Clinical trial NCT02350816
Conditions: Sanfilippo Syndrome Mucopolysaccharidosis (MPS)
Sponsor: Shire
Start date: 2015-04-08; Completion date: 2019-04-12
Enrollment: 17 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This extension study will allow participants to continue receiving treatment with HGT-1410 and to initiate treatment in patients who received no-treatment in Study HGT-SAN-093, and will evaluate the long-term safety and efficacy of the study drug.

Detailed description:

Arms: arm 1: Patients in Group 1 will continue HGT-1410 treatment at a dose of 45 mg administered every 2 weeks (Q2W) starting at Week 50, with a cumulative treatment period of up to 42 months (168 weeks) . HGT-1410 will be administered intrathecally (IT) by an indwelling intrathecal drug delivery device (IDDD).

HGT-SAN-093 = NCT02060526 arm 2: Patients in Group 2 will continue HGT-1410 treatment at a dose of 45 mg administered every 4 weeks (Q4W) starting at Week 52, with a cumulative treatment period of up to 42 months (168 weeks). HGT-1410 will be administered intrathecally (IT) by an indwelling intrathecal drug delivery device (IDDD). arm 3: Patients in Group 3A will receive an IDDD following informed consent and will be randomized in a 1:1 allocation ratio to begin HGT-1410 treatment at a dose of 45 mg administered every 2 weeks (Q2W) starting at Week 0 of the extension study, with a cumulative treatment period of up to 30 months (120 weeks). HGT-1410 will be administered intrathecally (IT) by an indwelling intrathecal drug delivery device (IDDD). arm 4: Patients in Group 3B will receive an IDDD following informed consent and will be randomized in a 1:1 allocation ratio to begin HGT-1410 treatment at a dose of 45 mg administered every 4 weeks (Q4W) starting at Week 0 of the extension study, with a cumulative treatment period of up to 30 months (120 weeks). HGT-1410 will be administered intrathecally (IT) by an indwelling intrathecal drug delivery device (IDDD).
Interventions: intervention 1: HGT-1410
Intervention descriptions: intervention 1: HGT-1410 administered according to Patient Group assignment.

Protocol documents:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
 
 
NCT Number:   
NCT02350816 
 
Study Title:  
An Open-Label Extension of Study HGT-SAN-093 Evaluating the Safety and 
Efficacy of HGT-1410 (Recombinant Human Heparan N Sulfatase) 
Administration via an Intrathecal Drug Delivery Device in Pediatric Patients 
with Mucopolysaccharidosis Type IIIA Disease 
 
 
Study Number:  
SHP610-201 
 
 
Protocol Version and Date:  
 
Original Protocol: 23 September 2014 
Amendment 1: 17 December 2015 
Amendment 2: 25 January 2017 


Clinical Trial Protocol:  SHP-610-201
Study Title:
An Open-Label Extension of Study HGT-SAN-093 Evaluating the 
Safety and Efficacy of HGT-1410 (Recombinant Human Heparan N 
Sulfatase) Administration via an Intrathecal Drug Delivery Device in 
Pediatric Patients with Mucopolysaccharidosis Type IIIA Disease
Study Number:
SHP-610-201
Study Phase:
IIb
Product Name:
HGT-1410
Device Name:
SOPH-A-PORT® Mini S, Implantable Access Port, Spinal, Mini 
Unattached, with Guidewire
IND Number:
102165
EUDRACT Number
2014-003960-20
Indication:
Long term treatment of Mucopolysaccharidosis Type IIIA (MPS IIIA 
or Sanfilippo Syndrome Type A)
Investigators:
Multicenter
Sponsor:
Shire Human Genetic Therapies, Inc.
Sponsor Contact:
300 Shire Way
Lexington, MA  02421 USA
+1-617-349-0200
Medical Monitor:
, MD
Date
Original Protocol:
23 September 2014
Confidentiality Statement
This document is the proprietary and confidential property of Shire Human Genetic 
Therapies, Inc.


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SYNOPSIS
Sponsor:
Shire Human Genetic Therapies, Inc. (Shire)
Name of Finished Product:
HGT-1410 (Recombinant Human Heparan N Sulfatase or rhHNS)
Name of Device:
SOPH-A-PORT® Mini S, Implantable Access Port, Spinal, Mini Unattached, with 
Guidewire (SOPH-A-PORT ® Mini S)
Study Title:
An Open-Label Extension of Study HGT-SAN-093 Evaluating the Safety and Efficacy of 
HGT-1410 (Recombinant Human Heparan N Sulfatase) Administration via an Intrathecal 
Drug Delivery Device in Pediatric Patients with Mucopolysaccharidosis Type IIIA 
Disease
Study Number:
SHP-610-201
Study Phase:  IIb
Investigational Product, Dose, and Mode of Administration:  
HGT-1410 at a dose of 45 mg administered every 2 weeks (Q2W) or 45 mg administered 
every 4 weeks (Q4W). HGT-1410 will be administered intrathecally (IT) by an 
indwelling intrathecal drug delivery device (IDDD).
Device, Intended Use
The SOPH-A-PORT ® Mini S is a system intended for implantation by physicians. The 
SOPH-A-PORT ® Mini S, once implanted, allows healthcare personnel to administer 
HGT-1410 indicated for intrathecal delivery intermittently over a long period of time.
Comparator, Dose, and Mode of Administration:
Not applicable
Primary Objective(s):  
To evaluate long-term safety in patients with mucopolysaccharidosis type IIIA disease 
(MPS IIIA or Sanfilippo Type A) who received HGT-1410
Secondary Objective(s):
To evaluate:

The long-term cognitive function as measured by the Bayley Scales of Infant and 
Toddler Development, 3rd Edition (BSID-III) or Kaufman Assessment Battery 
for Children, 2nd Edition (KABC-II), age-equivalent and developmental quotient
(DQ) scores in patients with MPS IIIA who received HGT-1410

The long-term adaptive behavioral function, assessed by Vineland Adaptive 
Behavior Scales, Second Edition (VABS-II) in patients who received HGT-1410

The total cortical grey matter volume, as assessed by volumetric MRI of the 
brain, in patients who received HGT-1410
Exploratory Objective


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Pharmacokinetic and Pharmacodynamic Objectives
To evaluate:

The pharmacokinetics (PK) of HGT-1410 in serum

The PK of HGT-1410 in cerebrospinal fluid (CSF), in patients who received 
no-treatment in Study HGT-SAN-093

The concentration of glycosaminoglycans (GAG) in CSF and urine in patients 
who received HGT-1410
Health Status Objective 
To evaluate health status as measured by the Infant Toddler Quality of Life 
Questionnaire™ (ITQoL) instrument in patients who received HGT-1410
Health Economics and Outcomes Research Objectives
To evaluate healthcare resource utilization, as evaluated by the Healthcare Utilization 
Questionnaire (HCUQ), in patients who received HGT-1410.
Study Endpoints:  
Safety evaluations include the assessment of adverse events (AEs), IDDD related issues, 
laboratory values, anti-rhHNS antibody development, vital signs, physical examination 
findings, and ECG results
The secondary endpoints of this study are:
The change from Baseline in BSID-III or KABC-II age-equivalent, DQ, and 
developmental delay scores
The change from Baseline in adaptive behavioral function domains, assessed by VABS 
II, using raw scores, age-equivalent scores, and DQ scores
The change from Baseline in total cortical grey matter volume, as assessed by MRI
The PK endpoint is to determine the pharmacokinetic behavior of HGT-1410 in serum. 
The pharmacokinetic behavior of HGT-1410 in CSF will also be determined in patients 
who received no-treatment in Study HGT-SAN-093.
The pharmacodynamic (PD) endpoint is to determine the GAG concentrations in CSF 
and urine.
The health status endpoint is the ITQoL scores at each assessment time and the 
corresponding change from Baseline.
The health economic and outcome research endpoints evaluate key HCUQ variables, 
such as the number of emergency room visits, caregiver employment status (full-time 
[FT], part-time [PT], or not working [NW]), and the number of hours of additional paid 
help needed by caregivers, over the course of the study.


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Study Population:  
A maximum of 18 patients with MPS IIIA and who completed Study HGT-SAN-093 are 
planned to enroll in this study. 
Study Design:
This is an open-label study for patients who completed through at least the Week 48 Visit 
of Study HGT-SAN-093. Patients who originally received HGT-1410 in Study 
HGT-SAN-093 will remain on the same dosing regimen as they received in Study 
HGT-SAN-093; Group 1 will receive HGT-1410 Q2W and Group 2 will received 
HGT-1410 Q4W. Patients in Groups 1 and 2 will begin treatment at Week 50 and Week 
52, respectively, of this extension study (Study SHP-610-201). Patients who originally 
received no-treatment in Study HGT-SAN-093 (Group 3) will receive an IDDD 
following informed consent and will be re-randomized in a 1:1 allocation ratio to receive 
HGT-1410 via a Q2W or Q4W dosing regimen (Groups 3A and 3B, respectively) in 
Study SHP-610-201. Patients in Groups 3A and 3B will begin treatment on Week 0 of 
the extension study.
It is anticipated that the IDDD will be used to obtain CSF samples and to deliver all IT 
injections of HGT-1410. If the IDDD appears to be non-functional, or if its use is 
precluded on a scheduled day of dosing, site personnel will refer to the IDDD Manual(s), 
which provides details on the investigation and management of any IDDD-related issues. 
This includes possible partial revision or complete replacement of the IDDD as indicated. 
If the IT space is not accessible via the IDDD, study drug may be administered and CSF 
sampled by lumbar puncture (LP). General anesthesia or sedation may be required for 
injections of study drug and some evaluations, and can be used at the discretion of the 
Investigator. Patients will have the IDDD removed when they discontinue from or 
complete the study, unless the patient is continuing to receive treatment through another 
mechanism (eg, extension study, expanded access program, commercially available etc.).
Safety and efficacy assessments will be performed at regular intervals over the 
approximate 2.5-year duration of Study SHP-610-201. For patients who received 
HGT-1410 in Study HGT-SAN-093, a serum PK sample will be obtained at the Week 96
visit (after approximately 2 full years of exposure to HGT-1410 across Study 
HGT-SAN-093 and SHP-610-201). For patients who received no-treatment in Study 
HGT-SAN-093, serum PK samples will be obtained at the Week 0, 48, and 96 visits, and 
CSF PK samples will be obtained on the Week 0 and 48 visits in Study SHP-610-201.
Study Duration:
Approximately 30 months of treatment with HGT-1410 will occur during the study.
Patients who received HGT-1410 in Study HGT-SAN-093 will undergo a cumulative 
exposure to HGT-1410 for up to 42 months (168 weeks), whereas patients who received 
no-treatment in Study HGT-SAN-093 will have a cumulative exposure to HGT-1410 for 
up to 30 months (120 weeks) in Study SHP-610-201.


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Study Inclusion and Exclusion Criteria:
Inclusion Criteria:
Patients must meet all of the following criteria to be considered eligible for enrollment:
1. Patient has completed through at least the Week 48 visit of Study HGT-SAN-093.
2. The patient’s parent(s) or legally authorized guardian(s) must have voluntarily signed 
an Institutional Review Board- (IRB-)/Independent Ethics Committee- (IEC-) 
approved informed consent form after all relevant aspects of the study have been 
explained and discussed. Consent of the patient’s parent(s) or legally authorized 
guardian(s) and the patient’s assent, as relevant, must be obtained.
Exclusion Criteria:
Patients will be excluded from the study if any of the following criteria are met:
1. The patient, if randomized to treatment in Study HGT-SAN-093, has experienced a 
decline of more than 20 points in the BSID-III cognitive DQ score between Baseline 
and the Week 48 visit in Study HGT-SAN-093, AND, upon individual evaluation by 
the Investigator, has been deemed a treatment failure*.
2. The patient has experienced, in the opinion of the Investigator, a safety or medical 
issue that contraindicates treatment with HGT-1410, including but not limited to 
clinically relevant intracranial hypertension,  severe infusion-related reactions after 
treatment with HGT-1410, uncontrollable seizure disorder.
3. The patient has a known hypersensitivity to any of the components of HGT-1410.
4. The patient is enrolled in another clinical study, other than HGT-SAN-093, that 
involves clinical investigations or use of any investigational product (drug or 
[intrathecal/spinal] device) within 30 days prior to study enrollment or at any time 
during the study.
5. The patient has any known or suspected hypersensitivity to anesthesia or is thought to 
be at an unacceptably high risk for anesthesia due to airway compromise or other 
conditions.
6. The patient has a condition that is contraindicated as described in the SOPH-A-
PORT ® Mini S IDDD Instructions for Use, including:
a
The patient has had, or may have, an allergic reaction to the materials of 
construction of the SOPH-A-PORT ® Mini S device
b
The patient’s body size is too small to support the size of the SOPH-A-PORT ®
Mini S Access Port, as judged by the Investigator
c
The patient’s drug therapy requires substances known to be incompatible with the 
materials of construction
d
The patient has a known or suspected local or general infection
e
The patient is at risk of abnormal bleeding due to a medical condition or therapy
f
The patient has one or more spinal abnormalities that could complicate safe 
implantation or fixation


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g
The patient has a functioning CSF shunt device
h
The patient has shown an intolerance to an implanted device
7. The patient is unable to comply with the protocol (eg, is unable to return for safety 
evaluations, or is otherwise unlikely to complete the study) as determined by the 
Investigator.
*All treated patients in Study HGT-SAN-093 will have their cognitive development 
assessed at the Week 48 Visit in Study HGT-SAN-093. If a decline from Baseline of 
20 points or less in the BSID-III DQ score is observed, then the patient may proceed into 
the Study SHP-610-201 without further evaluation. If a decline from Baseline of more 
than 20 points in DQ score is observed, then an individual evaluation by the Investigator 
will occur to determine if the patient is a treatment failure. This individual evaluation will 
take into account the DQ scores, VABS-II score, physical status, and any other 
information available for that patient at that time. If the Investigator deems the patient to 
be a treatment failure, then the patient may not enter the Study SHP-610-201.
Efficacy Assessments:
Efficacy variables to be assessed will include cognitive function expressed as a DQ
assessed by neurocognitive testing using the BSID-III/KABS-II; adaptive behavioral 
function over time, assessed by VABS-II; the total cortical grey matter volume and liver 
and spleen size as assessed by magnetic resonance imagining (MRI); as well as quality of 
life score (assessed using the ITQoL); and health care resource utilization (assessed using 
the HCUQ).
Pharmacokinetic Assessments:
The determination of HGT-1410 concentration in serum for all patients and in CSF for 
patients who received no-treatment in Study HGT-SAN-093.
Pharmacodynamic Assessments:
The determination of GAG concentrations in CSF and urine.
Safety Assessments:
Safety will be assessed during the study by the following:

collection of adverse events (by type, severity, and relationship to treatment 
[HGT-1410, the IDDD, device surgical procedure, or IT administration process])

changes in clinical laboratory testing (serum chemistry, hematology, urinalysis)

physical examination

vital signs

12-lead electrocardiogram (ECG) recordings 

CSF laboratory parameters (chemistries, cell counts)

anti-rhHNS antibodies in CSF and serum, including determination of antibodies 
having enzyme neutralizing activity
Statistical Methods:  
The statistical methodology supporting the trial will focus on descriptive rather than 
inferential approaches, given the design and objectives of this trial. Any hypothesis tests 
will be 2-sided and will be viewed as exploratory. It is planned that the data from all 
centers that participate in this protocol will be combined so that an adequate number of 
patients will be available for analysis. Summary statistics for continuous variables will 
include the n, mean, standard deviation, median, minimum and maximum. Categorical 


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variables will be summarized in a contingency table by the frequency and percentage of 
patients in each category. Data will be plotted to assess trends across time, as appropriate.
Unless otherwise indicated, all summary statistics will be presented by treatment group 
(either Q2W or Q4W) to which the patients were randomly assigned (patients who were 
initially assigned to Q2W or Q4W group in Study HGT-SAN-093 or patients who 
received no-treatment in Study HGT-SAN-093 and were randomly assigned to Q2W or 
Q4W in Study SHP-610-201). Additional analyses in the subgroup of patients who 
received no-treatment in Study HGT-SAN-093 may be performed. 
All safety data will be summarized descriptively. The change from baseline at each time 
point for efficacy outcomes will be summarized. Generally, the mean difference in the 
change at each time point between the 2 treatment groups and the corresponding 95% 
confidence interval of the mean difference will be presented. Additional efficacy 
analyses in the subgroups of patients previously treated and untreated in Study HGT-
SAN-093 may be performed.
Data from Study HGT-SAN-093 will be combined with that of Study SHP-610-201 for 
analysis. The data included for treated patients in HGT-SAN-093 starts from the baseline 
of Study HGT-SAN-093 and for patients who received no-treatment in HGT-SAN-093 
from the baseline of Study SHP-610-201. Baseline is the assessment obtained during the 
initial study period, prior to the first dose of HGT-1410, regardless of whether this 
occurred in Study HGT-SAN-093 or SHP-610-201.
Date of Original Protocol:  23 September 2014


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TABLE OF CONTENTS
SYNOPSIS.................................................................................................................................2
LIST OF IN-TEXT TABLES ..................................................................................................14
LIST OF FIGURES .................................................................................................................15
LIST OF APPENDICES..........................................................................................................16
LIST OF ABBREVIATIONS..................................................................................................17
1
INTRODUCTION ...........................................................................................................20
2
STUDY OBJECTIVES....................................................................................................22
2.1
Primary Objective..................................................................................................22
2.2
Secondary Objectives.............................................................................................22
2.3
Exploratory Objective............................................................................................22
2.4
Pharmacokinetic and Pharmacodynamic Objectives.............................................22
2.5
Health Status Objective..........................................................................................22
2.6
Health Economics and Outcome Research Objective ...........................................22
3
STUDY ENDPOINTS.....................................................................................................23
3.1
Primary Endpoint...................................................................................................23
3.2
Secondary Endpoints .............................................................................................23
3.3
Exploratory Endpoint(s).........................................................................................23
3.4
Pharmacokinetic and Pharmacodynamic Endpoints..............................................23
3.5
Health Status Endpoint ..........................................................................................24
3.6
Health Economics and Outcomes Research Endpoint...........................................24
4
INVESTIGATIONAL PLAN..........................................................................................25
4.1
Overall Study Design and Plan..............................................................................25
4.2
Rationale for Study Design, Device Use, and Comparator Group ........................27
4.3
Study Duration.......................................................................................................27
5
STUDY POPULATION SELECTION ...........................................................................28
5.1
Study Population....................................................................................................28
5.2
Inclusion Criteria ...................................................................................................28
5.3
Exclusion Criteria ..................................................................................................28
6
STUDY TREATMENT(S)..............................................................................................30
6.1
Description of Treatment(s)...................................................................................30
6.1.1
Investigational Product..................................................................................30
6.1.2
Intrathecal Drug Delivery Device .................................................................30
6.1.3
Comparator Product.......................................................................................30
6.2
Treatment Administered ........................................................................................30
6.3
Selection and Timing of Dose for Each Patient.....................................................31
6.3.1
Missed Doses.................................................................................................31


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6.4
Method of Assigning Patients to Treatment Groups..............................................31
6.5
Blinding..................................................................................................................32
6.6
Prior and Concomitant Medications, Therapies, and Medical/Surgical 
Interventions ..........................................................................................................32
6.7
Restrictions ............................................................................................................32
6.7.1
Fluid and Food Intake....................................................................................32
6.7.2
Patient Activity Restrictions..........................................................................32
6.8
Treatment Compliance...........................................................................................32
6.9
Packaging and Labeling.........................................................................................32
6.10
Storage and Accountability....................................................................................33
6.10.1
Investigational Product..................................................................................33
6.10.2
Intrathecal Drug Delivery Device .................................................................33
6.10.3
Comparator Product.......................................................................................34
7
STUDY PROCEDURES .................................................................................................35
7.1
Informed Consent...................................................................................................35
7.2
Study Entrance Criteria..........................................................................................35
7.3
Hearing and Vision Assessments...........................................................................36
7.3.1
Investigator Assessment of Hearing and Vision ...........................................36
7.4
Device Related Study Procedures..........................................................................36
7.4.1
IDDD Implantation or Revision Procedures .................................................36
7.4.2
X-ray Verification of Intrathecal Drug Delivery Device Placement.............36
7.4.3
CSF Sampling Procedure ..............................................................................36
7.4.4
Device Revision or Removal.........................................................................36
7.5
Investigational Product Administration.................................................................37
7.6
Efficacy Assessments.............................................................................................38
7.6.1
Neurocognitive and Developmental Assessments.........................................38
7.6.2
Quality of Life Indicator:   Infant Toddler Quality of Life Questionnaire....39
7.6.3
Health Economics and Outcomes Research:   Healthcare Utilization 
Questionnaire.................................................................................................39
7.7
Magnetic Resonance Imaging................................................................................39
7.7.1
Head...............................................................................................................39
7.7.2
Liver and Spleen............................................................................................39
7.8
Pharmacokinetic Assessments ...............................................................................39
7.9
Pharmacodynamic Biomarker Assessments (CSF and Urine GAG Levels) .........40
7.10
Concomitant Medications, Therapies, and Medical/Surgical Interventions..........40
7.11
Safety Assessments................................................................................................40
7.11.1
Vital Signs .....................................................................................................40
7.11.2
Physical Examination, including Height, Weight, and Head Circumference40
7.11.3
Electrocardiogram .........................................................................................41


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7.11.4
Clinical Laboratory Tests ..............................................................................41
7.11.5
Cerebrospinal Fluid Assessments..................................................................42
7.11.5.1
Standard CSF Safety Laboratory Assessments.....................................43
7.11.5.2
Anti-rhHNS Antibodies and Biomarkers in CSF..................................43
7.11.5.3
CSF GAG Levels and Biomarkers........................................................43
7.11.5.4
.......................................................43
7.11.6
Device Assessments ......................................................................................43
7.11.7
Collection and Storage of Biological Samples for Biomarker Studies .........43
7.12
Sample Collection, Storage, and Shipping ............................................................43
7.13
Adverse Events Assessments.................................................................................44
7.13.1
Definitions of Adverse Events and Serious Adverse Events.........................44
7.13.1.1
Adverse Event.......................................................................................44
7.13.1.2
Adverse Events Due to Systemic Exposure to HGT-1410 ...................44
7.13.1.3
IDDD-related Adverse Events ..............................................................45
7.13.1.4
Serious Adverse Event..........................................................................45
7.13.2
Device-associated Definitions.......................................................................46
7.13.2.1
Device Revision (Partial and Full)........................................................46
7.13.2.2
Device Malfunction...............................................................................46
7.13.2.3
Device Failure.......................................................................................46
7.13.3
Classification of Adverse Events and Serious Adverse Events.....................46
7.13.4
Clarification between Serious and Severe.....................................................47
7.13.5
Relatedness of Adverse Events and Serious Adverse Events .......................47
7.13.6
Procedures for Recording and Reporting Adverse Events............................47
7.13.6.1
Adverse Event Monitoring and Period of Observation.........................47
7.13.6.2
Reporting Serious Adverse Events........................................................48
7.14
Abuse, Overdose and Medication Error.................................................................49
7.15
Removal of Patients from the Trial or Investigational Product.............................49
7.16
Safety-Related Study Stopping Rules....................................................................50
7.17
Appropriateness of Measurements.........................................................................50
8
STUDY ACTIVITIES .....................................................................................................52
8.1
Group 1 (Maintaining Q2W Dosing).....................................................................52
8.1.1
Treatment Period (Weeks 50 through 168) ...................................................52
8.1.1.1
Pre-treatment Assessments ...................................................................52
8.1.1.2
Post-treatment Assessments..................................................................53
8.1.2
Safety Follow-up Visit:  Week 172 (±7 days)...............................................53
8.2
Group 2 (Maintaining Q4W Dosing).....................................................................53
8.2.1
Treatment Period (Weeks 52 through 168) ...................................................53
8.2.1.1
Pre-treatment Assessments ...................................................................53
8.2.1.2
Post-treatment Assessments..................................................................54


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8.2.2
Safety Follow-up Visit:  Week 172 (±7 days)...............................................54
8.3
Group 3 (Patients who were randomized to no-treatment in Study HGT-SAN-
093) ........................................................................................................................54
8.3.1
IDDD Implantation (Days -21 to Day -7) .....................................................55
8.3.1.1
Prior to IDDD Implantation ..................................................................55
8.3.1.2
Day of IDDD Implantation ...................................................................55
8.3.2
Post-operative Check - Days 1 to 3 ...............................................................56
8.3.3
Randomization (Can Occur Any Time After Meeting Study Entry Criteria)56
8.4
Group 3A (Initiating HGT-1410 Q2W Dosing) ....................................................56
8.4.1
Treatment Period (Weeks 0 through 120) .....................................................56
8.4.1.1
Pre-treatment Assessments ...................................................................56
8.4.1.2
Post-treatment Assessments..................................................................57
8.4.2
Safety Follow-up Visit:  Week 124 (±7 days)...............................................57
8.5
Group 3B (Initiating HGT-1410 Q4W Dosing).....................................................57
8.5.1
Treatment Period (Weeks 0 through 120) .....................................................57
8.5.1.1
Pre-treatment Assessments ...................................................................57
8.5.1.2
Post-treatment Assessments..................................................................58
8.5.2
Safety Follow-up Visit:  Week 124 (±7 days)...............................................58
9
QUALITY CONTROL AND ASSURANCE .................................................................59
10
STATISTICAL ANALYSES ..........................................................................................60
10.1
General Methodology ............................................................................................60
10.2
Determination of Sample Size ...............................................................................60
10.3
Method of Assigning Study Subjects to Treatment Groups ..................................61
10.4
Population Description and Exposure....................................................................61
10.4.1
Analysis Populations .....................................................................................61
10.4.2
Subject Disposition........................................................................................61
10.4.3
Protocol Deviations .......................................................................................61
10.4.4
Demographics and Baseline Characteristics .................................................61
10.4.5
Treatment Compliance and Extent of Exposure............................................62
10.5
Analysis of Efficacy...............................................................................................62
10.5.1
Primary Analysis ...........................................................................................62
10.5.2
Secondary Efficacy Analysis.........................................................................62
10.5.2.1
Bayley Scales of Infant Development III (BSID-III)/Kaufman 
Assessment Battery for Children-Second Edition (KABC-II)..............62
10.5.2.2
Vineland Adaptive Behavior Scales II (VABS II)................................63
10.5.2.3
Brain MRI .............................................................................................63
10.5.3
Subset Analyses.............................................................................................63
10.5.4
Exploratory Analyses ....................................................................................63
10.5.5
Analysis of Health Status ..............................................................................63


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10.5.6
Analysis Health Economics and Outcomes Research...................................63
10.6
Analysis of Pharmacokinetic and Pharmacodynamic Data ...................................64
10.6.1
Pharmacokinetic Measurement and Parameters............................................64
10.6.2
Pharmacodynamic Analyses..........................................................................64
10.7
Analysis of Safety..................................................................................................64
10.7.1
Adverse Events..............................................................................................65
10.7.1.1
Investigational Product..........................................................................65
10.7.1.2
IDDD and Surgical Procedure-Related AEs.........................................65
10.7.2
Clinical Laboratory Evaluation .....................................................................65
10.7.3
ECG Evaluations ...........................................................................................66
10.7.4
Vital Signs .....................................................................................................66
10.7.5
Anti-rhHNS antibody in Serum and CSF......................................................66
10.7.6
Concomitant Medications..............................................................................66
10.7.7
Other Observations Related to Safety ...........................................................66
10.7.7.1
IDDD Performance ...............................................................................66
10.8
Statistical/Analytical Issues ...................................................................................67
10.8.1
Adjustment for Covariates.............................................................................67
10.8.2
Handling of Dropouts or Missing Data .........................................................67
10.8.3
Interim Analyses and Data Monitoring .........................................................67
10.8.4
Multicenter Studies........................................................................................67
10.8.5
Multiple Comparisons/Multiplicity...............................................................67
10.8.6
Sensitivity Analyses ......................................................................................68
11
ADMINISTRATIVE CONSIDERATIONS....................................................................69
11.1
Investigators and Study Administrative Structure.................................................69
11.2
Institutional Review Board or Independent Ethics Committee Approval .............69
11.3
Ethical Conduct of the Study.................................................................................69
11.4
Patient Information and Consent ...........................................................................69
11.5
Patient Confidentiality ...........................................................................................70
11.6
Study Monitoring...................................................................................................71
11.7
Case Report Forms and Study Records .................................................................71
11.7.1
Case Report Forms ........................................................................................71
11.7.2
Critical Documents........................................................................................71
11.8
Data Monitoring Committee..................................................................................72
11.9
Device Failure Review Process .............................................................................72
11.10 Protocol Violations/Deviations..............................................................................72
11.11 Premature Closure of the Study.............................................................................73
11.12 Access to Source Documentation ..........................................................................73
11.13 Data Generation and Analysis ...............................................................................73
11.14 Retention of Data...................................................................................................74


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11.15 Financial Disclosure...............................................................................................74
11.16 Publication and Disclosure Policy .........................................................................74
12
LIST OF REFERENCES.................................................................................................75


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LIST OF IN-TEXT TABLES
Table 7-1
Neurodevelopmental Assessments Tests....................................................38
Table 7-2
Assessments for Physical Examinations ....................................................40
Table 7-3
List of Laboratory Tests .............................................................................42
Table 7-4
Adverse Event Severity..............................................................................46
Table 7-5
Adverse Event Relatedness ........................................................................47


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LIST OF FIGURES
Figure 1
SHP-610-201 Study Design .......................................................................26


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LIST OF APPENDICES
Appendix 1
Study Schedule of Events for Group 1:   Maintaining HGT-1410 
Q2W ...........................................................................................................76
Appendix 2
Study Schedule of Events for Group 2:   Maintaining HGT-1410 
Q4W ...........................................................................................................78
Appendix 3
Study Schedule of Events for Group 3A:  Initiating HGT-1410 Q2W......80
Appendix 4
Study Schedule of Events for Group 3B:  Initiating HGT-1410 Q4W ......84
Appendix 5
Pharmacokinetic and Pharmacodynamic Sample Schedule.......................87
Appendix 6
Expected SOPH-A-PORT ® Mini S Adverse Device Effects ...................88
Appendix 7
Protocol Signature Page .............................................................................90


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LIST OF ABBREVIATIONS
Abbreviation
Definition
Ab
antibody
AEs
adverse events
ALB
albumin
ALK-P
alkaline phosphatase
ALT; SGPT
alanine aminotransferase
aPTT
activated partial thromboplastin time
AST; SGOT
asparate aminotransferase
AUC
area under the serum concentration-time curve
BBB
blood brain barrier
BSID-III
Bayley Scales of Infant and Toddler Development, 3rd Edition  
BUN
blood urea nitrogen
Ca
calcium
CFR
Code of Federal Regulations
CK
creatine kinase
CL
clearance
Cl
chloride
Cmax
maximum observed serum concentration
CNS
central nervous system
CO2
carbon dioxide
con meds
concomitant medications
CRO
contract research organization
CS
clinically significant
CSF
cerebrospinal fluid
DMC
Data Monitoring Committee
DQ
developmental quotient
DS
dermatan sulfate
ECG
electrocardiogram
eCRF
electronic case report form
ERT
enzyme replacement therapy
EU
European Union
FDA
Food and Drug Administration
FT
full-time
GAG
glycosaminoglycans
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
Hct
hematocrit
HCUQ
Healthcare Utilization Questionnaire
Hgb
hemoglobin
HNS
heparan N-sulfatase


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Abbreviation
Definition
HS
heparan sulfate
ICH
International Conference on Harmonisation
IDDD
intrathecal drug delivery device
IEC
Independent Ethics Committee
IFU
Instructions for Use
IRB
Institutional Review Board
IT
intrathecally
ITQoL
Infant Toddler Quality of Life Questionnaire™
ITT
Intent-to-Treat
IV
intravenously
K
potassium
KABC-II
Kaufman Assessment Battery for Children, 2nd Edition
LDH
lactate dehydrogenase
LP
lumbar puncture
LSD
lysosomal storage disease
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MPS IIIA
Mucopolysaccharidosis Type IIIA or Sanfilippo Syndrome Type A
MRI
magnetic resonance imaging
NA
sodium
NCS
not clinically significant
NW
not working
PD
pharmacodynamics
PE
physical examination
PK
pharmacokinetics
PT
part-time
PT
prothrombin time
Q2W
every 2 weeks
Q4W
every 4 weeks
QoL
quality of life
RBC
red blood cell
rhHNS
recombinant human heparan N sulfatase
SAE
serious adverse event
SAP
statistical analysis plan
SGSH
sulfoglucosamine sulfohydrolase
SI
Standard International
SOC
System Organ Class
t1/2
terminal half-life
Tmax
time of maximum observed serum concentration


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Abbreviation
Definition
UADE
unanticipated adverse device effect
VABS-II
Vineland Adaptive Behavior Scales, Second Edition 
Vz/F
volume of distribution
WBC
white blood cell
WHO-DD
World Health Organization-Drug Dictionary
λZ
terminal rate constant


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1
INTRODUCTION
Mucopolysaccharidosis Type IIIA (MPS IIIA, also called Sanfilippo Syndrome Type A) is a 
rare, autosomal recessive, lysosomal storage disease (LSD) presenting in early childhood that 
causes progressive neurodegeneration associated with intractable behavioral problems and 
developmental regression. Ultimately, a vegetative state supervenes. Life span is shortened, with 
death usually occurring in the late teen years. The genetic defect in this disorder is a mutation in 
both copies of the sulfoglucosamine sulfohydrolase (SGSH) gene, located on chromosome 17, 
which encodes the lysosomal enzyme, sulfoglucosamine sulfohydrolase, also called 
heparan-N-sulfatase, or sulfamidase. This enzyme is necessary for the normal intralysosomal 
catabolism of the glycosaminoglycan (GAG) (formerly termed mucopolysaccharide), heparan 
sulfate (HS). SGSH deficiency therefore results in the accumulation of heparan sulfate in 
lysosomes. Although the metabolic defect is expressed in every organ, the clinical manifestations 
of disease are primarily neurological. These are not usually apparent until 1 to 4 years of age. 
The molecular events linking the primary metabolic defect to the consequent neuropathology are 
not understood. 
MPS III is the most prevalent of the mucopolysaccharidoses, and consists of 4 subtypes, A, B, C, 
and D.1  Each of these is characterized by a deficiency of a distinct lysosomal enzyme necessary 
for the degradation of heparan sulfate. Clinically, on an individual patient level, the 4 subtypes 
cannot be reliably distinguished. Globally, subtype A is the most prevalent, at approximately 
1 case in 100,000 live births, followed by subtype B, at approximately 1 in 250,000 live births.1-3
Among MPS IIIA patients, there is wide allelic heterogeneity, with at least 100 SGSH mutations 
described to date. Most of these are missense, but nonsense mutations, deletions, insertions and 
splice-site mutations also occur.4
MPS IIIA symptoms usually arise in the 1st or 2nd year of life, although diagnosis is delayed until 
an average age of 4.5 years.4, 5  Patients present a wide spectrum and severity of clinical 
symptoms. The central nervous system (CNS) is the most severely affected organ system in 
patients with MPS IIIA, evidenced by deficits in language development, motor skills, and 
intellectual development.5  In addition, there are abnormal behaviors that include aggression and 
excess motor activity/hyperactivity that contribute to disturbances in sleep.5-7 There are also 
reports of unexplained, recurrent and severe diarrhea.6  Overall, individuals with MPS IIIA 
exhibit progressive dementia with ultimate inanition and death resulting from the CNS disease. 
Lifespan is severely curtailed, with usual survival into the late teens.6  Milder variants are 
recognized, with slower progression and survival to later age. The latter has been reported in 
approximately 10% of German patients with MPS IIIA, in association with the presence of the 
S298P mutation.8
No effective, disease-modifying therapies are currently approved as treatments for this 
devastating and disabling disease. A goal of Shire is to develop recombinant human 
heparan-N-sulfatase (rhHNS, development name HGT-1410) as enzyme replacement therapy 
(ERT) for patients with MPS IIIA. A particular problem for lysosomal storage disorders that 
damage the brain, such as MPS III, is how to target ERT to the brain, as macromolecules cannot 
cross the blood brain barrier (BBB).9  In animal studies, ERT has been administered into the 
cerebrospinal fluid (CSF) via an intrathecal (IT) route, because when administered intravenously 
(IV) it does not cross the BBB after the immediate postnatal period of life. HGT-1410 has been 


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shown to be ineffective if administered intravenously in the MPS IIIA mouse model, in contrast 
to its efficacy in treating CNS pathology when administered into the CSF.10  
In order to traverse the blood-brain barrier, HGT-1410 will be administered directly to the CNS 
using an intrathecal drug delivery device (IDDD) or, if the IDDD is non-functional, via lumbar 
puncture (LP). The advantage of using an IDDD is the potential to obviate the need for multiple 
lumbar punctures for drug delivery. HGT-1410 will be administered through the IDDD or, if the 
IDDD is non-functional, via lumbar puncture.
Please refer to the current edition of the Investigator’s Brochure for further information 
concerning the nonclinical studies completed, including safety and clinical development of 
HGT-1410.


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2
STUDY OBJECTIVES
2.1
Primary Objective 
The primary objective of this study is to evaluate long-term safety in patients with 
mucopolysaccharidosis type IIIA disease (MPS IIIA or Sanfilippo Type A) who received 
HGT-1410.
2.2
Secondary Objectives 
The secondary objectives of this study are to evaluate:  

The long-term cognitive function as measured by the Bayley Scales of Infant and Toddler 
Development, 3rd Edition (BSID-III) or Kaufman Assessment Battery for Children, 2nd 
Edition (KABC-II), age-equivalent and developmental quotient (DQ) scores in patients 
with MPS IIIA who received HGT-1410

The long-term adaptive behavioral function, assessed by Vineland Adaptive Behavior 
Scales, Second Edition (VABS-II) in patients who received HGT-1410

The total cortical grey matter volume, as assessed by volumetric magnetic resonance 
imaging (MRI) of the brain, in patients who received HGT-1410
2.3
Exploratory Objective
The exploratory objective of this study is 
 
2.4
Pharmacokinetic and Pharmacodynamic Objectives
The pharmacokinetic and pharmacodynamics objectives of this study are to evaluate:

The pharmacokinetics (PK) of HGT-1410 in serum

The PK of HGT-1410 in CSF, in patients who received no-treatment in Study 
HGT-SAN-093

The concentration of GAG in CSF and urine in patients who received HGT-1410
2.5
Health Status Objective
The health status objective of this study is to evaluate health status as measured by the Infant 
Toddler Quality of Life Questionnaire™ (ITQoL) instrument in patients who received 
HGT-1410.
2.6
Health Economics and Outcome Research Objective
The health economics and outcome research objective of this study is to evaluate healthcare 
resource utilization, as evaluated by the Healthcare Utilization Questionnaire (HCUQ), in 
patients who received HGT-1410.


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3
STUDY ENDPOINTS
3.1
Primary Endpoint
Safety is the primary objective of the study and will be assessed during the study by the 
following:

collection of adverse events (by type, severity, and relationship to treatment [HGT-1410, 
the IDDD, device surgical procedure, or IT administration process])

changes in clinical laboratory testing (serum chemistry, hematology, urinalysis)

physical examination

vital signs

12-lead electrocardiogram (ECG) recordings 

CSF laboratory parameters (including chemistries, cell counts)

anti-rhHNS antibodies in CSF and serum, including determination of antibodies having 
enzyme neutralizing activity
3.2
Secondary Endpoints
The secondary endpoints of this study are:

The change from Baseline in BSID-III or KABC-II age-equivalent, DQ, and 
developmental delay scores

The change from Baseline in adaptive behavioral function domains, assessed by VABS 
II, using raw scores, age-equivalent scores, and DQ scores

The change from Baseline in total cortical grey matter volume, as assessed by MRI
3.3
Exploratory Endpoint(s)
3.4
Pharmacokinetic and Pharmacodynamic Endpoints
The pharmacokinetic endpoint is to determine the pharmacokinetic behavior of HGT-1410 in 
serum, based on the following parameters:

Maximum observed serum concentration (Cmax)

Time of Cmax (Tmax)

Area under the serum concentration-time curve from time zero to the last sampling time 
at which serum concentrations were measurable (AUC0-last)

Area under the serum concentration-time curve extrapolated to infinity (AUC0-∞)

Apparent terminal rate constant (λZ) derived from the slope of the log-linear regression of 
the log-linear terminal portion of the serum concentration-time curve.

Terminal half-life (t½) calculated as 0.693/ λZ


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
Clearance for IT-L administration (CL/F)

Volume of distribution based on the terminal phase for IT-L administration (Vz/F)  
The pharmacodynamic endpoint is to determine the GAG concentrations in CSF and urine.
3.5
Health Status Endpoint
The health status endpoint is the Infant Toddler Quality of Life™ (ITQoL) scores at each 
assessment time and the corresponding change from Baseline.
3.6
Health Economics and Outcomes Research Endpoint
The health economic and outcome research endpoints evaluate the key HCUQ variables, such as 
the number of emergency room visits, caregiver employment status (full-time [FT], part-time 
[PT], and not working [NW]), and the number of hours of additional paid help needed by 
caregivers, over the course of the study.


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4
INVESTIGATIONAL PLAN
4.1
Overall Study Design and Plan
This is an open-label extension study of HGT-1410 for patients who completed through at least 
the Week 48 Visit in Study HGT-SAN-093. The study design is presented in Figure 1. Patients 
who originally received HGT-1410 in Study HGT-SAN-093 will remain on the same dosing 
regimen as they received in Study HGT-SAN-093; Group 1 will receive HGT-1410 Q2W and 
Group 2 will received HGT-1410 Q4W. Patients in Groups 1 and 2 will begin treatment at 
Week 50 and Week 52, respectively, of this extension study (Study SHP-610-201). Patients who 
originally received no-treatment in Study HGT-SAN-093 (Group 3) will receive an IDDD 
following informed consent and will be re-randomized in a 1:1 allocation ratio to receive 
HGT-1410 via a Q2W or Q4W dosing regimen (Groups 3A and 3B, respectively) in Study 
SHP-610-201. Patients in Groups 3A and 3B will begin treatment on Week 0 of the extension 
study.
It is anticipated that the IDDD will be used to collect CSF samples and to deliver IT injections of 
HGT-1410 and preservative-free saline flushes. No other medication will be administered 
through the device. If the IDDD appears to be non-functional, or if its use is precluded on a 
scheduled day of dosing, site personnel will refer to the IDDD Manual, which provides details on 
the investigation and management of any IDDD-related issues. This includes possible partial 
revision or complete replacement of the IDDD as indicated. If the IT space is not accessible via 
the IDDD, study drug may be administered by LP. Should the IDDD become clogged, undergo 
mechanical complications or otherwise not be accessible, the CSF sample may also be obtained 
by LP. General anesthesia or sedation may be required for injections of study drug and some 
evaluations, and may be used at the discretion of the Investigator. The Data Monitoring 
Committee (DMC) will be notified of all IDDD failures and IDDD-related complications at 
times defined in the DMC charter (refer to Section 11.8).
Patients will have the IDDD removed when they discontinue from or complete the study unless 
the patient is continuing to receive product or treatment through another mechanism (eg, 
extension study, expanded access program, commercially available drug).
Safety and efficacy assessments will be performed at regular intervals over the approximate 
2.5-year duration of the extension study. A PK sample for patients who received HGT-1410 in 
Study HGT-SAN-093 will be obtained at the Week 96 visit (after approximately 2 full years of 
exposure to HGT-1410 across Studies HGT-SAN-093 and SHP-610-201). Serum PK samples for 
patients who received no-treatment in Study HGT-SAN-093 will be obtained at the Week 0, 48, 
and 96, and CSF PK samples will be obtained on the Week 0 and 48 visits in Study SHP-610-
201.
Patients who received HGT-1410 in Study HGT-SAN-093 will undergo a cumulative exposure 
to HGT-1410 for up to 42 months (168 weeks), whereas patients who received no-treatment in 
Study HGT-SAN-093 will have a cumulative exposure to HGT-1410 for up to 30 months 
(120 weeks) in Study SHP-610-201.
See Appendix 1 ,Appendix 2 ,Appendix 3, and Appendix 4 for the Study Schedule of Events 
Tables for Groups 1, 2, 3A and 3B, respectively.




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4.2
Rationale for Study Design, Device Use, and Comparator Group
The study design is intended to provide ongoing treatment with HGT-1410 to patients who 
received HGT-1410 in Study HGT-SAN-093 and to initiate treatment to patients who received
no-treatment in Study HGT-SAN-093. As such, all patients will be treated during this study; 
there is no control group.
In order to traverse the blood-brain barrier, HGT-1410 will be administered directly to the CNS 
using an IDDD or, if the IDDD is non-functional, via LP. The advantage of using an IDDD is the 
potential to obviate the need for multiple lumbar punctures for drug delivery. HGT-1410 will be 
administered through the IDDD or, if the IDDD is non-functional, via lumbar puncture.
Safety is the primary objective of the study, and the study duration has been designed to provide 
a reasonable time for safety follow-up.
4.3
Study Duration
Patients are expected to participate in this study for up to 30 months. Patients who received 
HGT-1410 in Study HGT-SAN-093 will undergo a cumulative exposure to HGT-1410 for up to 
42 months (168 weeks), whereas patients who received no-treatment in Study HGT-SAN-093 
will have a cumulative exposure to HGT-1410 for up to 30 months (120 weeks) in Study 
SHP-610-201.


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5
STUDY POPULATION SELECTION
5.1
Study Population
A maximum of 18 patients with MPS IIIA who completed Study HGT-SAN-093 are planned to 
enroll in this study. 
5.2
Inclusion Criteria
Patients must meet all of the following criteria to be considered eligible for enrollment:  
1. Patient has completed through at least the Week 48 visit of Study HGT-SAN-093.
2. The patient’s parent(s) or legally authorized guardian(s) has voluntarily signed an 
Institutional Review Board- (IRB-)/Independent Ethics Committee- (IEC-) approved 
informed consent form after all relevant aspects of the study have been explained and 
discussed. Consent of the patient’s parent(s) or legally authorized guardian(s) and the 
patient’s assent, as relevant, must be obtained.
5.3
Exclusion Criteria
Patients will be excluded from the study if any of the following criteria are met:
1. The patient, if randomized to treatment in Study HGT-SAN-093, has experienced a decline 
of more than 20 points in the BSID-III cognitive DQ score between Baseline and the Week 
48 visit in Study HGT-SAN-093, AND, upon individual evaluation by the Investigator, has 
been deemed a treatment failure.
2. The patient has experienced, in the opinion of the Investigator, a safety or medical issue that 
contraindicates treatment with HGT-1410, including but not limited to clinically relevant 
intracranial hypertension,  severe infusion-related reactions after treatment with HGT-1410, 
uncontrollable seizure disorder.
3. The patient has a known hypersensitivity to any of the components of HGT-1410.
4. The patient is enrolled in another clinical study, other than HGT-SAN-093, that involves 
clinical investigations or use of any investigational product (drug or [intrathecal/spinal] 
device) within 30 days prior to study enrollment or at any time during the study.
5. The patient has any known or suspected hypersensitivity to anesthesia or is thought to be at 
an unacceptably high risk for anesthesia due to airway compromise or other conditions.
6. The patient has a condition that is contraindicated as described in the SOPH-A-PORT ®
Mini S IDDD Instructions for Use, including:
The patient has had, or may have, an allergic reaction to the materials of construction of the 
SOPH-A-PORT ® Mini S device
a
The patient’s body size is too small to support the size of the SOPH-A-PORT ® Mini 
S Access Port, as judged by the Investigator
b
The patient’s drug therapy requires substances known to be incompatible with the 
materials of construction


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c
The patient has a known or suspected local or general infection
d
The patient is at risk of abnormal bleeding due to a medical condition or therapy
e
The patient has one or more spinal abnormalities that could complicate safe 
implantation or fixation
f
The patient has a functioning CSF shunt device
g
The patient has shown an intolerance to an implanted device
7. The patient is unable to comply with the protocol (eg, is unable to return for safety 
evaluations, or is otherwise unlikely to complete the study) as determined by the Investigator.


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6
STUDY TREATMENT(S)
6.1
Description of Treatment(s)
6.1.1
Investigational Product
The investigational product to be used in this study is HGT-1410, recombinant human heparan 
N-sulfatase (rhHNS) for IT use.
The HGT-1410 drug product is a sterile solution for injection in single-use vials for IT 
administration. It is formulated in an aqueous isotonic solution containing 15.0 mg/mL rhHNS in 
145 mM sodium chloride, 0.02% (v/v) polysorbate 20, 5 mM sodium phosphate at pH 7.0.
6.1.2
Intrathecal Drug Delivery Device
The drug product will be administered via the SOPH-A-PORT ® Mini S Implantable Access 
Port. The SOPH-A-PORT ® Mini S device is intended for long-term, intermittent access to the 
IT space for the delivery of investigational drug. The device is CE Marked in the European 
Union (EU) and investigational in non-EU countries.
The SOPH-A-PORT ® Mini S is comprised of the following 7 components:

One SOPH-A- PORT ® Mini S Access Port

One intrathecal port closed-tip catheter

One guidewire

Two suture wings

One 14-gauge Tuohy needle

One 22-gauge non-coring Huber needle

One Luer lock Connector.
Further details are provided in the SOPH-A-PORT ® Mini S Instructions for Use.
6.1.3
Comparator Product
Not applicable
6.2
Treatment Administered
The study drug will be administered through an IDDD. In the event of IDDD malfunction or 
failure, HGT-1410 may be administered via LP.
Patients who were randomized to receive HGT-1410 in Study HGT-SAN-093 will continue to 
have HGT-1410 administered through the IDDD that was implanted during Study 
HGT-SAN-093.
Patients who were randomized to no-treatment in Study HGT-SAN-093 will be scheduled to 
undergo surgical placement of the SOPH-A-PORT ® Mini S device. The initial implantation and
any revision and/or explantation of the SOPH-A-PORT ® Mini S will be performed by pediatric 


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or general neurosurgeons or anesthesiologists who have experience in port and catheter implant 
procedures and intrathecal-access procedures and have completed training for the 
SOPH-A-PORT ® Mini S. Please refer to the IFU for further details. At least 7 days will be 
allowed for recovery following the placement of the IDDD before the administration of the first 
intrathecal dose of HGT-1410. During this time, the patient will receive standard perioperative 
care.
Drug administration will be performed in a clinical setting by appropriately trained and skilled 
healthcare providers (nurses or physicians) with knowledge of the patient’s drug regimen and 
experienced in accessing vascular or CNS ports or CNS infusion pumps. Patients and patients’ 
families will not be directly using the device to administer drugs and will have limited direct 
interaction with the device as there is minimal care required both during the immediate 
postoperative period as the implant site heals, and at times of drug administration.
6.3
Selection and Timing of Dose for Each Patient
After meeting eligibility criteria, patients in Groups 1 and 2 (who received HGT-1410 in Study 
HGT-SAN-093) will begin treatment at Week 50 and 52, respectively, in Study SHP-610-201. 
Patients will be treated for up to 120 weeks in Study SHP-610-201, for a total cumulative 
exposure of 168 weeks across Studies HGT-SAN-093 and SHP-610-201.
After meeting eligibility criteria, patients who were randomized to no-treatment in Study 
HGT-SAN-093 will be scheduled to undergo surgical placement of the SOPH-A-PORT ® Mini 
S device, as described in Section 6.2. Thereafter, these patients will be administered HGT-1410 
45 mg as an IT injection either Q2W or Q4W (Groups 3A or 3B, respectively), as randomized, 
for up to 120 weeks. 
6.3.1
Missed Doses
Patients who are scheduled to receive Q2W dosing (Groups 1 and 3A) should receive their dose 
of HGT-1410 every 14 ± 3 days, and patients who are scheduled to receive Q4W dosing (Groups 
2 and 3B) should receive their dose of HGT-1410 every 28 ± 7 days. If dosing cannot be 
administered within the indicated time window, the dose will be considered missed, and the 
patient will resume their dosing schedule with the next dose of HGT-1410. The dosing schedule 
will not change or be reset.
6.4
Method of Assigning Patients to Treatment Groups
Patients who were randomized to no-treatment in Study HGT-SAN-093 (Group 3) will be re-
randomized in a 1:1 allocation ratio to receive Q2W or Q4W dosing (Groups 3A or 3B, 
respectively). To help ensure balance between the dose groups with respect to age at Baseline, 
the randomization will be stratified by age group (≤30 months and >30 months). (Refer to 
Section 10.3).
Patients who were randomized to receive HGT-1410 in Study HGT-SAN-093 will remain on the 
same treatment regimen in Study SHP-610-201.


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6.5
Blinding
This study will not be blinded.
6.6
Prior and Concomitant Medications, Therapies, and Medical/Surgical Interventions
Prior and/or concomitant therapy prohibited for all patients in this study consists of the 
following:

Psychotropic or other medications, which in the Investigator’s opinion, would be likely to 
substantially confound test results.

The use of medications which, in the opinion of the investigator, place patients at risk of 
bleeding complications following surgery or LP.

Any other investigational therapy (drug or device) at any time during the study.

Hematopoietic stem cell or bone marrow transplant.
6.7
Restrictions
6.7.1
Fluid and Food Intake 
Not applicable
6.7.2
Patient Activity Restrictions
Please refer to the SOPH-A-PORT Mini S IFU for details regarding patient activity 
restrictions for patients to be implanted with this device. Activities that may include sudden, 
excessive, or repetitive bending, twisting, bouncing, or stretching can damage or dislodge IDDD 
components and should be avoided.
6.8
Treatment Compliance
Treatment with HGT-1410 will be administered via an IDDD under the supervision of the 
investigator and in the controlled environment of a clinical center; therefore, full patient 
compliance with treatment is anticipated in this study.
6.9
Packaging and Labeling
All packaging and labeling will be in accordance with applicable regulatory requirements.
The SOPH-A-PORT ® Mini S Access Port is available in one size, individually packaged, with 
other SOPH-A-PORT ® Mini S components in double peel-off, sterile, pyrogen-free packaging, 
sterilized with Ethylene Oxide. Instructions for use are also included in the packaging. A 
guidewire is provided in separate double pouch, sterile, pyrogen-free packaging.
Labels are provided on the outer carton, and on both the SOPH-A-PORT ® Mini S box and 
guidewire/cannula package inside and will be in accordance with local regulatory requirements.


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6.10
Storage and Accountability
6.10.1
Investigational Product
HGT-1410 will be supplied at a concentration of 15 mg/mL in single-use vials for IT 
administration.
HGT-1410 will be shipped by Shire or a qualified distributor to the clinical study site(s) at 2 to 
8°C (36 to 46 °F).
Drug product should be stored refrigerated (2 to 8°C); drug product may not be used beyond the 
expiration date on the vial.
The disposition of all investigational product delivered to a Principal Investigator must be 
recorded on a patient-by-patient basis by completing the clinical trial material accountability log. 
The date and time of administration of the investigational product must be documented on the 
appropriate eCRF.
The Principal Investigator, Clinical Research Coordinator, or designee (eg, Pharmacist) must 
ensure that all documentation regarding investigational product receipt, storage, dispensing, 
loss/damaged and return of used/unused product is complete, accurate, and ready for review at 
each monitoring visit and/or audit. The sites must ensure that the investigational product is 
available for the monitor to inventory and prepare for return shipment to the Sponsor or 
designee, if required. 
The process for destruction of investigational product is provided in the Pharmacy Manual. 
See the Pharmacy Manual for additional details.
6.10.2
Intrathecal Drug Delivery Device
The disposition of all SOPH-A-PORT ® Mini S devices delivered to a Principal Investigator 
must be recorded on a patient-by-patient basis by completing the Accountability Log. The date 
and time of administration of the investigational product and use of the SOPH-A-PORT ® Mini 
S device must be documented on the patient’s appropriate eCRF.
The Principal Investigator, Clinical Research Coordinator, or designee (eg, Pharmacist) must 
ensure that all documentation regarding receipt, storage, dispensing, loss/damaged 
SOPH-A-PORT ® Mini S devices and return of used/unused SOPH-A-PORT ® Mini S 
device(s) is complete, accurate, and ready for review at each monitoring visit and/or audit. The 
sites must ensure that the SOPH-A-PORT ® Mini S devices are available for the monitor to 
inventory and prepare for product destruction or return shipment to the Sponsor or designee.
The SOPH-A-PORT ® Mini S and its components are sterile, single-use devices.
Please refer to the IDDD Manual for device destruction or return instructions.


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6.10.3
Comparator Product
Not applicable to this study.


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7
STUDY PROCEDURES
Detailed descriptions of patient procedures and evaluations required for this protocol are 
described in this section. These evaluations will be performed during the indicated days and 
weeks of the study (see Schedule of Events for Group 1 (patients who received HGT-1410 Q2W 
in Study HGT-SAN-093) in Appendix 1, for Group 2 (patients who received HGT-1410 Q4W in 
Study HGT-SAN-093 in Appendix 2, for Group 3A (patients who received no-treatment in Study 
HGT-SAN-093 and are randomized to receive HGT-1410 Q2W in Study SHP-610-201) in 
Appendix 3, and for Group 3B (patients who received no-treatment in Study HGT-SAN-093 and 
are randomized to receive HGT-1410 Q4W in Study SHP-610-201) in Appendix 4.
All data collected are to be recorded on the patient’s appropriate eCRF.
Details for sample collection are described in the Laboratory Manual for Study SHP-610-201.
7.1
Informed Consent
Prior to conducting any study-related procedures, written informed consent must be obtained 
from the patient’s parent(s) or legally authorized representative(s) and assent from the patient (if 
applicable).
The nature, scope, and possible consequences, including risks and benefits, of the study will be 
explained to the patient, the patient’s parent(s), or the patient’s legally authorized representative 
by the Investigator or designee in accordance with the guidelines described in Section 11.4. 
Documentation and filing of informed consent documents should be completed according to 
Section 11.4.
7.2
Study Entrance Criteria
Each patient in Groups 1 and 2 (those who received HGT-1410 in Study HGT-SAN-093) will be 
reviewed for eligibility against the study entrance criteria prior to receiving HGT-1410 on Week 
50 and 52, respectively.
All treated patients in Study HGT-SAN-093 will have their cognitive development assessed at 
the Week 48 Visit in Study HGT-SAN-093. If a decline from Baseline of 20 points or less in DQ 
score is observed, then the patient may proceed into the Study SHP-610-201 without further 
evaluation. If a decline from Baseline of more than 20 points in DQ score is observed, then 
an individual evaluation by the Investigator will occur to determine if the patient is a treatment 
failure. This individual evaluation will take into account the DQ scores, VABS score, physical 
status, and any other information available for that patient at that time. If the Investigator deems 
the patient to be a treatment failure, then the patient may not enter the Study SHP-610-201.
Each patient who received no-treatment in Study HGT-SAN-093 (Group 3) will be reviewed for 
eligibility against the study entrance criteria before IDDD implantation.
Patients who do not meet the study entrance criteria will not be allowed to participate in the 
study. The reason(s) for the patient’s ineligibility for the study will be documented.


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7.3
Hearing and Vision Assessments 
7.3.1
Investigator Assessment of Hearing and Vision
For patients who received no-treatment in Study HGT-SAN-093 (Group 3) only, the Investigator 
will use their clinical judgment to assess the patient’s vision during the initial physical 
examination. Investigator judgment will be used to determine whether the patient’s hearing and 
vision is adequate for cooperation with neurodevelopmental testing, as indicated in the study 
inclusion criteria.
7.4
Device Related Study Procedures
7.4.1
IDDD Implantation or Revision Procedures
The IDDD will be surgically implanted or revised at the clinical site. Procedures for implantation 
and revision are detailed in the device’s Instructions for Use (IFU). Standard hospital procedures 
for surgery will be followed; the patient will be under general anesthesia for this procedure.
An additional medical device, the catheter passer, is necessary for the implantation procedure. 
The catheter passer is a sterile, single use device that will be used in the subcutaneous placement 
of the catheter. The Phoenix Neuro Disposable Catheter Passer, manufactured by Sophysa is CE 
marked in the EU and cleared under K853370 in the US, may be provided; however, use of other 
catheter passers compatible with the SOPH-A-PORT ® Mini S is allowed.
Details of the implantation/revision and malfunctions/failure will be documented on the patient’s 
eCRF.
7.4.2
X-ray Verification of Intrathecal Drug Delivery Device Placement 
A postoperative x-ray check of the IDDD will be performed following surgery for Groups 3A 
and 3B to verify proper installation and confirmation of IDDD placement at the mid-thoracic 
level. The x-rays may be performed to check placement of the device, as needed, throughout the 
study. At a minimum, the date of the x-ray verifying correct IDDD placement will be 
documented on the patient’s eCRF. If the device requires revision or replacement during the 
study, additional x-rays will be taken to document proper positioning of the device. If an IDDD 
malfunctions, an X-ray will be performed to assess the potential cause of malfunction. 
Fluoroscopy should be used during device implantation procedures.
7.4.3
CSF Sampling Procedure
Cerebrospinal fluid will be sampled via the device. If this is not possible, and if CSF sampling is 
necessary, either for adherence to the protocol, or to investigate clinical concerns, an LP may be 
performed to sample CSF, either with or without administration of drug afterwards.
7.4.4
Device Revision or Removal
If at the time of a scheduled dosing it is not possible to administer a full medication dosage using 
the standard administration steps detailed in the device’s IFU due to a device-related issue, the 


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IDDD will be declared a device malfunction. If the device malfunction is irreversible and cannot 
be corrected without a device surgical intervention, the IDDD will be declared a device failure, 
starting from the date of the initial malfunction. 
The IDDD will then be surgically removed or revised and a new device and/or device 
components will be re-implanted at the earliest possible opportunity, preferably at the same time. 
Details of the device removal will be recorded in the patient’s electronic case report form 
(eCRF). Refer to the SOPH-A-PORT ® Mini S IFU for further details.
Patients will have the IDDD removed when they discontinue from or complete the study, unless 
the patient is continuing to receive treatment through another mechanism (eg, extension study, 
expanded access program, commercially available drug).
7.5
Investigational Product Administration
Patients will be administered HGT-1410 IT by means of an IDDD, either every 2 weeks or every 
4 weeks. A visual examination of both the port and catheter track will be performed before each 
IT injection.
Patients will remain under observation in the hospital setting for at least 4 hours post-dosing and 
will be discharged when deemed clinically stable by the Investigator. The number of IDDD 
revisions/ replacements is limited to 2 per patient in any 6-month period. Therefore, in the “worst 
case scenario” of 2 IDDD failures occurring within 1 month, up to 11 consecutive doses of 
HGT-1410 administered via LP will be necessary for patients in the Q2W dosing group, and up 
to 5 consecutive doses via LP will be necessary for patients in the Q4Wdosing group until the 
IDDD can be revised or replaced.
A 22-gauge Huber non-coring needle is to be used for access to the implanted port; standard 
hypodermic needles would damage the septum and may cause leakage. If no needle-free 
connector is present, a stopcock or the Huber needle infusion set’s clamp is to be used to prevent 
CSF backflow and to mitigate the risk of air entering the system. It is possible to use other 
brands of Huber non-coring needles, provided that their specifications are identical to that of the 
Huber needle supplied by Sophysa in a SOPH-A-PORT ® Mini S (22G).
It is expected that all or most doses of HGT-1410 will be successfully administered following the 
application of topical anesthetic cream to the skin overlying the IDDD access port (see IDDD
Manual for details). However, in some cases, sedation or general anesthesia may be required, and 
may be used at the discretion of the Investigator. Any sedative or anesthetic drugs used must be 
recorded as concomitant medications.
Intrathecal administration of investigational product will be preceded by CSF sampling for 
clinical laboratory analysis (cell count, protein, glucose), and storage for additional analyses 
which may include:  PD (GAG concentration), analyses of HGT-1410 enzyme and anti-rhHNS 
antibodies, according to the relevant Schedules of Events (Appendix 1, Appendix 2, Appendix 3, 
and Appendix 4).


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All HGT-1410 administrations will be followed by a flush with preservative-free saline of at 
least 2 mL. The total volume of investigational product and flush administered is targeted 
towards replenishing the volume of CSF withdrawn. If the total volume of HGT-1410 plus 2 mL 
saline flush is less than the total volume of CSF withdrawn, additional saline will be 
administered to balance the volumes withdrawn and injected.
The injection date, injection start/stop time, planned dose, injection volume, and flush volume 
will be recorded on the patient’s eCRF.
7.6
Efficacy Assessments
7.6.1
Neurocognitive and Developmental Assessments
The study methodology will include standardized neurodevelopmental assessments to provide a 
quantifiable measure of patient neurodevelopmental status (see Table 7-1).11  The assessments 
are estimated to last between 2 and 4 hours and must be conducted prior to any invasive 
procedures, such as blood draws, and prior to sedation or anesthesia. Neurodevelopmental status 
will be assessed over time by measuring cognitive and adaptive functions as follows:

Cognition:  the Bayley Scales of Infant and Toddler Development, Third Edition 
(BSID-III)12 will be used to assess all patients through the age of 42 months. Once 
patients reach 42 months chronological age, an attempt will be made to switch the 
cognitive assessment to the Kaufman Assessment Battery for Children-Second Edition 
(KABC-II). If the cognitive status of the patient does not allow for testing by the 
KABC-II, the BSID-III may be used.

Adaptive behaviors:  the Vineland Adaptive Behavioral Scales, Second Edition (VABS 
II)13 will be used to assess all patients.
For this study, outcome measures will be computed for each patient enrolled. The psychometric 
instruments are summarized below in Table 7-1. 
Table 7-1
Neurodevelopmental Assessments Tests 
Cognitive Test or Scale 
Developmental or Cognitive Areas of Assessment
Bayley Scales of Infant and Toddler 
Development, Third Edition (BSID-III)12
Summary score and sub-domains:
- Cognitive
- Motor
- Social/Emotional
- Language
Kaufman Assessment Battery for Children, 
Second Edition (KABC-II)
Cognitive and processing skills
ADAPTIVE BEHAVIOR
Vineland Adaptive Behavior Scales, 
Second Edition (VABS II)13
Communication
Daily Living
Socialization
Motor Skills


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7.6.2
Quality of Life Indicator:  Infant Toddler Quality of Life Questionnaire
The Infant Toddler Quality of Life Questionnaire™ (ITQoL) will be administered during the 
study. The ITQoL was developed for children at least 2 months of age up to 5 years and assesses 
the physical, mental, and social wellbeing of the child and assesses the quality of the 
parent/guardian’s life. If a patient is over 5 years of age, they do not have to complete the 
ITQoL.
7.6.3
Health Economics and Outcomes Research:  Healthcare Utilization 
Questionnaire
The Healthcare Utilization Questionnaire (HCUQ) will be administered during the study. This 
HCUQ focuses on the direct and indirect costs of care for patients with MPS-III.
7.7
Magnetic Resonance Imaging
7.7.1
Head
Regional brain volumes, including total cortical gray matter volume, will be assessed through an 
MRI of the head. The patient will be under general anesthesia for this assessment. Instrument 
standardization and central analysis of MRIs will be performed by a designated contract research 
laboratory.
7.7.2
Liver and Spleen
Liver and spleen volumes will be assessed through an MRI, performed at the same times as for 
the MRI of the head. The patient will be under general anesthesia for this assessment. Instrument 
standardization and central analysis of MRIs will be performed by a designated contract research 
laboratory.
7.8
Pharmacokinetic Assessments
Blood samples will be collected for measurement of serum concentrations of HGT-1410 and 
determination of PK parameters at the times specified in Schedules of Events (Appendix 1, 
Appendix 2, Appendix 3, Appendix 4, and Appendix 5). Additionally CSF samples will be
collected from patients who received no-treatment in Study HGT-SAN-093 at the times specified 
in the Schedules of Events (Appendix 3, Appendix 4, and Appendix 5). The results of these 
assessments will be addressed in a separate PK report.
Patients may be discharged from the hospital after the 24-hour blood draw. Patients will either 
stay locally in a hotel or return home (if they live in close proximity to the hospital); this will be 
decided in consultation with the Investigator. Patients will return to the hospital for PK blood and 
CSF sampling at the 48-hour time point. Patients will be discharged to home after the physical 
examination and blood draws have been completed at the 48-hour PK time point. See Appendix 
5 for more details regarding timing for PK sample collection.
Serum and CSF PK collection, processing, and shipping instructions will be provided in the 
Laboratory Operations Manual.


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7.9
Pharmacodynamic Biomarker Assessments (CSF and Urine GAG Levels)
CSF and urine samples will be obtained to measure the concentration of GAG according to the 
schedules of events (Appendix 1, Appendix 2, Appendix 3, and Appendix 4). Details about CSF 
collection are provided in Section 7.11.5.3.
7.10
Concomitant Medications, Therapies, and Medical/Surgical Interventions
All non-protocol treatments and medications that occur from the time of informed consent 
through the safety follow-up contact are regarded as concomitant and will be documented on the 
appropriate pages of the eCRF. Concomitant therapy includes any therapies/interventions 
administered to patients, and these will be recorded on the concomitant therapy eCRF. Any 
medical/surgical procedures performed on the patients will be recorded on the concomitant 
medical/surgical procedures eCRF. Concomitant medications, both prescribed and 
over-the-counter (including genistein and anesthesia medications) will be recorded on the 
concomitant medication eCRF.
Every effort should be made to keep symptomatic MPS IIIA treatment constant throughout the 
study. However, changes in medications are acceptable if necessary according to clinical 
judgment. All changes will be recorded on the appropriate eCRF. Concomitant medication will 
be coded using the World Health Organization-Drug Dictionary (WHO-DD).
7.11
Safety Assessments
7.11.1
Vital Signs
Vital signs are to be recorded on the eCRF for all patients and will include heart rate, blood 
pressure, respiration rate, and body temperature. Vital signs will be recorded for at least 4 hours 
following each dose of HGT-1410, as described in the Schedules of Events (Appendix 1, 
Appendix 2, Appendix 3, and Appendix 4).
7.11.2
Physical Examination, including Height, Weight, and Head Circumference
During the study, physical examinations will be performed at the time points indicated in the 
SOEs. For Groups 1 and 2, full physical examinations will be conducted at Weeks 96, 120, 144, 
and 168, and for Groups 3A and 3B, full physical examinations will be conducted during the 
IDDD implantation period and at Weeks 24, 48, 72, 96, and 120. The remainder of physical 
examinations will be symptom-directed.
Physical examinations will include a review of the patient’s general appearance, neurological 
examination, as well as evaluation of the body systems described in Table 7-2, including the port 
and catheter track. Any abnormal change in findings will be recorded as an AE on the 
appropriate eCRF.
Table 7-2
Assessments for Physical Examinations
Assessment
Assessment
General appearance
Endocrine
Head and neck
Cardiovascular


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Table 7-2
Assessments for Physical Examinations
Assessment
Assessment
Eyes
Abdomen
Ears
Genitourinary
Nose
Skin
Throat
Musculoskeletal
Chest and lungs
Neurological
Port and catheter track
Height and weight will be recorded for all patients.
The clinical site staff will be instructed to use calibrated scales for weight measurement where 
possible. The same scale is to be used at the clinical site for all patients at each specified time 
point during the study.
Head circumference will be measured for Groups 3A and 3B during the IDDD implantation 
period. All data will be recorded on the eCRF. 
7.11.3
Electrocardiogram
An ECG will be performed in accordance with the clinical site’s standard practice(s) and are to 
be performed after study drug administration. Electrocardiogram recordings will be read locally 
at the clinical site and will include an assessment of heart rate, sinus rhythm, atrial or ventricular 
hypertrophy, PR, QRS, and QT. Identification of any clinically significant findings and/or 
conduction abnormalities will be recorded on the eCRF. If the patient is unable to cooperate with 
electrocardiography, and if sedation or general anesthesia is employed during that study visit, the 
ECG may be performed under sedation / anesthesia.
7.11.4
Clinical Laboratory Tests
Blood and urine samples will be collected as described in this section for clinical laboratory 
testing. All blood samples will be collected via venipuncture. Patients will be in a seated or 
supine position during blood collection. Procedures for collection and handling of samples are 
included in the Laboratory Manual.
Clinical laboratory tests will include the following (See Table 7-3):


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Table 7-3
List of Laboratory Tests
Hematology:
-
Hematocrit (Hct)
-
Hemoglobin (Hgb)
-
Mean corpuscular hemoglobin (MCH)
-
Mean corpuscular hemoglobin 
concentration (MCHC)
-
Mean corpuscular volume (MCV)
-
Platelet count
-
Red blood cell (RBC) count 
-
White blood cell (WBC) count with 
differential 
Urinalysis: 
-
Appearance
-
Bilirubin
-
Color
-
Glucose
-
Ketones
-
Microscopic examination of sediment 
-
Microscopic examination
-
Nitrite 
-
Occult blood
-
pH
-
Protein
-
Specific gravity
-
Urobilinogen
-
Triglycerides
-
Uric acid
Anti-rhHNS antibody assessment
Serum Chemistry:
-
Albumin (ALB)
-
Alkaline phosphatase (ALK-P)
-
Alanine aminotransferase (ALT; SGPT)
-
Aspartate aminotransferase (AST; SGOT)
-
Blood urea nitrogen (BUN)
-
Calcium (Ca)
-
Carbon dioxide (CO2)
-
Chloride (Cl)
-
Creatinine
-
Creatine kinase (CK) and subtypes
-
Gamma-glutamyl transferase (GGT)
-
Globulin
-
Glucose
-
Lactate dehydrogenase (LDH)
-
Phosphorus
-
Potassium (K)
-
Sodium (Na)
-
Total bilirubin
-
Direct bilirubin
-
Total cholesterol
-
Total protein
-
Triglycerides
-
Uric acid
Coagulation (performed at IDDD implantation):  
-
Prothrombin time (PT)
-
Activated partial thromboplastin time 
(aPTT)
7.11.5
Cerebrospinal Fluid Assessments 
Cerebrospinal fluid will be obtained from patients during surgical implantation of the IDDD
(Groups 3A and 3B only), immediately prior to each injection of study drug, and at the safety 
follow-up visit. Should the IDDD become clogged or undergo mechanical complications, the 
CSF sample will be obtained via LP.
The volume of CSF collected at each visit will vary according to the number of CSF 
assessments. The initial 1 mL of CSF aspirated via the IDDD will be discarded, to eliminate fluid 
in the device “dead space”. The next 1 mL of CSF will be sent to the local laboratory. 
Subsequently drawn CSF will be stored, depending on the requirement for that visit (refer to the 
schedules of events in Appendix 1, Appendix 2, Appendix 3 Appendix 4 and the Laboratory 
ory Manual). If CSF is obtained via lumbar puncture, there is no need to discard the first mL of 
CSF, and this can be sent to the local laboratory for standard clinical assessments. If the patient 


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is clinically stable in the opinion of the investigator, HGT-1410 can be administered immediately 
following withdrawal of CSF, without awaiting the results of the CSF clinical laboratory data.
Each CSF sample collected will have the assessments described in Sections 7.11.5.1 through 
7.11.5.4.  Cerebrospinal fluid sample collection, processing, and shipping instructions are 
provided in the Laboratory Manual.
7.11.5.1
Standard CSF Safety Laboratory Assessments
An aliquot of each CSF sample collected will be evaluated for CSF standard chemistries, 
glucose, protein, and cell counts.
7.11.5.2
Anti-rhHNS Antibodies and Biomarkers in CSF
An aliquot of each CSF sample collected will be quick frozen for subsequent analysis of Anti-
rhHNS antibody evaluation, exploratory proteomics biomarkers, and/or other CSF biomarkers.
7.11.5.3
CSF GAG Levels and Biomarkers
An aliquot of each CSF sample collected will be quick frozen for subsequent analysis of CSF 
GAG, GAG degradation components, HS/dermatan sulfate (DS) oligosaccharides, or other CSF 
markers. The CSF PD sample will be obtained at the same visit as a serum sample as described 
in Section 7.9.
7.11.5.4
7.11.6
Device Assessments
. These data will be collected on the patient’s eCRF from the time of initial implantation.
7.11.7
Collection and Storage of Biological Samples for Biomarker Studies 
Biomarker analyses may be performed at the Shire research laboratory or at a Shire-designated 
research laboratory. Collection and processing of CSF samples will be performed as specified in 
the Laboratory Manual. Samples will be stored securely to ensure patient confidentiality. 
Samples obtained for this study will be stored for up to 10 years. Thereafter, samples will be 
destroyed. 
7.12
Sample Collection, Storage, and Shipping
Details for study procedures including sample collection are provided in the Laboratory Manual 
for this study.


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7.13
Adverse Events Assessments
7.13.1
Definitions of Adverse Events and Serious Adverse Events
7.13.1.1
Adverse Event
An AE is any noxious, pathologic, or unintended change in anatomical, physiologic, or 
metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in 
any phase of a clinical study, whether or not considered investigational product-related. This 
includes an exacerbation of a pre-existing condition. 
Adverse events include:

Worsening (change in nature, severity, or frequency) of conditions present at the onset of 
the study

Intercurrent illnesses

Drug interactions

Events related to or possibly related to concomitant medications

Abnormal laboratory values (this includes significant shifts from baseline  within the 
range of normal that the Investigator considers to be clinically important)

Clinically significant abnormalities in physical examination, vital signs, and weight
Throughout the study, the Investigator must record all AEs on the AE eCRF, regardless of the 
severity or relationship to investigational product. The Investigator should treat patients with 
AEs appropriately and observe them at suitable intervals until the events stabilize or resolve. 
Adverse events may be discovered through observation or examination of the patient, 
questioning of the patient, complaint by the patient, or by abnormal clinical laboratory values.
In addition, AEs may also include laboratory values that become significantly out of range. In 
the event of an out-of-range value, the laboratory test should be repeated until it returns to 
normal or can be explained and the patient’s safety is not at risk.
Additional illnesses present at the time when informed consent is given are regarded as 
concomitant illnesses and will be documented on the appropriate pages of the eCRF. Illnesses 
first occurring or detected during the study, and worsening of a concomitant illness during the 
study, are to be regarded as AEs and must be documented as such in the eCRF.
7.13.1.2
Adverse Events Due to Systemic Exposure to HGT-1410 
Although HGT-1410 is given intrathecally only, some proportion of the drug will diffuse from 
the CSF into the peripheral circulation. The resulting systemic exposure may cause events that 
are typically seen in patients receiving ERT via an intravenous administration. Investigators will 
judge the relationship of AEs to the drug infusion and describe the clinical details on the AE 
form. The temporal relationship of an AE to the drug infusion will be determined upon analysis 
of the AE and study treatment administration data. 


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7.13.1.3
IDDD-related Adverse Events
IDDD ADVERSE EVENTS
Examples of AEs related to use of the IDDD include, but are not limited to, the following:  
device failure, device malfunction, incorrect connection of IDDD components, erosion of the 
portal/catheter through the skin, fibrin sheath formation around the catheter tip, hematoma, 
implant rejection, migration of the portal/catheter, occlusion of the portal/catheter, portal site or 
subcutaneous tract infection. A malfunction of the device (defined in Section 7.13.2.2) should 
not be entered as an adverse event unless it has physiological consequences. In the event of a 
device failure (defined in Section 7.13.2.3), the device may need to be replaced or repaired. If 
overnight hospitalization is required for such a procedure (or the device failure meets any other 
serious criteria, eg, medically important), the device failure will be reported as a serious adverse 
event. Details of the cause of the IDDD malfunction or failure will be recorded on the device 
malfunction and failure eCRF and the serious adverse event (SAE) form (when applicable). A 
list of the most common IDDD AEs is included in Appendix 6.
DEVICE SURGICAL PROCEDURE-RELATED ADVERSE EVENTS (FOR IT STUDIES; AMEND/DELETE 
SECTION AS APPLICABLE)
Examples of AEs related to device surgical procedures include, but are not limited to, the 
following:  events that occur during or shortly following IDDD implant/explant, IDDD 
adjustment, full revision, partial revision, IDDD removal, and delayed re-implantation after 
previous IDDD removal (such as complications of anesthesia, excessive bleeding, wound 
hematoma), and post-operative complications (such as post-operative infection). These events 
are relat4ed to the surgical procedure itself.
IT ADMINISTRATION PROCESS ADVERSE EVENTS
Intrathecal administration process adverse events may include those caused by anesthesia during 
drug administration and other drug administration issues (eg, extravasation during infusion or 
hematoma due to Huber needle), or complications of lumbar puncture.
7.13.1.4
Serious Adverse Event
1. An SAE is any AE occurring at any dose of investigational drug or procedure that results in 
any of the following outcomes:

Death

Is life-threatening

Requires hospitalization

Requires prolongation of existing hospitalization

A persistent or significant disability or incapacity 

A congenital anomaly or birth defect
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. A life-threatening AE is defined as an AE that placed the 


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patient, in the view of the initial reporter, at immediate risk of death from the AE as it occurred 
(ie, it does not include an AE that, had it occurred in a more severe form, might have caused 
death).
2. Unanticipated Adverse Device Effect (UADE) - Any serious adverse effect on health or 
safety or any life-threatening problem or death caused by, or associated with, a device, if that 
effect, problem, or death was not previously identified in nature, severity, or degree of 
incidence in the investigational plan or application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with a device that relates 
to the rights, safety, or welfare of patients. (21 Code of Federal Regulations [CFR] 812.3[s] 
or other regulatory requirements, as applicable).
7.13.2
Device-associated Definitions
7.13.2.1
Device Revision (Partial and Full)
Partial device revision:  surgical revision/replacement of one or more component(s) of the 
device; other component(s) of the original device remain implanted and are not affected (eg, port 
revision)
Full device revision:  the device is removed (explanted) in its entirety and a completely new 
device is implanted.
7.13.2.2
Device Malfunction
The device does not perform as intended, based on the description in the device’s IFU, but does 
not require either a partial or full device revision.
7.13.2.3
Device Failure
The device irreversibly fails to perform as intended and requires either a partial or full device 
revision or removal.
7.13.3
Classification of Adverse Events and Serious Adverse Events
The severity of AEs will be assessed by the Investigator based on the definition indicated in 
Table 7-4. The severity of all AEs/SAEs should be recorded on the appropriate eCRF page to a 
severity of mild, moderate, or severe.
Table 7-4
Adverse Event Severity
Severity
Definition
Mild
No limitation of usual activities.
Moderate
Some limitation of usual activities.
Severe
Inability to carry out usual activities.


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7.13.4
Clarification between Serious and Severe
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache). This is not the same as “serious,” which is based 
on the outcome or action criteria usually associated with events that pose a threat to life or 
functioning. Seriousness (not severity) and causality serve as a guide for defining regulatory 
reporting obligations.
7.13.5
Relatedness of Adverse Events and Serious Adverse Events
Relationship of an AE or SAE to investigational product, device (IDDD), device surgical 
procedure, or IT administration process will be assessed by the Investigator based on the 
following definitions (See Table 7-5).
Table 7-5
Adverse Event Relatedness
Relationship
Definition
Not Related
Unrelated to investigational product, device, device surgical 
procedure, or IT administration process.
Possibly Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of investigational product, the presence of 
the device, device surgical procedure, or IT administration process but 
which could also be explained by concurrent disease or other drugs or 
chemicals.
Probably Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of investigational product, the presence of 
the device, device surgical procedure, or IT administration process
unlikely to be attributable to concurrent disease or other drugs and 
chemicals and which follows a clinically reasonable response on de-
challenge. The association of the clinical event or laboratory 
abnormality must also have some biologic plausibility, at least on 
theoretical grounds.
Definitely related
The event follows a reasonable temporal sequence from administration 
of the investigational product, the presence of the device, device 
surgical procedure, or IT administration process follows a known or 
suspected response pattern to the investigational product, is confirmed 
by improvement upon stopping the investigational product (de-
challenge), and reappears upon repeated exposure (re-challenge). Note 
that this is not to be construed as requiring re-exposure of the patient 
to investigational product; however, the determination of definitely 
related can only be used when recurrence of event is observed.
7.13.6
Procedures for Recording and Reporting Adverse Events
7.13.6.1
Adverse Event Monitoring and Period of Observation
Adverse events (AEs) will be monitored continuously throughout the study.
For the purposes of this study, the period of observation extends from the time at which the 
patient, the patient’s parent(s), or the patient’s legally authorized representative gives informed 


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consent until the patient’s final evaluation of the study. For safety purposes, the final evaluation 
will be defined as the follow-up evaluation performed approximately 30 days after the last dose 
for patients who complete the study.
If the Investigator considers it necessary to report an AE in a study patient after the end of the 
safety observation period, he or she should contact the Sponsor to determine how the AE should 
be documented and reported.
7.13.6.2
Reporting Serious Adverse Events
Any SAE, regardless of relationship to investigational product, device, device surgical 
procedure, or IT administration process which occurs in a patient after informed consent, should 
be recorded by the clinical site on an SAE form. The SAE must be completely described on the 
patient’s eCRF, including the judgment of the Investigator as to the relationship of the SAE to 
the investigational product and/or device. The Investigator will promptly supply all information 
identified and requested by the Sponsor (or contract research organization [CRO]) regarding the 
SAE. 
The Investigator must report the SAE to the Shire Pharmacovigilance and Risk Management 
Department AND to the Shire Medical Monitor on an SAE form. This form must be completed 
and FAXED or EMAILED within 24 hours of the Investigator’s learning of the event to:
Shire Pharmacovigilance and Risk Management Department:
International FAX:  
 (UK) OR United States FAX:  
Email:  
AND
Shire Medical Monitor:  
, MD
Email:  
FAX:  
 (USA)
Any follow-up information must also be completed on an SAE form and faxed or emailed to the 
same numbers or emails listed above.
In the event of a severe and unexpected, fatal, or life-threatening SAE, the clinical site must 
contact the Shire Medical Monitor by telephone; this is in addition to completing and 
transmitting the SAE form as stated above. The following provides contact information for the 
Shire Medical Monitor. 


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If an SAE is assessed as severe and unexpected, fatal or life-threatening, contact:
 MD
Shire Human Genetic Therapies, Inc.
300 Shire Way
Lexington, MA  02421  USA
Telephone:  
Mobile:  
(24 hr access)
Email:  
Fax:  
(USA)
The Investigator must promptly report all required information to the IRB/IEC. It is the 
responsibility of the Sponsor to ensure that each Investigator receives a copy of any CIOMS I/ 
MedWatch report that has been submitted to the appropriate regulatory agencies notifying them 
of an unexpected related SAE. The Investigator or Sponsor must ensure that the IRB/IEC 
receives a copy of the report and that a copy is also filed within their study files.
7.14
Abuse, Overdose and Medication Error
Abuse – Persistent or sporadic intentional intake of investigational medicinal product at a dose 
higher than prescribed per protocol (but below the dose defined for overdose) or when used for 
non-medical purpose (eg, altering one’s state of consciousness)
Misuse – Intentional or unintentional use of investigational medicinal product other than as 
directed or indicated at any dose, which is at or below the dose defined for overdose (Note:  This 
includes a situation where the test article is not used as directed at the dose prescribed by the 
protocol)
Overdose – Intentional or unintentional intake of a dose of investigational medicinal product 
higher than the protocol-mandated dose. No clinical information on overdose is available. 
Medication Error – A mistake made in prescribing, dispensing, administration and/or use of the 
investigational medicinal product.
All investigational medicinal product provided to pediatrics should be supervised by the 
parent/legally-authorized representative/caregiver.
7.15
Removal of Patients from the Trial or Investigational Product
A patient’s participation in the study may be discontinued at any time at the discretion of the 
Investigator. The following may be justifiable reasons for the Investigator to remove a patient 
from the study:

Non-compliance, including failure to appear at one or more study visits

The patient was erroneously included in the study

The patient develops an exclusion criterion 


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
The patient suffers an intolerable adverse event

The study is terminated by the Sponsor
The patient, the patient’s parent(s), or the patient’s legally authorized representative acting on 
behalf of the patient is free to withdraw consent and discontinue participation in the study at any 
time without prejudice to further treatment.
If a patient or the patient’s parent(s) or the patient’s legally authorized representative(s) acting on 
behalf of the patient, discontinues participation in the study, or the patient is discontinued by the 
Investigator, reasonable efforts will be made to follow the patient through the safety follow-up
assessments. The reason for refusal will be documented on the eCRF. Any AEs experienced up 
to the point of discontinuation must be documented on the AE eCRF. If AEs are present when 
the patient withdraws from the study, the patient will be re-evaluated within 30 days of 
withdrawal. All ongoing SAEs at the time of withdrawal will be followed until resolution.
7.16
Safety-Related Study Stopping Rules
In addition to safety monitoring by the Sponsor, patient safety in this study will be monitored by 
an independent DMC until the last patient completes their last scheduled study visit/assessment. 
The DMC will be an external group overseeing the safety of the study treatment, including both 
the investigational product and the IDDD, and will operate according to a charter determining 
the scope of its activities and frequency of meetings (See Section 11.8 for additional details).
This study will be stopped and safety data reviewed if any patient experiences a life-threatening 
or fatal SAE, either of which is considered possibly or probably related to the investigational 
product.
Following the review of safety data, the status of the study will be one of the following:

Resumed unchanged

Resumed with modifications to the protocol 

Terminated
Patient safety will be monitored on a continuous basis during this study until the last patient 
completes his or her last scheduled study visit/assessment. 
7.17
Appropriateness of Measurements
The neurocognitive and developmental assessments planned for this study are intended to gauge 
the potential treatment effect and safety of 2 dose levels of HGT-1410 over time on behavioral 
and cognitive criteria in patients with MPS IIIA. The selection of tests used for the cognitive 
assessment, and the expression of results as a ratio of mental age equivalence to calendar age to 
generate a DQ, were developed in collaboration with clinical psychologists with expertise in the 
assessment of severely disabled children with neurometabolic diseases. 
The BSID-III, KABC-II, and VABS II are instruments that have been used to assess 
development in healthy children and those with developmental delay. Their use in this study will 
contribute to their validation in patients with MPS IIIA. The utility of these measures to track 


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disease progression has been demonstrated in Shire’s natural history study of MPS IIIA 
(HGT-SAN-053). 
The BSID-III was selected for the following reasons:  

Widespread familiarity with the instrument 

Availability of age equivalent scores for severely impaired children 

Nonverbal content (ie, on the cognitive scale on the BSID-III) 

Availability of language and motor assessment (both are domains on the BSID-III). 
The BSID-III is validated for children through the age of 42 months. Patients are to be switched 
to another instrument, the KABC-II, to measure cognition after the age of 42 months. The 
KABC-II measures a child’s cognitive ability and processing skills and was designed to
minimize verbal instructions and responses. In addition, the assessment contains little cultural
content to provide a more accurate assessment of children from diverse backgrounds. Thus
language difficulties or cultural differences are minimized in the test battery’s results.
The VABS II, a parent-reported outcome, was selected as an adaptive measure for the same 
reasons. Of note, to maximize standardization and reduce bias, the “interview” form of the 
VABS II will be administered by the clinical psychologist/psychometrist at the same time as the 
BSID assessment.
The use of age equivalent scores rather than standard scores permits the assessment of children 
with severe disability in whom standard scores would otherwise be insensitive to change. Given 
the potentially rapid progression of MPS IIIA, a child who is assessable using a standard score at 
baseline may rapidly decline to such an extent that the assessment “floor” is reached and further 
change is not measurable. Additionally, the use of age equivalence scores permits comparison 
and correlation between the BSID-III and VABS II. The use of DQ yields a parameter that tracks 
the dynamic progression of MPS IIIA disease, as observed in Shire’s natural history study. 
This study will utilize standard safety assessments including; AEs, vital signs, standard clinical 
tests, and ECGs. Antibodies against the investigational drug will also be measured.


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8
STUDY ACTIVITIES
The timing of study activities are described for each of the 3 patient groups below, and in 
Appendix 1, Appendix 2, Appendix 3, and Appendix 4, respectively for Group 1 (initially 
randomized to receive HGT-1410 Q2W in Study HGT-SAN-093), Group 2 (initially randomized 
to receive HGT 1410 Q4W in Study HGT-SAN-093), Group 3A (initially randomized to 
no-treatment in Study HGT-SAN-093 and randomized to HGT-1410 Q2W in Study 
SHP-610-201), and Group 3B (initially randomized to no-treatment in Study HGT-SAN-093 and 
randomized to HGT-1410 Q4W in Study SHP-610-201). Study activities for all patients are 
detailed in Section 7.
8.1
Group 1 (Maintaining Q2W Dosing)
8.1.1
Treatment Period (Weeks 50 through 168)
The pre-treatment assessments may be performed on the same day as the administration of study 
drug if it is feasible for the patient to arrive at the study site early in the day, and if it is deemed 
clinically appropriate by the Investigator. Patients may be discharged from the clinical site 
4 hours after dosing, if deemed stable by the Investigator.
Patients in Group 1 will receive 45 mg HGT-1410 IT Q2W (ie, every 14 ±3 days). 
Administration of HGT-1410 can only occur following the completion of all pre-treatment 
assessments and procedures. 
The first 48 weeks of treatment for Group 1 occurred in Study HGT-SAN-093, and therefore 
patients in Group 1 will begin this study at Week 50. 
For patients in Group 1, HGT-1410 will be administered every other week from Week 50 
through Week 168.
8.1.1.1
Pre-treatment Assessments

Review of study eligibility and informed consent

Full physical examination, including height and weight at Weeks 72, 96, 120, 144, and 
168. Symptom-directed physical examination at all other visits.

Every visit:  Vital signs, concomitant medications, therapies, and procedures, and AE 
monitoring 

Cognitive / Behavioral Assessments:  BSID-III/KABS-II and VABS II:  Weeks 72, 96, 
120, 144, and 168.

Quality of Life (QoL) questionnaire:  ITQoL for patients ≤ 5 years of age:  Weeks 72, 
96, 120, 144, and 168

Health economics questionnaire:  HCUQ:  Weeks  72, 96, 120, 144, and 168

MRIs of head, liver, and spleen:  Weeks 96 and 144

Clinical laboratory tests:  hematology, serum chemistry, urinalysis:  Weeks 60, 72, 84, 
96, 108, 120, 132, 144, 156, and 168

Every study visit before dosing:  Standard CSF safety laboratory assessments

CSF and urine sample collection for GAG at Weeks 60, 72, 84, 96, 108, 120, 132, 144, 
156, and 168


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
Every study visit: CSF sample collection for storage for biomarkers

Anti-rhHNS antibody testing (serum and CSF) and CSF biomarker testing at Weeks 60, 
72, 84, 96, 108, 120, 132, 144, 156, and 168

Serum PK sampling at Week 96 – see Appendix 5 for the PK collection schedule
8.1.1.2
Post-treatment Assessments 

ECG at Weeks 96, 144, and 168

Serum PK sampling at Week 96  – see Appendix 5 for the PK collection schedule

Concomitant medications, therapies, and procedures

AE monitoring

Removal of IDDD if patient not continuing treatment
8.1.2
Safety Follow-up Visit:  Week 172 (±7 days) 
All patients will have a safety follow-up at Week 172 or 30 (±7) days after their last dose of 
HGT-1410. 

Symptom-directed physical examination

Vital signs

Clinical laboratory tests

Concomitant medications, therapies, and procedures

AE monitoring
8.2
Group 2 (Maintaining Q4W Dosing)
8.2.1
Treatment Period (Weeks 52 through 168)
The pre-treatment assessments may be performed on the same day as the administration of study 
drug if it is feasible for the patient to arrive at the study site early in the day, and if it is deemed 
clinically appropriate by the Investigator. Patients may be discharged from the clinical site 
4 hours after dosing, if deemed stable by the Investigator.
Patients in Group 2 will receive 45 mg HGT-1410 IT Q4W (ie, every 28 ±7 days). 
Administration of HGT-1410 can only occur following the completion of all pre-treatment 
assessments and procedures. 
The first 48 weeks of treatment for Group 2 occurred in Study HGT-SAN-093, and therefore 
patients in Group 2 will begin this study at Week 52. 
For patients in Group 2, HGT-1410-IT Q4W study drug will be administered Q4W from Week 
52 through Week 168.
8.2.1.1
Pre-treatment Assessments

Review of study eligibility and informed consent


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
Full physical examination, including height and weight at Weeks 72, 96, 120, 144, and 
168. Symptom-directed physical examination at all other visits.

Every visit:  Vital signs, concomitant medications, therapies, and procedures, and AE 
monitoring 

Cognitive / Behavioral Assessments:  BSID-III/KABS-II and VABS II:  Weeks 72, 96, 
120, 144, and 168.

QoL questionnaire:  ITQoL for patients ≤ 5 years of age:  Weeks 72, 96, 120, 144, and 
168

Health economics questionnaire:  HCUQ:  Weeks 72, 96, 120, 144, and 168

MRIs of head, liver, and spleen:  Weeks, 96 and 144

Clinical laboratory tests:  hematology, serum chemistry, urinalysis:  Weeks 60, 72, 84, 
96, 108, 120, 132, 144, 156, and 168

Every study visit before dosing:  Standard CSF safety laboratory assessments

CSF and urine sample collection for GAG at Weeks 60, 72, 84, 96, 108, 120, 132, 144, 
156, and 168

Every study visit: CSF sample collection for storage for biomarkers

Anti-rhHNS antibody testing (serum and CSF) and CSF biomarker testing at Weeks 60, 
72, 84, 96, 108, 120, 132, 144, 156, and 168

Serum PK sampling at Week 96  – see Appendix 5 for the PK collection schedule
8.2.1.2
Post-treatment Assessments 

ECG at Weeks 96, 144, and 168

Serum PK sampling at Week 96  – see Appendix 5 for the PK collection schedule

Concomitant medications, therapies, and procedures

AE monitoring

Removal of IDDD if patient not continuing treatment
8.2.2
Safety Follow-up Visit:  Week 172 (±7 days) 
All patients will have a safety follow-up at Week 172 or 30 (±7) days after their last dose of 
HGT-1410. 

Symptom-directed physical examination

Vital signs

Clinical laboratory tests

Concomitant medications, therapies, and procedures

AE monitoring
8.3
Group 3 (Patients who were randomized to no-treatment in Study HGT-SAN-093)
Patients in Group 3 received no-treatment in Study HGT-SAN-093, and therefore these patients 
will begin this study at Day -27 to -7.


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8.3.1
IDDD Implantation (Days -21 to Day -7)
8.3.1.1
Prior to IDDD Implantation
Prior to enrollment in the study, patients who were initially randomized to no-treatment in Study 
HGT-SAN-093 will undergo the following assessments during the IDDD implantation period, 
prior to IDDD implantation surgery:
Written informed consent
Assessment of eligibility according  to 
inclusion/exclusion criteria
Vital signs
Investigator assessment of vision and 
hearing ability 
Physical examination, including height, 
weight, and head circumference
ECG
Clinical laboratory tests, including PT 
and aPTT
BSID-III/KABC-II
VABS II
ITQoL (for patients ≤ 5 years of age)
HCUQ
Concomitant medications, therapies, 
and procedures
AE monitoring
The physical examination, ECG, height, weight, and clinical labs (hematology, serum chemistry, 
and urinalysis) need to be performed within 7 days prior to the IDDD implantation surgery date. 
If more than 7 days elapse between the date of these assessments and the IDDD implantation 
surgery date, the assessments must be repeated within 7 days prior to surgery.
8.3.1.2
Day of IDDD Implantation
Surgical implantation of the IDDD includes surgical implantation of the IDDD and a post-
surgical assessment. IDDD placement will require anesthesia.
Assessments to be performed on the day of IDDD implantation include:
Prior to anesthesia

Symptom-directed physical examination 
(PE)

ECG (before anesthesia if possible)

Vital signs 

AE monitoring

Concomitant medications, therapies, 
and procedures
During time patient is anesthetized

If logistically possible, head, liver and 
spleen MRI (before IDDD 
implantation) 

IDDD implantation

CSF samples collected for clinical 
laboratory analysis (chemistry, cell 
count), CSF GAG, CSF storage for 
biomarkers 

Post Operative:  X-ray to check IDDD 
placement


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8.3.2
Post-operative Check - Days 1 to 3 
The post-operative check can occur anytime 1-3 days after IDDD implantation. Assessments 
include:  post-operative check of the IDDD incision, vital signs, symptom-directed physical 
examination, concomitant medications, therapies, and procedures, and AE monitoring. 
8.3.3
Randomization (Can Occur Any Time After Meeting Study Entry Criteria)
All patients in Group 3 (patients who were initially randomized to no-treatment in Study 
HGT-SAN-093) will be randomized in a 1:1 allocation ratio to receive Q2W or Q4W dosing 
(Groups 3A or 3B, respectively), as described in Section 6.4. 
8.4
Group 3A (Initiating HGT-1410 Q2W Dosing)
8.4.1
Treatment Period (Weeks 0 through 120)
The pre-treatment assessments may be performed on the same day as the administration of study 
drug if it is feasible for the patient to arrive at the study site early in the day, and if it is deemed 
clinically appropriate by the Investigator. Patients may be discharged from the clinical site 
4 hours after dosing, if deemed stable by the Investigator.
Patients in Group 3A will receive 45 mg HGT-1410 IT Q2W (ie, every 14 ±3 days). 
Administration of HGT-1410 can only occur following the completion of all pre-treatment 
assessments and procedures. 
For patients in Group 3A, HGT-1410 will be administered every other week from Week 0 
through Week 120.
8.4.1.1
Pre-treatment Assessments

Full physical examination, including height and weight at Weeks 24, 48, 72, 96, and 120. 
Symptom-directed physical examination at all other visits.

Every visit:  Vital signs, concomitant medications, therapies, and procedures, and AE 
monitoring 

Cognitive / Behavioral Assessments:  BSID-III/KABS-II and VABS II:  Weeks 24, 48, 
72, 96, and 120

QoL questionnaire:  ITQoL for patients ≤ 5 years of age:  Weeks 24, 48, 72, 96, and 120

Health economics questionnaire:  HCUQ:  Weeks 24, 48, 72, 96, and 120

MRIs of head, liver, and spleen:  Weeks 24, 48, and 96

Clinical laboratory tests:  hematology, serum chemistry, urinalysis:  Weeks 0, 4, 8, 12, 
16, 20, 24, 36, 48, 60, 72, 84, 96, 108, and 120

Every study visit before dosing:  Standard CSF safety laboratory assessments

CSF and urine sample collection for GAG at Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 
44, 48, 60, 72, 84, 96, 108, and 120

Every study visit:  CSF sample collection for storage for biomarkers

Anti- rhHNS antibody testing (serum and CSF) and CSF biomarker testing at Weeks 0, 4, 
8, 12, 24, 36, 48, 60, 72, 84, 96, 108, and 120


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
Serum PK sampling at Weeks 0, 48, and 96 – see Appendix 5 for the PK collection 
schedule

CSF PK sampling at Weeks 0 and 48 – see Appendix 5 for the PK collection schedule
8.4.1.2
Post-treatment Assessments

ECG at Weeks 0, 4, 8, 12, 16, 20, 24, 48, 96, and 120

Serum PK sampling at Weeks 0, 48, and 96  – see Appendix 5 for the PK collection 
schedule

CSF PK sampling at Weeks 0 and 48 – see Appendix 5 for the PK collection schedule

Concomitant medications, therapies, and procedures

AE monitoring

Removal of IDDD if patient not continuing treatment
8.4.2
Safety Follow-up Visit:  Week 124 (±7 days) 
All patients will have a safety follow-up at Week 24 or 30 (±7) days after their last dose of 
HGT-1410. 

Symptom-directed physical examination

Vital signs

Clinical laboratory tests

Concomitant medications, therapies, and procedures

AE monitoring
8.5
Group 3B (Initiating HGT-1410 Q4W Dosing)
8.5.1
Treatment Period (Weeks 0 through 120)
The pre-treatment assessments may be performed on the same day as the administration of study 
drug if it is feasible for the patient to arrive at the study site early in the day, and if it is deemed 
clinically appropriate by the Investigator. Patients may be discharged from the clinical site 
4 hours after dosing, if deemed stable by the Investigator.
Patients in Group 3B will receive 45 mg HGT-1410 IT Q4W (ie, every 28 ±7 days). 
Administration of HGT-1410 can only occur following the completion of all pre-treatment 
assessments and procedures. 
For patients in Group 3B, HGT-1410 will be administered Q4W from Week 0 through Week 
120.
8.5.1.1
Pre-treatment Assessments

Full physical examination, including height and weight at Weeks 24, 48, 72, 96, and 120. 
Symptom-directed physical examination at all other visits.

Every visit:  Vital signs, concomitant medications, therapies, and procedures, and AE 
monitoring 


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
Cognitive / Behavioral Assessments:  BSID-III/KABS-II and VABS II:  Weeks 24, 48, 
72, 96, and 120

QoL questionnaire:  ITQoL for patients ≤ 5 years of age:  Weeks 24, 48, 72, 96, and 120

Health economics questionnaire:  HCUQ:  Weeks 24, 48, 72, 96, and 120

MRIs of head, liver, and spleen:  Weeks 24, 48, and 96

Clinical laboratory tests:  hematology, serum chemistry, urinalysis:  Weeks 0, 4, 8, 12, 
16, 20, 24, 36, 48, 60, 72, 84, 96, 108, and 120

Every study visit before dosing:  Standard CSF safety laboratory assessments

CSF and urine sample collection for GAG at Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 
44, 48, 60, 72, 84, 96, 108, and 120

Every study visit:  CSF sample collection for storage for biomarkers

Anti-rhHNS antibody testing (serum and CSF) and CSF biomarker testing at Weeks 0, 4, 
8, 12, 24, 36, 48, 60, 72, 84, 96, 108, and 120

Serum PK sampling at Weeks 0, 48, and 96  – see Appendix 5 for the PK collection 
schedule

CSF PK sampling at Weeks 0 and 48 – see Appendix 5 for the PK collection schedule
8.5.1.2
Post-treatment Assessments

ECG at Weeks 0, 4, 8, 12, 16, 20, 24, 48, 96, and 120

Serum PK sampling at Weeks 0, 48, and 96  – see Appendix 5 for the PK collection 
schedule

CSF PK sampling at Weeks 0 and 48 – see Appendix 5 for the PK collection schedule

Concomitant medications, therapies, and procedures

AE monitoring

Removal of IDDD if patient not continuing treatment
8.5.2
Safety Follow-up Visit:  Week 124 (±7 days) 
All patients will have a safety follow-up at Week 24 or 30 (±7) days after their last dose of 
HGT-1410. 

Symptom-directed physical examination

Vital signs

Clinical laboratory tests

Concomitant medications, therapies, and procedures

AE monitoring


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9
QUALITY CONTROL AND ASSURANCE
Training will occur at an Investigator meeting or at the site initiation visit or both, and instruction 
manuals will be provided to aid consistency in data collection and reporting across sites. The 
training will be documented.
Clinical sites will be monitored by the Sponsor or its designee to ensure the accuracy of data 
against source documents. The required data will be captured in a validated clinical data 
management system that is compliant with the Food and Drug Administration (FDA) 21 CFR 
Part 11 Guidance. The clinical trial database will include an audit trail to document any evidence 
of data processing or activity on each data field by each user. Users will be trained and given 
restricted access, based on their role(s) in the study, through a password-protected environment.
Data entered in the system will be reviewed manually for validity and completeness against the 
source documents by a clinical monitor from the Sponsor or its designee. If necessary, the study 
site will be contacted for corrections or clarifications; all missing data will be accounted for.
Serious adverse event information captured in the clinical trial database will be reconciled with 
the information captured in the Pharmacovigilance and Risk Management database.


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10
STATISTICAL ANALYSES
10.1
General Methodology
Statistical analysis will generally be performed by the Biometrics Department of Shire using 
SAS statistical software (SAS Institute, Cary, NC, USA). Analysis of any PK and health 
economics and outcomes data will be performed by the Shire Clinical Pharmacology and 
Pharmacokinetics group and the Health Economics and Outcomes Research groups, respectively. 
The analysis methods for all other study data (demographic and baseline characteristics, efficacy 
variables, and safety variables) will be detailed in the statistical analysis plan (SAP). The 
statistical methodology supporting the trial will focus on descriptive rather than inferential 
approaches, given the design and objectives of this trial.
Any hypothesis tests will be 2-sided and will be viewed as exploratory. It is planned that the data 
from all centers that participate in this protocol will be combined so that an adequate number of 
patients will be available for analysis. Summary statistics for continuous variables will include 
the n, mean, standard deviation, median, minimum, and maximum. Categorical variables will be 
summarized in a contingency table by the frequency and percentage of patients in each category. 
Data will be plotted to assess trends across time as appropriate.
Unless otherwise indicated, all summary statistics will be presented by treatment group (either 
Q2W or Q4W) to which the patients were randomly assigned (for patients who were initially 
assigned to Q2W or Q4W group in Study HGT-SAN-093 or patients who were assigned to 
no-treatment in HGT-SAN-093 and were randomly assigned to Q2W or Q4W in Study 
SHP-601-201).
All safety data will be summarized descriptively. The change from baseline at each time point 
for efficacy outcomes will be summarized. Generally, the mean difference in the change at each 
time point between the 2 treatment groups and the corresponding 95% confidence interval of the 
mean difference will be presented. If the parametric assumption for the distribution cannot be 
justified, a non-parametric approach will be utilized to estimate the treatment difference and the 
corresponding 95% confidence interval (ie, median difference or Hodges–Lehmann estimator 
and the corresponding confidence intervals). Developmental Quotients (DQ) will be computed as 
a ratio, expressed as a percentage using the age equivalent score divided by the age at testing (ie, 
[age equivalent score/chronological age] x 100). Developmental delay scores will be calculated 
as the age equivalent score minus the chronological age. Additional efficacy analyses in the 
subgroups of patients who received treatment or no-treatment in Study HGT-SAN-093 will be 
performed.
Data from Study HGT-SAN-093 will be combined with that of Study SHP-610-201 for analysis. 
The data included for treated patients in HGT-SAN-093 starts from the baseline of Study 
HGT-SAN-093 and for patients who received no-treatment in HGT-SAN-093 from the baseline 
of Study SHP-610-201. Baseline is the assessment obtained prior to the first dose of HGT-1410. 
10.2
Determination of Sample Size
As this is an extension study of Study HGT-SAN-093, any patients who enrolled and completed
that study are eligible to enroll in Study SHP-601-201, and no statistical estimation for sample 


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size calculation was performed. A maximum sample size of 18 patients in this study is expected 
based on the sample size in Study HGT-SAN-093.
10.3
Method of Assigning Study Subjects to Treatment Groups
Patients who were randomized to receive Q2W or Q4W dosing in Study HGT-SAN-093 (Groups 
1 and 2, respectively) will maintain their assigned dosing regimen in Study SHP-610-201.
Patients who were randomized to receive no-treatment in Study HGT-SAN-093 (Group 3) will 
be re-randomized in a 1:1 allocation ratio via a computer-generated randomization schedule to 
receive Q2W or Q4W dosing regimen (Groups 3A or 3B, respectively) in Study SHP-610-201. 
To help ensure balance between the dose groups with respect to age at Baseline, the 
randomization will be stratified by age group (≤30 months and >30 months).
10.4
Population Description and Exposure
10.4.1
Analysis Populations
The population for all safety analyses will be the Safety population, defined as all patients who 
had the IDDD implant or received at least one dose of study drug in the extension study. Safety 
analyses will be conducted according to the treatment received. Device related analyses will be 
conducted in the subset of patients in the Safety Population who had the device implanted.
The population for all efficacy analyses will be the Intent-to-Treat (ITT) population, defined as 
all randomized patient according to the treatment assigned.
All pharmacokinetic data analyses will be performed using the PK population, defined as all 
patients who received study drug and had sufficient serum samples collected to derive 
pharmacokinetic parameters.
10.4.2
Subject Disposition
The number of patients screened; the number and proportion of patients randomized, included in 
the Safety population, completed the study, and discontinued prematurely will be presented in a 
summary table by treatment group; reasons for discontinuation/withdrawal will also be 
summarized.
10.4.3
Protocol Deviations
Reported protocol deviations and patient data will be examined prior to database lock to 
determine if conditions set forth in the study protocol have been violated. The complete list of 
protocol deviations will not be summarized; however, if applicable, protocol violations identified 
will be listed for the Safety population.
10.4.4
Demographics and Baseline Characteristics
Demographic data and baseline characteristics will be summarized by the individual treatment 
group and the overall HGT-1410 treatment group for the Safety population. 


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10.4.5
Treatment Compliance and Extent of Exposure
The total number of doses of study drug, the number of doses received via IDDD, the number of 
doses received via LP, the average duration of IT administration and treatment compliance will 
be summarized by treatment group for the Safety population. 
The duration of IT administration is calculated by subtracting the IT administration start time 
from the IT administration end time.
Treatment compliance is defined as:  [(Number of Complete IT administrations) ÷ (Expected 
Number of IT administrations)] * 100.
10.5
Analysis of Efficacy
The analysis of efficacy data will be based on the ITT population.
10.5.1
Primary Analysis
The primary objective of this study is to evaluate long-term safety of HGT-1410 in patients with 
MPS-III. Therefore the primary analysis will be discussed in the safety analysis section, Section 
10.7.
10.5.2
Secondary Efficacy Analysis
10.5.2.1
Bayley Scales of Infant Development III (BSID-III)/Kaufman Assessment 
Battery for Children-Second Edition (KABC-II)
The observed values and changes from baseline in DQ, age equivalent, and developmental delay
scores for each subtest (Cognitive, Receptive Communication, Expressive Communication, Fine 
Motor, and Gross motor) will be summarized descriptively for each assessment time point by 
treatment group (Q2W and Q4W group). The mean difference in the change at each time point 
between the 2 treatment groups and the corresponding 95% confidence interval of the mean 
difference will be presented.
Graphical plots of mean age equivalent and DQ scores for the subtests across time will be 
presented. A trellis plot of the age equivalent and DQ scores within each patient will be 
presented. Furthermore, a spaghetti plot of the cognitive age equivalent score against 
chronological age will be presented.
The KABC-II is an alternative to BSID-III. The KABC-II cognitive DQ, age-equivalent and 
developmental delay scores will be combined with the corresponding BSID-III scores and
summarized at each assessment time point as described above. Most of the patients will have 
either only BSID-III data or KABC-II data. If a patient has data obtained by each of these 
methods, then the method for which data is available at both baseline and post-baseline time 
points will be used when combining the DQ scores and age-equivalent scores.


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10.5.2.2
Vineland Adaptive Behavior Scales II (VABS II)
Tabular summaries of the raw scores for each domain, the average domain raw scores, the mean 
age equivalent score and the corresponding overall DQ scores and the corresponding change 
from baseline will be presented for each assessment time point by treatment group (Q2W and 
Q4W group). The mean difference in the change at each time point between the 2 treatment 
groups and the corresponding 95% confidence interval of the mean difference will be presented.
Graphical plots of mean raw scores for the domains across time will be presented. In addition, a 
trellis plot of the raw scores within each patient will be presented. Similar plots will be presented 
for the average domain raw scores, the mean age equivalent score and the overall DQ score. A 
spaghetti plot of mean age equivalent score against chronological age will also be presented.
10.5.2.3
Brain MRI
Although several MRI parameters will be captured, the analysis will focus primarily on the grey 
matter volume, the white matter volume and the intracranial CSF volume (ventricles plus 
additional CSF space). The observed values and changes from baseline will be summarized for 
each assessment time by treatment group (Q2W and Q4W group). The mean difference in the 
change at each time point between the 2 treatment groups and the corresponding 95% confidence 
interval of the mean difference will be presented.
Graphical plots of mean MRI parameter levels across time will be presented. In addition, Trellis 
plots of MRI parameters across time for each patient will be presented. A spaghetti plot of grey 
matter volume against chronological age will also be presented. 
10.5.3
Subset Analyses 
Exploratory tabular and graphical analyses as described above for efficacy endpoints will be 
performed both by treatment group and whether or not the patient received treatment or no-
treatment in Study HGT-SAN-093 (4 groups).
10.5.4
Exploratory Analyses
10.5.5
Analysis of Health Status
Health status will be assessed by the ITQoL. The observed value and change from baseline in 
ITQOL Scale Scores will be summarized descriptively for each assessment time by treatment 
group (Q2W and Q4W groups). Graphical plots of mean scores across time will be presented.
10.5.6
Analysis Health Economics and Outcomes Research
Descriptive statistics, including N, mean, median, and range (for continuous variables), and N 
and proportions (for categorical variables), for key HCUQ variables, including the number of 


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emergency room visits, caregiver employment status (FT, PT, and NW), and the number of hours 
of additional paid help needed by caregivers, over the course of the study. A detailed description 
of analyses may be provided in a separate pharmacoeconomic analysis plan.
10.6
Analysis of Pharmacokinetic and Pharmacodynamic Data
10.6.1
Pharmacokinetic Measurement and Parameters
The PK population will be used to perform the analysis of the PK data. HGT-1410 
concentrations in all collected serum samples will be measured and reported. Individual patient 
HGT-1410 serum concentration-time profiles will be presented. Individual PK parameters will 
be derived by a noncompartmental analysis and reported. The actual PK blood sample collection 
times will be used to determine the individual patient HGT-1410 serum concentration-time 
profiles. Pharmacokinetic parameters will be calculated if sufficient HGT-1410 concentration-
time points exist to derive values. Individual patient CSF HGT-1410 concentrations at each 
collection time point will be reported.
Pharmacokinetic parameters calculated will include:

Maximum observed serum concentration (Cmax)

Time of Cmax (Tmax)

Area under the serum concentration-time curve from time zero to the last sampling time 
at which serum concentrations were measurable (AUC0-last)

Area under the serum concentration-time curve extrapolated to infinity (AUC0-∞)

Apparent terminal rate constant (λZ) derived from the slope of the log-linear regression of 
the log-linear terminal portion of the serum concentration-time curve.

Terminal half-life (t½) calculated as 0.693/ λZ

Clearance for IT-L administration (CL/F)

Volume of distribution based on the terminal phase for IT-L administration (Vz/F)  
10.6.2
Pharmacodynamic Analyses 
The levels of GAG in CSF and urine are PD endpoints. Analyses of PD endpoints will be 
performed in the Safety population.
The observed values and changes from baseline in CSF GAG levels will be summarized for each 
assessment time by treatment group (Q2W and Q4W group). Graphical plot(s) of mean CSF 
GAG levels across time will be presented. Additionally, Trellis plots of CSF GAG levels across 
time for each patient will be presented. Furthermore, CSF parameters will be plotted across time 
for each patient such that the values before and after the first instance of antibody positive status 
will be indicated using different colors.
The urine GAG levels will be analyzed in a manner similar to that described for CSF data.
10.7
Analysis of Safety
All analyses of safety data will be descriptive and based on the Safety population. 


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10.7.1
Adverse Events 
Once the patient has signed the informed consent form, AEs will be recorded throughout the 
study and at early termination. AEs will be coded using the Medical Dictionary for Regulatory 
Affairs (MedDRA) dictionary.
Treatment-emergent AEs, defined as all AEs from the time of initial IDDD implantation (or first 
dose if no IDDD implant), to the safety follow-up visit, defined as the last patient visit in the 
study, will be summarized. For each treatment group, the number and percentage of patients 
having an AE and the number of events, by system organ class (SOC) and preferred term will be 
presented. Treatment-emergent AEs will also be summarized by severity and degree of 
relationship to study drug. In the case of multiple occurrences of the same AE (at the preferred 
term level) in an individual patient, the AE that is classified as the most severe (ie, maximum 
severity) will be identified for the analysis by severity and the AE that has the closest 
relationship to study drug/procedure will be identified for the analysis by relationship. In general, 
an AE will be considered a treatment-emergent AE if it cannot be definitively categorized 
otherwise by documentation that its onset preceded either IDDD surgery or first dose.
Serious adverse events will be similarly tabulated according to SOC and preferred term and 
presented in a separate listing.
10.7.1.1
Investigational Product
Treatment-emergent AEs deemed by the investigator to be related to HGT-1410 will be 
summarized by presenting the number and percentage of patients having an AE and the number 
of events, by SOC and preferred term. 
10.7.1.2
IDDD and Surgical Procedure-Related AEs 
Intrathecal drug delivery devices and procedure-related AEs will be summarized within 
MedDRA SOC by preferred term. Separate tabulations will be provided for AEs related to the 
IDDD, device surgical procedure, and IT administration process.
Intrathecal drug delivery device and procedure related events will be analyzed in the subset of 
patients in the Safety Population who underwent surgery for IDDD implantation.
10.7.2
Clinical Laboratory Evaluation 
The measurements of each laboratory parameter (serum chemistry, hematology, urinalysis and 
CSF) and the corresponding normal ranges will be converted to Standard International (SI) units, 
if needed. 
Observed values and changes from baseline for continuous laboratory test results will be 
summarized for each assessment time from baseline. Each laboratory result will be categorized 
as a patient having had (1) an Abnormal and Clinically Significant (CS) value at any time post-
baseline, (2) no CS values at any time post-baseline, but had at least one Abnormal and not CS 
(NCS) value, and (3) no CS or NCS values at any time post-baseline; the number and percentage 
in each category will be presented. For any patient who experiences a CS laboratory result at any 


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time post-baseline that was not CS at baseline (or the most recent non-missing value prior to the 
start of the treatment), their entire profile for that particular laboratory parameter will be 
presented as a listing.
If more than one laboratory result is reported per assessment time per parameter, the last non-
missing result will be selected for analysis. 
10.7.3
ECG Evaluations 
The observed values and changes from baseline for continuous variables will be summarized for 
each assessment time by treatment group. Categorical variables, ie, sinus rhythm and 
atrial/ventricular hypertrophy, will be summarized in terms of number and percentage of patients 
in each response category for each assessment time from baseline.
10.7.4
Vital Signs 
The observed values and changes from baseline for IT-administration vital signs parameters will 
be summarized by treatment group. The IT-administration vital signs will also be presented in a 
trellis plot so that the vital signs data for each IT-administration within a patient will be 
presented on a single page.
10.7.5
Anti-rhHNS antibody in Serum and CSF
Serum and CSF anti-rhHNS antibody status (ie, positive or negative) at each assessment time 
from baseline will be summarized in terms of counts and proportion for the treatment groups. 
Additionally, semi-logarithmic plot of serum and CSF anti-rhHNS antibody titers across the 
study visits in the patients exhibiting seropositivity will also be presented. 
10.7.6
Concomitant Medications 
Concomitant medications will be coded using the WHO-DD. The concomitant medications that 
occur from the time of the surgery for IDDD implantation to the safety follow-up visit, defined 
as the last patient visit in the study, will be summarized by therapeutic class and preferred term. 
10.7.7
Other Observations Related to Safety
10.7.7.1
IDDD Performance
Safety and performance data for the SOPH-A-PORT ® Mini S IDDD will be analyzed and 
summaries will be provided for implanted patients. Difficulties associated with the implant 
procedure (e.g. excessive bleeding, CSF leakage, etc.) will be summarized. A summary of 
abnormal findings from the device radiological assessments will also be presented. 
The proportion of patients with at least one device failure and/or malfunction, as well as the 
number of and reasons for device failures/malfunctions will be summarized. The rate of device 
failures/malfunctions and 95% confidence interval will also be estimated. The time from initial 
implant surgery to first device failure and/or malfunction will be summarized. Patients without a 
device failure/malfunction will be censored at their last study drug injection date. A by-patient 
listing of the device failure/malfunction data will be displayed.


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The proportion of patients for whom a successful first injection of study drug occurred will be 
reported among those for whom a first injection was attempted (i.e. those who had an apparently 
successful implantation and did not suffer a device removal or revision prior to first scheduled 
injection). The proportion of patients who had no failed injection attempts during the study will 
also be summarized. The corresponding 95% confidence intervals of the proportion of interest 
will be estimated, where appropriate. Injections that are not administered for patient-related 
reasons (e.g. patient uncooperative, competing medical issue, etc) will not be included in the 
determination of the success of injection rate. 
10.8
Statistical/Analytical Issues
10.8.1
Adjustment for Covariates
No statistical modeling or covariate adjustment is planned due to the small sample size.
10.8.2
Handling of Dropouts or Missing Data
In general, no imputation will be performed and analyses will be based on available data. If data 
at the baseline visit are not available, then the most recent available pre-treatment assessment
will be considered as baseline. Missing or partial AE dates will not be imputed. However, a 
conservative approach will be adopted in such cases so that the AE will be deemed to be 
treatment emergent if it cannot be definitively categorized to have occurred prior to surgery for 
IDDD implantation. Similar logic will be applied to deal with missing and partial date for 
concomitant medications.
10.8.3
Interim Analyses and Data Monitoring
No formal interim analysis or interim statistical testing for early stopping of the trial is planned. 
Descriptive analyses of the data before trial completion may be performed for safety monitoring, 
regulatory reporting or general planning purposes. An independent DMC will be established to 
provide an ongoing, independent review and assessment of patient data, and to safeguard the 
interests and safety of the participating patients in the study (see Section 11.8). An analysis of the 
data for DMC review will occur at specific times during the study as specified in the DMC 
charter. Because no formal hypothesis testing is planned, multiplicity concerns regarding 
repeated analyses are not an issue.
10.8.4
Multicenter Studies
Data from all centers that participate in this protocol will be combined so that an adequate 
number of patients will be available for analysis. In order to maintain desirable level of 
inter-rater reliability for BSID-III/KABS-II and VABS-II assessments/interviews, standardized 
training of the raters and parents will be conducted. Furthermore, a central reader will evaluate 
all MRI data.
10.8.5
Multiple Comparisons/Multiplicity
No adjustment for multiplicity will be performed. 


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10.8.6
Sensitivity Analyses
Given the design and objectives of the study, no sensitivity analyses are planned.


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11
ADMINISTRATIVE CONSIDERATIONS
11.1
Investigators and Study Administrative Structure
Before initiation of the study, the Investigators must provide the Sponsor with a completed Form 
FDA 1572 or Investigator Agreement. Investigational product may be administered only under 
the supervision of the Investigators listed on these forms. Curriculum vitae must be provided for 
the Investigators and sub-investigators listed on Form FDA 1572 or Investigator Agreement.
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, any amendments to the protocol, the study treatments, and their study related 
duties and functions. The Investigator must maintain a list of sub-investigators and other 
appropriately qualified persons to whom he or she has delegated significant study related duties.
11.2
Institutional Review Board or Independent Ethics Committee Approval
Before initiation of the study, the Investigator must provide the Sponsor with a copy of the 
written IRB/IEC approval of the protocol and the informed consent form. This approval must 
refer to the informed consent form and to the study title, study number, and version and date of 
issue of the study protocol, as given by the Sponsor on the cover page of the protocol.
The protocol and any applicable documentation will be submitted or notified to the relevant 
Regulatory Authorities in accordance with the regulations of the countries involved in the trial.
Status reports must be submitted to the IRB/IEC at least once per year. The IRB/IEC must be 
notified of completion of the study. Within 3 months of study completion or termination, a final 
report must be provided to the IRB/IEC. A copy of these reports will be sent to the study clinical 
monitor. The Investigators must maintain an accurate and complete record of all submissions 
made to the IRB/IEC, including a list of all reports and documents submitted. Adverse events 
which are reported to the US FDA (IND/UADE Safety Reports) or other Regulatory agencies 
must be submitted promptly to the IRB/IEC.
11.3
Ethical Conduct of the Study
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor and Investigators abide by 
good clinical practice (GCP) as described in the 21 CFR Parts 50, 56, and 312 and the 
International Conference on Harmonisation (ICH) GCP Guidelines Compliance with these 
regulations and guidelines also constitutes compliance with the ethical principles described in the 
Declaration of Helsinki.
11.4
Patient Information and Consent
Before enrolling in the clinical study, the patient or the patient’s parent(s) or legally authorized 
representative(s) must consent to participate after the nature, scope, and possible consequences 
of the clinical study have been explained in a form understandable to him or her.
An informed consent form (assent form if applicable) that includes information about the study 
will be prepared and given to the patient or the patient’s parent(s) or legally authorized 


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representative(s). This document will contain all FDA and ICH-required elements. The informed 
consent (or assent) form must be in a language understandable to the patient or the patient’s 
parent(s) or legally authorized representative(s) and must specify who informed the patient, the 
patient’s parent(s), or the patient’s legally authorized representative(s).
After reading the informed consent document, the patient or the patient’s parent(s) or legally 
authorized representative(s) must give consent in writing. Consent must be confirmed at the time 
of consent by the personally dated signature of the patient, the patient’s parent(s) or the patient’s 
legally authorized representative(s) and by the personally dated signature of the person 
conducting the informed consent discussions.
If the patient or the patient’s parent(s) or legally authorized representative(s) is unable to read, 
oral presentation and explanation of the written informed consent form and information to be 
supplied must take place in the presence of an impartial witness. Consent must be confirmed at 
the time of consent orally and by the personally dated signature of the patient or by a local 
legally recognized alternative (eg, the patient’s thumbprint or mark) or by the personally dated 
signature of the patient’s parent(s) or the patient’s legally authorized representative. The witness 
and the person conducting the informed consent discussions must also sign and personally date 
the informed consent document. It should also be recorded and dated in the source document that 
consent was given.
A copy of the signed and dated consent document(s) must be given to the patient or the patient’s 
parent(s) or legal representative(s). The original signed and dated consent document will be 
retained by the Investigator.
The Investigator will not undertake any measures specifically required solely for the clinical 
study until valid consent has been obtained.
A model of the informed consent form to be used in this study will be provided to the sites 
separately from this protocol.
11.5
Patient Confidentiality
Patient names will not be supplied to the Sponsor. Only the patient number and patient initials 
will be recorded in the eCRF, and if the patient name appears on any other document, it must be 
obliterated before a copy of the document is supplied to the Sponsor. Study findings stored on a 
computer will be stored in accordance with local data protection laws. The patients will be told 
that representatives of the Sponsor, a designated CRO, the IRB/IEC, or regulatory authorities 
may inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. The Investigator will maintain a personal patient 
identification list (patient numbers with the corresponding patient names) to enable records to be 
identified.


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11.6
Study Monitoring
Monitoring procedures that comply with current GCP guidelines will be followed. Review of the 
eCRF's for completeness and clarity, cross-checking with source documents, and clarification of 
administrative matters will be performed.
The study will be monitored by the Sponsor or its designee. Monitoring will be performed by a 
representative of the Sponsor (Clinical Study Monitor) who will review the eCRFs and source 
documents. The site monitor will ensure that the investigation is conducted according to protocol 
design and regulatory requirements by frequent site visits and communications (letter, telephone, 
and facsimile).
11.7
Case Report Forms and Study Records
11.7.1
Case Report Forms
Case report forms (paper or electronic) are provided for each patient. All forms must be filled out 
by authorized study personnel. All corrections to the original eCRF entry must indicate the 
reason for change. The Investigator is required to sign the eCRF after all data have been captured 
for each patient. If corrections are made after review and signature by the Investigator, he or she 
must be made aware of the changes, and his or her awareness documented by resigning the 
eCRF.
11.7.2
Critical Documents
Before Shire initiates the trial (ie, obtains informed consent from the first patient), it is the 
responsibility of the Investigator to ensure that the following documents are available to Shire or 
their designee:

Completed FDA Form 1572 (Statement of Investigator), signed, dated, and accurate

Curricula vitae of Investigator and sub-investigator(s) (current, dated and signed within 
12 months of study initiation)

Copy of Investigator and sub-investigator(s) current medical license (indicating license 
number and expiration date)

Signed and dated agreement of the final protocol

Signed and dated agreement of any amendment(s), if applicable

Approval/favorable opinion from the IRB/IEC clearly identifying the documents 
reviewed by name, number and date of approval or re approval:  protocol, any 
amendments, Patient Information/Informed Consent Form, and any other written 
information to be provided regarding patient recruitment procedures

Copy of IRB/IEC approved Patient Information/Informed Consent Form/any other 
written information/advertisement (with IRB approval stamp and date of approval)

Current list of IRB/IEC Committee members/constitution (dated within 12 months prior 
to study initiation)

Financial Disclosure Form signed by Investigator and sub-investigator(s)

Current laboratory reference ranges (if applicable)

Certification/QA scheme/other documentation (if applicable)


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Regulatory approval and notification as required must also be available; these are the 
responsibility of Shire.
11.8
Data Monitoring Committee
An independent DMC will be established to provide an ongoing, independent review and 
assessment of the safety data, and to safeguard the interests and safety of the participating 
patients in the study. The DMC will consist of a biostatistician and 2 clinical experts.
It is anticipated that there will be scheduled meetings annually during the conduct of the study. 
The first meeting will be an orientation meeting and will take place prior to the start of the study. 
Subsequent meetings will occur at specific times during the study as specified in the DMC 
charter. The final meeting will be conducted when all patients have completed the study for a 
comprehensive safety overview of the study. A special DMC meeting will be convened if the 
safety-related study stopping rules are met (refer to Section 7.16).
The DMC will adhere to a prospectively determined charter, which will be written by Shire and 
approved by the DMC. The charter will define the responsibilities of the DMC and Shire, 
describe the conduct of the meetings and define the data sets to be reviewed. The DMC will also 
be notified of all IDDD failures and IDDD-related complications at times defined in the DMC 
charter.
The DMC will be notified of all IDDD failures and IDDD-related complications at times defined 
in the DMC charter.
11.9
Device Failure Review Process
The final cause for SOPH-A-PORT ® Mini S device failures will be reviewed by Shire by 
examining the device failure information in the clinical database, safety database, and 
manufacturer investigation of returned SOPH-A-PORT ® Mini S devices.
11.10 Protocol Violations/Deviations
The Investigator will conduct the study in compliance with the protocol. The protocol will not be 
initiated until the IRB/IEC and the appropriate regulatory authorities have given 
approval/favorable opinion. Modifications to the protocol will not be made without agreement of 
the Sponsor. Changes to the protocol will require written IRB/IEC approval/favorable opinion 
prior to implementation, except when the modification is needed to eliminate an immediate 
hazard(s) to patients. The IRB/IEC may provide, if applicable regulatory authorities permit, 
expedited review and approval/favorable opinion for minor change(s) in ongoing studies that 
have the approval/favorable opinion of the IRB/IEC. The Sponsor will submit all protocol 
modifications to the regulatory authorities in accordance with the governing regulations.
A record of patients screened, but not entered into the study, is also to be maintained. No 
protocol exemptions will be granted for this study.
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
patients, the Investigator will contact the Sponsor or its designee, if circumstances permit, to 


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discuss the planned course of action. Any departures from the protocol must be fully documented 
as a protocol deviation. Protocol deviations will need to be reviewed by the medical monitor and 
may also be required to be submitted to the IRB/IEC.
Protocol modifications will only be initiated by the Sponsor and must be approved by the 
IRB/IEC and submitted to the FDA or other applicable international regulatory authority before 
initiation.
11.11 Premature Closure of the Study
If the Sponsor, Investigator, or regulatory authorities discover conditions arising during the study 
which indicate that the clinical investigation should be halted due to an unacceptable patient risk, 
the study may be terminated after appropriate consultation between the Sponsor and the 
Investigator(s). In addition, a decision on the part of the Sponsor to suspend or discontinue 
development of the investigational product may be made at any time. Conditions that may 
warrant termination of the study or site include, but are not limited to:

The discovery of an unexpected, significant, or unacceptable risk to the patients enrolled 
in the study

Failure of the Investigator to comply with pertinent global regulations

Submission of knowingly false information from the study site to the Sponsor or other 
pertinent regulatory authorities

Insufficient adherence by the Investigator to protocol requirements
11.12 Access to Source Documentation
Regulatory authorities, the IRB/IEC, or the Sponsor (or its designee) may request access to all 
source documents, eCRFs, and other study documentation for onsite audit or inspection. Direct 
access to these documents must be guaranteed by the Investigator, who must provide support at 
all times for these activities. Monitoring and auditing procedures that comply with current GCP 
guidelines will be followed. On-site review of the eCRFs for completeness and clarity, 
crosschecking with source documents, and clarification of administrative matters may be 
performed.
11.13 Data Generation and Analysis
The clinical database will be developed and maintained by a contract research organization or an 
electronic data capture technology provider as designated by Shire. Shire or its designee will be 
responsible for performing study data management activities. 
Adverse events and medical history events will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA). Concomitant medication will be coded using WHO-DD. 
Centralized laboratories will be employed as described in the study manual to aid in consistent 
measurement of efficacy and safety parameters. 


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11.14 Retention of Data
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application and until there are no pending or contemplated marketing applications or 
at least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product. The Sponsor will notify the Investigator if these documents must be 
retained for a longer period of time. It is the responsibility of the Sponsor to inform the 
Investigator or institution as to when these documents no longer need to be retained.
11.15 Financial Disclosure
The Investigator should disclose any financial interests in the Sponsor as described in 21 CFR 
Part 54 prior to beginning this study. The appropriate form will be provided to the Investigator 
by the Sponsor, which will be signed and dated by the Investigator, prior to the start of the study. 
11.16 Publication and Disclosure Policy
All information concerning the study material, such as patent applications, manufacturing 
processes, basic scientific data, and formulation information supplied by the Sponsor and not 
previously published are considered confidential and will remain the sole property of the 
Sponsor. The Investigator agrees to use this information only in accomplishing this study and 
will not use it for other purposes.
It is understood by the Investigator that the information developed in the clinical study may be 
disclosed as required to the authorized regulatory authorities and governmental agencies. In 
order to allow for the use of the information derived from the clinical studies, it is understood 
that there is an obligation to provide the Sponsor with complete test results and all data 
developed in the study in a timely manner.
The Investigator and any other clinical personnel associated with this study will not publish the 
results of the study, in whole or in part, at any time, unless they have consulted with Shire, 
provided Shire a copy of the draft document intended for publication, and obtained Shire’s 
written consent for such publication. All information obtained during the conduct of this study 
will be regarded as confidential. 


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12
LIST OF REFERENCES
1. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. 
JAMA 1999;281:249-54.
2. Baehner F, Schmiedeskamp C, Krummenauer F, et al. Cumulative incidence rates of the 
mucopolysaccharidoses in Germany. J Inherited Metab Dis 2005;28:1011-7.
3. Poorthuis BJ, Wevers RA, Kleijer WJ, et al. The frequency of lysosomal storage diseases in 
The Netherlands. Hum Genet 1999;105:151-6.
4. Valstar MJ, Neijs S, Bruggenwirth HT, et al. Mucopolysaccharidosis type IIIA:  clinical 
spectrum and genotype-phenotype correlations. Ann Neurol 2010;68:876-87.
5. Meyer A, Kossow K, Gal A, et al. Scoring evaluation of the natural course of 
mucopolysaccharidosis type IIIA (Sanfilippo syndrome type A). Pediatr 2007;120:e1255-61.
6. Cleary MA, Wraith JE. Management of mucopolysaccharidosis type III. Arch Dis Child 
1993;69:403-6.
7. Fraser J, Wraith JE, Delatycki MB. Sleep disturbance in mucopolysaccharidosis type III 
(Sanfilippo syndrome):  a survey of managing clinicians. Clin Genet 2002;62:418-21.
8. Meyer A, Kossow K, Gal A, et al. The mutation p.Ser298Pro in the sulphamidase gene 
(SGSH) is associated with a slowly progressive clinical phenotype in mucopolysaccharidosis 
type IIIA (Sanfilippo A syndrome). Hum Mutat 2008;29:770.
9. Hemsley K, King B, Hopwood J. Injection of recombinant human sulfamidase into the CSF 
via the cerebellomedullary cistern in MPS IIIA mice. Mol Genet Metab 2007;90:313-28.
10. Hemsley KM, Hopwood JJ. Delivery of recombinant proteins via the cerebrospinal fluid as a 
therapy option for neurodegenerative lysosomal storage diseases. Int J Clin Pharmacol Ther 
2009;47 Suppl 1:S118-23.
11. Martin HR, Poe MD, Reinhartsen D, et al. Methods for Assessing Neurodevelopment in 
Lysosomal Storage Diseases and Related Disorders:  a Multidisciplinary Perspective. Acta 
Paediatr Supp 2008;97:69-75.
12. Bayley N. Bayley Scales of Infant and Toddler Development. 3 ed. San Antonio, TX The 
Psychological Corporation; 2005.
13. Sparrow S, Balla D, Cicchetti D. Vineland Adaptive Behavior Scales (Second Edition). 4201 
Woodland Road Circle Pines, MN 55014-1796:  American Guidance Service, Inc; 2005.
























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Appendix 5
Pharmacokinetic and Pharmacodynamic Sample Schedule
Drug 
Administration
PK / PD Sampling Times
Blood Sampling
HGT-1410 IT 
injection
Serum PK samples will be obtained at Weeks 0 (Groups 3A and 3B only), 48, and 96.
Immediately prior to IT injection (baseline), then at 0.5, 1, 2, 4, 8, 12, 24, and 48 (Day 
2) hours following completion of IT injection. Patients may be discharged from the 
hospital after the 24-hour blood draw. Patients will either stay locally in a hotel or 
return home (if they live in close proximity to the hospital); in consultation with the 
Investigator. Patients will return to the hospital for PK blood sampling at the 48-hour 
PK time point. Patients will be discharged for home following the last (48-hour) PK 
time point and following the completion of their final physical examination.
CSF Sampling
CSF PK and PK/PD samples will be obtained at Weeks 0 and 48 for Groups 3A and 3B 
only.
Immediately prior to IT injection (baseline), then at 4 hours and 48 hours after the 
completion of the IT injection. The 4 hour and 48 hour post-dose CSF samples will 
only be obtained if a functioning IDDD is in place. Patients will either stay locally in a 
hotel or return home (if they live in close proximity to the hospital); in consultation 
with the Investigator. Patients will return to the hospital for CSF sampling at the 
48 hour time points. 


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Appendix 6
Expected SOPH-A-PORT ® Mini S Adverse Device Effects
Procedure-Related Complications

Components handled improperly before, during, or after implantation 

Access port implanted incorrectly

Catheter positioned improperly

Injection through septum performed incorrectly

Injection of incorrect medication through access port

Injection outside the access port into pocket or subcutaneous tissue or extravasation

Pocket seroma, hematoma, erosion, or infection

Intrathecal Access Complications

Surgical complications such as hemorrhage or hematoma

Infection of the implant site or catheter track

Radiculitis or arachnoiditis

Intrathecal space infection resulting in meningitis or encephalitis

Bleeding 

Spinal cord damage or trauma to the spinal cord or nerve roots

Post-lumbar puncture, cerebrospinal fluid (CSF) leak, leading to headache, or  
subcutaneous CSF collection

Epidural instead of intrathecal placement of catheter

Inflammatory mass resulting in neurological impairment, including paralysis

Pain on injection

Complications of anesthesia

Pseudomeningocele
System-Related Complications

Improperly positioned access port

Erosion of the skin because of the underlying access port or the catheter

Wound dehiscence

Access port migration, fracture, breakage or occlusion

Catheter damage, dislodgement, migration, disconnection, kinking or occlusion, fibrosis, 
or hygroma, resulting in tissue damage or a loss of or change in therapy, or other 
potentially serious adverse health consequences


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
Catheter breakage and migration of residual catheter fragments, potentially resulting in 
serious adverse health consequences and the need for surgical removal 

Local immunological or fibrous reaction to the presence of a foreign body (the device)

End of device service life or component failure, requiring surgical replacement

Component failure, resulting in loss of therapy

Access port inversion (“flipping”), rotation, or extrusion

Access port or catheter rejection 

Fibrin sheath formation around catheter tip




Clinical Trial Protocol:  SHP-610-201
Study Title:
An Open-Label Extension of Study HGT-SAN-093 Evaluating the 
Safety and Efficacy of HGT-1410 (Recombinant Human Heparan N 
Sulfatase) Administration via an Intrathecal Drug Delivery Device in 
Pediatric Patients with Mucopolysaccharidosis Type IIIA Disease
Study Number:
SHP-610-201
Study Phase:
IIb
Product Name:
HGT-1410
Device Name:
SOPH-A-PORT® Mini S, Implantable Access Port, Spinal, Mini 
Unattached, with Guidewire
IND Number:
102165
EUDRACT Number
2014-003960-20
Indication:
Long-term Treatment of Mucopolysaccharidosis Type IIIA (MPS 
IIIA or Sanfilippo Syndrome Type A)
Investigators:
Multicenter
Sponsor:
Shire Human Genetic Therapies, Inc.
Sponsor Contact:
300 Shire Way
Lexington, MA  02421 USA
+1-617-349-0200
Medical Monitor:
, DO
Date
Original Protocol:
23 September 2014
Amendment 1:
17 December 2015
Confidentiality Statement
This document is the proprietary and confidential property of Shire Human Genetic 
Therapies, Inc.


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SYNOPSIS
Sponsor:
Shire Human Genetic Therapies, Inc. (Shire)
Name of Finished Product:
HGT-1410 (Recombinant Human Heparan N Sulfatase, or rhHNS)
Name of Device:
SOPH-A-PORT® Mini S, Implantable Access Port, Spinal, Mini Unattached, with 
Guidewire (SOPH-A-PORT® Mini S)
Study Title:
An Open-Label Extension of Study HGT-SAN-093 Evaluating the Safety and Efficacy of 
HGT-1410 (Recombinant Human Heparan N Sulfatase) Administration via an Intrathecal 
Drug Delivery Device in Pediatric Patients with Mucopolysaccharidosis Type IIIA 
Disease
Study Number:
SHP-610-201
Study Phase:  IIb
Investigational Product, Dose, and Mode of Administration:  
HGT-1410 at a dose of 45 mg administered every 2 weeks (Q2W) or 45 mg administered 
every 4 weeks (Q4W). HGT-1410 will be administered intrathecally (IT) by an 
indwelling IT drug delivery device (IDDD).
Device, Intended Use
The SOPH-A-PORT Mini S is a system intended for implantation by physicians. The 
SOPH-A-PORT Mini S, once implanted, allows healthcare personnel to administer HGT-
1410 indicated for intrathecal delivery intermittently over a long period of time.
Comparator, Dose, and Mode of Administration:
Not applicable
Primary Objective(s):  
To evaluate long-term safety in patients with mucopolysaccharidosis type IIIA disease 
(MPS IIIA or Sanfilippo syndrome type A) who received HGT-1410
Secondary Objective(s):
To evaluate:

The long-term cognitive function as measured by the Bayley Scales of Infant and 
Toddler Development, Third Edition (BSID-III) or Kaufman Assessment Battery for 
Children, Second Edition (KABC-II), age-equivalent and developmental quotient 
(DQ) scores in patients with MPS IIIA who received HGT-1410

The long-term adaptive behavioral function, assessed by Vineland Adaptive Behavior 
Scales, Second Edition (VABS-II) in patients who received HGT-1410

The total cortical grey matter volume, as assessed by volumetric magnetic  resonance 
imaging (MRI) of the brain, in patients who received HGT-1410


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Exploratory Objective:
Pharmacokinetic and Pharmacodynamic Objectives
To evaluate:

The pharmacokinetics of HGT-1410 in serum

The pharmacokinetics of HGT-1410 in cerebrospinal fluid (CSF), in patients who 
received no treatment in Study HGT-SAN-093

The concentration of glycosaminoglycans (GAG) in CSF and urine in patients who 
received HGT-1410
Health Status Objective 
To evaluate health status as measured by the Infant Toddler Quality of Life 
Questionnaire™ (ITQoL) instrument in patients who received HGT-1410
Health Economics and Outcomes Research Objectives
To evaluate healthcare resource utilization, as evaluated by the Healthcare Utilization 
Questionnaire (HCUQ), in patients who received HGT-1410
Study Endpoints:  
Safety evaluations include the assessment of adverse events (AEs), IDDD-related issues, 
laboratory values, anti-rhHNS antibody development, vital signs, physical examination 
findings, and electrocardiogram (ECG) results.
The secondary endpoints of this study are:

The change from Baseline in BSID-III or KABC-II age-equivalent, DQ, and 
developmental delay scores

The change from Baseline in adaptive behavioral function domains, assessed by 
VABS II, using raw scores, age-equivalent scores, and DQ scores

The change from Baseline in total cortical grey matter volume, as assessed by MRI
The pharmacokinetic endpoint is to determine the pharmacokinetic behavior of 
HGT-1410 in serum. The pharmacokinetic behavior of HGT-1410 in CSF will also be 
determined in patients who received no treatment in Study HGT-SAN-093.
The pharmacodynamic endpoint is to determine the GAG concentrations in CSF and 
urine.
The health status endpoint is the ITQoL scores at each assessment time and the 
corresponding change from Baseline.
The health economic and outcome research endpoints evaluate key HCUQ variables, 
such as the number of emergency room visits, caregiver employment status (full-time, 
part-time, or not working), and the number of hours of additional paid help needed by 
caregivers over the course of the study.


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Study Population:  
A maximum of 21 patients with MPS IIIA and who completed Study HGT-SAN-093 are 
planned to enroll in this study. 
Study Design:
This is an open-label study for patients who completed through at least the Week 48 Visit 
of Study HGT-SAN-093. Patients who originally received HGT-1410 in Study 
HGT-SAN-093 will remain on the same dosing regimen as they received in Study 
HGT-SAN-093; Group 1 will receive HGT-1410 Q2W and Group 2 will received 
HGT-1410 Q4W. Patients in Groups 1 and 2 will begin treatment at Week 50 and 
Week 52, respectively, of this extension study (Study SHP-610-201). Patients who 
originally received no treatment in Study HGT-SAN-093 (Group 3) will receive an 
IDDD following informed consent and will be re-randomized in a 1:1 allocation ratio to 
receive HGT-1410 via a Q2W or Q4W dosing regimen (Groups 3A and 3B, respectively) 
in Study SHP-610-201. Patients in Groups 3A and 3B will begin treatment on Week 0 of 
the extension study.
It is anticipated that the IDDD will be used to obtain CSF samples and to deliver all IT 
injections of HGT-1410. If the IDDD appears to be non-functional, or if its use is 
precluded on a scheduled day of dosing, site personnel will refer to the IDDD Manual(s), 
which provides details on the investigation and management of any IDDD-related issues. 
This includes possible partial revision or complete replacement of the IDDD as indicated. 
If the IT space is not accessible via the IDDD, study drug may be administered and CSF 
sampled by lumbar puncture (LP). General anesthesia or sedation may be required for 
injections of study drug and some evaluations and can be used at the discretion of the 
Investigator. Patients will have the IDDD removed when they discontinue from or 
complete the study, unless the patient is continuing to receive treatment through another 
mechanism (eg, extension study, expanded access program, commercially available,
etc.).
Safety and efficacy assessments will be performed at regular intervals over the 
approximate 2.5-year duration of Study SHP-610-201. For patients who received 
HGT-1410 in Study HGT-SAN-093, a serum pharmacokinetic sample will be obtained at 
the Week 96 visit (after approximately 2 full years of exposure to HGT-1410 across 
Study HGT-SAN-093 and SHP-610-201). For patients who received no treatment in 
Study HGT-SAN-093, serum pharmacokinetic samples will be obtained at the Week 0, 
48, and 96 visits, and CSF pharmacokinetic samples will be obtained at the Week 0 and 
48 visits in Study SHP-610-201.
Study Duration:
Approximately 30 months of treatment with HGT-1410 will occur during the study.
Patients who received HGT-1410 in Study HGT-SAN-093 will undergo a cumulative 
exposure to HGT-1410 for up to 42 months (168 weeks), whereas patients who received 
no-treatment in Study HGT-SAN-093 will have a cumulative exposure to HGT-1410 for 
up to 30 months (120 weeks) in Study SHP-610-201.


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Study Inclusion and Exclusion Criteria:
Inclusion Criteria:
Patients must meet all of the following criteria to be considered eligible for enrollment:
1. Patient has completed through at least the Week 48 visit of Study HGT-SAN-093.
2. The patient’s parent(s) or legally authorized guardian(s) must have voluntarily signed 
an Institutional Review Board/ethics committee–approved informed consent form 
after all relevant aspects of the study have been explained and discussed. Consent of 
the patient’s parent(s) or legally authorized guardian(s) and the patient’s assent, as 
relevant, must be obtained.
Exclusion Criteria:
Patients will be excluded from the study if any of the following criteria are met:
1. The patient, if randomized to treatment in Study HGT-SAN-093, has experienced a 
decline of more than 20 points in the BSID-III cognitive DQ score between Baseline 
and the Week 48 visit in Study HGT-SAN-093, AND, upon individual evaluation by 
the Investigator, has been deemed a treatment failure*.
2. The patient has experienced, in the opinion of the Investigator, a safety or medical 
issue that contraindicates treatment with HGT-1410, including but not limited to 
clinically relevant intracranial hypertension, severe infusion-related reactions after 
treatment with HGT-1410, or uncontrollable seizure disorder.
3. The patient has a known hypersensitivity to any of the components of HGT-1410. 
Patients with documented infusion-related reactions that are clinically manageable 
(for example, with pre-medication or slowing infusion rate) are not necessarily 
excluded based on the assessment of the investigator.
4. The patient is enrolled in another clinical study, other than HGT-SAN-093, that 
involves clinical investigations or use of any investigational product (drug or 
[intrathecal/spinal] device) within 30 days prior to study enrollment or at any time 
during the study.
5. The patient has any known or suspected hypersensitivity to anesthesia or is thought to 
be at an unacceptably high risk for anesthesia due to airway compromise or other 
conditions.
6. The patient has a condition that is contraindicated as described in the SOPH-A-PORT 
Mini S IDDD Instructions for Use, including:
a.
The patient has had, or may have, an allergic reaction to the materials of 
construction of the SOPH-A-PORT Mini S device.
b. The patient’s body size is too small to support the size of the SOPH-A-PORT 
Mini S Access Port, as judged by the Investigator.
c.
The patient’s drug therapy requires substances known to be incompatible with the 
materials of construction.
d. The patient has a known or suspected local or general infection.
e.
The patient is at risk of abnormal bleeding due to a medical condition or therapy.
f.
The patient has one or more spinal abnormalities that could complicate safe 
implantation or fixation.


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g. The patient has a functioning CSF shunt device.
h. The patient has shown an intolerance to an implanted device.
7. The patient is unable to comply with the protocol (eg, is unable to return for safety 
evaluations or is otherwise unlikely to complete the study) as determined by the 
Investigator.
*All treated patients in Study HGT-SAN-093 will have their cognitive development 
assessed at the Week 48 Visit in Study HGT-SAN-093. If a decline from Baseline of 
20 points or less in the BSID-III DQ score is observed, then the patient may proceed into 
the Study SHP-610-201 without further evaluation. If a decline from Baseline of more 
than 20 points in DQ score is observed, then an individual evaluation by the Investigator 
will occur to determine if the patient is a treatment failure. This individual evaluation will 
take into account the DQ scores, VABS-II score, physical status, and any other 
information available for that patient at that time. If the Investigator deems the patient to 
be a treatment failure, then the patient may not enter the Study SHP-610-201.
Efficacy Assessments:
Efficacy variables to be assessed will include cognitive function expressed as a DQ 
assessed by neurocognitive testing using the BSID-III/KABS-II; adaptive behavioral 
function over time, assessed by VABS-II; the total cortical grey matter volume and liver 
and spleen size as assessed by MRI; quality-of-life score (assessed using the ITQoL); and 
health care resource utilization (assessed using the HCUQ).
Pharmacokinetic Assessments:
The determination of HGT-1410 concentration in serum for all patients and in CSF for 
patients who received no treatment in Study HGT-SAN-093.
Pharmacodynamic Assessments:
The determination of GAG concentrations in CSF and urine
Safety Assessments:
Safety will be assessed during the study by the following:

Collection of AEs (by type, severity, and relationship to treatment [HGT-1410, the 
IDDD, device surgical procedure, or IT administration process])

Changes in clinical laboratory testing (serum chemistry, hematology, urinalysis)

Physical examination

Vital signs

Twelve-lead ECG recordings 

CSF laboratory parameters (chemistries, cell counts)

Anti-rhHNS antibodies in CSF and serum, including determination of antibodies 
having enzyme neutralizing activity
Statistical Methods:  
The statistical methodology supporting the trial will focus on descriptive rather than 
inferential approaches, given the design and objectives of this trial. Any hypothesis tests 
will be 2-sided and will be viewed as exploratory. It is planned that the data from all 
centers that participate in this protocol will be combined so that an adequate number of 
patients will be available for analysis. Summary statistics for continuous variables will 


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include the n, mean, standard deviation, median, minimum, and maximum. Categorical 
variables will be summarized in a contingency table by the frequency and percentage of 
patients in each category. Data will be plotted to assess trends across time, as appropriate.
Unless otherwise indicated, all summary statistics will be presented by treatment group 
(either Q2W or Q4W) to which the patients were randomly assigned (patients who were 
initially assigned to Q2W or Q4W group in Study HGT-SAN-093 or patients who 
received no-treatment in Study HGT-SAN-093 and were randomly assigned to Q2W or 
Q4W in Study SHP-610-201). Additional analyses in the subgroup of patients who 
received no-treatment in Study HGT-SAN-093 may be performed. 
All safety data will be summarized descriptively. The change from baseline at each time 
point for efficacy outcomes will be summarized. Generally, the mean difference in the 
change at each time point between the 2 treatment groups and the corresponding 95% 
confidence interval of the mean difference will be presented. Additional efficacy 
analyses in the subgroups of patients previously treated and untreated in Study 
HGT-SAN-093 may be performed.
Data from Study HGT-SAN-093 will be combined with that of Study SHP-610-201 for 
analysis. The data included for treated patients in HGT-SAN-093 starts from the baseline 
of Study HGT-SAN-093 and for patients who received no treatment in HGT-SAN-093 
from the baseline of Study SHP-610-201. Baseline is the assessment obtained during the 
initial study period, prior to the first dose of HGT-1410, regardless of whether this 
occurred in Study HGT-SAN-093 or SHP-610-201.
Date of Original Protocol:  23 September 2014
Date of Amendment 1:  17 December 2015


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TABLE OF CONTENTS
SYNOPSIS.................................................................................................................................2
LIST OF IN-TEXT TABLES ..................................................................................................14
LIST OF FIGURES .................................................................................................................15
LIST OF APPENDICES..........................................................................................................16
LIST OF ABBREVIATIONS..................................................................................................17
1
INTRODUCTION ...........................................................................................................20
2
STUDY OBJECTIVES....................................................................................................22
2.1
Primary Objective..................................................................................................22
2.2
Secondary Objectives.............................................................................................22
2.3
Exploratory Objective............................................................................................22
2.4
Pharmacokinetic and Pharmacodynamic Objectives.............................................22
2.5
Health Status Objective..........................................................................................22
2.6
Health Economics and Outcome Research Objective ...........................................22
3
STUDY ENDPOINTS.....................................................................................................23
3.1
Primary Endpoint...................................................................................................23
3.2
Secondary Endpoints .............................................................................................23
3.3
Exploratory Endpoint(s).........................................................................................23
3.4
Pharmacokinetic and Pharmacodynamic Endpoints..............................................23
3.5
Health Status Endpoint ..........................................................................................24
3.6
Health Economics and Outcomes Research Endpoint...........................................24
4
INVESTIGATIONAL PLAN..........................................................................................25
4.1
Overall Study Design and Plan..............................................................................25
4.2
Rationale for Study Design, Device Use, and Comparator Group ........................28
4.3
Study Duration.......................................................................................................28
5
STUDY POPULATION SELECTION ...........................................................................29
5.1
Study Population....................................................................................................29
5.2
Inclusion Criteria ...................................................................................................29
5.3
Exclusion Criteria ..................................................................................................29
6
STUDY TREATMENT(S)..............................................................................................31
6.1
Description of Treatment(s)...................................................................................31
6.1.1
Investigational Product..................................................................................31
6.1.2
Intrathecal Drug Delivery Device .................................................................31
6.1.3
Comparator Product.......................................................................................31
6.2
Treatment Administered ........................................................................................31
6.3
Selection and Timing of Dose for Each Patient.....................................................32
6.3.1
Missed Doses.................................................................................................32


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6.4
Method of Assigning Patients to Treatment Groups..............................................32
6.5
Blinding..................................................................................................................33
6.6
Prior and Concomitant Medications, Therapies, and Medical/Surgical 
Interventions ..........................................................................................................33
6.7
Restrictions ............................................................................................................33
6.7.1
Fluid and Food Intake....................................................................................33
6.7.2
Patient Activity Restrictions..........................................................................33
6.8
Treatment Compliance...........................................................................................33
6.9
Packaging and Labeling.........................................................................................33
6.10
Storage and Accountability....................................................................................34
6.10.1
Investigational Product..................................................................................34
6.10.2
Intrathecal Drug Delivery Device .................................................................34
6.10.3
Comparator Product.......................................................................................35
7
STUDY PROCEDURES .................................................................................................36
7.1
Informed Consent...................................................................................................36
7.2
Study Entrance Criteria..........................................................................................36
7.3
Hearing and Vision Assessments...........................................................................37
7.3.1
Investigator Assessment of Hearing and Vision ...........................................37
7.4
Device-related Study Procedures...........................................................................37
7.4.1
IDDD Implantation or Revision Procedures .................................................37
7.4.2
X-ray Verification of Intrathecal Drug Delivery Device Placement.............37
7.4.3
CSF Sampling Procedure ..............................................................................37
7.4.4
Device Adjustment, Revision, or Removal ...................................................37
7.5
Investigational Product Administration.................................................................38
7.6
Efficacy Assessments.............................................................................................39
7.6.1
Neurocognitive and Developmental Assessments.........................................39
7.6.2
Quality of Life Indicator:  Infant Toddler Quality of Life Questionnaire.....39
7.6.3
Health Economics and Outcomes Research:  Healthcare Utilization 
Questionnaire.................................................................................................40
7.7
Magnetic Resonance Imaging................................................................................40
7.7.1
Head...............................................................................................................40
7.7.2
Liver and Spleen............................................................................................40
7.8
Pharmacokinetic Assessments ...............................................................................40
7.9
Pharmacodynamic Biomarker Assessments (CSF and Urine GAG Levels) .........40
7.10
Concomitant Medications, Therapies, and Medical/Surgical Interventions..........41
7.11
Safety Assessments................................................................................................41
7.11.1
Vital Signs .....................................................................................................41
7.11.2
Physical Examination, Including Height, Weight, and Head Circumference41
7.11.3
Electrocardiogram .........................................................................................42


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7.11.4
Clinical Laboratory Tests ..............................................................................42
7.11.5
Cerebrospinal Fluid Assessments..................................................................43
7.11.5.1
Standard CSF Safety Laboratory Assessments.....................................44
7.11.5.2
Anti-rhHNS Antibodies and Biomarkers in CSF..................................44
7.11.5.3
CSF GAG Levels and Biomarkers........................................................44
7.11.5.4
.......................................................44
7.11.6
Device Assessments ......................................................................................44
7.11.7
Collection and Storage of Biological Samples for Biomarker Studies .........44
7.12
Sample Collection, Storage, and Shipping ............................................................45
7.13
Adverse Events Assessments.................................................................................45
7.13.1
Definitions of Adverse Events and Serious Adverse Events.........................45
7.13.1.1
Adverse Event.......................................................................................45
7.13.1.2
Adverse Events Due to Systemic Exposure to HGT-1410 ...................45
7.13.1.3
Infusion/Hypersensitivity Reactions and Management ........................46
7.13.1.4
IDDD-related Adverse Events ..............................................................46
7.13.1.5
Serious Adverse Event..........................................................................47
7.13.2
Device-associated Definitions.......................................................................47
7.13.2.1
Device Revision (Partial and Full)........................................................47
7.13.2.2
Device Malfunction...............................................................................48
7.13.2.3
Device Failure.......................................................................................48
7.13.3
Classification of Adverse Events and Serious Adverse Events.....................48
7.13.4
Clarification between Serious and Severe.....................................................48
7.13.5
Relatedness of Adverse Events and Serious Adverse Events .......................48
7.13.6
Procedures for Recording and Reporting Adverse Events............................49
7.13.6.1
Adverse Event Monitoring and Period of Observation.........................49
7.13.6.2
Reporting Serious Adverse Events........................................................49
7.14
Abuse, Overdose and Medication Error.................................................................51
7.15
Removal of Patients from the Trial or Investigational Product.............................51
7.16
Safety-Related Study Stopping Rules....................................................................52
7.17
Appropriateness of Measurements.........................................................................52
8
STUDY ACTIVITIES .....................................................................................................54
8.1
Group 1 (Maintaining Q2W Dosing).....................................................................54
8.1.1
Treatment Period (Weeks 50 through 168) ...................................................54
8.1.1.1
Pre-treatment Assessments ...................................................................54
8.1.1.2
Post-treatment Assessments..................................................................55
8.1.2
Safety Follow-up Visit:  Week 172 (±7 days)...............................................55
8.2
Group 2 (Maintaining Q4W Dosing).....................................................................55
8.2.1
Treatment Period (Weeks 52 through 168) ...................................................55


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8.2.1.1
Pre-treatment Assessments ...................................................................56
8.2.1.2
Post-treatment Assessments..................................................................56
8.2.2
Safety Follow-up Visit:  Week 172 (±7 days)...............................................56
8.3
Group 3 (Patients Randomized to No Treatment in Study HGT-SAN-093).........57
8.3.1
IDDD Implantation (Days -21 to Day -7) .....................................................57
8.3.1.1
Prior to IDDD Implantation ..................................................................57
8.3.1.2
Day of IDDD Implantation ...................................................................57
8.3.2
Postoperative Check – Days 1 to 3................................................................58
8.3.3
Randomization (Can Occur Any Time After Meeting Study Entry Criteria)58
8.4
Group 3A (Initiating HGT-1410 Q2W Dosing) ....................................................58
8.4.1
Treatment Period (Weeks 0 through 120) .....................................................58
8.4.1.1
Pre-treatment Assessments ...................................................................58
8.4.1.2
Post-treatment Assessments..................................................................59
8.4.2
Safety Follow-up Visit:  Week 124 (±7 days)...............................................59
8.5
Group 3B (Initiating HGT-1410 Q4W Dosing).....................................................59
8.5.1
Treatment Period (Weeks 0 through 120) .....................................................59
8.5.1.1
Pre-treatment Assessments ...................................................................59
8.5.1.2
Post-treatment Assessments..................................................................60
8.5.2
Safety Follow-up Visit:  Week 124 (±7 days)...............................................60
9
QUALITY CONTROL AND ASSURANCE .................................................................61
10
STATISTICAL ANALYSES ..........................................................................................62
10.1
General Methodology ............................................................................................62
10.2
Determination of Sample Size ...............................................................................62
10.3
Method of Assigning Study Subjects to Treatment Groups ..................................63
10.4
Population Description and Exposure....................................................................63
10.4.1
Analysis Populations .....................................................................................63
10.4.2
Subject Disposition........................................................................................63
10.4.3
Protocol Deviations .......................................................................................63
10.4.4
Demographics and Baseline Characteristics .................................................63
10.4.5
Treatment Compliance and Extent of Exposure............................................64
10.5
Analysis of Efficacy...............................................................................................64
10.5.1
Primary Analysis ...........................................................................................64
10.5.2
Secondary Efficacy Analysis.........................................................................64
10.5.2.1
Bayley Scales of Infant Development, Third Edition/Kaufman 
Assessment Battery for Children, Second Edition................................64
10.5.2.2
Vineland Adaptive Behavior Scales, Second Edition...........................65
10.5.2.3
Brain MRI .............................................................................................65
10.5.3
Subset Analyses.............................................................................................65


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10.5.4
Exploratory Analyses ....................................................................................65
10.5.5
Analysis of Health Status ..............................................................................65
10.5.6
Analysis Health Economics and Outcomes Research...................................65
10.6
Analysis of Pharmacokinetic and Pharmacodynamic Data ...................................66
10.6.1
Pharmacokinetic Measurement and Parameters............................................66
10.6.2
Pharmacodynamic Analyses..........................................................................66
10.7
Analysis of Safety..................................................................................................66
10.7.1
Adverse Events..............................................................................................67
10.7.1.1
Investigational Product..........................................................................67
10.7.1.2
IDDD and Surgical Procedure–related AEs..........................................67
10.7.2
Clinical Laboratory Evaluation .....................................................................67
10.7.3
ECG Evaluations ...........................................................................................68
10.7.4
Vital Signs .....................................................................................................68
10.7.5
Anti-rhHNS Antibody in Serum and CSF.....................................................68
10.7.6
Concomitant Medications..............................................................................68
10.7.7
Other Observations Related to Safety ...........................................................68
10.7.7.1
IDDD Performance ...............................................................................68
10.8
Statistical/Analytical Issues ...................................................................................69
10.8.1
Adjustment for Covariates.............................................................................69
10.8.2
Handling of Dropouts or Missing Data .........................................................69
10.8.3
Interim Analyses and Data Monitoring.........................................................69
10.8.4
Multicenter Studies........................................................................................69
10.8.5
Multiple Comparisons/Multiplicity...............................................................69
10.8.6
Sensitivity Analyses ......................................................................................70
11
ADMINISTRATIVE CONSIDERATIONS....................................................................71
11.1
Investigators and Study Administrative Structure.................................................71
11.2
Institutional Review Board or Ethics Committee Approval..................................71
11.3
Ethical Conduct of the Study.................................................................................71
11.4
Patient Information and Consent ...........................................................................71
11.5
Patient Confidentiality...........................................................................................72
11.6
Study Monitoring...................................................................................................73
11.7
Case Report Forms and Study Records .................................................................73
11.7.1
Case Report Forms ........................................................................................73
11.7.2
Critical Documents........................................................................................73
11.8
Data Monitoring Committee..................................................................................74
11.9
Device Failure Review Process .............................................................................74
11.10 Protocol Violations/Deviations..............................................................................74
11.11 Premature Closure of the Study.............................................................................75


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11.12 Access to Source Documentation ..........................................................................75
11.13 Data Generation and Analysis ...............................................................................75
11.14 Retention of Data...................................................................................................76
11.15 Financial Disclosure...............................................................................................76
11.16 Publication and Disclosure Policy .........................................................................76
12
LIST OF REFERENCES.................................................................................................77


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LIST OF IN-TEXT TABLES
Table 7-1
Neurodevelopmental Assessments Tests....................................................39
Table 7-2
Assessments for Physical Examinations ....................................................41
Table 7-3
List of Laboratory Tests .............................................................................43
Table 7-4
Adverse Event Severity..............................................................................48
Table 7-5
Adverse Event Relatedness ........................................................................48


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LIST OF FIGURES
Figure 1
SHP-610-201 Study Design .......................................................................27


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LIST OF APPENDICES
Appendix 1
Study Schedule of Events for Group 1:  Maintaining HGT-1410 Q2W....78
Appendix 2
Study Schedule of Events for Group 2:  Maintaining HGT-1410 Q4W....80
Appendix 3
Study Schedule of Events for Group 3A:  Initiating HGT-1410 Q2W......82
Appendix 4
Study Schedule of Events for Group 3B:  Initiating HGT-1410 Q4W ......85
Appendix 5
Blood and CSF Volumes............................................................................88
Appendix 6
Pharmacokinetic and Pharmacodynamic Sample Schedule.......................93
Appendix 7
Expected SOPH-A-PORT Mini S Adverse Device Effects .......................94
Appendix 8
Protocol Amendment Summary of Changes..............................................95
Appendix 9
Protocol Signature Page .............................................................................98


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LIST OF ABBREVIATIONS
Abbreviation
Definition
Ab
antibody
AE
adverse event
ALB
albumin
ALK-P
alkaline phosphatase
ALT; SGPT
alanine aminotransferase
aPTT
activated partial thromboplastin time
AST; SGOT
aspartate aminotransferase
AUC
area under the serum concentration-time curve
AUC0-last
area under the curve from the time of dosing to the last measurable 
concentration
AUC0-∞
area under the curve extrapolated to infinity, calculated using the observed value 
of the last non-zero concentration
BBB
blood-brain barrier
BSID-III
Bayley Scales of Infant and Toddler Development, Third Edition  
BUN
blood urea nitrogen
Ca
calcium
CE
Conformité Européenne
CFR
Code of Federal Regulations
CK
creatine kinase
CL/F
total body clearance for extravascular administration divided by the fraction of 
dose absorbed
Cl
chloride
Cmax
maximum concentration occurring at tmax
CNS
central nervous system
CO2
carbon dioxide
con meds
concomitant medications
CRO
contract research organization
CS
clinically significant
CSF
cerebrospinal fluid
DMC
Data Monitoring Committee
DQ
developmental quotient
DS
dermatan sulfate
EC
ethics committee
ECG
electrocardiogram
eCRF
electronic case report form
ERT
enzyme replacement therapy
EU
European Union
FDA
Food and Drug Administration
FT
full-time


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Abbreviation
Definition
GAG
glycosaminoglycan
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
Hct
hematocrit
HCUQ
Healthcare Utilization Questionnaire
Hgb
hemoglobin
HNS
heparan N-sulfatase
HS
heparan sulfate
ICH
International Conference on Harmonisation
IDDD
intrathecal drug delivery device
IFU
Instructions for Use
IRB
Institutional Review Board
IT
Intrathecal(ly)
ITQoL
Infant Toddler Quality of Life Questionnaire™
ITT
intent-to-treat
IV
intravenous(ly)
K
potassium
KABC-II
Kaufman Assessment Battery for Children, Second Edition
LDH
lactate dehydrogenase
LP
lumbar puncture
LSD
lysosomal storage disease
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MPS IIIA
mucopolysaccharidosis type IIIA or Sanfilippo syndrome type A
MRI
magnetic resonance imaging
NA
sodium
NCS
not clinically significant
NW
not working
PD
pharmacodynamics
PE
physical examination
PK
pharmacokinetics
PT
part-time
PT
prothrombin time
Q2W
every 2 weeks
Q4W
every 4 weeks
QoL
quality of life
RBC
red blood cell
rhHNS
recombinant human heparan N sulfatase


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Abbreviation
Definition
SAE
serious adverse event
SAP
statistical analysis plan
SGSH
sulfoglucosamine sulfohydrolase
SI
Standard International
SOC
system organ class
t1/2
terminal half-life
tmax
time of maximum observed concentration sampled during a dosing interval
UADE
unanticipated adverse device effect
US(A)
United States (of America)
VABS-II
Vineland Adaptive Behavior Scales, Second Edition 
Vz/F
volume of distribution associated with the terminal slope following 
extravascular administration divided by the fraction of dose absorbed
WBC
white blood cell
WHO-DD
World Health Organization-Drug Dictionary
λZ
first order rate constant associated with the terminal (log-linear) portion of the 
curve


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1
INTRODUCTION
Mucopolysaccharidosis type IIIA (MPS IIIA, also called Sanfilippo syndrome type A) is a rare, 
autosomal recessive, lysosomal storage disease (LSD) presenting in early childhood that causes 
progressive neurodegeneration associated with intractable behavioral problems and 
developmental regression. Ultimately, a vegetative state supervenes. Life span is shortened, with 
death usually occurring in the late teen years. The genetic defect in this disorder is a mutation in 
both copies of the sulfoglucosamine sulfohydrolase (SGSH) gene, located on chromosome 17, 
which encodes the lysosomal enzyme, sulfoglucosamine sulfohydrolase, also called 
heparan-N-sulfatase, or sulfamidase. This enzyme is necessary for the normal intralysosomal 
catabolism of the glycosaminoglycan (GAG) (formerly termed mucopolysaccharide), heparan 
sulfate (HS). Sulfoglucosamine sulfohydrolase deficiency therefore results in the accumulation 
of heparan sulfate in lysosomes. Although the metabolic defect is expressed in every organ, the 
clinical manifestations of disease are primarily neurological. These are not usually apparent until 
1 to 4 years of age. The molecular events linking the primary metabolic defect to the consequent 
neuropathology are not understood. 
MPS III is the most prevalent of the mucopolysaccharidoses and consists of 4 subtypes, A, B, C, 
and D.1 Each of these is characterized by a deficiency of a distinct lysosomal enzyme necessary 
for the degradation of heparan sulfate. Clinically, on an individual patient level, the 4 subtypes 
cannot be reliably distinguished. Globally, subtype A is the most prevalent, at approximately 
1 case in 100,000 live births, followed by subtype B, at approximately 1 in 250,000 live births.1-3
Among MPS IIIA patients, there is wide allelic heterogeneity, with at least 100 SGSH mutations 
described to date. Most of these are missense, but nonsense mutations, deletions, insertions and 
splice-site mutations also occur.4
MPS IIIA symptoms usually arise in the first or second year of life, although diagnosis is 
delayed until an average age of 4.5 years.4, 5 Patients present a wide spectrum and severity of 
clinical symptoms. The central nervous system (CNS) is the most severely affected organ system 
in patients with MPS IIIA, evidenced by deficits in language development, motor skills, and 
intellectual development.5 In addition, there are abnormal behaviors that include aggression and 
excess motor activity/hyperactivity that contribute to disturbances in sleep.5-7 There are also 
reports of unexplained, recurrent and severe diarrhea.6 Overall, individuals with MPS IIIA 
exhibit progressive dementia with ultimate inanition and death resulting from the CNS disease. 
Lifespan is severely curtailed, with usual survival into the late teens.6 Milder variants are 
recognized, with slower progression and survival to later age. The latter has been reported in 
approximately 10% of German patients with MPS IIIA, in association with the presence of the 
S298P mutation.8
No effective, disease-modifying therapies are currently approved as treatments for this 
devastating and disabling disease. A goal of Shire is to develop recombinant human 
heparan-N-sulfatase (rhHNS, development name HGT-1410) as enzyme replacement therapy 
(ERT) for patients with MPS IIIA. A particular problem for lysosomal storage disorders that 
damage the brain, such as MPS III, is how to target ERT to the brain, as macromolecules cannot 
cross the blood-brain barrier (BBB).9 In animal studies, ERT has been administered into the 
cerebrospinal fluid (CSF) via an intrathecal (IT) route, because when administered intravenously 
(IV) it does not cross the BBB after the immediate postnatal period of life. HGT-1410 has been 


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shown to be ineffective if administered intravenously in the MPS IIIA mouse model, in contrast 
to its efficacy in treating CNS pathology when administered into the CSF.10
In order to traverse the BBB, HGT-1410 will be administered directly to the CNS using an IT 
drug delivery device (IDDD) or, if the IDDD is non-functional, via lumbar puncture (LP). The 
advantage of using an IDDD is the potential to obviate the need for multiple LPs for drug 
delivery. HGT-1410 will be administered through the IDDD or, if the IDDD is non-functional, 
via LP.
Please refer to the current edition of the Investigator’s Brochure for further information 
concerning the nonclinical studies completed, including safety and clinical development of 
HGT-1410.


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2
STUDY OBJECTIVES
2.1
Primary Objective 
The primary objective of this study is to evaluate long-term safety in patients with 
mucopolysaccharidosis type IIIA disease (MPS IIIA or Sanfilippo syndrome type A) who 
received HGT-1410.
2.2
Secondary Objectives 
The secondary objectives of this study are to evaluate:  

The long-term cognitive function as measured by the Bayley Scales of Infant and Toddler 
Development, Third Edition (BSID-III) or Kaufman Assessment Battery for Children, 
Second Edition (KABC-II), age-equivalent and developmental quotient (DQ) scores in 
patients with MPS IIIA who received HGT-1410

The long-term adaptive behavioral function, assessed by Vineland Adaptive Behavior Scales, 
Second Edition (VABS-II) in patients who received HGT-1410

The total cortical grey matter volume, as assessed by volumetric magnetic resonance imaging 
(MRI) of the brain, in patients who received HGT-1410
2.3
Exploratory Objective
The exploratory objective of this study is 
 
.
2.4
Pharmacokinetic and Pharmacodynamic Objectives
The pharmacokinetic and pharmacodynamics objectives of this study are to evaluate:

The pharmacokinetics of HGT-1410 in serum

The pharmacokinetics of HGT-1410 in CSF, in patients who received no treatment in Study 
HGT-SAN-093

The concentration of GAG in CSF and urine in patients who received HGT-1410
2.5
Health Status Objective
The health status objective of this study is to evaluate health status as measured by the Infant 
Toddler Quality of Life Questionnaire™ (ITQoL) instrument in patients who received 
HGT-1410.
2.6
Health Economics and Outcome Research Objective
The health economics and outcome research objective of this study is to evaluate healthcare 
resource utilization, as evaluated by the Healthcare Utilization Questionnaire (HCUQ), in 
patients who received HGT-1410.


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3
STUDY ENDPOINTS
3.1
Primary Endpoint
Safety is the primary objective of the study and will be assessed during the study by the 
following:

Collection of adverse events (AEs; by type, severity, and relationship to treatment 
[HGT-1410, the IDDD, device surgical procedure, or IT administration process])

Changes in clinical laboratory testing (serum chemistry, hematology, urinalysis)

Physical examination

Vital signs

Twelve-lead electrocardiogram (ECG) recordings 

CSF laboratory parameters (including chemistries, cell counts)

Anti-rhHNS antibodies in CSF and serum, including determination of antibodies having 
enzyme neutralizing activity
3.2
Secondary Endpoints
The secondary endpoints of this study are:

The change from Baseline in BSID-III or KABC-II age-equivalent, DQ, and developmental 
delay scores

The change from Baseline in adaptive behavioral function domains, assessed by VABS II, 
using raw scores, age-equivalent scores, and DQ scores

The change from Baseline in total cortical grey matter volume, as assessed by MRI
3.3
Exploratory Endpoint(s)
3.4
Pharmacokinetic and Pharmacodynamic Endpoints
The pharmacokinetic endpoint is to determine the pharmacokinetic behavior of HGT-1410 in 
serum, based on the following parameters:

Maximum concentration occurring at tmax (Cmax)

Time of maximum observed concentration sampled during a dosing interval (tmax)

Area under the curve from the time of dosing to the last measurable concentration (AUC0-last)

Area under the curve extrapolated to infinity, calculated using the observed value of the last 
non-zero concentration (AUC0-∞)

First order rate constant associated with the terminal (log-linear) portion of the curve (λZ) 

Terminal half-life (t1/2) calculated as 0.693/λZ


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
total body clearance for extravascular administration divided by the fraction of dose absorbed
(CL/F)

Volume of distribution associated with the terminal slope following extravascular 
administration divided by the fraction of dose absorbed (Vz/F)  
The pharmacodynamic endpoint is to determine the GAG concentrations in CSF and urine.
3.5
Health Status Endpoint
The health status endpoint is the ITQoL scores at each assessment time and the corresponding 
change from Baseline.
3.6
Health Economics and Outcomes Research Endpoint
The health economic and outcome research endpoints evaluate the key HCUQ variables, such as 
the number of emergency room visits, caregiver employment status (full-time [FT], part-time 
[PT], and not working [NW]), and the number of hours of additional paid help needed by 
caregivers, over the course of the study.


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4
INVESTIGATIONAL PLAN
4.1
Overall Study Design and Plan
This is an open-label extension study of HGT-1410 for patients who completed through at least 
the Week 48 Visit in Study HGT-SAN-093. The study design is presented in Figure 1. Patients 
who originally received HGT-1410 in Study HGT-SAN-093 will remain on the same dosing 
regimen as they received in Study HGT-SAN-093; Group 1 will receive HGT-1410 Q2W and 
Group 2 will received HGT-1410 Q4W. Patients in Groups 1 and 2 will begin treatment at 
Week 50 and Week 52, respectively, of this extension study (Study SHP-610-201). Patients who 
originally received no-treatment in Study HGT-SAN-093 (Group 3) will receive an IDDD 
following informed consent and will be re-randomized in a 1:1 allocation ratio to receive 
HGT-1410 via a Q2W or Q4W dosing regimen (Groups 3A and 3B, respectively) in Study 
SHP-610-201. Patients in Groups 3A and 3B will begin treatment on Week 0 of the extension 
study. 
The Sponsor and Principal Investigator will consider the feasibility of transitioning the patient’s 
IT dosing to local sites to reduce the burden imposed by travel. The local sites will be selected 
and approved by the Sponsor, and the patient must have no safety or medical issues that would 
preclude transitioning to a local site (Note:  The main site may serve as a local site as needed, 
and in this case, the main site will follow the assessment schedule for a local site). The 
qualification requirements for physicians at local sites will be identical to those for the main 
sites. Local sites will be experienced with IT administration via an IDDD. For patients who were 
in the no-treatment group in the HGT-SAN-093 study, initial IT administrations will be at the 
main study site following IDDD implantation until in the opinion of the Principal Investigator 
there are no safety or medical concerns precluding the patient from transitioning. Patients will be 
discharged a minimum of 4 hours after dosing and when deemed clinically stable by the 
Investigator. Exceptions include the IT injections of HGT-1410 when scheduled study 
assessments are scheduled; these will take place at the main site. Patients that have already 
received IT drug administration at the main study site would be eligible to transfer to a local site 
starting at Week 50 (Group 1) or Week 52 (Group 2) in SHP-610-201 if in the opinion of the 
Principal Investigator there are no safety or medical concerns precluding the patient from 
transitioning. 
It is anticipated that the IDDD will be used to collect CSF samples and to deliver IT injections of 
HGT-1410 and preservative-free saline flushes. No other medication will be administered 
through the device. If the IDDD appears to be non-functional, or if its use is precluded on a 
scheduled day of dosing, site personnel will refer to the IDDD Manual, which provides details on 
the investigation and management of any IDDD-related issues. This includes possible partial 
revision or complete replacement of the IDDD as indicated. If the IT space is not accessible via 
the IDDD, study drug may be administered by LP. Should the IDDD become clogged, undergo 
mechanical complications or otherwise not be accessible, the CSF sample may also be obtained 
by LP. General anesthesia or sedation may be required for injections of study drug and some 
evaluations, and may be used at the discretion of the Investigator. The Data Monitoring 
Committee (DMC) will be notified of all IDDD failures and IDDD-related complications at 
times defined in the DMC charter (see Section 11.8).


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Patients will have the IDDD removed when they discontinue from or complete the study unless 
the patient is continuing to receive product or treatment through another mechanism (eg, 
extension study, expanded access program, commercially available drug).
Safety and efficacy assessments will be performed at regular intervals over the approximate 
2.5-year duration of the extension study. A pharmacokinetic sample for patients who received 
HGT-1410 in Study HGT-SAN-093 will be obtained at the Week 96 visit (after approximately 2 
full years of exposure to HGT-1410 across Studies HGT-SAN-093 and SHP-610-201). Serum 
pharmacokinetic samples for patients who received no-treatment in Study HGT-SAN-093 will be 
obtained at the Week 0, 48, and 96, and CSF pharmacokinetic samples will be obtained on the 
Week 0 and 48 visits in Study SHP-610-201.
Patients who received HGT-1410 in Study HGT-SAN-093 will undergo a cumulative exposure 
to HGT-1410 for up to 42 months (168 weeks), whereas patients who received no treatment in 
Study HGT-SAN-093 will have a cumulative exposure to HGT-1410 for up to 30 months 
(120 weeks) in Study SHP-610-201.
See Appendix 1, Appendix 2, Appendix 3, and Appendix 4 for the Study Schedule of Events 
tables for Groups 1, 2, 3A, and 3B, respectively.




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4.2
Rationale for Study Design, Device Use, and Comparator Group
The study design is intended to provide ongoing treatment with HGT-1410 to patients who 
received HGT-1410 in Study HGT-SAN-093 and to initiate treatment to patients who received 
no-treatment in Study HGT-SAN-093. As such, all patients will be treated during this study; 
there is no control group.
In order to traverse the blood-brain barrier, HGT-1410 will be administered directly to the CNS 
using an IDDD or, if the IDDD is non-functional, via LP. The advantage of using an IDDD is the 
potential to obviate the need for multiple lumbar punctures for drug delivery. HGT-1410 will be 
administered through the IDDD or, if the IDDD is non-functional, via lumbar puncture.
Safety is the primary objective of the study, and the study duration has been designed to provide 
a reasonable time for safety follow-up.
4.3
Study Duration
Patients are expected to participate in this study for up to 30 months. Patients who received 
HGT-1410 in Study HGT-SAN-093 will undergo a cumulative exposure to HGT-1410 for up to 
42 months (168 weeks), whereas patients who received no treatment in Study HGT-SAN-093 
will have a cumulative exposure to HGT-1410 for up to 30 months (120 weeks) in Study 
SHP-610-201.


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5
STUDY POPULATION SELECTION
5.1
Study Population
A maximum of 21 patients with MPS IIIA who completed Study HGT-SAN-093 are planned to 
enroll in this study. 
5.2
Inclusion Criteria
Patients must meet all of the following criteria to be considered eligible for enrollment:  
1. Patient has completed through at least the Week 48 visit of Study HGT-SAN-093.
2. The patient’s parent(s) or legally authorized guardian(s) has voluntarily signed an 
Institutional Review Board (IRB)/ ethics committee (EC)–approved informed consent form 
after all relevant aspects of the study have been explained and discussed. Consent of the 
patient’s parent(s) or legally authorized guardian(s) and the patient’s assent, as relevant, must 
be obtained.
5.3
Exclusion Criteria
Patients will be excluded from the study if any of the following criteria are met:
1. The patient, if randomized to treatment in Study HGT-SAN-093, has experienced a decline 
of more than 20 points in the BSID-III cognitive DQ score between Baseline and the 
Week 48 visit in Study HGT-SAN-093, AND, upon individual evaluation by the 
Investigator, has been deemed a treatment failure*.
2. The patient has experienced, in the opinion of the Investigator, a safety or medical issue that 
contraindicates treatment with HGT-1410, including but not limited to clinically relevant 
intracranial hypertension,  severe infusion-related reactions after treatment with HGT-1410, 
uncontrollable seizure disorder.
3. The patient has a known hypersensitivity to any of the components of HGT-1410. Patients 
with documented infusion-related reactions that are clinically manageable (for example, with 
pre-medication or slowing infusion rate) are not necessarily excluded based on the 
assessment of the Investigator.
4. The patient is enrolled in another clinical study, other than HGT-SAN-093, that involves 
clinical investigations or use of any investigational product (drug or [intrathecal/spinal] 
device) within 30 days prior to study enrollment or at any time during the study.
5. The patient has any known or suspected hypersensitivity to anesthesia or is thought to be at 
an unacceptably high risk for anesthesia due to airway compromise or other conditions.
6. The patient has a condition that is contraindicated as described in the SOPH-A-PORT Mini S 
IDDD Instructions for Use (IFU), including:
a.
The patient has had, or may have, an allergic reaction to the materials of construction of 
the SOPH-A-PORT Mini S device.
b. The patient’s body size is too small to support the size of the SOPH-A-PORT Mini S 
Access Port, as judged by the Investigator.


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c.
The patient’s drug therapy requires substances known to be incompatible with the 
materials of construction.
d. The patient has a known or suspected local or general infection.
e.
The patient is at risk of abnormal bleeding due to a medical condition or therapy.
f.
The patient has 1 or more spinal abnormalities that could complicate safe implantation or 
fixation.
g. The patient has a functioning CSF shunt device.
h. The patient has shown an intolerance to an implanted device.
7. The patient is unable to comply with the protocol (eg, is unable to return for safety 
evaluations or is otherwise unlikely to complete the study) as determined by the Investigator.
*All treated patients in Study HGT-SAN-093 will have their cognitive development assessed at 
the Week 48 Visit in Study HGT-SAN-093. If a decline from Baseline of 20 points or less in the 
BSID-III DQ score is observed, then the patient may proceed into the Study SHP-610-201 
without further evaluation. If a decline from Baseline of more than 20 points in DQ score is 
observed, then an individual evaluation by the Investigator will occur to determine if the patient 
is a treatment failure. This individual evaluation will take into account the DQ scores, VABS-II 
score, physical status, and any other information available for that patient at that time. If the 
Investigator deems the patient to be a treatment failure, then the patient may not enter the Study 
SHP-610-201.


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6
STUDY TREATMENT(S)
6.1
Description of Treatment(s)
6.1.1
Investigational Product
The investigational product to be used in this study is HGT-1410, rhHNS for IT use.
The HGT-1410 drug product is a sterile solution for injection in single-use vials for IT 
administration. It is formulated in an aqueous isotonic solution containing 15.0 mg/mL rhHNS in 
145 mM sodium chloride, 0.02% (v/v) polysorbate 20, 5 mM sodium phosphate at pH 7.0.
6.1.2
Intrathecal Drug Delivery Device
The drug product will be administered via the SOPH-A-PORT Mini S Implantable Access Port. 
The SOPH-A-PORT Mini S device is intended for long-term, intermittent access to the IT space 
for the delivery of investigational drug. The device is Conformité Européenne (CE)-marked in 
the European Union (EU) and investigational in non-EU countries.
The SOPH-A-PORT Mini S is comprised of the following 7 components:

One SOPH-A- PORT Mini S Access Port

One IT port closed-tip catheter

One guidewire

Two suture wings

One 14-gauge Tuohy needle

One 22-gauge non-coring Huber needle

One Luer lock connector
Further details are provided in the SOPH-A-PORT Mini S IFU.
6.1.3
Comparator Product
Not applicable
6.2
Treatment Administered
The study drug will be administered through an IDDD. In the event of IDDD malfunction or 
failure, HGT-1410 may be administered via LP.
Patients who were randomized to receive HGT-1410 in Study HGT-SAN-093 will continue to 
have HGT-1410 administered through the IDDD that was implanted during Study 
HGT-SAN-093.
Patients who were randomized to no treatment in Study HGT-SAN-093 will be scheduled to 
undergo surgical placement of the SOPH-A-PORT Mini S device. The initial implantation and 
any revision and/or explantation of the SOPH-A-PORT Mini S will be performed by pediatric or 
general neurosurgeons or anesthesiologists who have experience in port and catheter implant 


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procedures and IT-access procedures and have completed training for the SOPH-A-PORT Mini 
S. Please refer to the IFU for further details. At least 7 days will be allowed for recovery 
following the placement of the IDDD before the administration of the first intrathecal dose of 
HGT-1410. During this time, the patient will receive standard perioperative care.
Drug administration will be performed in a clinical setting by appropriately trained and skilled 
healthcare providers (nurses or physicians) with knowledge of the patient’s drug regimen and 
experienced in accessing vascular or CNS ports or CNS infusion pumps. Patients and patients’ 
families will not be directly using the device to administer drugs and will have limited direct 
interaction with the device as there is minimal care required both during the immediate 
postoperative period as the implant site heals, and at times of drug administration.
As previously noted, under the appropriate conditions, IT HGT-1410 may be administered at 
local sites rather than main sites to reduce the burden of monthly travel. This is further detailed 
in Section 4.1.
6.3
Selection and Timing of Dose for Each Patient
After meeting eligibility criteria, patients in Groups 1 and 2 (who received HGT-1410 in Study 
HGT-SAN-093) will begin treatment at Weeks 50 and 52, respectively, in Study SHP-610-201. 
Patients will be treated for up to 120 weeks in Study SHP-610-201, for a total cumulative 
exposure of 168 weeks across Studies HGT-SAN-093 and SHP-610-201.
After meeting eligibility criteria, patients who were randomized to no treatment in Study 
HGT-SAN-093 will be scheduled to undergo surgical placement of the SOPH-A-PORT Mini S 
device, as described in Section 6.2. Thereafter, these patients will be administered HGT-1410 
45 mg as an IT injection either Q2W or Q4W (Groups 3A or 3B, respectively), as randomized, 
for up to 120 weeks. 
6.3.1
Missed Doses
Patients who are scheduled to receive Q2W dosing (Groups 1 and 3A) should receive their dose 
of HGT-1410 every 14±3 days, and patients who are scheduled to receive Q4W dosing (Groups 
2 and 3B) should receive their dose of HGT-1410 every 28±7 days. If dosing cannot be 
administered within the indicated time window, the dose will be considered missed, and the 
patient will resume their dosing schedule with the next dose of HGT-1410. The dosing schedule 
will not change or be reset.
6.4
Method of Assigning Patients to Treatment Groups
Patients who were randomized to no-treatment in Study HGT-SAN-093 (Group 3) will be 
re-randomized in a 1:1 allocation ratio to receive Q2W or Q4W dosing (Groups 3A or 3B, 
respectively). To help ensure balance between the dose groups with respect to age at Baseline, 
the randomization will be stratified by age group (≤30 months and >30 months; see Section 
10.3).
Patients who were randomized to receive HGT-1410 in Study HGT-SAN-093 will remain on the 
same treatment regimen in Study SHP-610-201.


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6.5
Blinding
This study will not be blinded.
6.6
Prior and Concomitant Medications, Therapies, and Medical/Surgical Interventions
Prior and/or concomitant therapy prohibited for all patients in this study consists of the 
following:

Psychotropic or other medications, which in the Investigator’s opinion would be likely to 
substantially confound test results

The use of medications which, in the opinion of the Investigator, would place patients at risk 
of bleeding complications following surgery or LP

Any other investigational therapy (drug or device) at any time during the study

Hematopoietic stem cell or bone marrow transplant
6.7
Restrictions
6.7.1
Fluid and Food Intake 
Not applicable
6.7.2
Patient Activity Restrictions
Please refer to the SOPH-A-PORT Mini S IFU for details regarding patient activity restrictions 
for patients to be implanted with this device. Activities that may include sudden, excessive, or 
repetitive bending, twisting, bouncing, or stretching can damage or dislodge IDDD components 
and should be avoided.
6.8
Treatment Compliance
Treatment with HGT-1410 will be administered via an IDDD under the supervision of the 
investigator and in the controlled environment of a clinical center; therefore, full patient 
compliance with treatment is anticipated in this study.
6.9
Packaging and Labeling
All packaging and labeling will be in accordance with applicable regulatory requirements.
The SOPH-A-PORT Mini S Access Port is available in one size, individually packaged, with 
other SOPH-A-PORT Mini S components in double-peel-off, sterile, pyrogen-free packaging, 
sterilized with ethylene oxide. Instructions for use are also included in the packaging. A 
guidewire is provided in separate double-pouch, sterile, pyrogen-free packaging.
Labels are provided on the outer carton and on both the SOPH-A-PORT Mini S box and 
guidewire/cannula package inside and will be in accordance with local regulatory requirements.


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6.10
Storage and Accountability
6.10.1
Investigational Product
HGT-1410 will be supplied at a concentration of 15 mg/mL in single-use vials for IT 
administration.
HGT-1410 will be shipped by Shire or a qualified distributor to the clinical study site(s) at 2 to 
8°C (36-46°F).
Drug product should be stored refrigerated (2-8°C); drug product may not be used beyond the 
expiration date on the vial.
The disposition of all investigational product delivered to a Principal Investigator must be 
recorded on a patient-by-patient basis by completing the clinical trial material accountability log. 
The date and time of administration of the investigational product must be documented on the 
appropriate eCRF.
The Principal Investigator, Clinical Research Coordinator, or designee (eg, Pharmacist) must 
ensure that all documentation regarding investigational product receipt, storage, dispensing, 
loss/damaged and return of used/unused product is complete, accurate, and ready for review at 
each monitoring visit and/or audit. The sites must ensure that the investigational product is 
available for the monitor to inventory and prepare for return shipment to the Sponsor or 
designee, if required. 
The process for destruction of investigational product is provided in the Pharmacy Manual. 
See the Pharmacy Manual for additional details.
6.10.2
Intrathecal Drug Delivery Device
The disposition of all SOPH-A-PORT Mini S devices delivered to a Principal Investigator must 
be recorded on a patient-by-patient basis by completing the Accountability Log. The date and 
time of administration of the investigational product and use of the SOPH-A-PORT Mini S 
device must be documented on the patient’s appropriate eCRF.
The Principal Investigator, Clinical Research Coordinator, or designee (eg, Pharmacist) must 
ensure that all documentation regarding receipt, storage, dispensing, loss/damaged 
SOPH-A-PORT Mini S devices and return of used/unused SOPH-A-PORT Mini S device(s) is 
complete, accurate, and ready for review at each monitoring visit and/or audit. The sites must 
ensure that the SOPH-A-PORT Mini S devices are available for the monitor to inventory and 
prepare for product destruction or return shipment to the Sponsor or designee.
The SOPH-A-PORT Mini S and its components are sterile, single-use devices.
Please refer to the IDDD Manual for device destruction or return instructions.


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6.10.3
Comparator Product
Not applicable to this study.


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7
STUDY PROCEDURES
Detailed descriptions of patient procedures and evaluations required for this protocol are 
described in this section. These evaluations will be performed during the indicated days and 
weeks of the study (see Schedule of Events for Group 1 [patients who received HGT-1410 Q2W 
in Study HGT-SAN-093[ in Appendix 1, for Group 2 [patients who received HGT-1410 Q4W in 
Study HGT-SAN-093] in Appendix 2, for Group 3A [patients who received no treatment in 
Study HGT-SAN-093 and are randomized to receive HGT-1410 Q2W in Study SHP-610-201] in 
Appendix 3, and for Group 3B [patients who received no treatment in Study HGT-SAN-093 and 
are randomized to receive HGT-1410 Q4W in Study SHP-610-201] in Appendix 4).
All data collected are to be recorded on the patient’s appropriate eCRF.
Details for sample collection are described in the Laboratory Manual for Study SHP-610-201.
7.1
Informed Consent
Prior to conducting any study-related procedures, written informed consent must be obtained 
from the patient’s parent(s) or legally authorized representative(s) and assent from the patient (if 
applicable).
The nature, scope, and possible consequences, including risks and benefits, of the study will be 
explained to the patient, the patient’s parent(s), or the patient’s legally authorized representative 
by the Investigator or designee in accordance with the guidelines described in Section 11.4. 
Documentation and filing of informed consent documents should be completed according to 
Section 11.4.
7.2
Study Entrance Criteria
Each patient in Groups 1 and 2 (those who received HGT-1410 in Study HGT-SAN-093) will be 
reviewed for eligibility against the study entrance criteria prior to receiving HGT-1410 at Weeks
50 and 52, respectively. 
All treated patients in Study HGT-SAN-093 will have their cognitive development assessed at 
the Week 48 Visit in Study HGT-SAN-093. If a decline from Baseline of 20 points or less in DQ 
score is observed, then the patient may proceed into the Study SHP-610-201 without further 
evaluation. If a decline from Baseline of more than 20 points in DQ score is observed, then 
an individual evaluation by the Investigator will occur to determine if the patient is a treatment 
failure. This individual evaluation will take into account the DQ scores, VABS-II score, physical 
status, and any other information available for that patient at that time. If the Investigator deems 
the patient to be a treatment failure, then the patient may not enter the Study SHP-610-201.
Each patient who received no treatment in Study HGT-SAN-093 (Group 3) will be reviewed for 
eligibility against the study entrance criteria before IDDD implantation.
Patients who do not meet the study entrance criteria will not be allowed to participate in the 
study. The reason(s) for the patient’s ineligibility for the study will be documented.


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7.3
Hearing and Vision Assessments 
7.3.1
Investigator Assessment of Hearing and Vision
For patients who received no-treatment in Study HGT-SAN-093 (Group 3) only, the Investigator 
will use their clinical judgment to assess the patient’s vision during the initial physical 
examination. Investigator judgment will be used to determine whether the patient’s hearing and 
vision is adequate for cooperation with neurodevelopmental testing, as indicated in the study 
inclusion criteria.
7.4
Device-related Study Procedures
7.4.1
IDDD Implantation or Revision Procedures
The IDDD will be surgically implanted or revised at the clinical site. Procedures for implantation 
and revision are detailed in the device’s IFU. Standard hospital procedures for surgery will be 
followed; the patient will be under general anesthesia for this procedure.
An additional medical device, the catheter passer, is necessary for the implantation procedure. 
The catheter passer is a sterile, single-use device that will be used in the subcutaneous placement 
of the catheter. The Phoenix Neuro Disposable Catheter Passer, manufactured by Sophysa is CE-
marked in the EU and cleared under K853370 in the United States (US), may be provided; 
however, use of other catheter passers compatible with the SOPH-A-PORT Mini S is allowed.
Details of the implantation/revision and malfunctions/failure will be documented on the patient’s 
eCRF.
7.4.2
X-ray Verification of Intrathecal Drug Delivery Device Placement 
A postoperative X-ray check of the IDDD will be performed following surgery for Groups 3A 
and 3B to verify proper installation and confirmation of IDDD placement at the mid-thoracic 
level. The X-rays may be performed to check placement of the device, as needed, throughout the 
study. At a minimum, the date of the X-ray verifying correct IDDD placement will be 
documented on the patient’s eCRF. If the device requires revision or replacement during the 
study, additional X-rays will be taken to document proper positioning of the device. If an IDDD 
malfunctions, an X-ray will be performed to assess the potential cause of malfunction. 
Fluoroscopy should be used during device implantation procedures.
7.4.3
CSF Sampling Procedure
Cerebrospinal fluid will be sampled via the device. If this is not possible, and if CSF sampling is 
necessary, either for adherence to the protocol or to investigate clinical concerns, an LP may be 
performed to sample CSF, either with or without administration of drug afterward.
7.4.4
Device Adjustment, Revision, or Removal
If at the time of a scheduled dosing it is not possible to administer a full medication dosage using 
the standard administration steps detailed in the device’s IFU due to a device-related issue, the 
IDDD will be declared a device malfunction. If the device malfunction is irreversible and cannot 


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be corrected without a device surgical intervention, the IDDD will be declared a device failure, 
starting from the date of the initial malfunction. 
The IDDD will then be surgically adjusted, removed, or revised and a new device and/or device 
components will be re-implanted at the earliest possible opportunity, preferably at the same time. 
Details of the device removal will be recorded in the patient’s eCRF. Refer to the SOPH-A-
PORT Mini S IFU for further details.
Patients will have the IDDD removed when they discontinue from or complete the study, unless 
the patient is continuing to receive treatment through another mechanism (eg, extension study, 
expanded access program, commercially available drug).
7.5
Investigational Product Administration
Patients will be administered HGT-1410 by means of an IDDD, either every 2 weeks (Q2W) or 
every 4 weeks (Q4W). A visual examination of both the port and catheter track will be 
performed before each IT injection.
Patients will remain under observation in the hospital setting for at least 4 hours post-dosing and 
will be discharged when deemed clinically stable by the Investigator. The number of IDDD 
revisions/replacements is limited to 2 per patient in any 6-month period. Therefore, in the “worst 
case scenario” of 2 IDDD failures occurring within 1 month, up to 11 consecutive doses of 
HGT-1410 administered via LP will be necessary for patients in the Q2W dosing group, and up 
to 5 consecutive doses via LP will be necessary for patients in the Q4W dosing group until the 
IDDD can be revised or replaced.
A 22-gauge Huber non-coring needle is to be used for access to the implanted port; standard 
hypodermic needles would damage the septum and may cause leakage. If no needle-free 
connector is present, a stopcock or the Huber needle infusion set’s clamp is to be used to prevent 
CSF backflow and to mitigate the risk of air entering the system. It is possible to use other 
brands of Huber non-coring needles, provided that their specifications are identical to that of the 
Huber needle supplied by Sophysa in a SOPH-A-PORT Mini S (22G).
It is expected that all or most doses of HGT-1410 will be successfully administered following the 
application of topical anesthetic cream to the skin overlying the IDDD access port (see IDDD 
Manual for details). However, in some cases, sedation or general anesthesia may be required and 
may be used at the discretion of the Investigator. Any sedative or anesthetic drugs used must be 
recorded as concomitant medications.
Intrathecal administration of investigational product will be preceded by CSF sampling for 
clinical laboratory analysis (cell count, protein, glucose) and storage for additional analyses 
which may include pharmacodynamics (GAG concentration) and analyses of HGT-1410 enzyme 
and anti-rhHNS antibodies, according to the relevant Schedules of Events (Appendix 1, 
Appendix 2, Appendix 3, and Appendix 4).
All HGT-1410 administrations will be followed by a flush with preservative-free saline of at 
least 2 mL. The total volume of investigational product and flush administered is targeted 


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towards replenishing the volume of CSF withdrawn. If the total volume of HGT-1410 plus 2 mL 
saline flush is less than the total volume of CSF withdrawn, additional saline will be 
administered to balance the volumes withdrawn and injected.
The injection date, injection start/stop time, planned dose, injection volume, and flush volume 
will be recorded on the patient’s eCRF.
7.6
Efficacy Assessments
7.6.1
Neurocognitive and Developmental Assessments
The study methodology will include standardized neurodevelopmental assessments to provide a 
quantifiable measure of patient neurodevelopmental status (see Table 7-1).11 The assessments are 
estimated to last between 2 and 4 hours and must be conducted prior to any invasive procedures, 
such as blood draws, and prior to sedation or anesthesia. Neurodevelopmental status will be 
assessed over time by measuring cognitive and adaptive functions as follows:

Cognition:  The BSID-III12 will be used to assess all patients through the age of 42 months. 
Once patients reach age 42 months, an attempt will be made to switch the cognitive 
assessment to the KABC-II. If the cognitive status of the patient does not allow for testing by 
the KABC-II, the BSID-III may be used.

Adaptive behaviors: The VABS-II13 will be used to assess all patients.
For this study, outcome measures will be computed for each patient enrolled. The psychometric 
instruments are summarized below in Table 7-1. 
Table 7-1
Neurodevelopmental Assessments Tests 
Cognitive Test or Scale 
Developmental or Cognitive Areas of Assessment
BSID-III12
Summary score and sub-domains:
- Cognitive
- Motor
- Social/Emotional
- Language
KABC-II
Cognitive and processing skills
ADAPTIVE BEHAVIOR
VABS-II13
Communication
Daily Living
Socialization
Motor Skills
Abbreviations: BSID-III=Bayley Scales of Infant and Toddler Development, Third Edition; KABC-II=
Kaufman Assessment Battery for Children, Second Edition; VABS-II=Vineland Adaptive Behavior Scales, 
Second Edition
7.6.2
Quality of Life Indicator:  Infant Toddler Quality of Life Questionnaire
The ITQoL will be administered during the study. The ITQoL was developed for children at least 
2 months of age up to 5 years and assesses the physical, mental, and social well-being of the 


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child and assesses the quality of the parent/guardian’s life. If a patient is over 5 years of age, they 
do not have to complete the ITQoL.
7.6.3
Health Economics and Outcomes Research:  Healthcare Utilization Questionnaire
The HCUQ will be administered during the study. This HCUQ focuses on the direct and indirect 
costs of care for patients with MPS-III.
7.7
Magnetic Resonance Imaging
7.7.1
Head
Regional brain volumes, including total cortical gray matter volume, will be assessed through an 
MRI of the head. The patient will be under general anesthesia for this assessment. Instrument 
standardization and central analysis of MRIs will be performed by a designated contract research 
laboratory.
7.7.2
Liver and Spleen
Liver and spleen volumes will be assessed through an MRI, performed at the same times as for 
the MRI of the head. The patient will be under general anesthesia for this assessment. Instrument 
standardization and central analysis of MRIs will be performed by a designated contract research 
laboratory.
7.8
Pharmacokinetic Assessments
Blood samples will be collected for measurement of serum concentrations of HGT-1410 and 
determination of pharmacokinetic parameters at the times specified in the Schedules of Events 
(see Appendix 1, Appendix 2, Appendix 3, Appendix 4, and Appendix 6). Additionally, CSF 
samples will be collected from patients who received no treatment in Study HGT-SAN-093 at 
the times specified in the Schedules of Events (see Appendix 3, Appendix 4, and Appendix 6). 
The results of these assessments will be addressed in a separate pharmacokinetics report.
Patients may be discharged from the hospital after the 24-hour blood draw. Patients will either 
stay locally in a hotel or return home (if they live in close proximity to the hospital); this will be 
decided in consultation with the Investigator. Patients will return to the hospital for 
pharmacokinetic blood and CSF sampling at the 48-hour time point. Patients will be discharged 
to home after the physical examination and blood draws have been completed at the 48-hour PK 
time point. See Appendix 6 for more details regarding timing for pharmacokinetic sample 
collection.
Serum and CSF pharmacokinetic collection, processing, and shipping instructions will be 
provided in the Laboratory Operations Manual.
7.9
Pharmacodynamic Biomarker Assessments (CSF and Urine GAG Levels)
CSF and urine samples will be obtained to measure the concentration of GAG according to the 
schedules of events (Appendix 1, Appendix 2, Appendix 3, and Appendix 4). Details about CSF 
collection are provided in Section 7.11.5.3.


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7.10
Concomitant Medications, Therapies, and Medical/Surgical Interventions
All non-protocol treatments and medications that occur from the time of informed consent 
through the safety follow-up contact are regarded as concomitant and will be documented on the 
appropriate pages of the eCRF. Concomitant therapy includes any therapies/interventions 
administered to patients, and these will be recorded on the concomitant therapy eCRF. Any 
medical/surgical procedures performed on the patients will be recorded on the concomitant 
medical/surgical procedures eCRF. Concomitant medications, both prescribed and 
over-the-counter (including genistein and anesthesia medications) will be recorded on the 
concomitant medication eCRF.
Every effort should be made to keep symptomatic MPS IIIA treatment constant throughout the 
study. However, changes in medications are acceptable if necessary according to clinical 
judgment. All changes will be recorded on the appropriate eCRF. Concomitant medication will 
be coded using the World Health Organization-Drug Dictionary (WHO-DD).
7.11
Safety Assessments
7.11.1
Vital Signs
Vital signs are to be recorded on the eCRF for all patients and will include heart rate, blood 
pressure, respiration rate, and body temperature. Vital signs will be recorded for at least 4 hours 
following each dose of HGT-1410, as described in the Schedules of Events (Appendix 1, 
Appendix 2, Appendix 3, and Appendix 4).
7.11.2
Physical Examination, Including Height, Weight, and Head Circumference
During the study, physical examinations will be performed at the time points indicated in the 
Schedules of Events. For Groups 1 and 2, full physical examinations will be conducted at Weeks 
96, 120, 144, and 168, and for Groups 3A and 3B, full physical examinations will be conducted 
during the IDDD implantation period and at Weeks 24, 48, 72, 96, and 120. The remainder of 
physical examinations will be symptom-directed.
Physical examinations will include a review of the patient’s general appearance, neurological
examination, as well as evaluation of the body systems described in Table 7-2, including the port 
and catheter track. Any abnormal change in findings will be recorded as an AE on the 
appropriate eCRF.
Table 7-2
Assessments for Physical Examinations
Assessment
Assessment
General appearance
Endocrine
Head and neck
Cardiovascular
Eyes
Abdomen
Ears
Genitourinary
Nose
Skin
Throat
Musculoskeletal
Chest and lungs
Neurological


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Table 7-2
Assessments for Physical Examinations
Assessment
Assessment
Port and catheter track
Height and weight will be recorded for all patients.
The clinical site staff will be instructed to use calibrated scales for weight measurement where 
possible. The same scale is to be used at the clinical site for all patients at each specified time 
point during the study.
Head circumference will be measured for Groups 3A and 3B during the IDDD implantation 
period. All data will be recorded on the eCRF. 
7.11.3
Electrocardiogram
An ECG will be performed in accordance with the clinical site’s standard practice(s) and are to 
be performed after study drug administration. Electrocardiogram recordings will be read locally 
at the clinical site and will include an assessment of heart rate, sinus rhythm, atrial or ventricular 
hypertrophy, PR, QRS, and QT. Identification of any clinically significant findings and/or 
conduction abnormalities will be recorded on the eCRF. If the patient is unable to cooperate with 
electrocardiography, and if sedation or general anesthesia is employed during that study visit, the 
ECG may be performed under sedation/anesthesia.
7.11.4
Clinical Laboratory Tests
Blood and urine samples will be collected as described in this section for clinical laboratory 
testing. All blood samples will be collected via venipuncture. Patients will be in a seated or 
supine position during blood collection. Procedures for collection and handling of samples are 
included in the Laboratory Manual. Blood volumes are presented in Appendix 5.
Clinical laboratory tests will include the following (see Table 7-3):


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Table 7-3
List of Laboratory Tests
Hematology:
-
Hematocrit (Hct)
-
Hemoglobin (Hgb)
-
Mean corpuscular hemoglobin (MCH)
-
Mean corpuscular hemoglobin 
concentration (MCHC)
-
Mean corpuscular volume (MCV)
-
Platelet count
-
Red blood cell (RBC) count 
-
White blood cell (WBC) count with 
differential 
Urinalysis:  
-
Appearance
-
Bilirubin
-
Color
-
Glucose
-
Ketones
-
Microscopic examination of sediment 
-
Microscopic examination
-
Nitrite 
-
Occult blood
-
pH
-
Protein
-
Specific gravity
-
Urobilinogen
-
Triglycerides
-
Uric acid
Anti-rhHNS antibody assessment
Serum Chemistry:
-
Albumin (ALB)
-
Alkaline phosphatase (ALK-P)
-
Alanine aminotransferase (ALT; SGPT)
-
Aspartate aminotransferase (AST; SGOT)
-
Blood urea nitrogen (BUN)
-
Calcium (Ca)
-
Carbon dioxide (CO2)
-
Chloride (Cl)
-
Creatinine
-
Creatine kinase (CK) and subtypes
-
Gamma-glutamyl transferase (GGT)
-
Globulin
-
Glucose
-
Lactate dehydrogenase (LDH)
-
Phosphorus
-
Potassium (K)
-
Sodium (Na)
-
Total bilirubin
-
Direct bilirubin
-
Total cholesterol
-
Total protein
-
Triglycerides
-
Uric acid
Coagulation (performed at IDDD implantation):  
-
Prothrombin time (PT)
-
Activated partial thromboplastin time 
(aPTT)
7.11.5
Cerebrospinal Fluid Assessments 
Cerebrospinal fluid will be obtained from patients during surgical implantation of the IDDD 
(Groups 3A and 3B only), immediately prior to each injection of study drug and at the safety 
follow-up visit. Should the IDDD become clogged or undergo mechanical complications, the 
CSF sample will be obtained via LP.
The volume of CSF collected at each visit will vary according to the number of CSF 
assessments. The initial 1 mL of CSF aspirated via the IDDD will be discarded, to eliminate fluid 
in the device’s “dead space.” The next 1 mL of CSF will be sent to the local laboratory. 
Subsequently drawn CSF will be stored, depending on the requirement for that visit (see the 
Schedules of Events in Appendix 1, Appendix 2, Appendix 3, Appendix 4, and the Laboratory 
Manual). If CSF is obtained via LP, there is no need to discard the first mL of CSF, and this can 
be sent to the local laboratory for standard clinical assessments. If the patient is clinically stable 


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in the opinion of the Investigator, HGT-1410 can be administered immediately following 
withdrawal of CSF, without awaiting the results of the CSF clinical laboratory data. 
Each CSF sample collected will have the assessments described in Sections 7.11.5.1 through 
7.11.5.4. Cerebrospinal fluid sample collection, processing, and shipping instructions are 
provided in the Laboratory Manual. Total CSF volumes are presented in Appendix 5.
7.11.5.1
Standard CSF Safety Laboratory Assessments
An aliquot of each CSF sample collected will be evaluated for CSF standard chemistries, 
glucose, protein, and cell counts.
7.11.5.2
Anti-rhHNS Antibodies and Biomarkers in CSF
An aliquot of each CSF sample collected will be quick frozen for subsequent analysis of 
anti-rhHNS antibody evaluation, exploratory proteomics biomarkers, and/or other CSF 
biomarkers.
7.11.5.3
CSF GAG Levels and Biomarkers
An aliquot of each CSF sample collected will be quick frozen for subsequent analysis of CSF
GAG, GAG degradation components, HS/dermatan sulfate (DS) oligosaccharides, or other CSF 
markers. The CSF pharmacodynamic sample will be obtained at the same visit as a serum sample 
as described in Section 7.9.
7.11.5.4
7.11.6
Device Assessments
 These 
data will be collected on the patient’s eCRF from the time of initial implantation.
7.11.7
Collection and Storage of Biological Samples for Biomarker Studies 
Biomarker analyses may be performed at the Shire research laboratory or at a Shire-designated 
research laboratory. Collection and processing of CSF samples will be performed as specified in 
the Laboratory Manual. Samples will be stored securely to ensure patient confidentiality. 
Samples obtained for this study will be stored for up to 10 years. Thereafter, samples will be 
destroyed. 


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7.12
Sample Collection, Storage, and Shipping
Details for study procedures including sample collection are provided in the Laboratory Manual 
for this study.
7.13
Adverse Events Assessments
7.13.1
Definitions of Adverse Events and Serious Adverse Events
7.13.1.1
Adverse Event
An AE is any noxious, pathologic, or unintended change in anatomical, physiologic, or 
metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in 
any phase of a clinical study, whether or not considered investigational product-related. This 
includes an exacerbation of a pre-existing condition. 
Adverse events include:

Worsening (change in nature, severity, or frequency) of conditions present at the onset of the 
study

Intercurrent illnesses

Drug interactions

Events related to or possibly related to concomitant medications

Abnormal laboratory values (This includes significant shifts from baseline within the range 
of normal that the Investigator considers to be clinically important.)

Clinically significant abnormalities in physical examination, vital signs, and weight
Throughout the study, the Investigator must record all AEs on the AE eCRF, regardless of the 
severity or relationship to investigational product. The Investigator should treat patients with 
AEs appropriately and observe them at suitable intervals until the events stabilize or resolve. 
Adverse events may be discovered through observation or examination of the patient, 
questioning of the patient, complaint by the patient, or by abnormal clinical laboratory values.
In addition, AEs may also include laboratory values that become significantly out of range. In 
the event of an out-of-range value, the laboratory test should be repeated until it returns to 
normal or can be explained and the patient’s safety is not at risk.
Additional illnesses present at the time when informed consent is given are regarded as 
concomitant illnesses and will be documented on the appropriate pages of the eCRF. Illnesses 
first occurring or detected during the study, and worsening of a concomitant illness during the 
study, are to be regarded as AEs and must be documented as such in the eCRF.
7.13.1.2
Adverse Events Due to Systemic Exposure to HGT-1410 
Although HGT-1410 is given intrathecally only, some proportion of the drug will diffuse from 
the CSF into the peripheral circulation. The resulting systemic exposure may cause events that 
are typically seen in patients receiving ERT via an intravenous administration. Investigators will 
judge the relationship of AEs to the drug infusion and describe the clinical details on the AE 


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form. The temporal relationship of an AE to the drug infusion will be determined upon analysis 
of the AE and study treatment administration data. 
7.13.1.3
Infusion/Hypersensitivity Reactions and Management
Infusions of proteins can be associated with reactions to the infusion that may or may not be 
immune-mediated (hypersensitivity reactions). Thus, potential reactions to the infusion of 
investigational drug are unpredictable. It is often difficult to clinically distinguish infusion 
reactions from hypersensitivity reactions. Symptoms may include headache, fever, sensory 
paresthesias (including feeling of warmth, tingling, or pain), rash, pruritus, or autonomic 
symptoms, such as dry mouth or gustatory abnormalities (including loss of smell and metallic 
taste). Changes in mental status or level of consciousness that are not caused by pre-medication 
may either occur acutely or develop post-injection over time. 
The management of infusion reactions and hypersensitivity reactions is similar. The following 
steps may be taken, at the discretion of the Investigator, in the event of a suspected infusion 
related/hypersensitivity reaction and the management of such reactions should be based on the 
severity of the reaction:

Treatment with medications such as antihistamines, antipyretics, and/or corticosteroids

Stopping and resuming treatment

Pretreatment with antihistamines and/or corticosteroids may prevent subsequent reactions in 
those cases where symptomatic treatment was required
7.13.1.4
IDDD-related Adverse Events
IDDD ADVERSE EVENTS
Examples of AEs related to use of the IDDD include, but are not limited to, the following:  
device failure, device malfunction, incorrect connection of IDDD components, erosion of the 
portal/catheter through the skin, fibrin sheath formation around the catheter tip, hematoma, 
implant rejection, migration of the portal/catheter, and occlusion of the portal/catheter, portal site 
or subcutaneous tract infection. A malfunction of the device (defined in Section 7.13.2.2) should 
not be entered as an adverse event unless it has physiological consequences. In the event of a 
device failure (defined in Section 7.13.2.3), the device may need to be replaced or repaired. If 
overnight hospitalization is required for such a procedure (or the device failure meets any other 
serious criteria, eg, medically important), the device failure will be reported as a serious adverse 
event. Details of the cause of the IDDD malfunction or failure will be recorded on the device 
malfunction and failure eCRF and the serious adverse event (SAE) form (when applicable). A 
list of the most common IDDD AEs is included in Appendix 7.
DEVICE SURGICAL PROCEDURE-RELATED ADVERSE EVENTS (FOR IT STUDIES; AMEND/DELETE 
SECTION AS APPLICABLE)
Examples of AEs related to device surgical procedures include, but are not limited to, the 
following:  events that occur during or shortly following IDDD implant/explant, IDDD 
adjustment, full revision, partial revision, IDDD removal, and delayed re-implantation after 
previous IDDD removal (such as complications of anesthesia, excessive bleeding, wound 


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hematoma), and postoperative complications (such as postoperative infection). These events are 
related to the surgical procedure itself.
IT ADMINISTRATION PROCESS ADVERSE EVENTS
Intrathecal administration process adverse events may include those caused by anesthesia during 
drug administration and other drug administration issues (eg, extravasation during infusion or 
hematoma due to Huber needle) or complications of LP.
7.13.1.5
Serious Adverse Event
An SAE is any AE occurring at any dose of investigational drug or procedure that results in any 
of the following outcomes:

Death

Is life-threatening

Requires hospitalization

Requires prolongation of existing hospitalization

A persistent or significant disability or incapacity 

A congenital anomaly or birth defect
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. A life-threatening AE is defined as an AE that placed the 
patient, in the view of the initial reporter, at immediate risk of death from the AE as it occurred 
(ie, it does not include an AE that, had it occurred in a more severe form, might have caused 
death).
An unanticipated adverse device effect (UADE) is any SAE on health or safety or any life-
threatening problem or death caused by, or associated with, a device, if that effect, problem, or 
death was not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or 
welfare of patients (21 Code of Federal Regulations [CFR] 812.3[s] or other regulatory 
requirements, as applicable).
7.13.2
Device-associated Definitions
7.13.2.1
Device Revision (Partial and Full)
Partial device revision:  surgical revision/replacement of one or more component(s) of the 
device; other component(s) of the original device remain implanted and are not affected (eg, port 
revision).
Full device revision: The device is removed (explanted) in its entirety, and a completely new 
device is implanted.


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Device adjustment:  surgery that does not result in partial or full device revision (see definition 
above) or removal. Examples of device adjustment include surgical exploration only or 
placement of additional sutures, tissue glue, and/or fascial repair.
7.13.2.2
Device Malfunction
The device does not perform as intended, based on the description in the device’s IFU, but does 
not require either a partial or full device revision.
7.13.2.3
Device Failure
The device irreversibly fails to perform as intended and requires either a partial or full device 
revision or removal.
7.13.3
Classification of Adverse Events and Serious Adverse Events
The severity of AEs will be assessed by the Investigator based on the definition indicated in 
Table 7-4. The severity of all AEs/SAEs should be recorded on the appropriate eCRF page to a 
severity of mild, moderate, or severe.
Table 7-4
Adverse Event Severity
Severity
Definition
Mild
No limitation of usual activities.
Moderate
Some limitation of usual activities.
Severe
Inability to carry out usual activities.
7.13.4
Clarification between Serious and Severe
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache). This is not the same as “serious,” which is based 
on the outcome or action criteria usually associated with events that pose a threat to life or 
functioning. Seriousness (not severity) and causality serve as a guide for defining regulatory 
reporting obligations.
7.13.5
Relatedness of Adverse Events and Serious Adverse Events
Relationship of an AE or SAE to investigational product, device (IDDD), device surgical 
procedure, or IT administration process will be assessed by the Investigator based on the 
following definitions (see Table 7-5).
Table 7-5
Adverse Event Relatedness
Relationship
Definition
Not Related
Unrelated to investigational product, device, device surgical 
procedure, or IT administration process.
Possibly Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of investigational product, the presence of 


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Table 7-5
Adverse Event Relatedness
Relationship
Definition
the device, device surgical procedure, or IT administration process but 
which could also be explained by concurrent disease or other drugs or 
chemicals.
Probably Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of investigational product, the presence of 
the device, device surgical procedure, or IT administration process
unlikely to be attributable to concurrent disease or other drugs and 
chemicals and which follows a clinically reasonable response on de-
challenge. The association of the clinical event or laboratory 
abnormality must also have some biologic plausibility, at least on 
theoretical grounds.
Definitely related
The event follows a reasonable temporal sequence from administration 
of the investigational product, the presence of the device, device 
surgical procedure, or IT administration process follows a known or 
suspected response pattern to the investigational product, is confirmed 
by improvement upon stopping the investigational product 
(de-challenge), and reappears upon repeated exposure (re-challenge). 
Note that this is not to be construed as requiring re-exposure of the 
patient to investigational product; however, the determination of 
definitely related can only be used when recurrence of event is 
observed.
7.13.6
Procedures for Recording and Reporting Adverse Events
7.13.6.1
Adverse Event Monitoring and Period of Observation
Adverse events will be monitored continuously throughout the study.
For the purposes of this study, the period of observation extends from the time at which the 
patient, the patient’s parent(s), or the patient’s legally authorized representative gives informed 
consent until the patient’s final evaluation of the study. For safety purposes, the final evaluation 
will be defined as the follow-up evaluation performed approximately 30 days after the last dose 
for patients who complete the study.
If the Investigator considers it necessary to report an AE in a study patient after the end of the 
safety observation period, he or she should contact the Sponsor to determine how the AE should 
be documented and reported.
7.13.6.2
Reporting Serious Adverse Events
Any SAE, regardless of relationship to investigational product, device, device surgical 
procedure, or IT administration process which occurs in a patient after informed consent, should 
be recorded by the clinical site on an SAE form. The SAE must be completely described on the 
patient’s eCRF, including the judgment of the Investigator as to the relationship of the SAE to 
the investigational product and/or device. The Investigator will promptly supply all information 
identified and requested by the Sponsor (or contract research organization [CRO]) regarding the 
SAE. 


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The Investigator must report the SAE to the Shire Pharmacovigilance and Risk Management 
Department AND to the Shire Medical Monitor on an SAE form. This form must be completed 
and FAXED or EMAILED within 24 hours of the Investigator’s learning of the event to:
Shire Pharmacovigilance and Risk Management Department:
International FAX:  
 (UK) OR United States FAX:  
Email:  
AND
Shire Medical Monitor:  
, DO
Email:  
Any follow-up information must also be completed on an SAE form and faxed or emailed to the 
same numbers or emails listed above.
In the event of a severe and unexpected, fatal, or life-threatening SAE, the clinical site must 
contact the Shire Medical Monitor by telephone; this is in addition to completing and 
transmitting the SAE form as stated above. The following provides contact information for the 
Shire Medical Monitor. 


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If an SAE is assessed as severe and unexpected, fatal or life-threatening, contact:
 DO
Shire Human Genetic Therapies, Inc.
300 Shire Way
Lexington, MA 02421  USA
Telephone:  
Mobile Telephone: 
(24-hour access)
Email: 
The Investigator must promptly report all required information to the IRB/EC. It is the 
responsibility of the Sponsor to ensure that each Investigator receives a copy of any Council for 
International Organizations of Medical Sciences I/MedWatch report that has been submitted to 
the appropriate regulatory agencies notifying them of an unexpected related SAE. The 
Investigator or Sponsor must ensure that the IRB/EC receives a copy of the report and that a 
copy is also filed within their study files.
7.14
Abuse, Overdose and Medication Error
Abuse – Persistent or sporadic intentional intake of investigational medicinal product at a dose 
higher than prescribed per protocol (but below the dose defined for overdose) or when used for 
non-medical purpose (eg, altering one’s state of consciousness)
Misuse – Intentional or unintentional use of investigational medicinal product other than as 
directed or indicated at any dose, which is at or below the dose defined for overdose (Note:  This 
includes a situation where the test article is not used as directed at the dose prescribed by the 
protocol.)
Overdose – Intentional or unintentional intake of a dose of investigational medicinal product 
higher than the protocol-mandated dose. No clinical information on overdose is available. 
Medication Error – A mistake made in prescribing, dispensing, administration and/or use of the 
investigational medicinal product.
All investigational medicinal product provided to pediatrics should be supervised by the 
parent/legally authorized representative/caregiver.
7.15
Removal of Patients from the Trial or Investigational Product
A patient’s participation in the study may be discontinued at any time at the discretion of the 
Investigator. The following may be justifiable reasons for the Investigator to remove a patient 
from the study:

Non-compliance, including failure to appear at one or more study visits

The patient was erroneously included in the study.


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
The patient develops an exclusion criterion.

The patient suffers an intolerable AE.

The study is terminated by the Sponsor.
The patient, the patient’s parent(s), or the patient’s legally authorized representative acting on 
behalf of the patient is free to withdraw consent and discontinue participation in the study at any 
time without prejudice to further treatment.
If a patient or the patient’s parent(s) or the patient’s legally authorized representative(s) acting on 
behalf of the patient, discontinues participation in the study, or the patient is discontinued by the 
Investigator, reasonable efforts will be made to follow the patient through the safety follow-up 
assessments. The reason for refusal will be documented on the eCRF. Any AEs experienced up 
to the point of discontinuation must be documented on the AE eCRF. If AEs are present when 
the patient withdraws from the study, the patient will be re-evaluated within 30 days of 
withdrawal. All ongoing SAEs at the time of withdrawal will be followed until resolution.
7.16
Safety-Related Study Stopping Rules
In addition to safety monitoring by the Sponsor, patient safety in this study will be monitored by 
an independent DMC until the last patient completes their last scheduled study visit/assessment. 
The DMC will be an external group overseeing the safety of the study treatment, including both 
the investigational product and the IDDD, and will operate according to a charter determining 
the scope of its activities and frequency of meetings (see Section 11.8 for additional details).
This study will be stopped and safety data reviewed if any patient experiences a life-threatening 
or fatal SAE, either of which is considered possibly or probably related to the investigational 
product.
Following the review of safety data, the status of the study will be one of the following:

Resumed unchanged

Resumed with modifications to the protocol 

Terminated
Patient safety will be monitored on a continuous basis during this study until the last patient 
completes his or her last scheduled study visit/assessment. 
7.17
Appropriateness of Measurements
The neurocognitive and developmental assessments planned for this study are intended to gauge 
the potential treatment effect and safety of 2 dose levels of HGT-1410 over time on behavioral 
and cognitive criteria in patients with MPS IIIA. The selection of tests used for the cognitive 
assessment, and the expression of results as a ratio of mental age equivalence to calendar age to 
generate a DQ, were developed in collaboration with clinical psychologists with expertise in the 
assessment of severely disabled children with neurometabolic diseases. 
The BSID-III, KABC-II, and VABS-II are instruments that have been used to assess 
development in healthy children and those with developmental delay. Their use in this study will 


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contribute to their validation in patients with MPS IIIA. The utility of these measures to track 
disease progression has been demonstrated in Shire’s natural history study of MPS IIIA 
(HGT-SAN-053). 
The BSID-III was selected for the following reasons:  

Widespread familiarity with the instrument 

Availability of age equivalent scores for severely impaired children 

Nonverbal content (ie, on the cognitive scale on the BSID-III) 

Availability of language and motor assessment (Both are domains on the BSID-III.) 
The BSID-III is validated for children through the age of 42 months. Patients are to be switched 
to another instrument, the KABC-II, to measure cognition after the age of 42 months. The 
KABC-II measures a child’s cognitive ability and processing skills and was designed to 
minimize verbal instructions and responses. In addition, the assessment contains little cultural 
content to provide a more accurate assessment of children from diverse backgrounds. Thus 
language difficulties or cultural differences are minimized in the test battery’s results.
The VABS-II, a parent-reported outcome, was selected as an adaptive measure for the same 
reasons. Of note, to maximize standardization and reduce bias, the “interview” form of the 
VABS-II will be administered by the clinical psychologist/psychometrist at the same time as the 
BSID-III assessment.
The use of age equivalent scores rather than standard scores permits the assessment of children 
with severe disability in whom standard scores would otherwise be insensitive to change. Given 
the potentially rapid progression of MPS IIIA, a child who is assessable using a standard score at 
baseline may rapidly decline to such an extent that the assessment “floor” is reached and further 
change is not measurable. Additionally, the use of age equivalence scores permits comparison 
and correlation between the BSID-III and VABS-II. The use of DQ yields a parameter that tracks 
the dynamic progression of MPS IIIA disease, as observed in Shire’s natural history study. 
This study will utilize standard safety assessments including AEs, vital signs, standard clinical 
tests, and ECGs. Antibodies against the investigational drug will also be measured.


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8
STUDY ACTIVITIES
The timing of study activities are described for each of the 3 patient groups below, and in 
Appendix 1, Appendix 2, Appendix 3, and Appendix 4, respectively for Group 1 (initially 
randomized to receive HGT-1410 Q2W in Study HGT-SAN-093), Group 2 (initially randomized 
to receive HGT 1410 Q4W in Study HGT-SAN-093), Group 3A (initially randomized to 
no-treatment in Study HGT-SAN-093 and randomized to HGT-1410 Q2W in Study 
SHP-610-201), and Group 3B (initially randomized to no-treatment in Study HGT-SAN-093 and 
randomized to HGT-1410 Q4W in Study SHP-610-201). Study activities for all patients are 
detailed in Section 7.
8.1
Group 1 (Maintaining Q2W Dosing)
8.1.1
Treatment Period (Weeks 50 through 168)
The pre-treatment assessments may be performed on the same day as the administration of study 
drug if it is feasible for the patient to arrive at the study site early in the day, and if it is deemed 
clinically appropriate by the Investigator. Patients may be discharged from the clinical site 
4 hours after dosing, if deemed stable by the Investigator.
Patients in Group 1 will receive 45 mg HGT-1410 IT Q2W (ie, every 14±3 days). 
Administration of HGT-1410 can only occur following the completion of all pre-treatment 
assessments and procedures. 
The first 48 weeks of treatment for Group 1 occurred in Study HGT-SAN-093, and therefore 
patients in Group 1 will begin this study at Week 50. 
For patients in Group 1, HGT-1410 will be administered every other week from Week 50 
through Week 168.
8.1.1.1
Pre-treatment Assessments

Review of study eligibility and informed consent

Full physical examination (PE), including height and weight at Weeks 72, 96, 120, 144, and 
168; symptom-directed PE at all other visits

Every visit: vital signs, concomitant medications, therapies, and procedures, and AE 
monitoring 

Cognitive/behavioral assessments:  BSID-III/KABS-II and VABS-II:  Weeks 72, 96, 120, 
144, and 168

Quality of life (QoL) questionnaire:  ITQoL for patients ≤5 years of age:  Weeks 72, 96, 120, 
144, and 168

Health economics questionnaire:  HCUQ:  Weeks  72, 96, 120, 144, and 168

MRIs of head, liver, and spleen: Weeks 96 and 144

Clinical laboratory tests:  hematology, serum chemistry, urinalysis: Weeks 60, 72, 84, 96, 
108, 120, 132, 144, 156, and 168

Every study visit before dosing:  standard CSF safety laboratory assessments

CSF and urine sample collection for GAG at Weeks 60, 72, 84, 96, 108, 120, 132, 144, 156, 
and 168


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
Every study visit:  CSF sample collection for storage for biomarkers

Anti-rhHNS antibody testing (serum and CSF) and CSF biomarker testing at Weeks 60, 72, 
84, 96, 108, 120, 132, 144, 156, and 168

Serum pharmacokinetics sampling at Week 96 (see Appendix 6 for the pharmacokinetics 
collection schedule)
8.1.1.2
Post-treatment Assessments 

ECG at Weeks 96, 144, and 168

Serum pharmacokinetics sampling at Week 96 (see Appendix 6 for the pharmacokinetics 
collection schedule)

Concomitant medications, therapies, and procedures

AE monitoring

Removal of IDDD if patient not continuing treatment
8.1.2
Safety Follow-up Visit:  Week 172 (±7 days) 
All patients will have a safety follow-up at Week 172 or 30 (±7) days after their last dose of 
HGT-1410. 

Symptom-directed PE

Vital signs

Clinical laboratory tests

Concomitant medications, therapies, and procedures

AE monitoring
8.2
Group 2 (Maintaining Q4W Dosing)
8.2.1
Treatment Period (Weeks 52 through 168)
The pre-treatment assessments may be performed on the same day as the administration of study 
drug if it is feasible for the patient to arrive at the study site early in the day and if it is deemed 
clinically appropriate by the Investigator. Patients may be discharged from the clinical site 
4 hours after dosing, if deemed stable by the Investigator.
Patients in Group 2 will receive 45 mg HGT-1410 IT Q4W (ie, every 28±7 days). 
Administration of HGT-1410 can only occur following the completion of all pre-treatment 
assessments and procedures. 
The first 48 weeks of treatment for Group 2 occurred in Study HGT-SAN-093, and therefore 
patients in Group 2 will begin this study at Week 52. 
For patients in Group 2, HGT-1410-IT Q4W study drug will be administered Q4W from 
Week 52 through Week 168.


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8.2.1.1
Pre-treatment Assessments

Review of study eligibility and informed consent

Full PE, including height and weight at Weeks 72, 96, 120, 144, and 168; symptom-directed 
PE at all other visits

Every visit:  vital signs, concomitant medications, therapies, and procedures, and AE 
monitoring 

Cognitive/behavioral assessments:  BSID-III/KABS-II and VABS-II:  Weeks 72, 96, 120, 
144, and 168

QoL questionnaire:  ITQoL for patients ≤5 years of age:  Weeks 72, 96, 120, 144, and 168

Health economics questionnaire:  HCUQ:  Weeks 72, 96, 120, 144, and 168

MRIs of head, liver, and spleen: Weeks, 96 and 144

Clinical laboratory tests:  hematology, serum chemistry, urinalysis: Weeks 60, 72, 84, 96, 
108, 120, 132, 144, 156, and 168

Every study visit before dosing:  standard CSF safety laboratory assessments

CSF and urine sample collection for GAG at Weeks 60, 72, 84, 96, 108, 120, 132, 144, 156, 
and 168

Every study visit:  CSF sample collection for storage for biomarkers

Anti-rhHNS antibody testing (serum and CSF) and CSF biomarker testing at Weeks 60, 72, 
84, 96, 108, 120, 132, 144, 156, and 168

Serum PK sampling at Week 96 (see Appendix 6 for the pharmacokinetics collection 
schedule)_
8.2.1.2
Post-treatment Assessments 

ECG at Weeks 96, 144, and 168

Serum PK sampling at Week 96 (see Appendix 6 for the pharmacokinetics collection 
schedule)

Concomitant medications, therapies, and procedures

AE monitoring

Removal of IDDD if patient not continuing treatment
8.2.2
Safety Follow-up Visit:  Week 172 (±7 days) 
All patients will have a safety follow-up at Week 172 or 30 (±7) days after their last dose of 
HGT-1410:

Symptom-directed PE

Vital signs

Clinical laboratory tests

Concomitant medications, therapies, and procedures

AE monitoring


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8.3
Group 3 (Patients Randomized to No Treatment in Study HGT-SAN-093)
Patients in Group 3 received no treatment in Study HGT-SAN-093, and therefore these patients 
will begin this study at Day -27 to -7.
8.3.1
IDDD Implantation (Days -21 to Day -7)
8.3.1.1
Prior to IDDD Implantation
Prior to enrollment in the study, patients who were initially randomized to no treatment in Study 
HGT-SAN-093 will undergo the following assessments during the IDDD implantation period, 
prior to IDDD implantation surgery:
Written informed consent
Assessment of eligibility according  to 
inclusion/exclusion criteria
Vital signs
Investigator assessment of vision and 
hearing ability 
PE, including height, weight, and head 
circumference
ECG
Clinical laboratory tests, including PT 
and aPTT
BSID-III/KABC-II
VABS-II
ITQoL (for patients ≤5 years of age)
HCUQ
Concomitant medications, therapies, 
and procedures
AE monitoring
The PE, ECG, height, weight, and clinical labs (hematology, serum chemistry, and urinalysis) 
need to be performed within 7 days prior to the IDDD implantation surgery date. If more than 7 
days elapse between the date of these assessments and the IDDD implantation surgery date, the 
assessments must be repeated within 7 days prior to surgery.
8.3.1.2
Day of IDDD Implantation
Surgical implantation of the IDDD includes surgical implantation of the IDDD and a 
post-surgical assessment. IDDD placement will require anesthesia.
Assessments to be performed on the day of IDDD implantation include:
Prior to anesthesia:

Symptom-directed PE

ECG (before anesthesia if possible)

Vital signs 

AE monitoring

Concomitant medications, therapies, 
and procedures
During time patient is anesthetized:

If logistically possible, head, liver, and 
spleen MRI (before IDDD implantation) 

IDDD implantation

CSF samples collected for clinical 
laboratory analysis (chemistry, cell 
count), CSF GAG, CSF storage for 
biomarkers 

Postoperative:  X-ray to check IDDD 
placement


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8.3.2
Postoperative Check – Days 1 to 3 
The postoperative check can occur anytime 1 to 3 days after IDDD implantation. Assessments 
include postoperative check of the IDDD incision; vital signs; symptom-directed PE; 
concomitant medications, therapies, and procedures; and AE monitoring. 
8.3.3
Randomization (Can Occur Any Time After Meeting Study Entry Criteria)
All patients in Group 3 (patients who were initially randomized to no treatment in Study 
HGT-SAN-093) will be randomized in a 1:1 allocation ratio to receive Q2W or Q4W dosing 
(Groups 3A or 3B, respectively), as described in Section 6.4. 
8.4
Group 3A (Initiating HGT-1410 Q2W Dosing)
8.4.1
Treatment Period (Weeks 0 through 120)
The pre-treatment assessments may be performed on the same day as the administration of study 
drug if it is feasible for the patient to arrive at the study site early in the day, and if it is deemed 
clinically appropriate by the Investigator. Patients may be discharged from the clinical site 
4 hours after dosing, if deemed stable by the Investigator.
Patients in Group 3A will receive 45 mg HGT-1410 IT Q2W (ie, every 14±3 days). 
Administration of HGT-1410 can only occur following the completion of all pre-treatment 
assessments and procedures. 
For patients in Group 3A, HGT-1410 will be administered every other week from Week 0 
through Week 120.
8.4.1.1
Pre-treatment Assessments

Full PE, including height and weight at Weeks 24, 48, 72, 96, and 120; symptom-directed PE
at all other visits.

Every visit:  vital signs, concomitant medications, therapies, and procedures, and AE 
monitoring 

Cognitive/behavioral assessments:  BSID-III/KABS-II and VABS-II:  Weeks 24, 48, 72, 96, 
and 120

QoL questionnaire:  ITQoL for patients ≤5 years of age:  Weeks 24, 48, 72, 96, and 120

Health economics questionnaire:  HCUQ:  Weeks 24, 48, 72, 96, and 120

MRIs of head, liver, and spleen: Weeks 24, 48, and 96

Clinical laboratory tests:  hematology, serum chemistry, urinalysis: Weeks 0, 4, 8, 12, 16, 20, 
24, 36, 48, 60, 72, 84, 96, 108, and 120

Every study visit before dosing:  standard CSF safety laboratory assessments

CSF and urine sample collection for GAG at Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 
48, 60, 72, 84, 96, 108, and 120

Every study visit:  CSF sample collection for storage for biomarkers

Anti-rhHNS antibody testing (serum and CSF) and CSF biomarker testing at Weeks 0, 4, 8, 
12, 24, 36, 48, 60, 72, 84, 96, 108, and 120


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
Serum pharmacokinetics sampling at Weeks 0, 48, and 96 (see Appendix 6 for the 
pharmacokinetics collection schedule)

CSF pharmacokinetics sampling at Weeks 0 and 48 (see Appendix 6 for the 
pharmacokinetics collection schedule)
8.4.1.2
Post-treatment Assessments

ECG at Weeks 0, 4, 8, 12, 16, 20, 24, 48, 96, and 120

Serum pharmacokinetics sampling at Weeks 0, 48, and 96 (see Appendix 6 for the 
pharmacokinetics collection schedule)

CSF pharmacokinetics sampling at Weeks 0 and 48 (see Appendix 6 for the 
pharmacokinetics collection schedule)

Concomitant medications, therapies, and procedures

AE monitoring

Removal of IDDD if patient not continuing treatment
8.4.2
Safety Follow-up Visit:  Week 124 (±7 days) 
All patients will have a safety follow-up at Week 24 or 30 (±7) days after their last dose of 
HGT-1410. 

Symptom-directed PE

Vital signs

Clinical laboratory tests

Concomitant medications, therapies, and procedures

AE monitoring
8.5
Group 3B (Initiating HGT-1410 Q4W Dosing)
8.5.1
Treatment Period (Weeks 0 through 120)
The pre-treatment assessments may be performed on the same day as the administration of study 
drug if it is feasible for the patient to arrive at the study site early in the day, and if it is deemed 
clinically appropriate by the Investigator. Patients may be discharged from the clinical site 
4 hours after dosing, if deemed stable by the Investigator.
Patients in Group 3B will receive 45 mg HGT-1410 IT Q4W (ie, every 28±7 days). 
Administration of HGT-1410 can only occur following the completion of all pre-treatment 
assessments and procedures. 
For patients in Group 3B, HGT-1410 will be administered Q4W from Week 0 through Week 
120.
8.5.1.1
Pre-treatment Assessments

Full PE, including height and weight at Weeks 24, 48, 72, 96, and 120; symptom-directed PE
at all other visits


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
Every visit:  vital signs, concomitant medications, therapies, and procedures, and AE 
monitoring 

Cognitive/behavioral assessments:  BSID-III/KABS-II and VABS-II:  Weeks 24, 48, 72, 96, 
and 120

QoL questionnaire:  ITQoL for patients ≤5 years of age:  Weeks 24, 48, 72, 96, and 120

Health economics questionnaire: HCUQ:  Weeks 24, 48, 72, 96, and 120

MRIs of head, liver, and spleen: Weeks 24, 48, and 96

Clinical laboratory tests:  hematology, serum chemistry, urinalysis: Weeks 0, 4, 8, 12, 16, 20, 
24, 36, 48, 60, 72, 84, 96, 108, and 120

Every study visit before dosing:  standard CSF safety laboratory assessments

CSF and urine sample collection for GAG at Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 
48, 60, 72, 84, 96, 108, and 120

Every study visit:  CSF sample collection for storage for biomarkers

Anti-rhHNS antibody testing (serum and CSF) and CSF biomarker testing at Weeks 0, 4, 8, 
12, 24, 36, 48, 60, 72, 84, 96, 108, and 120

Serum pharmacokinetics sampling at Weeks 0, 48, and 96 (see Appendix 6 for the 
pharmacokinetics collection schedule)

CSF pharmacokinetics sampling at Weeks 0 and 48 (see Appendix 6 for the 
pharmacokinetics collection schedule)
8.5.1.2
Post-treatment Assessments

ECG at Weeks 0, 4, 8, 12, 16, 20, 24, 48, 96, and 120

Serum pharmacokinetics sampling at Weeks 0, 48, and 96 (see Appendix 6 for the 
pharmacokinetics collection schedule)

CSF pharmacokinetics sampling at Weeks 0 and 48 (see Appendix 6 for the 
pharmacokinetics collection schedule)

Concomitant medications, therapies, and procedures

AE monitoring

Removal of IDDD if patient not continuing treatment
8.5.2
Safety Follow-up Visit:  Week 124 (±7 days) 
All patients will have a safety follow-up at Week 24 or 30 (±7) days after their last dose of 
HGT-1410.

Symptom-directed PE

Vital signs

Clinical laboratory tests

Concomitant medications, therapies, and procedures

AE monitoring


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9
QUALITY CONTROL AND ASSURANCE
Training will occur at an Investigator meeting or at the site initiation visit or both, and instruction 
manuals will be provided to aid consistency in data collection and reporting across sites. The 
training will be documented.
Clinical sites will be monitored by the Sponsor or its designee to ensure the accuracy of data 
against source documents. The required data will be captured in a validated clinical data 
management system that is compliant with the Food and Drug Administration (FDA) 21 CFR 
Part 11 Guidance. The clinical trial database will include an audit trail to document any evidence 
of data processing or activity on each data field by each user. Users will be trained and given 
restricted access, based on their role(s) in the study, through a password-protected environment.
Data entered in the system will be reviewed manually for validity and completeness against the 
source documents by a clinical monitor from the Sponsor or its designee. If necessary, the study 
site will be contacted for corrections or clarifications; all missing data will be accounted for.
Serious adverse event information captured in the clinical trial database will be reconciled with 
the information captured in the Pharmacovigilance and Risk Management database.


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10
STATISTICAL ANALYSES
10.1
General Methodology
Statistical analysis will generally be performed by the Biometrics Department of Shire using 
SAS statistical software (SAS Institute, Cary, NC, USA). Analysis of any PK and health 
economics and outcomes data will be performed by the Shire Clinical Pharmacology and 
Pharmacokinetics group and the Health Economics and Outcomes Research groups, respectively. 
The analysis methods for all other study data (demographic and baseline characteristics, efficacy 
variables, and safety variables) will be detailed in the statistical analysis plan (SAP). The 
statistical methodology supporting the trial will focus on descriptive rather than inferential 
approaches, given the design and objectives of this trial.
Any hypothesis tests will be 2-sided and will be viewed as exploratory. It is planned that the data 
from all centers that participate in this protocol will be combined so that an adequate number of 
patients will be available for analysis. Summary statistics for continuous variables will include 
the n, mean, standard deviation, median, minimum, and maximum. Categorical variables will be 
summarized in a contingency table by the frequency and percentage of patients in each category. 
Data will be plotted to assess trends across time as appropriate.
Unless otherwise indicated, all summary statistics will be presented by treatment group (either 
Q2W or Q4W) to which the patients were randomly assigned (for patients who were initially 
assigned to Q2W or Q4W group in Study HGT-SAN-093 or patients who were assigned to 
no-treatment in HGT-SAN-093 and were randomly assigned to Q2W or Q4W in Study 
SHP-601-201).
All safety data will be summarized descriptively. The change from baseline at each time point 
for efficacy outcomes will be summarized. Generally, the mean difference in the change at each 
time point between the 2 treatment groups and the corresponding 95% confidence interval of the 
mean difference will be presented. If the parametric assumption for the distribution cannot be 
justified, a non-parametric approach will be utilized to estimate the treatment difference and the 
corresponding 95% confidence interval (ie, median difference or Hodges–Lehmann estimator 
and the corresponding confidence intervals). Developmental quotients will be computed as a 
ratio, expressed as a percentage using the age-equivalent score divided by the age at testing (ie, 
[age-equivalent score/chronological age] x 100). Developmental delay scores will be calculated 
as the age-equivalent score minus the chronological age. Additional efficacy analyses in the 
subgroups of patients who received treatment or no treatment in Study HGT-SAN-093 will be 
performed.
Data from Study HGT-SAN-093 will be combined with that of Study SHP-610-201 for analysis. 
The data included for treated patients in HGT-SAN-093 starts from the baseline of Study 
HGT-SAN-093 and for patients who received no treatment in HGT-SAN-093 from the baseline 
of Study SHP-610-201. Baseline is the assessment obtained prior to the first dose of HGT-1410. 
10.2
Determination of Sample Size
As this is an extension study of Study HGT-SAN-093, any patients who enrolled and completed 
that study are eligible to enroll in Study SHP-601-201, and no statistical estimation for sample 


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size calculation was performed. A maximum sample size of 21 patients in this study is expected 
based on the sample size in Study HGT-SAN-093.
10.3
Method of Assigning Study Subjects to Treatment Groups
Patients who were randomized to receive Q2W or Q4W dosing in Study HGT-SAN-093 (Groups 
1 and 2, respectively) will maintain their assigned dosing regimen in Study SHP-610-201.
Patients who were randomized to receive no-treatment in Study HGT-SAN-093 (Group 3) will 
be re-randomized in a 1:1 allocation ratio via a computer-generated randomization schedule to 
receive Q2W or Q4W dosing regimen (Groups 3A or 3B, respectively) in Study SHP-610-201. 
To help ensure balance between the dose groups with respect to age at Baseline, the 
randomization will be stratified by age group (≤30 months and >30 months).
10.4
Population Description and Exposure
10.4.1
Analysis Populations
The population for all safety analyses will be the safety population, defined as all patients who 
had the IDDD implant or received at least one dose of study drug in the extension study. Safety 
analyses will be conducted according to the treatment received. Device related analyses will be 
conducted in the subset of patients in the safety population who had the device implanted.
The population for all efficacy analyses will be the intent-to-treat (ITT) population, defined as all 
randomized patient according to the treatment assigned.
All pharmacokinetic data analyses will be performed using the pharmacokinetics population, 
defined as all patients who received study drug and had sufficient serum samples collected to 
derive pharmacokinetic parameters.
10.4.2
Subject Disposition
The number of patients screened; the number and proportion of patients randomized, included in 
the safety population, completed the study, and discontinued prematurely will be presented in a 
summary table by treatment group; reasons for discontinuation/withdrawal will also be 
summarized.
10.4.3
Protocol Deviations
Reported protocol deviations and patient data will be examined prior to database lock to 
determine if conditions set forth in the study protocol have been violated. The complete list of 
protocol deviations will not be summarized; however, if applicable, protocol violations identified 
will be listed for the safety population.
10.4.4
Demographics and Baseline Characteristics
Demographic data and baseline characteristics will be summarized by the individual treatment 
group and the overall HGT-1410 treatment group for the safety population. 


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10.4.5
Treatment Compliance and Extent of Exposure
The total number of doses of study drug, the number of doses received via IDDD, the number of 
doses received via LP, the average duration of IT administration and treatment compliance will 
be summarized by treatment group for the safety population. 
The duration of IT administration is calculated by subtracting the IT administration start time 
from the IT administration end time.
Treatment compliance is defined as:  [(Number of Complete IT administrations) ÷ (Expected 
Number of IT administrations)] * 100.
10.5
Analysis of Efficacy
The analysis of efficacy data will be based on the ITT population.
10.5.1
Primary Analysis
The primary objective of this study is to evaluate long-term safety of HGT-1410 in patients with 
MPS-III. Therefore the primary analysis will be discussed in the safety analysis section, 
Section 10.7.
10.5.2
Secondary Efficacy Analysis
10.5.2.1
Bayley Scales of Infant Development, Third Edition/Kaufman Assessment 
Battery for Children, Second Edition
The observed values and changes from baseline in DQ, age equivalent, and developmental delay 
scores for each subtest (Cognitive, Receptive Communication, Expressive Communication, Fine 
Motor, and Gross Motor) will be summarized descriptively for each assessment time point by 
treatment group (Q2W and Q4W group). The mean difference in the change at each time point 
between the 2 treatment groups and the corresponding 95% confidence interval of the mean 
difference will be presented.
Graphical plots of mean age equivalent and DQ scores for the subtests across time will be 
presented. A trellis plot of the age-equivalent and DQ scores within each patient will be 
presented. Furthermore, a spaghetti plot of the cognitive age-equivalent score against 
chronological age will be presented.
The KABC-II is an alternative to BSID-III. The KABC-II cognitive DQ, age-equivalent, and 
developmental delay scores will be combined with the corresponding BSID-III scores and 
summarized at each assessment time point as described above. Most of the patients will have 
either only BSID-III data or KABC-II data. If a patient has data obtained by each of these 
methods, then the method for which data is available at both baseline and post-baseline time 
points will be used when combining the DQ scores and age-equivalent scores.


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10.5.2.2
Vineland Adaptive Behavior Scales, Second Edition
Tabular summaries of the raw scores for each domain, the average domain raw scores, the mean 
age equivalent score and the corresponding overall DQ scores and the corresponding change 
from baseline will be presented for each assessment time point by treatment group (Q2W and 
Q4W group). The mean difference in the change at each time point between the 2 treatment 
groups and the corresponding 95% confidence interval of the mean difference will be presented.
Graphical plots of mean raw scores for the domains across time will be presented. In addition, a 
trellis plot of the raw scores within each patient will be presented. Similar plots will be presented 
for the average domain raw scores, the mean age equivalent score and the overall DQ score. A 
spaghetti plot of mean age equivalent score against chronological age will also be presented.
10.5.2.3
Brain MRI
Although several MRI parameters will be captured, the analysis will focus primarily on the grey
matter volume, the white matter volume and the intracranial CSF volume (ventricles plus 
additional CSF space). The observed values and changes from baseline will be summarized for 
each assessment time by treatment group (Q2W and Q4W group). The mean difference in the 
change at each time point between the 2 treatment groups and the corresponding 95% confidence 
interval of the mean difference will be presented.
Graphical plots of mean MRI parameter levels across time will be presented. In addition, Trellis 
plots of MRI parameters across time for each patient will be presented. A spaghetti plot of grey 
matter volume against chronological age will also be presented. 
10.5.3
Subset Analyses 
Exploratory tabular and graphical analyses as described above for efficacy endpoints will be 
performed both by treatment group and whether or not the patient received treatment or no
treatment in Study HGT-SAN-093 (4 groups).
10.5.4
Exploratory Analyses
10.5.5
Analysis of Health Status
Health status will be assessed by the ITQoL. The observed value and change from baseline in 
ITQOL scale scores will be summarized descriptively for each assessment time by treatment 
group (Q2W and Q4W groups). Graphical plots of mean scores across time will be presented.
10.5.6
Analysis Health Economics and Outcomes Research
Descriptive statistics, including N, mean, median, and range (for continuous variables), and N 
and proportions (for categorical variables), for key HCUQ variables, including the number of 


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emergency room visits, caregiver employment status (FT, PT, and NW), and the number of hours 
of additional paid help needed by caregivers, over the course of the study. A detailed description 
of analyses may be provided in a separate pharmacoeconomic analysis plan.
10.6
Analysis of Pharmacokinetic and Pharmacodynamic Data
10.6.1
Pharmacokinetic Measurement and Parameters
The pharmacokinetic population will be used to perform the analysis of the pharmacokinetic 
data. HGT-1410 concentrations in all collected serum samples will be measured and reported. 
Individual patient HGT-1410 serum concentration-time profiles will be presented. Individual 
pharmacokinetic parameters will be derived by a noncompartmental analysis and reported. The 
actual pharmacokinetic blood sample collection times will be used to determine the individual 
patient HGT-1410 serum concentration-time profiles. Pharmacokinetic parameters will be 
calculated if sufficient HGT-1410 concentration-time points exist to derive values. Individual 
patient CSF HGT-1410 concentrations at each collection time point will be reported.
Pharmacokinetic parameters calculated will include:

Cmax

tmax

AUC0-last

AUC0-∞

λZ

t1/2 calculated as 0.693/λZ

CL/F

Vz/F  
10.6.2
Pharmacodynamic Analyses 
The levels of GAG in CSF and urine are pharmacodynamic endpoints. Analyses of 
pharmacodynamic endpoints will be performed in the safety population.
The observed values and changes from baseline in CSF GAG levels will be summarized for each 
assessment time by treatment group (Q2W and Q4W group). Graphical plot(s) of mean CSF 
GAG levels across time will be presented. Additionally, Trellis plots of CSF GAG levels across 
time for each patient will be presented. Furthermore, CSF parameters will be plotted across time 
for each patient such that the values before and after the first instance of antibody positive status 
will be indicated using different colors.
The urine GAG levels will be analyzed in a manner similar to that described for CSF data.
10.7
Analysis of Safety
All analyses of safety data will be descriptive and based on the Safety population. 


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10.7.1
Adverse Events 
Once the patient has signed the informed consent form, AEs will be recorded throughout the 
study and at early termination. AEs will be coded using Medical Dictionary for Regulatory 
Affairs (MedDRA).
Treatment-emergent AEs, defined as all AEs from the time of initial IDDD implantation (or first 
dose if no IDDD implant), to the safety follow-up visit, defined as the last patient visit in the 
study, will be summarized. For each treatment group, the number and percentage of patients 
having an AE and the number of events, by system organ class (SOC) and preferred term will be 
presented. Treatment-emergent AEs will also be summarized by severity and degree of 
relationship to study drug. In the case of multiple occurrences of the same AE (at the preferred 
term level) in an individual patient, the AE that is classified as the most severe (ie, maximum 
severity) will be identified for the analysis by severity and the AE that has the closest 
relationship to study drug/procedure will be identified for the analysis by relationship. In general, 
an AE will be considered a treatment-emergent AE if it cannot be definitively categorized 
otherwise by documentation that its onset preceded either IDDD surgery or first dose.
Serious adverse events will be similarly tabulated according to SOC and preferred term and 
presented in a separate listing.
10.7.1.1
Investigational Product
Treatment-emergent AEs deemed by the investigator to be related to HGT-1410 will be 
summarized by presenting the number and percentage of patients having an AE and the number 
of events, by SOC and preferred term. 
10.7.1.2
IDDD and Surgical Procedure–related AEs 
Intrathecal drug delivery devices and procedure-related AEs will be summarized within 
MedDRA SOC by preferred term. Separate tabulations will be provided for AEs related to the 
IDDD, device surgical procedure, and IT administration process.
Intrathecal drug delivery device and procedure related events will be analyzed in the subset of 
patients in the safety population who underwent surgery for IDDD implantation.
10.7.2
Clinical Laboratory Evaluation 
The measurements of each laboratory parameter (serum chemistry, hematology, urinalysis and 
CSF) and the corresponding normal ranges will be converted to Standard International (SI) units, 
if needed. 
Observed values and changes from baseline for continuous laboratory test results will be 
summarized for each assessment time from baseline. Each laboratory result will be categorized 
as a patient having had (1) an abnormal and clinically significant (CS) value at any time post-
baseline, (2) no CS values at any time post-baseline, but had at least 1 abnormal and not CS 
(NCS) value, and (3) no CS or NCS values at any time post-baseline; the number and percentage 
in each category will be presented. For any patient who experiences a CS laboratory result at any 


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time post-baseline that was not CS at baseline (or the most recent non-missing value prior to the 
start of the treatment), their entire profile for that particular laboratory parameter will be 
presented as a listing.
If more than one laboratory result is reported per assessment time per parameter, the last non-
missing result will be selected for analysis. 
10.7.3
ECG Evaluations 
The observed values and changes from baseline for continuous variables will be summarized for 
each assessment time by treatment group. Categorical variables, ie, sinus rhythm and 
atrial/ventricular hypertrophy, will be summarized in terms of number and percentage of patients 
in each response category for each assessment time from baseline.
10.7.4
Vital Signs 
The observed values and changes from baseline for IT-administration vital signs parameters will 
be summarized by treatment group. The IT-administration vital signs will also be presented in a 
trellis plot so that the vital signs data for each IT-administration within a patient will be 
presented on a single page.
10.7.5
Anti-rhHNS Antibody in Serum and CSF
Serum and CSF anti-rhHNS antibody status (ie, positive or negative) at each assessment time 
from baseline will be summarized in terms of counts and proportion for the treatment groups. 
Additionally, semi-logarithmic plot of serum and CSF anti-rhHNS antibody titers across the 
study visits in the patients exhibiting seropositivity will also be presented. 
10.7.6
Concomitant Medications 
Concomitant medications will be coded using the WHO-DD. The concomitant medications that 
occur from the time of the surgery for IDDD implantation to the safety follow-up visit, defined 
as the last patient visit in the study, will be summarized by therapeutic class and preferred term. 
10.7.7
Other Observations Related to Safety
10.7.7.1
IDDD Performance
Safety and performance data for the SOPH-A-PORT Mini S IDDD will be analyzed and 
summaries will be provided for implanted patients. Difficulties associated with the implant 
procedure (eg, excessive bleeding, CSF leakage, etc.) will be summarized. A summary of 
abnormal findings from the device radiological assessments will also be presented. 
The proportion of patients with at least 1 device failure and/or malfunction, as well as the 
number of and reasons for device failures/malfunctions will be summarized. The rate of device 
failures/malfunctions and 95% confidence interval will also be estimated. The time from initial 
implant surgery to first device failure and/or malfunction will be summarized. Patients without a
device failure/malfunction will be censored at their last study drug injection date. A by-patient 
listing of the device failure/malfunction data will be displayed.


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The rate of successful IDDD injections will be calculated for each patient and summarized 
descriptively. The success rate will be calculated as the number of IDDD injections given as a 
percentage of IDDD injections given plus any malfunctions reported for inability to dose. The 
corresponding 95% confidence interval for the mean rate will be estimated, where appropriate. 
Injections that are not administered for patient-related reasons (eg, patient uncooperative, 
competing medical issue, etc.) will not be included in the determination of the injection success 
rate.
10.8
Statistical/Analytical Issues
10.8.1
Adjustment for Covariates
No statistical modeling or covariate adjustment is planned due to the small sample size.
10.8.2
Handling of Dropouts or Missing Data
In general, no imputation will be performed and analyses will be based on available data. If data 
at the baseline visit are not available, then the most recent available pre-treatment assessment
will be considered as baseline. Missing or partial AE dates will not be imputed. However, a 
conservative approach will be adopted in such cases so that the AE will be deemed to be 
treatment-emergent if it cannot be definitively categorized to have occurred prior to surgery for 
IDDD implantation. Similar logic will be applied to deal with missing and partial date for 
concomitant medications.
10.8.3
Interim Analyses and Data Monitoring
No formal interim analysis or interim statistical testing for early stopping of the trial is planned. 
Descriptive analyses of the data before trial completion may be performed for safety monitoring, 
regulatory reporting or general study planning purposes. An independent DMC will be 
established to provide an ongoing, independent review and assessment of patient data, and to 
safeguard the interests and safety of the participating patients in the study (see Section 11.8). An 
analysis of the data for DMC review will occur at specific times during the study as specified in 
the DMC charter. Because no formal hypothesis testing is planned, multiplicity concerns 
regarding repeated analyses are not an issue.
10.8.4
Multicenter Studies
Data from all centers that participate in this protocol will be combined so that an adequate 
number of patients will be available for analysis. In order to maintain desirable level of 
inter-rater reliability for BSID-III/KABS-II and VABS-II assessments/interviews, standardized 
training of the raters and parents will be conducted. Furthermore, a central reader will evaluate 
all MRI data.
10.8.5
Multiple Comparisons/Multiplicity
No adjustment for multiplicity will be performed. 


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10.8.6
Sensitivity Analyses
Given the design and objectives of the study, no sensitivity analyses are planned.


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11
ADMINISTRATIVE CONSIDERATIONS
11.1
Investigators and Study Administrative Structure
Before initiation of the study, the Investigators must provide the Sponsor with a completed Form 
FDA 1572 or Investigator Agreement. Investigational product may be administered only under 
the supervision of the Investigators listed on these forms. Curriculum vitae must be provided for 
the Investigators and sub-investigators listed on Form FDA 1572 or Investigator Agreement.
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, any amendments to the protocol, the study treatments, and their study related 
duties and functions. The Investigator must maintain a list of sub-investigators and other 
appropriately qualified persons to whom he or she has delegated significant study related duties.
11.2
Institutional Review Board or Ethics Committee Approval
Before initiation of the study, the Investigator must provide the Sponsor with a copy of the 
written IRB/EC approval of the protocol and the informed consent form. This approval must 
refer to the informed consent form and to the study title, study number, and version and date of 
issue of the study protocol, as given by the Sponsor on the cover page of the protocol.
The protocol and any applicable documentation will be submitted or notified to the relevant 
Regulatory Authorities in accordance with the regulations of the countries involved in the trial.
Status reports must be submitted to the IRB/EC at least once per year. The IRB/EC must be 
notified of completion of the study. Within 3 months of study completion or termination, a final 
report must be provided to the IRB/EC. A copy of these reports will be sent to the study clinical 
monitor. The Investigators must maintain an accurate and complete record of all submissions 
made to the IRB/EC, including a list of all reports and documents submitted. Adverse events that 
are reported to the US FDA (Investigational New Drug/UADE Safety Reports) or other 
regulatory agencies must be submitted promptly to the IRB/EC.
11.3
Ethical Conduct of the Study
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor and Investigators abide by 
good clinical practice (GCP) as described in the 21 CFR Parts 50, 56, and 312 and the 
International Conference on Harmonisation (ICH) GCP Guidelines Compliance with these 
regulations and guidelines also constitutes compliance with the ethical principles described in the 
Declaration of Helsinki.
11.4
Patient Information and Consent
Before enrolling in the clinical study, the patient or the patient’s parent(s) or legally authorized 
representative(s) must consent to participate after the nature, scope, and possible consequences 
of the clinical study have been explained in a form understandable to him or her.
An informed consent form (assent form if applicable) that includes information about the study 
will be prepared and given to the patient or the patient’s parent(s) or legally authorized 


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representative(s). This document will contain all FDA- and ICH-required elements. The 
informed consent (or assent) form must be in a language understandable to the patient or the 
patient’s parent(s) or legally authorized representative(s) and must specify who informed the 
patient, the patient’s parent(s), or the patient’s legally authorized representative(s).
After reading the informed consent document, the patient or the patient’s parent(s) or legally 
authorized representative(s) must give consent in writing. Consent must be confirmed at the time 
of consent by the personally dated signature of the patient, the patient’s parent(s) or the patient’s 
legally authorized representative(s) and by the personally dated signature of the person 
conducting the informed consent discussions.
If the patient or the patient’s parent(s) or legally authorized representative(s) is unable to read, 
oral presentation and explanation of the written informed consent form and information to be 
supplied must take place in the presence of an impartial witness. Consent must be confirmed at 
the time of consent orally and by the personally dated signature of the patient or by a local 
legally recognized alternative (eg, the patient’s thumbprint or mark) or by the personally dated 
signature of the patient’s parent(s) or the patient’s legally authorized representative. The witness 
and the person conducting the informed consent discussions must also sign and personally date 
the informed consent document. It should also be recorded and dated in the source document that 
consent was given.
A copy of the signed and dated consent document(s) must be given to the patient or the patient’s 
parent(s) or legal representative(s). The original signed and dated consent document will be 
retained by the Investigator.
The Investigator will not undertake any measures specifically required solely for the clinical 
study until valid consent has been obtained.
A model of the informed consent form to be used in this study will be provided to the sites 
separately from this protocol.
11.5
Patient Confidentiality
Patient names will not be supplied to the Sponsor. Only the patient number and patient initials 
will be recorded in the eCRF, and if the patient name appears on any other document, it must be 
obliterated before a copy of the document is supplied to the Sponsor. Study findings stored on a 
computer will be stored in accordance with local data protection laws. The patients will be told 
that representatives of the Sponsor, a designated CRO, the IRB/EC, or regulatory authorities may 
inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. The Investigator will maintain a personal patient 
identification list (patient numbers with the corresponding patient names) to enable records to be 
identified.


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11.6
Study Monitoring
Monitoring procedures that comply with current GCP guidelines will be followed. Review of the 
eCRFs for completeness and clarity, cross-checking with source documents, and clarification of 
administrative matters will be performed.
The study will be monitored by the Sponsor or its designee. Monitoring will be performed by a 
representative of the Sponsor (Clinical Study Monitor) who will review the eCRFs and source 
documents. The site monitor will ensure that the investigation is conducted according to protocol 
design and regulatory requirements by frequent site visits and communications (letter, telephone, 
and facsimile).
11.7
Case Report Forms and Study Records
11.7.1
Case Report Forms
Case report forms (paper or electronic) are provided for each patient. All forms must be filled out 
by authorized study personnel. All corrections to the original eCRF entry must indicate the 
reason for change. The Investigator is required to sign the eCRF after all data have been captured 
for each patient. If corrections are made after review and signature by the Investigator, he or she 
must be made aware of the changes, and his or her awareness documented by resigning the 
eCRF.
11.7.2
Critical Documents
Before Shire initiates the trial (ie, obtains informed consent from the first patient), it is the 
responsibility of the Investigator to ensure that the following documents are available to Shire or 
their designee:

Completed FDA Form 1572 (Statement of Investigator), signed, dated, and accurate

Curricula vitae of Investigator and sub-Investigator(s) (current, dated and signed within 
12 months of study initiation)

Copy of Investigator and sub-Investigator(s) current medical license (indicating license 
number and expiration date)

Signed and dated agreement of the final protocol

Signed and dated agreement of any amendment(s), if applicable

Approval/favorable opinion from the IRB/EC clearly identifying the documents reviewed by 
name, number and date of approval or regarding approval:  protocol, any amendments, 
Patient Information/Informed Consent Form, and any other written information to be 
provided regarding patient recruitment procedures

Copy of IRB-/EC-approved Patient Information/Informed Consent Form/any other written 
information/advertisement (with IRB approval stamp and date of approval)

Current list of IRB/EC Committee members/constitution (dated within 12 months prior to 
study initiation)

Financial Disclosure Form signed by Investigator and sub-Investigator(s)

Current laboratory reference ranges (if applicable)

Certification/QA scheme/other documentation (if applicable)


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Regulatory approval and notification as required must also be available; these are the 
responsibility of Shire.
11.8
Data Monitoring Committee
An independent DMC will be established to provide an ongoing, independent review and 
assessment of the safety data, and to safeguard the interests and safety of the participating 
patients in the study. The DMC will consist of a biostatistician and 2 clinical experts.
It is anticipated that there will be scheduled meetings annually during the conduct of the study. 
The first meeting will be an orientation meeting and will take place prior to the start of the study. 
Subsequent meetings will occur at specific times during the study as specified in the DMC 
charter. The final meeting will be conducted when all patients have completed the study for a 
comprehensive safety overview of the study. A special DMC meeting will be convened if the 
safety-related study stopping rules are met (see Section 7.16).
The DMC will adhere to a prospectively determined charter, which will be written by Shire and 
approved by the DMC. The charter will define the responsibilities of the DMC and Shire, 
describe the conduct of the meetings and define the data sets to be reviewed. The DMC will also 
be notified of all IDDD failures and IDDD-related complications at times defined in the DMC 
charter.
The DMC will be notified of all IDDD failures and IDDD-related complications at times defined 
in the DMC charter.
11.9
Device Failure Review Process
The final cause for SOPH-A-PORT Mini S device failures will be reviewed by Shire by 
examining the device failure information in the clinical database, safety database, and 
manufacturer investigation of returned SOPH-A-PORT Mini S devices.
11.10 Protocol Violations/Deviations
The Investigator will conduct the study in compliance with the protocol. The protocol will not be 
initiated until the IRB/EC and the appropriate regulatory authorities have given 
approval/favorable opinion. Modifications to the protocol will not be made without agreement of 
the Sponsor. Changes to the protocol will require written IRB/EC approval/favorable opinion 
prior to implementation, except when the modification is needed to eliminate an immediate 
hazard(s) to patients. The IRB/EC may provide, if applicable regulatory authorities permit, 
expedited review and approval/favorable opinion for minor change(s) in ongoing studies that 
have the approval/favorable opinion of the IRB/EC. The Sponsor will submit all protocol 
modifications to the regulatory authorities in accordance with the governing regulations.
A record of patients screened, but not entered into the study, is also to be maintained. No 
protocol exemptions will be granted for this study.
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
patients, the Investigator will contact the Sponsor or its designee, if circumstances permit, to 


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discuss the planned course of action. Any departures from the protocol must be fully documented 
as a protocol deviation. Protocol deviations will need to be reviewed by the medical monitor and 
may also be required to be submitted to the IRB/EC.
Protocol modifications will only be initiated by the Sponsor and must be approved by the 
IRB/EC and submitted to the FDA or other applicable international regulatory authority before 
initiation.
11.11 Premature Closure of the Study
If the Sponsor, Investigator, or regulatory authorities discover conditions arising during the study 
which indicate that the clinical investigation should be halted due to an unacceptable patient risk, 
the study may be terminated after appropriate consultation between the Sponsor and the 
Investigator(s). In addition, a decision on the part of the Sponsor to suspend or discontinue 
development of the investigational product may be made at any time. Conditions that may 
warrant termination of the study or site include but are not limited to:

The discovery of an unexpected, significant, or unacceptable risk to the patients enrolled in 
the study

Failure of the Investigator to comply with pertinent global regulations

Submission of knowingly false information from the study site to the Sponsor or other 
pertinent regulatory authorities

Insufficient adherence by the Investigator to protocol requirements
11.12 Access to Source Documentation
Regulatory authorities, the IRB/EC, or the Sponsor (or its designee) may request access to all 
source documents, eCRFs, and other study documentation for onsite audit or inspection. Direct 
access to these documents must be guaranteed by the Investigator, who must provide support at 
all times for these activities. Monitoring and auditing procedures that comply with current GCP 
guidelines will be followed. On-site review of the eCRFs for completeness and clarity, 
crosschecking with source documents, and clarification of administrative matters may be 
performed.
11.13 Data Generation and Analysis
The clinical database will be developed and maintained by a contract research organization or an 
electronic data capture technology provider as designated by Shire. Shire or its designee will be 
responsible for performing study data management activities. 
Adverse events and medical history events will be coded using MedDRA. Concomitant 
medication will be coded using WHO-DD. Centralized laboratories will be employed as 
described in the study manual to aid in consistent measurement of efficacy and safety 
parameters. 


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11.14 Retention of Data
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application and until there are no pending or contemplated marketing applications or 
at least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product. The Sponsor will notify the Investigator if these documents must be 
retained for a longer period of time. It is the responsibility of the Sponsor to inform the 
Investigator or institution as to when these documents no longer need to be retained.
11.15 Financial Disclosure
The Investigator should disclose any financial interests in the Sponsor as described in 21 CFR 
Part 54 prior to beginning this study. The appropriate form will be provided to the Investigator 
by the Sponsor, which will be signed and dated by the Investigator, prior to the start of the study. 
11.16 Publication and Disclosure Policy
All information concerning the study material, such as patent applications, manufacturing 
processes, basic scientific data, and formulation information supplied by the Sponsor and not 
previously published are considered confidential and will remain the sole property of the 
Sponsor. The Investigator agrees to use this information only in accomplishing this study and 
will not use it for other purposes.
It is understood by the Investigator that the information developed in the clinical study may be 
disclosed as required to the authorized regulatory authorities and governmental agencies. In 
order to allow for the use of the information derived from the clinical studies, it is understood 
that there is an obligation to provide the Sponsor with complete test results and all data 
developed in the study in a timely manner.
The Investigator and any other clinical personnel associated with this study will not publish the 
results of the study, in whole or in part, at any time, unless they have consulted with Shire, 
provided Shire a copy of the draft document intended for publication, and obtained Shire’s 
written consent for such publication. All information obtained during the conduct of this study 
will be regarded as confidential. 
Shire may perform analyses of interim or final locked study data for purposes of publication.


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12
LIST OF REFERENCES
1. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. 
JAMA 1999;281:249-54.
2. Baehner F, Schmiedeskamp C, Krummenauer F, et al. Cumulative incidence rates of the 
mucopolysaccharidoses in Germany. J Inherited Metab Dis 2005;28:1011-7.
3. Poorthuis BJ, Wevers RA, Kleijer WJ, et al. The frequency of lysosomal storage diseases in 
The Netherlands. Hum Genet 1999;105:151-6.
4. Valstar MJ, Neijs S, Bruggenwirth HT, et al. Mucopolysaccharidosis type IIIA:  clinical 
spectrum and genotype-phenotype correlations. Ann Neurol 2010;68:876-87.
5. Meyer A, Kossow K, Gal A, et al. Scoring evaluation of the natural course of 
mucopolysaccharidosis type IIIA (Sanfilippo syndrome type A). Pediatr 2007;120:e1255-61.
6. Cleary MA, Wraith JE. Management of mucopolysaccharidosis type III. Arch Dis Child 
1993;69:403-6.
7. Fraser J, Wraith JE, Delatycki MB. Sleep disturbance in mucopolysaccharidosis type III 
(Sanfilippo syndrome):  a survey of managing clinicians. Clin Genet 2002;62:418-21.
8. Meyer A, Kossow K, Gal A, et al. The mutation p.Ser298Pro in the sulphamidase gene 
(SGSH) is associated with a slowly progressive clinical phenotype in mucopolysaccharidosis 
type IIIA (Sanfilippo A syndrome). Hum Mutat 2008;29:770.
9. Hemsley K, King B, Hopwood J. Injection of recombinant human sulfamidase into the CSF 
via the cerebellomedullary cistern in MPS IIIA mice. Mol Genet Metab 2007;90:313-28.
10. Hemsley KM, Hopwood JJ. Delivery of recombinant proteins via the cerebrospinal fluid as a 
therapy option for neurodegenerative lysosomal storage diseases. Int J Clin Pharmacol Ther 
2009;47 Suppl 1:S118-23.
11. Martin HR, Poe MD, Reinhartsen D, et al. Methods for Assessing Neurodevelopment in 
Lysosomal Storage Diseases and Related Disorders:  a Multidisciplinary Perspective. Acta 
Paediatr Supp 2008;97:69-75.
12. Bayley N. Bayley Scales of Infant and Toddler Development. 3 ed. San Antonio, TX The 
Psychological Corporation; 2005.
13. Sparrow S, Balla D, Cicchetti D. Vineland Adaptive Behavior Scales (Second Edition). 4201 
Woodland Road Circle Pines, MN 55014-1796:  American Guidance Service, Inc; 2005.






















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Appendix 5
Blood and CSF Volumes
Treatment Period for Patients in Group 1:  Maintaining HGT-1410 Every Other Week Dosing
Follow-up
TOTAL
Weeks
Procedure
50
52, 54, 56, 58
60
62, 64, 66, 68, 70
72
74, 76, 78, 80, 82
84
86, 88, 90, 92, 94
96
98, 100, 102, 104, 106
108
110, 112, 114, 116, 118
120
122, 124, 126, 128, 130
132
134, 136, 138, 140, 142
144
146, 148, 150, 152, 154
156
158, 160, 162, 164, 166
168
172
CSF (mL)
Standard CSF safety labs
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
CSF sample for GAG testing
a
a
a
a
a
a
a
a
a
a
Anti-rhHNS Ab testing (CSF)
b
b
b
b
b
b
b
b
b
b
CSF for storage (for biomarkers 
and Ab testing)
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
Total CSF Volume
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
660
Blood (mL)
Hematology
2
2
2
2
2
2
2
2
2
2
2
Serum chemistry
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
Anti-rhHNS Ab testing (serum)
4
4
4
4
4
4
4
4
4
4
Serum PK sampling
9
Total Blood Volume
8.5
8.5
8.5
17.5
8.5
8.5
8.5
8.5
8.5
8.5
4.5
98.5
Abbreviations:  Ab=antibody; CSF=cerebrospinal fluid; GAG=glycosaminoglycan; PK=pharmacokinetics; rhHNS=recombinant human heparan N sulfatase
a
CSF for GAGs included in CSF storage sample
b
Anti-rhHNS Ab testing in CSF will be performed on stored samples.


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Treatment Period for Patients in Group 2: Maintaining HGT-1410 Dosing Every 4 Weeks
Follow-up
TOTAL
Weeks
Procedure
52
56
60
64, 68
72
76, 80
84
88, 92
96
100, 
104
108
112, 
116
120
124, 
128
132
136, 
140
144
148, 
152
156
160, 
164
168 172
CSF (mL)
Standard CSF safety labs
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
CSF sample for GAG testing
a
a
a
a
a
a
a
a
a
a
Anti-rhHNS Ab testing (CSF)
b
b
b
b
b
b
b
b
b
b
CSF for storage (for 
biomarkers and Ab testing)
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
Total CSF Volume
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
330
Blood (mL)
Hematology
2
2
2
2
2
2
2
2
2
2
2
Serum chemistry
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
Anti-rhHNS Ab testing (serum)
4
4
4
4
4
4
4
4
4
4
Serum PK sampling
9
Total Blood Volume
8.5
8.5
8.5
17.5
8.5
8.5
8.5
8.5
8.5
8.5
4.5
98.5
Abbreviations:  Ab=antibody; CSF=cerebrospinal fluid; GAG=glycosaminoglycan; PK=pharmacokinetics; rhHNS=recombinant human heparan N sulfatase
a
CSF for GAGs included in CSF storage sample
b
Anti-rhHNS Ab testing in CSF will be performed on stored samples.


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IDDD 
Implantation 
Period
Treatment Period for Patients in Group 3A:  Initiating HGT-1410 Every Other Week Dosing
Follow-up
TOTAL
Procedure
Days
Weeks
-21 to -7
Postop check
Day 0, Week 0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
38
40
42
44
46
48
50, 52, 54, 56, 58
60
62, 64, 66, 68, 70
72
74, 76, 78, 80, 82
84
86, 88, 90, 92, 94
96
98, 100, 102, 104, 106
108
110, 112, 114, 116, 118
120
124
CSF (mL)
Standard CSF safety 
labs
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
CSF sample for GAG 
testing
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
Anti-rhHNS Ab 
testing (CSF)
b
b
b
b
b
b
b
b
b
b
b
b
b
CSF PK sampling 
(Appendix 6)
4
4
CSF for storage (for 
biomarkers and Ab 
testing)
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
Total CSF Volume
11
15
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
15
11
11
11
11
11
11
11
11
11
11
11
11
690
Blood (mL)
Hematology
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
Serum chemistry
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
PT and aPTT 
(coagulation)
1.8
Anti-rhHNS Ab 
testing (serum)
4
4
4
4
4
4
4
4
4
4
4
4
4
Serum PK sampling 
(Appendix 6)
9
9
9
Total Blood Volume
6.3
17.5
8.5
8.5
8.5
4.5
4.5
8.5
8.5
17.5
8.5
8.5
8.5
17.5
8.5
8.5
4.5
157.3


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IDDD 
Implantation 
Period
Treatment Period for Patients in Group 3A:  Initiating HGT-1410 Every Other Week Dosing
Follow-up
TOTAL
Procedure
Days
Weeks
-21 to -7
Postop check
Day 0, Week 0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
38
40
42
44
46
48
50, 52, 54, 56, 58
60
62, 64, 66, 68, 70
72
74, 76, 78, 80, 82
84
86, 88, 90, 92, 94
96
98, 100, 102, 104, 106
108
110, 112, 114, 116, 118
120
124
Abbreviations:  Ab=antibody; aPTT=activated partial thromboplastin time; CSF=cerebrospinal fluid; GAG=glycosaminoglycan; IDDD=intrathecal drug delivery device; 
PK=pharmacokinetics; PT=prothrombin time; rhHNS=recombinant human heparan N sulfatase
a
CSF for GAGs included in CSF storage sample
b
Anti-rhHNS Ab testing in CSF will be performed on stored samples.


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IDDD 
Implant-
ation 
Period
Treatment Period for Patients in Group 3B:  Initiating HGT-1410 Dosing Every 4 Weeks
Follow-up
TOTAL
Procedure
Days
-21 to -7
Postop 
check
Day 0,
Week 0
4, 8
12
16, 20
24
28, 32
36
40, 44
48
52, 56
60
64, 68
72
76, 80
84
88, 92
96
100, 104
108
112, 116
120
124
CSF (mL)
Standard CSF 
safety labs
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
CSF sample for 
GAG testing
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
Anti-rhHNS Ab 
testing (CSF)
b
b
b
b
b
b
b
b
b
b
b
b
CSF PK 
sampling 
(Appendix 6)
4
4
CSF for storage 
(for biomarkers 
and Ab testing)
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
Total CSF 
Volume
11
15
11
11
11
11
11
11
11
15
11
11
1
1
11
11
11
11
11
11
11
11
11
360
Blood (mL)
Hematology
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
Serum 
chemistry
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
PT and aPTT 
(coagulation)
1.8
Anti-rhHNS Ab 
testing (serum)
4
4
4
4
4
4
4
4
4
4
4
4
Serum PK 
sampling 
(Appendix 5)
9
9
9
Total Blood 
Volume
6.3
17.5
8.5
8.5
4.5
8.5
8.5
17.5
8.5
8.5
8.5
17.5
8.5
8.5
4.5
157.3
Abbreviations:  Ab=antibody; aPTT=activated partial thromboplastin time; CSF=cerebrospinal fluid; GAG=glycosaminoglycan; IDDD=intrathecal drug delivery device; 
PK=pharmacokinetics; PT=prothrombin time; rhHNS=recombinant human heparan N sulfatase
a
CSF for GAGs included in CSF storage sample
b
Anti-rhHNS Ab testing in CSF will be performed on stored samples.


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Appendix 6
Pharmacokinetic and Pharmacodynamic Sample Schedule
Drug 
Administration
PK/PD Sampling Times
Blood Sampling
HGT-1410 IT 
injection
Serum PK samples will be obtained at Weeks 0, 48, and 96 for Groups 3a and 3b.
Serum PK samples will be obtained at Week 96 for Groups 1 and 2.
Immediately prior to IT injection (baseline), then at 0.5, 1, 2, 4, 8, 12, 24, and 48 (Day 
2) hours following completion of IT injection. Patients may be discharged from the 
hospital after the 24-hour blood draw. Patients will either stay locally in a hotel or 
return home (if they live in close proximity to the hospital); in consultation with the 
Investigator. Patients will return to the hospital for PK blood sampling at the 48-hour 
PK time point. Patients will be discharged for home following the last (48-hour) PK 
time point and following the completion of their final physical examination.
CSF Sampling
CSF PK and PK/PD samples will be obtained at Weeks 0 and 48 for Groups 3A and 3B 
only.
Immediately prior to IT injection (baseline), then at 4 hours and 48 hours after the 
completion of the IT injection. The 4-hour and 48-hour post-dose CSF samples will 
only be obtained if a functioning IDDD is in place. Patients will either stay locally in a 
hotel or return home (if they live in close proximity to the hospital); in consultation 
with the Investigator. Patients will return to the hospital for CSF sampling at the 
48 hour time points. 
Abbreviations:  CSF=cerebrospinal fluid; IDDD=intrathecal drug delivery device; IT=intrathecal; 
PD=pharmacodynamics; PK=pharmacokinetics


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Appendix 7
Expected SOPH-A-PORT Mini S Adverse Device Effects
Procedure-related Complications

Components handled improperly before, during, or after implantation 

Access port implanted incorrectly

Catheter positioned improperly

Injection through septum performed incorrectly

Injection of incorrect medication through access port

Injection outside the access port into pocket or subcutaneous tissue or extravasation

Pocket seroma, hematoma, erosion, or infection

Intrathecal access complications

Surgical complications such as hemorrhage or hematoma

Infection of the implant site or catheter track

Radiculitis or arachnoiditis

Intrathecal space infection resulting in meningitis or encephalitis

Bleeding 

Spinal cord damage or trauma to the spinal cord or nerve roots

Post-LP, CSF leak, leading to headache, or  subcutaneous CSF collection

Epidural instead of intrathecal placement of catheter

Inflammatory mass resulting in neurological impairment, including paralysis

Pain on injection

Complications of anesthesia

Pseudomeningocele
System-related Complications

Improperly positioned access port

Erosion of the skin because of the underlying access port or the catheter

Wound dehiscence

Access port migration, fracture, breakage or occlusion

Catheter damage, dislodgement, migration, disconnection, kinking or occlusion, fibrosis, or 
hygroma, resulting in tissue damage or a loss of or change in therapy, or other potentially 
serious adverse health consequences

Catheter breakage and migration of residual catheter fragments, potentially resulting in 
serious adverse health consequences and the need for surgical removal 

Local immunological or fibrous reaction to the presence of a foreign body (the device)

End of device service life or component failure, requiring surgical replacement

Component failure, resulting in loss of therapy

Access port inversion (“flipping”), rotation, or extrusion

Access port or catheter rejection 

Fibrin sheath formation around catheter tip


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Appendix 8
Protocol Amendment Summary of Changes
AMENDMENT SUMMARY AND RATIONALE
Clinical protocol SHP-610-201 has been amended to include language to allow for patients to be 
dosed at local sites and reduce the burden imposed by travel, the revision of exclusion criteria on 
hypersensitivity, the addition of blood and CSF volumes tables, clarification on publications and 
interim analysis, guidance on the management of infusion/hypersensitivity reactions, change in 
the medical monitor contact information, and the addition of device adjustment language to 
capture the full scope of device manipulations that can occur throughout the trial.
Changes in grammar, spelling, punctuation, format, minor editorial changes (including changes 
for consistency and clarity), and updates to the list of abbreviations and cross-references are not 
reflected in the change summary.
DETAILED SUMMARY OF CHANGES FOR THE AMENDMENT
This is a section that has been updated to describe the changes from the previous protocol 
version. Significant changes and additions to the protocol text are captured below. Bold text 
indicates new text. Strikethrough text indicates deleted text.
Change:  change to medical monitor contact
Section impacted by this change:  Cover page
Revised Text: 
Medical Monitor: 
, MD, PhD
, DO
Other sections impacted by this change:  7.13.6.2 Reporting Serious Adverse Events
Change:  Number of maximum patients in the study increased
Section impacted by this change:  Synopsis
A maximum of 1821 patients with MPS IIIA and who completed Study HGT-SAN-093 
are planned to enroll in this study.
Other sections impacted by this change:  5.1 Study Population, 10.2 Determination of 
Sample Size
Change:  Exclusion criteria revised
Section impacted by this change:  Synopsis
The patient has a known hypersensitivity to any of the components of HGT 1410. 
Patients with documented infusion-related reactions that are clinically manageable 
(for example, with pre-medication or slowing infusion rate) are not necessarily 
excluded based on the assessment of the Investigator.
Other sections impacted by this change:  5.3 Exclusion Criteria
Change:  Inclusion of language to allow for patients to be dosed at local sites
Section impacted by this change:  4.1 Overall Study Design and Plan
The Sponsor and Principal Investigator will consider the feasibility of transitioning 
the patient’s IT dosing to local sites to reduce the burden imposed by travel. The 


HGT-1410 – SOPH-A-PORT® Mini S
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Shire
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96
local sites will be selected and approved by the Sponsor, and the patient must have 
no safety or medical issues that would preclude transitioning to a local site (Note:  
The main site may serve as a local site as needed, and in this case, the main site will 
follow the assessment schedule for a local site). The qualification requirements for 
physicians at local sites will be identical to those for the main sites. Local sites will be 
experienced with IT administration via an IDDD. For patients who were in the no-
treatment group in the HGT-SAN-093 study, initial IT administrations will be at the 
main study site following IDDD implantation until in the opinion of the Principal 
Investigator there are no safety or medical concerns precluding the patient from 
transitioning. Patients will be discharged a minimum of 4 hours after dosing and 
when deemed clinically stable by the Investigator. Exceptions include the IT 
injections of HGT-1410 when scheduled study assessments are scheduled; these will 
take place at the main site. Patients that have already received IT drug 
administration at the main study site would be eligible to transfer to a local site 
starting at Week 50 (Group 1) or Week 52 (Group 2) in SHP-610-201 if in the 
opinion of the Principal Investigator there are no safety or medical concerns 
precluding the patient from transitioning.
Other sections impacted by this change:  6.2 Treatment Administered
Change:  Title of Section 7.4.4 revised
Section impacted by this change:  7.4.4 Device Revision or Removal
Device Adjustment, Revision, or Removal
Other sections impacted by this change:  N/A
Change:  Management of Infusion/hypersensitivity reactions
Section impacted by this change:  7.13.1.3 Infusion/Hypersensitivity Reactions and 
Management
Infusions of proteins can be associated with reactions to the infusion that may or 
may not be immune-mediated (hypersensitivity reactions). Thus, potential reactions 
to the infusion of investigational drug are unpredictable. It is often difficult to 
clinically distinguish infusion reactions from hypersensitivity reactions. Symptoms 
may include headache, fever, sensory paresthesias (including feeling of warmth, 
tingling, or pain), rash, pruritus, or autonomic symptoms, such as dry mouth or 
gustatory abnormalities (including loss of smell and metallic taste). Changes in 
mental status or level of consciousness that are not caused by pre-medication may 
either occur acutely or develop post-injection over time. 
The management of infusion reactions and hypersensitivity reactions is similar. The 
following steps may be taken, at the discretion of the Investigator, in the event of a 
suspected infusion related/hypersensitivity reaction and the management of such 
reactions should be based on the severity of the reaction:

Treatment with medications such as antihistamines, antipyretics, and/or 
corticosteroids

Stopping and resuming treatment

Pretreatment with antihistamines and/or corticosteroids may prevent subsequent 


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reactions in those cases where symptomatic treatment was required
Other sections impacted by this change:  N/A
Change:  Definition of device adjustment
Section impacted by this change:  7.13.2.1 Device Revision (Partial and Full)
Device adjustment:  surgery that does not result in partial or full device revision (see 
definition above) or removal. Examples of device adjustment include surgical 
exploration only or placement of additional sutures, tissue glue, and/or fascial repair.
Other sections impacted by this change:  N/A
Change:  Clarification on publications and interim analysis
Section impacted by this change:  11.16 Publication and Disclosure Policy
Shire may perform analyses of interim or final locked study data for purposes of 
publication.
Other sections impacted by this change:  N/A
Change:  Addition of Appendix 5 – blood and CSF volumes tables 
Section impacted by this change:  Appendix 5
N/A
Other sections impacted by this change:  N/A




Clinical Trial Protocol:  SHP-610-201
Study Title:
An Open-Label Extension of Study HGT-SAN-093 Evaluating the 
Safety and Efficacy of HGT-1410 (Recombinant Human Heparan N 
Sulfatase) Administration via an Intrathecal Drug Delivery Device in 
Pediatric Patients with Mucopolysaccharidosis Type IIIA Disease
Study Number:
SHP-610-201
Study Phase:
IIb
Product Name:
HGT-1410
Device Name:
SOPH-A-PORT® Mini S, Implantable Access Port, Spinal, Mini 
Unattached, with Guidewire
IND Number:
102165
EUDRACT Number
2014-003960-20
Indication:
Long-term Treatment of Mucopolysaccharidosis Type IIIA (MPS 
IIIA or Sanfilippo Syndrome Type A)
Investigators:
Multicenter
Sponsor:
Shire Human Genetic Therapies, Inc.
Sponsor Contact:
300 Shire Way
Lexington, MA  02421 USA
+1-617-349-0200
Medical Monitor:
, DO
Date
Original Protocol:
23 September 2014
Amendment 1:
17 December 2015
Amendment 2:
25 January 2017
Confidentiality Statement
This document is the proprietary and confidential property of Shire Human Genetic 
Therapies, Inc.


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CONFIDENTIAL
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Clinical Trial Protocol:  SHP-610-201
HGT-1410 – SOPH-A-PORT® Mini S
25 Jan 2017
SYNOPSIS
Sponsor:
Shire Human Genetic Therapies, Inc. (Shire)
Name of Finished Product:
HGT-1410 (Recombinant Human Heparan N Sulfatase, or rhHNS)
Name of Device:
SOPH-A-PORT® Mini S, Implantable Access Port, Spinal, Mini Unattached, with 
Guidewire (SOPH-A-PORT® Mini S)
Study Title:
An Open-Label Extension of Study HGT-SAN-093 Evaluating the Safety and Efficacy of 
HGT-1410 (Recombinant Human Heparan N Sulfatase) Administration via an Intrathecal 
Drug Delivery Device in Pediatric Patients with Mucopolysaccharidosis Type IIIA 
Disease
Study Number:
SHP-610-201
Study Phase:  IIb
Investigational Product, Dose, and Mode of Administration:  
HGT-1410 at a dose of 45 mg administered every 2 weeks (Q2W) or 45 mg administered 
every 4 weeks (Q4W). HGT-1410 will be administered intrathecally (IT) by an 
indwelling IT drug delivery device (IDDD).
Device, Intended Use
The SOPH-A-PORT Mini S is a system intended for implantation by physicians. The 
SOPH-A-PORT Mini S, once implanted, allows healthcare personnel to administer HGT-
1410 indicated for intrathecal delivery intermittently over a long period of time.
Comparator, Dose, and Mode of Administration:
Not applicable
Primary Objective(s):  
To evaluate long-term safety in patients with mucopolysaccharidosis type IIIA disease 
(MPS IIIA or Sanfilippo syndrome type A) who received HGT-1410
Secondary Objective(s):
To evaluate:

The long-term cognitive function as measured by the Bayley Scales of Infant and 
Toddler Development, Third Edition (BSID-III) or Kaufman Assessment Battery for 
Children, Second Edition (KABC-II), age-equivalent and developmental quotient 
(DQ) scores in patients with MPS IIIA who received HGT-1410

The long-term adaptive behavioral function, assessed by Vineland Adaptive Behavior 
Scales, Second Edition (VABS-II) in patients who received HGT-1410

The total cortical grey matter volume, as assessed by volumetric magnetic  resonance 
imaging (MRI) of the brain, in patients who received HGT-1410


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Clinical Trial Protocol:  SHP-610-201
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Exploratory Objective:
Pharmacokinetic and Pharmacodynamic Objectives
To evaluate:

The pharmacokinetics of HGT-1410 in serum

The pharmacokinetics of HGT-1410 in cerebrospinal fluid (CSF), in patients who 
received no treatment in Study HGT-SAN-093

The concentration of glycosaminoglycans (GAG) in CSF and urine in patients who 
received HGT-1410
Health Status Objective 
To evaluate health status as measured by the Infant Toddler Quality of Life 
Questionnaire™ (ITQoL) instrument in patients who received HGT-1410
Health Economics and Outcomes Research Objectives
To evaluate healthcare resource utilization, as evaluated by the Healthcare Utilization 
Questionnaire (HCUQ), in patients who received HGT-1410
Study Endpoints:  
Safety evaluations include the assessment of adverse events (AEs), IDDD-related issues, 
laboratory values, anti-rhHNS antibody development, vital signs, physical examination 
findings, and electrocardiogram (ECG) results.
The secondary endpoints of this study are:

The change from Baseline in BSID-III or KABC-II age-equivalent, DQ, and 
developmental delay scores

The change from Baseline in adaptive behavioral function domains, assessed by 
VABS II, using raw scores, age-equivalent scores, and DQ scores

The change from Baseline in total cortical grey matter volume, as assessed by MRI
The pharmacokinetic endpoint is to determine the pharmacokinetic behavior of 
HGT-1410 in serum. The pharmacokinetic behavior of HGT-1410 in CSF will also be 
determined in patients who received no treatment in Study HGT-SAN-093.
The pharmacodynamic endpoint is to determine the GAG concentrations in CSF and 
urine.
The health status endpoint is the ITQoL scores at each assessment time and the 
corresponding change from Baseline.
The health economic and outcome research endpoints evaluate key HCUQ variables, 
such as the number of emergency room visits, caregiver employment status (full-time, 
part-time, or not working), and the number of hours of additional paid help needed by 
caregivers over the course of the study.


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Clinical Trial Protocol:  SHP-610-201
HGT-1410 – SOPH-A-PORT® Mini S
25 Jan 2017
Study Population:  
A maximum of 21 patients with MPS IIIA and who completed Study HGT-SAN-093 are 
planned to enroll in this study. 
Study Design:
This is an open-label study for patients who completed through at least the Week 48 Visit 
of Study HGT-SAN-093. Patients who originally received HGT-1410 in Study 
HGT-SAN-093 will remain on the same dosing regimen as they received in Study 
HGT-SAN-093; Group 1 will receive HGT-1410 Q2W and Group 2 will received 
HGT-1410 Q4W. Patients in Groups 1 and 2 will begin treatment at Week 50 and 
Week 52, respectively, of this extension study (Study SHP-610-201). Patients who 
originally received no treatment in Study HGT-SAN-093 (Group 3) will receive an 
IDDD following informed consent and will be re-randomized in a 1:1 allocation ratio to 
receive HGT-1410 via a Q2W or Q4W dosing regimen (Groups 3A and 3B, respectively) 
in Study SHP-610-201. Patients in Groups 3A and 3B will begin treatment on Week 0 of 
the extension study.
It is anticipated that the IDDD will be used to obtain CSF samples and to deliver all IT 
injections of HGT-1410. If the IDDD appears to be non-functional, or if its use is 
precluded on a scheduled day of dosing, site personnel will refer to the IDDD Manual(s), 
which provides details on the investigation and management of any IDDD-related issues. 
This includes possible partial revision or complete replacement of the IDDD as indicated. 
If the IT space is not accessible via the IDDD, study drug may be administered and CSF 
sampled by lumbar puncture (LP). General anesthesia or sedation may be required for 
injections of study drug and some evaluations and can be used at the discretion of the 
Investigator. Patients should have the IDDD removed when they discontinue from or 
complete the treatment period of the study, unless the investigator determines that it 
should not be removed based upon safety assessments. The device can remain in the 
patient (partial [catheter only] or full [port, catheter, and suture wings]) if the patient is 
doing clinically well and there are no further known risk factors such as infection (eg, 
meningitis).  The device may be partially or fully removed as medically required and 
determined by the neurosurgeon at a future date.
Safety and efficacy assessments will be performed at regular intervals over the 
approximate 2.5-year duration of the treatment period of Study SHP-610-201. For 
patients who received HGT-1410 in Study HGT-SAN-093, a serum pharmacokinetic 
sample will be obtained at the Week 96 visit (after approximately 2 full years of exposure 
to HGT-1410 across Study HGT-SAN-093 and SHP-610-201). For patients who received 
no treatment in Study HGT-SAN-093, serum pharmacokinetic samples will be obtained 
at the Week 0, 48, and 96 visits, and CSF pharmacokinetic samples will be obtained at 
the Week 0 and 48 visits in Study SHP-610-201.
Patients who do not have the IDDD removed (partial or full device) at the end of the 
treatment period will continue to be observed during a safety follow-up period with visits 
at the site every 6 months to evaluate patient safety of the device until the IDDD has been 
fully explanted.


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Clinical Trial Protocol:  SHP-610-201
HGT-1410 – SOPH-A-PORT® Mini S
25 Jan 2017
Study Duration:
Approximately 30 months of treatment with HGT-1410 will occur during the study.  
Patients who received HGT-1410 in Study HGT-SAN-093 will undergo a cumulative 
exposure to HGT-1410 for up to 42 months (168 weeks), whereas patients who received 
no-treatment in Study HGT-SAN-093 will have a cumulative exposure to HGT-1410 for 
up to 30 months (120 weeks) in Study SHP-610-201.
For those patients with a partial or full device still in place after completion of the 
treatment period, patients may be followed for safety up to an additional 3 years or until 
the device is removed in the last patient.
The LPLV will be the safety follow-up visit after the final device (partial and/or full) is 
removed from the last patient during the safety follow-up period.


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Clinical Trial Protocol:  SHP-610-201
HGT-1410 – SOPH-A-PORT® Mini S
25 Jan 2017
Study Inclusion and Exclusion Criteria:
Inclusion Criteria:
Patients must meet all of the following criteria to be considered eligible for enrollment:
1. Patient has completed through at least the Week 48 visit of Study HGT-SAN-093.
2. The patient’s parent(s) or legally authorized guardian(s) must have voluntarily signed 
an Institutional Review Board/ethics committee–approved informed consent form 
after all relevant aspects of the study have been explained and discussed. Consent of 
the patient’s parent(s) or legally authorized guardian(s) and the patient’s assent, as 
relevant, must be obtained.
Exclusion Criteria:
Patients will be excluded from the study if any of the following criteria are met:
1. The patient, if randomized to treatment in Study HGT-SAN-093, has experienced a 
decline of more than 20 points in the BSID-III cognitive DQ score between Baseline 
and the Week 48 visit in Study HGT-SAN-093, AND, upon individual evaluation by 
the Investigator, has been deemed a treatment failure*.
2. The patient has experienced, in the opinion of the Investigator, a safety or medical 
issue that contraindicates treatment with HGT-1410, including but not limited to 
clinically relevant intracranial hypertension, severe infusion-related reactions after 
treatment with HGT-1410, or uncontrollable seizure disorder.
3. The patient has a known hypersensitivity to any of the components of HGT-1410. 
Patients with documented infusion-related reactions that are clinically manageable 
(for example, with pre-medication or slowing infusion rate) are not necessarily 
excluded based on the assessment of the investigator.
4. The patient is enrolled in another clinical study, other than HGT-SAN-093, that 
involves clinical investigations or use of any investigational product (drug or 
[intrathecal/spinal] device) within 30 days prior to study enrollment or at any time 
during the study.
5. The patient has any known or suspected hypersensitivity to anesthesia or is thought to 
be at an unacceptably high risk for anesthesia due to airway compromise or other 
conditions.
6. The patient has a condition that is contraindicated as described in the SOPH-A-PORT 
Mini S IDDD Instructions for Use, including:
a.
The patient has had, or may have, an allergic reaction to the materials of 
construction of the SOPH-A-PORT Mini S device.
b. The patient’s body size is too small to support the size of the SOPH-A-PORT 
Mini S Access Port, as judged by the Investigator.
c.
The patient’s drug therapy requires substances known to be incompatible with the 
materials of construction.
d. The patient has a known or suspected local or general infection.
e.
The patient is at risk of abnormal bleeding due to a medical condition or therapy.
f.
The patient has one or more spinal abnormalities that could complicate safe 
implantation or fixation.


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Clinical Trial Protocol:  SHP-610-201
HGT-1410 – SOPH-A-PORT® Mini S
25 Jan 2017
g. The patient has a functioning CSF shunt device.
h. The patient has shown an intolerance to an implanted device.
7. The patient is unable to comply with the protocol (eg, is unable to return for safety 
evaluations or is otherwise unlikely to complete the study) as determined by the 
Investigator.
*All treated patients in Study HGT-SAN-093 will have their cognitive development 
assessed at the Week 48 Visit in Study HGT-SAN-093. If a decline from Baseline of 
20 points or less in the BSID-III DQ score is observed, then the patient may proceed into 
the Study SHP-610-201 without further evaluation. If a decline from Baseline of more 
than 20 points in DQ score is observed, then an individual evaluation by the Investigator 
will occur to determine if the patient is a treatment failure. This individual evaluation will 
take into account the DQ scores, VABS-II score, physical status, and any other 
information available for that patient at that time. If the Investigator deems the patient to 
be a treatment failure, then the patient may not enter the Study SHP-610-201.
Efficacy Assessments:
Efficacy variables to be assessed will include cognitive function expressed as a DQ 
assessed by neurocognitive testing using the BSID-III/KABS-II; adaptive behavioral 
function over time, assessed by VABS-II; the total cortical grey matter volume and liver 
and spleen size as assessed by MRI; quality-of-life score (assessed using the ITQoL); and 
health care resource utilization (assessed using the HCUQ).
Pharmacokinetic Assessments:
The determination of HGT-1410 concentration in serum for all patients and in CSF for 
patients who received no treatment in Study HGT-SAN-093.
Pharmacodynamic Assessments:
The determination of GAG concentrations in CSF and urine
Safety Assessments:
Safety will be assessed during the study by the following:

Collection of AEs (by type, severity, and relationship to treatment [HGT-1410, the 
IDDD, device surgical procedure, or IT administration process])

Changes in clinical laboratory testing (serum chemistry, hematology, urinalysis)

Physical examination

Vital signs

Twelve-lead ECG recordings 

CSF laboratory parameters (chemistries, cell counts)

Anti-rhHNS antibodies in CSF and serum, including determination of antibodies 
having enzyme neutralizing activity
Statistical Methods:  
The statistical methodology supporting the trial will focus on descriptive rather than 
inferential approaches, given the design and objectives of this trial. Any hypothesis tests 
will be 2-sided and will be viewed as exploratory. It is planned that the data from all 
centers that participate in this protocol will be combined so that an adequate number of 


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Clinical Trial Protocol:  SHP-610-201
HGT-1410 – SOPH-A-PORT® Mini S
25 Jan 2017
patients will be available for analysis. Summary statistics for continuous variables will 
include the n, mean, standard deviation, median, minimum, and maximum. Categorical 
variables will be summarized in a contingency table by the frequency and percentage of 
patients in each category. Data will be plotted to assess trends across time, as appropriate.
Unless otherwise indicated, all summary statistics will be presented by treatment group 
(either Q2W or Q4W) to which the patients were randomly assigned (patients who were 
initially assigned to Q2W or Q4W group in Study HGT-SAN-093 or patients who 
received no-treatment in Study HGT-SAN-093 and were randomly assigned to Q2W or 
Q4W in Study SHP-610-201). Additional analyses in the subgroup of patients who 
received no-treatment in Study HGT-SAN-093 may be performed. 
All safety data will be summarized descriptively. The change from baseline at each time 
point for efficacy outcomes will be summarized. Generally, the mean difference in the 
change at each time point between the 2 treatment groups and the corresponding 95% 
confidence interval of the mean difference will be presented. Additional efficacy 
analyses in the subgroups of patients previously treated and untreated in Study 
HGT-SAN-093 may be performed.
Data from Study HGT-SAN-093 will be combined with that of Study SHP-610-201 for 
analysis. The data included for treated patients in HGT-SAN-093 starts from the baseline 
of Study HGT-SAN-093 and for patients who received no treatment in HGT-SAN-093 
from the baseline of Study SHP-610-201. Baseline is the assessment obtained during the 
initial study period, prior to the first dose of HGT-1410, regardless of whether this 
occurred in Study HGT-SAN-093 or SHP-610-201.
Date of Original Protocol:  23 September 2014
Date of Amendment 1:  17 December 2015
Date of Amendment 2:  25 January 2017


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HGT-1410 – SOPH-A-PORT® Mini S
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TABLE OF CONTENTS
SYNOPSIS.......................................................................................................................................2
LIST OF IN-TEXT TABLES ........................................................................................................15
LIST OF IN-TEXT FIGURES.......................................................................................................15
LIST OF APPENDICES................................................................................................................15
LIST OF ABBREVIATIONS........................................................................................................16
1
INTRODUCTION..................................................................................................................19
2
STUDY OBJECTIVES ..........................................................................................................21
2.1
Primary Objective ....................................................................................................21
2.2
Secondary Objectives...............................................................................................21
2.3
Exploratory Objective ..............................................................................................21
2.4
Pharmacokinetic and Pharmacodynamic Objectives ...............................................21
2.5
Health Status Objective............................................................................................21
2.6
Health Economics and Outcome Research Objective..............................................21
3
STUDY ENDPOINTS............................................................................................................22
3.1
Primary Endpoint .....................................................................................................22
3.2
Secondary Endpoints................................................................................................22
3.3
Exploratory Endpoint(s)...........................................................................................22
3.4
Pharmacokinetic and Pharmacodynamic Endpoints ................................................22
3.5
Health Status Endpoint.............................................................................................23
3.6
Health Economics and Outcomes Research Endpoint .............................................23
4
INVESTIGATIONAL PLAN.................................................................................................24
4.1
Overall Study Design and Plan ................................................................................24
4.2
Rationale for Study Design, Device Use, and Comparator Group...........................27
4.3
Study Duration .........................................................................................................27
5
STUDY POPULATION SELECTION ..................................................................................28
5.1
Study Population ......................................................................................................28
5.2
Inclusion Criteria......................................................................................................28
5.3
Exclusion Criteria.....................................................................................................28
6
STUDY TREATMENT(S).....................................................................................................30
6.1
Description of Treatment(s) .....................................................................................30
6.1.1
Investigational Product ..........................................................................................30
6.1.2
Intrathecal Drug Delivery Device..........................................................................30
6.1.3
Comparator Product...............................................................................................30
6.2
Treatment Administered...........................................................................................30
6.3
Selection and Timing of Dose for Each Patient .......................................................31


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6.3.1
Missed Doses .........................................................................................................31
6.4
Method of Assigning Patients to Treatment Groups................................................31
6.5
Blinding....................................................................................................................32
6.6
Prior and Concomitant Medications, Therapies, and Medical/Surgical 
Interventions.............................................................................................................32
6.7
Restrictions...............................................................................................................32
6.7.1
Fluid and Food Intake............................................................................................32
6.7.2
Patient Activity Restrictions ..................................................................................32
6.8
Treatment Compliance .............................................................................................32
6.9
Packaging and Labeling ...........................................................................................32
6.10
Storage and Accountability ......................................................................................33
6.10.1 Investigational Product ..........................................................................................33
6.10.2 Intrathecal Drug Delivery Device..........................................................................33
6.10.3 Comparator Product...............................................................................................33
7
STUDY PROCEDURES........................................................................................................34
7.1
Informed Consent.....................................................................................................34
7.2
Study Entrance Criteria ............................................................................................34
7.3
Hearing and Vision Assessments .............................................................................35
7.3.1
Investigator Assessment of Hearing and Vision....................................................35
7.4
Device-related Study Procedures .............................................................................35
7.4.1
IDDD Implantation or Revision Procedures..........................................................35
7.4.2
X-ray Verification of Intrathecal Drug Delivery Device Placement .....................35
7.4.3
CSF Sampling Procedure.......................................................................................35
7.4.4
Device Adjustment, Revision, or Removal............................................................36
7.5
Investigational Product Administration ...................................................................36
7.6
Efficacy Assessments...............................................................................................37
7.6.1
Neurocognitive and Developmental Assessments.................................................37
7.6.2
Quality of Life Indicator:  Infant Toddler Quality of Life Questionnaire .............38
7.6.3
Health Economics and Outcomes Research:  Healthcare Utilization 
Questionnaire.........................................................................................................38
7.7
Magnetic Resonance Imaging ..................................................................................38
7.7.1
Head.......................................................................................................................38
7.7.2
Liver and Spleen ....................................................................................................38
7.8
Pharmacokinetic Assessments..................................................................................38
7.9
Pharmacodynamic Biomarker Assessments (CSF and Urine GAG Levels)............39
7.10
Concomitant Medications, Therapies, and Medical/Surgical Interventions ............39
7.11
Safety Assessments ..................................................................................................39
7.11.1 Vital Signs..............................................................................................................39


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7.11.2 Physical Examination, Including Height, Weight, and Head Circumference........39
7.11.3 Electrocardiogram..................................................................................................40
7.11.4 Clinical Laboratory Tests.......................................................................................40
7.11.5 Cerebrospinal Fluid Assessments ..........................................................................41
7.11.5.1
Standard CSF Safety Laboratory Assessments ......................................42
7.11.5.2
Anti-rhHNS Antibodies and Biomarkers in CSF...................................42
7.11.5.3
CSF GAG Levels and Biomarkers.........................................................42
7.11.5.4
........................................................42
7.11.6 Device Assessments...............................................................................................42
7.11.7 Collection and Storage of Biological Samples for Biomarker Studies..................42
7.12
Sample Collection, Storage, and Shipping...............................................................42
7.13
Adverse Events Assessments ...................................................................................43
7.13.1 Definitions of Adverse Events and Serious Adverse Events.................................43
7.13.1.1
Adverse Event ........................................................................................43
7.13.1.2
Adverse Events Due to Systemic Exposure to HGT-1410.....................43
7.13.1.3
Infusion/Hypersensitivity Reactions and Management..........................44
7.13.1.4
IDDD-related Adverse Events ...............................................................44
7.13.1.5
Serious Adverse Event ...........................................................................45
7.13.2 Device-associated Definitions ...............................................................................45
7.13.2.1
Device Revision (Partial and Full).........................................................45
7.13.2.2
Device Malfunction................................................................................46
7.13.2.3
Device Failure ........................................................................................46
7.13.3 Classification of Adverse Events and Serious Adverse Events.............................46
7.13.4 Clarification between Serious and Severe .............................................................46
7.13.5 Relatedness of Adverse Events and Serious Adverse Events................................46
7.13.6 Procedures for Recording and Reporting Adverse Events ....................................47
7.13.6.1
Adverse Event Monitoring and Period of Observation..........................47
7.13.6.2
Reporting Serious Adverse Events.........................................................47
7.14
Abuse, Overdose and Medication Error...................................................................49
7.15
Removal of Patients from the Trial or Investigational Product ...............................49
7.15.1 Study Discontinuation Process ..............................................................................50
7.16
Safety-Related Study Stopping Rules ......................................................................50
7.17
Appropriateness of Measurements...........................................................................51
8
STUDY ACTIVITIES............................................................................................................53
8.1
Group 1 (Maintaining Q2W Dosing) .......................................................................53
8.1.1
Treatment Period (Weeks 50 through 168)............................................................53
8.1.1.1
Pre-treatment Assessments.....................................................................53
8.1.1.2
Post-treatment Assessments ...................................................................54


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8.1.2
Safety Follow-up Visit:  Week 172 (±7 days) .......................................................54
8.2
Group 2 (Maintaining Q4W Dosing) .......................................................................54
8.2.1
Treatment Period (Weeks 52 through 168)............................................................54
8.2.1.1
Pre-treatment Assessments.....................................................................55
8.2.1.2
Post-treatment Assessments ...................................................................55
8.2.2
Safety Follow-up Visit:  Week 172 (±7 days) .......................................................55
8.3
Group 3 (Patients Randomized to No Treatment in Study HGT-SAN-093) ...........56
8.3.1
IDDD Implantation (Days -21 to Day -7)..............................................................56
8.3.1.1
Prior to IDDD Implantation ...................................................................56
8.3.1.2
Day of IDDD Implantation ....................................................................56
8.3.2
Postoperative Check – Days 1 to 3 ........................................................................57
8.3.3
Randomization (Can Occur Any Time After Meeting Study Entry Criteria)........57
8.4
Group 3A (Initiating HGT-1410 Q2W Dosing).......................................................57
8.4.1
Treatment Period (Weeks 0 through 120)..............................................................57
8.4.1.1
Pre-treatment Assessments.....................................................................57
8.4.1.2
Post-treatment Assessments ...................................................................58
8.4.2
Safety Follow-up Visit:  Week 124 (±7 days) .......................................................58
8.5
Group 3B (Initiating HGT-1410 Q4W Dosing).......................................................58
8.5.1
Treatment Period (Weeks 0 through 120)..............................................................58
8.5.1.1
Pre-treatment Assessments.....................................................................58
8.5.1.2
Post-treatment Assessments ...................................................................59
8.5.2
Safety Follow-up Visit:  Week 124 (±7 days) .......................................................59
8.6
All Groups:  Safety Follow-up Period if Device Not Removed ..............................59
9
QUALITY CONTROL AND ASSURANCE ........................................................................61
10 STATISTICAL ANALYSES.................................................................................................62
10.1
General Methodology...............................................................................................62
10.2
Determination of Sample Size..................................................................................63
10.3
Method of Assigning Study Subjects to Treatment Groups.....................................63
10.4
Population Description and Exposure......................................................................63
10.4.1 Analysis Populations..............................................................................................63
10.4.2 Subject Disposition................................................................................................63
10.4.3 Protocol Deviations................................................................................................63
10.4.4 Demographics and Baseline Characteristics..........................................................64
10.4.5 Treatment Compliance and Extent of Exposure....................................................64
10.5
Analysis of Efficacy.................................................................................................64
10.5.1 Primary Analysis....................................................................................................64
10.5.2 Secondary Efficacy Analysis .................................................................................64


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10.5.2.1
Bayley Scales of Infant Development, Third Edition/Kaufman 
Assessment Battery for Children, Second Edition.................................64
10.5.2.2
Vineland Adaptive Behavior Scales, Second Edition ............................65
10.5.2.3
Brain MRI ..............................................................................................65
10.5.3 Subset Analyses .....................................................................................................65
10.5.4 Exploratory Analyses.............................................................................................65
10.5.5 Analysis of Health Status.......................................................................................65
10.5.6 Analysis Health Economics and Outcomes Research ...........................................65
10.6
Analysis of Pharmacokinetic and Pharmacodynamic Data......................................66
10.6.1 Pharmacokinetic Measurement and Parameters ....................................................66
10.6.2 Pharmacodynamic Analyses..................................................................................66
10.7
Analysis of Safety ....................................................................................................66
10.7.1 Adverse Events ......................................................................................................66
10.7.1.1
Investigational Product...........................................................................67
10.7.1.2
IDDD and Surgical Procedure–related AEs...........................................67
10.7.2 Clinical Laboratory Evaluation..............................................................................67
10.7.3 ECG Evaluations....................................................................................................68
10.7.4 Vital Signs..............................................................................................................68
10.7.5 Anti-rhHNS Antibody in Serum and CSF .............................................................68
10.7.6 Concomitant Medications......................................................................................68
10.7.7 Other Observations Related to Safety....................................................................68
10.7.7.1
IDDD Performance ................................................................................68
10.8
Statistical/Analytical Issues......................................................................................69
10.8.1 Adjustment for Covariates.....................................................................................69
10.8.2 Handling of Dropouts or Missing Data..................................................................69
10.8.3 Interim Analyses and Data Monitoring..................................................................69
10.8.4 Multicenter Studies................................................................................................69
10.8.5 Multiple Comparisons/Multiplicity .......................................................................69
10.8.6 Sensitivity Analyses...............................................................................................69
11 ADMINISTRATIVE CONSIDERATIONS ..........................................................................70
11.1
Investigators and Study Administrative Structure ...................................................70
11.2
Institutional Review Board or Ethics Committee Approval ....................................70
11.3
Ethical Conduct of the Study ...................................................................................70
11.4
Patient Information and Consent..............................................................................70
11.5
Patient Confidentiality..............................................................................................71
11.6
Study Monitoring .....................................................................................................72
11.7
Case Report Forms and Study Records....................................................................72
11.7.1 Case Report Forms.................................................................................................72


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11.7.2 Critical Documents ................................................................................................72
11.8
Data Monitoring Committee ....................................................................................73
11.9
Device Failure Review Process................................................................................73
11.10
Protocol Violations/Deviations ................................................................................73
11.11
Premature Closure of the Study ...............................................................................74
11.12
Access to Source Documentation.............................................................................74
11.13
Data Generation and Analysis..................................................................................74
11.14
Retention of Data .....................................................................................................75
11.15
Financial Disclosure.................................................................................................75
11.16
Publication and Disclosure Policy............................................................................75
12 LIST OF REFERENCES........................................................................................................76


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LIST OF IN-TEXT TABLES
Table 7-1
Neurodevelopmental Assessments Tests.......................................................37
Table 7-2
Assessments for Physical Examinations .......................................................40
Table 7-3
List of Laboratory Tests ................................................................................41
Table 7-4
Adverse Event Severity.................................................................................46
Table 7-5
Adverse Event Relatedness ...........................................................................46
LIST OF IN-TEXT FIGURES
Figure 1
SHP-610-201 Study Design .........................................................................26
LIST OF APPENDICES
Appendix 1
Study Schedule of Events for Group 1:  Maintaining HGT-1410 Q2W .......77
Appendix 2
Study Schedule of Events for Group 2:  Maintaining HGT-1410 Q4W .......79
Appendix 3
Study Schedule of Events for Group 3A:  Initiating HGT-1410 Q2W .........81
Appendix 4
Study Schedule of Events for Group 3B:  Initiating HGT-1410 Q4W .........84
Appendix 5
Study Schedule of Events for the Safety Follow-up Period for Patients 
with Implanted Partial or Full Device After Treatment Completion ............87
Appendix 6
Blood and CSF Volumes...............................................................................88
Appendix 7
Pharmacokinetic and Pharmacodynamic Sample Schedule..........................93
Appendix 8
Expected SOPH-A-PORT Mini S Adverse Device Effects ..........................94
Appendix 9
Protocol Amendment Summary of Changes .................................................95
Appendix 10
Protocol Signature Page ..............................................................................102


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LIST OF ABBREVIATIONS
Abbreviation
Definition
Ab
antibody
AE
adverse event
ALB
albumin
ALK-P
alkaline phosphatase
ALT; SGPT
alanine aminotransferase
aPTT
activated partial thromboplastin time
AST; SGOT
aspartate aminotransferase
AUC
area under the serum concentration-time curve
AUC0-last
area under the curve from the time of dosing to the last measurable concentration
AUC0-∞
area under the curve extrapolated to infinity, calculated using the observed value of 
the last non-zero concentration
BBB
blood-brain barrier
BSID-III
Bayley Scales of Infant and Toddler Development, Third Edition  
BUN
blood urea nitrogen
Ca
calcium
CE
Conformité Européenne
CFR
Code of Federal Regulations
CK
creatine kinase
CL/F
total body clearance for extravascular administration divided by the fraction of dose 
absorbed
Cl
chloride
Cmax
maximum concentration occurring at tmax
CNS
central nervous system
CO2
carbon dioxide
con meds
concomitant medications
CRO
contract research organization
CS
clinically significant
CSF
cerebrospinal fluid
DMC
Data Monitoring Committee
DQ
developmental quotient
DS
dermatan sulfate
EC
ethics committee
ECG
electrocardiogram
eCRF
electronic case report form
ERT
enzyme replacement therapy
EU
European Union
FDA
Food and Drug Administration
FT
full-time


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Abbreviation
Definition
GAG
glycosaminoglycan
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
Hct
hematocrit
HCUQ
Healthcare Utilization Questionnaire
Hgb
hemoglobin
HNS
heparan N-sulfatase
HS
heparan sulfate
ICH
International Conference on Harmonisation
IDDD
intrathecal drug delivery device
IFU
Instructions for Use
IRB
Institutional Review Board
IT
Intrathecal(ly)
ITQoL
Infant Toddler Quality of Life Questionnaire™
ITT
intent-to-treat
IV
intravenous(ly)
K
potassium
KABC-II
Kaufman Assessment Battery for Children, Second Edition
LDH
lactate dehydrogenase
LP
lumbar puncture
LSD
lysosomal storage disease
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MPS IIIA
mucopolysaccharidosis type IIIA or Sanfilippo syndrome type A
MRI
magnetic resonance imaging
NA
sodium
NCS
not clinically significant
NW
not working
PD
pharmacodynamics
PE
physical examination
PK
pharmacokinetics
PT
part-time
PT
prothrombin time
Q2W
every 2 weeks
Q4W
every 4 weeks
QoL
quality of life
RBC
red blood cell
rhHNS
recombinant human heparan N sulfatase


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Abbreviation
Definition
SAE
serious adverse event
SAP
statistical analysis plan
SGSH
sulfoglucosamine sulfohydrolase
SI
Standard International
SOC
system organ class
t1/2
terminal half-life
tmax
time of maximum observed concentration sampled during a dosing interval
UADE
unanticipated adverse device effect
US(A)
United States (of America)
VABS-II
Vineland Adaptive Behavior Scales, Second Edition 
Vz/F
volume of distribution associated with the terminal slope following extravascular 
administration divided by the fraction of dose absorbed
WBC
white blood cell
WHO-DD
World Health Organization-Drug Dictionary
λZ
first order rate constant associated with the terminal (log-linear) portion of the curve


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1
INTRODUCTION
Mucopolysaccharidosis type IIIA (MPS IIIA, also called Sanfilippo syndrome type A) is a rare, 
autosomal recessive, lysosomal storage disease (LSD) presenting in early childhood that causes 
progressive neurodegeneration associated with intractable behavioral problems and 
developmental regression. Ultimately, a vegetative state supervenes. Life span is shortened, with 
death usually occurring in the late teen years. The genetic defect in this disorder is a mutation in 
both copies of the sulfoglucosamine sulfohydrolase (SGSH) gene, located on chromosome 17, 
which encodes the lysosomal enzyme, sulfoglucosamine sulfohydrolase, also called 
heparan-N-sulfatase, or sulfamidase. This enzyme is necessary for the normal intralysosomal 
catabolism of the glycosaminoglycan (GAG) (formerly termed mucopolysaccharide), heparan 
sulfate (HS). Sulfoglucosamine sulfohydrolase deficiency therefore results in the accumulation 
of heparan sulfate in lysosomes. Although the metabolic defect is expressed in every organ, the 
clinical manifestations of disease are primarily neurological. These are not usually apparent until 
1 to 4 years of age. The molecular events linking the primary metabolic defect to the consequent 
neuropathology are not understood. 
MPS III is the most prevalent of the mucopolysaccharidoses and consists of 4 subtypes, A, B, C, 
and D.1 Each of these is characterized by a deficiency of a distinct lysosomal enzyme necessary 
for the degradation of heparan sulfate. Clinically, on an individual patient level, the 4 subtypes 
cannot be reliably distinguished. Globally, subtype A is the most prevalent, at approximately 
1 case in 100,000 live births, followed by subtype B, at approximately 1 in 250,000 live births.1-3
Among MPS IIIA patients, there is wide allelic heterogeneity, with at least 100 SGSH mutations 
described to date. Most of these are missense, but nonsense mutations, deletions, insertions and 
splice-site mutations also occur.4
MPS IIIA symptoms usually arise in the first or second year of life, although diagnosis is 
delayed until an average age of 4.5 years.4, 5 Patients present a wide spectrum and severity of 
clinical symptoms. The central nervous system (CNS) is the most severely affected organ system 
in patients with MPS IIIA, evidenced by deficits in language development, motor skills, and 
intellectual development.5 In addition, there are abnormal behaviors that include aggression and 
excess motor activity/hyperactivity that contribute to disturbances in sleep.5-7 There are also 
reports of unexplained, recurrent and severe diarrhea.6 Overall, individuals with MPS IIIA 
exhibit progressive dementia with ultimate inanition and death resulting from the CNS disease. 
Lifespan is severely curtailed, with usual survival into the late teens.6 Milder variants are 
recognized, with slower progression and survival to later age. The latter has been reported in 
approximately 10% of German patients with MPS IIIA, in association with the presence of the 
S298P mutation.8
No effective, disease-modifying therapies are currently approved as treatments for this 
devastating and disabling disease. A goal of Shire is to develop recombinant human 
heparan-N-sulfatase (rhHNS, development name HGT-1410) as enzyme replacement therapy 
(ERT) for patients with MPS IIIA. A particular problem for lysosomal storage disorders that 
damage the brain, such as MPS III, is how to target ERT to the brain, as macromolecules cannot 
cross the blood-brain barrier (BBB).9 In animal studies, ERT has been administered into the 
cerebrospinal fluid (CSF) via an intrathecal (IT) route, because when administered intravenously 


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(IV) it does not cross the BBB after the immediate postnatal period of life. HGT-1410 has been 
shown to be ineffective if administered intravenously in the MPS IIIA mouse model, in contrast 
to its efficacy in treating CNS pathology when administered into the CSF.10
In order to traverse the BBB, HGT-1410 will be administered directly to the CNS using an IT 
drug delivery device (IDDD) or, if the IDDD is non-functional, via lumbar puncture (LP). The 
advantage of using an IDDD is the potential to obviate the need for multiple LPs for drug 
delivery. HGT-1410 will be administered through the IDDD or, if the IDDD is non-functional, 
via LP.
Please refer to the current edition of the Investigator’s Brochure for further information 
concerning the nonclinical studies completed, including safety and clinical development of 
HGT-1410.


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2
STUDY OBJECTIVES
2.1
Primary Objective 
The primary objective of this study is to evaluate long-term safety in patients with 
mucopolysaccharidosis type IIIA disease (MPS IIIA or Sanfilippo syndrome type A) who 
received HGT-1410.
2.2
Secondary Objectives 
The secondary objectives of this study are to evaluate:  

The long-term cognitive function as measured by the Bayley Scales of Infant and Toddler 
Development, Third Edition (BSID-III) or Kaufman Assessment Battery for Children, 
Second Edition (KABC-II), age-equivalent and developmental quotient (DQ) scores in 
patients with MPS IIIA who received HGT-1410

The long-term adaptive behavioral function, assessed by Vineland Adaptive Behavior Scales, 
Second Edition (VABS-II) in patients who received HGT-1410

The total cortical grey matter volume, as assessed by volumetric magnetic resonance imaging 
(MRI) of the brain, in patients who received HGT-1410
2.3
Exploratory Objective
The exploratory objective of this study is
 
.
2.4
Pharmacokinetic and Pharmacodynamic Objectives
The pharmacokinetic and pharmacodynamics objectives of this study are to evaluate:

The pharmacokinetics of HGT-1410 in serum

The pharmacokinetics of HGT-1410 in CSF, in patients who received no treatment in Study 
HGT-SAN-093

The concentration of GAG in CSF and urine in patients who received HGT-1410
2.5
Health Status Objective
The health status objective of this study is to evaluate health status as measured by the Infant 
Toddler Quality of Life Questionnaire™ (ITQoL) instrument in patients who received 
HGT-1410.
2.6
Health Economics and Outcome Research Objective
The health economics and outcome research objective of this study is to evaluate healthcare 
resource utilization, as evaluated by the Healthcare Utilization Questionnaire (HCUQ), in 
patients who received HGT-1410.


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3
STUDY ENDPOINTS
3.1
Primary Endpoint
Safety is the primary objective of the study and will be assessed during the study by the 
following:

Collection of adverse events (AEs; by type, severity, and relationship to treatment 
[HGT-1410, the IDDD, device surgical procedure, or IT administration process])

Changes in clinical laboratory testing (serum chemistry, hematology, urinalysis)

Physical examination

Vital signs

Twelve-lead electrocardiogram (ECG) recordings 

CSF laboratory parameters (including chemistries, cell counts)

Anti-rhHNS antibodies in CSF and serum, including determination of antibodies having 
enzyme neutralizing activity
3.2
Secondary Endpoints
The secondary endpoints of this study are:

The change from Baseline in BSID-III or KABC-II age-equivalent, DQ, and developmental 
delay scores

The change from Baseline in adaptive behavioral function domains, assessed by VABS II, 
using raw scores, age-equivalent scores, and DQ scores

The change from Baseline in total cortical grey matter volume, as assessed by MRI
3.3
Exploratory Endpoint(s)
3.4
Pharmacokinetic and Pharmacodynamic Endpoints
The pharmacokinetic endpoint is to determine the pharmacokinetic behavior of HGT-1410 in 
serum, based on the following parameters:

Maximum concentration occurring at tmax (Cmax)

Time of maximum observed concentration sampled during a dosing interval (tmax)

Area under the curve from the time of dosing to the last measurable concentration (AUC0-last)

Area under the curve extrapolated to infinity, calculated using the observed value of the last 
non-zero concentration (AUC0-∞)

First order rate constant associated with the terminal (log-linear) portion of the curve (λZ) 

Terminal half-life (t1/2) calculated as 0.693/λZ


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
total body clearance for extravascular administration divided by the fraction of dose absorbed 
(CL/F)

Volume of distribution associated with the terminal slope following extravascular 
administration divided by the fraction of dose absorbed (Vz/F)  
The pharmacodynamic endpoint is to determine the GAG concentrations in CSF and urine.
3.5
Health Status Endpoint
The health status endpoint is the ITQoL scores at each assessment time and the corresponding 
change from Baseline.
3.6
Health Economics and Outcomes Research Endpoint
The health economic and outcome research endpoints evaluate the key HCUQ variables, such as 
the number of emergency room visits, caregiver employment status (full-time [FT], part-time 
[PT], and not working [NW]), and the number of hours of additional paid help needed by 
caregivers, over the course of the study.


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4
INVESTIGATIONAL PLAN
4.1
Overall Study Design and Plan
This is an open-label extension study of HGT-1410 for patients who completed through at least 
the Week 48 Visit in Study HGT-SAN-093. The study design is presented in Figure 1. Patients 
who originally received HGT-1410 in Study HGT-SAN-093 will remain on the same dosing 
regimen as they received in Study HGT-SAN-093; Group 1 will receive HGT-1410 Q2W and 
Group 2 will received HGT-1410 Q4W. Patients in Groups 1 and 2 will begin treatment at 
Week 50 and Week 52, respectively, of this extension study (Study SHP-610-201). Patients who 
originally received no-treatment in Study HGT-SAN-093 (Group 3) will receive an IDDD 
following informed consent and will be re-randomized in a 1:1 allocation ratio to receive 
HGT-1410 via a Q2W or Q4W dosing regimen (Groups 3A and 3B, respectively) in Study 
SHP-610-201. Patients in Groups 3A and 3B will begin treatment on Week 0 of the extension 
study. 
The Sponsor and Principal Investigator will consider the feasibility of transitioning the patient’s 
IT dosing to local sites to reduce the burden imposed by travel. The local sites will be selected 
and approved by the Sponsor, and the patient must have no safety or medical issues that would 
preclude transitioning to a local site (Note:  The main site may serve as a local site as needed, 
and in this case, the main site will follow the assessment schedule for a local site). The 
qualification requirements for physicians at local sites will be identical to those for the main 
sites. Local sites will be experienced with IT administration via an IDDD. For patients who were 
in the no-treatment group in the HGT-SAN-093 study, initial IT administrations will be at the 
main study site following IDDD implantation until in the opinion of the Principal Investigator 
there are no safety or medical concerns precluding the patient from transitioning. Patients will be 
discharged a minimum of 4 hours after dosing and when deemed clinically stable by the 
Investigator. Exceptions include the IT injections of HGT-1410 when scheduled study 
assessments are scheduled; these will take place at the main site. Patients that have already 
received IT drug administration at the main study site would be eligible to transfer to a local site 
starting at Week 50 (Group 1) or Week 52 (Group 2) in SHP-610-201 if in the opinion of the 
Principal Investigator there are no safety or medical concerns precluding the patient from 
transitioning. 
It is anticipated that the IDDD will be used to collect CSF samples and to deliver IT injections of 
HGT-1410 and preservative-free saline flushes. No other medication will be administered 
through the device. If the IDDD appears to be non-functional, or if its use is precluded on a 
scheduled day of dosing, site personnel will refer to the IDDD Manual, which provides details on 
the investigation and management of any IDDD-related issues. This includes possible partial 
revision or complete replacement of the IDDD as indicated. If the IT space is not accessible via 
the IDDD, study drug may be administered by LP. Should the IDDD become clogged, undergo 
mechanical complications or otherwise not be accessible, the CSF sample may also be obtained 
by LP. General anesthesia or sedation may be required for injections of study drug and some 
evaluations, and may be used at the discretion of the Investigator. The Data Monitoring 
Committee (DMC) will be notified of all IDDD failures and IDDD-related complications at 
times defined in the DMC charter (see Section 11.8).


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Patients should have the IDDD removed when they discontinue from or complete the treatment 
period of the study, unless the investigator determines that it should not be removed based upon 
safety assessments. The device can remain in the patient (partial [catheter only] or full [port, 
catheter, and suture wings]) if the patient is doing clinically well and there are no further known 
risk factors such as infection (eg, meningitis).  The device may be partially or fully removed as 
medically required and determined by the neurosurgeon at a future date.
Safety and efficacy assessments will be performed at regular intervals over the approximate 
2.5-year duration of the treatment period of the extension study. A pharmacokinetic sample for 
patients who received HGT-1410 in Study HGT-SAN-093 will be obtained at the Week 96 visit 
(after approximately 2 full years of exposure to HGT-1410 across Studies HGT-SAN-093 and 
SHP-610-201). Serum pharmacokinetic samples for patients who received no-treatment in Study 
HGT-SAN-093 will be obtained at the Week 0, 48, and 96, and CSF pharmacokinetic samples 
will be obtained on the Week 0 and 48 visits in Study SHP-610-201.
Patients who received HGT-1410 in Study HGT-SAN-093 will undergo a cumulative exposure 
to HGT-1410 for up to 42 months (168 weeks), whereas patients who received no treatment in 
Study HGT-SAN-093 will have a cumulative exposure to HGT-1410 for up to 30 months 
(120 weeks) in Study SHP-610-201.
Patients who do not have the IDDD removed (partial or full device) at the end of the treatment 
period will continue to be observed during a safety follow-up period with visits at the site every 
6 months to evaluate patient safety of the device until the IDDD has been fully explanted. 
See Appendix 1, Appendix 2, Appendix 3, and Appendix 4 for the Study Schedule of Events 
tables for Groups 1, 2, 3A, and 3B, respectively.  See Appendix 5 for the Study Schedule of 
Events for the safety follow-up period for patients with partial or full devices in place after the 
end of the treatment period.  




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4.2
Rationale for Study Design, Device Use, and Comparator Group
The study design is intended to provide ongoing treatment with HGT-1410 to patients who 
received HGT-1410 in Study HGT-SAN-093 and to initiate treatment to patients who received 
no-treatment in Study HGT-SAN-093. As such, all patients will be treated during this study; 
there is no control group.
In order to traverse the blood-brain barrier, HGT-1410 will be administered directly to the CNS 
using an IDDD or, if the IDDD is non-functional, via LP. The advantage of using an IDDD is the 
potential to obviate the need for multiple lumbar punctures for drug delivery. HGT-1410 will be 
administered through the IDDD or, if the IDDD is non-functional, via lumbar puncture.
Safety is the primary objective of the study, and the study duration has been designed to provide 
a reasonable time for safety follow-up.
4.3
Study Duration
Patients who received HGT-1410 in Study HGT-SAN-093 will undergo a cumulative exposure 
to HGT-1410 for up to 42 months (168 weeks), whereas patients who received no treatment in 
Study HGT-SAN-093 will have a cumulative exposure to HGT-1410 for up to 30 months (120 
weeks) in Study SHP-610-201.
Patients with a partial or full device still in place after completion of the treatment period may be 
followed for safety up to an additional 3 years or until the device is removed in the last patient. 
The LPLV will be the safety follow-up visit after the final device (partial and/or full) is removed 
from the last patient during the safety follow-up period.


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5
STUDY POPULATION SELECTION
5.1
Study Population
A maximum of 21 patients with MPS IIIA who completed Study HGT-SAN-093 are planned to 
enroll in this study. 
5.2
Inclusion Criteria
Patients must meet all of the following criteria to be considered eligible for enrollment:  
1. Patient has completed through at least the Week 48 visit of Study HGT-SAN-093.
2. The patient’s parent(s) or legally authorized guardian(s) has voluntarily signed an 
Institutional Review Board (IRB)/ ethics committee (EC)–approved informed consent form 
after all relevant aspects of the study have been explained and discussed. Consent of the 
patient’s parent(s) or legally authorized guardian(s) and the patient’s assent, as relevant, must 
be obtained.
5.3
Exclusion Criteria
Patients will be excluded from the study if any of the following criteria are met:
1. The patient, if randomized to treatment in Study HGT-SAN-093, has experienced a decline 
of more than 20 points in the BSID-III cognitive DQ score between Baseline and the 
Week 48 visit in Study HGT-SAN-093, AND, upon individual evaluation by the 
Investigator, has been deemed a treatment failure*.
2. The patient has experienced, in the opinion of the Investigator, a safety or medical issue that 
contraindicates treatment with HGT-1410, including but not limited to clinically relevant 
intracranial hypertension,  severe infusion-related reactions after treatment with HGT-1410, 
uncontrollable seizure disorder.
3. The patient has a known hypersensitivity to any of the components of HGT-1410. Patients 
with documented infusion-related reactions that are clinically manageable (for example, with 
pre-medication or slowing infusion rate) are not necessarily excluded based on the 
assessment of the Investigator.
4. The patient is enrolled in another clinical study, other than HGT-SAN-093, that involves 
clinical investigations or use of any investigational product (drug or [intrathecal/spinal] 
device) within 30 days prior to study enrollment or at any time during the study.
5. The patient has any known or suspected hypersensitivity to anesthesia or is thought to be at 
an unacceptably high risk for anesthesia due to airway compromise or other conditions.
6. The patient has a condition that is contraindicated as described in the SOPH-A-PORT Mini S 
IDDD Instructions for Use (IFU), including:
a.
The patient has had, or may have, an allergic reaction to the materials of construction of 
the SOPH-A-PORT Mini S device.
b. The patient’s body size is too small to support the size of the SOPH-A-PORT Mini S 
Access Port, as judged by the Investigator.


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c.
The patient’s drug therapy requires substances known to be incompatible with the 
materials of construction.
d. The patient has a known or suspected local or general infection.
e.
The patient is at risk of abnormal bleeding due to a medical condition or therapy.
f.
The patient has 1 or more spinal abnormalities that could complicate safe implantation or 
fixation.
g. The patient has a functioning CSF shunt device.
h. The patient has shown an intolerance to an implanted device.
7. The patient is unable to comply with the protocol (eg, is unable to return for safety 
evaluations or is otherwise unlikely to complete the study) as determined by the Investigator.
*All treated patients in Study HGT-SAN-093 will have their cognitive development assessed at 
the Week 48 Visit in Study HGT-SAN-093. If a decline from Baseline of 20 points or less in the 
BSID-III DQ score is observed, then the patient may proceed into the Study SHP-610-201 
without further evaluation. If a decline from Baseline of more than 20 points in DQ score is 
observed, then an individual evaluation by the Investigator will occur to determine if the patient 
is a treatment failure. This individual evaluation will take into account the DQ scores, VABS-II 
score, physical status, and any other information available for that patient at that time. If the 
Investigator deems the patient to be a treatment failure, then the patient may not enter the Study 
SHP-610-201.


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6
STUDY TREATMENT(S)
6.1
Description of Treatment(s)
6.1.1
Investigational Product
The investigational product to be used in this study is HGT-1410, rhHNS for IT use.
The HGT-1410 drug product is a sterile solution for injection in single-use vials for IT 
administration. It is formulated in an aqueous isotonic solution containing 15.0 mg/mL rhHNS in 
145 mM sodium chloride, 0.02% (v/v) polysorbate 20, 5 mM sodium phosphate at pH 7.0.
6.1.2
Intrathecal Drug Delivery Device
The drug product will be administered via the SOPH-A-PORT Mini S Implantable Access Port. 
The SOPH-A-PORT Mini S device is intended for long-term, intermittent access to the IT space 
for the delivery of investigational drug. The device is Conformité Européenne (CE)-marked in 
the European Union (EU) and investigational in non-EU countries.
The SOPH-A-PORT Mini S is comprised of the following 7 components:

One SOPH-A- PORT Mini S Access Port

One IT port closed-tip catheter

One guidewire

Two suture wings

One 14-gauge Tuohy needle

One 22-gauge non-coring Huber needle

One Luer lock connector
Further details are provided in the SOPH-A-PORT Mini S IFU.
6.1.3
Comparator Product
Not applicable
6.2
Treatment Administered
The study drug will be administered through an IDDD. In the event of IDDD malfunction or 
failure, HGT-1410 may be administered via LP.
Patients who were randomized to receive HGT-1410 in Study HGT-SAN-093 will continue to 
have HGT-1410 administered through the IDDD that was implanted during Study 
HGT-SAN-093.
Patients who were randomized to no treatment in Study HGT-SAN-093 will be scheduled to 
undergo surgical placement of the SOPH-A-PORT Mini S device. The initial implantation and 
any revision and/or explantation of the SOPH-A-PORT Mini S will be performed by pediatric or 
general neurosurgeons or anesthesiologists who have experience in port and catheter implant 
procedures and IT-access procedures and have completed training for the SOPH-A-PORT Mini 


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S. Please refer to the IFU for further details. At least 7 days will be allowed for recovery 
following the placement of the IDDD before the administration of the first intrathecal dose of 
HGT-1410. During this time, the patient will receive standard perioperative care.
Drug administration will be performed in a clinical setting by appropriately trained and skilled 
healthcare providers (nurses or physicians) with knowledge of the patient’s drug regimen and 
experienced in accessing vascular or CNS ports or CNS infusion pumps. Patients and patients’ 
families will not be directly using the device to administer drugs and will have limited direct 
interaction with the device as there is minimal care required both during the immediate 
postoperative period as the implant site heals, and at times of drug administration.
As previously noted, under the appropriate conditions, IT HGT-1410 may be administered at 
local sites rather than main sites to reduce the burden of monthly travel. This is further detailed 
in Section 4.1.
6.3
Selection and Timing of Dose for Each Patient
After meeting eligibility criteria, patients in Groups 1 and 2 (who received HGT-1410 in Study 
HGT-SAN-093) will begin treatment at Weeks 50 and 52, respectively, in Study SHP-610-201. 
Patients will be treated for up to 120 weeks in Study SHP-610-201, for a total cumulative 
exposure of 168 weeks across Studies HGT-SAN-093 and SHP-610-201.
After meeting eligibility criteria, patients who were randomized to no treatment in Study 
HGT-SAN-093 will be scheduled to undergo surgical placement of the SOPH-A-PORT Mini S 
device, as described in Section 6.2. Thereafter, these patients will be administered HGT-1410 
45 mg as an IT injection either Q2W or Q4W (Groups 3A or 3B, respectively), as randomized, 
for up to 120 weeks. 
6.3.1
Missed Doses
Patients who are scheduled to receive Q2W dosing (Groups 1 and 3A) should receive their dose 
of HGT-1410 every 14±3 days, and patients who are scheduled to receive Q4W dosing (Groups 
2 and 3B) should receive their dose of HGT-1410 every 28±7 days. If dosing cannot be 
administered within the indicated time window, the dose will be considered missed, and the 
patient will resume their dosing schedule with the next dose of HGT-1410. The dosing schedule 
will not change or be reset.
6.4
Method of Assigning Patients to Treatment Groups
Patients who were randomized to no-treatment in Study HGT-SAN-093 (Group 3) will be 
re-randomized in a 1:1 allocation ratio to receive Q2W or Q4W dosing (Groups 3A or 3B, 
respectively). To help ensure balance between the dose groups with respect to age at Baseline, 
the randomization will be stratified by age group (≤30 months and >30 months; see Section 
10.3).
Patients who were randomized to receive HGT-1410 in Study HGT-SAN-093 will remain on the 
same treatment regimen in Study SHP-610-201.


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6.5
Blinding
This study will not be blinded.
6.6
Prior and Concomitant Medications, Therapies, and Medical/Surgical Interventions
Prior and/or concomitant therapy prohibited for all patients in this study consists of the 
following:

Psychotropic or other medications, which in the Investigator’s opinion would be likely to 
substantially confound test results

The use of medications which, in the opinion of the Investigator, would place patients at risk 
of bleeding complications following surgery or LP

Any other investigational therapy (drug or device) at any time during the study

Hematopoietic stem cell or bone marrow transplant
6.7
Restrictions
6.7.1
Fluid and Food Intake 
Not applicable
6.7.2
Patient Activity Restrictions
Please refer to the SOPH-A-PORT Mini S IFU for details regarding patient activity restrictions 
for patients to be implanted with this device. Activities that may include sudden, excessive, or 
repetitive bending, twisting, bouncing, or stretching can damage or dislodge IDDD components 
and should be avoided.
6.8
Treatment Compliance
Treatment with HGT-1410 will be administered via an IDDD under the supervision of the 
investigator and in the controlled environment of a clinical center; therefore, full patient 
compliance with treatment is anticipated in this study.
6.9
Packaging and Labeling
All packaging and labeling will be in accordance with applicable regulatory requirements.
The SOPH-A-PORT Mini S Access Port is available in one size, individually packaged, with 
other SOPH-A-PORT Mini S components in double-peel-off, sterile, pyrogen-free packaging, 
sterilized with ethylene oxide. Instructions for use are also included in the packaging. A 
guidewire is provided in separate double-pouch, sterile, pyrogen-free packaging.
Labels are provided on the outer carton and on both the SOPH-A-PORT Mini S box and 
guidewire/cannula package inside and will be in accordance with local regulatory requirements.


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6.10
Storage and Accountability
6.10.1
Investigational Product
HGT-1410 will be supplied at a concentration of 15 mg/mL in single-use vials for IT 
administration.
HGT-1410 will be shipped by Shire or a qualified distributor to the clinical study site(s) at 2 to 
8°C (36-46°F).
Drug product should be stored refrigerated (2-8°C); drug product may not be used beyond the 
expiration date on the vial.
The disposition of all investigational product delivered to a Principal Investigator must be 
recorded on a patient-by-patient basis by completing the clinical trial material accountability log. 
The date and time of administration of the investigational product must be documented on the 
appropriate eCRF.
The Principal Investigator, Clinical Research Coordinator, or designee (eg, Pharmacist) must 
ensure that all documentation regarding investigational product receipt, storage, dispensing, 
loss/damaged and return of used/unused product is complete, accurate, and ready for review at 
each monitoring visit and/or audit. The sites must ensure that the investigational product is 
available for the monitor to inventory and prepare for return shipment to the Sponsor or 
designee, if required. 
The process for destruction of investigational product is provided in the Pharmacy Manual. 
See the Pharmacy Manual for additional details.
6.10.2
Intrathecal Drug Delivery Device
The disposition of all SOPH-A-PORT Mini S devices delivered to a Principal Investigator must 
be recorded on a patient-by-patient basis by completing the Accountability Log. The date and 
time of administration of the investigational product and use of the SOPH-A-PORT Mini S 
device must be documented on the patient’s appropriate eCRF.
The Principal Investigator, Clinical Research Coordinator, or designee (eg, Pharmacist) must 
ensure that all documentation regarding receipt, storage, dispensing, loss/damaged 
SOPH-A-PORT Mini S devices and return of used/unused SOPH-A-PORT Mini S device(s) is 
complete, accurate, and ready for review at each monitoring visit and/or audit. The sites must 
ensure that the SOPH-A-PORT Mini S devices are available for the monitor to inventory and 
prepare for product destruction or return shipment to the Sponsor or designee.
The SOPH-A-PORT Mini S and its components are sterile, single-use devices.
Please refer to the IDDD Manual for device destruction or return instructions.
6.10.3
Comparator Product
Not applicable to this study.


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7
STUDY PROCEDURES
Detailed descriptions of patient procedures and evaluations required for this protocol are 
described in this section. These evaluations will be performed during the indicated days and 
weeks of the study (see Schedule of Events for Group 1 [patients who received HGT-1410 Q2W 
in Study HGT-SAN-093[ in Appendix 1, for Group 2 [patients who received HGT-1410 Q4W in 
Study HGT-SAN-093] in Appendix 2, for Group 3A [patients who received no treatment in 
Study HGT-SAN-093 and are randomized to receive HGT-1410 Q2W in Study SHP-610-201] in 
Appendix 3, and for Group 3B [patients who received no treatment in Study HGT-SAN-093 and 
are randomized to receive HGT-1410 Q4W in Study SHP-610-201] in Appendix 4). 
See Appendix 5 for the Study Schedule of Events for the safety follow-up period for patients 
with partial or full devices in place after the end of the treatment period.
All data collected are to be recorded on the patient’s appropriate eCRF.
Details for sample collection are described in the Laboratory Manual for Study SHP-610-201.
7.1
Informed Consent
Prior to conducting any study-related procedures, written informed consent must be obtained 
from the patient’s parent(s) or legally authorized representative(s) and assent from the patient (if 
applicable).
The nature, scope, and possible consequences, including risks and benefits, of the study will be 
explained to the patient, the patient’s parent(s), or the patient’s legally authorized representative 
by the Investigator or designee in accordance with the guidelines described in Section 11.4. 
Documentation and filing of informed consent documents should be completed according to 
Section 11.4.
After the treatment period ends, informed consent from patients who do not have the IDDD 
removed (partial or full device) will be obtained for the safety follow-up period.
7.2
Study Entrance Criteria
Each patient in Groups 1 and 2 (those who received HGT-1410 in Study HGT-SAN-093) will be 
reviewed for eligibility against the study entrance criteria prior to receiving HGT-1410 at Weeks 
50 and 52, respectively. 
All treated patients in Study HGT-SAN-093 will have their cognitive development assessed at 
the Week 48 Visit in Study HGT-SAN-093. If a decline from Baseline of 20 points or less in DQ 
score is observed, then the patient may proceed into the Study SHP-610-201 without further 
evaluation. If a decline from Baseline of more than 20 points in DQ score is observed, then 
an individual evaluation by the Investigator will occur to determine if the patient is a treatment 
failure. This individual evaluation will take into account the DQ scores, VABS-II score, physical 
status, and any other information available for that patient at that time. If the Investigator deems 
the patient to be a treatment failure, then the patient may not enter the Study SHP-610-201.


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Each patient who received no treatment in Study HGT-SAN-093 (Group 3) will be reviewed for 
eligibility against the study entrance criteria before IDDD implantation.
Patients who do not meet the study entrance criteria will not be allowed to participate in the 
study. The reason(s) for the patient’s ineligibility for the study will be documented.
7.3
Hearing and Vision Assessments 
7.3.1
Investigator Assessment of Hearing and Vision
For patients who received no-treatment in Study HGT-SAN-093 (Group 3) only, the Investigator 
will use their clinical judgment to assess the patient’s vision during the initial physical 
examination. Investigator judgment will be used to determine whether the patient’s hearing and 
vision is adequate for cooperation with neurodevelopmental testing, as indicated in the study 
inclusion criteria.
7.4
Device-related Study Procedures
7.4.1
IDDD Implantation or Revision Procedures
The IDDD will be surgically implanted or revised at the clinical site. Procedures for implantation 
and revision are detailed in the device’s IFU. Standard hospital procedures for surgery will be 
followed; the patient will be under general anesthesia for this procedure.
An additional medical device, the catheter passer, is necessary for the implantation procedure. 
The catheter passer is a sterile, single-use device that will be used in the subcutaneous placement 
of the catheter. The Phoenix Neuro Disposable Catheter Passer, manufactured by Sophysa is CE-
marked in the EU and cleared under K853370 in the United States (US), may be provided; 
however, use of other catheter passers compatible with the SOPH-A-PORT Mini S is allowed.
Details of the implantation/revision and malfunctions/failure will be documented on the patient’s 
eCRF.
7.4.2
X-ray Verification of Intrathecal Drug Delivery Device Placement 
A postoperative X-ray check of the IDDD will be performed following surgery for Groups 3A 
and 3B to verify proper installation and confirmation of IDDD placement at the mid-thoracic 
level. The X-rays may be performed to check placement, migration, or malfunction of the device, 
as needed, throughout the treatment period or safety follow-up period of the study. At a 
minimum, the date of the X-ray verifying correct IDDD placement will be documented on the 
patient’s eCRF. If the device requires revision or replacement during the treatment period of the 
study, additional X-rays will be taken to document proper positioning of the device. If an IDDD 
malfunctions, an X-ray will be performed to assess the potential cause of malfunction. 
Fluoroscopy should be used during device implantation procedures.
7.4.3
CSF Sampling Procedure
Cerebrospinal fluid will be sampled via the device. If this is not possible, and if CSF sampling is 
necessary, either for adherence to the protocol or to investigate clinical concerns, an LP may be 
performed to sample CSF, either with or without administration of drug afterward.


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7.4.4
Device Adjustment, Revision, or Removal
If at the time of a scheduled dosing it is not possible to administer a full medication dosage using 
the standard administration steps detailed in the device’s IFU due to a device-related issue, the 
IDDD will be declared a device malfunction. If the device malfunction is irreversible and cannot 
be corrected without a device surgical intervention, the IDDD will be declared a device failure, 
starting from the date of the initial malfunction. 
The IDDD will then be surgically adjusted, removed, or revised and a new device and/or device 
components will be re-implanted at the earliest possible opportunity, preferably at the same time. 
Details of the device removal will be recorded in the patient’s eCRF. Refer to the SOPH-A-
PORT Mini S IFU for further details.
Patients should have the IDDD removed when they discontinue from or complete the treatment 
period of the study, unless the investigator determines that it should not be removed based upon 
safety assessments. The device can remain in the patient (partial [catheter only] or full [port, 
catheter, and suture wings]) if the patient is doing clinically well and there are no further known 
risk factors such as infection (eg, meningitis).  The device may be partially or fully removed as 
medically required and determined by the neurosurgeon at a future date.
7.5
Investigational Product Administration
Patients will be administered HGT-1410 by means of an IDDD, either every 2 weeks (Q2W) or 
every 4 weeks (Q4W). A visual examination of both the port and catheter track will be 
performed before each IT injection.
Patients will remain under observation in the hospital setting for at least 4 hours post-dosing and 
will be discharged when deemed clinically stable by the Investigator. The number of IDDD 
revisions/replacements is limited to 2 per patient in any 6-month period. Therefore, in the “worst 
case scenario” of 2 IDDD failures occurring within 1 month, up to 11 consecutive doses of 
HGT-1410 administered via LP will be necessary for patients in the Q2W dosing group, and up 
to 5 consecutive doses via LP will be necessary for patients in the Q4W dosing group until the 
IDDD can be revised or replaced.
A 22-gauge Huber non-coring needle is to be used for access to the implanted port; standard 
hypodermic needles would damage the septum and may cause leakage. If no needle-free 
connector is present, a stopcock or the Huber needle infusion set’s clamp is to be used to prevent 
CSF backflow and to mitigate the risk of air entering the system. It is possible to use other 
brands of Huber non-coring needles, provided that their specifications are identical to that of the 
Huber needle supplied by Sophysa in a SOPH-A-PORT Mini S (22G).
It is expected that all or most doses of HGT-1410 will be successfully administered following the 
application of topical anesthetic cream to the skin overlying the IDDD access port (see IDDD 
Manual for details). However, in some cases, sedation or general anesthesia may be required and 
may be used at the discretion of the Investigator. Any sedative or anesthetic drugs used must be 
recorded as concomitant medications.


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Intrathecal administration of investigational product will be preceded by CSF sampling for 
clinical laboratory analysis (cell count, protein, glucose) and storage for additional analyses 
which may include pharmacodynamics (GAG concentration) and analyses of HGT-1410 enzyme 
and anti-rhHNS antibodies, according to the relevant Schedules of Events (Appendix 1, 
Appendix 2, Appendix 3, and Appendix 4).
All HGT-1410 administrations will be followed by a flush with preservative-free saline of at 
least 2 mL. The total volume of investigational product and flush administered is targeted 
towards replenishing the volume of CSF withdrawn. If the total volume of HGT-1410 plus 2 mL 
saline flush is less than the total volume of CSF withdrawn, additional saline will be 
administered to balance the volumes withdrawn and injected.
The injection date, injection start/stop time, planned dose, injection volume, and flush volume 
will be recorded on the patient’s eCRF.
7.6
Efficacy Assessments
7.6.1
Neurocognitive and Developmental Assessments
The study methodology will include standardized neurodevelopmental assessments to provide a 
quantifiable measure of patient neurodevelopmental status (see Table 7-1).11 The assessments are 
estimated to last between 2 and 4 hours and must be conducted prior to any invasive procedures, 
such as blood draws, and prior to sedation or anesthesia. Neurodevelopmental status will be 
assessed over time by measuring cognitive and adaptive functions as follows:

Cognition:  The BSID-III12 will be used to assess all patients through the age of 42 months. 
Once patients reach age 42 months, an attempt will be made to switch the cognitive 
assessment to the KABC-II. If the cognitive status of the patient does not allow for testing by 
the KABC-II, the BSID-III may be used.

Adaptive behaviors:  The VABS-II13 will be used to assess all patients.
For this study, outcome measures will be computed for each patient enrolled. The psychometric 
instruments are summarized below in Table 7-1. 
Table 7-1
Neurodevelopmental Assessments Tests 
Cognitive Test or Scale 
Developmental or Cognitive Areas of Assessment
BSID-III12
Summary score and sub-domains:
- Cognitive
- Motor
- Social/Emotional
- Language
KABC-II
Cognitive and processing skills
ADAPTIVE BEHAVIOR
VABS-II13
Communication
Daily Living
Socialization
Motor Skills
Abbreviations: BSID-III=Bayley Scales of Infant and Toddler Development, Third Edition; KABC-II=


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Table 7-1
Neurodevelopmental Assessments Tests 
Cognitive Test or Scale 
Developmental or Cognitive Areas of Assessment
Kaufman Assessment Battery for Children, Second Edition; VABS-II=Vineland Adaptive Behavior Scales, 
Second Edition
7.6.2
Quality of Life Indicator:  Infant Toddler Quality of Life Questionnaire
The ITQoL will be administered during the study. The ITQoL was developed for children at least 
2 months of age up to 5 years and assesses the physical, mental, and social well-being of the 
child and assesses the quality of the parent/guardian’s life. If a patient is over 5 years of age, they 
do not have to complete the ITQoL.
7.6.3
Health Economics and Outcomes Research:  Healthcare Utilization 
Questionnaire
The HCUQ will be administered during the study. This HCUQ focuses on the direct and indirect 
costs of care for patients with MPS-III.
7.7
Magnetic Resonance Imaging
7.7.1
Head
Regional brain volumes, including total cortical gray matter volume, will be assessed through an 
MRI of the head. The patient will be under general anesthesia for this assessment. Instrument 
standardization and central analysis of MRIs will be performed by a designated contract research 
laboratory.
7.7.2
Liver and Spleen
Liver and spleen volumes will be assessed through an MRI, performed at the same times as for 
the MRI of the head. The patient will be under general anesthesia for this assessment. Instrument 
standardization and central analysis of MRIs will be performed by a designated contract research 
laboratory.
7.8
Pharmacokinetic Assessments
Blood samples will be collected for measurement of serum concentrations of HGT-1410 and 
determination of pharmacokinetic parameters at the times specified in the Schedules of Events 
(see Appendix 1, Appendix 2, Appendix 3, Appendix 4, and Appendix 7). Additionally, CSF 
samples will be collected from patients who received no treatment in Study HGT-SAN-093 at 
the times specified in the Schedules of Events (see Appendix 3, Appendix 4, and Appendix 7). 
The results of these assessments will be addressed in a separate pharmacokinetics report.
Patients may be discharged from the hospital after the 24-hour blood draw. Patients will either 
stay locally in a hotel or return home (if they live in close proximity to the hospital); this will be 
decided in consultation with the Investigator. Patients will return to the hospital for 
pharmacokinetic blood and CSF sampling at the 48-hour time point. Patients will be discharged 
to home after the physical examination and blood draws have been completed at the 48-hour PK 


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time point. See Appendix 7 for more details regarding timing for pharmacokinetic sample 
collection.
Serum and CSF pharmacokinetic collection, processing, and shipping instructions will be 
provided in the Laboratory Operations Manual.
7.9
Pharmacodynamic Biomarker Assessments (CSF and Urine GAG Levels)
CSF and urine samples will be obtained to measure the concentration of GAG according to the 
schedules of events (Appendix 1, Appendix 2, Appendix 3, and Appendix 4). Details about CSF 
collection are provided in Section 7.11.5.3.
7.10
Concomitant Medications, Therapies, and Medical/Surgical Interventions
All non-protocol treatments and medications that occur from the time of informed consent 
through the safety follow-up contact are regarded as concomitant and will be documented on the 
appropriate pages of the eCRF. Concomitant therapy includes any therapies/interventions 
administered to patients, and these will be recorded on the concomitant therapy eCRF. Any 
medical/surgical procedures performed on the patients will be recorded on the concomitant 
medical/surgical procedures eCRF. Concomitant medications, both prescribed and 
over-the-counter (including genistein and anesthesia medications) will be recorded on the 
concomitant medication eCRF.
Every effort should be made to keep symptomatic MPS IIIA treatment constant throughout the 
study. However, changes in medications are acceptable if necessary according to clinical 
judgment. All changes will be recorded on the appropriate eCRF. Concomitant medication will 
be coded using the World Health Organization-Drug Dictionary (WHO-DD).
7.11
Safety Assessments
7.11.1
Vital Signs
Vital signs are to be recorded on the eCRF for all patients and will include heart rate, blood 
pressure, respiration rate, and body temperature. Vital signs will be recorded for at least 4 hours 
following each dose of HGT-1410, as described in the Schedules of Events (Appendix 1, 
Appendix 2, Appendix 3, and Appendix 4).
7.11.2
Physical Examination, Including Height, Weight, and Head Circumference
During the study, physical examinations will be performed at the time points indicated in the 
Schedules of Events. For Groups 1 and 2, full physical examinations will be conducted at Weeks 
96, 120, 144, and 168, and for Groups 3A and 3B, full physical examinations will be conducted 
during the IDDD implantation period and at Weeks 24, 48, 72, 96, and 120. The remainder of 
physical examinations will be symptom-directed, including examinations during the safety 
follow-up period in patients who do not have the IDDD removed (partial or full device) at the 
end of the treatment period.
Physical examinations will include a review of the patient’s general appearance, neurological 
examination, as well as evaluation of the body systems described in Table 7-2, including the port 


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and catheter track. Any abnormal change in findings will be recorded as an AE on the 
appropriate eCRF.
Table 7-2
Assessments for Physical Examinations
Assessment
Assessment
General appearance
Endocrine
Head and neck
Cardiovascular
Eyes
Abdomen
Ears
Genitourinary
Nose
Skin
Throat
Musculoskeletal
Chest and lungs
Neurological
Port and catheter track
Height and weight will be recorded for all patients.
The clinical site staff will be instructed to use calibrated scales for weight measurement where 
possible. The same scale is to be used at the clinical site for all patients at each specified time 
point during the study.
Head circumference will be measured for Groups 3A and 3B during the IDDD implantation 
period. All data will be recorded on the eCRF. 
7.11.3
Electrocardiogram
An ECG will be performed in accordance with the clinical site’s standard practice(s) and are to 
be performed after study drug administration. Electrocardiogram recordings will be read locally 
at the clinical site and will include an assessment of heart rate, sinus rhythm, atrial or ventricular 
hypertrophy, PR, QRS, and QT. Identification of any clinically significant findings and/or 
conduction abnormalities will be recorded on the eCRF. If the patient is unable to cooperate with 
electrocardiography, and if sedation or general anesthesia is employed during that study visit, the 
ECG may be performed under sedation/anesthesia.
7.11.4
Clinical Laboratory Tests
Blood and urine samples will be collected as described in this section for clinical laboratory 
testing. All blood samples will be collected via venipuncture. Patients will be in a seated or 
supine position during blood collection. Procedures for collection and handling of samples are 
included in the Laboratory Manual. Blood volumes are presented in Appendix 6.
Clinical laboratory testing will only be performed when indicated for a device-related AE for 
patients who do not have the IDDD removed (partial or full device) at the end of the treatment 
period.
Clinical laboratory tests will include the following (see Table 7-3):


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Table 7-3
List of Laboratory Tests
Hematology:
-
Hematocrit (Hct)
-
Hemoglobin (Hgb)
-
Mean corpuscular hemoglobin (MCH)
-
Mean corpuscular hemoglobin 
concentration (MCHC)
-
Mean corpuscular volume (MCV)
-
Platelet count
-
Red blood cell (RBC) count 
-
White blood cell (WBC) count with 
differential 
Urinalysis:  
-
Appearance
-
Bilirubin
-
Color
-
Glucose
-
Ketones
-
Microscopic examination of sediment 
-
Microscopic examination
-
Nitrite 
-
Occult blood
-
pH
-
Protein
-
Specific gravity
-
Urobilinogen
-
Triglycerides
-
Uric acid
Anti-rhHNS antibody assessment
Serum Chemistry:
-
Albumin (ALB)
-
Alkaline phosphatase (ALK-P)
-
Alanine aminotransferase (ALT; SGPT)
-
Aspartate aminotransferase (AST; SGOT)
-
Blood urea nitrogen (BUN)
-
Calcium (Ca)
-
Carbon dioxide (CO2)
-
Chloride (Cl)
-
Creatinine
-
Creatine kinase (CK) and subtypes
-
Gamma-glutamyl transferase (GGT)
-
Globulin
-
Glucose
-
Lactate dehydrogenase (LDH)
-
Phosphorus
-
Potassium (K)
-
Sodium (Na)
-
Total bilirubin
-
Direct bilirubin
-
Total cholesterol
-
Total protein
-
Triglycerides
-
Uric acid
Coagulation (performed at IDDD implantation):  
-
Prothrombin time (PT)
-
Activated partial thromboplastin time 
(aPTT)
7.11.5
Cerebrospinal Fluid Assessments 
Cerebrospinal fluid will be obtained from patients during surgical implantation of the IDDD 
(Groups 3A and 3B only), immediately prior to each injection of study drug and at the safety 
follow-up visit. Should the IDDD become clogged or undergo mechanical complications, the 
CSF sample will be obtained via LP.
The volume of CSF collected at each visit will vary according to the number of CSF 
assessments. The initial 1 mL of CSF aspirated via the IDDD will be discarded, to eliminate fluid 
in the device’s “dead space.” The next 1 mL of CSF will be sent to the local laboratory. 
Subsequently drawn CSF will be stored, depending on the requirement for that visit (see the 
Schedules of Events in Appendix 1, Appendix 2, Appendix 3, Appendix 4, and the Laboratory 
Manual). If CSF is obtained via LP, there is no need to discard the first mL of CSF, and this can 
be sent to the local laboratory for standard clinical assessments. If the patient is clinically stable 


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in the opinion of the Investigator, HGT-1410 can be administered immediately following 
withdrawal of CSF, without awaiting the results of the CSF clinical laboratory data. 
Each CSF sample collected will have the assessments described in Sections 7.11.5.1 through 
7.11.5.4. Cerebrospinal fluid sample collection, processing, and shipping instructions are 
provided in the Laboratory Manual. Total CSF volumes are presented in Appendix 6.
7.11.5.1
Standard CSF Safety Laboratory Assessments
An aliquot of each CSF sample collected will be evaluated for CSF standard chemistries, 
glucose, protein, and cell counts.
7.11.5.2
Anti-rhHNS Antibodies and Biomarkers in CSF
An aliquot of each CSF sample collected will be quick frozen for subsequent analysis of 
anti-rhHNS antibody evaluation, exploratory proteomics biomarkers, and/or other CSF 
biomarkers.
7.11.5.3
CSF GAG Levels and Biomarkers
An aliquot of each CSF sample collected will be quick frozen for subsequent analysis of CSF 
GAG, GAG degradation components, HS/dermatan sulfate (DS) oligosaccharides, or other CSF 
markers. The CSF pharmacodynamic sample will be obtained at the same visit as a serum sample 
as described in Section 7.9.
7.11.5.4
7.11.6
Device Assessments
, 
 These 
data will be collected on the patient’s eCRF from the time of initial implantation.
7.11.7
Collection and Storage of Biological Samples for Biomarker Studies 
Biomarker analyses may be performed at the Shire research laboratory or at a Shire-designated 
research laboratory. Collection and processing of CSF samples will be performed as specified in 
the Laboratory Manual. Samples will be stored securely to ensure patient confidentiality. 
Samples obtained for this study will be stored for up to 10 years. Thereafter, samples will be 
destroyed. 
7.12
Sample Collection, Storage, and Shipping
Details for study procedures including sample collection are provided in the Laboratory Manual 
for this study.


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7.13
Adverse Events Assessments
7.13.1
Definitions of Adverse Events and Serious Adverse Events
7.13.1.1
Adverse Event
An AE is any noxious, pathologic, or unintended change in anatomical, physiologic, or 
metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in 
any phase of a clinical study, whether or not considered investigational product-related. This 
includes an exacerbation of a pre-existing condition. 
Adverse events include:

Worsening (change in nature, severity, or frequency) of conditions present at the onset of the 
study

Intercurrent illnesses

Drug interactions

Events related to or possibly related to concomitant medications

Abnormal laboratory values (This includes significant shifts from baseline within the range 
of normal that the Investigator considers to be clinically important.)

Clinically significant abnormalities in physical examination, vital signs, and weight
Throughout the study, the Investigator must record all AEs on the AE eCRF, regardless of the 
severity or relationship to investigational product. The Investigator should treat patients with 
AEs appropriately and observe them at suitable intervals until the events stabilize or resolve. 
Adverse events may be discovered through observation or examination of the patient, 
questioning of the patient, complaint by the patient, or by abnormal clinical laboratory values.
In addition, AEs may also include laboratory values that become significantly out of range. In 
the event of an out-of-range value, the laboratory test should be repeated until it returns to 
normal or can be explained and the patient’s safety is not at risk.
Additional illnesses present at the time when informed consent is given are regarded as 
concomitant illnesses and will be documented on the appropriate pages of the eCRF. Illnesses 
first occurring or detected during the study, and worsening of a concomitant illness during the 
study, are to be regarded as AEs and must be documented as such in the eCRF.
7.13.1.2
Adverse Events Due to Systemic Exposure to HGT-1410 
Although HGT-1410 is given intrathecally only, some proportion of the drug will diffuse from 
the CSF into the peripheral circulation. The resulting systemic exposure may cause events that 
are typically seen in patients receiving ERT via an intravenous administration. Investigators will 
judge the relationship of AEs to the drug infusion and describe the clinical details on the AE 
form. The temporal relationship of an AE to the drug infusion will be determined upon analysis 
of the AE and study treatment administration data. 


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7.13.1.3
Infusion/Hypersensitivity Reactions and Management
Infusions of proteins can be associated with reactions to the infusion that may or may not be 
immune-mediated (hypersensitivity reactions). Thus, potential reactions to the infusion of 
investigational drug are unpredictable. It is often difficult to clinically distinguish infusion 
reactions from hypersensitivity reactions. Symptoms may include headache, fever, sensory 
paresthesias (including feeling of warmth, tingling, or pain), rash, pruritus, or autonomic 
symptoms, such as dry mouth or gustatory abnormalities (including loss of smell and metallic 
taste). Changes in mental status or level of consciousness that are not caused by pre-medication 
may either occur acutely or develop post-injection over time. 
The management of infusion reactions and hypersensitivity reactions is similar. The following 
steps may be taken, at the discretion of the Investigator, in the event of a suspected infusion 
related/hypersensitivity reaction and the management of such reactions should be based on the 
severity of the reaction:

Treatment with medications such as antihistamines, antipyretics, and/or corticosteroids

Stopping and resuming treatment

Pretreatment with antihistamines and/or corticosteroids may prevent subsequent reactions in 
those cases where symptomatic treatment was required
7.13.1.4
IDDD-related Adverse Events
IDDD ADVERSE EVENTS
Examples of AEs related to use of the IDDD include, but are not limited to, the following:  
device failure, device malfunction, incorrect connection of IDDD components, erosion of the 
portal/catheter through the skin, fibrin sheath formation around the catheter tip, hematoma, 
implant rejection, migration of the portal/catheter, and occlusion of the portal/catheter, portal site 
or subcutaneous tract infection. A malfunction of the device (defined in Section 7.13.2.2) should 
not be entered as an adverse event unless it has physiological consequences. In the event of a 
device failure (defined in Section 7.13.2.3), the device may need to be replaced or repaired. If 
overnight hospitalization is required for such a procedure (or the device failure meets any other 
serious criteria, eg, medically important), the device failure will be reported as a serious adverse 
event. Details of the cause of the IDDD malfunction or failure will be recorded on the device 
malfunction and failure eCRF and the serious adverse event (SAE) form (when applicable). A 
list of the most common IDDD AEs is included in Appendix 8.
DEVICE SURGICAL PROCEDURE-RELATED ADVERSE EVENTS (FOR IT STUDIES; AMEND/DELETE 
SECTION AS APPLICABLE)
Examples of AEs related to device surgical procedures include, but are not limited to, the 
following:  events that occur during or shortly following IDDD implant/explant, IDDD 
adjustment, full revision, partial revision, IDDD removal, and delayed re-implantation after 
previous IDDD removal (such as complications of anesthesia, excessive bleeding, wound 
hematoma), and postoperative complications (such as postoperative infection). These events are 
related to the surgical procedure itself.


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IT ADMINISTRATION PROCESS ADVERSE EVENTS
Intrathecal administration process adverse events may include those caused by anesthesia during 
drug administration and other drug administration issues (eg, extravasation during infusion or 
hematoma due to Huber needle) or complications of LP.
7.13.1.5
Serious Adverse Event
An SAE is any AE occurring at any dose of investigational drug or procedure that results in any 
of the following outcomes:

Death

Is life-threatening

Requires hospitalization

Requires prolongation of existing hospitalization

A persistent or significant disability or incapacity 

A congenital anomaly or birth defect
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. A life-threatening AE is defined as an AE that placed the 
patient, in the view of the initial reporter, at immediate risk of death from the AE as it occurred 
(ie, it does not include an AE that, had it occurred in a more severe form, might have caused 
death).
An unanticipated adverse device effect (UADE) is any SAE on health or safety or any life-
threatening problem or death caused by, or associated with, a device, if that effect, problem, or 
death was not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that relates to the rights, safety, or 
welfare of patients (21 Code of Federal Regulations [CFR] 812.3[s] or other regulatory 
requirements, as applicable).
7.13.2
Device-associated Definitions
7.13.2.1
Device Revision (Partial and Full)
Partial device revision:  surgical revision/replacement of one or more component(s) of the 
device; other component(s) of the original device remain implanted and are not affected (eg, port 
revision).
Full device revision:  The device is removed (explanted) in its entirety, and a completely new 
device is implanted.
Device adjustment:  surgery that does not result in partial or full device revision (see definition 
above) or removal. Examples of device adjustment include surgical exploration only or 
placement of additional sutures, tissue glue, and/or fascial repair.


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7.13.2.2
Device Malfunction
The device does not perform as intended, based on the description in the device’s IFU, but does 
not require either a partial or full device revision.
7.13.2.3
Device Failure
The device irreversibly fails to perform as intended and requires either a partial or full device 
revision or removal.
7.13.3
Classification of Adverse Events and Serious Adverse Events
The severity of AEs will be assessed by the Investigator based on the definition indicated in 
Table 7-4. The severity of all AEs/SAEs should be recorded on the appropriate eCRF page to a 
severity of mild, moderate, or severe.
Table 7-4
Adverse Event Severity
Severity
Definition
Mild
No limitation of usual activities.
Moderate
Some limitation of usual activities.
Severe
Inability to carry out usual activities.
7.13.4
Clarification between Serious and Severe
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache). This is not the same as “serious,” which is based 
on the outcome or action criteria usually associated with events that pose a threat to life or 
functioning. Seriousness (not severity) and causality serve as a guide for defining regulatory 
reporting obligations.
7.13.5
Relatedness of Adverse Events and Serious Adverse Events
Relationship of an AE or SAE to investigational product, device (IDDD), device surgical 
procedure, or IT administration process will be assessed by the Investigator based on the 
following definitions (see Table 7-5).
Table 7-5
Adverse Event Relatedness
Relationship
Definition
Not Related
Unrelated to investigational product, device, device surgical 
procedure, or IT administration process.
Possibly Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of investigational product, the presence of 
the device, device surgical procedure, or IT administration process but 
which could also be explained by concurrent disease or other drugs or 
chemicals.
Probably Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of investigational product, the presence of 
the device, device surgical procedure, or IT administration process


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Table 7-5
Adverse Event Relatedness
Relationship
Definition
unlikely to be attributable to concurrent disease or other drugs and 
chemicals and which follows a clinically reasonable response on de-
challenge. The association of the clinical event or laboratory 
abnormality must also have some biologic plausibility, at least on 
theoretical grounds.
Definitely related
The event follows a reasonable temporal sequence from administration 
of the investigational product, the presence of the device, device 
surgical procedure, or IT administration process follows a known or 
suspected response pattern to the investigational product, is confirmed 
by improvement upon stopping the investigational product 
(de-challenge), and reappears upon repeated exposure (re-challenge). 
Note that this is not to be construed as requiring re-exposure of the 
patient to investigational product; however, the determination of 
definitely related can only be used when recurrence of event is 
observed.
7.13.6
Procedures for Recording and Reporting Adverse Events
7.13.6.1
Adverse Event Monitoring and Period of Observation
Adverse events will be monitored continuously throughout the study.
For the purposes of this study, the period of observation extends from the time at which the 
patient, the patient’s parent(s), or the patient’s legally authorized representative gives informed 
consent until the patient’s final evaluation of the study. For safety purposes, the final evaluation 
for the treatment period will be defined as the follow-up evaluation performed approximately 30 
days after the last dose for patients who complete the study. The final evaluation in the safety 
follow-up period for patients who do not have the IDDD removed (full or partial device) is 
defined as the follow-up evaluation performed for up to 3 years after the treatment period ends.
If the Investigator considers it necessary to report an AE in a study patient after the end of the 
safety observation period, he or she should contact the Sponsor to determine how the AE should 
be documented and reported.
7.13.6.2
Reporting Serious Adverse Events
Any SAE, regardless of relationship to investigational product, device, device surgical 
procedure, or IT administration process which occurs in a patient after informed consent, should 
be recorded by the clinical site on an SAE form. The SAE must be completely described on the 
patient’s eCRF, including the judgment of the Investigator as to the relationship of the SAE to 
the investigational product and/or device. The Investigator will promptly supply all information 
identified and requested by the Sponsor (or contract research organization [CRO]) regarding the 
SAE. 


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The Investigator must report the SAE to the Shire Pharmacovigilance and Risk Management 
Department AND to the Shire Medical Monitor on an SAE form. This form must be completed 
and FAXED or EMAILED within 24 hours of the Investigator’s learning of the event to:
Shire Pharmacovigilance and Risk Management Department:
International FAX:   
 (UK) OR United States FAX:  
Email:  
AND
Shire Medical Monitor:  
, DO
Email:  
Any follow-up information must also be completed on an SAE form and faxed or emailed to the 
same numbers or emails listed above.
In the event of a severe and unexpected, fatal, or life-threatening SAE, the clinical site must 
contact the Shire Medical Monitor by telephone; this is in addition to completing and 
transmitting the SAE form as stated above. The following provides contact information for the 
Shire Medical Monitor. 


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If an SAE is assessed as severe and unexpected, fatal or life-threatening, contact:
 DO
Shire Human Genetic Therapies, Inc.
300 Shire Way
Lexington, MA 02421  USA
Telephone:  
Mobile Telephone: 
(24-hour access)
Email:
The Investigator must promptly report all required information to the IRB/EC. It is the 
responsibility of the Sponsor to ensure that each Investigator receives a copy of any Council for 
International Organizations of Medical Sciences I/MedWatch report that has been submitted to 
the appropriate regulatory agencies notifying them of an unexpected related SAE. The 
Investigator or Sponsor must ensure that the IRB/EC receives a copy of the report and that a 
copy is also filed within their study files.
7.14
Abuse, Overdose and Medication Error
Abuse – Persistent or sporadic intentional intake of investigational medicinal product at a dose 
higher than prescribed per protocol (but below the dose defined for overdose) or when used for 
non-medical purpose (eg, altering one’s state of consciousness)
Misuse – Intentional or unintentional use of investigational medicinal product other than as 
directed or indicated at any dose, which is at or below the dose defined for overdose (Note:  This 
includes a situation where the test article is not used as directed at the dose prescribed by the 
protocol.)
Overdose – Intentional or unintentional intake of a dose of investigational medicinal product 
higher than the protocol-mandated dose. No clinical information on overdose is available. 
Medication Error – A mistake made in prescribing, dispensing, administration and/or use of the 
investigational medicinal product.
All investigational medicinal product provided to pediatrics should be supervised by the 
parent/legally authorized representative/caregiver.
7.15
Removal of Patients from the Trial or Investigational Product
A patient’s participation in the study may be discontinued at any time at the discretion of the 
Investigator. The following may be justifiable reasons for the Investigator to remove a patient 
from the study:

Non-compliance, including failure to appear at one or more study visits

The patient was erroneously included in the study.


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
The patient develops an exclusion criterion. 

The patient suffers an intolerable AE.

The study is terminated by the Sponsor.
The patient, the patient’s parent(s), or the patient’s legally authorized representative acting on 
behalf of the patient is free to withdraw consent and discontinue participation in the study at any 
time without prejudice to further treatment.
If a patient or the patient’s parent(s) or the patient’s legally authorized representative(s) acting on 
behalf of the patient, discontinues participation in the study, or the patient is discontinued by the 
Investigator, reasonable efforts will be made to follow the patient through the safety follow-up 
assessments. The reason for refusal will be documented on the eCRF. Any AEs experienced up 
to the point of discontinuation must be documented on the AE eCRF. If AEs are present when 
the patient withdraws from the study, the patient will be re-evaluated within 30 days of 
withdrawal. All ongoing SAEs at the time of withdrawal will be followed until resolution.
7.15.1
Study Discontinuation Process
If the patient is discontinued from the study, the IDDD should be removed and a modified 
end-of-study visit should be completed within 30 days after withdrawal. These visits may be 
combined into 1 visit, in which case follow-up via a phone call should be completed within 14 
days after the device removal to collect safety information. The end–of-study visit only requires 
collection of safety assessments, including symptom-directed physical exam, vital signs, clinical 
laboratory tests (hematology, serum chemistry, and urinalysis), concomitant medications, 
therapies, and procedures, and AE monitoring. No MRI or cognitive assessments are required. 
No study-required CSF collection is needed at the IDDD removal, unless required for AE 
resolution.
If the investigator determines that the IDDD should not be removed from the patient based upon 
a safety assessment and the IDDD (full or partial) remains in the patient, then the patient will 
continue in the study under the safety follow-up period upon completion of their last treatment 
period visit. This last treatment period visit only requires collection of safety assessments, 
including symptom-directed physical exam, vital signs, clinical laboratory tests (hematology, 
serum chemistry, and urinalysis), concomitant medications, therapies, and procedures, and AE 
monitoring. No MRI or cognitive assessments are required. No study-required CSF collection is 
needed at the IDDD removal, unless required for AE resolution. Once the patient completes their 
last treatment period visit, they will return for their first safety follow-up visit in 6 months. The 
patient will continue in the safety follow-up period with a clinic visit every 6 months for up to 
3 years or until the device is removed in the last patient.  An end-of-study follow-up via a phone 
call should be completed within 14 days after the device removal to collect safety information
(refer Section 8.6; Appendix 5).
7.16
Safety-Related Study Stopping Rules
In addition to safety monitoring by the Sponsor, patient safety in this study will be monitored by 
an independent DMC until the last patient completes their last scheduled study visit/assessment
during the treatment period. The DMC will be an external group overseeing the safety of the


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study treatment, including both the investigational product and the IDDD, and will operate 
according to a charter determining the scope of its activities and frequency of meetings (see 
Section 11.8 for additional details).
This study will be stopped and safety data reviewed if any patient experiences a life-threatening 
or fatal SAE, either of which is considered possibly or probably related to the investigational 
product.
Following the review of safety data, the status of the study will be one of the following:

Resumed unchanged

Resumed with modifications to the protocol 

Terminated
Patient safety will be monitored on a continuous basis during this study until the last patient 
completes his or her last scheduled study visit/assessment. 
7.17
Appropriateness of Measurements
The neurocognitive and developmental assessments planned for this study are intended to gauge 
the potential treatment effect and safety of 2 dose levels of HGT-1410 over time on behavioral 
and cognitive criteria in patients with MPS IIIA. The selection of tests used for the cognitive 
assessment, and the expression of results as a ratio of mental age equivalence to calendar age to 
generate a DQ, were developed in collaboration with clinical psychologists with expertise in the 
assessment of severely disabled children with neurometabolic diseases. 
The BSID-III, KABC-II, and VABS-II are instruments that have been used to assess 
development in healthy children and those with developmental delay. Their use in this study will 
contribute to their validation in patients with MPS IIIA. The utility of these measures to track 
disease progression has been demonstrated in Shire’s natural history study of MPS IIIA 
(HGT-SAN-053). 
The BSID-III was selected for the following reasons:  

Widespread familiarity with the instrument 

Availability of age equivalent scores for severely impaired children 

Nonverbal content (ie, on the cognitive scale on the BSID-III) 

Availability of language and motor assessment (Both are domains on the BSID-III.) 
The BSID-III is validated for children through the age of 42 months. Patients are to be switched 
to another instrument, the KABC-II, to measure cognition after the age of 42 months. The 
KABC-II measures a child’s cognitive ability and processing skills and was designed to 
minimize verbal instructions and responses. In addition, the assessment contains little cultural 
content to provide a more accurate assessment of children from diverse backgrounds. Thus 
language difficulties or cultural differences are minimized in the test battery’s results.


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The VABS-II, a parent-reported outcome, was selected as an adaptive measure for the same 
reasons. Of note, to maximize standardization and reduce bias, the “interview” form of the 
VABS-II will be administered by the clinical psychologist/psychometrist at the same time as the 
BSID-III assessment.
The use of age equivalent scores rather than standard scores permits the assessment of children 
with severe disability in whom standard scores would otherwise be insensitive to change. Given 
the potentially rapid progression of MPS IIIA, a child who is assessable using a standard score at 
baseline may rapidly decline to such an extent that the assessment “floor” is reached and further 
change is not measurable. Additionally, the use of age equivalence scores permits comparison 
and correlation between the BSID-III and VABS-II. The use of DQ yields a parameter that tracks 
the dynamic progression of MPS IIIA disease, as observed in Shire’s natural history study. 
This study will utilize standard safety assessments including AEs, vital signs, standard clinical 
tests, and ECGs. Antibodies against the investigational drug will also be measured.


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8
STUDY ACTIVITIES
The timing of study activities are described for each of the 3 patient groups below, and in 
Appendix 1, Appendix 2, Appendix 3, and Appendix 4, respectively for Group 1 (initially 
randomized to receive HGT-1410 Q2W in Study HGT-SAN-093), Group 2 (initially randomized 
to receive HGT 1410 Q4W in Study HGT-SAN-093), Group 3A (initially randomized to 
no-treatment in Study HGT-SAN-093 and randomized to HGT-1410 Q2W in Study 
SHP-610-201), and Group 3B (initially randomized to no-treatment in Study HGT-SAN-093 and 
randomized to HGT-1410 Q4W in Study SHP-610-201). See Appendix 5 for the timing of study 
activities for the safety follow-up period for patients with partial or full devices in place after the 
end of the treatment period.  Study activities for all patients are detailed in Section 7.
8.1
Group 1 (Maintaining Q2W Dosing)
8.1.1
Treatment Period (Weeks 50 through 168)
The pre-treatment assessments may be performed on the same day as the administration of study 
drug if it is feasible for the patient to arrive at the study site early in the day, and if it is deemed 
clinically appropriate by the Investigator. Patients may be discharged from the clinical site 
4 hours after dosing, if deemed stable by the Investigator.
Patients in Group 1 will receive 45 mg HGT-1410 IT Q2W (ie, every 14±3 days). 
Administration of HGT-1410 can only occur following the completion of all pre-treatment 
assessments and procedures. 
The first 48 weeks of treatment for Group 1 occurred in Study HGT-SAN-093, and therefore 
patients in Group 1 will begin this study at Week 50. 
For patients in Group 1, HGT-1410 will be administered every other week from Week 50 
through Week 168.
8.1.1.1
Pre-treatment Assessments

Review of study eligibility and informed consent

Full physical examination (PE), including height and weight at Weeks 72, 96, 120, 144, and 
168; symptom-directed PE at all other visits

Every visit:  vital signs, concomitant medications, therapies, and procedures, and AE 
monitoring 

Cognitive/behavioral assessments:  BSID-III/KABS-II and VABS-II:  Weeks 72, 96, 120, 
144, and 168

Quality of life (QoL) questionnaire:  ITQoL for patients ≤5 years of age: Weeks 72, 96, 120, 
144, and 168

Health economics questionnaire:  HCUQ:  Weeks  72, 96, 120, 144, and 168

MRIs of head, liver, and spleen: Weeks 96 and 144

Clinical laboratory tests:  hematology, serum chemistry, urinalysis: Weeks 60, 72, 84, 96, 
108, 120, 132, 144, 156, and 168

Every study visit before dosing:  standard CSF safety laboratory assessments


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
CSF and urine sample collection for GAG at Weeks 60, 72, 84, 96, 108, 120, 132, 144, 156, 
and 168

Every study visit:  CSF sample collection for storage for biomarkers

Anti-rhHNS antibody testing (serum and CSF) and CSF biomarker testing at Weeks 60, 72, 
84, 96, 108, 120, 132, 144, 156, and 168

Serum pharmacokinetics sampling at Week 96 (see Appendix 7 for the pharmacokinetics 
collection schedule)
8.1.1.2
Post-treatment Assessments 

ECG at Weeks 96, 144, and 168

Serum pharmacokinetics sampling at Week 96 (see Appendix 7 for the pharmacokinetics 
collection schedule)

Concomitant medications, therapies, and procedures

AE monitoring

Removal of IDDD if patient not continuing treatment (unless the Investigator determines that 
the device should not be removed for safety reasons)
8.1.2
Safety Follow-up Visit:  Week 172 (±7 days) 
All patients will have a safety follow-up visit at Week 172 or 30 (±7) days after their last dose of 
HGT-1410. 

Symptom-directed PE

Vital signs

Clinical laboratory tests

Concomitant medications, therapies, and procedures

AE monitoring
8.2
Group 2 (Maintaining Q4W Dosing)
8.2.1
Treatment Period (Weeks 52 through 168)
The pre-treatment assessments may be performed on the same day as the administration of study 
drug if it is feasible for the patient to arrive at the study site early in the day and if it is deemed 
clinically appropriate by the Investigator. Patients may be discharged from the clinical site 
4 hours after dosing, if deemed stable by the Investigator.
Patients in Group 2 will receive 45 mg HGT-1410 IT Q4W (ie, every 28±7 days). 
Administration of HGT-1410 can only occur following the completion of all pre-treatment 
assessments and procedures. 
The first 48 weeks of treatment for Group 2 occurred in Study HGT-SAN-093, and therefore 
patients in Group 2 will begin this study at Week 52. 
For patients in Group 2, HGT-1410-IT Q4W study drug will be administered Q4W from 
Week 52 through Week 168.


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8.2.1.1
Pre-treatment Assessments

Review of study eligibility and informed consent

Full PE, including height and weight at Weeks 72, 96, 120, 144, and 168; symptom-directed 
PE at all other visits

Every visit:  vital signs, concomitant medications, therapies, and procedures, and AE 
monitoring 

Cognitive/behavioral assessments:  BSID-III/KABS-II and VABS-II:  Weeks 72, 96, 120, 
144, and 168

QoL questionnaire:  ITQoL for patients ≤5 years of age:  Weeks 72, 96, 120, 144, and 168

Health economics questionnaire:  HCUQ:  Weeks 72, 96, 120, 144, and 168

MRIs of head, liver, and spleen: Weeks, 96 and 144

Clinical laboratory tests:  hematology, serum chemistry, urinalysis: Weeks 60, 72, 84, 96, 
108, 120, 132, 144, 156, and 168

Every study visit before dosing:  standard CSF safety laboratory assessments

CSF and urine sample collection for GAG at Weeks 60, 72, 84, 96, 108, 120, 132, 144, 156, 
and 168

Every study visit:  CSF sample collection for storage for biomarkers

Anti-rhHNS antibody testing (serum and CSF) and CSF biomarker testing at Weeks 60, 72, 
84, 96, 108, 120, 132, 144, 156, and 168

Serum PK sampling at Week 96  (see Appendix 7 for the pharmacokinetics collection 
schedule)_
8.2.1.2
Post-treatment Assessments 

ECG at Weeks 96, 144, and 168

Serum PK sampling at Week 96 (see Appendix 7 for the pharmacokinetics collection 
schedule)

Concomitant medications, therapies, and procedures

AE monitoring

Removal of IDDD if patient not continuing treatment (unless the Investigator determines that 
the device should not be removed for safety reasons, please see Section 8.6)
8.2.2
Safety Follow-up Visit:  Week 172 (±7 days) 
All patients will have a safety follow-up visit at Week 172 or 30 (±7) days after their last dose of 
HGT-1410:

Symptom-directed PE

Vital signs

Clinical laboratory tests

Concomitant medications, therapies, and procedures

AE monitoring


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8.3
Group 3 (Patients Randomized to No Treatment in Study HGT-SAN-093)
Patients in Group 3 received no treatment in Study HGT-SAN-093, and therefore these patients 
will begin this study at Day -27 to -7.
8.3.1
IDDD Implantation (Days -21 to Day -7)
8.3.1.1
Prior to IDDD Implantation
Prior to enrollment in the study, patients who were initially randomized to no treatment in Study 
HGT-SAN-093 will undergo the following assessments during the IDDD implantation period, 
prior to IDDD implantation surgery:
Written informed consent
Assessment of eligibility according  to 
inclusion/exclusion criteria
Vital signs
Investigator assessment of vision and 
hearing ability 
PE, including height, weight, and head 
circumference
ECG
Clinical laboratory tests, including PT 
and aPTT
BSID-III/KABC-II
VABS-II
ITQoL (for patients ≤5 years of age)
HCUQ
Concomitant medications, therapies, 
and procedures
AE monitoring
The PE, ECG, height, weight, and clinical labs (hematology, serum chemistry, and urinalysis) 
need to be performed within 7 days prior to the IDDD implantation surgery date. If more than 7 
days elapse between the date of these assessments and the IDDD implantation surgery date, the 
assessments must be repeated within 7 days prior to surgery.
8.3.1.2
Day of IDDD Implantation
Surgical implantation of the IDDD includes surgical implantation of the IDDD and a 
post-surgical assessment. IDDD placement will require anesthesia.
Assessments to be performed on the day of IDDD implantation include:
Prior to anesthesia:

Symptom-directed PE

ECG (before anesthesia if possible)

Vital signs 

AE monitoring

Concomitant medications, therapies, 
and procedures
During time patient is anesthetized:

If logistically possible, head, liver, and 
spleen MRI (before IDDD implantation) 

IDDD implantation

CSF samples collected for clinical 
laboratory analysis (chemistry, cell 
count), CSF GAG, CSF storage for 
biomarkers 

Postoperative:  X-ray to check IDDD 
placement


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8.3.2
Postoperative Check – Days 1 to 3 
The postoperative check can occur anytime 1 to 3 days after IDDD implantation. Assessments 
include postoperative check of the IDDD incision; vital signs; symptom-directed PE; 
concomitant medications, therapies, and procedures; and AE monitoring. 
8.3.3
Randomization (Can Occur Any Time After Meeting Study Entry Criteria)
All patients in Group 3 (patients who were initially randomized to no treatment in Study 
HGT-SAN-093) will be randomized in a 1:1 allocation ratio to receive Q2W or Q4W dosing 
(Groups 3A or 3B, respectively), as described in Section 6.4. 
8.4
Group 3A (Initiating HGT-1410 Q2W Dosing)
8.4.1
Treatment Period (Weeks 0 through 120)
The pre-treatment assessments may be performed on the same day as the administration of study 
drug if it is feasible for the patient to arrive at the study site early in the day, and if it is deemed 
clinically appropriate by the Investigator. Patients may be discharged from the clinical site 
4 hours after dosing, if deemed stable by the Investigator.
Patients in Group 3A will receive 45 mg HGT-1410 IT Q2W (ie, every 14±3 days). 
Administration of HGT-1410 can only occur following the completion of all pre-treatment 
assessments and procedures. 
For patients in Group 3A, HGT-1410 will be administered every other week from Week 0 
through Week 120.
8.4.1.1
Pre-treatment Assessments

Full PE, including height and weight at Weeks 24, 48, 72, 96, and 120; symptom-directed PE 
at all other visits.

Every visit:  vital signs, concomitant medications, therapies, and procedures, and AE 
monitoring 

Cognitive/behavioral assessments:  BSID-III/KABS-II and VABS-II:  Weeks 24, 48, 72, 96, 
and 120

QoL questionnaire:  ITQoL for patients ≤5 years of age:  Weeks 24, 48, 72, 96, and 120

Health economics questionnaire:  HCUQ:  Weeks 24, 48, 72, 96, and 120

MRIs of head, liver, and spleen: Weeks 24, 48, and 96

Clinical laboratory tests:  hematology, serum chemistry, urinalysis: Weeks 0, 4, 8, 12, 16, 20, 
24, 36, 48, 60, 72, 84, 96, 108, and 120

Every study visit before dosing:  standard CSF safety laboratory assessments

CSF and urine sample collection for GAG at Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 
48, 60, 72, 84, 96, 108, and 120

Every study visit:  CSF sample collection for storage for biomarkers

Anti-rhHNS antibody testing (serum and CSF) and CSF biomarker testing at Weeks 0, 4, 8, 
12, 24, 36, 48, 60, 72, 84, 96, 108, and 120

Serum pharmacokinetics sampling at Weeks 0, 48, and 96 (see Appendix 7 for the 
pharmacokinetics collection schedule)


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
CSF pharmacokinetics sampling at Weeks 0 and 48 (see Appendix 7 for the 
pharmacokinetics collection schedule)
8.4.1.2
Post-treatment Assessments

ECG at Weeks 0, 4, 8, 12, 16, 20, 24, 48, 96, and 120

Serum pharmacokinetics sampling at Weeks 0, 48, and 96 (see Appendix 7 for the 
pharmacokinetics collection schedule)

CSF pharmacokinetics sampling at Weeks 0 and 48 (see Appendix 7 for the 
pharmacokinetics collection schedule)

Concomitant medications, therapies, and procedures

AE monitoring

Removal of IDDD if patient not continuing treatment (unless the Investigator determines that 
the device should not be removed for safety reasons, please see Section 8.6)
8.4.2
Safety Follow-up Visit:  Week 124 (±7 days) 
All patients will have a safety follow-up visit at Week 24 or 30 (±7) days after their last dose of 
HGT-1410. 

Symptom-directed PE

Vital signs

Clinical laboratory tests

Concomitant medications, therapies, and procedures

AE monitoring
8.5
Group 3B (Initiating HGT-1410 Q4W Dosing)
8.5.1
Treatment Period (Weeks 0 through 120)
The pre-treatment assessments may be performed on the same day as the administration of study 
drug if it is feasible for the patient to arrive at the study site early in the day, and if it is deemed 
clinically appropriate by the Investigator. Patients may be discharged from the clinical site 
4 hours after dosing, if deemed stable by the Investigator.
Patients in Group 3B will receive 45 mg HGT-1410 IT Q4W (ie, every 28±7 days). 
Administration of HGT-1410 can only occur following the completion of all pre-treatment 
assessments and procedures. 
For patients in Group 3B, HGT-1410 will be administered Q4W from Week 0 through Week 
120.
8.5.1.1
Pre-treatment Assessments

Full PE, including height and weight at Weeks 24, 48, 72, 96, and 120; symptom-directed PE 
at all other visits

Every visit:  vital signs, concomitant medications, therapies, and procedures, and AE 
monitoring 


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
Cognitive/behavioral assessments:  BSID-III/KABS-II and VABS-II:   Weeks 24, 48, 72, 96, 
and 120

QoL questionnaire:  ITQoL for patients ≤5 years of age:  Weeks 24, 48, 72, 96, and 120

Health economics questionnaire:  HCUQ:  Weeks 24, 48, 72, 96, and 120

MRIs of head, liver, and spleen: Weeks 24, 48, and 96

Clinical laboratory tests:  hematology, serum chemistry, urinalysis: Weeks 0, 4, 8, 12, 16, 20, 
24, 36, 48, 60, 72, 84, 96, 108, and 120

Every study visit before dosing:  standard CSF safety laboratory assessments

CSF and urine sample collection for GAG at Weeks 0, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 
48, 60, 72, 84, 96, 108, and 120

Every study visit:  CSF sample collection for storage for biomarkers

Anti-rhHNS antibody testing (serum and CSF) and CSF biomarker testing at Weeks 0, 4, 8, 
12, 24, 36, 48, 60, 72, 84, 96, 108, and 120

Serum pharmacokinetics sampling at Weeks 0, 48, and 96 (see Appendix 7 for the 
pharmacokinetics collection schedule)

CSF pharmacokinetics sampling at Weeks 0 and 48 (see Appendix 7 for the 
pharmacokinetics collection schedule)
8.5.1.2
Post-treatment Assessments

ECG at Weeks 0, 4, 8, 12, 16, 20, 24, 48, 96, and 120

Serum pharmacokinetics sampling at Weeks 0, 48, and 96 (see Appendix 7 for the 
pharmacokinetics collection schedule)

CSF pharmacokinetics sampling at Weeks 0 and 48 (see Appendix 7 for the 
pharmacokinetics collection schedule)

Concomitant medications, therapies, and procedures

AE monitoring

Removal of IDDD if patient not continuing treatment (unless the Investigator determines that 
the device should not be removed for safety reasons, please see Section 8.6)
8.5.2
Safety Follow-up Visit:  Week 124 (±7 days) 
All patients will have a safety follow-up visit at Week 24 or 30 (±7) days after their last dose of 
HGT-1410. 

Symptom-directed PE

Vital signs

Clinical laboratory tests

Concomitant medications, therapies, and procedures

AE monitoring
8.6
All Groups:  Safety Follow-up Period if Device Not Removed
All patients who do not have the IDDD removed (partial or full device) will have safety follow-
up visits every 6 months at the site, with the following assessments performed: 


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
Informed consent

Symptom-directed PE

Clinical laboratory tests; only if indicated for a device-related AE

X-ray monitoring; only for migration or device-related issue

Concomitant medications, therapies, and procedures; only if indicated for a device-related 
AE

AE monitoring only for device-related events
During the 3-year safety follow-up period, the patient may have the device removed at any time, 
as deemed medically necessary. A post-operative evaluation, including a postoperative check of 
the incision and collection of safety information, should occur within 1-3 days after the IDDD 
explantation.  An end-of-study safety follow-up via a phone call should be completed within 
14 days after the device removal to collect safety information.


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9
QUALITY CONTROL AND ASSURANCE
Training will occur at an Investigator meeting or at the site initiation visit or both, and instruction 
manuals will be provided to aid consistency in data collection and reporting across sites. The 
training will be documented.
Clinical sites will be monitored by the Sponsor or its designee to ensure the accuracy of data 
against source documents. The required data will be captured in a validated clinical data 
management system that is compliant with the Food and Drug Administration (FDA) 21 CFR 
Part 11 Guidance. The clinical trial database will include an audit trail to document any evidence 
of data processing or activity on each data field by each user. Users will be trained and given 
restricted access, based on their role(s) in the study, through a password-protected environment.
Data entered in the system will be reviewed manually for validity and completeness against the 
source documents by a clinical monitor from the Sponsor or its designee. If necessary, the study
site will be contacted for corrections or clarifications; all missing data will be accounted for.
Serious adverse event information captured in the clinical trial database will be reconciled with 
the information captured in the Pharmacovigilance and Risk Management database.


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10
STATISTICAL ANALYSES
10.1
General Methodology
Statistical analysis will generally be performed by the Biometrics Department of Shire using 
SAS statistical software (SAS Institute, Cary, NC, USA). Analysis of any PK and health 
economics and outcomes data will be performed by the Shire Clinical Pharmacology and 
Pharmacokinetics group and the Health Economics and Outcomes Research groups, respectively. 
The analysis methods for all other study data (demographic and baseline characteristics, efficacy 
variables, and safety variables) will be detailed in the statistical analysis plan (SAP). The 
statistical methodology supporting the trial will focus on descriptive rather than inferential 
approaches, given the design and objectives of this trial.
Any hypothesis tests will be 2-sided and will be viewed as exploratory. It is planned that the data 
from all centers that participate in this protocol will be combined so that an adequate number of 
patients will be available for analysis. Summary statistics for continuous variables will include 
the n, mean, standard deviation, median, minimum, and maximum. Categorical variables will be 
summarized in a contingency table by the frequency and percentage of patients in each category. 
Data will be plotted to assess trends across time as appropriate.
Unless otherwise indicated, all summary statistics will be presented by treatment group (either 
Q2W or Q4W) to which the patients were randomly assigned (for patients who were initially 
assigned to Q2W or Q4W group in Study HGT-SAN-093 or patients who were assigned to 
no-treatment in HGT-SAN-093 and were randomly assigned to Q2W or Q4W in Study 
SHP-601-201).
All safety data will be summarized descriptively. The change from baseline at each time point 
for efficacy outcomes will be summarized. Generally, the mean difference in the change at each 
time point between the 2 treatment groups and the corresponding 95% confidence interval of the 
mean difference will be presented. If the parametric assumption for the distribution cannot be 
justified, a non-parametric approach will be utilized to estimate the treatment difference and the 
corresponding 95% confidence interval (ie, median difference or Hodges–Lehmann estimator 
and the corresponding confidence intervals). Developmental quotients will be computed as a 
ratio, expressed as a percentage using the age-equivalent score divided by the age at testing (ie, 
[age-equivalent score/chronological age] x 100). Developmental delay scores will be calculated 
as the age-equivalent score minus the chronological age. Additional efficacy analyses in the 
subgroups of patients who received treatment or no treatment in Study HGT-SAN-093 will be 
performed.
Data from Study HGT-SAN-093 will be combined with that of Study SHP-610-201 for analysis. 
The data included for treated patients in HGT-SAN-093 starts from the baseline of Study 
HGT-SAN-093 and for patients who received no treatment in HGT-SAN-093 from the baseline 
of Study SHP-610-201. Baseline is the assessment obtained prior to the first dose of HGT-1410. 


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10.2
Determination of Sample Size
As this is an extension study of Study HGT-SAN-093, any patients who enrolled and completed 
that study are eligible to enroll in Study SHP-601-201, and no statistical estimation for sample 
size calculation was performed. A maximum sample size of 21 patients in this study is expected 
based on the sample size in Study HGT-SAN-093.
10.3
Method of Assigning Study Subjects to Treatment Groups
Patients who were randomized to receive Q2W or Q4W dosing in Study HGT-SAN-093 (Groups 
1 and 2, respectively) will maintain their assigned dosing regimen in Study SHP-610-201.
Patients who were randomized to receive no-treatment in Study HGT-SAN-093 (Group 3) will 
be re-randomized in a 1:1 allocation ratio via a computer-generated randomization schedule to 
receive Q2W or Q4W dosing regimen (Groups 3A or 3B, respectively) in Study SHP-610-201. 
To help ensure balance between the dose groups with respect to age at Baseline, the 
randomization will be stratified by age group (≤30 months and >30 months).
10.4
Population Description and Exposure
10.4.1
Analysis Populations
The population for all safety analyses will be the safety population, defined as all patients who 
had the IDDD implant or received at least one dose of study drug in the extension study. Safety 
analyses will be conducted according to the treatment received. Device related analyses will be 
conducted in the subset of patients in the safety population who had the device implanted.
The population for all efficacy analyses will be the intent-to-treat (ITT) population, defined as all 
randomized patient according to the treatment assigned.
All pharmacokinetic data analyses will be performed using the pharmacokinetics population, 
defined as all patients who received study drug and had sufficient serum samples collected to 
derive pharmacokinetic parameters.
10.4.2
Subject Disposition
The number of patients screened; the number and proportion of patients randomized, included in 
the safety population, completed the study, and discontinued prematurely will be presented in a 
summary table by treatment group; reasons for discontinuation/withdrawal will also be 
summarized.
10.4.3
Protocol Deviations
Reported protocol deviations and patient data will be examined prior to database lock to 
determine if conditions set forth in the study protocol have been violated. The complete list of 
protocol deviations will not be summarized; however, if applicable, protocol violations identified 
will be listed for the safety population.


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10.4.4
Demographics and Baseline Characteristics
Demographic data and baseline characteristics will be summarized by the individual treatment 
group and the overall HGT-1410 treatment group for the safety population. 
10.4.5
Treatment Compliance and Extent of Exposure
The total number of doses of study drug, the number of doses received via IDDD, the number of 
doses received via LP, the average duration of IT administration and treatment compliance will 
be summarized by treatment group for the safety population. 
The duration of IT administration is calculated by subtracting the IT administration start time 
from the IT administration end time.
Treatment compliance is defined as:  [(Number of Complete IT administrations) ÷ (Expected 
Number of IT administrations)] * 100.
10.5
Analysis of Efficacy
The analysis of efficacy data will be based on the ITT population.
10.5.1
Primary Analysis
The primary objective of this study is to evaluate long-term safety of HGT-1410 in patients with 
MPS-III. Therefore the primary analysis will be discussed in the safety analysis section, 
Section 10.7.
10.5.2
Secondary Efficacy Analysis
10.5.2.1
Bayley Scales of Infant Development, Third Edition/Kaufman Assessment 
Battery for Children, Second Edition
The observed values and changes from baseline in DQ, age equivalent, and developmental delay 
scores for each subtest (Cognitive, Receptive Communication, Expressive Communication, Fine 
Motor, and Gross Motor) will be summarized descriptively for each assessment time point by 
treatment group (Q2W and Q4W group). The mean difference in the change at each time point 
between the 2 treatment groups and the corresponding 95% confidence interval of the mean 
difference will be presented.
Graphical plots of mean age equivalent and DQ scores for the subtests across time will be 
presented. A trellis plot of the age-equivalent and DQ scores within each patient will be 
presented. Furthermore, a spaghetti plot of the cognitive age-equivalent score against 
chronological age will be presented.
The KABC-II is an alternative to BSID-III. The KABC-II cognitive DQ, age-equivalent, and 
developmental delay scores will be combined with the corresponding BSID-III scores and 
summarized at each assessment time point as described above. Most of the patients will have 
either only BSID-III data or KABC-II data. If a patient has data obtained by each of these 
methods, then the method for which data is available at both baseline and post-baseline time 
points will be used when combining the DQ scores and age-equivalent scores.


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10.5.2.2
Vineland Adaptive Behavior Scales, Second Edition
Tabular summaries of the raw scores for each domain, the average domain raw scores, the mean 
age equivalent score and the corresponding overall DQ scores and the corresponding change 
from baseline will be presented for each assessment time point by treatment group (Q2W and 
Q4W group). The mean difference in the change at each time point between the 2 treatment 
groups and the corresponding 95% confidence interval of the mean difference will be presented.
Graphical plots of mean raw scores for the domains across time will be presented. In addition, a 
trellis plot of the raw scores within each patient will be presented. Similar plots will be presented 
for the average domain raw scores, the mean age equivalent score and the overall DQ score. A 
spaghetti plot of mean age equivalent score against chronological age will also be presented.
10.5.2.3
Brain MRI
Although several MRI parameters will be captured, the analysis will focus primarily on the grey 
matter volume, the white matter volume and the intracranial CSF volume (ventricles plus 
additional CSF space). The observed values and changes from baseline will be summarized for 
each assessment time by treatment group (Q2W and Q4W group). The mean difference in the 
change at each time point between the 2 treatment groups and the corresponding 95% confidence 
interval of the mean difference will be presented.
Graphical plots of mean MRI parameter levels across time will be presented. In addition, Trellis 
plots of MRI parameters across time for each patient will be presented. A spaghetti plot of grey 
matter volume against chronological age will also be presented. 
10.5.3
Subset Analyses 
Exploratory tabular and graphical analyses as described above for efficacy endpoints will be 
performed both by treatment group and whether or not the patient received treatment or no 
treatment in Study HGT-SAN-093 (4 groups).
10.5.4
Exploratory Analyses
10.5.5
Analysis of Health Status
Health status will be assessed by the ITQoL. The observed value and change from baseline in 
ITQOL scale scores will be summarized descriptively for each assessment time by treatment 
group (Q2W and Q4W groups). Graphical plots of mean scores across time will be presented.
10.5.6
Analysis Health Economics and Outcomes Research
Descriptive statistics, including N, mean, median, and range (for continuous variables), and N 
and proportions (for categorical variables), for key HCUQ variables, including the number of 
emergency room visits, caregiver employment status (FT, PT, and NW), and the number of hours 
of additional paid help needed by caregivers, over the course of the study. A detailed description 
of analyses may be provided in a separate pharmacoeconomic analysis plan.


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10.6
Analysis of Pharmacokinetic and Pharmacodynamic Data
10.6.1
Pharmacokinetic Measurement and Parameters
The pharmacokinetic population will be used to perform the analysis of the pharmacokinetic 
data. HGT-1410 concentrations in all collected serum samples will be measured and reported. 
Individual patient HGT-1410 serum concentration-time profiles will be presented. Individual 
pharmacokinetic parameters will be derived by a noncompartmental analysis and reported. The 
actual pharmacokinetic blood sample collection times will be used to determine the individual 
patient HGT-1410 serum concentration-time profiles. Pharmacokinetic parameters will be 
calculated if sufficient HGT-1410 concentration-time points exist to derive values. Individual 
patient CSF HGT-1410 concentrations at each collection time point will be reported.
Pharmacokinetic parameters calculated will include:

Cmax

tmax

AUC0-last

AUC0-∞

λZ

t1/2 calculated as 0.693/λZ

CL/F

Vz/F  
10.6.2
Pharmacodynamic Analyses 
The levels of GAG in CSF and urine are pharmacodynamic endpoints. Analyses of 
pharmacodynamic endpoints will be performed in the safety population.
The observed values and changes from baseline in CSF GAG levels will be summarized for each 
assessment time by treatment group (Q2W and Q4W group). Graphical plot(s) of mean CSF 
GAG levels across time will be presented. Additionally, Trellis plots of CSF GAG levels across 
time for each patient will be presented. Furthermore, CSF parameters will be plotted across time 
for each patient such that the values before and after the first instance of antibody positive status 
will be indicated using different colors.
The urine GAG levels will be analyzed in a manner similar to that described for CSF data.
10.7
Analysis of Safety
All analyses of safety data will be descriptive and based on the Safety population. 
10.7.1
Adverse Events 
Once the patient has signed the informed consent form, AEs will be recorded throughout the 
study and at early termination. AEs will be coded using Medical Dictionary for Regulatory 
Affairs (MedDRA).


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Treatment-emergent AEs, defined as all AEs from the time of initial IDDD implantation (or first 
dose if no IDDD implant), to the safety follow-up visit, defined as the last patient visit in the 
study during the treatment period, will be summarized. For each treatment group, the number 
and percentage of patients having an AE and the number of events, by system organ class (SOC) 
and preferred term will be presented. Treatment-emergent AEs will also be summarized by 
severity and degree of relationship to study drug. In the case of multiple occurrences of the same 
AE (at the preferred term level) in an individual patient, the AE that is classified as the most 
severe (ie, maximum severity) will be identified for the analysis by severity and the AE that has 
the closest relationship to study drug/procedure will be identified for the analysis by relationship. 
In general, an AE will be considered a treatment-emergent AE if it cannot be definitively 
categorized otherwise by documentation that its onset preceded either IDDD surgery or first 
dose.
Serious adverse events will be similarly tabulated according to SOC and preferred term and 
presented in a separate listing.
10.7.1.1
Investigational Product
Treatment-emergent AEs deemed by the investigator to be related to HGT-1410 will be 
summarized by presenting the number and percentage of patients having an AE and the number 
of events, by SOC and preferred term. 
10.7.1.2
IDDD and Surgical Procedure–related AEs 
Intrathecal drug delivery devices and procedure-related AEs will be summarized within 
MedDRA SOC by preferred term. Separate tabulations will be provided for AEs related to the 
IDDD, device surgical procedure, and IT administration process.
Intrathecal drug delivery device and procedure related events will be analyzed in the subset of 
patients in the safety population who underwent surgery for IDDD implantation.
10.7.2
Clinical Laboratory Evaluation 
The measurements of each laboratory parameter (serum chemistry, hematology, urinalysis and 
CSF) and the corresponding normal ranges will be converted to Standard International (SI) units, 
if needed. 
Observed values and changes from baseline for continuous laboratory test results will be 
summarized for each assessment time from baseline. Each laboratory result will be categorized 
as a patient having had (1) an abnormal and clinically significant (CS) value at any time post-
baseline, (2) no CS values at any time post-baseline, but had at least 1 abnormal and not CS 
(NCS) value, and (3) no CS or NCS values at any time post-baseline; the number and percentage 
in each category will be presented. For any patient who experiences a CS laboratory result at any 
time post-baseline that was not CS at baseline (or the most recent non-missing value prior to the 
start of the treatment), their entire profile for that particular laboratory parameter will be 
presented as a listing.
If more than one laboratory result is reported per assessment time per parameter, the last non-
missing result will be selected for analysis. 


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10.7.3
ECG Evaluations 
The observed values and changes from baseline for continuous variables will be summarized for 
each assessment time by treatment group. Categorical variables, ie, sinus rhythm and 
atrial/ventricular hypertrophy, will be summarized in terms of number and percentage of patients 
in each response category for each assessment time from baseline.
10.7.4
Vital Signs 
The observed values and changes from baseline for IT-administration vital signs parameters will 
be summarized by treatment group. The IT-administration vital signs will also be presented in a 
trellis plot so that the vital signs data for each IT-administration within a patient will be 
presented on a single page.
10.7.5
Anti-rhHNS Antibody in Serum and CSF
Serum and CSF anti-rhHNS antibody status (ie, positive or negative) at each assessment time 
from baseline will be summarized in terms of counts and proportion for the treatment groups. 
Additionally, semi-logarithmic plot of serum and CSF anti-rhHNS antibody titers across the 
study visits in the patients exhibiting seropositivity will also be presented. 
10.7.6
Concomitant Medications 
Concomitant medications will be coded using the WHO-DD. The concomitant medications that 
occur from the time of the surgery for IDDD implantation to the safety follow-up visit, defined 
as the last patient visit in the study during the treatment period, will be summarized by 
therapeutic class and preferred term. 
10.7.7
Other Observations Related to Safety
10.7.7.1
IDDD Performance
Safety and performance data for the SOPH-A-PORT Mini S IDDD will be analyzed and 
summaries will be provided for implanted patients. Difficulties associated with the implant 
procedure (eg, excessive bleeding, CSF leakage, etc.) will be summarized. A summary of 
abnormal findings from the device radiological assessments will also be presented. 
The proportion of patients with at least 1 device failure and/or malfunction, as well as the 
number of and reasons for device failures/malfunctions will be summarized. The rate of device 
failures/malfunctions and 95% confidence interval will also be estimated. The time from initial 
implant surgery to first device failure and/or malfunction will be summarized. Patients without a 
device failure/malfunction will be censored at their last study drug injection date. A by-patient 
listing of the device failure/malfunction data will be displayed.
The rate of successful IDDD injections will be calculated for each patient and summarized 
descriptively. The success rate will be calculated as the number of IDDD injections given as a 
percentage of IDDD injections given plus any malfunctions reported for inability to dose. The 
corresponding 95% confidence interval for the mean rate will be estimated, where appropriate. 
Injections that are not administered for patient-related reasons (eg, patient uncooperative, 
competing medical issue, etc.) will not be included in the determination of the injection success 
rate.


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10.8
Statistical/Analytical Issues
10.8.1
Adjustment for Covariates
No statistical modeling or covariate adjustment is planned due to the small sample size.
10.8.2
Handling of Dropouts or Missing Data
In general, no imputation will be performed and analyses will be based on available data. If data 
at the baseline visit are not available, then the most recent available pre-treatment assessment
will be considered as baseline. Missing or partial AE dates will not be imputed. However, a 
conservative approach will be adopted in such cases so that the AE will be deemed to be 
treatment-emergent if it cannot be definitively categorized to have occurred prior to surgery for 
IDDD implantation. Similar logic will be applied to deal with missing and partial date for 
concomitant medications.
10.8.3
Interim Analyses and Data Monitoring
Interim analyses may be conducted before trial completion for safety monitoring, regulatory 
reporting or general study planning purposes. Analyses will be descriptive in nature, with no 
formal comparisons planned and no hypotheses formally tested. An independent DMC will be 
established to provide an ongoing, independent review and assessment of patient data, and to 
safeguard the interests and safety of the participating patients in the study (see Section 11.8). An 
analysis of the data for DMC review will occur at specific times during the study as specified in 
the DMC charter. Because no formal hypothesis testing is planned, multiplicity concerns 
regarding repeated analyses are not an issue.
10.8.4
Multicenter Studies
Data from all centers that participate in this protocol will be combined so that an adequate 
number of patients will be available for analysis. In order to maintain desirable level of 
inter-rater reliability for BSID-III/KABS-II and VABS-II assessments/interviews, standardized 
training of the raters and parents will be conducted. Furthermore, a central reader will evaluate 
all MRI data.
10.8.5
Multiple Comparisons/Multiplicity
No adjustment for multiplicity will be performed. 
10.8.6
Sensitivity Analyses
Given the design and objectives of the study, no sensitivity analyses are planned.


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11
ADMINISTRATIVE CONSIDERATIONS
11.1
Investigators and Study Administrative Structure
Before initiation of the study, the Investigators must provide the Sponsor with a completed Form 
FDA 1572 or Investigator Agreement. Investigational product may be administered only under 
the supervision of the Investigators listed on these forms. Curriculum vitae must be provided for 
the Investigators and sub-investigators listed on Form FDA 1572 or Investigator Agreement.
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, any amendments to the protocol, the study treatments, and their study related 
duties and functions. The Investigator must maintain a list of sub-investigators and other 
appropriately qualified persons to whom he or she has delegated significant study related duties.
11.2
Institutional Review Board or Ethics Committee Approval
Before initiation of the study, the Investigator must provide the Sponsor with a copy of the 
written IRB/EC approval of the protocol and the informed consent form. This approval must 
refer to the informed consent form and to the study title, study number, and version and date of 
issue of the study protocol, as given by the Sponsor on the cover page of the protocol.
The protocol and any applicable documentation will be submitted or notified to the relevant 
Regulatory Authorities in accordance with the regulations of the countries involved in the trial.
Status reports must be submitted to the IRB/EC at least once per year. The IRB/EC must be
notified of completion of the study. Within 3 months of study completion or termination, a final 
report must be provided to the IRB/EC. A copy of these reports will be sent to the study clinical 
monitor. The Investigators must maintain an accurate and complete record of all submissions 
made to the IRB/EC, including a list of all reports and documents submitted. Adverse events that 
are reported to the US FDA (Investigational New Drug/UADE Safety Reports) or other 
regulatory agencies must be submitted promptly to the IRB/EC.
11.3
Ethical Conduct of the Study
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor and Investigators abide by 
good clinical practice (GCP) as described in the 21 CFR Parts 50, 56, and 312 and the 
International Conference on Harmonisation (ICH) GCP Guidelines Compliance with these 
regulations and guidelines also constitutes compliance with the ethical principles described in the 
Declaration of Helsinki.
11.4
Patient Information and Consent
Before enrolling in the clinical study, the patient or the patient’s parent(s) or legally authorized 
representative(s) must consent to participate after the nature, scope, and possible consequences 
of the clinical study have been explained in a form understandable to him or her.


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An informed consent form (assent form if applicable) that includes information about the study 
will be prepared and given to the patient or the patient’s parent(s) or legally authorized 
representative(s). This document will contain all FDA- and ICH-required elements. The 
informed consent (or assent) form must be in a language understandable to the patient or the 
patient’s parent(s) or legally authorized representative(s) and must specify who informed the 
patient, the patient’s parent(s), or the patient’s legally authorized representative(s).
After reading the informed consent document, the patient or the patient’s parent(s) or legally 
authorized representative(s) must give consent in writing. Consent must be confirmed at the time 
of consent by the personally dated signature of the patient, the patient’s parent(s) or the patient’s 
legally authorized representative(s) and by the personally dated signature of the person 
conducting the informed consent discussions.
If the patient or the patient’s parent(s) or legally authorized representative(s) is unable to read, 
oral presentation and explanation of the written informed consent form and information to be 
supplied must take place in the presence of an impartial witness. Consent must be confirmed at 
the time of consent orally and by the personally dated signature of the patient or by a local 
legally recognized alternative (eg, the patient’s thumbprint or mark) or by the personally dated 
signature of the patient’s parent(s) or the patient’s legally authorized representative. The witness 
and the person conducting the informed consent discussions must also sign and personally date 
the informed consent document. It should also be recorded and dated in the source document that 
consent was given.
A copy of the signed and dated consent document(s) must be given to the patient or the patient’s 
parent(s) or legal representative(s). The original signed and dated consent document will be 
retained by the Investigator.
The Investigator will not undertake any measures specifically required solely for the clinical 
study until valid consent has been obtained.
A model of the informed consent form to be used in this study will be provided to the sites 
separately from this protocol.
11.5
Patient Confidentiality
Patient names will not be supplied to the Sponsor. Only the patient number and patient initials 
will be recorded in the eCRF, and if the patient name appears on any other document, it must be 
obliterated before a copy of the document is supplied to the Sponsor. Study findings stored on a 
computer will be stored in accordance with local data protection laws. The patients will be told 
that representatives of the Sponsor, a designated CRO, the IRB/EC, or regulatory authorities may 
inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. The Investigator will maintain a personal patient 
identification list (patient numbers with the corresponding patient names) to enable records to be 
identified.


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11.6
Study Monitoring
Monitoring procedures that comply with current GCP guidelines will be followed. Review of the 
eCRFs for completeness and clarity, cross-checking with source documents, and clarification of 
administrative matters will be performed.
The study will be monitored by the Sponsor or its designee. Monitoring will be performed by a 
representative of the Sponsor (Clinical Study Monitor) who will review the eCRFs and source 
documents. The site monitor will ensure that the investigation is conducted according to protocol 
design and regulatory requirements by frequent site visits and communications (letter, telephone, 
and facsimile).
11.7
Case Report Forms and Study Records
11.7.1
Case Report Forms
Case report forms (paper or electronic) are provided for each patient. All forms must be filled out 
by authorized study personnel. All corrections to the original eCRF entry must indicate the 
reason for change. The Investigator is required to sign the eCRF after all data have been captured 
for each patient. If corrections are made after review and signature by the Investigator, he or she 
must be made aware of the changes, and his or her awareness documented by resigning the 
eCRF.
11.7.2
Critical Documents
Before Shire initiates the trial (ie, obtains informed consent from the first patient), it is the 
responsibility of the Investigator to ensure that the following documents are available to Shire or 
their designee:

Completed FDA Form 1572 (Statement of Investigator), signed, dated, and accurate

Curricula vitae of Investigator and sub-Investigator(s) (current, dated and signed within 
12 months of study initiation)

Copy of Investigator and sub-Investigator(s) current medical license (indicating license 
number and expiration date)

Signed and dated agreement of the final protocol

Signed and dated agreement of any amendment(s), if applicable

Approval/favorable opinion from the IRB/EC clearly identifying the documents reviewed by 
name, number and date of approval or regarding approval:  protocol, any amendments, 
Patient Information/Informed Consent Form, and any other written information to be 
provided regarding patient recruitment procedures

Copy of IRB-/EC-approved Patient Information/Informed Consent Form/any other written 
information/advertisement (with IRB approval stamp and date of approval)

Current list of IRB/EC Committee members/constitution (dated within 12 months prior to 
study initiation)

Financial Disclosure Form signed by Investigator and sub-Investigator(s)

Current laboratory reference ranges (if applicable)

Certification/QA scheme/other documentation (if applicable)


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Regulatory approval and notification as required must also be available; these are the 
responsibility of Shire.
11.8
Data Monitoring Committee
An independent DMC will be established to provide an ongoing, independent review and 
assessment of the safety data, and to safeguard the interests and safety of the participating 
patients in the study during the treatment period. The DMC will consist of a biostatistician and 2 
clinical experts.
It is anticipated that there will be scheduled meetings annually during the treatment period of the 
study. The first meeting will be an orientation meeting and will take place prior to the start of the 
study. Subsequent meetings will occur at specific times during the study as specified in the DMC 
charter. The final meeting will be conducted when all patients have completed treatment period 
of the study for a comprehensive safety overview of the study. A special DMC meeting will be 
convened if the safety-related study stopping rules are met during the treatment period of the 
study (see Section 7.16).
The DMC will adhere to a prospectively determined charter, which will be written by Shire and 
approved by the DMC. The charter will define the responsibilities of the DMC and Shire, 
describe the conduct of the meetings and define the data sets to be reviewed. The DMC will also 
be notified of all IDDD failures and IDDD-related complications at times defined in the DMC 
charter.
The DMC will be notified of all IDDD failures and IDDD-related complications at times defined 
in the DMC charter.
11.9
Device Failure Review Process
The final cause for SOPH-A-PORT Mini S device failures will be reviewed by Shire by 
examining the device failure information in the clinical database, safety database, and 
manufacturer investigation of returned SOPH-A-PORT Mini S devices.
11.10 Protocol Violations/Deviations
The Investigator will conduct the study in compliance with the protocol. The protocol will not be 
initiated until the IRB/EC and the appropriate regulatory authorities have given 
approval/favorable opinion. Modifications to the protocol will not be made without agreement of 
the Sponsor. Changes to the protocol will require written IRB/EC approval/favorable opinion 
prior to implementation, except when the modification is needed to eliminate an immediate 
hazard(s) to patients. The IRB/EC may provide, if applicable regulatory authorities permit, 
expedited review and approval/favorable opinion for minor change(s) in ongoing studies that 
have the approval/favorable opinion of the IRB/EC. The Sponsor will submit all protocol 
modifications to the regulatory authorities in accordance with the governing regulations.
A record of patients screened, but not entered into the study, is also to be maintained. No 
protocol exemptions will be granted for this study.


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When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
patients, the Investigator will contact the Sponsor or its designee, if circumstances permit, to 
discuss the planned course of action. Any departures from the protocol must be fully documented 
as a protocol deviation. Protocol deviations will need to be reviewed by the medical monitor and 
may also be required to be submitted to the IRB/EC.
Protocol modifications will only be initiated by the Sponsor and must be approved by the 
IRB/EC and submitted to the FDA or other applicable international regulatory authority before 
initiation.
11.11 Premature Closure of the Study
If the Sponsor, Investigator, or regulatory authorities discover conditions arising during the study 
which indicate that the clinical investigation should be halted due to an unacceptable patient risk, 
the study may be terminated after appropriate consultation between the Sponsor and the 
Investigator(s). In addition, a decision on the part of the Sponsor to suspend or discontinue 
development of the investigational product may be made at any time. Conditions that may 
warrant termination of the study or site include but are not limited to:

The discovery of an unexpected, significant, or unacceptable risk to the patients enrolled in 
the study

Failure of the Investigator to comply with pertinent global regulations

Submission of knowingly false information from the study site to the Sponsor or other 
pertinent regulatory authorities

Insufficient adherence by the Investigator to protocol requirements
11.12 Access to Source Documentation
Regulatory authorities, the IRB/EC, or the Sponsor (or its designee) may request access to all 
source documents, eCRFs, and other study documentation for onsite audit or inspection. Direct 
access to these documents must be guaranteed by the Investigator, who must provide support at 
all times for these activities. Monitoring and auditing procedures that comply with current GCP 
guidelines will be followed. On-site review of the eCRFs for completeness and clarity, 
crosschecking with source documents, and clarification of administrative matters may be 
performed.
11.13 Data Generation and Analysis
The clinical database will be developed and maintained by a contract research organization or an 
electronic data capture technology provider as designated by Shire. Shire or its designee will be 
responsible for performing study data management activities. 
Adverse events and medical history events will be coded using MedDRA. Concomitant 
medication will be coded using WHO-DD. Centralized laboratories will be employed as 
described in the study manual to aid in consistent measurement of efficacy and safety 
parameters. 


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11.14 Retention of Data
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application and until there are no pending or contemplated marketing applications or 
at least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product. The Sponsor will notify the Investigator if these documents must be 
retained for a longer period of time. It is the responsibility of the Sponsor to inform the 
Investigator or institution as to when these documents no longer need to be retained.
11.15 Financial Disclosure
The Investigator should disclose any financial interests in the Sponsor as described in 21 CFR 
Part 54 prior to beginning this study. The appropriate form will be provided to the Investigator 
by the Sponsor, which will be signed and dated by the Investigator, prior to the start of the study. 
11.16 Publication and Disclosure Policy
All information concerning the study material, such as patent applications, manufacturing 
processes, basic scientific data, and formulation information supplied by the Sponsor and not 
previously published are considered confidential and will remain the sole property of the 
Sponsor. The Investigator agrees to use this information only in accomplishing this study and 
will not use it for other purposes.
It is understood by the Investigator that the information developed in the clinical study may be 
disclosed as required to the authorized regulatory authorities and governmental agencies. In 
order to allow for the use of the information derived from the clinical studies, it is understood 
that there is an obligation to provide the Sponsor with complete test results and all data 
developed in the study in a timely manner.
The Investigator and any other clinical personnel associated with this study will not publish the 
results of the study, in whole or in part, at any time, unless they have consulted with Shire, 
provided Shire a copy of the draft document intended for publication, and obtained Shire’s 
written consent for such publication. All information obtained during the conduct of this study 
will be regarded as confidential. 
Shire may perform analyses of interim or final locked study data for purposes of publication.


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12
LIST OF REFERENCES
1. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. 
JAMA 1999;281:249-54.
2. Baehner F, Schmiedeskamp C, Krummenauer F, et al. Cumulative incidence rates of the 
mucopolysaccharidoses in Germany. J Inherited Metab Dis 2005;28:1011-7.
3. Poorthuis BJ, Wevers RA, Kleijer WJ, et al. The frequency of lysosomal storage diseases in 
The Netherlands. Hum Genet 1999;105:151-6.
4. Valstar MJ, Neijs S, Bruggenwirth HT, et al. Mucopolysaccharidosis type IIIA:  clinical 
spectrum and genotype-phenotype correlations. Ann Neurol 2010;68:876-87.
5. Meyer A, Kossow K, Gal A, et al. Scoring evaluation of the natural course of 
mucopolysaccharidosis type IIIA (Sanfilippo syndrome type A). Pediatr 2007;120:e1255-61.
6. Cleary MA, Wraith JE. Management of mucopolysaccharidosis type III. Arch Dis Child 
1993;69:403-6.
7. Fraser J, Wraith JE, Delatycki MB. Sleep disturbance in mucopolysaccharidosis type III 
(Sanfilippo syndrome):  a survey of managing clinicians. Clin Genet 2002;62:418-21.
8. Meyer A, Kossow K, Gal A, et al. The mutation p.Ser298Pro in the sulphamidase gene 
(SGSH) is associated with a slowly progressive clinical phenotype in mucopolysaccharidosis 
type IIIA (Sanfilippo A syndrome). Hum Mutat 2008;29:770.
9. Hemsley K, King B, Hopwood J. Injection of recombinant human sulfamidase into the CSF 
via the cerebellomedullary cistern in MPS IIIA mice. Mol Genet Metab 2007;90:313-28.
10. Hemsley KM, Hopwood JJ. Delivery of recombinant proteins via the cerebrospinal fluid as a 
therapy option for neurodegenerative lysosomal storage diseases. Int J Clin Pharmacol Ther 
2009;47 Suppl 1:S118-23.
11. Martin HR, Poe MD, Reinhartsen D, et al. Methods for Assessing Neurodevelopment in 
Lysosomal Storage Diseases and Related Disorders:  a Multidisciplinary Perspective. Acta 
Paediatr Supp 2008;97:69-75.
12. Bayley N. Bayley Scales of Infant and Toddler Development. 3 ed. San Antonio, TX The 
Psychological Corporation; 2005.
13. Sparrow S, Balla D, Cicchetti D. Vineland Adaptive Behavior Scales (Second Edition). 4201 
Woodland Road Circle Pines, MN 55014-1796:  American Guidance Service, Inc; 2005.
























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Appendix 6
Blood and CSF Volumes
Treatment Period for Patients in Group 1:  Maintaining HGT-1410 Every Other Week Dosing
Follow-up
TOTAL
Weeks
Procedure
50
52, 54, 56, 58
60
62, 64, 66, 68, 70
72
74, 76, 78, 80, 82
84
86, 88, 90, 92, 94
96
98, 100, 102, 104, 106
108
110, 112, 114, 116, 118
120
122, 124, 126, 128, 130
132
134, 136, 138, 140, 142
144
146, 148, 150, 152, 154
156
158, 160, 162, 164, 166
168
172
CSF (mL)
Standard CSF safety labs
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
CSF sample for GAG testing
a
a
a
a
a
a
a
a
a
a
Anti-rhHNS Ab testing (CSF)
b
b
b
b
b
b
b
b
b
b
CSF for storage (for biomarkers 
and Ab testing)
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
Total CSF Volume
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
660
Blood (mL)
Hematology
2
2
2
2
2
2
2
2
2
2
2
Serum chemistry
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
Anti-rhHNS Ab testing (serum)
4
4
4
4
4
4
4
4
4
4
Serum PK sampling
9
Total Blood Volume
8.5
8.5
8.5
17.5
8.5
8.5
8.5
8.5
8.5
8.5
4.5
98.5
Abbreviations:  Ab=antibody; CSF=cerebrospinal fluid; GAG=glycosaminoglycan; PK=pharmacokinetics; rhHNS=recombinant human heparan N sulfatase
a
CSF for GAGs included in CSF storage sample
b
Anti-rhHNS Ab testing in CSF will be performed on stored samples.


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CONFIDENTIAL 
Page 89
Clinical Trial Protocol:  SHP-610-201
HGT-1410 – SOPH-A-PORT® Mini S
25 Jan 2017
Treatment Period for Patients in Group 2:  Maintaining HGT-1410 Dosing Every 4 Weeks
Follow-up
TOTAL
Weeks
Procedure
52
56
60
64, 68
72
76, 80
84
88, 92
96
100,
104
108
112, 
116
120
124, 
128
132
136, 
140
144
148, 
152
156
160, 
164
168 172
CSF (mL)
Standard CSF safety labs
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
CSF sample for GAG testing
a
a
a
a
a
a
a
a
a
a
Anti-rhHNS Ab testing (CSF)
b
b
b
b
b
b
b
b
b
b
CSF for storage (for 
biomarkers and Ab testing)
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
Total CSF Volume
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
330
Blood (mL)
Hematology
2
2
2
2
2
2
2
2
2
2
2
Serum chemistry
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
Anti-rhHNS Ab testing (serum)
4
4
4
4
4
4
4
4
4
4
Serum PK sampling
9
Total Blood Volume
8.5
8.5
8.5
17.5
8.5
8.5
8.5
8.5
8.5
8.5
4.5
98.5
Abbreviations:  Ab=antibody; CSF=cerebrospinal fluid; GAG=glycosaminoglycan; PK=pharmacokinetics; rhHNS=recombinant human heparan N sulfatase
a
CSF for GAGs included in CSF storage sample
b
Anti-rhHNS Ab testing in CSF will be performed on stored samples.


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CONFIDENTIAL 
Page 90
Clinical Trial Protocol:  SHP-610-201
HGT-1410 – SOPH-A-PORT® Mini S
25 Jan 2017
IDDD 
Implantation 
Period
Treatment Period for Patients in Group 3A:  Initiating HGT-1410 Every Other Week Dosing
Follow-up
TOTAL
Procedure
Days
Weeks
-21 to -7
Postop check
Day 0, Week 0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
38
40
42
44
46
48
50, 52, 54, 56, 58
60
62, 64, 66, 68, 70
72
74, 76, 78, 80, 82
84
86, 88, 90, 92, 94
96
98, 100, 102, 104, 106
108
110, 112, 114, 116, 118
120
124
CSF (mL)
Standard CSF safety 
labs
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
CSF sample for GAG 
testing
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
Anti-rhHNS Ab 
testing (CSF)
b
b
b
b
b
b
b
b
b
b
b
b
b
CSF PK sampling 
(Appendix 7)
4
4
CSF for storage (for 
biomarkers and Ab 
testing)
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
Total CSF Volume
11
15
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
15
11
11
11
11
11
11
11
11
11
11
11
11
690
Blood (mL)
Hematology
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
Serum chemistry
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
PT and aPTT 
(coagulation)
1.8
Anti-rhHNS Ab 
testing (serum)
4
4
4
4
4
4
4
4
4
4
4
4
4
Serum PK sampling 
(Appendix 7)
9
9
9


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CONFIDENTIAL 
Page 91
Clinical Trial Protocol:  SHP-610-201
HGT-1410 – SOPH-A-PORT® Mini S
25 Jan 2017
IDDD 
Implantation 
Period
Treatment Period for Patients in Group 3A:  Initiating HGT-1410 Every Other Week Dosing
Follow-up
TOTAL
Procedure
Days
Weeks
-21 to -7
Postop check
Day 0, Week 0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
38
40
42
44
46
48
50, 52, 54, 56, 58
60
62, 64, 66, 68, 70
72
74, 76, 78, 80, 82
84
86, 88, 90, 92, 94
96
98, 100, 102, 104, 106
108
110, 112, 114, 116, 118
120
124
Total Blood Volume
6.3
17.5
8.5
8.5
8.5
4.5
4.5
8.5
8.5
17.5
8.5
8.5
8.5
17.5
8.5
8.5
4.5
157.3
Abbreviations:  Ab=antibody; aPTT=activated partial thromboplastin time; CSF=cerebrospinal fluid; GAG=glycosaminoglycan; IDDD=intrathecal drug delivery device; 
PK=pharmacokinetics; PT=prothrombin time; rhHNS=recombinant human heparan N sulfatase
a
CSF for GAGs included in CSF storage sample
b
Anti-rhHNS Ab testing in CSF will be performed on stored samples.


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CONFIDENTIAL 
Page 92
Clinical Trial Protocol:  SHP-610-201
HGT-1410 – SOPH-A-PORT® Mini S
25 Jan 2017
IDDD 
Implant-
ation 
Period
Treatment Period for Patients in Group 3B:  Initiating HGT-1410 Dosing Every 4 Weeks
Follow-up
TOTAL
Procedure
Days
-21 to -7
Postop 
check
Day 0, 
Week 0
4, 8
12
16, 20
24
28, 32
36
40, 44
48
52, 56
60
64, 68
72
76, 80
84
88, 92
96
100, 104
108
112, 116
120
124
CSF (mL)
Standard CSF 
safety labs
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
CSF sample for 
GAG testing
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
a
Anti-rhHNS Ab 
testing (CSF)
b
b
b
b
b
b
b
b
b
b
b
b
CSF PK 
sampling 
(Appendix 7)
4
4
CSF for storage 
(for biomarkers 
and Ab testing)
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
Total CSF 
Volume
11
15
11
11
11
11
11
11
11
15
11
11
1
1
11
11
11
11
11
11
11
11
11
360
Blood (mL)
Hematology
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
Serum 
chemistry
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
PT and aPTT 
(coagulation)
1.8
Anti-rhHNS Ab 
testing (serum)
4
4
4
4
4
4
4
4
4
4
4
4
Serum PK 
sampling 
(Appendix 6)
9
9
9
Total Blood 
Volume
6.3
17.5
8.5
8.5
4.5
8.5
8.5
17.5
8.5
8.5
8.5
17.5
8.5
8.5
4.5
157.3
Abbreviations:  Ab=antibody; aPTT=activated partial thromboplastin time; CSF=cerebrospinal fluid; GAG=glycosaminoglycan; IDDD=intrathecal drug delivery device; 
PK=pharmacokinetics; PT=prothrombin time; rhHNS=recombinant human heparan N sulfatase
a
CSF for GAGs included in CSF storage sample
b
Anti-rhHNS Ab testing in CSF will be performed on stored samples.


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CONFIDENTIAL
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Clinical Trial Protocol:  SHP-610-201
HGT-1410 – SOPH-A-PORT® Mini S
25 Jan 2017
Appendix 7
Pharmacokinetic and Pharmacodynamic Sample Schedule
Drug 
Administration
PK/PD Sampling Times
Blood Sampling
HGT-1410 IT 
injection
Serum PK samples will be obtained at Weeks 0, 48, and 96 for Groups 3a and 3b. 
Serum PK samples will be obtained at Week 96 for Groups 1 and 2.
Immediately prior to IT injection (baseline), then at 0.5, 1, 2, 4, 8, 12, 24, and 48 (Day 
2) hours following completion of IT injection. Patients may be discharged from the 
hospital after the 24-hour blood draw. Patients will either stay locally in a hotel or 
return home (if they live in close proximity to the hospital); in consultation with the 
Investigator. Patients will return to the hospital for PK blood sampling at the 48-hour 
PK time point. Patients will be discharged for home following the last (48-hour) PK 
time point and following the completion of their final physical examination.
CSF Sampling
CSF PK and PK/PD samples will be obtained at Weeks 0 and 48 for Groups 3A and 3B 
only.
Immediately prior to IT injection (baseline), then at 4 hours and 48 hours after the 
completion of the IT injection. The 4-hour and 48-hour post-dose CSF samples will 
only be obtained if a functioning IDDD is in place. Patients will either stay locally in a 
hotel or return home (if they live in close proximity to the hospital); in consultation 
with the Investigator. Patients will return to the hospital for CSF sampling at the 
48 hour time points. 
Abbreviations:  CSF=cerebrospinal fluid; IDDD=intrathecal drug delivery device; IT=intrathecal; 
PD=pharmacodynamics; PK=pharmacokinetics


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Clinical Trial Protocol:  SHP-610-201
HGT-1410 – SOPH-A-PORT® Mini S
25 Jan 2017
Appendix 8
Expected SOPH-A-PORT Mini S Adverse Device Effects
Procedure-related Complications

Components handled improperly before, during, or after implantation 

Access port implanted incorrectly

Catheter positioned improperly

Injection through septum performed incorrectly

Injection of incorrect medication through access port

Injection outside the access port into pocket or subcutaneous tissue or extravasation

Pocket seroma, hematoma, erosion, or infection

Intrathecal access complications

Surgical complications such as hemorrhage or hematoma

Infection of the implant site or catheter track

Radiculitis or arachnoiditis

Intrathecal space infection resulting in meningitis or encephalitis

Bleeding 

Spinal cord damage or trauma to the spinal cord or nerve roots

Post-LP, CSF leak, leading to headache, or  subcutaneous CSF collection

Epidural instead of intrathecal placement of catheter

Inflammatory mass resulting in neurological impairment, including paralysis

Pain on injection

Complications of anesthesia

Pseudomeningocele
System-related Complications

Improperly positioned access port

Erosion of the skin because of the underlying access port or the catheter

Wound dehiscence

Access port migration, fracture, breakage or occlusion

Catheter damage, dislodgement, migration, disconnection, kinking or occlusion, fibrosis, or 
hygroma, resulting in tissue damage or a loss of or change in therapy, or other potentially 
serious adverse health consequences

Catheter breakage and migration of residual catheter fragments, potentially resulting in 
serious adverse health consequences and the need for surgical removal 

Local immunological or fibrous reaction to the presence of a foreign body (the device)

End of device service life or component failure, requiring surgical replacement

Component failure, resulting in loss of therapy

Access port inversion (“flipping”), rotation, or extrusion

Access port or catheter rejection 

Fibrin sheath formation around catheter tip


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Clinical Trial Protocol:  SHP-610-201
HGT-1410 – SOPH-A-PORT® Mini S
25 Jan 2017
Appendix 9
Protocol Amendment Summary of Changes
AMENDMENT SUMMARY AND RATIONALE
Clinical protocol SHP-610-201 has been amended to include language to allow for patients to 
retain a full or partial IDDD in situ after they discontinue or complete the treatment period of the 
study, at the discretion of the investigator based upon safety assessment. These patients who do 
not have the IDDD removed at the end of the treatment period will continue to be observed 
during a safety follow-up period with visits every 6 months to evaluate patient safety of the 
device up to an additional 3 years or until the device is removed in the last patient.
Changes in grammar, spelling, punctuation, format, minor editorial changes (including changes 
for consistency and clarity), and updates to the list of abbreviations and cross-references are not 
reflected in the change summary.
DETAILED SUMMARY OF CHANGES FOR THE AMENDMENT
This is a section that has been updated to describe the changes from the previous protocol 
version. Significant changes and additions to the protocol text are captured below. Bold text 
indicates new text. Strikethrough text indicates deleted text.
Change:  Patients should have the IDDD removed; however, the Investigator may 
determine that the device should not be removed upon safety assessment.
Section impacted by this change:  Section 4.1, Overall Study Design and Plan
Revised Text: 
Patients will should have the IDDD removed when they discontinue from or complete the 
treatment period of the study, unless the patient is continuing to receive treatment 
through another mechanism (eg, extension study, expanded access program, commercially 
available, etc.) investigator determines that it should not be removed based upon 
safety assessments. The device can remain in the patient (partial [catheter only] or 
full [port, catheter, and suture wings]) if the patient is doing clinically well and there 
are no further known risk factors such as infection (eg, meningitis).  The device may 
be partially or fully removed as medically required and determined by the 
neurosurgeon at a future date.
Other sections impacted by this change:  Synopsis, Section 7.4.4, Device Adjustment, 
Revision, or Removal; Section 8.1.1.2, Post-treatment Assessments; Section 8.2.1.2, Post-
treatment Assessments; Section 8.4.1.2, Post-treatment Assessments; Section 8.5.1.2, 
Post-treatment Assessments


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Clinical Trial Protocol:  SHP-610-201
HGT-1410 – SOPH-A-PORT® Mini S
25 Jan 2017
Change:  Clarification that safety and efficacy assessments were performed in the 
treatment period of the study.
Section impacted by this change:  Section 4.1, Overall Study Design and Plan
Revised Text: 
Safety and efficacy assessments will be performed at regular intervals over the 
approximate 2.5-year duration of the treatment period of Study SHP-610-201.
Other sections impacted by this change:  Synopsis
Change:  Patients who do not have the device removed will be observed for safety during 
a safety follow-up period with visits every 6 months.
Section impacted by this change:  Section 4.1, Overall Study Design and Plan
Revised Text: 
Patients who do not have the IDDD removed (partial or full device) at the end of the 
treatment period will continue to be observed during a safety follow-up period with 
visits at the site every 6 months to evaluate patient safety of the device until the 
IDDD has been fully explanted.
Other sections impacted by this change:  Synopsis
Change:  The study duration may be longer than 30 months, as for patients in the safety 
follow-up period will be up to an additional 3 years or until the device is removed in the 
last patient.
Section impacted by this change:  Section 4.3, Study Duration
Revised Text: 
Patients are expected to participate in this study for up to 30 months. Patients who 
received HGT-1410 in Study HGT-SAN-093 will undergo a cumulative exposure to 
HGT-1410 for up to 42 months (168 weeks), whereas patients who received no treatment 
in Study HGT-SAN-093 will have a cumulative exposure to HGT-1410 for up to 
30 months (120 weeks) in Study SHP-610-201.
For those Patients with a partial or full device still in place after completion of the 
treatment period, patients may be followed for safety up to an additional 3 years or 
until the device is removed in the last patient.
Other sections impacted by this change:  Synopsis
Change:  Schedule of events added for the safety follow-up period.
Section impacted by this change:  Section 4.1 Overall Study Design and Plan
Revised Text: 
See Appendix 5 for the Study Schedule of Events for the safety follow-up period for 
patients with partial or full devices in place after the end of the treatment period.
Other sections impacted by this change:  Section 7, Study Procedures; Section 8, Study 
Activities, Appendix 5


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Clinical Trial Protocol:  SHP-610-201
HGT-1410 – SOPH-A-PORT® Mini S
25 Jan 2017
Change:  LPLV defined
Section impacted by this change:  Section 4.3, Study Duration
Revised Text: 
The LPLV will be the safety follow-up visit after the final device (partial and/or full) 
is removed from the last patient during the safety follow-up period.
Other sections impacted by this change:  Synopsis
Change:  Informed consent will be obtained from patients who did not have the device 
removed.
Section impacted by this change:  Section 7.1, Informed Consent
Revised Text: 
After the treatment period ends, informed consent from patients who do not have the 
IDDD removed (partial or full device) will be obtained for the safety follow-up 
period.
Other sections impacted by this change:  NA
Change:  Clarification regarding x-ray verification during safety follow-up period.
Section impacted by this change:  Section 7.4.2 X-ray Verification of Intrathecal Drug 
Delivery Device Placement
Revised Text: 
A postoperative X-ray check of the IDDD will be performed following surgery for Groups 
3A and 3B to verify proper installation and confirmation of IDDD placement at the mid-
thoracic level. The X-rays may be performed to check placement, migration, or 
malfunction of the device, as needed, throughout the treatment period or safety follow-
up period of the study. At a minimum, the date of the X-ray verifying correct IDDD 
placement will be documented on the patient’s eCRF. If the device requires revision or 
replacement during the treatment period of the study, additional X-rays will be taken to 
document proper positioning of the device. If an IDDD malfunctions, an X-ray will be 
performed to assess the potential cause of malfunction. Fluoroscopy should be used during 
device implantation procedures.
Other sections impacted by this change:  NA
Change:  Symptom-directed physical examinations to be performed during the safety 
follow-up period.
Section impacted by this change:  Section 7.11.2 Physical Examination, Including Height, 
Weight, and Head Circumference
Revised Text: 
During the study, physical examinations will be performed at the time points indicated in 
the Schedules of Events. For Groups 1 and 2, full physical examinations will be conducted 
at Weeks 96, 120, 144, and 168, and for Groups 3A and 3B, full physical examinations 
will be conducted during the IDDD implantation period and at Weeks 24, 48, 72, 96, and 
120. The remainder of physical examinations will be symptom-directed, including 
examinations during the safety follow-up period in patients who do not have the 


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25 Jan 2017
IDDD removed (partial or full device) at the end of the treatment period.
Other sections impacted by this change:  NA
Change: Clinical laboratory testing only performed for device-related AEs during the 
safety follow-up period.
Section impacted by this change: Section 7.11.4, Clinical Laboratory Testing 
Revised Text: 
Clinical laboratory testing will only be performed when indicated for a device-
related AE for patients who do not have the IDDD removed (partial or full device) at 
the end of the treatment period.
Other sections impacted by this change:  NA
Change:  Final evaluation in the safety follow-up period defined.
Section impacted by this change:  Section 7.13.6.1, Adverse Event Monitoring and Period 
of Observation
Revised Text: 
For the purposes of this study, the period of observation extends from the time at which 
the patient, the patient’s parent(s), or the patient’s legally authorized representative gives 
informed consent until the patient’s final evaluation of the study. For safety purposes, the 
final evaluation for the treatment period will be defined as the follow-up evaluation 
performed approximately 30 days after the last dose for patients who complete the study. 
The final evaluation in the safety follow-up period for patients who do not have the 
IDDD removed (full or partial device) is defined as the follow-up evaluation 
performed for up to 3 years after the treatment period ends.
Other sections impacted by this change:  NA
Change:  Study discontinuation process defined.
Section impacted by this change:  Section 7.15.1, Study Discontinuation Process
Revised Text: 
If the patient is discontinued from the study, the IDDD should be removed and a 
modified end-of-study visit should be completed within 30 days after withdrawal. 
These visits may be combined into 1 visit, in which case follow-up via a phone call 
should be completed within 14 days after the device removal to collect safety 
information. The end-of-study visit only requires collection of safety assessments, 
including symptom-directed physical exam, vital signs, clinical laboratory tests 
(hematology, serum chemistry, and urinalysis), concomitant medications, therapies, 
and procedures, and AE monitoring. No MRI or cognitive assessments are required. 
No study-required CSF collection is needed at the IDDD removal, unless required 
for AE resolution.
If the investigator determines that the IDDD should not be removed from the patient 


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25 Jan 2017
based upon a safety assessment and the IDDD (full or partial) remains in the patient, 
then the patient will continue in the study under the safety follow-up period upon 
completion of their last treatment period visit. This last treatment period visit only 
requires collection of safety assessments, including symptom-directed physical exam, 
vital signs, clinical laboratory tests (hematology, serum chemistry, and urinalysis), 
concomitant medications, therapies, and procedures, and AE monitoring. No MRI or 
cognitive assessments are required. No study-required CSF collection is needed at 
the IDDD removal, unless required for AE resolution. Once the patient completes 
their last treatment period visit, they will return for their first safety follow-up visit 
in 6 months. The patient will continue in the safety follow-up period with a clinic 
visit every 6 months for up to 3 years or until the device is removed in the last 
patient. An end-of-study follow-up via a phone call should be completed within 14 
days after the device removal to collect safety information (refer 
Section8.6;Appendix 5).
Other sections impacted by this change:  NA
Change:  Assessments during safety follow-up period if device not removed described.
Section impacted by this change:  Section 8.6, All Groups:  Safety Follow-up Period if 
Device Not Removed
Revised Text: 
All patients who do not have the IDDD removed (partial or full device) will have 
safety follow-up visits every 6 months at the site, with the following assessments 
performed: 

Informed consent

Symptom-directed PE

Clinical laboratory tests; only if indicated for a device-related AE

X-ray monitoring; only for migration or device-related issue

Concomitant medications, therapies, and procedures; only if indicated for a 
device-related AE

AE monitoring only for device-related events
During the 3-year safety follow-up period, the patient may have the device removed 
at any time, as deemed medically necessary.  A post-operative evaluation, including a 
postoperative check of the incision and collection of safety information, should occur 
within 1-3 days after the IDDD explantation.  An end-of-study safety follow-up via a 
phone call should be completed within 14 days after the device removal to collect 
safety information.
Other sections impacted by this change:  Section 7.16, Safety-Related Study Stopping 
Rules


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Change:  Clarification regarding statistical analysis of TEAEs and treatment period.
Section impacted by this change:  Section 10.7.1, Adverse Events
Revised Text: 
Treatment-emergent AEs, defined as all AEs from the time of initial IDDD implantation 
(or first dose if no IDDD implant), to the safety follow-up visit, defined as the last patient 
visit in the study during the treatment period, will be summarized.
Other sections impacted by this change:  NA
Change:  Clarification regarding statistical analysis of concomitant medications and 
treatment period.
Section impacted by this change:  Section 10.7.6, Concomitant Medications
Revised Text: 
Concomitant medications will be coded using the WHO-DD. The concomitant 
medications that occur from the time of the surgery for IDDD implantation to the safety 
follow-up visit, defined as the last patient visit in the study during the treatment period,
will be summarized by therapeutic class and preferred term. 
Other sections impacted by this change:  NA
Change:  Language added indicating interim analysis may be performed.
Section impacted by this change:  Section 10.8.3, Interim Analyses and Data Monitoring
Revised Text: 
Interim analyses may be conducted before trial completion for safety monitoring, 
regulatory reporting or general study planning purposes. Analyses will be 
descriptive in nature, with no formal comparisons planned and no hypotheses 
formally tested. No formal interim analysis or interim statistical testing for early 
stopping of the trialis planned. Descriptive analyses of the data before trial completion 
may be performed for safety monitoring, regulatory reporting or general study planning 
purposes.An independent DMC will be established to provide an ongoing, independent 
review and assessment of patient data, and to safeguard the interests and safety of the 
participating patients in the study (see Section 11.8). An analysis of the data for DMC 
review will occur at specific times during the study as specified in the DMC charter. 
Because no formal hypothesis testing is planned, multiplicity concerns regarding repeated 
analyses are not an issue.
Other sections impacted by this change:  NA
Change:  Clarification that the DMC monitoring will only be conducted during the 
treatment period.
Section impacted by this change:  Section 11.8, Data Monitoring Committee
Revised Text: 
An independent DMC will be established to provide an ongoing, independent review and 
assessment of the safety data, and to safeguard the interests and safety of the participating 
patients in the study during the treatment period. The DMC will consist of a 


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biostatistician and 2 clinical experts.
It is anticipated that there will be scheduled meetings annually during the treatment 
periodconduct of the study. The first meeting will be an orientation meeting and will take 
place prior to the start of the study. Subsequent meetings will occur at specific times 
during the study as specified in the DMC charter. The final meeting will be conducted 
when all patients have completed treatment period of the study for a comprehensive 
safety overview of the study. A special DMC meeting will be convened if the safety-
related study stopping rules are met during the treatment period of the study (see 
Section 7.16).
Other sections impacted by this change:  Section 7.16, Safety-Related Study Stopping 
Rules



SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
 
 
NCT Number:   
NCT02350816 
 
Study Title:  
An Open-Label Extension of Study HGT-SAN-093 Evaluating the Safety and 
Efficacy of HGT-1410 (Recombinant Human Heparan N Sulfatase) 
Administration via an Intrathecal Drug Delivery Device in Pediatric Patients 
with Mucopolysaccharidosis Type IIIA Disease 
 
 
Study Number:  
SHP610-201 
 
 
SAP Version and Date:   
Original: 22 November 2016 
SAP for Interim Analysis: 26 May 2017 
SAP Addendum for Safety Follow-Up Period: 21 June 2019 


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STATISTICAL ANALYSIS PLAN 
Protocol Title: 
An Open-Label Extension of Study HGT-SAN-093 
Evaluating the Safety and Efficacy of HGT-1410 
(Recombinant Human Heparan N Sulfatase) 
Administration via an Intrathecal Drug Delivery Device 
in Pediatric Patients with Mucopolysaccharidosis Type 
IIIA Disease 
Protocol Number: 
SHP-610-201 
Protocol Version/Date 
Amendment 1 
17 December 2015 
Indication: 
Long-term Treatment of Mucopolysaccharidosis Type 
IIIA (MPS IIIA or Sanfilippo Syndrome Type A) 
Study Phase 
IIb 
SAP Author 
, PhD 
SAP Analysis Type 
Final Analysis 
SAP Version/Date 
Final 
November 22, 2016 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This document is the proprietary and confidential property of Shire  
 
 
 




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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS AND DEFINITIONS ..................................................... 6 
1.1 
Abbreviations .................................................................................................................. 6 
2. 
INTRODUCTION .......................................................................................................... 8 
2.1 
Purpose of the Statistical Analysis Plan ......................................................................... 8 
2.2 
Background ..................................................................................................................... 8 
2.3 
Study Rationale ............................................................................................................... 8 
3. 
STUDY OBJECTIVES .................................................................................................. 9 
3.1 
Primary Objective ........................................................................................................... 9 
3.2 
Secondary Objectives ..................................................................................................... 9 
3.3 
Exploratory Objective ..................................................................................................... 9 
3.4 
Pharmacokinetic and Pharmacodynamic Objectives ...................................................... 9 
3.5 
Health Status Objective .................................................................................................. 9 
3.6 
Health Economics and Outcome Research Objective .................................................... 9 
4. 
STUDY DESIGN ......................................................................................................... 10 
4.1 
General Description ...................................................................................................... 10 
4.2 
Discussion of Study Design, Including the Choice of Control Group ......................... 11 
4.3 
Method of Assigning Subjects to Treatment Group ..................................................... 11 
4.4 
Blinding ........................................................................................................................ 11 
4.5 
Determination of Sample Size ...................................................................................... 11 
5. 
EFFICACY AND SAFETY ENDPOINTS .................................................................. 12 
5.1 
Primary Endpoint .......................................................................................................... 12 
5.2 
Secondary Endpoints .................................................................................................... 12 
5.3 
Exploratory Endpoint(s) ............................................................................................... 12 
5.4 
Pharmacokinetic and Pharmacodynamic Endpoints ..................................................... 12 
5.5 
Health Status Endpoint ................................................................................................. 13 
5.6 
Health Economics and Outcomes Research Endpoint ................................................. 13 
6. 
EFFICACY AND SAFETY VARIABLES .................................................................. 14 
6.1 
Schedule of Evaluations ............................................................................................... 14 
6.2 
Efficacy Assessments ................................................................................................... 14 
6.2.1 
Neurocognitive and Developmental Assessments ................................................. 14 
6.2.2 
Quality of Life Indicator: Infant Toddler Quality of Life Questionnaire .............. 15 
6.2.3 
Health Economics and Outcomes Research: Healthcare Utilization 
Questionnaire ......................................................................................................... 15 


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6.3 
Magnetic Resonance Imaging ...................................................................................... 15 
6.3.1 
Head ....................................................................................................................... 15 
6.3.2 
Liver and Spleen .................................................................................................... 15 
6.4 
Pharmacokinetic Assessments ...................................................................................... 16 
6.5 
Pharmacodynamic Biomarker Assessments (CSF and Urine GAG Levels) ................ 16 
6.6 
Concomitant Medications, Therapies, and Medical/Surgical Interventions ................. 16 
6.7 
Safety Assessments ....................................................................................................... 16 
6.7.1 
Vital Signs .............................................................................................................. 16 
6.7.2 
Physical Examination, Including Height, Weight, and Head Circumference ........ 17 
6.7.3 
Electrocardiogram .................................................................................................. 17 
6.7.4 
Clinical Laboratory Tests ....................................................................................... 18 
6.7.5 
Cerebrospinal Fluid Assessments .......................................................................... 18 
6.7.5.1 
Standard CSF Safety Laboratory Assessments ........................................... 18 
6.7.5.2 
Anti-rhHNS Antibodies and Biomarkers in CSF ........................................ 18 
6.7.5.3 
CSF GAG Levels and Biomarkers .............................................................. 18 
6.7.5.4 
 .............................................................. 18 
6.7.6 
Device Assessments ............................................................................................... 19 
6.8 
Adverse Events Assessments ........................................................................................ 19 
7. 
STATISTICAL ANALYSIS ........................................................................................ 20 
7.1 
General Methodology ................................................................................................... 20 
7.2 
Analysis Populations .................................................................................................... 20 
7.3 
Subject Disposition ....................................................................................................... 20 
7.4 
Demographics and Baseline Characteristics ................................................................. 21 
7.5 
Protocol Deviations ...................................................................................................... 21 
7.7 
Treatment Compliance and Extent of Exposure ........................................................... 21 
7.8 
Analysis of Efficacy ..................................................................................................... 21 
7.8.1 
Primary Analysis .................................................................................................... 21 
7.8.2 
Secondary Efficacy Analysis ................................................................................. 22 
7.8.2.1 
Bayley Scales of Infant Development, Third Edition (BSID-III)/ .............. 22 
7.8.2.2 
Vineland Adaptive Behavior Scales, Second Edition (VABS-II) ............... 22 
7.8.2.3 
Brain MRI .................................................................................................... 22 
7.9 
Analysis of Pharmacokinetic and Pharmacodynamic Data .......................................... 22 
7.9.1 
Pharmacokinetic Measurement and Parameters .................................................... 22 
7.9.2 
Pharmacodynamic Analyses .................................................................................. 22 
7.10 
Analysis of Safety ......................................................................................................... 22 
7.10.1 Adverse Events ...................................................................................................... 22 
7.10.2 Clinical Laboratory Evaluation .............................................................................. 23 
7.10.4 Vital Signs .............................................................................................................. 24 


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7.10.5 Anti-rhHNS Antibody in Serum and CSF ............................................................. 24 
7.10.6 Concomitant Medications ...................................................................................... 24 
7.10.7 Other Observations Related to Safety .................................................................... 24 
7.10.7.1 IDDD Performance ...................................................................................... 24 
8. 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES .... 25 
8.1 
Changes from the Analyses Planned in the Protocol .................................................... 25 
9. 
REFERENCES ............................................................................................................. 26 
10. 
APPENDICES .............................................................................................................. 27 
10.1 
APPENDIX II: List of Statistical Outputs .................................................................... 27 
10.2 
APPENDIX III: Definitions and Programming Conventions ...................................... 27 
10.2.1 Calculation of DQ Scores ...................................................................................... 27 


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1. 
LIST OF ABBREVIATIONS AND DEFINITIONS 
1.1 
Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
AUC 
area under the concentration curve 
AUC0-last 
area under the curve from the time of dosing to the last measurable 
concentration 
AUC0-∞ 
area under the curve extrapolated to infinity, calculated using the 
observed value of the last non-zero concentration 
BSID-III 
Bayley Scales of Infant Development, Third Edition 
CL/F 
total body clearance for extravascular administration divided by the 
fraction of dose absorbed 
Cmax 
maximum concentration occurring at tmax  
CS 
clinically significant 
CSF 
cerebrospinal fluid 
CSR 
clinical study report 
DQ 
developmental quotient 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
GAG 
glycosaminoglycan 
HGT 
human genetic therapies 
HS 
heparan sulfate 
IDDD 
intrathecal drug delivery device 
IT 
intrathecal 
KABC-II 
Kaufman Assessment Battery for Children, Second Edition  
LP 
lumbar puncture 
MedDRA 
Medical Dictionary for Regulatory Activities  
Min 
minimum 
Max 
maximum 
MPS IIIA 
Mucopolysaccharidosis Type IIIA 
MRI 
magnetic resonance imaging 
n 
Sample size 
NCS 
not clinically significant 
PK 
pharmacokinetic 
Q2W 
Every 2 weeks 
Q4W 
Every 4 weeks 
rhHNS 
Recombinant human heparan N-sulfatase 


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Abbreviation 
Definition 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
system organ class 
t1/2 
terminal half-life 
tmax 
time of maximum observed concentration sampled during a dosing 
interval 
TEAE 
treatment-emergent adverse event 
VABS-II 
Vineland Adaptive Behavior Scales, Second Edition 
Vz/F 
volume of distribution associated with the terminal slope following 
extravascular administration divided by the fraction of dose 
absorbed 
WHO 
World Health Organization 
 


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2. 
INTRODUCTION 
2.1 
Purpose of the Statistical Analysis Plan 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the planned 
statistical analyses for protocol SHP-610-201, a Phase IIb, open-label extension of study HGT-
SAN-093 evaluating the safety and efficacy of HGT-1410 (Recombinant Human Heparan N 
Sulfatase) administration via an intrathecal drug delivery device in pediatric patients with 
mucopolysaccharidosis type IIIA disease. Shire is terminating this study early due to the 
insufficient evidence of efficacy for HGT-1410 in study HGT-SAN-093. An abbreviated clinical 
study report (aCSR) will be written for this study, as the study is not intended to contribute to the 
evaluation of product effectiveness or to provide definitive information on clinical 
pharmacology.  This report will describe all the safety information included in a full report. 
2.2 
Background 
Study SHP-610-201 is a Phase IIb, open-label extension of study HGT-SAN-093 evaluating the 
safety and efficacy of HGT-1410 (Recombinant Human Heparan N Sulfatase) administration via 
an intrathecal drug delivery device in pediatric patients with mucopolysaccharidosis type IIIA 
disease. Details of the study design, rationale, and procedures are documented in Protocol SHP-
610-201. 
2.3 
Study Rationale 
The study design is intended to provide ongoing treatment with HGT-1410 to patients who 
received HGT-1410 in Study HGT-SAN-093 and to initiate treatment to patients who received 
no-treatment in Study HGT-SAN-093. As such, all patients will be treated during this study; 
there is no control group. 
In order to traverse the blood-brain barrier, HGT-1410 will be administered directly to the 
central nervous system using an intrathecal drug delivery device (IDDD) or, if the IDDD is non-
functional, via lumbar puncture (LP). The advantage of using an IDDD is the potential to obviate 
the need for multiple lumbar punctures for drug delivery.  
Safety is the primary objective of the study, and the study duration has been designed to provide 
a reasonable time for safety follow-up. 


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3. 
STUDY OBJECTIVES 
3.1 
Primary Objective  
The primary objective of this study is to evaluate long-term safety in patients with 
mucopolysaccharidosis type IIIA disease (MPS IIIA or Sanfilippo syndrome type A) who 
received HGT-1410. 
3.2 
Secondary Objectives  
The secondary objectives of this study are to evaluate:   
• The long-term cognitive function as measured by the Bayley Scales of Infant and Toddler 
Development, Third Edition (BSID-III) or Kaufman Assessment Battery for Children, 
Second Edition (KABC-II), age-equivalent and developmental quotient (DQ) scores in 
patients with MPS IIIA who received HGT-1410 
• The long-term adaptive behavioral function, assessed by Vineland Adaptive Behavior Scales, 
Second Edition (VABS-II) in patients who received HGT-1410 
• The total cortical grey matter volume, as assessed by volumetric magnetic resonance imaging 
(MRI) of the brain, in patients who received HGT-1410 
 
3.3 
Exploratory Objective 
The exploratory objective of this study is to 
 
. 
3.4 
Pharmacokinetic and Pharmacodynamic Objectives 
The pharmacokinetic (PK) and pharmacodynamics objectives of this study are to evaluate: 
• The pharmacokinetics of HGT-1410 in serum, in all patients with PK assessment 
• The pharmacokinetics of HGT-1410 in CSF, in patients who received no treatment in Study 
HGT-SAN-093 
• The concentration of GAG in CSF and urine in patients who received HGT-1410 
 
3.5 
Health Status Objective 
The health status objective of this study is to evaluate health status as measured by the Infant 
Toddler Quality of Life Questionnaire™ (ITQoL) instrument in patients who received 
HGT-1410. 
3.6 
Health Economics and Outcome Research Objective 
The health economics and outcome research objective of this study is to evaluate healthcare 
resource utilization, as evaluated by the Healthcare Utilization Questionnaire (HCUQ), in 
patients who received HGT-1410. 


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4. 
STUDY DESIGN 
4.1 
General Description 
This is an open-label extension study of HGT-1410 for patients who completed through at least 
the Week 48 Visit in Study HGT-SAN-093. Patients who originally received HGT-1410 in Study 
HGT-SAN-093 will remain on the same dosing regimen as they received in Study HGT-SAN-
093; Group 1 will receive HGT-1410 every 2 weeks (Q2W) and Group 2 will receive HGT-1410 
every 4 weeks (Q4W). Patients in Groups 1 and 2 will begin treatment at Week 50 and Week 52, 
respectively, of this extension study (Study SHP-610-201). Patients who originally received no-
treatment in Study HGT-SAN-093 (Group 3) will receive an IDDD following informed consent 
and will be re-randomized in a 1:1 allocation ratio to receive HGT-1410 via a Q2W or Q4W 
dosing regimen (Groups 3A and 3B, respectively) in Study SHP-610-201. Patients in Groups 3A 
and 3B will begin treatment on Week 0 of the extension study.  
It is anticipated that the IDDD will be used to collect CSF samples and to deliver IT injections of 
HGT-1410 and preservative-free saline flushes. No other medication will be administered 
through the device. If the IDDD appears to be non-functional, or if its use is precluded on a 
scheduled day of dosing, site personnel will refer to the IDDD Manual, which provides details on 
the investigation and management of any IDDD-related issues. This includes possible partial 
revision or complete replacement of the IDDD as indicated. If the IT space is not accessible via 
the IDDD, study drug may be administered by LP. Should the IDDD become clogged, undergo 
mechanical complications or otherwise not be accessible, the CSF sample may also be obtained 
by LP. General anesthesia or sedation may be required for injections of study drug and some 
evaluations, and may be used at the discretion of the Investigator. The Data Monitoring 
Committee (DMC) will be notified of all IDDD failures and IDDD-related complications at 
times defined in the DMC charter. 
Patients will have the IDDD removed when they discontinue from or complete the study unless 
the patient is continuing to receive product or treatment through another mechanism (eg, 
extension study, expanded access program, commercially available drug). 
Safety and efficacy assessments will be performed at regular intervals over the approximate 
2.5-year duration of the extension study. A pharmacokinetic sample for patients who received 
HGT-1410 in Study HGT-SAN-093 will be obtained at the Week 96 visit (after approximately 2 
full years of exposure to HGT-1410 across Studies HGT-SAN-093 and SHP-610-201). Serum 
pharmacokinetic samples for patients who received no-treatment in Study HGT-SAN-093 will be 
obtained at the Week 0, 48, and 96, and CSF pharmacokinetic samples will be obtained on the 
Week 0 and 48 visits in Study SHP-610-201. 
Patients who received HGT-1410 in Study HGT-SAN-093 will undergo a cumulative exposure 
to HGT-1410 for up to 42 months (168 weeks), whereas patients who received no treatment in 
Study HGT-SAN-093 will have a cumulative exposure to HGT-1410 for up to 30 months 
(120 weeks) in Study SHP-610-201. 
 


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4.2 
Discussion of Study Design, Including the Choice of Control Group 
This is an open-label extension study of Study HGT-SAN-093 intended to provide ongoing 
treatment with HGT-1410 to patients who received HGT-1410 in Study HGT-SAN-093 and to 
initiate treatment to patients who received no-treatment in Study HGT-SAN-093. As such, all 
patients will be treated during this study; there is no control group. 
4.3 
Method of Assigning Subjects to Treatment Group  
Patients who were randomized to no-treatment in Study HGT-SAN-093 (Group 3) will be re-
randomized in a 1:1 allocation ratio to receive Q2W or Q4W dosing (Groups 3A or 3B, 
respectively). To help ensure balance between the dose groups with respect to age at Baseline, 
the randomization will be stratified by age group (≤30 months and >30 months).  Patients who 
were randomized to receive HGT-1410 in Study HGT-SAN-093 will remain on the same 
treatment regimen in Study SHP-610-201. 
4.4 
Blinding  
This study will not be blinded. 
4.5 
Determination of Sample Size  
As this is an extension study of Study HGT-SAN-093, any patients who enrolled and completed 
that study are eligible to enroll in Study SHP-601-201, and no statistical estimation for sample 
size calculation was performed. A maximum sample size of 21 patients in this study is expected 
based on the sample size in Study HGT-SAN-093. 
 


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5. 
EFFICACY AND SAFETY ENDPOINTS 
5.1 
Primary Endpoint 
Safety is the primary objective of the study and will be assessed during the study by the 
following: 
• Collection of adverse events (AEs; by type, severity, and relationship to treatment 
[HGT-1410, the IDDD, device surgical procedure, or IT administration process]) 
• Changes in clinical laboratory testing (serum chemistry, hematology, urinalysis) 
• Physical examination 
• Vital signs 
• Twelve-lead electrocardiogram (ECG) recordings  
• CSF laboratory parameters (including chemistries, cell counts) 
• Anti-rhHNS antibodies in CSF and serum, including determination of antibodies having 
enzyme neutralizing activity 
 
5.2 
Secondary Endpoints 
The secondary endpoints of this study are: 
• The change from Baseline in BSID-III or KABC-II age-equivalent, DQ, and developmental 
delay scores 
• The change from Baseline in adaptive behavioral function domains, assessed by VABS II, 
using raw scores, age-equivalent scores, and DQ scores 
• The change from Baseline in total cortical grey matter volume, as assessed by MRI 
 
5.3 
Exploratory Endpoint(s) 
5.4 
Pharmacokinetic and Pharmacodynamic Endpoints 
The pharmacokinetic endpoint is to determine the pharmacokinetic behavior of HGT-1410 in 
serum, based on the following parameters: 
• Maximum concentration occurring at tmax (Cmax) 
• Time of maximum observed concentration sampled during a dosing interval (tmax) 
• Area under the curve from the time of dosing to the last measurable concentration (AUC0-last) 
• Area under the curve extrapolated to infinity, calculated using the observed value of the last 
non-zero concentration (AUC0-∞) 
• First order rate constant associated with the terminal (log-linear) portion of the curve (λZ)  
• Terminal half-life (t1/2) calculated as 0.693/λZ 


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• Total body clearance for extravascular administration divided by the fraction of dose 
absorbed (CL/F) 
• Volume of distribution associated with the terminal slope following extravascular 
administration divided by the fraction of dose absorbed (Vz/F)   
 
The pharmacodynamic endpoint is to determine the GAG concentrations in CSF and urine. 
5.5 
Health Status Endpoint 
The health status endpoint is the ITQoL scores at each assessment time and the corresponding 
change from Baseline. 
5.6 
Health Economics and Outcomes Research Endpoint 
The health economic and outcome research endpoints evaluate the key HCUQ variables, such as 
the number of emergency room visits, caregiver employment status (full-time [FT], part-time 
[PT], and not working [NW]), and the number of hours of additional paid help needed by 
caregivers, over the course of the study. 
 


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6. 
EFFICACY AND SAFETY VARIABLES 
6.1 
Schedule of Evaluations 
Please refer to Protocol SHP-610-201 for the Schedule of Events tables for Group 1 [patients 
who received HGT-1410 Q2W in Study HGT-SAN-093], for Group 2 [patients who received 
HGT-1410 Q4W in Study HGT-SAN-093], for Group 3A [patients who received no treatment in 
Study HGT-SAN-093 and are randomized to receive HGT-1410 Q2W in Study SHP-610-201], 
and for Group 3B [patients who received no treatment in Study HGT-SAN-093 and are 
randomized to receive HGT-1410 Q4W in Study SHP-610-201]). 
6.2 
Efficacy Assessments 
6.2.1 
Neurocognitive and Developmental Assessments 
The study methodology will include standardized neurodevelopmental assessments to provide a 
quantifiable measure of patient neurodevelopmental status (see Table 1).  The assessments are 
estimated to last between 2 and 4 hours and must be conducted prior to any invasive procedures, 
such as blood draws, and prior to sedation or anesthesia. Neurodevelopmental status will be 
assessed over time by measuring cognitive and adaptive functions as follows: 
• Cognition:  The BSID-III (Bayley, 2005) will be used to assess all patients through the 
age of 42 months. Once patients reach age 42 months, an attempt will be made to switch 
the cognitive assessment to the KABC-II. If the cognitive status of the patient does not 
allow for testing by the KABC-II, the BSID-III may be used. 
• Adaptive behaviors:  The VABS-II (Sparrow, 2005) will be used to assess all patients. 
 
For this study, outcome measures will be computed for each patient enrolled. The psychometric 
instruments are summarized below in Table 1.  
 
 


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Table 1 
Neurodevelopmental Assessments Tests  
Cognitive Test or Scale  
Developmental or Cognitive Areas of 
Assessment 
BSID-III  
Summary score and sub-domains: 
- Cognitive 
- Motor 
- Social/Emotional 
- Language 
KABC-II 
Cognitive and processing skills 
ADAPTIVE BEHAVIOR 
VABS-II 
Communication 
Daily Living 
Socialization 
Motor Skills 
Abbreviations: BSID-III=Bayley Scales of Infant and Toddler Development, Third Edition; KABC-II= 
Kaufman Assessment Battery for Children, Second Edition; VABS-II=Vineland Adaptive Behavior Scales, 
Second Edition 
 
6.2.2 
Quality of Life Indicator: Infant Toddler Quality of Life Questionnaire 
The ITQoL will be administered during the study. The ITQoL was developed for children at least 
2 months of age up to 5 years and assesses the physical, mental, and social well-being of the 
child and assesses the quality of the parent/guardian’s life. If a patient is over 5 years of age, they 
do not have to complete the ITQoL. 
6.2.3 
Health Economics and Outcomes Research: Healthcare Utilization Questionnaire 
The HCUQ will be administered during the study. This HCUQ focuses on the direct and indirect 
costs of care for patients with MPS-III. 
6.3 
Magnetic Resonance Imaging 
6.3.1 
Head 
Regional brain volumes, including total cortical gray matter volume, will be assessed through an 
MRI of the head. The patient will be under general anesthesia for this assessment. Instrument 
standardization and central analysis of MRIs will be performed by a designated contract research 
laboratory. 
6.3.2 
Liver and Spleen 
Liver and spleen volumes will be assessed through an MRI, performed at the same times as for 
the MRI of the head. The patient will be under general anesthesia for this assessment. Instrument 
standardization and central analysis of MRIs will be performed by a designated contract research 
laboratory. 


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6.4 
Pharmacokinetic Assessments 
Blood samples will be collected for measurement of serum concentrations of HGT-1410 and 
determination of pharmacokinetic parameters at the times specified in the schedules of events in 
Protocol SHP-610-201. Additionally, CSF samples will be collected from patients who received 
no treatment in Study HGT-SAN-093 at the times specified in the schedules of events in 
Protocol SHP-610-201. 
Patients may be discharged from the hospital after the 24-hour blood draw. Patients will either 
stay locally in a hotel or return home (if they live in close proximity to the hospital); this will be 
decided in consultation with the Investigator. Patients will return to the hospital for 
pharmacokinetic blood and CSF sampling at the 48-hour time point. Patients will be discharged 
to home after the physical examination and blood draws have been completed at the 48-hour PK 
time point. See Appendix 6 for more details regarding timing for pharmacokinetic sample 
collection. 
6.5 
Pharmacodynamic Biomarker Assessments (CSF and Urine GAG Levels) 
CSF and urine samples will be obtained to measure the concentration of GAG according to the 
schedules of events in Protocol SHP-610-201.  
6.6 
Concomitant Medications, Therapies, and Medical/Surgical Interventions 
All non-protocol treatments and medications that occur from the time of informed consent 
through the safety follow-up contact are regarded as concomitant and will be documented on the 
appropriate pages of the eCRF. Concomitant therapy includes any therapies/interventions 
administered to patients, and these will be recorded on the concomitant therapy eCRF. Any 
medical/surgical procedures performed on the patients will be recorded on the concomitant 
medical/surgical procedures eCRF. Concomitant medications, both prescribed and 
over-the-counter (including genistein and anesthesia medications) will be recorded on the 
concomitant medication eCRF. 
Every effort should be made to keep symptomatic MPS IIIA treatment constant throughout the 
study. However, changes in medications are acceptable if necessary according to clinical 
judgment. All changes will be recorded on the appropriate eCRF. Concomitant medication will 
be coded using the World Health Organization-Drug Dictionary (WHO-DD). 
6.7 
Safety Assessments 
6.7.1 
Vital Signs 
Vital signs are to be recorded on the eCRF for all patients and will include heart rate, blood 
pressure, respiration rate, and body temperature. Vital signs will be recorded for at least 4 hours 
following each dose of HGT-1410, as described in the schedules of events in Protocol SHP-610-
201. 


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6.7.2 
Physical Examination, Including Height, Weight, and Head Circumference 
During the study, physical examinations will be performed at the time points indicated in the 
Schedules of Events. For Groups 1 and 2, full physical examinations will be conducted at Weeks 
96, 120, 144, and 168, and for Groups 3A and 3B, full physical examinations will be conducted 
during the IDDD implantation period and at Weeks 24, 48, 72, 96, and 120. The remainder of 
physical examinations will be symptom-directed. 
Physical examinations will include a review of the patient’s general appearance, neurological 
examination, as well as evaluation of the body systems described in Table 2, including the port 
and catheter track. Any abnormal change in findings will be recorded as an AE on the 
appropriate eCRF. 
Table 2 
Assessments for Physical Examinations 
 
Assessment 
Assessment 
General appearance 
Endocrine 
Head and neck 
Cardiovascular 
Eyes 
Abdomen 
Ears 
Genitourinary 
Nose 
Skin 
Throat 
Musculoskeletal 
Chest and lungs 
Neurological 
Port and catheter track 
 
 
Height and weight will be recorded for all patients. 
The clinical site staff will be instructed to use calibrated scales for weight measurement where 
possible. The same scale is to be used at the clinical site for all patients at each specified time 
point during the study. 
Head circumference will be measured for Groups 3A and 3B during the IDDD implantation 
period. All data will be recorded on the eCRF.  
6.7.3 
Electrocardiogram 
An ECG will be performed in accordance with the clinical site’s standard practice(s) and are to 
be performed after study drug administration. Electrocardiogram recordings will be read locally 
at the clinical site and will include an assessment of heart rate, sinus rhythm, atrial or ventricular 
hypertrophy, PR, QRS, and QT. Identification of any clinically significant findings and/or 
conduction abnormalities will be recorded on the eCRF. If the patient is unable to cooperate with 
electrocardiography, and if sedation or general anesthesia is employed during that study visit, the 
ECG may be performed under sedation/anesthesia. 


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6.7.4 
Clinical Laboratory Tests 
Blood and urine samples will be collected as described in this section for clinical laboratory 
testing. 
Clinical laboratory tests will include the laboratory tests presented for the HGT-SAN-093 CSR. 
6.7.5 
Cerebrospinal Fluid Assessments  
Cerebrospinal fluid will be obtained from patients during surgical implantation of the IDDD 
(Groups 3A and 3B only), immediately prior to each injection of study drug and at the safety 
follow-up visit. Should the IDDD become clogged or undergo mechanical complications, the 
CSF sample will be obtained via LP. 
The volume of CSF collected at each visit will vary according to the number of CSF 
assessments. The initial 1 mL of CSF aspirated via the IDDD will be discarded, to eliminate fluid 
in the device’s “dead space.” The next 1 mL of CSF will be sent to the local laboratory. 
Subsequently drawn CSF will be stored, depending on the requirement for that visit (see the 
schedules of events in Protocol SHP-610-201, and the Laboratory Manual). If CSF is obtained 
via LP, there is no need to discard the first mL of CSF, and this can be sent to the local 
laboratory for standard clinical assessments. If the patient is clinically stable in the opinion of the 
Investigator, HGT-1410 can be administered immediately following withdrawal of CSF, without 
awaiting the results of the CSF clinical laboratory data.  
6.7.5.1 
Standard CSF Safety Laboratory Assessments 
An aliquot of each CSF sample collected will be evaluated for CSF standard chemistries, 
glucose, protein, and cell counts. 
6.7.5.2 
Anti-rhHNS Antibodies and Biomarkers in CSF 
An aliquot of each CSF sample collected will be quick frozen for subsequent analysis of 
anti-rhHNS antibody evaluation, exploratory proteomics biomarkers, and/or other CSF 
biomarkers. 
6.7.5.3 
CSF GAG Levels and Biomarkers 
An aliquot of each CSF sample collected will be quick frozen for subsequent analysis of CSF 
GAG, GAG degradation components, heparan sulfate (HS)/dermatan sulfate (DS) 
oligosaccharides, or other CSF markers. The CSF pharmacodynamic sample will be obtained at 
the same visit as a serum sample, as described in Section 6.4. 
6.7.5.4 
 


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6.7.6 
Device Assessments 
 These 
data will be collected on the patient’s eCRF from the time of initial implantation. 
6.8 
Adverse Events Assessments 
Adverse events will be monitored continuously throughout the study. 
For the purposes of this study, the period of observation extends from the time at which the 
patient, the patient’s parent(s), or the patient’s legally authorized representative gives informed 
consent until the patient’s final evaluation of the study. For safety purposes, the final evaluation 
will be defined as the follow-up evaluation performed approximately 30 days after the last dose 
for patients who complete the study. 
For a detailed definition on AEs, Serious AEs (SAEs), adverse events due to systemic exposure 
to HGT-1410, infusion/hypersensitivity reactions and management, IDDD-related adverse 
events, severity of AEs, and relatedness of AEs and SAEs, please refer to the SHP-610-201 
Protocol Section 7.13. 


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7. 
STATISTICAL ANALYSIS 
7.1 
General Methodology 
Statistical analysis will generally be performed by the Biometrics Department of Shire using 
SAS statistical software (SAS Institute, Cary, NC, USA). Analysis of any PK and health 
economics and outcomes data will be performed by the Shire Clinical Pharmacology and 
Pharmacokinetics group and the Health Economics and Outcomes Research groups, respectively. 
The analysis methods for all other study data (demographic and baseline characteristics, efficacy 
variables, and safety variables) will be detailed in this SAP. 
Summary statistics for continuous variables will include the n, mean, standard deviation, median, 
minimum, and maximum. Categorical variables will be summarized in a contingency table by 
the frequency and percentage of patients in each category.  
Unless otherwise indicated, all summary statistics will be presented by treatment groups (either 
Q2W or Q4W) to which the patients were randomly assigned (for patients who were initially 
assigned to Q2W or Q4W group in Study HGT-SAN-093 or patients who were assigned to 
no-treatment in HGT-SAN-093 and were randomly assigned to Q2W or Q4W in Study 
SHP-601-201). 
No summary statistics and hypothesis testing will be presented for efficacy data. Instead, subject 
listings will be presented for the selected efficacy endpoints. 
Data from Study HGT-SAN-093 will be combined with that of Study SHP-610-201 for analysis, 
for subjects who enrolled in SHP-610-201. The data included for treated patients in HGT-SAN-
093 starts from the baseline of Study HGT-SAN-093 and for patients who received no treatment 
in HGT-SAN-093 from the baseline of Study SHP-610-201. Baseline is the assessment obtained 
prior to the first dose of HGT-1410. 
7.2 
Analysis Populations 
The population for all analyses will be the safety population, defined as all patients who had the 
IDDD implant or received at least one dose of study drug in the extension study (SHP-610-201). 
Safety analyses will be conducted according to the treatment received. Device related analyses 
will be conducted in the subset of patients in the safety population who had the device implanted. 
7.3 
Subject Disposition 
The number of patients signed informed consent; the number and proportion of patients 
randomized, included in the safety population, completed the study, and discontinued 
prematurely will be presented in a summary table by treatment group; reasons for 
discontinuation/withdrawal will also be summarized. Subject disposition will also be presented 
in a listing. 


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7.4 
Demographics and Baseline Characteristics 
Demographic data and baseline characteristics will be summarized by the individual treatment 
group and the overall HGT-1410 treatment group for the safety population. Demographic data 
and baseline characteristics will be also presented in a listing. 
7.5 
Protocol Deviations 
Reported protocol deviations and patient data will be examined prior to database lock to 
determine if conditions set forth in the study protocol have been violated. The complete list of 
protocol deviations will not be summarized; however, if applicable, protocol violations identified 
will be listed for the safety population. 
7.6 
Medical History 
Medical history will be coded using Medical Dictionary for Regulatory activities (MedDRA) 
Version 17.1 and provided as a listing. 
7.7 
Treatment Compliance and Extent of Exposure 
The total number of doses of study drug, the number of doses received via IDDD, the number of 
doses received via LP, the average duration of IT administration and treatment compliance will 
be summarized by treatment group for the safety population.  
Duration of IT administration, summarized in weeks, is calculated by subtracting the date of first 
dose from date of last dose. 
Duration of each IT administration (in minutes) is calculated by subtracting the IT administration 
start time from the IT administration end time. 
Treatment compliance is defined as:  [(Number of Complete IT administrations) ÷ (Expected 
Number of IT administrations)] * 100. 
The IT administration of study drug will be also presented in a listing. 
7.8 
Analysis of Efficacy 
7.8.1 
Primary Analysis 
The primary objective of this study is to evaluate long-term safety of HGT-1410 in patients with 
MPS-III. Therefore, the primary analysis will be discussed in the safety analysis section, 
Section 7.10. 


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7.8.2 
Secondary Efficacy Analysis 
7.8.2.1 
Bayley Scales of Infant Development, Third Edition (BSID-III)/ 
The BSID-III data including developmental quotient (DQ), age equivalent scores, growth scores, 
total raw scores and scaled scores for each subtest (Cognitive, Receptive Communication, 
Expressive Communication, Fine Motor, and Gross Motor) will be presented in a listing only. 
The KABC-II is an alternative to BSID-III.  Few subjects were administered KABC-II scale; 
however, these scores were considered invalid by the sites, hence no data for KABC-II will be 
presented. 
7.8.2.2 
Vineland Adaptive Behavior Scales, Second Edition (VABS-II) 
The VABS-II data including age equivalent scores, DQ, raw scores, and standard scores for each 
domain will be presented in a listing only. 
7.8.2.3 
Brain MRI 
Although several MRI parameters will be captured, only the grey matter volume, the white 
matter volume, and the total intracranial CSF volume will be presented in a listing. 
7.9 
Analysis of Pharmacokinetic and Pharmacodynamic Data 
7.9.1 
Pharmacokinetic Measurement and Parameters 
As study was closed earlier than planned, there were few PK samples collected and hence no 
analysis on pharmacokinetic measurement and parameters will be provided. 
7.9.2 
Pharmacodynamic Analyses  
The levels of GAG (heparin sulfate) in CSF and urine (glycosaminoglycans/creatinine) are 
pharmacodynamic endpoints. The data for pharmacodynamic endpoints will be presented in a 
listing only, with the MRI data. 
7.10 
Analysis of Safety 
7.10.1 
Adverse Events  
Once the patient has signed the informed consent form, AEs will be recorded throughout the 
study and at early termination. AEs will be coded using Medical Dictionary for Regulatory 
Affairs (MedDRA). 
Treatment-emergent AEs, defined as all AEs from the time of initial IDDD implantation (or first 
dose if earlier) in either HGT-SAN-093 or SHP-610-210 to the safety follow-up visit, defined as 
the last patient visit in the study, will be summarized. For each treatment group, the number and 
percentage of patients having an AE and the number of events, by system organ class (SOC) and 
preferred term will be presented. Treatment-emergent AEs will also be summarized by severity 
and degree of relationship to study drug. In the case of multiple occurrences of the same AE (at 


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the preferred term level) in an individual patient, the AE that is classified as the most severe (ie, 
maximum severity) will be identified for the analysis by severity and the AE that has the closest 
relationship to study drug/procedure will be identified for the analysis by relationship. In general, 
an AE will be considered a treatment-emergent AE if it cannot be definitively categorized 
otherwise by documentation that its onset preceded either IDDD surgery or first dose. 
Serious adverse events will be similarly summarized by SOC and preferred term. 
All treatment-emergent AEs, serious or life-threatening treatment-emergent AEs, treatment-
emergent AEs leading to permanent discontinuation of study drug or resulting in death will be 
presented in a separate listing, respectively.  
7.10.1.1 
Investigational Product-Related AEs 
Treatment-emergent AEs deemed by the investigator to be related (probably, possibly, or 
definitely related) to the investigational product (HGT-1410) will be summarized by presenting 
the number and percentage of patients having an AE and the number of events, by SOC and 
preferred term.  
7.10.1.2 
IDDD and Surgical Procedure–Related AEs  
Intrathecal drug delivery devices and procedure-related AEs will be summarized within SOC by 
preferred term. Separate tabulations will be provided for AEs related to the IDDD, device 
surgical procedure, and IT administration process. 
Intrathecal drug delivery device and procedure related events will be analyzed in the subset of 
patients in the safety population who underwent surgery for IDDD implantation. 
 
7.10.2 
Clinical Laboratory Evaluation  
The measurements of each laboratory parameter (serum chemistry, hematology, urinalysis and 
CSF) and the corresponding normal ranges will be converted to Standard International (SI) units, 
if needed.  
Each laboratory result will be categorized as a patient having had (1) an abnormal and clinically 
significant (CS) value at any time post-baseline, (2) no CS values at any time post-baseline, but 
had at least 1 abnormal and not CS (NCS) value, and (3) no CS or NCS values at any time post-
baseline. For any patient who experiences a CS laboratory result at any time post-baseline that 
was not CS at baseline (or the most recent non-missing value prior to the start of the treatment), 
their entire profile for that particular laboratory parameter will be presented as a listing. 
If more than one laboratory result is reported per assessment time per parameter, the last non-
missing result will be selected for analysis.  


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7.10.3 
ECG Evaluations  
A listing of clinically significant ECG findings, as assessed by the investigator will be provided. 
7.10.4 
Vital Signs  
The IT-administration vital signs will be presented in a listing. 
7.10.5 
Anti-rhHNS Antibody in Serum and CSF 
Anti-rhHNS antibody status (ie, positive or negative) at each assessment time from baseline will 
be presented in listings based on serum and CSF samples.  
7.10.6 
Concomitant Medications  
Concomitant medications will be coded using the WHO DRUG Dictionary Enhanced December 
2014. The concomitant medications that occur from the time of the surgery for IDDD 
implantation to the safety follow-up visit, defined as the last patient visit in the study, will be 
presented in a listing.  
7.10.7 
Other Observations Related to Safety 
7.10.7.1 
IDDD Performance 
The device failure/malfunction data will be presented in a listing only 


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8. 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSES 
8.1 
Changes from the Analyses Planned in the Protocol 
As Shire has decided to terminate this study early, and to summarize the study with an 
abbreviated CSR, not all dated collected in this study will be analyzed. Summary statistics will 
only be presented for baseline characteristics, exposure of study drug, and adverse events. The 
data of selected efficacy endpoints will be presented in listings only. All outputs will be 
presented for safety population and no efficacy population will be defined. 
The following data will not be analyzed: health status (ITQoL) and pharmacokinetic assessments 
However, SDTM data will be available for these endpoints. 
 
 


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9. 
REFERENCES 
1. 
Bayley N. Bayley Scales of Infant and Toddler Development. 3 ed. San Antonio, TX 
The Psychological Corporation; 2005. 
2 
Sparrow S, Balla D, Cicchetti D. Vineland Adaptive Behavior Scales (Second 
Edition). 4201 Woodland Road Circle Pines, MN 55014-1796:  American Guidance 
Service, Inc; 2005. 
 


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10. 
APPENDICES 
10.1 
APPENDIX II: List of Statistical Outputs 
A list of statistical outputs is provided in the TFL shells. 
10.2 
APPENDIX III: Definitions and Programming Conventions 
10.2.1 
Calculation of DQ Scores 
BSID-III: Divide the Age-equivalent score for cognitive domain (expressed in months) by the 
Age at Testing (expressed in months). Multiply the result by 100 to obtain percentages. These 
values will be provided by an outside vendor, Prophase. 
VABS-II: First calculate the average age equivalent score by averaging out the age-equivalent 
scores for the following sub-domains – receptive, expressive, written, personal, domestic, 
community, interpersonal relationships, play and leisure time, coping skills. Divide the average 
Age-equivalent score (expressed in months) by the Age at Testing (expressed in months). 
Multiply the result by 100 to obtain percentages. NOTE: The average age-equivalent score 
(hence DQ) will be calculated based on the available items if at least two items have non-missing 
value. These values will be provided by an outside vendor, Prophase. 


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STATISTICAL ANALYSIS PLAN FOR INTERIM ANALYSIS 
Protocol Title: 
An Open-Label Extension of Study HGT-SAN-093 
Evaluating the Safety and Efficacy of HGT-1410 
(Recombinant Human Heparan N Sulfatase) 
Administration via an Intrathecal Drug Delivery Device 
in Pediatric Patients with Mucopolysaccharidosis Type 
IIIA Disease 
Protocol Number: 
SHP-610-201 
Protocol Version/Date 
Amendment 2 
25 January 2017 
Indication: 
Long-term Treatment of Mucopolysaccharidosis Type 
IIIA (MPS IIIA or Sanfilippo Syndrome Type A) 
Study Phase 
IIb 
SAP Author 
, PhD; 
, PhD 
SAP Analysis Type 
Interim Analysis 
SAP Version/Date 
1.0 
May 26, 2017 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This document is the proprietary and confidential property of Shire  
 
 
 




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TABLE OF CONTENTS 
1. 
LIST OF ABBREVIATIONS AND DEFINITIONS ..................................................... 6 
1.1 
Abbreviations .................................................................................................................. 6 
2. 
INTRODUCTION .......................................................................................................... 8 
2.1 
Purpose of the Statistical Analysis Plan ......................................................................... 8 
2.2 
Background ..................................................................................................................... 8 
2.3 
Study Rationale ............................................................................................................... 8 
3. 
STUDY OBJECTIVES .................................................................................................. 9 
3.1 
Primary Objective ........................................................................................................... 9 
3.2 
Secondary Objectives ..................................................................................................... 9 
3.3 
Exploratory Objective ..................................................................................................... 9 
3.4 
Pharmacokinetic and Pharmacodynamic Objectives ...................................................... 9 
3.5 
Health Status Objective .................................................................................................. 9 
3.6 
Health Economics and Outcome Research Objective .................................................... 9 
4. 
STUDY DESIGN ......................................................................................................... 10 
4.1 
General Description ...................................................................................................... 10 
4.2 
Discussion of Study Design, Including the Choice of Control Group ......................... 11 
4.3 
Method of Assigning Subjects to Treatment Group ..................................................... 11 
4.4 
Blinding ........................................................................................................................ 11 
4.5 
Determination of Sample Size ...................................................................................... 11 
5. 
EFFICACY AND SAFETY ENDPOINTS .................................................................. 12 
5.1 
Primary Endpoint .......................................................................................................... 12 
5.2 
Secondary Endpoints .................................................................................................... 12 
5.3 
Exploratory Endpoint(s) ............................................................................................... 12 
5.4 
Pharmacokinetic and Pharmacodynamic Endpoints ..................................................... 12 
5.5 
Health Status Endpoint ................................................................................................. 13 
5.6 
Health Economics and Outcomes Research Endpoint ................................................. 13 
6. 
EFFICACY AND SAFETY VARIABLES .................................................................. 14 
6.1 
Schedule of Evaluations ............................................................................................... 14 
6.2 
Efficacy Assessments ................................................................................................... 14 
6.2.1 
Neurocognitive and Developmental Assessments ................................................. 14 
6.2.2 
Quality of Life Indicator: Infant Toddler Quality of Life Questionnaire .............. 15 
6.2.3 
Health Economics and Outcomes Research: Healthcare Utilization 
Questionnaire ......................................................................................................... 15 


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6.3 
Magnetic Resonance Imaging ...................................................................................... 15 
6.3.1 
Head ....................................................................................................................... 15 
6.3.2 
Liver and Spleen .................................................................................................... 15 
6.4 
Pharmacokinetic Assessments ...................................................................................... 16 
6.5 
Pharmacodynamic Biomarker Assessments (CSF and Urine GAG Levels) ................ 16 
6.6 
Concomitant Medications, Therapies, and Medical/Surgical Interventions ................. 16 
6.7 
Safety Assessments ....................................................................................................... 16 
6.7.1 
Vital Signs .............................................................................................................. 16 
6.7.2 
Physical Examination, Including Height, Weight, and Head Circumference ........ 17 
6.7.3 
Electrocardiogram .................................................................................................. 17 
6.7.4 
Clinical Laboratory Tests ....................................................................................... 18 
6.7.5 
Cerebrospinal Fluid Assessments .......................................................................... 18 
6.7.5.1 
Standard CSF Safety Laboratory Assessments ........................................... 18 
6.7.5.2 
Anti-rhHNS Antibodies and Biomarkers in CSF ........................................ 18 
6.7.5.3 
CSF GAG Levels and Biomarkers .............................................................. 19 
6.7.5.4 
 .............................................................. 19 
6.7.6 
Device Assessments ............................................................................................... 19 
6.8 
Adverse Events Assessments ........................................................................................ 19 
7. 
STATISTICAL ANALYSIS ........................................................................................ 20 
7.1 
General Methodology ................................................................................................... 20 
7.2 
Analysis Populations .................................................................................................... 20 
7.3 
Subject Disposition ....................................................................................................... 20 
7.4 
Demographics and Baseline Characteristics ................................................................. 21 
7.5 
Protocol Deviations ...................................................................................................... 21 
7.7 
Treatment Compliance and Extent of Exposure ........................................................... 21 
7.8 
Analysis of Efficacy ..................................................................................................... 21 
7.8.1 
Primary Analysis .................................................................................................... 21 
7.8.2 
Secondary Efficacy Analysis ................................................................................. 22 
7.8.2.1 
Bayley Scales of Infant Development, Third Edition (BSID-III)/ .............. 22 
7.8.2.2 
Vineland Adaptive Behavior Scales, Second Edition (VABS-II) ............... 22 
7.8.2.3 
Brain MRI .................................................................................................... 22 
7.9 
Analysis of Pharmacokinetic and Pharmacodynamic Data .......................................... 22 
7.9.1 
Pharmacokinetic Measurement and Parameters .................................................... 22 
7.9.2 
Pharmacodynamic Analyses .................................................................................. 22 
7.10 
Analysis of Safety ......................................................................................................... 22 
7.10.1 Adverse Events ...................................................................................................... 22 
7.10.2 Clinical Laboratory Evaluation .............................................................................. 23 
7.10.4 Vital Signs .............................................................................................................. 24 


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7.10.5 Anti-rhHNS Antibody in Serum and CSF ............................................................. 24 
7.10.6 Concomitant Medications ...................................................................................... 24 
7.10.7 Other Observations Related to Safety .................................................................... 24 
7.10.7.1 IDDD Performance ...................................................................................... 24 
8. 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES .... 25 
8.1 
Changes from the Analyses Planned in the Protocol .................................................... 25 
9. 
REFERENCES ............................................................................................................. 26 
10. 
APPENDICES .............................................................................................................. 27 
10.1 
APPENDIX II: List of Statistical Outputs .................................................................... 27 
10.2 
APPENDIX III: Definitions and Programming Conventions ...................................... 27 
10.2.1 Calculation of DQ Scores ...................................................................................... 27 


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1. 
LIST OF ABBREVIATIONS AND DEFINITIONS 
1.1 
Abbreviations 
Abbreviation 
Definition 
AE 
adverse event 
AUC 
area under the concentration curve 
AUC0-last 
area under the curve from the time of dosing to the last measurable 
concentration 
AUC0-∞ 
area under the curve extrapolated to infinity, calculated using the 
observed value of the last non-zero concentration 
BSID-III 
Bayley Scales of Infant Development, Third Edition 
CL/F 
total body clearance for extravascular administration divided by the 
fraction of dose absorbed 
Cmax 
maximum concentration occurring at tmax  
CS 
clinically significant 
CSF 
cerebrospinal fluid 
CSR 
clinical study report 
DQ 
developmental quotient 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
GAG 
glycosaminoglycan 
HGT 
human genetic therapies 
HS 
heparan sulfate 
IDDD 
intrathecal drug delivery device 
IT 
intrathecal 
KABC-II 
Kaufman Assessment Battery for Children, Second Edition  
LP 
lumbar puncture 
MedDRA 
Medical Dictionary for Regulatory Activities  
Min 
minimum 
Max 
maximum 
MPS IIIA 
Mucopolysaccharidosis Type IIIA 
MRI 
magnetic resonance imaging 
n 
Sample size 
NCS 
not clinically significant 
PK 
pharmacokinetic 
Q2W 
Every 2 weeks 
Q4W 
Every 4 weeks 
rhHNS 
Recombinant human heparan N-sulfatase 


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Abbreviation 
Definition 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
system organ class 
t1/2 
terminal half-life 
tmax 
time of maximum observed concentration sampled during a dosing 
interval 
TEAE 
treatment-emergent adverse event 
VABS-II 
Vineland Adaptive Behavior Scales, Second Edition 
Vz/F 
volume of distribution associated with the terminal slope following 
extravascular administration divided by the fraction of dose 
absorbed 
WHO 
World Health Organization 
 


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2. 
INTRODUCTION 
2.1 
Purpose of the Statistical Analysis Plan 
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the planned 
interim analyses for protocol SHP-610-201 amendment 2, a Phase IIb, open-label extension of 
study HGT-SAN-093 evaluating the safety and efficacy of HGT-1410 (Recombinant Human 
Heparan N Sulfatase) administration via an intrathecal drug delivery device in pediatric patients 
with mucopolysaccharidosis type IIIA disease. Shire made a decision in August 2016 to 
terminate the Sanfilippo Syndrome Type A development program, including this extension 
study, due to the failure to meet the prespecified efficacy criteria in the pivotal Phase 2 study, 
HGT-SAN-093, and the resulting inability for the study to yield clinical proof-of-concept. After 
notification of early study termination, several investigators informed Shire that the IDDDs 
would remain implanted since in their opinion removal of devices would result in an increased 
risk to the patients. Therefore, this extension study (SHP-610-201) remains ongoing and has 
been extended to allow for safety follow-up of patients with partial or full devices still implanted 
after completion of the treatment period of the study. The statistical analyses and summary 
tabulations described in this interim SAP will provide the basis for the results sections of the 
abbreviated clinical study report (aCSR). An aCSR will be written to describe the results of the 
treatment period of the study, as the study is not intended to contribute to the evaluation of 
product effectiveness or to provide definitive information on clinical pharmacology. Full safety 
information will be reported.  
2.2 
Background 
Study SHP-610-201 is a Phase IIb, open-label extension of study HGT-SAN-093 evaluating the 
safety and efficacy of HGT-1410 (Recombinant Human Heparan N Sulfatase) administration via 
an intrathecal drug delivery device in pediatric patients with mucopolysaccharidosis type IIIA 
disease. Details of the study design, rationale, and procedures are documented in Protocol SHP-
610-201. 
2.3 
Study Rationale 
The study design is intended to provide ongoing treatment with HGT-1410 to patients who 
received HGT-1410 in Study HGT-SAN-093 and to initiate treatment to patients who received 
no-treatment in Study HGT-SAN-093. As such, all patients will be treated during this study; 
there is no control group. 
In order to traverse the blood-brain barrier, HGT-1410 will be administered directly to the 
central nervous system using an intrathecal drug delivery device (IDDD) or, if the IDDD is non-
functional, via lumbar puncture (LP). The advantage of using an IDDD is the potential to obviate 
the need for multiple lumbar punctures for drug delivery.  
Safety is the primary objective of the study, and the study duration has been designed to provide 
a reasonable time for safety follow-up. 


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3. 
STUDY OBJECTIVES 
3.1 
Primary Objective  
The primary objective of this study is to evaluate long-term safety in patients with 
mucopolysaccharidosis type IIIA disease (MPS IIIA or Sanfilippo syndrome type A) who 
received HGT-1410. 
3.2 
Secondary Objectives  
The secondary objectives of this study are to evaluate:   
• The long-term cognitive function as measured by the Bayley Scales of Infant and Toddler 
Development, Third Edition (BSID-III) or Kaufman Assessment Battery for Children, 
Second Edition (KABC-II), age-equivalent and developmental quotient (DQ) scores in 
patients with MPS IIIA who received HGT-1410 
• The long-term adaptive behavioral function, assessed by Vineland Adaptive Behavior Scales, 
Second Edition (VABS-II) in patients who received HGT-1410 
• The total cortical grey matter volume, as assessed by volumetric magnetic resonance imaging 
(MRI) of the brain, in patients who received HGT-1410 
 
3.3 
Exploratory Objective 
The exploratory objective of this study is to 
 
 
3.4 
Pharmacokinetic and Pharmacodynamic Objectives 
The pharmacokinetic (PK) and pharmacodynamics objectives of this study are to evaluate: 
• The pharmacokinetics of HGT-1410 in serum, in all patients with PK assessment 
• The pharmacokinetics of HGT-1410 in CSF, in patients who received no treatment in Study 
HGT-SAN-093 
• The concentration of GAG in CSF and urine in patients who received HGT-1410 
 
3.5 
Health Status Objective 
The health status objective of this study is to evaluate health status as measured by the Infant 
Toddler Quality of Life Questionnaire™ (ITQoL) instrument in patients who received 
HGT-1410. 
3.6 
Health Economics and Outcome Research Objective 
The health economics and outcome research objective of this study is to evaluate healthcare 
resource utilization, as evaluated by the Healthcare Utilization Questionnaire (HCUQ), in 
patients who received HGT-1410. 


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4. 
STUDY DESIGN 
4.1 
General Description 
This is an open-label extension study of HGT-1410 for patients who completed through at least 
the Week 48 Visit in Study HGT-SAN-093. Patients who originally received HGT-1410 in Study 
HGT-SAN-093 will remain on the same dosing regimen as they received in Study HGT-SAN-
093; Group 1 will receive HGT-1410 every 2 weeks (Q2W) and Group 2 will receive HGT-1410 
every 4 weeks (Q4W). Patients in Groups 1 and 2 will begin treatment at Week 50 and Week 52, 
respectively, of this extension study (Study SHP-610-201). Patients who originally received no-
treatment in Study HGT-SAN-093 (Group 3) will receive an IDDD following informed consent 
and will be re-randomized in a 1:1 allocation ratio to receive HGT-1410 via a Q2W or Q4W 
dosing regimen (Groups 3A and 3B, respectively) in Study SHP-610-201. Patients in Groups 3A 
and 3B will begin treatment on Week 0 of the extension study.  
It is anticipated that the IDDD will be used to collect CSF samples and to deliver IT injections of 
HGT-1410 and preservative-free saline flushes. No other medication will be administered 
through the device. If the IDDD appears to be non-functional, or if its use is precluded on a 
scheduled day of dosing, site personnel will refer to the IDDD Manual, which provides details on 
the investigation and management of any IDDD-related issues. This includes possible partial 
revision or complete replacement of the IDDD as indicated. If the IT space is not accessible via 
the IDDD, study drug may be administered by LP. Should the IDDD become clogged, undergo 
mechanical complications or otherwise not be accessible, the CSF sample may also be obtained 
by LP. General anesthesia or sedation may be required for injections of study drug and some 
evaluations, and may be used at the discretion of the Investigator. The Data Monitoring 
Committee (DMC) will be notified of all IDDD failures and IDDD-related complications at 
times defined in the DMC charter. 
Patients should have the IDDD removed when they discontinue from or complete the treatment 
period of the study unless the investigator determines that it should not be removed based upon 
safety assessments. The device can remain in the patient (partial [catheter or suture wing only] or 
full [port, catheter, and suture wings]) if the patient is doing clinically well and there are no 
further known risk factors such as infection (eg, meningitis). The device may be partially or fully 
removed as medically required and determined by the neurosurgeon at a future date. 
Safety and efficacy assessments will be performed at regular intervals over the approximate 
2.5-year duration of the treatment period of the extension study. A pharmacokinetic sample for 
patients who received HGT-1410 in Study HGT-SAN-093 will be obtained at the Week 96 visit 
(after approximately 2 full years of exposure to HGT-1410 across Studies HGT-SAN-093 and 
SHP-610-201). Serum pharmacokinetic samples for patients who received no-treatment in Study 
HGT-SAN-093 will be obtained at the Week 0, 48, and 96, and CSF pharmacokinetic samples 
will be obtained on the Week 0 and 48 visits in Study SHP-610-201. 
Patients who received HGT-1410 in Study HGT-SAN-093 will undergo a cumulative exposure 
to HGT-1410 for up to 42 months (168 weeks), whereas patients who received no treatment in 
Study HGT-SAN-093 will have a cumulative exposure to HGT-1410 for up to 30 months 
(120 weeks) in Study SHP-610-201. 


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Patients who do not have the IDDD removed (partial or full device) at the end of the treatment 
period will continue to be observed during a safety follow-up period with visits at the site every 
6 months to evaluate patient safety of the device until the IDDD has been fully explanted. 
 
4.2 
Discussion of Study Design, Including the Choice of Control Group 
This is an open-label extension study of Study HGT-SAN-093 intended to provide ongoing 
treatment with HGT-1410 during the treatment period to patients who received HGT-1410 in 
Study HGT-SAN-093 and to initiate treatment to patients who received no-treatment in Study 
HGT-SAN-093. As such, all patients will be treated during this study; there is no control group. 
4.3 
Method of Assigning Subjects to Treatment Group  
Patients who were randomized to no-treatment in Study HGT-SAN-093 (Group 3) will be re-
randomized in a 1:1 allocation ratio to receive Q2W or Q4W dosing (Groups 3A or 3B, 
respectively). To help ensure balance between the dose groups with respect to age at Baseline, 
the randomization will be stratified by age group (≤30 months and >30 months).  Patients who 
were randomized to receive HGT-1410 in Study HGT-SAN-093 will remain on the same 
treatment regimen in Study SHP-610-201. 
4.4 
Blinding  
This study will not be blinded. 
4.5 
Determination of Sample Size  
As this is an extension study of Study HGT-SAN-093, any patients who enrolled and completed 
that study are eligible to enroll in Study SHP-601-201, and no statistical estimation for sample 
size calculation was performed. A maximum sample size of 21 patients in this study is expected 
based on the sample size in Study HGT-SAN-093. 
 


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5. 
EFFICACY AND SAFETY ENDPOINTS 
5.1 
Primary Endpoint 
Safety is the primary objective of the study and will be assessed during the study by the 
following: 
• Collection of adverse events (AEs; by type, severity, and relationship to treatment 
[HGT-1410, the IDDD, device surgical procedure, or IT administration process]) 
• Changes in clinical laboratory testing (serum chemistry, hematology, urinalysis) 
• Physical examination 
• Vital signs 
• Twelve-lead electrocardiogram (ECG) recordings  
• CSF laboratory parameters (including chemistries, cell counts) 
• Anti-rhHNS antibodies in CSF and serum, including determination of antibodies having 
enzyme neutralizing activity 
 
5.2 
Secondary Endpoints 
The secondary endpoints of this study are: 
• The change from Baseline in BSID-III or KABC-II age-equivalent, DQ, and developmental 
delay scores 
• The change from Baseline in adaptive behavioral function domains, assessed by VABS II, 
using raw scores, age-equivalent scores, and DQ scores 
• The change from Baseline in total cortical grey matter volume, as assessed by MRI 
 
5.3 
Exploratory Endpoint(s) 
5.4 
Pharmacokinetic and Pharmacodynamic Endpoints 
The pharmacokinetic endpoint is to determine the pharmacokinetic behavior of HGT-1410 in 
serum, based on the following parameters: 
• Maximum concentration occurring at tmax (Cmax) 
• Time of maximum observed concentration sampled during a dosing interval (tmax) 
• Area under the curve from the time of dosing to the last measurable concentration (AUC0-last) 
• Area under the curve extrapolated to infinity, calculated using the observed value of the last 
non-zero concentration (AUC0-∞) 
• First order rate constant associated with the terminal (log-linear) portion of the curve (λZ)  
• Terminal half-life (t1/2) calculated as 0.693/λZ 


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• Total body clearance for extravascular administration divided by the fraction of dose 
absorbed (CL/F) 
• Volume of distribution associated with the terminal slope following extravascular 
administration divided by the fraction of dose absorbed (Vz/F)   
 
The pharmacodynamic endpoint is to determine the GAG concentrations in CSF and urine. 
5.5 
Health Status Endpoint 
The health status endpoint is the ITQoL scores at each assessment time and the corresponding 
change from Baseline. 
5.6 
Health Economics and Outcomes Research Endpoint 
The health economic and outcome research endpoints evaluate the key HCUQ variables, such as 
the number of emergency room visits, caregiver employment status (full-time [FT], part-time 
[PT], and not working [NW]), and the number of hours of additional paid help needed by 
caregivers, over the treatment period of the study. 
 


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6. 
EFFICACY AND SAFETY VARIABLES 
6.1 
Schedule of Evaluations 
Please refer to Protocol SHP-610-201 amendment 2 for the Schedule of Events tables for Group 
1 (patients who received HGT-1410 Q2W in Study HGT-SAN-093), for Group 2 (patients who 
received HGT-1410 Q4W in Study HGT-SAN-093), for Group 3A (patients who received no 
treatment in Study HGT-SAN-093 and are randomized to receive HGT-1410 Q2W in Study 
SHP-610-201), and for Group 3B (patients who received no treatment in Study HGT-SAN-093 
and are randomized to receive HGT-1410 Q4W in Study SHP-610-201). 
6.2 
Efficacy Assessments 
6.2.1 
Neurocognitive and Developmental Assessments 
The study methodology will include standardized neurodevelopmental assessments to provide a 
quantifiable measure of patient neurodevelopmental status (see Table 1).  The assessments are 
estimated to last between 2 and 4 hours and must be conducted prior to any invasive procedures, 
such as blood draws, and prior to sedation or anesthesia. Neurodevelopmental status will be 
assessed over time by measuring cognitive and adaptive functions as follows: 
• Cognition:  The BSID-III (Bayley, 2005) will be used to assess all patients through the 
age of 42 months. Once patients reach age 42 months, an attempt will be made to switch 
the cognitive assessment to the KABC-II. If the cognitive status of the patient does not 
allow for testing by the KABC-II, the BSID-III may be used. 
• Adaptive behaviors:  The VABS-II (Sparrow, 2005) will be used to assess all patients. 
 
For this study, outcome measures will be computed for each patient enrolled. The psychometric 
instruments are summarized below in Table 1.  
 
 


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Table 1 
Neurodevelopmental Assessments Tests  
Cognitive Test or Scale  
Developmental or Cognitive Areas of 
Assessment 
BSID-III  
Summary score and sub-domains: 
- Cognitive 
- Motor 
- Social/Emotional 
- Language 
KABC-II 
Cognitive and processing skills 
ADAPTIVE BEHAVIOR 
VABS-II 
Communication 
Daily Living 
Socialization 
Motor Skills 
Abbreviations: BSID-III=Bayley Scales of Infant and Toddler Development, Third Edition; KABC-II= 
Kaufman Assessment Battery for Children, Second Edition; VABS-II=Vineland Adaptive Behavior Scales, 
Second Edition 
 
6.2.2 
Quality of Life Indicator: Infant Toddler Quality of Life Questionnaire 
The ITQoL will be administered during the study. The ITQoL was developed for children at least 
2 months of age up to 5 years and assesses the physical, mental, and social well-being of the 
child and assesses the quality of the parent/guardian’s life. If a patient is over 5 years of age, they 
do not have to complete the ITQoL. 
6.2.3 
Health Economics and Outcomes Research: Healthcare Utilization Questionnaire 
The HCUQ will be administered during the study. This HCUQ focuses on the direct and indirect 
costs of care for patients with MPS-III. 
6.3 
Magnetic Resonance Imaging 
6.3.1 
Head 
Regional brain volumes, including total cortical gray matter volume, will be assessed through an 
MRI of the head. The patient will be under general anesthesia for this assessment. Instrument 
standardization and central analysis of MRIs will be performed by a designated contract research 
laboratory. 
6.3.2 
Liver and Spleen 
Liver and spleen volumes will be assessed through an MRI, performed at the same times as for 
the MRI of the head. The patient will be under general anesthesia for this assessment. Instrument 
standardization and central analysis of MRIs will be performed by a designated contract research 
laboratory. 


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6.4 
Pharmacokinetic Assessments 
Blood samples will be collected for measurement of serum concentrations of HGT-1410 and 
determination of pharmacokinetic parameters at the times specified in the schedules of events in 
Protocol SHP-610-201. Additionally, CSF samples will be collected from patients who received 
no treatment in Study HGT-SAN-093 at the times specified in the schedules of events in 
Protocol SHP-610-201. 
Patients may be discharged from the hospital after the 24-hour blood draw. Patients will either 
stay locally in a hotel or return home (if they live in close proximity to the hospital); this will be 
decided in consultation with the Investigator. Patients will return to the hospital for 
pharmacokinetic blood and CSF sampling at the 48-hour time point. Patients will be discharged 
to home after the physical examination and blood draws have been completed at the 48-hour PK 
time point. See Appendix 6 for more details regarding timing for pharmacokinetic sample 
collection. 
6.5 
Pharmacodynamic Biomarker Assessments (CSF and Urine GAG Levels) 
CSF and urine samples will be obtained to measure the concentration of GAG according to the 
schedules of events in Protocol SHP-610-201.  
6.6 
Concomitant Medications, Therapies, and Medical/Surgical Interventions 
All non-protocol treatments and medications that occur from the time of informed consent 
through the safety follow-up contact are regarded as concomitant and will be documented on the 
appropriate pages of the eCRF. Concomitant therapy includes any therapies/interventions 
administered to patients, and these will be recorded on the concomitant therapy eCRF. Any 
medical/surgical procedures performed on the patients will be recorded on the concomitant 
medical/surgical procedures eCRF. Concomitant medications, both prescribed and 
over-the-counter (including genistein and anesthesia medications) will be recorded on the 
concomitant medication eCRF. 
Every effort should be made to keep symptomatic MPS IIIA treatment constant throughout the 
study. However, changes in medications are acceptable if necessary according to clinical 
judgment. All changes will be recorded on the appropriate eCRF. Concomitant medication will 
be coded using the World Health Organization-Drug Dictionary (WHO-DD). 
6.7 
Safety Assessments 
6.7.1 
Vital Signs 
Vital signs are to be recorded on the eCRF for all patients and will include heart rate, blood 
pressure, respiration rate, and body temperature. Vital signs will be recorded for at least 4 hours 
following each dose of HGT-1410, as described in the schedules of events in Protocol SHP-610-
201. 


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6.7.2 
Physical Examination, Including Height, Weight, and Head Circumference 
During the study, physical examinations will be performed at the time points indicated in the 
Schedules of Events. For Groups 1 and 2, full physical examinations will be conducted at Weeks 
96, 120, 144, and 168, and for Groups 3A and 3B, full physical examinations will be conducted 
during the IDDD implantation period and at Weeks 24, 48, 72, 96, and 120. The remainder of 
physical examinations will be symptom-directed, including examinations during the safety 
follow-up period in patients who do not have the IDDD removed (partial or full device) at the 
end of the treatment period. 
 
Physical examinations will include a review of the patient’s general appearance, neurological 
examination, as well as evaluation of the body systems described in Table 2, including the port 
and catheter track. Any abnormal change in findings will be recorded as an AE on the 
appropriate eCRF. 
Table 2 
Assessments for Physical Examinations 
 
Assessment 
Assessment 
General appearance 
Endocrine 
Head and neck 
Cardiovascular 
Eyes 
Abdomen 
Ears 
Genitourinary 
Nose 
Skin 
Throat 
Musculoskeletal 
Chest and lungs 
Neurological 
Port and catheter track 
 
 
Height and weight will be recorded for all patients. 
The clinical site staff will be instructed to use calibrated scales for weight measurement where 
possible. The same scale is to be used at the clinical site for all patients at each specified time 
point during the study. 
Head circumference will be measured for Groups 3A and 3B during the IDDD implantation 
period. All data will be recorded on the eCRF.  
6.7.3 
Electrocardiogram 
An ECG will be performed in accordance with the clinical site’s standard practice(s) and are to 
be performed after study drug administration. Electrocardiogram recordings will be read locally 
at the clinical site and will include an assessment of heart rate, sinus rhythm, atrial or ventricular 
hypertrophy, PR, QRS, and QT. Identification of any clinically significant findings and/or 
conduction abnormalities will be recorded on the eCRF. If the patient is unable to cooperate with 


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electrocardiography, and if sedation or general anesthesia is employed during that study visit, the 
ECG may be performed under sedation/anesthesia. 
6.7.4 
Clinical Laboratory Tests 
Blood and urine samples will be collected as described in this section for clinical laboratory 
testing. 
Clinical laboratory testing will only be performed when indicated for a device-related AE for 
patients who do not have the IDDD removed (partial or full device) at the end of the treatment 
period. 
 
Clinical laboratory tests will include the laboratory tests presented for the HGT-SAN-093 CSR. 
6.7.5 
Cerebrospinal Fluid Assessments  
Cerebrospinal fluid will be obtained from patients during surgical implantation of the IDDD 
(Groups 3A and 3B only), immediately prior to each injection of study drug and at the safety 
follow-up visit. Should the IDDD become clogged or undergo mechanical complications, the 
CSF sample will be obtained via LP. 
The volume of CSF collected at each visit will vary according to the number of CSF 
assessments. The initial 1 mL of CSF aspirated via the IDDD will be discarded, to eliminate fluid 
in the device’s “dead space.” The next 1 mL of CSF will be sent to the local laboratory. 
Subsequently drawn CSF will be stored, depending on the requirement for that visit (see the 
schedules of events in Protocol SHP-610-201, and the Laboratory Manual). If CSF is obtained 
via LP, there is no need to discard the first mL of CSF, and this can be sent to the local 
laboratory for standard clinical assessments. If the patient is clinically stable in the opinion of the 
Investigator, HGT-1410 can be administered immediately following withdrawal of CSF, without 
awaiting the results of the CSF clinical laboratory data.  
6.7.5.1 
Standard CSF Safety Laboratory Assessments 
An aliquot of each CSF sample collected will be evaluated for CSF standard chemistries, 
glucose, protein, and cell counts. 
6.7.5.2 
Anti-rhHNS Antibodies and Biomarkers in CSF and Serum 
An aliquot of each CSF sample collected will be quick frozen for subsequent analysis of 
anti-rhHNS antibody evaluation, exploratory proteomics biomarkers, and/or other CSF 
biomarkers. 
Blood samples will be collected and evaluated at Shire or Shire-designated laboratories for the 
determination of serum anti-rhHNS antibodies. 


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6.7.5.3 
CSF GAG Levels and Biomarkers 
An aliquot of each CSF sample collected will be quick frozen for subsequent analysis of CSF 
GAG . The CSF pharmacodynamic sample will be obtained as described in protocol Section 
7.11.5.3. 
6.7.5.4 
 
6.7.6 
Device Assessments 
 
 These 
data will be collected on the patient’s eCRF from the time of initial implantation. 
6.8 
Adverse Events Assessments 
Adverse events will be monitored continuously throughout the study. 
For the purposes of this study, the period of observation extends from the time at which the 
patient, the patient’s parent(s), or the patient’s legally authorized representative gives informed 
consent until the patient’s final evaluation of the study. For safety purposes, the final evaluation 
for the treatment period will be defined as the follow-up evaluation performed approximately 30 
days after the last dose for patients who complete the study. 
For a detailed definition on AEs, Serious AEs (SAEs), adverse events due to systemic exposure 
to HGT-1410, infusion/hypersensitivity reactions and management, IDDD-related adverse 
events, severity of AEs, and relatedness of AEs and SAEs, please refer to the SHP-610-201 
Protocol Section 7.13. 


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7. 
STATISTICAL ANALYSIS 
7.1 
General Methodology 
Statistical analysis will generally be performed by the Biometrics Department of Shire using 
SAS statistical software (SAS Institute, Cary, NC, USA). Analysis of any PK and health 
economics and outcomes data will be performed by the Shire Clinical Pharmacology and 
Pharmacokinetics group and the Health Economics and Outcomes Research groups, respectively. 
The analysis methods for all other study data (demographic and baseline characteristics, efficacy 
variables, and safety variables) will be detailed in this SAP. 
Summary statistics for continuous variables will include the n, mean, standard deviation, median, 
minimum, and maximum. Categorical variables will be summarized in a contingency table by 
the frequency and percentage of patients in each category.  
Unless otherwise indicated, all summary statistics will be presented by treatment groups (either 
Q2W or Q4W) to which the patients were randomly assigned (for patients who were initially 
assigned to Q2W or Q4W group in Study HGT-SAN-093 or patients who were assigned to 
no-treatment in HGT-SAN-093 and were randomly assigned to Q2W or Q4W in Study 
SHP-601-201). 
No summary statistics and hypothesis testing will be presented for efficacy data. Instead, subject 
listings will be presented for the selected efficacy endpoints. 
Data from Study HGT-SAN-093 will be combined with that of Study SHP-610-201 for analysis, 
for subjects who enrolled in SHP-610-201. The data included for treated patients in HGT-SAN-
093 starts from the baseline of Study HGT-SAN-093 and for patients who received no treatment 
in HGT-SAN-093 from the baseline of Study SHP-610-201. Baseline is the assessment obtained 
prior to the first dose of HGT-1410. 
7.2 
Analysis Populations 
The population for all analyses will be the safety population, defined as all patients who had the 
IDDD implant or received at least one dose of study drug in the extension study (SHP-610-201). 
Safety analyses will be conducted according to the treatment received. Device related analyses 
will be conducted in the subset of patients in the safety population who had the device implanted. 
7.3 
Subject Disposition 
The number of patients signed informed consent; the number and proportion of patients 
randomized, included in the safety population, completed the study, discontinued prematurely, 
completed the treatment period, and still in study will be presented in a summary table by 
treatment group; reasons for discontinuation/withdrawal will also be summarized. Subject 
disposition will also be presented in a listing. 


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7.4 
Demographics and Baseline Characteristics 
Demographic data and baseline characteristics will be summarized by the individual treatment 
group and the overall HGT-1410 treatment group for the safety population. Demographic data 
and baseline characteristics will be also presented in a listing. 
7.5 
Protocol Deviations 
Reported protocol deviations and patient data will be examined prior to database lock to 
determine if conditions set forth in the study protocol have been violated. Protocol violations will 
be defined as any major protocol deviation that affects study evaluations, such as a significant 
violation of admission (inclusion/exclusion) criteria. The protocol deviations will be presented in 
a listing and all protocol violations will be indicated by a flag. 
7.6 
Medical History 
Medical history will be coded using Medical Dictionary for Regulatory activities (MedDRA) 
Version 17.1 and provided as a listing. 
7.7 
Treatment Compliance and Extent of Exposure 
The total number of doses of study drug, the number of doses received via IDDD, the number of 
doses received via LP, the average duration of IT administration and treatment compliance will 
be summarized by treatment group for the safety population.  
Duration of IT administration, summarized in weeks, is calculated by subtracting the date of first 
dose from date of last dose. 
Duration of each IT administration (in minutes) is calculated by subtracting the IT administration 
start time from the IT administration end time. 
Treatment compliance is defined as:  [(Number of Complete IT administrations) ÷ (Expected 
Number of IT administrations)] * 100. 
The IT administration of study drug will be also presented in a listing. 
7.8 
Analysis of Efficacy 
7.8.1 
Primary Analysis 
The primary objective of this study is to evaluate long-term safety of HGT-1410 in patients with 
MPS-III. Therefore, the primary analysis will be discussed in the safety analysis section, 
Section 7.10. 


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7.8.2 
Secondary Efficacy Analysis 
7.8.2.1 
Bayley Scales of Infant Development, Third Edition (BSID-III)/ 
The BSID-III data including developmental quotient (DQ), age equivalent scores, growth scores, 
total raw scores and scaled scores for each subtest (Cognitive, Receptive Communication, 
Expressive Communication, Fine Motor, and Gross Motor) will be presented in a listing only. 
The KABC-II is an alternative to BSID-III.  Few subjects were administered KABC-II scale; 
however, these scores were considered invalid by the sites, hence no data for KABC-II will be 
presented. 
7.8.2.2 
Vineland Adaptive Behavior Scales, Second Edition (VABS-II) 
The VABS-II data including age equivalent scores, DQ, raw scores, and standard scores for each 
domain will be presented in a listing only. 
7.8.2.3 
Brain MRI 
Although several MRI parameters will be captured, only the grey matter volume, the white 
matter volume, and the total intracranial CSF volume will be presented in a listing. 
7.9 
Analysis of Pharmacokinetic and Pharmacodynamic Data 
7.9.1 
Pharmacokinetic Measurement and Parameters 
As the treatment period of the study was closed earlier than planned, there were few PK samples 
collected and hence no analysis on pharmacokinetic measurement and parameters will be 
provided. 
7.9.2 
Pharmacodynamic Analyses  
The levels of GAG (heparin sulfate) in CSF and urine (glycosaminoglycans/creatinine) are 
pharmacodynamic endpoints. The data for pharmacodynamic endpoints will be presented in a 
listing only, with the MRI data. 
7.10 
Analysis of Safety 
7.10.1 
Adverse Events  
Once the patient has signed the informed consent form, AEs will be recorded throughout the 
study and at early termination. AEs will be coded using Medical Dictionary for Regulatory 
Affairs (MedDRA) version 17.1. 
Treatment-emergent AEs, defined as all AEs from the time of initial IDDD implantation (or first 
dose if earlier) in either HGT-SAN-093 or SHP-610-201 to the data cut-off date, or 30 days after 
the date of last dose or 2 weeks after the date of device explant (whichever is later) if early 
termination, will be summarized. For each treatment group, the number and percentage of 
patients having an AE and the number of events, by system organ class (SOC) and preferred 


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term will be presented. Treatment-emergent AEs will also be summarized by severity and degree 
of relationship to study drug. In the case of multiple occurrences of the same AE (at the preferred 
term level) in an individual patient, the AE that is classified as the most severe (ie, maximum 
severity) will be identified for the analysis by severity and the AE that has the closest 
relationship to study drug/procedure will be identified for the analysis by relationship. In general, 
an AE will be considered a treatment-emergent AE if it cannot be definitively categorized 
otherwise by documentation that its onset preceded either IDDD surgery or first dose. 
Serious adverse events will be similarly summarized by SOC and preferred term. 
All treatment-emergent AEs, serious or life-threatening treatment-emergent AEs, treatment-
emergent AEs leading to permanent discontinuation of study drug or resulting in death will be 
presented in a separate listing, respectively.  
7.10.1.1 
Investigational Product-Related AEs 
Treatment-emergent AEs deemed by the investigator to be related (probably, possibly, or 
definitely related) to the investigational product (HGT-1410) will be summarized by presenting 
the number and percentage of patients having an AE and the number of events, by SOC and 
preferred term.  
7.10.1.2 
IDDD and Surgical Procedure–Related AEs  
Intrathecal drug delivery devices and procedure-related AEs will be summarized within SOC by 
preferred term. Separate tabulations will be provided for AEs related to the IDDD, device 
surgical procedure, and IT administration process. 
Intrathecal drug delivery device and procedure related events will be analyzed in the subset of 
patients in the safety population who underwent surgery for IDDD implantation. 
 
7.10.2 
Clinical Laboratory Evaluation  
The measurements of each laboratory parameter (serum chemistry, hematology, urinalysis and 
CSF) and the corresponding normal ranges will be converted to Standard International (SI) units, 
if needed.  
Each laboratory result will be categorized as a patient having had (1) an abnormal and clinically 
significant (CS) value at any time between baseline and the data cut-off date, (2) no CS values at 
any time between baseline and the data cut-off date, but had at least 1 abnormal and not CS 
(NCS) value, and (3) no CS or NCS values at any time between baseline and the data cut-off 
date. For any patient who experiences a CS laboratory result at any time between baseline and 
the data cut-off date that was not CS at baseline (or the most recent non-missing value prior to 
the start of the treatment), their entire profile for that particular laboratory parameter will be 
presented as a listing. 


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If more than one laboratory result is reported per assessment time per parameter, the last non-
missing result will be selected for analysis.  
7.10.3 
ECG Evaluations  
A listing of clinically significant ECG findings, as assessed by the investigator will be provided. 
7.10.4 
Vital Signs  
The IT-administration vital signs will be presented in a listing. 
7.10.5 
Anti-rhHNS Antibody in Serum and CSF 
Anti-rhHNS antibody status (ie, positive or negative) at each assessment time from baseline to 
the data cut-off date will be presented in listings based on serum and CSF samples.  
7.10.6 
Concomitant Medications, Therapies, and Medical/Surgical Interventions  
All non-protocol treatments, including medications and over-the-counter medications, 
therapies/interventions administered to subjects, and medical/surgical procedures performed on 
the subjects that started on or after the reference date, which is the date of the  IDDD 
implantation surgery or the first dose of HGT-1410 (whichever is earlier) in either HGT-SAN-
093 or SHP-610-201, to the data cut-off date, or 30 days after the date of last dose or 2 weeks 
after the date of device explant (whichever is later) if early termination, are regarded as 
concomitant. Any medications/surgical procedures which ended before the reference date will be 
excluded; however, a medication/surgical procedure that started before the reference date and 
ended on or after the reference date will be included. The Concomitant medications will be 
coded using the WHO DRUG Dictionary Enhanced December 2014 and presented in a listing.  
7.10.7 
Other Observations Related to Safety 
7.10.7.1 
IDDD Performance 
The device failure/malfunction data will be presented in a listing only for the subjects in the 
safety population with an IDDD implant. 


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8. 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSES 
8.1 
Changes from the Analyses Planned in the Protocol 
As this extension study will remain ongoing to allow for safety follow-up for patients with 
implanted devices (partial or full), despite the decision by Shire to terminate the development 
program, data for the treatment period of the study will be summarized in an abbreviated CSR. 
Not all data collected in this study will be analyzed. Summary statistics will only be presented 
for baseline characteristics, exposure of study drug, and adverse events. The data of selected 
efficacy endpoints will be presented in listings only. All outputs will be presented for safety 
population and no efficacy population will be defined. Information regarding the safety follow-
up period will be analyzed after study completion and described in the final SAP. 
The following data will not be analyzed: health status (ITQoL) and pharmacokinetic 
assessments. 
However, SDTM data will be available for these endpoints. 
 
 


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9. 
REFERENCES 
1. 
Bayley N. Bayley Scales of Infant and Toddler Development. 3 ed. San Antonio, TX 
The Psychological Corporation; 2005. 
2 
Sparrow S, Balla D, Cicchetti D. Vineland Adaptive Behavior Scales (Second 
Edition). 4201 Woodland Road Circle Pines, MN 55014-1796:  American Guidance 
Service, Inc; 2005. 
 


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10. 
APPENDICES 
10.1 
APPENDIX II: List of Statistical Outputs 
A list of statistical outputs is provided in the TFL shells. 
10.2 
APPENDIX III: Definitions and Programming Conventions 
10.2.1 
Calculation of DQ Scores 
BSID-III: Divide the Age-equivalent score for cognitive domain (expressed in months) by the 
Age at Testing (expressed in months). Multiply the result by 100 to obtain percentages. These 
values will be provided by an outside vendor, Prophase. 
VABS-II: First calculate the average age equivalent score by averaging out the age-equivalent 
scores for the following sub-domains – receptive, expressive, written, personal, domestic, 
community, interpersonal relationships, play and leisure time, coping skills. Divide the average 
Age-equivalent score (expressed in months) by the Age at Testing (expressed in months). 
Multiply the result by 100 to obtain percentages. NOTE: The average age-equivalent score 
(hence DQ) will be calculated based on the available items if at least two items have non-missing 
value. These values will be provided by an outside vendor, Prophase. 


STATISTICAL ANALYSIS PLAN  
ADDENDUM 
FOR SAFETY FOLLOW-UP PERIOD 
Protocol Title: 
An Open-Label Extension of Study HGT-SAN-093 
Evaluating the Safety and Efficacy of HGT-1410 
(Recombinant Human Heparan N Sulfatase) Administration 
via an Intrathecal Drug Delivery Device in Pediatric Patients 
with Mucopolysaccharidosis Type IIIA Disease 
Protocol Number: 
SHP-610-201 
Protocol Date: 
25 January 2017 (Amendment 2) 
Investigational Product: 
Recombinant human heparan N-sulfatase (rhHNS, HGT-
1410) 
SOPH-A-PORT® Mini S, Implantable Access Port, Spinal, 
Mini Unattached, with Guidewire 
SAP Author(s): 
 
Release Date: 
21 Jun 2019 
Study Sponsor: 
Shire 
300 Shire Way 
Lexington, MA USA 02421 
Shire Medical Monitor: 
, DO 
 
Confidentiality Statement 
This document is the proprietary and confidential property of  
Shire, Inc. 


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Statistical Analysis Plan Addendum for Safety Follow-up Period 
 
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TABLE OF CONTENTS 
1. 
ABBREVIATIONS AND DEFINITION OF TERMS............................................................3 
2. 
RATIONALE FOR THE ADDENDUM .................................................................................4 
3. 
GENERAL DESCRIPTION ....................................................................................................5 
4. 
SAFETY VARIABLES ...........................................................................................................6 
4.1 
Schedule of Safety Evaluations .....................................................................................6 
4.2 
Safety Endpoints ............................................................................................................6 
5. 
STATISTICAL ANALYSIS ...................................................................................................7 
5.1 
General Methodology ....................................................................................................7 
5.2 
Analysis Populations ......................................................................................................7 
6. 
DATA DISPLAYS ..................................................................................................................8 
6.1 
Subject Disposition ........................................................................................................8 
6.2 
Protocol Deviations ........................................................................................................8 
6.3 
Demographics and Other Characteristics .......................................................................8 
6.4 
Extent of Exposure .........................................................................................................8 
6.5 
Safety Analysis ..............................................................................................................9 
 


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1. ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Definition 
AE 
adverse event 
IDDD 
intrathecal drug delivery device 
  MPS 
  Mucopolysaccharidosis  
  MPS IIIA 
  Mucopolysaccharidosis IIIA or Sanfilippo syndrome Type A 
IT 
intrathecal 
rhHNS 
recombinant human heparan N-sulfatase 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SOC 
system organ class 


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2. RATIONALE FOR THE ADDENDUM 
Study SHP-610-201 is a Phase IIb, open label extension of study HGT-SAN-093 evaluating the 
safety and efficacy of 45 mg HGT-1410 administered either every 2 weeks (Q2W) or every 4 
weeks (Q4W) via an intrathecal drug delivery device (IDDD), versus no treatment, in subjects at 
a relatively early stage of mucopolysaccharidosis Type IIIA (MPS IIIA) disease. The study was 
designed to provide ongoing treatment with HGT-1410 to patients who received HGT-1410 in 
Study HGT-SAN-093 and to initiate treatment to patients who received no-treatment in Study 
HGT-SAN-093. The statistical analysis plan (SAP) for interim analysis dated on 26 May 2017 
provided a technical and detailed elaboration of the planned interim analysis based on the data 
with cut-off date of 28 June 2017 (treatment period) for protocol SHP-610-201 amendment 2. 
During the treatment period, if a subject discontinued, or withdrew from the study, or the study 
was stopped by the sponsor, the IDDD was to be removed. If the investigator determined that the 
IDDD should not be removed (full or partial device) from the subject based upon a safety 
assessment, then the subject continued in the study under the safety follow-up period upon 
completion of their last treatment period visit. The safety follow-up period of study SHP-610-
201 will monitor the safety of the device up to an additional 3 years or until the device is 
removed in the last subject. 
As of 7 March 2019, Study SHP-610-201 is considered complete as the sponsor has determined 
that the safety follow-up period may be ended as no safety concerns have been raised and 
subjects will continue to be monitored by their physicians. This SAP addendum for the safety 
follow-up period provides the planned analysis on the safety of the device for the subjects who 
did not have the IDDD removed (full or partial) at the end of the treatment period, based on 
protocol SHP-610-201 Amendment 2, dated 25 January 2017. 


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3. GENERAL DESCRIPTION 
If the Investigator determined that the device should not be removed from a subject based upon 
safety assessments at the end of treatment period, the device could remain in the subject (partial 
[catheter only] or full [port, catheter, and suture wings]) if the subject was doing clinically well 
and there were no further known risk factors such as infection (eg, meningitis). The device may 
be partially or fully removed as medically required and determined by the neurosurgeon at a 
future date. 
Subjects who did not have the IDDD removed (partial or full device) at the end of the treatment 
period of HGT-SAN-093 continued to be observed during a safety follow-up period with visits at 
the site every 6 months up to an additional 3 years until the IDDD has been fully explanted. 
Determined by the sponsor to end the study, the global LPLV for the safety follow-up period was 
7 March 2019 and this was the last visit of the study. 


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4. SAFETY VARIABLES 
4.1 
Schedule of Safety Evaluations 
The schedule of safety evaluations of device was performed every 6 months (Refer to Appendix 
5 of the study protocol [Amendment 2]). 
4.2 
Safety Endpoints 
The safety endpoints for the safety follow-up period were: 
• Symptom-directed PE 
• Clinical laboratory tests (hematology, serum chemistry, urinalysis and standard CSF safety 
labs); only if indicated for a device-related AE 
• X-ray (to check IDDD placement or for any device-related AEs) 
• Concomitant medications, therapies, and procedures; only if indicated for a device-related 
AE 
• Device-related AE monitoring 
• Postoperative check of IDDD incision (postoperative evaluation can occur within 1-3 days 
after IDDD explantation) 


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5. STATISTICAL ANALYSIS 
5.1 
General Methodology 
All statistical analyses will be performed using SAS® Version 9.3 or later.   
Tabular summaries will be presented. Continuous variables will be summarized using descriptive 
statistics [sample size (N), mean, standard deviation (SD), minimum, median, and maximum]. 
Categorical variables will be summarized using the number and percentage.  
For samples associated with multiple tests performed at the same visit (e.g. lab results), the latest 
valid result will be selected for analysis. 
5.2 
Analysis Populations 
The safety population in safety follow-up period consists of subjects from HGT-SAN-093 whose 
IDDD was not removed (full or partial) at the end of the treatment period and agreed to 
participate in the safety follow-up period. 


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6. DATA DISPLAYS 
6.1 
Subject Disposition 
The number of subjects who signed the informed consent for the safety follow-up period, are in 
the safety population for safety follow-up period, completed the safety follow-up period, and 
withdrawn from the safety follow-up period. Reasons for withdrawal will be provided. 
Subject disposition will be presented in a by-subject listing. 
6.2 
Protocol Deviations 
An incident involving noncompliance with the protocol, but one which typically does not have 
significant effect on the subject’s rights, safety, or welfare, or the integrity of the resultant data 
will be considered a protocol deviation. 
Protocol violations will be defined as any major protocol deviation that affects study evaluations 
during safety follow-up period. Subjects will be examined on a case-by-case basis prior to final 
database lock to determine whether conditions set forth in the study protocol have been violated.  
The protocol deviations will be presented in a listing. 
6.3 
Demographics and Other Characteristics  
Demographic and characteristics at the beginning of safety follow-up period, eg, age (years), 
gender (male, female), race (American Indian or Alaskan Native, Asian, Black or African 
American, Native Hawaiian or other Pacific Islander, White, Other), and ethnicity (Hispanic or 
Latino, Not Hispanic or Latino) will be summarized for the safety population in the safety 
follow-up period.  Age, in years, will be calculated by subtracting the date of birth from the date 
of informed consent for safety follow-up period plus 1 and dividing by 365.25 and then rounding 
down to two decimal places.  
Demographic information will be presented in a by-subject listing. 
6.4 
Extent of Exposure 
Duration of subjects/devices (weeks) in the safety follow-up period will be summarized.  
The duration of the subject/device is calculated by subtracting the date of informed consent for 
safety follow-up period from the device removal date or end of safety follow-up period 
(whichever is earlier). 
A listing for the duration of the device exposure will be presented by subject. 


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6.5 
Safety Analysis 
6.5.1 
Adverse Events 
Device-related AEs were recorded throughout the safety follow-up period. AEs will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA) version 13.1 or higher. 
AEs will be summarized descriptively. The summary will include the number and percentage of 
subjects with any AE, device surgical procedure related AE, device-related AE, any device-
related serious AE (SAE), and any AE that lead to discontinuation. 
AEs will be summarized by system organ class (SOC) and preferred term. The number and 
percentage of subjects experiencing an AE will be tabulated. Furthermore, AEs deemed as 
possibly/probably or definitely related to device surgical procedure, or IDDD will be 
summarized separately. SAEs and AEs which lead to study discontinuation will be similarly 
summarized. 
By-subject listings will be provided for device-related AEs, device-related AEs resulting in 
death, SAEs, and AEs leading to discontinuation. 
6.5.2 
Laboratory Results 
Clinical laboratory results will be presented only if indicated for a device-related AE during the 
safety follow-up period. By-subject listing of laboratory results will be provided. 
6.5.3 
Concomitant Medications, Therapies and Procedures 
Concomitant medications, therapies and procedures will be reported only if indicated for a 
device-related AE, and will be coded using the WHO Drug Dictionary (Version 2009, Q4 or 
higher). 
The concomitant medications, therapies and procedures that occur on or after the date of 
informed content for the safety follow-up period will be presented in a listing.