Clinical trial NCT01506141
Conditions: Hunter Syndrome
Keywords: MPS II MPS 2 lysosomal storage disorder mps symptoms enlarged adenoids elaprase hunter's syndrome MPS2 hunters disease hunter's disease treatment hunter syndrome therapy iduronate sulfatase mps society MPSII hunter syndrome treatment hunter's disease iduronate 2 sulfatase mucopolysaccharides mps diagnosis chronic ear infection hunters syndrome ert treatment lysosomal storage disease hunter disease enzyme replacement therapy idursulfase hunter's syndrome treatment
Sponsor: Takeda
Start date: 2010-08-01; Completion date: 2024-04-30
Enrollment: 15 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This extension study of HGT-HIT-045 is designed to collect long-term safety data in pediatric participants with Hunter syndrome and cognitive impairment who are receiving intrathecal (IT) idursulfase-IT and intravenous (IV) Elaprase enzyme replacement therapy.

Detailed description:

Arms: arm 1: Participants will receive 1 mg idursulfase-IT intrathecally via intrathecal drug delivery device (IDDD) or lumbar puncture (LP) once monthly and standard-of-care (SoC) therapy of Elaprase intravenous (IV) infusions. arm 2: Participants will receive 10 mg idursulfase-IT intrathecally via IDDD or LP once monthly and SoC therapy of Elaprase IV infusions. arm 3: Participants will receive 30 mg idursulfase-IT intrathecally via IDDD or LP once monthly and SoC therapy of Elaprase IV infusions.
Interventions: intervention 1: Idursulfase-IT intervention 2: Elaprase
Intervention descriptions: intervention 1: Idursulfase-IT once monthly via IDDD. intervention 2: Weekly IV infusions of commercially available Elaprase.

Protocol documents:
Prot_000.pdf: 
For non-commercial use only


Clinical Trial Protocol: HGT-HIT-046 
Study Title: 
An Open-Label Extension of Study HGT-HIT-045 Evaluating Long-Term 
Safety and Clinical Outcomes of Intrathecal Idursulfase-IT Administered in 
Conjunction with Intravenous Elaprase® in Pediatric Patients with Hunter 
Syndrome and Cognitive Impairment 
Study Number: 
HGT-HIT-046 
Study Phase: 
I/II 
Product Name: 
Idursulfase for Intrathecal Administration (idursulfase-IT [HGT-2310]) 
Device(s) 
Name(s): 
SOPH-A-PORT® Mini S, Implantable Access Port, Spinal, Mini Unattached, 
with Guidewire  
PORT-A-CATH® II Low Profile™ Intrathecal Implantable Access System  
IND Number: 
100,610 
EudraCT 
Number: 
2011-000212-25 
 
Indication: 
Hunter syndrome with cognitive impairment 
Sponsor: 
Shire Human Genetic Therapies (HGT), Inc. 
Sponsor Contact: 
300 Shire Way 
Lexington, MA 02421 
Medical Monitor: 
, DO 
 
 
Date 
Original Protocol: 
29 April 2009 
Amendment 1 
03 May 2010 
Amendment 2 
20 September 2010 
Amendment 3 
29 March 2011 
Amendment 4 
28 July 2011 
Amendment 5 
17 July 2012 
Amendment 6 
07 May 2013 
Amendment 7  
07 November 2013 
Amendment 8 
16 July 2015 
Amendment 9 
03 January 2017 
Amendment 10 
17 January 2018 
Amendment 11 
14 March 2018 
Amendment 12 
29 May 2018 
Amendment 13 
17 August 2021 
Confidentiality Statement 
This document is the proprietary and confidential property of  
Shire Human Genetic Therapies, Inc. (Shire)  
(Shire is now a part of Takeda Pharmaceuticals and is a wholly owned subsidiary of Takeda) 
For non-commercial use only


Shire
CONFIDENTIAL
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Idursulfase-IT
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PROTOCOL SIGNATURE PAGE
I have read Protocol HGT-HIT-046 Amendment 13, “An Open-Label Extension of Study 
HGT-HIT-045 Evaluating Long-Term Safety and Clinical Outcomes of Intrathecal 
Idursulfase-IT Administered in Conjunction with Intravenous Elaprase® in Pediatric Patients 
with Hunter Syndrome and Cognitive Impairment,” and the current edition of the idursulfase-IT 
investigator's brochure.
I agree to conduct the study as outlined herein.
Signatory
Investigator
Signature
Date
Print Name
Institution
I have read and approved this protocol amendment.
Signatory
Shire Medical 
Monitor
Date
, DO, 
DocuSign Envelope ID: 514E16EF-D603-40FF-A688-324EDF44781E
For non-commercial use only


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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE .................................................................................................2 
LIST OF IN-TEXT TABLES ..........................................................................................................9 
LIST OF IN-TEXT FIGURES.........................................................................................................9 
LIST OF ABBREVIATIONS ........................................................................................................10 
1 
PROTOCOL SYNOPSIS .......................................................................................................12 
2 
INTRODUCTION ..................................................................................................................20 
2.1 
Disease Background .................................................................................................20 
2.2 
Human Enzyme Replacement Therapy Rationale ...................................................20 
2.3 
Idursulfase Administration in the Nonclinical Setting .............................................21 
2.4 
Previous Human Experience ....................................................................................22 
2.5 
Use of Repeat Lumbar Puncture to Administer Enzyme Replacement 
Therapy .....................................................................................................................24 
2.6 
Study Rationale ........................................................................................................25 
2.7 
Benefit/Risk Assessment ..........................................................................................25 
2.8 
Global Health Emergencies and Clinical Trial Continuity ......................................26 
3 
STUDY OBJECTIVES ..........................................................................................................27 
3.1 
Primary Objective ....................................................................................................27 
3.2 
Secondary Objectives ...............................................................................................27 
3.3 
Exploratory Objectives .............................................................................................27 
4 
STUDY ENDPOINTS ............................................................................................................28 
4.1 
Primary Endpoint .....................................................................................................28 
4.2 
Secondary Endpoints ................................................................................................28 
4.3 
Exploratory Endpoints ..............................................................................................28 
4.4 
SOPH-A-PORT Mini S Device Assessments ..........................................................28 
5 
OVERALL STUDY DESIGN AND PLAN ...........................................................................29 
5.1 
Study Design ............................................................................................................29 
5.2 
Rationale for Study Design, Device Use, and Comparator Group ...........................31 
5.2.1 
Initial Treatment Phase (Part A) .......................................................................32 
5.2.2 
Extended Treatment Phase (Parts B and C) ......................................................33 
5.3 
Study Duration .........................................................................................................35 
6 
SELECTION OF STUDY POPULATION ............................................................................36 
6.1 
Inclusion Criteria ......................................................................................................36 
6.2 
Exclusion Criteria .....................................................................................................36 
7 
STUDY TREATMENTS ........................................................................................................38 
7.1 
Treatment Schedule ..................................................................................................38 
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7.1.1 
Initial Treatment Phase (Part A) .......................................................................38 
7.1.2 
Extended Treatment Phase (Parts B and C) ......................................................38 
7.2 
Description of Study Drug .......................................................................................39 
7.3 
Selection and Timing of Dose ..................................................................................39 
7.4 
Intrathecal Administration ........................................................................................40 
7.4.1 
IDDD Implantation ...........................................................................................40 
7.5 
Treatment Compliance .............................................................................................40 
7.6 
Intrathecal Injection ..................................................................................................41 
7.6.1 
SOPH-A-PORT Mini S Intrathecal Drug Delivery Device ..............................41 
7.6.2 
PORT-A-CATH Intrathecal Drug Delivery Device .........................................42 
7.7 
Cerebrospinal Fluid Collection ................................................................................42 
7.8 
Guidance Concerning Performance of Lumbar Puncture for Study Drug 
Administration and CSF Sample Collection ............................................................42 
8 
STUDY PROCEDURES ........................................................................................................44 
8.1 
Study Evaluations and Procedures ...........................................................................44 
8.2 
Initial and Extended Treatment Phases (All Patients) ..............................................44 
8.3 
Initial Treatment Phase (Only for Patients Who Were Not Previously Treated 
with Intrathecal idursulfase-IT in Study HGT-HIT-045) (Part A) ...........................45 
8.3.1 
Screening/Baseline Visit (Study HGT-HIT-045 EOS Visit) ............................45 
8.3.2 
Physical Examinations ......................................................................................46 
8.3.3 
Height and Weight ............................................................................................47 
8.3.4 
Head Circumference..........................................................................................47 
8.3.5 
Vision Assessment ............................................................................................47 
8.3.6 
Hearing Assessment ..........................................................................................47 
8.3.7 
12-Lead Electrocardiogram (ECG) ...................................................................48 
8.3.8 
Vital Signs .........................................................................................................48 
8.3.9 
Clinical Laboratory Testing ..............................................................................49 
8.3.9.1 
Hematology ............................................................................................49 
8.3.9.2 
Serum Chemistry ....................................................................................49 
8.3.9.3 
Standard Urinalysis ................................................................................50 
8.3.9.4 
Urinary GAG Levels ..............................................................................50 
8.3.10 
Auditory Brainstem Response ..........................................................................51 
8.3.11 
Brain and Spinal Magnetic Resonance Imaging ...............................................51 
8.3.12 
Surgical Implantation of the IDDD ...................................................................51 
8.3.13 
Intracranial Pressure Measurement ...................................................................51 
8.3.14 
Cerebrospinal Fluid (CSF) Assessments ...........................................................52 
8.3.14.1 
CSF Cell Counts .....................................................................................52 
8.3.14.2 
Immunoassay for Idursulfase-specific Antibodies .................................52 
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8.3.14.3 
CSF Biomarker Analysis ........................................................................52 
8.3.14.4 
CSF Analysis of Idursulfase Enzyme Levels .........................................52 
8.3.15 
Intrathecal Idursulfase-IT Injection...................................................................53 
8.3.16 
Elaprase Infusion ...............................................................................................53 
8.3.17 
Neurological Examination ................................................................................53 
8.3.18 
Serum Anti-Idursulfase Antibody and Plasma Proteomic Biomarker 
Determination ....................................................................................................53 
8.3.19 
Neurodevelopmental Assessments ....................................................................54 
8.3.19.1 
Full Neurodevelopmental Assessment ...................................................54 
8.3.19.2 
Brief Neurodevelopmental Assessment .................................................55 
8.3.20 
Pharmacokinetic Evaluations ............................................................................55 
8.4 
Extended Treatment Phase (All Patients, Month 7 through Month 54) 
(Part B) .....................................................................................................................56 
8.4.1 
Study HGT-HIT-045 EOS Visit........................................................................56 
8.4.2 
Physical Examinations ......................................................................................57 
8.4.3 
Height and Weight ............................................................................................57 
8.4.4 
Head Circumference..........................................................................................57 
8.4.5 
Vision Assessment ............................................................................................58 
8.4.6 
Hearing Assessment ..........................................................................................58 
8.4.7 
12-Lead Electrocardiogram (ECG) ...................................................................58 
8.4.8 
Vital Signs .........................................................................................................58 
8.4.9 
Clinical Laboratory Testing ..............................................................................58 
8.4.9.1 
Hematology ............................................................................................58 
8.4.9.2 
Serum Chemistry ....................................................................................59 
8.4.9.3 
Standard Urinalysis ................................................................................59 
8.4.9.4 
Urinary GAG Levels ..............................................................................59 
8.4.10 
Auditory Brainstem Response ..........................................................................59 
8.4.11 
Brain and Spinal Magnetic Resonance Imaging ...............................................59 
8.4.12 
Intracranial Pressure Measurement ...................................................................60 
8.4.13 
Cerebrospinal Fluid (CSF) Assessments ...........................................................60 
8.4.13.1 
CSF Cell Counts .....................................................................................60 
8.4.13.2 
Immunoassay for Idursulfase-specific Antibodies .................................60 
8.4.13.3 
CSF Biomarker Analysis ........................................................................60 
8.4.13.4 
CSF Analysis of Idursulfase Enzyme Levels .........................................60 
8.4.14 
SOPH-A-PORT Mini S Device Assessments ...................................................61 
8.4.15 
Intrathecal Idursulfase-IT Injection...................................................................61 
8.4.16 
Elaprase Infusion ...............................................................................................61 
8.4.17 
Neurological Examination ................................................................................61 
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8.4.18 
Serum Anti-idursulfase Antibody and Plasma Proteomic Biomarker 
Determination ....................................................................................................61 
8.4.19 
Neurodevelopmental Assessments ....................................................................62 
8.4.19.1 
Full Neurodevelopmental Assessment ...................................................62 
8.4.20 
Pharmacokinetic Evaluations ............................................................................62 
8.5 
Extended Treatment Phase (All Patients, from Month 55 to EOS) (Part C) ............63 
8.5.1 
Physical Examinations ......................................................................................63 
8.5.2 
Height and Weight ............................................................................................63 
8.5.3 
Head Circumference..........................................................................................63 
8.5.4 
Vision Assessment ............................................................................................63 
8.5.5 
Hearing Assessment ..........................................................................................63 
8.5.6 
12-Lead Electrocardiogram (ECG) ...................................................................63 
8.5.7 
Vital Signs .........................................................................................................63 
8.5.8 
Clinical Laboratory Testing ..............................................................................64 
8.5.8.1 
Hematology ............................................................................................64 
8.5.8.2 
Serum Chemistry ....................................................................................64 
8.5.8.3 
Standard Urinalysis ................................................................................64 
8.5.8.4 
Urinary GAG Levels ..............................................................................64 
8.5.9 
Auditory Brainstem Response ..........................................................................64 
8.5.10 
Brain and Spinal Magnetic Resonance Imaging ...............................................65 
8.5.11 
Intracranial Pressure Measurement ...................................................................65 
8.5.12 
Cerebrospinal Fluid (CSF) Assessments ...........................................................65 
8.5.13 
SOPH-A-PORT Mini S Device Assessments ...................................................65 
8.5.14 
Intrathecal Idursulfase-IT Injection...................................................................65 
8.5.15 
Elaprase Infusion ...............................................................................................66 
8.5.16 
Neurological Examination ................................................................................66 
8.5.17 
Serum Anti-idursulfase Antibody .....................................................................66 
8.5.18 
Neurodevelopmental Assessments ....................................................................66 
8.6 
Device-related Study Procedures .............................................................................67 
8.6.1 
IDDD Implantation or Revision Procedures .....................................................67 
8.6.2 
Device Removal ................................................................................................67 
9 
ADVERSE EVENTS ..............................................................................................................69 
9.1 
Definitions of Adverse Events and Serious Adverse Events ...................................69 
9.1.1 
Adverse Events .................................................................................................69 
9.1.2 
Serious Adverse Event Definition .....................................................................70 
9.1.3 
Unanticipated Adverse Device Effect Definition .............................................70 
9.1.4 
SOPH-A-PORT Mini S Device-associated Definitions ....................................71 
9.1.4.1 
Device Revision (Partial and Full) .........................................................71 
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9.1.4.2 
Device Malfunction ................................................................................71 
9.1.4.3 
Device Failure ........................................................................................71 
9.1.4.4 
Device Adjustment .................................................................................71 
9.1.5 
Classification of Adverse Events and Serious Adverse Events ........................71 
9.1.5.1 
Categories of Adverse Events ................................................................73 
9.1.5.2 
Clarification between Serious and Severe ..............................................75 
9.2 
Adverse Event Monitoring and Period of Observation ............................................75 
9.3 
Procedures for Recording and Reporting Adverse Events .......................................75 
9.3.1 
Serious Adverse Event Reporting .....................................................................75 
9.3.2 
Eliciting Adverse Events ...................................................................................77 
9.3.3 
Protocol Deviations for Medical Emergency or Adverse Event .......................77 
9.4 
Abuse, Misuse, Overdose, and Medication Error ....................................................77 
9.5 
Safety-related Study Stopping Rules ........................................................................78 
9.6 
Concomitant Medications, Therapies, and Medical/Surgical Procedures ................79 
9.6.1 
Infusion Reactions and Management ................................................................79 
9.7 
Removal of Patients from the Trial ..........................................................................80 
10 STATISTICAL METHODS ...................................................................................................82 
10.1 
General Statistical Methodology ..............................................................................82 
10.2 
Patient Disposition and Demographics ....................................................................82 
10.3 
Efficacy, Safety, and Pharmacokinetic Evaluations .................................................82 
10.3.1 
Populations for Analyses...................................................................................82 
10.3.2 
Primary Analyses ..............................................................................................83 
10.3.2.1 
Safety and Tolerability Assessments ......................................................83 
10.3.2.2 
Laboratory Evaluations ..........................................................................84 
10.3.2.3 
Anti-Idursulfase Antibody Formation ....................................................84 
10.3.3 
Secondary Analyses ..........................................................................................84 
10.3.3.1 
Pharmacodynamic Analyses ..................................................................84 
10.3.3.2 
Pharmacokinetic Analyses .....................................................................84 
10.3.3.3 
SOPH-A-PORT Mini S IDDD Safety and Performance .......................86 
10.3.3.4 
Exploratory Endpoints ............................................................................87 
10.3.3.5 
Protocol Violations .................................................................................87 
11 ADMINISTRATIVE REQUIREMENTS ..............................................................................88 
11.1 
Good Clinical Practice .............................................................................................88 
11.2 
Investigators and Administrative Information .........................................................88 
11.3 
Delegation of Responsibilities .................................................................................88 
11.4 
Investigator Financial Disclosure .............................................................................88 
11.5 
Institutional Review Board/ Independent Ethics Committee/Research Ethics 
Board ........................................................................................................................88 
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11.6 
Data and Safety Monitoring Board ..........................................................................89 
11.7 
Patient Information and Informed Consent ..............................................................89 
11.8 
Patient Confidentiality ..............................................................................................90 
11.9 
Protocol Compliance ................................................................................................90 
11.10 
Protocol Amendments ..............................................................................................91 
11.11 
Case Report Form Completion .................................................................................91 
11.12 
Study Monitoring .....................................................................................................91 
11.13 
Packaging and Labeling ...........................................................................................92 
11.13.1 
Study Drug ........................................................................................................92 
11.13.2 
Intrathecal Drug Delivery Device(s) .................................................................92 
11.14 
Storage and Accountability ......................................................................................92 
11.14.1 
Study Drug ........................................................................................................92 
11.14.2 
Intrathecal Drug Delivery Device(s) .................................................................92 
11.15 
Device Failure Review Process ................................................................................93 
11.16 
Premature Closure of the Study ...............................................................................93 
11.16.1 
Study Termination .............................................................................................93 
11.16.2 
Site Termination ................................................................................................93 
11.16.3 
Record Retention ...............................................................................................94 
12 PUBLICATION OF STUDY FINDINGS ..............................................................................95 
13 REFERENCES .......................................................................................................................96 
14 APPENDIX 1: SCHEDULE OF STUDY PROCEDURES ...................................................99 
15 APPENDIX 2: NEURODEVELOPMENTAL ASSESSMENTS ........................................110 
16 APPENDIX 3: SAMPLE NEUROLOGICAL EXAM .........................................................116 
17 APPENDIX 4: ADVERSE DEVICE EFFECTS EXPECTED WITH THE 
SOPH-A-PORT IDDD.....................................................................................................117 
18 APPENDIX 5: DEVICE RELATED ADVERSE REACTIONS ASSOCIATED WITH 
THE PORT-A-CATH IDDD ...........................................................................................119 
19 APPENDIX 6: SUMMARY OF CHANGES FOR AMENDMENT 13 ..............................120 
 
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LIST OF IN-TEXT TABLES 
Table 8-1 
Physical Examination .......................................................................................47 
Table 8-2 
Serum Chemistry ..............................................................................................50 
Table 8-3 
Full Neurodevelopmental Assessment Tests ....................................................55 
Table 9-1 
Classification of AE/SAE Severity ..................................................................72 
Table 9-2 
Classification of AE/SAE Relatedness .............................................................73 
Table 14-1 
Study Procedures for the Initial Treatment Phase: For Patients Who 
Were Not Treated Previously in Study HGT-HIT-045 with 
Intrathecal Idursulfase-IT (Part A) ...................................................................99 
Table 14-2 
Study Procedures for the Extended Treatment Phase: For All Patients 
Who Have Received 6 Months of Treatment with Intrathecal 
Idursulfase-IT in Study HGT-HIT-045 or Study HGT-HIT-046 
(Part B) ...........................................................................................................103 
Table 14-3 
Study Procedures for the Extended Treatment Phase: For All Patients 
Who Have Received 54 Months of Treatment with Intrathecal 
Idursulfase-IT in Study HGT-HIT-045 or Study HGT-HIT-046 
(Part C) ...........................................................................................................106 
Table 14-4 
Pharmacokinetic Sampling Schedule (Parts A and B) ...................................109 
Table 15-1 
Summary of Neurodevelopmental Outcome Measures ..................................110 
 
LIST OF IN-TEXT FIGURES 
Figure 5-1 
 Planned Duration of Treatment (Study HGT-HIT-045 and/or HGT-
HIT-046) ...........................................................................................................35 
 
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LIST OF ABBREVIATIONS 
Term 
Definition 
ABR 
auditory brainstem response 
AE 
adverse event 
AUC 
area under the curve 
BOT-2 
Bruininks-Oseretsky Test of Motor Proficiency, Second Edition 
BSID-III 
Bayley Scales of Infant Development, Third Edition 
BRIEF 
Behavior Rating Inventory of Executive Function  
BRIEF-P 
Behavior Rating Inventory of Executive Function-Preschool 
BW 
body weight 
CBC 
complete blood count 
CFR 
Code of (United States) Federal Regulations 
CI 
confidence interval 
CL 
clearance 
Cmax 
maximum concentration 
CNS 
central nervous system 
COVID-19 
2019 novel coronavirus disease 
CRF 
case report form 
CRO 
contract research organization 
CS 
clinically significant 
CSF 
cerebrospinal fluid 
DAS-II 
Differential Ability Scales, Second Edition 
DS 
dermatan sulfate 
ECG 
electrocardiogram 
ELISA 
enzyme-linked immunosorbent assay 
EOS 
end of study 
ERT 
enzyme replacement therapy 
EU 
European Union 
FDA 
(United States) Food and Drug Administration 
GAG 
glycosaminoglycan 
GCA 
General Conceptual Ability 
GCP 
Good Clinical Practices 
HGT 
Human Genetic Therapies 
HS 
heparan sulfate 
IC 
intracranial 
ICH 
International Conference on Harmonisation 
ICP 
intracranial pressure 
ICV 
intracerebroventricular 
IDDD 
intrathecal drug delivery device 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
Ig 
immunoglobulin 
IKO 
idursulfase knockout 
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Term 
Definition 
IND 
Investigational New Drug Application 
IT 
intrathecal 
IV 
intravenous 
kg 
kilogram(s) 
LC-MS/MS 
liquid chromatography tandem mass spectrometry  
M6P 
mannose-6-phosphate 
MDR 
Medical Device Report 
MedDRA 
Medical Dictionary for Regulatory Activities  
MPS II 
Mucopolysaccharidosis II 
MRI 
magnetic resonance imaging 
MRT 
mean residence time 
N 
normal 
NCI CTC 
National Cancer Institute Common Terminology Criteria 
NCS 
not clinically significant 
NOAEL 
no observed adverse effect level 
PD 
pharmacodynamic(s) 
PDMS-2 
Peabody Developmental Motor Scales-2 
PET 
positron emission tomography  
PK 
pharmacokinetic(s) 
PORT-A-CATH 
PORT-A-CATH® II Low Profile™ Intrathecal Implantable Access System 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QTc 
corrected QT interval 
REB 
Research Ethics Board 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SIB-R 
Scale of Independent Behavior-revised 
SNC 
Special Nonverbal Composite 
SOC 
system organ class 
SOPH-A-PORT Mini S 
SOPH-A-PORT® Mini S, Implantable Access Port, Spinal, Mini Unattached, with 
Guidewire 
T4 
thyroxine 
t1/2 
terminal elimination half-life 
Tmax 
time to maximum concentration 
UADE 
Unanticipated Adverse Device Effect 
US 
United States 
Vss 
apparent volume of distribution at steady state 
WBC 
white blood cell (count) 
 
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1 
PROTOCOL SYNOPSIS  
Protocol Title: 
An Open-Label Extension of Study HGT-HIT-045 Evaluating Long-Term Safety and Clinical 
Outcomes of Intrathecal Idursulfase-IT Administered in Conjunction with Intravenous Elaprase® 
in Pediatric Patients with Hunter Syndrome and Cognitive Impairment 
Protocol Number: HGT-HIT-046 Amendment 13 
Phase of Development: I/II 
Investigational Product: 
idursulfase for intrathecal administration (idursulfase-IT, HGT-2310) 
Name(s) of Intrathecal Drug Delivery Device(s): 
SOPH-A-PORT® Mini S, Implantable Access Port, Spinal, Mini Unattached, with Guidewire 
(SOPH-A-PORT Mini S) 
PORT-A-CATH® II Low Profile™ Intrathecal Implantable Access System (PORT-A-CATH) 
Study Objectives: 
The primary objective of this study is:  
• To collect long-term safety data in pediatric patients with Hunter syndrome and cognitive 
impairment who are receiving intrathecal idursulfase-IT and intravenous (IV) Elaprase® 
enzyme replacement therapy (ERT) 
 
The secondary objectives of this study are: 
• To determine the serum pharmacokinetic (PK) profile of idursulfase when administered 
as intrathecal idursulfase-IT and in conjunction with Elaprase 
• To determine the effect of intrathecal idursulfase-IT, given in conjunction with Elaprase, 
on cerebrospinal fluid (CSF) biomarkers (eg, total glycosaminoglycan [GAG] including 
heparan sulfate [HS]/dermatan sulfate [DS]) 
• To determine the effects of intrathecal idursulfase-IT, given in conjunction with Elaprase, 
on urinary GAG 
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The exploratory objectives of this study are: 
• To evaluate the long-term effects of intrathecal idursulfase-IT, given in conjunction with 
Elaprase, on clinical parameters (eg, physiological assessments, neurocognitive 
assessments, neurologic function, and brain structure volumes) 
• To evaluate the long-term effects of intrathecal idursulfase-IT, given in conjunction with 
Elaprase, on functional activities of daily living, as determined by the Scales of 
Independent Behavior-Revised (SIB-R) 
• To explore potential relationships between biomarkers and central nervous system (CNS) 
symptomatology 
• To determine whether monthly idursulfase-IT administrations results in accumulation of 
idursulfase within the CSF compartment by measuring idursulfase levels in CSF 
immediately prior to idursulfase-IT administration 
• To determine the safety and performance of the SOPH-A-PORT Mini S 
 
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Study Endpoints: 
The primary endpoints of this study are: 
• Safety of intrathecal idursulfase-IT administration. Safety will be measured by adverse 
events (AEs, by type and severity), changes in clinical laboratory testing (serum 
chemistry including liver function tests, hematology, urinalysis), 12-lead 
electrocardiogram (ECG), CSF chemistries (contingent on sample availability; cell 
counts, glucose, and protein), anti-idursulfase antibodies and antibodies having enzyme 
neutralizing activity in CSF and serum  
 
The secondary endpoints include: 
• Serum idursulfase concentration-time profiles and serum PK parameters of idursulfase, 
administered as intrathecal idursulfase-IT and in conjunction with Elaprase  
• Change from baseline in CSF biomarkers (eg, GAG [HS/DS]) 
• Change from baseline in urinary GAG 
 
The exploratory endpoints for this study include: 
• Change from Baseline in additional clinical parameters (eg, physiological assessments, 
standardized neurocognitive assessments, neurologic function, brain magnetic resonance 
imaging [MRI]) 
• Change from Baseline in functional activities of daily living parameters 
• Levels of idursulfase in CSF immediately prior to idursulfase-IT administration 
 
Number of Patients Planned and Duration of Patient Participation: 
Patients who participated in Study HGT-HIT-045 and completed the HGT-HIT-045 end-of-study 
(EOS) evaluations, and meet all criteria for inclusion in this extension study will be eligible for 
enrollment. Up to 15 patients are expected. 
Patients will continue treatment in this extension study, unless they discontinue the study or 
Shire discontinues the study, for a maximum duration of 14 years of treatment across 
Studies HGT-HIT-045 and/or HGT-HIT-046. 
The study will conclude after the last patient has completed his last visit. 
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Treatments Administered and Treatment Schedule: 
In the original study design it was planned that idursulfase-IT would be administered once 
monthly (ie, every 28 days) via an intrathecal drug delivery device (IDDD) at doses of 1, 10, or 
30 mg. Because the 1 mg dose was assessed as suboptimal, all patients in the study are currently 
receiving doses of either 10 or 30 mg. In addition, to extend flexibility to patients the 
idursulfase-IT dosing visit window has been extended so that monthly administration may occur 
every 28 (±7) days. 
Device(s), Intended Use(s) 
The PORT-A-CATH system is intended for long-term, continuous access to the intraspinal space 
for the delivery of drugs approved for intraspinal delivery.  
Due to recurrent issues with the PORT-A-CATH IDDD in the intended patient population, Shire 
has qualified a new IDDD for use in this study, the SOPH-A-PORT Mini S®. 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 drugs indicated for intrathecal 
delivery intermittently over a long period of time. The device is CE Marked in the European 
Union (EU) and is considered investigational in non-EU countries. 
It is intended that use of the PORT-A-CATH will be phased out in favor of use of the 
SOPH-A-PORT Mini S device. An implanted PORT-A-CATH IDDD will be allowed to remain 
in situ for as long as it is functional, but when a PORT-A-CATH IDDD becomes nonfunctional 
and needs to be replaced, it will be replaced by a SOPH-A-PORT Mini S IDDD. 
Study Methodology: 
This is an open-label extension of Study HGT-HIT-045. This study is designed to evaluate the 
long-term safety and clinical outcomes of monthly (ie, every 28 [±7] days) intrathecal (IT) 
injections of idursulfase-IT (HGT-2310) in conjunction with weekly IV infusions of Elaprase in 
patients with Hunter syndrome and cognitive impairment. Elaprase will be prescribed by the 
patient’s physician and will be administered in accordance with local prescribing information. 
There are 2 patient groups in Study HGT-HIT-046: those that were previously treated in the 
antecedent study (HGT-HIT-045) and continue to receive treatment in Part B (defined as 
Months 7-54) of this extension study, and those that were not previously treated in the antecedent 
study and receive treatment in Parts A (defined as Months 0-6) and B (defined as Months 7-54) 
of this extension study. Once patients in Study HGT-HIT-046 have completed Part B, they may 
continue to receive treatment with idursulfase-IT in Part C (defined as Months 55-168) while 
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undergoing a reduced, and less burdensome, schedule of study assessments.  
Initial Treatment Phase (previously untreated patients only, Part A): Patients who did not receive 
treatment with intrathecal idursulfase-IT in Study HGT-HIT-045 will, during the Initial 
Treatment Phase of this study (ie, the first 6 months), undergo treatment and assessments 
corresponding in schedule and content to those performed for patients who were treated in Study 
HGT-HIT-045. After completion of the Initial Treatment Phase and if there are no safety 
concerns, patients may continue receiving monthly (ie, every 28 [±7] days) intrathecal 
idursulfase-IT in the Extended Treatment Phase of this study. 
Extended Treatment Phase (all patients, Parts B and C): Patients who received 6 months of 
treatment with intrathecal idursulfase-IT in Study HGT-HIT-045 will be eligible for enrollment 
after completing the EOS evaluations in HGT-HIT-045. If there are no safety concerns, 
previously treated patients may continue receiving monthly (ie, every 28 [±7] days) intrathecal 
idursulfase-IT in this extension study. Patients will receive their monthly doses of intrathecal 
idursulfase-IT at the main study site or at a local site. Patients will undergo pretreatment and 
safety assessments on Day 1 and will receive an IT injection of idursulfase-IT on Day 2 of each 
IT Dosing Week. Standardized neurodevelopmental assessments will be performed every 
6 months during Part B of the Extended Treatment Phase and annually during Part C of the 
Extended Treatment Phase. MRI of the spine and brain and any other procedures deemed 
necessary, such as auditory brainstem response (ABR), that require anesthesia will be performed 
annually. 
When a patient has received and tolerated a total of 9 monthly doses of intrathecal idursulfase-IT 
across Studies HGT-HIT-045 and HGT-HIT-046, the sponsor and principal investigator will 
consider the feasibility of transitioning the patient’s monthly IT dosing to local sites to reduce 
the burden imposed by monthly 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 first 3 IT injections of 
idursulfase-IT (Months 7-9) in this extension study will be administered at the main study site. 
Patients will be discharged a minimum of 24 hours after IT dosing and when deemed clinically 
stable by the investigator. Thereafter, IT injections of idursulfase-IT may be performed at either 
the main study site or at a local site and, through Month 54, patients may be discharged a 
minimum of 4 hours after dosing and when deemed clinically stable by the investigator (ie, a 
24-hour inpatient stay is no longer required). Exceptions include the IT injections of 
idursulfase-IT at Months 19, 31, and 43 when PK assessments are scheduled; these will take 
place at the main site. Due to PK sample collection at these visits, discharge at Months 19, 31, 
and 43 will be upon discretion of the investigator. Patients may undergo a streamlined schedule 
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of evaluation and assessment after completing at least 54 months of treatment in Study 
HGT-HIT-045 and/or HGT-HIT-046. Additionally, from Month 55 onward, patients may be 
discharged a minimum of 1 hour after IT dosing and if deemed clinically stable in the 
investigator’s judgment. 
All patients will receive their weekly IV infusions of Elaprase throughout the study. Elaprase 
infusions may be administered at the main study site, at a local site, or at the patient’s home 
depending upon the standard location as determined for each patient. Patients must provide a 
separate written informed consent/assent to participate in study procedures to be conducted at the 
local site prior to the conduct of any procedures. 
All patients in the study will undergo EOS procedures 30 (±7) days following their last 
administration of intrathecal idursulfase-IT. 
Surgical IDDD implantation and revision will be performed at the main study center only. 
Explantation of the IDDD will be performed at the main study center or at the patient’s local site, 
as necessary. 
It is intended that the IDDD will be used to deliver all IT injections of study drug and to obtain 
CSF samples. No other medication will be administered through the device. However, if the 
IDDD appears to be nonfunctional, 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 may include partial revision or complete 
replacement of the IDDD as indicated. 
If there are medical contra-indications to the re-implantation of a new device, repeat monthly 
lumbar punctures may be considered as an alternative way of delivering the study drug and 
obtaining CSF samples under limited circumstances. As long as no safety risks are identified by 
the investigator, consecutive lumbar punctures may be performed across Studies HGT-HIT-045 
and HGT-HIT-046. 
Continued treatment via repeat lumbar puncture should only be considered in individual cases of 
patients where this treatment is very well tolerated and the investigator has not identified any 
safety concerns associated with repeat lumbar puncture and repeat sedation/anesthesia. 
General anesthesia may be required for injections of study drug and some evaluations, and can 
be used at the discretion of the investigator as indicated in the study manuals. It is anticipated 
that study procedures such as lumbar puncture, MRI, and audiometry will have to be performed 
with sedation/anesthesiology support. 
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Patients should have the IDDD removed when they discontinue from the study, unless they are 
continuing to receive treatment through another mechanism (eg, supplemental study, expanded 
access program, etc) or 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 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. 
If patients in the study require revision and/or replacement of the PORT-A-CATH IDDD, it will 
be removed and replaced with the SOPH-A-PORT Mini S device at a time judged appropriate by 
the investigator. A nonfunctional PORT-A-CATH IDDD cannot be replaced by a new 
PORT-A-CATH device. 
Patients with a partial or full device still in place after completion of the study will not be 
followed for safety monitoring. However, the sponsor will arrange reimbursement when the 
device is eventually removed. 
Safety Assessments: 
Safety of intrathecal administration of idursulfase-IT will be measured by adverse events (AEs), 
changes in clinical laboratory testing (serum chemistry including liver function tests, 
hematology, urinalysis), 12-lead ECG, CSF chemistries (contingent on sample availability; cell 
counts, glucose, and protein), anti-idursulfase antibodies and antibodies having enzyme 
neutralizing activity in CSF and serum.  
SOPH-A-PORT Mini S Assessments:  
The SOPH-A-PORT Mini S device will be evaluated using assessments of device implantation, 
device function, device longevity and adverse events associated with the implant surgery or 
device. This data will be collected on the patient’s case report form (CRF) from the time of 
initial implantation. 
As part of the assessment of the SOPH-A-PORT Mini S, it may be necessary to determine the 
levels of leachables from the device into the CSF and blood. Samples of stored CSF and serum 
may be used to determine the levels of leachable materials related to the IDDD. 
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Pharmacodynamic and PK Assessments: 
Pharmacodynamic (PD) measures will include measurement of change from baseline in CSF 
biomarkers (eg, GAG [HS/DS]), and change from baseline in urinary GAG. 
Pharmacokinetic parameters of idursulfase, when administered as intrathecal idursulfase-IT in 
conjunction with Elaprase, will be measured in serum. 
Statistical Methodology: 
The statistical methodology will use descriptive rather than inferential approaches, given the 
early phase and objectives of the trial. Descriptive statistics will include the mean, standard 
deviation, median, minimum, and maximum. For continuous data, 95% confidence intervals (CI) 
for the mean change will also be presented. For categorical data, the number and percentage of 
patients in each category will be presented. The population for the safety analyses will consist of 
all eligible patients from Study HGT-HIT-045 who agreed to participate in the extension study, 
and had either surgical implantation of an IDDD or IT administration of study drug in the 
extension study. The data will be presented by dose group. 
An interim clinical study report has been prepared describing the results of Parts A and B. The 
complete results, including Part C, will be described in the final clinical study report. 
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2 
INTRODUCTION 
2.1 
Disease Background 
Idursulfase-IT, recombinant human iduronate-2-sulfatase for intrathecal (IT) administration, is in 
development for the treatment of patients with Hunter syndrome (Mucopolysaccharidosis II, 
[MPS II]) with cognitive impairment. Hunter syndrome is an inherited lysosomal storage disease 
caused by the missing or defective enzyme, iduronate-2-sulfatase, which acts to cleave O-linked 
sulfate moieties from two human glycosaminoglycan (GAG) molecules, dermatan sulfate and 
heparan sulfate.1-3 Insufficient levels of iduronate-2-sulfatase lead to progressive accumulation of 
these GAGs in nearly all organs and body tissues. Many patients with Hunter syndrome develop 
some degree of neurodevelopmental impairment, varying from severe neurodevelopmental 
delays and behavioral problems to mildly impaired cognition (approximately 66 and 77%, 
respectively).1-12 Other central nervous system (CNS) manifestations of Hunter syndrome 
include communicating hydrocephalus, increased intracranial pressure, seizures, and hearing 
problems.13  
2.2 
Human Enzyme Replacement Therapy Rationale 
The currently approved therapy for Hunter syndrome is Elaprase®, recombinant human 
iduronate-2-sulfatase for IV administration.14, 15 Enzyme replacement therapy with Elaprase in 
patients with Hunter syndrome has been demonstrated to be safe and efficacious in clinical 
studies. Elaprase is a large protein, and as such, is not expected to cross the blood-brain barrier 
when administered intravenously. 
Idursulfase-IT is a distinct formulation of idursulfase that is suitable for direct delivery into the 
cerebrospinal fluid (CSF) via IT administration, and differs from the IV formulation, Elaprase. 
Idursulfase-IT is a highly purified recombinant form of iduronate-2-sulfatase. It is expressed in a 
human cell line as a single polypeptide chain of 550 amino acids and is secreted into the medium 
as a monomeric protein of approximately 76 kDa following cleavage of the 25 amino acid signal 
peptide. The enzyme contains 8 occupied N-linked glycosylation sites composed of complex, 
hybrid, or high mannose oligosaccharide chains. The presence of mannose-6-phosphate (M6P) 
residues on the high mannose oligosaccharide chains facilitates internalization of the enzyme via 
the M6P receptors present on the cell surface, and subsequent delivery of the enzyme to the 
lysosomes. 
Idursulfase-IT is intended for administration to patients with Hunter syndrome who are 
concurrently receiving treatment with Elaprase. Long-term treatment with idursulfase is 
considered necessary for patients with Hunter syndrome, as GAG re-accumulates in the absence 
of treatment. Intravenous therapy with Elaprase is not adequate to treat the CNS manifestations 
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of Hunter syndrome; conversely, it is not anticipated that administration of idursulfase-IT will be 
sufficient to address the non-neurological aspects of the disease. Concomitant treatment with 
Elaprase and idursulfase-IT is proposed as a therapeutic strategy to improve both the somatic and 
CNS manifestations of Hunter syndrome. 
Extended access of idursulfase-IT treatment to patients with Hunter syndrome and cognitive 
impairment who have had an intrathecal drug delivery device (IDDD) implanted specifically for 
participation in Study HGT-HIT-045, and inclusion of the previously untreated patients of Study 
HGT-HIT-045, will provide an opportunity for evaluation of long-term safety and clinical 
outcomes in this patient population. 
There is precedent for the relative safety and potential benefit of repeated monthly IT 
administration (via lumbar puncture) of an ERT in populations of patients with MPS disorders. 
Intrathecal treatment studies have been conducted with small samples of patients with MPS I for 
spinal cord compression and cognitive impairment in adults, and in pediatric patients with 
MPS VI. Additionally, the effect of intrathecal -L-iduronidase in patients with MPS I 
undergoing bone marrow transplant is being evaluated.16-21 In these Phase I/II 
investigator-initiated trials, enzyme is repeatedly administered by lumbar puncture under 
controlled conditions. 
2.3 
Idursulfase Administration in the Nonclinical Setting 
The nonclinical program includes studies demonstrating efficacy of IT administered idursulfase 
in a mouse model of disease, exposure, and distribution in non-human primates, and safety of 
repeated IT dosing of HGT-2310 in non-human primates via an implanted port/catheter system 
for IT drug delivery. 
In the nonclinical pharmacodynamic assessment, IT administration of idursulfase demonstrated 
distribution and activity in the CNS of an idursulfase mouse model of Hunter syndrome. Based 
on the widespread histopathological improvement observed in a variety of regions in the brain 
and histological markers of disease, the nonclinical studies suggest beneficial pharmacodynamic 
activity following IT administration of idursulfase. 
In the pivotal repeat-dose toxicity studies, idursulfase-IT was administered to monkeys using an 
IDDD. Pharmacokinetic results showed that following repeated IT administration idursulfase-IT 
is present in the CSF and in the serum in a dose-dependent manner and that idursulfase-IT is well 
distributed within the CNS following IT administration. 
Positron emission tomography (PET) images following HGT-2310 injection (via IDDD) 
demonstrated appropriate distribution and showed that the presence of idursulfase-IT in the CSF 
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at doses ranging from 3-20 mg (approximately 30-200 mg/kg of brain weight) does not affect the 
intrinsic flow dynamics of the CSF in monkeys, and is unlikely to do so in humans. 
Based on brain biodistribution data in non-human primates, a therapeutic intrathecally 
administered dose of idursulfase-IT in humans was estimated to be in a range from 5-35 mg. 
Idursulfase-IT-related findings included a transient elevated white blood cell (WBC) and total 
protein in the CSF and slight to minimal inflammatory reactions in the meninges. In both the 
3- and 6-month studies, inflammatory infiltrates were observed in all groups, but were most 
pronounced in the high dose groups. In the 6-month study with recovery groups, the 
inflammation was resolved after a 4-week washout period in the 3 mg IT group, and largely 
resolved in the 100 mg IT group. The transient WBC elevation was considered nonadverse and 
non-specific because the inflammatory reaction was considered an unavoidable reaction to 
injection of a protein in the intrathecal space. As exhibited in the 6-month study in monkeys, 
monthly idursulfase-IT administration in combination with weekly IV idursulfase (0.5 mg/kg) 
was generally safe up to the 100 mg dose. 
The no observed adverse effect level (NOAEL) of 100 mg for idursulfase-IT in monkey 
corresponds to a dose level of 1000 mg/kg of brain weight. The 1 mg dose of idursulfase-IT 
employed in the Phase I/II clinical setting has a safety factor of 1,000-fold relative to the dose of 
100 mg established in the pivotal 6-month, repeat-dose toxicity study in monkey. The 10 mg and 
30 mg doses have 100-fold and a 33.3-fold safety factors, respectively. 
Support for the doses of idursulfase-IT to be evaluated in the clinical setting was provided by the 
results of safety and distribution studies conducted in non-human primates. Collectively, these 
data suggest that a therapeutic IT administered dose of HGT-2310 in humans is in a range from 
5-35 mg. 
2.4 
Previous Human Experience 
In the development program to date, one patient population comprising 15 pediatric MPS II 
males with cognitive impairment has received treatment with idursulfase-IT, in conjunction with 
Elaprase therapy as standard of care, at doses of 1, 10, and 30 mg under protocols HGT-HIT-045 
and its extension HGT-HIT-046. 
The initial investigation of the safety and tolerability of ascending IT doses (1, 10, or 30 mg) of 
idursulfase-IT was conducted in study HGT-HIT-045. This first-in-human study was a 
randomized, open-label, no-treatment controlled study in which idursulfase-IT was administered 
once monthly to MPS II patients via a surgically implanted IDDD, PORT-A-CATH (Smiths 
Medical, US), or lumbar puncture, for 6 months in conjunction with once weekly Elaprase. 
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Eligible patients who completed HGT-HIT-045 are continuing to receive monthly IT injections 
of idursulfase-IT in conjunction with Elaprase therapy in extension study HGT-HIT-046. Across 
the HGT-HIT-045 and HGT-HIT-046 studies, long-term safety, PK/pharmacodynamic 
properties, and the effect of intrathecally administered idursulfase-IT on neurodevelopmental 
health have been evaluated using standardized tests of cognitive and adaptive functions. 
Based on the data available from HGT-HIT-045 and HGT-HIT-046, idursulfase-IT has been 
found to be well tolerated at all doses administered, without safety concerns related to the study 
drug. Available results of neurodevelopmental assessments suggest the potential of intrathecal 
delivery of idursulfase-IT to halt or slow the progressive decline in neurodevelopmental status in 
this patient population. Several patients at earlier stages of cognitive decline who received 
treatment with idursulfase-IT at the 10 mg and 30 mg doses showed evidence of stabilization or 
improvement of cognitive and adaptive functions. 
Intrathecal administration of idursulfase-IT to MPS II patients in Studies HGT-HIT-045 and 
HGT-HIT-046 at the 10 and 30 mg dose regimens resulted in a pronounced PD reduction from 
baseline in the concentration of GAG in CSF, while the 1 mg dose regimen induced a less 
pronounced reduction in GAG concentration in CSF. The PD profiles associated with monthly 
idursulfase-IT administration indicated that the 1 mg dose was suboptimal, with the 10 mg dose 
achieving maximal PD response and the 30 mg dose demonstrating no appreciable added PD 
effect. This response correlates with the therapeutic dose range (5-35 mg) estimated from 
evaluation of HGT-2310 in non-human primates. 
There have been no deaths in any studies of idursulfase-IT. The majority of SAEs in 
HGT-HIT-045 and HGT-HIT-046 have been associated with the use of an IDDD, and designated 
as serious because of the requirement for overnight hospitalization for surgical revision/removal 
of the IDDD. Device-related events were not entirely unexpected, given published reports of IT 
delivery device failures,22, 23 and the need to rely on the device for long-term IT delivery of 
idursulfase-IT in HGT-HIT-045 and its extension study. As a result of the device-related 
concerns in Studies HGT-HIT-045 and HGT-HIT-046, additional guidelines and training 
materials were developed concerning the surgical implantation of the IDDD, and repeated 
lumbar punctures were permitted per protocol amendment as a means of IT delivery of study 
drug. 
Currently, there are 2 types of IDDD in use in the intrathecal programs. The original IDDD, the 
PORT-A-CATH® II Low Profile™ Intrathecal Implantable Access System (PORT-A-CATH), 
was implanted from 2009-2013. The events related to the use of the PORT-A-CATH IDDD 
included surgical removal and replacement of the device because of mechanical failures, such as 
connector pin breaks and catheter slippage, overnight admissions to the hospital for a suspected 
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device infection, and device removal because of wound issues. In response to the occurrence of 
failures of the PORT-A-CATH device in the MPS II patient population, Shire introduced a 
different IDDD, the SOPH-A-PORT Implantable Access Port, Spinal, Mini Unattached, with 
Guidewire (Sophysa SA, France; hereafter referred to as SOPH-A-PORT Mini S), in the 
idursulfase-IT development program. 
In HGT-HIT-046 some patients are still receiving idursulfase-IT via a functioning 
PORT-A-CATH device, which will be left in situ until a device failure occurs, at which point 
they will be replaced by a SOPH-A-PORT Mini S device. 
Please see the current edition of the investigator’s brochure for a detailed summary of safety 
information for idursulfase-IT. Further information concerning the SOPH-A-PORT Mini S 
device is provided as an addendum to the investigator’s brochure. 
Intravenous infusion of Elaprase has been well tolerated in patients with Hunter syndrome across 
the clinical development program and in the post-marketing setting. The most common adverse 
reactions are infusion-related, and include cutaneous reactions (rash, pruritus, urticaria), pyrexia, 
headache, hypertension, and flushing.14, 15 
2.5 
Use of Repeat Lumbar Puncture to Administer Enzyme Replacement Therapy  
In this study, it is intended that the IDDD be used to deliver all IT injections of study drug and to 
obtain CSF samples. However, should the IDDD become nonfunctional or if its use is otherwise 
precluded causing the IT space to be inaccessible via the device; repeat monthly lumbar 
punctures may be considered, under limited circumstances, as an alternative way of delivering 
the study drug and obtaining CSF samples. Guidance concerning the performance of lumbar 
puncture for study drug administration and CSF sample collection is provided in Section 7.8. 
The use of IV ERT is a well-established treatment modality in the MPS patient community, and 
as several of the MPS disorders are associated with cognitive impairment and/or spinal 
compression, the concept of administering ERT directly into the intrathecal space has been 
investigated. There are case histories of patients with MPS being treated with recombinant 
enzyme via repeat lumbar puncture, as well as trials investigating this therapeutic option in 
patients with non-malignant neurological diseases and CNS malignancies.24-29 These reports 
provide evidence that IT administration of medication by repeat lumbar puncture is a viable 
alternative to the implantation of IDDD. 
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2.6 
Study Rationale 
Concomitant treatment with idursulfase-IT and Elaprase is intended to address the CNS and 
somatic manifestations of Hunter syndrome. Elaprase has provided clinical benefit with respect 
to somatic pathologies in patients with Hunter syndrome, and has a well characterized safety 
profile. Although many of the physical symptoms of the disease can be reduced or eradicated by 
Elaprase therapy, IV enzyme replacement is not sufficient for treatment of CNS symptoms due 
to the acknowledged impermeability of the blood-brain barrier to macromolecules such as 
idursulfase. In addition, Elaprase is formulated for IV use only and is contraindicated for direct 
injection into the CNS. The idursulfase-IT formulation was developed specifically to access CNS 
tissues via IT administration and to overcome macromolecular distribution limits imposed by the 
blood-brain barrier. 
Monthly IT administration of idursulfase-IT in conjunction with weekly IV infusion of Elaprase 
was well tolerated in HGT-HIT-045, a completed Phase I/II safety and ascending dose ranging 
study in pediatric patients with Hunter syndrome and cognitive impairment. Extension study 
HGT-HIT-046 is intended to continue evaluation of the effects of IT administration of 
idursulfase-IT on long-term safety and clinical outcomes for patients who enrolled in 
HGT-HIT-045. This study will also provide an opportunity for patients who participated, but did 
not receive treatment, in HGT-HIT-045 to receive IT treatment with idursulfase-IT. 
2.7 
Benefit/Risk Assessment 
In patients with Hunter syndrome, the deficiency of iduronate-2-sulfatase causes accumulation of 
GAG in nearly all body organs and tissues. Systemic IV ERT with Elaprase improves somatic 
manifestations of Hunter syndrome and is associated with reduced levels of GAG in urine. 
Accumulation of GAG molecules in the CNS is associated with impairment of cognitive function 
and other CNS pathologies. No specific therapy exists for the CNS pathologies of Hunter 
syndrome. Treatment of the CNS manifestations of the disease remains an unmet medical need. 
Nonclinical experience with intrathecal administration of idursulfase-IT has demonstrated wide 
distribution to the CNS tissues. Idursulfase-IT has been shown to be well tolerated in several 
species, and to be active in a murine model of idursulfase deficiency. 
Repeat dosing by lumbar puncture requires repeat general anesthesia. Because of 
musculoskeletal abnormalities and potential airway obstruction, patients with MPS II represent a 
higher-than-average anesthesia risk. By using an easy-to-access IDDD, the need for multiple 
general anesthesias is reduced, compared to repeat access by lumbar puncture. 
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Clinical experience in studies of idursulfase-IT to date in pediatric patients with MPS II indicates 
no safety concerns for idursulfase-IT. The major safety signals in clinical studies were related to 
the use and functionality of the IDDD. 
In consideration of the occurrence of device failures observed with the PORT-A-CATH IDDD in 
Studies HGT-HIT-045 and HGT-HIT-046, the SOPH-A-PORT Mini S IDDD was made 
available to patients in HGT-HIT-046. The SOPH-A-PORT Mini S has a patented screw-lock 
mechanism to secure the catheter to the port pin and suture wings to anchor the catheter to the 
lumbar fascia near the insertion into the intrathecal space. 
In conclusion, assessment of the benefit/risk of intrathecally administered idursulfase-IT based 
on the clinical data collected to date indicates a positive benefit/risk balance. It is the sponsor’s 
view that IT administration of idursulfase-IT, concurrent with Elaprase therapy, represents a 
novel treatment that may provide clinical benefit to Hunter syndrome patients with cognitive 
impairment. 
2.8 
Global Health Emergencies and Clinical Trial Continuity 
Global health emergencies, such as the 2019 novel coronavirus disease (COVID-19) pandemic, 
present significant logistical challenges for many clinical sites around the world, with variable 
restrictions being placed on site resources and operations, and on an individual patient’s ability 
to attend clinic visits. In some places, medical visits are occurring, and in others, research clinics 
are operating with only emergency staff. 
Based on these challenges, it may be necessary to adopt additional measures and procedures to 
protect patient safety, and to ensure that there are no gaps in the conduct of the study for patients 
enrolled in this clinical trial. 
This protocol includes the measures which are approved for implementation within this clinical 
trial to protect patient safety and to ensure the integrity of the trial as a result of COVID-19 only. 
These measures may be implemented in accordance with any requirements and expectations set 
out by local Institutional Review Boards (IRBs)/Independent Ethics Committees (IECs) and 
National Competent Authorities, as necessary. 
These specific measures do not apply for patient management issues that are unrelated to a 
documented impact from a public health emergency, such as the COVID-19 pandemic. 
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3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of this study is: 
• To collect long-term safety data in pediatric patients with Hunter syndrome and cognitive 
impairment who are receiving intrathecal idursulfase-IT and IV Elaprase® ERT 
 
3.2 
Secondary Objectives 
The secondary objectives of this study are: 
• To determine the serum PK profile of idursulfase when administered as intrathecal 
idursulfase-IT and in conjunction with Elaprase 
• To determine the effect of intrathecal idursulfase-IT, given in conjunction with Elaprase, 
on CSF biomarkers (eg, total GAG including HS/DS) 
• To determine the effects of intrathecal idursulfase-IT, given in conjunction with Elaprase, 
on urinary GAG 
 
3.3 
Exploratory Objectives 
The exploratory objectives of this study are: 
• To evaluate the long-term effects of intrathecal idursulfase-IT, given in conjunction with 
Elaprase, on clinical parameters (eg, physiological assessments, neurocognitive 
assessments, neurologic function, and brain structure volumes) 
• To evaluate the long-term effects of intrathecal idursulfase-IT, given in conjunction with 
Elaprase, on functional activities of daily living, as determined by the Scales of 
Independent Behavior-Revised (SIB-R) 
• To explore potential relationships between biomarkers and CNS symptomatology 
• To determine whether monthly idursulfase-IT administrations results in accumulation of 
idursulfase within the CSF compartment by measuring idursulfase levels in CSF 
immediately prior to idursulfase-IT administration 
• To determine the safety and performance of the SOPH-A-PORT Mini S 
 
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4 
STUDY ENDPOINTS 
4.1 
Primary Endpoint 
The primary endpoints of this study are: 
• Safety of intrathecal idursulfase-IT administration. Safety will be measured by AEs (by 
type and severity), changes in clinical laboratory testing (serum chemistry including liver 
function tests, hematology, urinalysis), 12-lead ECG, CSF chemistries (contingent on 
sample availability; cell counts, glucose, and protein), anti-idursulfase antibodies and 
antibodies having enzyme neutralizing activity in CSF and serum  
 
4.2 
Secondary Endpoints  
The secondary endpoints of this study are:  
• Serum idursulfase concentration-time profiles and serum PK parameters of idursulfase, 
administered as intrathecal idursulfase-IT and in conjunction with Elaprase  
• Change from baseline in CSF biomarkers (eg, GAG [HS/DS])  
• Change from baseline in urinary GAG 
 
4.3 
Exploratory Endpoints  
The exploratory endpoints for this study are: 
• Change from Baseline in additional clinical parameters (eg, physiological assessments, 
standardized neurocognitive assessments, neurologic function, brain MRI) 
• Change from Baseline in functional activities of daily living parameters  
• Levels of idursulfase in CSF immediately prior to idursulfase-IT administration 
 
4.4 
SOPH-A-PORT Mini S Device Assessments 
The SOPH-A-PORT Mini S device will be evaluated using assessments of device implantation, 
device function, device longevity and adverse events associated with the implant surgery or 
device. This data will be collected on the patient’s CRF from the time of initial implantation. 
As part of the assessment of the SOPH-A-PORT Mini S, it may be necessary to determine the 
levels of leachables from the device into the CSF and blood. Samples of stored CSF and serum 
may be used to determine the levels of leachable materials related to the IDDD. 
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5 
OVERALL STUDY DESIGN AND PLAN 
5.1 
Study Design 
This is an open-label extension of Study HGT-HIT-045. This study is designed to evaluate the 
long-term safety and clinical outcomes of monthly (ie, every 28 [±7] days) IT injection of 
idursulfase-IT (HGT-2310) in conjunction with weekly IV infusion of Elaprase in patients with 
Hunter syndrome and cognitive impairment. 
Shire is evaluating administration of idursulfase-IT directly to the CNS using an IDDD in order 
to traverse the blood-brain barrier. The advantage of using an IDDD is the potential to obviate 
the need for multiple lumbar punctures for drug delivery. Idursulfase-IT will be administered 
through this port or, if the IDDD is nonfunctional, via lumbar puncture. 
Elaprase will be prescribed by the patient’s physician and will be administered in accordance 
with local prescribing information. 
Patients who participated in Study HGT-HIT-045 and completed the HGT-HIT-045 end-of-study 
(EOS) evaluations, and meet all criteria for inclusion in this extension study will be eligible for 
enrollment. Patients in Study HGT-HIT-046 who exceed the age of enrollment eligibility for 
Study HGT-HIT-045 during this study will be allowed to continue participation in Study 
HGT-HIT-046 until the end of the study. Patients will be re-consented once they have reached 
the applicable legal age of consent to participate in a clinical study. If the patient has been 
deemed by the investigator, in accordance with applicable law, as lacking mental capacity to 
provide informed consent, the patient’s parent(s) or legally authorized representative(s) will be 
asked to provide informed consent on behalf of the patient. Patients will be screened for entry 
into the study based on their known medical histories and participation in Study HGT-HIT-045. 
Once eligibility is determined, the investigator will fully inform, as appropriate, the patient 
and/or the patient’s parent(s) or legally authorized representative(s) of the nature and scope of 
the study, potential risks and benefits of participation, and the study procedures involved, and 
will answer all questions prior to the signing of the informed consent form. The date of study 
enrollment is defined as the date the patient’s parent(s) or the patient’s legally authorized 
representative(s) signs the informed consent form. The informed consent (and patient assent as 
relevant) must be obtained prior to performing any extension study-related procedures. 
There are 2 patient groups in Study HGT-HIT-046 (refer to Figure 5-1): those (Group 1) that 
were previously treated in the antecedent study (HGT-HIT-045) and continue to receive 
treatment in Part B (defined as Months 7 to 54) of this extension study, and those (Group 2) that 
were not previously treated in the antecedent study and receive treatment in Parts A (defined as 
Months 0-6) and B (defined as Months 7-54) of this extension study. Once patients in Study 
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HGT-HIT-046 have completed Part B, they may continue to receive treatment with 
idursulfase-IT in Part C (defined as Months 55-168) while undergoing a reduced, and less 
burdensome, schedule of study assessments. 
Initial Treatment Phase (previously untreated patients only, Part A): Patients who did not receive 
treatment with intrathecal idursulfase-IT in Study HGT-HIT-045 will, during the Initial 
Treatment Phase of this study (ie, the first 6 months), undergo treatment and assessments 
corresponding in schedule and content to those performed for patients who were treated in Study 
HGT-HIT-045. After completion of the Initial Treatment Phase and if there are no safety 
concerns, patients may continue receiving monthly (ie, every 28 [±7] days) intrathecal 
idursulfase-IT in the Extended Treatment Phase of this study. The dose of idursulfase-IT to be 
administered to a patient in the initial treatment phase was planned to correspond to the dose 
(1, 10, or 30 mg) received by other patients in the same cohort of Study HGT-HIT-045 within 
which the patient was randomized. 
Extended Treatment Phase (all patients, Parts B and C): Patients who received 6 months of 
treatment with intrathecal idursulfase-IT in HGT-HIT-045 will be eligible for enrollment after 
completing the EOS evaluations in Study HGT-HIT-045. If there are no safety concerns, 
previously treated patients may continue receiving monthly (ie, every 28 [±7] days) intrathecal 
idursulfase-IT in this extension study. The dose of idursulfase-IT to be administered to a patient 
in the extended treatment phase was planned to correspond to the dose (1, 10, or 30 mg) received 
by the patient in Study HGT-HIT-045. 
In the original study design, it was planned that idursulfase-IT would be administered 
intrathecally once monthly (ie, every 28 [±7] days) via an IDDD at doses of 1, 10, or 30 mg. 
Because the 1 mg dose was assessed as suboptimal, all patients in the study are currently 
receiving doses of either 10 or 30 mg (see Section 5.2). 
It is intended that the IDDD be used to deliver IT injections of study drug and to obtain CSF 
samples. No other medication will be administered through the device. Should the IDDD become 
nonfunctional during the study, causing the IT space to be inaccessible via the device, or its use 
is otherwise precluded on a scheduled day of dosing; lumbar puncture may be performed under 
prescribed circumstances (see Section 7.8) for the purposes of study drug administration and 
CSF sample collection. Site personnel will refer to the IDDD manual, which provides details on 
the investigation and management of any IDDD-related issues. 
General anesthesia may be required for injections of study drug and some evaluations, and can 
be used at the discretion of the investigator as indicated in the study manuals. It is anticipated 
that study procedures such as lumbar puncture, MRI, and audiometry will have to be performed 
with sedation/anesthesiology support. 
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Due to recurrent issues with the PORT-A-CATH IDDD, Shire has qualified a new IDDD for use 
in this study, the SOPH-A-PORT Mini S. It is intended that use of the PORT-A-CATH will be 
phased out in favor of use of the SOPH-A-PORT Mini S device. An implanted PORT-A-CATH 
IDDD will be allowed to remain in situ for as long as it is functional, but when a 
PORT-A-CATH IDDD becomes nonfunctional and needs to be replaced, it will be replaced by a 
SOPH-A-PORT Mini S IDDD. 
If patients in the study require revision and/or replacement of the PORT-A-CATH IDDD, it will 
be removed and replaced with the SOPH-A-PORT Mini S device at a time judged appropriate by 
the investigator. A nonfunctional PORT-A-CATH IDDD cannot be replaced by a new 
PORT-A-CATH device. 
Surgical IDDD implantation and revision will be performed at the main study center only. 
Explantation of the IDDD will be performed at the main study center or at the patient’s local site, 
as necessary. 
Patients should have the IDDD removed when they discontinue participation in the study, unless 
they are continuing to receive treatment through another mechanism (eg, supplemental study, 
expanded access program, etc) or 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 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. 
Patients who do not have the IDDD removed (partial or full device) when they discontinue from 
the study or the study ends will not be followed for safety monitoring. However, the sponsor will 
arrange reimbursement when the device is eventually removed. 
5.2 
Rationale for Study Design, Device Use, and Comparator Group 
The PD profiles associated with monthly idursulfase-IT administration in Study HGT-HIT-045 
indicated that the 1 mg dose was suboptimal, with the 10 mg dose achieving maximal PD 
response and the 30 mg dose demonstrating no appreciable added PD effect. The 3 doses 
evaluated in Study HGT-HIT-045 demonstrated equivalent safety profiles, and evaluation of 
effects on neurodevelopmental health showed evidence of stabilization or improvement of 
cognitive function at the 10 mg or 30 mg doses. Therefore, all patients in HGT-HIT-046 are 
currently receiving doses of either 10 or 30 mg idursulfase-IT. The patients assigned previously 
to the 1 mg dose have been switched to 10 mg dose; whereas, patients assigned previously to the 
10 mg and 30 mg doses have continued to receive those assigned doses. 
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5.2.1 
Initial Treatment Phase (Part A) 
After completion of EOS assessments in Study HGT-HIT-045 and enrollment in Study 
HGT-HIT-046, patients will undergo surgical insertion of the IDDD at the main study site. 
Approximately 2 weeks after surgery, Week 3 assessments will be conducted and the patient will 
begin receiving monthly (ie, every 28 [±7] days) administration of intrathecal idursulfase-IT at 
the main study site. Patients who receive and tolerate 6 monthly doses of intrathecal 
idursulfase-IT and complete the Month 7 (Week 27) evaluations will then follow the assessment 
schedule for the Extended Treatment Phase of this study (see Section 5.2.2). 
During their first 6 months in this study, patients who were previously untreated in Study 
HGT-HIT-045 will undergo study procedures corresponding in schedule and content to those 
performed for treated patients in Study HGT-HIT-045. These will include: 
• Surgical implantation of the IDDD: Surgical Week 1, Days 1-7. Includes pre-surgical 
assessments (Day 1 Pre-Surgery), surgical implantation of the IDDD (Day 2), and 
follow-up assessments at Days 3-6 and Day 7. 
• Post-operative recovery: Week 2 (Days 8-14). Approximately 14 days are expected for 
full recovery from surgery after implantation of the IDDD. 
• Initial Treatment Phase Week 3: Assessments for safety, biochemical, and neurological 
baseline measures will occur on Pre-Treatment Day 1 before the first IT injection of 
idursulfase-IT. CSF sample assessment will be obtained from these patients on Day 2 
immediately prior to the first IT injection. Note: “Week 3” will occur during the week of 
the first idursulfase-IT dose, irrespective of whether the period between IDDD 
implantation and the first dose of idursulfase-IT is 14 days or more than 14 days. 
• Initial Treatment Phase Week 3 through Week 23: Pre-treatment assessments will occur 
on Day 1, IT injection of idursulfase-IT on Day 2, and follow-up assessments on Days 3-
7 of each IT Dosing Week (Weeks 3, 7, 11, 15, 19, and 23). Assessments for safety, 
biochemical, and neurological measures will be completed before IT administration on 
Pre-Treatment Day 1 of each dosing week. A CSF sample will be obtained from these 
patients immediately prior to administration of idursulfase-IT on IT Injection Day 2 of 
each dosing week. Note: All study weeks are measured from the first dose of idursulfase-
IT, which is considered “Week 3” regardless of whether the period between IDDD 
implantation and the first dose of idursulfase-IT is 14 days or more than 14 days. 
• Safety Assessments and Evaluations: Month 7 (Week 27), 30 (±7) days after the last IT 
administration of idursulfase-IT. 
 
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During the Initial Treatment Phase only, patients who did not previously receive idursulfase-IT 
injections as part of Study HGT-HIT-045 will undergo a mid-cycle neurological examination 
during the time interval following each IT Dosing Week (ie, at Weeks 5, 9, 13, 17, 21, and 25). 
This mid-cycle neurological examination may be performed by the local site physician, by a 
physician at the patient’s home, or by an investigator at the main study site. 
If there are no safety concerns after administration of the Week 23 intrathecal idursulfase-IT 
dose, patients may continue to receive monthly administration of intrathecal idursulfase-IT in the 
Extended Treatment Phase of this study (see Section 5.2.2 below). 
5.2.2 
Extended Treatment Phase (Parts B and C) 
Patients who received 6 months of intrathecal idursulfase-IT in Study HGT-HIT-045 will be 
eligible for enrollment after completing the EOS evaluations in HGT-HIT-045. If there are no 
safety concerns identified by the investigator, previously treated patients may continue receiving 
monthly (ie, every 28 [±7] days) IT injections of idursulfase-IT in this extension study. 
Patients will receive their monthly (ie, every 28 [±7] days) IT doses of intrathecal idursulfase-IT 
at the main study site or at a local site, depending on the visit. Patients treated previously at the 
idursulfase-IT 10 mg and 30 mg dose levels will continue receiving treatment at the same dose of 
study drug as in Study HGT-HIT-045, or in the Initial Treatment Phase (see Section 5.2.1) of this 
study. Based on the results of Study HGT-HIT-045, it was determined that patients assigned to 
the suboptimal idursulfase-IT 1 mg dose level should be switched to the 10 mg dose. 
For their first 3 months on study (ie, Months 7-9), patients will undergo pretreatment and safety 
assessments on Day 1 and will receive an IT injection of idursulfase-IT on Day 2 of each IT 
Dosing Week. Standardized neurodevelopmental assessments will be performed every 6 months 
during Part B of the Extended Treatment Phase and annually during Part C of the Extended 
Treatment Phase. MRI of the spine and brain and any other procedures deemed necessary, such 
as ABR, that require anesthesia will be performed annually. 
When a patient has received and tolerated a total of 9 monthly doses of intrathecal idursulfase-IT 
across Studies HGT-HIT-045 and HGT-HIT-046, the sponsor and principal investigator will 
consider the feasibility of transitioning the patient’s monthly IT dosing to local sites to reduce 
the burden imposed by monthly 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 first 3 IT injections of 
idursulfase-IT (Months 7-9) in this extension study will be administered at the main study site. 
Patients will be discharged a minimum of 24 hours after IT dosing and when deemed clinically 
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stable by the investigator. Thereafter, IT injections of idursulfase-IT may be performed at either 
the main study site or at a local site and, through Month 54, patients may be discharged a 
minimum of 4 hours after dosing and when deemed clinically stable by the investigator (ie, a 
24-hour inpatient stay is no longer required). Exceptions include the IT injections of 
idursulfase-IT at Months 19, 31, and 43 when PK assessments are scheduled; these will take 
place at the main site. Due to PK sample collection at these visits, discharge at Months 19, 31, 
and 43 will be upon discretion of the investigator. Additionally, from Month 55 onward, patients 
may be discharged a minimum of 1 hour after IT dosing and if deemed clinically stable in the 
investigator’s judgment. 
All patients will receive their weekly IV infusions of Elaprase throughout the study. Elaprase 
infusions may be administered at the main study site, at a local site, or at the patient’s home 
depending on the standard treatment location for each patient. Patients must provide a separate 
written informed consent/assent to participate in study procedures to be conducted at the local 
site prior to the conduct of these procedures. 
Patients may undergo a streamlined schedule of assessments (Part C) after completing at least 
54 months of treatment in Study HGT-HIT-045 and/or HGT-HIT-046. As noted, there are 
2 patient groups in Study HGT-HIT-046: those that were previously treated in the antecedent 
study (HGT-HIT-045) and continue to receive treatment in Part B (Months 7-54) of this 
extension study, and those that were not previously treated in the antecedent study and receive 
treatment in Parts A (Months 0-6) and B (Months 7-54) of this extension study. Once patients in 
Study HGT-HIT-046 have completed Part B, they may continue to receive treatment with 
idursulfase-IT in Part C (Months 55-168) while undergoing a reduced, and less burdensome, 
schedule of study assessments. 
All patients will undergo EOS procedures at 30 (±7) days after the last IT injection of 
idursulfase-IT. 
The EOS procedures will include standard clinical laboratory tests (serum chemistry, 
hematology, and urinalysis), MRI of the lumbar spine and brain, 12-lead ECG, vision and 
hearing assessments, ABR evaluation, CSF sample collection, intracranial pressure (ICP) 
measurement, protocol-specific laboratory testing, and standardized developmental and cognitive 
tests. 
See Section 14 for the Schedules of Study Procedures for the Initial Treatment Phase (Part A: 
Table 14-1) and Extended Treatment Phase (Part B: Table 14-2) and (Part C: Table 14-3) of this 
study. 
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6 
SELECTION OF STUDY POPULATION 
Patients who participated in Study HGT-HIT-045 and completed the HGT-HIT-045 EOS 
evaluations, and meet all criteria for inclusion in this extension study will be eligible for 
enrollment. Up to 15 patients are expected. 
6.1 
Inclusion Criteria 
Patients must meet all of the following criteria to be considered eligible for enrollment: 
1. Patients must have completed all study requirements and EOS assessments for Study 
HGT-HIT-045 prior to enrolling in Study HGT-HIT-046 and must have no safety or medical 
issues that contraindicate participation. 
2. The patient’s parent(s) or legally authorized representative(s) must have voluntarily signed 
an IRB/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 
representative(s) and the patient’s assent, as relevant, must be obtained. 
3. The patient has received and tolerated a minimum of 12 months of treatment with weekly 
IV infusions of Elaprase and has received 80% of the total planned infusions within the last 
6 months. 
 
6.2 
Exclusion Criteria 
Patients who meet any of the following criteria are not eligible for participation in this study: 
1. The patient is enrolled in another clinical study that involves clinical investigations or use of 
any investigational product (drug or device) other than the PORT-A-CATH IDDD within 
30 days prior to study enrollment or at any time during the study. 
2. 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. 
3. The patient has experienced an adverse reaction to study drug in Study HGT-HIT-045 that 
contraindicates further treatment with intrathecal idursulfase-IT. 
4. The patient has a known hypersensitivity to any of the components of idursulfase-IT. 
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 
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f. The patient has one 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 
 
An additional exclusion criterion for patients who were previously untreated with intrathecal 
idursulfase-IT in Study HGT-HIT-045: 
1. The patient has an opening CSF pressure upon lumbar puncture that exceeds 30.0 cm H2O. 
 
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7 
STUDY TREATMENTS 
7.1 
Treatment Schedule 
7.1.1 
Initial Treatment Phase (Part A) 
Following successful surgical implantation of the IDDD at the main study site and a recovery 
period of at least 14 days (ie, for previously untreated patients or patients whose device was 
removed prior to their completion of Study HGT-HIT-045), patients will check in to the main 
study site approximately 24 hours prior to the first intrathecal idursulfase-IT dose (IT Dosing 
Week 3, Day 1) and subsequent (IT Dosing Weeks 7, 11, 15, 19, and 23) for safety and 
pretreatment assessments and will be required to be inpatient until approximately 24 hours after 
their IV Elaprase infusion (approximately 2 days after IT injection with idursulfase-IT). 
Each patient will be required to check in at the main site for neurological and physical 
assessments on Days 3 and 7 of the first and each subsequent IT Dosing Week, then return home 
for regular Elaprase infusions, as well as clinical and safety assessments, from his local treating 
physician during the 3 weeks following the idursulfase-IT dose. 
Patients will be evaluated for safety throughout the study both at a main clinical study site and by 
their local treating physician. Patients who have tolerated treatment with intrathecal 
idursulfase-IT through Week 23 may continue to receive monthly IT injection of idursulfase-IT 
and participate in assessments as described for the Extended Treatment Phase of this study. 
7.1.2 
Extended Treatment Phase (Parts B and C) 
Patients will check in to the main study site on Day 1 approximately 24 hours prior to intrathecal 
idursulfase-IT dosing for safety and pretreatment assessments and will subsequently receive an 
IT injection of idursulfase-IT on Day 2 of each IT Dosing Week. The first 3 IT injections of 
idursulfase-IT (Months 7-9) will be administered at the main study site. Patients will be 
discharged a minimum of 24 hours after dosing and when deemed clinically stable by the 
investigator. From Month 10 onward, Day 1 assessments may be performed on the same day as 
IT administration of idursulfase-IT, if the patient can arrive at the study site early in the day and 
if the investigator deems this clinically appropriate. 
Thereafter, with the exceptions noted in Section 5.2.2, IT injections of idursulfase-IT may be 
performed at either the main study site or at a local site. Through Month 54, patients may be 
discharged a minimum of 4 hours after dosing at the discretion of the investigator. From Month 
55 onward, patients may be discharged a minimum of 1 hour after IT dosing and when deemed 
clinically stable in the investigator’s judgment. 
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7.2 
Description of Study Drug 
The idursulfase-IT drug product is an isotonic sterile solution for intrathecal administration, 
formulated as a 10 mg/mL protein concentration in 154 mM NaCl, pH 6.0, 0.005% 
polysorbate 20. 
Note that the IT formulation differs from that of the IV idursulfase formulation, Elaprase. 
Compared to Elaprase, the protein concentration of idursulfase-IT has been increased based on 
the planned maximum dose and limited IT administration volume required for use in clinical 
studies. The IT formulation is suitable for direct introduction into the intrathecal space, as it is 
isotonic and contains excipients suitable for intrathecal administration. 
The idursulfase-IT drug product is stored at 5 (±3)°C borosilicate glass vials. Each vial recovers 
1 mL of idursulfase-IT. 
Idursulfase-IT for IT injection will be provided by the sponsor. 
Please refer to the Pharmacy Manual for further details concerning the idursulfase-IT drug 
product, dose preparation, and administration. 
Commercially available Elaprase for IV infusion will be prescribed by the patient’s treating 
physician and will be administered throughout the study in accordance with the local prescribing 
information. 
7.3 
Selection and Timing of Dose  
This is an open-label, non-randomized study; all patients enrolled in this study will be treated 
with intrathecal idursulfase-IT in conjunction with Elaprase therapy. The treatment schedule for 
the first 6 months of this study will vary for enrolled patients dependent upon their treatment 
assignment in HGT-HIT-045. Patients who participated in the untreated control arm in Study 
HGT-HIT-045 will receive an IDDD following receipt of informed consent by the patient’s 
parent(s)/legally authorized representative(s). 
All patients enrolled in HGT-HIT-046 are currently receiving monthly (ie, every 28 [±7] days) 
IT doses of either 10 or 30 mg idursulfase-IT (See Section 5.2). The patients assigned previously 
to the 1 mg dose have been switched to 10 mg dose; whereas, patients assigned previously to the 
10 mg and 30 mg doses have continued to receive those assigned doses. 
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7.4 
Intrathecal Administration  
7.4.1 
IDDD Implantation 
Implantation includes surgical implantation of the IDDD and a post-surgical assessment. 
Intrathecal drug delivery device placement will require anesthesia. An X-ray will be taken to 
confirm/document the position of the catheter tip in the spinal canal. 
• IDDD implantation 
• X-ray to verify IDDD is at the mid-thoracic level in the spinal canal and correctly 
installed 
• Obtain vital signs 
• Concomitant medications/ therapies/procedures monitoring 
• Record AEs 
 
The PORT-A-CATH system is intended for long-term, continuous access to the intraspinal space 
for the delivery of drugs approved for intraspinal delivery. Due to recurrent issues with the 
PORT-A-CATH IDDD, Shire has qualified a new IDDD for use in this study, the 
SOPH-A-PORT Mini S. 
The SOPH-A-PORT Mini S IDDD is a system intended for implantation by physicians. The 
SOPH-A-PORT Mini S, once implanted, allows healthcare personnel to administer 
idursulfase-IT indicated for intrathecal delivery intermittently over a long period of time. 
It is intended that the study drug will be administered through the IDDD. However, if the IDDD 
appears to be nonfunctional, or if its use is precluded on a scheduled day of dosing, consecutive 
monthly lumbar punctures may be considered as an alternative way of delivering the study drug 
and obtaining CSF samples (See Section 7.8). 
7.5 
Treatment Compliance 
The initial implantation and revision and/or explantation of the SOPH-A-PORT Mini S will be 
performed by pediatric or general neurosurgeons or anesthesiologists at the main study site who 
have experience in port and catheter implant procedures and intrathecal-access procedures and 
have completed training with the SOPH-A-PORT Mini S. Please refer to the Instructions for Use 
for further details and for information regarding patient activity restrictions for patients to be 
implanted with this device. 
Study 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 
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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. 
Please refer to the SOPH-A-PORT Mini S Instructions for Use 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. 
7.6 
Intrathecal Injection  
The patient must not receive aspirin, non-steroidal anti-inflammatory medications, or 
medications that affect clotting within 1 week prior to each intrathecal idursulfase-IT injection. 
Idursulfase-IT will be administered using the IDDD. After appropriate pretreatment assessments 
are completed, patients may receive mild sedation to alleviate anxiety and/or facilitate drug 
delivery. Anesthesia will be used at the discretion of the investigator. The appropriate dose of 
idursulfase-IT and the flush with preservative-free sterile saline will be administered via slow 
push/injection over 2 to 5 minutes. 
If use of the IDDD is precluded, the injection of idursulfase-IT may be administered via lumbar 
puncture (see Section 7.8). 
7.6.1 
SOPH-A-PORT Mini S Intrathecal Drug Delivery Device 
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 drugs 
indicated for intrathecal delivery intermittently over a long period of time. The device is CE 
Marked in the European Union (EU) and is considered investigational in non-EU countries. 
The SOPH-A-PORT Mini S comprises 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 
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A visual examination of both the port and catheter track will be performed before each IT 
injection administered via the SOPH-A-PORT Mini S device. A 22-gauge Huber noncoring 
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, either a stopcock of 
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 (22G) supplied by 
Sophysa in a SOPH-A-PORT Mini S. 
Further details are provided in the Instructions for Use, appended to the current version of the 
investigator’s brochure. 
7.6.2 
PORT-A-CATH Intrathecal Drug Delivery Device 
Details concerning the PORT-A-CATH IDDD system are provided in the Instructions for Use, 
appended to the current version of the investigator’s brochure. 
7.7 
Cerebrospinal Fluid Collection 
Cerebrospinal fluid samples will be obtained via the IDDD at every time point that the IDDD is 
accessed. If it is impossible to obtain a CSF sample using the IDDD, then lumbar puncture may 
be performed (see Section 7.8). If a lumbar puncture is to be performed, it is anticipated that the 
patient will be anesthetized with appropriate airway management/intubation. Once the patient is 
anesthetized, a lumbar puncture will be performed and a CSF sample will be obtained. A 
measurement of opening pressure may also be performed at that time. 
7.8 
Guidance Concerning Performance of Lumbar Puncture for Study Drug 
Administration and CSF Sample Collection 
It is intended that the IDDD will be used to deliver all IT injections of study drug and to obtain 
CSF samples. If the IDDD appears to be nonfunctional, 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 may include possible partial 
revision or complete replacement of the IDDD as indicated. If the nonfunctional IDDD is a 
PORT-A-CATH device, then it will be replaced by a SOPH-A-PORT Mini S device. 
If there are medical contra-indications to the re-implantation of a new device, repeat monthly 
lumbar punctures may be considered as an alternative way of delivering the study drug and 
obtaining CSF samples under limited circumstances. As long as no safety risks are identified by 
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the investigator, consecutive lumbar punctures may be performed across Studies HGT-HIT 045 
and HGT-HIT-046. 
Continued treatment via repeat lumbar puncture should only be considered in individual cases of 
patients where this treatment is very well tolerated and the investigator has not identified any 
safety concerns associated with repeat lumbar puncture and repeat sedation/anesthesia. 
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8 
STUDY PROCEDURES 
8.1 
Study Evaluations and Procedures 
In the event of a public health emergency, such as COVID-19, study activities may be disrupted 
due to hospital, local, state or national government restrictions, or other site related factors. In 
these circumstances, sites will make every effort to see patients in-person for clinical 
assessments; sites should use their judgment in conducting the study visits to collect as much 
data as possible while ensuring the protocol is being followed. Sites should reach out to their 
local IECs if they have questions. 
If a patient misses an in-person study visit, study site personnel may speak directly with the 
parent(s) or legally authorized representative(s) by telephone or other medium (eg, a 
computer-based video communication). Assessments that cannot be completed will be 
considered missing data and such departures will be recorded as protocol deviations in the study 
records, using already established procedures. Any protocol deviations surrounding COVID-19 
or any other public health emergencies will be clearly identified, described, and documented in a 
systematic way, and in line with regulatory authorities’ recommendations. These protocol 
deviations will be summarized separately in the clinical study report. These data may also be 
handled differently in the final data analysis; all details will be documented in the Statistical 
Analysis Plan (SAP). 
8.2 
Initial and Extended Treatment Phases (All Patients) 
Detailed descriptions of patient evaluations required for this protocol are described in this 
section. These evaluations will be performed during the indicated days and weeks of each study 
month (See Section 14). 
Prior to conducting any study-related procedures, written informed consent for participation in 
Study HGT-HIT-046 must be obtained from the patient’s parent(s) or legally authorized 
representative(s). The patient’s parent(s) or legal representative(s) must provide a separate 
written informed consent to participate in the study procedures to be conducted at the local site, 
prior to the conduct of these procedures. 
During the Initial Treatment Phase (ie, the first 6 months) of this study, patients who were not 
previously treated in Study HGT-HIT-045 will undergo assessments corresponding in schedule 
and content to the study procedures performed for patients who were treated with intrathecal 
idursulfase-IT in Study HGT-HIT-045. At completion of these procedures and if there are no 
safety concerns, patients may continue into the Extended Treatment Phase of this study. 
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During the Extended Treatment Phase (ie, from Month 7 onward), patients who were previously 
treated with study drug in Study HGT-HIT-045 may, if no safety concerns exist, continue 
receiving monthly (ie, every 28 [±7] days) IT injections of intrathecal idursulfase-IT in this 
extension study. 
All data collected throughout the study are to be recorded on the appropriate CRF. Details 
concerning study procedures, including sample collection, are described in the Study Operations 
Manual. 
All nonprotocol treatments from informed consent through the EOS visit are regarded as 
concomitant and will be documented on the CRF. These include medications (including 
Elaprase), therapies/interventions administered to patients, and medical/surgical procedures 
performed on the patients. 
Adverse events will be monitored continuously throughout the study for all patients from the 
time informed consent is provided through the EOS visit. Instructions for recording and reporting 
AEs are provided in Section 9. 
Patients may undergo a streamlined schedule of assessments (Part C, refer to Section 8.5) after 
completing at least 54 months of treatment in Study HGT-HIT-045 and/or HGT-HIT-046. 
8.3 
Initial Treatment Phase (Only for Patients Who Were Not Previously Treated with 
Intrathecal idursulfase-IT in Study HGT-HIT-045) (Part A) 
8.3.1 
Screening/Baseline Visit (Study HGT-HIT-045 EOS Visit) 
Screening/Baseline assessments for the Initial Treatment Phase of the study were to have been 
performed during the EOS procedures in HGT-HIT-045. If fewer than 30 days have elapsed 
since completion of the EOS assessments for HGT-HIT-045, Screening/Baseline assessments are 
not required to be repeated. 
However, if more than 30 days have elapsed since completion of HGT-HIT-045 EOS 
procedures, the following assessments are to be repeated within 30 days prior to scheduled 
surgical implantation of the IDDD in the Initial Treatment Phase of the Study: 
• Physical examination 
• Height and weight 
• Head circumference 
• 12-lead ECG 
• Vital signs 
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• Hematology 
• Serum chemistry 
• Standard Urinalysis 
• Urine GAG  
• Anti-idursulfase antibody testing 
• Sample collection for potential plasma proteomic marker testing 
• ICP measurement 
• CSF sample collection 
• Neurological examination 
 
If more than 3 months have elapsed since the completion of HGT-HIT-045 EOS procedures, the 
following assessments are to be repeated within 30 days prior to surgical implantation of the 
IDDD in the Initial Treatment Phase of the Study: 
• Vision assessment 
• Hearing assessment 
• General Anesthesia 
• ABR 
• Brain and spine MRI 
• Full neurodevelopmental assessment 
 
8.3.2 
Physical Examinations 
During the Initial Treatment Phase, physical examinations will be performed at 
Screening/Baseline (if >30 days have elapsed since HGT-HIT-045 EOS procedures), Day 1 and 
Day 7 of Surgery Week 1, at Days 1, 3, and 7 of each IT Dosing Week, and at the Month 7 
(Week 27) visit. Note: the Pre-Surgery Day 1 examination may not be necessary if performed 
within 7 days of the Screening/Baseline examination. 
Physical examinations will include a review of the patient’s general appearance as well as the 
evaluations listed in Table 8-1. 
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Table 8-1 
Physical Examination 
Head and neck 
Genitourinary 
Eyes, ears, nose, and throat 
Skin 
Chest and lungs 
Musculoskeletal 
Cardiovascular 
Neurological 
Abdomen 
Endocrine 
 
Lymphatic 
 
8.3.3 
Height and Weight 
During the Initial Treatment Phase, height and weight will be recorded at Screening/Baseline (if 
>30 days have elapsed since HGT-HIT-045 EOS procedures), Pre-Surgery Day 1 and Day 7 of 
Surgery Week 1, at Day 1 of each IT Dosing Week, and at the Month 7 (Week 27) visit. 
Note: the Pre-Surgery Day 1 measurement may not be necessary if performed within 7 days of 
the Screening/Baseline measurement. 
8.3.4 
Head Circumference 
During the Initial Treatment Phase, head circumference will be measured in a uniform manner at 
Screening/Baseline (if >30 days have elapsed since HGT-HIT-045 EOS procedures), on 
Pre-Treatment Day 1 of IT Dosing Week 3, and at the Month 7 (Week 27) visit. 
8.3.5 
Vision Assessment  
It is intended that all patients have a vision assessment during the Initial Treatment Phase at 
Screening/Baseline (if >3 months have elapsed since HGT-HIT-045 EOS procedures) and at the 
Month 7 (Week 27) visit. However, it is recognized that the ability to conduct this assessment 
will depend on the patient’s ability to cooperate, and that it might not be possible to complete a 
vision assessment for every patient. A reasonable effort should be made to perform a vision 
assessment for each patient; however, inability to collect these data may not be considered a 
protocol deviation. 
8.3.6 
Hearing Assessment 
It is intended that all patients have a hearing assessment during the Initial Treatment Phase at 
Screening/Baseline (if >3 months have elapsed since HGT-HIT-045 EOS procedures), 
Pre-Treatment Day 1 of IT Dosing Week 3, Pre-Treatment Day 1 of IT Dosing Week 15 (before 
the fourth IT injection), at the Month 7 (Week 27) visit. 
Hearing assessments will be performed using age-appropriate testing methods based on the 
patient’s age at the time of testing. Instructions for age-appropriate hearing testing are described 
in the Study Operations Manual. However, it is recognized that the ability to conduct this 
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assessment will depend on the patient’s ability to cooperate, and that it might not be possible to 
complete a hearing assessment for every patient. A reasonable effort should be made to perform 
a hearing assessment for each patient; however, inability to collect these data may not be 
considered a protocol deviation. 
8.3.7 
12-Lead Electrocardiogram 
During the Initial Treatment Phase, a 12-lead ECG will be performed at Screening/Baseline (if 
>30 days have elapsed since HGT-HIT-045 EOS procedures), Pre-Surgery Day 1 of Week 1, 
Pre-Treatment Day 1 of IT Dosing Week 3 only, Day 2 of each IT Dosing Week after injection 
of the study drug, and at the Month 7 (Week 27) visit. Note: the Pre-Surgery Day 1 assessment 
may not be necessary if performed within 7 days of the Screening/Baseline assessment. 
Each 12-lead ECG will include assessment of heart rate, sinus rhythm, atrial or ventricular 
hypertrophy, and assessment of PR, QRS, QT, and QTc intervals. The ECGs will be conducted 
in accordance with the clinical site’s standard practice(s) and will be read by a qualified 
cardiologist at the main clinical site. Identification of any clinically significant findings and/or 
conduction abnormalities will be recorded on the CRF. 
8.3.8 
Vital Signs 
In general, vital signs will be recorded during the Initial Treatment Phase at all main study site 
visits including the Screening/Baseline (if >30 days have elapsed since HGT-HIT-045 EOS 
procedures) and the Month 7 (Week 27) visit. In particular, vital signs will be collected for 
patients who will receive study drug during Surgery Week 1 at Day 1, Day 2, Days 3-6 
(ie, during IV infusion of Elaprase), Day 7, and during each IT Dosing Week at Pre-Treatment 
Day 1, IT Injection Day 2, and Days 3-7 (ie, during IV infusion of Elaprase). 
At a minimum, vital signs will be collected at the following time points on IT administration of 
idursulfase-IT and IV infusion of Elaprase: 
IT administration of idursulfase-IT: within 15 minutes prior to IT administration, 30 minutes 
(±10 minutes) post end of IT administration, 60 minutes (±10 minutes) post end of IT 
administration, 120 minutes (±10 minutes) post end of IT administration, 4 hours (±10 minutes) 
post end of IT administration, 6 hours (±10 minutes) post end of IT administration, 8 hours 
(±10 minutes) post end of IT administration, and 12 hours (±10 minutes) post end of IT 
administration.  
IV infusion of Elaprase: within 15 minutes prior to infusion, 30 minutes (±10 minutes) post start 
of infusion, 60 minutes (±10 minutes) post start of infusion, 90 minutes (±10 minutes) post start 
of infusion, 120 minutes (±10 minutes) post start of infusion, 150 minutes (±10 minutes) post 
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start of infusion, 180 minutes (±10 minutes) post start of infusion (ie, end of infusion), 
30 minutes (±10 minutes) post end of infusion and 60 minutes (±10 minutes) post end of 
infusion. 
Vital signs will include pulse, blood pressure, respiration rate, temperature, and pulse oxygen 
measurement. 
8.3.9 
Clinical Laboratory Testing 
Blood and urine samples will be collected as described in Section 8.3.9.1, Section 8.3.9.2, and 
Section 8.3.9.3 for clinical laboratory testing. A central laboratory will be responsible for 
analyzing samples and reporting clinical laboratory values, except where noted below. Sample 
collection, processing, and shipping instructions are provided in the Study Operations Manual. 
8.3.9.1 
Hematology 
Blood samples will be collected during the Initial Treatment Phase for hematology testing at 
Screening/Baseline (if >30 days have elapsed since HGT-HIT-045 EOS procedures), 
Pre-Surgery Day 1 of Week 1, Pre-Treatment Day 1 of each IT Dosing Week, and at the Month 7 
(Week 27) visit. Note: the Pre-Surgery Day 1 assessment may not be necessary if performed 
within 7 days of the Screening/Baseline assessment. 
The following hematology parameters will be evaluated: complete blood count (CBC) with 
differential, including basophils, and platelet count. 
8.3.9.2 
Serum Chemistry 
Blood samples will be collected during the Initial Treatment Phase for serum chemistry testing at 
Screening/Baseline (if >30 days have elapsed since HGT-HIT-045 EOS procedures), 
Pre-Surgery Day 1 of Week 1, Pre-Treatment Day 1 of each IT Dosing Week, and at the Month 7 
(Week 27) visit. 
Note: the Pre-Surgery Day 1 assessment may not be necessary if performed within 7 days of the 
Screening/Baseline assessment. 
The serum chemistry parameters to be evaluated are listed in Table 8-2. 
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Table 8-2 
Serum Chemistry 
Potassium 
Urea nitrogen 
Chloride 
Total and direct bilirubin 
Magnesium 
Alkaline phosphatase 
Phosphorous 
Alanine aminotransferase 
Uric acid 
Aspartate aminotransferase 
CO2 
Lactate dehydrogenase 
Glucose 
Gammaglutamyltransferase 
Calcium 
Creatine phosphokinase 
Total protein 
Triglycerides 
Albumin 
Cholesterol 
Creatinine 
 
Prothrombin time (PT)a  
Total thyroxine (T4) 
Partial thromboplastin time (PTT)a 
Thyroid stimulating hormone 
Sodium 
 
a 
PT and PTT will be collected at the Screening/Baseline visit only for patients previously untreated in Study 
HGT-HIT-045 who are to undergo surgical implantation of an IDDD in the Initial Treatment Phase of this 
study. An additional PT and PTT draw may be required if the Week 1 Pre-Surgery Day 1 visit is more than 2 
weeks after the Screening/Baseline visit. 
 
8.3.9.3 
Standard Urinalysis 
Urine samples will be collected during the Initial Treatment Phase for urinalysis at 
Screening/Baseline (if >30 days have elapsed since HGT-HIT-045 EOS procedures), 
Pre-Surgery Day 1 of Week 1, Pre-Treatment Day 1 of each IT Dosing Week, and at the Month 7 
(Week 27) visit. Note: the Pre-Surgery Day 1 assessment may not be necessary if performed 
within 7 days of the Screening/Baseline assessment. Pretreatment urine samples may be 
collected up to 24 hours prior to receipt of each IT dose. 
The following urinalysis parameters will be performed: pH, macroscopic evaluation, and 
microscopic evaluation. 
8.3.9.4 
Urinary GAG Levels 
Urine samples for determination of urinary GAG levels and urine creatinine will be collected 
during the Initial Treatment Phase at Screening/Baseline (if >30 days have elapsed since 
HGT-HIT-045 EOS procedures), on Pre-Treatment Day 1 of each IT Dosing Week, and at the 
Month 7 (Week 27) visit. Pretreatment urine samples may be collected up to 24 hours prior to 
administration of each IT dose. 
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Urinary GAG levels will be analyzed and reported by a Shire-designated laboratory. Urinary 
GAG levels will be normalized to urine creatinine and reported as mg GAG/mmol creatinine. 
Sample collection, processing, and shipping instructions are provided in the Study Operations 
Manual. 
8.3.10 
Auditory Brainstem Response  
Hearing assessment via audiometry measurement will be performed during the Initial Treatment 
Phase at Screening/Baseline (if >3 months have elapsed since HGT-HIT-045 EOS procedures) 
and at the Month 7 (Week 27) visit. It is anticipated that the patient will be under general 
anesthesia for this procedure. 
8.3.11 
Brain and Spinal Magnetic Resonance Imaging 
During the Initial Treatment Phase, patients will have MRI of the brain and spine at 
Screening/Baseline (if >3 months have elapsed since HGT-HIT-045 EOS procedures) and at the 
Month 7 (Week 27) visit. It is anticipated that the patient will be under general anesthesia for this 
procedure. Brain structure volumes will be measured and the brain and spine will be evaluated. 
Refer to the Study Operations Manual for specific procedures and precautions. 
8.3.12 
Surgical Implantation of the IDDD 
During the Initial Treatment Phase, the IDDD will be surgically implanted in patients on Day 2 
of Surgery Week 1. Procedures for implantation will be detailed in the device Instructions for 
Use Manual. The patient will be under general anesthesia for this procedure. 
Standard hospital procedures for surgery will be followed and will include an X-ray to confirm 
device placement. A post-operative check of the wound will be performed on Day 7 following 
surgery. X-rays may be performed to check placement of the device, as needed, throughout the 
study including prior to lumbar puncture at the Month 7 (Week 27) visit (see Section 8.3.13). 
Sutures will be removed when deemed appropriate by the investigator, and may need to be 
removed by the local treating physician during Week 2. 
If the device becomes nonfunctional or infected at any time during the study it will be removed 
and may be replaced. In the event that a patient does not receive the dose as scheduled at a study 
visit, the planned assessments should still be performed. If the patient discontinues from the 
study early, the device will be removed. 
8.3.13 
Intracranial Pressure Measurement 
During the Initial Treatment Phase, ICP measurement (cm of H2O) will be conducted at 
Screening/Baseline (if >30 days have elapsed since HGT-HIT-045 EOS procedures) and at the 
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Month 7 (Week 27) visit. Intracranial pressure measurement will be conducted concurrently with 
lumbar puncture and while the patient is under anesthesia. Patients should undergo X-ray prior to 
lumbar puncture at the Month 7 (Week 27) visit to verify the position of the IDDD catheter. 
8.3.14 
Cerebrospinal Fluid (CSF) Assessments  
Cerebrospinal fluid will be obtained during the Initial Treatment Phase at Screening/Baseline 
(if >30 days have elapsed since HGT-HIT-045 EOS procedures) by lumbar puncture and under 
general anesthesia during surgical implantation of the IDDD on Day 2 of Surgery Week 1, on 
Day 2 of each IT Dosing Week via the IDDD immediately prior to IT injection of idursulfase-IT, 
and at the Month 7 (Week 27) visit. Additional CSF samples may also be collected throughout 
the study during any assessment or revision of the IDDD. Should the IDDD become 
nonfunctional or its use is otherwise precluded on a scheduled day of dosing, the CSF sample 
may be obtained by lumbar puncture (see Section 7.8). 
Cerebrospinal fluid samples collected at scheduled or unscheduled visits will undergo the 
following assessments (Section 8.3.14.1 through to Section 8.3.14.4): 
8.3.14.1 
CSF Cell Counts 
An aliquot of the CSF sample collected will be evaluated for CSF standard chemistries, glucose, 
protein, and cell counts. 
8.3.14.2 
Immunoassay for Idursulfase-specific Antibodies 
An aliquot of the CSF sample collected will be quick frozen for subsequent analysis of 
idursulfase-specific antibodies. Note that it is not required to perform antibody testing on CSF 
samples collected at scheduled visits. 
8.3.14.3 
CSF Biomarker Analysis 
An aliquot of the CSF sample collected will be quick frozen for subsequent analysis of levels of 
biomarkers (eg, GAG [HS/DS]). 
8.3.14.4 
CSF Analysis of Idursulfase Enzyme Levels 
An aliquot of the CSF sample collected will be quick frozen for subsequent idursulfase enzyme 
analysis. 
Cerebrospinal fluid sample collection, processing, and shipping instructions are provided in the 
Study Operations Manual. 
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8.3.15 
Intrathecal Idursulfase-IT Injection 
During the Initial Treatment Phase, Idursulfase-IT will be injected intrathecally via the IDDD on 
Day 2 of Weeks 3, 7, 11, 15, 19, and 23. The patient may be mildly sedated for this procedure. 
Idursulfase-IT will be administered over 2 to 5 minutes. If the IT space is not accessible via the 
IDDD, idursulfase-IT may be administered by lumbar puncture (see Section 7.8). 
8.3.16 
Elaprase Infusion 
Elaprase will be administered during the Initial Treatment Phase as an IV infusion at a weekly 
dose of 0.5 mg/kg in accordance with local prescribing information. 
Patients will receive their weekly Elaprase infusion on every IT Dosing Week at the main study 
site approximately 2 days after receiving their IT injection of idursulfase-IT (note that the 
Elaprase infusion should be administered even in instances in which the IT dose is not). At other 
times during the study, IV infusion of Elaprase may be administered at the patient’s local 
infusion location (site or home). 
8.3.17 
Neurological Examination 
A neurological examination to monitor CNS status and any changes during the Initial Treatment 
Phase will be conducted at the main study site at Screening/Baseline (if >30 days have elapsed 
since HGT-HIT-045 EOS procedures), Pre-Surgery Day 1 of Week 1, post surgery at Day 4, on 
Days 1, 3, and 7 of each IT Dosing Week, and at the Month 7 (Week 27) visit. Note: the 
Pre-Surgery Day 1 examination may not be necessary if performed within 7 days of the 
Screening/Baseline examination. 
Neurological examinations will also be performed once during the time interval between each IT 
Dosing Week (at Weeks 5, 9, 13, 17, 21, and 25). This mid-cycle neurological examination may 
be performed by the local site physician, by a physician at the patient’s home, or by an 
investigator at the main study site. 
8.3.18 
Serum Anti-Idursulfase Antibody and Plasma Proteomic Biomarker 
Determination 
During the Initial Treatment Phase, patients will have blood samples collected at 
Screening/Baseline (if >30 days have elapsed since HGT-HIT-045 EOS procedures), on 
Pre-Treatment Day 1 of each IT Dosing Week, and at the Month 7 (Week 27) visit. A 10-mL 
blood sample will be collected from each patient for the first sample; a 5-mL sample will be 
collected for all subsequent blood collections. Blood samples collected will be evaluated for 
determination of anti-idursulfase antibodies, antibodies that have enzyme neutralizing activity, 
and potential exploratory plasma proteomic biomarkers of disease progression. Blood sample 
collection, processing, and shipping instructions are provided in the Study Operations Manual. 
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8.3.19 
Neurodevelopmental Assessments 
An extensive set of neurodevelopmental assessments are available to measure a wide range of 
cognitive, motor, and adaptive functions in children with Hunter syndrome. Patients in this study 
will undergo neurodevelopmental assessments using appropriate standardized tests to provide a 
surrogate and quantifiable measure of global CNS neurodevelopmental status. It is intended that 
full neurodevelopmental assessments of cognitive, motor, and adaptive functions be conducted 
for all patients; however, it is recognized that the feasibility of conducting these assessments is 
dependent on the patient’s ability to cooperate and/or level of cognitive impairment, and that it 
may not be possible to complete full neurodevelopmental evaluation of every patient. A 
reasonable effort should be made to perform neurodevelopmental assessments for each patient; 
however, inability to collect these data may not be considered a protocol deviation. 
8.3.19.1 
Full Neurodevelopmental Assessment 
A full neurodevelopmental assessment will be conducted during the Initial Treatment Phase at 
Screening/Baseline (if >3 months have elapsed since HGT-HIT-045 EOS procedures), 
Pre-Treatment Day 1 of IT Dosing Week 3, and at the Month 7 (Week 27) visit. 
For this study, outcome measures will be computed for each patient enrolled at each assessment. 
The instruments are summarized in Table 8-3. For cognitive testing the first item set of the 
6 main subtests of the Differential Ability Scales, Second Edition (DAS-II) will be administered. 
If the patient cannot complete these, the Bayley Scales of Infant Development, Third Edition 
(BSID-III) will be used to assess cognition. 
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Table 8-3 
Full Neurodevelopmental Assessment Tests 
Cognitive domain 
 
Patient age and representative cognitive test or scale 
Cognitivea 
Differential Ability Scales, Second Edition (DAS-II) 
(provides general conceptual ability through the 6 main subtests) 
 
OR 
 
Bayley Scales of Infant Development, Third Edition (BSID-III) 
(provides mental development index based on cognitive 
development, behavioral development, motor development) 
 
Adaptive 
Scale of Independent Behavior-Revised (SIB-R) 
 
Motor 
<6 years: Peabody Developmental Motor Scales-2 (PDMS-2) 
6 years: Bruininks-Oseretsky Test of Motor Proficiency, Second 
Edition (BOT-2) 
 
Measures of Executive Function 
<6 years: Behavior Rating Inventory of Executive Function-
Preschool version (BRIEF-P) 
6 years: Behavior Rating Inventory of Executive Function-Parent 
Form (BRIEF) 
a 
For cognitive testing the first item set of the 6 main subtests of the DAS-II will be administered. If the patient 
cannot complete these, the BSID-III will be used to assess cognition. 
 
8.3.19.2 
Brief Neurodevelopmental Assessment 
A brief neurodevelopmental assessment will be conducted during the Initial Treatment Phase on 
Pre-Treatment Day 1 of IT Dosing Week 15 (before the fourth IT injection) and will consist of 
the SIB-R and DAS-II or BSID-III tests. 
8.3.20 
Pharmacokinetic Evaluations 
During the Initial Treatment Phase, serum samples for PK evaluation of idursulfase will be 
collected at IT Dosing Weeks 3 and 23 and will be drawn at the following times: 
• Within 15 minutes prior to intrathecal idursulfase-IT injection (pre-injection baseline); 
then at 1, 2, 3, 4, 6, 8, 12, 24, 30, and 36 hours after intrathecal idursulfase-IT 
administration 
• Within 15 minutes prior to the Elaprase IV infusion (pre-infusion baseline); then at 0.5, 1, 
1.5, 2, 2.5, and 3 hours during the infusion; and at 3.5, 4, 5, 6, 7, 9, 11, and 24 hours after 
the infusion 
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The PK sampling schedule for the study is also located in Section 14 (Table 14-4). Sample 
collection, processing, and shipping instructions are provided in the Study Operations Manual. 
Note that when vital sign collection and collection of a sample for PK analysis are scheduled to 
occur at the same time, vital sign collection should occur first and the blood draw for PK 
sampling should be performed as soon as possible after vital collection. The actual time of 
collection of the PK sample should be recorded. 
8.4 
Extended Treatment Phase (All Patients, Month 7 through Month 54) (Part B) 
8.4.1 
Study HGT-HIT-045 EOS Visit 
If fewer than 30 days have elapsed since the completion of Study HGT-HIT-045 EOS 
procedures, pretreatment assessments are not required to be repeated. However, if more than 
30 days have elapsed since these procedures, the following pretreatment assessments are to be 
repeated within 30 days prior to the first scheduled intrathecal idursulfase-IT dose in the 
Extended Treatment Phase of the study: 
• Physical examination 
• Height and weight 
• Head circumference 
• 12-lead ECG 
• Vital signs 
• Hematology 
• Serum chemistry 
• Standard Urinalysis 
• Urine GAG  
• Anti-idursulfase antibody testing 
• Sample for potential plasma proteomic marker testing 
• Intracranial pressure (ICP) measurement 
• X-ray 
• Neurological examination 
 
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If more than 3 months have elapsed since the completion of HGT-HIT-045 EOS, the following 
pretreatment assessments are to be repeated within 30 days prior to the first scheduled intrathecal 
idursulfase-IT dose in the Extended Treatment Phase of the study: 
• Vision assessment 
• Hearing assessment 
• General Anesthesia 
• ABR 
• Brain and spine MRI 
• Full neurodevelopmental assessment 
 
Patients who have received 6 months of intrathecal idursulfase-IT during the Initial Treatment 
Phase of this study may, if no safety concerns exist, move immediately on to the next IT 
administration in the Extended Treatment Phase; ie, they will not need to repeat pretreatment 
assessments that may be redundant with Month 7 (Week 27) assessments. 
Note that during the Extended Treatment Phase from Month 10 onward, Day 1 assessments may 
be performed on the same day as IT administration of idursulfase-IT, if the patient can arrive at 
the study site early in the day and if the investigator deems this clinically appropriate. 
8.4.2 
Physical Examinations 
Physical examinations will be performed at a minimum on Pre-Treatment Day 1 of Month 7 
(only if >30 days have elapsed since HGT-HIT-045 EOS procedures), and the Pre-Treatment 
Day of each monthly IT Dosing Week. Physical examinations will include a review of the 
patient’s general appearance, device port and catheter track, and evaluations listed in Table 8-1. 
8.4.3 
Height and Weight 
Height and weight will be recorded on Pre-Treatment Day 1 of Month 7 (only if >30 days have 
elapsed since HGT-HIT-045 EOS procedures), on the Pre-Treatment Day of each Monthly IT 
Dosing Week. 
8.4.4 
Head Circumference 
Head circumference will be measured in a uniform manner on Pre-Treatment Day 1 of Month 7 
(only if >30 days have elapsed since HGT-HIT-045 EOS procedures), on the Pre-Treatment Day 
of the 12-Month visits (ie, at Months 19, 31, and 43). 
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8.4.5 
Vision Assessment  
A vision assessment will be performed as described in Section 8.3.5 on Pre-Treatment Day 1 of 
Month 7 (only if >3 months have elapsed since HGT-HIT-045 EOS procedures), on the 
Pre-Treatment Day of the 6-Month and 12-Month visits (ie, at Months 13, 19, 25, 31, 37, 43, 
and 49). 
8.4.6 
Hearing Assessment 
A hearing assessment will be performed as described in Section 8.3.6 at Month 7 on 
Pre-Treatment Day 1 (only if >3 months have elapsed since HGT-HIT-045 EOS procedures), on 
the Pre-Treatment Day of the 6-Month and 12-Month visits (ie, at Months 13, 19, 25, 31, 37, 43, 
and 49). 
8.4.7 
12-Lead Electrocardiogram 
A 12-lead ECG will be performed (at minimum) on Pre-Treatment Day 1 of Month 7 (only if 
>30 days have elapsed since HGT-HIT-045 EOS procedures), after injection of study drug on 
Monthly IT Dosing Weeks at Months 7 to 9, 19, 31, and 43. Each 12-lead ECG will include the 
assessments described in Section 8.3.7. 
8.4.8 
Vital Signs 
Vital signs will be collected on Pre-Treatment Day 1 and on the IT Injection Day of each 
monthly IT Dosing Week. 
At a minimum, vital signs will be collected at the following time points on IT administration of 
idursulfase-IT: within 15 minutes prior to IT administration, 30 minutes (±10 minutes) post end 
of IT administration, 60 minutes (±10 minutes) post end of IT administration, 120 minutes 
(±10 minutes) post end of IT administration, and 4 hours (±10 minutes) post end of IT 
administration. 
8.4.9 
Clinical Laboratory Testing 
Blood and urine samples will be collected for clinical laboratory testing as described in 
Section 8.4.9.1, Section 8.4.9.2, and Section 8.4.9.3. Sample collection, processing, and shipping 
instructions are provided in the Study Operations Manual. 
8.4.9.1 
Hematology 
Blood samples will be collected for hematology testing (at minimum) on Pre-Treatment Day 1 of 
Month 7 (only if >30 days have elapsed since HGT-HIT-045 EOS procedures), and at 3-month 
intervals on the Pre-Treatment Day of Monthly IT Dosing Weeks (ie, at Months 10, 13, 16, 19, 
22, 25, 28, 31, 34, 37, 40, 43, 46, 49, and 52). The hematology parameters to be evaluated are 
described in Section 8.3.9.1. 
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8.4.9.2 
Serum Chemistry 
Blood samples will be collected for serum chemistry testing (at minimum) on Pre-Treatment 
Day 1 of Month 7 (only if >30 days have elapsed since HGT-HIT-045 EOS procedures), and at 
3-month intervals on the Pre-Treatment Day of Monthly IT Dosing Weeks (ie, at Months 10, 13, 
16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, and 52). The serum chemistry parameters to be 
evaluated are described in Section 8.3.9.2 and listed in Table 8-2. 
8.4.9.3 
Standard Urinalysis 
Urine samples will be collected for urinalysis (at minimum) on Pre-Treatment Day 1 of Month 7 
(only if >30 days have elapsed since HGT-HIT-045 EOS procedures), and at 3-month intervals 
on the Pre-Treatment Day of Monthly IT Dosing Weeks (ie, at Months 10, 13, 16, 19, 22, 25, 28, 
31, 34, 37, 40, 43, 46, 49, and 52). Pre-treatment urine samples may be collected up to 24 hours 
prior to receipt of each IT dose. The urinalysis parameters to be evaluated are described in 
Section 8.3.9.3. 
8.4.9.4 
Urinary GAG Levels 
Urine samples for determination of urinary GAG levels and urine creatinine will be collected (at 
minimum) on Pre-Treatment Day 1 of Month 7 (only if >30 days have elapsed since 
HGT-HIT-045 EOS procedures), and at 3-month intervals on the Pre-Treatment Day of monthly 
IT Dosing Weeks (ie, at Months 10, 13, 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, and 52). 
Pre-treatment urine samples may be collected up to 24 hours prior to administration of each IT 
dose. Urinary GAG levels will be analyzed and reported as described in Section 8.3.9.4. 
8.4.10 
Auditory Brainstem Response 
Hearing assessment via audiometry measurement will be performed when deemed necessary as 
described in Section 8.3.10 on Pre-Treatment Day 1 of Month 7 (only if >3 months have elapsed 
since HGT-HIT-045 EOS procedures), and on the Pre-Treatment Day of the 12-Month visits 
(ie, at Months 19, 31, and 43). It is anticipated that the patient will be under general anesthesia 
for this procedure. 
8.4.11 
Brain and Spinal Magnetic Resonance Imaging 
Patients will have MRI of the brain and spine on Pre-Treatment Day 1 of Month 7 (only if 
>3 months have elapsed since HGT-HIT-045 EOS procedures), on the Pre-Treatment Day of the 
12-Month visits (ie, at Months 19, 31, and 43). It is anticipated that the patient will be under 
general anesthesia for this procedure. Brain structure volumes will be measured and the brain 
and spine will be evaluated. Refer to the Study Operations Manual for specific procedures and 
precautions. 
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8.4.12 
Intracranial Pressure Measurement 
ICP measurement (cm of H2O) will be performed at Month 7 on Pre-Treatment Day 1 (only if 
>30 days have elapsed since HGT-HIT-045 EOS), on the Pre-Treatment Day of the 12-Month 
visits (ie, at Months 19, 31, and 43). The ICP measurement will be conducted concurrently with 
the lumbar puncture (see Section 8.3.13) and while the patient is under anesthesia. Patients 
should undergo X-ray prior to the lumbar puncture to verify the position of the IDDD catheter. 
8.4.13 
Cerebrospinal Fluid (CSF) Assessments  
CSF will be obtained via the IDDD immediately prior to IT injection of idursulfase-IT on IT 
Injection Day 2 of Month 7, on the IT Injection Day of each monthly IT Dosing Week. 
Note: CSF standard chemistries, glucose, protein, and cell count assessments will be conducted 
at the local laboratory, however review of these results by the treating investigator is not required 
prior to each intrathecal idursulfase-IT dose. If a CSF sample cannot be obtained for 
6 consecutive months, then a lumbar puncture will be performed. Additional CSF samples may 
also be collected throughout the study during any assessment or revision of the IDDD. 
CSF samples collected at scheduled or unscheduled visits will undergo the following 
assessments (Section 8.4.13.1 through to Section 8.4.13.4). CSF sample collection, processing, 
and shipping instructions are provided in the Study Operations Manual. 
8.4.13.1 
CSF Cell Counts 
An aliquot of the CSF sample collected will be evaluated for CSF standard chemistries, glucose, 
protein, and cell counts. 
8.4.13.2 
Immunoassay for Idursulfase-specific Antibodies 
An aliquot of the CSF sample collected will be quick frozen for subsequent analysis of 
idursulfase-specific antibodies. Note that it is not required to perform antibody testing on CSF 
samples collected at unscheduled visits. 
8.4.13.3 
CSF Biomarker Analysis 
An aliquot of the CSF sample collected will be quick frozen for subsequent analysis of levels of 
biomarkers (eg, GAG [HS/DS]). 
8.4.13.4 
CSF Analysis of Idursulfase Enzyme Levels 
An aliquot of the CSF sample collected will be quick frozen for subsequent idursulfase enzyme 
analysis. 
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8.4.14 
SOPH-A-PORT Mini S Device Assessments 
SOPH-A-PORT Mini S device assessments will include measures of device implantation, device 
function, device longevity, and AEs associated with the device. These data will be collected on 
the patient’s CRF from the time of implantation and continue throughout the study as long as the 
SOPH-A-PORT Mini S remains implanted. Please refer to the IDDD manual for further 
information. 
8.4.15 
Intrathecal Idursulfase-IT Injection 
Idursulfase-IT will be injected intrathecally via the IDDD at each monthly (ie, every 
28 [±7] days) IT Dosing Week. The patient may be mildly sedated for this procedure. 
Idursulfase-IT will be administered over 2 to 5 minutes. A visual examination of both the port 
and catheter track will be performed before each IT injection. 
If the IT space is not accessible via the IDDD, idursulfase-IT may be administered by lumbar 
puncture (see Section 7.8). 
8.4.16 
Elaprase Infusion 
Elaprase will be administered as an IV infusion at a weekly dose of 0.5 mg/kg in accordance 
with local prescribing information. 
Patients will receive their weekly Elaprase infusion on every IT Dosing Week approximately 
2 days after receiving their IT injection of idursulfase-IT (note that the Elaprase infusion should 
be administered even in instances in which the IT dose is not). Elaprase infusion may be 
administered at the main site or at the patient’s local infusion location (site or home). 
8.4.17 
Neurological Examination 
Neurological examination to monitor CNS status and any changes will be performed at minimum 
on Pre-Treatment Day 1 of Month 7 (only if >30 days have elapsed since HGT-HIT-045 EOS 
procedures), on the Pre-Treatment Day of each monthly IT Dosing Week. 
8.4.18 
Serum Anti-idursulfase Antibody and Plasma Proteomic Biomarker 
Determination 
Patients will have blood samples collected at minimum on Pre-Treatment Day 1 of Month 7 
(only if >30 days have elapsed since HGT-HIT-045 EOS procedures), and at 3-month intervals 
on the Pre-Treatment Day of Monthly IT Dosing Weeks (ie, at Months 10, 13, 16, 19, 22, 25, 28, 
31, 34, 37, 40, 43, 46, 49, and 52). 
A 10-mL blood sample will be collected from each patient for the first sample; a 5-mL sample 
will be collected for all subsequent blood collections. Blood samples collected will be evaluated 
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for determination of anti-idursulfase antibodies, antibodies that have enzyme neutralizing 
activity, and potential exploratory plasma proteomic biomarkers of disease progression. Blood 
sample collection, processing, and shipping instructions are provided in the Study Operations 
Manual. 
8.4.19 
Neurodevelopmental Assessments  
Patients will undergo neurodevelopmental assessments using appropriate standardized tests to 
provide a surrogate and quantifiable measure of global CNS neurodevelopmental status as 
described in Section 8.3.19. It is intended that full neurodevelopmental assessments of cognitive, 
motor, and adaptive functions be conducted for all patients; however, it is recognized that the 
feasibility of conducting these assessments is dependent on the patient’s ability to cooperate 
and/or level of cognitive impairment, and that it may not be possible to complete full 
neurodevelopmental evaluation of every patient. A reasonable effort should be made to perform 
neurodevelopmental assessments for each patient; however, inability to collect these data may 
not be considered a protocol deviation. 
8.4.19.1 
Full Neurodevelopmental Assessment 
A full neurodevelopmental assessment will be conducted on Pre-Treatment Day 1 of Month 7 
(only if >3 months have elapsed since HGT-HIT-045 EOS procedures), and prior to treatment at 
the 6-Month and 12-Month IT Dosing Week visits (ie, at Months 13, 19, 25, 31, 37, 43, and 49). 
Full neurodevelopment assessment tests are summarized in Table 8-3. For cognitive testing the 
first item set of the 6 main subtests of the DAS-II will be administered. If the patient cannot 
complete these, the BSID-III will be used to assess cognition. 
8.4.20 
Pharmacokinetic Evaluations 
Serum samples for PK evaluation of idursulfase will be collected on IT Injection Day 2 of the 
12-Month visits (ie, at Months 19, 31, and 43) and will be drawn at the following times: 
• Within 15 minutes prior to IT injection, then at 1, 2, 3, 4, 6, 8, 12, 24, 30 and 36 hours 
following IT injection 
 
The PK sampling schedule for the study is also located in Section 14 (Table 14-4). Sample 
collection, processing, and shipping instructions are provided in the Study Operations Manual. 
Note that when vital sign collection and collection of a sample for PK analysis are scheduled to 
occur at the same time, vital sign collection should occur first and the blood draw for PK 
sampling should be performed as soon as possible after vital sign collection. The actual time of 
collection of the PK sample should be recorded. 
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8.5 
Extended Treatment Phase (All Patients, from Month 55 to EOS) (Part C) 
8.5.1 
Physical Examinations 
Physical examinations on Pre-Treatment Day 1 of the Month 55 visit will include a review of the 
patient’s general appearance, device port and catheter track, and evaluations listed in Table 8-1. 
Thereafter, symptom-directed physical examinations may be performed at the investigator’s 
discretion on the Pre-Treatment Day of each monthly IT Dosing Week, and at the EOS visit. 
8.5.2 
Height and Weight 
Height and weight will be recorded on Pre-Treatment Day 1 of the Month 55 visit, at the 
6-Month and 12-Month visits (ie, at Months 61, 67, 73, 79, 85, 91, 97, 103, 109, 115, 121, 127, 
133, 139, 145, 151, 157, and 163), and at the EOS visit. 
8.5.3 
Head Circumference 
Head circumference will be measured in a uniform manner on Pre-Treatment Day 1 of the 
Month 55 visit, and 12-Month visits (ie, at Months 67, 79, 91, 103, 115, 127, 139, 151, and 163), 
and at the EOS visit. 
8.5.4 
Vision Assessment  
A vision assessment will be performed as described in Section 8.3.5 on Pre-Treatment Day 1 of 
the Month 55 visit, and at the EOS visit. 
8.5.5 
Hearing Assessment 
A hearing assessment will be performed as described in Section 8.3.6 on Pre-Treatment Day 1 of 
the Month 55 visit, at the 12-Month visits (ie, at Months 67, 79, 91, 103, 115, 127, 139, 151, 
and 163), and at the EOS visit. 
8.5.6 
12-Lead Electrocardiogram 
A 12-lead ECG will be performed after injection of study drug on Monthly IT Dosing Weeks at 
Months 55, 67, 79, 91, 103, 115, 127, 139, 151, and 163, and at the EOS visit. Each 12-lead ECG 
will include the assessments described in Section 8.3.7. 
8.5.7 
Vital Signs 
Vital signs will be collected on Pre-Treatment Day 1 and on the IT Injection Day of each 
Monthly IT Dosing Week, and at the EOS visit. 
At a minimum, vital signs will be collected at the following time points on IT administration of 
idursulfase-IT: within 15 minutes prior to IT administration, 30 minutes (±10 minutes) post end 
of IT administration, and upon discharge. 
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8.5.8 
Clinical Laboratory Testing 
Blood and urine samples will be collected for clinical laboratory testing as described in 
Section 8.4.9.1, Section 8.4.9.2, and Section 8.4.9.3. Sample collection, processing, and shipping 
instructions are provided in the Study Operations Manual. 
8.5.8.1 
Hematology 
Blood samples will be collected for hematology testing (at minimum) at 6-month intervals on 
Pre-Treatment Day 1 of Monthly IT Dosing Weeks (ie, at Months 55, 61, 67, 73, 79, 85, 91, 97, 
103, 109, 115, 121, 127, 133, 139, 145, 151, 157, and 163), and at the EOS visit. The 
hematology parameters to be evaluated are described in Section 8.3.9.1. 
8.5.8.2 
Serum Chemistry 
Blood samples will be collected for serum chemistry testing (at minimum) at 6-month intervals 
on Pre-Treatment Day 1 of Monthly IT Dosing Weeks (ie, at Months 55, 61, 67, 73, 79, 85, 91, 
97, 103, 109, 115, 121, 127, 133, 139, 145, 151, 157, and 163), and at the EOS visit. The serum 
chemistry parameters to be evaluated are described in Section 8.3.9.2 and listed in Table 8-2. 
8.5.8.3 
Standard Urinalysis 
Urine samples will be collected for urinalysis (at minimum) at 6-month intervals on 
Pre-Treatment Day 1 of Monthly IT Dosing Weeks (ie, at Months 55, 61, 67, 73, 79, 85, 91, 97, 
103, 109, 115, 121, 127, 133, 139, 145, 151, 157, and 163), and at the EOS visit. Pre-treatment 
urine samples may be collected up to 24 hours prior to receipt of each IT dose. The urinalysis 
parameters to be evaluated are described in Section 8.3.9.3. 
8.5.8.4 
Urinary GAG Levels 
Urine samples for determination of GAG levels and urine creatinine will be collected (at 
minimum) at 6-month intervals on Pre-Treatment Day 1 of Monthly IT Dosing Weeks (ie, at 
Months 55, 61, 67, 73, 79, 85, 91, 97, 103, 109, 115, 121, 127, 133, 139, 145, 151, 157, 
and 163), and at the EOS visit.  
Pretreatment urine samples may be collected up to 24 hours prior to administration of each IT 
dose. Urinary GAG levels will be analyzed and reported as described in Section 8.3.9.4. 
8.5.9 
Auditory Brainstem Response 
Hearing assessment via audiometry measurement will be performed when deemed necessary as 
described in Section 8.3.10 on Pre-Treatment Day 1 of the Month 55 visit, at the 12-Month visits 
(ie, at Months 67, 79, 91, 103, 115, 127, 139, 151, and 163), and at the EOS visit. It is 
anticipated that patients will be under general anesthesia for this procedure. 
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8.5.10 
Brain and Spinal Magnetic Resonance Imaging 
Patients will have MRI of the brain and spine on Pre-Treatment Day 1 of the Month 55 visit, at 
the 12-Month visits (ie, at Months 67, 79, 91, 103, 115, 127, 139, 151, and 163), and at the EOS 
visit. It is anticipated that patients will be under general anesthesia for this procedure. Brain 
structure volumes will be measured and the brain and spine will be evaluated. Refer to the Study 
Operations Manual for specific procedures and precautions. 
8.5.11 
Intracranial Pressure Measurement 
ICP measurement (cm of H2O) will be performed on Pre-Treatment Day 1 of the Month 55 visit 
and at the EOS visit. The ICP measurement will be conducted concurrently with the lumbar 
puncture (see Section 8.3.13) and while the patient is under anesthesia. Patients should undergo 
X-ray prior to the lumbar puncture to verify the position of the IDDD catheter. 
8.5.12 
Cerebrospinal Fluid Assessments 
Cerebrospinal fluid will be obtained via the IDDD immediately prior to IT injection of 
idursulfase-IT on IT Injection Day 2 of Month 55 and on the IT Injection Day of each monthly 
IT Dosing Week. 
Note: CSF standard chemistries, glucose, protein, and cell count assessments will be conducted 
at the local laboratory, however review of these results by the treating investigator is not required 
prior to each intrathecal idursulfase-IT dose. If a CSF sample cannot be obtained for 
6 consecutive months, then a lumbar puncture will be performed. Additional CSF samples may 
also be collected throughout the study during any assessment or revision of the IDDD. 
Cerebrospinal fluid samples collected at scheduled or unscheduled visits will undergo the 
analyses described in Section 8.4.13.1 through to Section 8.4.13.4. Measurements of GAG, 
idursulfase enzyme, and anti- idursulfase antibody levels in CSF samples will be analyzed (at 
minimum) at 6-month intervals at Months 55, 61, 67, 73, 79, 85, 91, 97, 103, 109, 115, 121, 127, 
133, 139, 145, 151, 157, and 163), and at the EOS visit. 
Cerebrospinal fluid sample collection, processing, and shipping instructions are provided in the 
Study Operations Manual. 
8.5.13 
SOPH-A-PORT Mini S Device Assessments 
SOPH-A-PORT Mini S device assessments will be performed as described in Section 8.4.14. 
8.5.14 
Intrathecal Idursulfase-IT Injection 
Idursulfase-IT will be injected intrathecally via the IDDD at each monthly (ie, every 
28 [±7] days) IT Dosing Week. The patient may be mildly sedated for this procedure. 
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Idursulfase-IT will be administered over 2 to 5 minutes. A visual examination of both the port 
and catheter track will be performed before each IT injection. 
If the IT space is not accessible via the IDDD, idursulfase-IT may be administered by lumbar 
puncture (see Section 7.8). 
8.5.15 
Elaprase Infusion 
Elaprase will be administered as an IV infusion at a weekly dose of 0.5 mg/kg in accordance 
with local prescribing information. 
Patients will receive their weekly Elaprase infusion on every IT Dosing Week approximately 
2 days after receiving their IT injection of idursulfase-IT (note that the Elaprase infusion should 
be administered even in instances in which the IT dose is not). Elaprase infusion may be 
administered at the main site or at the patient’s local infusion location (site or home). 
8.5.16 
Neurological Examination 
Neurological examination to monitor CNS status and any changes will be performed on 
Pre-Treatment Day 1 of the Month 55 visit. Thereafter, symptom-directed neurological 
examinations will be performed at the investigator’s discretion on Pre-Treatment Day 1 of each 
monthly IT Dosing Week, and at the EOS visit.  
8.5.17 
Serum Anti-idursulfase Antibody 
Patients will have blood samples collected (at minimum) at 6-month intervals on Pre-Treatment 
Day 1 of Monthly IT Dosing Weeks (ie, at Months 55, 61, 67, 73, 79, 85, 91, 97, 103, 109, 115, 
121, 127, 133, 139, 145, 151, 157, and 163), and at the EOS visit for determination of 
anti-idursulfase antibodies. 
A 10-mL blood sample will be collected from each patient for the first sample; a 5-mL sample 
will be collected for all subsequent blood collections. Blood samples collected will be evaluated 
for determination of anti-idursulfase antibodies and antibodies that have enzyme neutralizing 
activity. Blood sample collection, processing, and shipping instructions are provided in the Study 
Operations Manual. 
8.5.18 
Neurodevelopmental Assessments 
A full neurodevelopmental assessment will be conducted on the Pre-Treatment Day 1 of the 
Month 55 visit. Full neurodevelopment assessment tests are summarized in Table 8-3. 
Thereafter, a limited neurodevelopmental assessment, focused on neurocognitive function, will 
be performed. The SIBR, BRIEF/BRIEF-P, PDMS, BOT-2 will no longer be administered. For 
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cognitive testing the first item set of the 6 main subtests of the DAS-II will be administered. If 
the patient cannot complete these, the BSID-III will be used to assess cognition. 
The limited neurodevelopmental assessment will be conducted on the Pre-Treatment Day 1 of 
the 12-Month visits (ie, at Months 67, 79, 91, 103, 115, 127, 139, 151, and 163), and at the EOS 
visit. Subjects exceeding 17 years 11 months of age will no longer undergo neurodevelopmental 
assessment using the DAS-II. 
8.6 
Device-related Study Procedures 
8.6.1 
IDDD Implantation or Revision Procedures 
The IDDD will be surgically implanted or revised at the main clinical site. Procedures for 
implantation and revision are detailed in the device’s Instructions for Use. 
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 and may be provided; however, use of 
other catheter passers compatible with the SOPH-A-PORT Mini S is allowed. Compatible 
catheter passers must be able to support a catheter with an outer diameter of 1.6 mm. 
8.6.2 
Device Removal 
It is planned that device explantation will occur at the main site unless urgent device removal is 
medically required to be performed at a local site. 
For the SOPH-A-PORT Mini S, if at the time of a scheduled dosing it is not possible due to a 
device-related issue to aspirate CSF prior to dose administration, administer a full medication 
dosage as per the standard administration steps detailed in the SOPH-A-PORT Mini S 
Instructions for Use, or flush the system following dose administration, the IDDD will be 
declared a device malfunction. If the device malfunction is irreversible and cannot be corrected 
without a device surgical intervention (ie, partial or full device revision or removal), 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 SOPH-A-PORT Mini S 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 
device’s Instructions for Use for further details. 
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Patients who have a PORT-A-CATH IDDD device failure may have this device replaced by a 
SOPH-A-PORT Mini S; the nonfunctional PORT-A-CATH IDDD will be removed and replaced 
with the SOPH-A-PORT Mini S device at a time judged appropriate by the investigator. A 
nonfunctional PORT-A-CATH IDDD cannot be replaced by a new PORT-A-CATH device. 
Patients should have the IDDD removed when they discontinue from the study, unless they are 
continuing to receive treatment through another mechanism (eg, supplemental study, expanded 
access program, etc) or 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 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. 
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9 
ADVERSE EVENTS 
9.1 
Definitions of Adverse Events and Serious Adverse Events 
9.1.1 
Adverse Events 
An adverse event (AE) is any noxious, pathologic, or unintended change in anatomical, 
physiologic, or metabolic function as indicated by physical signs, symptoms, and/or laboratory 
changes occurring in any phase of a clinical trial, and whether or not considered study 
drug-related. This includes an exacerbation of a pre-existing condition. Once the patient signs the 
informed consent/assent, any AE prior to the start of study drug must be reported. Adverse 
events will be collected until the EOS visit, and/or until the event has been resolved/stabilized or 
an outcome is reached, whichever comes first. 
AEs 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, weight, and ECG 
 
Throughout the study, the investigator must record all AEs on the CRF, regardless of the severity 
or relationship to study drug. The investigator should treat patients with AEs appropriately and 
observe them at suitable intervals until the events stabilize or resolve. AEs may be discovered 
through observation or examination of the patient, questioning of the patient, complaint by the 
patient, or by abnormal clinical laboratory values, or abnormal ECG. 
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. 
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9.1.2 
Serious Adverse Event Definition 
An (SAE) is any AE occurring at any dose that results in any of the following outcomes: 
• Death  
• Is life-threatening 
• Requires inpatient hospitalization 
• Requires prolongation of existing hospitalization 
• A persistent or significant disability/incapacity  
• A congenital anomaly/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). Hospitalizations, which are the 
result of elective or previously scheduled surgery for pre-existing conditions, which have not 
worsened after initiation of treatment, should not be classified as SAEs. For example, an 
admission for a previously scheduled ventral hernia repair would not be classified as an SAE; 
however, complication(s) resulting from a hospitalization for an elective or previously scheduled 
surgery that meet(s) serious criteria must be reported as SAE(s). Furthermore, this does not apply 
to device failures resulting in scheduled surgical revisions, which should be reported as SAEs. 
9.1.3 
Unanticipated Adverse Device Effect Definition 
An unanticipated adverse device effect (UADE) is 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). 
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9.1.4 
SOPH-A-PORT Mini S Device-associated Definitions 
9.1.4.1 
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. 
9.1.4.2 
Device Malfunction 
The device does not perform as intended, based on the description in the device’s Instructions for 
Use, but does not require either a partial or full device revision. 
9.1.4.3 
Device Failure 
The device irreversibly fails to perform as intended and requires either a partial or full device 
revision or removal. 
9.1.4.4 
Device Adjustment 
Device adjustment is defined as surgery of the device which does not result in partial or complete 
device revision or removal (eg, surgical exploration only or placement of additional sutures, 
tissue glue, and/or fascial repair). 
9.1.5 
Classification of Adverse Events and Serious Adverse Events 
The National Cancer Institute Common Terminology Criteria (NCI CTC) Version 4.0 grading 
scale should be referenced when assessing the severity of an AE (provided in the Study 
Operations Manual). 
If an AE is not described in the NCI CTC, the severity should be recorded based on the scale 
below (Table 9-1). The severity of AEs/SAEs should be recorded on the appropriate CRF page 
as Grade 1, 2, 3, 4, or 5 corresponding, respectively, to a severity of mild, moderate, severe, 
life-threatening, or fatal. 
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Table 9-1 
Classification of AE/SAE Severity  
Severity 
Definition 
Grade 1 (Mild) 
No limitation of usual activities 
Grade 2 (Moderate) 
Some limitation of usual activities 
Grade 3 (Severe) 
Inability to carry out usual activities 
Grade 4 (Life-threatening) 
Immediate risk of death 
Grade 5 (Fatal) 
Death 
 
The relationship of an AE or SAE to the study treatment (ie, study drug [idursulfase-IT], device 
[PORT-A-CATH or SOPH-A-PORT IDDD], device surgical procedure, or IT administration 
process) will be determined by the investigator and classified based on the relatedness definitions 
provided in Table 9-2. 
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Table 9-2 
Classification of AE/SAE Relatedness 
Relationship  
Definition 
Not Related 
Unrelated to study drug, device, device surgical 
procedure, or IT administration process. 
Possibly Related 
A clinical event/laboratory abnormality with a 
reasonable time sequence to administration of study 
drug, device, device surgical procedure, or IT 
administration process but which could also be 
explained by concurrent disease or other 
drugs/chemicals. 
Probably Related 
A clinical event/laboratory abnormality with a 
reasonable time sequence to administration of study 
drug, 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/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 study drug, 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. 
 
In addition, the relationship of an AE or SAE to IV Elaprase infusion will be assessed by the 
investigator as not related, possibly related, probably related, or definitely related. 
9.1.5.1 
Categories of Adverse Events 
Adverse events collected throughout this study will be categorized as follows: 
Device Surgical Procedure-related Adverse Events 
Examples of AEs related to device surgical procedures include, but are not limited to, the 
following: events that occur during or 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 post-operative infection). 
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Device-related Adverse Events 
Examples of IDDD-related AEs include, but are not limited to, the physiologic consequences 
(noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function as 
indicated by physical signs, symptoms, or laboratory changes) of the following: device failure 
(such as may occur with migration of the portal/catheter, occlusion of the portal/catheter, 
incorrect connection of IDDD components, fibrin sheath formation around the catheter tip), 
erosion of the portal/catheter through the skin, hematoma, implant rejection, or subcutaneous 
tract infection. A malfunction of the device (defined in Section 9.1.4.2) should not be entered as 
an AE unless it has physiopathological consequences such as those listed above. In the event of a 
device failure (defined in Section 9.1.4.3), the device will need a partial or complete revision or 
removal. 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 an 
SAE. Details of the cause of SOPH-A-PORT Mini S IDDD malfunction or failure will be 
recorded on the device malfunction and failure CRF and the SAE form (where applicable). 
A list of the most common AEs related to the SOPH-A-PORT Mini S is reproduced from the 
device Instructions for Use in Appendix 4. 
A list of the most common AEs related to the PORT-A-CATH is reproduced from the device 
Instructions for Use in Appendix 5. 
Intrathecal Administration Process Adverse Events 
Examples of AEs related to the IT administration process include, but are not limited to, the 
following: AEs caused by anesthesia during drug administration or other drug administration 
issues (eg, extravasation during infusion or hematoma due to the Huber needle), or complications 
of lumbar puncture. 
Idursulfase-IT-related Adverse Events 
It is not possible to predict study drug-related AEs in humans based on data from animals where 
intrathecally administered idursulfase was observed to be well tolerated. 
The most common (reported in at least 2 patients) events with a potential causal relationship to 
idursulfase-IT in Studies HGT-HIT-045 and HGT-HIT-046 have included agitation, vomiting, 
pyrexia, changes in heart rate, blood pressure, oxygen saturation, body temperature, CSF protein, 
and cell count. All of these events were nonserious. Please see the current edition of the 
investigator’s brochure for details. 
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Because idursulfase-IT is administered intrathecally in this study, it is not expected that systemic 
blood levels will be high enough to cause an infusion-related reaction. However, systemic 
exposure resulting from diffusion from the CSF into the peripheral circulation has the potential 
to cause events that have been seen in patients receiving Elaprase and other ERTs known as 
infusion-related reactions. 
IV Elaprase infusion-related Adverse Events 
Infusion-related reactions have been observed in patients receiving IV ERT with Elaprase, with 
symptoms including cutaneous reactions (rash, pruritus, and urticaria), pyrexia, headache, 
hypertension, and flushing. An Elaprase-associated infusion-related reaction will be defined as 
an AE that begins either during or within 24 hours after the start of IV infusion, and is judged as 
at least possibly related to the infusion. 
9.1.5.2 
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. 
9.2 
Adverse Event Monitoring and Period of Observation 
For the purposes of this study, the period of observation extends from the time the patient’s 
parent(s) or the patient’s legally authorized representative(s) gives informed consent until the 
EOS visit, and/or until the event has been resolved/stabilized or an outcome is reached, 
whichever comes first. 
If the investigator considers it necessary to report an AE in a study patient after the end of the 
observation period, he or she should contact the sponsor to determine how the AE should be 
documented and reported. 
9.3 
Procedures for Recording and Reporting Adverse Events 
9.3.1 
Serious Adverse Event Reporting 
Any SAE, regardless of the relationship to the study drug, device, device surgical procedure, IT 
administration process, or IV infusion of Elaprase 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 CRF, including the judgment of the investigator as to the relationship 
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of the SAE to the study drug, device, device surgical procedure, IT drug administration process, 
or IV infusion of Elaprase. 
The investigator will promptly supply all information identified and requested by the sponsor 
(and/or contract research organization [CRO]) regarding the SAE. The investigator must report 
the SAE to the sponsor’s safety 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 
learning of the event to: 
Sponsor’s Safety Department: 
International FAX: +1 484 595 8155 (Global) 
drugsafety@shire.com 
AND 
Shire Medical Monitor: 
, DO 
 
 
Shire 
MOBILE: 
 (24-hour access) 
 
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 contact information for the Shire medical monitor is provided 
above. 
The device manufacturer will submit mandatory medical device reports (MDRs) (ie, UADEs) to 
the relevant regulatory agencies consistent with applicable regulations and Shire will submit 
MDRs to the Investigational New Drug Application (IND). Shire will report expedited 
drug-related events (serious, unexpected/unlisted, causally related) to the relevant regulatory 
agencies consistent with applicable regulations. 
The investigator must promptly report all SAEs and any unanticipated problems involving risk to 
human patients in a timely manner to his/her IRB/IEC. It is the responsibility of the sponsor to 
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ensure that each investigator receives a copy of any MedWatch/CIOMS I/MDR report that has 
been submitted to the appropriate regulatory agencies notifying them of an unexpected 
drug-related SAE or UADE. 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. The investigator or 
sponsor must also ensure that the IRB/IEC receives copies of UADE reports that have been 
submitted by the device manufacturer (or designated agent) to the relevant regulatory agencies. 
9.3.2 
Eliciting Adverse Events 
Patients should be asked non-leading questions, eg, “How do you feel?” and further questions 
should be posed if there is indication of an AE. The questioning should be conducted with due 
regard for objectivity and, in particular, the questioner should gather information regarding AEs 
from questioning the patient, the patient’s parent/legally authorized representative, spontaneous 
report by the patient or parent/legally authorized representative, laboratory reports, and any 
health care provider’s observations. 
The onset date, resolution date, treatment administered, and outcome of each AE must be 
recorded on the appropriate CRF. In addition, the relationship of each AE to study drug must be 
recorded. 
9.3.3 
Protocol Deviations for Medical Emergency or Adverse Event 
During and following a patient’s participation in the study, the investigator should ensure that 
adequate medical care is provided to a patient for any AEs, including clinically significant 
laboratory test results. The investigator should inform the patient, the patient’s parent(s), or the 
patient’s legally authorized representative(s) when medical care is needed for intercurrent 
illness(es) of which the investigator becomes aware. In an emergency situation, the investigator 
should contact the Shire medical monitor (see Section 9.3.1). 
Only when an emergency occurs that requires an immediate deviation from the protocol for the 
safety of a patient, will there be such a deviation and this will be only for that patient. The 
investigator or other physician in attendance in such an emergency must contact the Shire 
medical monitor as soon as possible. The investigator, along with the Shire medical monitor, will 
make a decision as to whether or not the patient should continue in the study. The departure from 
the protocol and the grounds for it should be stated in the CRF. 
9.4 
Abuse, Misuse, Overdose, and Medication Error 
Abuse, misuse, overdose or medication error must be reported to the sponsor according to the 
SAE reporting procedure whether or not they result in an AE/SAE as described in Section 9.3.1. 
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• 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 that 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 the investigational medicinal 
product, with the exception of the protocol-specified dose and dose frequency, or a dose 
2-times higher than the protocol-specified dose. 
• Medication Error – A mistake made in prescribing, dispensing, administration and/or 
use of the investigational medicinal product. 
 
The investigator must report abuse, misuse, overdose, and medication errors to the sponsor’s 
safety department AND to the Shire medical monitor on the SAE form. This form must be 
completed and FAXED or EMAILED within 24 hours of the investigator’s learning of the event 
(refer to the contact information for reporting of SAEs provided in Section 9.3.1). 
9.5 
Safety-related Study Stopping Rules 
If at least 1 patient experiences a life-threatening (Grade 4) AE or death (Grade 5) which is 
considered either possibly, probably, or definitely related to the study treatment (study drug, 
device, device surgical procedure, or the IT administration process) or if 2 or more patients 
experience a Grade 3 or higher AE during the trial, which is considered possibly, probably, or 
definitely related to the study treatment (study drug, device, device surgical procedure, or the IT 
administration process), then all sites will be instructed to halt further intrathecal idursulfase-IT 
administration to all patients. All available data relating to the safety of idursulfase-IT will be 
reviewed. After review of the 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 last scheduled study visit/assessment. 
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9.6 
Concomitant Medications, Therapies, and Medical/Surgical Procedures 
All non-protocol treatments from informed consent and through the EOS visit are regarded as 
concomitant and will be documented on the appropriate pages of the CRF. 
These include medications (eg, Elaprase), therapies/interventions administered to patients, and 
medical/surgical procedures performed on the patients. 
All patients are to receive Elaprase during the study. Elaprase will be prescribed by the patient’s 
physician and will be administered in accordance with local prescribing information. 
9.6.1 
Infusion 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 an 
investigational product, including idursulfase-IT, 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 
- 
Pre-treatment with antihistamines and/or corticosteroids may prevent subsequent 
reactions in those cases where symptomatic treatment was required 
 
Infusion-related reactions have been observed in patients receiving IV ERT with Elaprase, with 
symptoms including cutaneous reactions (rash, pruritus, and urticaria), pyrexia, headache, 
hypertension, and flushing. Previous experience with Elaprase is fully described in the Elaprase 
US Package Insert and the EU Summary of Product Characteristics (SmPC). Pre-treatment with 
antihistamines and/or corticosteroids may prevent subsequent reactions in those cases where 
symptomatic treatment was required. The safety information reported from administration of 
Elaprase may be relevant to management of adverse events in relation to idursulfase-IT. 
Successful management of Elaprase infusion-related adverse events included slowing or 
interrupting the infusion at the time of the event or pretreatment with low-dose corticosteroids 
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and/or antihistamines. Most adverse events of this type were treated with antihistamines such as 
chlorpheniramine (IV administration preferred if available), oxygen, or mild glucocorticoids 
such as hydrocortisone and prednisolone. All were monitored closely until symptoms of the 
reactions had subsided. In clinical trials of Elaprase, an apparent decrease in the overall rates of 
adverse events, and specifically infusion-related adverse events, was observed over time, 
suggesting that patients may better tolerate infusions during long-term therapy. 
The ongoing clinical studies with idursulfase-IT have not revealed adverse events of the severity 
and frequency consistent with infusion-related reactions sometimes observed with IV Elaprase 
infusion. 
There have been no significant concerns regarding infusion-related immune reactions following 
IT administration in Studies HGT-HIT-045 and HGT-HIT-046. Note that any patient with prior 
experience of infusion-related anaphylactoid event(s) or evidence of consistent severe adverse 
events related to treatment with Elaprase is excluded from participating in this study. 
9.7 
Removal of Patients from the Trial  
The patient or the patient’s parent(s) or legally authorized representative(s) 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. For this protocol, withdrawn patients will not be replaced. 
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 suffers an intolerable AE 
• The study is terminated by the sponsor 
 
If the patient or the patient’s parent(s) or legally authorized representative(s), acting on behalf of 
the patient, discontinues participation in the study, or the patient is discontinued by the 
investigator, the Patient Completion/Discontinuation CRF describing the reason for 
discontinuation must be completed. Any AEs experienced up to the point of discontinuation must 
be documented on the AE CRF. 
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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 should be followed 
until resolution. 
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10 STATISTICAL METHODS  
10.1 
General Statistical Methodology 
This is an open-label extension of study HGT-HIT-045 to evaluate the long-term safety and 
clinical outcomes of intrathecal idursulfase-IT, administered in conjunction with Elaprase, in 
pediatric patients with Hunter syndrome and cognitive impairment. The statistical methodology 
supporting the trial will focus on descriptive rather than inferential approaches, given the early 
phase and objectives of the trial. 
The study data will be combined with that of studies HGT-HIT-045 and HGT-HIT-050 for 
analysis as appropriate. The efficacy and safety analyses will be based on the idursulfase-IT 
treatment baseline (abbreviated as treatment baseline), which is prior to the initial IDDD implant 
date. This treatment baseline for the treated patients in HGT-HIT-045 is the closest available 
screening assessment (including the HGT-HIT-050 screening data) on or before the 
randomization date in HGT-HIT-045. The treatment baseline for the untreated patients in 
HGT-HIT-045 is the closest available assessment (including HGT-HIT-045 and HGT-HIT-050 
data if necessary) prior to the IDDD implantation date in HGT-HIT-046. 
No formal statistical testing is planned. Descriptive analyses of the data before trial completion 
may be performed for safety monitoring, regulatory reporting, or general planning purposes. 
An interim clinical study report is planned describing the results of Parts A and B. The complete 
results, including Part C, will be described in the final clinical study report. 
10.2 
Patient Disposition and Demographics 
Patient disposition (signed informed consent, treatment status, completed, 
discontinued/withdrew) will be presented in summary tables using number and percentage of 
patients per dose. Reasons for discontinuation/withdrawal will be presented. 
Demographic and baseline characteristics (eg, age, race, ethnicity, and baseline disease status) 
will be reported in summary tables. 
10.3 
Efficacy, Safety, and Pharmacokinetic Evaluations 
10.3.1 
Populations for Analyses 
The following 2 classifications of patients based on their treatment status will determine how 
their data will be pooled for statistical analysis. 
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Population 
Criteria for Inclusion 
Safety 
All eligible patients from HGT-HIT-045 who have agreed to 
participate in the extension study and have had either surgical 
implantation of an IDDD or intrathecal administration of study 
drug in the extension study. 
Pharmacokinetic  
All patients who receive study drug and participate in the 
scheduled PK studies, and have at least 1 reported serum or 
CSF concentration of idursulfase. 
Abbreviations: CSF = cerebrospinal fluid; IDDD = intrathecal drug delivery device; PK = pharmacokinetic 
 
Device-related analyses will be conducted separately for the PORT-A-CATH and 
SOPH-A-PORT devices, as well as devices combined, in the set of patients in the safety 
population who had the corresponding device implant procedure performed. 
10.3.2 
Primary Analyses 
10.3.2.1 
Safety and Tolerability Assessments 
The assessment of safety will be performed in the safety population, primarily on the frequency 
of treatment-emergent AEs, and on the frequency of clinically notable abnormal laboratory 
values. 
Adverse events will be recorded throughout the study and at early termination. Adverse events 
and medical conditions will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 16 or later. 
Treatment-emergent AEs, defined as all AEs occurring on or after the first IDDD surgery date or 
first dose (whichever is earlier) for the patient (whether it is in this extension study or in 
HGT-HIT-045) and before the EOS visit (+30 days), will be summarized by dose group and 
overall. The number and percentage of patients having AEs will be presented by system organ 
class (SOC) and preferred term, and by severity and relationship to study drug and IV Elaprase 
infusion. In addition, any event which resulted in death or was otherwise classified as serious 
will be presented in a separate listing. 
Intrathecal drug delivery device and procedure-related AEs will also be summarized by SOC and 
preferred term. For the PORT-A-CATH and SOPH-A-PORT devices, separate tabulations will 
be provided for AEs related to the IDDD, device surgical procedure, and IT administration 
process. 
The infusion (IV) and injection (IT) vital sign measurements will be shown in individual patient 
line graphs over time by visit. 
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10.3.2.2 
Laboratory Evaluations 
Clinical laboratory results (hematology, serum chemistry, urinalysis) and the results of analysis 
of CSF parameters will be summarized and, for selected parameters, presented as the number and 
percentage of patients with post-baseline values categorized as follows: 
• Clinically significant (CS): The patient had at least one clinically significant value at any 
time during the study post baseline; 
• Not clinically significant (NCS): The patient had no clinically significant value at any 
time during the study post baseline, but had at least one abnormal value, 
• Normal (N): The patient had no abnormal or clinically significant value at any time 
during the study post baseline. 
 
10.3.2.3 
Anti-Idursulfase Antibody Formation 
Anti-idursulfase antibody formation and enzyme neutralizing activity in serum and CSF will be 
monitored throughout the study. Results will be summarized and presented graphically by visit, 
dose, and overall. 
Antibody and neutralizing antibody status will be presented as shift tables by visit, dose, and 
overall. The titer will be presented graphically by visit for each patient with a positive result. The 
percent inhibition will be graphed by visit for each patient with a positive neutralizing antibody 
result. 
10.3.3 
Secondary Analyses 
10.3.3.1 
Pharmacodynamic Analyses 
The observed CSF and urine GAG values, the change from baseline, and the percent change 
from baseline in these values will be summarized descriptively by dose and overall. 
10.3.3.2 
Pharmacokinetic Analyses 
The PK analysis will be conducted by the Clinical Pharmacology and PK Department of Shire 
Pharmaceuticals or its designee using Phoenix WinNonlin version 6.2 or higher (Pharsight 
Corporation, Mountain View, California, USA). 
Idursulfase concentrations in serum and CSF will be determined using a validated enzyme-linked 
immunosorbent assay (ELISA) method. The idursulfase concentrations in serum will also be 
determined by a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) 
method for the serum samples collected at Week 3 and Week 23 only. The LC-MS/MS method 
is expected to be less susceptible to interference by anti-idursulfase antibodies. 
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Pharmacokinetic parameters will be determined from serum concentration-time data using 
noncompartmental methods and all calculations will be based on actual sampling times. Serum 
concentration vs. time will be plotted for each patient. Mean serum concentration vs. time curves 
will also be presented by assay method (ELISA or LC-MS/MS), route of administration (IV and 
IT administration), dose (0.5mg/kg for IV administration; 10mg and 30mg for IT 
administration), and visit (Week 3 and Week 23 for the initial treatment phase [previously 
untreated patients in HGT-HIT-045], and Months 19, 31, and 43 for the Extended Treatment 
Phase). 
For the IT treatment, the PK parameters will include, but not be limited to, the following: 
• AUC0-∞ - Area under the curve extrapolated to infinity, calculated using the observed 
value of the last non-zero concentration 
• AUC0-t - Area under the curve from the time of dosing to the last measurable 
concentration 
• Cmax - Maximum concentration occurring at tmax 
• tmax - Time of maximum observed concentration sampled during a dosing interval 
• Cl/F - Total body clearance for extravascular administration divided by the fraction of 
dose absorbed. This parameter will be presented with and without normalization for body 
weight. 
• Vz/F - Volume of distribution associated with the terminal slope following extravascular 
administration divided by the fraction of dose absorbed. This parameter will be presented 
with and without normalization for body weight. 
• λz - First order rate constant associated with the terminal (log-linear) portion of the curve 
• t½ - Terminal half-life 
 
For the IV treatment, the PK parameters will include, but not be limited to the following: 
• AUC0-∞ - Area under the curve extrapolated to infinity, calculated using the observed 
value of the last non-zero concentration 
• AUC0-t - Area under the curve from the time of dosing to the last measurable 
concentration 
• Cmax - Maximum concentration occurring at tmax  
• tmax - Time of maximum observed concentration sampled during a dosing interval 
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• Cl - Total body clearance got IV administration. This will be presented with and without 
normalization for body weight. 
• Vz - Volume of distribution associated with the terminal slope. This parameter will be 
presented with and without normalization for body weight 
• Vss - Observed steady-state volume of distribution. This parameter will be presented with 
and without normalization for body weight. 
• MRT - Mean residence time 
• t½ - Terminal half-life 
 
Summary statistics (number of observations, mean, SD, coefficient of variation, median, 
maximum, minimum, and geometric mean) will be determined for all PK parameters and 
presented by assay method (ELISA or LC-MS/MS), route of administration, dose, and visit. 
Serum concentrations of idursulfase at each nominal sampling time will also be summarized by 
assay method, route of administration, dose, and visit using descriptive statistics. 
10.3.3.3 
SOPH-A-PORT Mini S IDDD Safety and Performance 
SOPH-A-PORT Mini S device safety and performance will be summarized 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 IDDD radiological 
assessments will also be presented. 
The proportion of patients with at least one IDDD failure and at least one malfunction, as well as 
the number of and reasons for IDDD failures and malfunctions will be summarized. The rate of 
IDDD failures and malfunctions and the 95% CI will also be estimated. The time from initial 
implant surgery to first IDDD failure and first malfunction will be summarized. Patients without 
an IDDD failure or malfunction will be censored at their last study drug injection date. A 
by-patient listing of the device failure and 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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10.3.3.4 
Exploratory Endpoints 
Descriptive statistics for the observed value and change from baseline of the neurodevelopment 
parameters will be summarized by visit, dose group, and overall. Individual patient values will 
be listed. Observed value and mean change from baseline line plots of neurodevelopment 
parameters by study visit (month) and patient will be presented for DAS-II and SIB-R 
parameters. Scatter plots and correlations between the following parameters will be presented: 
• Standard score for General Conceptual Ability (GCA) and Verbal, Nonverbal, Spatial 
and Special Nonverbal Composite (SNC) scores in DAS-II 
• Standard score for GCA in DAS-II and standard scores for SIB-R 
• Standard score for GCA and average CSF GAG level 
 
The planned analyses and presentations including any exploratory group comparisons will be 
defined in the SAP. 
10.3.3.5 
Protocol Violations 
Protocol violations will be defined as any major protocol deviation that affects study evaluations. 
A list of protocol violations will be presented. 
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11 ADMINISTRATIVE REQUIREMENTS 
11.1 
Good Clinical Practice 
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 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 current version 
of the Declaration of Helsinki. 
11.2 
Investigators and Administrative Information 
Before initiation of the study, the investigators must provide the sponsor with a completed Form 
Food and Drug Administration (FDA) 1572 or Investigator Agreement. Study drug 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. As 
the study involves use of an investigational device and is being conducted in compliance with 
21 CFR 812, the sponsor will obtain a signed agreement from each participating investigator per 
the requirements of 21 CFR 812.43 (c). 
11.3 
Delegation of Responsibilities 
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. 
11.4 
Investigator 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. 
11.5 
Institutional Review Board/ Independent Ethics Committee/Research Ethics Board 
Before initiation of the study, the investigator must provide the sponsor with a copy of the 
written IRB/IEC/research ethics board (REB) 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 study protocol, as given by the sponsor on the cover page of the 
protocol. 
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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 (or as 
required), a final report must be provided to the IRB/IEC. A copy of these reports shall be sent to 
the study clinical monitor. The investigator must maintain an accurate and complete record of all 
submissions made to the IRB/IEC, including a list of all reports and documents submitted. Drug-
related AEs which are reported to the US FDA (IND Safety Reports) or other regulatory 
agencies, and UADEs reported to regulatory agencies must be submitted promptly to the 
IRB/IEC/REB. Unanticipated adverse device effects will be reported to regulatory agencies by 
the device manufacturer consistent with applicable regulations. Copies of UADE reports will be 
submitted to the IRB/IEC/REB in a timely fashion. 
11.6 
Data and Safety Monitoring Board 
Not applicable to this study. 
11.7 
Patient Information and Informed Consent 
Before enrolling in the clinical study, each patient, the patient’s parent(s), or the patient’s 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/her. An 
informed consent form that includes information about the study will be prepared and given to 
the patient, the patient’s parent(s), or the patient’s legally authorized representative(s). This 
document will contain all required elements per ICH and meet all applicable regulatory 
requirements. The informed consent form must be in a language understandable to the patient, 
the patient’s parent(s), or the patient’s legally authorized representative(s) and must specify who 
informed the patient, the patient’s parent(s), or the patient’s legally authorized representative(s). 
Note: When a patient has reached the legal age of consent to participate in a clinical study, but 
has been deemed by the investigator, in accordance with applicable law, as lacking mental 
capacity to provide informed consent, the patient’s parent(s) or legally authorized 
representative(s) will be asked to provide informed consent on behalf of the patient to allow for 
continued participation in the trial. 
After reading the informed consent document, the patient, the patient’s parent(s), or the patient’s 
legally authorized representative(s) must give consent in writing. The patient’s assent (as 
relevant) 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, the patient’s parent(s), or the patient’s legally authorized representative(s) is unable to 
read, oral presentation and explanation of the written informed consent form and information to 
be supplied to the patient must take place in the presence of an impartial witness. 
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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(s). 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 must be given to the patient, the patient’s 
parent(s), or the patient’s legally authorized representative(s). The original signed 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(s) to be used in this study will be provided to the sites 
separately from this protocol. 
11.8 
Patient Confidentiality 
Patient names will not be supplied to the sponsor. Only the patient number and patient initials 
will be recorded in the CRF, 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. 
11.9 
Protocol Compliance 
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 authority(ies) 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 authority(ies) permit, 
expedited review and approval/favorable opinion for minor change(s) in ongoing studies that 
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have the approval/favorable opinion of the IRB/IEC. The sponsor will submit all protocol 
modifications to the regulatory authority(ies) in accordance with the governing regulations. 
A record of patients screened, but not entered into the study, is also to be maintained. There will 
be no protocol exemptions 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 
discuss the planned course of action. Any departures from the protocol must be fully documented 
on the appropriate page of the CRF. 
11.10 Protocol Amendments 
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 Case Report Form Completion 
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 CRF entry must indicate the reason 
for change. The investigator is required to sign the CRF 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 re-signing the 
CRF. 
11.12 Study Monitoring 
Monitoring and auditing procedures that comply with current GCP guidelines will be followed. 
On-site review of the CRFs for completeness and clarity, cross-checking with source documents, 
and clarification of administrative matters will be performed whenever possible; however, 
remote data review and verification may also be conducted during unavoidable circumstances 
(such as the COVID-19 pandemic) to ensure data quality and integrity and maintain patient 
safety. 
The study will be monitored by the sponsor or its designee. 
Whenever possible, monitoring will be done by personal visits from a representative of the 
sponsor (Clinical Study Monitor) who will review the CRFs and source documents to ensure data 
quality and integrity and maintain patient safety. Remote monitoring and data review may also 
be conducted to mitigate significant business disruption during unavoidable circumstances, such 
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as the COVID-19 pandemic. The 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). 
Regulatory authorities, the IEC/IRB, and/or the sponsor may request access to all source 
documents, CRFs, and other study documentation for audit or inspection. Access to these 
documents must be guaranteed by the investigator, who must provide support at all times for 
these activities. 
11.13 Packaging and Labeling 
All packaging and labeling will be in accordance with all applicable regulatory requirements. 
11.13.1 Study Drug 
Idursulfase-IT drug product is a sterile liquid formulation for IT administration that is packaged 
in borosilicate glass vials. The drug product is filled to deliver a minimum dose volume of 
1 mL per vial with minimal waste and for handling convenience in the clinical setting. 
11.13.2 Intrathecal Drug Delivery Device(s) 
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. 
11.14 Storage and Accountability 
11.14.1 Study Drug 
The idursulfase-IT drug product is stored at 5 (±3)°C. 
The fate of all idursulfase-IT study drug delivered to an investigator must be recorded on a 
patient-by-patient basis. The date and time of administration of the study drug will be 
documented on the appropriate CRF. 
All unused study drug and other study materials are to be returned to the sponsor or its designee 
or disposed after sponsor approval per site policy after accountability has been performed. 
11.14.2 Intrathecal Drug Delivery Device(s) 
The SOPH-A-PORT and PORT-A-CATH IDDDs are both sterile, single-use devices. The 
disposition of all devices delivered to a principal investigator must be recorded on a 
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patient-by-patient basis by completing the Accountability Log. The date and time of 
administration of the study drug and use of the 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 devices and 
return of used/unused device(s) is complete, accurate, and ready for review at each monitoring 
visit and/or audit. The sites must ensure that the devices are available for the monitor to 
inventory and prepare for return shipment to the sponsor or designee, if required. 
Please refer to the IDDD manuals for device return instructions. 
11.15 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. 
11.16 Premature Closure of the Study 
11.16.1 Study Termination 
If the sponsor or an investigator discovers 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 Shire and the investigator. In addition, a 
decision on the part of Shire to suspend or discontinue development of the study drug may be 
made at any time. 
11.16.2 Site Termination 
A specific site may be terminated separate from the general study for, but not limited to, the 
following conditions: 
• The discovery of an unexpected, significant, or unacceptable risk to the patients enrolled 
at the site. 
• Failure of the investigator to enter patients at an acceptable rate. 
• 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. 
 
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11.16.3 Record Retention 
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application and until there is 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/institution as to when 
these documents no longer need to be retained. 
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12 PUBLICATION OF STUDY FINDINGS 
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 investigators agree 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, ethics committees, REBs, 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. 
Shire may perform analyses of interim study data for the purpose of publication. 
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25. Blaney SM, Balis FM, Berg S, et al. Intrathecal mafosfamide: a preclinical pharmacology 
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patients with neoplastic meningitis. Journal of clinical oncology : official journal of the 
American Society of Clinical Oncology 2003;21:143-7. 
27. Hoffmann V, Schimrigk S, Islamova S, et al. Efficacy and safety of repeated intrathecal 
triamcinolone acetonide application in progressive multiple sclerosis patients. Journal of the 
neurological sciences 2003;211:81-4. 
28. Munoz-Rojas MV, Vieira T, Costa R, et al. Intrathecal enzyme replacement therapy in a 
patient with mucopolysaccharidosis type I and symptomatic spinal cord compression. Am J 
Med Genet 2008;146A:2538-44. 
29. Nathan PC, Whitcomb T, Wolters PL, et al. Very high-dose methotrexate (33.6 g/m(2)) as 
central nervous system preventive therapy for childhood acute lymphoblastic leukemia: 
results of National Cancer Institute/Children's Cancer Group trials CCG-191P, CCG-134P 
and CCG-144P. Leukemia & lymphoma 2006;47:2488-504. 
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30. Martin HR, Poe MD, Reinhartsen D, et al. Methods for assessing neurodevelopment in 
lysosomal storage diseases and related disorders: a multidisciplinary perspective. Acta 
Paediatr Suppl 2008;97:69-75. 
31. Elliot CD. The Differential Abilities Scales (DAS) San Antonio, TX The Psychological 
Corporation; 1995. 
32. Bayley N. Bayley Scales of Infant and Toddler Development: Third Edition. San Antonio, 
TX The Psychological Corporation; 2005. 
33. Bruininks RH, Woodcock RW, Weatherman RF, Hill BK. Scales of Independent Behavior – 
Revised. Itasca, IL: Riverside Publishing; 1996. 
34. Folio M, Fewell R. Peabody Developmental Motor Scales, Second Examiner's Manual. 
Austin, TX: Pro-ed; 2002. 
35. Folio MR, Fewell R. Peabody Developmental Motor Scales: Examiner’s Manual. 2nd ed. 
Austin TX; 2000. 
36. Bruininks RH, Bruininks BD. Bruininks-Oseretsky Test of Motor Proficiency. In: Pearson 
Assessment 2nd ed. Minneapolis; 2005. 
37. Isquith PK, Crawford JS, Espy KA, Gioia GA. Assessment of executive function in 
preschool-aged children. Ment Retard Dev Disabil Res Rev 2005;11:209-15. 
38. Gioia GA, Isquith PK, Guy SC, Kenworthy L. Behavior rating inventory of executive 
function. Child Neuropsychol 2000;6:235-8. 
39. Isquith PK, Gioia GA, Espy KA. Executive function in preschool children: examination 
through everyday behavior. Dev Neuropsychol 2004;26:403-22. 
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Table 14-4 
Pharmacokinetic Sampling Schedule (Parts A and B) 
Patients/Study Phase 
Drug Administration 
 
PK Sampling Times 
Previously untreated patients in HGT-
HIT-045, during the Initial Treatment 
Phase only  
Intrathecal idursulfase-IT 
Within 15 minutes prior to IT 
injection, then at 1, 2, 3, 4, 6, 8, 12, 
24, 30, and 36 hours following IT 
injection, at Weeks 3 and 23 only 
Elaprase 
Within 15 minutes prior to IV 
infusion; then at 0.5, 1, 1.5, 2, 2.5, 
and 3 hours during the infusion; and 
at 3.5, 4, 5, 6, 7, 9, 11, and 24 hours 
following IV infusion, at Weeks 3 and 
23 only 
All patients, during the Extended 
Treatment Phase 
Intrathecal idursulfase-IT 
Within 15 minutes prior to IT 
injection, then at 1, 2, 3, 4, 6, 8, 12, 
24, 30, and 36 hours following IT 
injection at Months 19, 31, and 43  
 
Note that when vital sign collection and collection of a blood sample for PK analysis are 
scheduled to occur at the same time, vital sign collection should occur first and the blood draw 
for PK sampling should be performed as soon as possible after vital sign collection. The actual 
time of PK sample collection should be recorded. 
 
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15 APPENDIX 2: NEURODEVELOPMENTAL ASSESSMENTS  
Table 15-1 details the specific psychometric instruments that will be used to provide measures of 
each of the relevant neurobehavioral or developmental domain to be assessed. The table also 
summarizes the rules used to select a test for a patient, the clusters/subtests included in each 
instrument and the subscales generated by the test battery. 
Table 15-1 
Summary of Neurodevelopmental Outcome Measures 
Neurobehavioral 
domain to be 
assessed  
Inclusion 
criteria for 
test 
Test battery 
Clusters/subtests for the test 
battery  
Overall outcome measure 
generated from the test 
battery  
 Cognition 
No criteria  Differential 
Ability Scale, 2nd 
edition (DAS II)  
 
OR 
 
Bayley Infant 
Scales of 
Development, 3rd 
edition 
(BSID-III)  
Verbal, Nonverbal, Spatial 
 
 
 
 
 
Cognitive development 
Language development 
Motor development 
General Conceptual Ability 
(GCA)  
Special Nonverbal 
Composite (SNC) 
 
 
Mental Development Index  
Adaptive  
No criteria  Scale of 
independent 
behavior – 
revised (SIB-R) 
  
Broad Independence  
Gross Motor 
<6 years 
Peabody 
Developmental 
Motor Scales 
Object manipulation 
Stationary 
Locomotion 
 
 
6 years 
Bruininks-
Oseretsky Test of 
Motor 
Proficiency, 2nd 
edition 
Fine Manual Control 
Manual Coordination 
Body Coordination 
Strength and Agility 
 
Measures of 
Executive Function 
<6 years  
 
Behavior Rating 
Inventory of 
Executive 
Function 
Preschool version 
(BRIEF-P)  
Behavioral Regulation 
Metacognition 
Global Executive 
Composite Score 
 
6 years 
Behavior Rating 
Inventory of 
Executive 
Function – Parent 
Form (BRIEF)  
Behavioral Regulation 
Metacognition 
Global Executive 
Composite Score 
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Neurodevelopmental Assessment: Clinical Trial Considerations 
The term “neurodevelopmental” refers to the process by which the neurological system matures 
and changes over time. Assessing these changes in a population of children whose neurological 
system is progressively more affected can be very challenging. Typically, neurodevelopmental 
progress is reflected by the child’s abilities to perform certain skills (sitting, walking, and 
talking). However, a child with a neurological disorder may be able to perform age appropriate 
skills but with atypical patterns. For example, the child may be able to walk but his gait is not 
normal. Most assessments will therefore measure the skills, but are not designed to capture the 
abnormalities in pattern or quality of the skill.30 
These qualitative differences will be evident to the skilled test administrator/clinician who is 
familiar with the disorder. However, only longitudinal tracking and repeated measures will 
reveal the significance of these abnormalities in overall function to the less experienced 
clinician.30 
The rate at which different skills develop or regress over time will give insight into the disease 
process. The next step is to determine how the learned skills are used for daily functional 
activities so that as the children grow up they become independent from caregivers. These 
functional skills can be tracked to reflect quality of life issues for both parents and children.30 
Neurodevelopmental assessments described below will be scheduled for administration in the 
morning and estimated to last between 2 and 6 hours. Patients in this study will be evaluated in a 
one-on-one format. 
The list of assessments is: 
Cognition 
• Differential Ability Scales, Second Edition (DAS-II)31 
• Bayley Infant Scales of Development, Third Edition (BSID-III)32 
 
Note: For cognitive testing, the first item set of the 6 main subtests of the DAS-II will be 
administered. If the patient cannot complete these, the BSID-III will be used to assess cognition. 
Adaptive 
• Scales of Independent Behavior-Revised (SIB-R)33 
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Hearing and Visual Abilities 
• Hearing assessment 
• Visual function: clinical assessment 
 
Motor Skills and Voluntary Movement  
• Peabody Developmental Motor Scales, Second Edition (PDMS-2)34, 35 
• Bruininks-Oseretsky Test of Motor Proficiency, Second Edition (BOT-2)36 
 
Executive Function 
• Behavior Rating Inventory of Executive Function-preschool (BRIEF-P)37 
• Behavior Rating Inventory of Executive Function-parent (BRIEF)38 
 
Domain: Cognitive Measures 
Rationale for Choice of Cognitive Assessments 
To achieve the goals of this assessment, the instrument chosen will be either DAS-II or the 
BSID-III. It is intended that the first item set of the 6 main subtests of the DAS-II be 
administered to the patient. If the patient cannot complete these, the BSID-III will be used to 
assess cognition. 
Differential Ability Scales, Second Edition (DAS-II)31 
Purpose: To assess cognitive abilities in children 2.6 years of age and older. 
Description: The DAS-II is a battery of cognitive and achievement tests for children and 
adolescents aged 2 years, 6 months through 17 years, 11 months. As such, it has a wider age 
range than any one of the Wechsler Scales, and it had standard deviations similar to other 
measures. The DAS-II cognitive clusters permit evaluation of strengths and weaknesses. It yields 
a composite standard score focused on reasoning and conceptual abilities called the General 
Conceptual Ability (GCA) score; lower level composite scores for Nonverbal and Verbal skills 
(at the preschool level) and for Nonverbal Reasoning, Verbal, and Spatial skills (at the 
school-age level); and diverse specific ability measures, including the core subsets, which 
compose the GCA, and diagnostic subtests. 
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Bayley Scales of Infant Development, Third Edition (BSID-III)32 
Purpose: To assess cognitive abilities in children 1-42 months years of age. 
Description: The BSID-III assesses 5 key developmental domains in children (ages 
1-42 months): language, social-emotional, motor and adaptive behavior. It consists of a core 
battery of 5 scales. Three scales are administered with child interaction; cognitive, motor, 
language. Two scales are conducted with parent questionnaires; social-emotional, adaptive 
behavior. The Bayley scale is recommended for low-functioning and nonverbal or preverbal 
children. 
Domain: Adaptive Behavior Assessment 
Purpose: To determine the patient’s ability to function independently at home and in a 
community setting via the Adaptive Behavior Assessments listed below. 
Assessment: Scales of Independent Behavior-Revised (SIB-R)33 
This scale measures adaptive functioning from infancy to adulthood. It is widely used scale with 
acceptable validity and reliability. It is designed as a questionnaire that can be easily completed 
by parents during the visit. 
Domain: Audiological Assessment 
The appropriate audiological test battery will be chosen, administered, and interpreted by trained 
clinicians at the test facility. 
Because study patients are at risk for permanent (sensorineural) hearing loss, and some are also 
at increased risk for chronic or recurrent middle ear disease, the assessment of the patient level of 
functioning is crucial for appropriate interpretation of these results with the assessment of speech 
and cognitive function. 
Domain: Motor Assessments 
The topics typically addressed by motor assessments include: a) engaging the environment 
through sensory-motor exploration, b) postural control, c) equilibrium/righting reactions, d) 
protective responses, muscle strength and tone, e) voluntary (automatic and conscious)/reflexive 
movements, balance, and ambulation. 
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Assessment: Peabody Developmental Motor Scales, Second Edition (PDMS-2)34, 35 
The PDMS-2 captures both quantitative and qualitative abilities on some items increasing the 
sensitivity to changing motor patterns as the children’s disease progresses or during recovery. 
There are 3 domains measured using T-scores: stationary, locomotion, and object manipulation. 
Assessment: Bruininks-Oseretsky Test of Motor Proficiency, Second Edition (BOT-2)36 
The Bruininks-Oseretsky Test of Motor Proficiency, Second Edition (BOT-2) is an individually 
administered test that uses engaging, goal-directed activities to measure a wide array of motor 
skills in individuals aged 4-21. It is designed to provide practitioners such as occupational 
therapists, physical therapists, developmental adaptive physical education teachers, and 
researchers, among others, with a reliable and efficient measure of fine and gross motor control 
skills. 
Assessment: Executive Function: Behavior Rating Inventory of Executive Function37-39 
The Behavior Rating Inventory of Executive Function (BRIEF) consists of 2 rating forms: a 
parent questionnaire and a teacher questionnaire designed to assess executive functioning in the 
home and school environments. The BRIEF is useful in evaluating children with a wide 
spectrum of developmental and acquired neurological conditions. Each questionnaire contains 
86 items in 8 nonoverlapping clinical scales and 2 validity scales. These theoretically and 
statistically derived scales form 2 broader Indexes: Behavioral Regulation (3 scales) and 
Metacognition (5 scales), as well as a Global Executive Composite score. 
The observations of parents and teachers provide a wealth of information about a child’s 
behavior that is directly relevant to an understanding of that child’s executive functioning. The 
assessment of executive function in preschool-aged children is often difficult because of the 
variable nature of behavior in this age range (ages 2.0-5.11 years); the limitations in motor and 
verbal proficiency at this age; and the many neuropsychological, psychological, developmental, 
and other medical conditions that begin to manifest during the preschool years. The BRIEF-P is 
the first standardized rating scale designed to specifically measure the range of behavioral 
manifestations of executive function in preschool-aged children—thus facilitating intervention at 
earlier stages of development. 
The BRIEF-P consists of a single rating form used by parents, teachers, and day care providers to 
rate a child’s executive functions within the context of his/her everyday environments - home 
and preschool. The original BRIEF was the basis for the development of the BRIEF-P. 
Consequently, the BRIEF-P is a valid and efficient toll for screening, assessing, and monitoring a 
young child’s executive functioning and development. 
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The hand-scorable BRIEF-P rating form consists of 63 items that measure various aspects of 
executive functioning: Inhibit, Shift, Emotional Control, Working Memory, and Plan/Organize. 
The clinical scales form 3 broad indexes (Inhibitory Self-Control, Flexibility, and Emergent 
Metacognition) and one composite score (Global Executive Composite). 
For this clinical study, only the parent form will be utilized. 
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16 APPENDIX 3: SAMPLE NEUROLOGICAL EXAM 
Performed as an outpatient exam 
Normal 
Abnormal 
Appearance 
 
 
 
Awareness 
 
 
 
Position and spontaneous movements of body 
 
 
 
Responsiveness to touch and handling 
 
 
 
Activity 
 
 
 
Orientation 
 
 
 
Behavior changes (parent’s report) 
 
 
 
Verbal responses 
 
 
Gait 
 
 
Eyes 
 
 
 
Visual changes 
 
 
 
Photophobia 
 
 
 
Pupillary reaction to light 
 
 
 
Spontaneous eye movements 
 
 
 
Vision fields 
 
 
 
Fundus (papilledema, papillitis) 
 
 
Strength 
 
 
Neck stiffness 
 
 
Muscle tone 
 
 
  
Hypertonia 
 
 
 
Hypotonia 
 
 
 
Asymmetry 
 
 
 
Other 
 
 
Cerebellar function 
 
 
 
Rapid alternating movements 
 
 
 
Finger to nose 
 
 
 
Romberg 
 
 
Involuntary movements 
 
 
 
Tics, fasciculations, chorea, athetosis, dystonia, tremor 
 
 
Cranial nerves 
 
 
Deep tendon reflexes 
 
 
 
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17 APPENDIX 4: ADVERSE DEVICE EFFECTS EXPECTED WITH THE 
SOPH-A-PORT IDDD 
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 
 
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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 
 
Note: These are potential complications noted in the Sophysa Instructions for Use for the 
SOPH-A-PORT® Mini S IDDD (Sophysa is the manufacturer of this IDDD). Date of 
Issue: April 2013. 
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18 APPENDIX 5: DEVICE RELATED ADVERSE REACTIONS ASSOCIATED WITH 
THE PORT-A-CATH IDDD 
Risks associated with insertion or use of IDDD 
• Catheter disconnection or fracture 
• Erosion of portal/catheter through the skin 
• Fibrin sheath formation around catheter tip 
• Hematoma 
• Implant rejection 
• Malposition of catheter 
• Migration of portal/catheter 
• Occlusion of portal/catheter 
• Portal site or subcutaneous tract infection 
• Sepsis 
 
Risks associated with intraspinal access 
• Cerebrospinal fluid leaks 
• Dura mater or epidural vein perforation 
• Epidural or intrathecal space infection, which could result in meningitis 
• Meningoencephalitis, which could result in brain injury (eg, seizures, loss of motor 
control or cognitive function) 
• Inadvertent epidural placement 
• Pain on injection 
• Spinal cord or nerve injury 
• Spinal cord pressure, which could lead to paralysis 
• Spinal headache 
 
Note: These are potential complications noted in the Smiths Medical Instructions for Use for the 
PORT-A-CATH® IDDD (Smiths Medical is the manufacturer of this IDDD). Date of 
Issue: September 2008. 
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19 APPENDIX 6: SUMMARY OF CHANGES FOR AMENDMENT 13 
Summary of Changes and the Rationale for the Amendment 
Clinical protocol HGT-HIT-046 has been revised from the previous version as follows: 
• To add language to allow a dosing window of ±7 days to the monthly idursulfase-IT 
injections (ie, every 28 [±7] days), as communicated to the study team on 11 Feb 2019 
• To remove out-of-date data from Study HGT-HIT-046 and reference the idursulfase-IT 
investigator’s brochure 
• To add language with regards to global health emergencies and clinical trial continuity 
• To clarify that neurodevelopmental assessments will be performed annually from 
Month 55 (ie, during Part C of the Extended Treatment Phase) 
• To clarify that ABR assessments will be performed annually during the Extended 
Treatment Phase (Parts B and C) when deemed necessary 
• To clarify that patients may discontinue treatment if an alternative mechanism for 
recombinant human iduronate-2-sulfatase access is developed 
• To clarify that patients with a partial or full device still in place after completion of the 
study will not be followed for safety monitoring 
• To clarify that consecutive lumbar punctures may be performed when there are no safety 
concerns associated with repeat lumbar puncture and repeat sedation/anesthesia 
• To clarify that for cognitive testing, the first item set of the 6 main subtests of the DAS-II 
will be administered, as communicated to the study team on 02 May 2019 
• To clarify and update the SAE reporting information 
• To add language to allow remote source data review and verification when on-site 
monitoring is not possible 
• To correct an error and clarify that brain and spine MRIs will be performed annually 
(rather than every 6 months) from Month 55 (ie, during Part C of the Extended Treatment 
Phase), as communicated to the study team on 02 May 2019 
 
Noteworthy changes and additions to the protocol text are captured below. Bold text indicates 
new or revised text. Strikethrough text indicates deleted text. 
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Changes in grammar, spelling, punctuation, format, minor editorial changes (including changes 
for consistency and clarity), list of abbreviations, and cross references are not reflected in the 
change summary. 
New or Deleted Text 
Change: Language added to allow monthly idursulfase-IT injections to be administered every 28 (±7) days 
Rationale: Clarification of an operational aspect of the study 
Section impacted by this change: Section 1, Protocol Synopsis 
Revised Text  
In the original study design it was planned that idursulfase-IT would be administered once monthly (ie, every 
28 days) via an intrathecal drug delivery device (IDDD) at doses of 1, 10, or 30 mg. Because the 1 mg dose was 
assessed as suboptimal, all patients in the study are currently receiving doses of either 10 or 30 mg. In addition, to 
extend flexibility to patients the idursulfase-IT dosing visit window has been extended so that monthly 
administration may occur every 28 (±7) days. 
… 
This is an open-label extension of Study HGT-HIT-045. This study is designed to evaluate the long term safety and 
clinical outcomes of monthly (ie, every 28 [±7] days) intrathecal (IT) injections of idursulfase-IT (HGT-2310) in 
conjunction with weekly intravenous (IV) infusions of Elaprase in patients with Hunter syndrome and cognitive 
impairment. 
Other sections impacted by this change: Section 5.1, Study Design; Section 5.2.1, Initial Treatment Phase (Part A); 
Section 5.2.2, Extended Treatment Phase (Parts B and C); Section 7.3, Selection and Timing of Dose; Section 8.2, 
Initial and Extended Treatment Phases (All Patients); Section 8.4.15, Intrathecal Idursulfase-IT Injection; 
Section 8.5.14, Intrathecal Idursulfase-IT Injection; Section 14, Appendix 1: Schedule of Study Procedures, 
Table 14-1, Study Procedures for the Initial Treatment Phase: For Patients Who Were Not Treated Previously in 
Study HGT-HIT-045 with Intrathecal Idursulfase-IT (Part A) footnote t; Section 14, Appendix 1: Schedule of Study 
Procedures, Table 14-2, Study Procedures for the Extended Treatment Phase: For All Patients Who Have Received 
6 Months of Treatment with Intrathecal Idursulfase-IT in Study HGT-HIT-045 or Study HGT-HIT-046 (Part B) 
footnote q; Section 14, Appendix 1: Schedule of Study Procedures, Table 14-3, Study Procedures for the Extended 
Treatment Phase: For All Patients Who Have Received 54 Months of Treatment with Intrathecal Idursulfase-IT in 
Study HGT-HIT-045 or Study HGT-HIT-046 (Part C) footnote o 
 
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Change: Removal of out-of-date data from Study HGT-HIT-046 and reference to the idursulfase-IT investigator’s 
brochure 
Rationale: A detailed summary of the latest idursulfase-IT safety information is included in the current edition of the 
investigator’s brochure 
Section impacted by this change: Section 2.4, Previous Human Experience 
Revised Text 
There have been no deaths in any studies of idursulfase-IT. There have been 2 discontinuations from Study HGT
HIT 046 through 12 January 2017. One patient was discontinued by the investigator for behavioral issues unrelated 
to the study. A second patient discontinued due to AEs of IDDD failure, vomiting, and coagulase negative 
staphylococcal CSF infection (which resolved without sequelae). As of 12 January 2017, there have been 14 SAEs 
reported that were related to idursulfase IT. 
… 
Please see the current edition of the investigator’s brochure for a detailed summary of safety information for 
idursulfase-IT. Further information concerning the SOPH-A-PORT Mini S device is provided as an addendum to 
the investigator’s brochure. 
Other sections impacted by this change: Section 2.5, Use of Repeat Lumbar Puncture to Administer Enzyme 
Replacement Therapy; Section 2.7, Benefit/Risk Assessment 
 
Change: Language added with regards to global health emergencies and clinical trial continuity 
Rationale: Clarification of an operational aspect of the study 
Section impacted by this change: Section 2.8, Global Health Emergencies and Clinical Trial Continuity 
Revised Text 
Global health emergencies, such as the COVID-19 pandemic, present significant logistical challenges for 
many clinical sites around the world, with variable restrictions being placed on site resources and operations, 
and on an individual patient’s ability to attend clinic visits. In some places, medical visits are occurring, and 
in others, research clinics are operating with only emergency staff. 
Based on these challenges, it may be necessary to adopt additional measures and procedures to protect 
patient safety, and to ensure that there are no gaps in the conduct of the study for patients enrolled in this 
clinical trial. 
This protocol includes the measures which are approved for implementation within this clinical trial to 
protect patient safety and to ensure the integrity of the trial as a result of COVID-19 only. These measures 
may be implemented in accordance with any requirements and expectations set out by local Institutional 
Review Boards (IRBs)/Independent Ethics Committees (IECs) and National Competent Authorities, as 
necessary. 
These specific measures do not apply for patient management issues that are unrelated to a documented 
impact from a public health emergency, such as the COVID-19 pandemic. 
Other sections impacted by this change: Section 8.1, Study Evaluations and Procedures 
 
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Change: Clarification that neurodevelopmental assessments will be performed annually from Month 55 (ie, during 
Part C of the Extended Treatment Phase) 
Rationale: Clarification of an operational aspect of the study 
Section impacted by this change: Section 5.2.2, Extended Treatment Phase (Parts B and C) 
Revised Text 
For their first 3 months on study (ie, Months 7-9), patients will undergo pretreatment and safety assessments on 
Day 1 and will receive an IT injection of idursulfase-IT on Day 2 of each IT Dosing Week. Standardized 
neurodevelopmental assessments will be performed every 6 months during Part B of the Extended Treatment 
Phase and annually during Part C of the Extended Treatment Phase. 
Other sections impacted by this change: Section 1, Protocol Synopsis; Section 8.5.18, Neurodevelopmental 
Assessments; Section 14, Appendix 1: Schedule of Study Procedures, Table 14-3, Study Procedures for the 
Extended Treatment Phase: For All Patients Who Have Received 54 Months of Treatment with Intrathecal 
Idursulfase-IT in Study HGT-HIT-045 or Study HGT-HIT-046 (Part C) 
 
Change: Clarification that ABR assessments will be performed annually during the Extended Treatment Phase 
(Parts B and C) when deemed necessary 
Rationale: Clarification of an operational aspect of the study 
Section impacted by this change: Section 5.2.2, Extended Treatment Phase (Parts B and C) 
Revised Text  
Auditory brainstem response (ABR), MRI of the spine and brain, and any other procedures deemed necessary, 
such as ABR, that requireing anesthesia will be performed annually. 
Other sections impacted by this change: Section 1, Protocol Synopsis; Section 8.4.10, Auditory Brainstem 
Response; Section 8.5.9, Auditory Brainstem Response; Section 14, Appendix 1: Schedule of Study Procedures, 
Table 14-2, Study Procedures for the Extended Treatment Phase: For All Patients Who Have Received 6 Months of 
Treatment with Intrathecal Idursulfase-IT in Study HGT-HIT-045 or Study HGT-HIT-046 (Part B) footnote r; 
Section 14, Appendix 1: Schedule of Study Procedures, Table 14-3, Study Procedures for the Extended Treatment 
Phase: For All Patients Who Have Received 54 Months of Treatment with Intrathecal Idursulfase-IT in Study 
HGT-HIT-045 or Study HGT-HIT-046 (Part C) footnote p 
 
Change: Clarification that patients may discontinue treatment if an alternative mechanism for recombinant human 
iduronate-2-sulfatase access is developed 
Rationale: Clarification of an operational aspect of the study 
Section impacted by this change: Section 5.3, Study Duration 
Revised Text  
Patients will continue treatment in this extension study, unless they discontinue the study or Shire discontinues the 
study, or an alternative mechanism for recombinant human iduronate-2-sulfatase access is developed, for a 
maximum duration of 14 years of treatment across Studies HGT-HIT-045 and/or HGT-HIT-046. Specifically, 
patients in Group 1 of Study HGT-HIT-046 will receive treatment for at least 4 years in Part B and patients in 
Group 2 of study HGT-HIT 046 will receive treatment for at least 4.5 years in Parts A and B the protocol. Patients 
will receive treatment in Part C for up to 9.5 years. 
Other sections impacted by this change: Not applicable 
 
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HGT-HIT-046 Protocol Amendment 13 
Idursulfase-IT 
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Change: Clarification that patients with a partial or full device still in place after completion of the study will not be 
followed for safety monitoring 
Rationale: Clarification of an operational aspect of the study 
Section impacted by this change: Section 5.3, Study Duration 
Revised Text  
The study will conclude after the last patient has completed his last visit. Patients with a partial or full device still in 
place after completion of the study may will not be followed for safety monitoring  up to an additional 3 years or 
until the device is removed in the last patient. However, the sponsor will arrange reimbursement when the 
device is eventually removed. 
Other sections impacted by this change: Section 1, Protocol Synopsis; Section 5.1, Study Design; Section 8.2, Initial 
and Extended Treatment Phases (All Patients); Section 8.4.2, Physical Examinations; Section 8.4.9, Clinical 
Laboratory Testing; Section 8.5.1, Physical Examinations; Section 8.5.8, Clinical Laboratory Testing 
 
Change: Clarification that consecutive lumbar punctures may be performed when there are no safety concerns 
associated with repeat lumbar puncture and repeat sedation/anesthesia 
Rationale: Clarification of an operational aspect of the study 
Section impacted by this change: Section 7.8, Guidance Concerning Performance of Lumbar Puncture for Study 
Drug Administration and CSF Sample Collection 
Revised Text  
If there are medical contra-indications to the re-implantation of a new device, repeat monthly lumbar punctures may 
be considered as an alternative way of delivering the study drug and obtaining CSF samples under limited 
circumstances. If As long as no safety risks are identified by the investigator, up to 12 consecutive lumbar punctures 
may be performed across Studies HGT-HIT-045 and HGT-HIT-046. Once a patient has reached the maximum of 
12 consecutive lumbar punctures, a new IDDD may be re implanted for subsequent dosing, unless, in the opinion of 
the investigator and medical monitor, assessment of risk/benefit favors continued dosing via lumbar puncture. 
Continued treatment via repeat lumbar puncture beyond the stipulated 12 consecutive monthly doses canshould 
only be considered only in individual cases of patients where this treatment is very well tolerated and the 
investigator has not identified any safety concerns associated with repeat lumbar puncture and repeat 
sedation/anesthesia. 
Other sections impacted by this change: Section 1, Protocol Synopsis; Section 2.5, Use of Repeat Lumbar Puncture 
to Administer Enzyme Replacement Therapy 
 
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Change: Language added to allow remote data review and verification when on-site monitoring is not possible 
Rationale: Clarification of an operational aspect of the study 
Section impacted by this change: Section 11.12, Study Monitoring 
Revised Text  
Monitoring and auditing procedures that comply with current GCP guidelines will be followed. On-site review of 
the CRFs for completeness and clarity, cross-checking with source documents, and clarification of administrative 
matters will be performed whenever possible; however, remote data review and verification may also be 
conducted during unavoidable circumstances (such as the COVID-19 pandemic) to ensure data quality and 
integrity and maintain patient safety. 
The study will be monitored by the sponsor or its designee. 
Whenever possible, Mmonitoring will be done by personal visits from a representative of the sponsor (Clinical 
Study Monitor) who will review the CRFs and source documents to ensure data quality and integrity and 
maintain patient safety. Remote monitoring and data review may also be conducted to mitigate significant 
business disruption during unavoidable circumstances, such as the COVID-19 pandemic. 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). 
Regulatory authorities, the IEC/IRB, and/or the sponsor may request access to all source documents, CRFs, and 
other study documentation for on site audit or inspection. Direct aAccess to these documents must be guaranteed by 
the investigator, who must provide support at all times for these activities. 
Other sections impacted by this change: Not applicable 
 
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19
APPENDIX 6: SUMMARY OF CHANGES FOR AMENDMENT 12
SUMMARY OF CHANGES AND THE RATIONALE FOR THE AMENDMENT
Clinical protocol HGT-HIT-046 has been revised from the previous version as follows:

To add language to clarify those patients who exceed the age of enrollment eligibility for
Study HGT-HIT-045 will be allowed to continue in Study HGT-HIT-046 until the end of
the study. Patients will be re-consented once reaching the applicable legal age of consent.

To indicate that if a patient is deemed as lacking mental capacity to provide informed
consent and in accordance with applicable law, either the patient’s parent(s) or their
legally authorized representative(s) will be asked to sign an informed consent form
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APPENDIX 6: SUMMARY OF CHANGES FOR AMENDMENT 11
SUMMARY OF CHANGES AND THE RATIONALE FOR THE AMENDMENT
Clinical protocol HGT-HIT-046 has been revised from the previous version as follows:

To extend the duration of the study by 5 years.

To allow for patients to retain a full or partial IDDD in situ after they discontinue the
study, at the discretion of the investigator based upon safety assessment, with safety
follow-up.
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APPENDIX 6:  SUMMARY OF CHANGES FOR AMENDMENT 10
SUMMARY OF CHANGES AND THE RATIONALE FOR THE AMENDMENT
Clinical protocol HGT-HIT-046 has been revised from the previous version as follows:

To clarify that patients enrolled in Study HGT-HIT-046 who reach their 18th birthday
while participating are allowed to remain in the study and continue to receive treatment
with idursulfase-IT according to the protocol.
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APPENDIX 6:  SUMMARY OF CHANGES FOR AMENDMENT 9
SUMMARY OF CHANGES AND THE RATIONALE FOR THE AMENDMENT
Clinical protocol HGT-HIT-046 has been revised from the previous version as follows:
A new Schedule of Study Procedures (Part C, Table 14-3) has been created for patients who have 
completed 54 months of treatment with idursulfase-IT in study HGT-HIT-046 or across studies 
HGT-HIT-045 and HGT-HIT 046. It is intended that these patients undergo a streamlined 
schedule of evaluation and assessment to reduce the burden of continued study participation. For 
example, in study Part C pharmacokinetic sampling will no longer be performed, and several 
other assessments have been eliminated or scheduled at a reduced frequency. 
The changes to the protocol in Part C (Month 55 to EOS) include the following:
-
Elimination of blood sample collection for PK and exploratory proteomic biomarker 
testing, and reduced frequency of sample collection for clinical laboratory and other 
(anti-idursulfase antibody, GAG) tests
-
Limited neurodevelopmental assessment focused on cognitive (DAS-II or BSID-III) 
testing; other tests (SIBR, BRIEF/BRIEF-P, PDMS, and BOT-2) no longer administered
after pre-treatment at the Month 55 visit.
-
Monthly symptom-directed physical and neurological exams performed at the 
Investigator’s discretion
-
After Month 55, ICP assessment not repeated until the EOS visit; no lumbar punctures 
are expected to be performed as long as patient has a functioning IDDD for the purpose 
of intrathecal dose administration.
-
Reduced frequency of height, weight, head circumference measurements; after Month 55, 
vision assessment not repeated until the EOS visit.
-
Reduced interval of inpatient stay after IT dosing and reduced frequency of vital signs 
collection after idursulfase-IT injection
-
Provision of additional guidance regarding management of infusion reactions
An interim clinical study report is planned describing the results of Parts A and B. The complete 
results, including Part C, will be described in the final clinical study report.
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APPENDIX 6:  SUMMARY OF CHANGES FOR AMENDMENT 8
SUMMARY OF CHANGES AND THE RATIONALE FOR THE AMENDMENT
Clinical protocol HGT-HIT-046 has been revised from the previous version as follows:

The duration of the study will be extended by 3 years. Patients will continue treatment in the
extension study, unless they discontinue the study or Shire discontinues the study, for a
maximum duration of 9 years of treatment with idursulfase-IT across studies HGT-HIT-045
and/or HGT-HIT-046.

Updates were made to text pertaining to use of the SOPH-A-PORT Mini S IDDD and
analysis of device-related data

The Shire Medical Monitor for the study has changed and the text updated accordingly.
 
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19
APPENDIX 6:  SUMMARY OF CHANGES FOR AMENDMENT 7

Summary of Changes and the Rationale for the Amendment

Clinical protocol HGT-HIT-046 has been revised from the previous version to:

Provide information concerning a new 10 mg/mL concentration of the idursulfase-IT
drug product to be used in the study;

Clarify that in the event of failure of an implanted intrathecal drug delivery device, a
nonfunctional PORT-A-CATH device cannot be replaced by a new PORT-A-CATH
device;

Allow for the assessment of device leachables from residual CSF;

Clarify the definitions of categories of adverse events collected during the study, ie,
events related to idursulfase-IT, device [PORT-A-CATH or SOPH-A-PORT IDDD],
device surgical procedure, IT administration process, or IV Elaprase infusion;

Provide guidance concerning the reporting procedure for abuse, misuse, overdose, or
medication error.

Listing of Changes for the Amendment
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18
APPENDIX 4:  SUMMARY OF CHANGES FOR AMENDMENT 5
1. Summary of Changes and the Rationale for the Amendment
Clinical protocol HGT-HIT-046 has been revised from the previous version (Amendment 4) to 
provide guidance concerning the performance of lumbar punctures during the study for the 
purposes of drug administration and CSF collection, and to align operational aspects of the study 
with recent changes to the protocol of study HGT-HIT-045, which have included the removal of 
the 100 mg dose cohort (HGT-HIT-045 Amendment 13) and the addition of a 1 mg dose cohort 
(HGT-HIT-045 Amendment 11).
Additionally, information concerning the safety of idursulfase-IT and the intrathecal drug 
delivery device in ongoing studies HGT-HIT-045 and HGT-HIT-046 has been updated based on 
a review of safety data available through May 2012 and with data summarized in the current 
edition of the idursulfase-IT Investigator’s Brochure.  Re-assessment of the benefit/risk ratio of 
intrathecal treatment with idursulfase-IT based on the safety data collected through May 2012 
showed that the previous assessment was maintained, ie, the benefit/risk ratio is considered to be 
positive.  Lastly, several refinements were made to the planned statistical analysis.  
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Appendix 4 
Summary of Changes and Justification for Amendment 
Clinical Trial Protocol HGT-HIT-046 has been revised from the previous version 
(29 April 2009).  HGT-HIT-046 is the extension study to Study HGT-HIT-045.  Changes 
incorporated in this protocol amendment are made consistent with revisions incorporated in 
HGT-HIT-045 Protocol Amendment 7, dated 23 March 2010. 
The primary purposes of this amendment were to: 
•
allow for more than one main clinical site.
•
revise safety objectives of the study to clarify that the study’s primary objective and
respective endpoint is the investigation of the safety and tolerability of the investigational
drug, idursulfase-IT, consistent with revision included in HGT-HIT-045 Amendment 7.
•
revise the “naming” of study visits, for patients who were previously untreated with
intrathecal idursulfase-IT  n Study HGT-HIT-045.  The visit previously described as
Baseline/Week 3, initiating the Treatment Period of the protocol, is now defined as Week
1, and subsequent visits are re-numbered accordingly.  The post-surgical follow-up visit
previously described as occurring at Day 3 6 and the post intrathecal idursulfase-IT visit
previously described as occurring at Day 3-7 have each been revised to Day 4, consistent
with the timing detailed in HGT-HIT-045 Amendment 7.
•
For patients who were previously untreated with intrathecal idursulfase-IT in Study the
Safety Follow Up Visit which was previously described at Week 31 has been deleted.
After the completion of the first 6 months of intrathecal idursulfase-IT treatment, these
patients will continue to be treated and monitored in Study HGT-HIT-046 in the
Extended Treatment Phase of the study, following the same treatment and assessment
schedule as that detailed for patients who were previously treated in Study HGT-HIT-
045. Therefore, a Safety Follow Up at Week 31 would be redundant with the
assessments being completed as part of the Extended Treatment Phase.
•
Clarification added to Section 4.3, Study Duration and Dates, to define the maximum
duration of treatment in the study as 3 years for each enrolled patient.
•
Clarification of different requirements for CSF sample assessment prior to administration
of intrathecal idursulfase-IT, for patients participating in the Initial Treatment Phase of
the study vs the Extended Treatment Phase.  During the Initial Treatment Phase of this
study (for patients who were not previously treated with intrathecal idursulfase-IT in
Study HGT-HIT-045), the results of the CSF chemistry and cell count assessment must
be reviewed by the treating Investigator prior to each IT dose.
•
Revision to planned assessments included in the Full Neurodevelopmental Assessment,
consistent with changes previously described in Study HGT-HIT-045 Amendments 5 and
6.
•
Revision to Section 10, Planned Statistical Methods, specifically Section 10.1 and 10.2.
Addition of detail, to clarify that the data will be summarized by Study HGT-HIT-045
treatment group assignment (10 mg, 30 mg, 100 mg and no treatment with intrathecal
idursulfase-IT.)  Extraneous language related to exploratory analyses deleted.  Language
revised consistent with revised safety objectives, to clarify that the study’s primary
objective and respective endpoint is the investigation of the safety and tolerability of the
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investigational drug, idursulfase-IT (consistent with revision included in HGT-HIT-045 
Amendment 7.) 
 
Additional clarifications or changes incorporated in this amendment include: 
• Section 1.3, Idursulfase-IT (Introduction).  Sentence added to reflect initiation of Study 
HGT-HIT-045 in June 2009.  No clinical information available to date. 
• deletion of the Exploratory Endpoint describing the exploration of potential relationships 
between biomarkers and CNS symptomatology.  Although this is defined as one of the 
Exploratory Objectives of Study HGT-HIT-046, defining exploration of a relationship 
between assessments as an endpoint is not appropriate.   
• minor revision to exclusion criterion #5 (applicable only to patients previously untreated 
with intrathecal idursulfase-IT in Study HGT-HIT-045, to clarify that measurement of 
opening CSF pressure upon lumbar puncture may not exceed 30.0 cm H2O (previously 
defined as 30 cm H2O), consistent with revision included in HGT-HIT-045 Amendment 
7 
• • 
addition of a statement (and addition to Schedule of Events) to clarify that a separate 
written informed consent/assent will be required to approve the patient’s participation in 
the study procedures to be conducted at the local site, consistent with revision included in 
HGT-HIT-045 Amendment 7. 
• requirement for additional PT and PTT blood draw (for patients previously untreated with 
idursulfase-IT, participating in the Initial Treatment Phase) if the Pre-Surgery visit is 
more than 2 weeks following the EOS visit for Study HGT-HIT-045 (or Screening Visit, 
if applicable), consistent with revision included in HGT-HIT-045 Amendment 7 
• Section (previously 6.4) Concomitant Therapy separated into 2 Sections, now Section 
6.5, Concomitant Therapy and Section 6.5 Restrictions, per Shire’s standard protocol 
template.  Changes in standard text; no affect on study design. 
• minor corrections to Section 7, Study Procedures to ensure consistency with study plan 
(and consistent with study procedures for Study HGT-HIT-045, Amendment 7, 23 Mar 
2010) as outlined in Schedule of Events and throughout protocol.   
• addition of Section 7.2, Echocardiogram, to the Study Procedures section of the protocol.  
This assessment was previously described in the Schedule of Events but was missing 
from this section. 
• addition of Section 7.9.7, Surgical Implantation of the IDDD to the Study Procedures 
section of the protocol to describe the procedures associated with IDDD implantation, for 
patients who were not previously treated with intrathecal idursulfase-IT in Study HGT-
HIT-045.  Procedures are consistent with those described in Study HGT-HIT-045, 
Amendment 7.  This section was inadvertently missing from the original protocol.   
• addition of Section 7.9.8, Intracranial Pressure Measurement, to the Study Procedures 
section of the protocol to describe the measurement of intracranial pressure.  This is not a 
new addition to the protocol and was previously described in the Schedule of Events 
(Appendix 1 and Appendix 2), but was previously missing from this section. 
• addition of Section 7.12, Elaprase Infusion, to the Study Procedures section of the 
protocol.  This section was inadvertently missing from the original protocol,  
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• addition of Section 7.13.1, Brief Neurodevelopmental Assessments to the Study 
Procedures section of the protocol.  This section was inadvertently missing from the 
original protocol.  A brief neurodevelopmental assessment will be conducted during the 
Initial Treatment Phase, in patients who were previously untreated in Study HGT-HIT-
045, on Week 9 Day 1 (before the 3rd IT injection) and will consist of the SIB-R and 
DAS II tests.   
 
This is also added to the Schedule of Events for the Initial Treatment Phase, consistent 
      with the study design for HGT-HIT-045. 
• clarification that, in the event of early discontinuation, the IDDD will be removed from 
the patient (Section 7.9.7 and Synopsis), consistent with HGT-HIT-045 Amendment 7 
• minor clarifications/corrections to the Schedule of Events (Appendix 1 and Appendix 2) 
and corresponding text in protocol   
• Section 7.12.1.2 in the original Protocol, Infusion-Related Reactions Definition has been 
deleted, consistent with a revision described in Study HGT-HIT-045 Amendment 5 (08 
July 2009).  Upon review by Shire Pharmacovigilance and Risk Management, this section 
has been deemed appropriate for deletion as it contains information that is specific to 
Elaprase and that can be found in the Elaprase package insert.   
• addition of Shire’s Global Pharmacovigilance e-mail contact information for purposes of 
SAE reporting 
• addition of Section 7.14.3, specifying the period of observation for adverse event 
monitoring in Study HGT-HIT-046 ( from time of informed consent until 28 (+7) days 
after the patient’s EOS visit. 
 
In addition, several language changes have been made throughout the protocol, including: 
• references to idursulfase-IT administration throughout protocol were revised to read 
"intrathecal idursulfase-IT" to clarify both the route of administration and formulation, 
and references to idursulfase-IT infusion were revised to "injection", to be more accurate 
• adoption of the terms “Initial Treatment Phase” to describe the study schedule during the 
first 6 months of the extension study, for patients who were previously untreated with 
intrathecal idursulfase-IT in Study HGT-HIT-045, and “Extended Treatment Phase” to 
describe the study schedule for patients who were previously treated with intrathecal 
idursulfase-IT in Study HGT-HIT-045, and for patients continuing in this extension study 
after completion of the Initial Treatment Phase.   
• references to CNS involvement were revised to "early cognitive impairment", providing a 
more accurate description of the patient population being studied, consistent with revision 
included in HGT-HIT-045 Amendment 7 
 
The changes summarized above and detailed below in this document have been made in 
Protocol Amendment 1 (03 May 2010).  The more substantial changes are summarized below 
by section number; new or additional text is indicated in bold and deleted text is indicated as 
strikethrough below.  Editorial changes have been made throughout for consistency and 
grammar.  Other sections affected by the same change are listed below each change.   
 
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CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document constitutes the 
agreement by the recipient that no information contained herein will be published or disclosed without 
written authorization from Takeda. 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN FOR SHP609-046 Final Abbreviated 
CSR  
Protocol Title:  
An Open-Label Extension of Study HGT-HIT-045 Evaluating Long-Term Safety and 
Clinical Outcomes of Intrathecal Idursulfase-IT Administered in Conjunction with 
Intravenous Elaprase® in Pediatric Patients with Hunter Syndrome and Cognitive 
Impairment 
 
    Protocol Number: 
   HGT-HIT-046 (Amendment 13) 
 
    Protocol Date: 
17 Aug 2021 
 
     Investigation Product: idursulfase for intrathecal use (idursulfase-IT [HGT-2310]),  
Device Name:               SOPH-A-PORT® Mini S, Implantable Access Port, Spinal, Mini Unattached, with  
Guidewire (SOPH-A-PORT® Mini S) 
PORT-A-CATH® II Low Profile™ Intrathecal Implantable Access System 
 
     SAP Version:  
  3.0, an addendum to SAP for interim analysis 2.0 
 
 Date: 
 
   21 Feb 2023 
Prepared by:   
  
 
 
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SHP609-046 
STATISTICAL ANALYSIS PLAN FOR FINAL ABBREVIATED CSR
CONFIDENTIAL  
 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS ............................................................................................................................. 3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................................. 4 
1.
INTRODUCTION ............................................................................................................................... 5 
2.
OBJECTIVES AND ENDPOINTS ...................................................................................................... 5 
2.1 Objectives ............................................................................................................................................5
2.2 Endpoints ............................................................................................................................................. 5 
3.
ANALYSIS SETS ............................................................................................................................... 6 
4.
STATISTICAL ANALYSIS ............................................................................................................... 6 
4.1 Patient Disposition ............................................................................................................................... 6 
4.2 Protocol Deviations .............................................................................................................................. 6 
4.3 Demographic and Baseline Characteristics ......................................................................................... 6 
4.4 Treatment Compliance and Extent of Exposure .................................................................................. 6 
4.5 Secondary Pharmacodynamic Analyses .............................................................................................. 7 
4.6 Analysis of Safety ................................................................................................................................ 7 
4.7 SOPH-A-PORT Mini S Device Performance ...................................................................................... 8 
4.8 Concomitant Medications .................................................................................................................... 8 
5.
STATISTICAL/ANALYTIC ISSUES ................................................................................................ 8 
6.
REFERENCES .................................................................................................................................... 8 
7.
APPENDICES ..................................................................................................................................... 8 
 
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STATISTICAL ANALYSIS PLAN FOR FINAL ABBREVIATED CSR
CONFIDENTIAL  
 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
Adverse Event 
CRF 
case report form 
CRO 
contract research organization 
CSF 
cerebrospinal fluid 
CSR 
clinical study report 
ECG 
electrocardiogram 
GAG 
Glycosaminoglycan(s) 
IA 
interim analysis 
ICP 
intracranial pressure 
IDDD 
intrathecal drug delivery device 
IT 
intrathecal 
IV 
intravenous 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
SAP 
statistical analysis plan 
SAS 
Statistical Analysis System© 
SQS 
 
    Statistical & Quantitative Sciences 
  
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SHP609-046 
STATISTICAL ANALYSIS PLAN FOR FINAL ABBREVIATED CSR
CONFIDENTIAL  
 
 
1. 
INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide specifications for the final 
analysis which will appear in the final abbreviated clinical study report (CSR).  
Unless otherwise specified, the analyses in this SAP will apply the same methodologies as 
specified in the SAP for interim analysis (IA) (v2.0, dated 30 Mar 2017). Only safety and 
pharmacodynamic (PD) analyses will be presented in the final abbreviated CSR.  
2. 
OBJECTIVES AND ENDPOINTS 
2.1
Objectives 
The primary objective of this study is to collect long-term safety data in pediatric patients with 
Hunter syndrome and cognitive impairment who are receiving intrathecal idursulfase-IT and 
intravenous (IV) Elaprase® enzyme replacement therapy (ERT).  
The secondary and exploratory objectives are as noted in the SAP for IA in section 4.1. The final 
analyses will not address pharmacokinetic (PK) related or exploratory objectives.  
The device objective is to evaluate the safety and performance of the SOPH-A-PORT Mini S. 
2.2
Endpoints 
The endpoints are defined in section 4.1 of the SAP for IA. The final analyses will focus on the 
safety and PD related endpoints as stated in section 4.1, 5.3 and 5.5 of the SAP for IA. The 
endpoints for the final abbreviated CSR are reiterated below.
The primary endpoint of this study is the safety of intrathecal idursulfase-IT administration. 
Safety will be measured by adverse events (AEs, by type and severity), changes in clinical 
laboratory testing (serum chemistry including liver function tests, hematology, urinalysis), 12-
lead electrocardiogram (ECG), cerebral spinal fluid (CSF) chemistries (contingent on sample 
availability; cell counts, glucose, and protein), anti-idursulfase antibodies, and antibodies having 
enzyme neutralizing activity in CSF and serum. 
The secondary PD endpoints include the change from baseline in CSF biomarkers; e.g., 
glycosaminoglycan (GAG) including heparan sulfate /dermatan sulfate) and the change from 
baseline in urinary GAGs. 
The SOPH-A-PORT Mini S device will be evaluated using assessments of device implantation, 
device function, device longevity and adverse events associated with the implant surgery or 
device. This data will be collected on the patient’s CRF from the time of initial implantation.   
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STATISTICAL ANALYSIS PLAN FOR FINAL ABBREVIATED CSR
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3.
ANALYSIS SETS
All PD and safety data analysis will be performed using the Safety Population which is defined 
as follows: all eligible patients from HGT-HIT-045 who have agreed to participate in the 
extension study and have had either surgical implantation of an intrathecal drug delivery device 
(IDDD) or intrathecal administration of study drug in the extension study. The definitions of 
each analysis population are stated in section 6.2 of the SAP for IA; however, the focus of the 
final analyses will be safety and PD endpoints. 
4. 
STATISTICAL ANALYSIS 
All statistical analyses will be performed by Statistics & Quantitative Sciences (SQS) 
Department at Takeda or its designated contract research organization (CRO) unless otherwise 
specified, using SAS® software version 9.4 or higher (SAS Institute, Cary, N.C., USA). 
The statistical methodology supporting the trial will focus on descriptive rather than inferential 
approaches, given the early phase and objectives of the trial.  
Summary tables will be tabulated as the format noted in section 6.1 of the SAP for IA. The 
complete results including Parts A, B & C will be described in the final abbreviated CSR.  
4.1
Patient Disposition 
The patient disposition (signed informed consent, patient population, and treatment status 
[completed, discontinued/withdrew]) will be presented in summary tables using number and 
percentage of subjects by treatment dose and overall, for the Safety Population. Reasons for 
discontinuation/withdrawal will be presented. 
4.2
Protocol Deviations
Protocol deviations will be presented in a listing as noted in section 6.4 of the SAP for IA. 
4.3
Demographic and Baseline Characteristics
Demographic and baseline characteristics (as detailed in section 6.5 of the SAP for IA) will be 
presented in summary tables by treatment dose and overall, for the Safety Population. 
4.4
Treatment Compliance and Extent of Exposure
The same methodology as in SAP for IA Section 6.6 will be used. Treatment compliance and 
extent of exposure will be summarized for the Safety Population.
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4.5
Secondary Pharmacodynamic Analyses 
The CSF GAG levels will be presented in graphs (individual patient data as well as mean 
observed data by visit) and descriptive statistics will be in summary tables (observed values, 
change from baseline and percent change from baseline) as noted in section 6.7.2.1 of the SAP 
for IA; however, they will not be limited to Month 55. All available scheduled visits to the end of 
study (including Part C) will be included in tables by treatment dose and overall. 
The urine GAG levels will be presented in graphs (individual patient data as well as mean 
observed data by visit) and descriptive statistics will be in summary tables (observed values, 
change from baseline and percent change from baseline) as noted in section 6.7.2.2 of the SAP 
for IA; however, they will not be limited to Month 55. All available scheduled visits to the end of 
study (including Part C) will be included in tables by treatment dose and overall. 
4.6
Analysis of Safety 
Similar methodology as in the SAP for IA section 6.8 will be used for the Safety Population. 
The primary assessments of this study are the safety of idursulfase-IT administration. Safety will 
be measured by AEs (by type and severity), changes in clinical laboratory testing (serum 
chemistry including liver function tests, hematology, urinalysis), 12-lead ECG, CSF chemistries 
(contingent on sample availability; cell counts, glucose, and protein), anti-idursulfase antibodies 
and antibodies having enzyme neutralizing activity in CSF and serum. 
Adverse events will be presented as detailed in section 6.8.1 of the SAP for IA. The clinical and 
CSF laboratory results will be presented as detailed in section 6.8.2 of the SAP for IA; however, 
they will be summarized for all available scheduled study visits to the end of study. The 12-lead 
ECG results will be presented as detailed in section 6.8.3 of the SAP for IA; however, they will 
be summarized for all available scheduled study visits to the end of study. The infusion (IV) and 
injection (IT) vital signs and regular vital signs will be listed as detailed in section 6.8.4 of the 
SAP for IA; however, they will be summarized for all available scheduled visits up to the end of 
the study. 
Similar methodology as in SAP for IA section 6.8.6 will be applied to the Safety Population for:  
 Anti-idursulfase antibody formation (specifics in section 6.8.6.1)  
 The idursulfase enzyme levels in CSF (specifics in section 6.8.6.2) 
 Intracranial pressure (ICP) measurement (cm of H2O) (specifics in section 6.8.6.3) 
 Height (cm), weight (kg), and head circumference (cm) (specifics in section 6.8.6.4). 
 
The details are in sections of the SAP for IA mentioned above; however, presentations will not 
be limited to Month 55. They will include all available scheduled study visits to the end of study.  
For non-commercial use only


SHP609-046 
STATISTICAL ANALYSIS PLAN FOR FINAL ABBREVIATED CSR
CONFIDENTIAL  
 
 
All safety analyses will be descriptive, no statistical testing will be performed. 
4.7
SOPH-A-PORT Mini S Device Performance
The SOPH-A-PORT Mini S device will be evaluated using assessments of device implantation, 
device function, device longevity and adverse events associated with the implant surgery or 
device. This data will be collected on the patient’s case report form (CRF) from the time of 
initial implantation. 
See section 6.8.6.5 of the SAP for IA for details regarding device-related terminology as well as 
well as device performance analyses to be presented. 
4.8
Concomitant Medications 
See section 6.8.7 of the SAP for IA regarding concomitant medications related presentations.   
5. 
STATISTICAL/ANALYTIC ISSUES 
See section 8 of the SAP for IA. This section has 9 subsections which give details on adjustment 
for covariates, handling of dropouts/missing data, IA and data monitoring, multicenter studies, 
multiple comparisons/multiplicity, examination of subgroups or interactions, sensitivity analyses, 
windowing visits, and data listings. 
6. 
REFERENCES 
1. Statistical Analysis Plan for Interim Analyses (for Protocol HGT-HIT-046, amendment 
9). Version 2.0. 30 March 2017. 
7. 
APPENDICES 
See section 10 of the SAP for IA for appendix I: list of statistical outputs and appendix II: 
protocol violations definitions.
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For non-commercial use only


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TABLE OF CONTENTS
TABLE OF CONTENTS.................................................................................................................3
1
ABBREVIATIONS AND DEFINITIONS OF TERMS ...........................................................6
2
INTRODUCTION .....................................................................................................................9
2.1
Background ................................................................................................................9
2.2
Study Rationale ..........................................................................................................9
3
PURPOSE OF STATISTICAL ANALYSIS PLAN ...............................................................10
4
SUMMARY OF CLINICAL TRIAL FEATURES.................................................................11
4.1
General Description..................................................................................................11
4.2
Determination of Sample size/Randomization.........................................................14
5
EFFICACY AND SAFETY VARIABLES.............................................................................15
5.1
Schedule of Evaluations...........................................................................................15
5.2
Primary Efficacy Variable(s) ...................................................................................15
5.3
Secondary Pharmacodynamic (PD) Variables .........................................................15
5.4
Pharmacokinetic (PK) Assessments.........................................................................15
5.5
Safety Assessments ..................................................................................................15
5.6
Exploratory Endpoints..............................................................................................15
5.7
SOPH-A-PORT Mini S Device Assessment............................................................16
6
STATISTICAL ANALYSIS ...................................................................................................17
6.1
General Methodology...............................................................................................17
6.2
Analysis Populations................................................................................................18
6.3
Patient Disposition ...................................................................................................18
6.4
Protocol Deviations..................................................................................................18
6.5
Demographic and Other Baseline Characteristics....................................................18
6.6
Treatment Compliance and Extent of Exposure ......................................................19
6.7
Analysis of Efficacy.................................................................................................19
6.7.1
Primary Efficacy Analysis.....................................................................................19
6.7.2
Secondary Pharmacodynamics Analyses...............................................................19
6.7.2.1
CSF GAG levels.....................................................................................19
6.7.2.2
Urine GAG levels...................................................................................20
6.7.3
Subset Analyses .....................................................................................................20
6.7.4
Exploratory Analyses.............................................................................................20
6.7.4.1
Differential Ability Scale, second edition (DAS-II) and Bayley 
Scales of Infant Development (BSID-III) Analyses...............................21
6.7.4.2
Scale of Independent Behavior- revised (SIB-R) Analyses...................22
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6.7.4.3
Behavior Rating Inventory of Executive Function (BRIEF) Analysis 
– Regular Version and Preschool Version (BRIEF-P)...........................23
6.7.4.4
Peabody Developmental Motor Scales-2 (PDMS-2) and Bruininks-
Oseretsky Test of Motor Proficiency 2nd edition (BOT-2) Analyses....23
6.7.4.5
Correlation Analyses..............................................................................24
6.7.4.6
Brain MRI ..............................................................................................25
6.7.4.7
Auditory Brain Stem Response (ABR) ..................................................25
6.7.4.8
Hearing Assessment ...............................................................................26
6.7.4.9
Vision Assessment .................................................................................26
6.8
Analysis of Safety ....................................................................................................26
6.8.1
Adverse Events ......................................................................................................27
6.8.2
Clinical and CSF Laboratory Evaluations .............................................................28
6.8.3
12-Lead ECG Evaluations .....................................................................................28
6.8.4
Vital Signs..............................................................................................................29
6.8.5
Physical and Neurological Findings ......................................................................30
6.8.6
Other Observations Related to Safety....................................................................30
6.8.6.1
Anti-Idursulfase Antibody Formation....................................................30
6.8.6.2
CSF Enzyme Level.................................................................................30
6.8.6.3
Intracranial Pressure...............................................................................31
6.8.6.4
Height, Weight, and Head Circumference .............................................31
6.8.6.5
SOPH-A-PORT Mini S Device Performance ........................................32
6.8.7
Concomitant Medications......................................................................................34
6.9
Analysis of Pharmacokinetic Data ...........................................................................34
6.9.1
Concentration Data ................................................................................................34
6.9.2
Handling BLQ Values............................................................................................34
6.9.3
Pharmacokinetic Parameters..................................................................................35
6.10
Drug-Drug and Drug-Disease Interactions ..............................................................36
7
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES...............37
7.1
Changes in the Conduct of the Study.......................................................................37
7.2
Changes from the Analyses Planned in the Protocol ...............................................37
8
STATISTICAL/ANALYTIC ISSUES ....................................................................................38
8.1
Adjustment for Covariates .......................................................................................38
8.2
Handling of Dropouts or Missing Data....................................................................38
8.3
Interim Analyses and Data Monitoring....................................................................38
8.4
Multicenter Studies ..................................................................................................38
8.5
Multiple Comparisons/Multiplicity..........................................................................38
8.6
Examination of Subgroups and Interactions ............................................................38
8.7
Sensitivity Analyses .................................................................................................38
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8.8
Windowing Visits.....................................................................................................38
8.9
Data Listings ............................................................................................................39
9
REFERENCES ........................................................................................................................40
10 APPENDICES .........................................................................................................................41
10.1
Appendix I  List of Statistical Outputs.....................................................................41
10.2
Appendix II Protocol Violations Definitions ...........................................................41
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1
ABBREVIATIONS AND DEFINITIONS OF TERMS
ABR
auditory brainstem response
AE
adverse event
ATC
Anatomic therapeutic class
AUC0-∞
Area under the curve extrapolated to infinity, calculated using the observed value 
of the last non-zero concentration
AUC0-t
Area under the curve from the time of dosing to the last measureable concentration
BBB
Blood brain barrier
BLQ
Below the lower limit of quantification
BOT-2
Bruininks-Oseretsky Test of Motor Proficiency, Second Edition
BRI
Behavioral Regulation Index
BRIEF
Behavior Rating Inventory of Executive Function 
BRIEF-P
Behavior Rating Inventory of Executive Function-Preschool
BSID-III
Bayley Scales of Infant Development, Third Edition
CBC
complete blood count
CI
confidence interval
CL
Total body clearance for intravenous administration
CL/F
Total body clearance for extravascular administration divided by fraction of dose 
absorbed
Cmax
Maximum serum concentration at tmax 
CNS
central nervous system
CS
clinically significant
CSF
cerebrospinal fluid
CSR
Clinical study report
DAS-II
Differential Ability Scales, Second Edition
DQ
Developmental Quotient
DS
dermatan sulfate
eCRF
Electronic case report form
EC
Emotional Control
ECG
electrocardiogram
EMI
Emergent Metacognition Index
EOS
end of study
ERT
enzyme replacement therapy
FI
Flexibility Index
FMQ
Fine Motor Quotient
GAG
glycosaminoglycan
GCA
General Conceptual Ability
GEC
Global Executive Composite
GMQ
Gross Motor Quotient
HS
heparan sulfate
IA
ICP
interim analysis
intracranial pressure
IDDD
intrathecal drug delivery device
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ILP
Inter-peak latency
ISCI
Inhibitor Self-Control Index
IT
intrathecal
IV
intravenous
KM
Kaplan-Meier
LLOQ
Lower limit of quantification
LP
Lumbar puncture
MedDRA
Medical Dictionary for Regulatory Activities 
mg
milligram(s)
MI
Megacognition Index
Min
minimum
Max
maximum
MMRM
Mixed Model for Repeated Measures
MRI
magnetic resonance imaging
MRT
Mean residence time
NA
Not applicable
NCS
not clinically significant
PDMS-2
Peabody Developmental Motor Scales-2
PK
pharmacokinetic(s)
PO
Plan/Organize
PORT-A-CATH
PORT-A-CATH® II Low Profile™Intrathecal Implantable Access System
PT
prothrombin time
PTA
Pure tone average
PTT
partial thromboplastin time
Q1
25th percentile
Q3
75th percentile
QTc
corrected QT interval
SAE
serious adverse event
SAP
Statistical Analysis Plan
SIB-R
Scale of Independent Behavior-revised
SNC
Special Nonverbal Composite
SOC
system organ class
SOPH-A-PORT Mini S
SOPH-A-PORT® Mini S, Implantable Access Port, Spinal, Mini Unattached, with 
Guidewire
SD
Standard deviation
Std. Err.
Standard error
SS
Standard score
t1/2
Terminal half-life
T4
thyroxine
tmax
Time to maximum serum concentration during a dosing interval
TEAE
Treatment-emergent adverse event
TMQ
Total Motor Quotient
Vss
Apparent volume of distribution at steady-state
Vss(%BW)
Vss normalized for body weight
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Vz
Volume of distribution associated with the terminal slope
Vz/F
Volume of distribution associated with the terminal slope following extravascular 
administration divided by the fraction of dose absorbed
WHO
World Health Organization
WM
Working Memory
λz
First order rate constant associated with the terminal (log-linear) portion of the 
curve
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2
INTRODUCTION
2.1
Background
Hunter syndrome is an extremely rare disease with an estimated incidence of 1 in 162,000 live 
births worldwide. It is expected that approximately 67%-77% of these patients will present with 
the severe phenotype of the disease that includes progressive cognitive impairment 
(communicating hydrocephalus, increased intracranial pressure, seizures and hearing problems) 
and serious somatic disease.
2.2
Study Rationale 
The active ingredient of idursulfase-IT (for intrathecal use) drug product is idursulfase 
(recombinant human iduronate-2-sulfatase), which is the same active ingredient in commercially 
available Elaprase® (for intravenous use). Elaprase is approved in the EU, the USA, Canada, 
Japan, and other countries as an intravenously administered enzyme replacement therapy (ERT) 
for patients with Hunter syndrome. Large proteins such as Elaprase are not expected to cross the 
blood brain barrier (BBB) in sufficient amounts to be therapeutically beneficial. Therefore, it is 
not possible to treat the progressive brain disease in severe Hunter syndrome with Elaprase, and 
direct administration of the active enzyme to the central nervous system is required. A 
formulation appropriate for intrathecal administration of idursulfase (idursulfase-IT) using an 
intrathecal drug delivery device (IDDD) has been developed to address this unmet medical need 
in an extremely rare population. The advantage of using an IDDD in a chronic disease such as 
Hunter syndrome is the potential to obviate the need for multiple lumbar punctures for drug 
delivery.
Nonclinical experience with intrathecal administration of idursulfase-IT has demonstrated wide 
distribution of idursulfase to the central nervous system (CNS) tissues. Idursulfase-IT has been 
shown to be well tolerated in several species and to be active in a murine disease model of 
idursulfase deficiency.
Extended access of idursulfase-IT treatment to patients with Hunter syndrome and cognitive 
impairment who have had an IDDD implanted specifically for participation in Study HGT-HIT-
045, and inclusion of the previously untreated patients of Study HGT-HIT-045, will provide an 
opportunity for evaluation of long-term safety and clinical outcomes in this patient population.
Monthly IT administration of idursulfase-IT in conjunction with weekly IV infusion of Elaprase 
was well tolerated in HGT-HIT-045, a completed Phase I/II safety and ascending dose ranging 
study in pediatric patients with Hunter syndrome and cognitive impairment. Extension study 
HGT-HIT-046 is intended to continue evaluation of the effects of IT administration of 
idursulfase-IT on long-term safety and clinical outcomes for patients who enrolled in HGT-HIT-
045. This study will also provide an opportunity for patients who participated, but did not receive 
treatment in HGT-HIT-045 to receive IT treatment with idursulfase-IT.
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3
PURPOSE OF STATISTICAL ANALYSIS PLAN
The Study HGT-HIT-046 is an open-label extension of Study HGT-HIT-045. One interim 
analysis (IA) is planned for this extension study. The interim analysis of study data will be 
conducted at the completion of the 6 months of the antecedent study (HGT-HIT-045) or the 6 
months of Initial Treatment Phase (Part A) of this extension study and the 54 months of the 
Extended Treatment Phase Part B of this extension study. The purpose of this statistical analysis 
plan (SAP) is to document technical and detailed specifications for the interim analysis of data 
collected for protocol HGT-HIT-046 Amendment 9. Results of the interim analysis described in 
this SAP will be included in the interim clinical study report (CSR). Additionally, the planned 
analyses identified in this SAP will be included in regulatory submissions or future manuscripts. 
Any post-hoc, or unplanned analyses performed to provide results for inclusion in the interim 
CSR but not identified in this prospective SAP will be clearly identified in the interim CSR.
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4
SUMMARY OF CLINICAL TRIAL FEATURES
4.1
General Description
Study Objectives
The primary objective of this study is:

To collect long-term safety data in pediatric patients with Hunter syndrome and 
cognitive impairment who are receiving intrathecal idursulfase-IT and 
intravenous (IV) Elaprase® enzyme replacement therapy (ERT)
The secondary objectives of this study are:

To determine the serum pharmacokinetic (PK) profile of idursulfase when 
administered as intrathecal idursulfase-IT and in conjunction with Elaprase

To determine the effect of intrathecal idursulfase-IT, given in conjunction with 
Elaprase, on cerebral spinal fluid (CSF) biomarkers (eg, total glycosaminoglycan 
[GAG] including heparan sulfate [HS]/dermatan sulfate [DS])

To determine the effects of intrathecal idursulfase-IT, given in conjunction with 
Elaprase, on urinary GAG 
The exploratory objectives of this study are:

To evaluate the long-term effects of intrathecal idursulfase-IT, given in 
conjunction with Elaprase, on clinical parameters (e.g., physiological 
assessments, neurocognitive assessments, neurologic function, and brain 
structure volumes)

To evaluate the long-term effects of intrathecal idursulfase-IT, given in 
conjunction with Elaprase, on functional activities of daily living, as determined 
by the Scales of Independent Behavior-Revised (SIB-R)

To explore potential relationships between biomarkers and CNS 
symptomatology

To determine whether monthly idursulfase-IT administrations results in 
accumulation of idursulfase within the CSF compartment by measuring 
idursulfase levels in CSF immediately prior to idursulfase-IT administration

To determine the safety and performance of the SOPH-A-PORT Mini S
Study Endpoints
The primary endpoints of this study are:

Safety of intrathecal idursulfase-IT administration. Safety will be measured by 
adverse events (AEs) (by type and severity), changes in clinical laboratory 
testing (serum chemistry including liver function tests, hematology, urinalysis), 
12-lead electrocardiogram (ECG), CSF chemistries (contingent on sample 
availability; cell counts, glucose, and protein), anti-idursulfase antibodies and 
antibodies having enzyme neutralizing activity in CSF and serum
The secondary endpoints of this study are:

Serum idursulfase concentration-time profiles and serum PK parameters of 
idursulfase, administered as intrathecal idursulfase-IT and in conjunction with 
Elaprase

Change from baseline in CSF biomarkers (eg, GAG [HS/DS])

Change from baseline in urinary GAGs
The exploratory endpoints for this study are:

Change from baseline in additional clinical parameters (e.g., physiological 
assessments, standardized neurocognitive assessments, neurologic function, brain 
magnetic resonance imaging [MRI])

Change from baseline in functional activities of daily living parameters

Levels of idursulfase in CSF immediately prior to idursulfase-IT administration
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
Exploration of potential relationships between biomarkers and CNS 
symptomatology
SOPH-A-PORT Mini S assessments will include:

The SOPH-A-PORT Mini S device will be evaluated using assessments of 
device implantation, device function, device longevity and adverse events 
associated with the implant surgery or device. This data will be collected on the 
patient’s CRF from the time of initial implantation.

As part of the assessment of the SOPH-A-PORT Mini S, it may be necessary to 
determine the levels of leachables from the device into the CSF and blood. 
Samples of stored CSF and serum may be used to determine the levels of 
leachable materials related to the IDDD
Study Design
This is an open-label extension of Study HGT-HIT-045.  This study is designed to 
evaluate the long term safety and clinical outcomes of monthly IT injection of idursulfase-
IT (HGT-2310) in conjunction with weekly IV infusion of Elaprase in patients with 
Hunter syndrome and cognitive impairment. 
Patients who participated in Study HGT-HIT-045 and completed the HGT-HIT-045 end-
of-study (EOS) evaluations, and meet all criteria for inclusion in this extension study will 
be eligible for enrollment.  
There are 2 patient groups in Study HGT-HIT-046: those (Group 1) that
were previously treated in the antecedent study (HGT-HIT-045) and continue to receive
treatment in Part B (defined as Months 7 to 54) of this extension study, and those (Group 
2) that were not previously treated in the antecedent study and receive treatment in Parts 
A (defined as Months 0 to 6) and B (defined as Months 7 to 54) of this extension study. 
Once patients in Study HGT-HIT-046 have completed Part B, they may continue to 
receive treatment with idursulfase-IT in Part C (defined as Months 55 to 108) while 
undergoing a reduced, and less burdensome, schedule of study assessments. The 
completion of 54 months of treatment is assessed at Pre-Treatment Month 55 Visit.
Initial Treatment Phase (previously untreated patients only, Part A):  Patients who did not 
receive treatment with intrathecal idursulfase-IT in Study HGT-HIT-045 will, during the 
Initial Treatment Phase of this study (i.e., the first 6 months), undergo treatment and 
assessments corresponding in schedule and content to those performed for patients who 
were treated in Study HGT-HIT-045.  After completion of the Initial Treatment Phase and 
if there are no safety concerns, patients may continue receiving monthly intrathecal 
idursulfase-IT in the Extended Treatment Phase of this study.  The dose of idursulfase-IT 
to be administered to a patient in the initial treatment phase was planned to correspond to 
the dose (1, 10, or 30 mg) received by other patients in the same cohort of Study HGT-
HIT-045 within which the patient was randomized.  
Extended Treatment Phase (all patients, Parts B and C):  Patients who received 6 months 
of treatment with intrathecal idursulfase-IT in HGT-HIT-045 will be eligible for 
enrollment after completing the EOS evaluations in Study HGT-HIT-045.  If there are no 
safety concerns, previously treated patients may continue receiving monthly intrathecal 
idursulfase-IT in this extension study.  The dose of idursulfase-IT to be administered to a 
patient in the extended treatment phase was planned to correspond to the dose (1, 10, or 
30 mg) received by the patient in Study HGT-HIT-045. 
In the original study design, it was planned that idursulfase-IT would be administered 
intrathecally once monthly (i.e., every 28 days) via an IDDD at doses of 1, 10, or 30 mg.  
Because the 1 mg dose was assessed as suboptimal, all patients in the study are currently 
receiving doses of either 10 or 30 mg.
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It is intended that the IDDD be used to deliver IT injections of study drug and to obtain 
CSF samples.  No other medication will be administered through the device. Should the 
IDDD become nonfunctional during the study, causing the IT space to be inaccessible via 
the device, or its use is otherwise precluded on a scheduled day of dosing, lumbar 
puncture may be performed under prescribed circumstances for the purposes of study drug 
administration and CSF sample collection. Site personnel will refer to the IDDD manual, 
which provides details on the investigation and management of any IDDD-related issues.
General anesthesia may be required for injections of study drug and some evaluations, and 
can be used at the discretion of the Investigator as indicated in the study manuals. It is 
anticipated that study procedures such as lumbar puncture, MRI, and audiometry will 
have to be performed with sedation/anesthesiology support.
Due to recurrent issues with the PORT-A-CATH IDDD, Shire has qualified a new IDDD 
for use in this study, the SOPH-A-PORT Mini S.  It is intended that use of the PORT-A-
CATH will be phased out in favor of use of the SOPH-A-PORT Mini S device.  An 
implanted PORT-A-CATH IDDD will be allowed to remain in situ for as long as it is 
functional, but when a PORT-A-CATH IDDD becomes nonfunctional and needs to be 
replaced, it will be replaced by a SOPH-A-PORT Mini S IDDD. 
If patients in the study require revision and/or replacement of the PORT-A-CATH IDDD, 
it will be removed and replaced with the SOPH-A-PORT Mini S device at a time judged 
appropriate by the Investigator. A nonfunctional PORT-A-CATH IDDD cannot be 
replaced by a new PORT-A-CATH device.
Surgical IDDD implantation and revision will be performed at the main study center only.
Explanation of the IDDD will be performed at the main study center or at the patient’s 
local site, as necessary.
Patients will have the IDDD removed when they discontinue participation in the study, 
unless they are continuing to receive treatment through another mechanism (eg, 
supplemental study, expanded access program, etc).
Number of 
Patients
Patients who participated in Study HGT-HIT-045 and completed the HGT-HIT-045 EOS 
evaluations, and meet all criteria for inclusion in this extension study will be eligible for 
enrollment. Up to 15 patients are expected.
Study Product
Idursulfase for intrathecal administration (idursulfase-IT, HGT-2310) 1, 10 or 30 mg, 
once monthly, using either SOPH-A-PORT® Mini S, Implantable Access Port, Spinal, 
Mini Unattached, with Guidewire (SOPH-A-PORT Mini S) or PORT-A-CATH® II Low 
Profile™Intrathecal Implantable Access System (PORT-A-CATH)
Commercially available Elaprase for IV infusion will be prescribed by the patient’s 
treating physician and will be administered throughout the study as an IV infusion at a 
weekly dose of 0.5 mg/kg in accordance with the local prescribing information.
Treatment and 
Study Duration
Patients will continue treatment in this extension study, unless they discontinue the study 
or Shire discontinues the study, for a maximum duration of 9 years of treatment across 
studies HGT-HIT-045 and HGT-HIT-046. Specifically, patients in Group 1 of Study 
HGT-HIT-046 will receive treatment for at least 4 years in Part B and patients in Group 2 
of study HGT-HIT-046 will receive treatment for at least 4.5 years in Parts A and B the 
protocol.
The study will conclude after the last patient has completed his last visit.
Randomization 
and Blinding
Patients entering the Initial Treatment Phase (previously untreated patients only) received 
the dose of idursulfase-IT during the initial treatment dose corresponding to the dose 
(1,10, or 30 mg) received by other patients in the same cohort of Study HGT-HIT-045 
within which the patient had originally been randomized.
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4.2
Determination of Sample size/Randomization
This is an open-label extension of Study HGT-HIT-045. Patients who participated in Study 
HGT-HIT-045 and completed the HGT-HIT-045 EOS evaluations, and met all criteria for 
inclusion in this extension study were eligible for enrollment. Up to 15 patients are expected. 
Patients entering the Initial Treatment Phase (previously untreated patients only) received the 
dose of idursulfase-IT  corresponding to the dose (1,10, or 30 mg) received by other patients in 
the same cohort of Study HGT-HIT-045 within which the patient had originally been 
randomized. No new randomization scheme was utilized. Because the 1 mg dose was assessed as 
suboptimal, all patients in the study are currently receiving doses of either 10 or 30 mg.
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5
EFFICACY AND SAFETY VARIABLES
5.1
Schedule of Evaluations
This extension study has 2 phases: an Initial Treatment Phase (previously untreated patients only, 
Part A) and an Extended Treatment Phase (all patients, Parts B and C). The detailed schedule of 
evaluations is located in the HGT-HIT-046 protocol (Amendment 9).
5.2
Primary Efficacy Variable(s)
Efficacy is not a primary endpoint of this study.
5.3
Secondary Pharmacodynamic (PD) Variables
The secondary PD endpoints include:

Change from baseline in CSF biomarkers (eg, GAG [HS/DS])

Change from baseline in urinary GAGs
5.4
Pharmacokinetic (PK) Assessments
The PK variables of this study are:

Serum and CSF concentrations of idursulfase

Pharmacokinetic variables are described in Section 6.9.3
5.5
Safety Assessments
The primary endpoint of this study is the safety of intrathecal idursulfase-IT administration. 
Safety will be measured by adverse events (by type and severity), changes in clinical laboratory 
testing (serum chemistry including liver function tests, hematology, urinalysis), 12-lead ECG, 
CSF chemistries (contingent on sample availability; cell counts, glucose, and protein), anti-
idursulfase antibodies, and antibodies having enzyme neutralizing activity in CSF and serum.
5.6
Exploratory Endpoints
The exploratory endpoints include:

Change from baseline in additional clinical parameters (e.g., physiological assessments, 
standardized neurocognitive assessments, neurologic function, brain magnetic resonance 
imaging [MRI])

Change from baseline in functional activities of daily living parameters

Levels of idursulfase in CSF immediately prior to each idursulfase-IT administration 

Exploration of potential relationships between biomarkers and CNS symptomatology
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5.7
SOPH-A-PORT Mini S Device Assessment
The SOPH-A-PORT Mini S device will be evaluated using assessments of device implantation, 
device function, device longevity and adverse events associated with the implant surgery or 
device.  This data will be collected on the patient’s case report form (CRF) from the time of 
initial implantation.
As part of the assessment of the SOPH-A-PORT Mini S, it may be necessary to determine the 
levels of leachables from the device into the CSF and blood.  Samples of stored CSF and serum 
may be used to determine the levels of leachable materials related to the IDDD.
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6
STATISTICAL ANALYSIS
6.1
General Methodology
All statistical analysis of data will be performed by the Biometrics Department at Shire (except 
for the PK data, which will be performed by the Clinical Pharmacology and Pharmacokinetics 
group at Shire) using SAS® statistical software version 9.3 or higher (SAS Institute, NC, USA).
This is an open-label extension of Study HGT-HIT-045 to evaluate the long-term safety and 
clinical outcomes of intrathecal idursulfase-IT, administered in conjunction with Elaprase, in 
pediatric patients with Hunter syndrome and cognitive impairment.  The statistical methodology 
supporting the trial will focus on descriptive rather than inferential approaches, given the early 
phase and objectives of the trial.  
The study data will be combined with that of studies HGT-HIT-045 and HGT-HIT-050 for 
analysis as appropriate. The efficacy and safety analyses will be based on the idursulfase-IT 
treatment baseline (abbreviated as treatment baseline), which is prior to the date of first IDDD 
implant surgery or first dose (whichever is earlier). This treatment baseline for the treated 
patients in HGT-HIT-045 is the closest available Screening/Baseline assessment (including the 
HGT-HIT-050 screening data) on or before the randomization date in Study HGT-HIT-045, 
unless specified otherwise. The treatment baseline for the untreated patients in HGT-HIT-045 is 
the closest available Screening/Baseline assessment prior to the date of first IDDD implant 
surgery or first dose (whichever is earlier) during the Initial Treatment Phase in HGT-HIT-046, 
unless specified otherwise. The Screening/Baseline assessments for the untreated patients in 
HGT-HIT-045 will be performed during the EOS procedures in HGT-HIT-045. If fewer than 30 
days had elapsed since completion of the EOS assessments for HGT-HIT-045, 
Screening/Baseline assessments were not required to be repeated. 
Summary tables will tabulate the number, mean, standard deviation (SD) and/or standard error 
(Std. Err.), median, minimum (min), and maximum (max) values for continuous variables, and 
the number and percentage of patients for categorical variables; a missing category may be added 
as needed.  For changes from baseline variables the 95% confidence intervals (CI) will also be 
provided.  As appropriate, data plots will be provided.
Data will be summarized by treatment dose (1 mg, 1 or 10 mg and 30 mg) and overall. The 
treatment dose group 1 or 10 mg includes patients who were initially treated with 10 mg and 
patients who were initially treated with 1 mg during the Initial Treatment Phase and then 
switched to 10 mg during the Extended Treatment Phase.
Listing will be provided as per Shire’s standard recommended listings. Additional listings may 
be produced as deemed appropriate.
An interim clinical study report is planned describing the results of Parts A and B. The complete 
results, including Part C, will be described in the final clinical study report. 
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The interim analysis data cutoff date was 12 Jan 2017, which was the date by which all patients 
completed at least 54 months of treatment in Study HGT-HIT-045 and / or HGT-HIT-046, and 
also completed Pre-treatment assessment at the Month 55 Visit.
6.2
Analysis Populations
The following 2 classifications of patients based on their treatment status will determine how 
their data will be pooled for statistical analysis. 
All efficacy, pharmacodynamic (PD), safety data analysis will be performed using the Safety 
Population. All pharmacokinetic (PK) data analyses will be performed using the 
Pharmacokinetic Population. Device-related analyses will be conducted separately for the 
SOPH-A-PORT and PORT-A-CATH devices, as well as devices combined, in the set of patients 
in the Safety Population who had the corresponding device implant procedure performed.      
Population
Criteria for Inclusion
Safety 
All eligible patients from HGT-HIT-045 who have agreed to participate 
in the extension study and have had either surgical implantation of an 
IDDD or intrathecal administration of study drug in the extension study.
Pharmacokinetic 
All patients who receive study drug and participate in the scheduled 
pharmacokinetic studies, and for whom at least 1 post-dose PK blood 
sample was collected.
6.3
Patient Disposition
Patient disposition (signed informed consent, patient population [Safety and PK Population], 
treatment status [completed, discontinued/withdrew]) will be presented in summary tables using 
number and percentage of patients by treatment dose and overall. Reasons for 
discontinuation/withdrawal will be presented.
6.4
Protocol Deviations
An incident involving noncompliance with the protocol, but one which typically does not have 
significant effects on the patient’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.  
Patients will be examined on a case-by-case basis prior to final 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, a list of protocol deviation will be presented.
6.5
Demographic and Other Baseline Characteristics
Demographic and baseline characteristics (eg, age [years], race, ethnicity, weight [kg], height 
[cm], and baseline disease status) will be reported in summary tables for the Safety Population
by treatment dose and overall.
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For patients previously receiving active treatment in study HGT-HIT-045, age (in years) = 
(randomization date from study HGT-HIT-045 – birth date + 1)/365.25. For patients previously 
receiving no treatment in study HGT-HIT-045, age (in years) = (date of informed consent for the 
Initial Treatment Phase of study HGT-HIT-046 – birth date + 1)/365.25. When age is presented 
in the table, it will be rounded down to the first decimal point. Since height and weight may be 
measured for multiple times during a visit, the average, if any, of these measurements for the 
same visit will be used as the value for that visit.
6.6
Treatment Compliance and Extent of Exposure
The number of IT injections received, the number of patients who received IT injections via 
lumbar puncture (LP), actual average dose, the actual average duration of administrations, the 
duration of idursulfase-IT treatment, and the percent doses received will be summarized for the 
Safety Population. 
The duration of idursulfase-IT treatment, summarized in months, is defined as the time from the 
first IT administration to the last administration.
The duration for each idursulfase-IT administrations (in minutes) is calculated by subtracting the 
administration start time from the administration end time. The actual average duration of 
idursulfase-IT administration (in minutes) will be calculated as an average value of the 
idursulfase-IT administrations across all available administrations for the same patient.
Treatment compliance will be summarized in terms of the percent of scheduled doses received.
The percent of scheduled doses received for each patient is defined as: [(Number of Complete IT 
injections Received) ÷ (Expected Number of IT injections at date cut)] * 100.
6.7
Analysis of Efficacy
6.7.1
Primary Efficacy Analysis
Not applicable since there is no primary efficacy endpoint.
6.7.2
Secondary Pharmacodynamics Analyses
6.7.2.1
CSF GAG levels
Individual patient data as well as mean observed data by visit will be graphed for CSF GAG 
levels.  In addition, the observed CSF GAG values, change from baseline, and the percent 
change from baseline in these values will be summarized descriptively by treatment dose and 
overall at scheduled study visits.  Other CSF biomarkers may be analyzed if deemed necessary.

During the HGT-HIT-045/Initial Treatment Phase, descriptive statistics at observed values, 
changes from baseline, and the percent change from baseline will be summarized at 
Screening/Baseline, on Day 2 of each IT Dosing Week via IDDD immediately prior to IT 
injection of idursulfase-IT, and at the Month 7 (Week 27) visit. 

During the Extended Treatment Phase Part B, descriptive statistics at observed values, 
changes from baseline, and the percent change from baseline will be summarized on IT 
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Injection Day 2 of Month 7 via IDDD immediately prior to IT injection of idursulfase-IT and
at 6-month intervals on the IT Injection Day of Monthly IT Dosing Weeks (ie, at Months 13, 
19, 25, 31, 37, 43, 49 and 55).
6.7.2.2
Urine GAG levels
Individual patient data as well as mean observed data by visit will be graphed for urine GAG 
levels.  In addition, the observed urine GAG values, change from baseline, and the percent 
change from baseline in these values will be summarized descriptively by treatment dose and 
overall at scheduled study visits. Baseline is defined as the Pre-Treatment Day 1 of Week 3 
measurement.

During the HGT-HIT-045/Initial Treatment Phase, descriptive statistics at observed values, 
changes from baseline, and the percent change from baseline will be summarized at 
Screening/Baseline, on Pre-Treatment Day 1 of each IT Dosing Week, and at the Month 7 
(Week 27) visit. 

During the Extended Treatment Phase Part B, descriptive statistics at observed values, 
changes from baseline, and the percent change from baseline will be summarized on Pre-
Treatment of Day 1 of Month 7 and at 6-month intervals on the Pre Treatment Day of 
Monthly IT Dosing Weeks (ie, at Months 13, 19, 25, 31, 37, 43, 49 and 55).
6.7.3
Subset Analyses
Due to small sample size, no subset analyses are planned.
6.7.4
Exploratory Analyses
For the parameters listed in each subsection below except as noted, the following analyses will 
be done:

The observed values and change from baseline will be summarized at the scheduled study 
visits, unless specified otherwise.

During the HGT-HIT-045/Initial Treatment Phase, descriptive statistics at observed 
values and changes from baseline will be summarized at Screening/Baseline, on Pre-
Treatment Day 1 of IT Dosing Week 3, and at the Month 7 (Week 27) visit. 

During the Extended Treatment Phase Part B, descriptive statistics at observed values and 
changes from baseline will be summarized on Pre-Treatment of IT Day 1 of Month 7 and  
at 6-month intervals on the Pre Treatment Day of Monthly IT Dosing Weeks (ie, at 
Months 13, 19, 25, 31, 37, 43, 49 and 55).

Individual patient data of the parameters by time since first IT dose will be also graphed. 
Chronological age, when presented, is the age of the patient at the time of the test. It will be 
calculated by (test date – birth date + 1)/365.25 and 2 decimals will be kept in the dataset.
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6.7.4.1
Differential Ability Scale, second edition (DAS-II) and Bayley Scales of 
Infant Development (BSID-III) Analyses
DAS-II
Descriptive statistics at observed values and changes from baseline will be summarized for the 
following:

Standard scores in patients who had taken DAS-II test (either version) for each cluster: 

Verbal 

Nonverbal 

Spatial 

General Conceptual Ability (GCA) 

Special Nonverbal Composite (SNC)

T scores in patients who had taken a DAS-II test for Early Years for each core subtest: 

Verbal Comprehension (Vcom)

Picture Similarities (Psim)

Naming Vocabulary (Nvoc)

Pattern Construction (Pcon) 

Matrices (Mat) 

Coping (Copy) 

T scores in patients who had a DAS-II test for School Age for each core subtest: 

Recall of Designs (RDes)

Word Definitions (WDef)

Pattern Construction

Matrices (Mat)

Verbal Similarities (VSim)

Sequential & Quantitative Reasoning (SQR)
Listings will be presented for the above parameters as well as the parameters below:

Standard Scores / percentiles in each patient who had taken a DAS-II test for each cluster: 

Verbal 

Nonverbal 

Spatial 

GCA 

SNC

T-scores, percentiles of the T-scores and age equivalents (directly from eCRF) versus 
chronological age as well as Developmental Quotient (DQ) in each patient who had taken a 
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DAS-II test for Early Years for each core subtest, where DQ=Age 
equivalent*100/Chronological age:

Verbal Comprehension 

Picture Similarities

Naming Vocabulary

Pattern Construction 

Matrices

Copying

T-scores, percentiles of the T-scores and age equivalents versus chronological age as well as 
DQ in each patient who had taken a DAS-II test for School Age for each core subtest: 

Recall of Designs (RDes)

Word Definitions (WDef)

Pattern Construction (Pcon)

Matrices

Verbal Similarities (VSim) 

Sequential & Quantitative Reasoning (SQR) 
Individual patient data of DAS-II standard scores, core subtests for DAS-II for early years, and 
core subtests for DAS-II for school age by time on treatment will be graphed.
BSID-III
Listings will be presented for:

Composite scores, age equivalents versus chronological age as well as DQ and percentiles in 
each patients who had taken BSID-III test for each domain

Cognitive

Language

Social-emotional

Adaptive behavior 
6.7.4.2
Scale of Independent Behavior- revised (SIB-R) Analyses
Listings will be presented for:

Standard scores and percentiles for each category

Motor skills 

Social interaction/communication skills

Personal living skills

Community living skills
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
Broad Independence
6.7.4.3
Behavior Rating Inventory of Executive Function (BRIEF) Analysis –
Regular Version and Preschool Version (BRIEF-P)
Listings will be presented for:

The common scales and indexes that exist in both versions of BRIEF tests and for each 
patient for whom either version of BRIEF test has been performed. Note: for school version 
(5-18 years old) of BRIEF, GEC= Behavioral Regulation Index (BRI) + Metacognition Index 
(MI); for preschool version BRIEF test, GEC= Inhibit + Shift + EC + WM+PO.

The common scales: 

Inhibit 

Shift 

Emotional Control (EC) 

Working Memory (WM) 

Plan/Organize (PO) 

The common index: 

Global Executive Composite (GEC)  

Each index that is unique to the BRIEF-P test:

Inhibitor Self-Control Index (ISCI) = Inhibit+EC 

Flexibility Index (FI) = Shift+EC 

Emergent Metacognition Index (EMI) = WM+PO 

Each scale and index that are unique to the BRIEF test:

Scales: 

Initiate

Organization of Material 

Monitor 

Indexes:

Behavior Regulation Index (BRI) = Inhibit + Shift + Emotional Control 

Megacognition Index (MI) = Initiate + WM + PO + Organization of Materials + 
Monitor 
6.7.4.4
Peabody Developmental Motor Scales-2 (PDMS-2) and Bruininks-
Oseretsky Test of Motor Proficiency 2nd edition (BOT-2) Analyses
PDMS-2
Listings will be presented for:

Standard Scores and DQ=Age equivalent*100/Chronological age of the PDMS-2 subtests:
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
Reflexes 

Stationary 

Locomotion 

Object Manipulation 

Grasping 

Visual-Motor Integration:

Gross Motor Quotient (GMQ) 

Fine Motor Quotient (FMQ) 

Total Motor Quotient (TMQ)
BOT-2
Listings will be presented for:

Composite Standard Scores and percentiles of Total Motor and the each subtest: 

Fine Manual Control 

Manual Coordination 

Body Coordination 

Strength and Agility 
6.7.4.5
Correlation Analyses
Correlation coefficients between the following parameters will be calculated using a Mixed 
Model for Repeated Measures (MMRM):

Standard scores for GCA and SNC in DAS-II

Standard scores for GCA in DAS-II and standard scores for SIB-R, including the following: 

Motor skills 

Social interaction/communication skills

Personal living skills

Community living skills

Broad Independence

Standard scores for GCA and CSF GAG level
Scatter plots of the above paired variables and their correlation coefficients will be presented in 
graphs. 
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6.7.4.6
Brain MRI
The Brain MRI measurements will be summarized descriptively for the following parameters:

Brain Total Intracranial Volume (cm3)

Brain Total Tissue Volume (cm3)

Brain Total White Matter (cm3)

Brain Total Gray Matter (cm3)

Total CSF Volume (cm3)
Descriptive statistics of observed values and changes from baseline will be summarized by 
treatment dose and overall at scheduled study visits.

During the HGT-HIT-045/Initial Treatment Phase, descriptive statistics at observed values 
and changes from baseline will be summarized at Screening/Baseline and at Month 7 (Week 
27) visit. 

During the Extended Treatment Phase Part B, descriptive statistics at observed values and 
changes from baseline will be summarized on Pre-Treatment of IT Day 1 of Month 7 and  at 
12-month intervals on the Pre Treatment Day of Monthly IT Dosing Weeks (ie, at Months 
19, 31, 43 and 55).
6.7.4.7
Auditory Brain Stem Response (ABR)
Hearing assessment via audiometric measurement will be performed on all patients. The 
following parameters will be calculated: 

Inter-peak latency (IPL) for each ear

IPL I-III = Wave III latency minus Wave I latency (unit in ms) 

IPL III-V= Wave V latency minus Wave III latency (unit in ms)

Inter-aural latency = Wave V latency of the right ear minus that of left ear

Mean air conduction (dBnHL) and Bone conduction Threshold (dBnHL) at 0.25 KHz, 0.5 
KHz, 1 KHz, 2 KHz and 4 KHz for each ear
The observed values of IPL 1-V (unit in ms), the absolute latencies [Wave I, III and V (unit in 
ms)], the above calculated parameters, and the estimated pure tone average (PTA) for each ear 
(directly from eCRF) and change from baseline for those variables will be summarized by 
treatment dose and overall at scheduled study visits for each ear. 

During the HGT-HIT-045/Initial Treatment Phase, descriptive statistics at observed values 
and changes from baseline will be summarized at Screening/Baseline and at Month 7 (Week 
27) visit. 

During the Extended Treatment Phase Part B, descriptive statistics at observed values and 
changes from baseline will be summarized on Pre-Treatment Day 1 of Month 7, on the Pre-
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Treatment Day of the 12- Month Visits  (ie, at Months 19, 31, 43 and 55).
6.7.4.8
Hearing Assessment
It is intended that patients who receive study drug will have hearing assessments performed at 
scheduled study visits. The number and percentage of patients in the hearing assessment 
categories (hearing aid, right ear test results, left ear test results, right ear level of hearing loss 
and left ear level of hearing loss) will be summarized by treatment dose and overall at scheduled 
study visits.

During the HGT-HIT-045/Initial Treatment Phase, descriptive statistics will be summarized 
at Screening/Baseline, Pre-Treatment Day 1 of IT Dosing Week 3, Pre-Treatment Day 1 of 
IT Dosing Week 15 (before the fourth IT injection),  and at Month 7 (Week 27) visit. 

During the Extended Treatment Phase Part B, descriptive statistics will be summarized on 
Pre-Treatment of IT Day 1 of Month 7 and  at 6-month intervals on the Pre Treatment Day of 
Monthly IT Dosing Weeks (ie, at Months 13, 19, 25, 31, 37, 43, 49 and 55).
6.7.4.9
Vision Assessment
It is intended that all patients have a vision assessment performed at scheduled study visits. The 
number and percentage of patients of the vision assessment results (normal, abnormal or 
missing) will be summarized by treatment dose and overall at scheduled study visits. 

During the HGT-HIT-045/Initial Treatment Phase, descriptive statistics will be summarized 
at Screening/Baseline, and at Month 7 (Week 27) visit. 

During the Extended Treatment Phase Part B, descriptive statistics will be summarized on 
Pre-Treatment of IT Day 1 of Month 7 and  at 6-month intervals on the Pre Treatment Day of 
Monthly IT Dosing Weeks (ie, at Months 13, 19, 25, 31, 37, 43, 49 and 55).
6.8
Analysis of Safety
As specified in Section 5.4, the primary assessments of this study are the safety of idursulfase-IT 
administration.  Safety will be measured by AEs (by type and severity), changes in clinical 
laboratory testing (serum chemistry including liver function tests, hematology, urinalysis), 12-
lead ECG, CSF chemistries (contingent on sample availability; cell counts, glucose, and protein), 
anti-idursulfase antibodies and antibodies having enzyme neutralizing activity in CSF and serum.
The SOPH-A-PORT Mini S device will be evaluated using assessments of device implantation, 
device function, device longevity and adverse events associated with the implant surgery or 
device.  This data will be collected on the patient’s case report form (CRF) from the time of 
initial implantation.  
All safety analyses will be descriptive, no statistical testing will be performed.
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6.8.1
Adverse Events
AEs will be recorded throughout the study and at early termination.  AEs and medical conditions 
will be coded using the MedDRA version 16.0 or higher.
For IA analysis, treatment-emergent AEs (TEAE) are defined as all AEs occurring on or after the 
date of the first IDDD implant surgery or first dose (whichever is earlier) and on or before the 
EOS visit (+30 days) or 2 weeks after the removal of the last IDDD if early termination
(whichever is later). In general, an AE will be deemed TEAE if it cannot be definitively 
categorized by the available components (day, month, year) of the AE onset date with respect to 
the date of intervention (the date of the first IDDD implant surgery or first dose [whichever is 
earlier]). Summaries for the following TEAE categories will be presented: 
1. Patients who experienced no AEs, 
2. Patients who experienced at least one AE 
3. Patients who discontinued due to an AE(s)
4. Patients who died
5. Patients who experienced at least one serious adverse event (SAE),
6. Patients who experienced at least one severe/life-threatening AE,
7. Patients who experienced at least one IV Elaprase infusion-related adverse event
8. Patients who experienced at least one idursulfase-IT-related adverse event 
9. Patients who experienced at least one IT Treatment Regimen-related adverse event (i.e., 
related to one or more of the following: study drug, IDDD, device surgical procedure, lumbar 
puncture, and IT-administration process)
10. Patients who experienced at least one IDDD surgical procedure-related adverse event
11. Patients who experienced at least one IDDD-related adverse event
12. Patients who experienced at least one IT Administration Process-related adverse event
The AE categories 1-7 will be presented by each treatment dose and overall, while the AE 
categories 8-12 will be presented for patients in the Safety Population who received idursulfase-
IT. IT administration process-related AEs will be summarized by IT administration method (LP 
or IDDD) as well. The AE categories 10-11 will be presented for patients in the Safety 
Population with the device implanted.
The number and percentage of patients, and the number of corresponding AEs will be 
summarized in the overall summary tables. In addition, the number and percentage of patients 
having any treatment-emergent AE within the AE categories 2, 5, 7-12 and the number of 
corresponding AEs will be displayed by MedDRA System Organ Class (SOC), Preferred Term 
(PT) and treatment dose group. The most common treatment-emergent AEs which happened in 
>20% patients in any treatment dose group will also be summarized by SOC and PT.  
The number and percentage of patients having any treatment-emergent AE, and the number of 
corresponding AEs will be summarized by severity; at the patient level, a patient is counted only 
once by any event, SOC, or PT under the most severe category.
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The number and percentage of patients having any treatment-emergent AE, and the number of 
corresponding AEs will be summarized by relationship to IV Elaprase, idursulfase-IT, and at 
least one IT treatment regimen, and displayed by MedDRA SOC, PT and treatment dose; at the 
patient level, a patient is counted only once by any event, SOC, or PT under the most related 
category. 
Furthermore, listings of all the AEs of categories 3-6 will be provided if applicable.
6.8.2
Clinical and CSF Laboratory Evaluations
Chemistry and hematology serum laboratory and CSF (standard chemistries, glucose, protein, 
and cell counts) values will be summarized in terms of the absolute value and change from 
baseline by treatment dose at scheduled study visits.  

During the HGT-HIT-045/Initial Treatment Phase, descriptive statistics at observed values 
and changes from baseline will be summarized at Screening/Baseline, Pre-Surgery Day 1 of 
Week 1, Pre-Treatment Day 1 of each IT Dosing Week, and at the Month 7 (Week 27) visit. 

During the Extended Treatment Phase Part B, descriptive statistics at observed values and 
changes from baseline will be summarized on Pre-Treatment of IT Day 1 of Month 7 and  at 
6-month intervals on the Pre-Treatment Day of Monthly IT Dosing Weeks (ie, at Months 13, 
19, 25, 31, 37, 43, 49 and 55).
Box plots for total protein, glucose, and total nucleated cells by treatment dose will be presented 
at each scheduled study visit.
All the laboratory (chemistry, hematology, urinalysis and CSF) values will be categorized as a 
patient having had: (1) an Abnormal and Clinically Significant (CS) value at any time during the 
study post baseline, (2) no CS values at any time during the study post baseline but had at least 
one Abnormal value, and (3) Normal values at all time during the study post baseline. The 
number and percentage of patients in each category will be presented by treatment dose and 
overall. Patients with a Normal or non-CS value for a particular laboratory parameter at baseline 
who experience a change to CS for that laboratory parameter post-baseline will be identified and 
listed separately along with the corresponding laboratory values over time. The baseline is 
defined as the Screening/Baseline measurement. If it is not available, the Pre-Surgery Day 1 of 
Week 1 measurement will be used as baseline.
If a particular laboratory measurement has been either repeated or retested, then the repeated or 
retested measurement for that laboratory parameter, with respect to date/time, will be used in the 
statistical analysis unless this value is invalid/missing. The handling of repeated or retested 
laboratory measurements should only consider the specific laboratory measurement that was 
repeated or retested.
6.8.3
12-Lead ECG Evaluations
The 12-lead ECG parameters (heart rate [bpm], PR interval [msec], QRS interval [msec], QT 
interval [msec] and the corrected QT interval (QTc) [msec]) will be summarized in terms of 
absolute value and change from baseline by treatment dose at scheduled study visits. The QTc 
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interval will be calculated using Bazett's formula as QT divided by the square root of RR 
interval. The number and percentage of patients with ECG abnormalities post baseline will be 
presented by treatment dose and overall at scheduled study visits.

During the HGT-HIT-045/Initial Treatment Phase, descriptive statistics at observed 
values and changes from baseline will be summarized at Screening/Baseline, Pre-Surgery 
Day 1 of Week 1, Pre-Treatment Day 1 of IT Dosing Week 3 only, Day 2 of each IT 
Dosing Week after injection of the study drug, and at Month 7 (Week 27) visit. 

During the Extended Treatment Phase Part B, descriptive statistics of observed values 
and changes from baseline will be summarized on Pre-Treatment of IT Day 1 of Month 7, 
after injection of study drug on Monthly IT Dosing Weeks at Months 7, 8, and 9, and at 
12-month intervals of after injection of study drug on Monthly IT Dosing Weeks (ie, at 
Months 19, 31, 43 and 55).
Additionally, the 12-Lead ECG will assess if patients experience normal or abnormal sinus 
rhythm, and atrial or ventricular hypertrophy (normal or abnormal, where normal means that 
atrial or ventricular hypertrophy was absent and abnormal means that atrial or ventricular 
hypertrophy was present). Both of these 12-Lead ECG results will be categorized as abnormal 
post baseline for the patient as long as at least one abnormal finding is reported at any time 
during the study post baseline; the number and percentage in each category will be presented. 
The baseline is defined as the Screening/Baseline measurement. If it is not available, the Pre-
Surgery Day 1 of Week 1 measurement will be used as baseline.
A list of Clinical Significant ECG findings will be presented. Additionally, individual patients’ 
plots of ECG parameters at each visit will be graphed.
6.8.4
Vital Signs
The infusion (IV), injection (IT) vital signs and regular vital signs (temperature [C], pulse [bpm], 
blood pressure [systolic and diastolic, mmHg], oxygen saturation, and respiration rate [per min] 
will be listed.

During the HGT-HIT-045/Initial Treatment Phase, vital signs will be collected at 
Screening/Baseline, during Surgery Week 1 at Day 1, Day 2, Days 3-6 (ie, during IV 
infusion of Elaprase), Pre-Treatment Day 1 of each IT Dosing Week, Day 2 and Days 3-7 (ie,
during IV infusion of Elaprase) of each IT Dosing Week after injection of the study drug, and 
at Month 7 (Week 27) visit.  
At a minimum, vital signs will be collected at the following time points on IT administration 
of idursulfase-IT and IV infusion of Elaprase: 

IT administration of idursulfase-IT: within 15 minutes prior to IT administration, 30 
minutes (±10 minutes) post end of IT administration, 60 minutes (±10 minutes) post 
end of IT administration, 120 minutes (±10 minutes) post end of IT administration, 4 
hours (±10 minutes) post end of IT administration, 6 hours (±10 minutes) post end of 
IT administration, 8 hours (±10 minutes) post end of IT administration, and 12 hours 
(±10 minutes) post end of IT administration.
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
IV infusion of Elaprase: within 15 minutes prior to infusion, 30 minutes (±10 
minutes) post start of infusion, 60 minutes (±10 minutes) post start of infusion, 90 
minutes (±10 minutes) post start of infusion, 120 minutes (±10 minutes) post start of 
infusion, 150 minutes (±10 minutes) post start of infusion, 180 minutes (±10 minutes) 
post start of infusion (ie, end of infusion), 30 minutes (±10 minutes) post end of 
infusion and 60 minutes (±10 minutes) post end of infusion.

During the Extended Treatment Phase Part B, vital signs will be collected on Pre-Treatment 
Day 1 and on the IT Injection Day of Month 7 and 6-month intervals of Pre-Treatment Day 1 
and on the IT Injection Day on Monthly IT Dosing Weeks (ie, at Months 13, 19, 25, 31, 37, 
43, 49 and 55).

At a minimum, vital signs will be collected at the following time points on IT 
administration of idursulfase-IT: within 15 minutes prior to IT administration, 30 
minutes (±10 minutes) post end of IT administration, 60 minutes (±10 minutes) post 
end of IT administration, 120 minutes (±10 minutes) post end of IT administration, 
and 4 hours (±10 minutes) post end of IT administration.
6.8.5
Physical and Neurological Findings
Clinically significant physical and neurological examination findings will be recorded and 
summarized either as part of the medical history or adverse event data. No additional summary 
or listing will be provided.
6.8.6
Other Observations Related to Safety 
6.8.6.1
Anti-Idursulfase Antibody Formation
Anti-idursulfase antibody formation will be monitored throughout the study for both serum and 
CSF. The number and percentage of patients testing anti-idursulfase antibody will be 
summarized by treatment dose at baseline, any time post-baseline and scheduled study visits. 
Baseline is defined as the Pre-Treatment Day 1 of Week 3 measurement for the serum 
antibodies. Baseline is defined as the Screening/Baseline measurement for the CSF antibodies.

During the HGT-HIT-045/Initial Treatment Phase, descriptive statistics at observed values 
will be summarized at Screening/Baseline, on Pre-Treatment Day 1 of each IT Dosing Week, 
and at the Month 7 (Week 27) visit.

During the Extended Treatment Phase Part B, descriptive statistics at observed values will be 
summarized on Pre-Treatment of IT Day 1 of Month 7, and at 6-month intervals on the Pre-
Treatment Day of Monthly IT Dosing Weeks (ie, at Months 13, 19, 25, 31, 37, 43, 49 and 
55).
Titer values will be summarized as box plots over time in patients with positive antibodies at the 
scheduled visit. A similar plot for patients who developed positive neutralizing antibodies at the 
scheduled visit will be presented by treatment dose. 
6.8.6.2
CSF Enzyme Level
The Idursulfase enzyme levels in CSF will be plotted for individual patient. If a measurement is 
less than the lower level of quantification (LLOQ), then it will be replaced by zero.
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6.8.6.3
Intracranial Pressure
Intracranial pressure (ICP) measurement (cm of H2O) for those patients undergoing lumbar 
puncture will be summarized at scheduled study visits. Additionally, the change from baseline to 
each applicable post-baseline assessment will also be summarized.

During the HGT-HIT-045/Initial Treatment Phase, descriptive statistics at observed values 
and changes from baseline will be summarized at Screening/Baseline, and at the Month 7 
(Week 27) visit.

During the Extended Treatment Phase Part B, descriptive statistics at observed values and 
changes from baseline will be summarized on Pre-Treatment of IT Day 1 of Month 7 and  at 
12-month intervals on the Pre Treatment Day of Monthly IT Dosing Weeks (ie, at Months 
19, 31, 43 and 55).
6.8.6.4
Height, Weight, and Head Circumference
Height (cm), weight (kg), and head circumference (cm) observed values, and the change from 
baseline will be summarized by treatment dose at scheduled study visits.  If multiple 
measurements were taken for the same visit, their mean will be the measurement for that visit.
For height and weight,

During the HGT-HIT-045/Initial Treatment Phase, descriptive statistics at observed values 
and changes from baseline will be summarized at Screening/Baseline, Pre-Surgery Day 1 and 
Day 7 of Surgery Week 1, at Day 1 of each IT Dosing Week, and at the Month 7 (Week 27) 
visit. 

During the Extended Treatment Phase Part B, descriptive statistics at observed values and 
changes from baseline will be summarized on Pre-Treatment Day 1 of Month 7 and at 6-
month intervals on the Pre Treatment Day of Monthly IT Dosing Weeks (ie, at Months 13, 
19, 25, 31, 37, 43, 49 and 55). 
For head circumference,

During the Initial Treatment Phase, descriptive statistics at observed values and changes from 
baseline will be summarized at Screening/Baseline, on Pre-Treatment Day 1 of IT Dosing 
Week 3, and at the Month 7 (Week 27) visit.

During the Extended Treatment Phase Part B, descriptive statistics at observed values and 
changes from baseline will be summarized at on Pre-Treatment Day 1 of Month 7, and  at 12-
month intervals on the Pre Treatment Day of Monthly IT Dosing Weeks (ie, at Months 19, 
31, 43 and 55). 
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6.8.6.5
SOPH-A-PORT Mini S Device Performance
Device-related Terminology

Initial device implant:  The first IDDD implant that a patient ever receives

Partial device revision:  Surgical revision/replacement of 1 or more component(s) of the 
device; other component(s) of the original device remain implanted and are not affected (e.g., 
port revision).

Full device revision:  The device is removed (explanted) in its entirety, and a completely new 
device is implanted.

Complete device removal without immediate replacement:  All parts of the device (both port 
and catheter) are removed, and there is no new device implant. 

Device adjustment:  A surgical procedure where the device is adjusted but all existing 
components remain implanted

Delayed device implant after previous removal:  Implant of a new device after a previous 
device had been completely removed without immediate replacement on a separate and 
earlier occasion 

Device malfunction:  The device does not perform as intended, based on the description in 
the device’s Instructions for Use, but does not require either a partial or full device revision. 
If at the time of a scheduled dosing it is not possible to administer a full medication dosage as 
per the standard administration steps detailed in the device’s Instructions for Use due to a 
device-related issue, the IDDD will be declared a device malfunction.  

Resolved device malfunction: A temporary device malfunction that resolves without the need 
for a full or partial device revision. Programmatically, it is when the malfunction date is 
present and outcome of malfunction is resolved.

Device failure: When the device irreversibly fails to perform as intended and cannot be 
corrected without a device surgical intervention (either a partial or full device revision or 
removal). The IDDD will be declared a device failure, starting from the date of the initial 
malfunction that persisted and lead to the surgical intervention. Intrathecal drug delivery 
devices that are considered to be malfunctioning at the end of the study will be categorized as 
failures. For programming purposes, a device failure is when the malfunction date is present 
and outcome of malfunction is device failure. The date of the device failure is the date of the 
initial malfunction.

IDDD Longevity: Total number of IDDD failures and explant divided by the total time at 
risk across all subjects in years (sum of time to IDDD failure or the last injection if not failed 
at the end of the data cut or explant date, from initial implantation, delayed implantation, or 
revision for all IDDDs).
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Device Performance Analyses
SOPH-A-PORT safety and performance will be summarized for IDDD-implanted patients in the 
Safety population. The number and proportion of patients of the following categories and the 
corresponding event count and event percentage will be summarized: 

With the initial device implant only (i.e., no additional surgeries) 

Who had any post-initial implantation device surgeries and type of surgery

Who had difficulties associated with the implant procedure (e.g., difficulty accessing spinal 
canal, etc.)
IDDD-related surgical procedure details for initial implants, delayed implantation, and full 
system revisions across all IDDD implantations for all patients will be summarized by failed or 
not failed IDDDs and overall, including incision region (paramedian vs. other), identification of 
the catheter passer used (Phoenix Neuro vs. other), number of suture wings implanted, interspace 
for catheter insertion into lumbar spine (L1-2, L2-3, L3-4, L4-5, L5-S1), spinal vertebral level of 
catheter tip (cervical, thoracic, lumbar, and sacral), and clinical site. 
The number and proportion of patients who had at least 1 abnormal IDDD radiological 
assessment finding and the number of abnormal findings from the IDDD radiological 
assessments will be also summarized by types of the abnormality.
The number and proportion of patients and IDDDs with 1 or more total malfunctions (including 
malfunctions leading to failure, resolved malfunctions, and malfunctions that are ongoing), 
malfunctions leading to failure, resolved or ongoing malfunctions, as well as the corresponding 
number of events, will be presented. The types of total malfunctions and the reasons for IDDD 
failures reported by the site will be summarized at the patient, IDDD, and event level. 
The annual event rate of IDDD failures and malfunctions will be calculated for each patient, and 
the descriptive statistics will be summarized. The overall IDDD failure rate and the 
corresponding 95% CI will be presented. The overall IDDD failure rate is calculated as the total 
number of IDDD failures for all patients divided by the total IDDD time at risk, which is defined 
as the total time to IDDD failure or the last injection if IDDD is not failed, from initial 
implantation, delayed implantation, or revision for all IDDDs. 
The time from initial implant surgery to first IDDD failure and the time to first malfunction will 
be analyzed using the Kaplan Meier (KM) method for each patient who is in the Safety 
Population and had at least one IDDD implanted. The time to first IDDD failure or malfunction 
(weeks) will be obtained by subtracting the date of the first IDDD implantation for the patient 
from the date of first failure or malfunction plus 1, divided by 7, and one decimal will be kept. 
Patients without an IDDD failure or malfunction will be censored at their last study drug 
injection date. For the interim analysis, patients without an IDDD failure or malfunction will be 
censored at the data cutoff date, which is January 12, 2017. The number of IDDDs at risk, the 
cumulative number of IDDDs failed and censored, and the cumulative probability of failure with 
the corresponding standard error will be summarized in a table at each event time. The 25th 
percentile (Q1), median and 75th percentile (Q3) of the time to first failure or malfunction 
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distribution and the 95% confidence interval (CI) will be presented together with the KM plots. 
A by-patient listing of the device failure and malfunction data will be displayed. 
The number of doses received via IDDD will be summarized. 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 (e.g. patient uncooperative, competing medical issue, 
etc.) will not be included in the determination of the injection success rate.
Whether any device component was implanted will be summarized for all IDDD kits which were 
opened. For the implanted IDDDs, their status (i.e., removed or not) at the end of the study will 
be reported. If an IDDD was removed, whether the catheter was removed along with the port will 
also be summarized.
By-patient listings of SOPH-A-PORT malfunctions and failures, and IDDD exposure will be 
provided.
6.8.7
Concomitant Medications
For IA analysis, concomitant medications are defined as all medications taken on or after the 
date of the first IDDD surgery or first dose (whichever is earlier) and on or before the EOS visit 
(+30 days) or 2 weeks after the removal of the last IDDD if early termination (whichever is
later). Concomitant medications will be coded using the World Health Organization (WHO) 
Drug Dictionary version 16.0 or higher. Concomitant medication use will be summarized by 
Therapeutic Class and Preferred Term for each treatment dose group and overall for the Safety 
Population.
6.9
Analysis of Pharmacokinetic Data
All pharmacokinetic analyses will be performed using the PK Population.
6.9.1
Concentration Data
Blood samples will be collected for determination of idursulfase serum concentration-time 
profiles and serum pharmacokinetic parameters after IT administration.  Serum samples will be 
assayed for idursulfase using validated analytical methods.
6.9.2
Handling BLQ Values
The following procedures will be used for serum concentrations below the lower limit of 
quantification (LLOQ) (reported as BLQ):
Samples that are BLQ are treated as zero in the calculation of summary statistics (e.g., mean, SD, 
etc.) for the serum concentrations at individual time points.
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Mean concentrations are reported as zero if all values are BLQ, and no descriptive statistics are 
reported.  If the calculated mean (± SD) concentration is less than the LLOQ, the value will be 
reported as calculated.  The mean values derived using these conventions will be used to create 
the mean serum concentration versus time plots.
For calculation of area under the serum concentration curve (AUC), BLQ values are set equal to 
zero in the dataset loaded into WinNonlin for pharmacokientic analysis.  WinNonlin uses the 
zero values that occur before the first time point with a concentration greater than LLOQ, but 
WinNonlin excludes the zero values from AUC calculation for all later time points.
Serum samples that are BLQ are reported as zero on the data listings.
6.9.3
Pharmacokinetic Parameters
The pharmacokinetic analysis will be conducted by the Clinical Pharmacology and 
Pharmacokinetics Department of Shire Pharmaceuticals using Phoenix WinNonlin version 6.3 or 
higher (Pharsight Corporation, Mountain View, California, USA).
Pharmacokinetic parameters will be determined from serum concentration-time data using 
noncompartmental methods and all calculations will be based on actual sampling times.  Serum 
concentration vs. time will be plotted for each patient.  Mean serum concentration vs. time 
curves will also be presented by route of administration (IV and IT administration), treatment 
dose (0.5mg/kg for IV administration, and 1mg, 10mg, and 30mg for IT administration) at 
scheduled study visits.
For the IT treatment, the pharmacokinetic parameters will include, but not be limited to, the 
following:

AUC0-∞- Area under the curve extrapolated to infinity, calculated using the observed value 
of the last non-zero concentration

AUC0-t - Area under the curve from the time of dosing to the last measureable concentration

Cmax - Maximum concentration occurring at tmax

tmax - Time of maximum observed concentration sampled during a dosing interval 

CL/F – Total body clearance for extravascular administration divided by the fraction of dose 
absorbed. This parameter will be presented with and without normalization for body weight.

Vz/F – Volume of distribution associated with the terminal slope following extravascular 
administration divided by the fraction of dose absorbed.  This parameter will be presented 
with and without normalization for body weight.

λz – First order rate constant associated with the terminal (log-linear) portion of the curve

t½ - Terminal half-life
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For the IV treatment, the pharmacokinetic parameters will include, but not be limited to the 
following:

AUC0-∞- Area under the curve extrapolated to infinity, calculated using the observed value 
of the last non-zero concentration

AUC0-t - Area under the curve from the time of dosing to the last measureable concentration

Cmax - Maximum concentration occurring at tmax

tmax - Time of maximum observed concentration sampled during a dosing interval 

CL – Total body clearance for intravenous administration. This will be presented with and 
without normalization for body weight.

Vz – Volume of distribution associated with the terminal slope.  This parameter will be 
presented with and without normalization for body weight

Vss – Observed steady-state volume of distribution.  This parameter will be presented with 
and without normalization for body weight.

MRT - Mean residence time

t½ - Terminal half-life
Summary statistics (number of observations, mean, standard deviation, coefficient of variation, 
median, maximum, minimum, and geometric mean) will be determined for all pharmacokinetic 
parameters and presented by route of administration and treatment dose at scheduled study visits.  
Serum concentrations of idursulfase at each nominal sampling time will also be summarized by 
dose and visit using descriptive statistics.
6.10
Drug-Drug and Drug-Disease Interactions
This study was not designed to evaluate drug-drug or drug-disease interactions and therefore the 
interactions will not be assessed in the study.
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7
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES
7.1
Changes in the Conduct of the Study
Please see the amendment summaries in the HGT-HIT-046 protocol Amendment 9.
7.2
Changes from the Analyses Planned in the Protocol
There were no changes proposed from those planned in the protocol.
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8
STATISTICAL/ANALYTIC ISSUES
8.1
Adjustment for Covariates
All analyses will be descriptive in nature, therefore there will be no adjustment for covariates.
8.2
Handling of Dropouts or Missing Data
No data imputation will be performed.
8.3
Interim Analyses and Data Monitoring
One interim analysis and an interim clinical study report are planned describing the results of 
Parts A and B. Descriptive analyses of the data before trial completion may be performed for 
safety monitoring, regulatory reporting or general planning purposes. Because no formal 
hypothesis testing is planned, multiplicity concerns regarding repeated analyses in the final are 
not an issue.
8.4
Multicenter Studies
There are two centers planned for this study. No subset analyses of center effect will be 
conducted. No adjustment due to multi-centers will be utilized in the analyses.
8.5
Multiple Comparisons/Multiplicity
Analyses are descriptive in nature.  No multiple comparison procedure or multiplicity adjustment 
will be performed.
8.6
Examination of Subgroups and Interactions
No subgroup analyses are planned. In addition, interaction effects will not be examined for the 
outcome measurements due to the small sample size.
8.7
Sensitivity Analyses
Not applicable
8.8
Windowing Visits
Although there is a visit window of +/- 7 days around the expected visit date, nominal visits will 
be used for the per-visit analyses.  Therefore, no windowing of visits by actual study day will be 
done for data obtained at the scheduled visits. For subjects who withdraw from the study pre-
maturely, if the early termination visit falls into the window of a scheduled visit as defined in the 
protocol, the early termination visit is also summarized for that scheduled visit, unless the 
scheduled visit already took place.
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8.9
Data Listings
All data will be presented as SAS datasets in CDISC format.  Unless specifically stated in above 
sections, no other by-patient data listings will be provided.
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9
REFERENCES
1.
Elliot CD. The Differential Abilities Scales (DAS) San Antonio, TX The Psychological 
Corporation; 1995.
2.
Bayley N. Bayley Scales of Infant and Toddler Development: Third Edition. San 
Antonio, TX The Psychological Corporation; 2005.
3.
Bruininks RH, Woodcock RW, Weatherman RF, Hill BK. Scales of Independent 
Behavior – Revised. Itasca, IL: Riverside Publishing; 1996.
4.
Folio M, Fewell R. Peabody Developmental Motor Scales, Second Examiner's Manual. 
Austin, TX: Pro-ed; 2002.
5.
Folio MR, Fewell R. Peabody Developmental Motor Scales: Examiner’s Manual. 2nd ed. 
Austin TX; 2000.
6.
Bruininks RH, Bruininks BD. Bruininks-Oseretsky Test of Motor Proficiency. In: 
Pearson Assessment 2nd ed. Minneapolis; 2005.
7.
Elliot CD. The Differential Abilities Scales (DAS) San Antonio, TX The Psychological 
Corporation; 1995.
8.
Bayley N. Bayley Scales of Infant and Toddler Development: Third Edition. San 
Antonio, TX The Psychological Corporation; 2005.
9.
Bruininks RH, Woodcock RW, Weatherman RF, Hill BK. Scales of Independent 
Behavior – Revised. Itasca, IL: Riverside Publishing; 1996.
10.
Folio M, Fewell R. Peabody Developmental Motor Scales, Second Examiner's Manual. 
Austin, TX: Pro-ed; 2002.
11.
Folio MR, Fewell R. Peabody Developmental Motor Scales: Examiner’s Manual. 2nd ed. 
Austin TX; 2000.
12.
Bruininks RH, Bruininks BD. Bruininks-Oseretsky Test of Motor Proficiency. In: 
Pearson Assessment 2nd ed. Minneapolis; 2005.
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10
APPENDICES
10.1
Appendix I 
List of Statistical Outputs
These are attached as a separate document called “Table Shells” including Tables, Figures and 
Listings.
10.2
Appendix II Protocol Violations Definitions
A list of possible protocol violations is given below.  A more comprehensive list will be 
constructed once the review of patient data has been completed, immediately prior to locking the 
database.
Violations

Violation of admission (inclusion/exclusion) criteria (i.e., eligibility violation) for which no 
exemption was obtained

Occurrence of a treatment dispensing error
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