Clinical trial NCT04088734
Conditions: MPS IIIA Sanfilippo Syndrome Sanfilippo A Mucopolysaccharidosis III
Keywords: MPS IIIA Sanfilippo Gene therapy
Sponsor: Ultragenyx Pharmaceutical Inc
Start date: 2019-09-18; Completion date: 2022-03-10
Enrollment: 5 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Open-label, clinical trial of scAAV9.U1a.hSGSH injected intravenously through a peripheral limb vein

Detailed description:
This is an open-label, single dose clinical trial. All participants will receive 3 X 10\^13 vg/kg of ABO-102 delivered one time through a venous catheter inserted into a peripheral limb vein. The target population includes MPS IIIA participants with a DQ lower than 60 in middle and advanced phases of the disease. Similar numbers of MPS IIIA participants with age equivalent above and below 18 months of age will be enrolled to ensure a representation of middle and advanced phases of the disease.

This study was previously posted by Abeona Therapeutics, Inc and was transferred to Ultragenyx in August 2022.

Arms: arm 1: Dose of 3x10\^13 vg/kg
Interventions: intervention 1: ABO-102
Intervention descriptions: intervention 1: Single dose of ABO-102 (scAAV9.U1a.hSGSH) administered by intravenous injection through a peripheral limb vein at a dose of 3 X 10\^13 vg/kg

Protocol documents:
Prot_000.pdf: 
Protocol 
 
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A Phase I/II Open Label, Single-dose, Gene Transfer Study of scAAV9.U1a.hSGSH (ABO-102) in 
Patients with Middle and Advanced Phases of MPS IIIA Disease  
Protocol Number: ABT-003 
Version: 5.0, 22 September 2022 
 
 
Product number: 
ABO-102/UX111 
Indication: 
Mucopolysaccharidosis (MPS) IIIA 
IND Number:  
16850 
EudraCT Number: 
2018-000504-42 
Sponsor:  
Ultragenyx Pharmaceutical Inc. 
60 Leveroni Court 
Novato, CA 94949  
USA 
Medical Monitor: 
 
 
 
Confidentiality Statement: This document and the information it contains is confidential and proprietary 
and is the property of Ultragenyx Pharmaceutical Inc. (Ultragenyx). Unauthorized disclosure, 
reproduction, transmission, or use of this document or information is strictly prohibited. By accepting this 
document, the recipient agrees that the information it contains will not be disclosed without prior written 
authorization from Ultragenyx, except to the extent required to satisfy Institutional Review 
Board/Independent Ethics Committee procedures, to obtain written informed consent from potential 
subjects, or as required by law. 
 
 
 
 
 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLES 
DOCUMENT HISTORY 
Document 
Date 
Original Clinical Trial Protocol v1.0 
09Mar2018 
Clinical Trial Protocol v2.0 
12Apr2018 
Clinical Trial Protocol v3.0 
25Feb2019 
Clinical Trial Protocol v4.0 
05Mar2020 
 
RATIONALE FOR THE PROTOCOL AMENDMENTS 
Protocol Version 
Description of Changes 
1.0 
• 
Original protocol sent to FDA in IND 16850 
2.0 
• 
Added clarification to Secondary Outcome and Statistical Analysis that the 
Vineland Adaptive Behavior Scale II will be used 
• 
Clarified sample types for lab work to include: 
o 
Screening, Pre-infusion, Days 7, 14, 30, 90, 180, Months 12, 18, 24 
visits: Serum/plasma total protein, AST, ALT, serum/plasma GGT, 
Serum/plasma total bilirubin 
o 
Day 1: Serum/plasma total bilirubin 
o 
Days 45, 60, 75, 120, 150, 2-weeks post steroid taper visits: 
Aspartate aminotransferase (AST), alanine transaminase (ALT), 
serum/plasma gamma-glutamyl transpeptidase (serum/plasma 
GGT) 
• 
Clarified for Screening, Day 30, 180, Month 12 visit regarding abdominal 
MRI to measure liver and spleen volumes 
• 
Clarified Section 6.3.1 Day of Gene Transfer (Day 0) instructions 
• 
Section 6.4.1.1, added clarification regarding tapering instructions 
• 
Added assessment at Day 30 for amylase levels 
• 
Section 7.4.1, deleted ‘recession’ 
• 
Section 7.4.3: Updated with new data available 
• 
Updated References 
3.0 
• 
Separated signature pages for Sponsor and Principal Investigator 
• 
Added tables to describe document history 
• 
Clarified clinical phase of study 
• 
Clarified study population and updated inclusion/exclusion criteria 
• 
Updated primary, secondary and exploratory outcomes 
• 
Reorganized the introduction sections according to a new template 
• 
Removed age criteria 
• 
Added inclusion criterion: Cognitive Development Quotient (DQ) lower than 
60 
• 
Added exclusion criteria: 
• 
Participants with concomitant illness or requirement for chronic drug 
treatment that in the opinion of the PI creates unnecessary risks for 
gene transfer, or precludes the child from participating in the protocol 
assessments and follow up 
• 
Participants with a positive response for the ELISPOT for T-cell 
responses to AAV9 


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RATIONALE FOR THE PROTOCOL AMENDMENTS 
x 
Any vaccination with viral attenuated vaccines less than 30 days prior to 
the scheduled date of treatment (and use of prednisolone) 
x 
Previous treatment by Haematopoietic Stem Cell transplantation 
x Previous participation in a gene/cell therapy or ERT clinical trial 
x Deleted exclusion criteria: 
x Prior treatment with SGSH enzyme replacement therapy (ERT) 
x Updated Primary and Secondary Outcome Measures and added Exploratory 
Measures 
x Remove the Dose Limiting Toxicity section 
x Included a section with Dosing New Participants, to clarify that patients will 
be treated with a 14-day interval 
x Modify the Stopping Rules, to indicate that study will be halted if 2 or more 
SAEs (not Grade III AEs) are reported. 
x Deleted neurocognitive assessment using Leiter scale 
x Inclusion of a neurocognitive validity form 
x Inclusion of the Vineland, Bayley, Mullen and Kaufman (depending on 
developmental age) scale neurocognitive assessment for all participants 
participating. 
x Added PedsQL, PSI-4 and CSHQ clinical questionnaires. 
x Added 
 Parent Global Impression Score, Clinical 
Global Impression Improvement Scale and Parent Symptom Score 
Questionnaire 
x 
. 
x Changed the patient weight for dosing to the one obtained in Screening visit 
2. 
x 
 
x Provided more detailed information about the vital sign collection after 
treatment 
x Changed some study visit windows to allow more flexibility. 
x 
 
 
x Added CSF biobanking 
x 
 
x Included a participant questionnaire to collect information on the quality of 
the service provided by vendors interacting with participants. 
x Reorganized the safety sections according to a new template 
x Limited the SAEs to those who are following the regulatory definition by 
ICH and not all grade 3, 4 or 5. 
x Replaced terminology of ‘subject’ with ‘participant’ 
x Added 60-minute EEG at Months, 6, 2, 18, and 24 
4.0 
x 
Added inclusion criterion: ‘Age range of 2 years up to 18 years (excluded)’. 
x 
Updated the version of CTCAE to be referenced for AEs, to v4.03. 
x 
 
 
 
x 
. 
x 
Clarification of the scale to be used for the two arms in the study above and 
below 18 months of chronological age. 
x 
Removed medical history assessment at Visits 2 and 3. 
x 
Added urine pregnancy test (if applicable) at Day 0, Months 12 and 24. 
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RATIONALE FOR THE PROTOCOL AMENDMENTS 
 
x 
Added troponin in the panel of labs, to be assessed at Visit 1, Days -1 and 1, 
and at Visits 4 to 12. 
x 
ELISpot assessment: removed from Day 7 and added at Days 45, 75, 120, and 
at 2-weeks post-steroid, if needed based on previous results. 
x 
Corrected several inconsistencies between the schedule of evaluations table 
and Section 5, study procedures. 
x 
Revised the EEG assessment from 60-minute EEG to 45-minute EEG. 
x 
 
 
x 
Added the acceptable method of contraception for the study and instructions on 
reporting of pregnancy during the study. 
x 
Specified the prohibited medications for the study and instructions on capturing 
concomitant medication/therapy. 
x 
Specified that the blood sample schedule and collection allows for a maximum 
blood volume of 35 ml per study visit, with flexibility to the sites to reduce 
volume as per site policy if needed and that additional ad-hoc analysis on blood 
samples collected at any particular visit may be performed at the discretion of 
the PI. 
x 
Specified the order of certain scales to be administered and the provision for use 
of an external qualified and trained rater, if the family signed the consent annex. 
x 
Added that prophylactic enteral prednisone or prednisolone will not be provided 
by the Sponsor; the standard of care at the site/country should be used for 
prophylaxis. 
x 
Revised the wording on long-term monitoring to include the long-term follow-
up study designed to enroll participants who complete the current study. 
x 
Provided rationale on the choice of primary and secondary outcomes. 
x 
Clarified the definitions and reporting of AEs, SAEs and SAR. 
x 
Clarified the stopping/discontinuation rules for the study (Section 7.2). 
x 
Added that the date of birth and age of the participant at screening will be 
collected to ensure that the appropriate age-based assessments are performed 
throughout the study. Demographic data including age, gender, race and date of 
birth will be collect at Visit 1. 
x 
Clarified the DSMB roles and requirements, including an update to the 
minimum number of members required, from 3 to 4 members. 
x 
Several editorial changes for clarity and correction of errors throughout the 
protocol. 
5.0 
x 
Study sponsor changed to Ultragenyx Pharmaceutical Inc.  
x 
Indicated that ABO-102 is also known as UX111 
x 
Medical Monitor changed to 
 
x 
Long-term monitoring language updated to indicate a minimum follow-up period 
of 3 years in Study LTFU-ABO-102 
 
 
 
 
 
 
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1. 
PROTOCOL SYNOPSIS 
Title 
A Phase I/II Open Label, Single-dose, Gene Transfer Study of 
scAAV9.U1a.hSGSH (ABO-102) in Patients with Middle and Advanced Phases 
of MPS IIIA Disease 
Protocol Number 
ABT-003 
Number of 
participants 
Approximately n = 12 
Target population includes MPSIIIA participants with a DQ lower than 60 in 
middle and advanced phases of the MPSIIIA disease that would not be eligible 
for the clinical trial ABT-001. 
To ensure that both the middle phase and advanced phase of the disease are 
adequately represented in the study, a similar number of participants with a 
cognitive age-equivalent of above 18 months (middle) and below 18 months 
(advanced), as assessed by the Bayley Scales of Infant and Toddler 
Development, will be enrolled. 
Clinical Phase 
Phase I/II trial 
Number of 
Centers 
Up to five (5) centers worldwide 
Study Objectives 
To evaluate the safety and efficacy of ABO-102 (also known as UX111) in 
patients with middle and advanced phases of MPS IIIA disease. 
Study Design 
Open-label, single-dose clinical trial of ABO-102 (scAAV9.U1a.hSGSH) 
injected intravenously through a peripheral limb vein 
Study Population 
Inclusion Criteria 
1. Diagnosis of MPS IIIA confirmed by the following methods: 
a. No detectable or significantly reduced SGSH enzyme activity 
by leukocyte assay, and 
b. Genomic DNA analysis demonstrating homozygous or 
compound heterozygous mutations in the SGSH gene 
2. Cognitive Development Quotient (DQ) lower than 60 (calculated by 
Bayley Scales of Infant and Toddler Development - Third Edition) 
3. Must be ambulatory, though may receive assistance with 
ambulation 
4. Age range of 2 years up to 18 years (excluded). 
Exclusion Criteria 
1. Inability to participate in the clinical evaluation as determined by Principal 
Investigator 
2. Identification of two nonsense or null variants on genetic testing of the 
SGSH gene 
3. At least one S298P mutation in the SGSH gene 
4. Has evidence of an attenuated phenotype of MPS IIIA 
5. Presence of a concomitant medical condition that precludes lumbar 
puncture or use of anesthetics 
6. Active viral infection based on clinical observations 
7. Concomitant illness or requirement for chronic drug treatment that in the 
opinion of the PI creates unnecessary risks for gene transfer, 


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or precludes the child from participating in the protocol assessments and 
follow up 
8. Participants with total anti-AAV9 antibody titers ≥ 1:100 as determined by 
ELISA binding immunoassay 
9. Participants with a positive response for the ELISPOT for T-cell responses 
to AAV9 
10. Serology consistent with exposure to HIV, or serology consistent with 
active hepatitis B or C infection 
11. Bleeding disorder or any other medical condition or circumstance in which 
a lumbar puncture (for collection of CSF) is contraindicated according to 
local institutional policy 
12. Visual or hearing impairment sufficient to preclude cooperation with 
neurodevelopmental testing 
13. Any item (braces, etc.) which would exclude the participant from being 
able to undergo MRI according to local institutional policy 
14. Any other situation that precludes the participant from undergoing 
procedures required in this study 
15. Participants with cardiomyopathy or significant congenital heart 
abnormalities 
16. The presence of significant non-MPS IlIA related CNS impairment or 
behavioral disturbances that would confound the scientific rigor or 
interpretation of results of the study 
17. Abnormal laboratory values Grade 2 or higher as defined in CTCAE v4.03 
for GGT, total bilirubin (except in subjects diagnosed with Gilbert’s 
syndrome), creatinine, hemoglobin, WBC count, platelet count, PT and 
aPTT 
18. Female participant who is pregnant or demonstrates a positive urine or β-
hCG result at screening assessment (if applicable) 
19. Any vaccination with viral attenuated vaccines less than 30 days prior to 
the scheduled date of treatment (and use of prednisolone) 
20. Previous treatment by Haematopoietic Stem Cell transplantation 
21. Previous participation in a gene/cell therapy or ERT clinical trial 
22. Participants who are anticipated to undergo a procedure involving 
anesthesia within 6 months post- drug administration 
23. Dysphagia present at Grade 3 or higher, as defined in CTCAE v4.03 
Study Treatment 
Self-complementary adeno-associated virus serotype 9 carrying the human 
SGSH gene under the control of a U1a promoter (scAAV9.U1a.hSGSH) will be 
delivered one time through a venous catheter inserted into a peripheral limb 
vein. A tapering course of prophylactic enteral prednisone or prednisolone will 
be administered. 
Primary Outcome 
• 
Product safety as defined by the incidence, type and severity of treatment-
related adverse events and serious adverse events [Time frame: Month 1, 2, 
3, 6, 12, 18, 24]. 
• 
Change from baseline in CSF heparan sulfate levels after treatment [Time 
frame: Month 1, 6, 12, 24] 
• 
Change from baseline in liver and/or spleen volumes after treatment, as 
measured by magnetic resonance imaging (MRI) [Time frame: Month 1, 6, 
12, 24] 
Secondary 
Outcomes 
• 
Change from baseline in plasma or urine glycosaminoglycans or heparan 
sulfate after treatment [Time frame: Month 1, 6, 12, 18, 24] 


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• 
Change from baseline in CSF or plasma or leukocyte SGSH enzyme 
activity levels after treatment [Time frame: Month 1, 6, 12, 24] 
• 
Change from baseline in brain volumes after treatment, as measured by 
MRI [Time frame: Month 12, 24] 
• 
Change from baseline in the Age Equivalent and Developmental Quotient 
(DQ) after treatment compared to Natural History Study data calculated by 
the Mullen Scales of Early Learning or the Kaufman Assessment Battery 
for Children; Second Edition, based on chronological and developmental 
age [Time frame: Month 6, 12, 18, 24] 
• 
Change from baseline in the Cognitive Age Equivalent and Developmental 
Quotient after treatment compared to Natural History Study, calculated 
using the Bayley Scales of Infant and Toddler Development – Third edition 
or the Kaufman Assessment Battery for Children. Second Edition, based on 
developmental age [Time Frame: Month 6, 12, 18, 24] 
• 
Change from baseline in the Adaptive Age Equivalent score after treatment 
compared to Natural History Study data, as assessed by parent report using 
the Vineland Adaptive Behavior Scale II Survey form [Time frame: Month 
6, 12, 18, 24] 
• 
Change from baseline in sleep pattern as measured by the modified 
Children’s Sleep Habits Questionnaire (CSHQ) [Time Frame: Month 6, 12, 
18, 24] 
• 
Change from baseline in Pediatric Quality of Life Inventory (PedsQL™) 
Core Generic Scales total score [Time Frame: Month 6, 12, 18, 24] 
• 
Change from baseline in parent quality of life, using the Parenting Stress 
Index, 4th Edition (PSI-4) [Time Frame: Month 6, 12, 18, 24] 
• 
Change from baseline in gastrointestinal symptoms using the PedsQL™ 
Gastrointestinal Symptoms Scales [Time Frame: Month 6, 12 18, 24] 
• 
Parent Global Impression Score [Time Frame: Month 6, 12, 18, 24] 
• 
Clinical Global Impression Improvement Scale Score [Time Frame: Month 
6, 12, 18, 24] 
• 
Change from baseline in Parent Symptoms Score Questionnaire [Time 
Frame: Month 6, 12, 18, 24] 
• 
Change from baseline in Body Mass Index after treatment [Time Frame: 
Month 6, 12, 18, 24] 
• 
Incidence and change from baseline in abnormalities in standard awake 45-
minutes- EEG monitoring [Time frame: Month 6, 12, 18, 24] 
• 
Determination of vector shedding analysis in plasma, saliva, urine and feces 
will provide preliminary data for the Environmental Risk Assessment 
(ERA) 


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Exploratory 
Outcomes 
x 
 
 
 
x 
 
 
x 
 
 
 
 
 
Study Duration 
Participants will be tested at baseline and return for follow up visits on Days 7, 
14, 30, 60, 90, 180, and at 12, 18, and 24 Months for active monitoring. 
Sample Size 
This is an open label study in up to 12 participants with middle and advanced 
phase of MPS IIIA. Participants will receive a single intravascular infusion at a 
dose of 3 x 1013 vg/kg. 
Statistical 
Analysis 
This is a Phase I/II trial with safety and efficacy (change in CSF heparan sulfate 
levels and liver volume after treatment) as the primary outcomes. Secondary 
outcomes include additional efficacy measures several of which are 
exploratory. These include changes in heparan sulfate and/or total GAGs in 
plasma/urine, changes in SGSH enzymatic activity in CSF/leukocytes/plasma, 
changes in liver and brain volumes, changes in cognitive and behavioural 
measures, and changes in quality of life, sleep or seizures. Data of post-gene 
transfer monitoring will be compared with baseline data and a set of natural 
history data using the appropriate statistical analysis. 
 
A final Statistical Analysis Plan will be prepared before the database lock, 
including a stratification of participants based on Age Equivalent scores above 
or below 18 months. This SAP will include an interim analysis to be conducted 
when all participants have reached Month 12 
follow-up. 
Long-term 
follow-up 
After the 24-month visit, participants will be requested to participate in a long 
term follow up study (LTFU-ABO-102, EudraCT number 2019- 002979-34) 
consisting of monitoring for a minimum of 3 years for a total period of five 
years posttreatment. 
 
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TABLE OF CONTENTS 
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLES ..........................................2 
1. 
PROTOCOL SYNOPSIS .............................................................................................5 
TABLE OF CONTENTS .................................................................................................................9 
SCHEDULE OF EVALUATIONS ...............................................................................................12 
2. 
LIST OF ABBREVIATIONS .....................................................................................17 
3. 
INTRODUCTION ......................................................................................................20 
3.1. 
Background .................................................................................................................20 
3.2. 
Nonclinical Studies .....................................................................................................20 
3.3. 
Clinical Program .........................................................................................................21 
4. 
STUDY DESIGN .......................................................................................................23 
4.1. 
Study Population .........................................................................................................23 
4.2. 
Inclusion/Exclusion Criteria .......................................................................................23 
4.2.1. 
Inclusion Criteria ........................................................................................................23 
4.2.2. 
Exclusion Criteria .......................................................................................................23 
4.3. 
Dosing Plan .................................................................................................................25 
4.4. 
Prior and Concomitant Therapy ..................................................................................25 
4.4.1. 
Prohibited Medications ...............................................................................................25 
5. 
STUDY PROCEDURES ............................................................................................26 
5.1. 
Schedule of Evaluations .............................................................................................26 
5.2. 
Clinical Trial Documentation .....................................................................................26 
5.3. 
Screening and Enrollment ...........................................................................................26 
5.3.1. 
Screening Visits 1 and 2 (Day -45 through Day -1) ...................................................26 
5.3.2. 
Pre-Infusion Visit (Day -1) .........................................................................................30 
5.4. 
Gene Transfer .............................................................................................................31 
5.4.1 
Day of Gene Transfer (Day 0) ....................................................................................31 
5.5. 
Post Gene Transfer Monitoring Plan ..........................................................................33 
5.5.1. 
Up to 48-Hours Inpatient Monitoring (Days 1 and 2) ................................................33 
5.5.1.1. 
Day 1 ...........................................................................................................................33 
5.5.1.2. 
Day 2 ...........................................................................................................................35 
5.5.2. 
Post-Gene Transfer Monitoring (Days 7, 14, 30) .......................................................35 
5.5.2.1. 
Day 7 (+/- 2 days) .......................................................................................................35 


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5.5.2.2. 
Day 14 (+/- 2 days) .....................................................................................................36 
5.5.2.3. 
Day 30 (+/- 3 days) .....................................................................................................37 
5.5.2.4. 
5.5.2.4 Day 45 (+/- 3 days) .........................................................................................38 
5.5.2.5. 
Day 60 (+/- 7 days) .....................................................................................................38 
5.5.2.6. 
Day 75 (+/- 3 days) .....................................................................................................39 
5.5.2.7. 
Day 90 (+/- 7 days) .....................................................................................................39 
5.5.2.8. 
Two Weeks Post Steroids Taper (+/- 7 days) .............................................................40 
5.5.2.9. 
Day 120 (+/- 7 days) and Day 150 (+/- 7 days) ..........................................................40 
5.5.2.10. 
Day 180 (+/- 21 days) .................................................................................................40 
5.5.2.11. 
Month 12 (+/- 30 days) ...............................................................................................43 
5.5.2.12. 
Month 18 (+/- 30 days) ...............................................................................................45 
5.5.2.13. 
Month 24 (+/- 30 days) ...............................................................................................47 
5.6. 
Long-Term Monitoring ...............................................................................................49 
5.7. 
Outcome Measures .....................................................................................................49 
6. 
SAFETY .....................................................................................................................52 
6.1. 
Definitions ..................................................................................................................52 
6.1.1. 
Adverse Event (AE) and Adverse Reaction (AR) ......................................................52 
6.1.2. 
Serious Adverse Event (SAE) and Serious Adverse Reaction (SAR) ........................53 
6.1.3. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) .....................................54 
6.2. 
Assessment of Severity (Intensity) .............................................................................54 
6.2.1. 
Grade 1 ........................................................................................................................54 
6.2.2. 
Grade 2 ........................................................................................................................54 
6.2.3. 
Grade 3 ........................................................................................................................54 
6.2.4. 
Grade 4 ........................................................................................................................54 
6.2.5. 
Grade 5 ........................................................................................................................54 
6.3. 
Assessment of Causality .............................................................................................54 
6.4. 
Recording ....................................................................................................................55 
6.5. 
Reporting of SAEs and SARs .....................................................................................56 
6.6. 
Reporting of pregnancy ..............................................................................................58 
7. 
DOSING NEW PARTICIPANTS AND STOPPING/DISCONTINUATION 
RULES ........................................................................................................................59 
7.1. 
Dose New Participants ................................................................................................59 
7.2. 
Stopping/Discontinuation Rules .................................................................................59 


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8. 
ETHICAL AND REGULATORY ASPECTS ...........................................................60 
8.1. 
Ethical Review Board .................................................................................................60 
8.2. 
Informed Consent .......................................................................................................60 
8.3. 
Confidentiality Information ........................................................................................61 
8.4. 
Compensation for Participants ....................................................................................61 
8.5. 
Insurance Policy ..........................................................................................................61 
8.6. 
Notifications to Health Authorities .............................................................................62 
9. 
STUDY REPORTS ....................................................................................................63 
9.1. 
Final Study Report ......................................................................................................63 
9.2. 
Annual Study Reports .................................................................................................63 
9.3. 
Data Safety Monitoring Plan ......................................................................................63 
9.3.1. 
The Data Safety Monitoring Board ............................................................................63 
9.3.2. 
DSMB Reporting and Meetings .................................................................................64 
9.3.3. 
Membership ................................................................................................................64 
9.4. 
Clinical Monitoring of the Study ................................................................................64 
9.4.1. 
Data Management and Study Forms...........................................................................64 
10. 
SAMPLE MANAGEMENT .......................................................................................66 
11. 
GMO RISK MANAGEMENT ...................................................................................67 
12. 
REFERENCES ...........................................................................................................70 
STATEMENT OF COMPLIANCE ...............................................................................................72 
 
 


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SCHEDULE OF EVALUATIONS 
STUDY TIMELINE OF EVENTS 
 
Study Interval 
 
Screening 
 
Pre 
Infusion 
Visit 
Hospital 
Admission/ 
Vector 
Injection 
(Inpatient) 
 
Inpatient 
 
Follow-Up (Outpatient) 
Visit # 
Visit 1 Visit 2 
Visit 3 
Visit 4 Visit 5 Visit 6 Labs Visit 7 Lab
s 
Visit 8 
Labs Labs 
Labs 
Visit 9 Visit 10 Visit 11 Visit 12 
 
Study Procedures 
 
Day -45 
through -1 
 
Day -1 
 
Day 0 
Day 1 
(24 
hrs) 
Day 
2 
(48 
hrs) 
Day 7 
+/- 2 
days 
Day 14 
+/- 2 
days 
Day 
30 
+/- 3 
days 
Day 
45 
+/- 3 
days 
Day 
60 
+/- 7 
days 
Day 
75 
+/- 3 
days 
Day 90 
+/- 7 
days 
2 
weeks 
post 
steroi
ds 
+/- 7 
days 
Day 
120 
+/- 7 
days 
Day 
150 
+/- 7 
days 
Day 
180 
+/- 21 
days 
Month 
12 
+/- 30 
days 
Month 
18 
+/- 30 
days 
Month 
24 
+/- 30 
days 
Informed consent 
X1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
X 
Head circumference 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Physical exam 
X 
 
X 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
X 
Vital signs 
X 
 
X 
X2 
X 
X 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
X 
X 
Weight 
X 
X16 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 of injection site  
 
 
X9 
X9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Echocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
ECG 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
 
X 
45-minute EEG 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Vineland scales 
assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Bayley scales assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Mullen scales assessment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Kaufman Battery 
assessment 
 
X11  
 
 
 
 
 
 
 
 
 
 
 
 
 
X11 
X11 
X11 
X11 
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STUDY TIMELINE OF EVENTS 
 
Study Interval 
 
Screening 
 
Pre 
Infusion 
Visit 
Hospital 
Admission/ 
Vector 
Injection 
(Inpatient) 
 
Inpatient 
 
Follow-Up (Outpatient) 
Visit # 
Visit 1 Visit 2 
Visit 3 
Visit 4 Visit 5 Visit 6 Labs Visit 7 Lab
s 
Visit 8 
Labs Labs 
Labs 
Visit 9 Visit 10 Visit 11 Visit 12 
 
Study Procedures 
 
Day -45 
through -1 
 
Day -1 
 
Day 0 
Day 1 
(24 
hrs) 
Day 
2 
(48 
hrs) 
Day 7 
+/- 2 
days 
Day 14 
+/- 2 
days 
Day 
30 
+/- 3 
days 
Day 
45 
+/- 3 
days 
Day 
60 
+/- 7 
days 
Day 
75 
+/- 3 
days 
Day 90 
+/- 7 
days 
2 
weeks 
post 
steroi
ds 
+/- 7 
days 
Day 
120 
+/- 7 
days 
Day 
150 
+/- 7 
days 
Day 
180 
+/- 21 
days 
Month 
12 
+/- 30 
days 
Month 
18 
+/- 30 
days 
Month 
24 
+/- 30 
days 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurocognitive Validity 
Form 
X12 
X 13  
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Parent Global Impression 
Score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Clinical Global Impression 
Improvement Score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Parent Symptom Score 
Questionnaire 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 25m walk 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
CBC/Diff/Platelet 
X 
 
X 
 
X  
X 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
Electrolytes 
X 
 
X 
 
X  
X 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
Serum/plasma total 
protein, serum albumin 
X 
 
X 
 
X  
X 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
PT/INR/PTT 
X 
 
X 
 
X  
X 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
Creatinine/BUN 
X 
 
X 
 
X  
X 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
AST/ALT 
X 
 
X 
 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum/plasma GGT 
X 
 
X 
 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Alkaline phosphatase 
X 
 
X 
 
X  
X 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
Alpha-fetoprotein 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
X 
Amylase 
X 
 
X 
 
X  
X 
X 
X 
X10 
X10 
X10 
X10 
X10 
X10 
X10 
X10 
X10 
X10 
X10 
Serum/plasma total 
bilirubin 
X 
 
X 
 
X  
X 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
Random glucose 
X 
 
X 
 
X  
X 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
Troponin 
X 
 
X 
 
X  
X 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
X 
Plasma and leukocyte 
SGSH enzyme activity 
levels 
 
X 
 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
X 
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STUDY TIMELINE OF EVENTS 
 
Study Interval 
 
Screening 
 
Pre 
Infusion 
Visit 
Hospital 
Admission/ 
Vector 
Injection 
(Inpatient) 
 
Inpatient 
 
Follow-Up (Outpatient) 
Visit # 
Visit 1 Visit 2 
Visit 3 
Visit 4 Visit 5 Visit 6 Labs Visit 7 Lab
s 
Visit 8 
Labs Labs 
Labs 
Visit 9 Visit 10 Visit 11 Visit 12 
 
Study Procedures 
 
Day -45 
through -1 
 
Day -1 
 
Day 0 
Day 1 
(24 
hrs) 
Day 
2 
(48 
hrs) 
Day 7 
+/- 2 
days 
Day 14 
+/- 2 
days 
Day 
30 
+/- 3 
days 
Day 
45 
+/- 3 
days 
Day 
60 
+/- 7 
days 
Day 
75 
+/- 3 
days 
Day 90 
+/- 7 
days 
2 
weeks 
post 
steroi
ds 
+/- 7 
days 
Day 
120 
+/- 7 
days 
Day 
150 
+/- 7 
days 
Day 
180 
+/- 21 
days 
Month 
12 
+/- 30 
days 
Month 
18 
+/- 30 
days 
Month 
24 
+/- 30 
days 
Urine GAG/heparan sulfate 
levels 
X 
 
 
 
X  
X 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
X 
Raw plasma heparan 
sulfate 
X 
X 
 
 
X  
X 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
X 
Urinalysis 
X 
 
 
 
X  
X 
X 
X 
 
 
 
X 
 
 
 
X 
X 
X 
X 
Vector Shedding Samples: 
Plasma, Urine, Feces, 
Saliva 
 
X5 
 
X5 
 
 
X6 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X7 
 
 
X7 
 
 
 
 
X7 
 
X7 
 
X7 
 
X7 
Urine or Serum pregnancy 
test (if applicable) 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Gene sequencing to confirm 
MPS IIIA diagnosis 
X8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ELISpot 
X 
 
 
 
 
 
 
X 
X 
X17 
X 
X17 
X 
X17 
X17  
X 
X 
X 
X 
ELISA 
X 
 
 
 
 
 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
X 
Plasma biobanking 
 
X 
 
X 
 
 
X 
X 
X 
 
X 
 
X 
 
 
 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
X 
X 
X 
 
X 
 
 
 
 
 
X 
X 
X 
X 
Serum nAbs 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
X 
Serology: hepatitis B, C, 
and HIV 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sedation/Anesthesia 
 
X 
 
X3 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
Lumbar puncture 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
CSF enzyme activity & 
heparan sulfate levels 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
CSF protein, glucose, cell 
count and diff 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
CSF Biobanking 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
Brain MRI 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
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STUDY TIMELINE OF EVENTS 
 
Study Interval 
 
Screening 
 
Pre 
Infusion 
Visit 
Hospital 
Admission/ 
Vector 
Injection 
(Inpatient) 
 
Inpatient 
 
Follow-Up (Outpatient) 
Visit # 
Visit 1 Visit 2 
Visit 3 
Visit 4 Visit 5 Visit 6 Labs Visit 7 Lab
s 
Visit 8 
Labs Labs 
Labs 
Visit 9 Visit 10 Visit 11 Visit 12 
 
Study Procedures 
 
Day -45 
through -1 
 
Day -1 
 
Day 0 
Day 1 
(24 
hrs) 
Day 
2 
(48 
hrs) 
Day 7 
+/- 2 
days 
Day 14 
+/- 2 
days 
Day 
30 
+/- 3 
days 
Day 
45 
+/- 3 
days 
Day 
60 
+/- 7 
days 
Day 
75 
+/- 3 
days 
Day 90 
+/- 7 
days 
2 
weeks 
post 
steroi
ds 
+/- 7 
days 
Day 
120 
+/- 7 
days 
Day 
150 
+/- 7 
days 
Day 
180 
+/- 21 
days 
Month 
12 
+/- 30 
days 
Month 
18 
+/- 30 
days 
Month 
24 
+/- 30 
days 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Abdominal MRI 
 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
 
 
X14  
 
 
 
 
 
 
 
 
 
 
 
 
 
X18 
X18  
X18 
PedsQL Core Generic 
Scales 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
PedsQL Gastrointestinal 
Symptoms Scales 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
CSHQ 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X19 
X19 
X19 
X19 
PSI4 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Admit to Hospital 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study agent administration 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prophylactic 
Prednisolone/Prednisolone 
 
 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
X4 
X4  
 
 
 
 
 
 
Participant Survey 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X15 
1. If there are changes to the study, parents will be re-consented at their next visit. 
2. Day 0 Vital Signs (Heart rate, respiratory rate, pulse oximetry, temperature, and blood pressure) will be measured before and immediately after the infusion, and at least every 
five minutes during the infusion, and repeated at 15 minutes post-infusion. VS will be obtained hourly for 4 hours following the injection and then every 4 hours until discharge. 
Only the following time point will be recorded in EDC: Day 0 pre and post infusion; 1-hour post infusion, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours and 48 hours post infusion. 
3. Need for sedation during gene transfer will be decided upon by the PI/designee, in discussion with the anesthesiologist and parent(s) on that day. Appropriate anesthesia 
(single event per visit) will be provided at Screening, Days 30 and 180, Month 12, and Month 24 with MRI imaging preceding lumbar puncture for safety. 
4. Prophylactic prednisolone/prednisone taper begins on Day -1 and is tapered according to AST, ALT, and ELISpot results. Anticipate that most participants will be on 
prednisolone for 90 to 120 days. 
5. Urine, feces and saliva vector shedding samples collected at Screening Visit 1. Plasma vector shedding sample collected at Screening Visit 2. If urine, feces and saliva 
are not obtained at Screening Visit 1, they will be obtained at Screening Visit 2. 
6. Plasma, urine, feces and saliva vector shedding samples collected at 4- and 8-hours post gene transfer. 
7. Vector shedding analysis post dosing will be performed on DNA isolated from different biological fluids (plasma, urine, saliva and feces) until two consecutive 
samples are negative for the presence of viral DNA for each specimen type. 
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8. To be performed if not previously documented. 
9. 
of the injection site to be taken prior to and after (approximately 24 h after infusion) vector administration. 
10. Further analysis only to be performed if previous results remain abnormal. 
11. Kaufman Battery will be used together with or replacing to the Mullen and/or Bayley scales based on developmental age results obtained with those scales. 
12. Neurocognitive Validity Form part 1 for Bayley Scales Infant and Toddler Development/Kaufman Battery and Vineland Adaptive Behavior Scale II- Survey form. 
13. Neurocognitive Validity Form part 2 for Mullen Scales of Early Learning, 
PSI-4, PedsQL, and CSHQ if applicable. 
14.
 
 
15. This survey should also be assessed in the last visit of screening failures and withdrawals. 
16. The weight obtained at Screening Visit 2 will be used to calculate the viral vector dose. 
17. To be performed if applicable based on results from previous visit. 
18.
 
19. This assessment should be performed only if a sleep problem has been identified during the initial evaluation at the Screening Visit 1 or the medical history suggests there is a 
problem affecting child’s sleep. 
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2. 
LIST OF ABBREVIATIONS 
‘suspected’ SARs 
‘suspected’ serious adverse reactions 
°C 
degrees Celsius 
AAV9 
associated virus serotype 9 
 
 
ACDP 
Advisory Committee on Dangerous Pathogens 
AE 
adverse event 
ALT 
alanine transaminase 
AR 
ADVERSE REACTION 
AST 
Aspartate aminotransferase 
BBB 
blood-brain barrier 
BUN 
Blood urea nitrogen 
CBC 
Complete blood cell count 
CFR 
Code of Federal Regulations 
CNS 
central nervous system 
CRF 
Case Report Forms 
CRO 
Contract Research Organization 
CSF 
Cerebral spinal fluid 
CSHQ 
Children’s Sleep Habits Questionnaire 
CTCAE 
Common Terminology Criteria for Adverse Events v4.03 
DNA 
deoxyribonucleic acid 
DQ 
Development Quotient 
DSMB 
Data Safety Monitoring Board 
DSUR 
Development safety update report 
EC 
European Commission 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
EDC 
electronic data capture 
EEG 
Electroencephalogram 
ELISA 
enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 
ERA 
Environmental Risk Assessment 
ERT 
enzyme replacement therapy 
EU 
European Union 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
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F 
bioavailability 
FCI 
Fluid-Crystalized Index 
g 
gram 
GAG 
glycosaminoglycan 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
GLP 
Good Laboratory Practice 
GMO 
genetically modified organism 
hSGSH 
human N-sulfoglucosamine sulfohydrolase 
IB 
Investigator’s brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IND 
Investigational New Drug (application) 
INR 
international normalized ratio 
IRB 
Institutional Review Board 
IV 
intravenous 
kg 
kilogram 
L 
liter/litre(s) 
LP 
Lumbar puncture 
m 
meter 
min 
minute(s) 
mL 
milliliter(s) 
MPS 
Mucopolysaccharidosis 
MRI 
magnetic resonance imaging 
NCH 
Nationwide Children’s Hospital 
NOAEL 
no-observable-adverse-effect-level 
 
 
PedsQL 
Pediatric Quality of Life Inventory™ 
PICFs 
Patient Informed Consent Forms 
PSI-4 
Parenting Stress Index, 4th Edition 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
RH 
relative humidity 
RSI 
Reference Safety Information 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
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SAR 
SERIOUS ADVERSE REACTION 
 
 
serum/plasma GGT 
serum/plasma gamma-glutamyl transpeptidase 
SGSH 
sulfoglucosamine sulfohydrolase 
SMP 
Safety Management Plan 
SUSAR 
SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION 
Ultragenyx 
Ultragenyx Pharmaceutical Inc. 
USA 
United States of America 
UV 
ultraviolet 
WBC 
White blood cell 
WHO 
World Health Organisation 
WMA 
World Medical Association 
 
 
 
 
 
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3. 
INTRODUCTION 
3.1. 
Background 
MPS IIIA is a devastating lysosomal storage disease, caused by a single gene  defect (Neufeld 
and Cantz, 1971; Neufeld and Muezner, 2014; Weber et al., 1999). Somatic manifestations of 
MPS IIIA occur in all patients and can vary compared to other MPS disorders. Infants with MPS 
IIIA may demonstrate normal development at birth. However, the disease is relentlessly 
progressive, with deterioration of social and adaptive abilities, neurocognitive decline, and 
premature death. It can be divided into three phases (Wijburg et al., 2013). In the first phase, after 
1-2 years of normal development, developmental delay (speech/language delays) and somatic 
changes (mild coarsening of facial features, frequent otitis media and hearing loss, 
hepatomegaly, mild dysostosis multiplex) become apparent between ages 1 and 4 years. In the 
second phase, which typically presents around ages 3-4 years, neurological manifestations 
become apparent, including severe behavioral problems, regression of skills and progressive 
mental deterioration. In the final phase, behavioral problems slowly disappear but cognitive 
decline progresses to a vegetative state with spasticity, seizures and swallowing problems. 
In MPS IIIA, approximately 70% of children die from complications of the disease prior to 
reaching their 18th birthday (USA MPS Society and Greenwood labs, unpublished data available 
on request). 
Quite importantly, there is no treatment currently available for the disease (de Ruijter et al., 
2011). AAV-mediated gene transfer to restore SGSH activity has emerged as a therapeutic 
strategy with great potential for MPS IIIA patients. 
3.2. 
Nonclinical Studies 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
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Our ABO-102 gene transfer findings are well positioned to move forward to test in a clinical 
gene   transfer   trial   for   patients   with   MPSIIIA. To date, a single IV administration of 
scAAV9.U1a.hSGSH has been well tolerated in an ongoing clinical study, ABT-001 
(NCT02716246). 
3.3. 
Clinical Program 
An observational study in MPS IIIA and MPS IIIB patients was conducted at Nationwide 
Children’s Hospital (NCH) (Columbus, OH) prior to the initiation of the ABO-102 program. 
This study enrolled 15 participants with MPS IIIA and 10 participants with MPS IIIB (Truxal et 
al., 2016). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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This proposed Phase I/II study is designed to assess the safety and clinical response to the 
restoration of N-sulfoglucosamine sulfohydrolase (SGSH) enzyme activity in the CNS and 
periphery following intravenous injection of a self-complementary adeno-associated vector 
(scAAV9) carrying the human SGSH transgene under the control of the U1a promoter. Based on 
pre-clinical studies, scAAV9 and the U1a promoter will permit the efficient long-term transgene 
expression and secretion of functional SGSH, with great potential for achieving clinical benefits 
in treating neurological, as well as somatic disorders, in MPS IIIA patients. The selected dose is 
based on the preclinical proof of concept data in the animal model as well as clinical safety data 
from the ongoing Phase I/II dose escalation study, ABT-001, which also utilizes ABO-102 
administered by IV in a pediatric population. In the ABT-001 study, three (3) patients have been 
treated in Cohort 1 (5 x 1012 vg/kg), three (3) in Cohort 2 (1 x 1013 vg/kg) and eight (8)  
participants have  been treated  in the  highest  dose cohort at 3 x 1013  vg/kg with a favorable 
safety profile and no treatment-related SAEs reported through more than two years of follow-up 
in Cohort 1,and Cohort 2 and two years in several participants in Cohort 3. 
The intravenous route of administration was selected based on nonclinical studies, and from the 
clinical perspective brings advantages based on the minimal participant intervention, avoiding 
safety complications associated with other administration routes (i.e., intrathecal, 
intracerebroventricular or intraparenchymal injections). 
Several gene therapy studies using other transgenes and similar vectors have been conducted 
without significant adverse events. Clinical studies to date suggest that an immune response will 
be generated to AAV capsid proteins, but whether an immune response will develop against 
SGSH remains to be determined. Because the immune system of participants in this study will be 
exposed to two antigens upon infusion of the gene therapy vector, the AAV9 capsid (a foreign 
antigen) and the newly synthesized SGSH (a “self-antigen”), humoral and cellular immune 
responses against both antigens will be monitored. 
Following transduction, CD8 T cells may be induced (or memory CD8 T cells be reactivated in 
participants exposed previously to AAV9) to eliminate transduced cells that express AAV 
protein-derived epitopes. Results from several clinical trials suggest that immunosuppression, for 
example with corticosteroids, may be necessary to control the development of a cellular immune 
response and achieve sustained expression of the enzyme. In the proposed clinical trial, 
participants will be treated with a short course of prednisolone (1 mg/kg/day from one day prior 
to the gene transfer to Day 60, with tapering over the ensuing 4-6 weeks). 
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4. 
STUDY DESIGN 
This Phase I/II clinical trial is an open-label, single dose study of recombinant, self-
complementary AAV9 carrying the human N-sulfoglucosamine sulfohydrolase (hSGSH) gene 
under the control of the U1a promoter, scAAV9.U1a.hSGSH, also known as ABO-102, 
delivered one time intravenously to MPS IIIA participants. 
4.1. 
Study Population 
The target population includes MPSIIIA participants with a DQ lower than 60 in middle and 
advanced phases of the disease that would not be eligible for the clinical trial ABT-001. 
To ensure that both the middle phase and advanced phase of the disease are adequately 
represented in the study, a similar number of participants with a cognitive age equivalent of 
above 18 months (middle) and below 18 months (advanced), as assessed by the Bayley Scales of 
Infant and Toddler Development, will be enrolled. 
Although highly unlikely due to the natural evolution of the disease, the clinical trial may 
potentially include female adolescents that  would  represent  women of childbearing  potential 
in a normal population, as defined in the Clinical Trial Facilitation Group document (HMA, 
2014) (Buhrman et al., 2014) for clarification of effective contraception titled Recommendations 
Related to Contraception and Pregnancy Testing in Clinical Trials. MPS III participants with a 
severe phenotype in the middle and advanced phases of the disease would present with a very 
advanced cognitive decline. This means that the female adolescents with MPS III fitting these 
characteristics do not have sexual relationships and so, are highly unlikely to be in the position to 
get pregnant. There are no references of any progeny from MPS III patients, so the sponsor 
considers there is no need to use any additional contraception measures other than the “de facto” 
sexual abstinence. This should be a reliable contraceptive method during the entire period of risk 
associated with the study that represents the usual lifestyle of the participant. For safety reasons, 
pregnancy test will be performed on screening, infusion and all MRI/LP study visits; and 
pregnancy forms will be developed as part of the Safety Management Plan. 
4.2. 
Inclusion/Exclusion Criteria 
4.2.1. 
Inclusion Criteria 
1. 
Diagnosis of MPS IIIA confirmed by the following methods: 
a. No detectable or significantly reduced SGSH enzyme activity by leukocyte assay, and 
b. Genomic DNA analysis demonstrating homozygous or compound heterozygous 
mutations in the SGSH gene 
2. 
Cognitive Development Quotient (DQ) lower than 60 (calculated by Bayley Scales of 
Infant and Toddler Development - Third Edition) 
3. 
Must be ambulatory, though may receive assistance with ambulation 
4. 
Age range of 2 years up to 18 years (excluded). 
4.2.2. 
Exclusion Criteria 
1. 
Inability to participate in the clinical evaluation as determined by Principal Investigator 


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2. 
Identification of two nonsense or null variants on genetic testing of the SGSH gene 
3. 
At least one S298P mutation in the SGSH gene 
4. 
Has evidence of an attenuated phenotype of MPS IIIA 
5. 
Presence of a concomitant medical condition that precludes lumbar puncture or use of 
anesthetics 
6. 
Active viral infection based on clinical observations 
7. 
Concomitant illness or requirement for chronic drug treatment that in the opinion of the 
PI creates unnecessary risks for gene transfer, or precludes the child from participating in 
the protocol assessments and follow-up 
8. 
Participants with total anti-AAV9 antibody titers ≥ 1:100 as determined by ELISA 
binding immunoassay 
9. 
Participants with a positive response for the ELISPOT for T-cell responses to AAV9 
10. 
Serology consistent with exposure to HIV, or serology consistent with active hepatitis B 
or C infection 
11. 
Bleeding disorder or any other medical condition or circumstance in which a lumbar 
puncture (for collection of CSF) is contraindicated according to local institutional policy 
12. 
Visual or hearing impairment sufficient to preclude cooperation with neurodevelopmental 
testing 
13. 
Any item (braces, etc.) which would exclude the participant from being able to undergo 
MRI according to local institutional policy 
14. 
Any other situation that precludes the participant from undergoing procedures required in 
this study 
15. 
Participants with cardiomyopathy or significant congenital heart abnormalities 
16. 
The presence of significant non-MPS IlIA related CNS impairment or behavioral 
disturbances that would confound the scientific rigor or interpretation of results of the 
study 
17. 
Abnormal laboratory values Grade 2 or higher as defined in CTCAE v4.03 for GGT, total 
bilirubin (except in subjects diagnosed with Gilbert’s syndrome), creatinine, hemoglobin, 
WBC count, platelet count, PT and aPTT 
18. 
Female participant who is pregnant or demonstrates a positive urine or βhCG result at 
screening assessment (if applicable). 
19. 
Any vaccination with viral-attenuated vaccines less than 30 days prior to the scheduled 
date of treatment (and use of prednisolone) 
20. 
Previous treatment by Haematopoietic Stem Cell transplantation 
21. 
Previous participation in a gene/cell therapy or ERT clinical trial. 
22. 
Participants who are anticipated to undergo a procedure involving anesthesia within 
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23. 
Dysphagia present at Grade 3 or higher, as defined in CTCAE v4.03 
NOTE: Potential participants with abnormal laboratory values may be re-screened for specific 
laboratory tests within the screening period (the 45 days prior to dosing) before being designated 
a screen failure. Repeat values within the normal range will be acceptable for inclusion. 
4.3. 
Dosing Plan 
This is a single dose open-label clinical trial. All participants will receive 3 x 1013  vg/kg of 
ABO-102 delivered one time through a venous catheter inserted into a peripheral limb vein. 
4.4. 
Prior and Concomitant Therapy 
All medicinal products that are already being prescribed to participants as common routine care 
will be continued during the clinical trial, with the exception of the prohibited medications listed 
in Section 4.4.1. 
Any concomitant medications administered or discontinued during the study should be recorded 
on the eCRF. 
In the event of an emergency, any needed medications may be prescribed without prior approval, 
but the medical monitor must be notified of the use of any excluded medications immediately 
thereafter. 
4.4.1. 
Prohibited Medications 
Any immune modifying medication other than the prescribed oral prednisolone (other than use 
of inhaled corticosteroids to manage chronic respiratory conditions) is prohibited. 


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5. 
STUDY PROCEDURES 
5.1. 
Schedule of Evaluations 
This clinical trial protocol is based in large part on observations from MPS IIIA and MPS IIIB 
participants enrolled in the observational study previously described, and the ABT-001 clinical 
trial which is currently ongoing (NCT02716246, EudraCT number 2015-003904-21). 
Additionally, according to local regulatory requirements, a plan for vector shedding in blood and 
other body fluids is included as part of an environmental risk assessment. 
For a general overview of the procedure and visits, please see the Schedule of Evaluations. 
5.2. 
Clinical Trial Documentation 
All the information regarding study IMP request, shipment, storage, management and destruction 
is described in the study specific Pharmacy Manual. 
The procedures that describe the collection, processing, labelling, storage, and shipment for the 
study samples are described in the Laboratory Manual. The study samples have been scheduled 
to allow a maximum blood volume of 35 ml per study visit, providing flexibility to the sites to 
reduce volume as per site policy if needed. Additional adhoc analysis on blood samples collected 
at any particular visit may be performed at the discretion of the PI. 
5.3. 
Screening and Enrollment 
5.3.1. 
Screening Visits 1 and 2 (Day -45 through Day -1) 
The screening evaluations  will take place over two visits (preferentially two weeks apart) to 
allow time for ELISA and ELISPOT results to be available before the participant undergoes 
sedation/anesthesia and other invasive clinical  assessments, as the  former tests present a 
significant chance of being exclusionary and the latter assessments puts the children under 
additional risks and therefore should not  be conducted unless the probabilities  to be enrolled  in 
the trial are high. 
Each screening visit may take place over multiple consecutive days if deemed necessary by the 
Principal Investigator to accommodate all the clinical assessments that need to be performed. 
The following evaluations will be conducted during Screening Visit 1: 
• Informed consent process 
• Demographics (including age, gender, race, and date of birth) 
• Medical history (general and MPS related) 
• A complete physical examination with a head circumference measurement 
• Adverse events (upon ICF signature) 
• Concomitant medications 
• Vital signs (temperature, respiratory rate, heart rate, blood pressure) 


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x Height and weight 
x The participant will be 
walking a 25-meter distance 
x 
 
x Echocardiogram 
x ECG 
x Lab work will include: 
 Complete blood cell count (CBC) and differential 
 Electrolytes 
 Serum/plasma total protein 
 Albumin 
 Prothrombin time (PT), partial thromboplastin time (PTT), international 
normalized ratio (INR) 
 Creatinine/Blood urea nitrogen (BUN) 
 Aspartate aminotransferase (AST), alanine transaminase (ALT), serum/plasma 
gamma-glutamyl transpeptidase (serum/plasma GGT) 
 Alkaline phosphatase 
 Amylase 
 Serum/plasma total bilirubin 
 Random glucose 
 Troponin 
 Plasma and leukocyte SGSH enzyme activity levels 
 Plasma heparan sulfate levels 
 
 
 Urine GAG and heparan sulfate levels 
 Urinalysis 
 Urine or Serum pregnancy test (if applicable) 
x Samples for vector shedding (urine, saliva and feces) 
x ELISpots for T-cell responses to AAV9 and SGSH 
x ELISA for detection of total antibodies to AAV9 and antibodies to SGSH 
x 
 
x Confirm diagnosis of MPS IIIA via gene sequencing (if not previously done) 
x Cognitive function and adaptive functioning assessment using: 
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 Neurocognitive validity form (initial set up for first scales) 
 Vineland Adaptive Behavior Scale II- Survey form, parental rating of adaptive 
functioning 
 Bayley Scales of Infant and Toddler Development – Version III - Cognitive, 
Language and Motor. If children obtain a developmental age older than 
36 months with the Bayley, the Kaufman Assessment Battery for Children, 
Second Edition, will be used also and will replace the Bayley Scales in the next 
visits 
 Pediatric Quality of Life Inventory (PedsQL™) Core Generic Scales for parents 
 Pediatric Quality of Life Inventory PedsQL™ Gastrointestinal Symptoms Scales 
for parents 
The neurocognitive evaluations at this visit and along all other visits during the 
study will be 
to allow for the possibility of future auditing by an 
external psychologist. 
The Vineland Adaptive Behaviour scale will always be the first cognitive/adaptive 
functioning scale to be used in all visits, to obtain an estimate of the child’s 
developmental level that will help for following evaluations. 
The KABC-II subtests required for the Fluid-Crystalized Index (FCI) will be 
administered. After the FCI is completed, the subtests required for the Nonverbal 
Index will be administered if the child is able to continue with the testing session. 
The rater/s and parent participating on the evaluation should be consistently the 
same during the trial for each participant as much as possible. These assessments 
may be performed locally with an external rater, if the family signed the consent 
annex and there is a qualified rater trained for the study procedures. 
x Modified Children’s Sleep Habits Questionnaire (CSHQ) 
x Parent Symptom Score Questionnaire, to collect list of symptoms and associated 
ranking. 
Vector shedding samples for urine, feces and saliva are collected at Screening Visit 1. In the 
event that urine, saliva and/or feces samples are unable to be obtained at Screening Visit 1, they 
will be obtained at Screening Visit 2. 
The following evaluations will be conducted during Screening Visit 2: 
x Weight 
 The weight obtained at Screening Visit 2 will be used to calculate the viral vector 
dose 
x Adverse events 
x Concomitant medications 
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x 
 
 
x Cognitive function and adaptive functioning assessment using: 
 Neurocognitive validity form (final set up for following scales) 
 Mullen Scales of Early Learning, both non-verbal assessments of cognitive 
function. If children obtain a developmental age older than 60 months with the 
Mullen, the Kaufman Assessment Battery for Children, Second Edition, will be 
used also and will replace the Mullen Scales in the next visits 
 
 
 Parenting Stress Index, 4th Edition (PSI-4) short form 
x Plasma and leukocyte SGSH enzyme activity levels 
x Plasma heparan sulfate levels 
x 
 
x Abdominal MRI to measure liver and spleen volumes 
x 45-min EEG 
x Lumbar puncture (LP) will be performed 
 CSF analysis 
 
SGSH enzyme activity 
 
heparan sulfate levels 
 
 
 
protein, glucose, cell count and differential 
 
 
 
CSF biobanking 
x Labs will be obtained, including: 
 Alpha-fetoprotein 
 Hepatitis (B, C) and HIV 
 Plasma biobanking 
x Samples for vector shedding (plasma) 
x The MRI and LP, 
 will be 
performed while the participant is under a single sedation/anesthesia event under the 
direction of a qualified anesthesiologist. The same apply to other visits throughout the 
protocol. 
x Vector shedding samples for plasma will be taken at Screening Visit 2. In the event 
that urine, saliva and/or feces samples are unable to be obtained at Screening Visit 1, 
they will be obtained at Screening Visit 2. 
 
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Scale 
Development Age 
Assessment 
performed by 
6-24 
months 
24-42 
months 
42-68 
months 
Above 68 
months 
Vineland Adaptive Behavior Scale II- Survey 
form 
X 
X 
X 
X 
Rater 
 
X 
X 
X 
X 
Caregiver 
Mullen Scales of Early Learning 
X 
X 
X* 
 
Rater 
Bayley Scales of Infant and Toddler 
Development 
– Version III- Cognitive, Language and Motor 
X 
X 
 
 
Rater 
Kaufman Assessment Battery for Children, 
Second Edition 
 
 
X* 
X 
Rater 
PedsQL™ Core Generic Scales 
X 
X 
X 
X 
Caregiver 
PedsQL™ Gastrointestinal Symptoms Scales X 
X 
X 
X 
Caregiver 
PSI-4 
X 
X 
X 
X 
Caregiver 
CSHQ 
X 
X 
X 
X 
Caregiver 
Parent Global Impression Score 
X 
X 
X 
X 
Caregiver 
Clinical Global Impression Improvement 
Scale 
X 
X 
X 
X 
Principal 
Investigator 
Parent Symptom Score Questionnaire 
X 
X 
X 
X 
Caregiver 
Total number of scales 
11 
11 
11 
10 
 
* At least one assessment done in parallel for both scales to ensure a correct transition. 
5.3.2. 
Pre-Infusion Visit (Day -1) 
Participants enrolled based on the screening data will arrive to the hospital within 24 hours prior 
to gene transfer. 
They will undergo the following evaluations: 
x Adverse events 
x Physical Examination 
x Vital signs (temperature, respiratory rate, heart rate, blood pressure) 
 Weight 
x Concomitant medications 
x Prophylactic enteral prednisone or prednisolone will be started 
x Labs will be obtained, including 
 CBC and differential 
 Electrolytes 
 Serum/plasma total protein 
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 Albumin 
 PT, PTT, INR 
 Creatinine/BUN 
 AST, ALT, serum/plasma GGT 
 Alkaline phosphatase 
 Amylase 
 Serum/plasma total bilirubin 
 Random glucose 
 Troponin 
In previous gene therapy studies, antigen-specific T-cell response to the AAV9 vector have been 
reported (Mingozzi and High, 2011). This is an expected response between 2 - 12 weeks 
following gene transfer. One possible consequence of such antigen-specific T-cell responses is 
clearance of the transduced cells and loss of transgene expression. 
In order to reduce the risk of the host immune response to our AAV9-based therapy, participants 
will be started on prophylactic enteral prednisone or prednisolone (glucocorticoid) (approximately 1 
mg/kg/day) one day prior to the gene transfer and only after passing all inclusion and exclusion 
criteria (in the event that a measure is repeated on Day -1). This will be continued after gene 
transfer as discussed in Section 5.5.1. 
Prophylactic enteral prednisone or prednisolone will not be provided by the Sponsor; the standard 
of care at the site/country should be used for prophylaxis. 
5.4. 
Gene Transfer 
5.4.1 
Day of Gene Transfer (Day 0) 
Participants will be admitted to the hospital on the day of gene transfer (Day 0) and transferred to 
an independent hospital room after the gene transfer. 
On the day of gene transfer (Day 0) prior to vector infusion, the participant will undergo the 
following evaluations: 
x Adverse events 
x Concomitant medications 
x Vital signs (temperature, heart rate, respiratory rate, blood pressure, pulse oximetry) 
x A 
 will be taken of the chosen injection site prior to and after vector 
administration (approximately 4 hours after treatment end) 
x Labs including: 
 Plasma biobanking 
 Urine pregnancy test (if applicable) 
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• Samples for vector shedding (plasma, urine, saliva and feces) at approximately 4 and   
8 hours after completion of gene transfer 
An independent assessment will be performed by sedation/anesthesia staff per local procedures 
with vitals collected for clinical purposes to ensure the participant is cleared for gene transfer. 
If the participant appears inadequately hydrated in the judgment of the Principal Investigator, 
bolus(es) of 10-20 mL/kg normal saline may be given during the time between participant check-
in and gene transfer. Participants will be continued on their usual diet until eight hours prior to 
gene transfer, after which they will have no solid food; clear liquids will be allowed up until two 
hours prior to gene transfer, after which they will be fully NPO. They will resume their usual diet 
after they have returned to pre-sedation/anesthesia baseline. 
Gene transfer will be performed under sterile conditions in an appropriate in-patient facility, 
under light to moderate sedation/anesthesia if considered necessary by the clinical investigator, 
under the direction of a qualified anesthesiologist / intensivist. The specific approach may vary, 
but the participant may be sedated using inhaled nitrous prior to induction with propofol via      
an IV and maintained with inhaled sevoflurane or a propofol drip. Sedation/anesthesia is being 
utilized in this instance due to the frequently hyperactive and uncooperative behavior of the 
participants, along with the undefined safety of this biologic study agent, and with an aim   of 
maximizing potential study participation benefit to the pediatric participant by preventing study 
agent subcutaneous infiltration or IV loss with study agent spillage. In those participants who in 
the opinion of the Principal Investigator (and in consultation with the anesthesiologist/intensivist 
and parents) are determined to not need sedation/anesthesia in order to safely deliver the vector, 
sedation/anesthesia may be deferred. 
All participants in this trial will receive an intravenous injection of ABO-102 via peripheral limb 
vein at a dose of 3.0 x 1013 vg/kg. 
The vector request, shipment, storage, preparation and management are described in the 
Pharmacy Manual. Site should keep records of Investigational Product and prednisone/ 
prednisolone medication accountability. 
Each vector dose will be given undiluted from syringes determined to be compatible with the 
vector and, prepared   by   the   Investigational/Research   Drug   Pharmacy.   Infusion   will   be 
performed using an infusion pump compatible with the supplied infusion kits. At the estimated 
vector product concentration of 1 x 1013 vg/mL, this would equate to 3 mL/kg. The vector salt 
solution is expected to be approximately 400 mOsmol/L. 
The infusion rate will not be slower than the slowest rate at which the infusion set up 
compatibility testing was done. The infusion rate will not approach or exceed 2 mL/kg/min (a 
rapid bolus rate) for any pediatric participant. The infusion will be given over approximately 15 
to 45 minutes, incorporating competing concerns including maximizing uptake across the blood-
brain barrier and limiting sedation/anesthesia time versus limiting risk for IV infiltration and 
infusing slowly enough to observe for evidence of infusion reaction before entire dose is given. 
Depending on vector lot concentration and other factors, infusion rate is expected to be around 
0.03-0.08 mL/kg/min. The vector will be flushed from the infusion tubing using 20 mL Lactated 
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Participants will be closely monitored for side effects during the infusion, including continuous 
heart rate, respiratory rate, and pulse oximetry; and intermittent blood pressure monitoring. Heart 
rate, respiratory rate, pulse oximetry, temperature, and blood pressure will be measured before 
and immediately after the infusion. Monitoring will be repeated at: 
• 15 minutes post-infusion 
• 1 hour post-infusion (window ± 15 minutes) 
• 2 hours post-infusion (window ± 15 minutes) 
• 4 hours post-infusion (window ± 60 minutes) 
• 8 hours post-infusion (window ± 2 hours) 
• 12 hours post-infusion (window ± 3 hours) 
• 24 hours post-infusion (window ± 3 hours) 
• 48 hours post-infusion (window ± 3 hours) 
Infusion reactions: Infusion will be terminated for evidence of an allergic reaction of Grade 2 or 
greater, including anaphylaxis (based upon CTCAE v4.03 criteria) and reported using these 
criteria: 
Grade 1: Transient flushing or rash, drug fever <38 degrees C (<100.4 degrees F); intervention 
not indicated 
Grade 2: Rash, flushing, urticaria, dyspnea, drug fever >38°C: 
Intervention or infusion interruption indicated; responds promptly to symptomatic treatment 
(e.g., antihistamines, NSAIDS, narcotics); prophylactic medications indicated for ≤24 hrs 
Grade 3: Prolonged (e.g., not rapidly responsive to symptomatic medication and/or brief 
interruption of infusion); recurrence of symptoms following initial improvement; hospitalization 
indicated for clinical sequelae (e.g., renal impairment, pulmonary infiltrates) 
Grade 4: Life-threatening consequences; urgent intervention indicated Grade 5: Death 
Under CTCAE v4.03 criteria, anaphylaxis is by definition a Grade 3 (Symptomatic 
bronchospasm with or without urticaria; allergy-related edema/angioedema, hypotension), and 
would result in infusion termination and systemic treatment. 
Participants will remain in an independent hospital room following gene transfer and remain 
hospitalized for up to 48 hours post gene transfer. 
5.5. 
Post Gene Transfer Monitoring Plan 
5.5.1. 
Up to 48-Hours Inpatient Monitoring (Days 1 and 2) 
The participant will see the Principal Investigator or designee on the morning of both Day 1 and 
Day 2 for the following evaluations: 
5.5.1.1. 
Day 1 
The following evaluations will be conducted at Day 1: 


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x Adverse events 
x Concomitant medications 
x Physical examination 
x Vital signs (temperature, heart rate, respiratory rate, blood pressure, pulse oximetry) 
x Labs will be obtained, including 
 CBC and differential 
 Electrolytes 
 Serum total protein 
 Albumin 
 PT, PTT, INR 
 Creatinine/BUN 
 AST, ALT, serum/plasma GGT 
 Alkaline phosphatase 
 Amylase 
 Serum/plasma total bilirubin 
 Random glucose 
 Troponin 
 Urinalysis 
 Plasma heparan sulfate levels. 
 
 
 Urine GAG and heparan sulfate levels 
x Samples for vector shedding (plasma, urine, saliva and feces) 
x A 
will be taken of the injection site (approximately 24 h after infusion) 
Oral prednisone or prednisolone administration will continue after the gene transfer itself and be 
tapered according to liver function testing and IFN-gamma T-cell studies (ELISpot assay) in the 
following weeks. If post-infusion IFN-gamma T-cell responses remain negative per the 
performing lab’s criteria, the participant’s prednisone or prednisolone dos will begin to be 
tapered around Day 60 post gene transfer. Tapering will proceed slowly, typically over 4 to 7 
weeks. 
 
 
 
 
 
 Based on other 
studies, it is anticipated that oral prednisone or prednisolone administration should not exceed 
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120 days post gene transfer.  Liver function testing (AST, ALT, GGT) will be repeated 2 weeks 
after the last dose of steroid. All prednisone or prednisolone administration and tapering details 
should be recorded in the EDC, including dose, start and end dates. 
5.5.1.2. 
Day 2 
The following evaluations will be conducted at Day 2: 
• Adverse events 
• Concomitant medications 
• Physical examination 
• Vital signs (temperature, heart rate, respiratory rate, blood pressure, pulse oximetry) 
• Samples for vector shedding (plasma, urine, saliva and feces) 
5.5.2. 
Post-Gene Transfer Monitoring (Days 7, 14, 30) 
5.5.2.1. 
Day 7 (+/- 2 days) 
The following evaluations will be conducted at Day 7: 
• Medical history 
• Adverse events 
• Concomitant medications 
• Physical examination 
• Vital signs (temperature, heart rate, respiratory rate, blood pressure) 
• Labs will be obtained, including 
− CBC and differential 
− Electrolytes 
− Serum/plasma total protein 
− Albumin 
− PT, PTT, INR 
− Creatinine/BUN 
− AST, ALT, serum/plasma GGT 
− Alkaline phosphatase 
− Amylase 
− Serum/plasma total bilirubin 
− Random glucose 
− Troponin 


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 ELISA for detection of total antibodies to AAV9 and antibodies to SGSH 
 Plasma and leukocyte SGSH enzyme activity levels 
 Plasma heparan sulfate levels 
 
 
 Urine GAG and heparan sulfate levels 
 Urinalysis 
 Plasma biobanking 
x Samples for vector shedding (plasma, urine, saliva and feces) 
5.5.2.2. 
Day 14 (+/- 2 days) 
The following evaluations will be conducted at Day 14: 
x Medical history 
x Adverse events 
x Concomitant medications 
x Physical examination 
x Vital signs (temperature, heart rate, respiratory rate, blood pressure) 
x Labs will be obtained, including 
 CBC and differential 
 Electrolytes 
 Serum/plasma total protein 
 Albumin 
 PT, PTT, INR 
 Creatinine/BUN 
 AST, ALT, serum/plasma GGT 
 Alkaline phosphatase 
 Amylase 
 Serum/plasma total bilirubin 
 Random glucose 
 Troponin 
 ELISA for detection of total antibodies to AAV9 and antibodies to SGSH 
 Plasma and leukocyte SGSH enzyme activity levels 
 Plasma heparan sulfate levels. 
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 
 
 Urine GAG and heparan sulfate levels 
 Urinalysis 
 ELISpots for T-cell responses to AAV9 and SGSH 
 Plasma biobanking 
x Samples for vector shedding (plasma, urine, saliva and feces) 
5.5.2.3. 
Day 30 (+/- 3 days) 
The following evaluations will be conducted at Day 30: 
x Medical history 
x Adverse events 
x Concomitant medications 
x Physical examination 
x Vital signs (temperature, heart rate, respiratory rate, blood pressure) 
x Height and weight 
x Abdominal MRI to measure liver and spleen volumes 
x Labs will be obtained, including 
 CBC and differential 
 Electrolytes 
 Serum/plasma total protein 
 Albumin 
 PT, PTT, INR 
 Creatinine/BUN 
 AST, ALT, serum/plasma GGT 
 Alkaline phosphatase 
 Amylase 
 Serum/plasma total bilirubin 
 Random glucose 
 Troponin 
 Plasma and leukocyte SGSH enzyme activity levels 
 Plasma heparan sulfate levels 
 Urine GAG and heparan sulfate levels 
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 Urinalysis 
 ELISpots for T-cell responses to AAV9 and SGSH 
 ELISA for detection of total antibodies to AAV9 and antibodies to SGSH 
 
 
 Plasma biobanking 
x Lumbar puncture (LP) will be performed under sedation/anesthesia 
o CSF analysis 
 
SGSH enzyme activity 
 
heparan sulfate levels 
 
 
 
Protein, glucose, cell count and differential 
 
 
 
CSF biobanking 
x Samples for vector shedding (plasma, urine, saliva and feces) 
If an elevation in amylase levels is observed after gene transfer and has not returned to baseline 
values by Day 30, amylase will continue to be analyzed in further visits until levels return to 
baseline values. Those analyses will include lab collections performed at home if the participant 
is unable to travel to the hospital. 
5.5.2.4. 
5.5.2.4 Day 45 (+/- 3 days) 
Lab work at Day 45 will be done to evaluate safety. Participants unable to travel to the hospital 
will have their blood drawn by a contracted home care service. 
The labs will evaluate: 
x o AST, ALT, serum/plasma GGT 
5.5.2.5. 
Day 60 (+/- 7 days) 
The following evaluations will be conducted at Day 60: 
x Medical history 
x Adverse events 
x Concomitant medications 
x Physical examination 
x Vital signs (temperature, heart rate, respiratory rate, blood pressure) 
x Weight 
 Labs will be obtained, including: AST, ALT, serum/plasma GGT 
 Plasma and leukocyte SGSH enzyme activity levels 
 Plasma heparan sulfate levels 
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 Troponin 
 Urine GAG and heparan sulfate levels 
 ELISpots for T-cell responses to AAV9 and SGSH 
 ELISA for detection of total antibodies to AAV9 and antibodies to SGSH 
 
 
 Plasma biobanking 
 Amylase (if applicable) 
x Samples for vector shedding if applicable (plasma, urine, saliva and feces) 
Vector shedding analysis post dosing, after Day 30, will be performed on DNA isolated from 
different biological fluids (plasma, urine, saliva and feces) until two consecutive samples are 
negative for the presence of viral DNA for each specimen type. 
5.5.2.6. 
Day 75 (+/- 3 days) 
Lab work at day 75 will be done to evaluate safety. Participants unable to travel to the hospital 
will have their blood drawn by a contracted home care service. 
The labs will evaluate: 
 AST, ALT, serum/plasma GGT 
5.5.2.7. 
Day 90 (+/- 7 days) 
The following evaluations will be conducted at Day 90: 
x Medical history 
x Adverse events 
x Concomitant medications 
x Physical examination 
x Vital signs (temperature, heart rate, respiratory rate, blood pressure) 
x Weight 
x Echocardiogram 
x ECG 
x Labs will be obtained, including 
 CBC and differential 
 Electrolytes 
 Serum/plasma total protein 
 Albumin 
 PT, PTT, INR 
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− Creatinine/BUN 
− AST, ALT, serum/plasma GGT 
− Alkaline phosphatase 
− Alpha-fetoprotein 
− Amylase (if applicable) 
− Serum/plasma total bilirubin 
− Random glucose 
− Troponin 
− Plasma and leukocyte SGSH enzyme activity levels 
− Plasma heparan sulfate levels 
− Urine GAG and heparan sulfate levels 
− Urinalysis 
− ELISpots for T-cell responses to AAV9 and SGSH 
− ELISA for detection of total antibodies to AAV9 and antibodies to SGSH 
− Plasma biobanking 
• Samples for vector shedding if applicable (plasma, urine, saliva and feces) 
(see instructions at Day 60) 
5.5.2.8. 
Two Weeks Post Steroids Taper (+/- 7 days) 
Participants unable to travel to the hospital will have their blood drawn by a contracted home 
care service. 
The following labs will be conducted at a timepoint two weeks post last steroids dose and will 
evaluate: 
• AST, ALT, serum/plasma GGT 
5.5.2.9. 
Day 120 (+/- 7 days) and Day 150 (+/- 7 days) 
Lab work at Days 120 and 150 will be done to evaluate safety. Participants unable to travel to the 
hospital will have their blood drawn by a contracted home care service. 
The labs will evaluate: 
• AST, ALT, serum/plasma GGT 
5.5.2.10. Day 180 (+/- 21 days) 
The following evaluations will be conducted at Day 180: 
• Medical history 
• Adverse events 


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x Concomitant medications 
x Physical examination with a head circumference measurement 
x Vital signs (temperature, heart rate, respiratory rate, blood pressure) 
x Height and weight 
x Neurocognitive validity form 
x Cognitive function assessment using: 
 Vineland Adaptive Behavior Scale II-Survey form, parental rating of adaptive 
functioning 
 Mullen Scales of Early Learning, both non-verbal assessments of cognitive 
function. If children obtain a developmental age older than 60 months with the 
Mullen, the Kaufman Assessment Battery for Children, Second Edition, will also 
be used and will replace the Mullen Scales in the next visits 
 Bayley Scales of Infant and Toddler Development – Version III- Cognitive, 
Language and Motor. If children obtain a developmental age older than 
36 months with the Bayley, the Kaufman Assessment Battery for Children, 
Second Edition, will also be used and will replace the Bayley Scales in the next 
visits 
 
 
 Parenting Stress Index, 4th Edition (PSI-4) short form 
 Pediatric Quality of Life Inventory (PedsQL™) Core Generic Scales for parents 
o Pediatric Quality of Life Inventory PedsQL™ Gastrointestinal Symptoms 
Scales for parents 
x Modified Children’s Sleep Habits Questionnaire (CSHQ) (This scale will be used if a 
sleep problem has been identified during the initial evaluation in Screening visit 1 or 
the medical history suggests there is a problem affecting child’s sleep) 
x Parent Global Impression Score 
x Clinical Global Impression Improvement Scale 
x Parent Symptom Score Questionnaire 
x The participant will be 
 walking a 25-meter distance 
x Abdominal MRI to measure liver and spleen volumes 
x 45-min EEG 
x 
 
x Echocardiogram 
x ECG 
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x 
 
 
 
 
x Labs will be performed including 
 CBC and differential 
 Electrolytes 
 Serum/plasma total protein 
 Albumin 
 PT, PTT, INR 
 Creatinine/BUN 
 AST, ALT, serum/plasma GGT 
 Alkaline phosphatase 
 Alpha-fetoprotein 
 Serum/plasma total bilirubin 
 Random glucose 
 Troponin 
 Plasma and leukocyte SGSH enzyme activity levels 
 Plasma heparan sulfate levels 
 
 
 Urine GAG and heparan sulfate levels 
 Urinalysis 
 ELISpots for T-cell responses to AAV9 and SGSH 
 ELISA for detection of total antibodies to AAV9 and antibodies to SGSH 
 
 
 Plasma biobanking 
x Lumbar puncture (LP) will be performed under sedation/anesthesia 
 CSF analysis 
 
SGSH enzyme activity 
 
Heparan sulfate levels 
 
 
 
Protein, glucose, cell count and differential 
 
 
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 
CSF biobanking 
x Samples for vector shedding if applicable (plasma, urine, saliva and feces) 
(see instructions at Day 60) 
This visit as well as those of Months 12, 18 and 24 will be conducted over two or more days to 
ensure that appropriate time is allocated for neurocognitive assessments, as well for 
caregiver-based evaluations. Breaks will be taken as needed for the family and the child. 
5.5.2.11. Month 12 (+/- 30 days) 
The following evaluations will be conducted at Month 12: 
x Medical history 
x Adverse events 
x Concomitant medications 
x Physical examination with a head circumference measurement 
x Vital signs (temperature, heart rate, respiratory rate, blood pressure) 
x Height and weight 
x Neurocognitive validity form 
x Cognitive function assessment using: 
 Vineland Adaptive Behavior Scale II-Survey form, parental rating of adaptive 
functioning 
 Mullen Scales of Early Learning, both non-verbal assessments of cognitive 
function. If children obtain a developmental age older than 60 months with the 
Mullen, the Kaufman Assessment Battery for Children, Second Edition, will be 
used also and will replace the Mullen Scales in the next visits 
 Bayley Scales of Infant and Toddler Development – Version III – Cognitive, 
Language and Motor. If children obtain a developmental age older than 36 
months with the Bayley, the Kaufman Assessment Battery for Children, Second 
Edition, will be used also and will replace the Bayley Scales in the next visits 
 
 
 Parenting Stress Index, 4th Edition (PSI-4) short form 
 Pediatric Quality of Life Inventory (PedsQL™) Core Generic Scales for parents 
 Pediatric Quality of Life Inventory PedsQL™ Gastrointestinal Symptoms Scales 
for parents 
x Modified Children’s Sleep Habits Questionnaire (CSHQ) (This scale will be used if a 
sleep problem has been identified during the initial evaluation in Screening visit 1 or 
the medical history suggest there is a problem affecting child’s sleep) 
x Parent Global Impression Score 
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x Clinical Global Impression Improvement Scale 
x Parent Symptom Score Questionnaire 
x The participant will be 
walking a 25-meter distance 
x 
 
x Abdominal MRI to measure liver and spleen volumes 
x 45-min EEG 
x 
 
x Echocardiogram 
x ECG 
x 
 
 
 
 
 
x Labs will be performed including: 
 CBC and differential 
 Electrolytes 
 Serum/plasma total protein 
 Albumin 
 PT, PTT, INR 
 Creatinine/BUN 
 AST, ALT, serum/plasma GGT 
 Alkaline phosphatase 
 Alpha-fetoprotein 
 Serum/plasma total bilirubin 
 Random glucose 
 Troponin 
 Plasma and leukocyte SGSH enzyme activity levels 
 Plasma heparan sulfate levels 
 
 
 Urine GAG and heparan sulfate levels 
 Urinalysis 
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 ELISpots for T-cell responses to AAV9 and SGSH 
 ELISA for detection of total antibodies to AAV9 and antibodies to SGSH 
 
 
 Urine pregnancy test (if applicable) 
 Plasma biobanking 
x Lumbar puncture (LP) will be performed under sedation/anesthesia 
 CSF analysis 
 
SGSH enzyme activity 
 
Heparan sulfate levels 
 
 
 
Protein, glucose, and cell count and differential 
 
 
 
CSF biobanking 
x Samples for vector shedding if applicable (plasma, urine, saliva and feces) 
(see instructions at Day 60) 
5.5.2.12. Month 18 (+/- 30 days) 
The following evaluations will be conducted at Month 18: 
x Medical history 
x Adverse events 
x Concomitant medications 
x Physical examination with a head circumference measurement 
x Vital signs (temperature, heart rate, respiratory rate, blood pressure) 
 Height and weight 
x Neurocognitive validity form 
x Cognitive function assessment using: 
 Vineland Adaptive Behavior Scale II-Survey form, parental rating of adaptive 
functioning 
 Mullen Scales of Early Learning, both non-verbal assessments of cognitive 
function. If children obtain a developmental age older than 60 months with the 
Mullen, the Kaufman Assessment Battery for Children, Second Edition, will also 
be used and will replace the Mullen Scales in the next visits 
 Bayley Scales of Infant and Toddler Development – Third edition- Cognitive, 
Language and Motor. If children obtain a developmental age older than 
36 months with the Bayley, the Kaufman Assessment Battery for Children, 
Second Edition, will also be used and will replace the Bayley Scales in the next 
visits 
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 
 
 Parenting Stress Index, 4th Edition (PSI-4) short form 
 Pediatric Quality of Life Inventory (PedsQL™) Core Generic Scales for parents 
 Pediatric Quality of Life Inventory PedsQL™ Gastrointestinal Symptoms Scales 
for parents 
x Modified Children’s Sleep Habits Questionnaire (CSHQ)This scale will be used if a 
sleep problem has been identified during the initial evaluation in Screening visit 1 or 
the medical history suggest there is a problem affecting child’s sleep) 
x Parent Global Impression Score 
x Clinical Global Impression Improvement Scale 
x Parent Symptom Score Questionnaire 
x The participant will be 
 walking a 25-meter distance 
x 
 
x 45-min EEG 
x Labs will be performed, including 
 CBC and differential 
 Electrolytes 
 Serum/plasma total protein 
 Albumin 
 PT, PTT, INR 
 Creatinine/BUN 
 AST, ALT, serum/plasma GGT 
 Alkaline phosphatase 
 Alpha-fetoprotein 
 Serum/plasma total bilirubin 
 Random glucose 
 Troponin 
 Plasma and leukocyte SGSH enzyme activity levels 
 Plasma heparan sulfate levels 
 
 
 Urine GAG and heparan sulfate levels 
 Urinalysis 
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 ELISpots for T-cell responses to AAV9 and SGSH 
 ELISA for detection of total antibodies to AAV9 and antibodies to SGSH 
 Plasma biobanking 
x Samples for vector shedding if applicable (plasma, urine, saliva and feces) 
(see instructions at Day 60) 
5.5.2.13. Month 24 (+/- 30 days) 
The following evaluations will be conducted at Month 24: 
x Medical history 
x Adverse events 
x Concomitant medications 
x Physical examination with a head circumference measurement 
x Vital signs (temperature, heart rate, respiratory rate, blood pressure) 
x Height and weight 
x Neurocognitive validity form 
x Cognitive function assessment using: 
 Vineland Adaptive Behavior Scale II-Survey form, parental rating of adaptive 
functioning 
 Bayley Scales of Infant and Toddler Development – Third edition- Cognitive, 
Language and Motor. If children obtain a developmental age older than 
36 months with the Bayley, the Kaufman Assessment Battery for Children, 
Second Edition, will also be used and will replace the Bayley Scales in the next 
visits 
 Mullen Scales of Early Learning, both non-verbal assessments of cognitive 
function. – Third edition. If children obtain a developmental age older than 60 
months with the Bayley, the Kaufman Assessment Battery for Children, Second 
Edition, will also be used and will replace the Bayley Scales in the next visits 
 
 
 Parenting Stress Index, 4th Edition (PSI-4) short form 
 Pediatric Quality of Life Inventory (PedsQL™) Core Generic Scales for parents 
 Pediatric Quality of Life Inventory PedsQL™ Gastrointestinal Symptoms Scales 
for parents 
x Modified Children’s Sleep Habits Questionnaire (CSHQ) (This scale will be used if a 
sleep problem has been identified during the initial evaluation in Screening visit 1 or 
the medical history suggest there is a problem affecting child’s sleep) 
x Parent Global Impression Score 
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x Clinical Global Impression Improvement Scale 
x Parent Symptom Score Questionnaire 
x The participant will be 
 walking a 25-meter distance 
x 
 
x Echocardiogram 
x ECG 
x 
 
 
 
x Labs will be performed including 
 CBC and differential 
 Electrolytes 
 Serum/plasma total protein 
 Albumin 
 PT, PTT, INR 
 Creatinine/BUN 
 AST, ALT, serum/plasma GGT 
 Alkaline phosphatase 
 Alpha-fetoprotein 
 Serum/plasma total bilirubin 
 Random glucose 
 Troponin 
 Plasma and leukocyte SGSH enzyme activity levels 
 Plasma heparan sulfate levels 
 
 
 Urine GAG and heparan sulfate levels 
 Urinalysis 
 ELISpots for T-cell responses to AAV9 and SGSH 
 ELISA for detection of total antibodies to AAV9 and antibodies to SGSH 
 
 
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 Urine pregnancy test (if applicable) 
 Plasma biobanking 
x 
 
x Abdominal MRI to measure liver and spleen volumes 
x 45-min EEG 
x Lumbar puncture (LP) will be performed under sedation/anesthesia 
 CSF analysis 
 
SGSH enzyme activity 
 
Heparan sulfate levels 
 
 
 
Protein, glucose, cell count and differential 
 
 
 
CSF biobanking 
x Samples for vector shedding if applicable (plasma, urine, saliva and feces) 
(see instructions at Day 60) 
x Participant Survey to assess the service providers for travelling, patient 
reimbursement, home nursing* 
*This survey should also be assessed in the last visit of screening failures and withdrawal. 
5.6. 
Long-Term Monitoring 
The end of the clinical trial is defined as the Last Participant Last Visit. A participant is 
considered to have completed the study follow up period after completion of the 24-month visit. 
When a participant has completed the 24-month study follow up for safety and efficacy, he or 
she will be requested to participate in a long-term follow-up study (LTFU-ABO-102, EudraCT 
number 2019-002979-34). During the long-term follow-up study participants will be followed 
for a minimum period of three years. 
5.7. 
Outcome Measures 
Due to the highly heterogenous population that will be enrolled in this trial and the degree of 
neurodegeneration associated with middle and advanced stages of MPS IIIA evolution, the 
possibilities that the treatment has a meaningful impact in the cognitive condition of the patients 
are very limited. For this reason we 
 
 
 selected the 
following primary outcome measures: 
x Product safety as defined by the incidence, type and severity of treatment-related 
adverse events and serious adverse events [Time frame: Month 1, 2, 3, 6, 12, 18, 24] 
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• Change from baseline in CSF heparan sulfate levels after treatment [Time frame: 
Month 1, 6, 12, 24] 
• Change from baseline in liver and/or spleen volumes after treatment, as measured by 
MRI [Time frame: Month 1, 6, 12, 24] 
Cognitive evolution evaluation is proposed as secondary outcome, as well as adaptive 
functioning, biomarkers and biophysical changes and a series of potentially important assessment 
including sleep, quality of life of the child and the parents, gastrointestinal problems, body mass 
index or even other relevant symptoms identified by the parents in a Parent Symptom Score 
Questionnaire that will be used at screening and followed every 6 months. A list of secondary 
outcomes includes: 
• Change from baseline in plasma or urine glycosaminoglycans or heparan sulfate after 
treatment [Time frame: Month 1, 6, 12, 18, 24] 
• Change from baseline in CSF or plasma or leukocyte SGSH enzyme activity levels 
after treatment [Time frame: Month 1, 6, 12, 24] 
• Change from baseline in brain volumes after treatment, as measured by MRI [Time 
frame: Month 12, 24] 
• Change from baseline in the Age Equivalent and Developmental Quotient (DQ) after 
treatment compared to Natural History Study data calculated by the Mullen Scales of 
Early Learning or the Kaufman Assessment Battery for Children. Second Edition, 
based on chronological and developmental age [Time frame: Month 6, 12, 18, 24] 
• Change from baseline in the Cognitive Age Equivalent and Developmental Quotient 
(DQ) after treatment compared to Natural History Study, calculated using the Bayley 
Scales of Infant and Toddler Development – Third edition or the Kaufman 
Assessment Battery for Children. Second Edition, based on developmental age 
[Time Frame: Month 6, 12, 18, 24] 
• Change from baseline in the Adaptive Age Equivalent score after treatment compared 
to Natural History Study data, as assessed by parent report using the Vineland 
Adaptive Behavior Scale II Survey form [Time frame: Month 6, 12, 18, 24] 
• Change from baseline in sleep pattern as measured by the CSHQ [Time Frame: 
Month 6, 12, 18, 24] 
• Change from baseline in PedsQL™ Core Generic Scales score [Time Frame: Month 
6, 12, 18, 24] 
• Change from baseline in parent quality of life, using the PSI-4, 4th Edition [Time 
Frame: Month 6,12, 18, 24] 
• Change from baseline in gastrointestinal symptoms using the PedsQL™ 
Gastrointestinal Symptoms Scales [Time Frame: Month 6,12, 18, 24] 
• Parent Global Impression Score [Time Frame: Month 6,12, 18, 24] 
• Clinical Global Impression Improvement Scale Score [Time Frame: Month 6, 12, 18, 
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x Change from baseline in Parent Symptom Score Questionnaire [Time Frame: Month 
6, 12, 18, 24] 
x Change from Baseline in Body Mass Index after treatment [Time Frame: Month 6, 
12, 18, 24] 
x Incidence and change from baseline in abnormalities in standard awake 45-minute 
EEG monitoring [Time frame: Month 6, 12, 18, 24] 
x Determination of vector shedding analysis in plasma, saliva, urine and feces will 
provide preliminary data for the Environmental Risk Assessment (ERA). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6. 
SAFETY 
The Investigator or site staff is responsible for detecting, documenting and reporting events that 
meet the definition of an adverse event (AE) or a serious adverse event (SAE). All AEs (serious 
and not serious) occurring during the observation period established in this protocol must be 
documented. All adverse events will be followed until resolution or stabilization. 
The study period during which adverse events must be reported is defined as the period from 
signature of the informed consent to the end of the study treatment follow-up. For this study, the 
study treatment follow-up is defined as 24 months following the administration of study 
treatment and is considered the Final Visit for each participant. The Principal Investigator will 
adhere to any other SAE reporting requirements in accordance with national regulations, local 
laws, and the national institutional policies and procedures, as applicable. The Principal 
Investigator will be responsible for ensuring that the reporting requirements are fulfilled and will 
be held accountable for any reporting lapses. 
It is important to note that for this clinical trial, Principal Investigators should only report the 
following AEs: 
• All Grade 2 or greater AEs 
• Grade 1 AEs considered by the Principal Investigator as clinically significant, 
independent of the association or relatedness to the study agent 
• Grade 1 AEs assessed by the Principal Investigator as possibly, probably or definitely 
related to the study agent 
Abnormal laboratory findings should be recorded as AEs when judged by the Principal 
Investigator/Sub-Investigator as clinically significant. Special attention should be considered for 
changes in AST/ALT, platelets and amylase. 
There are no drug comparators used in this study, so there is only one Investigational Medicinal 
Product to assess the causality/expectedness evaluation, the gene therapy vector described in the 
Investigational Brochure. 
6.1. 
Definitions 
6.1.1. 
Adverse Event (AE) and Adverse Reaction (AR) 
An AE is any untoward medical occurrence or unintended change (including physical, 
psychological, or behavioral) from the time ICF is signed, including inter-current illness, which 
occurs during the course of a clinical trial after treatment has started, whether considered related 
to treatment or not. An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal product, whether or not considered related to the medicinal product. 
Changes associated with normal growth and development that do not vary in frequency or 
magnitude from that ordinarily anticipated clinically are not AEs (e.g., onset of menstruation 
occurring at a physiologically appropriate time). 
Clinical AEs should be described by diagnosis and not by symptoms when possible (e.g., cold, 
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An adverse reaction is any untoward and unintended response in a participant to an 
investigational medicinal product which is related to any dose administered to the participant. 
6.1.2. 
Serious Adverse Event (SAE) and Serious Adverse Reaction (SAR) 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
In the case of death, the PI will request permission from the family to perform an 
autopsy. 
b. Is life threatening 
The term life threatening in the definition of serious refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event 
that hypothetically might have caused death if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization or emergency ward for observation and/or intervention that 
would not have been appropriate in the physician’s office or outpatient setting 
signifies that the participant has been detained (usually involving at least an overnight 
stay) at the hospital. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether hospitalization occurred or was necessary, the 
AE should be considered serious. 
Hospitalization for elective intervention of a pre-existing condition that did not 
worsen from baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. This definition is not intended to include experiences of 
relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (eg, sprained ankle), which may 
interfere with or prevent everyday life functions but do not constitute a substantial 
disruption. 
e. Is a congenital anomaly/birth defect 
f. Other situations 
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious. Examples of such events include invasive or malignant 
cancers, intensive intervention in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, 
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A SAR is defined as a SAE which is considered related to any dose of the product 
that is administered to the participant. 
6.1.3. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A Suspected Unexpected Serious Adverse Reaction (SUSAR) is defined as an untoward and 
unintended response to a study drug, which is not listed in the applicable product information, 
and meets one of the following serious criteria: results in death, is life-threatening, requires 
hospitalisation or prolongation of an existing hospitalisation, results in persistent or significant 
disability or incapacity, or is a congenital anomaly or birth defect. 
The Reference Safety Information (RSI) of the Investigational Brochure is to serve as the basis 
for expectedness assessments of ‘suspected’ serious adverse reactions (‘suspected’ SARs) for 
expedited reporting of suspected unexpected serious adverse reactions (SUSARs). The sponsor is 
responsible for performing the assessment of expectedness. 
6.2. 
Assessment of Severity (Intensity) 
The classification for adverse events will follow NIH guidelines outlined in Common 
Terminology Criteria for Adverse Events v4.03 (CTCAE; published May 28, 2009), which 
includes: 
6.2.1. 
Grade 1 
A type of adverse event that is mild, usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of daily 
living. 
6.2.2. 
Grade 2 
A type of adverse event that is moderate, usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing discomfort but 
poses no significant or permanent risk of harm to the research participant. 
6.2.3. 
Grade 3 
A type of adverse event that is severe, interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. 
6.2.4. 
Grade 4 
Life- threatening consequences; urgent intervention indicated 
6.2.5. 
Grade 5 
Results in death 
6.3. 
Assessment of Causality 
The causality assessment decisions must be made by a medically qualified doctor, as these 
decisions require medical and scientific judgement as well as knowledge of the participant 
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The Principal Investigator should then assess any relationship between an adverse event and the 
trial drug. Association or relatedness to the study agent will be graded as follows: 5 = unrelated, 
4 = unlikely, 3 = possibly, 2 = probably, and 1 = definitely related. If an Investigator uses the 
WHO classification categories of causality when assessing causality, ‘highly probable’, 
‘probable’, ‘possible’ should be regarded as related by the sponsor, while ‘unlikely’ and ‘not’ 
may be considered to be not related. This cause and event appraisal is to be carried out using the 
following classification: 
• Unrelated: The adverse event is unrelated to the use of the trial drug. 
• Unlikely related: There are other, more likely causes to the adverse event, and the 
trial drug is not suspected to play a role. 
• Possibly related: A direct cause and effect between the trial drug and the adverse 
event is not proven, but there is a reasonable possibility that the adverse event was 
caused by the drug. 
• Probably related: It is likely that there is a direct cause and effect relationship 
between the trial drug and the adverse event. 
• Definitely related: When it is absolutely certain that there is a connection between the 
investigational gene therapy product and the Adverse Event. 
A reasonable possibility of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. The 
Investigator will use clinical judgment to determine the relationship. Alternative causes, such as 
underlying disease(s), concomitant therapy, and other risk factors, as well as the temporal 
relationship of the event to study intervention administration will be considered and investigated. 
The Investigator will also consult the IB in his/her assessment, as there is a specific list of 
anticipated Adverse Events that have been observed and reported along the clinical trial as 
potentially related to the study drug. For each AE or SAE, the Investigator must document in the 
medical notes that he/she has reviewed the AE or SAE and has provided an assessment of 
causality. There may be situations in which an SAE has occurred and the Investigator has 
minimal information to include in the initial report to sponsor or designee. However, it is very 
important that the Investigator always make an assessment of causality for every event before the 
initial transmission of the SAE data to the sponsor or designee. The Investigator may change 
his/her opinion of causality in light of follow-up information and send an SAE follow-up report 
with the updated causality assessment. The causality assessment is one of the criteria used when 
determining regulatory reporting requirements. 
6.4. 
Recording 
When an AE or SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) related to 
the event. The Investigator will then record all relevant AE or SAE information in the 
participant’s medical records, in accordance with the Investigator’s normal clinical practice and 
on the appropriate form of the [e]CRF. It is not acceptable for the Investigator to send 
photocopies of the participant’s medical records to the sponsor or designee in lieu of completion 
of the sponsor or designee AE or SAE [e]CRF page. There may be instances when copies of 


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medical records for certain cases are requested by the sponsor or designee. In this case, all 
participant identifiers, with the exception of the participant number, will be redacted on the 
copies of the medical records before submission to the sponsor or designee. The Investigator will 
attempt to establish a diagnosis of the event based on signs, symptoms, and/or other clinical 
information. Whenever possible, the diagnosis (not the individual signs/symptoms) will be 
documented as the AE/SAE. 
6.5. 
Reporting of SAEs and SARs 
The sponsor, the Investigator or his designee will report all serious and unexpected adverse 
events to the IRB, Regulatory or Competent Authorities (i.e. CBER/FDA, OBA/NIH, AEMPS, 
CCAA, TGA, HREC and other) and DSMB according to regulatory requirements described as 
follows: 
Any SAE event will be reported to the Sponsor and/or their safety representative within 
24 hours. The Sponsor will then inform the DSMB within 48 hours from notification of the site 
to the Sponsor and before enrollment of additional participants. The DSMB will decide then on 
the relationship of the SAE to the study agent (as possibly, probably or definitely related to the 
study agent). 
Any unexpected event that is fatal or life-threatening, and associated with the use of the gene 
transfer (SUSAR) product will be reported to Competent Authorities as soon as possible, but not 
later than 7 calendar days after the sponsor’s initial receipt of the information. SUSARs that are 
unexpected and associated with the use of the gene transfer product, but are not fatal or life-
threatening, will be reported to Competent Authorities as soon as possible, but not later than 
15 calendar days after the sponsor’s initial receipt of the information. 
If, after further evaluation, a SAE initially considered not to be associated with the use of the 
gene transfer product is subsequently determined to be associated, then the event will be reported 
to the Competent Authorities within 15 days of the determination. 
Relevant additional clinical and laboratory data will become available following the initial SAE 
report. Any follow-up information relevant to a SAE will be reported within 15 calendar days of 
the sponsor’s receipt of the information. If a SAE occurs after the end of a clinical trial and is 
determined to be associated with the use of the gene transfer product, that event will be reported 
to the Competent Authorities within 15 calendar days of the determination. 
Should a SAE deemed possibly, probably or definitely related to the study agent occur during 
administration, the study agent will be discontinued, appropriate treatment will be given under 
medical supervision and the participant will be examined as frequently as necessary thereafter 
until symptoms cease or stabilize. 
Any SAE or study-related unanticipated problem posing risk of harm to participants or others 
must be reported by the Investigator to the Sponsor and/or their safety representative within 
24 hours of the event detection. To report such events, a SAE reporting form must be completed 
by the Investigator and sent to the study sponsor or pharmacovigilance CRO as delegated. 
The Investigator will keep a copy of this SAE form on file at the study site. The delegated CRO 
will report the event to the study sponsor in a maximum period of 24 hours after SAE form 
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Within the following 48 hours, if there is further information on the SAE or the unanticipated 
problem it should be provided by the Investigator as a follow-up to the initial SAE report. 
This may include a copy of any diagnostic information that will assist the understanding of the 
event. Any other significant new information on ongoing SAEs should be provided to the study 
sponsor or pharmacovigilance CRO delegated as soon as possible. 
The final SAE report will include, but need not be limited to: 
(1) The date of the event; 
(2) Clinical site; 
(3) The Principal Investigator; 
(4) Route of administration, e.g., intramuscular; 
(5) Dosing schedule; 
(6) A complete description of the event; 
(7) Relevant clinical observations; 
(8) Relevant clinical history; 
(9) Relevant tests that were or are planned to be conducted; 
(10) Date of any treatment of the event; and 
(11) the suspected cause of the event. 
The study sponsor or pharmacovigilance CRO delegated following current law dispositions is 
responsible for: 
• Continuously evaluating the safety of all drugs under investigation and 
communicating any important information regarding safety to the FDA, AEMPS and 
other Competent Authorities, including Ethical Committee (Comite Ético de la 
Investigación con medicamento - CEIm) and Authonomous Regions (Comunidades 
Autónomas - CCAA) involved if applicable 
• Notification to the Competent Authorities in accordance with local regulations about 
all suspected SAEs and also unexpected SAEs regarding the drug under investigation, 
having occurred within the country where the clinical trial is being conducted, having 
occurred within this authorized clinical trial, any other clinical trial, or in a different  
context of use, in case these drugs are not authorized for human use. 
Study sponsor is responsible to ensure that only SARs with "reasonable causal relationship" are 
assessed for expectedness and considered for SUSAR reporting. The following describes the 
general safety reporting requirements by timeline for reporting and associated type of event: 


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• Within 7 calendar days, any study event that is: 
 associated with the use of the study drug 
 unexpected 
 fatal or life-threatening 
• Within 15 calendar days, any study event that is: 
 associated with the use of the study drug 
 unexpected and serious, but not fatal or life-threatening 
 a previous adverse event that was not initially deemed reportable but is later 
found to fit the criteria for reporting (reporting within 15 calendar days from 
when event was deemed reportable). 
Should an SAE be deemed possibly, probably or definitely related to the study agent occur 
during administration, the study agent will be discontinued, appropriate treatment will be given 
under medical supervision and the participant will be examined as frequently as necessary 
thereafter until symptoms cease or stabilize. 
A detailed Safety Management Plan (SMP) is developed for the study to define all the forms, 
timelines and responsibilities for SAE/SAR reporting. 
6.6. 
Reporting of pregnancy 
If a participant becomes or is found to be pregnant during the subject’s participation in the study, 
the pregnancy will be reported to the Sponsor and/or their safety representative within 24 hours 
of the Investigator being aware of the pregnancy. Pregnancy in itself is not regarded as an AE 
and/or SAE. The pregnancy and the outcome of the pregnancy (spontaneous miscarriage, 
elective termination, normal birth or congenital abnormality) will be followed and documented, 
even if the participant was discontinued from the study. The pregnancy and outcome will be 
reported using the pregnancy forms. 


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7. 
DOSING NEW PARTICIPANTS AND 
STOPPING/DISCONTINUATION RULES 
7.1. 
Dose New Participants 
Participants will be dosed with a 14-day interval between them, after clinical information and 
safety data from Day 1, 7 and 14 from the previous participant have been reviewed and 
communicated by the Principal Investigator to the Sponsor. 
7.2. 
Stopping/Discontinuation Rules 
Study enrollment will be halted by the investigators when two or more serious adverse events are 
experienced within the same or different participants that are possibly, probably, or definitely 
related to the study drug (SAR) (as attributed by the DSMB), or when two participants 
experience the same serious adverse event that is possibly, probably, or definitely related to the 
study drug (SAR) (as attributed by the DSMB). This will include any participant death not 
related to underlying disease condition, important clinical laboratory finding, or any severe local 
complication in the injected area related to administration of the study agent. If after review by 
the DSMB the decision is made to continue, the study will proceed. 
Additionally, an independent Data Safety Monitoring Board (DSMB) and designated monitor 
will monitor safety data on a continual basis throughout the trial. The DSMB can recommend 
early termination of the trial for reasons of safety or further review by ethical committees and 
competent authorities. Further details about DSMB constitution, meeting, responsibilities and 
functions are described in Section 9.3.1. 
In any case, if the study is halted, the Competent Authorities will be consulted prior to study 
restart, in the form of a substantial amendment. The protocol will be amended accordingly. 


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8. 
ETHICAL AND REGULATORY ASPECTS 
This study will be conducted in accordance with the ethical principles that have their origin in 
the World Medical Association (WMA) Declaration of Helsinki and will be consistent with 
Good Clinical Practice (GCP) guidelines. It will also follow the local regulatory requirements for 
each country. 
8.1. 
Ethical Review Board 
Before initiating the clinical trial, this protocol and all required documents will be submitted to 
the relevant Institutional Review/Ethical Review Boards in each country for approval. 
This approval will remain in the Investigators Coordinator Archive, and a copy will be kept in 
the study general archive. The study will only commence after obtaining written approval from 
the relevant Ethical Review Boards. 
Any amendment to the protocol will also be presented to the relevant Competent Authorities and 
Ethical Review Boards. The Ethical Review Boards, and Competent Authorities (where 
required), will also be notified in case of any SAEs, according to law dispositions. 
8.2. 
Informed Consent 
There is a wide spectrum of severity of this disorder. Based on the known natural history of this 
currently untreatable, progressive and neurodegenerative disease, patients of any age with the 
severe phenotype of Sanfilippo A disease will not have the cognitive and executive capacity to 
enable them to give their informed consent for participation in the clinical trial. The sponsor of 
this proposed clinical trial intends to include only an informed consent form (ICF) that will be 
suitable for caregivers /parents of adults and children with Sanfilippo A disease. There is no need 
for an assent form and informed consent for children and adults with this condition as they are 
unlikely to be able to understand the patient information sheet and provide informed consent or 
assent. 
As a consequence, all parents and/or legal guardians of the participant will be provided with an 
Information Sheet and/or Consent Form describing this study and providing sufficient 
information for participants to make an informed decision about the participation of their 
represented participant in this study. Where required, consent will be sought from the parents 
and/or legal guardian of the participant. The Informed Consent Forms (ICFs) and Patient 
Informed Consent Forms (PICFs) will include all elements required by ICH, GCP and applicable 
regulatory requirements. 
The Information Sheet and/or Consent Form will be submitted with the protocol for review and 
approval by the relevant Ethical Review Board for the study in each country. The formal consent 
of a participant, using the Informed Consent Form approved by the relevant Ethical Review 
Board, must be obtained before that participant undergoes any study procedure. The consent 
form must be signed by the participant’s parent/legal guardian, and the Investigator-designated 
research professional obtaining the consent. Where required by the relevant Ethical Review 
Board, a witness may sign the consent form. 
If there is a need to re-consent participants, the Investigator or a person designated by the 
Investigator should inform the participant’s parents/legal guardian of any new information 


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relevant to their willingness to continue to provide consent for their participation in the study, 
before obtaining the written consent. 
8.3. 
Confidentiality Information 
Participants will be assigned a unique identifier by the sponsor.  The participant code will be a 
composite of two numbers: 
• The first number with three digits will correspond to the site number such as 001, 
002, 003. 
• The second number with two digits will correspond to the participant number for each 
site that will be assigned sequentially (01, 02, 03, 04, 05, 10) to all participants 
enrolled. 
Any participant records or datasets that are transferred to the sponsor will contain the identifier 
only; participant names or any information which would make the participant identifiable will 
not be transferred. 
The collection and processing of personal data from the participants enrolled in this study will be 
limited to those data that are necessary to achieve the study objectives previous described. The 
date of birth and age of the participant at screening will be collected to ensure that the 
appropriate age-based assessments are performed throughout the study. The data must be 
collected and processed with adequate precautions to ensure confidentiality and compliance with 
applicable data privacy protection laws and regulations. Explicit consent for the processing of 
personal data will be obtained from the participating participant before data collection, if 
applicable, and this consent should also address the transfer of the data to other entities and 
countries. 
The trial monitor, the Sponsor, the Sponsor(s)’s auditor, the relevant Ethical Review Board, and 
the Competent Authorities should have direct access to all requested study-related records and 
agree to keep the identity of study participants confidential. The sponsor shall comply with all 
local regulatory requirements in the United States, Spain and Australia. 
Information about study participants will be kept confidential and managed according to the 
applicable laws in each country. 
8.4. 
Compensation for Participants 
Participants will receive reimbursement for the travel expenses for attending the visits, if 
necessary. Travel expenses include but are not restricted to transportation (and associated costs), 
accommodations, and meals for the participant and their parents/legal guardian and siblings (if 
necessary). To receive this refund, the participant’s parents/legal guardian must follow the 
process for reimbursement provided by the Investigators at the beginning of the study. 
8.5. 
Insurance Policy 
The Sponsor will provide insurance and/or indemnity in accordance with the applicable 
regulatory requirements for each of the participating sites. 


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8.6. 
Notifications to Health Authorities 
The amendments to the protocol will be made only when such changes have been agreed in 
writing, and signed, by the principal Investigators and the sponsor. The protocol changes may 
represent changes in the informed consent of all participants, both prospective and already 
included. The participant and/or parent/legal guardian must sign a new consent if such changes 
occur. Any subsequent protocol amendments will be submitted to the relevant Ethical Review 
Boards and Competent Authorities in accordance with the local regulatory requirements in each 
country. When an amendment to a protocol substantially alters the study design or increases 
potential risk to the study participant, the Informed Consent Form will be revised and the 
participant's consent to continue participation will again be obtained. 
Deviations from the Protocol should be avoided, however if a deviation from the protocol is 
required for the safety of a participant the deviation will be made only for that participant. 
Within 48 hours of the deviation the principal Investigator and/or treating Investigator must 
inform the study sponsor or delegated CRO regarding the protocol deviation and rationale for the 
deviation. The principal Investigator and the sponsor will determine if the participant who has 
deviated from the protocol is able to continue in the study. These deviations will be described in 
the participant medical record and in the case report form, specifying the circumstances leading 
to the deviation. Where required by local regulations, the Institutional Review/Ethical Review 
Board and/or the Competent Authorities in the country where the deviation occurred will be 
informed. 


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9. 
STUDY REPORTS 
9.1. 
Final Study Report 
The sponsor will prepare a final Clinical Study Report that will include all data, results and 
observations through the final study visit for the final participant but will not include long-term 
follow-up information. The summary of this report will be submitted to the relevant authorities. 
The management, or publication, of any information relevant to this clinical trial will be in 
accordance with local and international regulatory requirements. 
9.2. 
Annual Study Reports 
According to national legislation, the Study sponsor or delegated CRO will submit information 
set forth as follows: 
a. Clinical Trial Annual Report. This will be a brief summary of the status of the trial in 
progress or completed during the previous year.  The summary will include   
information required by application relations of each country where the trial is being 
conducted. 
b. Annual Safety Report or Development safety update report (DSUR).  An annual 
summary   of all serious adverse events for an active compound in clinical evaluation 
with a safety evaluation relating to the ongoing study(ies). US and EU regulators 
consider that the DSUR, submitted annually, would meet national and regional 
requirements of each country where the trial is being conducted. 
For advanced therapy products such as gene therapy products, the long-term 
follow-up section should provide information from long-term follow-up of 
participants from clinical trials of investigational drugs. When the development 
program is completed and long-term follow-up is the only ongoing activity 
generating data for the DSUR, this could be the only section where new information 
is presented. 
c. Update Investigator’s brochure (IB). At least once per year according to Good 
Clinical Practice. This update should include any relevant new (including safety 
related) data on IMP, toxicology, clinical experience, etc. 
9.3. 
Data Safety Monitoring Plan 
9.3.1. 
The Data Safety Monitoring Board 
A DSMB will be established and act in an advisory capacity to review participant safety and 
study progress throughout the duration of the study. The DSMB will accomplish this advisory 
capacity through preplanned and possibly ad hoc reviews of accumulated data. Based on the 
findings of these reviews, the DSMB will make recommendations to the Sponsor regarding the 
study(ies). The Sponsor will be responsible for discussing and implementing the DSMB 
recommendations, if considered appropriate. 
Primary Responsibilities of the DSMB are to protect the safety and privacy of study participants, 
evaluate the progress of the study, monitor all SAEs and assess the risk/benefit balance in 
relation to the Investigational Medicinal Product. 


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The full scope of the DSMB members’ and relevant parties’ responsibilities, the organizational 
and communication structure, frequency and conduct of the meetings, and its membership will 
be documented in a DSMB charter. Study specific requirements will be documented and attached 
to the charter. 
9.3.2. 
DSMB Reporting and Meetings 
The DSMB will hold planned meetings during the course of the study. DSMB reviews will occur 
at least once per a year (or at other interval determined by the DSMB and based on study 
activities). The time period will encompass the start of the study with the first participant dosed 
and end with the conclusion of all study activities. 
The Sponsor (or designee) will provide the DSMB members with a report describing the status 
of the study and the current safety information prior to each DSMB meeting. The details of the 
data being included in the report to the DSMB will be documented in the charter. 
9.3.3. 
Membership 
DSMB will be comprised of a minimum of 4 members. DSMB members shall be completely 
independent of the Investigators and have no financial, scientific, or other conflicts of interest 
with the clinical studies. The DSMB is integrated by recognized experts and representatives 
from different fields relevant for the study. 
9.4. 
Clinical Monitoring of the Study 
The study will be monitored in compliance with the relevant regulation of each country, (for 
example parts of 21 CFR and ICH GCP Guidelines). The procedures outlined in the protocol and 
case report forms will be carefully reviewed by the PI and staff prior to study initiation to ensure 
appropriate interpretation and implementation. No deviations from the protocol shall 
be made except in emergency situations where alternative treatment is necessary for the 
protection, proper care and wellbeing of participants. 
Amendments will be submitted to the site’s local IRB/EC for their review and approval prior to 
implementation. When an amendment to a protocol substantially alters the study design or 
increases potential risk to the study participant, the Informed Consent Form will be revised and if 
applicable, participant's consent to continue participation will again be obtained. 
9.4.1. 
Data Management and Study Forms 
All data and observations will be documented on Case Report Forms (CRF) by source 
documentation. A Monitor will have access to the data to monitor adherence to the protocol and 
to applicable regulations, and the maintenance of adequate and accurate clinical records. A CRF 
will be completed for every participant that was registered for participation in the study. 
Case Report Forms will be reviewed in detail by the Monitor on a regular basis for which the 
Monitor will have access to participant medical records, laboratory data, and other source 
documentation. Monitor will make a decision as to data acceptability. If errors or omissions are 
found in the course of a data audit, or if clarification of data is required, the Case Report Form(s) 
in question will be corrected by the PI or his designee.  Data Resolution may be generated on 


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omissions or clarifications, to be completed, signed and dated, and maintained as a part of the 
CRF. 
The PI will sign and accept the indicated Case Report Form. This signature will indicate that 
thorough inspection of the data therein has been made and will thereby certify the contents of the 
form. 
The Sponsor will design a data collection system for managing the clinical trial. A web-based 
database will be created and managed by authorized users. CRFs will be transcribed to this 
web-based database. Data will be extracted from source documents (lab reports, echo reports, 
etc.) and transferred to the database as well. All source documents will be kept in a Participant 
Research Chart. 
An external Contract Research Organization (CRO) may also monitor the study on a regular 
basis to make sure the study is conducted in compliance with all regulatory aspects of the 
protocol. 


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10. 
SAMPLE MANAGEMENT 
In Spain, biological samples are regulated according to the Law 14/2007 of Biomedical Research 
which treatment regimen is developed by Royal Decree 1716/2011, of November 18, by which 
the basic requirements for authorization and operation of biobanks are established for biomedical 
research and treatment of biological samples of human origin, and the operation and organization 
of the  National  Registry  of  Biobanks  for  biomedical  research  are  regulated.  In addition, 
because the samples will be sent to be analyzed and stored to the USA, it needs to be in 
compliance with Royal Decree 65/2006, of 30 January, laying down requirements for the import 
and export of biological samples. 
Sample management will be performed according to National Statement on Ethical Conduct in 
Human Research 2007- Update (https://www.nhmrc.gov.au/guidelines-publications/e72) 
Any future research not related to the objectives of this clinical trial, in which the use of these 
biological samples is proposed must be approved by the IRB/EC. Future research may have 
different purposes, although the biological samples used in this study are to be kept only as long 
as they are necessary for the purposes for which they were collected. 
 


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11. 
GMO RISK MANAGEMENT 
For Europe, in regard to risk-based management plan for this type of advanced therapy medicinal 
products (EMA/CAT/CPWP/686637/2011), environmental risk assessment is described at the 
end of this point and other potential risk factors due to natural characteristics of the virus from 
which the vector is derived are described in the following paragraphs. 
The genetically modified organism (GMO), scAAV9.U1A.SGSH, is a recombinant vector 
derived from adeno-associated virus serotype 9 (AAV9), The vector is replication defective due 
to complete replacement of adeno-associated viral genes with a cassette of expression for human 
SGSH. The complete description of vector elements and vector production is described in the 
Investigational Brochure; however, some elementary risk factors are described here. 
This vector is classified as nonintegrating and nonpathogenic by research publication and 
regulatory guidelines (EMA/CAT/190186/2012), so insertional mutagenesis is not a risk concern 
with the recombinant vector. The potential risk for insertional oncogenesis is negligible. 
Therefore, there is minimal risk for potential chromosomal integration and resulting 
genotoxicity. 
It is worth mentioning that there is minimal risk of the vector for latency/reactivation and/or 
mobilization or potential for recombination/re-assortment. Vector tropism and immunogenicity 
are equivalent to wild type AAV9 virus. The genetic modification does not allow the viral vector 
to revert to wild type virus due to the absence of viral genes and inability to replicate or spread 
further from the transduced cell. Genetic stability is ensured due to similar size of the wild-type 
and recombinant viral expression cassettes, so genome rearrangements are not expected. The 
vector genome is completely sequenced in the DNA plasmid used for its generation. 
Recombinant AAV vectors are nonpathogenic, lack toxicity and avirulent and they do not 
activate latent virus and are not able to colonize other organisms. The most commonly known 
host range includes humans and nonhuman primates. 
Wild type AAV is not classified in Risk Groups 2, 3 or 4 in the European Union (EU) according 
to Directive 2000/54/EC on the protection of workers from risks related to exposure to biological 
agents at work. Therefore, it is most appropriately designated as a Risk Group 1 biological agent, 
defined in the EU as ‘one that is unlikely to cause human disease’. Additionally, AAVs are not 
assigned an Advisory Committee on Dangerous Pathogens (ACDP) category, so recombinant 
AAV viruses are also classified biosafety Group/Class 1. Similar classifications of hazard have 
been assigned to AAV according to the definitions of the World Health Organisation (WHO), 
and in the USA, Canada and Australia. This all means that the risk is null or insignificant. 
However, the hospital staff will receive, store, manipulate and destroy the gene therapy product 
and all biological samples (potentially containing also GMO) under biosafety rules type 1 
(BSL1). Hospital will follow internal procedures for biological product management. Briefly, the 
recombinant adeno-associated vector will be received by the pharmacy department according to 
the instructions of the sponsor in the Pharmacy Manual.  The storage will be performed in 
a -80ºC freezer located at pharmacy with a limited access. The final product preparation 
(defrost, potential dilution and syringe preparation) will be performed in a biosafety cabinet type 
2 (vertical flow for complete protection of environment and hospital staff) if required by the 
Competent Authorities. The syringe prepared for administration will be transported to the 
individual room where the participant is hospitalized in a proper box to avoid spills and labeled 


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as "containing GMO". All material used for GMO delivery and manipulation (empty vials, guide 
tube, cannula, stylet, injection needle and syringe) will be destroyed following internal 
procedures for biological management and BSL1. In addition, any disposable surgical 
instruments or other materials used during the administration procedure or collection of body 
fluids will be disposed according to standard biosafety practice of the institution. All non-
disposable surgical equipment will be cleaned using a chemical disinfectant with proven viricidal 
activity (e.g. hypochlorite 1% solution) and then sterilized by autoclaving according to standard 
practice of the institution. 
All health personnel involved in this trial will use biosafety practices level 1 during transport 
prior to and after administration and final disposal. In case of spillover, the perimeter of the spill 
will be limited with paper towels and appropriate virucidal agent will be used to clean the area: 
As all vectors based on adeno-associated viruses, scAAV9.U1A.SGSH is susceptible to 
appropriate virucidal disinfectants with activity for non-enveloped viruses such as 1-10% sodium 
hypochlorite (for at least 20 minutes), alkaline solutions at pH >9, 5% phenol, heat (>80°C for  
60 minutes), UV  radiation  and  extreme  pHs  (<2  and  >12).  Effective disinfectants require a 
minimum of 20 minutes contact time. In case of injury, the injured site will be disinfected 
appropriately according to the best biosafety practice standard and internal procedures. 
Participants will be admitted to the Hospital one by one, for a single intravenous administration. 
Participants will stay in an individual hospital room for at least 48 hours after gene transfer for 
close monitoring and then they will come back to the hospital for periodic visits (Days 7, 14, 30, 
etc). Testing for the release of vector will be conducted until the participant shows two 
consecutive negative results in previously collected samples. 
According to legislation for environmental risk assessments (guidelines 
EMEA/CHMP/ICH/449035/2009 and EMEA/CHMP/GTWP/125491/2006), shedding is defined 
as the dissemination of the virus/vector through secreta and/or excreta of the participant. 
Assessment of the shedding can be utilized to understand the potential risk associated with 
transmission to third parties and potential risk to the environment. It is worth mentioning that a 
limited release of the GMO to wastewater is expected after the administration to the participants. 
Preclinical data in relevant animal model for vector transduction (mice) is showing a positive 
shedding in feces and urine samples for a period of 35 days with a very low number of vector 
genomes. Additionally, the pH and biological conditions in urine and feces diminish the potential 
survival of the genetically modified organism.  However, the wastewater is not an ecosystem 
where GMO can survive for a long period of time. It is expected that GMO will be degraded 
after administration to humans by endogenous protein and DNA catabolic pathways. Shed vector 
DNA is expected not to be stable in wastewater. Taking into account these characteristics and the 
GMO replication incapacity, no interaction of the GMO with the flora, fauna, livestock or 
migratory species is expected. 
The potential GMO release to the environment will be analyzed in serum and biological fluids 
samples obtained from all treated participants according to the protocol of the clinical trial.       
As suggested by regulatory guidelines, samples will be taken more frequently in the first days 
following administration in order to detect a transient shedding profile. Serum, saliva, urine and 
feces will be collected at Day 0, 1, 2, 7, 14, and 30 after vector administration. Vector shedding 
analysis will continue to be collected and analyzed until two consecutive negative samples are 
collected or completion of the study by the participant, whichever comes first. Analysis will be 


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performed in order to obtain multiple consecutive negative measurements as suggested. 
Guidelines established that quantitative assays are preferred for shedding studies as this will aid 
in quantifying the probability of transmission. In fact, the use of quantitative PCR assays to 
detect viral/vector genetic material is recommended, because they are sensitive, reproducible and 
rapid.  The samples will be analyzed for GMO detection and quantification based on a specific 
qPCR.  It is worth mentioning that ELISpot, ELISA and PBLs samples will also be obtained to 
monitor the humoral and T cellular response that will also be assayed to monitor the indirect 
effect of the GMO presence by means of antibodies and T reactive cells. 
The risk of horizontal gene transfer to bacteria is most likely minimal but cannot be excluded. 
Even if horizontal gene transfer occurred, the sequences would not confer a selective advantage 
to other organisms (such as bacteria) since scAAV9.U1A.SGSH does not contain any 
prokaryotic promoters, any antibiotic- or other types of resistance genes or any genes, which 
would enhance or constrain their growth. Therefore, it is unlikely that scAAV9.U1A.SGSH 
would interfere with the control of pathogenic microorganisms or that it would have an effect    
on the natural dynamics of microbial populations or the biogeochemical cycles at any given site 
in the environment. 
The GMO is not pathogenic, and no side-effects have been reported for the environment or 
human health after the release of similar GMOs (adeno-associated virus from serotypes 2, 5, 8 
and 9), thus no undesirable effects are expected. However, if an undesirable effect occurs then 
the use of scAAV9.U1A.SGSH would-be put-on hold until the effects are fully assessed, and 
measures are put in place to mitigate further risks. In Spain, authorization, notification and report 
to the Ministry of Agriculture, Food and Environment (CIOMG) is part of the study management 
which fulfills with the applicable voluntary release defined in Law 9/2003, of April 25, 
approving the legal regime of the confined use, voluntary release and marketing of genetically 
modified organisms. 


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12. 
REFERENCES 
Bax MC and Colville GA (1995) Behaviour in mucopolysaccharide disorders. Arch Dis Child 
73(1): 77-81. 
Buhrman D, Thakkar K, Poe M, et al. (2014) Natural history of Sanfilippo syndrome type A. J 
Inherit Metab Dis 37(3): 431-437. 
de Ruijter J, Valstar MJ and Wijburg FA (2011) Mucopolysaccharidosis type III (Sanfilippo 
Syndrome): emerging treatment strategies. Curr Pharm Biotechnol 12: 923-930. 
Delgadillo V, O'Callaghan Mdel M, Gort L, et al. (2013) Natural history of Sanfilippo syndrome 
in Spain. Orphanet J Rare Dis 8: 189. 
Heron B, Mikaeloff Y, Froissart R, et al. (2011) Incidence and natural history of 
mucopolysaccharidosis type III in France and comparison with United Kingdom and Greece. Am 
J Med Genet A 155A(1): 58-68. 
Malm G and Mansson JE (2010) Mucopolysaccharidosis type III (Sanfilippo disease) in Sweden: 
clinical presentation of 22 children diagnosed during a 30-year period. Acta Paediatr 99(8): 1253-
1257. 
Meyer A, Kossow K, Gal A, et al. (2007) Scoring evaluation of the natural course of 
mucopolysaccharidosis type IIIA (Sanfilippo syndrome type A). Pediatrics 120(5): e1255-1261. 
Mingozzi F and High KA (2011) Immune responses to AAV in clinical trials. Curr Gene Ther 
11(4): 321-330. 
Neufeld EF and Cantz MJ (1971) Corrective factors for inborn errors of mucopolysaccharide 
metabolism. Ann N Y Acad Sci 179: 580-587. 
Neufeld EF and Muezner J (2014) The Mucopolysaccharidoses. he McGraw-Hill Companies, Inc., 
New York, NY,. 
Ruzo A, Marco S, Garcia M, et al. (2012) Correction of pathological accumulation of 
glycosaminoglycans in central nervous system and peripheral tissues of MPSIIIA mice through 
systemic AAV9 gene transfer. Hum Gene Ther 23(12): 1237-1246. 
Tardieu M (2014) ntracerebral administration of adeno-associated viral vector serotype rh.10 
carrying human SGSH and SUMF1 cDNAs in children with mucopolysaccharidosis type IIIA 
disease: results of a phase I/II trial. Hum Gene Ther 25: 506-516. 
Truxal KV, Fu H, McCarty DM, et al. (2016) A prospective one-year natural history study of 
mucopolysaccharidosis types IIIA and IIIB: Implications for clinical trial design. Mol Genet Metab 
119(3): 239-248. 


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Valstar MJ, Marchal JP, Grootenhuis M, et al. (2011) Cognitive development in patients with 
Mucopolysaccharidosis type III (Sanfilippo syndrome). Orphanet J Rare Dis 6: 43. 
Weber B, Guo XH, Kleijer WJ, et al. (1999) Sanfilippo type B syndrome (mucopolysaccharidosis 
III B): allelic heterogeneity corresponds to the wide spectrum of clinical phenotypes. Eur J Hum 
Genet 7(1): 34-44. 
Wijburg FA, Wegrzyn G, Burton BK, et al. (2013) Mucopolysaccharidosis type III (Sanfilippo 
syndrome) and misdiagnosis of idiopathic developmental delay, attention deficit/hyperactivity 
disorder or autism spectrum disorder. Acta Paediatr 102(5): 462-470. 
 


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STATEMENT OF COMPLIANCE 
Protocol Title: A Phase I/II Open Label, Single-dose, Gene Transfer Study of 
scAAV9.U1a.hSGSH (ABO-102) in Patients with Middle and Advanced Phases of MPS IIIA 
Disease   
Protocol Number: ABT-003 Version 5.0 22 September 2022 
INVESTIGATOR SIGNATURE: 
I have read the protocol and agree to conduct the study as detailed in this protocol and in 
compliance with the Declaration of Helsinki, Good Clinical Practice (GCP), and all applicable 
regulatory requirements and guidelines. 
 
 
 
 
 
 
Investigator Signature 
 
Date 
 
Printed Name: _______________________________________________________________ 
 
 
SPONSOR SIGNATURE: 
As the Sponsor representative, I confirm that Ultragenyx Pharmaceutical Inc. will comply with 
all Sponsor obligations as detailed in this protocol and in compliance with the Declaration of 
Helsinki, GCP, and all applicable regulation requirements and guidelines. I will ensure that the 
Investigator is informed of all relevant information that becomes available during the conduct of 
this study. 
 
 
 
 
 
 
  
Executive Director, Global Clinical Development 
Ultragenyx Pharmaceutical Inc. 
 
Date 
 
PPD

SAP_001.pdf: 
ABT-003 Statistical Analysis Plan Version 1.0
Statistical Analysis Plan
Protocol Version 4.0, 05 March 2020
Ultragenyx Pharmaceutical, Inc
A PHASE I/II OPEN LABEL, SINGLE-DOSE, GENE TRANSFER STUDY OF
SCAAV9.U1A.HSGSH (ABO-102) IN PATIENTS WITH MIDDLE AND ADVANCED 
PHASES OF MPS IIIA DISEASE
Phase I/II
Prepared by: __________________________
Statistician II
Pharmapace, Inc.
Version:
1.0
Date:
December 15, 2022
PPD
PPD


ABT-003 Statistical Analysis Plan Version 1.0
Statistical Analysis Plan
Protocol Version 4.0, 05 March 2020
A PHASE I/II OPEN LABEL, SINGLE-DOSE, GENE TRANSFER STUDY OF 
SCAAV9.U1A.HSGSH (ABO-102) IN PATIENTS WITH MIDDLE AND ADVANCED 
PHASES OF MPS IIIA DISEASE
Phase I/II
This Statistical Analysis Plan has been reviewed and approved by:
Date
Date
Date
PPD


 
ABT-003 Statistical Analysis Plan Version 1.0
 
3 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ........................................................................... 5 
1 
INTRODUCTION ........................................................................................................................................... 7 
2 
STUDY OBJECTIVES ................................................................................................................................... 7 
3 
STUDY OVERVIEW ..................................................................................................................................... 7 
3.1 
Study Design ........................................................................................................................................ 7 
3.2 
Study Procedures and Visit Structure ................................................................................................... 7 
4 
STUDY ENDPOINTS .................................................................................................................................. 13 
4.1 
Primary Endpoints .............................................................................................................................. 13 
4.2 
Secondary Endpoints .......................................................................................................................... 13 
4.3 
Exploratory Endpoints ........................................................................................................................ 13 
5 
ANALYSIS SETS ......................................................................................................................................... 14 
5.1 
Intent-to-Treat Set (ITT) ..................................................................................................................... 14 
6 
INTERIM ANALYSIS.................................................................................................................................. 14 
7 
STUDY SUBJECTS ..................................................................................................................................... 14 
7.1 
Subject Disposition ............................................................................................................................. 14 
7.2 
Demographic and Baseline Characteristics ........................................................................................ 14 
7.3 
Medical History .................................................................................................................................. 15 
7.4 
Inclusion/Exclusion Criteria ............................................................................................................... 15 
7.5 
Protocol Deviations ............................................................................................................................ 15 
7.6 
Treatment Administration and Study Duration ................................................................................... 15 
7.7 
Concomitant Medications and Non-drug Treatments ......................................................................... 15 
8 
STATISTICAL METHODS OF ANALYSIS ............................................................................................... 16 
8.1 
General Considerations ....................................................................................................................... 16 
8.1.1 
Descriptive Statistics ............................................................................................................ 16 
8.1.2 
Defining the Study Baseline ................................................................................................. 16 
8.1.3 
Handling of Multiple Observations ...................................................................................... 16 
8.1.4 
Handling of Missing or Partial Data ..................................................................................... 17 
8.2 
Efficacy Analyses ............................................................................................................................... 18 
8.2.1 
Analyses of Primary Efficacy Endpoints .............................................................................. 18 
8.2.2 
Analyses of Secondary Efficacy Endpoints .......................................................................... 18 
8.2.3 
 ...................................................................................... 19 
8.3 
Safety Analyses .................................................................................................................................. 19 
8.3.1 
Adverse Events (AEs) .......................................................................................................... 19 
8.3.2 
Clinical Laboratory Evaluations ........................................................................................... 20 
8.3.3 
Vital Signs and Physical Examination .................................................................................. 20 
8.3.4 
Electrocardiogram (ECG) and Echocardiogram ................................................................... 21 
8.4 
Definitions and Derived Variables ..................................................................................................... 22 
8.4.1 
Chronological Age ................................................................................................................ 22 
8.4.2 
Body Mass Index (BMI) ....................................................................................................... 22 
8.4.3 
Mullen Developmental Age (DA) and Developmental Quotient (DQ) ................................ 22 
8.4.4 
Vineland Adaptive Age Equivalent and Adaptive Developmental Quotient (DQ) .............. 22 
8.4.5 
Cognitive Bayley Developmental Age (DA) and Cognitive Developmental Quotient 
(DQ) ..................................................................................................................................... 23 
8.4.6 
 ........................................................................... 23 
8.4.7 
ire (CSHQ) ................................................... 23 
8.4.8 
 .................................................................. 23 
8.4.9 
Parenting Stress Index, 4th Edition (PSI-4) .......................................................................... 24 
8.4.10 Parent Global Impression Score (PGI) ................................................................................. 24 
8.4.11 Clinical Global Impression Improvement (CGI) .................................................................. 24 
8.4.12 Parent Symptoms Score Questionnaire (PSSQ) ................................................................... 24 
9 
STATISTICAL SOFTWARE ....................................................................................................................... 24 
10 CHANGES FROM THE PROTOCOL ......................................................................................................... 24 
CCI
CCI


 
ABT-003 Statistical Analysis Plan Version 1.0
 
4 
 
LIST OF TABLES 
Table 1. 
Schedule of Evaluations .................................................................................................................. 9 
 
 
 
 
 


 
ABT-003 Statistical Analysis Plan Version 1.0
 
5 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AAV9 
Adeno-Associated Viral Vector 
   
  
AE   
Adverse Event  
ALT   
Alanine Transaminase  
AST   
Aspartate Aminotransferase  
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
BUN   
Blood Urea Nitrogen  
CBC   
Complete Blood Cell Count  
CGI 
Clinical Global Impression Improvement Scale 
CRF   
Case Report Forms  
CSF   
Cerebrospinal Fluid  
CSHQ  
 
DA 
Developmental Age 
DNA   
Deoxyribonucleic Acid  
DQ   
Development Quotient  
 
 
ECG   
Electrocardiogram  
EDC 
Electronic Data Capture 
ELISA/ELISPOT Enzyme-Linked Immunosorbent Assay / Enzyme-Linked 
Immunospot Assay 
ERA   
Environmental Risk Assessment  
GAG   
Glycosaminoglycan  
GGT   
Gamma-Glutamyl Transpeptidase  
HIV   
Human Immunodeficiency Virus  
IMP 
Investigational Medicinal Product 
INR   
International Normalized Ratio (also known as 
prothrombin time [PT]) 
ITT 
Intention-to-Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI   
Magnetic Resonance Imaging  
MPS 
Mucopolysaccharidosis 
   
  
PedsQL   
Pediatric Quality of Life Inventory  
PGI 
Parent Global Impression Score 
PI   
Principal Investigator  
PSI-4   
Parenting Stress Index, 4th Edition 
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Abbreviation 
Definition 
PSSQ 
Parent Symptoms Score Questionnaire 
PT   
Prothrombin Time  
PTT   
Partial Thromboplastin Time  
AAV9   
Adeno-Associated Viral Vector  
SAE   
Serious Adverse Event  
SAP 
Statistical Analysis Plan 
   
  
SD 
Standard Deviation 
SE 
Standard Error 
SGSH   
N-Sulfoglucosamine Sulfohydrolase  
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Events 
vg/kg   
Vector genomes per kilogram  
WHODD 
World Health Organization Drug Dictionary 
 
 
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1 
INTRODUCTION 
This document provides a detailed description of the statistical methods and procedures to be 
implemented during the analysis of Ultragenyx Pharmaceutical, Inc. ABO-102 ABT-003. 
The proposed methods and approaches to the data analysis should be viewed as flexible. If 
the data suggest and warrant it, deviations from this plan will be considered. However, any 
deviations from this statistical analysis plan (SAP) must be substantiated by sound statistical 
rationale and documented in the clinical study report. 
2 
STUDY OBJECTIVES 
To evaluate the safety and efficacy of ABO-102 in patients with middle and advanced phases 
of Mucopolysaccharidosis (MPS) IIIA disease. 
3 
STUDY OVERVIEW 
3.1 
Study Design 
This Phase I/II clinical trial is an open-label, single dose study of recombinant, self-
complementary Adeno-Associated Viral Vector (AAV9) carrying the human N-
sulfoglucosamine sulfohydrolase (hSGSH) gene under the control of the U1a promoter, 
scAAV9.U1a.hSGSH, also known as ABO-102, delivered one time intravenously to MPS IIIA 
participants. The target population includes MPSIIIA participants with a Developmental 
Quotient (DQ) lower than 60 in middle and advanced phases of the disease that would not be 
eligible for the clinical trial ABT-001. To ensure that both the middle phase and advanced 
phase of the disease are adequately represented in the study, a similar number of participants 
with a cognitive age equivalent of above 18 months (middle) and below 18 months (advanced), 
as assessed by the Bayley Scales of Infant and Toddler Development, will be enrolled.  
During the active phase of the protocol, subjects will have 12 clinic visits and 5 labs visit 
over a two-year period. However, due to the study early termination, there will be at most 10 
clinic visits and 5 lab visits over a one-year period. Unscheduled visits may be needed per the 
discretion of the investigator. Efficacy and safety will be evaluated. 
3.2 
Study Procedures and Visit Structure 
After screening evaluations, eligible subjects will receive 3 x 1013 vg/kg of ABO-102 
(scAAV9.U1a.hSGSH) delivered one time through a venous catheter inserted into a 
peripheral limb vein. A tapering course of prophylactic enteral prednisone or prednisolone 
will be administered. Subjects will remain in hospital following gene transfer for up to 48 
hours post gene transfer for close monitoring, after which they will come back to the hospital 
for periodic visits over a two-year period. Subjects will be requested to participate in a 
separate 3 years long-term follow-up study (LTFU-ABO-102, EudraCT number 2019-


 
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002979-34). If subjects do not consent to participate in the new study, the annual medical 
records will be collected for the same period.  
Visits and procedures are summarized in the Error! Reference source not found. table 1 
below. 


 
 
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Table 1. 
Schedule of Evaluations 
STUDY TIMELINE OF EVENTS 
 
 
 
 
 
 
 
 
 
 
 
Admission/ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
steroids 
 
 
 
 
 
 
Month 
 
Month 
 
Month 
 
 
 
 
 
 
 
 
+/- 2 days +/- 2 days +/- 3 days +/- 3 days +/- 7 days +/- 3 days +/- 7 days +/- 7 days 
+/- 7 days 
+/- 7 days +/- 21 days 
+/- 30 
days 
+/- 30 
days 
+/- 30 
days 
 
1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
2 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
16
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9 
9 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
11 
11 
11 
11 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12 
13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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STUDY TIMELINE OF EVENTS 
 
 
 
 
 
 
 
 
 
 
 
Admission/ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
steroids 
 
 
 
 
 
 
Month 
 
Month 
 
Month 
 
 
 
 
 
 
 
 
+/- 2 days +/- 2 days +/- 3 days +/- 3 days +/- 7 days +/- 3 days +/- 7 days +/- 7 days 
+/- 7 days 
+/- 7 days +/- 21 days 
+/- 30 
days 
+/- 30 
days 
+/- 30 
days 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10 
10 
10 
10 
10 
10 
10 
10 
10 
10 
10 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
5 
5 
 
6 
 
 
 
 
  
7  
7  
 
 
7 
7 
7 
7 
 
 
 
 
8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
17
17
17
17
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3 
 
 
 
 
  
 
 
 
 
 
 
 
 
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STUDY TIMELINE OF EVENTS 
 
 
 
 
 
 
 
 
 
 
 
Admission/ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
steroids 
 
 
 
 
 
 
Month 
 
Month 
 
Month 
 
 
 
 
 
 
 
 
+/- 2 days +/- 2 days +/- 3 days +/- 3 days +/- 7 days +/- 3 days +/- 7 days +/- 7 days 
+/- 7 days 
+/- 7 days +/- 21 days 
+/- 30 
days 
+/- 30 
days 
+/- 30 
days 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
18 
18  
18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PedsQL  Gastrointestinal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
19 
19 
19 
19 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prednisolone/Prednisolone 
 
 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4 
 
4  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
15 
 
 
 
 
 
 
 
 
 
 
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STUDY TIMELINE OF EVENTS 
 
 
 
 
 
 
 
 
 
 
 
Admission/ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
steroids 
 
 
 
 
 
 
Month 
 
Month 
 
Month 
 
 
 
 
 
 
 
 
+/- 2 days +/- 2 days +/- 3 days +/- 3 days +/- 7 days +/- 3 days +/- 7 days +/- 7 days 
+/- 7 days 
+/- 7 days +/- 21 days 
+/- 30 
days 
+/- 30 
days 
+/- 30 
days 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4 
STUDY ENDPOINTS 
4.1 
Primary Endpoints 
 Product Safety as defined by the incidence, type and severity of treatment-related 
adverse events (AEs) and serious adverse events (SAEs) at Month 1, 2, 3, 6, 12 
 Change from baseline in Cerebrospinal Fluid (CSF) heparan sulfate levels after 
treatment at Month 1, 6, 12 
 Change from baseline in liver and/or spleen volumes after treatment, as measured by 
magnetic resonance imaging (MRI) at Month 1, 6, 12 
4.2 
Secondary Endpoints 
 Change from baseline in plasma or urine glycosaminoglycans or heparan sulfate after 
treatment at Month 1, 6, 12 
 Change from baseline in CSF or plasma or leukocyte SGSH enzyme activity levels 
after treatment at Month 1, 6, 12 
 Change from baseline in brain volumes after treatment, as measured by MRI at 
Month 12 
 
Habits Questionnaire (CSHQ) at Month 6, 12  
 
Generic Scales total score at Month 6, 12 
 Change from baseline in parent quality of life, using the Parenting Stress Index, 4th 
Edition (PSI-4) at Month 6, 12 
 
Gastrointestinal Symptoms Scales at Month 6, 12 
 Parent Global Impression Score at Month 6, 12 
 Clinical Global Impression Improvement Scale at Month 6, 12  
 Change from baseline in Parent Symptoms Score Questionnaire at Month 6, 12  
 Change from baseline in Body Mass Index (BMI) after treatment at Month 6, 12  
 Incidence and change from baseline in abnormalities in standard awake 45-minutes-
EEG monitoring at Month 6, 12 
 Determination of vector shedding analysis in plasma, saliva, urine and feces will 
provide preliminary data for the Environmental Risk Assessment (ERA)  
4.3 
Exploratory Endpoints 
 
 
 
  
 
 
 
 
 
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5 
ANALYSIS SETS 
The following population will be defined for study summaries and analyses.  
5.1 
Intent-to-Treat Set (ITT) 
The ITT Set will include all enrolled subjects who received ABO-102 and have at least one 
post-baseline efficacy measurement. Efficacy and safety analyses will be conducted based on 
the ITT Population. 
The primary endpoints, secondary endpoints, 
 endpoints will be analyzed 
using the ITT Set. At the time of the study termination, all 5 enrolled subjects were treated 
and had at least one post-baseline assessment. Therefore, the ITT Population is equivalent to 
all patients enrolled and will be used to evaluate both safety and efficacy data and for 
populating listings. 
6 
INTERIM ANALYSIS 
Interim analysis will not be conducted due to the early study termination. 
7 
STUDY SUBJECTS 
7.1 
Subject Disposition 
Subject disposition will be summarized and listed for the ITT Set. Counts and percentages of 
subjects who completed the trial or discontinued from the trial, as well as the discontinuation 
reasons, will be summarized. Subject enrollment by site will also be summarized. 
Subject counts and percentages in each category will be provided in the summary table. The 
number of enrolled subjects will be used as the denominator for calculating percentages. 
7.2 
Demographic and Baseline Characteristics 
Patient characteristics such as patient age, gender, race, ethnicity, and height, weight, and 
BMI at baseline will be summarized for the ITT Set. 
Continuous variables (including: age, height, weight, BMI) will be summarized using 
descriptive statistics. Categorical variables (including: gender, race, ethnicity) will be 
summarized using group frequencies and percentages, as appropriate. 
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7.3 
Medical History 
Medical history will be summarized and listed for the ITT Set. Medical history will be coded 
using system organ class (SOC) and preferred terms from the latest version of the Medical 
Dictionary for Regulatory Activities (MedDRA). The number and percentage of subjects 
within each SOC and PTs will be presented. 
7.4 
Inclusion/Exclusion Criteria 
Inclusion and exclusion criteria failures will be provided in a listing for the ITT Set. 
7.5 
Protocol Deviations 
Protocol deviations will be listed for the ITT Set. Protocol deviations may include but are not 
limited to deviation from informed consent, study procedure, study medication 
administration, or study restrictions. All protocol deviations will be reviewed by clinical and 
statistical teams to identify major protocol deviation prior to database lock. 
Each protocol deviation will be classified into minor or major by subject matter experts based 
on ICH guidelines: 
 Major: Major protocol deviations are defined as a subset of protocol deviations that 
may significantly impact the completeness, accuracy, and/or reliability of the study 
data or 
-being. 
 Minor: Minor protocol deviations are defined as any change, divergence, or departure 
from the study design or procedures defined in the protocol. These deviations would 
not be expected to adversely affect the rights, safety or well-being of the subjects 
and/or the quality and integrity of data. 
7.6 
Treatment Administration and Study Duration  
The extent of treatment will be summarized as follows:  
 Descriptive statistics for Duration of study (months) 
 The number and percentage of patients in the following categories of duration of 
study:  < 1 month, 1-< 2 months, 2-< 6 months, 6-< 12 months, 12+ months. Study 
duration (days) is defined as last visit date  dose date + 1, and 1 month = 30 days. 
7.7 
Concomitant Medications and Non-drug Treatments 
Concomitant and non-drug treatments refer to all drug and non-drug treatments taken during 
the study, whether or not they are recorded at baseline (i.e., have stop day greater than or 
equal to day 1 relative to first dose of study drug). All medications will be classified using 
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dictionary. The Anatomical Therapeutic Chemical (ATC) classification and preferred term 
will be included after coded.  
ATC and preferred term will be used to list and summarize the data. If a subject records 
multiple drugs with the same preferred term, these shall be summarized once within the 
count for N (%) of subjects.  
8 
STATISTICAL METHODS OF ANALYSIS 
8.1 
General Considerations 
Efficacy and Safety analyses will be performed using the ITT Set. All data collected during 
the study for the ITT Set will be included in data listings. 
8.1.1 Descriptive Statistics 
For descriptive statistical summaries, continuous variables will be summarized by number of 
observations (n), mean, standard deviation (SD), standard error (SE), median, minimum 
(MIN), and maximum (MAX). For categorical variables, frequency/count and percentage of 
subjects in each category will be provided. 
Minimum and maximum values will be presented at the same precision as the original value. 
Mean and median values will be rounded to one decimal place greater than the precision of 
the original value. SDs and SEs will be rounded to two decimal places greater than the 
precision of the original value. Percentages for summarizing categorical data will be rounded 
to one decimal place. 
The by-subject listings, including data at scheduled and unscheduled visits, will be sorted by 
subject number, and then by date/time of the records.  
8.1.2 Defining the Study Baseline 
Baseline is defined as the last non-missing measurement obtained prior to the administration 
of the study drug for all efficacy and safety measures. Screening visits will not be 
summarized and will only be listed, unless an assessment taken at screening is considered 
baseline by definition.  
8.1.3 Handling of Multiple Observations 
For efficacy data, if multiple records were recorded for the same protocol-defined visit, the 
re-assayed data will be used for data summary and analysis. Re-assayed data from 
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If a subject has a scheduled visit, the assessment obtained at the scheduled visit will be used 
for data summary and analysis. Otherwise, if no scheduled visit assessment exists but at least 
one unscheduled visit assessment is available within the protocol-defined visit window, then 
the data at the latest unscheduled visit within the protocol-defined visit window will be used 
for data summary and analysis.  
Any unscheduled visits that cannot be attributed to a scheduled visit according to a protocol-
defined visit window will not be included in descriptive statistical summaries but will be 
presented in listings. 
8.1.4 Handling of Missing or Partial Data 
 Missing baseline values will not be imputed in any situation. 
 Missing post-baseline values for by-visit data will be summarized using the protocol-
defined visit windows. If a value is not available within a given window, no 
imputation will be done. 
 If day of birth is missing, the 1st day of the month will be used to calculate 
chronological age. 
 Missing data for AE relationship will be imputed 
. 
 For incomplete dates for AEs or non-study medications, the missing component(s) 
will be assumed as the most conservative value(s) possible. Actual data values, as 
they appear in the clinical database, will be shown in the data listings. Rules for 
partial dates are described in the table below. If the AE year is missing or AE is 
ongoing, the end date will not be imputed. Note: in the table, D = day, M = month, 
and Y = year. 
Parameter 
Missing 
Additional Conditions 
Imputation 
Start date for AEs 
Time only 
 
Time will not be imputed; but 
will be assumed to be after gene 
transfer time 
D only 
M and Y same as M and Y of gene 
transfer date 
Date of gene transfer 
M and/or Y not same as M and Y 
of gene transfer date 
First day of non-missing month 
D and M 
Y same as Y of gene transfer date 
Date of gene transfer 
Y not same as Y of gene transfer 
date 
Use January 1 of non-missing 
year 
M, D and Y 
None  date completely missing 
Date of gene transfer 
Stop date for AEs 
Time only 
 
Time will not be imputed 
D only 
 
Last day of non-missing month      
D and M 
 
Use December 31 of non-
missing year 
M, D and Y 
Deceased  
Date of death 


 
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Parameter 
Missing 
Additional Conditions 
Imputation 
Not deceased 
Date of the end of trial 
participation 
Start date for 
concomitant meds 
D only 
M and Y same as M and Y of gene 
transfer date 
Date of gene transfer 
M and/or Y not same as M and Y 
of gene transfer date 
First day of non-missing month 
D and M 
Y same as Y of gene transfer date 
Date of gene transfer 
Y not same as Y of gene transfer 
date 
Use January 1 of non-missing 
year 
M, D and Y 
None  date completely missing 
Date of gene transfer 
Stop date for 
concomitant meds 
D only 
M and Y same as M and Y of gene 
transfer date 
Last day of non-missing month      
M and/or Y not same as M and Y 
of gene transfer date 
Last day of non-missing month      
D and M 
Y same as Y of gene transfer date 
Use December 31 of non-
missing year 
Y not same as Y of gene transfer 
date 
Use December 31 of non-
missing year 
M, D and Y 
None  date completely missing 
Date will not be imputed 
8.2 
Efficacy Analyses 
8.2.1 Analyses of Primary Efficacy Endpoints 
 Change from baseline in CSF heparan sulfate levels after treatment at Month 1, 6, 12 
 Change from baseline in liver and/or spleen volumes after treatment, as measured by 
MRI at Month 1, 6, 12 
Descriptive statistics (N, mean, SD, SE, median, MIN, and MAX) will be calculated at 
baseline and each post-baseline time point for observed values and change from baseline. 
8.2.2 Analyses of Secondary Efficacy Endpoints 
 Change from baseline in plasma or urine glycosaminoglycans or heparan sulfate after 
treatment at Month 1, 6, 12 
 Change from baseline in CSF or plasma or leukocyte SGSH enzyme activity levels 
after treatment at Month 1, 6, 12 
 Change from baseline in brain volumes after treatment, as measured by MRI at 
Month 12 
 Change from baseline in sleep pattern as measured by the modified CSHQ at Month 
6, 12  
 
nth 6, 12 
 Change from baseline in parent quality of life, using the PSI-4 at Month 6, 12 


 
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Gastrointestinal Symptoms Scales at Month 6, 12 
 Change from baseline in Parent Symptoms Score Questionnaire at Month 6, 12 
 Parent Symptoms Score Questionnaire at Month 6, 12 
 Parent Global Impression Score at Month 6, 12 
 Clinical Global Impression Improvement Scale at Month 6, 12 
 Incidence and change from baseline in abnormalities in standard awake 45-minutes-
EEG monitoring at Month 6, 12 
All of the above secondary efficacy endpoints will be presented by listings only. 
 Determination of vector shedding analysis in plasma, saliva, urine and feces will 
provide preliminary data for the ERA 
 
Vector shedding samples will continue to be collected and analyzed until two consecutive 
negative samples are collected or completion of the study by the subject, whichever comes 
first. 
Observed values and change from baseline in copies per 1mL of specimen in plasma, saliva, 
urine and feces will be summarized descriptively at baseline and each post-baseline time 
point. Copies per 1mL of specimen in feces will be presented as a spaghetti plot over each 
visit by subject.  
8.2.3 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
8.3 
Safety Analyses 
8.3.1 Adverse Events (AEs) 
AE tables (except for AE overview table) will only include summaries of treatment-emergent 
adverse events (TEAE). TEAEs will be defined as those occurring during or after gene 
transfer on Visit 3 (Day 0). All AEs should be reviewed by Medical Monitor or Designee 
before the database is locked.  All reported terms (investigator descriptions) for AEs should 
be reviewed by Medical Monitor or Designee before the database locked and will be coded 
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using the latest version of MedDRA. Number and percentage of subjects with TEAEs will be 
summarized by system organ classification and preferred term. 
An overview table will be provided with the number and percent of the following categories, 
if applicable: 
 Number of total AEs, TEAEs, and deaths 
 Incidence of patients with at least one: TEAE, TEAEs related to study treatment 
(IMP-related TEAE), SAE, IMP-related SAE, non-serious TEAEs, and deaths 
 Incidence of patients who discontinued due to: TEAE, IMP-related TEAE, SAE, and 
IMP-related SAE 
 Incidence of deaths and deaths due to IMP-related TEAE 
TEAEs leading to discontinuation of study drug, IMP-related TEAE, serious TEAEs, non-
serious TEAEs, and TEAEs by severity will be summarized and listed. Deaths will be listed, 
if any. 
AEs occurring prior to gene transfer are defined as pre-treatment AEs and will be listed only. 
AEs with relationship P
, 
 IMP are defined as AEs 
related to study treatment. 
Safety primary endpoint 
 Product Safety as defined by the incidence, type and severity of treatment-related 
AEs and SAEs at Month 1, 2, 3, 6, 12 
Product safety will be assessed by the incidences of treatment-related AEs and SAEs type 
and severity at each time point (<1 month, 1-<2 months, 2-< 3 months, 3-<6 months, 6-<12 
months, and >= 12 months from treatment date to AE onset date). Counts of subjects and 
percentages will be provided for baseline and post-baseline visits. Treatment-related AE is 
defined as AE 
D
 study drug. 
8.3.2 Clinical Laboratory Evaluations 
Hematologic, chemistry, coagulation and urinalysis laboratory measurements will be 
summarized by visit. For the continuous data, descriptive statistics (n, mean, SD, median, 
minimum, maximum) in change (absolute and percent) will be presented. For the categorical 
data, the number and the percentage of subjects for each observed category under each 
analyte will be summarized.  
8.3.3 Vital Signs and Physical Examination 
Vital Signs 
Vital signs will include weight, height, BMI, head circumference, body temperature, heart 
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points. Summary statistics will be calculated at baseline and follow-up time points as well as 
the nominal and percent changes from baseline for each visit. 
Physical Exams 
Adverse physical examination changes are captured as AEs. Physical Exam findings and 
vital signs will be included in the listings. Physical exam findings will be listed at each visit. 
8.3.4 Electrocardiogram (ECG) and Echocardiogram 
Electrocardiogram 
The following ECG measurements are taken in 12-lead ECG at Screening/Visit 1, Visit 8 
(Day 90), Visit 9 (Day 180), Visit 10 (Month 12): 
 Overall evaluation (normal; abnormal-clinically significant; abnormal-not clinically 
significant). 
The number and percentage of individuals on overall evaluation with normal, abnormal-not 
clinically significant, abnormal-clinically 
 
All reported abnormal values will be listed.  
Echocardiogram 
The following measurements are taken at Screening/Visit 1, Visit 8 (Day 90), Visit 9 (Day 
180), Visit 10 (Month 12): 
 Fractional shortening % 
 LV Ejection fraction % 
 Overall evaluation (normal; abnormal-clinically significant; abnormal-not clinically 
significant) 
For the continuous data, descriptive statistics (n, mean, standard deviation, median, 
minimum, maximum) in raw and change (absolute and percent) will be presented.  
The number and percentage of individuals on overall evaluation with normal, abnormal-not 
clinically significant, abnormal-clinically significant results will be tabulated.  
All reported abnormal values will be listed. 


 
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8.4 
Definitions and Derived Variables 
8.4.1 Chronological Age 
Chronological Age (months) will be calculated using the Date of Birth and the testing date.  
Chronological Age = (Testing Date  Date of Birth +1) / 30   
8.4.2 Body Mass Index (BMI) 
in meters. 
BMI = weight in kilograms / (height in meters)2 
8.4.3 Mullen Developmental Age (DA) and Developmental Quotient (DQ) 
Mullen Developmental Age (in months) is calculated as the mean of the age equivalents 
obtained from the scores of four out of the five domains of the scale except Gross motor.  
Mullen DA = (Fine Motor Age Eq + Receptive Language Age Eq + Expressive 
Language Age Eq + Visual Reception Age Eq) / 4 
Mullen DQ = (Mullen DA / Chronological Age) * 100 
8.4.4 Vineland Adaptive Age Equivalent and Adaptive Developmental Quotient (DQ) 
Vineland Adaptive Developmental (in months) is calculated using the Age Equivalents from 
the 11 subdomains of the scale. Instead of using the mean of the 11 subdomains, the 
subdomains are first grouped into four areas, and the Adaptive Age Equivalent is calculated 
from the mean of those four areas. Example: 
 Communication Age Equivalent is calculated as the mean of: Receptive Age Eq + 
Expressive Age Eq + Written Age Eq 
 Daily living skills Age Equivalent is calculated as the mean of: Personal Age Eq + 
Domestic Age Eq + Community Age Eq 
 Socialization Age Eq is calculated as the mean of: Interpersonal relationships Age Eq 
+ Play and Leisure Time Age Eq + Copying Skills Age Eq 
 Motor Skills Age Eq is calculated as the mean of: Fine Age Eq 
Vineland Adaptive Age Equivalent = (Communication Age Eq + Daily living skills 
Age Eq + Socialization Age Eq + Motor Skills Age Eq) / 4  
Vineland DQ = (Vineland Age equivalent / Chronological Age) * 100 


 
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The Vineland Adaptive AE and Adaptive DQ scores will be collected through Case Report 
Forms (CRF) and will not be recalculated during programming. 
8.4.5 Cognitive Bayley Developmental Age (DA) and Cognitive Developmental 
Quotient (DQ) 
Mean Developmental Age (DA) = (Developmental Age for Cognitive + 
Developmental Age for Receptive Language + Developmental Age for Expressive 
Language + Developmental Age for Fine Motor) / 4  
Cognitive DQ = (Cognitive Developmental Age / Chronological age) *100  
DQ = (Mean Developmental Age/ Chronological age) *100 
8.4.6 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.4.7 M
 
CSHQ total score is calculated by adding all the 8 subscores. All scores will be collected 
through CRF and will not be recalculated during programming. 
8.4.8 
 
The PedsQL Core Generic Scales will use PedsQL Core Total Score in CRF. The PedsQL 
Gastrointestinal Symptoms Scales will use PedsQL GI Symptoms Score in CRF.   
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8.4.9 Parenting Stress Index, 4th Edition (PSI-4) 
Total raw score is calculated by adding the three subscores: Raw score = (PD) + (P-CDI) + 
(DC). The raw score will be converted to total stress score. All scores will be collected through 
CRF and will not be recalculated during programming. 
8.4.10 Parent Global Impression Score (PGI) 
PGI total score is calculated by adding all the 9 subscores. All scores will be collected through 
CRF and will not be recalculated during programming. 
8.4.11 Clinical Global Impression Improvement (CGI) 
The Clinical Global Impression Improvement Scale Score will use CGI Global Improvement 
score in CRF. 
8.4.12 Parent Symptoms Score Questionnaire (PSSQ) 
The Parent Symptoms Score Questionnaire contains 29 symptoms with an indicator of 
whether the symptom was present or absent, and if present, a ranking value. Number of 
patients who have the symptom and average rank for each symptom will be calculated by 
visit.  
9 
STATISTICAL SOFTWARE 
All statistical analyses will be performed using SAS® version 9.4. 
10 CHANGES FROM THE PROTOCOL 
Due to the study early termination and only 5 subjects being enrolled, there will be no 
comparison to natural history study data.