instead of a SAE form. 
All attempts will be made to follow the pregnancy until the outcome of the pregnancy has been 
determined, and to capture information on the development of the infant in the period up until 
and including the age of 1 year. This information will only be collected if separate informed 
consent is given by the subject and by the subject’s pregnant partner/infant’s mother. 
Any report of a congenital abnormality/birth defect is an SAE and should be reported as such. 
Any complication of a pregnancy occurring during this trial, including elective termination for 
medical reasons, must be reported with the pregnancy reporting form. 
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7.8 Reporting of Occupational Exposure 
Occupational exposure refers to the exposure to the IMP as a result of one’s professional or non-
professional occupation and will be reported in a manner identical to the reporting of SAEs, 
however via the use of an occupational exposure form instead of a SAE form. 
Occupational Exposure with or without an AE, should be reported within 24 hours of becoming 
aware of the Exposure. 
7.9 Follow-up on Adverse Events 
All S(AE)s should be followed until resolved or they have reached a “final outcome” or the 
subject’s participation in the trial ends, whichever comes first. 
Severe, non-serious AEs assessed as “Related” to IMP and all SAEs and AEs qualifying for 
special notification (regardless of their relationship to IMP) still ongoing after ended trial 
participation, should be followed on a regular basis according to the Investigator’s clinical 
judgment until a “final outcome” has been established. 
The outcome “recovering” can be used as the “final outcome” for events that are stabilized (i.e., 
no further worsening is expected) and expected by the Investigator to resolve over time. 
The outcome “not recovered” can be used as the “final outcome” for events that are not expected 
to resolve over time (e.g., cancer). 
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8 DATA MANAGEMENT 
8.1 Data Collection 
The Investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRF (note that authorized personnel from the data management vendor will enter the 
 and 
 summary data). A trial monitor will visit each site or perform 
virtual monitoring in accordance with the monitoring plan and review the eCRF data against the 
source data for completeness and accuracy. Discrepancies between source data and data entered 
by the site on the eCRF will be addressed by qualified site personnel or the data management 
vendor for 
 and 
 summary data. When a data discrepancy warrants 
correction, the correction will be made by authorized site personnel or by authorized personnel 
from the data management vendor, where applicable. Data collection procedures will be 
discussed with the site personnel at the site initiation visit and/or at the Investigator’s Meeting. It 
is expected that site personnel will complete the eCRF entry within 5 business days of the 
subject’s visit. 
The subject reported e-diary data will be directly loaded from the application into the eCRF up to 
Week 52, without source documentation. All other data will have separate source documentation; 
these data will not be recorded directly onto the eCRF. 
8.2 Clinical Data Management 
Data are to be entered into the eCRF as specified in data entry instruction. Quality control and 
data validation procedures are applied to ensure the validity and accuracy of the clinical 
database. 
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner. 
To aid in CSR reporting of missed visits due to COVID-19, the eCRFs will capture if a visit is 
missed and reason(s) why. 
8.3 Study Data 
Study data identified in this protocol are collected, and source verified, on eCRF. All study data 
will be formulated into data sets to provide transparency, traceability, and integrity of trial 
analysis results from collection source to meet regulatory obligations for standardized study data. 
Observed study data will be mapped to the CDISC Study Data Tabulation Model (SDTM) and 
serve as the source data from the trial. Study analyses will be completed using analysis data sets 
that are derived from the SDTM and follow the CDISC Analysis Data Model (ADaM) 
architecture. 
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8.3.1 Clinical Data – CDISC Study Data Tabulation Model (SDTM) 
Domains will be mapped to CDISC SDTM version 3.2. No derived data required for analysis are 
included in the SDTM domains. All SDTM domains will be fully documented with define 
documents (DEFINE.XML) and a reviewer’s guide after database lock and final analyses are 
completed. 
8.3.2 Analysis Data – CDISC Analysis Data Model (ADaM) 
Planned and 
 will be completed using the ADaM data sets derived from the 
SDTM domains for this study. Analysis data sets will contain all derived study endpoints 
required for analysis. All analysis data sets will be fully documented with define documents 
(DEFINE.XML) and a reviewer’s guide after database lock and final analyses are completed. 
 
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9 STATISTICAL METHODS 
9.1 Statistical Analysis 
Details regarding the statistical methods and definitions will be provided in the statistical 
analysis plan (SAP), and will include templates for the tables, figures and listings to be provided.  
The SAP will be finalized before the interim analysis. 
Any agreed deviations from the SAP are to be justified in the clinical trial report. 
Statistical analyses will be performed using SAS Version 9.4 or higher (SAS Institute, Cary, 
NC 27513).  
Considering the small sample size used in this trial, all presentations will be descriptive in 
nature. No formal, inferential statistical analyses will be performed. Plots, tabular displays, and 
listings will be created, visualizing individual effects for selected efficacy and safety measures. If 
applicable, continuous variables will be summarized with descriptive statistics including: the 
number of non-missing values, mean, standard deviation, median, minimum, and maximum. In 
some cases, the standard error of the mean and/or confidence intervals may be presented. 
Categorical variables will be summarized by number, percent of subjects and, if applicable, the 
number of events. No formal inferential statistical analyses will be performed, and no analysis 
population will be defined. All available data will be used in the presentations. 
9.2 Planned Interim Analysis 
At six weeks after administration of AMT-061, a data cleaning round will be performed to 
provide data for one interim analysis for efficacy using the available data on the primary efficacy 
parameter - factor IX activity at six weeks. The rationale for the six weeks cut-off is based on 
data from the Phase 1/2 trial that demonstrated a very fast initial transduction of AAV5 and 
expression of the endogenous factor IX protein within the first week, which reached a relatively 
stable peak level within the first six weeks of follow-up. The results will be reported in an 
interim Clinical Study Report (iCSR). 
Furthermore, for this interim analysis, plots, tabulations, and/or listings will be provided for 
other efficacy and safety data collected at six weeks (as detailed in the SAP), to provide 
additional information on the factor IX activity levels.  
9.3 Full Analyses 
After 52 weeks post-dose, and 2.5 years post-dose, efficacy and safety data will be collected on 
all subjects. The data will be locked, analyzed, and reported in a CSR (52-week analysis) and a 
CSR addendum (2.5-year analysis).  
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At the end of the 4-year long-term follow-up period (60 weeks/5 years post-dose), all safety and 
efficacy data will be reported in a CSR addendum (5-year analysis). 
The CSR and CSR addenda will summarize contingency measures implemented to manage study 
conduct due to COVID-19 control measures, protocol deviations due to COVID-19, and the 
impact COVID-19 had on visit schedules, missed visits, and missing information. 
9.4 Selection of Subjects to be Included in the Analyses 
No formal analysis population is defined. All available data on treated subjects will be included 
in the efficacy and/or safety analysis of the data. 
9.5 Subject Disposition 
The data on subject disposition and informed consent will be listed, containing details on treated 
and completed subjects, as well as information regarding withdrawal reasons or protocol 
deviations (including those related to COVID-19), if applicable. 
9.6 Demographic and Baseline Characteristics 
Descriptive summaries of demographic and baseline characteristics will be presented. The 
following descriptive statistics will be included: number of observations, mean, standard 
deviation, median, minimum, and maximum for quantitative data. For qualitative data, frequency 
counts and percentage will be determined. 
Other baseline data will only be listed. 
Medical history will be coded using the most recent version of the Medical Dictionary for 
Regulatory Activities (MedDRA) and listed for each subject. 
9.7 Investigational Product Exposure 
Listings for exposure to IMP will be presented.  
9.8 Prior and Concomitant Medication 
Prior and concomitant medications will be coded using the most recent World Health 
Organization drug dictionary. Prior and concomitant medications will be listed. 
9.9 Efficacy Analyses 
All efficacy analyses will be performed for all treated subjects. All presentations will be done on 
an individual level or by using descriptive statistics. Plots and tabular displays will be created, 
visualizing individual effects for the selected efficacy measures as specified in the following 
sections. Analyses will be based on central laboratory measurements if results are available from 
both local and central laboratories.  
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9.9.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the factor IX activity level at six weeks after dosing. 
Factor IX activity levels will be presented in % of normal units. Descriptive statistics will 
include mean, standard deviation, median, minimum, and maximum over time for per subject 
factor IX activity levels presented at six weeks after dosing by subject and also by visit across 
subjects. Subject plots of factor IX activity levels over time will be presented. Descriptive 
statistics and plots will only display uncontaminated results, i.e., factor IX activity levels that are 
not affected by exogenous factor IX use during the trial. The required wash out period (in order 
to consider a factor IX activity level to be “unaffected” – i.e., “uncontaminated”) will be 10 days. 
Listings will present all factor IX activity levels measured, and will include a flag for 
contaminated results. 
9.9.2 Secondary Efficacy Endpoints 
Secondary efficacy endpoints comprise of factor IX activity at 52 weeks, bleeding rates 
(including a further break down of the reported bleeding episodes) and usage of factor IX 
replacement therapy. Data will be presented using descriptive statistics. Plots of selected 
endpoints will be provided. All data will also be listed. 
 
9.10 Safety Analyses 
All treatment-emergent AEs are tabulated by SOC and preferred terms within each SOC 
according to the MedDRA terminology list. TEAEs will also be tabulated by severity 
(mild/moderate/severe using the Common Terminology Criterion for Adverse Events severity 
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grades) and by relationship (related/not related) to trial medication, using frequency counts 
(number of subjects with event and number of events) and percentages. Similar tables will be 
created for TEAEs leading to premature discontinuation, deaths, and SAEs, if applicable. 
These summary tables will be presented by decreasing frequency of occurrence based on SOC 
and Preferred Term. 
An AE overview table will be created displaying the number of subjects (and percentage) 
experiencing an event and the number of events for: Any TEAE, mild/moderate/severe TEAE, 
related/unrelated TEAE, serious TEAE, TEAE for special notification, TEAE leading to 
discontinuation. 
The summary tables will be accompanied by individual subject listings of all AEs, including 
information on AE number, actual AE description, date/time of start and end of AE, preferred 
term (MedDRA), SOC (MedDRA), severity, relationship/causality, type of AE, seriousness and 
outcome. Pre-existing AEs will be flagged. Pre-existing AEs are not considered to be treatment-
emergent, except in case of worsening during/after trial treatment (to be collected as separate 
AE). Separate listings will be created for TEAEs for special notification, deaths, and SAEs, if 
applicable. 
Summary statistics for the baseline assessment and change from baseline at each post-baseline 
visit for scheduled lab assessments of continuous laboratory variables will be tabulated. 
Clinically significant laboratory values will be tabulated. Clinical laboratory tests will be listed 
and summarized by visit, with reference range and flag indicating if the measurement in question 
is outside the reference range provided. 
Summary statistics of the absolute value and change from baseline for vital sign measurements 
will be tabulated by visit, and time point. Vital sign measurements will be listed. 
All data for anti-factor IX antibodies, factor IX inhibitors, factor IX recovery, total (IgG and 
IgM) and neutralizing antibodies to AAV5, AAV5 capsid-specific T-cells, inflammatory 
markers, vector DNA in semen and blood, will be listed. Plots of IgM and IgG neutralizing 
antibodies, AAV5 capsid-specific T cells, and vector DNA in semen and blood over time will be 
provided.  
9.11 Sample Size Justification 
There is no formal sample size calculation performed for this trial. From a clinical perspective, 
N=3 subjects is considered sufficient to provide a reliable impression of the factor IX activity 
levels and safety profile that will be demonstrated with a single dose of 2 x 1013 gc/kg AMT-061 
at six weeks after dosing.  
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9.12 Data Monitoring Committee 
A data monitoring committee (DMC) will be involved in the management of the overall 
AMT-061 program including this clinical trial. The purpose of the DMC in this trial is to monitor 
safety of the subjects in the trial as well as to evaluate response to the treatment in terms of 
factor IX activity levels. The DMC will assess whether observed factor IX activity levels are 
within an expected range to determine if the administered dose is suitable for administration in a 
pivotal phase 3 trial (range to be defined in DMC charter). If the DMC determines that the 
observed response is not within the expected range, or they do not observe enough consistency of 
effect, to proceed to Phase 3 dosing they can elect to recommend up to three more subjects be 
treated at the same dose or recommend a second dose be studied. DMC meetings will be held at 
set times during the trial as outlined in the DMC charter. Further details regarding the DMC can 
be found in the DMC charter, which will be available prior to the administration of IMP.  
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10 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES 
This trial is conducted in accordance with current applicable regulations, ICH GCP (E6[R2]), 
EU Directive 2001/20/EC, EU Directive 2005/28/EC, FDA guidelines, ATMP guidelines and its 
updates, and local ethical and legal requirements.  
10.1 Sponsor’s Responsibilities 
10.1.1 Good Clinical Practice Compliance 
The trial sponsor and any third party to whom aspects of the trial management or monitoring 
have been delegated will undertake their assigned roles for this trial in compliance with the ICH 
GCP Guideline E6(R2), and related detailed guidelines specific to ATMPs (ENTR/F/2/SF/dn 
D(2009) 35810), as well as with applicable regulatory requirements in the countries where the 
trial will take place. 
Representatives of the trial sponsor, and/or the company organizing/managing the research on 
behalf of the Sponsor, conduct visits to sites to inspect trial data, subjects’ medical records, and 
eCRFs in accordance with current ICH GCP and the respective local and inter/national 
government regulations and guidelines. Records and data may additionally be reviewed by 
auditors or by regulatory authorities. 
The Sponsor ensures that Local Regulatory Authority requirements are met before the start of the 
trial. The Sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any Regulatory Authority and IRB/IEC approvals required prior to 
release of IMP for shipment to the site. 
10.1.2 Indemnity/Liability and Insurance 
The Sponsor ensures that a fully executed contract is in place prior to initiation of the trial, 
including appropriate wording on indemnification of the Investigator/the institution against 
claims arising from the trial, as per applicable regulations. 
The Sponsor ensures that suitable clinical trial insurance coverage is in place prior to the start of 
the trial. An insurance certificate is supplied to the Investigator as necessary. 
10.1.3 Public Posting of Trial Information 
The Sponsor will assure that key design elements of this protocol will be posted in a publicly 
accessible database such as Clinical Trials.gov, prior to the start of the trial. In addition, upon 
trial completion and finalization of the trial report the results of this trial will be either submitted 
for publication and/or posted in a publicly accessible database of clinical trial results. 
Information included in clinical trial registries may include participating Investigators’ names 
and contact information. 
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The Sponsor will retain ownership of all data. 
10.1.4 Submission of Summary of Clinical Trial Report to Competent Authorities of 
Member States Concerned and Independent Ethics Committees 
The Sponsor will provide a summary of the CSR within 1 year of the end of the trial completion 
date to the competent authority of the Member State(s) concerned as required by regulatory 
requirement(s) and to comply with the Community guideline on ICH GCP. The Sponsor will 
provide the IRBs/IECs with a copy of the same summary. 
10.1.5 Trial Suspension, Termination, and Completion 
The Sponsor may suspend or terminate the trial or part of the trial at any time for any reason. If 
the trial is suspended or terminated, the Sponsor will ensure that the Investigator as well as 
applicable regulatory agencies and IRBs/IECs are notified as appropriate. Additionally, the 
discontinuation of a registered clinical trial will be published on the publicly available database 
(as applicable). 
The Sponsor will make an end-of-trial declaration to the relevant competent authority as required 
by Directive 2001/20/EC.  
10.2 Investigator’s Responsibilities 
10.2.1 Good Clinical Practice Compliance 
The Investigator must agree to conduct the trial in accordance with ICH GCP Guideline E6, 
including related detailed guidelines specific to ATMPs and applicable regulatory requirements 
and guidelines.  
It is the Investigator’s responsibility to ensure that adequate time and appropriate trained 
resources are available at the site prior to commitment to participate in this trial. The Investigator 
should also be able to estimate or demonstrate a potential for recruiting the required number of 
suitable subjects within the agreed recruitment period. 
The Investigator will maintain a list of appropriately qualified persons to whom the Investigator 
has delegated significant trial-related tasks. Curriculum vitae for Investigators and 
sub-investigators are provided to the trial Sponsor (or designee) before starting the trial. 
If a potential research subject has a primary care physician, the Investigator should, with the 
subject’s consent, inform him or her of the subject’s participation in the trial. 
An international coordinating Investigator is appointed to review the final Clinical Trial Report. 
Agreement with the final Clinical Trial Report is documented by the signed and dated signature 
of the coordinating Investigator, in compliance with Directive 2001/83/EC as amended by 
Directive 2003/63/EC and ICH Guidance E3 (1995). 
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10.2.2 Protocol Adherence and Investigator Agreement 
The Investigator and any sub-investigators must adhere to the protocol as detailed in this 
document. The Investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an Investigator Agreement to 
confirm acceptance and willingness to comply with the trial protocol. 
If the Investigator suspends or terminates the trial at his or her site, the Investigator will promptly 
inform the Sponsor, the IEC/IRB, and, where applicable, the regulatory authority, and provide 
them with a detailed written explanation. If the trial is prematurely terminated or suspended for 
any reason, the Investigator will promptly inform the trial subject(s) and will assure appropriate 
medical care and follow-up for the subjects. The Investigator will also return all IMPs, 
containers, and other trial materials to the Sponsor. Upon trial completion, the Investigator will 
provide the Sponsor, IEC/IRB, and regulatory agency with final reports and summaries as 
required by (inter)national regulations. 
Communication with local IECs/IRBs, to ensure accurate and timely information is provided at 
all phases during the trial, may be done by the Sponsor, applicable Contract Research 
Organization (CRO), Investigator, or for multi-site trials, the coordinating Investigator according 
to national provisions and will be documented in the Investigator Agreement. 
10.2.3 Documentation and Retention of Records 
10.2.3.1 Electronic Case Report Forms 
Access to the eCRF system and data capture by the Sponsor/CRO should be supported, and 
should be handled in accordance with instructions from the Sponsor. 
The Investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Electronic case report forms 
must be completed by the Investigator or designee as stated in the site delegation log (note that 
authorized personnel from the data management vendor will enter 
 and 
 
summary data on the appropriate eCRF pages).  
The subject reported e-diary data will be directly loaded from the application into the eCRF, 
without source documentation. All other data will have separate source documentation; will not 
be recorded directly onto the eCRF. 
All data sent to the Sponsor must be endorsed by the Investigator.  
The clinical research associate (CRA)/Trial Monitor will verify the contents against the source 
data per the Monitoring Plan. If the data are unclear or contradictory, queries are sent for 
corrections or verification of data. 
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The 
 include the patient (
) questionnaires. It also includes the 
e-diary in which the subjects will record their use of factor IX replacement therapy and bleeding 
episodes. 
10.2.3.3 Recording, Access, and Retention of Source Data and Trial Documents 
Original source data to be reviewed during this trial will include, but are not limited to: subject’s 
medical file, original clinical laboratory requisition forms and reports, 
 summary score 
sheets, 
 and data available from the subjects e-diary device. 
All key data must be recorded in the subject’s medical records. 
The Investigator must permit authorized representatives of the Sponsor, the respective national, 
local, or foreign regulatory authorities, the IEC/IRB, and auditors to inspect facilities and to have 
direct access to original source records relevant to this trial, regardless of media. 
The CRA/Trial Monitor (and auditors, IEC/IRB or regulatory inspectors) may check the eCRF 
entries against the source documents. The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the Sponsor or its representatives, national or local 
regulatory authorities, or the IEC/IRB having access to source data (e.g., subject’s medical file, 
appointment books, original laboratory reports, X-rays etc.). Non-trial site personnel will not 
disclose any personal information or personal medical information. 
These records must be made available within reasonable times for inspection, if required, by a 
properly authorized representative of any regulatory agency (e.g., the US FDA, EMA, UK 
Medicines and Healthcare products Regulatory Agency [MHRA]) or other).  
Essential documents must be maintained according to local regulations or ICH GCP (E6[R2]) 
requirements, whichever is longer. Essential documents may not be destroyed without written 
permission from the Sponsor. Note that traceability records should be kept for a minimum of 30 
years after the expiry date of the product, or longer if required by the terms of the clinical trial 
authorization or by the agreement with the Sponsor.  
10.2.3.4 Audit/Inspection 
To ensure compliance with relevant regulations, data generated by this trial must be available for 
inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the EMA, the MHRA, other regulatory authorities, the 
Sponsor or its representatives, and the IEC/IRB for each site. 
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10.2.3.5 Financial Disclosure 
The Investigator is required to disclose any financial arrangement prior to participating in the 
trial and for up to one year after, whereby the value of the compensation for conducting the trial 
could be influenced by the outcome of the trial.  
The Investigator should provide the following information: any significant payments from the 
Sponsor or subsidiaries such as a grant to fund ongoing research, compensation in the form of 
equipment, retainer for ongoing consultation or honoraria; any proprietary interest in IMP; any 
significant equity interest in the Sponsor or subsidiaries as defined in 21 Code of Federal 
Regulations (CFR) 54 2(b) (1998).  
In consideration of participation in the trial, the Sponsor pays the Investigator or nominated 
payee the sums set out in the payment schedule attached to the Investigator agreement. 
10.2.4 Compliance to all Regional, Local, State, and National Controlled-substance, 
Biohazard and Infectious Disease Regulations and Legislation 
When using controlled substances, biohazardous material, or substances for infectious diseases, 
the Investigator must at all times comply with all regional, local, state, and national laws 
pertaining to registration, reporting with the appropriate regulatory body and control and 
handling of such substances. 
10.3 Ethical Considerations 
10.3.1 Informed Consent 
It is the responsibility of the Investigator, or designee, to obtain voluntary written informed 
consent from all trial subjects prior to any trial related procedures including screening 
assessments. All consent documentation must be in accordance with applicable regulations, the 
GCP specific to ATMPs (ENTR/F/2/SF/dn D(2009) 35810) and ICH GCP (E6[R2]). In 
accordance with the ATMP guideline, the informed consent form and any other written 
information should include an explanation of particular issues associated with ATMPs, e.g., 
inconveniences of long-term follow-up, specific risks such as shedding and the irreversible 
nature of the ATMP and other issues as further listed in the guideline. 
Each subject is requested to sign the Subject Informed Consent Form in their local language, 
after the subject has received and read (or been read) the written subject information and 
received an explanation of what the trial involves, the particular issues arising with ATMPs, 
including but not limited to: the objectives, potential benefits and risk, inconveniences, and the 
subject’s rights and responsibilities.  
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If the ICF is revised with important new information that must be shared with the study subjects, 
the amended ICF will be presented, as required by the IRB/IEC for review and consideration by 
the subject, and signed re-consent is to be obtained.  
Separate written informed consents are to be obtained for the factor IX gene sequencing and 
future research samples prior to collection of the samples, as detailed in Section 6.2.1.6 and 
Section 6.2.4.1, respectively. 
A copy of all informed consent documentation (i.e., a complete set of subject information sheets 
and fully executed signature pages) must be given to the subject. If applicable, it is provided in a 
certified translation of the local language. Signed consent forms must remain in each subject’s 
trial file and must be available for verification at any time. 
The principal Investigator provides the Sponsor with a copy of the local consent form which was 
reviewed by the IEC/IRB and which received their favorable opinion/approval. A copy of the 
IEC/IRB’s written favorable opinion/approval of these documents must be provided to the 
Sponsor, prior to the start of the trial unless it is agreed to and documented (abiding by 
regulatory guidelines and national provisions) prior to trial start that another party (i.e., Sponsor 
or coordinating Investigator) is responsible for this action. Additionally, if the IEC/IRB requires 
modification of the sample Subject Information and Consent document provided by the Sponsor, 
the documentation supporting this requirement must be provided to the Sponsor. 
The Sponsor will also provide an optional consent to ask subjects to agree with providing a tissue 
sample from their liver in case of death, or if the liver becomes available for any other reason 
(e.g., liver transplantation or resection) during the long-term follow-up phase of this study. Liver 
samples will be analyzed to investigate how the gene therapy sequences are maintained within 
the cells of the liver over time, tolerance and/or stress within the cells of the liver, and/or how the 
gene therapy is expressed in different parts of the liver and across the liver cells. This is entirely 
voluntary, and subjects may still participate in the study if they do not wish to agree to donate a 
liver tissue sample. 
10.3.2 Institutional Review Board or Independent Ethics Committee 
For sites outside the EU, it is the responsibility of the Investigator to submit this protocol, the 
informed consent document (approved by the Sponsor or its designee), relevant supporting 
information and all types of subject recruitment information to the IECs/IRBs for review, and all 
must be approved prior to site initiation. 
For sites within the EU, the applicant for an IEC opinion can be the Sponsor, the Investigator, or 
for multi-site trials the coordinating Investigator or Sponsor, according to national provisions. 
Responsibility for coordinating with IECs/IRBs is defined in the Investigator Agreement. 
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Prior to implementing changes in the trial, the Sponsor and the IECs/IRBs must approve any 
revisions of any revised informed consent documents and amendments to the protocol unless 
there is a subject safety issue (in that case approval can be after implementation). 
Investigational product supplies will not be released until the Sponsor has received written 
IECs/IRBs approval of and copies of revised documents. 
For sites outside the EU, the Investigator is responsible for keeping the IECs/IRBs appraised of 
the progress of the trial and of any changes made to the protocol, but in any case at least once a 
year. For sites within the EU, this can be done by the Sponsor, the Investigator or for multi-site 
trials the coordinating Investigator, according to national provisions. The Investigator must also 
keep the local IECs/IRBs informed of any serious and significant AEs. 
The names of the IECs/IRBs chairperson and the members of the IECs/IRBs will be collected as 
well as a statement that the IECs/IRBs works in accordance with the principles of ICH GCP. 
10.3.3 Subject Treatment Cards 
All subjects will receive a subject treatment card, which has been approved by the sponsor and 
the IEC/IRB, containing at a minimum: 
-
The name of the subject
-
The Investigator’s contact number
-
Information regarding the IMP received
10.4 Privacy and Confidentiality 
All US-based sites and laboratories or entities providing support for this trial, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act of 1996 
(HIPAA). A site that is not a Covered Entity as defined by HIPAA, must provide documentation 
of this fact to the Sponsor. 
All EU-based sites and laboratories or entities providing support for this trial, must, where 
applicable, comply with the Data Protection Directive 95/46/EC (24 Oct 1995), EU data 
protection regulations No. 45/2001 (18 Dec 2001), and EU General Data Protection Regulation 
(GDPR) 2016/679 (27 Apr 2016). 
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines. 
After subjects have consented to take part in the trial, the Sponsor and/or its representative 
reviews their medical records and data collected during the trial. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the Sponsor; third parties with whom the Sponsor may develop, register, or 
market AMT-061; national or local regulatory authorities; and the IRBs/IECs, which gave 
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approval for the trial to proceed. The Sponsor and/or its representatives accessing the records and 
data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects' identities. 
Subjects are assigned a unique identifying number. However, age and birth year may be 
collected and used to assist the Sponsor to verify the accuracy of the data, for example, to 
confirm that laboratory results have been assigned to the correct subject. 
The results of trials – containing subjects’ unique identifying number, relevant medical records, 
and possibly age and birth year – will be recorded. They may be transferred to, and used in, other 
countries that may not afford the same level of protection that applies within the countries where 
this trial is conducted. The purpose of any such transfer would include: to support regulatory 
submissions, to conduct new data analyses to publish or present the trial results, or to answer 
questions asked by regulatory or health authorities. 
10.5 Publication Policy 
All manuscripts, abstracts, or other modes of presentation arising from the results of the trial 
must be reviewed and approved in writing by the Sponsor, in advance of submission. The review 
is aimed at protecting the Sponsor’s proprietary information either existing at the date of the 
commencement of the trial, or generated during the trial. Authorship will follow guidelines 
established by the International Committee of Medical Journal Editors (ICMJE, 2015). The 
publication policy with respect to the Investigator and clinical trial site will be further detailed in 
a separate document. 
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11 ADMINISTRATIVE ASPECTS 
11.1 Investigator(s) 
One principal Investigator and one or more sub-investigators will be appointed for each clinical 
trial site. Name and title of the Investigator(s) who is (are) responsible for conducting the trial, 
and the address and telephone number(s) of the trial site will be contained in other documents 
such as the Trial Procedures Manual and Clinical Trial Application forms.  
One National Coordinating Investigator will be appointed for each participating country. This 
Investigator will be responsible for national issues relating to the trial. 
Responsibilities of the Investigator are described in Section 10.2. 
11.2 International Coordinating Investigator 
The International Coordinating Investigator is responsible for approval of the clinical trial report 
on behalf of all trial Investigators. 
11.3 Clinical Trial Sites 
Clinical trial sites should also have immediate access to equipment and staff for resuscitating and 
stabilizing individuals in an acute emergency (such as cardiac emergencies, anaphylaxis, 
cytokine release syndrome, convulsions, hypotension), and ready availability of Intensive Care 
Unit facilities. Procedures should be established between the clinical trial site and its nearby 
Intensive Care Unit regarding the responsibilities and undertakings of each in the transfer and 
care of subjects. 
11.4 Vendors 
Trial management, vendor oversight, and medical monitoring oversight will be provided by 
uniQure biopharma B.V. 
The sponsor will engage vendors to perform the following services: 
- Laboratory analysis 
o Individual central laboratories will be applied for specific laboratory analyses. 
o One coordinating central laboratory will prepare the Laboratory Manual, sampling 
kits, perform training of clinical trial site personnel, arrange for courier shipments, 
and manage central preparation and storage of samples. 
- Clinical monitoring and project management 
- Regulatory 
- Medical Monitoring 
- Data Management 
- DMC Administration 
- Statistics 
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- Medical Writing 
- The provision of the 
 
- The provision of the e-diaries 
- eTMF 
- Investigator Meeting organization  
- Subject travel organization and reimbursement 
 
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12 REFERENCE LIST 
Publications 
Bolton-Maggs P and Pasi K. Haemophilias A and B. Lancet. 2003;361:1801-09 
Boutin S, Monteilhet V, Veron P, Leborgne C, Benveniste O, Montus MF et al. Prevalence of 
serum IgG and neutralizing factors against adeno-associated virus (AAV) types 1, 2, 5, 6, 8, and 
9 in the healthy population: implications for gene therapy using AAV vectors. Hum Gene Ther. 
2010;21:704-12 
Cantore A, Nair N, Della Valle P, Di Matteo M, Màtrai J, Sanvito F et al. Hyperfunctional 
coagulation factor IX improves the efficacy of gene therapy in hemophilic mice. The American 
Society of Hematology. 2012;120;4517-20 
Crudele JM, Finn JD, Siner JI, Martin NB, Niemeyer GP, Zhou S, et al. AAV liver expression of 
FIX-Padua prevents and eradicates FIX inhibitor without increasing thrombogenicity in 
hemophilia B dogs and mice. The American Society of Hematology. 2015;125:1553-1561 
Darby S, Kan S, Spooner R, Giangrande P, Hill F, Hay C et al. Mortality rates, life expectancy, 
and causes of death in people with hemophilia A or B in the United Kingdom who were not 
infected with HIV. Blood. 2007;110:815-25 
D’Avola, D, López-Franco, E, Sangro, B, Pañeda, A, Grossios, N., Gil-Farina, I et al. Phase I 
open label liver-directed gene therapy clinical trial for acute intermittent porphyria. J Hepatol. 
2016;65(4):776-83 
Gater A, Thomson T, Strandberg-Larsen M. Haemophilia B: impact on patients and economic 
burden of disease. Thromb Haemost. 2011;1:1349-55 
George L, Sullivan S, Giermasz A, Ducore J, Rasko J, Teitel J et al. Initiation of Oral Steroid 
Therapy Produced Rapid Normalization of Transaminase Levels and Stabilization of FIX 
Activity in Subjects Who Developed T-Cell Responses in the SPK9001: AAV Gene Transfer for 
Hemophilia B Phase 1/2 Trial. Haemophilia 2017;23 (Suppl. 3):3-49 
Jiang H, Pierce GF, Ozelo MC, de Paula EV, Vargas JA, Smith P et al. Evidence of multiyear 
factor IX expression by AAV-mediated gene transfer to skeletal muscle in an individual with 
severe hemophilia B. Mol Ther., 2006;14(3):452-5 
Kao CY, Yang SJ, Tao MH, Jeng YM, Yu IS, Lin SW. Incorporation of the factor IX Padua 
mutation into FIX-Triple improves clotting activity in vitro and in vivo. Thromb Haemost. 2013; 
110:244–56 
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Kay MA, Manno CS, Ragni MV, Larson PJ, Couto LB, McClelland A et al. Evidence for gene 
transfer and expression of factor IX in haemophilia B patients treated with an AAV vector. Nat 
Genet. 2000;24(3):257-61 
Kessler C and Mariani G. Clinical manifestations and therapy of the haemophilias. In: Colman 
R, Hirsh J, Marder V, Clowes A, George J, eds. Hemostasis and Thrombosis: Basic Principles 
and Clinical Practice. 5th ed. Philadelphia: Lippincott-Raven; 2006. p 887-904 
Lu DR, Zhou JM, Zheng B, Qiu XF, Xue JL, Wang JM et al. Stage I clinical trial of gene therapy 
for hemophilia B. Sci China B. 1993 Nov;36(11):1342-51 
Manno C, Chew A, Hutchison S, et al. AAV-mediated factor IX gene transfer to skeletal muscle 
in patients with severe haemophilia B. Blood 2003;101:2963-72 
Manno C, Pierce G, Arruda V, et al. Successful transduction of liver in haemophilia by AAV 
factor IX and limitations imposed by the host immune response. Nat Med.2006;12:342-47 
Monahan P.E. Gene therapy in an era of emerging treatment options for hemophilia B. J Thromb 
Haemost. 2015;13(Suppl. 1):S151-60 
Nathwani A, Tuddenham E, Rangarajan S, et al. Adenovirus-associated virus vector mediated 
gene transfer in haemophilia B. N Engl J Med. 2011;365:2357-65 
Nathwani A, Reiss U, Tuddenham E, et al. Long-term safety and efficacy of factor IX gene 
therapy in haemophilia B. N Engl J Med. 2014;371:1994-2004 
National Heart, Lung, and Blood Institute (2013). How Is Hemophilia Diagnosed? 
https://www.nhlbi.nih.gov/health/health-topics/topics/hemophilia/diagnosis (accessed 06 July 
2016).  
O’Hara J, Hughes D, Camp C, et al. The cost of severe haemophilia in Europe: the CHESS 
study. Orphanet J Rare Dis. 2017;12:106 
Osooli M, Steen Carlsson K, Astermark J, Bertorp E. Surgery and survival in birth cohorts with 
severe haemophilia and differences in access to replacement therapy: The Malmö experience. 
Haemophilia. 2017:1-6 
Pasi j, Wong W, Rangarajan S, Wilde J, Perry D, Madan B et al. Interim results of an open-label, 
phase 1/2 study of BMN 270, an AAV5-FVIII gene transfer in severe hemophilia A. 
Haemophilia 2016;22(Suppl. 4):151–2 
Plug I, Van Der Bom JG, Peters M, et al. Mortality and causes of death in patients with 
hemophilia, 1992- 2001: a prospective cohort study. J Thromb Haemost. 2006;4:510-6 
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Schramm W and Berger K. Economics of prophylactic treatment. Haemophilia. 2003;9(suppl 
s1):111-6  
Simioni P, Tormene D, Tognin G, Gavasso S, Bulato C, Iacobelli NP et al. X-Linked 
Thrombophilia with a Mutant Factor IX (Factor IX Padua). N Engl J Med. 2009; 1671-5 
Srivastava A, Brewer AK, Mauser-Bunschoten EP, Key NS, Kitchen S, Llina A et al. Guidelines 
for the management of hemophilia. Haemophilia. 2013;19:e1-47 
Stonebraker S, Bolton-Maggs H, Brooker M, Farrugia A, Srivastava A. A study of reported 
factor IX use around the world. Haemophilia. 2011;17:446-55 
Taylor JA, Kruse-Jarres R. A new era for hemophilia B treatment. Blood.;127(14):1734-6 
Witkop M, Neff A, Buckner TW, Wang M, Batt K., et al. Self-reported prevalence, description 
and management of pain in adults with haemophilia: methods, demographics and results from the 
Pain, Functional Impairment, and Quality of life (P-FiQ) study. Haemophilia. 2017;23(4):556-65 
 
Guidelines 
Committee for Medicinal Products for Human Use (CHMP). Guideline on Follow-up of Patients 
Administered with Gene Therapy Medicinal Products. EMA/CHMP/GTWP/60436/2007. 
London, 22 October 2009. 
FDA Guidance for Industry. Long Term Follow-up After Administration of Human Gene 
Therapy Products. January 2020. 
Detailed guidelines on good clinical practice specific to advanced therapy medicinal products., 
ENTR/F/2/SF/dn D(2009) 35810. Brussels, 03/12/2009. Available from: 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/2009_11_03_guideline.pdf 
ICH Guideline E2A: Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting. Finalised under Step 4 in October 1994. Available from: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E2A/Step4/E
2A_Guideline.pdf 
ICH Guideline E3: Structure and Content of Clinical Study Reports. Finalised under Step 4 in 
November 1995. Available from: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E3/E3_Guide
line.pdf 
Integrated Addendum to ICH Guideline E6(R1): Guideline for Good Clinical Practice E6(R2). 
Finalised under Step 4 in Nov 2016. Available from: 
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http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__
Step_4.pdf 
Other 
Investigator’s Brochure AAV5-hFIX and AAV5-hFIXco-Padua (AMT-060 and AMT-061 
[etranacogene dezaparvovec]). Current Edition. 
World Federation of Haemophilia. Available from http://www.wfh.org/. 
Treatment Guidelines Working Group, on behalf of the World Federation of Hemophilia (WFH). 
Guidelines for the management of hemophilia. 2nd ed., originally published in Haemophilia; 
Epub 6 Jul 2012. Available from: http://www.wfh.org/. 
 
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13 APPENDICES 
13.1 Laboratory Information 
Laboratory 
Test/Profile 
 
Central Laboratory: 
Coagulation 
Chemistry 
Inflammatory markers/cytokines 
Serology 
Hematology 
CD4 counts 
PBMC isolation for AAV5-capsid specific T-cell response 
 
 
 
Referral testing: 
Vector genome detection (blood and semen) 
Neutralizing antibodies to AAV5 
 
 
 
Referral Testing: 
FIX Activity: one-stage aPTT, chromogenic assay 
FIX protein concentration 
FIX inhibitors 
Anti-FIX antibodies 
IgG antibodies AAV5/IgM antibodies AAV5 
 
 
Referral Testing: 
AAV5-capsid specific T-cell  
 
 
Referral Testing: 
FIX genetic sequencing 
 
 
Confirmation Testing: 
HIV-1/2 Antibody differentiation test 
 
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PPD
PPD
PPD
PPD
PPD
PPD
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13.2 Summary of Changes in Current Amendment 
Summary of Change(s) Since Last Version of Approved Protocol 
Amendment Number: 
3.0 (Version 4.0) 
Amendment Date: 
08 Feb 2022 
Global/Country/Site-
Specific:  
Global 
Description of Change 
Section(s) Affected by 
Change 
The Sponsor was changed from uniQure to CSL Behring.  
All 
Minor administrative text and formatting updates. 
All 
It was clarified that uniQure will provide oversight to 
Medpace, the Monitoring CRO. 
Title Page 
Administrative changes to the identified Sponsor 
representative. 
Signature Page 
The entity responsibile for safety oversight including 
SAE/AESI/pregnancy reporting was updated to CSL 
Behring, with details provided for contacting CSL Global 
Clinical Safety & Pharmacovigilance. 
Emergency Contact 
Information 
Section 7.5 
Section 7.6 
The identity and details for the uniQure Medical Director 
were updated. 
Emergency Contact 
Information 
Optional consent to ask subjects to agree with providing a 
tissue sample from their liver in case of death, or if the liver 
becomes available for any other reason (e.g., liver 
transplantation or resection) during the long-term follow-up 
phase of this study was added. 
Section 6.2.4.2 
Section 10.3.1 
It was clarified that trial management, vendor oversight, and 
medical monitoring oversight will be provided by uniQure. 
Pharmacovigilance was removed from the list of services 
that the Sponsor will engage vendors to perform. 
Section 11.4 
 
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13.3 Previous Amendments 
Summary of Changes 
Amendment Number: 
2.0 (Version 3.0) 
Amendment Date: 
10 Feb 2021 
Global/Country/Site-
Specific:  
Global 
Description of Change 
Section(s) Affected by 
Change 
Administration changes to identified sponsor representatives, 
abbreviation use, formatting, etc, for consistency. 
All 
Update to uniQure Medical Director details. 
Emergency Contact 
Information 
Addition of “etranacogene dezaparvovec” to the description 
of the IMP identity 
Title Page 
Synopsis 
Section 5.1 
Addition of comment that adjustments to the visit location 
and/or schedule may be made to accommodate safety 
concerns and restrictions due to the COVID-19 pandemic 
was added in discussion of the long-term follow-up phase. 
Synopsis 
Addition of a CSR Addendum for analyses after 2.5 years of 
follow-up post treatment. 
Synopsis 
Section 3.1 
Section 6.1.3 
Section 9.3 
Clarification that study-specific paper diaries are to be used 
during the long-term follow-up for bleeds (long-term 
follow-up bleed diary) and factor IX use (long-term 
follow-up factor IX use diary) and brought to all clinic visits 
in this phase for reporting. Paper diaries will be distributed at 
the Week 52 visit. 
Synopsis 
Table 1 
Table 3 
Section 6.1.3, 6.1.4 
Section 6.2.2.1, 6.2.2.2 
An abdominal ultrasound to monitor subjects for liver 
fibrosis and potential occurrences of liver malignancy was 
added as a safety objective and assessment, with assessments 
occuring in the the long-term follow-up phase beginning at 
the Month 30 visit and at every visit thereafter until study 
completion (i.e., at Month 30, 36, 42, 48, 54, and 60). 
Details related to permitted visit window adjustments were 
included; adjustments to the visit timing within the allowed 
visit window are to be documented. 
Section 6.2.3.4 Abdominal Ultrasound was added. 
Synopsis 
Table 3 
Section 1.6 
Section 2.3 
Section 3.3.2 
Section 6.1.4 
Section 6.2.3.4 
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The label for the event of “Hematology parameters” was 
updated to “Hematology and coagulation parameters” to be 
more representative of the parameters being collected, as 
specified in the associated footnote. 
Table 2 
Table 4 
Clarification that the sampling schedule for vector genome 
detection assessments can be increased (in frequency) as 
agreed between the Investigator and subject following the 
notification of a first negative result on blood and/or semen. 
Table 2 
Table 4 
Section 6.2.3.9 
Addition of a visit window for 
 to be 
completed for the Month 24, Month 36, Month 48, and 
Month 60 visits during the Long-term Follow-up Phase, if 
those visits are impacted by COVID-19. Adjustments to the 
visit timing within the allowed visit window are to be 
documented. 
Table 3 
Section 6.2.2.4 
Local laboratory assessments of factor IX (one-stage aPTT 
for factor IX activity) and transaminases (AST/ALT) for 
local monitoring were added to the long-term follow-up 
activities (starting at Month 30 as all subjects were 
approaching this visit at the time of the protocol 
amendment). 
Reference to the schedule of events for laboratory 
parameters (Table 2 and Table 4) was added to the following 
sections, for clarity on the timing of these assessments 
during the study: 
Section 6.2.3.12 (Other Safety Laboratory Evaluations) 
Section 6.2.5 (General Information Regarding Laboratory 
Sampling and Results). 
Table 4 
Section 6.2.3.12 
Section 6.2.5 
Section 1.6 “Accommodations Due to the COVID-19 
Pandemic” was added as an introduction to the COVID-19 
pandemic and its impact on clinical trial procedures. 
Section 1.6 (new) 
Section 3.1.1 “Considerations due to the COVID-19 
Pandemic” was added to discuss potential adjustments to the 
meeting schedule or visit location/method due to the 
COVID-19 pandemic and to indicate that all deviations from 
the protocol due to the pandemic are to be documented. 
Section 3.1.1 (new) 
Recommendations on use of antithrombotic treatment was 
added for subjects with factor IX activity in the 
non-hemophilic (≥40% of normal) range and with a 
confirmed COVID-19 infection. 
Section 5.6.2, 5.6.3 
Section 6.2.2.1 
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Additional clarification and recommendations on 
transaminase elevation management was added including 
discussions on corticosteroid tapering, considerations with 
prolonged high dose corticosteroid use, and considerations 
with potential and confirmed COVID-19 infections. 
Section 5.6.4 
Addition of phrase indicating that the 5 years of follow-up 
after administration of AMT-061 is in line with the FDA 
guidance on long-term follow-up after administration of 
human gene therapy products. 
Section 6.1.4 
Removal of use of international criteria for assessment of 
laboratory value abnormalities. 
Section 7.3.1 
To align with the eCRFs, the possible options for causality 
assessments for AEs were updated, with options being 
related, possibly related, unlikely related, and not related. 
Section 7.3.2 
Clarification that trial monitor visits may be virtual. 
Section 8.1 
Mention of update to eCRFs to include COVID-19 reasons 
for missed visits. 
Section 8.2 
Specification that the CSR and CSR addenda will summarize 
contingency measures implemented to manage study conduct 
due to COVID-19 control measures, protocol deviations due 
to COVID-19, and the impact COVID-19 had on visit 
schedules, missed visits, and missing information. 
Section 9.3 
Specification that the protocol deviations includes those 
related to COVID-19. 
Section 9.5 
The Investigator’s Brochure references were updated, to 
refer to the combined document for AMT-060 and AMT-061 
(Version 1; February 2020) 
Section 12 
Section 13.3 Previous Amendments added 
Section 13.3 
 
Amendment Number: 
1.0 (Version 2.0) 
Amendment Date: 
21 May 2019 
Global/Country/Site-
Specific:  
Global 
Description of Change 
Section(s) Affected by 
Change 
The title page was updated to show the name of the 
Monitoring CRO in place of the monitor’s name. 
Title Page 
Update of amendment version throughout. 
Addition of “Summary of Changes” section 
Addition of Section 13.1 “Summary of Changes in Current 
Amendment”. 
Throughout 
Summary of Changes 
Section 13.1 
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Contact information for Medpace Clinical Safety was added.  
The Medpace Monitor was updated to the Medpace Medical 
Director and contact information for the uniQure Medical 
Director was added, with clarification and protocol- or 
safety-related issues must be sent to both of these 
individuals. 
Emergency Contact 
Information 
FIX was changed to factor IX throughout except in the name 
of the IMP. 
Throughout 
Definition of gc was updated to genome copies from gene 
copies in the List of Abbreviations. 
List of Abbreviations 
It was clarified tht for ALT level increments of at least 2-
fold baseline and > ULN, and for AST level increments of at 
least 2-fold ULN, the Investigator should contact the 
Medpace and uniQure Medical Directors to discuss a clinical 
management plan on a case-by-case basis, including 
potential re-tests and/or initiation of corticosteroid treatment. 
Section 5.6.4 was created as the section for Guidelines for 
ALT Elevations. 
Synopsis 
Trial Schedules (Table 1) 
Section 5.6.4 
Update to language stating that Investigators will assess each 
bleeding episode, not adjudicate each bleeding episode. 
Synopsis 
Trial Schedules (Table 1) 
Section 6.1.2 
Section 6.1.6 
Section 6.2.2.2 
It was clarified that 
 being completed by 
the subject prior to other assessments are performed was a 
recommendation. Questions should be completed in the same 
order at each visit, following the order presented in the 
protocol. 
Synopsis 
Trial Schedules 
Section 6.1.2.1 
Section 6.1.3 
Section 6.1.4 
Section 6.2.2.4 
Descriptions of statistical analyses were expanded, including 
providing a full list of objectives and endpoints in the 
synopsis and body. In the body, expanded descriptions 
included specifying how continuous and categorical 
variables will be summarized, addition of a 10 day required 
wash out period for factor IX activity levels to be considered 
“uncontaminated”, 
 
 specification that summary statistics of change 
from baseline measurements for lab assessments and vital 
sign measurements will be presented, and addition that data 
Synopsis 
Section 2.2 
Section 3.3.2 
Section 9 
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for anti-factor IX antibodies, factor IX inhibitors, factor IX 
recovery, total (IgG and IgM) and neutralizing antibodies to 
AAV5, AAV5 capsid-specific T-cells, inflammatory 
markers, vector DNA in semen and blood, will be listed. 
Section 9.3 Final Analyses was added to separate how the 
final analyses will be reported compared to the interim 
analysis (included in Section 9.2).  
Alpha-fetoprotein (AFP) was added as an assessment 
(measured at Week 52 and all long-term follow-up visits), as 
part of the safety objective, and as a safety endpoint. 
Synopsis 
Trial Schedules 
Section 3.3.2 
Table 8 
Text describing management of endogeneous factor IX 
activity was updated to always present what should be done 
if endogenous factor IX activity is ≥5% followed by if it is 
between 2 and 5% and then <2%. 
Synopsis 
Section 5.6.2 
Specification that subjects are expected to document factor 
IX usage and bleeding episode during the long-term follow-
up, but not in the e-diary. 
Synopsis 
Section 6.1.4 
Section 6.2.2.1 
Section 6.2.2.2 
Clarification that analyses will be based on central laboratory 
measurements if results are available from both local and 
central laboratories. 
Synopsis 
Section 6.2.2.3 
Section 9.9 
Sampling for vector genome detection from semen sample at 
Week 52 was added. 
Trial Schedules (Table 2) 
It was clarified that assessment of blood pressure, pulse, and 
body temperature was assessment of vital signs. 
Title for Section 6.2.3.2 was updated to “Vital Signs” instead 
of “Blood Pressure, Pulse, and Body Temperature”. 
Trial Schedules 
Section 3.3.2 
Section 6.2.3.2 
It was clarified that study visits should be scheduled to 
ensure they take place when factor IX activity is at its 
trough, on the day that routine prophylactic factor IX 
replacement treatment is planned to be administered. 
Trial Schedules 
Section 6.2.2.3 
Addition of a chromogenic assay for factor IX activity 
assessments. Specification that no additional blood will be 
drawn for this; tests will be performed on back-up. 
Trial Schedules (Table 2 and 
Table 4) 
Section 6.2.2.3 
Section 6.2.3.6 
Update on the number of people with hemophilia B and the 
number of live male newborns with haemophila B based on 
updated references. 
Section 1.1 
CSL Behring 

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
Page 111 of 112 
Details for the second and last reference listed in Table 5 
were updated. 
Table 5 
Section 1.5 was updated to align with the text in the related 
CT-AMT-061-01 protocol amendment dated 07 Dec 2018. 
The title of Section 1.5.2 was updated to refer to AAV5 
Gene Therapeutic Vector rather than AAV5 Gene 
Transfection. 
Section 1.5 
Clarification that transaminase increase alone may warrant 
the initiation of a corticosteroid was made in Section 1.5.3, 
for consistency with Section 5.6.4. 
Section 1.5.3 
Addition of “Withdrawal by principal Investigator” as a 
possible reason for discontinuation. 
Section 4.5.1 
 
 
Section 5.2 
Table 6 
Section 5.6.3 Guidelines for Use of Factor IX for Patients 
Undergoing Major Surgery was added. 
Section 5.6.3 
For assessment of endogenous factor IX activity, the upper 
factor IX activity limit was set to >5% for consistency with 
the other limits of 2-5% and <2%. 
Section 6.1.4 
Information on what will be collected for concomitant 
medications/therapys was updated to align with the study 
eCRFs. 
Section 6.2.1.3 
Information on what will be collected for medical history 
related to hemophilia B was updated to align with the study 
eCRFs. 
Section 6.2.1.4 
Information on what will be collected with respect to 
factor IX replacement therapy was updated to align with the 
e-diary questions. 
Section 6.2.2.1 
Information on what will be collected with respect to 
bleeding episodes was updated to align with the e-diary 
questions. 
Definitions for joint and muscle bleeds were removed. 
The definition for persistent bleed was added. 
Section 6.2.2.2 
Clarification that local laboratory results should be provided 
to the Investigator as soon as possible. 
Section 6.2.3.11 
CSL Behring 
CCI

AMT-061 (AAV5-hFIXco-Padua; etranacogene dezaparvovec) 
 
Protocol ID: CT-AMT-061-01 
Version: 4.0 (Amendment 3.0) 
CONFIDENTIAL 
Date: 08 Feb 2022 
 
Page 112 of 112 
Section 7.3.2 Relationship to IMP was updated to reflect 
what is actually being done for assessment of (S)AE 
causality, using terms of definitely related, probably related, 
possibly related, and not related rather than related or not 
related. 
Section 7.3.2 
Clarification that consent of the pregnant partner is required 
to follow any pregnancies and outcomes. 
Section 7.7 
Clarification that authorized personnel from the data 
management vendor will enter the 
 and 
 summary data and that subject reported e-diary data 
will be directed loaded into the eCRF without source 
documentation was added. 
Section 8.1 
Section 10.2.3.1 
Section 8.3 Study Data was added to be reflective of what is 
being done. 
Section 8.3 
Language around indemnity/liability and insurance was 
updated. 
Section 10.1.2 
Clarification and re-consent will be necessary if the ICF is 
revised with important new information. 
Section 10.3.1 
Appendix on Laboratory Information was added. 
Section 13.1 
 
 
CSL Behring 
CCI
CCI

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