Phase I/II Open-Label Safety and Dose Finding Study of Adeno-Associated Virus (AAV) rh10-Mediated Gene Transfer of Human Factor IX in Adults With Moderate/Severe to Severe Hemophilia B
Phase: PHASE1
Conditions: Hemophilia B
Sponsor: Ultragenyx Pharmaceutical Inc

CLINICAL STUDY PROTOCOL 
IND NUMBER: 16543 
EUDRACT NUMBER: 2015-001486-67 
 
A Phase I/II Open-Label Safety and Dose-Finding Study of Adeno-
Associated Virus (AAV) rh10-Mediated Gene Transfer of Human Factor IX 
in Adults With Moderate/Severe to Severe Hemophilia B 
 
 
101HEMB01 
 
Sponsor: 
Dimension Therapeutics, Inc 
840 Memorial Drive 
Cambridge, MA 02139 
Sponsor Contact: 
 
Vice President, Clinical Development 
Telephone: 
 
Medical Monitor: 
 
Medical Director, Pharmacovigilance 
PPD 
929 North Front Street 
Wilmington, NC 28401 
Telephone: 
 
Version of Protocol:  
04 
Date of Protocol:  
Original: 10 April 2015 
Amendment 1: 10 June 2015 
Amendment 2: 29 July 2015 
Amendment 3: 03 September 2015 
 
CONFIDENTIAL 
All financial and nonfinancial support for this study will be provided by Dimension 
Therapeutics, Inc. The concepts and information contained in this document or generated 
during the study are considered proprietary and may not be disclosed in whole or in part 
without the expressed, written consent of Dimension Therapeutics, Inc. 
The study will be conducted according to the International Conference on Harmonisation 
harmonised tripartite guideline E6(R1): Good Clinical Practice. 
 
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Protocol Amendment History and Summary of Changes 
Version 
Date 
Summary of Changes 
Version 01 
10 April 2015 
Original Protocol 
Version 02 
10 June 2015 
Overview of significant changes includes the following: 
• The protocol was originally designed to seamlessly 
move from a Phase 1/2 (Part 1) into a larger 
registration study (Part 2). Part 2 has been removed 
from this study and will be a separate study. The text 
has been revised throughout the protocol to reflect 
this change. 
• Assessment of the subject’s quality of life (QoL) 
following treatment with DTX101 was originally 
planned for Part 2 of the study. With the removal of 
Part 2, the QoL questionnaires have been included as 
a secondary endpoint in this dose-finding study. 
• The frequency of clinical chemistry samples to 
monitor liver function tests (LFTs) has been 
increased to occur approximately every 4 days for the 
first 12 weeks after DTX101 administration to ensure 
that any elevation in LFTs, potentially as a result of 
autoimmune hepatitis, are discovered quickly and 
adequately managed. 
• The sampling scheme monitoring for viral shedding 
has been increased from 3 weeks to 12 weeks. 
• The frequency of site visits over the first 12 weeks 
has been reduced from weekly to bi-weekly (Week 2 
through Week 12).  
• In order to accommodate the increased frequency of 
clinical chemistry sampling, subjects will be seen at 
home by clinically trained and qualified personnel 
approximately every 4 days (unless a study visit is 
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scheduled) to minimize the frequency of study visits. 
• Elevated liver function test results associated with 
potential autoimmune hepatitis and infusion site 
reactions are no longer designated as adverse events 
(AEs) of special interest. They will continue to be 
recorded as AEs/serious adverse events (SAEs) in the 
clinical database. 
Version 03 
29 July 2015 
Overview of significant changes include the following: 
• The no observed adverse event level (NOAEL) used 
to develop the rationale for the starting dose of 
DTX101 was originally determined from a non-Good 
Laboratory Practice (GLP) nonclinical toxicology 
study and reported as 1.35 × 1013 genome copies 
(GC)/kg. A GLP-compliant nonclinical toxicology 
study has recently been completed and the NOAEL 
has changed to 5.0 × 1012 GC/mL. The dosing 
rationale and safety margins for each of the proposed 
doses of DTX101 have been revised to reflect this 
change. 
• The development of AAVrh10 binding antibodies has 
been added as an exploratory endpoint. 
• The optimal biological dose has been updated to be 
the dose that achieves or is closest to achieving the 
target peak Factor IX activity of ≥20% of normal. 
• Amendment 1 of the protocol added home visits to 
accommodate the increased frequency of clinical 
chemistry sampling. The language has been revised 
to allow subjects to either visit the clinic or have 
samples taken at home by clinically trained and 
qualified personnel. 
• The safety stopping criteria has been updated to 
clarify that the study will be suspended so that the 
results can be reviewed and any risks to subjects can 
be mitigated. 
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Version 04 
03 September 
2015 
Overview of significant changes include the following: 
• Exclusion Criterion 2 was revised so that subjects 
with alanine aminotransferase and aspartate 
aminotransferase elevations >2.0 × the upper limit of 
normal will not be eligible for the study. This has 
been reduced from >3.0 × the upper limit of normal. 
• Language has been added to reflect that an interim 
analysis will be performed once the last subject 
enrolled in the study has completed Week 6. 
 
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Table of Contents 
List of Tables ............................................................................................................................ 10 
List of Figures .......................................................................................................................... 11 
Protocol Synopsis..................................................................................................................... 12 
List of Abbreviations................................................................................................................ 24 
1 
Introduction ...................................................................................................................... 27 
1.1 
Adeno-Associated Viral Vectors ............................................................................. 29 
1.2 
Selection of the AAV Clinical Candidate ................................................................ 29 
1.3 
Study Rationale ....................................................................................................... 31 
1.3.1 
Design Rationale ...................................................................................... 31 
1.3.2 
Dosing Rationale ..................................................................................... 32 
2 
Study Objectives and Endpoints ....................................................................................... 36 
3 
Investigational Plan .......................................................................................................... 38 
3.1 
Study Overview ...................................................................................................... 38 
3.2 
Overall Study Duration and Follow-Up .................................................................. 39 
3.2.1 
Screening Period ...................................................................................... 40 
3.2.2 
Treatment Period ...................................................................................... 41 
3.2.3 
Prophylactic Factor IX Washout Periods ................................................. 41 
3.2.3.1 
Screening Period ...................................................................................... 41 
3.2.3.2 
Treatment Period ...................................................................................... 42 
3.2.4 
Safety Stopping Criteria ........................................................................... 44 
3.2.5 
End of Study ............................................................................................ 44 
4 
Subject Selection .............................................................................................................. 46 
4.1 
Inclusion Criteria .................................................................................................... 46 
4.2 
Exclusion Criteria ................................................................................................... 47 
5 
Screening and Randomization Procedures ....................................................................... 49 
5.1 
Subject Screening.................................................................................................... 49 
5.2 
Subject Randomization ........................................................................................... 49 
6 
Study Treatment ............................................................................................................... 50 
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6.1 
Identity of Study Product ........................................................................................ 50 
6.1.1 
Description of DTX101 ........................................................................... 50 
6.1.2 
Components Used for Manufacturing ..................................................... 50 
6.2 
Management of Clinical Supplies ........................................................................... 50 
6.2.1 
Packaging and Labeling ........................................................................... 50 
6.2.2 
Storage of DTX101 .................................................................................. 51 
6.2.3 
Study Product Accountability .................................................................. 51 
6.2.4 
Transmission of Infectious Agents ........................................................... 51 
6.3 
Treatment Schedule and Administration ................................................................. 51 
6.3.1 
Treatment Compliance ............................................................................. 52 
6.4 
Prior and Concomitant Therapy .............................................................................. 52 
6.4.1 
Permitted Medications ............................................................................. 52 
6.4.1.1 
Medications for the Treatment of Hemophilia B ..................................... 52 
6.4.1.2 
Other Medications ................................................................................... 53 
6.4.2 
Prohibited Medications ............................................................................ 53 
7 
Withdrawal of Subjects From the Study ........................................................................... 54 
7.1 
Study Withdrawal .................................................................................................... 54 
7.2 
Subject Replacement ............................................................................................... 54 
8 
Study Assessments and Procedures .................................................................................. 55 
8.1 
Efficacy and Pharmacodynamic Assessments ........................................................ 55 
8.1.1 
Factor IX Activity .................................................................................... 55 
8.1.2 
Bleeding Episodes ................................................................................... 55 
8.1.3 
Factor IX Replacement Therapy .............................................................. 56 
8.1.4 
Quality-of-Life Assessments ................................................................... 56 
8.1.4.1 
EuroQol 5D 5 Level Questionnaire ......................................................... 56 
8.1.4.2 
Haemophilia-Specific Quality of Life Questionnaire .............................. 56 
8.2 
Safety Assessments ................................................................................................. 57 
8.2.1 
Demographic, Medical, and Hemophilia B History Assessments ........... 57 
8.2.2 
Physical Examination .............................................................................. 58 
8.2.3 
Vital Sign Measurements ......................................................................... 58 
8.2.4 
Electrocardiograms .................................................................................. 59 
8.2.5 
Clinical Laboratory Analyses................................................................... 59 
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8.2.6 
Clinical Laboratory Parameters ............................................................... 60 
8.2.6.1 
Elevation of Liver Function Tests ............................................................ 61 
8.2.6.2 
Treatment for Potential Immune Hepatitis .............................................. 61 
8.3 
Other Laboratory Parameters .................................................................................. 62 
8.3.1 
Factor IX Inhibitor ................................................................................... 62 
8.3.2 
Neutralizing Antibodies to Adeno-Associated Virus rh10 ....................... 62 
8.3.3 
Adeno-Associated Virus rh10 Binding Antibody IgG Assay .................. 62 
8.3.4 
Viral Shedding ......................................................................................... 63 
8.3.5 
Cell-Mediated Immune Response ............................................................ 63 
8.4 
Genotyping .............................................................................................................. 63 
8.4.1 
Factor IX Genotyping .............................................................................. 63 
8.4.2 
Human Leukocyte Antigen Genotyping .................................................. 64 
9 
Safety Monitoring and Reporting ..................................................................................... 65 
9.1 
Adverse Events and Serious Adverse Events ......................................................... 65 
9.1.1 
Definitions ............................................................................................... 65 
9.1.1.1 
Adverse Events ........................................................................................ 65 
9.1.1.2 
Serious Adverse Events ........................................................................... 66 
9.1.2 
Safety Reporting ...................................................................................... 66 
9.1.2.1 
Adverse Events ........................................................................................ 66 
9.1.2.2 
Serious Adverse Events ........................................................................... 67 
9.1.2.2.1 
Expedited Reporting .................................................................... 67 
9.1.3 
Assessment of Severity/Toxicity ............................................................. 68 
9.1.4 
Assessment of Causality .......................................................................... 69 
9.1.5 
Follow-Up of Subjects Reporting Adverse Events .................................. 69 
9.2 
Procedures for Handling Special Situations ........................................................... 70 
9.2.1 
Pregnancy ................................................................................................ 70 
9.2.2 
Treatment Noncompliance ....................................................................... 70 
9.2.2.1 
Overdose Management ............................................................................ 70 
9.2.2.2 
Medication Errors .................................................................................... 70 
9.3 
Data Safety Monitoring Committee ........................................................................ 70 
10 Statistical and Analytical Plan .......................................................................................... 72 
10.1 Dose-Finding Algorithm and Process ..................................................................... 72 
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10.2 Primary Endpoints .................................................................................................. 72 
10.3 Secondary Endpoints .............................................................................................. 72 
10.4 Other Endpoints ...................................................................................................... 73 
10.5 Statistical Analysis Methodology ........................................................................... 73 
10.5.1 
Determination of the Optimal Biological Dose ....................................... 73 
10.5.2 
Efficacy Analysis ..................................................................................... 75 
10.5.2.1 Annualized Bleeding Rate ....................................................................... 75 
10.5.2.2 Factor IX Replacement Therapy .............................................................. 75 
10.5.3 
Safety Analyses ........................................................................................ 75 
10.5.3.1 Adverse Events ........................................................................................ 75 
10.5.3.2 Clinical Laboratory Assessment Results ................................................. 76 
10.5.3.3 Vital Sign Measurements ......................................................................... 76 
10.5.3.4 Electrocardiogram Results ....................................................................... 76 
10.5.4 
Pharmacodynamic Analyses .................................................................... 76 
10.5.5 
Other Laboratory Results ......................................................................... 76 
10.5.6 
Quality-of-Life Assessments ................................................................... 77 
10.5.7 
Other Analyses ......................................................................................... 77 
10.5.8 
Interim Analysis ....................................................................................... 77 
10.6 Data Quality Assurance........................................................................................... 77 
10.6.1 
Data Management .................................................................................... 78 
11 Ethics ................................................................................................................................ 80 
11.1 Institutional Review Board, Independent Ethics Committee, and Institutional 
Biosafety Committee ....................................................................................... 80 
11.2 Ethical Conduct of the Study .................................................................................. 80 
11.3 Subject Information and Consent ........................................................................... 80 
12 Investigator’s Obligations ................................................................................................ 82 
12.1 Confidentiality ........................................................................................................ 82 
12.2 Financial Disclosure and Obligations ..................................................................... 82 
12.3 Investigator Documentation .................................................................................... 83 
12.4 Study Conduct ......................................................................................................... 83 
12.5 Adherence to Protocol ............................................................................................ 84 
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12.6 Adverse Events and Study Report Requirements ................................................... 84 
12.7 Investigator’s Final Report ..................................................................................... 84 
12.8 Record Retention .................................................................................................... 84 
12.9 Publications ............................................................................................................. 84 
13 Study Management ........................................................................................................... 86 
13.1 Monitoring .............................................................................................................. 86 
13.1.1 
Monitoring of the Study ........................................................................... 86 
13.1.2 
Inspection of Records .............................................................................. 86 
13.2 Management of Protocol Amendments and Deviations.......................................... 87 
13.2.1 
Modification of the Protocol .................................................................... 87 
13.2.2 
Protocol Deviations ................................................................................. 87 
13.3 Study Termination ................................................................................................... 88 
13.4 Final Report ............................................................................................................ 88 
14 Reference List................................................................................................................... 90 
15 Appendices ....................................................................................................................... 95 
15.1 Appendix: Schedules of Events .............................................................................. 95 
15.2 Appendix: Quality-of-Life Questionnaires ........................................................... 102 
15.2.1 
EuroQol 5D 5 Level (EQ-5D-5L QoL) ................................................. 102 
15.2.2 
Haemophilia-Specific Quality of Life (Haem-A-QoL) Questionnaire .. 103 
 
List of Tables 
Table 1–1 
Predicted Total Vector Titer of DTX101 Following IV Infusion and Exposure 
Margins to a Nonclinical GLP Toxicology Study ........................................... 34 
Table 8–1 
Clinical Laboratory Parameters ...................................................................... 60 
Table 9–1 
PPD PVG Contact Information for SAE Reporting ....................................... 67 
Table 15–1 
Schedule of Events – Scheduled Clinic Visits ................................................ 96 
Table 15–2 
Schedule of Events – Clinic or Home Visits During the Treatment Period .. 101 
 
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List of Figures 
Figure 3–1 
Study Design ................................................................................................... 40 
Figure 3–2 
Recombinant FIX Washout During the Screening Period .............................. 42 
Figure 3–3 
Recombinant FIX Washout During the Treatment Period .............................. 43 
Figure 10–1 
Overview of Potential Dosing Scheme to Determine the Optimal Biological 
Dose of DTX101 ............................................................................................. 74 
 
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Protocol Synopsis 
Protocol Number: 
101HEMB01 
Title: 
A Phase I/II Open-Label Safety and Dose-Finding Study of 
Adeno-Associated Virus (AAV) rh10-Mediated Gene Transfer of 
Human Factor IX in Adults With Moderate/Severe to Severe 
Hemophilia B 
Sponsor: 
Dimension Therapeutics, Inc 
840 Memorial Drive 
Cambridge, MA 02139 
Study Phase: 
I/II 
Study Sites: 
Up to 14 global study sites. 
Sample Size: 
The study is anticipated to enroll approximately 12 to 
18 subjects.  
Indication: 
Moderate/severe to severe hemophilia B 
Primary 
Objectives: 
• To determine the safety of single ascending intravenous (IV) 
doses of DTX101 in adults with moderate/severe to severe 
hemophilia B. 
• To establish a dose of DTX101 that achieves a peak plasma 
level of vector-derived factor IX (FIX) at 6 weeks after IV 
administration to allow further clinical development. 
Secondary 
Objectives: 
• To assess the impact of DTX101 on the number of bleeding 
episodes requiring recombinant FIX infusion during the 
study. 
• To evaluate the kinetics, duration, and magnitude of plasma 
FIX activity, by dose, after IV administration of DTX101 in 
adults with hemophilia B. 
• To assess the impact of DTX101 on the frequency of FIX 
replacement therapy during the study. 
• To describe the immune response to the FIX transgene after 
IV administration of DTX101. 
• To assess the impact of DTX101 on the subject’s quality of 
life. 
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Exploratory 
Objective: 
• To describe the immune response to adeno-associated virus 
serotype rh10 (AAVrh10) capsid proteins after IV 
administration of DTX101. 
Primary 
Endpoints: 
• The incidence of adverse events (AEs), treatment-emergent 
adverse events (TEAEs), and serious adverse events (SAEs), 
will be summarized for each dosing cohort by severity and 
relationship to study product. 
• The change from baseline in FIX activity at Week 6 as 
determined by the activated partial thromboplastin time 
(aPTT) clot-based assay. 
Secondary 
Endpoints: 
• The annualized bleeding rate (ABR) will be calculated for all 
subjects through Week 52 (±7 days). 
• The time course of FIX activity, as determined by aPTT, will 
be summarized by time point and dose level of DTX101. 
• The annualized and average weekly use of FIX replacement 
therapy will be calculated for all subjects through Week 52 
(±7 days). 
• The development of neutralizing antibodies to FIX (FIX 
inhibitor), as determined by a Bethesda assay, will be 
summarized by time point and dose level of DTX101. 
• The development of a cell-mediated immune response to 
FIX, as determined by enzyme-linked immunospot 
(ELISPOT) assay, will be summarized by time point and 
dose level of DTX101. 
• Responses to the EuroQol 5D 5 level (EQ-5D-5L™) and 
Haemophilia-Specific Quality of Life (Haem-A-QoL) 
questionnaires will be summarized. 
Exploratory 
Endpoints: 
• The development of neutralizing antibodies to AAVrh10, as 
determined by enzyme-linked immunosorbent assay 
(ELISA), will be summarized by time point and dose level of 
DTX101. 
• The development of a cell-mediated immune response to 
AAVrh10, as determined by ELISPOT assay, will be 
summarized by time point and dose level of DTX101. 
• The development of anti-AAVrh10 binding antibodies, as 
determined by ELISA, will be summarized by time point and 
dose level of DTX101. 
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Subject 
Population: 
Inclusion Criteria 
Each subject must meet all of the following criteria at screening 
to be enrolled in this study: 
1. Male ≥18 years of age. 
2. Moderate/severe or severe hemophilia B (baseline FIX 
activity ≤2% of normal or documented history of FIX 
activity ≤2%).  
3. At least 3 bleeding episodes per year that require 
on-demand treatment with FIX OR are treated with a 
prophylactic regimen of FIX. 
4. At least 100 days exposure history to FIX. 
5. No documented history of inhibitors (neutralizing 
antibodies) to exogenous FIX.  
6. No known allergic reaction to exogenous FIX or any 
component of DTX101. 
7. Willing to stop prophylactic treatment with recombinant 
FIX at specified time points during the study.  
8. Willing and able to provide written informed consent. 
9. Willing and able to comply with study procedures and 
requirements. 
10. Willing to use effective contraception at the time of 
administration of DTX101 and for 3 months following 
administration of DTX101. Appropriate contraceptive 
methods include a condom with spermicide. Abstinence, 
defined as sexual inactivity, is an acceptable form of 
birth control; however, appropriate contraception must be 
used if the subject becomes sexually active. 
Exclusion Criteria 
Subjects meeting any of the following criteria at screening will 
be excluded from the study: 
1. History of liver disease as evidenced by any of the 
following: portal hypertension, ascites, splenomegaly, 
esophageal varices, hepatic encephalopathy, or a liver 
biopsy with evidence of stage 3 fibrosis. 
2. Significant hepatic inflammation or cirrhosis as 
evidenced by any of the following: aspartate 
aminotransferase (AST) or alanine aminotransferase 
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(ALT) >2.0 × upper limit of normal (ULN), total 
bilirubin >1.5 × ULN, alkaline phosphatase (ALP) 
>2.5 × ULN, platelet count <75,000 cells/µL, or 
prothrombin time (PT) or international normalized ratio 
(INR) >1.5 × ULN. 
3. Evidence of active hepatitis B virus (HBV) or hepatitis C 
virus (HCV) infection, documented by current use of 
antiviral therapy for HBV or HCV or by hepatitis B 
surface antigen (HBsAg) or HCV RNA positivity. 
NOTE: Two negative viral assays by polymerase chain 
reaction (PCR), collected at least 6 months apart, will be 
required to be considered negative for HCV. Subjects can 
be rescreened once if they have one negative sample and 
must wait to have the second sample collected within the 
following 6 months. 
4. History of human immunodeficiency virus (HIV) 
infection AND any of the following: CD4+ cell count 
<350 cells/mm3, change in antiretroviral therapy regimen 
within 6 months prior to Day 0, or plasma viral load 
>200 copies/mL, on 2 separate occasions, as measured 
by PCR. 
5. Anti-AAVrh10 neutralizing antibody titer >1:5. 
6. Participation (current or previous) in another gene 
therapy study.  
7. Participation in another investigational medicine study 
within 3 months before screening.  
8. History of a malignancy for which the subject has 
received treatment in the past 2 years except for prostate 
cancer treated with watchful waiting, or surgically 
removed non-melanoma skin cancer. 
9. Has any other significant medical condition that the 
investigator feels would be a risk to the subject or would 
impede the study. 
Study Design: 
This is a Phase I/II, open-label, single-arm, multicenter, 
dose-finding safety study to determine the safety, tolerability, 
and efficacy of DTX101 in adult males with moderate/severe to 
severe hemophilia B. The primary objectives of the study are to 
determine the safety of single ascending IV doses of DTX101 
and to identify the optimal biological dose (OBD) of DTX101 
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that either achieves or is the closest to achieving the target peak 
FIX activity of ≥20% of normal.  
Eligible subjects will receive a single IV infusion of DTX101. 
Subjects will be dosed sequentially in cohorts with a minimum 
of 3 subjects each. Dose escalation will be conducted according 
to a model that uses safety and efficacy data to predict the OBD. 
The recommendation to proceed to the next dose cohort will be 
made by the Data Safety Monitoring Committee after evaluation 
of the safety data for all subjects in a dosing cohort after they 
have completed Week 6. 
Subjects will be followed for 52 weeks after dosing. After 
completion of this study, subjects will be offered enrollment in 
an extension study to evaluate the long-term safety and effect of 
DTX101 on clinical outcome measures. 
Study 
Methodology: 
Screening Period 
After a subject has provided written informed consent, and 
within 30 days before DTX101 infusion (Day 0), the 
investigator or other qualified study personnel will determine if 
the subject is eligible for the study. This will be accomplished by 
reviewing the inclusion and exclusion criteria and completing all 
of the screening assessments. If the subject does not have a 
documented history of FIX activity, a blood sample will be 
needed to confirm the severity of hemophilia B for inclusion 
after washout of recombinant FIX. For subjects taking long 
acting recombinant FIX prophylactically to prevent bleeding 
episodes, the washout period is to start at approximately Day -29 
and last for 21 days (approximately Day –8). For subjects taking 
traditional recombinant FIX prophylactically to prevent bleeding 
episodes, the washout period is to start at approximately Day -29 
and last for 7 days (approximately Day -22). 
The screening assessments may be performed on more than 
1 day, provided that all of the assessments are completed and the 
results are available within the 30-day screening window and 
prior to Day 0. 
Screening Assessments: Demographic data; medical and 
hemophilia history; prior medications, therapies, and procedures; 
vital sign measurements; height and weight will be recorded. A 
12-lead electrocardiogram (ECG) and a complete physical 
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examination will be performed. Samples will be collected for 
FIX and human leukocyte antigen genotyping; HIV, HBV, and 
HCV status; FIX inhibitor determination; AAVrh10 binding 
antibody immunoglobulin G (IgG) assay; AAVrh10 neutralizing 
antibody testing; FIX activity; clinical laboratory assessments 
(hematology, coagulation, clinical chemistry, and urinalysis); 
and record spontaneous bleeding episodes and recombinant FIX 
use.  
Day 0 – DTX101 Infusion 
Subjects will be admitted for DTX101 administration and for 
continuous safety monitoring. Subjects will be discharged 
24 hours after completion of the infusion.  
Prior to dosing, blood samples will be collected for FIX inhibitor 
determination, AAVrh10 binding antibody IgG assay, AAVrh10 
neutralizing antibody testing, FIX activity, cell-mediated 
immune response to AAVrh10 and FIX, and clinical laboratory 
assessments (hematology, coagulation, and clinical chemistry). 
Saliva, urine, and stool samples will be collected for assessment 
of viral shedding. An ECG (in triplicate) and a targeted physical 
examination will be performed. Vital sign measurements and 
weight will be recorded. The use of concomitant medications, 
spontaneous bleeding episodes and recombinant FIX use will be 
recorded. 
Subjects will be provided a paper or electronic diary (eDiary). 
The subject will complete the EQ-5D-5L and the Haem-A-QoL 
questionnaires. 
After dosing, a sample will be collected for clinical laboratory 
assessments (hematology and clinical chemistry) at 0.5, 4, and 
8 hours after the start of infusion. Vital sign measurements will 
be recorded at 5 minutes after the start of infusion, and at 0.5, 1, 
2, 4, 6, 8, and 22 hours after the start of infusion. A single 
12-lead ECG will be performed at 1 hour after the start of 
infusion. 
At All Visits (Day 1 Through Week 52) 
Subjects will be asked to visit the study site approximately every 
4 days through Week 12. Following the Week 12 visit, subjects 
will visit the study site once every 4 weeks through Week 52 or 
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their early withdrawal from the study. 
At each visit, samples will be collected for FIX activity and 
clinical laboratory assessments (hematology, coagulation, and 
clinical chemistry). Vital sign measurements will be recorded. 
Adverse events and SAEs will be monitored; concomitant 
medications, therapies, and procedures will be recorded; and the 
paper or eDiary will be reviewed with the subject. 
Clinic or Home Visits 
Subjects will be asked to provide clinical laboratory samples 
approximately every 4 days through Week 12 of the study. If 
subjects cannot visit the study site in person, subjects can be 
visited by clinically trained and qualified personnel 
approximately every 4 days at their home through Week 12, the 
exception being those weeks when a site visit is scheduled, to 
collect a clinical laboratory sample to monitor liver function 
tests (LFTs). Saliva, urine, and stool samples will also be 
collected for assessment of viral shedding on Days 8, 20, 36, 48, 
64, and 76. These samples will continue to be collected until 
3 consecutive negative results are obtained from each sample 
matrix. 
Weeks 2, 4, 6, 8, 10, and 12 
Saliva, urine, and stool samples will be collected for assessment 
of viral shedding. These will continue to be collected until 
3 consecutive negative results are obtained from each sample 
matrix. Subjects will be asked to provide a sample for urinalysis 
(Weeks 2, 4, 6, 8, and 12). 
In order to accurately assess vector-derived FIX activity as a 
result of DTX101 infusion, subjects will stop taking FIX 
prophylactically prior to the assessment of peak FIX activity at 
Week 6 and transition to an on-demand regimen for the 
remainder of the study. Subjects prophylactically using 
traditional recombinant FIX will be asked to begin the washout 
period starting at Week 5. Due to the longer half-life, subjects 
prophylactically taking long-acting recombinant FIX (eg, 
Alprolix) will be asked to begin the washout period starting at 
Week 3. 
 
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Weeks 6, 8, 16, 32, 40, and 48 
Samples will be collected for FIX inhibitor determination, 
coagulation panel, AAVrh10 binding antibody IgG assay, 
AAVrh10 neutralizing antibody testing, and cell-mediated 
immune response to AAVrh10 and FIX.  
If, at any time during the study, a subject experiences bleeding 
episodes frequent enough to consider prophylactic treatment, the 
investigator will discuss treatment options with the medical 
monitor. If a subject resumes prophylactic FIX replacement 
therapy, as rescue treatment after Week 6, additional washout 
periods prior to Week 24 and Week 52 will also be performed. 
Subjects prophylactically using traditional recombinant FIX will 
be asked to begin the washout period starting at Week 23 and 
Week 51. Due to the longer half-life, subjects taking long-acting 
recombinant FIX (eg, Alprolix) will be asked to begin the 
washout period starting at Week 21 and Week 49. 
Weeks 6, 12, 24, 36, and 48 
The subject will complete the EQ-5D-5L and the Haem-A-QoL 
questionnaires (Weeks 24, 36, and 48 only). 
A targeted physical examination will be performed.  
Week 52/Early Withdrawal 
Samples will be collected for FIX inhibitor determination, 
coagulation panel, AAVrh10 binding antibody IgG assay, 
AAVrh10 neutralizing antibody testing, and cell-mediated 
immune response to AAVrh10 and FIX. 
The subject will complete the EQ-5D-5L and the Haem-A-QoL 
questionnaires. 
A complete physical examination will be performed. A 12-lead 
ECG will be performed. 
Steroid Use: 
Steroid treatment for potential vector-induced immune hepatitis 
will be allowed if there is a >1.5-fold increase from baseline 
(predose, Day 0) in the subject’s ALT that is considered related 
to treatment with DTX101 by the investigator. Within 24 hours 
of learning of the elevation, the site will repeat the test at their 
local laboratory and, if still elevated, will initiate steroid 
treatment following the treatment algorithm outlined in this 
protocol. 
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Safety Stopping 
Criteria: 
Enrollment will be suspended and the study will be discussed 
with regulators if, at any time during the study, any of the 
following occur: 
• Death of a subject, at any time, that is considered related 
to DTX101 by the investigator, 
• Fivefold increase from baseline (predose, Day 0) ALT 
within 8 weeks after vector infusion that is considered 
related to DTX101 by the investigator, 
• Grade 2 toxicity develops that persists for more than 
7 days and that is considered related to DTX101 by the 
investigator, 
• At least Grade 3 toxicity develops, including an 
infusion-related reaction ≥Grade 3, that is considered 
related to DTX101 by the investigator, or 
• Occurrence of a malignancy, at any point after 
administration of vector, that is considered related to 
DTX101 by the investigator. 
Abnormal clinically significant laboratory values (hematology, 
coagulation panel, and clinical chemistry) as assessed by the 
investigator will be considered AEs. Laboratory values that meet 
any of the above criteria will result in the suspension of the 
study.  
Any event that meets the above criteria will be reported 
immediately and captured as an AE/SAE in the electronic case 
report form (eCRF), as appropriate. Enrollment and dosing will 
be temporarily suspended until the situation can be assessed and 
risks to subjects mitigated. If study enrollment is suspended, all 
subjects who have been enrolled will remain in the study and 
will continue to be monitored through their completion or 
withdrawal from the study. All AEs will be graded according to 
the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) v4.03. 
Efficacy 
Assessments: 
Efficacy will be assessed based on the change from baseline in 
FIX activity, the number of bleeding episodes, and the dosing 
requirements for FIX replacement therapy. 
Factor IX Activity 
The change from baseline in FIX activity at Week 6 and at 
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additional time points throughout the study will be assessed. 
Factor IX activity will be determined using an aPTT clot-based 
assay. 
Bleeding Episodes 
Bleeding episodes will be recorded in a paper or eDiary and will 
include: the start/stop date, the location of the bleed (joint, 
muscle, skin/mucosa, or internal), and the type of bleed 
(spontaneous or traumatic). The start date of a bleeding episode 
is defined as the first onset of symptoms of a bleed. The stop 
date of a bleeding episode is defined as 72 hours after the last 
on-demand treatment for a bleed, during which no additional 
bleeding episodes were noted in that location. If a bleeding event 
occurs in the same location within 72 hours of on-demand 
therapy, it will be considered part of the same episode. The site 
will review the diary with the subject at each clinic visit and 
record bleeding episodes on the appropriate page of the eCRF. 
Any event considered an AE should be recorded on the 
appropriate page of the eCRF. The annualized number of bleeds 
per subject, per location, and by type of bleed will be calculated 
for all subjects through Week 52 (±7 days). 
Factor IX Replacement Therapy 
The use of on-demand FIX replacement therapy will be recorded 
in a paper or eDiary and will include: the date(s) and dose 
(IU/kg) administered. The site will review the diary with the 
subject at each clinic visit and record the use of FIX replacement 
therapy on the appropriate page of the eCRF. The annualized and 
average weekly use of FIX replacement therapy will be 
calculated for all subjects through Week 52 (±7 days). 
Safety 
Assessments: 
Safety will be assessed based on AEs, SAEs, complete and 
targeted physical examination findings (including weight), vital 
sign measurements, ECG results, clinical laboratory assessments 
(hematology, coagulation panel, clinical chemistry, and 
urinalysis), viral shedding, measurement of neutralizing 
antibody titer to AAVrh10, measurement of AAVrh10 binding 
antibodies, measurement of FIX inhibitor, and assessment of any 
cell-mediated immune responses to AAVrh10 and FIX.  
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Estimated Study 
Duration: 
The duration of the study is defined for each subject as the date 
signed written informed consent is provided through the visit at 
Week 52. Subjects will be in the study for approximately 
56 weeks (including the screening period).  
Study Product, 
Dose, and Route of 
Administration: 
DTX101 will be administered as a single peripheral IV infusion. 
The following dose candidates will be assessed using a continual 
reassessment method (CRM) method to determine OBD: 
• Dose 1: 1.6 × 1012 GC/kg 
• Dose 2: 3.0 × 1012 GC/kg 
• Dose 3: 5.0 × 1012 GC/kg 
• Dose 4: 1.0 × 1013 GC/kg 
Statistical 
Methods: 
Determination of the Optimal Biological Dose 
A CRM will be used for dose-finding in this study. A 
2-parameter logistic regression model will be used to predict 
both the probability of experiencing a dose-limiting toxicity 
(DLT) and the probability of achieving the target peak FIX 
activity (≥20% of normal) within the first 6 weeks after DTX101 
infusion. A noninformative prior, in the form of a product of beta 
and exponential density functions, will be used. 
The maximum tolerated dose (MTD) is the dose when the 
posterior probability of the dosing cohort experiencing a DLT, 
based on the NCI CTCAE v4.03, is ≥25%. For this study, a DLT 
is defined as any AE/SAE ≥Grade 3 that is considered to be 
related to study product by the investigator. The MTD can also 
be the OBD if target FIX activity is achieved. A dose will be 
considered the minimal effective dose (MED) if the predicted 
probability of achieving the target peak FIX activity (≥20% of 
normal) reaches 90%. At each dose, a Euclidian distance 
between the posterior probabilities of safety and efficacy signals 
will be minimized to identify the dose for the next cohort. 
Subjects will be dosed sequentially in cohorts of a minimum of 
3 subjects each. Subjects in the first cohort (Cohort 1) will be 
assigned to Dose 1. Subjects will be assigned to subsequent 
cohorts depending on the safety and FIX activity of the 
preceding doses. The potential dosing scheme allows for, at 
most, bypassing one dose level (eg, Dose 1 to Dose 3) during 
dose-finding. Similarly, the potential dosing scheme allows for 
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de-escalation if the MTD is reached as well as cohort expansion 
to confirm a dose is the OBD. The protocol will also allow for 
adding an intermediate dose, relative to the candidate doses, if 
the CRM predicts it could be the OBD. 
Dose escalation will stop if at least one of the following 
conditions are met:  
1) The MTD is reached; 
2) The MED is found; 
3) If a dose is sufficiently close to either the MTD or MED 
(within 5% credible interval); 
4) If the posterior probability of a dose being either the 
MTD or the MED is over a threshold (10% and 20%, 
respectively); 
5) If all of the dosing cohorts have been enrolled. 
Interim Analysis 
An interim analysis will be conducted when the last subject 
dosed completes Week 6 of the study. The purpose of this 
interim analysis is to determine FIX activity in all cohorts to 
determine the OBD of DTX101 and provide an initial safety and 
efficacy assessment of DTX101. 
Safety Analyses 
All statistical analyses of safety outcomes will be descriptive. 
The incidence of AEs and TEAEs will be summarized for each 
dosing cohort by severity and relationship to study product. 
Serious AEs will be presented for each dosing cohort by 
relationship to study product. Summary tables will present 
incidence estimates and individual event rates by system organ 
class as well as within each system organ class. Subjects 
experiencing an event more than once with varying severity will 
be counted only once, in the maximum severity within each 
system organ class and preferred term. For incidence of 
relationship to study product, subjects will be counted only once, 
in the category of the strongest relationship to study product 
within each system organ class and preferred term. 
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List of Abbreviations 
Abbreviation 
Definition 
AAV 
adeno-associated virus 
AAV2 
adeno-associated virus serotype 2 
AAV8 
adeno-associated virus serotype 8 
AAVrh10 
adeno-associated virus serotype rh10 
ABR 
annualized bleeding rate 
ADL 
activities of daily living 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
CFR 
Code of Federal Regulations 
CRA 
clinical research associate 
CRM 
continual reassessment method 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLs 
cytotoxic T lymphocytes 
DLT 
dose-limiting toxicity 
DSMC 
Data Safety Monitoring Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eDiary 
electronic diary 
ELISA 
enzyme-linked immunosorbent assay 
ELISPOT 
enzyme-linked immunospot 
EQ-5D-5L 
EuroQol 5D 5 level 
EQ-VAS 
EuroQol visual analogue scale 
FDA 
US Food and Drug Administration 
FIX 
factor IX 
GC 
genome copies 
GCP 
Good Clinical Practice 
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Abbreviation 
Definition 
GLP 
Good Laboratory Practice 
Haem-A-QoL 
Haemophilia-Specific Quality of Life questionnaire 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HLA 
human leukocyte antigen 
IB 
Investigator’s Brochure 
IBC 
institutional biosafety committee 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
INR 
international normalized ratio 
IRB 
institutional review board 
IV 
intravenous 
LFT 
liver function test 
MED 
minimal effective dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NOAEL 
no observed adverse effect level 
OBD 
optimal biological dose 
OTC 
over-the-counter 
PCR 
polymerase chain reaction 
PT 
prothrombin time 
PVG 
pharmacovigilance 
qPCR 
quantitative polymerase chain reaction 
QTcF 
QT interval corrected by Fridericia’s formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SUSAR 
suspected, unexpected, serious adverse reactions 
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Abbreviation 
Definition 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
 
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1 
Introduction 
Hemophilia B is an X-linked recessive bleeding disorder that affects approximately 1 in 
20,000 to 25,000 male births. Mutations in the factor IX (FIX) gene, which encodes for a 
serine protease produced by the liver and is critical for fibrin clot formation, lead to 
deficiencies in coagulation. The disease is characterized by frequent, spontaneous internal 
bleeding that can lead to chronic arthropathy (joint damage), intracranial hemorrhage, and 
even death. In patients with moderate/severe to severe hemophilia B, 90% of all bleeding 
episodes occur in the joints and, if not treated properly, lead to debilitating damage and a 
decreased quality of life [Simpson 2012]. Depending on the residual activity of FIX, disease 
severity is classified as mild (>5% to <40% of normal), moderate (1% to 5% of normal), or 
severe (<1% of normal) [White 2001]. The current standard of care for hemophilia B is 
intravenous (IV) injections of either recombinant or plasma-derived FIX concentrates at the 
time of a bleed (on-demand therapy) or prophylactically to prevent bleeding 
[Peyvandi 2013]. The current standard of care is a reasonable means to prevent and arrest 
hemorrhaging; however, there remains a high burden of use for these life-long therapies and 
current treatment options do not completely prevent the chronic and debilitating damage to 
joints and soft tissues that follows a bleeding episode. 
Although the administration of these recombinant and plasma-derived FIX concentrates has 
significantly improved the clinical management of hemophilia B [Kaufman 2013], their use 
is limited in several ways: 
1. The majority of recombinant FIX products have a short half-life, requiring IV 
infusions 2 to 3 times per week to maintain circulating FIX levels above 1% of normal 
activity, which is effective for preventing spontaneous bleeding episodes 
[Nilsson 1992]. Recently approved recombinant coagulation FIX concentrates 
indicated for hemophilia B still require IV injections approximately once weekly or 
every 10 days for routine prophylaxis, and per label stipulate that dosing regimen 
should be adjusted based on individual response [Alprolix™ Prescribing 
Information 2014]; 
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2. Replacement therapy, including recently approved concentrates, does not provide 
constant, clinically important FIX activity levels. Patients on replacement therapy still 
experience FIX trough levels between dosing regimens that place them at risk for 
spontaneous bleeding, leading to chronic and debilitating arthropathy, intracranial 
hemorrhage, and even death; 
3. Neutralizing antibodies (inhibitors) occur in up to 3% of patients with hemophilia B, 
rendering replacement FIX therapy ineffective [Di Michele 2007]. Recent publications 
have suggested that FIX production through gene therapy is unlikely to result in 
neutralizing antibodies and may even reverse existing immune response in patients 
with pre-existing inhibitors developed in response to replacement therapy 
[Niemeyer 2009; Scott 2012; Crudele 2015]; 
4. Current treatment options do not adequately prevent the chronic damage to joints and 
soft tissue associated with breakthrough bleeding episodes; and 
5. When used prophylactically, only approximately 20% of the world’s hemophilia 
population has access to these treatments [Mingozzi 2011].  
There remains a significant unmet medical need for a less invasive treatment option for 
sustained management and prevention of bleeding episodes associated with hemophilia B. 
Factor IX gene therapy is expected to be effective for hemophilia B because the disease is 
caused by the lack of the single gene product, FIX [Kay 2011]. The continuous synthesis of 
FIX by transduced liver cells is not expected to have the trough levels associated with 
prophylactic or on-demand FIX replacement therapy [Collins 2011]. Factor IX gene therapy 
is likely to promote the normal coagulation process and is expected to be more effective at 
preventing bleeds in patients with moderate to severe hemophilia B than repeated infusions 
of recombinant FIX. Factor IX gene therapy would also allow patients to avoid the risks and 
inconvenience of regular IV infusions. The overall reduction in bleeding frequency will have 
a positive impact on secondary effects, such as joint damage and improving the patient’s 
quality of life. 
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1.1 
Adeno-Associated Viral Vectors 
Adeno-associated virus (AAV) is a non-enveloped, icosahedral, single-stranded DNA virus. 
Given that wild-type AAV displays wide tissue tropism and is capable of persisting in tissues 
for long durations without pathogenic effects, the use of recombinant AAV vectors has 
become a popular tool for gene delivery. Additionally, recombinant AAV vectors are 
non-replicating and the vector genomes exist as an episome following tissue transduction, 
minimizing the risk of insertional mutagenesis [Nakai 2001]. Since the first genetic 
engineering of wild-type AAV as a gene delivery vector in the early 1980s, recombinant AAV 
has shown great promise as an effective and safe gene delivery vehicle for treatment of 
diseases [Gao 2005].  
Adeno-associated virus serotype 2 (AAV2) was the first AAV that was used for gene transfer 
applications and has been used in numerous studies for a variety of diseases such as 
alpha 1-antitrypsin deficiency, Batten disease, and cystic fibrosis [Mingozzi 2011]. 
Specifically, animal models for hemophilia B have shown that AAV-mediated delivery of 
FIX can treat the disease for many years [Snyder 1999; Mount 2002; Wang 2005; 
Nichols 2010]. However, similar results have not been recapitulated in humans, where the 
expression of FIX from AAV2-mediated delivery was either sub-therapeutic or only lasted a 
few months [Manno 2003; Manno 2006]. This was due to several limitations of AAV2 
vectors including low transduction efficiency [Yan 2002], high seroprevalence of neutralizing 
antibodies against AAV2 in humans [Boutin 2010], and potentially destructive T-cell 
responses to capsids [Gao 2009; Vandenberghe 2006; Wang 2007]. There has also been 
evidence of B-cell responses against the transgene product in certain indications 
[Mingozzi 2011]. 
1.2 
Selection of the AAV Clinical Candidate 
The host immune response (ie, neutralizing antibodies and T-cell responses) limiting the 
efficacy of AAV2-mediated gene transfer (Section 1.1) was not predicted in the initial animal 
studies, due to AAV2 being endemic to humans and not these other species. Novel AAV 
serotypes, isolated from nonhuman primates, are divergent enough from endemic human 
serotypes to circumvent the neutralizing antibodies existing in most human subjects while 
retaining similar tissue tropism [Gao 2002].  
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One of these serotypes, AAV serotype 8 (AAV8), displays strong tropism for the liver 
[Gao 2002] and has been tested extensively in nonclinical and clinical models of hemophilia 
[Davidoff 2005; Jiang 2006; Nathwani 2006; Nathwani 2007; Nathwani 2011a]. These 
studies have shown that AAV8 has clear advantages over AAV2 including: excellent 
transduction efficiency; liver-specific tropism; stable transgene expression; a lack of 
hepatotoxicity as measured by peak serum transaminases; a lack of liver histopathology; a 
lack of T-cell activation to the transgene product; and low levels of pre-existing neutralizing 
antibodies in human populations, minimizing their inhibition of in vivo transduction. 
Given the clinical experience with AAV8 in gene therapy studies for hemophilia B, adeno-
associated virus serotype rh10 (AAVrh10), which shares 93.5% homology with AAV8, was 
pursued. Adeno-associated virus serotype rh10, as a clade E AAV, has strong tropism for the 
liver and transduces the liver highly efficiently when administered intravenously [Gao 2003; 
Gao 2004] and has shown impressive efficacy and safety in multiple pre-clinical animal 
models, such as Batten disease, Sanfilippo syndrome type A (mucopolysaccharidosis IIIA), 
and metachromatic leukodystrophy. Additionally, several US Food and Drug Administration 
(FDA)-approved Phase I clinical studies using AAVrh10 are ongoing or have recently 
completed enrollment (refer to ClinicalTrials.gov Identifiers: NCT01161576, NCT01414985, 
NCT01474343, and NCT01801709).  
DTX101, the study product, is AAVrh10FIX, a non-replicating recombinant AAVrh10 
encoding human FIX (hFIX) for the treatment of patients with hemophilia B. DTX101 
encodes a codon-optimized hFIX gene with expression driven by both a liver-specific 
enhancer element and a liver-specific promoter element encapsulated within AAVrh10.  
The proposed clinical study differs from previous hemophilia B AAV-mediated gene therapy 
approaches in 3 important aspects: 
1. Adeno-associated virus serotype rh10 demonstrates high liver tropism and can achieve 
efficient liver gene transfer following IV infusion; 
2. Adeno-associated virus rh10 is not thought to be endemic in the human population 
and, therefore, the prevalence of neutralizing antibodies to AAVrh10 in hemophilia B 
patients is expected to be lower than other AAV serotypes, such as AAV2; 
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3. DTX101 will be manufactured using a process that will result in the generation of 
fewer empty particles (ie, particles lacking the FIX transgene). This is anticipated to 
achieve a clinically meaningful rise in FIX activity, while potentially resulting in less 
frequent or less severe adverse events (AEs) than noted with other AAV preparations.  
1.3 
Study Rationale 
1.3.1 
Design Rationale 
The design of this study is consistent with global regulatory guidelines for protocol design, 
including: subject selection, dose estimation, precautions applied between dosing cohorts, 
risk mitigation, and study stopping criteria.  
Study 101HEMB01 is a Phase I/II, open-label, single-arm, multicenter, dose-finding safety 
study to determine the safety, tolerability, and efficacy of DTX101 in adult males with 
moderate/severe to severe hemophilia B. The primary objectives of the study are to 
determine the safety of single ascending IV doses of DTX101 and to identify the optimal 
biological dose (OBD) of DTX101 that either achieves or is the closest to achieving the 
target peak FIX activity of ≥20% of normal. 
Eligible subjects will receive a single IV infusion of DTX101. A minimum of 3 subjects will 
be enrolled per cohort. Subjects within a cohort will be dosed at a minimum of 1 week apart. 
Dose escalation will be conducted according to a model that uses both safety and efficacy 
data to predict the OBD (Section 10.5.1).  
A Data Safety Monitoring Committee (DSMC) will meet after each dosing cohort to review 
subject safety (eg, AEs, physical examination findings, vital sign measurements, 
electrocardiogram [ECG] results, and clinical laboratory assessments including assessment of 
liver function) and provide their recommendation for progressing to the next dosing level 
(Section 9.3).  
Subjects will be followed for 52 weeks after dosing. After completion of this study, subjects 
will be offered enrollment in an extension study to evaluate the long-term safety and effect of 
DTX101 on clinical outcome measures.  
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1.3.2 
Dosing Rationale 
The nonclinical pharmacology of a single IV dose of DTX101 in FIX knockout and 
wild-type mice demonstrated selective distribution to the liver, effective gene expression, and 
predictable dose-related increases in FIX associated with expected physiological changes in 
the biomarkers of the intrinsic clotting cascade. 
The nonclinical findings with DTX101 and research of peer-reviewed literature on the  effect 
of FIX transgene expression in humans provides supports that DTX101 administered as a 
single IV dose to patients with moderate/severe to severe hemophilia B will promote the 
normal coagulation process and thereby, reduce the total number of annual bleeding episodes 
associated with the disease. Reduced bleeding frequency will also have a positive impact on 
secondary effects, such as joint damage. The clinical dosing rationale selects doses expected 
to provide maximal therapeutic benefit, with minimal risk to subject safety. 
Based on the formal DTX101 minimal effective dose (MED) study (Study DTX150226; refer 
to Section 4.2.1.3 of the Investigator’s Brochure [IB]), the MED of DTX101 in FIX knockout 
mice falls between 1.6 × 1010 to 5.0 × 1010 genome copies (GC)/kg, which produces between 
4% and 34% of normal FIX levels, respectively. Previous nonclinical studies have estimated 
that a 10-fold higher dose of AAV vector is required in nonhuman primates to achieve similar 
expression levels as compared to mice (refer to Section 2.2 of the IB), however transduction 
rates of human hepatocytes are thought to be even lower. The most similar nonhuman 
primate to human comparison that is available for clade E AAV liver-directed gene therapy 
for hemophilia B is with scAAV8-FIX, a closely related vector to DTX101, and suggests that 
transduction and expression in humans is significantly lower than in nonhuman primates. 
In nonclinical studies by Nathwani et al, rhesus macaques inoculated with scAAV8-FIX at a 
dose of 2.0 × 1011 GC/kg expressed a peak of 35% to 40% of normal FIX levels in serum by 
Day 15 [Nathwani 2011b]. It must be noted that later correction of dosage methods suggested 
these animals actually received a dose of 2.0 × 1012 GC/kg [Nathwani 2011a]. In comparison, 
when administered to human patients in a Phase I dose-escalation clinical trial, 
2.0 × 1012 GC/kg resulted in sustained average levels of only 5.1±1.7% of normal FIX 
activity [Nathwani 2011a; Nathwani 2014]. Based on the corrected dosing, this represents 
approximately a 10-fold difference in transduction and expression levels between nonhuman 
primates and humans. 
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When considering a clinical dosing rationale, in light of the available comparison data 
between mice, nonhuman primates and humans, it seems reasonable to consider a 100-fold 
increase in dose from mice to humans to achieve similar target levels of FIX. Therefore, the 
proposed MED range for human dosing with a target peak expression level of 20% would fall 
between 1.6 × 1012 and 5.0 × 1012 GC/kg. The proposed initial clinical dose of DTX101 is 
1.6 × 1012 GC/kg, 100-fold above the lower end of the MED range in the mouse. Dose 
escalation would follow at either 3.0 × 1012 GC/kg or 5.0 × 1012 GC/kg. The final dose, 
1.0 × 1013 GC/kg, is consistent with a half log increase over the upper end of the proposed 
human MED range. 
A starting dose of 1.6 × 1012 GC/kg has a safety margin of 3-fold versus the no observed 
adverse effect level (NOAEL) determined in the formal GLP toxicology study (Study 2371-
002; refer to section Section 4.4.1.2 of the IB). The primary safety finding from this study 
was the prolongation of aPTT times that correlated with supraphysiological FIX expression 
and activity levels. The highest dose tested, 5.0 × 1013 GC/kg, resulted in a peak average 
prolongation of aPTT of 63% at Day 15. This prolongation began to resolve by Day 29, 
being 43% at Day 29 and 15% by Day 90. Mice in this dose group (5.0 × 1013GC/kg) were 
expressing supraphysiological levels of FIX at more than 2500% of normal. 
Although prolongation of aPTT was present, these animals exhibited no related clinical signs 
or complications. Lower doses of DTX101 resulted in minimal to moderate increases of 
aPTT that were often not statistically significant.  
Unlike wild-type mice, FIX knockout mice dosed at 1.35 × 1014 GC/kg demonstrated a 
reduction in aPTT time from 74.3 seconds (average for FIX knockout mice) to 45 seconds 
(below the control group average of 50 seconds), likely due to the absence of endogenous 
FIX at baseline in the knockout mice (Study W2234; refer to Section 4.4.1.1 of the IB). This 
finding in the FIX knockout mouse, a model used to explore the human condition, is 
expected to more closely represent the clinical outcome in the target patient population of 
moderate/severe to severe hemophilia B patients. It is believed to be unlikely that the 
proposed starting clinical dose of 1.6 × 1012 GC/kg in a patient with moderate/severe to 
severe hemophilia B would achieve supraphysiological levels of over 2500% normal FIX 
expression. Therefore, it is not likely that associated prolongation of aPTT, as a direct result 
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of marked supraphysiological levels of FIX, will occur in the target population at the starting 
dose proposed. 
The second and third dose candidates in this study have approximately a 1.7-fold and 1.0-
fold safety margin, respectively. The fourth and final candidate dose in the study is 
1.0 × 1013 GC/kg (Table 1–1). 
Table 1–1 
Predicted Total Vector Titer of DTX101 Following IV Infusion and 
Exposure Margins to a Nonclinical GLP Toxicology Study 
Candidate Dosing Levels 
DTX101 Dose 
(GC/kg) 
Safety Margina 
Dose 1 
1.6 × 1012 
3.1 
Dose 2 
3.0 × 1012 
1.7 
Dose 3 
5.0 × 1012 
1 
Dose 4 
1.0 × 1013 
– 
Abbreviations: GC, genome copies; GLP, Good Laboratory Practice; IV, intravenous. 
a. 
Mouse no observed adverse effect level of 5.0 × 1012 GC/kg / Human DTX101 dose. 
Taking into consideration the nonclinical pharmacology of DTX101 in knockout mice and 
the NOAEL combined with the known differential efficiency of transgene uptake and 
expression between animals and humans, the proposed initial starting dose for DTX101 of 
1.6 × 1012 GC/kg is assessed to offer an acceptable balance between safety and the potential 
for clinically meaningful FIX expression in moderately/severe and severe hemophilia B 
patients. 
It has been hypothesized that the AEs of elevated liver function tests (LFTs) experienced to 
date in other clinical studies using AAV8-derived vectors were due to the total capsid protein 
load administered to subjects [Mingozzi 2011; Nathwani 2011a; Nathwani 2014]. Based on 
the manufacturing process used to prepare DTX101, it is estimated that >50% of the 
DTX101 study product will contain full particles (ie, particles that contain the FIX 
transgene). This reduces the total particle dose that each subject is exposed to with each 
increase in dose (Table 1–1). In a previous study with AAV8, a transient rise in ALT was 
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elicited at the highest dose tested, 2.0 × 1012 GC/kg, which is approximately 
2.0 × 1013 particles/mL and contains 10% full particles [Nathwani 2011a; Nathwani 2014].  
Because dosing is based on genome copies, the total particle amount (full capsids + empty 
capsids) for Dose 1 to Dose 3 is estimated to be lower than the total AAV8 particle amount 
used in other studies. The total particle amount at the highest dose of DTX101 
(1.0 × 1013 GC/kg) is estimated to be similar or slightly lower than the total AAV8 particle 
amount previously studied [Nathwani 2011a; Nathwani 2014]. It is expected that the higher 
ratio of full to empty capsids may decrease or possibly eliminate the AE of elevated LFTs 
observed in other gene therapy programs and increase the benefit-to-risk ratio for subjects 
participating in this study. 
For additional nonclinical information, please refer to the DTX101 IB. 
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2 
Study Objectives and Endpoints 
Objective 
Endpoint 
Primary 
To determine the safety of single ascending 
intravenous (IV) doses of DTX101 in adults with 
moderate/severe to severe hemophilia B. 
The incidence of adverse events (AEs), 
treatment-emergent adverse events (TEAEs), and 
serious AEs will be summarized for each dosing 
cohort by severity and relationship to study 
product. 
To establish a dose of DTX101 that achieves a 
peak plasma level of vector-derived factor IX 
(FIX) at 6 weeks after IV administration to allow 
further clinical development. 
The change from baseline in FIX activity at 
Week 6 as determined by the activated partial 
thromboplastin time (aPTT) clot-based assay. 
Secondary 
To assess the impact of DTX101 on the number 
of bleeding episodes requiring recombinant FIX 
infusion during the study. 
The annualized bleeding rate (ABR) will be 
calculated for all subjects through Week 52 
(±7 days). 
To evaluate the kinetics, duration, and magnitude 
of plasma FIX activity, by dose, after IV 
administration of DTX101 in adults with 
hemophilia B. 
The time course of FIX activity, as determined 
by aPTT, will be summarized by time point and 
dose level of DTX101. 
To assess the impact of DTX101 on the 
frequency of FIX replacement therapy during the 
study. 
The annualized and average weekly use of FIX 
replacement therapy will be calculated for all 
subjects through Week 52 (±7 days). 
To describe the immune response to the FIX 
transgene after IV administration of DTX101. 
• 
The development of neutralizing antibodies 
to FIX (FIX inhibitor), as determined by a 
Bethesda assay, will be summarized by time 
point and dose level of DTX101. 
• 
The development of a cell-mediated immune 
response to FIX, as determined by ELISPOT 
assay, will be summarized by time point and 
dose level of DTX101. 
To assess the impact of DTX101 on the subject’s 
quality of life 
Responses to the EQ-5D-5L and Haem-A-QoL 
questionnaires will be summarized. 
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Objective 
Endpoint 
Exploratory 
To describe the immune response to AAVrh10 
capsid proteins after IV administration of 
DTX101. 
• 
The development of neutralizing antibodies 
to AAVrh10, as determined by ELISA, will 
be summarized by time point and dose level 
of DTX101. 
• 
The development of a cell-mediated immune 
response to AAVrh10, as determined by 
ELISPOT assay, will be summarized by time 
point and dose level of DTX101. 
• 
The development of anti-AAVrh10 binding 
antibodies, as determined by ELISA, will be 
summarized by time point and dose level of 
DTX101. 
Abbreviations: AAVrh10, adeno-associated virus serotype rh10; ABR, annualized bleeding rate; 
ELISA, enzyme-linked immunosorbent assay; ELISPOT, enzyme-linked immunospot; EQ-5D-5L, 
EuroQoL 5D 5 level; Haem-A-QoL, haemophilia-specific quality of life. 
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3 
Investigational Plan 
3.1 
Study Overview 
Study 101HEMEB01 is a Phase I/II, open-label, single-arm, multicenter, dose-finding safety 
study to determine the safety, tolerability, and efficacy of DTX101 in adults with 
moderate/severe to severe hemophilia B. The primary objectives of the study are to 
determine the safety of single ascending IV doses of DTX101 and to identify the OBD of 
DTX101 that either achieves or is the closest to achieving the target peak FIX activity of 
≥20% of normal. 
Eligible subjects will receive a single IV infusion of DTX101. Subjects will be dosed 
sequentially in cohorts with a minimum of 3 subjects each. Dose escalation will be conducted 
according to a model that uses safety and efficacy data to predict the OBD (Section 10.5.1).  
The following candidate doses (per kg of body weight) will be used to identify the OBD: 
• Dose 1: 1.6 × 1012 GC/kg 
• Dose 2: 3.0 × 1012 GC/kg 
• Dose 3: 5.0 × 1012 GC/kg 
• Dose 4: 1.0 × 1013 GC/kg 
There will be a minimum of 7 days between dosing of each subject within a cohort and a 
minimum of 42 days between the dosing of the last subject in one dosing cohort and the first 
subject in the next dosing cohort. The recommendation to proceed to the next dose cohort 
will be made by the DSMC (Section 9.3) after evaluation of the safety data for all subjects in 
a dosing cohort after they have completed Week 6, as outlined in the DSMC charter. There 
will be no intra cohort dose escalations. 
Study enrollment will be suspended if any of the safety stopping criteria are met 
(Section 3.2.4). 
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Subjects will be followed for 52 weeks after dosing. After completion of this study, subjects 
will be offered enrollment in an extension study to evaluate the long-term safety and effect of 
DTX101 on clinical outcome measures. 
3.2 
Overall Study Duration and Follow-Up 
The duration of the study is defined for each subject as the date written informed consent is 
provided through the visit at Week 52. Subjects will be in the study for approximately 
56 weeks (including the screening period). 
The study is anticipated to enroll approximately 12 to 18 subjects at up to 14 sites globally.  
Subjects will be asked to visit the study site a total of approximately 30 times; however, if a 
subject cannot visit the site for every visit, they may be visited at home through Week 12 for 
sample collection (ie, clinical chemistry and viral shedding). All study visits, clinic or home 
visits, and the timing of assessments are detailed in Table 15–1 and Table 15–2.  
A schematic of the study design is provided in Figure 3–1. 
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Figure 3–1 
Study Design 
 
Abbreviations: DSMC, Data Safety Monitoring Committee; FIX, factor IX; IV, intravenous. 
3.2.1 
Screening Period 
After a subject has provided written informed consent, and within 30 days before DTX101 
infusion (Day 0), the investigator or other qualified study personnel will determine if the 
subject is eligible for the study. This will be accomplished by reviewing the inclusion and 
exclusion criteria and completing all of the screening assessments outlined in the Schedule of 
Events (Table 15–1). The screening assessments may be performed on more than 1 day, 
provided that all of the assessments are completed and the results are available within the 
30-day screening window and prior to Day 0. 
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3.2.2 
Treatment Period 
Subjects will be admitted for DTX101 administration and for continuous safety monitoring 
(Section 8.2). Subjects will be discharged 24 hours after completion of the infusion. 
On Day 0, subjects will be provided a paper or an electronic diary (eDiary), depending on 
availability, to record bleeding episodes and use of recombinant FIX replacement therapy 
during the study. The diary will be reviewed with the subject at each visit. 
Subjects will be asked to visit the clinic every 4 days through Week 12. Following the 
Week 12 visit, subjects will visit the study site once every 4 weeks through Week 52 or early 
withdrawal from the study. 
Subjects will be asked to provide clinical laboratory samples approximately every 4 days 
through Week 12 of the study. If subjects cannot visit the study site in person, subjects can be 
seen by clinically trained and qualified personnel approximately every 4 days at their home 
through Week 12, the exception being those weeks when a site visit is scheduled, to collect a 
clinical laboratory sample to monitor LFTs. Saliva, urine, and stool samples will also be 
collected for assessment of viral shedding on Days 8, 20, 36, 48, 64, and 76. These samples 
will continue to be collected until 3 consecutive negative results are obtained from each 
sample matrix (Table 15–2). 
3.2.3 
Prophylactic Factor IX Washout Periods 
3.2.3.1 
Screening Period 
If the subject does not have a documented history of FIX activity, a blood sample will be 
needed to confirm the severity of hemophilia B for inclusion (Section 4.1) after washout of 
recombinant FIX (Figure 3–2). For subjects taking long-acting recombinant FIX 
prophylactically to prevent bleeding episodes, the washout period is to start at approximately 
Day –29 and last for 21 days (approximately Day –8). For subjects taking traditional 
recombinant FIX prophylactically to prevent bleeding episodes, the washout period is to start 
at approximately Day –29 and last for 7 days (approximately Day –22). The blood sample 
must be obtained and results available prior to dosing on Day 0. Subjects can then transition 
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back onto their prophylactic regimen until the washout period during the treatment period 
(prior to Week 6) is to begin (Section 3.2.3.2). 
NOTE: This washout period is not needed for subjects with a documented history of FIX 
activity. 
Figure 3–2 
Recombinant FIX Washout During the Screening Period 
 
Abbreviations: FIX, factor IX. 
a. 
Washout required for subjects that do not have a documented history of FIX activity to meet eligibility 
criterion (ie, ≤2% of normal). 
b. Following assessment of FIX activity, subjects can transition back on to their prophylactic regimen until the 
protocol mandated washout period prior to the Week 6 assessment of FIX activity. 
3.2.3.2 
Treatment Period 
In order to accurately assess vector-derived FIX activity as a result of DTX101 infusion, 
subjects will stop taking FIX prophylactically prior to the assessment of peak FIX activity at 
Week 6 and transition to an on-demand regimen for the remainder of the study. Subjects 
prophylactically using traditional recombinant FIX will be asked to begin the washout period 
starting at Week 5. Due to the longer half-life, subjects prophylactically taking long-acting 
recombinant FIX (eg, Alprolix) will be asked to begin the washout period starting at Week 3 
(Figure 3–3).  
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If, at any time during the study, a subject experiences bleeding episodes frequent enough to 
consider prophylactic treatment, the investigator will discuss treatment options with the 
medical monitor. If a subject resumes prophylactic FIX replacement therapy, as rescue 
treatment after Week 6, additional washout periods prior to Week 24 and Week 52 will also 
be performed. Subjects prophylactically using traditional recombinant FIX will be asked to 
begin the washout period starting at Week 23 and Week 51. Due to the longer half-life, 
subjects taking long-acting recombinant FIX (eg, Alprolix) will be asked to begin the 
washout period starting at Week 21 and Week 49 (Figure 3–3). 
Figure 3–3 
Recombinant FIX Washout During the Treatment Period 
 
Abbreviations: FIX, factor IX. 
a. 
Following washout, subjects will be transitioned to an on-demand regimen for the remainder of the study. 
b. Washout needed if, at any time during the study after Week 6, a subject experiences bleeding episodes 
frequent enough to consider re-initiating prophylactic treatment. 
The on-demand use of recombinant FIX is not prohibited and may be used at any time during 
the study. Subjects will be asked to record this use as outlined in Section 8.1.3. 
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3.2.4 
Safety Stopping Criteria 
Enrollment will be suspended and the study will be discussed with regulators if, at any time 
during the study, any of the following occur: 
• Death of a subject, at any time, that is considered related to DTX101 by the 
investigator, 
• Fivefold increase in baseline (predose, Day 0) ALT within 8 weeks after vector 
infusion that is considered related to DTX101 by the investigator, 
• Grade 2 toxicity develops that persists for more than 7 days and is considered related 
to DTX101 by the investigator, 
• At least Grade 3 toxicity develops, including an infusion-related reaction ≥Grade 3, 
that is considered related to DTX101 by the investigator, or 
• Occurrence of a malignancy, at any point after administration of vector, that is 
considered related to DTX101 by the investigator. 
Abnormal clinically significant laboratory values (hematology, coagulation panel, and 
clinical chemistry) as assessed by the investigator will be considered AEs. Laboratory values 
that meet any of the above criteria will result in the suspension of the study. 
Any event that meets the above criteria will be reported immediately as outlined in 
Section 9.1.2.2, and the appropriate pages of the electronic case report form (eCRF) must be 
completed. Enrollment and dosing will be temporarily suspended until the situation can be 
assessed and risks to subjects mitigated. If study enrollment is suspended, all subjects who 
have been enrolled will remain in the study and will continue to be monitored through their 
completion or withdrawal from the study. 
3.2.5 
End of Study 
Subjects who complete all visits up to and including the Week 52 visit will have completed 
the study. Subjects who discontinue early will be asked to return for an Early Withdrawal 
visit. Subjects with any on-going AEs at this visit will continue to be monitored as outlined in 
Section 9.1.5. After completion of this study, subjects will be offered enrollment in an 
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extension study to evaluate the long-term safety and effect of DTX101 on clinical outcome 
measures. 
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4 
Subject Selection 
Subjects will be assigned to study treatment only if they meet all of the inclusion criteria and 
none of the exclusion criteria. 
4.1 
Inclusion Criteria 
Each subject must meet all of the following criteria at screening to be enrolled in this study: 
1. Male ≥18 years of age. 
2. Moderate/severe or severe hemophilia B (baseline FIX activity ≤2% of normal or 
documented history of FIX activity ≤2%).  
3. At least 3 bleeding episodes per year that require on-demand treatment with FIX OR 
are treated with a prophylactic regimen of FIX. 
4. At least 100 days exposure history to FIX. 
5. No documented history of inhibitors (neutralizing antibodies) to exogenous FIX.  
6. No known allergic reaction to exogenous FIX or any component of DTX101. 
7. Willing to stop prophylactic treatment with recombinant FIX at specified time points 
during the study. 
8. Willing and able to provide written informed consent. 
9. Willing and able to comply with study procedures and requirements. 
10. Willing to use effective contraception at the time of administration of DTX101 and for 
3 months following administration of DTX101. Appropriate contraceptive methods 
include a condom with spermicide. Abstinence, defined as sexual inactivity, is an 
acceptable form of birth control; however, appropriate contraception must be used if 
the subject becomes sexually active. 
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4.2 
Exclusion Criteria 
Subjects who meet any of the following criteria at screening will be excluded from the study: 
1. History of liver disease as evidenced by any of the following: portal hypertension, 
ascites, splenomegaly, esophageal varices, hepatic encephalopathy, or a liver biopsy 
with evidence of stage 3 fibrosis. 
2. Significant hepatic inflammation or cirrhosis as evidenced by any of the following: 
aspartate aminotransferase (AST) or ALT >2.0 × upper limit of normal (ULN), total 
bilirubin >1.5 × ULN, alkaline phosphatase (ALP) >2.5 × ULN, platelet count 
<75,000 cells/µL, and prothrombin time (PT) or international normalized ratio (INR) 
>1.5 × ULN. 
3. Evidence of active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, 
documented by current use of antiviral therapy for HBV or HCV or by hepatitis B 
surface antigen (HBsAg) or HCV RNA positivity. NOTE: Two negative viral assays 
by polymerase chain reaction (PCR), collected at least 6 months apart, will be required 
to be considered negative for HCV. Subjects can be rescreened once if they have one 
negative sample and must wait to have the second sample collected within the 
following 6 months. 
4. History of human immunodeficiency virus (HIV) infection AND any of the following: 
CD4+ cell count <350 cells/mm3, change in antiretroviral therapy regimen within 
6 months prior to Day 0, or plasma viral load >200 copies/mL, on 2 separate 
occasions, as measured by PCR. 
5. Anti-AAVrh10 neutralizing antibody titer >1:5. 
6. Participation (current or previous) in another gene therapy study. 
7. Participation in another investigational medicine study within 3 months before 
screening.  
8. History of a malignancy for which the subject has received treatment in the past 
2 years except for prostate cancer treated with watchful waiting or surgically removed 
non-melanoma skin cancer. 
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9. Has any other significant medical condition that the investigator feels would be a risk 
to the subject or would impede the study. 
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5 
Screening and Randomization Procedures 
5.1 
Subject Screening 
All potential subjects will sign an informed consent form (ICF) before any study procedures 
or the washout period (if needed) are performed or initiated (Section 11.3). Subjects will 
have the opportunity to have any questions answered before signing the ICF. All questions 
raised by the subject must be addressed before the investigator also signs the ICF. A copy of 
the signed consent will be given to the subject. 
Subjects can be rescreened once if they have 1 negative HCV viral assay by PCR at the time 
of screening and must wait 6 months for receipt of the second sample result. NOTE: To be 
eligible to participate in the trial, subjects must have 2 negative HCV viral assays by PCR at 
least 6 months apart. 
Sites will maintain documentation of all potential subjects screened for inclusion in the study. 
If a subject is excluded from the study, the reasons for exclusion will be documented in the 
subject's source documents and on the screening log. 
5.2 
Subject Randomization 
This is an open-label study; subjects will be enrolled sequentially into cohorts of a minimum 
of 3 subjects each as described in Section 3.1.  
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6 
Study Treatment 
6.1 
Identity of Study Product 
6.1.1 
Description of DTX101 
DTX101 is a replication defective, recombinant AAV vector of the rh10 serotype. It is a 
thermally stable recombinant parvovirus [Rayaprolu 2013]. DTX101 is supplied in a 
hyperosmotic buffered formulation solution of approximately 400 milliosmole and at pH 8.0. 
DTX101 is a homogeneous, monodisperse solution that is clear and colorless without visible 
particulates. 
6.1.2 
Components Used for Manufacturing 
DTX101 will be produced by triple plasmid DNA transfection of human embryonic kidney 
293 (HEK293) master cell bank cells with the following:  
• The pDTX.hFIX.101 vector plasmid; 
• An AAV helper plasmid termed pAAV2.rh10.KanR containing the AAV rep2 and cap 
AAVrh10 wild-type genes; and 
• A helper adenovirus plasmid termed pAdDeltaF6(Kan). 
The size of the DTX101 packaged vector genome is 3972 nucleotides. For additional 
information, please refer to the DTX101 Investigator’s Brochure. 
6.2 
Management of Clinical Supplies 
6.2.1 
Packaging and Labeling 
One (1) mL of study product will be provided to study sites frozen in 2 mL sterile glass vials 
with a primary label on the vial. Study product will have secondary packaging with a 
secondary label. The primary label meets all requirements for blister and small packaging 
units and will contain a unique identifier. The secondary label will contain required text for 
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all countries participating in the study and will also contain a unique identifier. Secondary 
labeling will appear in the appropriate language for the country supplied. 
6.2.2 
Storage of DTX101 
DTX101 must be stored in a secure freezer at a controlled temperature ≤–60°C. The site is to 
maintain a daily log documenting the temperature. 
6.2.3 
Study Product Accountability 
The investigator or designated personnel will maintain accurate records of receipt of all study 
product, including dates of receipt. In addition, accurate records will be kept regarding when 
and how much study product is dispensed and used by each subject in the study. Reasons for 
departure from the expected dispensing regimen must also be recorded. At the completion of 
the study, all study product will be reconciled and retained or destroyed according to 
instructions provided by the sponsor. 
6.2.4 
Transmission of Infectious Agents 
Recombinant AAV vectors are non-replicative and are not expected to pose a risk of 
transmission. However, all sexually active male subjects must use approved contraception 
from the time of dosing and for 3 months following. The study product and post-treatment 
study samples should be handled using standard universal precautions. 
6.3 
Treatment Schedule and Administration 
Subjects will receive a single peripheral IV infusion of DTX101, administered by qualified 
study personnel as designated by the investigator. The dose will be determined by the cohort 
and candidate dose (Section 3.1). 
The dose of DTX101 to be administered will be calculated using the subject’s weight 
recorded at screening. The subject’s weight will be verified prior to administration of 
DTX101 to ensure that their current weight is within 10% of their screening weight. Prior to 
infusion, all infusion bag labels will be checked by the site pharmacist and a minimum of 
2 medical personnel charged with administration of DTX101. 
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The study site must be equipped with emergency resuscitation capabilities. The subject will 
be admitted on the day of infusion (Day 0). An IV catheter will be inserted into a peripheral 
vein and flushed with saline. Recombinant FIX treatment is not needed as venipuncture is a 
minimally invasive procedure. 
Detailed instructions for dose preparation and subsequent infusion of DTX101 are provided 
in the pharmacy manual. 
6.3.1 
Treatment Compliance 
DTX101 will be administered at the infusion center via a single IV infusion administered by 
qualified personnel. The dose, start time, stop time, and volume of infusion will be recorded 
in the subject’s eCRF. 
6.4 
Prior and Concomitant Therapy 
Use of all prior and concomitant medications will be recorded in the subject’s eCRF. The 
minimum requirement is that the drug name, the dates of administration, and the reason for 
use are to be recorded. This will include all prescription drugs, herbal products, vitamins, 
minerals, and over-the-counter (OTC) medications. Any changes in concomitant medication 
use will also be recorded in the subject’s eCRF. 
6.4.1 
Permitted Medications 
The use of permitted medications (date, dosage, reason for therapy) will be recorded on the 
relevant page of the eCRF. 
6.4.1.1 
Medications for the Treatment of Hemophilia B 
• On-demand recombinant FIX replacement therapy, as needed; 
• Standard supportive care medications for the treatment of symptoms associated with a 
bleeding episode. 
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6.4.1.2 
Other Medications 
If a subject starts a new medication, including OTC medications and herbal supplements, it 
should be discussed with the investigator. 
Any concomitant medication deemed necessary for the welfare of the subject during the 
study may be given. It is the responsibility of the investigator to ensure that details regarding 
the medication are recorded in full in the eCRF. 
6.4.2 
Prohibited Medications 
Use of any of the following medications is prohibited, unless the investigator feels these 
medications are medically indicated. If medically indicated, the use of prohibited 
medications (date, dosage, reason for therapy) will be recorded on the relevant page of the 
eCRF: 
• Acetylsalicylic acid or nonsteroidal anti-inflammatory drugs; 
• Another investigational product to treat hemophilia B; 
• Another gene therapy product; 
• Any other medication currently under investigation; or 
• Immunosuppressive agents except steroids. 
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7 
Withdrawal of Subjects From the Study 
7.1 
Study Withdrawal 
Subjects may withdraw from the study at any time and for any reason without prejudice to 
their future medical care by the investigator or at the study site. Any subject who withdraws 
consent to participate in the study will be removed from further treatment and/or study 
observation immediately upon the date of request. 
The investigator must record the reason for withdrawal on the relevant page of the eCRF. The 
reason for withdrawal may include the following:  
1. Withdrawal of consent 
2. Administrative decision by the investigator or the sponsor 
3. Ineligibility 
4. Significant protocol deviation 
5. Subject noncompliance 
6. Adverse event 
If a subject is withdrawn due to an AE, the investigator will arrange for the subject to have 
follow-up visits until the AE has resolved or stabilized (Section 9.1.5).  
If a subject requests or decides to withdraw from the study, all efforts will be made to 
complete and report the observations as thoroughly as possible up to the date of withdrawal, 
and an early withdrawal visit will be performed. 
7.2 
Subject Replacement 
If a subject withdraws from the study after receiving DTX101, the subject will not be 
replaced. Subjects who withdraw from the study after signing the ICF, but before receiving 
DTX101, will be replaced and the replacement subject will be sequentially assigned to 
treatment with a new subject identification number. 
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8 
Study Assessments and Procedures 
8.1 
Efficacy and Pharmacodynamic Assessments 
Planned time points for all efficacy and pharmacodynamic measurements in the study are 
listed in Table 15–1. Efficacy will be assessed based on the change from baseline in FIX 
activity, the number of bleeding episodes, and the dosing requirements for FIX replacement 
therapy. 
8.1.1 
Factor IX Activity 
The change from baseline in FIX activity at Week 6 and at additional time points throughout 
the study will be assessed. Factor IX activity will be determined using an aPTT clot-based 
assay. Planned time points for the assessment of FIX activity are listed in Table 15–1. Details 
for the preparation and shipment of samples are included in the laboratory manual. 
8.1.2 
Bleeding Episodes 
Bleeding episodes will be recorded in a paper or eDiary and will include: the start/stop date, 
the location of the bleed (joint, muscle, skin/mucosa, or internal), and the type of bleed 
(spontaneous or traumatic). The start date of a bleeding episode is defined as the first onset of 
symptoms of a bleed. The stop date of a bleeding episode is defined as 72 hours after the last 
on-demand treatment for a bleed, during which no additional bleeding episodes were noted in 
that location. If a bleeding event occurs in the same location within 72 hours of on-demand 
therapy, it will be considered part of the same episode. The site will review the diary with the 
subject at each clinic visit and record bleeding episodes on the appropriate page of the eCRF. 
Any event considered an AE should be recorded on the appropriate page of the eCRF 
(Section 9.1.2). 
The annualized number of bleeds per subject, per location, and by type of bleed will be 
calculated for all subjects through Week 52 (±7 days).  
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8.1.3 
Factor IX Replacement Therapy 
The use of on-demand FIX replacement therapy will be recorded in a paper or eDiary and 
will include: the date(s) and dose (IU/kg) administered. The site will review the diary with 
the subject at each clinic visit and record the use of FIX replacement therapy on the 
appropriate page of the eCRF.  
The annualized and average weekly use of FIX replacement therapy will be calculated for all 
subjects through Week 52 (±7 days).  
8.1.4 
Quality-of-Life Assessments 
8.1.4.1 
EuroQol 5D 5 Level Questionnaire 
Subjects will be asked to complete the EuroQol 5D 5 level (EQ-5D-5L) questionnaire 
(Appendix 15.2.1) on Day 0 (predose) and then at Weeks 24, 36, 48, and 52 during the study 
(Table 15–1). If the subject is provided an eDiary, this questionnaire will be preloaded onto 
the device. If either the eDiary or a validated translation for the eDiary is not available, the 
subject will be provided with a paper form to complete.  
This questionnaire consists of 2 pages: the EQ-5D™ (EuroQol, Rotterdam, The Netherlands) 
descriptive system and the EQ visual analogue scale (EQ-VAS). The descriptive system is 
based on 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety 
depression. Each dimension has the following 5 levels: no problems, slight problems, 
moderate problems, severe problems, and extreme problems. The EQ-VAS will record the 
subject’s self-rated health on a vertical visual analogue scale. The results will be transmitted 
for analysis following completion of the Week 52 visit. 
8.1.4.2 
Haemophilia-Specific Quality of Life Questionnaire 
Subjects will be asked to complete the Haem-A-QoL questionnaire (Appendix 15.2.2) on 
Day 0 (predose) and then at Weeks 24, 36, 48, and 52 during the study (Table 15–1). If the 
subject is provided an eDiary, this questionnaire will be preloaded onto the device. If either 
the eDiary or a validated translation for the eDiary is not available, the subject will be 
provided with a paper form to complete.  
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This questionnaire asks subjects about their perceptions of their health and treatment. The 
questionnaire is divided into the following 10 dimensions: physical health, feelings, view of 
themselves, sports & leisure, work & school, dealing with hemophilia, treatment, future, 
family planning, and partnership & sexuality. Questions are based on a 5-point Likert-scale 
(1=never, 2=rarely, 3=sometimes, 4=often, 5=all the time). If the question does not apply to 
the subject, the “not applicable” response is allowed in 3 of the domains (sport & leisure, 
work & school, family planning). Positively worded items need to be re-coded and domains 
will be transformed ranging from 0 to 100; higher domain and total scores indicating a higher 
impairment of health-related QoL. The results will be transmitted for analysis following 
completion of the Week 52 visit. 
8.2 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedules of Events 
(Table 15–1 and Table 15–2). 
Safety will be assessed based on AEs, serious adverse events (SAEs), complete and targeted 
physical examination findings (including weight), vital sign measurements, ECG results, 
clinical laboratory assessments (hematology, clinical chemistry, coagulation panel, and 
urinalysis), viral shedding, measurement of neutralizing antibody titer to AAVrh10, 
measurement of AAVrh10 binding antibodies, measurement of FIX inhibitor, and assessment 
of any cell-mediated immune responses to AAVrh10 and FIX. 
8.2.1 
Demographic, Medical, and Hemophilia B History Assessments 
As allowed by local laws and regulations, the following demographic data will be captured 
on the appropriate page of the eCRF: date of birth, sex, race, and ethnicity. 
Medical, medication, and hemophilia B history will be assessed as related to the eligibility 
criteria listed in Section 4.1 and Section 4.2. 
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8.2.2 
Physical Examination 
A complete physical examination will include assessments of the head, eyes, ears, nose, and 
throat; skin; and the endocrine metabolic, neurological, respiratory, cardiovascular, 
gastrointestinal, and musculoskeletal systems. 
A targeted physical examination will include assessment of the skin and the respiratory, 
cardiovascular, and gastrointestinal systems. 
Physical examination findings will be captured on the appropriate page of the eCRF. 
8.2.3 
Vital Sign Measurements 
During the study, vital sign measurements are to be collected before any stimulating or 
anxiety-provoking procedures (eg, phlebotomy). Vital sign measurements will include heart 
rate, blood pressure (systolic and diastolic), and respiratory rate. Height (at the screening visit 
only) and weight will also be recorded. 
• Vital signs should be measured with the subject in a semi-supine or supine position, 
having rested in this position for at least 5 minutes beforehand. It is preferred that the 
measurement be late with the subject rested, rather than on-time with the subject not 
sufficiently rested. If the subject is not sufficiently rested, this needs to be stated in 
the source documents. 
• On Day 0, vital signs will be measured at predose, 5 minutes, and 0.5, 1, 2, 4, 6, and 
8 hours after the start of infusion (±5 minutes). Vital signs will also be measured at 
22 hours (±1 hour) after the start of infusion, prior to subject discharge. 
• Blood pressure and heart rate will be recorded in triplicate before dosing, with 
measurements taken at least 2 minutes apart. 
• It is acceptable for heart rate to be captured from the 12-lead ECG. 
• On Day 0, weight will be measured prior to dosing with DTX101 to ensure that the 
weight is within 10% of the screening weight used to calculate the dose of DTX101. 
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Vital sign measurements will be recorded on the appropriate page of the eCRF. The medical 
monitor should be notified of any clinically significant changes or abnormal value in vital 
sign measurements (Section 9.1.2).  
8.2.4 
Electrocardiograms 
• Three ECG measurements will be taken before dosing, at least 5 minutes apart. The 
PR interval, QRS duration, QT interval, and QTcF (QT interval corrected by 
Fridericia’s formula) will be obtained from automated ECG readings. The mean value 
obtained before dosing on Day 0 will be classified as baseline; 
• A single 12-lead ECG will be obtained at 1 hour after the start of infusion and at 
Week 52, using an ECG machine that automatically calculates the heart rate and 
measures PR, QRS, QT, and QTc intervals.  
Twelve-lead ECGs should be measured with the subject in a semi-supine or supine position, 
having rested in this position for at least 5 minutes beforehand. It is preferred that the 
measurement be late with the subject rested, rather than on-time with the subject not 
sufficiently rested. If the subject is not sufficiently rested, this needs to be stated in the source 
documents. Electrocardiogram results will be recorded on the appropriate page of the eCRF. 
8.2.5 
Clinical Laboratory Analyses 
Laboratory tests, including ALT and coagulation panel, will be closely monitored throughout 
the duration of the study. Investigators will receive flagged notification of any laboratory 
values that are outside of the normal range. Any abnormal laboratory test results 
(hematology, coagulation panel, clinical chemistry, urinalysis, or other laboratory 
parameters), including those that worsen from baseline or are felt to be clinically significant 
in the medical and scientific judgment of the investigator, are to be recorded as AEs or SAEs 
(Section 9.1.2). 
However, any clinically significant safety assessments that are associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the subject’s 
condition, are not to be reported as AEs or SAEs. 
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All laboratory tests with results that are significantly abnormal during participation in the 
study should be repeated until the values return to normal or baseline. If such values do not 
return to normal within a period judged reasonable by the investigator, the etiology should be 
identified and the sponsor notified. 
Samples of blood, urine, saliva, and stool will be collected for study assessments. Any 
samples remaining at the end of the study may be stored for up to 15 years and analyzed to 
better understand the effect of DTX101 on hemophilia B or other related blood disorders. 
The choice to allow retention and future analysis will be optional. 
8.2.6 
Clinical Laboratory Parameters 
The clinical laboratory parameters to be measured are listed in Table 8–1. Samples are to be 
collected at the time points specified in the Schedules of Events (Table 15–1 and Table 15–2 
[clinical chemistry only]).  
Table 8–1 
Clinical Laboratory Parameters 
Clinical chemistry: 
Sodium, potassium, chloride, carbon dioxide, blood urea nitrogen, creatinine, glucose, 
calcium, phosphate, magnesium, albumin, total protein, creatine kinase, bilirubin (total 
and indirect), ALT, AST, ALP, gamma-glutamyl transferase, and lactate dehydrogenase 
Hematology: 
Complete blood count with differential 
Urinalysis: 
Specific gravity, pH, glucose, protein, blood (by dipstick), ketones (by dipstick), and 
microscopic examination (if blood or protein is found) 
Other: 
HBV surface antigen (HBsAg), HCV RNA, HIV  
Coagulation panel: 
PT/INR, fibrin degradation product (D-dimer), aPTT 
Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; aPTT, activated partial 
thromboplastin time; AST, aspartate aminotransferase; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, 
human immunodeficiency virus; PT/INR, prothrombin time/international normalized ratio. 
Details for the preparation and shipment of samples will be provided by the central 
laboratory. Reference ranges for all parameters will be provided to the study site by the 
central laboratory. 
If additional non-protocol specified laboratory assessments are performed at the site’s local 
laboratory and result in a change in subject management or the results are considered 
clinically significant by the investigator (eg, SAE, AE, or dose modification), the results must 
be captured and sent to the sponsor along with other study data as defined in Section 9.1.2. 
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A laboratory parameter may be repeated if there is any concern about the values obtained. 
Laboratory values must be repeated if ≥2-fold the ULN or ≤0.5-fold the lower limit of 
normal. 
8.2.6.1 
Elevation of Liver Function Tests 
In clinical studies with AAV-mediated gene transfer, a transient rise in liver transaminases 
and concurrent decline in transgene expression has been observed [Manno 2006; 
Nathwani 2011a; Nathwani 2014]. This has been hypothesized to be due to the activation of 
capsid-specific cytotoxic T lymphocytes (CTLs) and destruction of transduced liver cells 
[Mingozzi 2007]. However, in mice, T-cells activated against AAV capsid were not able to 
target and eliminate transduced hepatocytes [Wang 2007; Li C 2007; Li H 2007; Siders 2009] 
unless the wild-type AAV genome was present [Li C 2007].  
The inability to reproduce the observed effects in animal models has made it difficult to 
assess the validity of the hypothesis or to develop strategies to overcome or minimize 
transaminase elevations. Despite a lack of clear resolution that activation of CTLs leads to a 
reduction in transgene expression from hepatocytes, appropriate precautions have been 
incorporated into this study. In addition to monitoring for capsid and FIX-specific T-cell 
activation, the use of oral steroids is allowed if a subject experiences elevations in liver 
transaminases.  
If a subject experiences a >1.5-fold increase in LFTs following treatment with DTX101, the 
investigator should consider the initiation of steroid treatment as outlined in Section 8.2.6.2. 
The event should be recorded as an AE or SAE, as defined in Section 9.1.2, on the 
appropriate pages of the eCRF if it is felt to be clinically significant in the medical and 
scientific judgment of the investigator. 
8.2.6.2 
Treatment for Potential Immune Hepatitis 
In the absence of a specific etiology, steroid treatment for potential vector-induced immune 
hepatitis will be allowed if there is a >1.5-fold increase from baseline in the subject’s ALT 
that is considered related to treatment with DTX101 by the investigator. Within 24 hours of 
learning of the elevation, the site will repeat the test at their local laboratory and, if still 
elevated, will initiate steroid treatment. 
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The site is encouraged to consult with the medical monitor prior to initiating treatment. 
Based on available evidence, it is expected that vector-induced viral hepatitis will be 
self-limiting. Therefore, prednisone (or prednisolone) will be the sole medication used per 
the American Association for the Study of Liver Disease guidelines, with a slight 
modification: 
• Week 1: prednisone 60 mg/day 
• Week 2: prednisone 40 mg/day 
• Week 3 and Week 4: prednisone 30 mg/day 
Starting at Week 5, prednisone will be tapered by 5 mg/week until liver enzymes return to 
baseline levels. The use of prednisone will be recorded on the appropriate page of the eCRF. 
8.3 
Other Laboratory Parameters 
8.3.1 
Factor IX Inhibitor 
Samples for FIX inhibitor will be collected at the time points specified in the Schedule of 
Events (Table 15–1) to monitor for an immune response to FIX. The Bethesda assay will be 
performed using a validated method. Details for the preparation and shipment of samples are 
included in the laboratory manual. 
8.3.2 
Neutralizing Antibodies to Adeno-Associated Virus rh10 
Samples for neutralizing antibodies to AAVrh10 will be collected at the time points specified 
in the Schedule of Events (Table 15–1) to monitor for a humoral immune response to 
AAVrh10. The assay will be performed using a research method (enzyme-linked 
immunosorbent assay [ELISA]). Details for the preparation and shipment of samples are 
included in the laboratory manual. 
8.3.3 
Adeno-Associated Virus rh10 Binding Antibody IgG Assay 
Samples for the AAVrh10 binding antibody IgG assay will be collected at the time points 
specified in the Schedule of Events (Table 15–1) to monitor for circulating anti-AAVrh10 
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antibodies. The assay will be performed using a research method (ELISA). Details for the 
preparation and shipment of samples are included in the laboratory manual. 
8.3.4 
Viral Shedding 
Saliva, urine, and stool will be collected at the time points specified in the Schedules of 
Events (Table 15–1 and Table 15–2) to monitor for the presence of shed virus. The presence 
of DTX101 will be determined by quantitative polymerase chain reaction (qPCR). Subjects 
will be given an appropriate container to collect a stool sample at home. Saliva and urine 
samples will be collected at the site. In the event the assay is positive, subjects will continue 
to provide weekly samples until the results are negative on 3 separate occasions for each 
sample matrix. Details for the preparation and shipment of samples are included in the 
laboratory manual. 
8.3.5 
Cell-Mediated Immune Response 
The presence of T-cells specific for AAVrh10 and FIX will be determined by an enzyme-
linked immunospot (ELISPOT) assay. Samples will be collected at the time points specified 
in the Schedule of Events (Table 15–1). Details for the preparation and shipment of samples 
are included in the laboratory manual. 
8.4 
Genotyping 
8.4.1 
Factor IX Genotyping 
At baseline, subjects will be asked to provide a single whole-blood sample for FIX 
genotyping. The objective of this research is to provide a background understanding to the 
etiology of the subject’s hemophilia B and to investigate any relationship between genetic 
factors and the subject’s response to DTX101. The choice to provide this sample will be 
optional. If analyzed, the results will be reported separately. If not analyzed, the sample may 
be stored for future biological testing for a period of ≤15 years. 
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8.4.2 
Human Leukocyte Antigen Genotyping 
At baseline, subjects will be asked to provide an additional whole blood sample for human 
leukocyte antigen genotyping. The sample will only be analyzed if the result from the 
ELISPOT assay for cell-mediated immune response to AAVrh10 is ≥200 spot-forming 
units/1 × 106 peripheral blood mononuclear cells (Section 8.3.5). The objective of this 
research is to investigate any relationship between genetic factors and the subject’s immune 
response to DTX101. The choice to provide this sample will be optional. If analyzed, the 
results will be reported separately. If not analyzed, the sample may be stored for future 
biological testing for a period of ≤15 years. 
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9 
Safety Monitoring and Reporting 
9.1 
Adverse Events and Serious Adverse Events 
Adverse events will be assessed from the time the subject signs the ICF until their exit from 
the study. 
At every study visit, subjects will be asked a standard nonleading question to elicit any 
medically related changes in their well-being.  
In addition to subject observations, AEs identified from any study data (eg, laboratory values, 
physical examination findings, ECG changes) or identified from review of other documents 
(eg, subject diaries) that are relevant to subject safety will be documented on the AE page in 
the eCRF. 
9.1.1 
Definitions 
9.1.1.1 
Adverse Events 
The investigator is responsible for reporting all AEs that are observed or reported during the 
study, regardless of their relationship to study product or their clinical significance. 
An AE is defined as any untoward medical occurrence in a subject enrolled into this study 
regardless of its causal relationship to study product. Subjects will be instructed to contact 
the investigator at any time after the subject signs the informed consent if any signs or 
symptoms develop. 
A treatment-emergent adverse event (TEAE) is defined as any event not present before 
exposure to study product or any event already present that worsens in either intensity or 
frequency after exposure to study product. 
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9.1.1.2 
Serious Adverse Events 
An SAE is defined as any event that:  
• Results in death 
• Is immediately life threatening 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity, or  
• Results in a congenital anomaly/birth defect.  
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, 
they may jeopardize the subject or may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
9.1.2 
Safety Reporting 
9.1.2.1 
Adverse Events 
All AEs reported or observed during the study will be recorded on the AE page in the eCRF. 
Information to be collected includes drug treatment, dose, event term, time of onset, 
investigator-specified assessment of severity and relationship to study product, time of 
resolution of the event, seriousness, any required treatment or evaluations, and outcome. 
Adverse events resulting from concurrent illnesses, reactions to concurrent illnesses, 
reactions to concurrent medications, or progression of disease states must also be reported. 
All AEs will be followed to adequate resolution. The Medical Dictionary for Regulatory 
Activities (MedDRA) will be used to code all AEs.  
Any medical condition that is present at the time that the subject is screened but does not 
deteriorate should not be reported as an AE. However, if the condition deteriorates at any 
time during the study, it should be recorded as an AE. 
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9.1.2.2 
Serious Adverse Events 
Any AE that meets SAE criteria (Section 9.1.1.2) must be reported to PPD 
Pharmacovigilance (PVG) immediately (ie, within 24 hours) after the time site personnel first 
learn about the event. The site should record all SAE information in the SAE eCRF and 
submit the report via the electronic data capture (EDC) system.  
In the event of any fatal or life-threatening SAE, the investigator must immediately 
inform PPD PVG by telephone (Table 9–1) and report the SAE in the EDC system. If, 
for any reason, it is not possible to report the SAE in the EDC system (eg, the EDC 
system is unavailable), the site should record the SAE on the paper SAE Reporting 
Form and fax it to PPD PVG (Table 9–1). As soon as it is possible, any SAE reported via 
fax must be entered into the EDC system. 
Table 9–1 
PPD PVG Contact Information for SAE Reporting 
Region 
Contact Information 
Rest of World 
Safety hotline: 
 
Safety faxa: 
 
North America 
Safety hotline: 1
 
Safety faxa: 
 
Abbreviations: PVG, pharmacovigilance; SAE, serious adverse event. 
a. 
This is the preferred fax number for all regions. The toll free fax number for North America can be 
provided upon request. 
 
9.1.2.2.1 
Expedited Reporting 
The sponsor is responsible for reporting suspected, unexpected, serious adverse reactions 
(SUSARs) involving the study product(s) to all regulatory authorities and participating 
investigators in accordance with ICH guidelines and/or local regulatory requirements, as 
applicable. It is the responsibility of the investigator or designee to promptly notify the local 
institutional review board (IRB)/independent ethics committee (IEC)/institutional biosafety 
committee (IBC) of all SUSARs involving risk to human subjects. Serious adverse reactions 
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will be assessed for expectedness using reference safety information specified in the 
Investigator’s Brochure, as applicable. 
9.1.3 
Assessment of Severity/Toxicity 
The severity/toxicity, or intensity, of an AE refers to the extent to which an AE affects the 
subject’s daily activities. The intensity of the AE will be rated as Grade 1, 2, 3, 4, or 5 using 
the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) v4.03 [NCI CTCAE 2010]. The CTCAE provides descriptive terminology that can 
be used to standardize AE reporting. A severity/toxicity grade is provided for each AE term 
that is grouped by the highest level of MedDRA classification [NCI CTCAE 2010]. Specific 
symptoms and medical conditions have a clinical description for each level of 
severity/toxicity. In the event that an AE occurs during the study that is not captured by the 
CTCAE, the AE should be graded according to the following general guidelines: 
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2: 
Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental ADLa. 
Grade 3: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADLb. 
Grade 4: 
Life-threatening consequences; urgent intervention indicated. 
Grade 5: 
Death related to AE. 
Abbreviation: ADL, activities of daily living; AE, adverse event. 
a. 
Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc. 
b. Self-care ADL refers to bathing, dressing and undressing, feeding self, using the toilet, taking medications, 
and not bedridden. 
 
Changes in the severity/toxicity of an AE should be documented to allow an assessment of 
the duration of the event at each level of intensity to be performed. Adverse events 
characterized as intermittent do not require documentation of onset and duration of each 
episode. 
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9.1.4 
Assessment of Causality 
The investigator’s assessment of an AE’s relationship to study product is part of the 
documentation process, but it is not a factor in determining what is or is not reported in the 
study. If there is any doubt as to whether a clinical observation is an AE, the event should be 
reported. 
The relationship or association of the study product in causing or contributing to the AE will 
be characterized using the following classification and criteria: 
Unrelated: 
This relationship suggests that there is no association between the study product 
and the reported event. 
Possible: 
This relationship suggests that treatment with the study product is causing or 
contributing to the adverse event (AE); ie, the event follows a reasonable 
temporal sequence from the time of the study product administration or follows 
a known response pattern to the study product, but could also be produced by 
other factors. 
Probable: 
This relationship suggests that a reasonable temporal sequence of the event 
with the study product administration exists and, based upon the known 
pharmacological action of the study product, known or previously reported 
adverse reactions to the drug or class of drugs, or judgment based on the 
investigator’s clinical experience, the association of the event with the study 
product seems likely. The event disappears or decreases on cessation or 
reduction of the dose of study product. 
Definite: 
This relationship suggests that a definite causal relationship exists between the 
study product administration and the AE, and other conditions (concurrent 
illness, progression/expression of disease state, or concurrent medication 
reaction) do not appear to explain the event. The event reappears or worsens if 
the study product is re-administered. 
 
9.1.5 
Follow-Up of Subjects Reporting Adverse Events 
All AEs must be reported in detail on the appropriate page in the eCRF and followed to 
satisfactory resolution, until the investigator deems the event to be chronic or not clinically 
significant, or until the subject is considered to be stable. 
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9.2 
Procedures for Handling Special Situations 
9.2.1 
Pregnancy 
The population under study is male; therefore, pregnancies will not be tracked. 
9.2.2 
Treatment Noncompliance 
9.2.2.1 
Overdose Management 
An overdose is any dose of study product given to or taken by a subject that intentionally or 
unintentionally exceeds the dose, based on body weight (kg), described in Section 3.1. 
Overdoses without signs or symptoms do not need to be recorded as AEs; in case of any AEs 
associated with the overdose, these should be reported on the relevant AE or SAE section in 
the eCRF. The actual dose infused will be recorded on the appropriate page of the eCRF. 
There is no treatment for overdose. All subjects will be closely monitored at the time of 
infusion for any adverse effects and supportive care will be administered at the discretion of 
the investigator, as needed, should an overdose be suspected. 
9.2.2.2 
Medication Errors 
A medication error is defined as a mistake made in prescribing, dispensing, administration, or 
use of the study product. The treatment will be open-label and is to be administered by 
trained medical personnel at the site. 
9.3 
Data Safety Monitoring Committee 
An independent DSMC will be responsible for monitoring safety data from the study. The 
DSMC will meet after all subjects in a dosing cohort have completed Week 6 of the study to 
review the safety data and provide their recommendation for progressing to the next dosing 
cohort. 
The DSMC will meet on an ad hoc basis if an investigator reports an AE/SAE that meets any 
of the safety stopping criteria (Section 3.2.4). The DSMC may, at any time, recommend 
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modifying or stopping the study early due to safety concerns based on these periodic data 
reviews. The full scope of each review will be outline in the DSMC charter. 
The DSMC will have 2 independent medical professionals and an independent biostatistician 
who are qualified to review the data and provide recommendations for progressing to the 
next dosing level. The DSMC charter details the members’ roles and responsibilities as part 
of the DSMC as well as the process for each data review (ad hoc or scheduled). 
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10 Statistical and Analytical Plan 
A statistical analysis plan (SAP) will be written and finalized prior to the start of the study 
and will provide a detailed description of the statistical methods and expand on the details 
provided in this protocol. Additional analyses may be added. 
10.1 Dose-Finding Algorithm and Process 
• Data sources and methodologies used to determine the parameter values of the prior 
distributions of the toxicity and efficacy models; 
• Data elements and formats required in order to conduct modeling needed for 
producing dosing recommendation for the next dose; 
• Validation process of the modeling results and format and data to be provided to the 
DSMC for dossing decisions. 
10.2 Primary Endpoints 
The primary endpoints are: 
• The incidence of AEs, TEAEs, and SAEs (Section 9.1); 
• The change from baseline in FIX activity at Week 6 (Section 8.1.1). 
10.3 Secondary Endpoints 
The secondary endpoints are: 
• The annualized bleeding rate (ABR) (Section 8.1.2); 
• The time course of FIX activity (Section 8.1.1); 
• The annual and weekly use of FIX replacement therapy (Section 8.1.3); 
• Development of FIX inhibitor (Section 8.3.1); 
• Development of a cell-mediated immune response to FIX (Section 8.3.5); 
• Quality-of-life assessments (Section 8.1.4). 
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10.4 Other Endpoints 
Additional endpoints include: 
• 
Vital sign measurements (Section 8.2.3); 
• 
Electrocardiograms (Section 8.2.4); 
• 
Clinical laboratory parameters (Section 8.2.6); 
• 
Development of neutralizing antibodies to AAVrh10 (Section 8.3.2); 
• Adeno-associated virus rh10 binding antibody IgG assay (Section 8.3.3); 
• 
Viral shedding (Section 8.3.4). 
10.5 Statistical Analysis Methodology 
Dose-finding modeling will be conducted through specialized software that has been 
validated by PPD. SAS® software (SAS Institute, Inc, Cary, North Carolina, United States) 
Version 9.2 or later will be used for general data manipulation and statistical analyses. 
Continuous variables will be summarized using the mean, the standard deviation, median, 
minimum value, and maximum value. Categorical variables will be summarized using 
frequency counts and percentages. Data will be listed in data listings. 
Details of the statistical analyses, methods, and data conventions are described in the SAP. 
10.5.1 
Determination of the Optimal Biological Dose 
The continual reassessment method (CRM) chosen for the study is a bivariate approach 
[Braun 2002]. This method uses a 2-parameter logistic regression model to predict both the 
probability of experiencing a dose-limiting toxicity (DLT) and the probability of achieving 
the target peak FIX activity (≥20% of normal) within the first 6 weeks after DTX101 
infusion. A noninformative prior [Braun 2002], in the form of a product of beta and 
exponential density functions, will be used. A dose will be considered the maximum tolerated 
dose (MTD) if the posterior probability of a DLT reaches 25%. For this study, a DLT is 
defined as any AE/serious AE (SAE) ≥Grade 3 that is considered to be related to study 
product by the investigator [NCI CTCAE 2010]. The MTD can also be the OBD if target FIX 
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activity is achieved. A dose will be considered the MED if the predicted probability of 
achieving the target peak FIX activity (≥20% of normal) reaches 90%. At each dose, a 
Euclidian distance between the posterior probabilities of safety and efficacy signals will be 
minimized to identify the dose for the next cohort. 
Subjects will be dosed sequentially in cohorts of a minimum of 3 subjects each. Subjects in 
the first cohort (Cohort 1) will be assigned to Dose 1. Subjects will be assigned to subsequent 
cohorts depending on the safety and FIX activity of the preceding doses. The potential dosing 
scheme allows, at most, bypassing one dose level (eg, Dose 1 to Dose 3) during dose-finding. 
Similarly, the potential dosing scheme allows for de-escalation if the MTD is reached as well 
as cohort expansion to confirm a dose is the OBD (Figure 10–1). The protocol will also allow 
for adding an intermediate dose, relative to the candidate doses outlined in Section 3.1, if the 
CRM predicts it could be the OBD. 
Figure 10–1 
Overview of Potential Dosing Scheme to Determine the Optimal 
Biological Dose of DTX101 
 
Abbreviations: CRM, continual reassessment method; DLT, dose-limiting toxicity; FIX, factor IX; 
OBD, optimal biological dose. 
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Dose escalation will stop if at least one of the following conditions is met:  
1) The MTD is reached; 
2) The MED is found; 
3) If a dose is sufficiently close to either the MTD or MED (within 5% credible 
interval); 
4) If the posterior probability of a dose being either the MTD or the MED is over a 
threshold (10% and 20%, respectively); 
5) If all of the dosing cohorts have been enrolled. 
10.5.2 
Efficacy Analysis 
10.5.2.1 
Annualized Bleeding Rate 
The annualized number of bleeds per subject, per location, and by type of bleed will be 
calculated for all subjects through Week 52 (±7 days). Full details of the analysis will be 
provided in the SAP. 
10.5.2.2 
Factor IX Replacement Therapy 
The annualized and average weekly use of FIX replacement therapy will be calculated for all 
subjects through Week 52 (±7 days). Full details of the analysis will be provided in the SAP. 
10.5.3 
Safety Analyses 
All subjects who receive DTX101 will be included in the safety analysis. 
10.5.3.1 
Adverse Events 
All statistical analyses of safety outcomes will be descriptive. The incidence of AEs and 
TEAEs will be summarized for each dosing cohort by severity and relationship to study 
product. Serious AEs will be presented for each dosing cohort by relationship to study 
product. Summary tables will present incidence estimates and individual event rates by 
system organ class as well as within each system organ class. Subjects experiencing an event 
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more than once with varying severity will be counted only once, in the maximum severity 
within each system organ class and preferred term. For incidence of relationship to study 
product, subjects will be counted only once, in the category of the strongest relationship to 
study product within each system organ class and preferred term. 
10.5.3.2 
Clinical Laboratory Assessment Results 
For all laboratory assessments with continuous results, absolute values and changes from 
baseline will be summarized by visit and dosing cohort. For laboratory tests with categorical 
results, shifts from baseline will be summarized by visit and dosing cohort. 
10.5.3.3 
Vital Sign Measurements 
Vital sign measurements (heart rate, blood pressure [systolic and diastolic], and respiratory 
rate) will be summarized over time in terms of absolute values and changes from baseline by 
visit and dosing cohort. Height and weight will be summarized. 
10.5.3.4 
Electrocardiogram Results 
Electrocardiogram data will be summarized by visit and dosing cohort. Each ECG will be 
classified as “abnormal” or “normal,” and the relevance of the abnormality will be 
summarized as “clinically significant” or “not clinically significant.” 
10.5.4 
Pharmacodynamic Analyses 
Factor IX activity will be summarized by time point and dosing cohort. Associations between 
FIX activity and dose will be undertaken using tabular summaries and appropriate statistical 
methods as outlined in the SAP. 
10.5.5 
Other Laboratory Results 
Factor IX inhibitor, neutralizing antibodies (AAVrh10), AAVrh10 binding antibody IgG 
assay, viral shedding, and cell-mediated immune response (to AAVrh10) will be summarized 
by time point and dosing cohort. Associations between these parameters and dose will be 
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undertaken using tabular summaries and appropriate statistical methods as outlined in the 
SAP. 
10.5.6 
Quality-of-Life Assessments 
Associations between quality of life and dose will be undertaken using tabular summaries 
and appropriate statistical methods as outlined in the SAP. 
10.5.7 
Other Analyses 
Summary statistical analyses will be provided for demographics, medical history, hemophilia 
history, physical examination, and prior and concomitant medications. A summary of subject 
disposition will be prepared. 
10.5.8 
Interim Analysis 
An interim analysis will be conducted when the last subject dosed completes Week 6 of the 
study. The purpose of this interim analysis is to determine FIX activity in all cohorts to 
determine the OBD of DTX101 and provide an initial safety and efficacy assessment of 
DTX101. Results and their dissemination will be at the sponsor’s discretion. Any interim 
analyses conducted will not bias the conduct of the study. A detailed plan for the analysis of 
the safety and efficacy data will be presented in the SAP. 
10.6 Data Quality Assurance 
The sites will maintain source documentation and enter subject data into the eCRF as 
accurately as possible and will rapidly respond to any reported discrepancies. The eCRFs are 
accessed through Medidata Rave® (New York, New York, United States). This EDC system 
is validated and compliant with US Title 21 Code of Federal Regulations (CFR) Part A1. 
Each person involved with the study will have an individual user name and password that 
allows for record traceability. Thus, the system, and subsequently any investigative reviews, 
can identify coordinators, investigators, and individuals who have entered or modified 
records, as well as the time and date of any modifications. A quality review of the data will 
be performed by the site with additional reviews by the clinical monitor.  
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Each eCRF is presented as an electronic copy, allowing data entry by study site personnel, 
who can add and edit data, add new subjects, identify and resolve discrepancies, and view 
records. This system provides immediate direct data transfer to the database, as well as 
immediate detection of discrepancies, enabling site coordinators to resolve and manage 
discrepancies in a timely manner.  
Paper copies of the eCRFs and other database reports may be printed and signed by the 
investigator. This system provides study site personnel, monitors, and reviewers with access 
to hardcopy audits, discrepancy reviews, and investigator comment information.  
After all queries have been resolved, the SAP is approved and signed, and any 
summary/analysis populations are approved, the database will be locked. All summary and 
analysis of the data will be performed using SAS software Version 9.2 or later. 
10.6.1 
Data Management 
As part of the responsibilities assumed by participating in the study, the investigator agrees to 
maintain adequate case histories for the subjects treated as part of the research under this 
protocol. The investigator agrees to maintain accurate eCRFs and source documentation as 
part of the case histories. These source documents may include diary cards, laboratory 
reports, ECG strips, and other materials. 
The sponsor (or sponsor designee) will supply the eCRF. Study personnel must have 
documented training in the use of the EDC system before the system can be authorized.  
All eCRF information is to be completed. If an item is not available or is not applicable, this 
fact should be indicated. 
Investigative site personnel will enter subject data into the EDC system. The analysis data 
sets will be a combination of these data and data from other sources (eg, laboratory data). All 
entries and changes to the data in the eCRF will be recorded electronically with an audit trail 
specifying the date and time of entry or change and the name of the authorized person 
making the entry or change. The investigator will answer all queries issued, if applicable. 
Data queries and query correspondence will be included in the audit trail. 
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Clinical data management will be performed in accordance with applicable sponsor (or 
sponsor designee) standards and data cleaning procedures to ensure the integrity of the data 
(eg, removing errors and inconsistencies in the data). Adverse events and concomitant 
medication terms will be coded using MedDRA terminology. 
After database lock, each study site will receive an electronic copy of their site-specific 
eCRF data as entered into the EDC system for the study, including full discrepancy and audit 
history. Additionally, an electronic copy of all of the study site’s data from the study will be 
created and sent to the sponsor for storage. The sponsor (or sponsor designee) will maintain a 
duplicate electronic copy for their records. In all cases, subject initials will not be collected or 
transmitted to the sponsor. 
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11 Ethics 
11.1 Institutional Review Board, Independent Ethics Committee, and 
Institutional Biosafety Committee 
Federal regulations and the International Conference on Harmonisation (ICH) guidelines 
require that approval be obtained from an IRB/IEC/IBC before participation of human 
subjects in research studies. Before study onset, the protocol, ICF, advertisements to be used 
for the recruitment of study subjects, and any other written information regarding this study 
to be provided to the subject or the subject’s legal guardian must be approved by an 
IRB/IEC/IBC. Documentation of all IRB/IEC/IBC approvals and of the IRB/IEC/IBC 
compliance with ICH harmonised tripartite guideline E6(R1): Good Clinical Practice (GCP) 
will be maintained by the site and will be available for review by the sponsor or its designee. 
All IRB/IEC/IBC approvals should be signed by the IRB/IEC/IBC chair or designee and 
must identify the IRB/IEC/IBC name and address, the clinical protocol by title or protocol 
number or both, and the date approval or a favorable opinion was granted. 
The investigator is responsible for providing written summaries of the progress and status of 
the study at intervals not exceeding 1 year or otherwise specified by the IRB/IEC/IBC. The 
investigator must promptly supply the sponsor or its designee, the IRB/IEC/IBC, and, where 
applicable, the institution, with written reports on any changes significantly affecting the 
conduct of the study or increasing the risk to subjects. 
11.2 Ethical Conduct of the Study 
The study will be performed in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki, ICH GCP, and all applicable local laws and regulations. 
11.3 Subject Information and Consent 
A written ICF in compliance with regulatory authority regulations and 21 CFR §50 shall be 
obtained from each subject before entering the study or performing any unusual or 
nonroutine procedure that involves risk to the subject. An ICF template may be provided by 
the sponsor to investigative sites. If any institution-specific modifications to study-related 
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procedures are proposed or made by the site, the ICF should be reviewed by the sponsor or 
its designee or both before IRB/IEC/IBC submission. Once reviewed, the ICF will be 
submitted by the investigator to his or her IRB/IEC/IBC for review and approval before the 
start of the study. If the ICF is revised during the course of the study, all active participating 
subjects must sign the revised form. 
Before recruitment and enrollment, each prospective subject or their legal guardian will be 
given a full explanation of the study and be given the opportunity to read the approved ICF. 
Once the investigator is assured that the subject or their legal guardian understands the 
implications of participating in the study, the subject or their legal guardian will be asked to 
give consent to participate in the study by signing the ICF. 
The investigator shall retain the signed original ICF(s) and must provide a copy of the signed 
original form to the subject or their legal guardian. 
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12 Investigator’s Obligations 
The following administrative items are meant to guide the investigator in the conduct of the 
study but may be subject to change based on industry and government standard operating 
procedures, working practice documents, or guidelines. Any change will be reported to the 
IRB/IEC/IBC but will not require a protocol amendment. 
12.1 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain subject confidentiality. All records will be kept in a secure 
storage area with limited access. Clinical information will not be released without the written 
permission of the subject (or the subject’s legal guardian), except as necessary for monitoring 
and auditing by the sponsor, its designee, the FDA, other applicable regulatory agencies, or 
the IRB/IEC/IBC. 
The investigator and all employees and coworkers involved with this study may not disclose 
or use for any purpose other than performance of the study any data, record, or other 
unpublished, confidential information disclosed to those individuals for the purpose of the 
study. Prior written agreement from the sponsor must be obtained for the disclosure of any 
said confidential information to other parties. 
12.2 Financial Disclosure and Obligations 
Investigators are required to provide financial disclosure information to allow the sponsor to 
submit the complete and accurate certification or disclosure statements required under 
21 CFR §54. In addition, the investigator must provide to the sponsor a commitment to 
promptly update this information if any relevant changes occur during the course of the 
investigation and for 1 year following the completion of the study. 
Neither the sponsor nor PPD is financially responsible for further testing or treatment of any 
medical condition that may be detected during the screening process. In addition, in the 
absence of specific arrangements, neither the sponsor nor PPD is financially responsible for 
further treatment of the subject’s disease. 
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12.3 Investigator Documentation 
Prior to beginning the study, the investigator will be asked to comply with ICH E6(R1) 8.2 
and Title 21 of the CFR by providing the following essential documents, including but not 
limited to: 
• 
IRB/IEC/IBC approvals; 
• 
Original investigator-signed investigator agreement page of the protocol; 
• 
Form FDA 1572 (or equivalent), fully executed, and all updates on a new fully 
executed Form FDA 1572 (or equivalent); 
• 
Curriculum vitae for the investigator and each subinvestigator; 
• 
Financial disclosure information to allow the sponsor to submit complete and 
accurate certification or disclosure statements required under 21 CFR §54. In 
addition, the investigators must provide to the sponsor a commitment to 
promptly update this information if any relevant changes occur during the 
course of the investigation and for 1 year after the completion of the study; 
• 
IRB/IEC/IBC-approved ICF, samples of site advertisements for recruitment for 
this study, and any other written information regarding this study that is to be 
provided to the subject or their legal guardian; and 
• 
Laboratory certifications and normal ranges for any local laboratories used by 
the site, in accordance with 42 CFR §493. 
12.4 Study Conduct 
The investigator agrees that the study will be conducted according to the principles of 
ICH E6(R1). The investigator will conduct all aspects of this study in accordance with all 
national, state, and local laws or regulations. Study information from this protocol will be 
posted on publicly available clinical study registers before enrollment of subjects begins. 
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12.5 Adherence to Protocol 
The investigator agrees to conduct the study as outlined in this protocol in accordance with 
ICH E6(R1) and all applicable guidelines and regulations. 
12.6 Adverse Events and Study Report Requirements 
By participating in this study the investigator agrees to submit reports of SAEs according to 
the time line and method outlined in the protocol. In addition, the investigator agrees to 
submit annual reports to the study site IRB/IEC/IBC as appropriate. 
12.7 Investigator’s Final Report 
Upon completion of the study, the investigator, where applicable, should inform the 
institution; the investigator/institution should provide the IRB/IEC/IBC with a summary of 
the study’s outcome and the sponsor and regulatory authority(ies) with any reports required. 
12.8 Record Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated 
marketing applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the study product. These documents should be 
retained for a longer period, however, if required by the applicable regulatory requirements 
or by an agreement with the sponsor. It is the responsibility of the sponsor to inform the 
investigator/institution as to when these documents no longer need to be retained. 
12.9 Publications 
After completion of the study, the data may be considered for reporting at a scientific 
meeting or for publication in a scientific journal. In these cases, the sponsor will be 
responsible for these activities and will work with the investigators to determine how the 
manuscript is written and edited, the number and order of authors, the publication to which it 
will be submitted, and other related issues. The sponsor has final approval authority over all 
such issues. 
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Data are the property of the sponsor and cannot be published without prior authorization 
from the sponsor, but data and publication thereof will not be unduly withheld. 
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13 Study Management 
The administrative structure will include a DSMC (Section 9.3). 
13.1 Monitoring 
13.1.1 
Monitoring of the Study 
The clinical monitor, as a representative of the sponsor, has the obligation to closely follow 
the study. In doing so, the monitor will visit the investigator and study site at periodic 
intervals, in addition to maintaining necessary telephone and letter contact. The monitor will 
maintain current personal knowledge of the study through observation, review of study 
records and source documentation, and discussion of the conduct of the study with the 
investigator and personnel. 
All aspects of the study will be carefully monitored, by the sponsor or its designee, for 
compliance with applicable government regulation with respect to current GCP and current 
standard operating procedures. 
13.1.2 
Inspection of Records 
Investigators and institutions involved in the study will permit study-related monitoring, 
audits, IRB/IEC/IBC review, and regulatory inspections by providing direct access to all 
study records. In the event of either an audit or inspection, the investigator agrees to allow 
the sponsor, representatives of the sponsor, or a regulatory agency (eg, FDA or other 
regulatory agency) access to all study records. 
The investigator should promptly notify the clinical research associate (CRA) of any audits 
or inspections scheduled by any regulatory authorities and promptly forward copies of any 
reports received to the CRA. The CRA will then inform and forward any reports to the 
sponsor. 
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13.2 Management of Protocol Amendments and Deviations 
13.2.1 
Modification of the Protocol 
Any changes in this research activity, except those necessary to remove an apparent, 
immediate hazard to the subject, must be reviewed and approved by the sponsor or its 
designee. Amendments to the protocol must be submitted in writing to the investigator’s 
IRB/IEC/IBC for approval before subjects can be enrolled into an amended protocol. 
13.2.2 
Protocol Deviations 
A deviation from the protocol is a departure from the written procedures or processes. A 
significant deviation occurs when there is nonadherence to the protocol by the subject or 
investigator that results in a significant, additional risk to the subject. Significant deviations 
can include nonadherence to inclusion or exclusion criteria, enrollment of the subject without 
prior sponsor approval, or nonadherence to FDA regulations or ICH GCP guidelines, and will 
lead to the subject being withdrawn from the study (Section 7.1). Protocol waivers or 
exemptions are not permitted. Adherence to the study design requirements, including those 
specified in the Schedules of Events (Table 15–1 and Table 15–2), is essential for study 
conduct. 
The investigator or designee must document and explain in the subject’s source 
documentation any deviation from the approved protocol. The investigator may implement a 
deviation from, or a change of, the protocol to eliminate an immediate hazard to study 
subjects without prior IRB/IEC/IBC approval. As soon as possible after such an occurrence, 
the implemented deviation or change, the reasons for it, and any proposed protocol 
amendments should be submitted to the IRB/IEC/IBC for review and approval, to the 
sponsor for agreement, and to the regulatory authorities, if required. 
Protocol deviations will be documented by the clinical monitor throughout the course of 
monitoring visits. Principal investigators will be notified in writing by the monitor of 
deviations. The IRB/IEC/IBC should be notified of all protocol deviations in a timely 
manner, as required. 
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13.3 Study Termination 
Although the sponsor has every intention of completing the study, the sponsor reserves the 
right to discontinue the study at any time for clinical or administrative reasons. 
The end of the study is defined as the date on which the last subject completes the last visit 
(includes follow-up visit). 
13.4 Final Report 
Whether the study is completed or prematurely terminated, the sponsor will ensure that the 
clinical study reports are prepared and provided to the regulatory agency(ies) as required by 
the applicable regulatory requirement(s). The sponsor will also ensure that the clinical study 
reports in marketing applications meet the standards of the ICH harmonised tripartite 
guideline E3: Structure and content of clinical study reports. 
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results. 
Upon completion of the clinical study report, the sponsor will provide the investigator with a 
summary of the cumulative study results. The investigator is encouraged to share the 
cumulative summary results and will provide each subject with their individual data. The 
study results will be posted on publicly available clinical study registers, where required. 
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Declaration of Investigator 
I have read and understood all sections of the protocol entitled “A Phase I/II Open-Label 
Safety and Dose-Finding Study of Adeno-Associated Virus (AAV) rh10-Mediated Gene 
Transfer of Human Factor IX in Adults With Moderate/Severe to Severe Hemophilia B.” 
I have read and agree to supervise all aspects of the protocol and to conduct the clinical 
investigation in accordance with the Final Protocol Version 04, dated 03 September 2015, the 
International Conference on Harmonisation harmonised tripartite guideline E6(R1): Good 
Clinical Practice and all applicable government regulations and inform all who assist me in 
the conduct of this study of their responsibilities and obligations. 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
Printed Name of Principal Investigator 
 
 
 
 
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Gao G, Vandenberghe LH, Alvira MR, et al. Clades of adeno-associated viruses are widely 
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progress and challenges. Nat Rev Genet. 2011;12(5):341-55. 
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Nathwani AC, Gray JT, Ng CY, et al., Self-complementary adeno-associated virus vectors 
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transduction of murine and nonhuman primate liver. Blood. 2006;107(7):2653-61. 
Nathwani AC, Gray JT, McIntosh J, et al. Safe and efficient transduction of the liver after 
peripheral vein infusion of self-complementary AAV vector results in stable therapeutic 
expression of human FIX in nonhuman primates. Blood. 2007;109(4):1414-21. 
Nathwani AC, Tuddenham EG, Rangarajan S, et al. Adenovirus-associated virus 
vector-mediated gene transfer in hemophilia B. N Engl J Med. 2011a;365(25):2357-65. 
Nathwani AC, Rosales C, McIntosh J, et al. Long-term safety and efficacy following 
systemic administration of a self-complementary AAV vector encoding human FIX 
pseudotyped with serotype 5 and 8 capsid proteins. Mol Ther. 2011b;19(5):876-85. 
Nathwani ACV, Reiss UM, Tuddenham EG, et al. Long-term safety and efficacy of factor IX 
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Niemeyer GP, Herzog RW, Mount J, et al. Long-term correction of inhibitor-prone 
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Peyvandi F, Garagiola I, Seregni S. Future of coagulation therapy replacement. J Thromb 
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White GC 2nd, Rosendaal F, Aledort LM, et al. Definitions in hemophilia. Recommendation 
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15 Appendices 
15.1 Appendix: Schedules of Events 
 
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Table 15–1 
Schedule of Events – Scheduled Clinic Visits 
Procedure 
Period 
Screening 
Dosing 
Treatment Period: Week 2 through Week 52 (includes clinic 
or home visits [see Table 15–2]) 
Unscheduled 
End of 
Study/Early 
Withdrawal 
Week 
Days –30 
to –1 
Day 0 
2 
4 
6 
8 
10 
12 
16-48a 
 
52 
Visit 
Window 
(Days) 
- 
- 
±2 
±2 
±2 
±2 
±2 
±2 
±4 
- 
±7 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Hemophilia history 
X 
 
 
 
 
 
 
 
 
 
 
Prior medication / 
therapies / procedures 
X 
 
 
 
 
 
 
 
 
 
 
Review of eligibility 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
FIX genotyping 
X 
 
 
 
 
 
 
 
 
 
 
HLA genotyping 
X 
 
 
 
 
 
 
 
 
 
 
HBV, HCV, and HIV 
status 
X 
 
 
 
 
 
 
 
 
 
 
FIX inhibitor (Bethesda 
assay) 
X 
Xb 
 
 
X 
X 
 
 
Xc 
Xd 
X 
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Procedure 
Period 
Screening 
Dosing 
Treatment Period: Week 2 through Week 52 (includes clinic 
or home visits [see Table 15–2]) 
Unscheduled 
End of 
Study/Early 
Withdrawal 
Week 
Days –30 
to –1 
Day 0 
2 
4 
6 
8 
10 
12 
16-48a 
 
52 
Visit 
Window 
(Days) 
- 
- 
±2 
±2 
±2 
±2 
±2 
±2 
±4 
- 
±7 
Coagulation panel 
(PT/INR, D-dimer assay, 
aPTT) 
X 
Xb 
X 
X 
X 
X 
X 
X 
X 
Xd 
X 
AAVrh10 neutralizing 
antibody test (ELISA) 
X 
Xb 
 
 
X 
X 
 
 
Xc 
Xd 
X 
Cell-mediated immune 
response to AAVrh10 and 
FIX (ELISPOT assay) 
 
Xb 
 
 
X 
X 
 
 
Xc 
Xd 
X 
AAVrh10 binding 
antibody IgG assay 
(ELISA) 
X 
Xb 
 
 
X 
X 
 
 
Xc 
Xd 
X 
Saliva, urine, and stool for 
viral shedding (qPCR)f 
 
Xe 
X 
X 
X 
X 
X 
X 
X 
Xd 
X 
FIX activity (aPTT 
clot-based assay) 
X 
Xb 
X 
X 
X 
X 
X 
X 
X 
Xd 
X 
Hematology / clinical 
chemistryg 
X 
Xh 
X 
X 
X 
X 
X 
X 
X 
Xd 
X 
Urinalysis 
X 
 
X 
X 
X 
X 
 
X 
 
Xd 
X 
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Procedure 
Period 
Screening 
Dosing 
Treatment Period: Week 2 through Week 52 (includes clinic 
or home visits [see Table 15–2]) 
Unscheduled 
End of 
Study/Early 
Withdrawal 
Week 
Days –30 
to –1 
Day 0 
2 
4 
6 
8 
10 
12 
16-48a 
 
52 
Visit 
Window 
(Days) 
- 
- 
±2 
±2 
±2 
±2 
±2 
±2 
±4 
- 
±7 
12-lead ECG 
X 
Xi 
 
 
 
 
 
 
 
 
X 
Vital sign measurements 
(heart rate, blood pressure, 
respiratory rate) 
X 
Xj 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height and weightk 
X 
Xb, l 
 
 
 
 
 
 
 
 
Xl 
Complete physical 
examination 
X 
 
 
 
 
 
 
 
 
 
X 
Targeted physical 
examinationm 
 
Xb 
 
 
X 
 
 
X 
Xn 
 
 
AE/SAE monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
/ therapies / procedures 
 
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diary distributed 
 
X 
 
 
 
 
 
 
 
 
 
Diary reviewed 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Diary returned 
 
 
 
 
 
 
 
 
 
 
X 
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Procedure 
Period 
Screening 
Dosing 
Treatment Period: Week 2 through Week 52 (includes clinic 
or home visits [see Table 15–2]) 
Unscheduled 
End of 
Study/Early 
Withdrawal 
Week 
Days –30 
to –1 
Day 0 
2 
4 
6 
8 
10 
12 
16-48a 
 
52 
Visit 
Window 
(Days) 
- 
- 
±2 
±2 
±2 
±2 
±2 
±2 
±4 
- 
±7 
Record of spontaneous 
bleeding episodes 
X 
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record recombinant FIX 
use 
X 
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prophylactic recombinant 
FIX washout  
Xo 
 
 
 
Xp, q 
 
 
 
Xr, s 
 
Xr, s 
EQ-5D-5L QoL 
questionnaire 
 
Xb 
 
 
 
 
 
 
Xn 
 
X 
Haem-A-QoL 
questionnaire 
 
Xb 
 
 
 
 
 
 
Xn 
 
X 
DTX101 infusion 
 
X 
 
 
 
 
 
 
 
 
 
Abbreviations: AAVrh10, adeno-associated virus serotype rh10; AE, adverse event; aPPT, activated partial thromboplastin time; ECG, 
electrocardiogram; ELISA, enzyme-linked immunosorbent assay; ELISPOT, enzyme-linked immunospot; EQ-5D-5L, EuroQoL 5D 5 level; FIX, 
factor IX; Haem-A-QoL, Haemophilia-Specific Quality of Life; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency 
virus; HLA, human leukocyte antigen; IgG, immunoglobulin G; INR, international normalized ratio; PT, prothrombin time; QoL, quality of life; 
qPCR, quantitative polymerase chain reaction; SAE, serious adverse event. 
a. 
Following the Week 12 visit, subjects will return to the study site once every 4 weeks starting at Week 16. 
b. To be collected before DTX101 administration. 
c. 
Samples to be obtained at Weeks 16, 32, 40, and 48. 
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d. A laboratory parameter may be repeated if there is any concern about the values obtained. Laboratory values must be repeated if ≥2-fold the upper 
limit of normal or ≤0.5-fold the lower limit of normal. 
e. 
Saliva and urine samples for viral shedding to be collected before DTX101 administration. Subjects will be provided with an appropriate 
container to collect a stool sample at home prior to the visit. 
f. 
Samples for viral shedding to be collected at Weeks 2, 4, 6, 8, 10, and 12 and on Days 8, 20, 36, 48, 64, and 76 (see Table 15–2) until negative on 
3 consecutive occasions for each sample matrix. 
g. Hematology to include: complete blood count and differential. Clinical chemistry to include: sodium, potassium, chloride, carbon dioxide, blood 
urea nitrogen, creatinine, glucose, calcium, phosphate, magnesium, albumin, total protein, creatine kinase, bilirubin (total and indirect), alanine 
aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, and lactate dehydrogenase. 
h. Samples for clinical laboratory assessments to be collected before DTX101 administration and 0.5, 4, and 8 hours after the start of the infusion. 
i. 
A 12-lead electrocardiogram to be performed in triplicate before the start of infusion. A single 12-lead electrocardiogram to be performed 1 hour 
after the start of the infusion. The ECGs should be measured with the subject in a semi-supine or supine position, having rested in this position for 
at least 5 minutes beforehand. 
j. 
Vital signs to be measured at predose, at 5 minutes after the start of the infusion, and at 0.5, 1, 2, 4, 6, and 8 hours after the start of infusion 
(±5 minutes). The predose measurement of heart rate and blood pressure is to be performed in triplicate, with measurements taken 2 minutes 
apart. Vital signs will also be measured at 22 hours (±1 hour) after the start of infusion, prior to subject discharge. Vital signs should be measured 
with the subject in a semi-supine or supine position, having rested in this position for at least 5 minutes beforehand. 
k. Height to be collected at screening only. 
l. 
Only weight to be collected. 
m. Targeted physical examination to include assessment of the skin and the respiratory, cardiovascular, and gastrointestinal systems. 
n. To be recorded at Weeks 24, 36, and 48. 
o. This is only applicable if a subject does not have a documented history of FIX activity and a baseline sample is needed to confirm severity of 
hemophilia B. For subjects taking long-acting recombinant FIX prophylactically, washout is to start at Day –28 and last at least 21 days (Day –7). 
For subjects taking traditional recombinant FIX prophylactically, washout is to start at Day –14 and last at least 7 days (Day –7). The baseline 
sample must be obtained and results available prior to dosing on Day 0. 
p. For subjects who take long-acting recombinant FIX prophylactically, start washout at Week 3 for the Week 6 FIX measurement. 
q. For subjects who take traditional recombinant FIX prophylactically, start washout at Week 5 for the Week 6 FIX measurement. 
r. 
For subjects who continue to take long-acting recombinant FIX prophylactically, start washout at Week 21 for the Week 24 FIX measurement and 
again at Week 49 for the Week 52 FIX measurement. 
s. 
For subjects who continue to take traditional recombinant FIX prophylactically, start washout at Week 23 for the Week 24 FIX measurement and 
again at Week 51 for the Week 52 FIX measurement. 
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Table 15–2 
Schedule of Events – Clinic or Home Visits During the Treatment Period 
Procedure 
 
Treatment Period 
Day 
4 
8 
20 
24 
32 
36 
48 
52 
60 
64 
76 
80 
Visit Window (Days) 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
±1 
Clinical chemistrya, b 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Saliva, urine, and stool for viral shedding (qPCR)c, d 
 
X 
X 
 
 
X 
X 
 
 
X 
X 
 
Abbreviations: qPCR, quantitative polymerase chain reaction. 
a. 
Clinical chemistry to include: sodium, potassium, chloride, carbon dioxide, blood urea nitrogen, creatinine, glucose, calcium, phosphate, 
magnesium, albumin, total protein, creatine kinase, bilirubin (total and indirect), alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase, gamma-glutamyl transferase, and lactate dehydrogenase. 
b. A laboratory parameter may be repeated if there is any concern about the values obtained. Laboratory values must be repeated if ≥2-fold the upper 
limit of normal or ≤0.5-fold the lower limit of normal. 
c. 
Subjects will be provided with an appropriate container to collect a stool sample at home prior to the visit. 
d. Samples for viral shedding to be collected at Weeks 2, 4, 6, 8, 10, and 12 (see Table Table 15–1) and on Days 8, 20, 36, 48, 64, and 76 until 
negative on 3 consecutive occasions for each sample matrix. 
 
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