Clinical trial NCT03517085
Conditions: GSD1
Keywords: glycogen storage disorder Ia AAV gene therapy von Gierke disease glucose metabolism disorder
Sponsor: Ultragenyx Pharmaceutical Inc
Start date: 2018-05-18; Completion date: 2021-11-02
Enrollment: 12 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the study is to determine the safety of single doses of DTX401, including the incidence of dose-limiting toxicities (DLTs) at each dose level.

Detailed description:
Participants enrolled in the 401GSDIA01 study will be monitored for 52 weeks following DTX401 administration. Participants in Cohorts 1, 2, and 3 will receive reactive oral steroid treatment for possible vector-induced hepatitis following treatment with DTX401. Participants in Cohort 4 will receive prophylactic oral steroid treatment to prevent possible vector-induced hepatitis. After completion of the Week 52 visit or early withdrawal, participants will be offered enrollment into a 4-year extension study.

Arms: arm 1: Dose 1 (2.0 × 10\^12 GC/kg) with a reactive steroid regimen (6 weeks, at a starting dose of 40 mg/day, after alanine aminotransferase \[ALT\] elevation) arm 2: Dose 2 (6.0 × 10\^12 GC/kg) with a reactive steroid regimen (6 weeks, at a starting dose of 40 mg/day, after ALT elevation) arm 3: Dose 2 (6.0 × 10\^12 GC/kg) with an optimized reactive steroid regimen (7 weeks, at a starting dose of 60 mg/day, after ALT elevation) arm 4: Dose 2 (6.0 × 10\^12 GC/kg) with a prophylactic steroid regimen (8 weeks, at a starting dose of 60 mg/day, starting on Day 1)
Interventions: intervention 1: DTX401 intervention 2: steroid regimen
Intervention descriptions: intervention 1: DTX401 administered as a single peripheral intravenous (IV) infusion intervention 2: prednisone or prednisolone to manage alanine aminotransferase (ALT) elevation

Protocol documents:
Prot_000.pdf: 
Confidential and Proprietary – Property of Ultragenyx Pharmaceutical Inc. 
CLINICAL STUDY PROTOCOL 
IND NUMBER: 17965 
EUDRACT NUMBER: 2016-003023-30 
 
A Phase 1/2, Open-Label Safety and Dose-Finding Study of Adeno-Associated Virus 
(AAV) Serotype 8 (AAV8)-Mediated Gene Transfer of Glucose-6-Phosphatase (G6Pase) 
in Adults with Glycogen Storage Disease Type Ia (GSDIa) 
 
Protocol Number: 401GSDIA01 
Sponsor: 
Ultragenyx Pharmaceutical Inc. 
60 Leveroni Court 
Novato, CA 94949 
Sponsor Contact: 
Vassili Valayannopoulos, MD 
Vice President, Clinical Development 
Ultragenyx Pharmaceutical Inc. 
Telephone: 
 
Email: 
 
Medical Monitor: 
 
Associate Medical Director, Pharmacovigilance 
PPD 
Telephone: 
 
Version of Protocol: 
7.0 
Date of Protocol: 
Amendment 6: 16 February 2021 
Previous Versions and Dates: 
Amendment 5: 28 October 2019 
Amendment 4: 10 September 2019 
Amendment 3: 18 February 2019 
Amendment 2: 02 March 2018 
Amendment 1: 13 December 2017 
Version 1.0: 17 May 2017 
CONFIDENTIAL 
All financial and nonfinancial support for this study will be provided by Ultragenyx Pharmaceutical 
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 Ultragenyx Pharmaceutical Inc. The study will be conducted according to the International 
Council for Harmonisation harmonised tripartite guideline E6(R2): Good Clinical Practice. 


Protocol 401GSDIA01 Version 7.0 
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PROTOCOL APPROVAL 
 
Study Title 
A Phase 1/2, Open-Label Safety and Dose-Finding Study of 
Adeno-Associated Virus (AAV) Serotype 8 (AAV8)-Mediated 
Gene Transfer of Glucose-6-Phosphatase (G6Pase) in Adults with 
Glycogen Storage Disease Type Ia (GSDIa) 
Protocol Number 
401GSDIA01 
Protocol Version 
7.0 
Protocol Date 
Amendment 6: 16 February 2021 
 
Protocol accepted and approved by: 
 
Sponsor Signatory 
 
Vassili Valayannopoulos, MD 
Vice President, Clinical Development 
 
 
 
 
 
 
 
Signature 
 
Date 


Protocol 401GSDIA01 Version 7.0 
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PROTOCOL AMENDMENT HISTORY AND SUMMARY OF CHANGES 
The following overview summarizes significant changes to the protocol. 
Version 
Date 
Summary of Changes 
Version 1.0 
07 May 2017 
Original Protocol 
Version 2.0 
13 December 2017 
An overview of changes includes the following: 
• 
Lactic acid was updated globally to lactate for consistency. 
Lactate testing was removed globally, with the exception of 
samples collected during the controlled fasting challenge 
(Sections 1, 2, 8.2, 8.2.6.1, 8.2.6.3, 9.1.1.2, 15.1, Table 6). 
• 
The terminology for the human and mouse gene 
glucose-6-phosphatase was updated globally to G6PC and 
G6pc, respectively. The terminology for the glucose-6-
phosphatase protein was updated globally to G6Pase 
(Sections 1, 1.2, 1.3, 1.3.2, 6.1.1, 6.1.2, 8.3.1, 15.1, Table 6). 
• 
ClinicalTrials.gov identifiers for clinical studies with AAV8 
were updated as of 11 August 2017 (Section 1.2). 
• 
It was updated that subjects in each cohort will be dosed at a 
minimum of 2 weeks (14 days) apart (Sections 1.3.1, 3.1, 
3.2). 
• 
It was added that subjects will be informed of the long-term 
follow-up study during the informed consent process for this 
study. Additional regulations were cited regarding this 
process (Sections 1.3.1, 3.2.5). 
• 
It was clarified that if a stopping criterion is met, enrollment 
will be stopped, the data monitoring committee and 
regulators will be notified, and the data monitoring 
committee will meet (Sections 1.3.1, 3.1, 3.2.4, 9.3). 
• 
The clinical laboratory test sample types (eg, blood, serum, 
plasma) were removed from the protocol; this level of detail 
is included in the collection flow chart (Sections 1.3.1, 1.3.2, 
2, 3.2.2.1, 3.2.3.3, 4.1, 4.2, 5.1, 8.1.1, 8.2.6.3, 15.1, Table 6). 
 
 
• 
The primary objective and endpoint were updated to 
explicitly state the incidence of dose-limiting toxicities at 
each dose level; this is a clarifying update and does not 
affect the content of the objective or endpoint (Sections 
1.3.1, 2, 3.1). 
• 
It was clarified that dose escalation is conducted to predict 
the maximum tolerated dose (rather than the optimal 
biological dose; Sections 1.3.1, 3.1). 
• 
The maximum feasible dose of vector was updated from 
7.0 × 1013 genome copies (GC)/kg to 6.5 × 1013 GC/kg in 
mice and the safety margin was updated to 6.5-fold in terms 
of actual dose and 65-fold safety margin relative to transgene 
expression (Section 1.3.2). 


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Version 
Date 
Summary of Changes 
• 
Glomerular filtration rate assessment was removed globally 
(Sections 2, 3.2, 3.2.2.1, 3.2.2.2, 3.2.3.3, 4.1, 8.2, 15.1, 
Table 6). 
• 
Magnetic resonance imaging at Week 6 was removed 
globally (Sections 2, 8.2, 8.1.4, 10.2.3.5, 15.1, Table 6). 
• 
Anti-G6Pase antibody testing was added as an exploratory 
objective and endpoint and as a safety assessment (Sections 
2, 8.2, 8.2.6.9). 
• 
It was clarified that the decision to proceed to the next 
dosing cohort will be based on the CRM proposed dose and 
after the DMC has evaluated all safety data for all subjects in 
a dosing cohort (Section 3.1). 
• 
Text was added to allow outpatient or home study visits to 
be performed at a second participating study site other than 
the dosing site and to extend the visit duration from 1.5 
hours to 1.5 to 2 hours (Section 3.2). 
• 
Figure 2 was updated to align with the Schedule of Events 
table. 
• 
The definition of screen failures was added (Section 3.2.1). 
• 
Text was added to allow flexibility in the personalized 
dinner meal before each fasting challenge (Sections 3.2.2.1, 
3.2.3.3, 8.1.1, 15.1, and Table 6 [footnote x]). 
• 
Continuous glucose monitoring was removed globally 
(Sections 3.2, 3.2.3.3, 8.2.5, 10.2.4.5, 15.1, Table 6). 
• 
Viral shedding was replaced with vector shedding globally 
(Sections 3.2, 3.2.3.1, 8.1.3, 8.2.6.10, 10.2.4.7, 15.1, 
Table 6). 
• 
The Week 2 visit was removed globally, and inpatient study 
site visits were reduced accordingly from 6 to 5 (Section 3.2, 
15.1, Table 6). 
• 
Text stating that laboratory values meeting stopping criteria 
will result in a pause in enrollment was removed. Text was 
added to clarify that a stopping criterion must be met for 
study enrollment to be suspended. Text mandating a 
substantial amendment if a stopping criterion is met was 
revised to clarify that regulatory requirements for each 
country will be followed (Section 3.2.4). 
• 
Specific screen failure test results that could necessitate 
rescreening were removed as a general statement regarding 
rescreening is included in Section 3.2.1 (Sections 4.1, 5.1). 
• 
Exclusion criterion #8 was updated to exclude subjects based 
on the presence of, or history of treatment for, hepatitis B or 
hepatitis C (Section 4.2). 
• 
A unique identifier was removed from the primary label 
(Section 6.2.1). 


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Date 
Summary of Changes 
• 
During the fasting challenge, it was updated that either a 
central or peripheral indwelling catheter may be used for 
sample collection (Sections 8.1.1, 8.2.6.3). 
• 
 were moved to 
efficacy assessments and additional details were added 
(Sections 8.1.3, 10.2.3.5). 
• 
Vital sign measurements were removed from 2 and 6 hours 
after the start of DTX401 infusion (Sections 8.2.1, 15.1, 
Table 6 [footnote e]). 
• 
Electrocardiograms were removed from 1 hour after the start 
of infusion (Sections 8.2.3, 15.1, Table 6). 
• 
A statement was added that instructions for transmitting 
magnetic resonance imaging results will be provided 
separately (Section 8.1.4). 
 
 
• 
The names for the
 
were added to Sections 8.1.3 and 15.1 
and the questionnaires were added as appendices 
(Sections 8.1.3, 15.1, 15.3, 15.4, 15.5, Table 6). 
• 
Text on monitoring metabolic and lipid panels during steroid 
use was removed to allow Investigator discretion to 
determine the need for testing (Sections 8.2.6.1, 8.2.6.2, 
15.1, Table 6). 
• 
It was added that if genotyping results were previously 
documented from a qualified laboratory the results can be 
used to satisfy the entry criteria (Section 8.3.1). 
• 
It was added that the number of hospitalizations for 
hypoglycemic events will be collected and recorded in the 
electronic case report form (Section 8.4.1). 
• 
The definition of a dose-limiting toxicity was added (Section 
9.1.1.1). 
• 
The phone number for North America serious adverse event 
reporting was updated to 
 (Section 9.1.2.2). 
• 
Text was removed that stated the statistical analysis plan will 
be finalized prior to the start of the study (Section 10). 
• 
Detailed endpoint text was removed and a cross reference to 
Section 2 was added (Section 10.1). 
• 
The details of the continual reassessment method were 
updated to reflect the model and target toxicity 
(Sections 10.2, 10.2.1, 15.2). 
• 
The section entitled, Determination of the Optimal 
Biological Dose, and associated modeling figures were 
removed. 
• 
Sample size justification was added (Section 10.2.2). 


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Date 
Summary of Changes 
• 
The plans for adverse event presentation were updated 
(Section 10.2.4.1). 
• 
The statement that interim analyses will not bias the conduct 
of the study was removed (Section 10.2.6). 
• 
The Schedule of Events table (Table 6) was updated to 
reflect that eligibility criteria are confirmed on Day 0 
(Section 15.1, Table 6). 
 
 
• 
Sample collection for clinical chemistry was removed at 0.5, 
4, and 8 hours after the start of infusion (Section 15.1, 
Table 6 [footnote l]). 
• 
An outpatient study site or home visit was added at Day 13 
(Section 15.1, Table 6). 
• 
The references were updated. 
 
 
• 
A STAT sample was removed from the LFT sampling at 22 
hours after the start of DTX401 infusion (Section 15.1, 
Table 6). 
• 
Additional details related to the continual reassessment 
method were added (Section 15.2). 
Version 3.0 
02 March 2018 
An overview of changes includes the following: 
• 
The Sponsor name was updated globally from Dimension 
Therapeutics, Inc. to Ultragenyx Pharmaceutical, Inc. 
• 
Dosing rationale text was updated to reflect updated 
nonclinical data (Section 1.3.2). 
• 
Instructions for treating the subject’s hypoglycemia after the 
controlled fasting challenge were added (Sections 3.2.2.1, 
3.2.3.3, 8.1.1). 
Version 4.0 
18 February 2019 
An overview of changes includes the following: 
• 
The medical monitor name and contact information were 
updated (title page). 
• 
Quality of life was updated globally to health-related quality 
of life. 
• 
The stopping criteria for the controlled fasting challenge was 
updated to include symptoms of hypoglycemia 
(Sections 1.3.1, 3.1, 3.2.2.1, 3.2.3.3, 8.1.1, 8.2.6.3, Table 6). 
• 
It was added that subjects who withdraw early from Study 
401GSDIA01 will also be offered enrollment into the 
extension study (Sections 1.3.1, 3.1, 3.2.5). 
• 
An exploratory objective and endpoint were added to assess 
the impact of DTX401 on morning glucose levels. 
Corresponding assessments and analyses were added 
(Sections 2, 8.1.3, 10.2.3.4). 


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Version 
Date 
Summary of Changes 
• 
A Morning Glucose Level worksheet was added to allow the 
subject to collect glucose levels at least 2 mornings per week 
throughout the study (Section 3.2, Figure 2, Table 6). 
 
 
• 
It was added that the controlled fasting challenge, if 
clinically indicated, can be performed at an unscheduled visit 
(Section 8.1.1, Table 6). 
• 
Details related to the magnetic resonance imaging results 
were added (Sections 8.1.4, 10.2.3.5). 
• 
The version of the National Cancer Institute Common 
Terminology Criteria for Adverse Events was updated to the 
most current version rather than the previously stated version 
number (Sections 9.1.1.1, 9.1.3, 14). 
• 
The North American toll-free safety fax number was added 
(Section 9.1.2.2, Table 3). 
• 
It was clarified that pregnancy complications and elective 
terminations for medical reasons should be reported as an 
AE or SAE (Section 9.2.1). 
• 
Use of cornstarch was updated from other analyses to 
efficacy analyses (Sections 10.2.3.3, 10.2.5). 
• 
The electronic data capture system was updated from 
Medidata Rave® to Oracle Health Sciences InForm (Section 
10.3). 
• 
 
Version 5.0 
10 September 2019 
An overview of changes includes the following: 
• 
The dosing interval for subjects enrolled after 
completion of Cohort 2 was decreased from a 
minimum of 2 weeks to a minimum of 1 week 
(Sections 1.3.1, 3.1). 
• 
Language regarding dosing interval rationale was 
reorganized to aid readability (Section 1.3.1). 
• 
The starting dose for steroids for treatment of possible 
vector-induced hepatitis was increased from 40 mg/day 
to 60 mg/day (Section 8.2.6.2.1). 
• 
 
 
 
 
• 
 
 
 
 
 
• 
Language was added to specify that, following 
DTX401 administration, subjects will be discharged 
with prednisone to allow rapid treatment of possible 


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Summary of Changes 
vector-induced hepatitis if it occurs (Section 3.2.2.2). 
• 
The recommended target carbohydrate range of the 
prefasting challenge dinner meal was decreased from 
20 g to 30 g to 15 g to 20 g, and the prefasting 
challenge cornstarch dose was decreased from 35 g to 
5 g, to minimize a potential insulin spike that could 
result in abrupt hypoglycemia and to normalize 
baseline glucose levels (Sections 1.3.1, 3.2.2.1, 3.2.3.3, 
8.1.1, Table 6). 
• 
Blood sample collection for measurement of glucose 
and lactate levels was added at the beginning of the 
fasting challenge to provide baseline levels 
(Sections 8.1.1, 8.2.6.3, Table 6). 
• 
Symptoms of hypoglycemia was removed as a fasting 
challenge stopping criterion (Sections 3.2.2.1, 3.2.3.3, 
8.1.1). 
• 
Instructions for glucose and lactate samples collected 
during the fasting challenge were corrected to state that 
samples should be prepared and transported in 
accordance with the site’s standard procedures 
(Sections 8.1.1, 8.2.6.1, 8.2.6.3). 
• 
Fasting challenge data to be captured in the eCRF was 
updated (Section 8.1.1). 
• 
The wording of the secondary objective was corrected 
(Sections 1.3.1, 3.1). 
• 
Continuous glucose monitoring was added to collect 
supplemental information on glucose level trends 
throughout the study (Sections 8.1.2, 10.2.3.2, 
Table 6). 
• 
The exploratory study objective and endpoint related to 
morning glucose level were modified to glucose level 
due to the addition of continuous glucose monitoring 
(Section 2). 
• 
Collection of blood for measurement of lipid levels 
was added on the morning of hospital admission for the 
fasting challenge (Sections 3.2.2, 3.2.3.3, 8.1.1, 
Table 6). 
• 
Collection of blood for measurement of cortisol, fatty 
acid, glucagon, insulin, and ketone levels was added at 
the beginning and end of the fasting challenge, or more 
frequently at the Investigator’s discretion 
(Sections 3.2.2.1, 3.2.3.3, 8.1.1, 8.2.6.4, Table 6). 
 
 
• 
Collection of blood for measurement of cortisol levels 
was added approximately 1 week before the Week 12 
visit (Section 8.1.1, Table 6). 
• 
The interval for liver function testing was decreased 
from approximately every 4 to 5 days to a minimum of 


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Summary of Changes 
every 3 to 4 days through Week 12, and liver function 
testing may continue beyond Week 12 if clinically 
indicated (Sections 3.2.3, 3.2.3.1, 8.2.6.2, Table 6). 
• 
Assessments to be completed during outpatient study 
site or home visits were clarified (Section 3.2.3.1). 
• 
Details regarding the collection of morning glucose 
levels were clarified (Section 8.1.3). 
• 
The reporting period for hypoglycemic events was 
clarified (Section 8.2.5, Table 6). 
• 
The table of Clinical Laboratory Parameters (Table 2) 
was updated for completeness (Section 8.2.6.1). 
• 
New health-related quality of life assessments (GSDIa 
Morning Diary, GSDIa Evening Diary, Patient Global 
Impression of Severity, and Patient Global Impression 
of Change) and a subject interview at Weeks 24 and 52 
were added to guide further development of these 
assessments (Section 8.1.5, Table 6). 
• 
Language was added to clarify that a clinically 
significant change or abnormal vital sign measurement 
will be recorded as an AE or SAE if it is felt to be 
clinically significant in the medical and scientific 
judgment of the Investigator (Section 8.2.1). 
• 
Language was added to clarify that nonemergent 
hospitalization for cornstarch management or glucose 
monitoring during steroid administration for vector-
induced hepatitis will not be considered an SAE 
(Section 9.1.1.3). 
• 
The reference to clinical experience with DTX401 was 
updated from no prior experience to limited clinical 
experience (Section 9.1.2.2.1). 
• 
Language was added to clarify that Investigators 
should rate AE intensity based on medical judgment 
and that the current version of the National Cancer 
Institute Common Terminology Criteria for Adverse 
Events can be used to guide the rating of an adverse 
event (Section 9.1.3). 
 
 
• 
Language was added to clarify that, if considered 
clinically significant, increases in aminotransferase 
levels following DTX401 administration should be 
recorded as an AE or SAE with an event term of 
elevated liver function tests and graded according to 
the General Guidelines for Grading Events Not 
Captured by the CTCAE (Section 9.1.3, Table 4). 
• 
Language regarding DMC review was updated to 
include review at the end of the study; language 
regarding DMC membership was updated to reflect 
current DMC membership; and section content was 


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Summary of Changes 
reorganized to aid readability (Sections 1.3.1, 3.1, 9.3). 
• 
Language was added to clarify that the study will stop 
when the maximum sample size has been enrolled or at 
the Sponsor’s discretion (Section 10.2.1). 
• 
Language was added to indicate that additional interim 
analyses may be conducted at the Sponsor’s discretion 
(Section 10.2.6). 
• 
The Screening Period was increased from 42 days to 56 
days to allow additional time for screening assessments 
to be completed (Section 3.2.1, Table 6). 
• 
The overall study duration was increased from 
58 weeks to 60 weeks due to the increased Screening 
Period (Section 3.2). 
• 
Figure 2 was updated to align with modifications to the 
protocol. 
• 
A recommendation to collect blood samples for AAV8 
neutralizing antibody testing and G6PC genotyping at 
the time written informed consent is provided was 
added due to the time required to analyze these samples 
(Sections 3.2.1, 8.2.6.6, 8.3.1, Table 6). 
• 
Screening assessments to be repeated for screen failure 
subjects who are rescreened were clarified 
(Section 3.2.1). 
• 
Recording of prior and concomitant medications, 
therapies, and procedures was limited to relevant 
information (Section 6.4). 
• 
Recording of medical history was limited to relevant 
information (Section 8.4.1). 
• 
The type of sample to be collected was specified 
(Sections 8.2.6.6, 8.2.6.7, 8.2.6.8, 8.2.6.9). 
 
 
• 
The frequency of assessing prescribed diet and diet 
intake was increased to weekly for the duration of the 
study (Section 8.4.2, Table 6). 
• 
The frequency of assessing prescribed cornstarch (or 
equivalent) and cornstarch (or equivalent) intake was 
increased to weekly for the duration of the study 
(Section 8.4.3, Table 6). 
• 
Measurement of weight was added at Weeks 6, 12, 24, 
and 36 (Table 6). 
• 
Magnetic resonance imaging was moved from safety 
assessments to efficacy assessments (Sections 8.1.4, 
8.2, 10.2.3.5). 
• 
The reference to the electrocardiogram following 
DTX401 administration was removed (Section 3.2.2.2). 
This assessment was removed in Amendment 1.  
• 
Language regarding management of GSDIa was 


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Summary of Changes 
clarified (Sections 1, 1.3). 
• 
ClinicalTrials.gov identifiers for clinical studies using 
AAV8-mediated gene transfer was updated to include 
current relevant examples (Section 1.2). 
• 
The Schedules of Events were combined into 1 table, 
assessments were grouped by category, and the 
footnotes were updated to aid readability (Table 6). 
• 
The term of record retention was updated to 25 years to 
align with regulatory requirements (Section 12.8). 
• 
The reference list was updated (Section 14). 
• 
The protocol was reformatted, and numbering of 
sections, figures, and tables was updated. 
Version 6.0 
28 October 2019 
An overview of changes includes the following: 
• 
A cohort was added to assess a prophylactic oral 
steroid regimen for the prevention of vector-induced 
hepatitis following DTX401 administration 
(Sections 1.3.1, 3.1). 
• 
A prophylactic oral steroid regimen was added for 
Cohort 4, which will be initiated on Day 1 after 
completion of the Day 0 controlled fasting challenge 
and before DTX401 administration (Sections 1.3.1, 3.1, 
3.2.2.1, 8.2.6.2, 8.2.6.2.2). 
• 
Language was added to specify that Cohorts 1, 2, and 3 
will receive reactive oral steroid treatment for possible 
vector-induced hepatitis (Sections 1.3.1, 3.1, 8.2.6.2.1). 
 
 
• 
Language was added to specify that, if it is necessary to 
modify the reactive steroid regimen, the agreed upon 
regimen should be documented in the subject’s source 
documentation (Section 8.2.6.2.1). 
• 
The design rationale description was reorganized to aid 
readability (Section 1.3.1). 
• 
The design rationale and study overview were updated 
to include doses and steroid regimens administered, 
and outcome of DMC reviews, for Cohorts 1 and 2; 
doses and steroid regimens planned for Cohorts 3 and 
4; and a description of modifications to the controlled 
fasting challenge (Sections 1.3.1, 3.1). 
• 
Language was added to clarify that blood samples for 
measurement of cortisol, fatty acid, glucagon, insulin, 
and ketone levels should be collected at the beginning 
and end of the fasting challenge, or more frequently at 
the Investigator’s discretion, if possible 
(Sections 3.2.2.1, 3.2.3.3, 8.1.1, 8.2.6.4, Table 6). 
• 
Language was added to clarify that a blood sample for 
measurement of cortisol levels should be collected 
approximately 1 week before the Week 12 visit if 


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possible (Section 8.1.1, Table 6). 
• 
Language was added to specify that subjects in Cohort 
4 will be discharged with prednisone per the 
prophylactic steroid regimen (Section 3.2.2.2). 
• 
Language was added to clarify that the subject 
interview at Week 52 will include questions about the 
subject’s experience in the study (Section 8.1.5, 
Table 6). 
• 
Language was added to clarify that prescribed diet and 
diet intake should be assessed during scheduled study 
visits and, if possible, on a weekly basis for the 
duration of the study (Section 8.4.2, Table 6). 
• 
Language was added to clarify that prescribed 
cornstarch (or equivalent) and cornstarch (or 
equivalent) intake should be assessed during scheduled 
study visits and, if possible, on a weekly basis for the 
duration of the study (Section 8.4.3, Table 6). 
• 
Instructions for reviewing the Morning Glucose Level 
monitoring worksheet were clarified (Table 6). 
• 
The timing of DMC reviews was updated 
(Sections 1.3.1, 9.3). 
 
 
 
• 
The sample size was increased from approximately 
12 subjects to approximately 18 subjects due to the 
addition of Cohort 4 and the possibility to expand a 
cohort to confirm the findings of the cohort 
(Sections 3.2, 10.2.1, 10.2.2). 
• 
Language was added to clarify that the CRM model 
will estimate the MTD of DTX401 regardless of the 
steroid approach used, reactive vs prophylactic 
(Section 10.2.2). 
• 
Figure 2 was updated to align with modifications to the 
protocol. 
• 
A date field was added to the new health-related 
quality of life assessments and the document version 
was updated (Sections 15.6, 15.7, 15.8, 15.9). 
Version 7.0 
16 February 2021 
An overview of changes includes the following: 
• 
The Sponsor Contact was changed from 
, 
MD to Vassili Valayannopoulos, MD 
• 
The sample size was decreased from approximately 
18 subjects to approximately 12 subjects based on 
current plans to end the study after Cohort 4. 
(Sections 3.2, 10.2.1, 10.2.2). 
• 
The definition of euglycemia for the end of the 
controlled fasting challenge changed from ≥ 60 mg/dL 
(≥ 3.33 mmol/L) to ≥ 54 mg/dL (≥ 3.0 mmol/L). 


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Summary of Changes 
(Sections 1.3.1, 1.3.2, 2, 3.1, 3.2.2.1, 3.2.3.3, 8.1.1, 
8.2.6.3, 10.2.3.1, 15.1).   
• 
The following changes were made to the controlled 
fasting challenge assessment (Sections 1.3.1, 3.1, 
3.2.2.1, 8.1.1, 8.2.6.1, 8.2.6.3, 8.2.6.4, 15.1): 
o The schedule was updated to remove the CFC 
assessment at Week 6, and make it optional at 
Week 12 to ensure the safety of subjects who 
are taking steroids. This is a specific 
amendment for Cohort 4 where all subjects 
will be receiving a prophylactic steroid 
regimen between Day 0 and Week 8. Steroids 
can be responsible for adverse events in GSDIa 
patients, and require caution in any situation 
that could cause metabolic stress such as a 
fasting challenge. 
o The composition of the dinner meal was 
updated from a prespecified carbohydrate 
range (15–20 g) to a personalized meal for 
each subject, including a target carbohydrate 
range and overall composition in protein, fats 
and dietary fiber that is as close as possible to 
the subject’s most current dinner prescription 
but not higher than the carbohydrate content of 
the dinner consumed at their baseline fasting 
challenge  
o The prefasting cornstarch dose was updated 
from 5 g to match the respective subject’s most 
recent cornstarch prescription and timing post 
dinner 
o Blood sample assessments at the beginning and 
end of the controlled fasting challenge were 
updated to include cortisol, ACTH, free fatty 
acids, glucagon, insulin, C-peptide, growth 
hormone, IGFBP1, alanine and ketone levels 
(3-hydroxy butyrate), and the instructions 
regarding laboratory sample collection before 
and during the controlled fasting challenge 
have been revised for clarity. 
o A final sample for glucose, lactate, growth 
hormone, IGFBP1, ACTH, and cortisol 
measurement has been added 30 minutes after 
the end of the controlled fasting challenge. 
o Capillary glucose measurement has been 
added, to be performed at the same time points 
as blood collection for STAT analyse.  


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Version 
Date 
Summary of Changes 
• 
Week 6 visit was changed to an outpatient visit, and the 
following assessments were removed from this visit: 
controlled fasting challenge (including all laboratory 
assessments required before and during the controlled 
fasting challenge),
 
 
, GSDIa morning diary, 
GSDIa evening diary, pregnancy test (as applicable 
(Sections 2, 3.2, Figure 2, 3.2.3.2, 3.2.3.3, 8.1.5, 
8.2.6.3, 8.2.6.4, 10.2.3.1, 15.1) 
• 
Week 12 was changed from IP to OP if the subject is 
still receiving prednisone at the time of the Week 12 
Visit. (Section 15.1)  
• 
Language has been added to Section 8.2.6.2.2 to 
provide guidance on additional prednisone use after the 
protocol-specified prednisone taper has been competed, 
and guidance regarding the timing of routine 
vaccinations relative to prednisone use.   
• 
Targeted physical examinations were added to 
outpatient visits at Weeks 4, 6, and 36 (Figure 2, 
Section 15.1) 
• 
Language was added to specify that 
 will be 
conducted after the controlled fasting challenge is 
complete (Figure 2, Sections 3.2.2.1, 3.2.3.3, 8.1.4, 
15.1) 
• 
The contact information for SAE and pregnancy 
reporting was updated (Section Sections 9.1.2.2 and 
Section 9.2.1) 
• 
A new section, Section 3.3, was added to address 
changes to the study schedule and/or study operations 
due to the COVID-19 pandemic. 
• 
A new section, Section 8.1.6, has been added to 
provide details regarding the telephone interviews that 
are conducted at Weeks 24 and 52.  Text related to 
these interviews has been removed from Section 8.1.5. 
• 
The definition of dose-limiting toxicity was revised to 
include events based on the Sponsor’s evaluation of 
relatedness to DTX401, as well as the Investigator’s. 
(Section 9.1.1.1) 
• 
Text was added to specify that the dose of DTX401 in 
this study is in genome copies as measured by 
 
(Section 10.2.2) 
• 
Statistical analysis methodology sections were revised 
and reference to the Statistical Analysis Plan added  
(Sections 10.2.3.2, 10.2.3.3, 10.2.3.6)  


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Version 
Date 
Summary of Changes 
• 
A sample for ACTH assessment was added 1 week 
before the Week 12 visit (in addition to cortisol) 
(Sections 8.2.6.4, 15.1) 
• 
Reference citations to outdated CFR, ICH GCP 
guidelines, and CTCAE version have been removed; 
this study adheres to current GCP guidance and applies 
current CTCAE criteria (Sections 1.3.1 3.2.5, 
9.1.1.1, 9.1.3) 


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TABLE OF CONTENTS 
PROTOCOL AMENDMENT HISTORY AND SUMMARY OF CHANGES ..............................3 
PROTOCOL SYNOPSIS...............................................................................................................22 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................35 
1. 
INTRODUCTION ......................................................................................................37 
1.1. 
Adeno-Associated Viral Vectors ................................................................................38 
1.2. 
Selection of the AAV Clinical Candidate ...................................................................39 
1.3. 
Study Rationale ...........................................................................................................40 
1.3.1. 
Design Rationale .........................................................................................................40 
1.3.2. 
Dosing Rationale ........................................................................................................44 
2. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................46 
3. 
INVESTIGATIONAL PLAN .....................................................................................48 
3.1. 
Study Overview ..........................................................................................................48 
3.2. 
Overall Study Duration and Follow-Up .....................................................................50 
3.2.1. 
Screening Period .........................................................................................................53 
3.2.2. 
Baseline Period ...........................................................................................................54 
3.2.2.1. 
Baseline Visit – Day 0 ................................................................................................54 
3.2.2.2. 
Baseline Visit – Day 1 ................................................................................................55 
3.2.3. 
Follow-up Period ........................................................................................................55 
3.2.3.1. 
Outpatient Study Site or Home Visits ........................................................................56 
3.2.3.2. 
Outpatient Visits .........................................................................................................56 
3.2.3.3. 
Inpatient Visits ............................................................................................................56 
3.2.4. 
Safety Stopping Criteria .............................................................................................57 
3.2.5. 
End of Study ...............................................................................................................58 
3.3. 
Changes to the Protocol due to COVID-19 ................................................................58 
4. 
SUBJECT SELECTION .............................................................................................59 
4.1. 
Inclusion Criteria ........................................................................................................59 
4.2. 
Exclusion Criteria .......................................................................................................59 
5. 
SCREENING AND DOSING PROCEDURES .........................................................61 
5.1. 
Subject Screening .......................................................................................................61 
5.2. 
Subject Dosing ............................................................................................................61 
6. 
STUDY TREATMENT ..............................................................................................62 


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6.1. 
Identity of Study Product ............................................................................................62 
6.1.1. 
Description of DTX401 ..............................................................................................62 
6.1.2. 
Components Used for Manufacturing ........................................................................62 
6.2. 
Management of Clinical Supplies ...............................................................................62 
6.2.1. 
Packaging and Labeling ..............................................................................................62 
6.2.2. 
Storage of DTX401 .....................................................................................................62 
6.2.3. 
Study Product Accountability .....................................................................................63 
6.2.4. 
Transmission of Infectious Agents .............................................................................63 
6.3. 
Treatment Schedule and Administration ....................................................................63 
6.3.1. 
Administration of DTX401 .........................................................................................63 
6.3.2. 
Treatment Compliance ................................................................................................63 
6.4. 
Prior and Concomitant Medications, Therapies, and Procedures ...............................64 
6.4.1. 
Permitted Medications ................................................................................................64 
6.4.2. 
Prohibited Medications ...............................................................................................64 
7. 
WITHDRAWAL OF SUBJECTS FROM THE STUDY ...........................................65 
7.1. 
Study Withdrawal .......................................................................................................65 
7.2. 
Subject Replacement ..................................................................................................65 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................66 
8.1. 
Efficacy Assessments .................................................................................................66 
8.1.1. 
Symptom-Free Euglycemia (Controlled Fasting Challenge) .....................................66 
8.1.2. 
Continuous Glucose Monitoring .................................................................................68 
8.1.3. 
Morning Glucose Levels .............................................................................................68 
8.1.4. 
Magnetic Resonance Imaging .....................................................................................68 
8.1.5. 
 ................................69 
8.1.6. 
Endpoint Outcomes Interviews ...................................................................................69 
8.2. 
Safety Assessments .....................................................................................................70 
8.2.1. 
Vital Sign Measurements ............................................................................................70 
8.2.2. 
Physical Examination .................................................................................................71 
8.2.3. 
Electrocardiograms .....................................................................................................71 
8.2.4. 
Liver Ultrasound .........................................................................................................72 
8.2.5. 
Hypoglycemic Events .................................................................................................72 
8.2.6. 
Clinical Laboratory Assessments ...............................................................................72 
8.2.6.1. 
Clinical Laboratory Parameters ..................................................................................72 


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8.2.6.2. 
Elevation of Liver Function Tests ..............................................................................73 
8.2.6.3. 
Lactate .........................................................................................................................76 
8.2.6.4. 
Other Controlled Fasting Challenge Laboratory Assessments ...................................77 
8.2.6.5. 
24-Hour Urine Collection ...........................................................................................77 
8.2.6.6. 
Neutralizing Antibodies to Adeno-Associated Virus Serotype 8 ...............................77 
8.2.6.7. 
Cell-Mediated Immune Response ...............................................................................77 
8.2.6.8. 
Adeno-Associated Virus Serotype 8 Binding Antibody Immunoglobulin G 
Assay ...........................................................................................................................78 
8.2.6.9. 
Anti-Glucose-6-Phosphatase Antibody Assay ...........................................................78 
8.2.6.10. 
Vector Shedding .........................................................................................................78 
8.2.6.11. 
Blood for Vector Genome Determination ..................................................................78 
8.3. 
Genotyping .................................................................................................................78 
8.3.1. 
Glucose-6-Phosphatase Genotyping ...........................................................................78 
8.4. 
Demographic and Other Assessments ........................................................................78 
8.4.1. 
Demographic, Medical, and GSDIa History Assessments .........................................78 
8.4.2. 
Assessment of Daily Prescribed Diet and Daily Diet Intake ......................................79 
8.4.3. 
Assessment of Daily Prescribed Cornstarch (or Equivalent) and Daily 
Cornstarch (or Equivalent) Intake ..............................................................................79 
9. 
SAFETY MONITORING AND REPORTING .........................................................80 
9.1. 
Adverse Events and Serious Adverse Events .............................................................80 
9.1.1. 
Definitions ..................................................................................................................80 
9.1.1.1. 
Dose-Limiting Toxicity ..............................................................................................80 
9.1.1.2. 
Adverse Events ...........................................................................................................80 
9.1.1.3. 
Serious Adverse Events ..............................................................................................80 
9.1.2. 
Safety Reporting .........................................................................................................81 
9.1.2.1. 
Adverse Events ...........................................................................................................81 
9.1.2.2. 
Serious Adverse Events ..............................................................................................81 
9.1.3. 
Assessment of Severity/Toxicity ................................................................................82 
9.1.4. 
Assessment of Causality .............................................................................................83 
9.1.5. 
Follow-Up of Subjects Reporting Adverse Events .....................................................84 
9.2. 
Procedures for Handling Special Situations ...............................................................84 
9.2.1. 
Pregnancy and Birth Control ......................................................................................84 
9.2.2. 
Treatment Noncompliance ..........................................................................................85 


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9.2.2.1. 
Overdose Management ...............................................................................................85 
9.2.2.2. 
Medication Errors .......................................................................................................85 
9.3. 
Data Monitoring Committee .......................................................................................86 
10. 
STATISTICAL AND ANALYTICAL PLAN ...........................................................87 
10.1. 
Endpoints ....................................................................................................................87 
10.2. 
Statistical Analysis Methodology ...............................................................................87 
10.2.1. 
The Continual Reassessment Method .........................................................................87 
10.2.2. 
Sample Size Justification ............................................................................................88 
10.2.3. 
Efficacy Analyses .......................................................................................................88 
10.2.3.1. 
Symptom-Free Euglycemia ........................................................................................88 
10.2.3.2. 
Continuous Glucose Monitoring .................................................................................88 
10.2.3.3. 
Use of Cornstarch (or Equivalent) ..............................................................................89 
10.2.3.4. 
Morning Glucose Levels .............................................................................................89 
10.2.3.5. 
 .....................................................................................89 
10.2.3.6. 
 .....................................................89 
10.2.4. 
Safety Analyses ..........................................................................................................89 
10.2.4.1. 
Adverse Events ...........................................................................................................89 
10.2.4.2. 
Physical Examination Findings ..................................................................................89 
10.2.4.3. 
Vital Sign Measurements ............................................................................................89 
10.2.4.4. 
Electrocardiogram Results ..........................................................................................90 
10.2.4.5. 
Hypoglycemic Events .................................................................................................90 
10.2.4.6. 
Clinical Laboratory Assessment Results ....................................................................90 
10.2.4.7. 
Other Laboratory Results ............................................................................................90 
10.2.5. 
Other Analyses ............................................................................................................90 
10.2.6. 
Interim Analysis ..........................................................................................................90 
10.3. 
Data Quality Assurance ..............................................................................................91 
10.3.1. 
Data Management .......................................................................................................91 
11. 
ETHICS ......................................................................................................................93 
11.1. 
Institutional Review Board, Independent Ethics Committee, and Institutional 
Biosafety Committee ..................................................................................................93 
11.2. 
Ethical Conduct of the Study ......................................................................................93 
11.3. 
Subject Information and Consent ...............................................................................93 
12. 
INVESTIGATOR’S OBLIGATIONS ........................................................................94 


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12.1. 
Confidentiality ............................................................................................................94 
12.2. 
Financial Disclosure and Obligations .........................................................................94 
12.3. 
Investigator Documentation ........................................................................................95 
12.4. 
Study Conduct ............................................................................................................95 
12.5. 
Adherence to Protocol ................................................................................................95 
12.6. 
Adverse Events and Study Report Requirements .......................................................95 
12.7. 
Investigator’s Final Report .........................................................................................96 
12.8. 
Record Retention ........................................................................................................96 
12.9. 
Publications .................................................................................................................96 
13. 
STUDY MANAGEMENT .........................................................................................97 
13.1. 
Monitoring ..................................................................................................................97 
13.1.1. 
Monitoring of the Study ..............................................................................................97 
13.1.2. 
Inspection of Records .................................................................................................97 
13.2. 
Management of Protocol Amendments and Deviations .............................................97 
13.2.1. 
Modification of the Protocol .......................................................................................97 
13.2.2. 
Protocol Deviations ....................................................................................................97 
13.3. 
Study Termination ......................................................................................................98 
13.4. 
Final Report ................................................................................................................98 
14. 
REFERENCE LIST ..................................................................................................100 
15. 
APPENDICES ..........................................................................................................106 
15.1. 
Appendix 1: Schedule of Events ...............................................................................106 
15.2. 
Appendix 2: Continual Reassessment Method Details .............................................113 
15.3. 
Appendix 3: 
.........................................................................................114 
15.4. 
Appendix 4: 
 .........................................118 
15.5. 
Appendix 5: 
 ................................................120 
15.6. 
Appendix 6: Glycogen Storage Disease Type Ia (GSDIa) Morning Diary ..............125 
15.7. 
Appendix 7: Glycogen Storage Disease Type Ia (GSDIa) Evening Diary ...............127 
15.8. 
Appendix 8: 
 .....................................133 
15.9. 
Appendix 9: 
 .....................................135 


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LIST OF TABLES 
Table 1: 
Allometric Scaling and Dilution Factors for Determining the Minimal 
Effective Dose of DTX401 in Humans ......................................................................45 
Table 2: 
Clinical Laboratory Parameters ..................................................................................73 
Table 3: 
Ultragenyx Contact Information for SAE Reporting ..................................................82 
Table 4: 
General Guidelines for Grading Events Not Captured by the CTCAE ......................83 
Table 5: 
Classification and Criteria for AE Relationship to Study Product .............................83 
Table 6: 
Schedule of Events – Scheduled Study Visits ..........................................................107 
 
LIST OF FIGURES 
Figure 1: 
Overview of Glycogenesis and Glycogenolysis .........................................................37 
Figure 2: 
Study Overview ..........................................................................................................51 
 


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PROTOCOL SYNOPSIS 
Protocol Number: 
401GSDIA01 
Title: 
A Phase 1/2, Open-Label Safety and Dose-Finding Study of Adeno-Associated Virus 
(AAV) Serotype 8 (AAV8)-Mediated Gene Transfer of Glucose-6-Phosphatase (G6Pase) 
in Adults with Glycogen Storage Disease Type Ia (GSDIa) 
Sponsor: 
Ultragenyx Pharmaceutical Inc. (Ultragenyx) 
840 Memorial Drive 
Cambridge, MA 02139 
Study Phase: 
Phase 1/2 
Sample Size: 
The study is anticipated to enroll approximately 12 subjects 
Study Sites: 
Up to 12 global study sites 
Indication: 
Glycogen storage disease type Ia (GSDIa) 
Primary 
Objective: 
• 
To determine the safety of single intravenous (IV) doses of DTX401 in adults with 
GSDIa, including the incidence of dose-limiting toxicities (DLTs). 
Secondary 
Objective: 
• 
To establish a dose of DTX401 that achieves symptom-free euglycemia (glucose 
≥ 54 mg/dL [≥ 3.0 mmol/L]) in a setting of a controlled fasting challenge to allow 
further clinical development. 
Exploratory 
Objectives: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary 
Endpoints: 
• 
The incidence of adverse events (AEs), including the incidence of DLTs at each dose 
level, treatment-emergent adverse events (TEAEs), and serious adverse events (SAEs) 
for each dosing cohort, assessed by severity and relationship to study product. 
Secondary 
Endpoints: 
• 
The change from Baseline in time (in minutes) to first hypoglycemic event (defined as 
glucose < 54 mg/dL [< 3.0 mmol/L]) during a controlled fasting challenge at 12, 24, 
and 52 weeks after IV administration of DTX401. 


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Exploratory 
Endpoints: 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject 
Population: 
Inclusion Criteria 
Each subject must meet all of the following criteria at Screening to be enrolled in this 
study: 
1. Willing and able to provide written informed consent. 
2. Males and females ≥ 18 years of age. 
3. Documented GSDIa with confirmation by molecular testing. 
4. Documented history of ≥ 1 hypoglycemic event with glucose < 60 mg/dL 
(< 3.33 mmol/L). 
5. Subject’s GSDIa disease is stable as evidenced by no hospitalization for severe 
hypoglycemia during the 4-week period preceding the Screening Visit. 
6. Hematology and coagulation panel results are within the normal range or, if outside 
the normal range, are deemed not clinically significant in the opinion of the 
Investigator. 
7. No known allergic reaction to any component of DTX401. 
8. Willing and able to comply with study procedures and requirements, including 
periodic inpatient hospitalization, frequent blood collections, and 24-hour urine 
collection. 


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9. Males and females of childbearing potential must be willing to use effective 
contraception at the time of administration of DTX401 and for 52 weeks following 
administration of DTX401 to prevent the potential transmission of the AAV vector 
(Section 9.2.1). 
Exclusion Criteria: 
Subjects who meet any of the following criteria at Screening will be excluded from the 
study: 
1. Screening or Baseline (Day 0) glucose level < 60 mg/dL (< 3.33 mmol/L); subjects 
may be rescreened after glucose is controlled and stable, at the discretion of the 
Investigator. 
2. Liver transplant, including hepatocyte cell therapy/transplant. 
3. Presence of liver adenoma > 5 cm in size. 
4. Presence of liver adenoma > 3 cm and ≤ 5 cm in size that has a documented annual 
growth rate of ≥ 0.5 cm per year. 
5. Significant hepatic inflammation or cirrhosis as evidenced by imaging or any of the 
following laboratory abnormalities: alanine aminotransferase (ALT) or aspartate 
aminotransferase > the upper limit of normal (ULN), total bilirubin > 1.5 × ULN, or 
alkaline phosphatase > 2.5 × ULN. Liver function tests may be repeated during the 
Screening Period at the Investigator’s discretion. 
6. Serum creatinine > 2.0 mg/dL. 
7. Triglycerides ≥ 1000 mg/dL at the time of the Screening Visit. 
8. Presence of active, or history of treatment for, hepatitis B virus or hepatitis C virus 
infection. 
9. History of human immunodeficiency virus 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 viral load > 200 copies/mL, on 2 separate occasions, as measured by 
polymerase chain reaction. 
10. 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 
nonmelanoma skin cancer. 
11. Active infection (viral or bacterial). 
12. Anti-AAV8 neutralizing antibody titer ≥ 1:5. 
13. Participation (current or previous) in another gene transfer study. 
14. Participation in another investigational product study within 3 months of Screening. 
15. Has a positive serum pregnancy test at Screening (females of childbearing potential 
only), a positive urine pregnancy test at Baseline (Day 0; females of childbearing 
potential only), or is nursing. 
16. 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 1/2, open-label, single-arm, multicenter, safety and dose-finding study of 
DTX401 in adults with GSDIa. The primary objective of the study is to determine the 
safety of single IV doses of DTX401, including the incidence of DLTs. The secondary 
objective of the study is to establish a dose of DTX401 that achieves symptom-free 
euglycemia (glucose ≥ 54 mg/dL [≥ 3.0 mmol/L]) in a setting of a controlled fasting 
challenge to allow further clinical development. 


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Eligible subjects may be enrolled into 1 of the following cohorts of 3 subjects each and 
receive a single IV infusion of DTX401. 
• 
Cohort 1: Dose 1 (2.0 × 1012 genome copies [GC]/kg) with a reactive steroid regimen 
(prednisone starting dose of 40 mg/day) 
• 
Cohort 2: Dose 2 (6.0 × 1012 GC/kg) with a reactive steroid regimen (prednisone 
starting dose of 40 mg/day) 
• 
Cohort 3: Dose 2 (6.0 × 1012 GC/kg) with an optimized reactive steroid regimen 
(prednisone starting dose of 60 mg/day) 
• 
Cohort 4: Dose 2 (6.0 × 1012 GC/kg) with a prophylactic steroid regimen 
A cohort may be expanded to include additional subjects to confirm the findings for the 
cohort. 
Subjects in Cohorts 1 and 2 were dosed at a minimum of 2 weeks (14 days) apart. Subjects 
in subsequent cohorts will be dosed at a minimum of 1 week (7 days) apart. 
For Cohorts 1 and 2, there was a minimum of 12 weeks (84 days) between dosing of the 
last subject in a dosing cohort and the first subject in the next dosing cohort. After the third 
subject in each cohort reached the 12-week time point, the continual reassessment method 
(CRM) proposed a dose for the next cohort using the collected data from the previous 
cohort. The decision to proceed was made after the data monitoring committee (DMC) 
evaluated at least 12 weeks of safety data for all subjects in the dosing cohort. 
After reviewing Week 12 data from all subjects in Cohort 1, the DMC concluded that it 
was safe to enroll 3 additional subjects into Cohort 2 at Dose 2 (6.0 × 1012 GC/kg). After 
reviewing Week 12 data from all subjects in Cohort 2, the DMC concluded that it was safe 
to enroll 3 additional subjects into Cohort 3 at Dose 2 (6.0 × 1012 GC/kg) with an 
optimized reactive steroid regimen. An optimized reactive steroid regimen is expected to 
manage the elevations in liver aminotransferase levels observed in Cohorts 1 and 2 
following DTX401 administration. If the optimized reactive steroid regimen does not 
sufficiently manage elevations in liver aminotransferase levels in Cohort 3, then Cohort 4 
will be enrolled. Subjects in Cohort 4 will receive a prophylactic steroid regimen. 
Enrollment into Cohort 4 may begin following completion of enrollment into Cohort 3. 
The controlled fasting challenge was also modified following DMC review of Week 12 
data from subjects in Cohort 2. To minimize a potential insulin spike that could result in 
abrupt hypoglycemia and normalize baseline glucose levels, the recommended target 
carbohydrate range of the prefasting challenge dinner meal was decreased from 20 g to 
30 g to 15 g to 20 g and the prefasting challenge cornstarch dose was decreased from 35 g 
to 5 g. 
However, further analysis and review of fasting challenge data after changing the 
prefasting cornstarch dose to 5g showed significantly lower fasting times in cohorts 2 
(W52 and W78) and 3 (W24, W32 and W52). In most instances, low post-prandial levels 
of blood glucose associates, persistence of high circulating insulin levels, and an 
inadequate adrenergic response exemplified by the absence of a cortisol increase to 
hypoglycemia make it challenging to interpret these results. Available CGM recordings 
have shown an absence of nocturnal hypoglycemia in these subjects despite an overall 
reduced frequency and total amount of cornstarch. The reason that several subjects can 
now sleep through the night at home without experiencing hypoglycemia in the absence of 
cornstarch consumption, but have shorter time to hypoglycemia during the inpatient fasting 
challenge is unclear. It could be attributed to the artificial threshold of 60 mg/dL for 
stopping the fasting challenge. This threshold may not allow adequate glucose release to be 
induced in subjects with higher insulin and lower cortisol levels. In the home setting, in the 
absence of prolonged fasting, subjects clearly do better as their glucose release seems to be 


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better induced under their personalized dietary management, thereby preventing their 
glucose levels from falling to dangerous levels. 
With Protocol Amendment 6, the dinner meal will be personalized for each subject, and 
will include a target carbohydrate range and overall composition in protein, fats and dietary 
fibers that is as close as possible to the subject’s most current dinner prescription but not 
higher than the carbohydrate content of the dinner consumed at their baseline fasting 
challenge. The prefasting cornstarch dose and time of consumption will be per the 
respective subject’s most recent cornstarch prescription and daily regimen at home. In 
addition, the threshold for stopping the test was lowered to 54 mg/dL (3 mmol/L) or when 
the subjects present signs and symptoms of hypoglycemia. Signs and symptoms of 
hypoglycemia associated with an adrenergic reaction and cerebral glucopenia and most 
physiological hormonal and metabolic responses to hypoglycemia may not occur in these 
subjects until they reach these levels of blood glucose values. CGM recording during the 
fasting test will provide continuous glucose measurement data that will allow Investigators 
to closely monitor subjects when they reach the lower range of blood glucose (ie, below 60 
mg/dL). 
Subjects enrolled in Study 401GSDIA01 will be monitored for 52 weeks following 
DTX401 administration. After completion of the Week 52 visit or early withdrawal, 
subjects will be offered enrollment into a 4-year extension study in accordance with 
regulatory authority regulations and ICH GCP. During the informed consent process for 
this study, subjects will be informed of the 4-year extension study in order to maximize 
subject enrollment into the extension study. 
Study 
Methodology: 
Screening Period 
After a subject has provided written informed consent and within the 56 days prior to 
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. Screening assessments may be 
performed on more than 1 day; all assessments must be completed and results available and 
reviewed within the 56-day Screening Period prior to Day 0. 
Screening assessments include recording of the following: demographic data; medical and 
GSDIa history; prior medications, therapies, and procedures; vital sign measurements; and 
height and weight. A 12-lead electrocardiogram (ECG) and a complete physical 
examination will be performed. Blood samples will be collected for hepatitis B virus, 
hepatitis C virus, and human immunodeficiency virus status; serum pregnancy testing (for 
females of childbearing potential only); G6PC genotyping; AAV8 neutralizing antibody 
testing; AAV8 binding antibody immunoglobulin G (IgG) testing; and clinical laboratory 
assessments (clinical chemistry [including liver function tests], hematology, and 
coagulation panel). It is recommended that blood samples for G6PC genotyping and AAV8 
neutralizing antibody testing be collected at the time written informed consent is provided. 
A urine sample will be collected for urinalysis. 
An ultrasound of the liver will be performed. Adverse events and SAEs will be monitored 
after the subject has provided written informed consent. The number of symptomatic 
hypoglycemic events with documented glucose of < 60 mg/dL (< 3.0 mmol/L) that 
occurred during the previous 52 weeks will be recorded. The subject’s daily prescribed 
diet, daily diet intake, daily prescribed cornstarch (or equivalent), and daily cornstarch (or 
equivalent) intake will be recorded during scheduled study visits and, if possible, on a 
weekly basis through the Week 52 visit or early withdrawal. 
The site will provide copies of the GSDIa Morning Diary and GSDIa Evening Diary to 
subjects and instruct them to bring the completed assessments to the Day 0 and Weeks 12, 
24, and 52 visits. 
The site will provide a continuous glucose monitoring (CGM) device to the subject after 
determining that the subject is eligible for the study. Subjects will be educated on the 


Protocol 401GSDIA01 Version 7.0 
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appropriate care and use of the CGM device and sensors, and instructed to wear the CGM 
device through the Week 52 visit or early withdrawal. 
Day 0 – Baseline Assessments 
Subjects will be admitted to the study site or hospital on Day 0 and discharged 
approximately 24 hours after administration of DTX401 (on Day 2). Each subject will 
remain on his or her prescribed diet for the duration of the inpatient stay. A blood sample 
for measurement of lipid levels will be collected on the morning of hospital admission. The 
sample should be collected at least 2 to 4 hours after the subject’s last meal. 
A urine pregnancy test will be administered (for females of childbearing potential only). 
Blood samples will be collected for clinical laboratory assessments (clinical chemistry 
[including liver function tests], hematology, and coagulation panel), AAV8 neutralizing 
antibody testing, AAV8 binding antibody IgG testing, cell-mediated immune response to 
AAV8 and G6Pase testing, and anti-G6Pase antibody testing. A urine sample will be 
collected for urinalysis. Saliva, urine, and stool samples will be collected to provide a 
baseline for assessment of vector shedding. A 12-lead ECG and a targeted physical 
examination will be performed. Vital sign measurements and weight will be recorded. 
Adverse events and SAEs will be monitored. The number of symptomatic hypoglycemic 
events with documented glucose of < 60 mg/dL (< 3.0 mmol/L) that occurred since the last 
visit; concomitant medications, therapies, and procedures; and the subject’s daily 
prescribed diet, daily diet intake, daily prescribed cornstarch (or equivalent), and daily 
cornstarch (or equivalent) intake will be recorded. 
Subjects will complete the 
 
 prior to invasive 
assessments being conducted. Subjects will complete the GSDIa Morning Diary and 
GSDIa Evening Diary daily for 7 days leading up to and including the Day 0 visit. 
Subjects will participate in a controlled fasting challenge. The Investigator or delegated 
sub-investigator will review the results of all laboratory assessments performed on the first 
day of the inpatient visit, including morning cortisol. Subjects should wear their CGM 
device throughout the fasting challenge, and should not change the sensor prior to the 
assessment. Before the controlled fasting challenge begins, the study site will provide 
dinner for the subject. The dinner meal will be personalized for each subject and will 
include a target carbohydrate range and overall composition in protein, fats and dietary 
fibers that is as close as possible to the subject’s most current dinner dietary prescription. 
The content of the dinner and quantities consumed will be recorded. 
After dinner, subjects will be given an oral dose of cornstarch equivalent per their most 
recent cornstarch prescription at approximately the same time that they typically take it, but 
no later than 3 hours post dinner. The time of ingestion of prefasting cornstarch and the 
amount consumed will be recorded. After the cornstarch is ingested, the controlled fasting 
challenge will begin, and the start time will be recorded accordingly. If subjects do not 
receive cornstarch overnight, or receive continuous overnight feedings, the fasting test will 
begin after they complete their dinner. Subjects will be instructed to minimize activity after 
they finish eating dinner until the end of the fasting challenge.  
During the fast, subjects may not ingest any food or drink other than water. The controlled 
fasting challenge will end when the subject’s glucose level decreases to < 54 mg/dL (< 3.0 
mmol/L) or when the subjects present signs and symptoms of hypoglycemia, or the fast 
reaches 15 hours without hypoglycemia, whichever occurs first. The stop time of the 
controlled fasting challenge will be recorded. At the end of the controlled fasting challenge, 
the subject’s hypoglycemia should be treated per the institution’s standard procedure, 
which may include providing the subject with a meal, cornstarch, or IV glucose, if 
medically indicated.  
Blood samples for measurement of cortisol, fatty acid, glucagon, insulin, C-peptide, growth 
hormone, insulin-like growth factor-binding protein 1 (IGFBP1), alanine and ketone levels 


Protocol 401GSDIA01 Version 7.0 
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will be collected at the beginning and end of the fasting challenge, or more frequently at 
the Investigator’s discretion. A final sample for glucose, lactate, growth hormone, IGFBP1, 
ACTH, and cortisol measurement will be collected 30 minutes after the end of the 
controlled fasting challenge. Samples should be prepared and transported to the local 
laboratory in accordance with the site’s standard procedures. Blood samples for STAT 
analysis of glucose and lactate will be collected per the schedule of events. Capillary 
glucose will also be assessed.  
Urine will be collected over 24 hours for the determination of total protein, microalbumin, 
and creatinine. The collection of urine can overlap with the controlled fasting challenge. A 
 will be performed after the controlled fasting challenge is complete.  
For subjects enrolled in Cohort 4, the Investigator will initiate a prophylactic steroid 
regimen after completion of the controlled fasting challenge (Section 8.2.6.2.2). 
Day 1 – DTX401 Infusion 
Subjects will receive a single IV infusion of DTX401. The start of the DTX401 infusion 
should be after all samples and procedures specified for Day 1 predose have been 
completed. Subjects will be discharged after a 24-hour observation period. 
Prior to dosing with DTX401, blood samples will be collected for clinical chemistry 
(including liver function tests) and vector genome determination. A 12-lead ECG will be 
performed, and vital sign measurements will be recorded. Adverse events and SAEs will be 
monitored. The number of symptomatic hypoglycemic events with documented glucose of 
< 60 mg/dL (< 3.3 mmol/L) and concomitant medications, therapies, and procedures will 
be recorded. 
After dosing with DTX401, a blood sample will be collected approximately 22 hours after 
the start of the infusion for clinical chemistry (including liver function tests) and vector 
genome determination. Vital sign measurements will be recorded approximately 5 minutes 
after the start of the infusion and approximately 0.5, 1, 4, 8, and 22 hours after the start of 
the infusion. Adverse events and SAEs will be monitored. The number of symptomatic 
hypoglycemic events with documented glucose of < 60 mg/dL (< 3.3 mmol/L) and 
concomitant medications, therapies, and procedures will be recorded. At the end of the 
visit, the Morning Glucose Level monitoring worksheet and instructions for completing it 
will be provided to the subject (Section 8.1.3). 
Subjects in Cohort 3 will be discharged with prednisone to allow rapid treatment of 
possible vector-induced hepatitis if it occurs following treatment with DTX401 
(Section 8.2.6.2.1). Subjects in Cohort 4 will be discharged with prednisone per the 
prophylactic steroid regimen (Section 8.2.6.2.2). 
Outpatient Study Site or Home Visits 
Subjects will be asked to provide clinical laboratory samples at a minimum of every 
3 to 4 days through Week 12 of the study, or longer if clinically indicated. Subjects may 
have the option of having these samples collected at their homes by clinically trained and 
qualified personnel (if arranged by the Investigator), unless there is a scheduled study site 
visit that the subject must attend in person. 
A blood sample will be collected for determination of clinical chemistry (including liver 
function tests) and sent to the central laboratory. A second blood sample will be collected 
for liver function tests and sent to the local laboratory (STAT sample). A blood sample will 
be collected for determination of cell-mediated immune response to AAV8 and G6Pase 
testing approximately weekly. 
Saliva, urine, and stool samples will be collected for assessment of vector shedding until at 
least 3 consecutive negative results are obtained from each sample matrix. 


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Weeks 12 and 24 (Inpatient Visits) 
Subjects will be admitted to the study site or hospital for approximately 24 hours for all 
assessments. Each subject will remain on his or her prescribed diet for the duration of each 
inpatient stay. 
If the subject is off steroid treatments and the Investigator considers it is safe to proceed 
with the inpatient Week 12 visit, approximately 1 week before the Week 12 visit, a blood 
sample for measurement of ACTH and cortisol levels will be collected if possible. A blood 
sample for measurement of lipid levels will be collected on the morning of hospital 
admission at approximately the same time as collected on Day 0. The sample should be 
collected at least 2 to 4 hours after the subject’s last meal. If the subject continues to be on 
steroid regimen and the Investigator determines that it is not safe to proceed with the CFC, 
the Week 12 visit will become an outpatient visit. Investigators should try to complete an 
ad hoc CFC assessment as soon as the subject has completed steroid treatment and within 8 
weeks of the Week 12 visit, as an unscheduled visit.  
A urine pregnancy test will be performed (for females of childbearing potential only). 
Blood samples will be collected for clinical laboratory assessments (clinical chemistry 
[including liver function tests], hematology, and coagulation panel), AAV8 neutralizing 
antibody testing, AAV8 binding antibody IgG testing, cell-mediated immune response to 
AAV8 and G6Pase testing, anti-G6Pase antibody testing (Week 12 only), and vector 
genome determination. A urine sample will be collected for urinalysis. A second blood 
sample will be collected for liver function tests and sent to the local laboratory (STAT 
sample) through Week 12, or longer if clinically indicated. Saliva, urine, and stool samples 
will be collected for assessment of vector shedding through Week 12. If still positive at the 
Week 12 visit, vector shedding samples will continue to be collected during scheduled 
study visits until at least 3 consecutive negative results are obtained from each sample 
matrix. 
A targeted physical examination will be performed. Vital sign measurements and weight 
will be recorded. Adverse events and SAEs will be monitored. The number of symptomatic 
hypoglycemic events with documented glucose of < 60 mg/dL (< 3.3 mmol/L) that 
occurred since the last visit; concomitant medications, therapies, and procedures; and the 
subject’s daily prescribed diet, daily diet intake, daily prescribed cornstarch (or equivalent), 
and daily cornstarch (or equivalent) intake will be recorded. If the subject was unable to 
use the assigned CGM but was able to complete the Morning Glucose Level monitoring 
worksheet, the subject’s worksheet will be reviewed and a new worksheet will be provided 
to the subject. 
Subjects will complete the
 
prior to invasive assessments being conducted. 
Subjects will complete the GSDIa Morning Diary and GSDIa Evening Diary daily for 
7 days leading up to and including each inpatient visit. Subjects will be asked to complete a 
brief telephone interview at Week 24 regarding their experience completing the 
assessments. 
Subjects will participate in a controlled fasting challenge. The Investigator or delegated 
sub-investigator will review the results of all laboratory assessments performed on the first 
day of the inpatient visit, including the latest cortisol values. Subjects should wear their 
CGM device throughout the fasting challenge, and should not change the sensor prior to 
the assessment. Before the controlled fasting challenge begins, the study site will provide 
dinner for the subject. The dinner meal will be personalized for each subject and will 
include a target carbohydrate range and overall composition in protein, fats and dietary 
fibers that is as close as possible to the subject’s most current dinner dietary prescription. 
The content of the dinner and quantities consumed will be recorded. 


Protocol 401GSDIA01 Version 7.0 
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After dinner, subjects will be given an oral dose of cornstarch equivalent per their most 
recent cornstarch prescription at approximately the same time that they typically take it, but 
no later than 3 hours post dinner. The time of ingestion of prefasting cornstarch and the 
amount consumed will be recorded. After the cornstarch is ingested, the controlled fasting 
challenge will begin, and the start time will be recorded accordingly. If subjects do not 
receive cornstarch overnight, the fasting test will begin after they complete their dinner. 
Subjects will be instructed to minimize activity after they finish eating dinner until the end 
of the fasting challenge. 
During the fast, subjects may not ingest any food or drink other than water.  The controlled 
fasting challenge will end when the subject’s glucose level decreases to < 54 mg/dL (< 3.0 
mmol/L) or the subject develops signs and symptoms of hypoglycemia, or the fast reaches 
15 hours without hypoglycemia, whichever occurs first. The stop time of the controlled 
fasting challenge will be recorded.  
At the end of the controlled fasting challenge, the subject’s hypoglycemia should be treated 
per the institution’s standard procedure, which may include providing the subject with a 
meal, cornstarch, or IV glucose, if medically indicated. 
Blood samples for measurement of cortisol, fatty acid, glucagon, insulin, C-peptide, growth 
hormone, IGFBP1, ACTH, and alanine and ketone levels will be collected at the beginning 
and end of the fasting challenge, or more frequently at the Investigator’s discretion. A final 
sample for glucose, lactate, growth hormone, IGFBP1, ACTH, and cortisol measurement 
will be collected 30 minutes after the end of the controlled fasting challenge. Samples 
should be prepared and transported to the local laboratory in accordance with the site’s 
standard procedures. Blood samples for STAT analysis of glucose and lactate will be 
collected per the schedule of events. Capillary glucose will also be assessed. 
Urine will be collected over 24 hours for the determination of total protein, microalbumin, 
and creatinine. The collection of urine can overlap with the controlled fasting challenge. 
An 
 will be performed after the controlled fasting challenge is complete. 
Weeks 4, 6 and 36 (Outpatient Study Site Visits) 
Blood samples will be collected for clinical laboratory assessments (clinical chemistry 
[including liver function tests], hematology, and coagulation panel), AAV8 neutralizing 
antibody testing, AAV8 binding antibody IgG testing, cell-mediated immune response to 
AAV8 and G6Pase testing, and vector genome determination. A urine sample will be 
collected for urinalysis. A second blood sample will be collected for liver function tests and 
sent to the local laboratory (STAT sample) through Week 12, or longer if clinically 
indicated. Saliva, urine, and stool samples will be collected for assessment of vector 
shedding at the Week 4 visit. If still positive at the Week 24 inpatient visit, vector shedding 
samples will be collected during the Week 36 outpatient visit. 
A targeted physical examination will be performed. Vital sign measurements and weight 
(Week 36 only) will be recorded. Adverse events and SAEs will be monitored. The number 
of symptomatic hypoglycemic events with documented glucose of < 60 mg/dL 
(< 3.3 mmol/L) that occurred since the last visit; concomitant medications, therapies, and 
procedures; and the subject’s daily prescribed diet, daily diet intake, daily prescribed 
cornstarch (or equivalent), and daily cornstarch (or equivalent) intake will be recorded. If 
the subject was unable to use the assigned CGM but was able to complete the Morning 
Glucose Level monitoring worksheet, the subject’s worksheet will be reviewed and a new 
worksheet will be provided to the subject. 
End of Study (Week 52)/Early Withdrawal Visit (Inpatient Visit) 
Subjects will be admitted to the study site or hospital for approximately 24 hours for all 
assessments. Each subject will remain on his or her prescribed diet for the duration of the 
inpatient stay. A blood sample for measurement of lipid levels will be collected on the 


Protocol 401GSDIA01 Version 7.0 
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morning of hospital admission at approximately the same time as collected on Day 0. The 
sample should be collected at least 2 to 4 hours after the subject’s last meal. 
A urine pregnancy test will be performed (for females of childbearing potential only). 
Blood samples will be collected for clinical laboratory assessments (clinical chemistry 
[including liver function tests], hematology, and coagulation panel), AAV8 neutralizing 
antibody testing, AAV8 binding antibody IgG testing, cell-mediated immune response to 
AAV8 and G6Pase testing, anti-G6Pase antibody testing, and vector genome 
determination. A urine sample will be collected for urinalysis. Saliva, urine, and stool 
samples will be collected for assessment of vector shedding if samples are still positive at 
the Week 36 outpatient visit. 
A complete physical examination and a 12-lead ECG will be performed. Vital sign 
measurements and weight will be recorded. Adverse events and SAEs will be monitored. 
The number of symptomatic hypoglycemic events with documented glucose of < 60 mg/dL 
(< 3.3 mmol/L) that occurred since the last visit; concomitant medications, therapies, and 
procedures; and the subject’s daily prescribed diet, daily diet intake, daily prescribed 
cornstarch (or equivalent), and daily cornstarch (or equivalent) intake will be recorded. If 
the subject was unable to use the assigned CGM but was able to complete the Morning 
Glucose Level monitoring worksheet, the subject’s worksheet will be reviewed and a new 
worksheet will be provided to the subject. 
Subjects will complete the
 
 prior to invasive assessments being conducted. Subjects will complete 
the GSDIa Morning Diary and GSDIa Evening Diary daily for 7 days leading up to and 
including the visit. Subjects will be asked to complete a brief telephone interview regarding 
their experience in the study and completing the assessments. 
Subjects will participate in a controlled fasting challenge. The Investigator or delegated 
sub-investigator will review the results of all laboratory assessments performed on the first 
day of the inpatient visit, including the latest cortisol values. Subjects should wear their 
CGM device throughout the fasting challenge, and should not change the sensor prior to 
the assessment. Before the controlled fasting challenge begins, the study site will provide 
dinner for the subject. The dinner meal will be personalized for each subject and will 
include a target carbohydrate range and overall composition in protein, fats and dietary 
fibers that is as close as possible to the subject’s most current dinner dietary prescription. 
The content of the dinner and quantities consumed will be recorded. 
After dinner, subjects will be given an oral dose of cornstarch equivalent per their most 
recent cornstarch prescription at approximately the same time that they typically take it, but 
no later than 3 hours post dinner. The time of ingestion of prefasting cornstarch and the 
amount consumed will be recorded. After the cornstarch is ingested, the controlled fasting 
challenge will begin, and the start time will be recorded accordingly. If subjects do not 
receive cornstarch overnight, the fasting test will begin after they complete their dinner. 
Subjects will be instructed to minimize activity after they finish eating dinner until the end 
of the fasting challenge. 
During the fast, subjects may not ingest any food or drink other than water. The controlled 
fasting challenge will end when the subject’s glucose level decreases to < 54 mg/dL (< 3.0 
mmol/L) or the subject experiences signs and symptoms of hypoglycemia, or the fast 
reaches 15 hours without hypoglycemia, whichever occurs first. The stop time of the 
controlled fasting challenge will be recorded.  
At the end of the controlled fasting challenge, the subject’s hypoglycemia should be treated 
per the institution’s standard procedure, which may include providing the subject with a 
meal, cornstarch, or IV glucose, if medically indicated. 
Blood samples for measurement of cortisol, free fatty acids, glucagon, insulin, C-peptide, 
growth hormone, IGFBP1, ACTH, alanine and ketone levels will be collected at the 


Protocol 401GSDIA01 Version 7.0 
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beginning and end of the fasting challenge, or more frequently at the Investigator’s 
discretion. A final sample for glucose, lactate, growth hormone, IGFBP1, ACTH, and 
cortisol measurement will be collected 30 minutes after the end of the controlled fasting 
challenge. Samples should be prepared and transported to the local laboratory in 
accordance with the site’s standard procedures. Blood samples for STAT analysis of 
glucose and lactate will be collected per the schedule of events. Capillary glucose will also 
be assessed. 
Urine will be collected over 24 hours for the determination of total protein, microalbumin, 
and creatinine. The collection of urine can overlap with the controlled fasting challenge. A 
 will be performed after the controlled fasting challenge is complete.  
After completion of the Week 52 visit or early withdrawal, subjects will be offered 
enrollment in a 4-year extension study to evaluate the long-term (a total of 5 years) safety 
and efficacy of DTX401. 
Treatment for 
Vector-Induced 
Hepatitis: 
Reactive Steroid Treatment for Possible Vector-Induced Hepatitis 
Subjects in Cohorts 1, 2, and 3 will receive reactive oral steroid treatment for possible 
vector-induced hepatitis if liver aminotransferase levels increase following treatment with 
DTX401. The Investigator, in conjunction with the Ultragenyx medical lead, will consider 
starting oral steroid treatment for possible vector-induced hepatitis if a subject’s ALT 
levels increase from the subject’s baseline or recently drawn levels, and are considered by 
the Investigator to be possibly related to treatment with DTX401. If repeat testing is 
deemed necessary, every effort should be made to repeat the testing within 24 hours from 
receipt of test results indicating elevated levels of ALT. 
Based on available evidence, it is expected that vector-induced hepatitis will be 
self-limiting. Therefore, prednisone (or prednisolone) will be used to treat vector-induced 
hepatitis according to the American Association for the Study of Liver Disease guidelines, 
which have been modified for subjects with GSDIa so that the starting dose/duration is 
lower/shorter: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The Investigator, in conjunction with the Ultragenyx medical lead, may consider modifying 
this regimen if a subject’s ALT levels do not normalize during the steroid taper. The 
Investigator should document the agreed upon steroid regimen in the subject’s source 
documentation. 
Prophylactic Steroid Treatment for Vector-Induced Hepatitis 
Subjects in Cohort 4 will receive prophylactic oral steroid treatment to prevent possible 
vector-induced hepatitis. Prophylactic oral steroid regimens have been used in 
AAV-mediated gene transfer clinical trials for other indications (eg, Clinicaltrials.gov 
identifiers: NCT03223194, NCT03306277). 
Oral prednisone (or prednisolone) will be initiated on Day 1 following completion of the 
Day 0 controlled fasting challenge and before DTX401 administration as follows: 
 
 


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The Investigator, in conjunction with the Ultragenyx medical lead, may consider modifying 
this regimen if a subject’s ALT levels do not normalize during the steroid taper. If, in the 
Investigator’s medical judgment, the subject may not safely tolerate initiation of oral 
steroid treatment on Day 1, the steroid regimen may be modified based on discussion 
between the Investigator and the Ultragenyx medical lead. The Investigator should 
document the agreed upon steroid regimen in the subject’s source documentation. 
The Investigator may consider additional assessments or medical care, such as 
hospitalization or daily clinic visits, during steroid administration if, in the Investigator’s 
medical judgment, these measures would provide additional safety benefits. 
Safety Stopping 
Criteria: 
Enrollment will be stopped and the DMC and regulators will be notified if, at any time 
during the study, any of the events listed below occur following administration of 
DTX401: 
• 
Death of a subject 
• 
An event with an intensity ≥ Grade 3 (according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events) develops 
• 
Occurrence of a hepatic malignancy 
If a stopping rule is met, enrollment will be paused and the DMC will meet to review 
available data. If a decision is made to resume enrollment, this decision will be 
communicated to and, if required, approved by regulatory authorities according to country 
requirements. 
An event that meets any of the above criteria will be reported immediately and captured as 
an AE/SAE in the electronic case report form by the study site. If a stopping criterion is 
met and 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. 
Efficacy 
Assessments: 
Efficacy assessments include the following: the change from Baseline in time (in minutes) 
to first hypoglycemic event (defined as glucose < 54 mg/dL [< 3.0 mmol/L]) during a 
controlled fasting challenge at 12, 24, and 52; cornstarch intake; glucose level trends; 
morning glucose levels; 
; and 
. 
Safety 
Assessments: 
Safety assessments include the following: AEs, SAEs, vital sign measurements, complete 
and targeted physical examination findings, ECG results, documented symptomatic 
hypoglycemic events, clinical laboratory assessments (clinical chemistry [including liver 
function tests], hematology, coagulation panel, and urinalysis), vector shedding, vector 
genome determination, measurement of neutralizing antibody titer to AAV8, measurement 
of AAV8 binding antibody IgG, assessment of any cell-mediated immune response to 
AAV8 and G6Pase, and measurement of anti-G6Pase antibodies. 


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Estimated Study 
Duration: 
The duration of the study for each subject is defined as the date the subject provides written 
informed consent through the Week 52 visit. Subjects will be in the study for 
approximately 60 weeks (including the Screening Period). 
After completion of the Week 52 visit or early withdrawal, subjects will be offered 
enrollment into a 4-year extension study to evaluate the long-term (for a total of 5 years) 
safety and efficacy of DTX401. 
Study Product, 
Dose, and Route 
of 
Administration: 
DTX401 will be administered as a single peripheral IV infusion. The following doses may 
be evaluated using a CRM to estimate the maximum tolerated dose (MTD) of DTX401 
regardless of the steroid approach used (ie, reactive vs prophylactic): 
Dose 1: 2.0 × 1012 GC/kg 
Dose 2: 6.0 × 1012 GC/kg 
Dose 3: 1.0 × 1013 GC/kg 
Statistical 
Methods: 
Determination of the Maximum Tolerated and Optimal Biological Doses 
The optimal biological dose (OBD) will be based on the MTD and an assessment of 
clinical benefit. 
A CRM will be used for dose escalation to estimate the MTD of DTX401. The CRM uses 
the Bayesian method to model the probability of experiencing a DLT for each given dose 
in order to recommend the dose for the next cohort. The CRM will evaluate subjects based 
on the dose administered regardless of the steroid approach used (ie, reactive vs 
prophylactic). A DLT is defined as any AE/SAE ≥ Grade 3 that is considered by the 
Investigator and/or Sponsor to be related to DTX401. The MTD is defined as the highest 
dose where the predicted probability of experiencing a DLT is less than or equal to the 
target toxicity rate. In this study, the target toxicity rate is 0.25. 
Interim Analysis 
An interim analysis will be conducted when a minimum of 12-week data are available for 
all subjects from at least 2 dosing cohorts. Additional interim analyses may be conducted at 
the Sponsor’s discretion. 
Safety Analyses 
All statistical analyses of safety outcomes will be descriptive, with the exception of the 
CRM modelling. The incidence of AEs and TEAEs will be summarized for each dose by 
system organ class and preferred term. Additionally, TEAEs may be summarized for each 
dose by severity and relationship to study product, if applicable. SAEs will be presented for 
each dose by relationship to study product. Summary tables will present the total numbers 
of TEAEs as well as the number of subjects with TEAE incidence by system organ class 
and preferred term. 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/preferred term. 
Other safety data, including vital sign measurements, complete and targeted physical 
examination findings, ECG results, documented symptomatic hypoglycemic events, 
clinical laboratory data, vector shedding, vector genome determination, measurement of 
neutralizing antibody titer to AAV8, measurement of AAV8 binding antibody IgG, 
assessment of any cell mediated immune responses to AAV8 and G6Pase, and 
measurement of antiG6Pase antibodies will be summarized. 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
AAV 
adeno-associated virus 
AAV2 
adeno-associated virus serotype 2 
AAV8 
adeno-associated virus serotype 8 
ACTH 
adrenocorticotropic hormone 
AE 
adverse event 
ALT 
alanine aminotransferase 
CFR 
Code of Federal Regulations 
CGM 
continuous glucose monitoring 
CRM 
continual reassessment method 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
dose-limiting toxicity 
DMC 
data monitoring committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
 
 
 
 
FDA 
US Food and Drug Administration 
G6P 
glucose-6-phosphate 
G6Pase 
glucose-6-phosphatase (protein) 
G6PC 
glucose-6-phosphatase (gene) 
G6pc-/- 
glucose-6-phosphatase knockout mice 
GC 
genome copies 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GSDIa 
glycogen storage disease type Ia 
HCA 
hepatocellular adenoma 
HCC 
hepatocellular carcinoma 
 
 
IBC 
institutional biosafety committee 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 


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Abbreviation 
Definition 
IEC 
independent ethics committee 
IGFBP1 
insulin-like growth factor-binding protein 1 
IgG 
immunoglobulin G 
IRB 
institutional review board 
IV 
Intravenous 
MED 
minimal effective dose 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
OBD 
optimal biological dose 
PVG 
pharmacovigilance 
 
 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SUSAR 
serious, unexpected, suspected adverse drug reaction 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
 


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1. 
INTRODUCTION 
Glucose-6-phosphatase is a glucose-6-phosphate (G6P) hydrolase located in the endoplasmic 
reticulum that is primarily expressed in the liver, kidneys, and intestine. It is a highly 
hydrophobic protein with 9 transmembrane domains (Pan et al., 1998). The amino and carboxyl 
termini of the glucose-6-phosphatase (G6Pase) protein are located on opposite sides of the 
endoplasmic reticulum membrane, with the active site of the enzyme facing the endoplasmic 
reticulum lumen (Lei et al., 1993; Lei et al., 1995b; Lei et al., 1995c). Glucose-6-phosphatase is 
responsible for catalyzing the terminal step in hepatic and renal glycogenolysis and 
gluconeogenesis (Figure 1): the hydrolysis of glucose-6-phosphate to glucose and inorganic 
phosphate provides a significant amount of circulating glucose (Foster and Nordlie, 2002). In 
patients with glycogen storage disease type Ia (GSDIa), free glucose molecules are not generated 
for export into the body’s circulation, and as a result, glucose from glycogen stores is unavailable 
during periods of fasting, resulting in severe hypoglycemia. The excess glucose-6-phosphate 
molecules are shunted toward the production of triglycerides (eventually stored as fat) and the 
pentose-phosphate pathway (leading to increased uric acid production). Additionally, during 
periods of prolonged hypoglycemia, an increased rate of glycolysis and catabolism of muscle and 
fats results in a build-up of lactate (Chou and Mansfield, 1999; Chou, 2001; van Schaftingen and 
Gerin, 2002). 
Figure 1: 
Overview of Glycogenesis and Glycogenolysis 
 
Glycogen storage disease type Ia, also known as von Gierke disease, is a severe autosomal 
recessive inborn error of metabolism that is caused by mutations of the G6PC gene located on 
chromosome 17q21 (Lei et al., 1993; Chou, 2001). Patients with GSDIa present with severe 
hypoglycemia and seizures at a few months of age. Like many other inherited disorders, GSDIa 
can be readily detected by screening a bloodspot sample for one of several common mutations 
(Lei et al., 1995a). The importance of diagnosing and treating GSDIa early is emphasized by the 
severe complications that arise when the disease is left untreated, including life-threatening 
hypoglycemia, severe lactic acidosis, growth failure, renal Fanconi syndrome, and pancreatitis. 
Acute complications of GSDIa, such as hypoglycemia, severe metabolic acidosis, and renal 


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tubular- dysfunction, respond favorably to and can be prevented with strict dietary restrictions 
and frequent consumption of uncooked cornstarch. However, these restrictions have significant 
limitations and require constant vigilance to avoid acute metabolic decompensation that is 
accompanied by life-threatening hypoglycemia and lactic acidosis. In addition, dietary 
restrictions are often not an effective means of preventing the long-term clinical complications 
associated with GSDIa, including proteinuria (that may progress to renal failure), growth 
retardation, osteopenia, and the formation of hepatocellular adenomas (HCAs) and hepatocellular 
carcinomas (HCCs) (Chen et al., 1988; Wolfsdorf and Crigler, 1997; Wolfsdorf et al., 1997; 
Wolfsdorf et al., 1999). 
Complications, such as hepatomegaly (resulting from the pathological accumulation of glycogen 
in the liver), an increase in the number and size of HCAs, and the development of HCCs become 
more common as individuals with GSDIa age (Franco et al., 2005). For example, HCAs are 
present in 70% to 80% of GSDIa patients over the age of 25 years (Lee et al., 2012), with up to 
10% of HCAs developing into life--threatening HCCs (Franco et al., 2005; Reddy et al., 2007; 
Lee et al., 2012). Orthotopic liver transplantation has become a treatment option for patients and 
has been shown to correct hypoglycemia and other biochemical abnormalities associated with 
GSDIa, as well as result in an increase in body height (Matern et al., 1999; Boers et al., 2014). 
These results provide evidence for the efficacy and benefit of restoring G6PC expression in the 
liver of patients with GSDIa. However, given that liver transplantation is limited by donor 
availability and is associated with significant risk of morbidity and mortality including a very 
high rate of renal failure (Davis and Weinstein, 2008; Boers et al., 2014), there is a significant 
unmet medical need for a treatment that allows for sustained euglycemia and prevention of the 
long-term complications and life-threatening hypoglycemia that are associated with GSDIa. In 
nonclinical studies, adeno-associated virus (AAV) serotype 8-mediated delivery of G6PC in 
mice and dogs with GSDIa has restored G6Pase activity and ameliorated disease sequelae 
(Koeberl et al., 2008; Koeberl et al., 2009; Weinstein et al., 2010; Chou and Mansfield, 2011), 
providing evidence that gene transfer could have significant benefit in patients with GSDIa. 
1.1. 
Adeno-Associated Viral Vectors 
Adeno-associated virus is a nonenveloped, 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 nonreplicating and the vector 
genomes exist as an episome following tissue transduction, minimizing the risk of insertional 
mutagenesis (Nakai et al., 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 et al., 2005; Mingozzi and High, 
2011). 
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 and High, 2011). In 
animal models, AAV2-mediated gene transfer was shown to treat the underlying disease for 
many years (Snyder et al., 1999; Mount et al., 2002; Wang et al., 2005; Nichols et al., 2010). 


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However, in humans, AAV2-mediated delivery was either subtherapeutic or only lasted a few 
months (Manno et al., 2003; Manno et al., 2006). This was attributed to several limitations of 
AAV2 vectors including low transduction efficiency (Yan et al., 2002), high seroprevalence of 
neutralizing antibodies against AAV2 in humans (Boutin et al., 2010), and potentially destructive 
T-cell responses to capsids (Gao et al., 2009; Vandenberghe et al., 2006; Wang et al., 2007). 
There has also been evidence of B-cell responses against the transgene product in an animal 
model of hemophilia (Herzog et al., 2001). 
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 not being endemic to the nonhuman species under investigation. Novel AAV 
serotypes, isolated from nonhuman primates, are divergent enough from endemic human 
serotypes to circumvent the neutralizing antibodies that exist in most humans while retaining 
similar tissue tropism (Gao et al., 2002). 
One of these serotypes, AAV serotype 8 (AAV8), displays strong tropism for the liver (Gao et 
al., 2002) and has been tested extensively as a vector for gene transfer in nonclinical and clinical 
models of hemophilia (Davidoff et al., 2005; Jiang et al., 2006; Nathwani et al., 2011b; Nathwani 
et al., 2006; Nathwani et al., 2007). 
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 aminotransferases; a lack of liver histopathology; a 
lack of T-cell activation to the transgene product; and low levels of pre-existing neutralizing 
antibodies in humans, minimizing their inhibition of in vivo transduction. Furthermore, AAV8 
has shown impressive efficacy and safety in clinical studies for hemophilia B (Nathwani et al., 
2011b; Nathwani et al., 2014) and is being studied in multiple indications, including hemophilia 
A (ClinicalTrials.gov identifier: NCT03001830, NCT03370172), hemophilia B 
(ClinicalTrials.gov identifiers: NCT00979238, NCT01687608), late-onset ornithine 
transcarbamylase deficiency (ClinicalTrials.gov identifier: NCT02991144), Pompe disease 
(ClinicalTrials.gov identifier: NCT03533673), and Crigler-Najjar syndrome (Clinicaltrials.gov 
identifier: NCT03223194). The study product, DTX401, contains a codon-optimized human 
wild-type G6PC with expression driven by both the native G6PC-specific promoter and 
enhancer elements encapsidated within a nonreplicating recombinant AAV8 vector. In G6pc 
knockout (G6pc -/-) mice, a vector similar to DTX401 showed a sustained, dose-dependent 
improvement in plasma glucose levels following a single intravenous (IV) injection that was 
similar to the improvement in wild-type mice (Yiu et al., 2010; Lee et al., 2012). Furthermore, 
restoring G6Pase activity (from 3% to 63% of wild-type levels) prevented the formation of HCA 
for up to 90 weeks, which had previously been reported in a liver-specific knock out model 
(Mutel et al., 2011; Lee et al., 2012). These data provide support for the feasibility of this 
therapeutic approach in humans. 


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DTX401 offers the following advantages for patients with GSDIa: 
• The liver is a natural site of G6Pase synthesis. The AAV8 serotype demonstrates high 
liver tropism and can achieve efficient liver gene transfer following IV infusion (Gao 
et al., 2002). 
• The AAV8 serotype is not thought to be endemic in the human population; therefore, 
the prevalence of neutralizing antibodies to AAV8 that would prevent efficient 
transduction of the liver is expected to be low in patients with GSDIa (Calcedo and 
Wilson, 2013). 
1.3. 
Study Rationale 
The use of gene transfer for treating GSDIa in G6pc-/- mice and in a naturally occurring canine 
model of GSDIa has been tested using both adenoviral (murine model only) (Koeberl et al., 
2007) and AAV delivery systems (both murine and canine models) (Beaty et al., 2002; Sun et al., 
2002; Ghosh et al., 2006; Koeberl et al., 2006; Koeberl et al., 2008; Chou and Mansfield, 2007; 
Kishnani et al., 2010; Yiu et al., 2010; Chou and Mansfield, 2011; Lee et al., 2012). These 
studies demonstrated long-term correction of the disease sequelae, including correction of fasting 
hypoglycemia; reduction of uric acid, triglycerides, and cholesterol; improved growth; reduction 
in hepatomegaly and nephromegaly; and a reduction in lactic acidosis (canine model). 
Histologically, there was also a reduction in glycogen deposition in the liver, and recent data 
demonstrated prevention of both HCAs and HCCs (Lee et al., 2012). 
Glucose-6-phosphatase gene transfer is expected to be effective for the treatment of GSDIa 
because the disease is caused by mutations within a single gene (Lei et al., 1995a; Lei et al., 
1993; Chou, 2001). Currently, no gene transfer product has been approved for the treatment of 
GSDIa. Based on previous clinical experience with AAV8, DTX401 is expected to result in 
sustained (at least 3 years following vector infusion) expression of G6PC (Nathwani et al., 
2011b; Nathwani et al., 2014). Therefore, unlike current treatment options (ie, strict dietary 
restrictions and frequent consumption of uncooked cornstarch), G6PC gene transfer offers the 
potential to correct the underlying deficiency for a prolonged period of time with a single IV 
infusion. Furthermore, increasing G6Pase activity should allow patients with GSDIa to avoid 
hypoglycemic episodes and long-term complications associated with GSDIa, which should 
greatly improve their health-related quality of life (HRQoL). 
1.3.1. 
Design Rationale 
The design of this first-in-human 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 401GSDIA01 is a Phase 1/2, open-label, single-arm, multicenter, safety and dose-finding 
study to determine the safety, tolerability, and efficacy of DTX401 in adults with GSDIa. 
The primary objective of the study is to determine the safety of single IV doses of DTX401, 
including the incidence of dose-limiting toxicities (DLTs). The secondary objective of the study 
is to establish a dose of DTX401 that achieves symptom-free euglycemia (glucose ≥ 54 mg/dL 


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[≥ 3.0 mmol/L]) in a setting of a controlled fasting challenge to allow further clinical 
development. 
Patients with GSDIa will typically develop hypoglycemia within 2 to 4 hours of a meal in the 
absence of treatment (ie, cornstarch) (Bali et al., 2016). Ingestion of uncooked or modified 
cornstarch has been shown to maintain glucose above 3.0 mmol/L for up to 10 hours (median 
7 hours) in patients with GSDIa during a controlled fasting challenge (Bhattacharya et al., 2007); 
however, there are limited data to estimate intraperson variability in time to reaching 
hypoglycemia. Patients with GSDIa have a more consistent fasting profile than patients with 
other glycogen storage diseases (Wolfsdorf et al., 1999). Therefore, a conservative estimate for 
intraperson variability would be ± 2 hours. In this study, subjects will be administered a 5 g oral 
dose of cornstarch just prior to starting the controlled fasting challenge. This dose of cornstarch 
is expected to minimize a potential insulin spike following dinner that could result in abrupt 
hypoglycemia, normalize baseline glucose values, allow subjects to fast for a few hours, and 
minimize intraperson variability. In nonclinical studies, G6pc-/- mice were able to survive a 
24-hour fast following treatment with a vector similar to DTX401 (Lee et al., 2012). Based on 
these data, it is expected that DTX401 gene transfer should prevent hypoglycemia for at least 
8 hours during the controlled fasting challenge. This clinically meaningful change from baseline 
(ie, 2 to 4 hours (Bali et al., 2016)) would represent a clear efficacy signal outside an effect that 
can be attributed to anticipated intraperson variability (ie, ± 2 hours). 
Eligible subjects will be enrolled into cohorts of 3 subjects each and receive a single IV infusion 
of DTX401. Subjects in Cohorts 1 and 2 were dosed at a minimum of 2 weeks (14 days) apart. 
Subjects in subsequent cohorts will be dosed at a minimum of 1 week (7 days) apart. 
The proposed dosing interval of 14 days between subjects in Cohorts 1 and 2, followed by a 
dosing interval of 7 days in subsequent cohorts, is supported by the safety profile and lack of 
serious adverse reactions reported in AAV-mediated gene transfer in human subjects, including a 
hemophilia B clinical study using an AAV8 vector (Manno et al., 2006; Nathwani et al., 2011b; 
Nathwani et al., 2014) and this study (Derks et al., 2019; Weinstein et al., 2019). Moreover, a 
Phase 1/2 clinical study in hemophilia B that used AAV-mediated gene transfer at a starting dose 
of 5.0 × 1012 genome copies (GC)/kg (higher than the proposed DTX401 starting dose of 
2.0 × 1012 GC/kg) at multiple European study sites dosed subjects within a cohort at a minimum 
of only 1 day (24 hours) apart (uniQure, 2014)(Clinicaltrials.gov identifier: NCT02396342; 
EudraCT Number: 2013-005579-42). 
The most common product-related adverse event (AE) observed in clinical studies with 
AAV-mediated gene transfer to subjects with moderate to severe hemophilia B has been an 
asymptomatic transient increase in liver aminotransferase levels (though still within the normal 
reference range for these laboratory parameters) and concurrent decline in transgene expression 
approximately 7 to 10 weeks following vector administration (Manno et al., 2006; Nathwani et 
al., 2011b; Nathwani et al., 2014). In all cases, the transient increase in liver aminotransferase 
levels resolved without clinical sequelae. It has been hypothesized that this vector-induced 
hepatitis is due to the activation of capsid-specific cytotoxic T lymphocytes and destruction of 
transduced liver cells (Mingozzi et al., 2007). As this is the only identified AE with AAV gene 
transfer, and given that subjects in this study will be closely monitored for vector-induced 


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hepatitis and treated with corticosteroids if needed (Section 8.2.6.2), having an interval of more 
than 14 days between subjects in Cohorts 1 and 2 and more than 7 days between subjects in 
subsequent cohorts does not change either safety evaluations or the medical management of 
study subjects. To date, no related serious adverse events (SAEs) or DLTs have been reported for 
DTX401. Consistent with previous experience (Manno et al., 2006; Nathwani et al., 2011b; 
Nathwani et al., 2014), mild, transient, asymptomatic increases in liver aminotransferase levels 
have been observed following DTX401 administration that resolved with steroids (Derks et al., 
2019; Weinstein et al., 2019). 
Subject safety will be closely monitored throughout the study, including assessment of 
hypoglycemic events, frequent monitoring of liver enzymes, and inpatient observation following 
dosing and at multiple time points throughout the 52-week study duration. 
For Cohorts 1 and 2, there was a minimum of 12 weeks (84 days) between dosing of the last 
subject in a dosing cohort and the first subject in the next dosing cohort. After all subjects in 
Cohorts 1 and 2 completed Week 12, the continual reassessment method (CRM) proposed a dose 
for the next cohort using the collected data from the previous cohort. The DMC met to review 
safety data (ie, AEs/SAEs, physical examination findings, vital sign measurements, 
electrocardiogram [ECG] results, and clinical laboratory assessments [including assessment of 
liver function]) and provide a recommendation for progressing to the next dosing level 
(Section 9.3). The CRM will be used for dose escalation to estimate the maximum tolerated dose 
(MTD) of DTX401 (Section 10.2.1). 
After reviewing Week 12 data from all subjects in Cohort 1, the DMC concluded that it was safe 
to enroll 3 additional subjects into Cohort 2 at Dose 2 (6.0 × 1012 GC/kg). After reviewing 
Week 12 data from all subjects in Cohort 2, the DMC concluded that it was safe to enroll 
3 additional subjects into Cohort 3 at Dose 2 (6.0 × 1012 GC/kg) with an optimized reactive 
steroid regimen. An optimized reactive steroid regimen is expected to manage the elevations in 
liver aminotransferase levels observed in Cohorts 1 and 2 following DTX401 administration. 
If the optimized reactive steroid regimen does not sufficiently manage elevations in liver 
aminotransferase levels in Cohort 3, then Cohort 4 will be enrolled. Subjects in Cohort 4 will 
receive a prophylactic steroid regimen. Enrollment into Cohort 4 may begin following 
completion of enrollment into Cohort 3 (Section 3.1). 
In Cohort 4, oral prednisone (or prednisolone) will be initiated on Day 1 after completion of the 
Day 0 controlled fasting challenge and before DTX401 administration, sustained for 4 weeks, 
and then tapered (Section 8.2.6.2.2). Prophylactic oral steroid regimens have been used in 
AAV-mediated gene transfer clinical trials for other indications (eg, Clinicaltrials.gov identifiers: 
NCT03306277, NCT03223194). 
The controlled fasting challenge was also modified following DMC review of Week 12 data 
from subjects in Cohort 2. To minimize a potential insulin spike that could result in abrupt 
hypoglycemia and normalize baseline glucose levels, the recommended target carbohydrate 
range of the prefasting challenge dinner meal was decreased from 20 g to 30 g to 15 g to 20 g 
and the prefasting challenge cornstarch dose was decreased from 35 g to 5 g. 


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However, further analysis and review of fasting challenge data after changing the prefasting 
cornstarch dose to 5g showed significantly lower fasting times in cohorts 2 (W52 and W78) and 
3 (W24, W32 and W52). In most instances, low post-prandial levels of blood glucose associates, 
persistence of high circulating insulin levels, and slow cortisol response to hypoglycemia make it 
challenging to interpret these results. Available CGM recordings have shown an absence of 
nocturnal hypoglycemia in these subjects despite an overall reduced frequency and total amount 
of cornstarch. The reason that several subjects can now sleep through the night at home without 
experiencing hypoglycemia in the absence of cornstarch consumption, but have shorter time to 
hypoglycemia during the inpatient fasting challenge is unclear. It could be attributed to the 
artificial threshold of 60 mg/dL for stopping the fasting challenge. This threshold may not allow 
adequate glucose release to be induced in subjects with higher insulin and lower cortisol levels. 
In the home setting, subjects clearly do better as their glucose release seems to be better induced, 
thereby preventing their glucose levels from falling to dangerous levels. 
With Protocol Amendment 6, the dinner meal will be personalized for each subject, and will 
include a target carbohydrate range and overall composition in protein, fats and dietary fibers 
that is as close as possible to the subject’s most current dinner prescription but not higher than 
the carbohydrate content of the dinner consumed at their baseline fasting challenge. The 
prefasting cornstarch dose and time of consumption will be per the respective subject’s most 
recent cornstarch prescription and daily regimen at home. In addition, the threshold for stopping 
the test was lowered to 54 mg/dL (3.0 mmol/L) or when the subject experiences signs and 
symptoms of hypoglycemia. The new threshold is justified by the fact that signs and symptoms 
of hypoglycemia associated with an adrenergic reaction and cerebral glucopenia and most 
physiological hormonal and metabolic responses responses to hypoglycemia may not occur in 
GSDIa subjects until they reach these levels of blood glucose values. CGM recording during the 
fasting test will provide continuous glucose measurement data that will allow Investigators to 
closely monitor subjects when they reach the lower range of blood glucose (ie, below 60 mg/dL). 
The DMC will meet at the end of the study and may, at any time, recommend modifying or 
pausing enrollment due to safety concerns based on their periodic data reviews. Additionally, if 
an Investigator reports an AE/SAE that meets any of the safety stopping criteria (Section 3.2.4), 
enrollment will be paused and the DMC will meet to review available data. If a decision is made 
to resume enrollment, this decision will be communicated to and, if required, approved by 
regulatory authorities according to country requirements. The full scope of each DMC review 
will be outlined in the DMC charter. 
AAV vectors represent a class of viral vectors that are nonreplicating, nonintegrating, and 
present a low risk for gene therapy-related delayed adverse reactions. Recommended long-term 
safety monitoring for subjects enrolled in AAV gene therapy clinical trials is a minimum of 
5 years (FDA, 2006; CHMP, 2009). 
Subjects enrolled in Study 401GSDIA01 will be monitored for 52 weeks following DTX401 
administration. After completion of the Week 52 visit or early withdrawal, subjects will be 
offered enrollment into a 4-year extension study in accordance with regulatory authority 
regulations and ICH GCP. During the informed consent process for this study, subjects will be 


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informed of the 4-year extension study in order to maximize subject enrollment into the 
extension study. 
1.3.2. 
Dosing Rationale 
The clinical target for DTX401 is to achieve euglycemia in the fasting state (defined as glucose 
≥ 54 mg/dL [≥ 3.0 mmol/L]). The determination of a clinical starting dose is based on available 
nonclinical data with DTX401, including the minimal effective dose (MED) and optimal 
effective dose of DTX401 in mice, clinical experience with other AAV8 products, and known 
limitations when scaling between species. 
To provide information to support the selection of a safe clinical starting dose, Ultragenyx 
Pharmaceutical Inc. (Ultragenyx) conducted a pharmacology proof-of-concept efficacy study in 
G6pc-/- mice to characterize the biological activity of 2 different transgenes in an animal model 
of GSDIa and a Good Laboratory Practice (GLP) toxicity and biodistribution study in male and 
female wild-type C57 black 6 (C57BL/6) mice. 
In order to estimate the allometric scaling needed for AAV8-mediated delivery of the G6PC 
transgene in this study between mice and humans, the following 2 data sets using AAV-mediated 
transfer of human factor IX were examined: the uniQure data set (Amsterdam, The Netherlands) 
(uniQure, 2015; uniQure, 2016) and the Nathwani data set (Nathwani et al., 2007; Nathwani et 
al., 2011a; Nathwani et al., 2011b). The AAV serotype 5 vector used in the uniQure studies was 
shown to have a 10-fold scaling between mouse and human (uniQure, 2015; uniQure, 2016). The 
AAV8 vector used in the Nathwani studies supports a 10-fold scaling from mouse to nonhuman 
primates and a 4-fold scaling between nonhuman primates and humans, for a total of 40-fold 
between mouse and human (Nathwani et al., 2007; Nathwani et al., 2011a; Nathwani et al., 
2011b). Therefore, when considering a clinical dosing rationale, in light of the available 
comparison data between mice and humans, it seems reasonable to consider a 10- to 40-fold 
increase in dose from mice to humans to achieve similar target levels for the expression and 
activity of G6Pase. The MED for DTX401 was 5 × 1011 GC/kg in neonatal G6pc-/- mice that 
were observed for a 2-week period. Due to the growth of the animals during this time, vector 
dilution in the liver also needs to be considered and was estimated to be approximately 2.5- to 5-
fold (Wang et al., 2012). Similar results were reported in G6pc-/- mice treated at 2 weeks of age, 
where there was an approximate 2.7-fold decrease in G6Pase activity between 4 and 6 weeks 
after dosing (from 243.3% to 87.6% of wild-type activity) (Yiu et al., 2010). Therefore, both the 
increase in dose due to allometric scaling from mice to humans and vector dilution were 
considered when choosing candidate doses of DTX401 for this study. The use of these correction 
factors provides a range for the potential MED in humans (Table 1). The minimum dose that 
could provide benefit in humans is estimated to fall between 1.0 × 1012 GC/kg (ie, a 2-fold 
increase) and 8.0 × 1012 GC/kg (ie, a 16-fold increase). 


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Table 1: 
Allometric Scaling and Dilution Factors for Determining the Minimal 
Effective Dose of DTX401 in Humans 
Mouse MED 
(GC/kg) 
Mouse to NHP/Human 
Conversion Factor 
Human Dose 
(GC/kg) 
Dilution Factor 
(Neonate to Adult 
Mouse) 
Corrected Human 
Dose 
(GC/kg) 
5 × 1011 
× 10 
5 × 1012 
5 
1 × 1012 
(minimum) 
5 × 1011 
× 10 
5 × 1012 
2.5 
2 × 1012 
5 × 1011 
× 40 
2 × 1013 
5 
4 × 1012 
5 × 1011 
× 40 
2 × 1013 
2.5 
8 × 1012 
(maximum) 
Abbreviations: GC = genome copies; MED = minimal effective dose; NHP = nonhuman primate. 
In comparison to the clinical development of traditional small molecule and biologic therapies, 
clinical studies for AAV-mediated gene transfer have an additional consideration: after initial 
dosing, it is expected that subjects who are administered DTX401 will develop neutralizing 
antibodies to AAV8 and will likely receive limited benefit from subsequent dosing with this 
vector. Therefore, unlike classic dose-escalation studies, there is a greater focus on targeting 
efficacy in addition to safety. Taking into consideration the uncertainty in projecting a human 
dose, as noted in the US Food and Drug Administration (FDA) guidance (FDA, 2015), a dose of 
2.0 × 1012 GC/kg, which is twice the minimum projected human MED (1.0 × 1012 GC/kg), was 
selected as the starting dose for the Phase 1/2 study (Table 1). This dose is expected to provide a 
reasonable chance for study subjects to achieve a clinically meaningful normalization of glucose 
and will provide critical safety information in humans for DTX401. 
A standard approach for dose finding in gene transfer studies is to adjust the dose (up or down) 
in half-log increments; therefore, if 2.0 × 1012 GC/kg is projected to provide G6Pase activity at 
the minimum level to prevent hypoglycemia, a dose that is a half-log more is 6.0 × 1012 GC/kg. 
The highest clinical dose planned is 1.0 × 1013 GC/kg. The candidate doses of 2.0 × 1012 GC/kg, 
6.0 × 1012 GC/kg, and 1.0 × 1013 GC/kg in this study (Study 401GSDIA01) are also being 
studied in the DTX301 Phase 1/2 clinical study (Study 301OTC01) for ornithine 
transcarbamylase, another gene transfer study in an inborn error of metabolism condition, based 
on similar allometric scaling derived from mouse MED data. 
Based on existing safety data from clinical studies using AAV-mediated gene transfer (including 
multiple hemophilia programs), substantial toxicity in the predicted therapeutic range is not 
anticipated. Ultragenyx is also taking into account the amount of DTX401 Chemistry, 
Manufacturing, and Controls material that can be produced over the anticipated timeline of this 
Phase 1/2 study and the maximal feasible dose of vector that can be administered to mice in GLP 
toxicology studies (based on dose volume and concentration of vector). Assuming that an MTD 
is not identified in nonclinical studies, the proposed dose-finding approach for this Phase 1/2 
study is consistent with the FDA Guidance for Industry on the Considerations for the Design of 
Early-Phase Clinical Trials of Cellular and Gene Therapy Products, which indicates that 
achieving a specified target range of exposure is the focus of a cellular or gene therapy program 
when “there are significant practical limits of the dose of the product that can be produced or 
delivered” (FDA, 2015). 
For additional nonclinical information, please refer to the DTX401 Investigator’s Brochure. 


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2. 
STUDY OBJECTIVES AND ENDPOINTS 
Objective 
Endpoint 
Primary 
To determine the safety of single IV doses of DTX401 
in adults with GSDIa, including the incidence of 
DLTs. 
The incidence of AEs, including the incidence of 
DLTs at each dose level, TEAEs, and SAEs for each 
dosing cohort, assessed by severity and relationship to 
study product. 
Secondary 
To establish a dose of DTX401 that achieves 
symptom-free euglycemia (glucose ≥ 54 mg/dL 
[≥ 3.0 mmol/L]) in a setting of a controlled fasting 
challenge to allow further clinical development. 
The change from Baseline in time (in minutes) to first 
hypoglycemic event (defined as glucose < 54 mg/dL 
[< 3.0 mmol/L]) during a controlled fasting challenge 
at 12, 24, and 52 weeks after IV administration of 
DTX401. 
Exploratory 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Objective 
Endpoint 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AAV8 = adeno-associated virus serotype 8; AE = adverse event; DLT = dose-limiting toxicity; 
 
G6Pase = glucose-6-phosphatase; GSDIa = glycogen storage disease type Ia; 
 
; IV = intravenous; 
 SAE = serious 
adverse event; TEAE = treatment-emergent adverse event. 


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3. 
INVESTIGATIONAL PLAN 
3.1. 
Study Overview 
Study 401GSDIA01 is a Phase 1/2, open-label, single-arm, multicenter, safety and dose-finding 
study to determine the safety, tolerability, and efficacy of DTX401 in adults with GSDIa. 
The primary objective of the study is to determine the safety of single IV doses of DTX401, 
including the incidence of DLTs. The secondary objective of the study is to establish a dose of 
DTX401 that achieves symptom-free euglycemia (glucose ≥ 54 mg/dL [≥ 3.0 mmol/L]) in a 
setting of a controlled fasting challenge to allow further clinical development. 
DTX401 will be administered as a single peripheral IV infusion. The following doses (per 
kilogram of body weight) may be evaluated using a CRM to estimate the MTD of DTX401: 
• Dose 1: 2.0 × 1012 GC/kg 
• Dose 2: 6.0 × 1012 GC/kg 
• Dose 3: 1.0 × 1013 GC/kg 
Eligible subjects may be enrolled into 1 of the following cohorts of 3 subjects each and receive a 
single IV infusion of DTX401. 
• Cohort 1: Dose 1 (2.0 × 1012 GC/kg) with a reactive steroid regimen (prednisone 
starting dose of 40 mg/day) 
• Cohort 2: Dose 2 (6.0 × 1012 GC/kg) with a reactive steroid regimen (prednisone 
starting dose of 40 mg/day) 
• Cohort 3: Dose 2 (6.0 × 1012 GC/kg) with an optimized reactive steroid regimen 
(prednisone starting dose of 60 mg/day) 
• Cohort 4: Dose 2 (6.0 × 1012 GC/kg) with a prophylactic steroid regimen 
A cohort may be expanded to include additional subjects to confirm the findings for the cohort. 
Subjects in Cohorts 1 and 2 were dosed at a minimum of 2 weeks (14 days) apart. Subjects in 
subsequent cohorts will be dosed at a minimum of 1 week (7 days) apart. 
For Cohorts 1 and 2, there was a minimum of 12 weeks (84 days) between dosing of the last 
subject in a dosing cohort and the first subject in the next dosing cohort. After the third subject in 
each cohort reached the 12-week time point, the CRM (Section 10.2.1) proposed a dose for the 
next cohort using the collected data from the previous cohort. The decision to proceed was made 
after the DMC evaluated at least 12 weeks of safety data for all subjects in the dosing cohort, as 
outlined in the DMC charter (Section 9.3). There were no intracohort dose escalations. 


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After reviewing Week 12 data from all subjects in Cohort 1, the DMC concluded that it was safe 
to enroll 3 additional subjects into Cohort 2 at Dose 2 (6.0 × 1012 GC/kg). After reviewing 
Week 12 data from all subjects in Cohort 2, the DMC concluded that it was safe to enroll 
3 additional subjects into Cohort 3 at Dose 2 (6.0 × 1012 GC/kg) with an optimized reactive 
steroid regimen. An optimized reactive steroid regimen is expected to manage the elevations in 
liver aminotransferase levels observed in Cohorts 1 and 2 following DTX401 administration. 
If the optimized reactive steroid regimen does not sufficiently manage elevations in liver 
aminotransferase levels in Cohort 3, then Cohort 4 will be enrolled. Enrollment into Cohort 4 
may begin following completion of enrollment into Cohort 3. 
Subjects in Cohorts 1, 2, and 3 will receive reactive oral steroid treatment for possible 
vector-induced hepatitis if liver aminotransferase levels increase following treatment with 
DTX401. The Investigator, in conjunction with the Ultragenyx medical lead, will consider 
starting oral steroid treatment for possible vector-induced hepatitis if a subject’s ALT levels 
increase from the subject’s baseline or recently drawn levels, and are considered by the 
Investigator to be possibly related to treatment with DTX401 (Section 8.2.6.2.1). For Cohort 3, 
the reactive steroid regimen was modified to include a higher prednisone starting dose of 
60 mg/day vs 40 mg/day. 
Subjects in Cohort 4 will receive a prophylactic oral steroid regimen to prevent possible 
vector-induced hepatitis (Section 8.2.6.2.2). The Investigator may consider additional 
assessments or medical care, such as hospitalization or daily clinic visits, during steroid 
administration if, in the Investigator’s medical judgment, these measures would provide 
additional safety benefits. 
The controlled fasting challenge was also modified following DMC review of Week 12 data 
from subjects in Cohort 2. To minimize a potential insulin spike that could result in abrupt 
hypoglycemia and normalize baseline glucose levels, the recommended target carbohydrate 
range of the prefasting challenge dinner meal was decreased from 20 g to 30 g to 15 g to 20 g, 
and the prefasting challenge cornstarch dose was decreased from 35 g to 5 g. 
However, further analysis and review of fasting challenge data after changing the prefasting 
cornstarch dose to 5g showed significantly lower fasting times in cohorts 2 (W52 and W78) and 
3 (W24, W32 and W52). In most instances, low post-prandial levels of blood glucose associates, 
persistence of high circulating insulin levels, and slow cortisol response to hypoglycemia make it 
challenging to interpret these results. Available CGM recordings have shown an absence of 
nocturnal hypoglycemia in these subjects despite an overall reduced frequency and total amount 
of cornstarch. The reason that several subjects can now sleep through the night at home without 
experiencing hypoglycemia in the absence of cornstarch consumption, but have shorter time to 
hypoglycemia during the inpatient fasting challenge is unclear. It could be attributed to the 
artificial threshold of 60 mg/dL for stopping the fasting challenge. This threshold may not allow 
adequate glucose release to be induced in subjects with higher insulin and lower cortisol levels. 
In the home setting, subjects clearly do better as their glucose release seems to be better induced, 
thereby preventing their glucose levels from falling to dangerous levels. 
With Protocol Amendment 6, the dinner meal will be personalized for each subject, and will 
include a target carbohydrate range and overall composition in protein, fats and dietary fibers 


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that is as close as possible to the subject’s most current dinner prescription but not higher than 
the carbohydrate content of the dinner consumed at their baseline fasting challenge. The 
prefasting cornstarch dose and time of consumption will be per the respective subject’s most 
recent cornstarch prescription and daily regimen at home. In addition, the threshold for stopping 
the test was lowered to 54 mg/dL (3 mmol/L) or when the subjects present signs and symptoms 
of hypoglycemia. Justification of the new threshold is based on the fact that signs and symptoms 
of hypoglycemia associated with an adrenergic reaction and cerebral glucopenia and most 
physiological hormonal and metabolic responses to hypoglycemia may not occur in GSDIa 
subjects until they reach these levels of blood glucose values. CGM recording during the fasting 
test will provide continuous glucose measurement data that will allow Investigators to closely 
monitor subjects when they reach the lower range of blood glucose (ie, below 60 mg/dL) 
(Section 8.1.1). 
Study enrollment will be stopped and the DMC and regulators will be notified if, at any time 
during the study, any of the safety stopping criteria are met (Section 3.2.4). 
Subjects will be followed for 52 weeks following DTX401 administration. After completion of 
the Week 52 visit or early withdrawal, subjects will be offered enrollment into a 4-year extension 
study to evaluate the long-term (a total of 5 years) safety and efficacy of DTX401. 
3.2. 
Overall Study Duration and Follow-Up 
The study is anticipated to enroll approximately 12 subjects at up to 12 study sites globally. The 
duration of the study for each subject is defined as the date the subject provides written informed 
consent through the Week 52 visit. Subjects will be in the study for approximately 60 weeks 
(including the Screening Period). 
Subjects will be asked to complete up to 4 inpatient study site visits (each approximately 24 to 
48 hours in length) and 23 outpatient or home study visits (each approximately 1.5 to 2 hours in 
length). Outpatient or home study visits may be performed at a second participating study site 
other than the dosing site. The schedule of study visits and the assessments and procedures to be 
performed at each study visit are listed in the Schedule of Events (Table 6). 
A high-level overview of the study is provided in Figure 2. 


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Figure 2: 
Study Overview 
Screening Period (Day −56 to Day −1) 
• 
Obtain informed consent 
o 
Collect samples (blood) for G6PC genotyping and AAV8 neutralizing antibody testing 
• 
Determine subject eligibility 
• 
Perform ECG and liver ultrasound 
• 
Collect samples (blood and urine) for clinical and specialty laboratory assessments 
• 
Record the subject’s daily prescribed diet, daily diet intake, daily prescribed cornstarch (or equivalent), and 
daily cornstarch (or equivalent) intake during scheduled study visits and, if possible, on a weekly basis 
through the Week 52 visit or early withdrawal 
• 
Assess symptomatic hypoglycemic events 
• 
Provide copies of the GSDIa Morning Diary and GSDIa Evening Diary to subject 
• 
Provide CGM device to subject 
Baseline (Day 0 through Day 2) 
Inpatient stay (approximately 48 hours) 
• 
Confirm subject eligibility 
• 
Collect samples (blood and urine) for clinical and specialty laboratory assessments 
• 
Collect samples (saliva, urine, and stool) for vector shedding analysis (Day 0) 
• 
Perform ECG  
• 
Record the subject’s daily prescribed diet, daily diet intake, daily prescribed cornstarch (or equivalent), and 
daily cornstarch (or equivalent) intake (Day 0) 
• 
Assess symptomatic hypoglycemic events 
• 
 
 
• 
Subject will complete GSDIa Morning Diary and GSDIa Evening Diary for 7 days leading up to and 
including Day 0 
• 
Complete controlled fasting challenge and 24-hour urine collection (Day 0) 
• 
Perform 
 (after the controlled fasting challenge is complete) 
• 
For Cohort 4, initiate prophylactic steroid regimen after completion of the controlled fasting challenge and 
before DTX401 administration (Day 1) 
• 
Administer DTX401 (Day 1) 
• 
Collect sample (blood) for vector genome determination (Day 1 [predose] and Day 2 [postdose]) 
• 
Discharge subject (24 hours after DTX401 administration) with prednisone per the reactive (Cohort 3) or 
prophylactic (Cohort 4) steroid regimen 
Enrollment Period 
• 
Subjects in Cohorts 1 and 2 were dosed at a minimum of 2 weeks (14 days) apart. Subjects in subsequent 
cohorts will be dosed at a minimum of 1 week (7 days) apart. 


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• 
For Cohorts 1 and 2, there was a minimum of 12 weeks (84 days) between dosing of the last subject in a 
dosing cohort and the first subject in the next dosing cohort. The decision to proceed to the proposed next 
dose cohort was made after the DMC reviewed safety data for all subjects in a cohort after all subjects in the 
cohort completed Week 12. 
• 
Following DMC evaluation of 12-week data from Cohorts 1 and 2, subjects may be enrolled into Cohort 3 
with an optimized reactive steroid regimen. If the optimized reactive steroid regimen does not sufficiently 
manage elevations in liver aminotransferase levels in Cohort 3, then Cohort 4 will be enrolled. Subjects in 
Cohort 4 will receive a prophylactic steroid regimen. Enrollment into Cohort 4 may begin following 
completion of enrollment into Cohort 3. 
Follow-up Period: Inpatient Visits (Weeks 12 and 24) 
Inpatient stay (approximately 24 hours) 
• 
Perform targeted physical examination 
• 
Collect samples (blood and urine) for clinical and specialty laboratory assessments 
• 
Collect samples (saliva, urine, and stool) for vector shedding analysis 
• 
Collect sample (blood) for vector genome determination 
• 
Record the subject’s daily prescribed diet, daily diet intake, daily prescribed cornstarch (or equivalent), and 
daily cornstarch (or equivalent) intake during scheduled study visits and, if possible, on a weekly basis 
through the Week 52 visit or early withdrawal 
• 
If the subject was unable to use the assigned CGM but was able to complete the Morning Glucose Level 
monitoring worksheet, review the subject’s worksheet and provide a new worksheet to the subject 
• 
Assess symptomatic hypoglycemic events 
• 
 
• 
Subject will complete GSDIa Morning Diary and GSDIa Evening Diary for 7 days leading up to and 
including each inpatient visit 
• 
Subject will complete a brief telephone interview regarding their experience completing 
 
(Week 24 only) 
• 
Complete controlled fasting challenge and 24-hour urine collection 
• 
Perform 
 (after the controlled fasting challenge is complete) 
Follow-up Period: Outpatient Study Site Visits (Weeks 4, 6, and 36) 
• 
Perform targeted physical examination 
• 
Collect samples (blood and urine) for clinical and specialty laboratory assessments 
• 
Collect samples (saliva, urine, and stool) for vector shedding analysis 
• 
Collect sample (blood) for vector genome determination 
• 
Record the subject’s daily prescribed diet, daily diet intake, daily prescribed cornstarch (or equivalent), and 
daily cornstarch (or equivalent) intake during scheduled study visits and, if possible, on a weekly basis 
through the Week 52 visit or early withdrawal 
• 
If the subject was unable to use the assigned CGM but was able to complete the Morning Glucose Level 
monitoring worksheet, review the subject’s worksheet and provide a new worksheet to the subject 
• 
Assess symptomatic hypoglycemic events 


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Follow-up Period: Outpatient Study Site or Home Visits 
• 
Biological samples will be collected at a minimum of every 3 to 4 days through Week 12, or longer if 
clinically indicated, either at the study site or by a home healthcare nurse (if arranged by the Investigator). 
Outpatient or home study visits may be performed at a second participating study site other than the dosing 
site. 
End of Study (Week 52)/Early Withdrawal 
Inpatient stay (approximately 24 hours) 
• 
Collect samples (blood and urine) for clinical and specialty laboratory assessments 
• 
Collect samples (saliva, urine, and stool) for vector shedding analysis 
• 
Collect sample (blood) for vector genome determination 
• 
Perform ECG  
• 
Record the subject’s daily prescribed diet, daily diet intake, daily prescribed cornstarch (or equivalent), and 
daily cornstarch (or equivalent) intake 
• 
If the subject was unable to use the assigned CGM but was able to complete the Morning Glucose Level 
monitoring worksheet, review the subject’s worksheet and provide a new worksheet to the subject 
• 
Assess symptomatic hypoglycemic events 
• 
 
 
• 
Subject will complete GSDIa Morning Diary and GSDIa Evening Diary for 7 days leading up to and 
including Week 52 visit 
• 
Subject will complete a brief telephone interview regarding their experience in the study and completing 
 
• 
Complete controlled fasting challenge and 24-hour urine collection 
• 
Perform 
 (after the controlled fasting challenge is complete) 
• 
Offer subject enrollment into the long-term (4-year) extension study 
• 
Discharge subject 
Abbreviations: AAV8 = adeno-associated virus serotype 8; CGM = continuous glucose monitoring; DMC = data 
monitoring committee; ECG = electrocardiogram; G6PC = glucose-6-phosphatase (gene); GSDIa = glycogen 
storage disease type Ia; 
; 
. 
3.2.1. 
Screening Period 
After a subject has provided written informed consent and within the 56 days prior to 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 (Section 4) 
and completing all of the screening assessments outlined in the Schedule of Events (Table 6). 
Screening assessments may be performed on more than 1 day; all assessments must be 
completed and results available and reviewed within the 56-day Screening Period prior to Day 0. 
It is recommended that blood samples for AAV8 neutralizing antibody testing (Section 8.2.6.6) 
and G6PC genotyping (Section 8.3) be collected at the time written informed consent is 
provided. 


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Subjects with screening assessment results that do not fulfill eligibility requirements may have 
those assessments repeated if the study team determines that the underlying issue may resolve or 
reverse during the Screening Period (eg, Screening laboratory assessments, such as liver function 
tests and triglyceride levels). Only the screening assessments that do not meet eligibility 
requirements need to be repeated, but any or all screening procedures may be repeated at the 
Investigator's discretion. 
Subjects who do not meet eligibility requirements within the Screening Period are considered 
screen failures. Subjects who are screen failures may be rescreened once during the study. In this 
case, only AAV8 neutralizing antibody testing (Section 8.2.6.6) and the screening assessments 
that did not meet eligibility requirements need to be repeated, but any or all screening procedures 
may be repeated at the Investigator's discretion. 
3.2.2. 
Baseline Period 
Subjects will be admitted to the study site or hospital on Day 0 and will be discharged 
approximately 24 hours after administration of DTX401 (on Day 2). Each subject will remain on 
his or her prescribed diet for the duration of the inpatient stay. 
A blood sample for measurement of lipid levels will be collected on the morning of hospital 
admission. The sample should be collected at least 2 to 4 hours after the subject’s last meal. 
3.2.2.1. 
Baseline Visit – Day 0 
The assessments and procedures to be performed during the Baseline (Day 0) visit are listed in 
the Schedule of Events (Table 6). 
 will be 
performed after the controlled fasting challenge is complete to avoid having to replace the sensor  
prior to the fasting challenge. (Section 8.1.4). 
Subjects will participate in a controlled fasting challenge. The Investigator or delegated sub-
investigator will review the results of all laboratory assessments performed on the first day of the 
inpatient visit, including cortisol. Subjects should wear their CGM device throughout the fasting 
challenge, and should not change the sensor prior to the assessment. Before the controlled fasting 
challenge begins, the study site will provide dinner for the subject. The dinner meal will be 
personalized for each subject and will include a target carbohydrate range and overall 
composition in protein, fats and dietary fibers that is as close as possible to the subject’s most 
current dinner dietary prescription. The content of the dinner and quantities consumed will be 
recorded. 
After dinner, subjects will be given an oral dose of cornstarch equivalent per their most recent 
cornstarch prescription at approximately the same time that they typically take it, but no later 
than 3 hours post dinner. The time of ingestion of prefasting cornstarch and the amount 
consumed will be recorded. After the cornstarch is ingested, the controlled fasting challenge will 
begin, and the start time will be recorded accordingly. If subjects do not receive cornstarch 
overnight, the fasting test will begin after they complete their dinner. Subjects will be instructed 
to minimize activity after they finish eating dinner until the end of the fasting challenge.  


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During the fast, subjects may not ingest any food or drink other than water.  The controlled 
fasting challenge will end when the subject’s glucose level decreases to < 54 mg/dL (< 3.0 
mmol/L) or subjects experience signs and symptoms of hypoglycemia, or the fast reaches 15 
hours without hypoglycemia, whichever occurs first. The stop time of the controlled fasting 
challenge will be recorded. At the end of the controlled fasting challenge, the subject’s 
hypoglycemia should be treated per the institution’s standard procedure, which may include 
providing the subject with a meal, cornstarch, or IV glucose, if medically indicated.  
Blood samples for measurement of cortisol, fatty acid, glucagon, insulin, C-peptide, growth 
hormone, insulin-like growth factor-binding protein 1 (IGFBP1), adrenocorticotropic hormone 
(ACTH), alanine and ketone levels will be collected at the beginning and end of the fasting 
challenge, or more frequently at the Investigator’s discretion. A final sample for glucose, lactate, 
growth hormone, IGFBP1, ACTH, and cortisol measurement will be collected 30 minutes after 
the end of the controlled fasting challenge. Samples should be prepared and transported to the 
local laboratory in accordance with the site’s standard procedures. Blood samples for STAT 
analysis of glucose and lactate will be collected per the schedule of events. Capillary glucose will 
also be assessed.  
Urine will be collected over 24 hours for the determination of total protein, microalbumin, and 
creatinine. The collection of urine can overlap with the controlled fasting challenge. A 
 
will be performed after the controlled fasting challenge is complete.  
For subjects enrolled in Cohort 4, the Investigator will initiate a prophylactic steroid regimen 
after completion of the controlled fasting challenge and before DTX401 administration 
(Section 8.2.6.2.2). 
3.2.2.2. 
Baseline Visit – Day 1 
The assessments and procedures to be performed on Day 1 are listed in the Schedule of Events 
(Table 6). 
Following completion of the Day 0 assessments (ie, controlled fasting challenge and 24-hour 
urine collection), subjects will receive a single, peripheral IV infusion of DTX401. 
Safety (vital sign measurements [Section 8.2.1], clinical laboratory assessments [Section 8.2.6], 
and AEs and SAEs [Section 9.1]) will be monitored over 24 hours following infusion of 
DTX401 (Table 6). Any AEs that occur during this 24-hour observation period will be treated 
with appropriate supportive and medical care deemed necessary for the well-being of the subject. 
Subjects will be discharged after a 24-hour observation period. Subjects in Cohort 3 will be 
discharged with prednisone to allow rapid treatment of possible vector-induced hepatitis if it 
occurs following treatment with DTX401 (Section 8.2.6.2.1). Subjects in Cohort 4 will be 
discharged with prednisone per the prophylactic steroid regimen (Section 8.2.6.2.2). 
3.2.3. 
Follow-up Period 
Subjects will be asked to visit the study site at a minimum of every 3 to 4 days through Week 12, 
or longer if clinically indicated (Table 6). Following the Week 12 visit, subjects will visit the 


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study site approximately once every 12 weeks through Week 36 and at Week 52 or their early 
withdrawal from the study (Table 6). 
3.2.3.1. 
Outpatient Study Site or Home Visits 
Subjects will be asked to provide clinical laboratory samples at a minimum of every 3 to 4 days 
through Week 12 of the study, or longer if clinically indicated (Table 6). Subjects may have the 
option of having these samples collected at their homes by clinically trained and qualified 
personnel (if arranged by the Investigator), unless there is a scheduled study site visit that the 
subject must attend in person (Table 6). 
During these visits, a blood sample will be collected for determination of clinical chemistry 
(including liver function tests) and sent to the central laboratory. A second blood sample will be 
collected for liver function tests and sent to the local laboratory (STAT sample; Section 8.2.6.2). 
Saliva, urine, and stool samples will also be collected during these visits for assessment of vector 
shedding until at least 3 consecutive negative results are obtained from each sample matrix 
(Section 8.2.6.10). A blood sample will be collected for determination of cell-mediated immune 
response to AAV8 and G6Pase testing approximately weekly (Section 8.2.6.7). 
3.2.3.2. 
Outpatient Visits 
Subjects will visit the study site on an outpatient basis at Weeks 4, 6, and 36 for efficacy and 
safety assessments as outlined in the Schedule of Events (Table 6). 
3.2.3.3. 
Inpatient Visits 
Subjects will be admitted to the study site or hospital at Weeks 12, 24, and 52 for an 
 
(Section 8.1.4), the controlled fasting challenge (Section 8.1.1), and 24-hour urine 
collection (Section 8.2.6.5). Each inpatient visit will last approximately 24 hours. Each subject 
will remain on his or her prescribed diet for the duration of each inpatient stay. The assessments 
and procedures to be performed at each visit are listed in the Schedule of Events (Table 6). The 
will be performed on the day after the controlled fasting challenge to avoid having to 
replace the sensor prior to the fasting challenge.  
A blood sample for measurement of lipid levels will be collected on the morning of hospital 
admission at approximately the same time as collected on Day 0. The sample should be collected 
at least 2 to 4 hours after the subject’s last meal. 
Subjects will participate in a controlled fasting challenge (Section 8.1.1). The Investigator or 
delegated sub-investigator will review the results of all laboratory assessments performed on the 
first day of the inpatient visit, including the latest cortisol values. Subjects should wear their 
CGM device throughout the fasting challenge, and should not change the sensor prior to the 
assessment. Before the controlled fasting challenge begins, the study site will provide dinner for 
the subject. The dinner meal will be personalized for each subject and will include a target 
carbohydrate range and overall composition in protein, fats and dietary fibers that is as close as 
possible to the subject’s most current dinner dietary prescription. The content of the dinner and 
quantities consumed will be recorded. 


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After dinner, subjects will be given an oral dose of cornstarch equivalent per their most recent 
cornstarch prescription at approximately the same time that they typically take it, but no later 
than 3 hours post dinner. The time of ingestion of prefasting cornstarch and the amount 
consumed will be recorded. After the cornstarch is ingested, the controlled fasting challenge will 
begin, and the start time will be recorded accordingly. If subjects do not receive cornstarch 
overnight, the fasting test will begin after they complete their dinner. Subjects will be instructed 
to minimize activity after they finish eating dinner until the end of the fasting challenge. 
During the fast, subjects may not ingest any food or drink other than water. The controlled 
fasting challenge will end when the subject’s glucose level decreases to < 54 mg/dL (< 3.0 
mmol/L) or when the subjects experience signs and symptoms of hypoglycemia, or when the fast 
reaches 15 hours without hypoglycemia, whichever occurs first. The stop time of the controlled 
fasting challenge will be recorded.  
At the end of the controlled fasting challenge, the subject’s hypoglycemia should be treated per 
the institution’s standard procedure, which may include providing the subject with a meal, 
cornstarch, or IV glucose, if medically indicated. 
Blood samples for measurement of cortisol, fatty acid, glucagon, insulin, C-peptide, growth 
hormone, IGFBP1, ACTH, alanine and ketone levels will be collected at the beginning and end 
of the fasting challenge, or more frequently at the Investigator’s discretion. A final sample for 
glucose, lactate, growth hormone, IGFBP1, ACTH, and cortisol measurement will be collected 
30 minutes after the end of the controlled fasting challenge. Samples should be prepared and 
transported to the local laboratory in accordance with the site’s standard procedures. Blood 
samples for STAT analysis of glucose and lactate will be collected per the schedule of events. 
Capillary glucose will also be assessed. Urine will be collected over 24 hours (Section 8.2.6.5) 
for the determination of total protein, microalbumin, and creatinine. The collection of urine can 
overlap with the controlled fasting challenge.  Subjects will be discharged following the 
completion of the 24-hour urine collection and the 
. 
3.2.4. 
Safety Stopping Criteria 
Enrollment will be stopped and the DMC and regulators will be notified if, at any time during the 
study, any of the events listed below occur following administration of DTX401: 
• Death of a subject 
• An event with an intensity ≥ Grade 3 (according to the National Cancer Institute 
[NCI] Common Terminology Criteria for Adverse Events [CTCAE]) develops 
• Occurrence of a hepatic malignancy 
If a stopping rule is met, enrollment will be paused and the DMC will meet to review available 
data. If a decision is made to resume enrollment, this decision will be communicated to and, if 
required, approved by regulatory authorities according to country requirements. 
An event that meets the above criteria will be reported immediately to the Sponsor once the 
study site has become aware (within 24 hours). SAEs will be reported as outlined in 


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Section 9.1.2.2. For AEs and SAEs, the appropriate pages of the electronic case report form 
(eCRF) must be completed. If a stopping criterion is met and 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 (Section 3.2.3.3) will 
have completed the study. Subjects who discontinue before the Week 52 visit will be asked to 
return for an Early Withdrawal visit, during which all safety assessments should be performed 
(Table 6). Subjects with any ongoing AEs at this visit will continue to be monitored, as outlined 
in Section 9.1.5. After completion of the Week 52 visit or early withdrawal, subjects will be 
offered enrollment into this extension study in accordance with regulatory authority regulations 
and ICH GCP. 
3.3. 
Changes to the Protocol due to COVID-19 
Changes to the protocol or Investigational Plan to minimize or eliminate immediate hazards or to 
protect the life and well-being of research participants and/or study staff may be implemented 
without IRB/EC approval or before filing an amendment to the competent authority but are 
required to be reported afterward. Investigators should contact Ultragenyx or Designee to 
determine an appropriate course of action, which may include but is not limited to remote visits, 
home health visits, and out of window visits or assessments.  Any changes to the protocol or 
investigational plan must be documented. The Investigator will work with Ultragenyx or 
Designee and IRB/EC to prioritize reporting of protocol deviations that impact safety of trial 
participants. 


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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. Willing and able to provide written informed consent. 
2. Males and females ≥ 18 years of age. 
3. Documented GSDIa with confirmation by molecular testing. 
4. Documented history of ≥ 1 hypoglycemic event with glucose < 60 mg/dL 
(< 3.33 mmol/L). 
5. Subject’s GSDIa disease is stable as evidenced by no hospitalization for severe 
hypoglycemia during the 4-week period preceding the Screening Visit. 
6. Hematology and coagulation panel results are within the normal range or, if outside the 
normal range, are deemed not clinically significant in the opinion of the Investigator. 
7. No known allergic reaction to any component of DTX401. 
8. Willing and able to comply with study procedures and requirements, including periodic 
inpatient hospitalization, frequent blood collections, and 24-hour urine collection. 
9. Males and females of childbearing potential must be willing to use effective 
contraception at the time of administration of DTX401 and for 52 weeks following 
administration of DTX401 to prevent the potential transmission of the AAV vector 
(Section 9.2.1). 
4.2. 
Exclusion Criteria 
Subjects who meet any of the following criteria at Screening will be excluded from the study: 
1. Screening or Baseline (Day 0) glucose level < 60 mg/dL (< 3.33 mmol/L); subjects may 
be rescreened after glucose is controlled and stable, at the discretion of the Investigator. 
2. Liver transplant, including hepatocyte cell therapy/transplant. 
3. Presence of liver adenoma > 5 cm in size.  
4. Presence of liver adenoma > 3 cm and ≤ 5 cm in size that has a documented annual 
growth rate of ≥ 0.5 cm per year. 


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5. Significant hepatic inflammation or cirrhosis as evidenced by imaging or any of the 
following laboratory abnormalities: alanine aminotransferase (ALT) or aspartate 
aminotransferase > the upper limit of normal (ULN), total bilirubin > 1.5 × ULN, or 
alkaline phosphatase > 2.5 × ULN. Liver function tests may be repeated during the 
Screening Period at the Investigator’s discretion. 
6. Serum creatinine > 2.0 mg/dL. 
7. Triglycerides ≥ 1000 mg/dL at the time of the Screening Visit. 
8. Presence of active, or history of treatment for, hepatitis B virus or hepatitis C virus 
infection. 
9. History of human immunodeficiency virus 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 viral load > 200 copies/mL, on 2 separate occasions, as measured by 
polymerase chain reaction. 
10. 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 
nonmelanoma skin cancer. 
11. Active infection (viral or bacterial). 
12. Anti-AAV8 neutralizing antibody titer ≥ 1:5. 
13. Participation (current or previous) in another gene transfer study. 
14. Participation in another investigational product study within 3 months of Screening. 
15. Has a positive serum pregnancy test at Screening (females of childbearing potential 
only), a positive urine pregnancy test at Baseline (Day 0; females of childbearing 
potential only), or is nursing. 
16. 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 DOSING PROCEDURES 
5.1. 
Subject Screening 
All potential subjects must sign an informed consent form (ICF) before any study procedures or 
assessments 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 ICF will be given to 
the subject. 
Rescreening is allowed as described in Section 3.2.1. Study 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 Dosing 
This is an open-label study; subjects will be assigned to treatment using an interactive web 
response system. Three subjects will be enrolled in each cohort as described in Section 3.1. 


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6. 
STUDY TREATMENT 
6.1. 
Identity of Study Product 
6.1.1. 
Description of DTX401 
DTX401 is a nonreplicating, recombinant AAV8 vector that contains a codon-optimized, 
wild-type human G6PC coding sequence. DTX401 demonstrates thermal stability, which is a 
general property of AAV and parvoviruses. DTX401 is supplied as a slightly hyperosmotic 
buffered formulation solution of approximately 400 milliosmole at pH 8.0. DTX401 is a 
homogeneous, monodisperse solution that is clear and colorless without visible particulates. 
6.1.2. 
Components Used for Manufacturing 
 
 
 
 
 
 
 
 
 
 For additional 
information, please refer to the DTX401 Investigator’s Brochure. 
6.2. 
Management of Clinical Supplies 
The study site will be provided with supplies required for infusion of DTX401. 
6.2.1. 
Packaging and Labeling 
Each vial of study product provided to study sites will contain approximately 1 mL of DTX401 
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. The secondary label will contain required text for all countries 
participating in the study and will include a unique identifier. Secondary labeling will appear in 
the appropriate language for the country supplied. 
6.2.2. 
Storage of DTX401 
DTX401 must be stored in a secure freezer at a controlled temperature at or below −60°C. 
The study site is to maintain a daily log documenting the temperature. 


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6.2.3. 
Study Product Accountability 
The Investigator or designated study site staff 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 nonreplicative and are not expected to pose a risk of 
transmission. However, all sexually active subjects must use approved contraception from the 
time of DTX401 dosing and for 52 weeks following administration (Section 4.1). All subjects 
enrolled in the study should be encouraged to discuss the use of approved contraception with his 
or her partner in order to prevent possible transmission of vector via seminal or vaginal fluid. 
The study product and post treatment study samples should be handled using standard universal 
precautions. 
6.3. 
Treatment Schedule and Administration 
6.3.1. 
Administration of DTX401 
Subjects will receive a single peripheral IV infusion of DTX401 on Day 1, administered by 
qualified study personnel, as designated by the Investigator (Table 6). The dose will be 
determined by the cohort and candidate dose (Section 3.1). 
The dose of DTX401 to be administered will be calculated using the subject’s weight recorded at 
Screening. The subject’s weight will be verified on Day 0, prior to administration of DTX401, to 
ensure that their current weight is within 10% of their screening weight (Section 8.2.1). 
Any subject weighing > 100 kg (> 220 lb) will be dosed as if his or her weight is 100 kg. Prior to 
infusion, all infusion bag labels will be checked by the study site pharmacist and a minimum of 
2 medical personnel charged with administration of DTX401. 
The study site must be equipped with emergency resuscitation capabilities. On Day 1, an IV 
catheter will be inserted into a peripheral vein and flushed with saline. 
Detailed instructions for dose preparation and subsequent infusion of DTX401 are provided in 
the pharmacy manual. 
6.3.2. 
Treatment Compliance 
DTX401 will be administered at the study site 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. 


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6.4. 
Prior and Concomitant Medications, Therapies, and Procedures 
Relevant prior and concomitant medications, therapies, and procedures will be recorded in the 
subject’s eCRF. The minimum requirement for medications is to record the drug name, the dates 
of administration, and the reason for use. This includes all prescription drugs, herbal products, 
vitamins, minerals, and over-the-counter medications. Any changes in concomitant medication 
use will also be recorded in the subject’s eCRF. The minimum requirement for therapies and 
procedures is to record the name and date of the therapy or procedure and the reason it was 
performed. 
6.4.1. 
Permitted Medications 
The use of permitted medications (including drug name, dates of administration, dosage, reason 
for use) will be recorded on the appropriate page of the eCRF. 
The subject will be instructed to discuss all new medications, including medications to alleviate 
complications associated with GSDIa and herbal supplements, with the Investigator at each study 
visit. 
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 another investigational product is prohibited from Screening through Week 52. 


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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 appropriate page of the eCRF. 
The reason for withdrawal may include the following: 
• Withdrawal of consent 
• Administrative decision by the Investigator or the Sponsor 
• Ineligibility 
• Significant protocol deviation 
• Subject noncompliance 
• 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 requested. 
7.2. 
Subject Replacement 
If a subject withdraws from the study after receiving DTX401, the subject will not be replaced. 
Subjects who withdraw from the study after signing the ICF, but before receiving DTX401, will 
be replaced. 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 Assessments 
Planned time points for all efficacy measurements in the study are listed in Table 6. 
8.1.1. 
Symptom-Free Euglycemia (Controlled Fasting Challenge) 
The subject's ability to maintain symptom-free euglycemia during a controlled fasting challenge 
will be assessed at time points specified in the Schedule of Events. However, if clinically 
indicated, the controlled fasting challenge can also be performed at an unscheduled visit.  
The controlled fasting challenge requires a 24-hour inpatient stay in a hospital or research facility 
and will be performed after all other study visit assessments (except 
) have been completed 
and the required laboratory assessments (as specified below) have been reviewed by the 
Investigator (or a subinvestigator assigned to review results and make clinical decisions per the 
site delegation log). Subjects should wear their CGM device throughout the fasting challenge, 
and should not change the sensor prior to the assessment.  
If a subject is suspected to have HPA axis impairment (eg, due to prolonged steroid treatment;  
may be confirmed by morning cortisol or stimulation tests), the fasting challenge may have to be 
rescheduled to a later date in order to ensure subject safety and provide interpretable results. 
Before the controlled fasting challenge begins, the study site will provide dinner for the subject. 
The dinner meal will be personalized for each subject, and will include a target carbohydrate 
range and overall composition in protein, fats and dietary fibers that is as close as possible to the 
subject’s most current dinner prescription, but not higher in carbohydrate content than the dinner 
consumed at their baseline fasting challenge. The start and stop time of the dinner meal and its 
full dietary composition including amount of carbohydrates consumed will be recorded. After 
dinner, subjects will be given an oral dose of cornstarch equivalent per their most recent 
cornstarch prescription, at approximately the same time that they typically take it, but no later 
than 3 hours post dinner. The amount of cornstarch administered should not be higher than that 
consumed by the subject at the baseline fasting challenge. The time of ingestion of prefasting 
cornstarch and the amount consumed will be recorded. After the cornstarch is ingested, the 
controlled fasting challenge will begin, and the start time will be recorded accordingly. If a 
subject does not receive cornstarch before going to bed at the time of the CFC, the fasting 
challenge will start after they complete their dinner. Subjects will be instructed to minimize 
activity after they finish eating dinner until the end of the controlled fasting challenge.   
During the fast, subjects may not ingest any food or drink other than water. The controlled 
fasting challenge will end when the subject’s glucose level decreases to < 54 mg/dL (< 3.0 
mmol/L) or when the subjects experience signs and symptoms of hypoglycemia, or when the fast 
reaches 15 hours without hypoglycemia, whichever occurs first. The stop time of the controlled 
fasting challenge will be recorded. At the end of the controlled fasting challenge, the subject’s 
hypoglycemia should be treated per the institution’s standard procedure, which may include 
providing the subject with a meal, cornstarch, or IV glucose, if medically indicated.  


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In cases where the controlled fasting challenge is terminated prematurely before the subject 
reaches a glucose level of < 54mg/dL or without the subject experiencing signs and symptoms of 
hypoglycemia, or due to any deviation in the fasting challenge protocol, an ad hoc fasting 
challenge may be scheduled within 6 weeks from the scheduled fasting challenge.   
Laboratory sample collection before and during the controlled fasting challenge 
On the morning of inpatient visit for the controlled fasting challenge, after vital signs and other 
non-interventional assessments have been performed, samples will be collected for standard 
clinical chemistry (including lipid levels), hematology, coagulation panel, and urinalysis. These 
samples should be collected at least 2 to 4 hours after the subject’s last meal prior to admission 
and sent to the central lab. A sample for STAT AST and ALT level analysis will also be 
collected at this time and sent to the local laboratory; the Investigator or delegated 
subinvestigator should review the results before starting the controlled fasting challenge. 
All subjects should have a morning cortisol and ACTH measurement prior to their baseline 
fasting challenge. Cortisol and ACTH results should be reviewed by the Investigator or delegate 
before starting the fasting challenge. Abnormal morning cortisol results might require postponing 
the fasting challenge until further HPA axis testing is performed.  
For subjects with suspected HPA axis dysfunction (eg, after prolonged steroid treatment) 
supplemental tests can be conducted (eg, stimulation tests) before deciding if it is safe to conduct 
the fasting challenge. In most cases, morning cortisol and supplemental tests will be conducted 
one week prior to the visit. It is also possible to perform these tests at the site on Day 1 of the 
visit under the conditions that all results will be available prior to the beginning of the CFC.  
Total urine voided over the 24-hour period starting at the time of inpatient admission will be 
collected during the controlled fasting challenge.  
Blood samples for measurement of cortisol, ACTH, free fatty acids, glucagon, insulin, C-peptide, 
growth hormone, IGFBP1, alanine and ketone levels (3-hydroxy butyrate) will be collected at the 
beginning (ie, immediately after the post-dinner dose of cornstarch, or immediately after dinner 
for subjects who do not take a post-dinner dose of cornstarch) and end of the controlled fasting 
challenge, or more frequently at the Investigator’s discretion. A final sample for glucose, lactate, 
growth hormone, IGFBP1, ACTH and cortisol measurement will be collected 30 minutes after 
the end of the controlled fasting challenge. Samples should be prepared and transported to the 
local laboratory in accordance with the site’s standard procedures. 
Blood samples for STAT analysis of glucose and lactate will be collected through an indwelling 
catheter (central or peripheral) at the following time points: 
• At the beginning of the fast (ie, immediately after the post-dinner dose of cornstarch, or 
immediately after dinner for subjects who do not take a post-dinner dose of cornstarch) 
• Approximately every 60 minutes (± 5 minutes) until the glucose level decreases to ≤ 70 
mg/dL (≤ 3.9 mmol/L) 


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• Approximately every 30 minutes (± 5 minutes) until the glucose level decreases to 
< 54 mg/dL (< 3.0 mmol/L) or when the subjects experience signs and symptoms of 
hypoglycemia, or when the fast reaches 15 hours without hypoglycemia, whichever occurs 
first 
Samples should be prepared and transported to the local laboratory in accordance with the site’s 
standard procedures. To ensure the safety of the study subjects, results from these tests should be 
available within 30 minutes after the blood sample collection. Capillary glucose will be 
performed at the same time points as blood samples for STAT analysis of glucose and lactate. 
Results of the capillary glucose and readings from CGM at corresponding time points will be 
noted on a controlled fasting challenge results sheet. 
8.1.2. 
Continuous Glucose Monitoring 
Supplemental information on glucose level trends will be collected using a continuous glucose 
monitoring (CGM) device. The site will provide a CGM device to the subject during the 
Screening Period after determining that the subject is eligible for the study (Table 6). 
Subjects will be educated on the appropriate care and use of the CGM device and sensors, and 
instructed to wear the CGM device through the Week 52 visit or early withdrawal. Data from the 
subject’s CGM device will be transferred to the Sponsor throughout the study, including a final 
data transfer at the end of the Week 52 visit or early withdrawal. Details regarding the care and 
use of the CGM device and sensors and data transfer to the Sponsor are provided in the Manual 
of Operations. 
8.1.3. 
Morning Glucose Levels 
If a subject is unable to use the assigned CGM, the subject should collect morning glucose levels 
at least 2 mornings per week throughout the study (Table 6). Subjects should adhere to their 
prescribed overnight cornstarch diet. Morning glucose levels should be measured using the 
subject’s own glucose monitoring device before taking their morning dose of cornstarch. 
The collection date, collection time, glucose level, and prior day’s overnight cornstarch dose 
taken should be collected on the Morning Glucose Level monitoring worksheet provided by the 
site. Subjects will be instructed to bring the completed worksheets to each study visit. 
Data collected on the worksheet will be captured on the appropriate page of the eCRF. 
8.1.4. 
 
 
 
 


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8.1.5. 
 
Subjects will be asked to complete the following 
: 
• 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.1.6. 
Endpoint Outcomes Interviews 
Up to two 30-minute scripted telephone interviews will be conducted during the Week 24 and 
52 study visits to better quantify the subject experience in the study. The interviews will be 
conducted by a third-party vendor, Endpoint Outcomes, specializing in the capture of caregiver 
and subject-reported data. Endpoint Outcome uses a script as an interview guide to serve as a 
basis for the discussion. The interview will be conducted by phone.  


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The subject has consented to the interview per the study’s main ICF. However, prior to the start 
for the interview, Endpoint Outcomes will verbally ask for the subject’s consent for the interview 
to be audio-recorded. With the subject’s verbal consent, the interview will be audio-recorded, 
and the interviewer will proceed through a script. If the subject does not give permission for the 
session to be audio-recorded, the interview will not proceed. Subjects will be asked about their 
experience in the study. They may refuse to answer any question in the interview and may stop at 
any time.  
Site staff will facilitate the phone call so that the subject’s contact information remains 
anonymous. Personal information (including subject’s name and telephone number) will remain 
anonymous and will not be provided to the Sponsor or Endpoint Outcomes. Subjects will be 
identified only by their study specific subject IDs.  
All digital recordings will be stored by Endpoint Outcomes in a secure place where only 
Endpoints Outcome personnel directly related to this study will be able to access it. The audio 
interviews will be transcribed by a transcription company under contract and a confidentiality 
agreement, who will provide the written transcripts that will be further analyzed by Endpoint 
Outcomes. The transcription company is also contracted to ensure that transcripts will not 
contain any personal identifying information (eg, reference of first names) that may have been 
revealed during the interview process; personal identifying information will be removed and will 
not appear in the final transcript. Data from the interview will be shared with the Sponsor only 
after all identifying information has been removed. 
8.2. 
Safety Assessments 
Planned time points for all safety assessments are listed in the Schedule of Events (Table 6). 
Safety will be assessed based on AEs, SAEs, vital sign measurements, complete and targeted 
physical examination findings, ECG results, documented symptomatic hypoglycemic events, 
clinical laboratory assessments (clinical chemistry [including liver function tests], hematology, 
coagulation panel, and urinalysis), vector shedding, vector genome determination, measurement 
of neutralizing antibody titer to AAV8, measurement of AAV8 binding antibody 
immunoglobulin G (IgG), assessment of any cell-mediated immune responses to AAV8 and 
G6Pase, and measurement of anti-G6Pase antibodies. 
8.2.1. 
Vital Sign Measurements 
Vital sign measurements will be made at the time points specified in the Schedule of Events 
(Table 6). 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. 
• On Day 0, weight will be measured to ensure that the weight is within 10% of the 
screening weight used to calculate the dose of DTX401. Subjects with a confirmed 
change in weight that is > 10% from Screening should be further evaluated to exclude 
the presence of an acute condition or illness. If a benign explanation for the weight 


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change is identified and documented, DTX401 can be given and dosed using the 
weight obtained on Day 0. 
• Vital signs should be measured with the subject having rested 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 1, vital signs will be measured at predose, approximately 5 minutes, and 
0.5 (± 5 minutes), 1 (± 5 minutes), 4 and 8 hours (± 15 minutes) after the start of 
DTX401 infusion. Vital signs will also be measured approximately 22 hours 
(± 1 hour) after the start of infusion, prior to subject discharge. 
• It is acceptable for heart rate to be captured from the 12-lead ECG (Section 8.2.3). 
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). If, in the medical and scientific judgment of the Investigator, a 
clinically significant change or abnormal vital sign measurement is observed, it should be 
recorded as an AE or SAE, as defined in Section 9.1.2, on the appropriate pages of the eCRF. 
8.2.2. 
Physical Examination 
A complete or targeted physical examination will be performed at the time points specified in the 
Schedule of Events (Table 6). 
A complete physical examination will include assessments of the head, eyes, ears, nose, and 
throat; skin; abdomen with documentation of liver and spleen size; and the endocrine, metabolic, 
neurological, respiratory, cardiovascular, gastrointestinal, and musculoskeletal systems. 
A targeted physical examination will include assessment of the skin, the abdomen with 
documentation of liver and spleen size, and the respiratory, cardiovascular, and gastrointestinal 
systems. 
Physical examination findings will be captured on the appropriate page of the eCRF. 
8.2.3. 
Electrocardiograms 
An ECG will be performed at the time points specified in the Schedule of Events (Table 6). 
• A single 12-lead ECG will be obtained at Screening, on Day 0 (Baseline), predose on 
Day 1, and at Week 52, using an ECG machine that automatically calculates the heart 
rate and measures PR, QRS, QT, and corrected QT intervals. 
Twelve-lead ECGs should be measured with the subject having rested 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 


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be stated in the source documents. Electrocardiogram results will be recorded on the appropriate 
page of the eCRF. 
8.2.4. 
Liver Ultrasound 
An ultrasound of the liver will be conducted during the Screening Period. The ultrasound will be 
conducted and assessed at the study site. Ultrasound results will be recorded on the appropriate 
page of the eCRF. 
8.2.5. 
Hypoglycemic Events 
At each visit, the study site will instruct subjects on proper home glucose monitoring, the signs 
and symptoms of hypoglycemia, and supplemental glucose treatment if needed. 
During Screening, the study site will record the number of symptomatic hypoglycemic events 
that occurred during the previous 52 weeks in the eCRF. During each subsequent visit, the study 
site will record the number of symptomatic hypoglycemic events that occurred since the last visit 
in the eCRF (Table 6). 
8.2.6. 
Clinical Laboratory Assessments 
Laboratory tests, including ALT, 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 (clinical chemistry [including liver function 
tests], hematology, coagulation panel, 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 GSDIa are not to 
be reported as AEs, unless they are judged by the Investigator to be more severe than expected 
for the subject’s condition. 
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 DTX401 on GSDIa or other metabolic deficiencies. The choice to allow 
retention and future analysis will be optional. 
8.2.6.1. 
Clinical Laboratory Parameters 
The clinical laboratory parameters to be measured are listed in Table 2. Samples are to be 
collected at the time points specified in the Schedule of Events (Table 6). 


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Table 2: 
Clinical Laboratory Parameters 
Clinical chemistry: 
Lipid panel, uric acid, sodium, potassium, chloride, carbon dioxide, blood urea nitrogen, 
creatinine, glucose, calcium, phosphate, magnesium, albumin, total protein, creatine 
kinase, bilirubin (total, direct, and indirect), ALT, AST, ALP, gamma-glutamyl 
transferase, and lactate dehydrogenase 
Clinical chemistry 
(other):a 
Glucose, lactate 
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,b HCV RNA,b HIV,b G6PC genotyping,b serum pregnancy,b 
cortisol, free fatty acids, glucagon, insulin, C-peptide, growth hormone, 
ACTH, IGFBP1, alanine, ketones, AAV8 neutralizing antibody, 
AAV8 binding antibody IgG, cell-mediated immune response to AAV8 and 
G6Pase, anti-G6Pase antibody, vector genome, vector shedding 
Coagulation panel: 
PT/INR, aPTT 
Abbreviations: ACTH: Adrenocorticotropic hormone; ALP = alkaline phosphatase; ALT = alanine 
aminotransferase; aPTT = activated partial thromboplastin time; AST = aspartate aminotransferase; AAV8 = 
adeno-associated virus serotype 8; G6Pase = glucose-6-phosphatase (protein); G6PC = glucose-6-phosphatase 
(gene); HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; IGFBP1 = 
insulin-like growth factor-binding protein 1; IgG = immunoglobulin G; PT/INR = prothrombin time/international 
normalized ratio. 
a Samples collected during the controlled fasting challenge should be sent to the local laboratory (STAT samples) 
for analysis. 
b To be performed at Screening only. 
Samples for measurement of glucose and lactate levels collected during the controlled fasting 
challenge should be prepared and transported to the local laboratory in accordance with the site’s 
standard procedures. Details for the preparation and shipment of all other samples will be 
provided by the central or specialty laboratory. Reference ranges for all parameters will be 
provided to the study site by the central or specialty laboratory. 
If additional nonprotocol-specified laboratory assessments are performed at the study site’s local 
laboratory and result in a change in subject management or the results are considered clinically 
significant by the Investigator (eg, SAE or AE), the results must be captured and sent to the 
Sponsor along with other study data, as defined in Section 9.1.2. 
A laboratory parameter may be repeated if there is any concern about the values obtained. 
8.2.6.2. 
Elevation of Liver Function Tests 
In clinical studies with AAV-mediated gene transfer, a transient increase in liver 
aminotransferases and a concurrent decline in transgene expression have been observed (Manno 
et al., 2006; Nathwani et al., 2011b; Nathwani et al., 2014). This has been hypothesized to be due 
to the activation of capsid-specific cytotoxic T lymphocytes and destruction of transduced liver 
cells (Mingozzi et al., 2007). However, in mice, T cells activated against AAV capsid were not 
able to target and eliminate transduced hepatocytes (Wang et al., 2007; Li et al., 2007a; Li et al., 


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2007b; Siders et al., 2009) unless the transduced hepatocytes co-expressed the wild-type AAV 
capsid protein (Li et al., 2007a). 
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 aminotransferase 
elevations. Despite a lack of clear resolution that activation of cytotoxic T lymphocytes leads to a 
reduction in transgene expression from hepatocytes, appropriate precautions have been 
incorporated into this study. In addition to monitoring for capsid-specific and G6Pase-specific 
T-cell activation, subjects will receive oral steroid treatment for possible vector-induced hepatitis 
if liver function tests increase following treatment with DTX401 as outlined in Section 8.2.6.2.1. 
Subjects in Cohort 4 will receive prophylactic oral steroid treatment to prevent possible 
vector-induced hepatitis as outlined in Section 8.2.6.2.2. 
Liver function tests will be assessed as part of clinical chemistry (Section 8.2.6.1) at the time 
points specified in the Schedule of Events (Table 6). Liver function tests will be assessed at the 
central laboratory and the local laboratory (STAT sample) at a minimum of every 3 to 4 days 
through Week 12, or longer if clinically indicated, to allow for a rapid detection of any liver 
aminotransferase elevations following administration of DTX401. An increase in liver function 
tests following treatment with DTX401 will 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. 
8.2.6.2.1. Reactive Steroid Treatment for Possible Vector-Induced Hepatitis 
Subjects in Cohorts 1, 2, and 3 will receive reactive oral steroid treatment for possible 
vector-induced hepatitis if liver aminotransferase levels increase following treatment with 
DTX401. The Investigator, in conjunction with the Ultragenyx medical lead, will consider 
starting oral steroid treatment for possible vector-induced hepatitis if a subject’s ALT levels 
increase from the subject’s baseline or recently drawn levels, and are considered by the 
Investigator to be possibly related to treatment with DTX401. If repeat testing is deemed 
necessary, every effort should be made to repeat the testing within 24 hours from receipt of test 
results indicating elevated levels of ALT. 
Based on available evidence, it is expected that vector-induced hepatitis will be self-limiting. 
Therefore, prednisone (or prednisolone) will be used to treat vector-induced hepatitis according 
to the American Association for the Study of Liver Disease guidelines, which have been 
modified for subjects with GSDIa so that the starting dose/duration is lower/shorter: 
 
 
 
 
 
 
 
 
 
 


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The Investigator, in conjunction with the Ultragenyx medical lead, may consider modifying this 
regimen if a subject’s ALT levels do not normalize during the steroid taper. The Investigator 
should document the agreed upon steroid regimen in the subject’s source documentation. 
The use of prednisone will be recorded on the appropriate page of the eCRF. 
8.2.6.2.2. Prophylactic Steroid Treatment for Vector-Induced Hepatitis 
Subjects in Cohort 4 will receive prophylactic oral steroid treatment to prevent possible 
vector-induced hepatitis. Prophylactic oral steroid regimens have been used in AAV-mediated 
gene transfer clinical trials for other indications (eg, Clinicaltrials.gov identifiers: 
NCT03223194, NCT03306277). 
Oral prednisone (or prednisolone) will be initiated on Day 1 following completion of the Day 0 
controlled fasting challenge and before DTX401 administration as follows: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The Investigator, in conjunction with the Ultragenyx medical lead, may consider modifying this 
regimen if a subject’s ALT levels do not normalize during the steroid taper.  
Additional oral prednisolone/placebo may be administered after completion of the taper if a 
subject’s alanine aminotransferase (ALT) levels increase from Baseline and/or above the ULN of 
recently drawn levels repeated one more time as soon as possible. 
 
 


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If, in the Investigator’s medical judgment, the subject may not safely tolerate initiation of oral 
steroid treatment on Day 1, the steroid regimen may be modified based on discussion between 
the Investigator and the Ultragenyx medical lead. The Investigator should document the agreed 
upon steroid regimen in the subject’s source documentation. 
The Investigator may consider additional assessments or medical care, such as hospitalization or 
daily clinic visits, during steroid administration if, in the Investigator’s medical judgment, these 
measures would provide additional safety benefits. 
The use of prednisone will be recorded on the appropriate page of the eCRF. 
Vaccination and Oral Prednisone Regimen 
To comply with international and regional guidelines on vaccination, as well as slight variations 
in regional schedules, where feasible, subjects’ vaccination schedules should be adjusted to 
accommodate prophylactic prednisone taper regimen administration prior to and following 
DTX301 infusion.  
Live vaccines (such as MMR and varicella) are contraindicated for patients on a substantially 
immunosuppressive steroid dose (ie, ≥ 2 weeks of daily receipt of 20 mg of prednisone, or 
equivalent or 1 mg/kg/day in children under 20 kg) for more than 14 days. Thus, Investigators 
should time administration of live vaccines to at least 14 days prior to inception of the 
prednisone regimen, or after completion of the 8-week prednisone regimen.  
Inactivated vaccines and seasonal influenza prophylaxis vaccination are not precluded to patients 
treated with immunosuppressive agents in accordance to international guidelines (Ezeanolue et 
al.; Rubin et al., 2014; Public Health England, 2020; ECDC, 2017; Public Health England, 
2017). All inactivated vaccines can be administered safely to persons with altered 
immunocompetence, whether the vaccine is a killed whole-organism or a recombinant, subunit, 
split-virus, toxoid, polysaccharide, or polysaccharide protein-conjugate vaccine.  
8.2.6.3. 
Lactate 
At Baseline (Day 0) and Weeks 12, 24, and 52, lactate levels will be measured during the 
controlled fasting challenge (Section 8.1.1). A venous blood sample for lactate will be collected 
through an indwelling catheter (central or peripheral) as follows: 
• At the beginning of the fasting challenge (ie, immediately after the post-dinner dose 
of cornstarch, or immediately after dinner for subjects who do not take a post-dinner 
dose of cornstarch) 
• Approximately every 60 minutes (± 5 minutes) until the glucose level decreases to 
≤ 70 mg/dL (≤ 3.9 mmol/L) 


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• Approximately every 30 minutes (± 5 minutes) until the glucose level decreases to 
< 54 mg/dL (< 3.0 mmol/L) or when the subjects experience signs and symptoms of 
hypoglycemia, or when the fast reaches 15 hours without hypoglycemia, whichever 
occurs first. 
Lactate samples should be sent to the local laboratory (STAT sample) and results should be 
available within 30 minutes or less of blood sample collection. Samples should be prepared and 
transported to the local laboratory in accordance with the site’s standard procedures. 
8.2.6.4. 
Other Controlled Fasting Challenge Laboratory Assessments 
At Baseline (Day 0) and Weeks 12, 24, and 52, blood samples for measurement of cortisol, 
ACTH, free fatty acids, glucagon, insulin, C-peptide, growth hormone, IGFBP1, alanine, and 
ketone levels will be collected at the beginning and end of the controlled fasting challenge, or 
more frequently at the Investigator’s discretion (Section 8.1.1). A final sample for glucose, 
lactate, growth hormone, IGFBP1, ACTH, and cortisol measurement will be collected 30 
minutes after the end of the controlled fasting challenge. Samples should be prepared and 
transported to the local laboratory in accordance with the site’s standard procedures. 
Additionally, if possible, a blood sample for measurement of ACTH and cortisol levels will be 
collected approximately 1 week before the Week 12 visit. Details for the preparation and 
shipment of samples are included in the laboratory manual. 
8.2.6.5. 
24-Hour Urine Collection 
The excretion of total protein, microalbumin, and creatinine in the urine will be determined over 
a 24-hour period. Timed 24-hour complete urine samples will be collected at Baseline (Day 0) 
and during inpatient visits as specified in the Schedule of Events (Table 6). Details for the 
preparation and shipment of samples are included in the laboratory manual. 
8.2.6.6. 
Neutralizing Antibodies to Adeno-Associated Virus Serotype 8 
A blood sample for determination of neutralizing antibodies to AAV8 will be collected at the 
time points specified in the Schedule of Events (Table 6) to monitor for a humoral immune 
response to AAV8. It is recommended that the Screening sample be collected at the time written 
informed consent is provided. The assay will be performed using a research method (cell-based 
assay). 
8.2.6.7. 
Cell-Mediated Immune Response 
The presence of T cells specific for AAV8 and G6Pase will be determined by an 
 
A blood sample will be collected at the time points specified in 
the Schedule of Events (Table 6). Samples for the 
assay will be collected 
approximately weekly through Week 12 and at Weeks 24, 36, and 52. 


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8.2.6.8. 
Adeno-Associated Virus Serotype 8 Binding Antibody Immunoglobulin G Assay 
A blood sample for the AAV8 binding antibody IgG assay will be collected at the time points 
specified in the Schedule of Events (Table 6) to monitor for circulating anti-AAV8 antibodies. 
The assay will be performed using a research method 
 
 
8.2.6.9. 
Anti-Glucose-6-Phosphatase Antibody Assay 
A blood sample for the anti-G6Pase antibody assay will be collected at the time points specified 
in the Schedule of Events (Table 6) to monitor for circulating anti-G6Pase antibodies. The assay 
will be performed using a research method. 
8.2.6.10. Vector Shedding 
Saliva, urine, and stool samples will be collected at the time points specified in the Schedule of 
Events (Table 6) to monitor for vector shedding. The presence of DTX401 will be determined by 
. Subjects will be given an appropriate container 
to collect a stool sample at home. Saliva and urine samples will be collected at the study site for 
inpatient visits (Table 6). Subjects may have the option of having these samples collected at their 
homes by clinically trained and qualified personnel (if arranged by the Investigator), unless there 
is a scheduled study site visit that the subject must attend in person. Samples for vector shedding 
analysis will be collected until at least 3 consecutive negative results are obtained for each 
sample matrix. 
8.2.6.11. Blood for Vector Genome Determination 
A blood sample will be collected at the time points specified in the Schedule of Events (Table 6) 
for the determination of vector genome (ie, DTX401) by 
 
8.3. 
Genotyping 
8.3.1. 
Glucose-6-Phosphatase Genotyping 
At Screening, subjects will be asked to provide a single whole-blood sample for G6PC 
genotyping. It is recommended that the Screening sample be collected at the time written 
informed consent is provided. The objective of this testing is to confirm the presence of a G6PC 
mutation and to provide an understanding of a potential relationship between genetic factors and 
the subject’s response to DTX401. If genotyping results were previously documented from a 
qualified laboratory, these results can be used to satisfy the subject eligibility criteria. 
8.4. 
Demographic and Other Assessments 
8.4.1. 
Demographic, Medical, and GSDIa History Assessments 
As allowed by local laws and regulations, the following demographic data may be captured on 
the appropriate page of the eCRF: year of birth, age, sex, ethnicity, and race. 


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Relevant medical and GSDIa history will be assessed as related to the eligibility criteria listed in 
Section 4.1 and Section 4.2. Medical condition or event, start date, end date, and status will be 
recorded on the appropriate page of the eCRF. The number of hospitalizations for hypoglycemic 
events (total and in the year prior to enrollment) will be collected and recorded on the 
appropriate page of the eCRF. 
8.4.2. 
Assessment of Daily Prescribed Diet and Daily Diet Intake 
The subject’s daily prescribed diet and daily diet intake will be reviewed at the time points 
specified in the Schedule of Events (Table 6) and, if possible, on a weekly basis through the 
Week 52 visit or early withdrawal. Total calories, total carbohydrates and non-utilizable sugars, 
total protein, and total fat will be recorded on the appropriate page of the eCRF. 
8.4.3. 
Assessment of Daily Prescribed Cornstarch (or Equivalent) and Daily 
Cornstarch (or Equivalent) Intake 
The subject’s daily prescribed cornstarch (or equivalent) and daily cornstarch (or equivalent) 
intake will be reviewed at the time points specified in the Schedule of Events (Table 6) and, if 
possible, on a weekly basis through the Week 52 visit or early withdrawal. Total daily cornstarch 
and frequency of intake will be recorded on the appropriate page of the eCRF. 


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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 and for up to 30 days 
after the End of Study/Early Withdrawal visit. SAEs that occur more than 30 days after the End 
of Study/Early Withdrawal visit need not be reported unless the Investigator considers them 
related to study product. 
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 from review of other documents that are 
relevant to subject safety will be documented on the AE page in the eCRF. 
9.1.1. 
Definitions 
9.1.1.1. 
Dose-Limiting Toxicity 
A DLT is defined as any AE/SAE ≥ Grade 3 that is considered by the Investigator and/or 
Sponsor to be related to DTX401, based on NCI CTCAE Version 5.0 (NCI, 2018) or later 
version. 
9.1.1.2. 
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 (ie, DTX401) 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 ICF if any signs or symptoms develop. 
Abnormal clinically significant laboratory values (clinical chemistry [including liver function 
tests], hematology, coagulation panel, and urinalysis) as assessed by the Investigator will be 
considered AEs. 
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 the study product. 
9.1.1.3. 
Serious Adverse Events 
An SAE is defined as any event that:  
• Results in death 
• Is immediately life threatening 


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• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• 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. 
Nonemergent hospitalization for cornstarch management or glucose monitoring during steroid 
administration for vector-induced hepatitis (Section 8.2.6.2) will not be considered an SAE. 
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. 
9.1.2.2. 
Serious Adverse Events 
Any AE that meets SAE criteria (Section 9.1.1.3) or any of the safety stopping criteria 
(Section 3.2.4) must be reported by the study site to Ultragenyx immediately (ie, within 
24 hours) after the time study site personnel first learn about the event (Table 3).  
The study site should record all SAE information on the SAE page in the eCRF and submit the 
report via the electronic data capture (EDC) system. An event meeting any of the safety stopping 
criteria should only be reported as an SAE in the EDC if it meets the SAE criteria 
(Section 9.1.1.3). 
If, for any reason, it is not possible to report the SAE in the EDC system (eg, the EDC system is 
unavailable), the study site should record the SAE on the paper SAE Reporting Form and fax or 


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email it to Ultragenyx (Table 3). Any SAE reported via fax or email must be entered into the 
EDC system as soon as it is possible. 
Table 3: 
Ultragenyx Contact Information for SAE Reporting 
Ultragenyx 
Email: 
 
Fax: 
 
9.1.2.2.1. Expedited Reporting 
The Sponsor is responsible for reporting serious, unexpected, suspected adverse drug reactions 
(SUSARs) involving the study product to all regulatory authorities and participating 
investigators in accordance with International Council for Harmonisation (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. 
Due to the limited clinical experience with DTX401, reference safety information for assessing 
whether an AE is a SUSAR is currently not available. Therefore, any SAE considered related to 
DTX401 will be considered a SUSAR and reported immediately, as detailed in Section 9.1.2. 
The SAE should be treated with appropriate supportive and medical care deemed necessary for 
the well-being of the subject. 
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 Investigator should rate the intensity of an AE as Grade 1, 2, 3, 4, 
or 5 based on their medical judgment. The most current version of the NCI CTCAE can be used 
to guide the rating of an AE. 
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. Specific symptoms and medical conditions have a clinical description 
for each level of severity/toxicity. 
Increases in liver aminotransferase levels following DTX401 administration that are considered 
related to vector-induced hepatitis are expected, transient, asymptomatic, and self-limiting based 
on available evidence. If considered clinically significant in the Investigator’s medical judgment 
(Section 8.2.6.2), these events should be recorded as an AE (Section 9.1.2.1) or SAE 
(Section 9.1.2.2) with an event term of elevated liver function tests and graded according to the 
general guidelines outlined in Table 4. 
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 general guidelines outlined in Table 4. 


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Table 4: 
General Guidelines for Grading Events Not Captured by the CTCAE 
Grade 
Criteria 
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 ADL.a 
Grade 3 
Severe or medically significant but not immediately life threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL.b 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
Abbreviations: ADL = activities of daily living; AE = adverse event; CTCAE = Common Terminology Criteria 
for Adverse Events. 
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. 
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 according to the classification and criteria outlined in Table 5. 
Table 5: 
Classification and Criteria for AE Relationship to Study Product 
Classification 
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 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. 


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Classification 
Criteria 
Unrelated 
This relationship suggests that there is no association between the study product and the 
reported event. 
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. 
Abbreviation: AE = adverse event. 
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. 
9.2. 
Procedures for Handling Special Situations 
9.2.1. 
Pregnancy and Birth Control 
A serum pregnancy test will be performed on all female study subjects of childbearing potential 
during screening. A urine pregnancy test will be performed on all female study subjects of 
childbearing potential at each visit as specified in the Schedule of Events (Table 6). 
Females of childbearing potential are defined as females physiologically capable of becoming 
pregnant. Females are considered postmenopausal and not of childbearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (eg, age 
appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy 
(with or without hysterectomy) or tubal ligation at least 6 weeks prior to enrollment. In the case 
of oophorectomy alone, only when the reproductive status of the woman has been confirmed by 
follow-up hormone level assessment is she considered not of childbearing potential. 
Males and females of childbearing potential must be willing to use effective contraception at the 
time of administration of DTX401 and for 52 weeks following administration of DTX401 to 
prevent the potential transmission of the AAV vector. For male subjects, appropriate 
contraceptive methods include the use of a condom with spermicide. For female subjects, 
appropriate contraceptive methods include the use of a condom with spermicide plus at least 1 of 
the following: 
• Hormonal contraceptives (vaginal products, skin patches, or implanted or injectable 
products), or mechanical products such as an intrauterine device; 
• Use of a diaphragm or cervical/vault cap; or 
• Previous sterilization (surgical bilateral oophorectomy with or without hysterectomy 
or tubal ligation) at least 6 weeks prior to DTX401 administration. In case of an 
oophorectomy alone, the reproductive status of the subject must have been confirmed 
by follow-up hormone level assessment. 


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Abstinence is an acceptable form of birth control; however, appropriate contraception must be 
used if the subject becomes sexually active. Abstinence is defined as sexual inactivity consistent 
with the preferred and usual lifestyle of the subject. Periodic abstinence (calendar, 
symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea methods are not acceptable methods of contraception. A condom with 
spermicide is required to be used by all sexually active vasectomized males in the study in order 
to prevent potential transmission of the vector via seminal fluid. 
Pregnancy is not regarded as an AE unless there is a suspicion that a study drug may have 
interfered with the effectiveness of a contraceptive medication. Any pregnancy in a female study 
subject that occurs during study participation must be reported using the paper Pregnancy Report 
Form. The study site should record the pregnancy on the paper Pregnancy Report Form and fax it 
to PrimeVigilance (Table 3). To ensure subject safety, each pregnancy in a female study subject 
must be reported to PrimeVigilance (contact information in Section 9.1.2.2) within 2 weeks of 
learning of its occurrence. 
The pregnancy in a female study subject must be followed up to determine outcome (including 
spontaneous miscarriage, elective termination, normal birth, or congenital abnormality) and 
status of mother and child, even if the subject discontinued from the study. Pregnancy 
complications and elective terminations for medical reasons should be reported as an AE or 
SAE. Spontaneous miscarriages or congenital abnormalities must be reported as an SAE. 
All neonatal deaths that occur within 28 days of birth should be reported as an SAE. 
Any SAE occurring in association with a pregnancy in a female study subject brought to the 
Investigator’s attention after the subject has completed the study, and considered by the 
Investigator as possibly related to the study product, must be promptly reported to Ultragenyx. 
9.2.2. 
Treatment Noncompliance 
9.2.2.1. 
Overdose Management 
An overdose is any dose of the 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 in the appropriate AE or SAE page of 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 study site. 


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9.3. 
Data Monitoring Committee 
An independent DMC will be responsible for monitoring safety data from the study. For Cohorts 
1 and 2, the DMC met after all evaluable subjects in the dosing cohort completed Week 12 of the 
study to review the safety data and provide their recommendation for progressing to the next 
dosing cohort or enrollment of subjects into additional cohorts. 
The DMC will meet at the end of the study and may, at any time, recommend modifying or 
pausing enrollment due to safety concerns based on their periodic data reviews. Additionally, if 
an Investigator reports an AE/SAE that meets any of the safety stopping criteria (Section 3.2.4), 
enrollment will be paused and the DMC will meet to review available data. If a decision is made 
to resume enrollment, this decision will be communicated to and, if required, approved by 
regulatory authorities according to country requirements. 
The DMC comprises 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 or enrollment of subjects into additional cohorts. The DMC charter details the 
members’ roles and responsibilities as part of the DMC, the process for each data review 
(scheduled or ad hoc), and the full scope of each review. 


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10. 
STATISTICAL AND ANALYTICAL PLAN 
A statistical analysis plan (SAP) will be written 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. 
Endpoints 
The primary, secondary, and exploratory endpoints are detailed in Section 2. 
The following general analysis summaries and listings will be conducted for subjects who 
receive at least 1 dose of study drug. The MTD dose escalation evaluation will be performed for 
MTD evaluable subjects. Statistical analysis sets for all the tables, listings, and figures will be 
defined in the SAP. 
10.2. 
Statistical Analysis Methodology 
The CRM model will be used to evaluate each dose for dose escalation using software FACTS 
(Berry Consultants, Austin, Texas, United States) Version 6.0 or later. The OBD will be based 
on the MTD and an assessment of clinical benefit. SAS® software (SAS Institute, Inc, Cary, 
North Carolina, United States) Version 9.2 or later will be used for general data presentation and 
statistical analyses. Continuous variables will be summarized using the mean, standard deviation, 
median, minimum, and maximum values. 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 will be described in the SAP. 
10.2.1. 
The Continual Reassessment Method 
Neuenschwander’s CRM (or nCRM) (Neuenschwander et al., 2008) will be used to make 
recommendations for the dose to be administered in each cohort using all evaluable subjects 
(ie, subjects who remain in the study for at least 12 weeks after dosing or for whom a DLT is 
observed within 12 weeks of dosing). The DLT assessment for each subject is based on the 
definition in Section 9.1.1.1. The DLT evaluation window for each subject starts on the date of 
administration of DTX401 and continues for up to 12 weeks (84 days) thereafter, or until all 
Week 12 safety assessments have been completed, whichever occurs later. 
The target toxicity rate is 0.25. The cohort size is 3 subjects. The dose levels that may be studied 
are specified in Section 3.1. The first cohort will be treated at 2 × 1012 GC/kg. Subsequent doses 
will be treated at the lower of the current estimate of the MTD and the highest dose allowed by 
the escalation rule. 
A logistic model will be used to model the dose-toxicity curve; further details on that are 
provided in Section 15.2, Appendix 2. 


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The CRM model will recommend that the study is stopped for having the MTD determined the 
first time any of the following criteria are satisfied after a CRM model update: 
• Six evaluable subjects have been treated at 1 × 1013 GC/kg and the current estimate of 
the MTD is > 1 × 1013 GC/kg 
• Six evaluable subjects have been treated at the current estimate of the MTD 
• The current estimate of the MTD is < 2 × 1012 GC/kg (insufficient safety) 
The study will stop when the maximum sample size of 12 subjects have been enrolled or at the 
Sponsor’s discretion. If 12 subjects have been enrolled and the definition of having an MTD 
determined has not been reached, then the highest dose considered at or below the MTD will be 
considered the MTD. 
Enrollment will be limited so that each dosing cohort initially includes no more than 3 subjects. 
A cohort may be expanded to include additional subjects to confirm the findings for the cohort. 
10.2.2. 
Sample Size Justification 
Simulations (result on file at PPD) show that if all 3 doses are safe and no DLTs occur, the CRM 
will recommend dose escalation to 1 × 1013 GC/kg (genome copies measured by 
) and the 
recruitment of 12 subjects. Based on safety and efficacy observations in Cohorts 1, 2, and 3 (3 
subjects each) and a positive recommendation from the DMC, it was decided to enroll a fourth 
cohort of 3 subjects. The planned sample size of the study will therefore be 12 subjects including 
4 cohorts.  
The protocol allows multiple cohorts to be enrolled to assess varied oral steroid regimens to 
manage the mild, asymptomatic elevations in liver aminotransferase levels that have been 
observed following DTX401 administration (Derks et al., 2019; Weinstein et al., 2019). The 
CRM model will evaluate subjects based on the dose administered regardless of the steroid 
approach used (ie, reactive vs prophylactic). 
10.2.3. 
Efficacy Analyses 
10.2.3.1. Symptom-Free Euglycemia 
The time (in minutes) to the first hypoglycemic event (defined as glucose < 54 mg/dL 
[< 3.0 mmol/L]) during a controlled fasting challenge will be determined for all subjects at Day 0 
and Weeks 12, 24, and 52. Full details of the analysis will be provided in the SAP. 
10.2.3.2. Continuous Glucose Monitoring 
Continuous glucose monitoring device data will be summarized in tables, figures and provided in 
the listings. All analyses details will be specified in the SAP. 


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10.2.3.3. Use of Cornstarch (or Equivalent) 
Use (both quantity and frequency) of cornstarch over time will be summarized in tables, figures 
and provided in the listings. All analyses details will be specified in the SAP. 
10.2.3.4. Morning Glucose Levels 
Morning glucose levels will be summarized in a table and provided in the listings. 
10.2.3.5. 
 
 
 
10.2.3.6. 
 
 
 
10.2.4. 
Safety Analyses 
All subjects who receive DTX401 will be included in the safety analysis. 
10.2.4.1. Adverse Events 
With the exception of the CRM modelling described above, all statistical analyses of safety 
outcomes will be descriptive. The incidence of AEs and TEAEs will be summarized by system 
organ class and preferred term. Additionally, TEAEs may be summarized for each dose by 
severity and relationship to study product, if applicable. SAEs will be presented for each dose by 
relationship to study product. Summary tables will present the total number of TEAEs as well as 
the number of subjects with TEAE incidence by system organ class and preferred term. For 
summaries of TEAEs, subjects experiencing an event more than once with varying severity will 
be counted only once, using only the maximum severity observed 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. 
10.2.4.2. Physical Examination Findings 
Complete and targeted physical examination findings will be summarized by visit and dose. 
10.2.4.3. 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. 


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10.2.4.4. 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.” 
10.2.4.5. Hypoglycemic Events 
The number of symptomatic hypoglycemic events will be summarized by dose level of DTX401. 
Hypoglycemic events reported by the subject will be summarized separately for each dose of 
DTX401. 
10.2.4.6. Clinical Laboratory Assessment Results 
For all clinical laboratory parameters (Section 8.2.6.1) with continuous results, absolute values 
and changes from Baseline will be summarized by visit and dosing cohort. For laboratory 
parameters with categorical results, shifts from Baseline will be summarized by visit and dosing 
cohort. Laboratory values from the central laboratory and local laboratories will be analyzed. 
10.2.4.7. Other Laboratory Results 
Neutralizing antibodies to AAV8, cell-mediated immune response to AAV8 and G6Pase, AAV8 
binding antibody IgG assay, anti-G6Pase antibody assay, vector shedding, and vector genome 
determination will be summarized by time point and dosing cohort. Associations between these 
parameters and dose will be undertaken using tabular summaries and appropriate statistical 
methods, as will be outlined in the SAP. 
10.2.5. 
Other Analyses 
Demographics and other background information will be summarized by dose group. 
Background information includes prior medications, medical conditions, GSDIa medical history 
(including number of hospitalizations for hypoglycemic events [total and in the year prior to 
enrollment]). Current medical conditions and concomitant medications will be summarized. 
A summary of subject disposition and treatment exposure will be prepared. 
Other data described in Section 8.4 will be summarized accordingly, including assessments of 
prescribed diet (including daily carbohydrate intake). 
10.2.6. 
Interim Analysis 
An interim analysis will be conducted when a minimum of 12-week data are available for all 
subjects from at least 2 dosing cohorts. Additional interim analyses may be conducted at the 
Sponsor’s discretion. Results and their dissemination will be at the Sponsor’s discretion. 
A detailed plan for the analysis of the safety and efficacy data will be presented in the SAP. 


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10.3. 
Data Quality Assurance 
Study sites will maintain source documentation and enter subject data in the eCRF as accurately 
as possible and will rapidly respond to any reported discrepancies. The eCRFs are accessed 
through Oracle Health Sciences InForm. This EDC system is validated and compliant with US 
Title 21 Code of Federal Regulations (CFR) Part 11. Each person involved with the study will 
have an individual username 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 study site with additional 
reviews by the clinical monitor. 
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 study 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. 
10.3.1. 
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 laboratory reports, ECG strips, and 
other materials. 
The Sponsor (or Sponsor designee) will supply the eCRF. Study personnel must have 
documented training of 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. 
Study 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 and WHO Drug dictionary terminology, respectively. 
After database lock, each study site will receive an electronic copy of their study 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 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(R2): Good 
Clinical Practice (GCP) will be maintained by the study 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 
study sites. If any institution-specific modifications to study-related procedures are proposed or 
made by the study site, the ICF should be reviewed by the Sponsor, 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(R2) 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 study 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 
• Laboratory certifications and normal ranges for any local laboratories used by the 
study 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(R2). 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. 
12.5. 
Adherence to Protocol 
The Investigator agrees to conduct the study as outlined in this protocol in accordance with ICH 
E6(R2) 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 
timeline and method outlined in the protocol. In addition, the Investigator agrees to submit 
annual reports to the study site IRB/IEC/IBC, as appropriate. 


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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 authorities with any reports required. 
12.8. 
Record Retention 
For study monitoring, audit, or inspection, the IRB/IEC and Sponsor or its designees have the 
right to access all CRFs, source documents, and other study documentation. The Investigator or 
study site will retain such documents from the start of the study to at least 25 years after the close 
of the study, guarantee access to these documents, and cooperate with and support such audits 
and inspections. 
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. 
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 DMC (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 
progression of the study, ensuring that it is being conducted in compliance with the protocol, 
ICH E6(R2), all applicable local laws and regulations, and with current and applicable standard 
operating procedures. In doing so, the monitor will visit the Investigator and study site at 
periodic intervals, in addition to maintaining necessary telephone and written 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 study site personnel. 
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 of any audits or 
inspections scheduled by any regulatory authorities and promptly forward copies of any reports 
received to the clinical research associate. The clinical research associate will then inform and 
forward any reports to the Sponsor. 
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 or important change to the 
study design. Significant deviations can include nonadherence to inclusion or exclusion criteria, 
nonadherence to safety and efficacy-related assessments, or nonadherence to FDA regulations or 
ICH GCP guidelines, that could lead to the subject being withdrawn from the study (Section 7.1). 


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Protocol waivers or exemptions are not permitted. Adherence to the study design requirements, 
including those specified in the Schedule of Events (Table 6), 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. 
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 report (CSR) is prepared and provided to the regulatory agencies as required by the 
applicable regulatory requirements. The Sponsor will also ensure that the CSR in marketing 
applications meets the standards of the ICH harmonised tripartite guideline E3: Structure and 
Content of CSRs. 
Where required by applicable regulatory requirements, an Investigator signatory will be 
identified for the approval of the CSR. 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 CSR, 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 1/2, Open-Label Safety 
and Dose-Finding Study of Adeno-Associated Virus (AAV) Serotype 8 (AAV8)-Mediated Gene 
Transfer of Glucose-6-Phosphatase (G6Pase) in Adults with Glycogen Storage Disease Type Ia 
(GSDIa)” 
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 6.0, dated 28 October 2019, the 
International Council for Harmonisation harmonised tripartite guideline E6(R2): 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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Pan CJ, Lei KJ, Chen H, et al. (1998) Ontogeny of the murine glucose-6-phosphatase system. 
Arch Biochem Biophys 358: 17-24. 
Public Health England. (2017) Immunisation against infectious disease : The Green Book. 
Chapter 6,  Contraindications and special considerations. Available at: 
https://www.gov.uk/government/publications/contraindications-and-special-considerations-the-
green-book-chapter-6. 
Public Health England. (2020) Immunisation against infectious disease : The Green Book, 
Chapter 7, Immunisation of individuals with underlying medical conditions:. 
Reddy SK, Kishnani PS, Sullivan JA, et al. (2007) Resection of hepatocellular adenoma in 
patients with glycogen storage disease type Ia. J Hepatol 47: 658-663. 
Rubin LG, Levin MJ, Ljungman P, et al. (2014) 2013 IDSA clinical practice guideline for 
vaccination of the immunocompromised host. Clin Infect Dis 58: e44-100. 
Siders WM, Shields J, Kaplan J, et al. (2009) Cytotoxic T lymphocyte responses to transgene 
product, not adeno-associated viral capsid protein, limit transgene expression in mice. Hum Gene 
Ther 20: 11-20. 
Snyder RO, Miao C, Meuse L, et al. (1999) Correction of hemophilia B in canine and murine 
models using recombinant adeno-associated viral vectors. Nat Med 5: 64-70. 
Sun MS, Pan CJ, Shieh JJ, et al. (2002) Sustained hepatic and renal glucose-6-phosphatase 
expression corrects glycogen storage disease type Ia in mice. Hum Mol Genet 11: 2155-2164. 
uniQure. (2014) uniQure: Hemophilia -- the challenge for gene therapy. Talk preesented at 
Investor Day; December 1, 2014; New York City, NY. Data on file. Accessed November 1, 
2016. 
uniQure. (2015) Corzo D. Gene Therapy for Liver Disease and Metabolic Disorder. Talk 
presented at uniQure R&D Day; October 15, 2015; New York City, NY. Data on file. Accessed 
November 1, 2016. 
uniQure. (2016) Corzo D. Interim Topline Results from Hemophilia B Phase I/II Study AMT-
060-01 in Hemophilia B. Webcast. January 7, 2016: Data on file. Accessed November 1, 2016. 
van Schaftingen E and Gerin I. (2002) The glucose-6-phosphatase system. Biochem J 362: 513-
532. 
Vandenberghe LH, Wang L, Somanathan S, et al. (2006) Heparin binding directs activation of T 
cells against adeno-associated virus serotype 2 capsid. Nat Med 12: 967-971. 
Wang D, Pascual JM and De Vivo D. (2012) Glucose Transporter Type 1 Deficiency Syndrome. 
In: Pagon RA, Adam MP, Bird TD, et al. (eds) GeneReviews. Seattle (WA). 


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Wang L, Calcedo R, Nichols TC, et al. (2005) Sustained correction of disease in naive and 
AAV2-pretreated hemophilia B dogs: AAV2/8-mediated, liver-directed gene therapy. Blood 105: 
3079-3086. 
Wang L, Figueredo J, Calcedo R, et al. (2007) Cross-presentation of adeno-associated virus 
serotype 2 capsids activates cytotoxic T cells but does not render hepatocytes effective cytolytic 
targets. Hum Gene Ther 18: 185-194. 
Weinstein DA, Ahmad A, C. L, et al. (2019) Positive cohort 1 results from the phase 1/2 trial 
with AAV8-mediated liver-directed gene therapy in adults with glycogen storage disease type Ia. 
Molecular Therapy 27: 12. 
Weinstein DA, Correia CE, Conlon T, et al. (2010) Adeno-associated virus-mediated correction 
of a canine model of glycogen storage disease type Ia. Hum Gene Ther 21: 903-910. 
Wolfsdorf JI and Crigler JF, Jr. (1997) Cornstarch regimens for nocturnal treatment of young 
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Wolfsdorf JI, Holm IA and Weinstein DA. (1999) Glycogen storage diseases. Phenotypic, 
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823. 
Wolfsdorf JI, Laffel LM and Crigler JF, Jr. (1997) Metabolic control and renal dysfunction in 
type I glycogen storage disease. J Inherit Metab Dis 20: 559-568. 
Yan Z, Zak R, Luxton GW, et al. (2002) Ubiquitination of both adeno-associated virus type 2 
and 5 capsid proteins affects the transduction efficiency of recombinant vectors. J Virol 76: 
2043-2053. 
Yiu WH, Lee YM, Peng WT, et al. (2010) Complete normalization of hepatic G6PC deficiency 
in murine glycogen storage disease type Ia using gene therapy. Mol Ther 18: 1076-1084. 
 


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15. 
APPENDICES 
15.1. 
Appendix 1: Schedule of Events 
 


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Table 6: 
Schedule of Events – Scheduled Study Visits 
Period 
SVa 
BL 
Dosing 
Follow-up Period 
EOS/ 
EW 
Visit Time 
(Day/Week) 
D−56 
to 
D−1 
D0 
D1 
D4 D8 D12 D16 D20 D24 
D28 
D32 D36 D39 
D42 
D45 D48 D52 D56 D60 D64 D68 D72 D76 D80 
D84 
D168 D252 D365 
Predose Dosing/ 
Postdose 
W4 
W6 
W12 
W24 
W36 
W52 
Visit Window (Days) 
– 
– 
– 
– 
±1 
±2 
±1 
±2 
±1 
±2 
±7 
±7 
±7 
Visit Type 
OP 
IP 
OP/HH 
OP 
OP/HH 
OP 
OP/HH 
IPdd 
IP 
OP 
IP 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Admission to study site or 
hospital 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relevant medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
GSDIa medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Relevant prior medications/ 
therapies/ procedures 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Relevant concomitant 
medications/ therapies/ 
procedures 
 
X 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Health-related Quality of Life 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
GSDIa Morning Diaryb,c 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
GSDIa Evening Diaryb,c 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Subject interview 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xd 
 
Xd 


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Period 
SVa 
BL 
Dosing 
Follow-up Period 
EOS/ 
EW 
Visit Time 
(Day/Week) 
D−56 
to 
D−1 
D0 
D1 
D4 D8 D12 D16 D20 D24 
D28 
D32 D36 D39 
D42 
D45 D48 D52 D56 D60 D64 D68 D72 D76 D80 
D84 
D168 D252 D365 
Predose Dosing/ 
Postdose 
W4 
W6 
W12 
W24 
W36 
W52 
Visit Window (Days) 
– 
– 
– 
– 
±1 
±2 
±1 
±2 
±1 
±2 
±7 
±7 
±7 
Visit Type 
OP 
IP 
OP/HH 
OP 
OP/HH 
OP 
OP/HH 
IPdd 
IP 
OP 
IP 
Safety Assessments 
AE/SAE monitoring 
X 
X 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Assessment of symptomatic 
hypoglycemic events 
X 
X 
X 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Vital sign measurement (HR, 
BP, RR) 
X 
X 
X 
Xe 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Complete physical examinationf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Targeted physical examinationg 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
12-lead ECG 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Laboratory Assessments 
G6PC genotyping 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HBV, HCV, HIV status 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test (females 
of childbearing potential only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test (females 
of childbearing potential only) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
Clinical chemistry (includes 
lipid panel and LFTs [LFT 
STAT sample])i  
Xj 
Xk 
X 
Xl 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Xk 
Xk 
X 
Xk 
Hematology 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Coagulation panel 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Urinalysis 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Cortisol, fatty acid, glucagon, 
insulin, C-peptide, growth 
hormone, IGFBP1, ACTH, 
alanine, and ketone blood 
levelsm 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xn 
X 
 
X 


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Period 
SVa 
BL 
Dosing 
Follow-up Period 
EOS/ 
EW 
Visit Time 
(Day/Week) 
D−56 
to 
D−1 
D0 
D1 
D4 D8 D12 D16 D20 D24 
D28 
D32 D36 D39 
D42 
D45 D48 D52 D56 D60 D64 D68 D72 D76 D80 
D84 
D168 D252 D365 
Predose Dosing/ 
Postdose 
W4 
W6 
W12 
W24 
W36 
W52 
Visit Window (Days) 
– 
– 
– 
– 
±1 
±2 
±1 
±2 
±1 
±2 
±7 
±7 
±7 
Visit Type 
OP 
IP 
OP/HH 
OP 
OP/HH 
OP 
OP/HH 
IPdd 
IP 
OP 
IP 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
 
 
Xo 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
Xp 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
  
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Xq 
Xq 
Xq 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
Diet and Cornstarch Assessments 
Assessment of prescribed diet 
and dietary intaker 
X 
Xs 
 
 
 
 
 
 
 
 
X 
 
 
 
Xs 
 
 
 
 
 
 
 
 
 
 
Xs 
Xs 
X 
Xs 
Assessment of cornstarch (or 
equivalent) intaket 
X 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 


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Period 
SVa 
BL 
Dosing 
Follow-up Period 
EOS/ 
EW 
Visit Time 
(Day/Week) 
D−56 
to 
D−1 
D0 
D1 
D4 D8 D12 D16 D20 D24 
D28 
D32 D36 D39 
D42 
D45 D48 D52 D56 D60 D64 D68 D72 D76 D80 
D84 
D168 D252 D365 
Predose Dosing/ 
Postdose 
W4 
W6 
W12 
W24 
W36 
W52 
Visit Window (Days) 
– 
– 
– 
– 
±1 
±2 
±1 
±2 
±1 
±2 
±7 
±7 
±7 
Visit Type 
OP 
IP 
OP/HH 
OP 
OP/HH 
OP 
OP/HH 
IPdd 
IP 
OP 
IP 
Glucose Monitoring 
Provide CGM device to 
subjectu 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Distribute and collect Morning 
Glucose Level monitoring 
worksheetv 
 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Assessment of morning glucose 
levelsw 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Controlled Fasting Challenge Assessments 
Dinner before controlled fasting 
challengex 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
Cornstarch dose prior to 
starting controlled fasting 
challengey 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
Controlled fasting challengez 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
Glucose, lactate, growth 
hormone, IGFBP1 cortisol, and 
ACTH blood levels (local 
laboratory; 30 min after the end 
of the fasting challenge) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
Glucose and lactate (venous) 
sample (local laboratory [STAT 
sample])aa  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
Screening, Enrollment, and Infusion 
IWRSbb 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DTX401 infusioncc 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AAV8 = adeno-associated virus serotype 8; ACTH= adrenocorticotropic hormone, AE = adverse event; BL = Baseline; BP = blood pressure; CGM = 
continuous glucose monitoring; D = day; ECG = electrocardiogram; 
 EOS = end 
of study; EW = early withdrawal; G6Pase = glucose-6-phosphatase (protein); G6PC = glucose-6-phosphatase (gene); GSDIa = glycogen storage disease type Ia; 


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HBV = hepatitis B virus; HCV = hepatitis C virus; HH = home visit; HIV = human immunodeficiency virus; HR = heart rate; IGFBP1 = insulin-like growth factor-
binding protein 1; IgG = immunoglobulin G; IP = inpatient study visit; IWRS = interactive web response system; LFTs = liver function tests; 
 
 nAb = neutralizing antibody; OP = outpatient study visit; 
 RR = respiratory rate; SAE = serious adverse event; 
SV = Screening Visit; W = week. 
a Screening assessments may be completed in any reasonable order (except where indicated) and on more than 1 day at the Investigator’s discretion. All screening assessments must be 
completed within the Screening Period before Day 0. 
b 
 should be completed prior to invasive assessments being conducted. 
c Subjects will complete the GSDIa Morning Diary and GSDIa Evening Diary daily for 7 days leading up to and including the Day 0 and 12, 24, and 52 study visits. Subjects will complete 
the GSDIa Morning Diary in the morning upon awakening. Subjects will complete the GSDIa Evening Diary at the end of the day. Subjects will be provided with copies of the GSDIa 
Morning Diary and GSDIa Evening Diary during the Screening Period and instructed to bring the completed assessments to each study inpatient visit. 
d Subjects will be asked to complete a brief telephone interview at Weeks 24 and 52 regarding their experience completing the 
assessments to guide further development of the 
assessments. At Week 52, subjects will also be asked about their experience in the study. 
e Vital signs will be measured approximately 5 minutes after the start of the infusion, and approximately 0.5 (± 5 minutes), 1 (± 5 minutes), 4, 8 hours (± 15 minutes), and 22 hours 
(± 1 hour) after the start of infusion. 
f Complete physical examination will include assessments of the head, eyes, ears, nose, and throat; the skin; the abdomen with documentation of liver and spleen size; and the endocrine, 
metabolic, neurological, respiratory, cardiovascular, gastrointestinal, and musculoskeletal systems. 
g Targeted physical examination will include assessments of the skin; the abdomen with documentation of liver and spleen size; and the respiratory, cardiovascular, and gastrointestinal 
systems. 
h It is recommended that the Screening sample for G6PC genotyping be collected at the time written informed consent is provided. 
i Liver function tests will be assessed at a minimum of every 3 to 4 days starting at DTX401 post dose Day 4 through Week 12, or longer if clinically indicated. One blood sample will be 
collected for determination of clinical chemistry (including LFTs) and sent to the central laboratory for analysis. A second blood sample will be collected for determination of LFTs and 
sent to the local laboratory (STAT sample), as described in the laboratory manual. 
j Liver function tests and triglyceride levels can be repeated during the Screening Period at the Investigator’s discretion. 
k A blood sample for measurement of lipid levels will be collected on the morning of hospital admission for each controlled fasting challenge at approximately the same time starting at 
Day 0. The sample should be collected at least 2 to 4 hours after the subject’s last meal. 
l A blood sample for determination of clinical chemistry (including LFTs) will be collected approximately 22 hours after the start of DTX401 infusion. 
m Blood samples for measurement of cortisol, fatty acid, glucagon, insulin, C-peptide, growth hormone, IGFBP1, ACTH, alanine, and ketone levels will be collected at the beginning and 
end of each controlled fasting challenge, or more frequently at the Investigator’s discretion.  
n If possible, a blood sample for measurement of ACTH and cortisol levels will be collected approximately 1 week before the Week 12 visit. 
o It is recommended that the Screening sample for AAV8 neutralizing antibody testing be collected at the time written informed consent is provided. 
p A blood sample for vector genome determination will be collected approximately 22 hours after the start of DTX401 infusion. 
q 
 
r The subject's daily prescribed diet and daily diet intake will be recorded at the time points specified in Table 6 and, if possible, on a weekly basis through the Week 52 visit or early 
withdrawal. 
s The subject will remain on his or her prescribed diet for the duration of each inpatient study visit. 
t The subject's daily prescribed cornstarch (or equivalent) and daily cornstarch (or equivalent) intake will be recorded at the time points specified in Table 6 and, if possible, on a weekly 
basis through the Week 52 visit or early withdrawal. 
u Supplemental information on glucose level trends will be collected using a CGM device. The site will provide a CGM device to the subject during the Screening Period after determining 
that the subject is eligible for the study. Subjects will be educated on the appropriate care and use of the CGM device and sensors, and instructed to wear the CGM device through the 
Week 52 visit or early withdrawal. Data from the subject’s CGM device will be transferred to the Sponsor throughout the study, including a final data transfer at the end of the Week 52 
visit or early withdrawal. 


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v Subjects will receive the Morning Glucose Level monitoring worksheet and instructions for completing it following DTX401 administration. If a subject is unable to use the assigned 
CGM, the subject should collect morning glucose levels at least 2 mornings per week throughout the study and record the values on the Morning Glucose Level monitoring worksheet. 
Subjects should measure their morning glucose level using their own glucose monitoring device before taking their morning dose of cornstarch. Subjects will be instructed to bring the 
completed worksheet to each study visit. 
w If the subject was unable to use the assigned CGM but was able to complete the Morning Glucose Level monitoring worksheet, the subject’s worksheet will be collected and reviewed at 
the time points specified in Table 6, and a new worksheet will be provided to the subject. 
x Before the controlled fasting challenge begins, the study site will provide dinner for the subject. The dinner meal will be personalized for each subject, and will include a target 
carbohydrate range and overall composition in protein, fats and dietary fibers that is as close as possible to the subject’s most current dinner dietary prescription, but not higher than the 
carbohydrate content of the dinner consumed at their baseline fasting challenge. 
y Subjects will be given an oral dose of cornstarch equivalent per their most recent cornstarch prescription at approximately the same time that they typically take it, but no later than 3 hours 
post dinner.  
z The controlled fasting challenge requires a 24-hour inpatient stay and should be performed after all other assessments are completed except for 24-hour urine collection, which may be 
completed concurrently, and 
 which will be completed after the controlled fasting challenge. In addition to the specified time points, if clinically indicated, the controlled fasting 
challenge can be performed at an unscheduled visit. 
aa Blood samples for measurement of glucose and lactate (venous) levels will be collected at the beginning of the controlled fasting challenge, then approximately every 60 minutes 
(± 5 minutes) until the glucose level decreases to ≤ 70 mg/dL (≤ 3.9 mmol/L), then approximately every 30 minutes (± 5 minutes) until the glucose level decreases to < 54 mg/dL 
(< 3.0 mmol/L) or the fast reaches 15 hours without hypoglycemia, whichever occurs first. Samples should be sent to the local laboratory (STAT sample) and results should be available 
within 30 minutes or less of blood sample collection for the safety of the subject. 
bb Subjects will be registered in the IWRS at Screening and after eligibility for enrollment is confirmed. 
cc The site will schedule the dosing visit in the IWRS no less than 3 days before, preferably 7 days before, the DTX401 infusion to allow time for DTX401 to be shipped and delivered to the 
site. 
dd If the subject continues to be on steroid regimen and the Investigator determines that it is not safe to proceed with the CFC, the Week 12 visit may become an outpatient visit. Investigators 
should try to complete an adhoc CFC assessment as soon as the subject has completed steroid treatment and within 8 weeks of the Week 12 visit, as an unscheduled visit. 
 
 
 
 
 


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15.2. 
Appendix 2: Continual Reassessment Method Details 
 
The nominal doses used in the continual reassessment method, the x-hats, will be derived as: 
 
𝑥𝑥ො𝑖𝑖= log ቆ𝑑𝑑𝑖𝑖
𝑑𝑑𝑟𝑟𝑟𝑟𝑟𝑟
ቇ 
 
Where d1 = 2, d2 = 6, d3 = 10 and dref = 6. The di correspond to the amount of DTX401 
administered at each dose level, in units of 1012 genome copies/kg.  
 
A logistic model will be used to model the dose-toxicity curve. Let 
 
𝑌𝑌𝑖𝑖= ቄ0 𝑖𝑖𝑖𝑖 𝑡𝑡ℎ𝑒𝑒 𝑖𝑖𝑖𝑖ℎ 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑛𝑛𝑛𝑛𝑛𝑛 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑎𝑎 𝐷𝐷𝐿𝐿𝐿𝐿
1 𝑜𝑜𝑜𝑜ℎ𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒
 
 
Then 
 
𝑝𝑝(𝑌𝑌= 1|𝑥𝑥ො𝑖𝑖, 𝛼𝛼, 𝛽𝛽) =
𝑒𝑒𝛼𝛼+𝛽𝛽𝑥𝑥ො𝑖𝑖
1 + 𝑒𝑒𝛼𝛼+𝛽𝛽𝑥𝑥ො𝑖𝑖 
 
The joint distribution of α and β is given by 
 
ቀ𝛼𝛼
log 𝛽𝛽ቁ~𝑁𝑁ቆቀ
𝜇𝜇𝛼𝛼
𝜇𝜇𝛽𝛽ቁ, ൬
𝜎𝜎𝛼𝛼× 𝜎𝜎𝛼𝛼
𝜎𝜎𝛼𝛼× 𝜎𝜎𝛽𝛽× 𝜌𝜌
𝜎𝜎𝛼𝛼× 𝜎𝜎𝛽𝛽× 𝜌𝜌
𝜎𝜎𝛽𝛽× 𝜎𝜎𝛽𝛽
൰ቇ 
 
Initial (prior) values μα= -2.3097, logμβ = -0.4323, σα = 1.6604, logσβ = 0.0044 and  
ρ = -0.2405 are used based on simulations. 
 
The estimate of the maximum tolerated dose will be the highest dose for which the full Bayes 
posterior estimate of p(DLT|di) is strictly less than or equal to the target toxicity rate. 
 
A dose is cleared if it is either 2 × 1012 genome copies/kg or if it is no more than 1 dose level 
higher than the highest dose at which at least 3 subjects have been treated. 


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15.3. 
Appendix 3: 
 
 


 
Please respond to each question or statement by marking one box per row. 
 
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15.4. 
Appendix 4: 
 
 


 
 
 
 
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15.6. 
Appendix 6: Glycogen Storage Disease Type Ia (GSDIa) Morning 
Diary 
 


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15.7. 
Appendix 7: Glycogen Storage Disease Type Ia (GSDIa) Evening 
Diary 
 


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15.8. 
Appendix 8: 
 
 


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15.9. 
Appendix 9: 
 
 


 
 
 
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SAP_001.pdf: 
Ultragenyx  
 
 
401GSDIA01 
Statistical Analysis Plan, Version 2.0 
 
 
04 MAR 2022 
1 
Confidential 
 
 
STATISTICAL ANALYSIS PLAN 
(SAP) 
 
Title: 
A Phase 1/2, Open-Label Safety and Dose-Finding Study of 
Adeno-Associated Virus (AAV) Serotype 8 (AAV8)-Mediated 
Gene Transfer of Glucose-6-Phosphatase (G6Pase) in Adults 
with Glycogen Storage Disease Type Ia (GSDIa) 
Protocol: 
401GSDIA01 
Investigational Product: 
DTX401 (Nonreplicating, recombinant AAV8 vector that 
contains a codon-optimized, human G6PC coding sequence) 
Phase: 
1/2 
Sponsor: 
Ultragenyx Pharmaceutical Inc. 
60 Leveroni Court 
Novato, CA, USA 94949 
Author: 
 
Senior Director, Biostatistics, Biometrics 
 
Director, Biostatistics, Biometrics 
Date: 
12 July 2021 
Date Amended: 
04 March 2022 
Version Number: 
Version 2.0 
 
 
 


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CHANGE HISTORY 
Version 
Changes and Rationale for Changes 
1.0 
Initial Version 
2.0 
Minor changes in the document include changes to match the language in the 
SAP with the corresponding language in the protocol, removing redundancy in 
analyses that were described multiple times in the document, and adding 
clarifications around endpoint or analysis. 
Major changes in the document are summarized below. 
Section 3.7:  
•
Added update on latest data monitoring committee (DMC) conducted
for the study
•
Removed text about the roles and responsibilities of the DMC because
that is outside the scope of the SAP.
Section 8.4.1: Added derivation of actual dose administered to the subject 
Section 8.5.1: Added summary of cornstarch used and amount of 
carbohydrates in the dinner prior to controlled fasting challenge (CFC) upon 
request from medical monitor to understand use of these quantities in CFC. 
Section 8.5.2: Added analysis window for analysis of cornstarch data. Added 
plot for daytime, bedtime, and nighttime frequency of cornstarch doses. 
Section 8.5.3: 
•
Added exploratory analyses of continuous glucose monitoring (CGM)
data based on the request from medical monitor of the study to gain
better understanding of this data.
•
Added derivation for percentage of time spent in any glucose range in a
week
•
Removed text about the use of both Cenduit and Clarity data for
analysis of CGM data because Clarity data will not be part of clinical
dataset.
Section 8.6.7: Removed reference of few safety labs parameters from this 
section because analyses planned for these parameters are already described in 
other sections. Further, clarified that this section focuses on analyses for lab 
parameters collected at the central lab. 
Section 8.6.8: Added detailed description of analyses planned for vector 
shedding and vector genome determination tables  
Section 8.7: Added language about assessment of impact of COVID-19 on 
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TABLE OF CONTENTS 
CHANGE HISTORY.......................................................................................................................2 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
INTRODUCTION ........................................................................................................8 
2. 
STUDY OBJECTIVE(S) ..............................................................................................9 
2.1. 
Primary Objective .........................................................................................................9 
2.2. 
Secondary Objective .....................................................................................................9 
2.3. 
Exploratory Objectives .................................................................................................9 
3. 
STUDY DESIGN .......................................................................................................10 
3.1. 
Study Overview ..........................................................................................................10 
3.2. 
Dosage and Administration ........................................................................................10 
3.3. 
Blinding and Randomization Methods .......................................................................10 
3.4. 
Stratification Factors ...................................................................................................10 
3.5. 
Sample Size Considerations .......................................................................................11 
3.6. 
Interim Analysis ..........................................................................................................11 
3.7. 
Data Monitoring Committee .......................................................................................11 
4. 
STUDY ENDPOINTS AND COVARIATES ............................................................12 
4.1. 
Primary Endpoint(s) ....................................................................................................12 
4.2. 
Secondary Endpoint(s) ................................................................................................12 
4.3. 
Exploratory Endpoints ................................................................................................12 
5. 
DEFINITIONS ...........................................................................................................14 
5.1. 
Baseline .......................................................................................................................14 
5.2. 
Study Day ...................................................................................................................14 
5.3. 
Prior and Concomitant Medication .............................................................................14 
5.4. 
Dose-Limiting Toxicity ..............................................................................................14 
5.5. 
) ..............14 
5.6. 
 ...................................................................................15 
6. 
ANALYSIS POPULATIONS ....................................................................................16 
6.1. 
Full Analysis Set .........................................................................................................16 
7. 
DATA SCREENING AND ACCEPTANCE .............................................................17 
7.1. 
General Principles .......................................................................................................17 
7.2. 
Handling of Missing and Incomplete Data .................................................................17 


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7.2.1. 
Missing Medical History Related Dates .....................................................................17 
7.2.2. 
Missing Date Imputation for Adverse Events and Concomitant Medications ...........17 
7.2.3. 
Missing Causal Relationship to Investigational Product for Adverse Events ............18 
7.3. 
Testing/Validation Plan ..............................................................................................18 
7.4. 
Software ......................................................................................................................18 
8. 
STATISTICAL METHODS OF ANALYSES ...........................................................19 
8.1. 
General Principles .......................................................................................................19 
8.1.1. 
The Continual Reassessment Method .........................................................................19 
8.2. 
Subject Accountability ................................................................................................20 
8.3. 
Protocol Deviations ....................................................................................................20 
8.4. 
Investigational Product Administration ......................................................................20 
8.4.1. 
Extent of Exposure .....................................................................................................20 
8.4.2. 
Demographic and Baseline Characteristics ................................................................20 
8.4.3. 
Medical History and GSDIa Medical History ............................................................20 
8.4.4. 
Prior and Concomitant Medication .............................................................................20 
8.4.5. 
GSDIa Diet .................................................................................................................21 
8.5. 
Efficacy Analysis ........................................................................................................21 
8.5.1. 
Symptom-Free Euglycemia ........................................................................................21 
8.5.2. 
Use of Cornstarch (or Glycosade) ..............................................................................21 
8.5.3. 
Continuous Glucose Monitoring.................................................................................21 
8.5.4. 
Morning Glucose Levels .............................................................................................23 
8.5.5. 
....................................................................................23 
8.5.6. 
 .....................................................23 
8.6. 
Safety Analysis ...........................................................................................................23 
8.6.1. 
Adverse Events ...........................................................................................................24 
8.6.2. 
Physical Examination .................................................................................................24 
8.6.3. 
Vital Signs ..................................................................................................................24 
8.6.4. 
Electrocardiogram .......................................................................................................25 
8.6.5. 
Liver Ultrasound .........................................................................................................25 
8.6.6. 
Symptomatic Hypoglycemic Events ...........................................................................25 
8.6.7. 
Clinical Laboratory Assessments ...............................................................................25 
8.6.7.1. 
Liver Function Tests and Treatment ...........................................................................26 
8.6.8. 
Other Safety Parameters .............................................................................................26 


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8.7. 
Impact of COVID-19 on Study Participation .............................................................26 
9. 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL .....................................27 
10. 
LIST OF PLANNED TABLES, FIGURES, AND LISTINGS ..................................28 
11. 
REFERENCES ...........................................................................................................29 
12. 
APPENDICES ............................................................................................................30 
APPENDIX 1. SCHEDULE OF EVENTS .................................................................................30 
APPENDIX 2. CONTINUAL REASSESSMENT METHOD DETAILS .................................36 
APPENDIX 3. 
........................................................................................................37 
APPENDIX 4. 
 ....................................40 
APPENDIX 5. 
 ..........................................41 
APPENDIX 6. GLYCOGEN STORAGE DISEASE TYPE IA (GSDIA) MORNING 
DIARY ........................................................................................................................47 
APPENDIX 7. GLYCOGEN STORAGE DISEASE TYPE IA (GSDIA) EVENING 
DIARY ........................................................................................................................48 
APPENDIX 8. 
 ...........................53 
APPENDIX 9. 
.............................54 
 
LIST OF TABLES 
Table 1: 
Numerical Scoring of Adult Domains ........................................................................15 
Table 2: 
Central Clinical Laboratory Parameters .....................................................................25 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AAV8 
adeno-associated virus serotype 8 
AE 
adverse event 
ALT 
alanine aminotransferase 
BMI 
body mass index 
CRF 
case report form 
CRM 
continual reassessment method 
CGM 
continuous glucose monitoring 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DLT 
dose-limiting toxicity 
DMC 
data monitoring committee 
ECG 
electrocardiogram, electrocardiographic 
eCRF 
electronic case report form 
 
 
 
 
G6P 
glucose-6-phosphate 
G6Pase 
glucose-6-phosphatase (protein) 
G6PC 
glucose-6-phosphatase (gene) 
GC 
genome copies 
GSDIa 
glycogen storage disease type Ia 
IgG 
immunoglobulin G 
IV 
intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
 
MTD 
maximum tolerated dose 
NCI 
national cancer institute 
OBD 
optimal biological dose 
PDFF 
proton density fat fraction 
PT 
preferred term 


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Abbreviation 
Definition 
 
 
QTc 
QT interval corrected for heart rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 


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1. 
INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide details of the statistical analyses 
that have been outlined within the 401GSDIA01 original Protocol dated 17 May 2017, Protocol 
Amendment 1 dated 13 December 2017, Amendment 2 dated 02 March 2018, Amendment 3 
dated 18 February 2019, Amendment 4 dated 10 September 2019, Amendment 5 dated 
28 October 2019, and Amendment 6 dated 16 February 2021.  


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2. 
STUDY OBJECTIVE(S) 
2.1. 
Primary Objective 
• To determine the safety of single intravenous (IV) doses of DTX401 in adults with 
GSDIa, including the incidence of dose-limiting toxicities (DLTs). 
2.2. 
Secondary Objective 
• To establish a dose of DTX401 that achieves symptom-free euglycemia (glucose 
≥54 mg/dL [≥3.0 mmol/L])* in a setting of a controlled fasting challenge to allow 
further clinical development. 
* Following protocol amendment 6, the definition of euglycemia for the end of the 
controlled fasting challenge changed from ≥60 mg/dL (≥3.3 mmol/L) to ≥54 mg/dL 
(≥3.0 mmol/L) 
2.3. 
Exploratory Objectives 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


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3. 
STUDY DESIGN 
3.1. 
Study Overview 
401GSDIA01 is a Phase 1/2, open-label, single-arm, multicenter, safety and dose-finding study 
to determine the safety, tolerability, and efficacy of DTX401 in adults with GSDIa. 
3.2. 
Dosage and Administration 
DTX401 will be administered as a single peripheral IV infusion. The following doses will be 
evaluated using a continual reassessment method (CRM) to estimate the maximum tolerated dose 
(MTD): 
• Dose 1: 2.0 × 1012 genome copies (GC)/kg 
• Dose 2: 6.0 × 1012 GC/kg 
• Dose 3: 1.0 × 1013 GC/kg 
Eligible subjects may be enrolled into 1 of the following cohorts of 3 subjects each and receive a 
single IV infusion of DTX401. 
• Cohort 1: Dose 1 (2.0 × 1012 GC/kg) with a reactive steroid regimen (prednisone 
starting dose of 40 mg/day) 
• Cohort 2: Dose 2 (6.0 × 1012 GC/kg) with a reactive steroid regimen (prednisone 
starting dose of 40 mg/day) 
• Cohort 3: Dose 2 (6.0 × 1012 GC/kg) with an optimized reactive steroid regimen 
(prednisone starting dose of 60 mg/day) 
• Cohort 4: Dose 2 (6.0 × 1012 GC/kg) with a prophylactic steroid regimen 
A cohort may be expanded to include additional subjects to confirm the findings for the cohort.  
Subjects in Cohorts 1 and 2 were dosed at a minimum of 2 weeks (14 days) apart. Subjects in 
subsequent cohorts will be dosed at a minimum of 1 week (7 days) apart. 
After the third patient in a cohort reaches the 12-week time point, the CRM will propose a dose 
for the next cohort using the collected data from the previous cohort. The decision to proceed 
will be made after the data monitoring committee (DMC) has evaluated at least 12 weeks of 
safety data for all subjects in a dosing cohort.  
Subjects will be followed for 52 weeks following DTX401 administration. After completion of 
the Week 52 visit or early withdrawal, subjects will be offered enrollment in a 4-year extension 
study to evaluate the long-term (a total of 5 years) safety and efficacy of DTX401. 
3.3. 
Blinding and Randomization Methods 
Not applicable. 
3.4. 
Stratification Factors 
Not applicable. 


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3.5. 
Sample Size Considerations 
Simulations show that if all 3 doses are safe and no DLTs occur, the CRM will recommend dose 
escalation to 1 × 1013 GC/kg (genome copies measured by 
 and the recruitment of 
12 subjects. Based on safety and efficacy observations in Cohorts 1, 2, and 3 (3 subjects each) 
and a positive recommendation from the DMC, it was decided to enroll a fourth cohort of 
3 subjects. The planned sample size of the study will therefore be 12 subjects including 
4 cohorts. 
3.6. 
Interim Analysis 
No interim analyses were performed.  
3.7. 
Data Monitoring Committee 
An independent DMC will be responsible for monitoring safety data from the study. For Cohorts 
1 and 2, the DMC met after all evaluable subjects in the dosing cohort completed Week 12 of the 
study to review the safety data and provided their recommendation for progressing to the next 
dosing cohort or enrollment of subjects into additional cohorts. So far, DMC has reviewed safety 
data up to Week 52 for Cohorts 1-3 and Week 24 for Cohort 4; there were no safety concerns 
from the DMC and the recommendation has been to continue the study.  The DMC will meet at 
the end of the study and may, at any time, recommend modifying or pausing enrollment due to 
safety concerns based on their periodic data reviews. 
Enrollment will be paused, and the DMC and regulators will be notified if, at any time during the 
study, any of the events listed below occur following administration of DTX401: 
• Death of a subject 
• An event with an intensity ≥Grade 3 (according to the National Cancer Institute 
Common Terminology Criteria for Adverse Events) develops 
• Occurrence of a hepatic malignancy 
If a stopping rule is met, enrollment will be paused, and the DMC will meet to review available 
data. If a decision is made to resume enrollment, this decision will be communicated to and, if 
required, approved by regulatory authorities according to country requirements. 


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4. 
STUDY ENDPOINTS AND COVARIATES  
The full schedule of assessments is shown in Appendix 1.  
4.1. 
Primary Endpoint(s) 
The incidence of adverse events (AEs), including the incidence of DLTs at each dose level, 
treatment-emergent adverse events (TEAEs), and serious adverse events (SAEs) for each dosing 
cohort, assessed by severity and relationship to study product. Specifically,  
• TEAEs by SOC and PT 
• DLTs by SOC and PT 
• Related TEAEs by SOC and PT  
• Serious TEAEs by SOC and PT  
• Serious Related TEAEs by SOC and PT 
• TEAEs by PT and greatest severity 
4.2. 
Secondary Endpoint(s) 
• The change from baseline in time (in minutes) to first hypoglycemic event (defined as 
glucose <54 mg/dL [<3.3 mmol/L])* during a controlled fasting challenge at 12, 24, 
and 52 weeks after IV administration of DTX401. 
* Following protocol amendment 6, the definition of euglycemia for the end of the 
controlled fasting challenge changed from ≥60 mg/dL (≥3.3 mmol/L) to ≥54 mg/dL 
(≥3.0 mmol/L 
4.3. 
Exploratory Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


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5. 
DEFINITIONS 
5.1. 
Baseline 
Baseline is defined as the last non-missing assessment taken prior to the dose of DTX401, unless 
specified otherwise. 
5.2. 
Study Day 
If the visit date is on or after the date of the dose of DTX401: 
Study day = (visit date – date of the dose of DTX401 + 1) 
If the visit date is prior the date of the dose of DTX401: 
Study day = visit date – date of the dose of DTX401. 
5.3. 
Prior and Concomitant Medication 
Prior medication is defined as any medication started before the DTX401 dose date (medication 
start date prior to the DTX401 dose date).  
Concomitant medication is defined as any medication taken on or after the DTX401 dose date 
(medication end date on or after the DTX401 dose date, or ongoing). 
5.4. 
Dose-Limiting Toxicity 
A DLT is defined as any AE/SAE ≥Grade 3 that is considered by the Investigator and/or Sponsor 
to be related to DTX401, based on the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE), the most recent version. 
5.5. 
 
 
 
 
  
 
 
 
 
 


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5.6. 
 
 
 
 
 
 


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6. 
ANALYSIS POPULATIONS 
6.1. 
Full Analysis Set 
The full analysis set will consist of all enrolled subjects who received DTX401. The full analysis 
set will be used for all the analyses.  


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7. 
DATA SCREENING AND ACCEPTANCE 
7.1. 
General Principles 
Data will be reviewed periodically, and any questionable data will be reported to the data 
manager promptly for query and resolution. 
7.2. 
Handling of Missing and Incomplete Data 
Missing clinical outcome data can occur for multiple reasons, including missed subject visits and 
scales or measures with missing item scores. Missing and incomplete data will be identified 
through the data quality review plan for this study. Missing and incomplete data will be 
identified for investigation, and possible resolution, by Data Management prior to the study 
database lock or snapshot. 
Unless specified otherwise, only the observed data (not imputed data) will be presented in 
listings. 
7.2.1. 
Missing Medical History Related Dates  
• If only day is missing, impute 1. 
• If month is missing, impute January 1st. 
• If year is missing, then no imputation will be done; the date will be missing.  
If the imputed date is earlier than the birth date, then the birth date will be used. 
7.2.2. 
Missing Date Imputation for Adverse Events and Concomitant Medications 
The following conventions will be used to impute missing portions of dates for adverse events 
and concomitant medications. Note that the imputed values outlined here may not always 
provide the most conservative date.   
Missing Start Dates 
• If the day is unknown, then: 
− If the month and year match the month and year of the DTX401 dose date, then 
impute the day of the DTX401 dose date. 
− Otherwise, assign the first day of the month. 
• If the month is unknown, then: 
− If the year matches the year of the DTX401 dose date, then impute the month and 
day of the DTX401 dose date. 
− Otherwise, assign ‘January’  
• If the year is unknown, then the date will not be imputed and will be assigned a 
missing value.  


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Missing Stop Dates and not ongoing 
• If the day is unknown, then assign the last day of the month. 
• If the month is unknown, then assign ‘December.’ 
• If the year is unknown, then the date will not be imputed and will be assigned a 
missing value, and the event will be considered ongoing. If the AE has been recorded 
as resolved/recovered, all efforts should be made to obtain the date from the 
Investigator. 
• If the resulting end date is after the date of study completion / discontinuation / data 
cutoff, set the imputed end date as close to the date of study completion / 
discontinuation / data cutoff as possible without overwriting existing information. 
• If the year is missing for the start date and stop date (observed or imputed) is on or 
after the DTX401 dose or event is ongoing, the start date will be imputed as the 
DTX401 dose date. 
7.2.3. 
Missing Causal Relationship to Investigational Product for Adverse Events 
If the causal relationship to investigational product (DTX401) is missing for an AE that started 
on or after the date of the DTX401 dose, a causality of “related” will be assigned. The imputed 
values for causal relationship to DTX401 will be used for the incidence summary; the values will 
be shown as missing in the data listings. 
7.3. 
Testing/Validation Plan 
Data will be reviewed by a cross functional team periodically and issues will be addressed by 
data management.  
7.4. 
Software 
The CRM model will be used to evaluate each dose for dose escalation using software Fixed and 
Adaptive Clinical Trial Simulator (FACTS™; Berry Consultants, Austin, Texas, United States) 
Version 6.0 or later. SAS® software (SAS® Institute, Inc., Cary, North Carolina, United States) 
version 9.4 or higher will be used to perform statistical analyses unless otherwise specified. 


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8. 
STATISTICAL METHODS OF ANALYSES 
8.1. 
General Principles 
Continuous variables will be summarized by number of subjects and mean, standard deviation 
(SD), standard error (SE), median, Q1, Q3, minimum, and maximum values. Categorical 
variables will be summarized by number and percentage of subjects. All summary tables will be 
presented by scheduled study visit and no analysis windows will be used, unless specified 
otherwise.  All the summary tables will be presented by dosing cohort of DTX401 and overall, 
unless specified otherwise. The dosing cohorts are: 
• Cohort 1: Dose 1 (2.0 × 1012 GC/kg) with a reactive steroid regimen (prednisone 
starting dose of 40 mg/day) 
• Cohort 2: Dose 2 (6.0 × 1012 GC/kg) with a reactive steroid regimen (prednisone 
starting dose of 40 mg/day) 
• Cohort 3: Dose 2 (6.0 × 1012 GC/kg) with an optimized reactive steroid regimen 
(prednisone starting dose of 60 mg/day) 
• Cohort 4: Dose 2 (6.0 × 1012 GC/kg) with a prophylactic steroid regimen 
8.1.1. 
The Continual Reassessment Method 
Neuenschwander’s CRM (or nCRM) (Neuenschwander et al., 2008) will be used to make 
recommendations for the dose to be administered in each cohort using all evaluable subjects 
(i.e., subjects who remain in the study for at least 12 weeks after dosing or for whom a DLT is 
observed within 12 weeks of dosing). The DLT assessment for each subject is based on the 
definition in Section 5.4. The DLT evaluation window for each subject starts on the date of 
administration of DTX401 and continues for up to 12 weeks (84 days) thereafter, or until all 
Week 12 safety assessments have been completed, whichever occurs later. Results of CRM 
model will be presented as part of DMC data review.  
The target toxicity rate is 0.25. The cohort size is 3 subjects. The dose levels studied are 
specified in Section 3.2. The first cohort will be treated at 2 × 1012 GC/kg. Subsequent cohorts 
will be treated at the lower of the current estimate of the MTD and the highest dose allowed by 
the escalation rule. The CRM model will evaluate subjects based on the dose administered 
regardless of the steroid approach used. 
A logistic model will be used to model the dose-toxicity curve; further details are provided in 
Appendix 2. 
The CRM model will recommend that the study is stopped once the MTD is determined the first 
time any of the following criteria are satisfied after a CRM model update: 
• Six evaluable subjects have been treated at 1 × 1013 GC/kg and the current estimate of 
the MTD is >1 × 1013 GC/kg 
• Six evaluable subjects have been treated at the current estimate of the MTD 
• The current estimate of the MTD is <2 × 1012 GC/kg (insufficient safety) 


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The study will stop when the maximum sample size of 12 subjects have been enrolled or at the 
Sponsor’s discretion. If 12 subjects have been enrolled and the definition of having an MTD 
determined has not been reached, then the highest dose considered at or below the MTD will be 
considered the MTD. 
Enrollment will be limited so that each dosing cohort includes no more than 3 subjects. 
The optimal biological dose (OBD) will be based on the MTD and an assessment of clinical 
benefit. 
8.2. 
Subject Accountability 
The number and percentage of subjects in the full analysis set will be summarized. The number 
and percentage of subjects who complete the study and of subjects who prematurely discontinue 
will be summarized. The reasons for premature discontinuation from the study will be 
summarized as recorded in the electronic case report forms (eCRFs). The study duration will be 
summarized. A subject disposition listing, including study duration, will be provided for 
individual subjects.  
The glucose-6-phosphatease (G6PC) genotyping results at screening will be listed. For subjects 
who fail to meet eligibility criteria, the inclusion/exclusion criteria the subjects fail will be listed.  
8.3. 
Protocol Deviations 
Major protocol deviations will be summarized for each type. Both major and minor protocol 
deviations will be listed. 
8.4. 
Investigational Product Administration 
8.4.1. 
Extent of Exposure 
The actual dose and volume administered will be summarized and will also be listed. The actual 
dose will be calculated as dose level (GC/kg) multiplied by screening weight (kg) of the subject. 
8.4.2. 
Demographic and Baseline Characteristics 
Demographic parameters (age; race; ethnicity; sex; weight; height, body mass index [BMI]) will 
be summarized descriptively and will also be listed by subject. 
8.4.3. 
Medical History and GSDIa Medical History 
Medical history will be summarized by body system and will also be listed by subject. GSDIa 
medical history data will be summarized and will also be listed by subject.  
8.4.4. 
Prior and Concomitant Medication 
Both prior and concomitant medications will be coded by drug name and therapeutic class using 
WHO Drug dictionary. If a subject received a specific medication multiple times or received 
multiple medications within a specific therapeutic class, that subject will be counted only once 
for the coded drug name or therapeutic class. Prior and concomitant medications will be 
summarized in tables and will also be provided in listings. 


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8.4.5. 
GSDIa Diet 
The prescribed and actual daily GSDIa diet parameters (including total calories, carbohydrates 
and non-utilizable sugars, protein, and fat) and change from baseline values will be summarized 
by study visit. Individual subject listing of GSDIa diet data will be provided. 
8.5. 
Efficacy Analysis 
8.5.1. 
Symptom-Free Euglycemia 
The time (in minutes) to the first hypoglycemic event (defined as glucose <60 mg/dL 
[<3.3 mmol/L]) during a controlled fasting challenge at baseline (Day 0), Week 12, 24 and 52, 
and the change from baseline in time (in minutes) to first hypoglycemic event at Weeks 12, 24, 
and 52 will be summarized. If the controlled fasting challenge has to be stopped due to 
symptomatic hypoglycemic event, or the subject is administered intervention (e.g., cornstarch), 
the time to the first hypoglycemic event will be defined as the time to the controlled fasting 
challenge is terminated. If there is no hypoglycemic event during the fasting challenge, the time 
will be censored at the maximum evaluable time (15 hours). 
A listing of the controlled fasting challenges and the glucose, lactate, and other local lab 
parameters (cortisol, free fatty acids, glucagon etc.), and capillary glucose levels (if available) 
collected during the controlled fasting challenges will be provided. Use of cornstarch and 
carbohydrates in the dinner prior to controlled fasting challenge and change from baseline will be 
summarized by visit.  
In addition, plots for individual patient profile of controlled fasting challenge hours, plots for 
individual patient profile of glucose and lactate during controlled fasting challenges will be 
presented by study visits.  
8.5.2. 
Use of Cornstarch (or Glycosade) 
The prescribed and actual daily amount and frequency of cornstarch over time will be 
summarized by study visit in a table and provided in the listings. In addition, the percent change 
from baseline in daily cornstarch amount by study visit by subject by dosing cohort will be 
plotted. Daily frequency of cornstarch (total and by daytime, nighttime, and bedtime) by study 
visit will be plotted for each subject.  
Data collected at a scheduled visit within an analysis window of +/- 14 days of the target day for 
a visit will be included in the analysis. If such a scheduled visit is not performed, data collected 
at the nearest unscheduled visit (if any) completed within that analysis window will be included. 
8.5.3. 
Continuous Glucose Monitoring 
Continuous glucose monitoring (CGM) device data will be collected from cohort 3 and 
4 subjects for this study. Glucose data will be summarized per subject per week and per subject 
per week per day (24 hours) Raw summary statistics will be provided. Study weeks are derived 
by (assessment dates – dosing date +1)/7. 
 Percentage of time  spent in normal glucose ranges (between 60 mg/dL -120 mg/dL,  between 
70 mg/dL – 120 mg/dL),  percentage of time spent in low and high glucose values (< 60 mg/dL, 
< 70 mg/dL, < 50mg/dL, > 120 mg/dL), number of low glycemic events (< 60 mg/dL, 


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<70 mg/dL, <50 mg/dL), time spent in minutes under glucose values (< 60 mg/dL , < 70 mg/dL, 
< 50 mg/dL), time spent in minutes for glucose ranging in (60 -120,  70 – 120 and >120 mg/dL) 
will be summarized by subject by week and by subject by week by day ( 24 hours).  
Percentage of time spent in any glucose range in a week is calculated as time duration (minutes) 
of glucose values spent in that range in a week, divided by total time duration (minutes) in a 
week and multiplied by 100 where 
• Time duration (in minutes) of glucose values spent in that range in a week= sum of all 
the time intervals where glucose value is in the range where time interval for any 
glucose value is calculated as the difference between collection time of that glucose 
value and the next collection time. If the glucose value is missing at any collection 
time between first glucose value and last glucose value collected in that week, the last 
available glucose value prior to the collection time will be carried over.  
• Total time duration (in minutes) in a week= (Last time/date of non-missing glucose 
value of the week – first time/date of non-missing glucose value) + 5 minutes 
• Only glucose value between 40 and 400 mg/dL collected by CGM device will be 
considered as non-missing value. 
The percentage of time spent in a glucose range in an hour will be calculated in similar fashion 
where only recordings in that hour will be considered. Percentage time spent in a glucose range 
in a month (4-weeks) will be calculated by calculating the percentage time spent in each week 
and taking average of these weekly values. 
The percentage of subjects with >=85% of weekly glucose values in the range 60-120 mg/dL and 
>=90% of glucose values in the range 60-120 mg/dL will be summarized by week for each 
cohort. Summary of total time spent, percent of time spent, and average time of episodes in 
glucose ranges (<60, <70, 60-120, 70-120, > 120 mg/dL) will be provided by week and by day 
(24 hours) for all subjects combined.  
In addition, individual glucose profile over 24 hours together with cornstarch prescription will be 
plotted weekly (up to 7 days) by subject. Summary of glucose values (mean, median, min, max, 
etc.) will be plotted by study days for each subject. Summary of glucose values (mean, min, 
max) will be plotted by day (24 hours) and week for each subject. Variability (SD) of glucose 
values in a week will be plotted by week for each subject.  
Number of low glycemic events and their duration will be summarized by week for each subject.  
Number of low glycemic events will be plotted by study days and by week for each subject. 
A low glycemic (hypoglycemic) event is defined as a series of at least two sensor glucose values 
less than 60 mg/dL, lasting at least 15 min, with no intervening values of 60 mg/dL or more. 
The end of a hypoglycemic event is defined as a minimum of 15 consecutive minutes with at 
least two sensor glucose values of at least 60 mg/dL and at least 10 mg/dL above the nadir of the 
event or at the end of a week. Further, daily, and weekly number of low glycemic events together 
with cornstarch use will be plotted for each subject. For cornstarch use, data collected at all visits 
(scheduled and unscheduled) will be included in the analysis.  
Percentage of time of glucose values under 60 mg/dL, percentage of time spent in normal 
glucose ranges (between 60mg – 120 mg/dL), total time (minutes) of glucose values under 
60 mg/dL will be plotted by subject by week. 


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Percentage of time spent in normal glucose ranges (60–120 mg/dL) together with cornstarch 
intake will be plotted by week for each subject, by week for each cohort, and by month 
(4-weeks) for each cohort. Percentage of time spent in different glucose ranges (<60, 60 – 120, 
>120 mg/dL) together with cornstarch intake (in grams) will be plotted by month (4-weeks) for 
each cohort. Total time (minutes) of glucose values under 60 mg/dL together with cornstarch 
intake will be plotted by week for each subject.  
Additional cutoffs and glucose variability may be analyzed as appropriate. Additional summary 
may be performed by dosing cohort by week. 
8.5.4. 
Morning Glucose Levels 
Morning glucose levels will be summarized in a table and provided in the listings. Plots for 
individual patient profile of morning glucose level and overnight cornstarch dose will be 
presented by study day. Plots for individual patient profile of weekly mean morning glucose 
level and overnight cornstarch dose will also be presented.  
8.5.5. 
 
 
 
 
 
  
 
8.5.6. 
 
 
 
 
 
 
8.6. 
Safety Analysis 
The safety parameters will include AEs, SAEs, vital sign measurements, complete and targeted 
physical examination findings, electrocardiogram (ECG) results, documented symptomatic 
hypoglycemic events, clinical laboratory assessments (clinical chemistry [including liver 
function tests], hematology, coagulation panel, and urinalysis), vector shedding, vector genome 
determination, measurement of neutralizing antibody titer to AAV8, measurement of AAV8 
binding antibody immunoglobulin G (IgG), assessment of any cell-mediated immune responses 
to AAV8 and G6Pase, and measurement of anti-G6Pase antibodies. 
Except for the CRM modelling described above, all statistical analyses of safety outcomes will 
be descriptive. 


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8.6.1. 
Adverse Events 
Adverse events will be coded by system organ class (SOC) and preferred term (PT) using the 
current version of Medical Dictionary for Regulatory Activities. 
An AE (classified by preferred term) will be considered a treatment emergent adverse event 
(TEAE) if it occurs on or after the DTX401 dose and is not present prior to the DTX401 dose, or 
it is present at the DTX401 dose but increases in intensity, severity, or frequency during the 
study.  
Subject incidence of AEs will be tabulated as the following: 
• Summary of AEs 
• TEAEs by SOC and PT 
• DLTs by SOC and PT 
• Related TEAEs by SOC and PT  
• Serious TEAEs by SOC and PT  
• Serious Related TEAEs by SOC and PT 
• Grade 3 or 4 TEAEs by SOC and PT  
• Fatal TEAEs by SOC and PT 
• TEAEs leading to discontinuation of study by SOC and PT 
• TEAEs by PT 
• TEAEs by PT and greatest severity 
Summary tables by SOC and PT will include number of subjects as well as number of events. 
Detailed listings for all AEs, DLT, TEAEs leading to the discontinuation of study, and death will 
also be generated.  
The severity will be based on the most current version of CTCAE. If an AE cannot be graded 
based on CTCAE, the investigator will assign a severity based on 1 = mild, 2 = moderate, 
3 = severe, 4 = life threatening, and 5 = death. 
8.6.2. 
Physical Examination 
Physical examination date will be listed by study visit. Physical examination findings that are 
clinically significant per study investigator are documented and summarized as AEs.  
8.6.3. 
Vital Signs 
Vital sign measurements (heart rate, blood pressure [systolic and diastolic], and respiratory rate) 
and changes from baseline values will be summarized by study visit. Height, weight, and BMI 
will be summarized. Individual profile of weight and BMI over time will be plotted. Individual 
subject listing of vital signs will be provided.  


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8.6.4. 
Electrocardiogram 
Each ECG will be interpreted as “normal”, “abnormal not clinically significant”, or “abnormal 
clinically significant” by the study investigator and captured on eCRF. Shift from baseline in 
ECG interpretation will be summarized at Week 52/EOS. The interpretation of the ECG data will 
be listed by study visit.  
A listing of ECG results will be provided.  
8.6.5. 
Liver Ultrasound  
An ultrasound of the liver will be conducted during the screening period. Ultrasound results will 
be provided in a listing. 
8.6.6. 
Symptomatic Hypoglycemic Events 
The number of subjects who reported symptomatic hypoglycemic events will be summarized by 
study visit. Symptomatic hypoglycemic events resulting in a visit to the emergency room or 
hospitalization are also reported as AEs on AE eCRF.  
Details of the symptomatic hypoglycemic events will be provided in a listing. 
8.6.7. 
Clinical Laboratory Assessments 
Clinical laboratory assessments are mainly collected at central laboratory (Table 2), except for 
data collected during CFC which is collected at local laboratory and analyzed as described in 
Section 8.5.1. For all central clinical laboratory parameters (Table 2) with continuous results, 
absolute values and changes from baseline will be summarized by study visit. For central 
laboratory parameters with categorical results, results will be included in a listing because these 
parameters are either non-critical for analysis (e.g., Urinalysis blood (by dipstick), or 
microscopic examination parameters, etc.) or they are collected only at screening visit 
(e.g., HBV surface antigen). 
Listings of laboratory parameters will be provided. Individual patient profile of triglyceride with 
daily cornstarch intake over time will be plotted. 
Table 2: 
Central Clinical Laboratory Parameters  
Clinical chemistry: 
Lipid panel, uric acid, sodium, potassium, chloride, carbon dioxide, blood 
urea nitrogen, creatinine, glucose, calcium, phosphate, magnesium, albumin, 
total protein, creatine kinase, bilirubin (total, direct, 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:  
(collected only at Screening) 
HBV surface antigen, HCV RNA, HIV,  
Coagulation panel: 
PT/INR, aPTT 
24-Hour urine: 
Total protein, microalbumin, and creatinine 
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. 


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8.6.7.1. 
Liver Function Tests and Treatment 
Liver function tests will be assessed as part of clinical chemistry. When a subject’s ALT level is 
greater than the upper limit of normal (ULN) and is considered by the investigator to be related 
to treatment with DTX401, prednisone (or prednisolone) treatment, per protocol, for possible 
vector-induced hepatitis will be started. Individual patient profile of ALT and 
prednisone/prednisolone dose over time will be plotted.  
8.6.8. 
Other Safety Parameters 
Neutralizing antibodies to AAV8, cell-mediated immune response to AAV8 and G6Pase, AAV8 
binding antibody IgG assay, anti-G6Pase antibody assay, vector shedding, and vector genome 
determination will be summarized by study visit. Listings for these safety parameters will be 
provided. Associations between these parameters and dose may be explored using these listings.  
In addition, vector shedding and vector genome determination below limit of detection will be 
summarized by study visits. Summary table for individual subject will be provided depicting the 
peak value of GC, time for peak, and timepoint when GC reaches below level of detection which 
is the 3rd consecutive post-baseline timepoint with negative result. Individual patient profile of 
vector shedding over time will be plotted and median vector shedding over time will be plotted 
for each cohort.  
For female subjects of childbearing potential, serum pregnancy test results at screening and urine 
pregnancy test results at scheduled visits will be listed.  
8.7. 
Impact of COVID-19 on Study Participation 
The study has been ongoing during the COVID-19 pandemic. To capture the impact of 
COVID-19 on subjects’ study participation, the study eCRFs and eCRF completion guidelines 
were modified during the study as per the regulatory guidance to capture COVID-19 related AEs 
and reasons for study discontinuation, missed/delayed visits, and missed assessments due to 
COVID-19 as “COVID-19 related reason”. Study data listings will include this information 
e.g., listing of AEs will include any AEs related to COVID-19 and listing of protocol deviations 
will include deviations related to missed visits and missed assessments due to COVID-19. 
These listings will be used to assess any potential impact of COVID-19 on subjects’ study 
participation. 


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9. 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
None 


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10. 
LIST OF PLANNED TABLES, FIGURES, AND LISTINGS 
List of planned tables, figures, and listings will be included in the shell document which will be 
maintained separately.  


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11. 
REFERENCES 
 
Broderick JE, DeWitt EM, Rothrock N, et al. (2013) Advances in Patient-Reported Outcomes: 
The NIH PROMIS Measures. EGEMS (Wash DC) 1: 1015. 
Neuenschwander B, Branson M and Gsponer T. (2008) Critical aspects of the Bayesian approach 
to phase I cancer trials. Stat Med 27: 2420-2439. 
NIH. (2015) PROMIS. Available at: http://www.nihpromis.org/default.aspx#6. 


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12. 
APPENDICES 
APPENDIX 1. SCHEDULE OF EVENTS 


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APPENDIX 2. CONTINUAL REASSESSMENT METHOD DETAILS 
The nominal doses used in the continual reassessment method, the x-hats, will be derived as: 
 
𝑥𝑥ො𝑖𝑖= log ቆ𝑑𝑑𝑖𝑖
𝑑𝑑𝑟𝑟𝑟𝑟𝑟𝑟
ቇ 
 
Where d1 = 2, d2 = 6, d3 = 10 and dref = 6. The di correspond to the amount of DTX401 
administered at each dose level, in units of 1012 genome copies/kg.  
A logistic model will be used to model the dose-toxicity curve. Let 
 
𝑌𝑌𝑖𝑖= ቄ0 𝑖𝑖𝑖𝑖 𝑡𝑡ℎ𝑒𝑒 𝑖𝑖𝑖𝑖ℎ 𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 𝑛𝑛𝑛𝑛𝑛𝑛 𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑎𝑎 𝐷𝐷𝐿𝐿𝑇𝑇
1 𝑜𝑜𝑜𝑜ℎ𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒
 
 
Then 
 
𝑝𝑝(𝑌𝑌= 1|𝑥𝑥ො𝑖𝑖, 𝛼𝛼, 𝛽𝛽) =
𝑒𝑒𝛼𝛼+𝛽𝛽𝑥𝑥ො𝑖𝑖
1 + 𝑒𝑒𝛼𝛼+𝛽𝛽𝑥𝑥ො𝑖𝑖 
 
The joint distribution of α and β is given by 
 
ቀ𝛼𝛼
log 𝛽𝛽ቁ~𝑁𝑁ቆቀ
𝜇𝜇𝛼𝛼
𝜇𝜇𝛽𝛽ቁ, ൬
𝜎𝜎𝛼𝛼× 𝜎𝜎𝛼𝛼
𝜎𝜎𝛼𝛼× 𝜎𝜎𝛽𝛽× 𝜌𝜌
𝜎𝜎𝛼𝛼× 𝜎𝜎𝛽𝛽× 𝜌𝜌
𝜎𝜎𝛽𝛽× 𝜎𝜎𝛽𝛽
൰ቇ 
 
Initial (prior) values μα= -2.3097, logμβ = -0.4323, σα = 1.6604, logσβ = 0.0044 and  
ρ = -0.2405 are used based on simulations. 
The estimate of the maximum tolerated dose will be the highest dose for which the full Bayes 
posterior estimate of p(DLT|di) is strictly less than or equal to the target toxicity rate. 
A dose is cleared if it is either 2 × 1012 genome copies/kg or if it is no more than 1 dose level 
higher than the highest dose at which at least 3 subjects have been treated. 


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APPENDIX 4. 
 
 
 
 


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APPENDIX 5. 
  


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APPENDIX 6. GLYCOGEN STORAGE DISEASE TYPE IA (GSDIA) 
MORNING DIARY 
 
 


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APPENDIX 7. GLYCOGEN STORAGE DISEASE TYPE IA (GSDIA) 
EVENING DIARY 


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APPENDIX 8. 
 
 
 


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APPENDIX 9.