A Controlled, Randomized, Two-arm, Open-label, Assessor-blinded, Multicenter Study of Intrathecal Idursulfase-IT Administered in Conjunction With Elaprase® in Pediatric Patients With Hunter Syndrome and Early Cognitive Impairment
Phase: PHASE2
Conditions: Hunter Syndrome
Sponsor: Shire

Clinical Trial Protocol:  HGT-HIT-094
Study Title:
A Controlled, Randomized, Two-arm, Open-label, Assessor-blinded, 
Multicenter Study of Intrathecal Idursulfase-IT Administered in 
Conjunction with Elaprase® in Pediatric Patients with Hunter 
Syndrome and Early Cognitive Impairment
Study Number:
HGT-HIT-094
Study Phase:
Phase II/III
Investigational 
Product and 
Device:
idursulfase for intrathecal use (idursulfase-IT [HGT-2310]), 
SOPH-A-PORT® Mini S, Implantable Access Port, Spinal, Mini 
Unattached, with Guidewire (SOPH-A-PORT Mini S)
IND Number:
100,610
EudraCT 
Number:
2013-002885-38
Indication:
Long-term treatment of Hunter syndrome in patients with cognitive 
impairment to slow progression of cognitive and functional 
impairment
Study Center(s):
Multicenter
Lead 
Investigator:
Joseph Muenzer, MD, PhD 
Sponsor:
Shire Human Genetic Therapies, Inc.
Sponsor Contact:
300 Shire Way
Lexington, MA 02421 USA
Medical Monitor:
, DO
Date
Original Protocol:
04 April 2013
Amendment 1
14 August 2013
Amendment 2
16 December 2013 
Amendment 3
09 February 2015
Amendment 4
21 December 2015
Confidentiality Statement
This document is the proprietary and confidential property of 
Shire Human Genetic Therapies, Inc.  
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TABLE OF CONTENTS
SYNOPSIS.................................................................................................................................9
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..........................................20
1
INTRODUCTION ...........................................................................................................23
1.1
Mucopolysaccharidosis II (Hunter syndrome).......................................................23
1.2
Unmet Medical Need.............................................................................................24
1.3
Overview of Results of Phase I/II Studies .............................................................24
1.3.1
Rationale for Current Phase II/III Study......................................................25
2
STUDY OBJECTIVES....................................................................................................27
2.1
Primary Objective..................................................................................................27
2.2
Secondary Objectives.............................................................................................27
2.3
Safety Objectives ...................................................................................................27
2.4
SOPH-A-PORT Mini S Device Objectives:..........................................................27
2.5
Pharmacokinetic and Pharmacodynamic Objectives.............................................28
2.6
Health Status Objective..........................................................................................28
2.7
Substudy Objective................................................................................................28
3
STUDY ENDPOINTS.....................................................................................................29
3.1
Primary Efficacy Endpoint ....................................................................................29
3.2
Secondary Efficacy Endpoints...............................................................................29
3.3
Pharmacokinetic and Pharmacodynamic Endpoints..............................................29
3.4
Safety Assessments................................................................................................30
3.5
SOPH-A-PORT Mini S Device Assessments........................................................30
3.6
Health Status Assessment ......................................................................................30
4
INVESTIGATIONAL PLAN..........................................................................................31
4.1
Overall Study Design and Plan..............................................................................31
4.1.1
Intrathecal Drug Delivery ............................................................................31
4.2
Rationale for Study Design and Comparator Group..............................................32
4.2.1
Rationale for Dose Selection .......................................................................34
4.3
Study Duration.......................................................................................................34
5
STUDY POPULATION SELECTION ...........................................................................35
5.1
Study Population....................................................................................................35
5.2
Inclusion Criteria ...................................................................................................35
5.2.1
Inclusion Criteria for the Pivotal Study.......................................................35
5.2.2
Inclusion Criteria for the Substudy..............................................................36
5.3
Exclusion Criteria ..................................................................................................37
6
STUDY TREATMENT...................................................................................................39
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6.1
Description of Treatments......................................................................................39
6.1.1
Investigational Product ................................................................................39
6.1.2
Intrathecal Drug Delivery Device................................................................39
6.1.3
Comparator ..................................................................................................39
6.2
Treatments Administered.......................................................................................40
6.3
Selection and Timing of Dose for Each Patient.....................................................40
6.4
Method of Assigning Patients to Treatment Groups..............................................41
6.5
Blinding..................................................................................................................41
6.6
Concomitant Medications, Therapies, and Medical/Surgical Interventions..........41
6.6.1
Infusion Reactions and Management...........................................................42
6.7
Restrictions ............................................................................................................43
6.7.1
Prior Therapies.............................................................................................43
6.7.2
Fluid and Food Intake..................................................................................43
6.7.3
Patient Activity Restrictions ........................................................................43
6.8
Treatment Compliance...........................................................................................43
6.9
Packaging and Labeling.........................................................................................44
6.9.1
Investigational Product ................................................................................44
6.9.2
Intrathecal Drug Delivery Device................................................................44
6.10
Storage and Accountability....................................................................................44
6.10.1
Investigational Product ................................................................................44
6.10.2
Intrathecal Drug Delivery Device................................................................45
6.10.3
Comparator Product.....................................................................................45
7
STUDY PROCEDURES .................................................................................................46
7.1
Informed Consent...................................................................................................47
7.2
Study Entrance Criteria..........................................................................................47
7.3
Medical History .....................................................................................................48
7.3.1
Genotype......................................................................................................48
7.4
Echocardiogram .....................................................................................................49
7.5
Device Related Procedures ....................................................................................49
7.5.1
IDDD Implantation and Revision................................................................49
7.5.2
X-ray Verification of Intrathecal Drug Delivery Device Placement ...........50
7.5.3
CSF Sampling Procedure.............................................................................50
7.5.4
Device Removal...........................................................................................50
7.6
Investigational Product Administration.................................................................50
7.7
Pharmacokinetic Assessments ...............................................................................51
7.8
Pharmacodynamic/Biomarker Assessments..........................................................52
7.8.1
CSF Glycosaminoglycan .............................................................................52
7.8.2
CSF and Serum Albumin.............................................................................52
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7.9
Efficacy Assessments.............................................................................................52
7.9.1
Neurodevelopmental Assessment Tools......................................................52
7.10
Health Status Assessment ......................................................................................53
7.11
Safety Assessments................................................................................................53
7.11.1
Physical and Neurological Examination......................................................53
7.11.2
Height and Weight .......................................................................................54
7.11.3
Head Circumference ....................................................................................54
7.11.4
Hearing Assessment.....................................................................................54
7.11.5
Vital Signs....................................................................................................54
7.11.6
Electrocardiogram........................................................................................54
7.11.7
Intracranial Pressure Measurement..............................................................54
7.11.8
Brain Magnetic Resonance Imaging............................................................55
7.11.9
Clinical and Other Laboratory Tests............................................................55
7.11.10
Cerebrospinal Fluid Assessments ................................................................56
7.11.11
Antibody Assessments.................................................................................56
7.11.12
Device Assessments.....................................................................................56
7.11.13
Pregnancy Testing........................................................................................56
7.12
Sample Collection, Storage, and Shipping ............................................................56
7.13
Concomitant Medications, Therapies/Interventions, and Medical/Surgical 
Procedures Assessments ........................................................................................57
7.14
Adverse Events Assessments.................................................................................57
7.14.1
Definitions of Adverse Events and Serious Adverse Events.......................57
7.14.1.1
Adverse Events ..................................................................................57
7.14.1.2
Elaprase-related Adverse Events .......................................................58
7.14.1.3
IDDD-related Adverse Events ...........................................................58
7.14.1.4
Device Surgical Procedure-related Adverse Events ..........................58
7.14.1.5
Intrathecal Administration Process Adverse Events..........................58
7.14.1.6
Serious Adverse Events .....................................................................59
7.14.1.7
Unanticipated Adverse Device Effect................................................59
7.14.2
Device-associated Definitions .....................................................................60
7.14.2.1
Device Revision (Partial and Full).....................................................60
7.14.2.2
Device Malfunction ...........................................................................60
7.14.2.3
Device Failure....................................................................................60
7.14.3
Classification of Adverse Events and Serious Adverse Events...................60
7.14.3.1
Clarification between Serious and Severe .........................................60
7.14.4
Relatedness of Adverse Events and Serious Adverse Events......................60
7.14.5
Procedures for Recording and Reporting Adverse Events ..........................61
7.14.5.1
Adverse Event Monitoring and Period of Observation......................61
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7.14.5.2
Reporting Serious Adverse Events ....................................................62
7.15
Pregnancy...............................................................................................................63
7.16
Abuse, Misuse, Overdose, and Medication Error..................................................63
7.17
Removal of Patients from the Trial or Investigational Product.............................64
7.18
Other Study Procedures .........................................................................................64
7.18.1
Safety-related Study Stopping Rules ...........................................................64
7.19
Appropriateness of Measurements.........................................................................65
8
STUDY ACTIVITIES .....................................................................................................67
8.1
Screening (Month -1, Week -4 to -1).....................................................................67
8.1.1
All Patients in the Pivotal Study and Substudy ...........................................67
8.2
Randomization/Enrollment: Clinic Admission (Month 0, Week 0, Day 0) ..........68
8.2.1
All Patients (IT Treatment and No IT Treatment Groups) in the Pivotal 
Study ............................................................................................................68
8.2.2
All Patients in the Substudy.........................................................................68
8.3
Treatment Period (Months 1 to 12)........................................................................68
8.3.1
Patients in the IT Treatment Group of the Pivotal Study and All Patients in 
the Substudy: Pre-surgery, Surgery, Follow-up, and Post-op Recovery 
(Week 2 [+7 days]) ......................................................................................68
8.3.1.1
Pre-surgery.........................................................................................69
8.3.1.2
Surgery...............................................................................................69
8.3.1.3
Follow-up...........................................................................................69
8.3.1.4
Post-op Recovery...............................................................................69
8.3.2
Patients in the IT Treatment Group of the Pivotal Study and All Patients in 
the Substudy: IT Dosing (Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 
[±7 days]).....................................................................................................70
8.3.2.1
Pre-treatment......................................................................................70
8.3.2.2
IT Injection.........................................................................................70
8.3.2.3
Follow-up (Post IT Injection) ............................................................71
8.3.3
Patients in the No IT Treatment Group of the Pivotal Study (Months 1 to 
12) ................................................................................................................71
8.3.3.1
Week 2 (+7 days)...............................................................................71
8.3.3.2
Weeks 4, 16, 28, 40 (± 7 days)...........................................................72
8.3.3.3
Weeks 8, 12, 20, 24, 32, 36, 44, 48 (± 7 days)...................................72
8.4
End of Study: Month 13 (Week 52[± 7 days]) ......................................................72
8.4.1
Patients in the IT Treatment Group of the Pivotal Study and All Patients in 
the Substudy.................................................................................................72
8.4.2
Patients in the No IT Treatment Group of the Pivotal Study.......................73
8.5
Follow-up (Day 7 [±2 Days] Post EOS)................................................................74
8.5.1
Patients in the Pivotal Study and Substudy..................................................74
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9
QUALITY CONTROL AND ASSURANCE .................................................................75
10
STATISTICAL ANALYSIS ...........................................................................................76
10.1
General Methodology ............................................................................................76
10.2
Determination of Sample Size ...............................................................................76
10.3
Method of Assigning Study Patients to Treatment Groups ...................................77
10.4
Population Description and Exposure....................................................................77
10.4.1
Analysis Populations....................................................................................77
10.4.2
Patient Disposition.......................................................................................78
10.4.3
Protocol Deviations......................................................................................78
10.4.4
Demographics and Baseline Characteristics................................................78
10.4.5
Treatment Compliance.................................................................................78
10.4.6
Extent of Exposure.......................................................................................78
10.5
Analysis of Efficacy...............................................................................................79
10.5.1
Primary Efficacy Endpoint Analysis ...........................................................79
10.5.2
Key Secondary Efficacy Endpoint Analysis................................................79
10.5.3
Other Secondary Efficacy Endpoints Analyses ...........................................80
10.5.4
Exploratory Analyses...................................................................................80
10.6
Pharmacokinetic, Pharmacodynamic and Health Status Outcomes ......................81
10.6.1
Pharmacokinetic Measurements and Parameters.........................................81
10.6.2
Pharmacodynamic Outcome........................................................................82
10.6.3
Health Status Outcome ................................................................................82
10.7
Safety Assessments................................................................................................82
10.7.1
Adverse Events ............................................................................................83
10.7.2
IDDD and Procedure Related Adverse Events ............................................83
10.7.3
Clinical Laboratory Evaluations ..................................................................83
10.7.4
Electrocardiogram Evaluations....................................................................83
10.7.5
Vital Signs and Physical Measurements......................................................83
10.7.6
Physical Findings.........................................................................................84
10.7.7
Other Observations Related to Safety..........................................................84
10.7.7.1
Hearing Assessments .........................................................................84
10.7.7.2
Immunogenicity.................................................................................84
10.7.7.3
Device Performance...........................................................................84
10.7.8
Concomitant Medications/Therapies ...........................................................85
10.8
Statistical/Analytical Issues ...................................................................................85
10.8.1
Handling of Drop-outs and Missing Data....................................................85
10.8.2
Adjustment for Covariates...........................................................................85
10.8.3
Interim Analysis...........................................................................................85
10.8.4
Multicenter Studies......................................................................................85
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10.8.5
Multiple Comparisons/Multiplicity .............................................................86
10.8.6
Sensitivity Analyses.....................................................................................87
11
ADMINISTRATIVE CONSIDERATIONS....................................................................88
11.1
Investigators and Study Administrative Structure.................................................88
11.2
Institutional Review Board or Independent Ethics Committee Approval .............88
11.3
Ethical Conduct of the Study.................................................................................88
11.4
Patient Information and Consent ...........................................................................89
11.5
Patient Confidentiality...........................................................................................89
11.6
Study Monitoring...................................................................................................90
11.7
Case Report Forms and Study Records .................................................................90
11.7.1
Critical Documents ......................................................................................90
11.8
Data Monitoring Committee..................................................................................91
11.9
Device Failure Review Process .............................................................................91
11.10 Protocol Violations/Deviations..............................................................................91
11.11 Premature Closure of the Study.............................................................................92
11.12 Access to Source Documentation ..........................................................................92
11.13 Data Generation and Analysis ...............................................................................93
11.14 Retention of Data...................................................................................................93
11.15 Financial Disclosure...............................................................................................93
11.16 Publication and Disclosure Policy .........................................................................93
12
LIST OF REFERENCES.................................................................................................94
13
APPENDICES .................................................................................................................96
LIST OF IN-TEXT TABLES
Table 7-1
Assessments for Physical and Neurological Examinations..........................53
Table 7-2
List of Laboratory Tests ...............................................................................55
Table 7-3
Adverse Event Severity................................................................................60
Table 7-4
Adverse Event Relatedness ..........................................................................61
Table 7-5
Endpoint Model............................................................................................66
LIST OF APPENDICES
Appendix 1 Schedule of Events for Patients Randomized to Treatment in the 
Pivotal Study ................................................................................................96
Appendix 2 Schedule of Events for Patients Randomized to No Treatment in the 
Pivotal Study ................................................................................................99
Appendix 3 Schedule of Events for Patients Enrolled in the Substudy.........................101
Appendix 4 Expected Adverse Device Effects..............................................................104
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Appendix 5 Protocol Amendment Summary of Changes..............................................106
Appendix 6 Protocol Signature Page .............................................................................113
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SYNOPSIS
Sponsor:
Shire Human Genetic Therapies, Inc.
Names of Investigational Product and Device:
idursulfase for intrathecal use (idursulfase-IT [HGT-2310])
SOPH-A-PORT® Mini S, Implantable Access Port, Spinal, Mini Unattached, with 
Guidewire (SOPH-A-PORT Mini S)
Study Title:
A Controlled, Randomized, Two-arm, Open-label, Assessor-blinded, Multicenter Study of 
Intrathecal Idursulfase-IT Administered in Conjunction with Elaprase® in Pediatric 
Patients with Hunter Syndrome and Early Cognitive Impairment
Study Number:
HGT-HIT-094
Study Phase: 
Phase II/III
Investigational Product Dose, Mode of Administration: 
Investigational Product Dose:
Pivotal study - idursulfase-IT 10 mg 
Substudy - Dose adjustment for patients below 3 years of age based on reference brain 
weight: up to 8 months of age at dosing, idursulfase-IT 5 mg; >8 months to 30 months of 
age at dosing, idursulfase-IT 7.5 mg; >30 months to 3 years of age at dosing, 
idursulfase-IT 10 mg
Mode of Administration:
intrathecal (IT) injection
Device, Intended Use:
The SOPH-A-PORT® Mini S is a system intended for implantation by physicians. The 
SOPH-A-PORT Mini S, once implanted, allows healthcare personnel to administer 
idursulfase-IT (HGT-2310) indicated for IT delivery intermittently over a long period of 
time. 
Comparator, Dose, and Mode of Administration:
No treatment
Treatment Regimen:
Once monthly (ie, every 28 days) IT administration of idursulfase-IT for 12 months via a 
surgically implanted intrathecal drug delivery device (IDDD), or lumbar puncture 
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Primary Objective: 

To determine the effect of the treatment regimen in pediatric patients with Hunter 
syndrome and early cognitive impairment on the General Conceptual Ability 
(GCA) score as measured by the DAS-II, in conjunction with Elaprase therapy
Key Secondary Objective:

To determine the effect of the treatment regimen in pediatric patients with Hunter 
syndrome and early cognitive impairment on the Adaptive Behavior Composite 
(ABC) score as measured by the VABS-II, in conjunction with Elaprase therapy
Secondary Objectives:
To determine the effect of the treatment regimen in pediatric patients with Hunter 
syndrome and early cognitive impairment, in conjunction with Elaprase therapy, on:

Cognitive function as measured by the cluster areas and subtests of the DAS-II

Adaptive behavior as measured by the domains of the VABS-II
Safety Objectives:

To determine the effect of the treatment regimen on safety as assessed by adverse 
events, clinical laboratory testing, physical and neurological examination findings, 
vital signs, and electrocardiogram (ECG) results

To evaluate the anti-idursulfase antibody response in serum and cerebrospinal 
fluid (CSF) during the treatment regimen
SOPH-A-PORT Mini S Device Objectives:

To determine the safety and performance of the SOPH-A-PORT Mini S device
Pharmacokinetic and Pharmacodynamic Objectives:

To evaluate the concentration of idursulfase and determine pharmacokinetic (PK) 
parameters in serum after IT administration

To evaluate the concentration of idursulfase in CSF prior to each monthly 
administration of idursulfase-IT

To determine the effect of the treatment regimen on the concentration of 
glycosaminoglycan (GAG) in CSF 
Health Status Objective:

To evaluate health status as measured by the EuroQol-5D (EQ-5D) instrument
Substudy Objective:

To examine the effect of the treatment regimen on safety and efficacy measures in 
pediatric patients with Hunter syndrome and early cognitive impairment who are 
below 3 years of age
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Study Efficacy Endpoints: 
The primary efficacy endpoint of this study is:

Change from baseline in the GCA score after 12 months of treatment at Visit 
Week 52 as obtained by DAS-II testing
The key secondary efficacy endpoint of this study is:

Change from baseline in the ABC score after 12 months of treatment at Visit 
Week 52 as obtained by VABS-II testing
The secondary efficacy endpoints of this study are:

Change from baseline to Visit Weeks 16, 28, and 40 in the GCA score as obtained 
by DAS-II testing

Change from baseline to Visit Weeks 16, 28, and 40 in the ABC score as obtained 
by VABS-II testing

Change from baseline to Visit Weeks 16, 28, 40, and 52 in standard scores in 
cluster areas of the DAS-II: Verbal, Nonverbal, Spatial, and Special Nonverbal 
Composite (SNC)

Change from baseline to Visit Weeks 16, 28, 40, and 52 in standard scores of the 
VABS-II domains: Communication, Daily Living Skills, Socialization, and Motor 
Skills

Change from baseline to Visit Weeks 16, 28, 40, and 52 in age equivalents, 
developmental quotients, and T-scores for the subtests of the DAS-II: Verbal 
Comprehension, Picture Similarities, Naming Vocabulary, Pattern Construction, 
Matrices, and Copying for the DAS-II/Early Years and Recall of Designs, Word 
Definitions, Pattern Construction, Matrices, Verbal Similarities, and Sequential 
and Quantitative Reasoning for the DAS-II/School Years

Change from baseline to Visit Weeks 16, 28, 40, and 52 in age equivalents, 
developmental quotients, and V-scale scores of the VABS-II subdomains: 
Communication (Receptive, Expressive, Written), Daily Living Skills (Personal, 
Domestic, Community), Socialization (Interpersonal Relationships, Play and 
Leisure Time, Coping Skills), Motor Skills (Gross, Fine) 

Change from baseline to Visit Weeks 16, 28, 40, and 52 in the V-scale scores and 
the observed maladaptive levels of the VABS-II Maladaptive Behavior Index and 
its subscales (Internalizing, Externalizing) 
Study Population: 
Pivotal study – approximately 48 male patients (about 32 treated, 16 untreated) are 
planned. 
Substudy - enrollment of patients below 3 years of age into the separate substudy will be 
considered additional to the number of patients planned for the pivotal study, and will 
conclude when enrollment of patients in the pivotal study closes.
Study Design:
This is a controlled, randomized, two-arm, open-label, assessor-blinded, multicenter study 
to determine the effect on clinical parameters of neurodevelopmental status of monthly IT 
administration of idursulfase-IT for 12 months in pediatric patients with Hunter syndrome 
and early cognitive impairment who have previously received and tolerated a minimum of 
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4 months of therapy with Elaprase.  
All patients will continue to receive Elaprase therapy as standard of care throughout the 
study. Elaprase will not be provided by the Sponsor, but rather will be prescribed by the 
patient’s physician in accordance with local prescribing information. 
The pivotal study design is “no IT treatment-controlled”. Approximately 48 patients will 
be randomized in a 2:1 ratio to IT treatment or no IT treatment arms.
The pivotal study will consist of a Screening period of up to 28 days prior to 
randomization (Day 0). It is planned that patients randomized to IT treatment will undergo 
surgical implantation of the SOPH-A-PORT Mini S IDDD followed by a post-operative 
recovery period of at least 14 days prior to the first IT administration of idursulfase-IT. 
Treated patients will then receive 12 monthly IT injections of 10 mg idursulfase-IT 
corresponding to a treatment and assessment interval of 13 (28-day) months from 
randomization to the end-of-study (EOS) evaluations. Likewise, patients randomized to no 
IT treatment will be assessed over 13 (28-day) months after randomization.
Patients in the IT treatment arm of the pivotal study will be assessed according to the 
following schedule: 

Screening (Weeks -4 to -1 [Day -28 to Day -1])

Randomization (Week 0 [Day 0])

Pre-surgery, Surgery, Follow-up, and Post-operative Recovery (Week 2 [+7 days])

Treatment and Assessments (Week 4 through Week 48 [±7 days])

End of Study (EOS, Week 52 [±7 days])

Follow-up (telephone contact) 7 (±2) days from the Week 52 (or EOS)
Patients in the no IT treatment arm of the pivotal study will be assessed according to the 
following schedule: 

Screening (Weeks -4 to -1 [Day -28 to Day -1])

Randomization (Week 0 [Day 0])

Telephone Contact (Week 2 [+7 days])

Assessments (Week 4 through Week 48 [±7 days])

End of Study (EOS, Week 52 [±7 days])

Follow-up (telephone contact) 7 (±2) days from the Week 52 (or EOS) 
The separate substudy is open label and single arm. Patients who meet all entry criteria for 
participation in the substudy will be considered enrolled on Day 0. Thereafter, it is 
planned that patients in the separate substudy will undergo surgical implantation of the 
SOPH-A-PORT Mini S IDDD for the purpose of IT administration of idursulfase-IT and 
will follow a similar schedule of treatment and assessments as idursulfase-IT-treated 
patients in the pivotal study.  
Patients in the substudy will be assessed according to the following schedule: 

Screening (Weeks -4 to -1 [Day -28 to Day -1])

Enrollment (Week 0 [Day 0])

Pre-surgery, Surgery, Follow-up, and Post-operative Recovery (Week 2 [+7 days])
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
Treatments and Assessments (Week 4 through Week 48 [±7 days])

End of Study (EOS, Week 52 [±7 days])

Follow-up (telephone contact) 7 (±2) days from the Week 52 (or EOS) 
Patients will complete EOS assessments at Week 52 (Visit Month 13) and will participate 
in a follow-up contact (by telephone) approximately 7 days after the EOS visit. (Note that 
for those patients who enroll in extension study SHP-609-302 within the 7 ±2 day window 
of the EOS visit the follow-up contact is not required. If, however, a patient is not enrolled 
in the SHP-609-302 study within the 7 ±2 day window of the EOS visit, then the follow-
up contact should be completed.)
A patient who discontinues or is withdrawn prior to study completion will be asked to 
participate in an EOS visit within approximately 30 days after withdrawal or 
discontinuation (EOS assessments for such patients will be the same as Week 52 
assessments), and also to complete a follow-up contact approximately 7 days after the 
patient’s EOS visit. There is no replacement of patients who do not complete the study.
It is planned that the SOPH-A-PORT Mini S IDDD will be used to obtain CSF samples 
and to deliver IT injections of idursulfase-IT. If the IDDD appears to be non-functional, or 
if its use is precluded on a scheduled day of dosing, site personnel will refer to the IDDD 
Manual, which provides details on the investigation and management of any IDDD-
related issues. If the IT space is not accessible via the IDDD, lumbar puncture may be 
utilized under defined circumstances for administration of idursulfase-IT or to obtain a 
CSF sample.
General anesthesia/sedation may be required for injections of study drug and some 
evaluations, and can be used at the discretion of the Investigator.  
A Data Monitoring Committee (DMC) will oversee both idursulfase-IT and device safety. 
The DMC will be notified of IDDD failures and related complications on a periodic basis 
according to the DMC charter.  
Patients will have the IDDD removed when they discontinue from the study, unless the 
patient is continuing to receive treatment through another mechanism (eg, extension study, 
expanded access program).
Study Duration:
The planned overall duration of each patient’s participation in the study is approximately 
14 to 15 months from Screening to the last scheduled contact.  
An extension study is planned during which patients who complete HGT-HIT-094 and are 
eligible according to the inclusion/exclusion criteria for the extension study may continue, 
or begin, to receive IT treatment with idursulfase-IT via the SOPH-A-PORT Mini S 
device.
Study Inclusion and Exclusion Criteria:
Inclusion Criteria
Patients must meet the following criteria to be considered eligible for randomization in the 
pivotal study: 
1. The patient is male and is ≥3 and <18 years of age at the time of informed consent. 
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Note that patients who are younger than 3 years of age may be enrolled in a separate 
substudy provided that they meet other inclusion criteria, provided below. 
2. The patient must have a documented diagnosis of MPS II. Of the three criteria below, 
the combinations (2a AND 2b) or (2a AND 2c) will be accepted as diagnostic of MPS 
II:
a.
The patient has a deficiency in iduronate-2-sulfatase enzyme activity of ≤10% of 
the lower limit of the normal range as measured in plasma, fibroblasts, or 
leukocytes (based on the reference laboratory’s normal range).
AND
b. The patient has a documented mutation in the iduronate-2-sulfatase gene that 
leaves the FMR1 and FMR2 genes intact.  
OR
c.
The patient has a normal enzyme activity level of one other sulfatase as measured 
in plasma, fibroblasts, or leukocytes (based on the normal range of measuring 
laboratory).
3. The patient has evidence at Screening of Hunter syndrome-related cognitive 
impairment, defined as follows:  
Note that separate inclusion criteria with respect to patient cognitive status at 
Screening apply to patients ≥3 and <13 years of age and patients ≥13 and <18 years 
of age.
A patient who is ≥3 and <13 years of age must have one of the following criteria (3a 
OR 3b):
a.
A GCA score ≥55 and ≤85.  
OR
b. If the patient has a GCA score at Screening >85, there must be evidence of a 
decrease in GCA score of ≥10 points over 12 months from a previously 
documented test result in observational study HGT-HIT-090.
A patient who is ≥13 and <18 years of age must have both of the following criteria 
(3c AND 3d):
c.
A GCA score of ≥55 and ≤85  
AND
d. There must be evidence of a decrease in GCA score of ≥10 points over 12 months 
from a previously documented test result in observational study HGT-HIT-090.
4. The patient has received and tolerated a minimum of 4 months of therapy with 
Elaprase during the period immediately prior to Screening.
5. The patient must have sufficient auditory capacity, with a hearing aid(s), if needed, in 
the Investigator’s judgment to complete the required protocol testing and must be 
compliant with wearing the hearing aid(s), if needed, on scheduled testing days.
6. The patient’s parent(s) or legally authorized guardian(s) must have voluntarily signed 
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an Institutional Review Board/Independent Ethics Committee (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 guardian(s) and the 
patient’s assent, if applicable, must be obtained prior to the start of any study 
procedures.
Patients must meet all of the following criteria to be considered eligible for enrollment in 
the separate substudy: 
1. The patient is male and is <3 years of age at the time of informed consent.
2. The patient must have a documented diagnosis of MPS II.   Of the three criteria below, 
the combinations (2a AND 2b) or (2a AND 2c) will be accepted as diagnostic of MPS 
II:
a.
The patient has a deficiency in iduronate-2-sulfatase enzyme activity of ≤10% of 
the lower limit of the normal range as measured in plasma, fibroblasts, or 
leukocytes (based on the reference laboratory’s normal range).
AND
b. The patient has a documented mutation in the iduronate-2-sulfatase gene that 
leaves the FMR1 and FMR2 genes intact. 
OR
c.
The patient has a normal enzyme activity level of one other sulfatase as measured 
in plasma, fibroblasts, or leukocytes (based on the normal range of measuring 
laboratory).
3. The patient has evidence at Screening of Hunter syndrome-related cognitive 
impairment as assessed using the BSID-III and defined as a DQ ≥55 and ≤85. 
4. The patient has received and tolerated a minimum of 4 months of therapy with 
Elaprase during the period immediately prior to Screening.
5. The patient must have sufficient auditory capacity, with a hearing aid(s), if needed, in 
the Investigator’s judgment, to complete the required protocol testing, and must be 
compliant with wearing the hearing aid(s) on scheduled testing days.
6. The patient’s parent(s) or legally authorized guardian(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 guardian(s) and the patient’s assent must be obtained prior to the start of 
any study procedures. 
Exclusion Criteria
Patients who meet any of the following criteria are not eligible to be randomized into the 
pivotal study or enrolled in the separate substudy:  
1. The patient has clinically significant non-Hunter syndrome-related CNS involvement 
(such as Fragile-X syndrome) which is judged by the Investigator to be likely to 
interfere with the accurate administration and interpretation of protocol assessments.
2. The patient has a large chromosomal deletion or complex rearrangement that includes 
a deletion of the FMR1 and/or FMR2 genes. 
3. The patient has a significant medical or psychiatric comorbidity(ies) that might affect 
study data or confound the integrity of study results.
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4. The patient has contra-indications for performance of lumbar puncture such as 
musculoskeletal/spinal abnormalities or risk of abnormal bleeding. 
5. The patient has a history of complications from previous lumbar punctures or 
technical challenges in conducting lumbar punctures such that the potential risks 
would exceed possible benefits for the patient. 
6. The patient has an opening CSF pressure upon lumbar puncture that exceeds 30.0 cm 
H2O.
7. The patient has experienced infusion-related anaphylactoid event(s) or has evidence of 
consistent severe adverse events related to treatment with Elaprase which, in the 
Investigator’s opinion, may pose an unnecessary risk to the patient.
8. The patient has received a cord blood or bone marrow transplant at any time or has 
received blood product transfusions within 90 days prior to Screening.
9. The patient has a history of poorly controlled seizure disorder.
10. The patient is unable to comply with the protocol (eg, has significant hearing or vision 
impairment, a clinically relevant medical condition making implementation of the 
protocol difficult, unstable social situation, known clinically significant 
psychiatric/behavioral instability, is unable to return for safety evaluations, or is 
otherwise unlikely to complete the study), as determined by the Investigator.
11. The patient is enrolled in another clinical study that involves clinical investigation or 
use of any investigational product (drug or [intrathecal/spinal] device) within 30 days 
prior to study enrollment or at any time during the study.
12. The patient has any known or suspected hypersensitivity to anesthesia or is thought to 
be at an unacceptably high risk for anesthesia due to compromised airways or other 
conditions.
13. The patient has a condition that is contraindicated as described in the SOPH-A-PORT 
Mini S IDDD Instructions for Use (IFU), including:
a.
The patient has had, or may have, an allergic reaction to the materials of 
construction of the SOPH-A-PORT Mini S device
b. The patient’s body size is too small to support the size of the SOPH-A-PORT 
Mini S Access Port, as judged by the Investigator 
c.
The patient’s drug therapy requires substances known to be incompatible with 
the materials of construction 
d. The patient has a known or suspected local or general infection
e.
The patient is at risk of abnormal bleeding due to a medical condition or 
therapy
f.
The patient has one or more spinal abnormalities that could complicate safe 
implantation or fixation
g. The patient has a functioning CSF shunt device
h. The patient has shown an intolerance to an implanted device
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Pharmacokinetic Assessments:
Determination of idursulfase serum concentration-time profiles and serum 
pharmacokinetic parameters after IT administration.  
Measurement of idursulfase concentration in CSF samples obtained immediately prior to 
each IT administration (and at the EOS Visit) to determine the degree of accumulation of 
monthly idursulfase-IT administrations in the CSF.
Pharmacodynamic Assessments:
Determination of the concentration of GAG in CSF samples.
Efficacy Assessments:
Neurodevelopmental status will be assessed over time by measuring cognitive and 
adaptive functions as follows:
Cognition: the Differential Ability Scales, Second Edition (DAS-II) will be used to assess 
all patients randomized in the pivotal study. For patients participating in the separate 
substudy only (ie, patients who are below the age of 3 years and who have early cognitive 
impairment) cognition will be assessed initially using the Bayley Scales of Infant 
Development, Third Edition (BSID-III). When these patients reach at least 42 months of 
age, if considered evaluable using the DAS-II instrument, they will transition to use of the 
DAS-II for continued assessment of cognition.
Adaptive Behaviors: the Vineland Adaptive Behavioral Scales, Second Edition (VABS-II) 
will be used to assess all patients. The Expanded Interview Form will be utilized. 
Safety Assessments:
Safety will be assessed by adverse events (by type, severity, and relationship to treatment 
[idursulfase-IT, IDDD, device surgical procedure, IT administration process] and IV 
Elaprase infusion), changes in clinical laboratory testing (serum chemistry, hematology, 
urinalysis), physical and neurological examination, vital signs, 12-lead ECG, CSF 
laboratory parameters (chemistries, cell counts), anti-idursulfase antibodies in CSF and 
serum, and determination of antibodies having enzyme neutralizing activity.
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 case report form 
(CRF) from the time of initial implantation.
Statistical Methods: 
General Methods 
Continuous variables will be summarized using descriptive statistics (N, mean, standard 
deviation, minimum, median, and maximum). Categorical variables will be summarized 
using the number and percentage of patients in each category. Data will be summarized 
with respect to patient disposition, demographic and baseline characteristics and 
concomitant medication use. The efficacy endpoints, safety assessments and other 
outcome results for each treatment group will be summarized descriptively unless 
otherwise indicated. Statistical model estimates of least squares means, p-values and 95% 
confidence intervals (CIs) for least squares mean treatment differences will also be 
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provided where relevant for efficacy endpoints. All statistical tests will be two-sided and 
will be performed at the 0.05 level of significance unless stated otherwise.  
Safety and efficacy data from the single-arm substudy will be summarized separately or 
listed separately. 
Analysis Populations 
For the pivotal trial, all efficacy data analyses will be performed using the Intent-to-Treat 
(ITT) Population, which is defined as all randomized patients.  
All safety data analyses will be performed according to treatment received using the 
Safety Population, which is defined as all randomized patients with any 
post-randomization safety assessments. Device related analyses will be conducted in the 
set of patients in the Safety Population who had the device implant procedure performed.
For the substudy, analyses will be performed on the Substudy Population, defined as all 
patients enrolled and treated with study drug in the substudy. 
All PK data analyses will be performed using the PK population. The PK population will 
be defined as all patients for whom the primary pharmacokinetic data are considered 
sufficient and interpretable.
Analysis of Efficacy
For the pivotal trial, the primary efficacy endpoint is the change from study baseline 
(Screening Visit) to Visit Week 52 in the General Conceptual Ability (GCA) score as 
measured by the DAS-II. The primary analysis will compare the treatment groups using a 
linear mixed model repeated measures (MMRM) analysis. The repeated measures are the 
change from baseline GCA scores obtained at the scheduled Visit Weeks 16, 28, 40, and 
52, respectively. The model will include fixed categorical effects for treatment, visit week, 
treatment by visit week interaction, baseline GCA classification factor (either ≤70 or >70), 
and the baseline GCA score as a continuous covariate. From this model, least squares 
means, standard errors, treatment differences in least squares means, and 95% CIs will be 
estimated for each time point. Primary inference is based on the treatment comparison of 
least squares means at Visit Week 52 from this model, and a p-value will be presented for 
this time point only.   
The key secondary efficacy endpoint is the change from study baseline (Screening Visit) 
to Visit Week 52 in the Adaptive Behavior Composite (ABC) score as measured by the 
VABS-II. This endpoint will be analyzed using an MMRM analysis with effects of 
treatment, visit week, treatment by visit week interaction, baseline GCA classification 
factor (either ≤70 or >70), and the baseline ABC score as a continuous covariate. The 
significance test will be based on the difference in least squares means at Visit Week 52 
and a p-value will be presented for this time point only.  
The following secondary efficacy endpoints will be analyzed using an MMRM analysis in 
the same manner as described above for the key secondary endpoint with the continuous 
covariate corresponding to the baseline score for each measure: 

The change from baseline to Visit Weeks 16, 28, 40, and 52 in standard scores in 
cluster areas of the DAS-II: Verbal, Nonverbal, Spatial, and Special Nonverbal 
Composite (SNC) 

The change from baseline to Visit Weeks 16, 28, 40, and 52 in the standard 
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domain scores of the VABS-II: Communication, Daily Living Skills, 
Socialization, and Motor Skills 
All other secondary efficacy endpoints will be summarized descriptively by treatment 
group. 
The family wise type-I error rate (FWER) for the statistical tests of the primary, key 
secondary and other selected secondary efficacy endpoints from the MMRM analyses will 
be controlled at 0.05. To strongly control the FWER at this level, a Gatekeeping approach 
will be utilized in which each family of statistical tests will be conducted in a sequential 
manner. The test for the primary endpoint will be conducted first at the 5% significance 
level and, if significant, the key secondary endpoint will be similarly tested at the 
5% significance level. If these two tests are both significant, tests of the additional 
secondary efficacy endpoints specified below will be conducted using the Hommel closed 
testing procedure1 to control the FWER.
Analysis of Safety 
All safety analyses will be descriptive. Adverse events will be summarized by treatment 
group, both overall and within system organ class by preferred term. Adverse events will 
also be tabulated by severity (mild, moderate, severe) and by relationship to study drug 
(not related, related) for treated patients. Separate tabulations will be provided for adverse 
events related to study drug, IV Elaprase infusion, the IDDD, device surgical procedure, 
and the IT-administration process. 
SOPH-A-PORT safety and performance will be summarized for implanted patients. The 
proportion of patients with at least one IDDD failure and the proportion with malfunction 
only, as well as the number of and reasons for IDDD failures and malfunctions will be 
summarized. The annual event rate of IDDD failures and the time to first failure will be 
summarized.  
Laboratory values in serum and CSF components, vital signs, ECG parameters, and other 
safety assessments will be summarized descriptively by treatment group. The number and 
percentage of patients testing anti-idursulfase antibody positive and negative at each time 
point will be summarized. 
All safety data from the separate substudy will be similarly summarized in a descriptive 
manner or listed, as appropriate.
Date: 21 December 2015
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Term
Definition
ABC
adaptive behavior composite
AE
adverse event
ALB
albumin
ALK
alkaline phosphatase
ALT
alanine aminotransferase (SGPT)
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
AR(1)
autoregressive 
BMI
body mass index
BSID-III
Bayley Scales of Infant Development, Third Edition
BUN
blood urea nitrogen
BVA
blinded variability assessment
CFR
Code of Federal Regulations
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
Cmax
maximal concentration
CNS
central nervous system
CRF
case report form (paper or electronic)
CRO
contract research organization
CSF
cerebrospinal fluid
DAS-II
Differential Ability Scales, Second Edition
DQ
developmental quotient
DS
dermatan sulfate
DMC
Data Monitoring Committee
ECG
electrocardiogram
EOS
end of study
EQ-5D
EuroQol-5D instrument for use as a measure of health outcome
ERT
enzyme replacement therapy
EU
European Union
FDA
United States Food and Drug Administration
FWER
familywise type-I error rate
GAG
glycosaminoglycan
GCA
general conceptual ability
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Term
Definition
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
Hct
hematocrit
Hgb
hemoglobin
HGT-2310
drug code name for formulation of recombinant iduronate-2-sulfatase (idursulfase) 
for intrathecal administration 
HS
heparan sulfate
ICH
International Conference on Harmonisation
ICP
intracranial pressure
IDS
iduronate-2-sulfatase gene
IDDD
intrathecal drug delivery device
IEC
Independent Ethics Committee
IFU
Instructions for Use
IND
Investigational New Drug application
IRB
Institutional Review Board
IT
intrathecal
ITT
intent-to-treat
IV
intravenous(ly)
IVR
interactive voice response
KM
Kaplan Meier
LDH
lactate dehydrogenase
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MDR
medical device report
MedDRA
Medical Dictionary for Regulatory Activities 
MMRM
mixed model repeated measures
MPS II
Mucopolysaccharidosis II (Hunter syndrome)
MRI
magnetic resonance imaging
PACU
post-anesthesia care unit
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PORT-A-CATH
PORT-A-CATH® II Low Profile™ Intrathecal Implantable Access System 
PPD
Pharmaceutical Product Development, LLC
PRO
patient reported outcome
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Term
Definition
PT
prothrombin time
PTT
partial thromboplastin time
QTc
corrected QT interval
RBC
red blood cell(s)
SAE
serious adverse event
SAS
Statistical Analysis System©
SD
standard deviation
SE
standard error 
SGOT
serum glutamic oxaloacetic transaminase (ast)
SGPT
serum glutamic pyruvic transaminase (alt)
Shire HGT
Shire Human Genetic Therapies, Inc. (Shire)
SmPC
Summary of Product Characteristics
SNC
special nonverbal composite
SOC
system organ class
SOE
schedule of events
SOPH-A-PORT 
Mini S
SOPH-A-PORT® Mini S, Implantable Access Port, Spinal, Mini Unattached, with 
Guidewire 
T4
thyroxine
TSH
thyroid-stimulating hormone
UADE
unanticipated adverse device effect
UK
United Kingdom
US
United States
VAS
visual analog scale
VABS-II
Vineland Adaptive Behavior Scales, Second Edition
WBC
white blood cell(s)
WHO-DD
World Health Organization Drug Dictionary
WOCF
worst observation carried forward
WRS
Wilcoxon rank-sum test
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1
INTRODUCTION
1.1
Mucopolysaccharidosis II (Hunter syndrome)
Mucopolysaccharidosis II (MPS II) is a rare, X-linked, inherited disease that affects males nearly 
exclusively. Its estimated incidence is 1 in approximately 162,000 live births.2-3 Though typically 
appearing normal at birth, all MPS II patients suffer from a progressive, serious, life-limiting 
disease.4, 5
The disease is caused by the absence of, or deficiency in, the activity of the lysosomal enzyme, 
iduronate-2-sulfatase which acts to cleave O-linked sulfate moieties from the glycosaminoglycan 
(GAG) molecules dermatan sulfate (DS) and heparan sulfate (HS).6 Insufficient activity of 
iduronate-2-sulfatase leads to progressive accumulation of GAG in nearly all organs and body 
tissues.
The central underlying pathophysiological process leading to the clinical manifestations of MPS 
II is the chronic accumulation of dermatan sulfate and heparan sulfate inside cellular lysosomes, 
resulting in cellular engorgement, organomegaly, tissue destruction, and organ system 
dysfunction. Accumulation of GAG affects nearly all cell types, tissues, and organs of the body 
including the respiratory tract, heart, liver, spleen, leptomeninges, bones, joints, oropharynx, 
head, neck, and central nervous system (CNS).7 Clinical manifestations include severe airway 
obstruction, skeletal deformities, cardiomyopathy and, in most patients, neurological decline.8
Death may occur in the first or second decade of life. Patients with attenuated disease may 
survive into adulthood, with airway obstruction and cardiac causes often contributing to death.5
Phenotypic expression of the disease spans a wide spectrum of clinical severity. However, two 
extremes at either end of the continuum of MPS II have been identified based on cognitive 
status.5, 9 The first is broadly characterized as an “attenuated” or milder form in which 
intellectual and neurodevelopment faculties are largely intact, although somatic pathology is 
present. The term “severe” has been adopted to describe a second broad phenotype of MPS II 
patients who suffer from neurodevelopmental impairment in addition to somatic manifestations 
of the disease. It has been estimated that approximately three-quarters of MPS II patients will 
develop CNS involvement and be characterized as “severe.9 Despite these characterizations, 
patients with predominantly somatic involvement may nevertheless have a life-limiting disease 
course.
Although there is heterogeneity with respect to disease progression, the onset of signs and 
symptoms typically occurs at about 2 to 4 years of age.7-10 An earlier appearance of clinical 
symptoms generally, but not always, predicts a more severe clinical course.5-7, 11 Knowledge of 
the genotype is of limited value in predicting a patient’s clinical course with respect to CNS 
involvement. An exception is represented by children with complete absence of functional 
enzyme due to deletion/rearrangement of the iduronate-2-sulfatase gene (IDS), who manifest 
severe neurodevelopmental impairment.12-13
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1.2
Unmet Medical Need
The currently approved therapy for Hunter syndrome is Elaprase® (idursulfase), recombinant 
human iduronate-2-sulfatase for intravenous (IV) administration. 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 IV enzyme replacement,14-16 Elaprase has not been evaluated 
specifically regarding its independent quantifiable impact on CNS pathology, 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. Thus, no specific therapy exists for the CNS pathologies of Hunter syndrome.
A distinct formulation, designated idursulfase-IT (HGT-2310), was developed specifically for 
delivery into the cerebrospinal fluid (CSF) via intrathecal (IT) administration to access CNS 
tissues. The active ingredient of the idursulfase-IT product [recombinant human 
iduronate-2-sulfatase] is the same active ingredient as in commercially available Elaprase. In 
contrast to Elaprase, however, idursulfase-IT is specially formulated for, and compatible with, 
direct introduction into CSF since it is isotonic and contains excipients suitable for IT use.
In order to traverse the blood-brain barrier, Shire is evaluating delivery of idursulfase-IT directly 
into the CNS using an intrathecal drug delivery device (IDDD), the SOPH-A-PORT® Mini S, 
Implantable Access Port, Spinal, Mini Unattached, with Guidewire (SOPH-A-PORT Mini S). 
The advantage of using an IDDD is the potential to obviate the need for multiple lumbar 
punctures for drug delivery.
1.3
Overview of Results of Phase I/II Studies 
The safety and tolerability of ascending doses (1, 10, or 30 mg) of intrathecally administered 
idursulfase-IT were investigated in the first-in-human study HGT-HIT-045, a randomized, open-
label, no-treatment controlled Phase I/II study in which idursulfase-IT was administered once 
monthly to pediatric MPS II patients via a surgically implanted IDDD (PORT-A-CATH® II Low 
Profile™Intrathecal Implantable Access System [PORT-A-CATH]) for 6 months in conjunction 
with once weekly IV infusion of Elaprase.  Eligible patients who completed HGT-HIT-045 are 
receiving 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, pharmacokinetics (PK), and pharmacodynamics (PD) (effect on GAG concentration in 
CSF) have been evaluated. Effects of IT administration of 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. There have been no deaths or discontinuations due to adverse events (AEs) in either study, 
and no serious adverse events related to idursulfase-IT. The majority of serious adverse events in 
both studies have been associated with the PORT-A-CATH device, and designated as serious 
because of the requirement for overnight hospitalization for surgical revision/removal of the 
IDDD. The events related to the use of the IDDD included surgical removal and replacement of 
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the device because of mechanical failures, primarily connector pin breaks and catheter slippage, 
to overnight admissions to the clinical site for a suspected device infection, and device removal 
because of wound issues.
As a result of the device-related concerns in the Phase I/II program, additional guidelines and 
training materials were developed for implanting neurosurgeons 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 in the event of device malfunction. To 
address the frequent occurrence of device failures observed with use of the PORT-A-CATH 
IDDD in the Phase I/II studies, the SOPH-A-PORT Mini S will be used in this Phase II/III study. 
The SOPH-A-PORT Mini S device is intended to address the frequent occurrence of device 
failures observed with use of the PORT-A-CATH IDDD in the Phase I/II studies.
Intrathecal administration of idursulfase-IT to MPS II patients in HGT-HIT-045 and 
HGT-HIT-046 at the 10 and 30 mg dose regimens resulted in a pronounced pharmacodynamic 
reduction from baseline in the concentration of GAG in CSF; the 1 mg dose regimen induced a 
slower and less pronounced reduction in GAG concentration in CSF. Available results of 
neurodevelopmental assessments performed across HGT-HIT-045 and HGT-HIT-046 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.
1.3.1
Rationale for Current Phase II/III Study
Because intravenously administered idursulfase has not been shown to traverse the blood-brain 
barrier due to its impermeability to large macromolecules such as proteins, there is an unmet 
medical need in the population of MPS II patients with CNS disease to support clinical 
development of idursulfase-IT for intrathecal use.  
It is planned that the SOPH-A-PORT Mini S delivery device will be used for IT administration 
of idursulfase-IT to MPS II patients in this study. In contrast to IT administration via lumbar 
puncture, the use of an IDDD does not always require full anesthesia; in many cases, sedation 
may be appropriate. Multiple drug administrations, therefore, may require only a single episode 
of general anesthesia (for device implantation), in contrast to the multiple episodes of general 
anesthesia that would be required for repeated lumbar punctures in this patient population.
Nonclinical experience with IT administration of idursulfase-IT has demonstrated wide 
distribution of idursulfase to the 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. 
In Phase I/II clinical studies in MPS II patients, idursulfase-IT has been generally well tolerated. 
Stabilization or improvement in cognitive and adaptive functions has been noted in some of the 
children enrolled in the trials. The available data support the Sponsor’s hypothesis that a 
therapeutic benefit may be expected in MPS II children with cognitive impairment.
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The therapeutic strategy consisting of idursulfase-IT administered intrathecally via the 
SOPH-A-PORT Mini S device and concomitant IV Elaprase therapy is intended to address both 
the CNS and somatic manifestations of Hunter syndrome. Idursulfase-IT is intended for long-
term treatment of Hunter syndrome in patients with cognitive impairment to slow progression of 
cognitive and functional impairment.
The design of the proposed study, including the neurodevelopmental assessment tools and 
endpoints, and the selection of idursulfase-IT 10 mg dose, have been informed by the results of 
Phase I/II studies HGT-HIT-045 and HGT-HIT-046 (See Section 1.3). Please refer to the current 
edition of the Investigator’s Brochure for additional information concerning the safety and 
clinical development of idursulfase-IT and for information concerning the SOPH-A-PORT Mini 
S delivery device. 
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2
STUDY OBJECTIVES
The treatment regimen is defined as once monthly (ie, every 28 days) intrathecal administration 
of idursulfase-IT for 12 months via a surgically implanted IDDD (or lumbar puncture).
2.1
Primary Objective 
The primary objective of this study is:

To determine the effect of the treatment regimen in pediatric patients with Hunter 
syndrome and early cognitive impairment on the General Conceptual Ability (GCA) 
score as measured by the Differential Ability Scale, Second Edition (DAS-II), in 
conjunction with Elaprase therapy
2.2
Secondary Objectives 
The key secondary objective of this study is:

To determine the effect of the treatment regimen in pediatric patients with Hunter 
syndrome and early cognitive impairment on the Adaptive Behavior Composite (ABC) 
score as measured by the Vineland Adaptive Behavior Scales, Second Edition 
(VABS-II), in conjunction with Elaprase therapy
The secondary objectives of this study are:

To determine the effect of the treatment regimen in pediatric patients with Hunter 
syndrome and early cognitive impairment, in conjunction with Elaprase therapy, on:
o
Cognitive function as measured by the cluster areas and subtests of the DAS-II
o
Adaptive behavior as measured by the domains of the VABS-II
2.3
Safety Objectives

To determine the effect of the treatment regimen on safety as assessed by adverse events, 
clinical laboratory testing, physical and neurological examination findings, vital signs, 
and electrocardiogram (ECG) results

To evaluate the anti-idursulfase antibody response in serum and CSF during the treatment 
regimen
2.4
SOPH-A-PORT Mini S Device Objectives:

To determine the safety and performance of the SOPH-A-PORT Mini S device
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2.5
Pharmacokinetic and Pharmacodynamic Objectives
The PK and PD objectives of this study are:

To evaluate the concentration of idursulfase and determine PK parameters in serum after 
IT administration 

To evaluate the concentration of idursulfase in CSF prior to each monthly administration 
of idursulfase-IT 

To determine the effect of the treatment regimen on the concentration of GAG in CSF 
2.6
Health Status Objective

To evaluate health status as measured by the EuroQol-5D (EQ-5D) instrument
2.7
Substudy Objective
The objective of the substudy is:

To examine the effect of the treatment regimen on safety and efficacy measures in 
pediatric patients with Hunter syndrome and early cognitive impairment who are below 
3 years of age
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3
STUDY ENDPOINTS
3.1
Primary Efficacy Endpoint 
The primary efficacy endpoint of this study is:

Change from baseline in the GCA score after 12 months of treatment at Visit Week 52 as 
obtained by DAS-II testing
3.2
Secondary Efficacy Endpoints 
The key secondary efficacy endpoint of this study is:

Change from baseline in the ABC score after 12 months of treatment at Visit Week 52 as 
obtained by VABS-II testing
The secondary efficacy endpoints of this study are:

Change from baseline to Visit Weeks 16, 28, and 40 in the GCA score as obtained by 
DAS-II testing

Change from baseline to Visit Weeks 16, 28, and 40 in the ABC score as obtained by 
VABS-II testing

Change from baseline to Visit Weeks 16, 28, 40, and 52 in standard scores in cluster 
areas of the DAS-II: Verbal, Nonverbal, Spatial, and SNC

Change from baseline to Visit Weeks 16, 28, 40, and 52 in standard scores of the 
VABS-II domains: Communication, Daily Living Skills, Socialization, and Motor Skills

Change from baseline to Visit Weeks 16, 28, 40, and 52 in age equivalents, 
developmental quotients, and T-scores for the subtests of the DAS-II: Verbal 
Comprehension, Picture Similarities, Naming Vocabulary, Pattern Construction, 
Matrices, and Copying for the DAS-II/Early Years and Recall of Designs, Word 
Definitions, Pattern Construction, Matrices, Verbal Similarities, and Sequential and 
Quantitative Reasoning for the DAS-II/School Years

Change from baseline to Visit Weeks 16, 28, 40, and 52 in age equivalents, 
developmental quotients, and V-scale scores of the VABS-II subdomains: 
Communication (Receptive, Expressive, Written), Daily Living Skills (Personal, 
Domestic, Community), Socialization (Interpersonal Relationships, Play and Leisure 
Time, Coping Skills), Motor Skills (Gross, Fine) 

Change from baseline to Visit Weeks 16, 28, 40, and 52 in the V-scale scores and 
observed maladaptive levels of the VABS-II Maladaptive Behavior Index and its 
subscales (Internalizing, Externalizing) 
3.3
Pharmacokinetic and Pharmacodynamic Endpoints
The PK and PD endpoints of this study are:
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
Serum concentration of idursulfase and serum PK parameters after IT administration 

CSF concentration of idursulfase prior to each monthly IT administration 

Change from baseline in the concentration of GAG in CSF 
3.4
Safety Assessments
Safety will be assessed during the study by collection of adverse events (by type, severity, and 
relationship to treatment [idursulfase-IT, the IDDD, device surgical procedure, or IT 
administration process] and IV Elaprase infusion), changes in clinical laboratory testing (serum 
chemistry, hematology, urinalysis), physical and neurological examination, vital signs, 12-lead 
ECG recordings, CSF laboratory parameters (chemistries, cell counts), anti-idursulfase 
antibodies in CSF and serum, and determination of antibodies having enzyme neutralizing 
activity.
3.5
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 case report form (CRF) from the time of 
initial implantation.
3.6
Health Status Assessment
Health status dimensions as obtained by the EQ-5D questionnaire.
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4
INVESTIGATIONAL PLAN
4.1
Overall Study Design and Plan
This is a controlled, randomized, two-arm, open-label, assessor-blinded, multicenter study to 
determine the effect on clinical parameters of neurodevelopmental status of monthly IT 
administration of idursulfase-IT for 12 months in pediatric patients with Hunter syndrome and 
early cognitive impairment who have previously received and tolerated a minimum of 4 months 
of therapy with Elaprase.  
All patients will continue to receive Elaprase therapy as standard of care throughout the study.  
The pivotal study design is “no IT treatment-controlled”. Approximately 48 patients will be 
randomized in a 2:1 ratio to IT treatment or no IT treatment arms. 
Those patients randomized to the IT treatment arm will undergo surgical implantation of the 
SOPH-A-PORT Mini S IDDD followed by a post-operative recovery period of at least 14 days 
prior to the first IT administration of idursulfase-IT. Treated patients will then receive 
12 monthly IT injections of 10 mg idursulfase-IT corresponding to a treatment and assessment 
interval of 13 (28-day) months from randomization to the end-of-study (EOS) evaluations. 
Likewise, patients randomized to the no IT treatment arm will be assessed over 13 (28-day) 
months after randomization.
The separate substudy is open label and single arm. Patients who are enrolled in the substudy 
will follow a similar schedule of study visits as idursulfase-IT-treated patients in the pivotal 
study.  
4.1.1
Intrathecal Drug Delivery 
It is planned that the study drug, idursulfase-IT (HGT-2310) will be administered to patients via 
the SOPH-A-PORT® Mini S, Implantable Access Port, Spinal, Mini Unattached, with Guidewire 
(SOPH-A-PORT Mini S), manufactured by Sophysa SA (Orsay, France) or, alternatively, via 
lumbar puncture in the event of device malfunction. This IDDD will be used to obtain CSF 
samples and to deliver IT injections of idursulfase-IT. 
If the IDDD appears to be non-functional, or if its use is precluded on a scheduled day of dosing, 
site personnel will refer to the IDDD Manual, which provides details on the investigation and 
management of any IDDD-related issues. This includes possible partial revision or complete 
replacement of the IDDD as indicated. If the intrathecal space is not accessible via the IDDD, 
study drug may be administered to a patient by lumbar puncture up to 12 times. Should the 
IDDD become clogged, undergo mechanical complications, or otherwise not be accessible, the 
CSF sample may also be obtained from a patient by lumbar puncture up to 12 times during the 
treatment phase of the study.
General anesthesia/sedation may be required for injections of study drug and some evaluations, 
and may be used at the discretion of the Investigator.  
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A Data Monitoring Committee (DMC) will oversee both idursulfase-IT and device safety. The 
DMC will be notified of IDDD failures and related complications on a periodic basis according 
to the DMC charter (See Section 11.8).  
Patients will have the IDDD removed when they discontinue from the study, unless the patient is 
continuing to receive treatment through another mechanism (eg, extension study, expanded 
access program).
See Section 13 for the Schedule of Events (SOE) for the pivotal study (Appendix 1 and 
Appendix 2) and separate substudy (Appendix 3).
4.2
Rationale for Study Design and Comparator Group
Hunter syndrome (MPS II) is an X-linked genetic disease that occurs predominantly in males; 
affected females are exceedingly rare. The primary analysis of efficacy in the pivotal study will 
focus on pediatric MPS II patients ([male] ≥3 and <18 years of age) with evidence of cognitive 
impairment. Note that for the purpose of this study, cognitive impairment is defined as a 
DAS-II17 GCA standard score at Screening between 85 and 55. Patients with a GCA score at 
Screening >85 who are ≥3 to ≤13 years of age may still be eligible to participate if there is 
demonstrated evidence of a decrease in GCA score of ≥10 points within a 12-month period in 
observational study HGT-HIT-090.  
Eligible patients will be assigned randomly to either the monthly IT injection of 10 mg 
idursulfase-IT group or to the no treatment group in a 2:1 allocation ratio. The randomization 
scheme will be stratified by the baseline GCA score (≤70 or >70). The duration of treatment will 
be 12 months, based on 12 consecutive monthly IT injections in the treated group. The treated 
patients will be implanted with a SOPH-A-PORT Mini S IDDD with the intent that 
idursulfase-IT will be administered via this IDDD. However, in case of IDDD malfunction, the 
drug may also be administered via lumbar puncture (refer to Section 4.1.1). 
The intrathecally administered dose of idursulfase-IT (10 mg) to be used in this study and the 
treatment regimen were based on findings from studies HGT-HIT-045 and HGT-HIT-046 (See 
Section 4.2.1).
The comparator group in this study is randomized to “no IT treatment.” Surgical implantation of 
a device, performance of sham injections, and use of a placebo control were not considered 
appropriate for this group for ethical reasons.
All patients will receive standard-of-care treatment with Elaprase during the study. Elaprase will 
not be provided by the Sponsor, but rather will be prescribed by the patient’s physician in 
accordance with local prescribing information.
The endpoints will be clinical in nature, namely, changes in cognitive and adaptive functioning 
over time. The proposed primary efficacy endpoint is the change from baseline in the GCA score 
after 12 months of treatment at Visit Week 52 as obtained by DAS-II testing and a comparison of 
treated versus untreated patients will be performed. This primary endpoint was chosen because 
of its clinical relevance. Data from the scientific literature concerning the rate of cognitive 
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decline in children with MPS II10, 18 and the Sponsor’s clinical trial experience with cognitively 
impaired MPS II patients suggest that an annual 11 to 14 point drop in GCA may be expected in 
the absence of an effective treatment. The change from baseline in GCA score after 12 months of 
treatment is a suitable endpoint for the development of idursulfase-IT in the proposed indication, 
and a 10 to 11 point difference compared with control in mean GCA change over that time frame 
represents a clinically meaningful benefit to patients. Secondary efficacy measures proposed 
include tests for activities of daily living using the VABS-II.19 The proposed key secondary 
efficacy endpoint is the change from baseline in the ABC score after 12 months of treatment at 
Visit Week 52 as obtained by VABS-II testing and a comparison of treated versus untreated 
patients will be performed.
Given that the pivotal study will enroll only those patients with early cognitive impairment, it is 
expected, based on the Sponsor’s Phase I/II experience, that such children will be able to 
complete serial neurodevelopmental assessments using the DAS-II and VABS-II assessment 
tools.
As discussed in Section 1.1, the age distribution of cognitive and functional impairment in 
MPS II indicates that cognitive deficit begins to become quantifiable at around the age of 2 to 
4 years.10, 11 By the time a child with MPS II is 12 years old, he is typically either at the final 
stages of the neurodegenerative process or has largely escaped cognitive impairment. This was 
confirmed by the data from Phase I/II study HGT-HIT-045, where the patients with the mildest 
and earliest forms of cognitive impairment were in the age range of 3 to 7 years. There are two 
exceptions to this general pattern. In rare cases, cognitive and functional impairment may be 
noticeable prior to the age of 3 years. This is, for instance, observed in children with a complex 
rearrangement/large deletion of the iduronate-2-sulfatase gene who are at the severe end of the 
spectrum both for physical and CNS disease. Even more rarely, children may exhibit a slow 
progression of CNS disease.10, 13 Such children may have measurable cognitive and functional 
abilities into their mid teens. MPS II patients within these two subcategories, ie, those <3 years 
of age and those ≥13 to <18 years of age, may be eligible for participation in HGT-HIT-094 and 
are discussed in further detail below.
Patients in whom cognitive impairment can be identified below 3 years of age are ineligible to be 
part of the pivotal study and will not be randomized, but rather, will be enrolled into a separate 
substudy to receive IT treatment with idursulfase-IT. Because the primary assessment tool of the 
pivotal study, the DAS-II, is not suitable for the evaluation of these younger children, a more 
suitable tool, the BSID-III,20 will be used. As these children will be identified infrequently, no 
enrollment target will be implemented. The analysis of substudy data will be descriptive only 
and will not be part of the efficacy analysis of the pivotal study. Like patients in the pivotal 
study, patients in the substudy will continue to receive the standard of care, Elaprase, under the 
supervision of their treating physician.
Children ≥13 years of age with slowly progressing CNS disease were not identified in study 
HGT-HIT-045 or in conversations with MPS II experts, but have been described sporadically in 
the literature.10, 13 It is a reasonable hypothesis that the clinical course in these children with an 
attenuated disease subtype may be different from the typical course of neurodevelopmental 
decline. To mitigate this risk, children ≥13 years of age with cognitive impairment, should they 
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be identified during the enrollment period of this trial, will be required to have shown a decrease 
in GCA of at least 10 points over a 12-month period in the observational study HGT-HIT-090 
and to have a DAS-II GCA standard score at Phase II/III study entry between 85 and 55. These 
criteria will be implemented to ensure that the clinical course of cognitive decline in these 
children is similar in rate to that in children for whom the cognitive decline manifested earlier, 
thereby ensuring a more homogeneous target population for the trial. If these and other eligibility 
criteria are met, such patients will be randomized (2:1) to receive IT treatment with idursulfase-
IT or no IT treatment in the pivotal study.
4.2.1
Rationale for Dose Selection
Extrapolation to humans from data in non-human primates suggests that a dose from 5 to 35 mg 
delivered intrathecally would result in sufficient exposure to potentially elicit a clinical treatment 
response in MPS II patients. The selection of the 10 mg dose of idursulfase-IT to be given in this 
study was further informed by the PK and PD data of Phase I/II studies, HGT-HIT-045 and 
HGT-HIT-046.
The serum PK profiles of idursulfase-IT were dose proportional with respect to Cmax between the 
1 mg and 10 mg idursulfase IT dose groups. However, the 10 and 30 mg idursulfase-IT groups 
exhibited overlapping serum concentration-time profiles indicative of saturation of the transport 
processes from the CSF to the serum and CNS tissue compartments.
The PD properties of idursulfase IT were evaluated in HGT-HIT-045 and HGT-HIT-046 by 
measuring GAG concentration in CSF at 1 month after each idursulfase-IT administration. 
Compared with the 1 mg idursulfase-IT dose, the 10 mg and 30 mg doses produced equivalent, 
sustained reductions of CSF GAG concentrations. No appreciable change in CSF GAG 
concentration was observed in the untreated group (note that patients in this group, as well as the 
treated group, received weekly Elaprase infusions throughout the study). Thus, 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 benefit. This response correlates with the therapeutic dose 
range (5 to 35 mg) estimated from evaluation of HGT-2310 in non-human primates.
The doses (1, 10, 30 mg) of idursulfase-IT evaluated in the Phase I/II studies demonstrated 
equivalent safety profiles. The clinical PK and PD profiles of idursulfase-IT in MPS II patients 
indicated that the 10 mg dose provides a maximum pharmacologic response. Therefore, the 
10 mg dose of idursulfase-IT was selected for Phase II/III investigation in this study.
4.3
Study Duration
The planned overall duration of each patient’s participation in the study is approximately 14 to 
15 months from Screening to the last scheduled contact.  
An extension study is planned during which patients who complete HGT-HIT-094 and are 
eligible according to the inclusion/exclusion criteria for the extension study may continue, or 
begin, to receive IT treatment with idursulfase-IT via the SOPH-A-PORT Mini S device.
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5
STUDY POPULATION SELECTION
5.1
Study Population
For the pivotal study, it is planned that approximately 48 patients (about 32 treated, 16 untreated) 
with early cognitive impairment who are ≥3 to <18 years of age at the time of informed consent 
and meet all study entrance criteria will be randomized. Note that, to meet study entry criteria, 
patients who are ≥13 to <18 years of age at the time of informed consent must have documented 
evidence of cognitive decline over 12 months in observational study HGT-HIT-090 in order to 
participate in this study.
A separate substudy will enroll patients who have early cognitive impairment and are below the 
age of 3 years at the time of informed consent. Such patients are ineligible for the pivotal study 
and will not be randomized, but may receive treatment with idursulfase-IT in the substudy. In 
view of the rarity of such patients, no enrollment target will be proposed. The enrollment of 
patients below 3 years of age into this separate substudy will be considered additional to the 
number of patients planned for the pivotal study, and will conclude when enrollment of patients 
in the pivotal study closes.
5.2
Inclusion Criteria
5.2.1
Inclusion Criteria for the Pivotal Study
Patients must meet all of the following criteria to be considered eligible for randomization in the 
pivotal study: 
1. The patient is male and is ≥3 and <18 years of age at the time of informed consent.
Note that patients who are younger than 3 years of age may be enrolled in a separate 
substudy provided that they meet other inclusion criteria, provided below.
2. The patient must have a documented diagnosis of MPS II. Of the three criteria below, the 
combinations (2a AND 2b) or (2a AND 2c) will be accepted as diagnostic of MPS II:
a.
The patient has a deficiency in iduronate-2-sulfatase enzyme activity of ≤10% of the 
lower limit of the normal range as measured in plasma, fibroblasts, or leukocytes (based 
on the reference laboratory’s normal range).
AND
b. The patient has a documented mutation in the iduronate-2-sulfatase gene that leaves the 
FMR1 and FMR2 genes intact.  
OR
c.
The patient has a normal enzyme activity level of one other sulfatase as measured in 
plasma, fibroblasts, or leukocytes (based on the normal range of measuring laboratory).
3. The patient has evidence at Screening of Hunter syndrome-related cognitive impairment, 
defined as follows: 
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Note that separate inclusion criteria with respect to patient cognitive status at Screening apply to 
patients ≥3 and <13 years of age and to patients ≥13 and <18 years of age.
A patient who is ≥3 and <13 years of age must have one of the following criteria (3a OR 3b):
a.
A GCA score ≥55 and ≤85
OR
b. If the patient has a GCA score at Screening >85, there must be evidence of a decrease in 
GCA score of ≥10 points over 12 months from a previously documented test result in 
observational study HGT-HIT-090.  
A patient who is ≥13 and <18 years of age must have both of the following criteria (3c AND 
3d):
c.
A GCA score of ≥55 and ≤85.  
AND
d. There must be evidence of a decrease in GCA score of ≥10 points over 12 months from a 
previously documented test result in observational study HGT-HIT-090.  
4. The patient has received and tolerated a minimum of 4 months of therapy with Elaprase 
during the period immediately prior to Screening.
5. The patient must have sufficient auditory capacity, with a hearing aid(s), if needed, in the 
Investigator’s judgment to complete the required protocol testing and must be compliant with 
wearing the hearing aid(s), if needed, on scheduled testing days.
6. The patient’s parent(s) or legally authorized guardian(s) must have voluntarily signed an 
Institutional Review Board/Independent Ethics Committee-approved informed consent form 
after all relevant aspects of the study have been explained and discussed. Consent of the 
patient’s parent(s) or legally authorized guardian(s) and the patient’s assent, if applicable, 
must be obtained prior to the start of any study procedures.
5.2.2
Inclusion Criteria for the Substudy
Patients must meet all of the following criteria to be considered eligible for enrollment in the 
separate substudy: 
1. The patient is male and is <3 years of age at the time of informed consent.
2. The patient must have a documented diagnosis of MPS II. Of the three criteria below, the 
combinations (2a AND 2b) or (2a AND 2c) will be accepted as diagnostic of MPS II:
a.
The patient has a deficiency in iduronate-2-sulfatase enzyme activity of ≤10% of the 
lower limit of the normal range as measured in plasma, fibroblasts, or leukocytes (based 
on the reference laboratory’s normal range).
AND
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b. The patient has a documented mutation in the iduronate-2-sulfatase gene that leaves the 
FMR1 and FMR2 genes intact.
OR
c.
The patient has a normal enzyme activity level of one other sulfatase as measured in 
plasma, fibroblasts, or leukocytes (based on the normal range of measuring laboratory).
3. The patient has evidence at Screening of Hunter syndrome-related cognitive impairment as 
assessed using the BSID-III and defined as a developmental quotient (DQ) ≥55 and ≤85. 
4. The patient has received and tolerated a minimum of 4 months of therapy with Elaprase 
during the period immediately prior to Screening.
5. The patient must have sufficient auditory capacity, with a hearing aid(s), if needed, in the 
Investigator’s judgment to complete the required protocol testing and must be compliant with 
wearing the hearing aid(s), if needed, on scheduled testing days.
6. The patient’s parent(s) or legally authorized guardian(s) must have voluntarily signed an 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved informed 
consent form after all relevant aspects of the study have been explained and discussed. 
Consent of the patient’s parent(s) or legally authorized guardian(s) must be obtained prior to 
the start of any study procedures.
5.3
Exclusion Criteria
Patients who meet any of the following criteria are not eligible to be randomized into the pivotal 
study or enrolled in the separate substudy: 
1. The patient has clinically significant non-Hunter syndrome-related CNS involvement (such 
as Fragile-X syndrome) which is judged by the Investigator to be likely to interfere with the 
accurate administration and interpretation of protocol assessments.
2. The patient has a large chromosomal deletion or complex rearrangement that includes a 
deletion of the FMR1 and/or FMR2 genes. 
3. The patient has a significant medical or psychiatric comorbidity(ies) that might affect study 
data or confound the integrity of study results.
4. The patient has contra-indications for performance of lumbar puncture such as 
musculoskeletal/spinal abnormalities or risk of abnormal bleeding. 
5. The patient has a history of complications from previous lumbar punctures or technical 
challenges in conducting lumbar punctures such that the potential risks would exceed 
possible benefits for the patient. 
6. The patient has an opening CSF pressure upon lumbar puncture that exceeds 30.0 cm H2O.
7. The patient has experienced infusion-related anaphylactoid event(s) or has evidence of 
consistent severe adverse events related to treatment with Elaprase which, in the 
Investigator’s opinion, may pose an unnecessary risk to the patient.
8. The patient has received a cord blood or bone marrow transplant at any time or has received 
blood product transfusions within 90 days prior to Screening.
9. The patient has a history of poorly controlled seizure disorder.
10. The patient is unable to comply with the protocol (eg, has significant hearing or vision 
impairment, a clinically relevant medical condition making implementation of the protocol 
difficult, unstable social situation, known clinically significant psychiatric/behavioral 
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instability, is unable to return for safety evaluations, or is otherwise unlikely to complete the 
study), as determined by the Investigator.
11. The patient is enrolled in another clinical study that involves clinical investigation or use of 
any investigational product (drug or [intrathecal/spinal] device) within 30 days prior to 
study enrollment or at any time during the study.
12. The patient has any known or suspected hypersensitivity to anesthesia or is thought to be at 
an unacceptably high risk for anesthesia due to compromised airways or other conditions.
13. The patient has a condition that is contraindicated as described in the SOPH-A-PORT Mini 
S IDDD Instructions for Use (IFU), including:
a.
The patient has had, or may have, an allergic reaction to the materials of construction of 
the SOPH-A-PORT Mini S device
b. The patient’s body size is too small to support the size of the SOPH-A-PORT Mini S 
Access Port, as judged by the Investigator 
c.
The patient’s drug therapy requires substances known to be incompatible with the 
materials of construction 
d. The patient has a known or suspected local or general infection
e.
The patient is at risk of abnormal bleeding due to a medical condition or therapy
f.
The patient has one or more spinal abnormalities that could complicate safe implantation 
or fixation
g. The patient has a functioning CSF shunt device
h. The patient has shown an intolerance to an implanted device
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6
STUDY TREATMENT
6.1
Description of Treatments
6.1.1
Investigational Product
The investigational product to be used in this study is idursulfase-IT for intrathecal use.
The idursulfase-IT drug product is an isotonic, sterile solution intended for IT administration. It 
is formulated as a 10 mg/mL protein concentration in 154 mM NaCl, pH 6.0, 0.005% 
polysorbate 20. It does not contain any preservatives and is intended for single use.
The active ingredient of the idursulfase-IT drug product is idursulfase (recombinant human 
iduronate-2-sulfatase) the same active ingredient in the commercially available drug Elaprase. 
However, Elaprase and idursulfase-IT are specifically formulated for the IV and IT 
compartments respectively; they cannot be interchanged.  
In contrast to Elaprase, idursulfase-IT is specially formulated for, and compatible with, direct 
introduction into the IT space, because it is isotonic and contains excipients suitable for IT 
administration.  
6.1.2
Intrathecal Drug Delivery Device
The investigational product will be administered via the SOPH-A-PORT Mini S Implantable 
Access Port. 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 device comprises the following seven components:

One SOPH-A-PORT Mini S Access Port

One intrathecal port closed-tip catheter

One guidewire

Two suture wings

One 14-gauge Tuohy needle

One 22-gauge non-coring Huber needle

One Luer lock Connector
Further details are provided in the IFU.
6.1.3
Comparator
The comparator group receives no study treatment.
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6.2
Treatments Administered
After informed consent is signed, all patients who meet the eligibility requirements for the 
pivotal study will be randomized on a 2:1 allocation to one of the following pivotal study arms:

IT Treatment Arm: treatment with idursulfase-IT 10 mg administered intrathecally via 
the surgically implanted IDDD (or lumbar puncture) once every 28 days 

No IT Treatment Arm: no study treatment 
All patients will continue to receive standard-of-care therapy with Elaprase during the study. 
Elaprase will not be provided by the Sponsor, but rather will be prescribed by the patient’s 
physician in accordance with local prescribing information.
Patients who are randomized to receive treatment with idursulfase-IT will be scheduled to 
undergo surgical placement of the SOPH-A-PORT Mini S device. At least 14 days will be 
allowed for recovery following the placement of the IDDD before the administration of the first 
intrathecal idursulfase-IT dose. During this time, the patient will receive standard perioperative 
care. Thereafter, these patients will be administered idursulfase-IT 10 mg as an IT injection once 
monthly for 12 months.  
Patients who are randomized to no IT treatment will not undergo surgical placement of an IDDD 
and will not be administered idursulfase-IT during the study.  
The separate substudy is an open-label, single arm study. Patients who are enrolled in the 
separate substudy will undergo surgical placement of the SOPH-A-PORT Mini S device and 
receive treatment with idursulfase-IT administered intrathecally via IDDD (or lumbar puncture) 
once monthly for 12 months in addition to standard-of-care therapy with Elaprase prescribed by 
their physician.  
6.3
Selection and Timing of Dose for Each Patient
The dosing schedule for the study is described above in Section 6.2.
It is planned that patients randomized to treatment in the pivotal study will undergo surgical 
implantation of the IDDD. Treated patients will then receive 12 monthly IT injections of 
idursulfase-IT 10 mg, once every 28 days.
It is planned that patients who are enrolled in the separate substudy will undergo surgical 
implantation of the IDDD. Patients in the substudy will receive 12 monthly IT injections of 
idursulfase-IT, once every 28 days. The IT dose of idursulfase-IT to be administered to patients 
below 3 years of age will be adjusted as follows based on reference brain weight.21

Up to 8 months of age at dosing, idursulfase-IT 5 mg 

>8 months to 30 months of age at dosing, idursulfase-IT 7.5 mg 

>30 months to 3 years of age at dosing, idursulfase-IT 10 mg
Please refer to the Pharmacy Manual for complete details.
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For treated patients in the pivotal study and patients in the substudy, on IT Dosing Weeks, the IV 
infusion of Elaprase should be scheduled to occur a minimum of 48 hours after IT administration 
of idursulfase-IT.
6.4
Method of Assigning Patients to Treatment Groups
The pivotal trial is randomized and open label. Patients who have met the eligibility criteria will 
be randomized (open-label, assessor-blinded) in a 2:1 randomization scheme to either IT 
treatment or no IT treatment. The randomization will be stratified according to baseline 
(Screening Visit) GCA score (≤70 or >70). The randomization schedule will be generated and 
administered by a third-party (eg, interactive voice response [IVR] vendor) independent of the 
project team.
In a separate substudy, additional patients may be enrolled who are below the age of 3 years at 
the time of informed consent and have early cognitive impairment. Such patients are ineligible 
for the pivotal study and will not be randomized, but will receive idursulfase-IT treatment. The 
separate substudy is an open-label, single arm study. Data from patients participating in this 
separate substudy will be analyzed separately.
6.5
Blinding
Single and double blinding of patients, their families, and the Principal Investigator is not 
possible due to the absence of a sham device, sham injections, or placebo. The Sponsor will 
work with each site to clarify the process for assessor blinding and each site will document the 
manner in which blinding will be maintained at the site.
Every effort will be made to blind the assessors of the primary and secondary endpoints obtained 
from the DAS-II and VABS-II. The assessors responsible for these evaluations will not be 
informed of patients’ randomization assignments. The families will be instructed not to share this 
information with the assessors. Different assessors will be responsible for administration of the 
DAS-II and VABS-II. The assessors will not be part of the study team or participate in study 
team meetings.  
6.6
Concomitant Medications, Therapies, and Medical/Surgical Interventions
Treatment with any other investigational therapies at any time during this study is prohibited.
All patients are to receive Elaprase therapy throughout this study. Elaprase will be prescribed by 
the patient’s physician and will be administered in accordance with local prescribing 
information. Elaprase will not be provided by the study Sponsor.
Concomitant therapies such as speech therapy, ergotherapy, music therapy, and physical therapy 
are permitted, and will be captured during the study.
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6.6.1
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

Pretreatment 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 enzyme replacement 
therapy (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). Pretreatment 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 pre-treatment with low-dose corticosteroids 
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 
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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. 
6.7
Restrictions
6.7.1
Prior Therapies
All patients must have received and tolerated 4 months of therapy with idursulfase IV (Elaprase) 
therapy prior to participation in this study.
Prior therapies that are exclusion criteria for the study include the following: treatment with 
another investigational product (drug or [intrathecal/spinal] device) within the 30 days prior to 
study enrollment (or at any time during the study, see Section 6.6), receipt of blood product 
transfusions within 90 days prior to Screening, receipt of a cord blood or bone marrow transplant 
at any time.
6.7.2
Fluid and Food Intake 
Not applicable.
6.7.3
Patient Activity Restrictions
Please refer to the SOPH-A-PORT Mini S IFU for details regarding patient activity restrictions 
for patients to be implanted with this device. Activities that may include sudden, excessive, or 
repetitive bending, twisting, bouncing, or stretching can damage or dislodge IDDD components 
and should be avoided.
6.8
Treatment Compliance
Treatment with the investigational product will be administered via an IDDD (or lumbar 
puncture) under the supervision of the Investigator and in the controlled environment of a 
clinical center; therefore, full patient compliance with treatment is anticipated in this study.
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 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 IFU for further details.
Investigational product administration will be performed in a clinical setting by appropriately 
trained and skilled healthcare providers (nurses or physicians) with knowledge of the patient’s 
drug regimen and experienced in accessing vascular or CNS ports or CNS infusion pumps. 
Patients and patients’ families will not be directly using the device to administer drugs and will 
have limited direct interaction with the device as there is minimal care required both during the 
immediate postoperative period as the implant site heals, and at times of drug administration.
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6.9
Packaging and Labeling
All packaging and labeling will be in accordance with applicable regulatory requirements.
6.9.1
Investigational Product
Idursulfase-IT drug product is a sterile liquid formulation for IT administration that is packaged 
in 2-mL type-I 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.
6.9.2
Intrathecal Drug Delivery Device
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.
6.10
Storage and Accountability
6.10.1
Investigational Product 
Idursulfase-IT will be shipped by Shire or a qualified distributor to the clinical study site(s) at 
2 to 8 °C (36 to 46 °F). The investigational product should be handled as follows:

idursulfase-IT vials should be stored at 2 to 8ºC (36 to 46°F). 

idursulfase-IT is intended for IT use only.

It is recommended that idursulfase-IT be filtered prior to use through a standard 0.22 µm 
filter.

Perform a visual inspection of each vial. Idursulfase-IT is a clear to slightly opalescent, 
colorless solution. Do not use if the solution in the vials is discolored or particulate matter 
is present.

DO NOT SHAKE. Idursulfase-IT should not be agitated vigorously at any time.  

Withdraw the volume of idursulfase-IT from the vial.

Do not mix with, or administer in conjunction with other drug solutions.

Because it does not contain preservatives, idursulfase-IT should be used as soon as 
possible after it is prepared.  

Idursulfase-IT is supplied in single-use vials. Only 1 dose of idursulfase-IT is to be 
withdrawn from a vial. 
See the Pharmacy Manual for additional details.
The disposition of all investigational product delivered to a Principal Investigator must be 
recorded on a patient-by-patient basis by completing the Accountability Log. The date and time 
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of administration of the investigational product and use of the device must be documented on the 
patient’s appropriate CRF.
The Principal Investigator, Clinical Research Coordinator, or designee (eg, Pharmacist) must 
ensure that all documentation regarding investigational product receipt, storage, dispensing, 
loss/damaged and return of used/unused product is complete, accurate, and ready for review at 
each monitoring visit and/or audit. The sites must ensure that the investigational product is 
available for the monitor to inventory and prepare for return shipment to the Sponsor or 
designee, if required.
6.10.2
Intrathecal Drug Delivery Device
The disposition of all SOPH-A-PORT Mini S devices delivered to a Principal Investigator must 
be recorded on a patient-by-patient basis by completing the Accountability Log. The date and 
time of administration of the investigational product and use of the SOPH-A-PORT Mini S 
device must be documented on the patient’s appropriate CRF.
The Principal Investigator, Clinical Research Coordinator, or designee (eg, Pharmacist) must 
ensure that all documentation regarding receipt, storage, dispensing, loss/damaged 
SOPH-A-PORT Mini S devices and return of used/unused SOPH-A-PORT Mini S device(s) is 
complete, accurate, and ready for review at each monitoring visit and/or audit. The sites must 
ensure that the SOPH-A-PORT Mini S devices are available for the monitor to inventory and 
prepare for return shipment to the Sponsor or designee, if required.
The SOPH-A-PORT Mini S and its components are sterile, single-use devices.
Please refer to the IDDD Manual for device return instructions.
6.10.3
Comparator Product 
Not applicable to this study.
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7
STUDY PROCEDURES
The pivotal study will consist of a Screening period of up to 28 days (during which re-testing of 
patients who were initially unwilling or unable to comply with all scheduled screening 
assessments is permitted) prior to randomization (Day 0).  
It is planned that patients randomized to the IT treatment arm will undergo surgical implantation 
of the SOPH-A-PORT Mini S IDDD followed by a post-operative recovery period of at least 
14 days prior to the first IT administration of idursulfase-IT. Treated patients will then receive 12 
monthly IT injections of idursulfase-IT corresponding to a treatment and assessment interval of 
13 (28-day) months from randomization to the EOS evaluations. Likewise, patients randomized 
to the no IT treatment arm will be assessed over 13 (28-day) months after randomization.
Patients in the IT treatment arm of the pivotal study will be assessed according to the following 
schedule: 

Screening (Weeks -4 to -1 [Day -28 to Day -1])

Randomization (Week 0 [Day 0])

Pre-surgery, Surgery, Follow-up, and Post-operative Recovery (Week 2 [+7 days])

Treatment and Assessments (Week 4 through Week 48 [±7 days])

End of Study (EOS, Week 52 [±7 days])

Follow-up (telephone contact) 7 (±2) days from the Week 52 (or EOS)
Patients in the no IT treatment arm of the pivotal study will be assessed according to the 
following schedule: 

Screening (Weeks -4 to -1 [Day -28 to Day -1])

Randomization (Week 0 [Day 0])

Telephone Contact (Week 2 [+7 days])

Assessments (Week 4 through Week 48 [±7 days])

End of Study (EOS, Week 52 [±7 days])

Follow-up (telephone contact) 7 (±2) days from the Week 52 (or EOS) 
The separate substudy is open label and single arm. Patients who meet all entry criteria for 
participation in the substudy will be considered enrolled on Day 0. Thereafter, it is planned that 
patients in the separate substudy will undergo surgical implantation of the SOPH-A-PORT 
Mini S IDDD for the purpose of IT administration of idursulfase-IT and will follow a similar 
schedule of treatment and assessments as idursulfase-IT-treated patients in the pivotal study.  
Patients in the substudy will be assessed according to the following schedule: 
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
Screening (Weeks -4 to -1 [Day -28 to Day -1])

Enrollment (Week 0 [Day 0])

Pre-surgery, Surgery, Follow-up, and Post-operative Recovery (Week 2 [+7 days])

Treatments and Assessments (Week 4 through Week 48 [±7 days])

End of Study (EOS, Week 52 [±7 days])

Follow-up (telephone contact) 7 (±2) days from the Week 52 (or EOS) 
Patients will complete EOS assessments at Week 52 (Visit Month 13) and will participate in a 
follow-up contact (by telephone) approximately 7 days after the EOS visit. (Note that for those 
patients who enroll in extension study SHP-609-302 within the 7 ±2 day window of the EOS 
visit the follow-up contact is not required. If, however, a patient is not enrolled in the SHP-609-
302 study within the 7 ±2 day window of the EOS visit, then the follow-up contact should be 
completed.)
A patient who discontinues or is withdrawn prior to study completion will be asked to participate 
in an EOS visit within approximately 30 days after withdrawal or discontinuation (EOS 
assessments for such patients will be the same as Week 52 assessments), and also to complete a 
follow-up contact approximately 7 days after the patient’s EOS visit. There is no replacement of 
patients who do not complete the study.
All patients will receive weekly IV Elaprase infusions as prescribed throughout the study.  
For treated patients in the pivotal study and patients in the substudy, on IT Dosing Weeks the IV 
infusion of Elaprase should be scheduled to occur a minimum of 48 hours after IT administration 
of idursulfase-IT.
See Section 13 for the Schedules of Events for the pivotal study (Appendix 1 and Appendix 2) 
and separate substudy (Appendix 3).
All data collected are to be recorded on the appropriate CRF.
Details for study procedures including sample collection are described in the Study Operations 
Manual.
7.1
Informed Consent
Prior to conducting any study-related procedures, written informed consent (signed and dated) 
must be obtained from the patient’s parent(s) or legally authorized guardian(s) (and assent from 
the patient, if applicable). The nature, scope, and possible consequences, including risks and 
benefits, of the study will be explained by the Investigator or designee in accordance with the 
guidelines described in Section 11.4. Documentation and filing of informed consent documents 
should be completed according to Section 11.4.
7.2
Study Entrance Criteria
Each patient will be reviewed for eligibility against the study entrance criteria. Patients who do 
not meet the study entrance criteria will not be allowed to participate in the study. The reason(s) 
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for the patient’s ineligibility for the study will be documented. No protocol exemptions will be 
permitted.
7.3
Medical History 
A standard medical history of each patient will be obtained at Screening and will include age at 
onset of Hunter syndrome symptoms, age of Hunter syndrome diagnosis, evidence of 
iduronate-2-sulfatase deficiency, genotype, family history of Hunter syndrome, Hunter syndrome 
signs and symptoms in the following domains:  head/neck, eyes, mouth, ear, nose, throat, 
chest/lung, cardiovascular system, abdomen, gastrointestinal system, genitourinary system, skin, 
skeletal system, neurological system, psychiatric disorders and surgical history.
Patients who do not have a documented diagnosis of Hunter syndrome in their medical history 
will provide a blood sample at Screening to assay for iduronate-2-sulfatase enzyme activity in 
plasma, fibroblasts, or leukocytes (patients must exhibit ≤10% of the reference laboratory’s 
lower limit of the normal range to confirm diagnosis). These samples will also be assayed for 
normal enzyme activity level of one other sulfatase in plasma, fibroblasts, or leukocytes (based 
on the reference laboratory’s normal range).
7.3.1
Genotype
Patients who have not had a previous iduronate-2-sulfatase gene (IDS) genotype analysis 
performed at Greenwood Genetic Center’s Diagnostic Laboratory (Greenwood, South Carolina, 
USA), referred to here as “Greenwood Labs,” will provide a blood sample for genotyping to 
document the diagnosis of Hunter syndrome. Even patients for whom prior genotyping was 
performed at Greenwood Labs may need to have a repeat analysis performed, if the original 
information was insufficient for an unambiguous classification of genotype (eg, to document the 
integrity of the FMR1 and FMR2 genes in patients with large deletion/rearrangement mutations).  
Specific instructions concerning genotyping and the timing of enrollment are provided below:
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
A Greenwood Labs IDS genotype will be obtained for all patients in the study. If the 
patient has no Greenwood Labs IDS genotype in his file at the time of informed consent, 
a blood sample will be drawn at Screening. If the patient has a prior Greenwood Labs 
genotype in his file, and it indicates the presence of a mutation(s) that is within the IDS 
locus (eg, small deletion or point mutation), the test will not have to be redone. If the 
patient has a prior Greenwood Labs genotype in his file, and it indicates the presence of a 
large deletion/rearrangement mutation but does not confirm the integrity of the FMR1 
and FMR2 genes, a new sample may have to be drawn. 

If the patient has no documented IDS genotype at Screening, then 
enrollment/randomization will have to await the arrival of the Greenwood Labs genotype 
results. 

If the patient has a locally determined IDS genotype indicating the presence of a small 
deletion or point mutation, the site may proceed and enroll/randomize him while awaiting 
the confirmatory results from Greenwood Labs. 

If the patient has a locally determined IDS genotype indicating the presence of a large 
deletion/rearrangement mutation, then enrollment/randomization will have to await the 
results of the Greenwood Labs genotype analysis to confirm the integrity of the FMR1 
and FMR2 genes. 

If the patient has a Greenwood Labs IDS genotype indicating the presence of a small 
deletion or point mutation, he can be enrolled/randomized at once. 

If the patient has a Greenwood Labs IDS genotype indicating the presence of a large 
deletion/rearrangement mutation, he may only be enrolled/randomized if and when a 
Greenwood Labs genotype confirming the integrity of the FMR1 and FMR2 genes is 
available, either in his original genotype documentation, or by analysis of a new sample.
7.4
Echocardiogram
An echocardiogram will be performed as part of the study screening assessments. This procedure 
will not be necessary if the patient has had an echocardiogram performed within 3 months of 
study entry, the data are available, and deemed satisfactory for evaluation of anesthesia risk.
7.5
Device Related Procedures
7.5.1
IDDD Implantation and Revision
The IDDD will be surgically implanted or revised at the clinical site. Procedures for implantation 
and revision are detailed in the device’s IFU. Standard hospital procedures for surgery will be 
followed; the patient will be under general anesthesia for this procedure.
An additional medical device, the catheter passer, is necessary for the implantation procedure. 
The catheter passer is a sterile, single use device that will be used in the subcutaneous placement 
of the catheter. The Phoenix Neuro Disposable Catheter Passer, manufactured by Sophysa is CE 
marked in the EU and cleared under K853370 in the US and may be provided; however, use of 
other catheter passers compatible with the SOPH-A-PORT Mini S is allowed.
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Details of the implantation/revision and malfunctions/failure will be documented on the patient’s 
CRF.
7.5.2
X-ray Verification of Intrathecal Drug Delivery Device Placement 
A postoperative X-ray check of the IDDD will be performed following surgery to verify proper 
installation and confirmation of IDDD placement at the mid-thoracic level. The X-rays may be 
performed to check placement of the device, as needed, throughout the study, and will be 
performed at the end of the study (to verify that the IDDD is in the correct position). At a 
minimum, the date of the X-ray verifying correct IDDD placement will be documented on the 
patient’s CRF. If the device requires revision or replacement during the study, additional X-rays 
will be taken to document the proper positioning of the device. If the IDDD malfunctions, an 
X-ray will be performed to assess the potential cause of malfunction.  
7.5.3
CSF Sampling Procedure
Cerebrospinal fluid will be sampled via the device. If this is not possible, and if CSF sampling is 
necessary, either for adherence to the protocol, or to investigate clinical concerns, a lumbar 
puncture may be performed to sample CSF, either with or without administration of drug 
afterwards (See Section 4.1.1).  
7.5.4
Device Removal
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 IFU due to a device related issue, 
the IDDD will be declared a device malfunction. If the device malfunction is irreversible and 
cannot be corrected without a device surgical intervention, the IDDD will be declared a device 
failure, starting from the date of the initial malfunction. 
The IDDD will then be surgically removed or revised and a new device and/or device 
components will be re-implanted at the earliest possible opportunity, preferably at the same time. 
Details of the device removal will be recorded in the patient’s CRF. For further details, please 
refer to the SOPH-A-PORT Mini S IFU.
Patients will have the IDDD removed when they discontinue from the study, unless the patient is 
continuing to receive treatment through another mechanism (eg, extension study, expanded 
access program).
7.6
Investigational Product Administration
It is planned that idursulfase-IT will be administered every 28 days by means of the IDDD (or 
lumbar puncture, see Section 4.1.1). A visual examination of both the port and catheter track will 
be performed before each IT injection.
A 22-gauge Huber non-coring needle is to be used for access to the implanted port; standard 
hypodermic needles would damage the septum and may cause leakage. If no needle free 
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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.
If the intrathecal space is not accessible via the IDDD, idursulfase-IT may be administered by 
lumbar puncture (See Section 4.1.1).  
The injection date, injection start/stop time, planned dose, injection volume, and flush volume 
will be recorded on the patient’s CRF.  
Intrathecal administration of investigational product will be preceded by CSF sampling for 
laboratory analysis, pharmacodynamic analysis (GAG concentration), and analyses of 
idursulfase enzyme concentration and anti-idursulfase antibodies. The total volume of 
investigational product and flush administered is targeted towards replenishing the volume of 
CSF withdrawn. Therefore, while the total volume of idursulfase-IT administered will be less 
than the total volume of CSF withdrawn, additional saline will be administered to ensure a 
balance between the amount administered and the amount withdrawn.
Specifically, the investigational product will be administered in a volume of 1 mL (1 mL of a 
10 mg/mL solution) (See Section 6.1.1). The minimal proposed flush volume is 2 mL, so the 
minimal volume administered will be 3 mL. Additional volume of preservative-free saline will 
be administered to add up to a total volume that is equal to that which was withdrawn.
This design was intended to mitigate any risk of overfilling or underfilling the IT compartment 
as well as the risk of inducing acute intracranial hypertension or brain herniation.
Patients will remain under the observation of study personnel in the hospital setting (eg, may 
include infusion center, PACU (recovery suite), observation unit, short stay center) for 4 hours 
post administration of investigational product for safety assessments. Thereafter, if deemed 
clinically stable by the Investigator, patients may leave the hospital setting (with exception of 
study visit weeks at which serial blood sampling for pharmacokinetic evaluation is planned). For 
the first 6 months of treatment with idursulfase-IT, patients must return to the clinic the day after 
each IT administration for a safety follow-up visit. Note that, under these circumstances, there is 
no requirement for an overnight hospital stay; if a decision is made to keep the patient overnight 
for convenience, this hospitalization should not initiate a serious adverse event report. For the 
latter 6 months of treatment with idursulfase-IT (ie, from Week 28 onward) and in the absence of 
any safety concerns, patients may complete the safety follow-up visit on the same day as IT 
administration prior to discharge. 
7.7
Pharmacokinetic Assessments
Blood samples will be collected for determination of idursulfase serum concentration-time 
profiles and serum pharmacokinetic parameters after IT administration.  
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Idursulfase concentrations will be measured in CSF samples obtained immediately prior to each 
IT administration (and at the EOS Visit) to determine the degree of accumulation of monthly 
idursulfase-IT administrations in the CSF.
The blood and CSF sampling schedules for pharmacokinetic assessments are provided in the 
SOE for patients in the treated arm of the pivotal study (Appendix 1) and in the separate 
substudy (Appendix 3).
7.8
Pharmacodynamic/Biomarker Assessments
7.8.1
CSF Glycosaminoglycan
Cerebrospinal fluid will be collected for measurement of the concentration of GAG (refer to the 
SOE for the pivotal study [Appendix 1 and Appendix 2] and separate substudy [Appendix 3]). 
7.8.2
CSF and Serum Albumin
Albumin levels will be measured in samples of CSF (refer to the SOE for the pivotal study 
(Appendix 1 and Appendix 2) and separate substudy (Appendix 3) to monitor the permeability of 
the blood-brain barrier. Measurement of albumin levels in serum is included in the panel of 
clinical laboratory tests (Table 7-2).
7.9
Efficacy Assessments
The efficacy endpoints are specified in Section 3.  
7.9.1
Neurodevelopmental Assessment Tools
The study methodology will include standardized neurodevelopmental assessments to provide a 
quantifiable measure of patient neurodevelopmental status.7  Neurodevelopmental status will be 
assessed over time by measuring cognitive and adaptive functions as follows.
Cognition: the Differential Ability Scales, Second Edition (DAS-II)17 will be used to assess all 
randomized patients. The DAS-II comprises 2 overlapping batteries. The Early Years battery is 
designed for children ages 2 years 6 months through 6 years 11 months. The School Age Battery 
is designed for children ages 7 years 0 months through 17 years 11 months. These batteries are 
fully co-normed for ages 5 years 0 months through 8 years 11 months. 
For patients participating in the separate substudy only (ie, patients who are below the age of 
3 years and who have early cognitive impairment) cognition will be assessed initially using the 
Bayley Scales of Infant Development, Third Edition (BSID-III).20 When these patients reach at 
least 42 months of age, if considered evaluable using the DAS-II instrument, they will transition 
to use of the DAS-II for continued assessment of cognition.
Adaptive Behaviors: the Vineland Adaptive Behavioral Scales, Second Edition (VABS-II)19 will 
be used to assess all patients. The Expanded Interview Form will be utilized.
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It is intended that full neurodevelopmental assessments be conducted for all patients; however, it 
is recognized that the feasibility of conducting these assessments may be dependent on the 
patient’s ability to cooperate and/or level of cognitive impairment.  
All assessments will be administered by qualified study personnel. The DAS-II will be 
administered by a trained practitioner. 
7.10
Health Status Assessment
The health status of patients will be assessed using the EuroQol-5D (EQ-5D) questionnaire, a 
standardized instrument for use as a measure of health status which is applicable to a wide range 
of health conditions and treatments.22, 23 The EQ-5D provides a descriptive profile and index 
value for health status.
7.11
Safety Assessments
Safety will be assessed by adverse events (by type, severity, and relationship to treatment 
[idursulfase-IT, the IDDD, device surgical procedure, or IT administration process] and IV 
Elaprase infusion), changes in clinical laboratory testing (serum chemistry, hematology, 
urinalysis), physical and neurological examination, vital signs, 12-lead ECG recordings, CSF 
laboratory parameters (chemistries, cell counts), anti-idursulfase antibodies in CSF and serum, 
and determination of antibodies having enzyme neutralizing activity.
SOPH-A-PORT Mini S assessments will include measures 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.
7.11.1
Physical and Neurological Examination
A physical examination will be performed with a thorough review of body systems on specified 
study days.  
Physical examinations will include a review of the patient’s general appearance, neurological 
examination, as well as evaluation of the body systems listed in Table 7-1 and the device port 
and catheter track. Any abnormal change in findings will be recorded as an adverse event on the 
appropriate CRF.
Table 7-1
Assessments for Physical and Neurological Examinations
Assessment
Assessment
General appearance
Endocrine
Head and neck
Cardiovascular
Eyes
Abdomen
Ears
Genitourinary
Nose
Skin
Throat
Musculoskeletal
Chest and lungs
Neurological
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Table 7-1
Assessments for Physical and Neurological Examinations
Assessment
Assessment
Port and catheter 
7.11.2
Height and Weight 
Height (cm) and weight (kg) will be recorded for all patients at Screening and during the study at 
time points specified in the SOE. The clinical site staff will be instructed to use a calibrated scale 
for weight measurement.  
7.11.3
Head Circumference
Head circumference (cm) will be measured in a uniform manner for all patients.
7.11.4
Hearing Assessment
Each patient must have sufficient auditory capacity, with a hearing aid(s), if needed, in the 
Investigator’s judgment, to complete the required protocol testing and must be compliant with 
wearing the hearing aid(s), if needed, on scheduled testing days.  
The Investigator will confirm that, with hearing aids in place if needed, each patient has 
sufficient understanding to participate in study assessments.
7.11.5
Vital Signs
Vital signs are to be recorded for all patients and will include pulse, blood pressure, respiration 
rate, oxygen saturation, and temperature.
7.11.6
Electrocardiogram
An electrocardiogram (ECG, 12-lead) will be performed in accordance with the clinical site’s 
standard practice(s). Electrocardiogram recordings will be read locally at the clinical site by a 
qualified cardiologist. The ECG will include assessment of heart rate, sinus rhythm, atrial or 
ventricular hypertrophy, and assessment of PR, RR, QRS, and QT intervals. Identification of any 
clinically significant findings and/or conduction abnormalities will be recorded on the CRF.   
7.11.7
Intracranial Pressure Measurement
Intracranial pressure (ICP) measurement (cm of H2O) will be assessed for all patients. The ICP 
measurement will be conducted by lumbar puncture and while the patient is under anesthesia.  
Patients with a surgically implanted IDDD should undergo X-ray prior to lumbar puncture to 
verify the position of the catheter.
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7.11.8
Brain Magnetic Resonance Imaging
Patients will undergo magnetic resonance imaging (MRI) of the brain. Brain structure volumes 
will be measured. Refer to the Study Operations Manual and/or MRI Manual for specific 
procedures and precautions.  
7.11.9
Clinical and Other Laboratory Tests
Blood and urine samples will be collected as described in this section for clinical laboratory 
testing. All blood samples will be collected by venipuncture or via central line.  
Clinical laboratory tests will include the following (See Table 7-2): 
Table 7-2
List of Laboratory Tests
Hematology:
-
Hematocrit (Hct)
-
Hemoglobin (Hgb)
-
Mean corpuscular hemoglobin (MCH)
-
Mean corpuscular hemoglobin 
concentration (MCHC)
-
Mean corpuscular volume (MCV)
-
Platelet count
-
Red blood cell (RBC) count 
-
White blood cell (WBC) count with 
differential 
Urinalysis: 
-
Appearance (clarity and color)
-
Bilirubin
-
Blood
-
Glucose
-
Ketones
-
Leukocyte esterase
-
Microscopic examination of sediment 
-
Nitrite 
-
pH
-
Protein
-
Specific gravity
-
Urobilinogen
Coagulation: 
-
Prothrombin time (PT)
-
Partial thromboplastin time (PTT)
Serum Chemistry:
-
Albumin (ALB)
-
Alkaline phosphatase (ALK-P)
-
Alanine aminotransferase (ALT; SGPT)
-
Aspartate aminotransferase (AST; SGOT)
-
Blood urea nitrogen (BUN)
-
Calcium (Ca)
-
Carbon dioxide (CO2)
-
Chloride (Cl)
-
Creatinine
-
Creatine phosphokinase
-
Gamma-glutamyl transferase (GGT)
-
Glucose
-
Lactate dehydrogenase (LDH)
-
Magnesium (Mg)
-
Phosphorus (P)
-
Potassium (K)
-
Sodium (Na)
-
Total and direct bilirubin
-
Total cholesterol
-
Total protein
-
Total thyroxine (T4)
-
Thyroid-stimulating hormone (TSH)
-
Triglycerides
-
Uric acid
Urine samples will be collected for determination of GAG concentration. Urine GAG will be 
analyzed and reported by a Sponsor-designated laboratory. Urine creatinine will be analyzed in 
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the collected samples. Urine GAG concentration will be normalized to urine creatinine and 
reported as mg GAG/mmol creatinine.  
7.11.10
Cerebrospinal Fluid Assessments
Cerebrospinal fluid samples will be collected via the IDDD or lumbar puncture and used to 
analyze standard safety laboratory parameters (chemistries, cell counts), albumin, GAG, and 
concentration of idursulfase enzyme. The CSF samples will also be analyzed for idursulfase-
specific antibodies and antibodies with enzyme neutralizing activity (See Section 7.11.11).  
Cerebrospinal fluid will be obtained from patients in the treated arm of the pivotal study and in 
the substudy at Screening (by lumbar puncture and under general anesthesia), during surgical 
implantation of the IDDD, prior to each intrathecal injection of investigational product, and at 
the EOS visit. Should the IDDD become clogged, undergo mechanical complications or 
otherwise not be accessible, the CSF sample may be obtained by lumbar puncture up to 12 times 
during the treatment phase of the study.
Patients in the no-treatment arm of the pivotal study will undergo lumbar puncture (under 
general anesthesia) to obtain CSF samples at the Screening and EOS Visits.
7.11.11
Antibody Assessments
Blood and CSF samples will be collected and evaluated by a Shire-designated laboratory for the 
presence of anti-idursulfase antibodies and antibodies with enzyme neutralizing activity.
7.11.12
Device Assessments
SOPH-A-PORT Mini S assessments will include measures of device implantation, device 
function, device longevity, and adverse events associated with the implant surgery or device. 
These 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.
7.11.13
Pregnancy Testing
Not applicable.
7.12
Sample Collection, Storage, and Shipping
Details for study procedures, including sample collection, are provided in the Study Operations 
Manual and/or Laboratory Manual for this study.
A variety of biological specimens will be collected from patients at the intervals indicated in the 
SOEs. These will be stored securely until analyzed. The patients’ IDs will be kept confidential.  
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Samples will be stored until used up or for a maximum of 10 years after the last patient visit in 
this trial, after which any residual material will be destroyed.
7.13
Concomitant Medications, Therapies/Interventions, and Medical/Surgical 
Procedures Assessments
All medications, therapies/interventions administered to and medical/surgical procedures 
performed on patients from the time of informed consent through the follow-up contact are 
regarded as concomitant and will be documented on the CRF.  
Non-permitted (per the exclusion criteria) medications, therapies, or surgical interventions will 
lead to exclusion from the study or a possible protocol violation depending on when the non-
permitted event occurs.
7.14
Adverse Events Assessments
7.14.1
Definitions of Adverse Events and Serious Adverse Events
7.14.1.1
Adverse Events
An adverse event is any noxious, pathologic, or unintended change in anatomical, physiologic, or 
metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in 
any phase of a clinical study, whether or not considered investigational product-related. This 
includes an exacerbation of a pre-existing condition.  
Adverse events include:

Worsening (change in nature, severity, or frequency) of conditions present at the onset of 
the study

Intercurrent illnesses

Drug interactions

Events related to or possibly related to concomitant medications

Clinically significant abnormal laboratory values (includes shifts from baseline within the 
range of normal that the Investigator considers to be clinically important)

Clinically significant abnormalities in physical and neurological examination, vital signs, 
ECG
Throughout the study, the Investigator must record all adverse events on the AE CRF, regardless 
of the severity or relationship to investigational product. The Investigator should treat patients 
with adverse events appropriately and observe them at suitable intervals until the events stabilize 
or resolve. Adverse events may be discovered through observation or examination of the patient, 
questioning of the patient or his parent(s)/legally authorized guardian(s), complaint by the patient 
or his parent(s)/legally authorized guardian(s), or by abnormal clinical laboratory values or 
physical findings.
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In addition, adverse events may also include laboratory values that become significantly out of 
range. In the event of an out-of-range value, the laboratory test should be repeated until it returns 
to normal or can be explained and the patient’s safety is not at risk.
Additional illnesses present at the time when informed consent is given are regarded as 
concomitant illnesses and will be documented on the appropriate pages of the CRF. Illnesses first 
occurring or detected during the study, and worsening of a concomitant illness during the study, 
are to be regarded as adverse events and must be documented as such in the CRF.
7.14.1.2
Elaprase-related Adverse Events
All patients will receive concomitant IV therapy with Elaprase throughout their participation in 
this study. Adverse events that are potentially related to IV Elaprase infusion will be captured. 
The most commonly reported adverse events that have been assessed as related to Elaprase in 
patients with Hunter syndrome are listed in Section 6.6.1. Note that, during weeks of IT dose 
administration, the IV infusion of Elaprase should be scheduled to occur a minimum of 48 hours 
after IT dosing in order to help distinguish adverse events related to IV compared to IT 
administration.
7.14.1.3
IDDD-related Adverse Events 
Examples of adverse events related to use of the IDDD include, but are not limited to, 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 7.14.2.2) should 
not be entered as an adverse event unless this has physiopathological consequences such as those 
listed above. In the event of device failure (defined in Section 7.14.2.3), the device may need to 
be replaced or repaired as needed. Hospitalization for such a procedure will be reported as a 
serious adverse event. Details of the cause of IDDD malfunction or failure will be recorded on 
the device Malfunction/Failure CRF. A list of the most common IDDD adverse events is 
included in Appendix 4.
7.14.1.4
Device Surgical Procedure-related Adverse Events
Examples of adverse events 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 
post-operative complications (such as post-operative infection). 
7.14.1.5
Intrathecal Administration Process Adverse Events
Intrathecal administration process adverse events may include those caused by anesthesia during 
drug administration and other drug administration issues (eg, extravasation during infusion or 
hematoma due to the Huber needle), or complications of lumbar puncture.
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7.14.1.6
Serious Adverse Events
A serious adverse event (SAE) is any adverse event occurring at any dose that results in any of 
the following outcomes:

Death

Is life-threatening

Requires hospitalization (Note, however, for the purpose of this study, overnight 
hospitalizations post intrathecal administration of idursulfase-IT that are based on 
practical or logistical considerations, rather than safety will not result in a serious adverse 
event designation [See Section 7.6])

Requires prolongation of existing hospitalization

A persistent or significant disability or incapacity 

A congenital anomaly or birth defect
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse event 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 adverse event is defined 
as an adverse event that placed the patient, in the view of the initial reporter, at immediate risk of 
death from the adverse event as it occurred (ie, this definition does not include an adverse event 
that, had it occurred in a more severe form, might have caused death).
Hospitalization, which is the result of elective or previously scheduled surgery for pre-existing 
condition that has not worsened after initiation of treatment, should not result in a serious 
adverse event designation. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as a serious adverse event; however, complication(s) resulting 
from a hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as serious adverse event(s). Furthermore, this does not apply to device failures 
resulting in scheduled surgical revisions, which should be reported as serious adverse events.
7.14.1.7
Unanticipated Adverse Device Effect
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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7.14.2
Device-associated Definitions
7.14.2.1
Device Revision (Partial and Full)
Partial device revision: surgical revision/replacement of one or more component(s) of the device; 
other component(s) of the original device remain implanted and are not affected (eg, port 
revision).
Full device revision: the device is removed (explanted) in its entirety and a completely new 
device is implanted.
7.14.2.2
Device Malfunction
The device does not perform as intended, based on the description in the device’s IFU, but does 
not require either a partial or full device revision.
7.14.2.3
Device Failure
The device irreversibly fails to perform as intended and requires either a partial or full device 
revision or removal.
7.14.3
Classification of Adverse Events and Serious Adverse Events
The severity of adverse events will be assessed by the Investigator based on the definitions 
shown in Table 7-3. The severity of all adverse events and serious adverse events should be 
recorded on the appropriate CRF page as mild, moderate, or severe.  
Table 7-3
Adverse Event Severity
Severity
Definition
Mild
No limitation of usual activities.
Moderate
Some limitation of usual activities.
Severe
Inability to carry out usual activities.
7.14.3.1
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 may pose a threat to life or 
functioning (see Section 7.14.1.6). Seriousness (not severity) and causality serve as a guide for 
defining regulatory reporting obligations.
7.14.4
Relatedness of Adverse Events and Serious Adverse Events
The relationship of an adverse event or serious adverse event to study treatment (study drug, the 
IDDD, device surgical procedure, or IT administration process) will be assessed by the 
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Investigator as follows. The relationship to study treatment will be categorized based on the 
definitions provided in Table 7-4.

Relationship to idursulfase-IT

Relationship to the IDDD (examples of IDDD-related adverse events are listed in Section 
7.14.1.3)

Relationship to a device surgical procedure (surgical implantation of the IDDD, partial or 
full device revision as described in Section 7.14.1.4)

Relationship to the IT administration process (examples of IT administration process-
related adverse events are listed in Section 7.14.1.5)
Table 7-4
Adverse Event Relatedness
Relationship to Treatment
Definition
Not Related
Unrelated to investigational product, device, device surgical 
procedure, or IT administration process.
Possibly Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of investigational product, device, device 
surgical procedure, or IT administration process, but which could also 
be explained by concurrent disease or other drugs or chemicals.
Probably Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of investigational product, device, device 
surgical procedure, or IT administration process unlikely to be 
attributable to concurrent disease or other drugs and chemicals and 
which follows a clinically reasonable response on de-challenge. The 
association of the clinical event or laboratory abnormality must also 
have some biologic plausibility, at least on theoretical grounds.
Definitely related 
The event follows a reasonable temporal sequence from administration 
of the investigational product, 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.
The relationship of an adverse event or serious adverse event to IV Elaprase infusion will be 
assessed by the Investigator as described in Section 7.14.1.2.
7.14.5
Procedures for Recording and Reporting Adverse Events
7.14.5.1
Adverse Event Monitoring and Period of Observation
Adverse events will be monitored continuously throughout the study.
For the purposes of this study, the period of observation extends from the time at which informed 
consent is obtained until the patient’s final evaluation of the study. For safety purposes, the final 
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evaluation for patients who complete this study will be defined as the follow-up evaluation 
performed 7 (±2) days after the EOS visit.
If the Investigator considers it necessary to report an adverse event in a study patient occurring 
after the end of the safety observation period, he or she should contact the Sponsor to determine 
how the adverse event should be documented and reported.
7.14.5.2
Reporting Serious Adverse Events
Any serious adverse event, regardless of relationship to investigational product, device, device 
surgical procedure, IT administration process, or IV Elaprase infusion, which occurs in a patient 
after informed consent will be recorded by the clinical site on the SAE form. The serious adverse 
event must be completely described on the patient’s CRF, including the judgment of the 
Investigator as to the relationship of the serious adverse event to the investigational product 
and/or device. The Investigator will promptly supply all information identified and requested by 
the Sponsor (or contract research organization [CRO]) regarding the serious adverse event.  
The Investigator must report the serious adverse event to the Shire Pharmacovigilance and Risk 
Management 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 to:
Shire Pharmacovigilance and Risk Management Department:
International FAX:  
 (UK) OR United States FAX:  
Email:  
AND
Shire Medical Monitor: 
, DO
Email: 
FAX:  
 (USA)
Any follow-up information must also be completed on the 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.  
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Medication Error – A mistake made in prescribing, dispensing, administration and/or use of the 
investigational product.
The Investigator must report abuse, misuse, overdose, and medication error to the Shire 
Pharmacovigilance and Risk Management 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 7.14.5.2).
7.17
Removal of Patients from the Trial or Investigational Product
A patient’s participation in the study may be discontinued at the discretion of the Investigator. 
The following may be justifiable reasons for the Investigator to remove a patient from the study:

The patient exhibits non-compliance with the study protocol that is considered disruptive 
to study conduct.

The patient was erroneously included in the study.

The patient develops an exclusion criterion.

The patient suffers an intolerable adverse event.

The study is terminated by the Sponsor.
The patient’s parent(s) or legally authorized guardian(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.
If the patient’s parent(s) or legally authorized guardian(s) acting on behalf of the patient 
discontinues participation in the study, or the patient is discontinued by the Investigator,
reasonable efforts will be made to follow the patient through the end of study assessments. The 
reason for refusal will be documented on the CRF. Any adverse events experienced up to the 
point of discontinuation must be documented on the AE CRF. If adverse events are present when 
the patient withdraws from the study, the patient will be re-evaluated within approximately 30 
days of withdrawal. All ongoing serious adverse events at the time of withdrawal will be 
followed until resolution.
7.18
Other Study Procedures
7.18.1
Safety-related Study Stopping Rules
This study will be stopped and the safety data reviewed if any patient experiences a life-
threatening serious adverse event or a death occurs, if either is considered possibly or probably 
related to the study treatment (investigational product, the IDDD, device surgical procedure, or 
the IT administration process). After review of the safety data, the status of the study will be one 
of the following:
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
Resumed unchanged

Resumed with modifications to the protocol 

Terminated
Patient safety in this study will be monitored by an independent DMC until the last patient 
completes his last scheduled study visit/assessment. The DMC will be an external group 
overseeing the safety of the study treatment, including both the investigational product and the 
IDDD, and will operate according to a charter determining the scope of its activities and 
frequency of meetings (See Section 11.8 for additional details).
7.19
Appropriateness of Measurements
The measures of safety to be used in the study are appropriate for an interventional study in MPS 
II patients. These include monitoring of adverse events and medication use, both standard 
parameters for the assessment of safety, as well as measurement of ICP and imaging.
Cognitive impairment is a key symptom of MPS II; however, clinical research in this area has 
been broadly lacking, instead focusing on the biological and physical aspects of the disease, and 
remains an unmet medical need. This highlights the need for a treatment that targets the 
cognitive involvement of MPS II, and an endpoint strategy that specifically targets the cognitive 
and behavioral symptoms associated with MPS II. The neurodevelopment measures planned for 
this study will assess cognitive and adaptive functions in children with MPS II. These assessment 
tools (DAS-II, VABS-II) will provide a quantifiable measure of CNS neurodevelopment status 
and are appropriate for use in the target population.
The DAS-II has been found to be valid and reliable. Evidence from published studies and 
previous Shire clinical trials demonstrates that the DAS-II is able to detect both changes in a 
child’s ability and stabilization of functioning over time following treatment.  
The rating of the child by the parent format of the VABS-II via the Expanded Interview Form is 
consistent with the Food and Drug Administration (FDA) Patient Reported Outcome (PRO) 
Guidance, which states that caregiver reports must be based on observable behaviors only.  
The concepts measured by the DAS-II were mapped onto an MPS II conceptual model. The 
concept mapping exercise indicated adequate concept coverage across the three assessment tools, 
collectively. Following feedback from experts in the field of neurodevelopmental functioning, 
the concept mapping exercise was repeated for the VABS-II. The VABS-II was found to have 
strong concept coverage when combined with the DAS-II. Based on this evidence, the DAS-II 
and VABS-II will be utilized as the primary and secondary assessment tools for efficacy. 
A model illustrating the efficacy endpoints in this study is presented in Table 7-5. The endpoints 
have been classified as primary, key secondary, and secondary based on their clinical 
importance. Secondary efficacy endpoints have been included for the purposes of providing 
additional data to support both the primary and key secondary endpoints. The change from 
baseline in GCA, as assessed by the DAS-II, will be the primary endpoint. The DAS-II will be 
used to measure secondary endpoints, including standard scores in cluster areas and 
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developmental quotients. Key secondary and other secondary endpoints are derived from the 
VABS-II to assess adaptive behaviors.  
Table 7-5
Endpoint Model
Concept
Subconcept
Assessment Tool
Primary Endpoint
Cognitive 
Function
General Conceptual Ability (GCA)
DAS II
Key Secondary Endpoint
Adaptive 
Behavior
Adaptive Behavior Composite (ABC) 
VABS-II
Secondary Endpoints
Cognitive 
Function
Standard score in DAS-II cluster areas: Verbal, 
Nonverbal, Spatial, GCA, and Special Nonverbal 
Composite (SNC)
Developmental quotient for the following:
Group 1 a
     or:
Verbal Comprehension
Picture Similarities
Naming Vocabulary
Pattern Construction
Matrices 
Copying
DAS-II - Early Years
Group 2a
Recall of Designs
Word Definition
Pattern Construction
Matrices
Verbal Similarities 
Sequential Reasoning 
Quantitative Reasoning
DAS-II - School Age
Adaptive 
Behavior
Standard scores and developmental quotients (based 
on age equivalents) in VABS-II domains:
Communication
Daily Living Skills
Socialization
Motor Skills
Maladaptive Behavior
VABS-II
Abbreviations: ABC = adaptive behavior composite; DAS-II = Differential Ability Scales, Second Edition; 
GCA = general conceptual ability; VABS-II = Vineland Adaptive Behavior Scales, Second Edition
a
The concepts assessed will be dependent on the chronological age of the child. The child will be given 
the relevant version of the DAS-II (Early Years or School Age) per their age and ability. 
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8
STUDY ACTIVITIES
Each activity will be performed as specified in the Schedule of Events (SOE). See Section 13 for 
the SOE for the pivotal study (Appendix 1 and Appendix 2) and separate substudy (Appendix 3).
8.1
Screening (Month -1, Week -4 to -1)
8.1.1
All Patients in the Pivotal Study and Substudy
The following procedures will be performed up to 28 days prior to randomization/enrollment 
(ie, Day -28 to Day -1): 

Written informed consent (assent if applicable) by patient’s parent(s) or legally 
authorized guardian(s) prior to any study-related procedures

Assessment of eligibility according to review of study entry criteria 

Medical history

Hunter syndrome diagnosis (blood sample collection for testing of iduronate-2-sulfatase 
activity and genotyping, as appropriate based on the patient’s medical history). Note that 
analysis of genotype will be required for all patients who have not had a previous 
genotyping performed at Greenwood Genetic Center’s Diagnostic Laboratory 
(Greenwood, South Carolina, USA). Even patients for whom prior genotyping was 
performed at Greenwood Genetic Center’s Diagnostic Laboratory may need have a repeat 
analysis performed, if the original information was insufficient for an unambiguous 
classification of genotype (eg, to document the integrity of the FMR1 and FMR2 genes in 
patients with large deletion/rearrangement mutations). Please refer to Section 7.3.1 for 
specific instructions.

Echocardiogram (note: this assessment will not need to be performed if an 
echocardiogram taken within 3 months of study start is available and deemed satisfactory 
for evaluation of anesthesia risk.)

Physical and neurological examination

Height and weight

Head circumference

Hearing assessment

Neurodevelopmental assessments:

Differential Ability Scales, Second Edition (DAS-II) 

Bayley Scales of Infant Development, Third Edition (BSID-III) for patients in the 
substudy only who are too young (<3 years of age) or unable to complete the DAS-II 

Vineland Adaptive Behavior Scales, Second Edition (VABS-II)

12-lead ECG

Vital signs

Clinical laboratory tests (hematology, serum chemistry, urinalysis)

Urine GAG and creatinine

Anti-idursulfase antibody testing (serum and CSF)

General anesthesia

Brain MRI
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
ICP measurement (by lumbar puncture)

CSF sample collection (by lumbar puncture). CSF samples will be used to analyze 
standard laboratory parameters (chemistries, cell counts), as well as GAG, concentration 
of idursulfase enzyme, albumin, and presence of idursulfase-specific antibodies.

Health status assessment (EQ-5D questionnaire)

Concomitant medications, therapies/interventions, and medical/surgical procedures

Adverse events
8.2
Randomization/Enrollment: Clinic Admission (Month 0, Week 0, Day 0) 
8.2.1
All Patients (IT Treatment and No IT Treatment Groups) in the Pivotal Study

Randomization

Concomitant medications, therapies/interventions, and medical/surgical procedures*

Adverse events*
*These assessments may occur by telephone.
8.2.2
All Patients in the Substudy

Documentation of entry criteria for enrollment

Concomitant medications, therapies/interventions, and medical/surgical procedures*

Adverse events*
*These assessments may occur by telephone.
8.3
Treatment Period (Months 1 to 12)
During this period, several phases of activity will occur. These are designated in the SOE as: Pre-
surgery, Surgery, Follow-up, and Post-op Recovery at Week 2 (+7 days) and IT Dosing at Weeks 
4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 [±7 days ] (Pre-treatment, IT Injection, Follow-up). 
8.3.1
Patients in the IT Treatment Group of the Pivotal Study and All Patients in the 
Substudy: Pre-surgery, Surgery, Follow-up, and Post-op Recovery (Week 2 [+7 
days])
IDDD placement will require surgical implantation under general anesthesia and post-surgical 
assessment.  
Note:  Patients in the USA who were randomized in the pivotal study prior to FDA authorization 
of investigational use of the SOPH-A-PORT Mini S IDDD and treated with idursulfase-IT via 
lumbar puncture will have the assessments originally planned at Week 2 [+7 days] performed at 
the time of the delayed device implantation surgery.
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8.3.1.1
Pre-surgery

Physical and neurological examination*

Height and weight*

12-lead ECG*

Vital signs*

Clinical laboratory tests (hematology, serum chemistry, urinalysis)*

Coagulation tests ([PT, PTT] to be performed by the local laboratory)

Concomitant medications, therapies/interventions, and medical/surgical procedures

Adverse events
*The assessments indicated do not need to be repeated if completed as part of Screening 
assessments within 7 days prior to surgery.
8.3.1.2
Surgery

Vital signs

General anesthesia

CSF sample collection

IDDD implantation

X-ray (to verify IDDD is at the mid-thoracic level in the spinal canal and correctly 
installed)

Concomitant medications, therapies/interventions, and medical/surgical procedures

Adverse events
8.3.1.3
Follow-up
The following assessments will be performed after surgery and prior to discharge. It is expected 
that, for most patients, post-surgical follow-up will occur within Week 2 (ie, within 1 to 2 days 
of surgery).

Physical and neurological examination

Concomitant medications, therapies/interventions, and medical/surgical procedures

Adverse events
8.3.1.4
Post-op Recovery
Surgical implantation of the IDDD will be followed by a post-operative recovery period of at 
least 14 days prior to the first IT administration of idursulfase-IT. 
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8.3.2
Patients in the IT Treatment Group of the Pivotal Study and All Patients in the 
Substudy: IT Dosing (Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48 [±7 days])
8.3.2.1
Pre-treatment

Physical and neurological examination 

Height and weight (performed at Weeks 4, 16, 28, 40)

Head circumference (performed at Weeks 4, 16, 28, 40)

Hearing assessment (performed at Weeks 16, 28, 40)

Neurodevelopmental assessments (performed at Weeks 16, 28, and 40)

Differential Ability Scales, Second Edition (DAS-II) 

Bayley Scales of Infant Development, Third Edition (BSID-III) for patients in the 
substudy only who are too young (<3 years of age) or unable to complete the DAS-II 

Vineland Adaptive Behavior Scales, Second Edition (VABS-II)

12-lead ECG

Vital signs

Clinical laboratory tests (hematology, serum chemistry, urinalysis, performed at Weeks 4, 
16, 28 and 40)

Urine GAG and creatinine (performed at Weeks 4, 16, 28, 40)

Anti-idursulfase antibody testing (serum [and CSF, see Section 8.3.2.2], performed at 
Weeks 4, 16, 28, and 40)

Concomitant medications, therapies/interventions, and medical/surgical procedures

Adverse events
From Week 28 onward, pre-treatment 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.
8.3.2.2
IT Injection
Patients will remain under observation in the hospital setting (eg, may include infusion center, 
post-anesthesia care unit [PACU; recovery suite], observation unit, short stay center) for 4 hours 
post IT injection for vital signs and other safety assessments. Thereafter, if deemed clinically 
stable by the Investigator, patients may leave the hospital setting (with exception of Visit Weeks 
4, 24, and 48 at which serial blood sampling for PK evaluation is planned). The patient may need 
to be examined the following day (See Follow-up, Section 8.3.2.3) by the Investigator; however, 
there is no requirement for an overnight hospital stay. Note that, on IT Dosing Weeks, the IV 
infusion of Elaprase should be scheduled to occur a minimum of 48 hours after IT administration 
of idursulfase-IT.
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
12-lead ECG (performed within 4 hours of IT injection at Weeks 4, 16, 28, 40)

Vital signs (collected at the following time points (±10 minutes) in association with IT 
administration of idursulfase-IT: within 15 minutes prior to IT administration, 30 minutes 
post end of IT administration, 60 minutes post end of IT administration, 120 minutes post 
end of IT administration, and 4 hours post end of IT administration)

CSF sample collection (performed at each IT Dosing Week prior to idursulfase-IT 
injection). Cerebrospinal fluid samples will be collected via the IDDD or lumbar 
puncture and used to analyze standard laboratory parameters (chemistries, cell counts), as 
well as GAG, concentration of idursulfase enzyme, albumin, and presence of idursulfase-
specific antibodies. Analyses of CSF samples for antibodies and albumin will be 
performed at IT Dosing Weeks 4, 16, 28, and 40.

idursulfase-IT injection  

Serum sampling for PK analysis (performed at Weeks 4, 24, and 48). Samples will be 
collected within 15 minutes (±5 minutes) prior to intrathecal administration of 
idursulfase-IT and at 30 minutes (±5 minutes), 60 minutes (±5 minutes), 120 minutes 
(±5 minutes), 4 hours (±5 minutes), 6 hours (±5 minutes), 8 hours (±15 minutes), 
12 hours (±15 minutes), 24 hours (±15 minutes), 30 hours (±15 minutes), 36 hours 
(±15 minutes) after the start of intrathecal administration.

Concomitant medications, therapies/interventions, and medical/surgical procedures

Adverse events
8.3.2.3
Follow-up (Post IT Injection)
For the first 6 months of treatment with idursulfase-IT (ie, Weeks 4, 8, 12, 16, 20, 24), patients 
must return to the clinic the day after each IT administration for a safety follow-up visit. Note 
that, under these circumstances, there is no requirement for an overnight hospital stay; if a 
decision is made to keep the patient overnight for convenience, this hospitalization should not 
initiate a serious adverse event report. For the latter 6 months of treatment with idursulfase-IT 
(ie, from Week 28 onward) and in the absence of any safety concerns, patients may complete the 
safety follow-up visit on the same day as IT administration prior to discharge.

Physical and neurological examination

Concomitant medications, therapies/interventions, and medical/surgical procedures

Adverse events
8.3.3
Patients in the No IT Treatment Group of the Pivotal Study (Months 1 to 12)
8.3.3.1
Week 2 (+7 days)
The following will be assessed by telephone contact:

Concomitant medications, therapies/interventions, and medical/surgical procedures

Adverse events
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Note:  Week 2 [+7 days] assessments are not applicable to patients in the USA who are 
randomized in the pivotal study prior to FDA authorization of use of the SOPH-A-PORT Mini S 
IDDD.
8.3.3.2
Weeks 4, 16, 28, 40 (± 7 days)

Physical and neurological examination 

Height and weight

Head circumference

Hearing assessment (performed at Weeks 16, 28, and 40)

Neurodevelopmental assessments (performed at Weeks 16, 28, and 40)

Differential Ability Scales, Second Edition (DAS-II) 

Vineland Adaptive Behavior Scales, Second Edition (VABS-II)

12-lead ECG

Vital signs

Clinical laboratory tests (hematology, serum chemistry, urinalysis)

Urine GAG and creatinine

Anti-idursulfase antibody testing (serum)

Concomitant medications, therapies/interventions, and medical/surgical procedures

Adverse events
8.3.3.3
Weeks 8, 12, 20, 24, 32, 36, 44, 48 (± 7 days) 
The following will be assessed by telephone contact:

Concomitant medications, therapies/interventions, and medical/surgical procedures

Adverse events
8.4
End of Study: Month 13 (Week 52[± 7 days])
8.4.1
Patients in the IT Treatment Group of the Pivotal Study and All Patients in the 
Substudy

Physical and neurological examination

Height and weight

Head circumference

Hearing assessment

Neurodevelopmental assessments 

Differential Ability Scales, Second Edition (DAS-II) 

Bayley Scales of Infant Development, Third Edition (BSID-III) for patients in the 
substudy only who are too young (<3 years of age) or unable to complete the DAS-II 

Vineland Adaptive Behavior Scales, Second Edition (VABS-II)

12-lead ECG

Vital signs

Clinical laboratory tests (hematology, serum chemistry, urinalysis)
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
Urine GAG and creatinine

Anti-idursulfase antibody testing (serum and CSF)

General anesthesia

Brain MRI

ICP measurement (by lumbar puncture)

CSF sample collection. CSF samples will be used to analyze standard laboratory 
parameters (chemistries, cell counts), as well as GAG, concentration of idursulfase 
enzyme, albumin, and presence of idursulfase-specific antibodies.

X-ray

Health status assessment (EQ-5D questionnaire)

Concomitant medications, therapies/interventions, and medical/surgical procedures

Adverse events
8.4.2
Patients in the No IT Treatment Group of the Pivotal Study

Physical and neurological examination

Height and weight

Head circumference

Hearing assessment

Neurodevelopmental assessments:

Differential Ability Scales, Second Edition (DAS-II) 

Vineland Adaptive Behavior Scales, Second Edition (VABS-II)

12-lead ECG

Vital signs

Clinical laboratory tests (hematology, serum chemistry, urinalysis)

Urine GAG and creatinine

Anti-idursulfase antibody testing (serum and CSF)

General anesthesia

Brain MRI

ICP Measurement (by lumbar puncture)

CSF sample collection (by lumbar puncture). CSF samples will be used to analyze 
standard laboratory parameters (chemistries, cell counts), as well as GAG, concentration 
of idursulfase enzyme, albumin, and presence of idursulfase-specific antibodies.

Health status assessment (EQ-5D questionnaire)

Concomitant medications, therapies/interventions, and medical/surgical procedures

Adverse events
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8.5
Follow-up (Day 7 [±2 Days] Post EOS)
8.5.1
Patients in the Pivotal Study and Substudy
The following will be assessed by telephone contact:

Concomitant medications, therapies/interventions, and medical/surgical procedures

Adverse events
(Note that for those patients who enroll in extension study SHP-609-302 within the 7 ±2 day 
window of the EOS visit the follow-up contact is not required. If, however, a patient is not 
enrolled in the SHP-609-302 study within the 7 ±2 day window of the EOS visit, then the follow-
up contact should be completed.)
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9
QUALITY CONTROL AND ASSURANCE
Training on the study protocol, device usage, and investigational product administration will 
occur at an Investigator meeting, at the site initiation visit, or both. Instructions will be provided 
to aid consistency in data collection and reporting across sites.
Clinical sites will be monitored by the Sponsor or its designee to ensure the accuracy of data 
against source documents. The required data will be captured in a validated clinical data 
management system that is compliant with the FDA 21 CFR Part 11 Guidance. The clinical trial 
database will include an audit trail to document any evidence of data processing or activity on 
each data field by each user.  Users will be trained and given restricted access, based on their 
role(s) in the study, through a password-protected environment.
Data entered in the system will be reviewed manually for validity and completeness against the 
source documents by a clinical monitor from the Sponsor or its designee. If necessary, the study 
site will be contacted for corrections or clarifications; all missing data will be accounted for.
Serious adverse event information captured in the clinical trial database will be reconciled with 
the information captured in the Pharmacovigilance and Risk Management database.
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10
STATISTICAL ANALYSIS
10.1
General Methodology
All statistical analysis will be performed by Shire Biometrics Department using Statistical 
Analysis System (SAS) software version 9.3 or higher (SAS Institute, Cary, NC, USA) unless 
otherwise specified.
Continuous variables will be summarized using descriptive statistics (N, mean, standard 
deviation, minimum, median, and maximum). Categorical variables will be summarized using 
the number and percentage of patients in each category. Data will be summarized with respect to 
patient disposition, demographic and baseline characteristics and concomitant medication use. 
The efficacy endpoints, safety assessments and other outcome results for each treatment group 
will be summarized descriptively unless otherwise indicated. Statistical model estimates of least 
squares means, treatment differences, p-values and 95% confidence intervals (CIs) for least 
squares mean treatment differences will also be provided where relevant for efficacy endpoints. 
The fit of linear models will be assessed using residual plots and/or other diagnostic plots as 
appropriate. All statistical tests will be 2-sided and will be performed at the 0.05 level of 
significance unless stated otherwise.  
The separate substudy is an open-label, single arm study. Data from patients participating in this 
separate substudy will be analyzed separately. The safety and efficacy data from the substudy 
will be summarized descriptively or listed, as appropriate, in a manner similar to that of the 
pivotal study.
10.2
Determination of Sample Size
Based on study HGT-HIT-050/045 Phase I/II data, the observed decline in mean GCA score in 
untreated patients was estimated to be 13.7 points with a standard deviation of 9.4 after 
12 months. For the sample size calculation, we conservatively assumed an approximately 1 point 
per month rate of decline in the untreated control arm, so that the theoretical decline would be 
13 points from baseline (screening) to Visit Week 52. As up to 2 months may elapse between the 
screening assessment and the start of idursulfase-IT treatment, a mean decline of 2 points at end 
of study would be expected if idursulfase was effective in stabilizing the decline. Therefore, in 
such a case, the mean projected treatment difference at Visit Week 52 would be 11 points, which 
is considered a clinically meaningful treatment difference.
Using a 2:1 allocation ratio, a sample size of approximately 48 randomized patients (about 32 IT 
treated patients, 16 no IT control patients) will yield 80% power to detect a clinically meaningful 
mean treatment difference of 11 points in the primary endpoint, GCA change from baseline to 
Visit Week 52. This calculation further assumes a common standard deviation for the change 
from baseline of 11.6 points, a type-I error rate of 0.05 for a two-sided two-sample t-test, with 
approximately up to 10% missing an assessment at Visit Week 52. Given this sample size, and 
conditional on rejection of the null hypothesis for the primary endpoint, the power would be 80% 
to detect a mean difference of 10 points in the key secondary endpoint, assuming a common 
standard deviation for the change from baseline of 10.5 points for a two-sided two-sample t-test 
with a significance level of 5% and 10% missing an assessment at Visit Week 52. The variance 
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estimate for this sample size was determined based on a blinded variability assessment (BVA) 
performed as specified in the prior protocol version (Amendment 3); refer to Appendix 5 for 
details. Given that uncertainty around this variability estimate remains, a second BVA using the 
same approach as specified in Appendix 5 is planned to confirm the estimate after approximately 
27 patients complete the Week 52 primary endpoint assessment. Based on this second blinded 
assessment, the sample size may be increased to a maximum of 54 patients while maintaining the 
2:1 allocation ratio.
For the separate substudy, there is no target sample size. All patients meeting eligibility criteria 
for the substudy will be enrolled until enrollment for the pivotal trial is completed.
10.3
Method of Assigning Study Patients to Treatment Groups
Patients will be randomized (open-label, assessor-blinded) in a 2:1 allocation ratio between the 
active (idursulfase-IT treatment regimen) and control groups. Although this is a multi-center 
study, the randomization will not be stratified by center. The baseline GCA score (at Screening 
Visit) is expected to be a key prognostic factor. Therefore, the randomization will be stratified 
according to baseline GCA score: less than or equal to 70 versus greater than 70. The 
randomization schedule will be generated and administered centrally by Pharmaceutical Product 
Development, LLC (PPD), independent of the Sponsor’s project team. There is no replacement 
of patients who do not complete the study.
In a separate substudy, additional patients with cognitive impairment may be enrolled who are 
below the age of 3 years at the time of informed consent. Such patients are ineligible for the 
pivotal trial and will not be randomized, but will receive idursulfase-IT treatment monthly.
10.4
Population Description and Exposure
10.4.1
Analysis Populations
For the pivotal trial, all efficacy data analyses will be performed using the Intent-to-Treat (ITT) 
Population, which is defined as all randomized patients.  
All safety data analyses will be performed according to treatment received using the Safety 
Population, which is defined as all randomized patients with any post-randomization safety 
assessments. IDDD and procedure related analyses will be conducted in the set of patients in the 
Safety Population who had the device implant procedure performed.
For the substudy, analyses will be performed on the Substudy Population, defined as all patients 
enrolled and treated with study drug in the substudy.
All pharmacokinetic data analyses will be performed using the Pharmacokinetic Population. The 
Pharmacokinetic Population is defined as all patients for whom the primary pharmacokinetic 
data are considered sufficient and interpretable. 
The planned analyses described below pertain to the pivotal study data. Similar descriptive 
summaries or listings as appropriate will be provided for the substudy data.
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10.4.2
Patient Disposition
The total number of patients screened (ie, signed informed consent) will be presented. The 
number and percentage of patients screened (ie, signed informed consent), randomized, 
completed, and discontinued prematurely by reason for withdrawal will be summarized by 
treatment group. The number of patients included in the ITT and Safety populations will be 
summarized.  
10.4.3
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. An incident involving noncompliance with the protocol 
which may affect the patient’s rights, safety, or welfare, or the integrity of the resultant data will 
be known as a protocol violation. In particular, any serious deviation that affects the collection of 
data for the primary endpoint will be considered a protocol violation. 
Examples of potential protocol violations may include violation of important admission 
(inclusion/exclusion) criteria, occurrence of a treatment dispensing error, treatment 
noncompliance or substantial use of a prohibited medication during the study. Reported protocol 
deviations and patient data will be examined prior to database lock to determine if conditions set 
forth in the study protocol have been violated and a more comprehensive list will be constructed 
at that time. The list of protocol deviations will not be presented; however, identified protocol 
violations will be summarized.
10.4.4
Demographics and Baseline Characteristics
Demographic and baseline characteristics (eg, age [years], race, ethnicity, genotype, weight [kg], 
height [cm], body mass index [BMI, kg/m2], country, age at onset of Hunter syndrome 
symptoms, age of Hunter syndrome diagnosis, family history of Hunter syndrome) will be 
summarized by treatment group and overall in the pivotal study.  
10.4.5
Treatment Compliance
Treatment compliance will be summarized in terms of the percent of scheduled doses received in 
the idursulfase-IT arm. Percent compliance is defined as: 
[(No. of Complete IT injections Received) ÷ (Expected No. of IT injections at EOS)] *100
10.4.6
Extent of Exposure 
The number of IT injections received overall and by lumbar puncture, average dose, the duration 
of idursulfase-IT treatment and IT administration duration will be summarized descriptively in 
the idursulfase-IT arm. The duration of idursulfase-IT treatment, summarized in months, is 
defined as the time from first to last IT administration during the study. The duration for each 
idursulfase-IT administration (in minutes) is calculated by subtracting the administration start 
time from the administration end time.
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10.5
Analysis of Efficacy
All efficacy analyses described below refer to the pivotal trial; all efficacy data from patients 
treated in the separate substudy will be listed, including any measurements from the BSID-III 
and VABS-II.
10.5.1
Primary Efficacy Endpoint Analysis
For the pivotal trial, the primary efficacy endpoint is the change from study baseline (screening 
visit) to Visit Week 52 in the GCA score as measured by the DAS-II. The primary analysis will 
compare the treatment groups using a linear mixed model repeated measures (MMRM) analysis.
24, 25 The repeated measures are the change from baseline GCA scores obtained at the scheduled 
Visit Weeks 16, 28, 40, and 52, respectively. The model will include fixed categorical effects for 
treatment, visit week, treatment by visit week interaction, baseline GCA classification factor 
(either ≤70 or >70), and the baseline GCA score as a continuous covariate. SAS Proc Mixed with 
restricted maximum likelihood estimation (REML) and an unstructured within-patient 
covariance structure will be used. If this model fails to converge, a first order autoregressive 
(AR[1]) covariance structure will be used for the primary analysis. The Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom for tests of fixed effects. 
The assumptions of the model, including normality, will be evaluated using residual and other 
diagnostic plots of model fit.
From this model, least squares means, standard errors, treatment differences in least squares 
means, and 95% CIs will be estimated for each time point. Primary inference is based on the 
treatment comparison of least squares means at Visit Week 52 from this model, and a p-value 
will be presented for this time point only. The null hypothesis is that the mean difference in the 
primary endpoint between the two treatment groups is zero, versus the alternative hypothesis that 
this difference is not zero. The hypotheses can be expressed as follows:
H0: μIT - μcontrol = 0  versus  H1: μIT - μcontrol ≠ 0
Where μIT refers to the mean change from baseline to Visit Week 52 in GCA score in the 
idursulfase-IT treated group and μcontrol refers to the mean change from baseline to Visit Week 52 
in GCA score in the untreated control group. The test will be performed using the final, MMRM 
model-based t-test with a two-sided significance level of 5%. Estimated least squares means 
(±SE) by treatment group will be plotted over time.
10.5.2
Key Secondary Efficacy Endpoint Analysis
The key secondary efficacy endpoint is the change from study baseline (Screening Visit) to Visit 
Week 52 in the ABC score as measured by the VABS-II. The key secondary analysis will 
compare the treatment groups using a linear mixed model repeated measures (MMRM) analysis. 
The repeated measures are the change from baseline ABC scores obtained at the scheduled Visit 
Weeks 16, 28, 40, and 52, respectively. The model will include effects of treatment, visit week, 
treatment by visit week interaction, baseline GCA classification factor (either ≤70 or >70) and 
the baseline ABC score as a continuous covariate. SAS Proc Mixed with REML and an 
unstructured within-patient covariance structure will be used. If this model fails to converge, a 
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first order AR(1) covariance structure will be used instead. The Kenward-Roger approximation 
will be used to estimate denominator degrees of freedom for tests of fixed effects. The 
assumptions of the model, including normality, will be evaluated using residual and other 
diagnostic plots of model fit. From this model, least squares means, standard errors, treatment 
differences in least squares means, and 95% CIs will be estimated for each time point. The 
significance test will be based on the difference in least squares means at Visit Week 52 and a 
p-value will be presented for this time point only. Estimated least squares means (±SE) by 
treatment group will be plotted over time.
10.5.3
Other Secondary Efficacy Endpoints Analyses
The following secondary efficacy endpoints will be analyzed using an MMRM analysis in the 
same manner as described above for the key secondary endpoint with the continuous covariate 
corresponding to the baseline score for each measure: 

The change from baseline to Visit Weeks 16, 28, 40, and 52 in standard scores in cluster 
areas of the DAS-II: Verbal, Nonverbal, Spatial, and SNC 

The change from baseline to Visit Weeks 16, 28, 40, and 52 in standard scores of the 
VABS-II domains: Communication, Daily Living Skills, Socialization, and Motor Skills
All other secondary efficacy endpoints will be summarized descriptively by treatment group. 
Mean values by treatment group will be plotted over time. This includes the following endpoints:

The change from baseline to Visit Weeks 16, 28, 40, and 52 in the age equivalents, 
developmental quotients, and T-scores for the subtests of the DAS-II: Verbal 
Comprehension, Picture Similarities, Naming Vocabulary, Pattern Construction, Matrices 
and Copying for the DAS-II/Early Years; and Recall of Designs, Word Definitions, 
Pattern Construction, Matrices, Verbal Similarities and Sequential and Quantitative 
Reasoning for the DAS-II/School Years

The change from baseline to Visit Weeks 16, 28, 40, and 52 in the age equivalents, 
developmental quotients, and V-scale scores of the VABS-II subdomains: 
Communication (Receptive, Expressive, Written), Daily Living Skills (Personal, 
Domestic, Community), Socialization (Interpersonal Relationships, Play and Leisure 
Time, Coping Skills), Motor Skills (Gross, Fine)

The change from baseline to Visit Weeks 16, 28, 40, and 52 in V-scale scores and 
observed maladaptive levels of the VABS-II Maladaptive Behavior Index and its 
subscales (Internalizing, Externalizing) 
10.5.4
Exploratory Analyses
As exploratory analyses, the primary and key secondary MMRM models will be refit including 
the continuous baseline covariate by treatment interaction term in the model. Estimated least 
square means and 95% CIs for each treatment adjusting at the 25th, 50th, and 75th percentiles of 
the pooled baseline covariate distribution will be evaluated.
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Additional subgroup analyses are planned for exploratory purposes for the change from baseline 
in GCA and ABC scores. An MMRM model will be used to test for subgroup interactions at the 
10% significance level. In general, the model will include effects for treatment, visit week, 
treatment by visit week interaction, subgroup, treatment by subgroup interaction, subgroup by 
visit interaction and the 3-way interaction between treatment, visit and subgroup. The p-values 
from interaction tests will be presented, as well as the least square means and 95% CIs by 
treatment and visit within each subgroup. Descriptive statistics of observed values and change 
from baseline will also be presented by treatment and visit week within each subgroup.   
A subgroup analysis will be performed for baseline GCA groups. For this analysis, patients with 
a baseline GCA score of greater than 70 will be classified as having “Moderate” cognitive 
impairment, while patients with a baseline GCA score equal to or below 70 will be classified as 
having “Severe” cognitive impairment. The randomization is stratified by this classification 
variable to ensure treatment group balance within these subgroups. Similar exploratory subgroup 
analyses may be performed for age group (either ≤6 years or >6 years), language, geographic 
region or other baseline factors using MMRM.
A linear random coefficients model (ie, random slope and intercept for continuous time) will be 
fit for the primary and key secondary endpoints if appropriate. The average of the subject-
specific slope estimates from the model will be compared between treatment groups using the 
two-sample t-test. To explore the relationship between composite scores and their components, 
correlations between the GCA and ABC scores (absolute value and change from baseline) and 
their respective domain scores will be estimated. Scatter plots will also be presented.
10.6
Pharmacokinetic, Pharmacodynamic and Health Status Outcomes
10.6.1
Pharmacokinetic Measurements and Parameters
All pharmacokinetic analyses will be performed using the Pharmacokinetic Analysis Population.
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.
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 dose (5 mg, 7.5 mg, and 10 mg) and visit (Week 4, Week 24, and Week 
48).
The pharmacokinetic parameters to be determined will include, but not be limited to, the 
following:
Cmax
Maximum concentration occurring at tmax
tmax
Time of maximum observed concentration sampled during a dosing 
interval
t½ 
Terminal half-life
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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
CL/F
Total body clearance for extravascular administration divided by the 
fraction of dose absorbed
Vz/F
Volume of distribution associated with the terminal slope following 
extravascular administration divided by the fraction of dose absorbed
λz
First order rate constant associated with the terminal (log-linear) portion of 
the curve
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 dose and visit. Serum concentrations of idursulfase at each nominal 
sampling time will also be summarized by dose and visit using descriptive statistics.
Additionally, idursulfase concentrations in CSF will be listed by patient and summarized by 
study visit.
10.6.2
Pharmacodynamic Outcome
Glycosaminoglycan levels in CSF and urine and the change from baseline (Screening Visit) will 
be summarized by visit and treatment group. Mean (±SE) values will be plotted over time. A 
Wilcoxon Rank Sum test will be used to compare treatment groups on the CSF GAG change and 
percent change from baseline to the Week 52/EOS visit. Analysis of both total GAG and heparan 
sulfate, if available, will be performed. 
10.6.3
Health Status Outcome
The EQ-5D measures 5 dimensions of health status: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. For each dimension, there are 5 levels of response. The 
number and percent of patients with each response will be presented by dimension at each visit. 
The visual analog scale (VAS) records the patient’s parent/caregiver-rated health on a 0 (worst 
health) to 100 (best health) scale. The VAS score, as well as the change from baseline (screening 
visit to Week 52/EOS) will be summarized. A Wilcoxon Rank Sum test will be used to compare 
treatment groups on the change from baseline to Week 52/EOS visit in VAS score. 
Pharmacoeconomic analyses may be performed by the Sponsor staff in the Health Economics 
and Outcomes Research group or designee and reported separately in a pharmacoeconomic 
report to be appended to the Clinical Study Report. Accordingly, any planned 
pharmacoeconomic analyses related to this data may be described elsewhere.
10.7
Safety Assessments
All safety analyses will be descriptive, no statistical testing will be performed. All analyses 
described below refer to the pivotal trial; safety data from the separate substudy will be similarly 
summarized or listed as relevant.
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10.7.1
Adverse Events
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 16.0 or later. Adverse events occurring on or after randomization and on or 
before the follow-up visit (scheduled 7 days after EOS Visit) will be summarized by treatment 
group, both overall and within system organ class (SOC) by preferred term. A summary of 
adverse events related to study drug will be presented. An adverse event will be considered 
related if indicated to be “possibly,” “probably,” or “definitely” related. A separate tabulation of 
IV Elaprase infusion-related adverse events will also be presented by treatment group. Adverse 
events will be tabulated by severity (mild, moderate, severe) and treatment group. In addition, 
those events which resulted in death or were otherwise classified as serious will be summarized 
and presented in a separate listing.
10.7.2
IDDD and Procedure Related Adverse Events
IDDD and procedure related adverse events will be summarized within SOC by preferred term. 
Separate tabulations will be provided for adverse events related to the IDDD, device surgical 
procedure, and IT-administration process. An overall summary of adverse events related to the 
IT treatment regimen (ie, related to one or more of the following: study drug, IDDD, device 
surgical procedure, and IT-administration process) will also be presented. IDDD and procedure 
related events will be analyzed in the set of treated patients in the Safety Population with the 
device implanted.
10.7.3
Clinical Laboratory Evaluations
Laboratory values (eg, chemistries, hematology, etc) including CSF components will be 
summarized in terms of the absolute value and change from baseline at each time point by 
treatment group. The number and percentage of patients with any clinically significant post-
baseline laboratory result will be presented by treatment group.   
10.7.4
Electrocardiogram Evaluations
The 12-lead ECG parameters (heart rate [bpm], PR interval [msec], RR interval [msec], QRS 
interval [msec], QT interval [msec] and QTc [msec] interval) will be summarized in terms of 
absolute value and change from baseline. The corrected QT interval (QTc) 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 by treatment group will be presented.
10.7.5
Vital Signs and Physical Measurements
Vital signs (temperature [C], pulse [bpm], blood pressure [systolic and diastolic, mmHg], 
respiration [per min], and oxygen saturation [%]) will be summarized graphically by study time 
point and treatment group.  
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Height (cm), weight (kg), and head circumference (cm) and the change from baseline (Screening 
Visit) will be summarized by study time point and treatment group. Intracranial pressure 
measurements (cm of H2O) and brain MRI volumes will be similarly summarized.
10.7.6
Physical Findings
Clinically significant physical and neurological examination findings will be recorded and 
summarized as part of the medical history or adverse event data.
10.7.7
Other Observations Related to Safety
10.7.7.1
Hearing Assessments
Any hearing assessment data will be summarized by treatment group or listed as appropriate.
10.7.7.2
Immunogenicity
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 positive and 
negative at each time point will be summarized by treatment group. Titer values will be 
summarized using box plots over time in patients with positive antibodies at or prior to each 
scheduled visit. The percent inhibition and titer will be plotted similarly for patients who 
developed positive neutralizing antibodies at or prior to each scheduled visit.
10.7.7.3
Device Performance
SOPH-A-PORT safety and performance will be summarized for implanted patients. The 
proportion of patients with at least one IDDD failure and the proportion with malfunction only, 
as well as the number of and reasons for IDDD failures and malfunctions will be summarized. 
The annual event rate of IDDD failures and malfunctions will be calculated for each patient and 
summarized descriptively. 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. Patients without 
an IDDD failure or malfunction will be censored at their last study drug injection date. The 
IDDD longevity (time to failure in weeks) and time to first malfunction for all implanted IDDDs 
will also be plotted using the KM method. 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 IDDD 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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10.7.8
Concomitant Medications/Therapies
Concomitant medications are defined as all medications taken on or after the time of the 
randomization and on or before the last follow-up date (scheduled 7 days after EOS Visit). 
Concomitant medications will be mapped using the World Health Organization Drug Dictionary 
(WHO-DD) and summarized by the therapeutic class and preferred term for each treatment 
group. Concomitant therapies will be mapped using the MedDRA Version 16.0 or higher and 
summarized by the SOC and preferred term for each treatment group.
10.8
Statistical/Analytical Issues
10.8.1
Handling of Drop-outs and Missing Data
For randomized patients who discontinue early from the study, their early EOS efficacy 
evaluations will be used for the next scheduled time point only if the EOS evaluation is 
performed within 45 days of the next scheduled visit. In general, no further imputation will be 
used for descriptive analyses, or for primary and secondary efficacy analyses utilizing MMRM 
methodology. However, in the unlikely event that a patient has no post-baseline efficacy 
assessments, the first post-baseline assessment (Visit Week 16) will be imputed so that all 
randomized patients are included in MMRM analyses. The median value estimated from the 
pooled data at Week 16 across all randomized patients with available data will be used for this 
purpose. Imputation of missing primary and key secondary endpoint values at the Visit Week 52 
time point will be performed in sensitivity analyses only. The planned imputation methods for 
sensitivity analyses are described below in Section 10.8.6.  
10.8.2
Adjustment for Covariates
Analyses of the change from baseline in efficacy endpoints utilizing MMRM methodology will 
adjust for the baseline score of the parameter of interest as a continuous covariate in the model. 
As the randomization of the study is stratified by the baseline GCA classification factor (either 
≤70 or >70), MMRM analyses will also take into account the GCA strata as a classification 
factor.  
10.8.3
Interim Analysis
No interim analysis for treatment comparison is planned during the course of the study. The 
DMC will monitor safety data periodically. Following the completion of the study and collection
and verification of all final data, the database will be locked and the results of the planned 
statistical analysis will be described in a final study report.
10.8.4
Multicenter Studies
This is a multicenter study utilizing a central randomization. The randomization is not stratified 
by center. It is planned that the data from all centers that participate in this protocol will be 
combined so that an adequate number of patients will be available for analysis. Because of the 
potential for a relatively large number of centers, and small numbers of patients at some centers, 
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no subset analyses by center are planned. No adjustment for center effect will be utilized in the 
statistical analyses.
10.8.5
Multiple Comparisons/Multiplicity
The familywise type-I error rate (FWER) for the statistical tests of the primary, key secondary 
and other selected secondary efficacy endpoints from the MMRM analyses specified above will 
be controlled at 0.05. To strongly control the FWER at this level, a Gatekeeping approach will be 
utilized in which each family of statistical tests will be conducted in a sequential manner. The 
test for the primary endpoint will be conducted first at the 5% significance level and, if 
significant, the key secondary endpoint will be similarly tested at the 5% significance level. If 
these two tests are both significant, tests of the additional secondary efficacy endpoints specified 
below will be conducted using the Hommel closed testing procedure1 to control the FWER.
The hypotheses for the primary, key secondary and other selected secondary efficacy endpoints 
will therefore be grouped into 3 ordered Gatekeeper families defined as follows:

Family 1 (F1): Hypothesis test for primary endpoint

Family 2 (F2): Hypothesis test for key secondary endpoint

Family 3 (F3): Hypothesis tests for the change from baseline to Visit Week 52 for the 
following 6 endpoints: 

Verbal, Nonverbal, and Spatial standard scores in cluster areas of the DAS-II

Communication, Daily Living Skills, and Socialization standard domain scores of the 
VABS-II.
The 3 sets of hypotheses in F1, F2 and F3 will be tested sequentially, with F1 and F2 serving as 
serial gatekeepers. The null hypothesis of no treatment difference for the primary endpoint will 
be tested first in F1. The statistical test for the key secondary endpoint in F2 may only be 
declared statistically significant if a significant result is also achieved for the primary efficacy 
endpoint. Since F1 and F2 each contain a single null hypothesis to be tested, each of the two tests 
will be conducted at the 5% significance level.
Further, only if the null hypotheses for both the primary and key secondary endpoints are 
rejected in F1 and F2, can any of the tests for the endpoints specified in F3 be declared 
statistically significant. If statistical significance is obtained for F1 and F2, the Hommel closed 
testing procedure1 will be used to control the FWER within F3, with each hypothesis test in F3 
equally weighted. In this case, SAS Proc MULTTEST will be used to calculate and report 
adjusted p-values for each endpoint in F3.  
All other endpoints not included in F1, F2 or F3 above are considered supportive and any 
statistical tests comparing treatments will be made without adjustment for multiplicity. The 
resulting unadjusted p-values from these supportive analyses will be interpreted descriptively as 
summarizing the weight of evidence for a treatment difference and may suggest avenues for 
further exploratory analyses or generate formal hypotheses to be tested in future trials.
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10.8.6
Sensitivity Analyses
Sensitivity analyses for the primary and key secondary endpoints will be conducted to assess 
missing data assumptions in the MMRM analyses. The sensitivity analyses below will use worst-
observation-carried forward (WOCF) to impute missing data at the Visit Week 52 time point. 
Within a given patient, the worst (lowest) observed score prior to Visit Week 52 (including the 
baseline value) will be used for the imputation of their missing Visit Week 52 value.  
The first sensitivity analysis will compare the treatment groups at the Visit Week 52 time point 
using an analysis of covariance model with WOCF (ANCOVA-WOCF). The ANCOVA-WOCF 
model will include fixed categorical effects for treatment and baseline GCA classification factor 
(either ≤70 or >70), and the corresponding baseline score as a continuous covariate. The 
treatment difference in least squares means, 95% CI and p-value from this model will be 
compared to the corresponding inferential statistics at Visit Week 52 from the primary or key 
secondary MMRM model. As a second sensitivity analysis, the Wilcoxon Rank-Sum test with 
WOCF (WRS-WOCF) will be used to compare treatment groups at Visit Week 52. This test is 
based on the ranked changes from baseline after imputation of the Visit Week 52 value using 
WOCF.  
If the model for the primary or key secondary endpoint fails to converge using an unstructured 
covariance matrix, an AR(1) covariance structure will be used. In this case, additional covariance 
structures will be tried as sensitivity analyses to assess the robustness of the results, including 
compound symmetric and Toeplitz structures.  
Additional sensitivity analyses and imputation methods will be specified in the statistical 
analysis plan.
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11
ADMINISTRATIVE CONSIDERATIONS
11.1
Investigators and Study Administrative Structure
Before initiation of the study, the Investigator must provide the Sponsor with a completed Form 
FDA 1572 or Investigator Agreement. Investigational product may be administered only under 
the supervision of the Investigators and Sub-investigators listed on these forms. Curriculum vitae 
must be provided for the Investigators and Sub-investigators listed on Form FDA 1572 or the 
Investigator Agreement. If the study involves use of an investigational device and the study 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).  
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.
The Lead Investigator for this study is Joseph Muenzer, MD, PhD, Professor at the Departments 
of Pediatrics and Genetics, School of Medicine, University of North Carolina at Chapel Hill 
(North Carolina, USA).
11.2
Institutional Review Board or Independent Ethics Committee Approval
Before initiation of the study, the Investigator must provide the Sponsor with a copy of the 
written IRB/IEC approval of the protocol and the informed consent form. This approval must 
refer to the informed consent form and to the study title, study number, and version and date of 
issue of the study protocol, as given by the Sponsor on the cover page of the protocol.
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; a final status report must be provided to the IRB/IEC within 
3 months of study completion or termination (or as required). Copies of the status reports will be 
sent to the study clinical monitor. The Investigators must maintain an accurate and complete 
record of all submissions made to the IRB/IEC, including a list of all reports and documents 
submitted. Drug-related adverse events which are reported to the US FDA or other regulatory 
agencies (IND Safety Reports) and UADEs reported to regulatory agencies must be submitted 
promptly to the IRB/IEC. Unanticipated adverse device effects will be reported to regulatory 
agencies by the device manufacturer consistent with relevant regulations. Copies of UADE 
reports will be submitted to the IRB/IEC in a timely fashion.
11.3
Ethical Conduct of the Study
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor and Investigators abide by 
Good Clinical Practice (GCP) as described in the 21 CFR Parts 50, 56, and 312 and the 
International Conference on Harmonisation (ICH) GCP Guidelines Compliance with these 
regulations and guidelines also constitutes compliance with the ethical principles described in the 
Declaration of Helsinki.
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11.4
Patient Information and Consent
Before enrolling in the clinical study, the patient or the patient’s parent(s) or legally authorized 
guardian(s)/representative(s), as appropriate, must consent to participate after the nature, scope, 
and possible consequences of the clinical study have been explained in a form understandable to 
him or her.
An informed consent form (assent form if applicable) that includes information about the study 
will be prepared and given to the patient or the patient’s parent(s) or legally authorized 
representative(s). This document will contain all FDA and ICH-required elements. The informed 
consent (or assent, if applicable) form must be in a language understandable to the patient or the 
patient’s parent(s) or legally authorized representative(s) and must specify who informed the 
patient, the patient’s parent(s), or the patient’s legally authorized representative(s).
After reading the informed consent document, the patient or the patient’s parent(s) or legally 
authorized representative(s) must give consent in writing. Consent (or assent, if applicable) must 
be confirmed at the time of consent by the personally dated signature of the patient, the patient’s 
parent(s) or the patient’s legally authorized representative(s) and by the personally dated 
signature of the person conducting the informed consent discussions.
If the patient or the patient’s parent(s) or legally authorized representative(s) is unable to read, 
oral presentation and explanation of the written informed consent form and information to be 
supplied must take place in the presence of an impartial witness. Consent (or assent, if 
applicable) 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 (or assent, if applicable) was given.
A copy of the signed and dated consent document(s) must be given to the patient or the patient’s 
parent(s) or legally authorized representative(s). The original signed and dated consent document 
will be retained by the Investigator.
The Investigator will not undertake any measures specifically required solely for the clinical 
study until valid consent (or assent, if applicable) has been obtained.
A model of the informed consent form to be used in this study will be provided to the sites 
separately from this protocol.
11.5
Patient Confidentiality
Patient names will not be supplied to the Sponsor. The patient number (and in some regions, 
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 
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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.
11.6
Study Monitoring
Monitoring procedures that comply with current GCP guidelines will be followed. Review of the 
CRFs for completeness and clarity, cross-checking with source documents, and clarification of 
administrative matters will be performed.
The study will be monitored by the Sponsor or its designee. Monitoring will be performed by a 
representative of the Sponsor (Clinical Study Monitor) who will review the CRFs and source 
documents. The site monitor will ensure that the investigation is conducted according to protocol 
design and regulatory requirements by frequent site visits and communications (letter, telephone, 
and facsimile).
11.7
Case Report Forms and Study Records
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 resigning the CRF.
11.7.1
Critical Documents
Before the Sponsor initiates the trial (ie, obtains informed consent [and assent, if applicable] 
from the first patient’s parent[s] and/or legally authorized guardian(s), it is the responsibility of 
the Investigator to ensure that the following documents are available to the Sponsor or its 
designee:

Applicable local regulatory documentation (eg, FDA 1572 Form); signed, dated, and 
accurate

Curricula vitae of Investigator and Sub-investigator(s) (current, dated and signed within 
24 months of study initiation)

Copy of Investigator and Sub-investigator(s) current medical license (indicating license 
number and expiration date)

Signed and dated agreement of the final protocol

Signed and dated agreement of any amendment(s), if applicable

Approval/favorable opinion from the IRB/IEC clearly identifying the documents 
reviewed by name, number and date of approval or re approval: protocol, any 
amendments, Subject Information/Informed Consent Form, and any other written
information to be provided to subjects regarding recruitment procedures
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
Copy of IRB/IEC approved Subject Information/Informed Consent Form/any other 
written information/advertisement (with IRB approval stamp and date of approval, if 
applicable)

Current list of IRB/IEC Committee members/constitution (dated within 12 months prior 
to study initiation)

Financial Disclosure Form signed by Investigator and Sub-investigator(s)

Current laboratory reference ranges (if applicable)

Certification/QA scheme/other documentation (if applicable)
Regulatory approval and notification as required must also be available. The protocol will not be 
initiated until regulatory approval and notification are obtained; these are the responsibility of the 
Sponsor.
11.8
Data Monitoring Committee
An independent, external DMC will be established to provide an ongoing, independent review 
and assessment of the safety data, and to safeguard the interests and safety of the participating 
patients in the study.  
The DMC will be notified of all IDDD failures and IDDD-related complications at times defined 
in the DMC charter.
The DMC will consist of a biostatistician and two clinical experts. The DMC will adhere to a 
prospectively determined charter, which will be written by Shire or its designee and approved by 
the DMC. The charter will define the responsibilities of the DMC and Shire, describe the 
conduct of the meetings, and define the data sets to be reviewed. Serious adverse events and 
other data will be distributed to the members of the DMC periodically for review.
The first meeting of the DMC will be an orientation meeting and will be held prior to the start of 
the study. Thereafter, it is anticipated that the DMC will meet at least annually. The DMC will 
keep detailed minutes of their discussions during the meetings, which will be kept in strict 
confidence.
11.9
Device Failure Review Process
The final cause for SOPH-A-PORT Mini S device failures will be reviewed by Shire by 
examining the device failure information in the clinical database, safety database, and 
manufacturer investigation of returned SOPH-A-PORT Mini S devices.
11.10 Protocol Violations/Deviations
Any violation of the protocol as described can be considered a protocol violation including not 
meeting inclusion/exclusion criteria during the study, not adhering to the study treatment and 
other issues of noncompliance.
The Investigator will conduct the study in compliance with the protocol. The protocol will not be 
initiated until the IRB/IEC and the appropriate regulatory authorities have given 
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approval/favorable opinion. Modifications to the protocol will not be made without agreement of 
the Sponsor. Changes to the protocol will require written IRB/IEC approval/favorable opinion 
prior to implementation, except when the modification is needed to eliminate an immediate 
hazard(s) to patients. The IRB/IEC may provide, if applicable regulatory authorities permit, 
expedited review and approval/favorable opinion for minor change(s) in ongoing studies that 
have the approval/favorable opinion of the IRB/IEC. The Sponsor will submit all protocol 
modifications to the regulatory authorities in accordance with the governing regulations.
A record of patients screened, but not entered into the study, is also to be maintained. No 
protocol exemption will be granted for this study.
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
patients, the Investigator will contact the Sponsor or its designee, if circumstances permit, to 
discuss the planned course of action. Any departures from the protocol must be fully documented 
as a protocol deviation. Protocol deviations will need to be reviewed by the medical monitor and 
may also be required to be submitted to the IRB/IEC.
Protocol modifications will only be initiated by the Sponsor and must be approved by the 
IRB/IEC and submitted to the FDA or other applicable international regulatory authority before 
initiation.
11.11 Premature Closure of the Study
If the Sponsor, Investigator, DMC, or regulatory authorities discover conditions arising during 
the study which indicate that the clinical investigation should be halted due to an unacceptable 
patient risk, the study may be terminated after appropriate consultation between the Sponsor and 
the Investigator. In addition, a decision on the part of the Sponsor to suspend or discontinue 
development of the investigational product may be made at any time. Conditions that may 
warrant termination of the study or site include, but are not limited to:

The discovery of an unexpected, significant, or unacceptable risk to the patients enrolled 
in the study

Failure of the Investigator to comply with pertinent global regulations

Submission of knowingly false information from the study site to the Sponsor or other 
pertinent regulatory authorities

Insufficient adherence by the Investigator to protocol requirements
11.12 Access to Source Documentation
Regulatory authorities, the IRB/IEC, and the Sponsor (or its representatives) may request access 
to all source documents, CRFs, and other study documentation for onsite audit or inspection. 
Direct access to these documents must be guaranteed by the Investigator, who must provide 
support at all times for these activities. Monitoring and auditing procedures that comply with 
current GCP guidelines will be followed. On-site review of the CRFs for completeness and 
clarity, crosschecking with source documents, and clarification of administrative matters may be 
performed.
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11.13 Data Generation and Analysis
The clinical database will be developed and maintained by a contract research organization or an 
electronic data capture technology provider as designated by the Sponsor. Shire or its designee 
will be responsible for performing study data management activities. 
Adverse events will be coded using MedDRA. Concomitant medication will be coded using the 
WHO-DD. Centralized laboratories will be employed as described in the study manual to aid in 
consistent measurement of efficacy and safety parameters.  
11.14 Retention of Data
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application and until there are no pending or contemplated marketing applications or 
at least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product. The Sponsor will notify the Investigator if these documents must be 
retained for a longer period of time. It is the responsibility of the Sponsor to inform the 
Investigator or institution as to when these documents no longer need to be retained.
11.15 Financial Disclosure
The Investigator should disclose any financial interests in the Sponsor as described in 21 CFR 
Part 54 prior to beginning this study. The appropriate form will be provided to the Investigator 
by the Sponsor, which will be signed and dated by the Investigator, prior to the start of the study. 
Changes in status concerning financial interests during the study and after its completion will be 
disclosed by the Investigator in accordance 21 CFR Part 54.
11.16 Publication and Disclosure Policy
All information concerning the study material, such as patent applications, manufacturing 
processes, basic scientific data, and formulation information supplied by the Sponsor and not 
previously published are considered confidential and will remain the sole property of the 
Sponsor. The Investigator agrees to use this information only in accomplishing this study and 
will not use it for other purposes.
It is understood by the Investigator that the information developed in the clinical study may be 
disclosed as required to the authorized regulatory authorities and governmental agencies. In 
order to allow for the use of the information derived from the clinical studies, it is understood 
that there is an obligation to provide the Sponsor with complete test results and all data 
developed in the study in a timely manner.
The Investigator and any other clinical personnel associated with this study will not publish the 
results of the study, in whole or in part, at any time, unless they have consulted with Shire, 
provided Shire a copy of the draft document intended for publication, and obtained Shire’s 
written consent for such publication. All information obtained during the conduct of this study 
will be regarded as confidential.  
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12
LIST OF REFERENCES 
1. Hommel G. A stagewise rejective multiple test procedure based on a modified Bonferroni 
test. Biometrika 1988;75:383-6.
2. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. 
JAMA 1999;281:249-54.
3. Young ID, Harper PS. Incidence of Hunter syndrome. Hum Genet 1982;60:391-2.
4. Beck M. Mucopolysaccharidosis type II (Hunter syndrome): clinical picture and treatment. 
Curr Pharm Biotechnol 2011.
5. Martin R, Beck M, Eng C, et al. Recognition and diagnosis of Mucopolysaccharidosis II 
(Hunter syndrome). Pediatr 2008;121:e377-86.
6. Neufeld E, Muenzer J. The Mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, 
Valle D, eds. The metabolic and molecular bases of inherited disease. 8th ed. New York: 
McGraw-Hill; 2001:4 v. (xivii, 6338, I-104 p.).
7. Martin HR, Poe MD, Reinhartsen D, et al. Methods for assessing neurodevelopment in 
lysosomal storage diseases and related disorders: a multidisciplinary perspective. Acta 
Paediatr Supp 2008;97:69-75.
8. Wraith EGR, Burton BK, Muenzer J, Clarke JT, Meirleir L De, Kroepfl T, Malm G, Beck M. 
Early clinical manifestations in patients diagnosed with Hunter syndrome: data from the 
Hunter Outcome Survey. Arch Dis Child 2008;93:1.
9. Young ID, Harper PS, Newcombe RG, Archer IM. A clinical and genetic study of Hunter 
syndrome. 2. Differences between the mild and severe forms. J Med Genet 1982;19:408-11.
10. Holt JB, Poe MD, Escolar ML. Natural progression of neurological disease in 
Mucopolysaccharidosis type II. Pediatr 2011;127:e1258-65.
11. Holt J, Poe MD, Escolar ML. Early clinical markers of central nervous system involvement 
in Mucopolysaccharidosis type II. J Pediatr 2011;159:320-6.e2.
12. Froissart R, Moreira da Silva I, Guffon N, Bozon D, Maire I. Mucopolysaccharidosis type II-
-genotype/phenotype aspects. Acta Paediatr Supp 2002;91:82-7.
13. Guffon N, Bertrand Y, Forest I, Fouilhoux A, Froissart R. Bone marrow transplantation in 
children with Hunter syndrome: outcome after 7 to 17 years. J Pediatr 2009;154:733-7.
14. Muenzer J, Beck M, Eng CM, et al. Multidisciplinary management of Hunter syndrome. 
Pediatr 2009;124:e1228-39.
15. Muenzer J, Gucsavas-Calikoglu M, McCandless SE, Schuetz TJ, Kimura A. A phase I/II 
clinical trial of enzyme replacement therapy in Mucopolysaccharidosis II (Hunter syndrome). 
Mol Genet Metab 2007;90:329-37.
16. Wraith JE, Scarpa M, Beck M, et al. Mucopolysacharidosis type II (Hunter syndrome): a 
clinical review and recommendations for treatment in the era of enzyme replacement therapy. 
Eur J Pediatr 2008;167:267-77.
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17. Elliot CD. The Differential Abilities Scales (DAS) San Antonio, TX The Psychological
Corporation; 1995.
18. Young ID, Harper PS. The natural history of the severe form of Hunter syndrome: a study 
based on 52 cases. In: Dev Med Child Neurol; 1983:481-9.
19. Sparrow S, Balla D, Cicchetti D. Vineland Adaptive Behavior Scales 2nd ed. 4201 Woodland 
Road Circle Pines, MN 55014-1796: American Guidance Service, Inc; 2005.
20. Bayley N. Bayley Scales of Infant and Toddler Development. 3rd ed. San Antonio, TX The 
Psychological Corporation; 2005.
21. Dekaban AS. Changes in brain weights during the span of human life: relation of brain 
weights to body heights and body weights. Ann Neurol 1978;4:345-56.
22. EuroQol-a new facility for the measurement of health-related quality of life. The EuroQol 
Group. Health Policy 1990;16:199-208.
23. Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQol Group. Annals of 
medicine 2001;33:337-43.
24. Hamlett A, Ryan L, Serrano-Trespalacios P, Wolfinger R. Mixed models for assessing 
correlation in the presence of replication. J Air Waste Manag Associ (1995) 2003;53:442-50.
25. Malinckrodt C, Lane P, Schnell D, Peng Y, Mancuso J. Recommendations for the primary 
analysis of continuous endpoints in longitudinal clinical trials. Drug Inf J 2008;42:303-19.
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Appendix 2
Schedule of Events for Patients Randomized to No Treatment in the 
Pivotal Study
Month -1
Month 0
Months 1 to 12
Month 
13
Follow-up
Weeks -4 
to -1
Screening
Day -28 to 
-1 
Week 0
Randomization, 
Week 2
(+7 days)
Weeks 4, 8, 12, 16, 
20, 24, 28, 32, 36, 
40, 44, 48 
(± 7 days)
Week 
52
End of 
Study 
(EOS) 
(±7 
days)
7 (±2) 
Days Post 
EOS 
Weeks 
4, 16, 
28 40
Weeks 8, 
12, 20, 24, 
32, 36, 44, 
48
Assessment
Day -28 to 
Day -1
Day 0
Telephone
Telephone
Telephone
Informed Consenta
●
Review of Study Entry 
Criteria
●
Medical History
●
Hunter Syndrome 
Diagnosis and Genotype
●f
Echocardiogramd
●
Physical and Neurological 
Examination
●
●
●
Height and Weight
●
●
●
Head Circumference
●
●
●
Hearing Assessment
●
●e
●
Neurodevelopmental 
Assessment
●
●e
●
12-lead ECG
●
●
●
Vital Signs
●
●
●
Clinical Laboratory Tests
(Hematology, Serum 
Chemistry, Urinalysis)
●
●
●
General Anesthesia
●
●
Urine GAG and creatinine
●
●
●
Anti-idursulfase Antibody 
Testing (serum)
●
●
●
Anti-idursulfase Antibody 
Testing 
●
●
Brain MRI
●
●
ICP measurement (by 
lumbar puncture)
●
●
CSF Sample Collectionc
●
●
Randomization 
●b
Health status 
Questionnaire 
●
●
Concomitant Medications, 
Therapies/Interventions, 
Medical/Surgical 
Procedures
●
●
●
●
●
●
●
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Month -1
Month 0
Months 1 to 12
Month 
13
Follow-up
Weeks -4 
to -1
Screening
Day -28 to 
-1 
Week 0
Randomization, 
Week 2
(+7 days)
Weeks 4, 8, 12, 16, 
20, 24, 28, 32, 36, 
40, 44, 48 
(± 7 days)
Week 
52
End of 
Study 
(EOS) 
(±7 
days)
7 (±2) 
Days Post 
EOS 
Weeks 
4, 16, 
28 40
Weeks 8, 
12, 20, 24, 
32, 36, 44, 
48
Assessment
Day -28 to 
Day -1
Day 0
Telephone
Telephone
Telephone
Adverse Events
●
●
●
●
●
●
●
Abbreviations:  CSF = cerebrospinal fluid; ECG = electrocardiogram; GAG = glycosaminoglycan; ICP = 
intracranial pressure; MRI = magnetic resonance imaging.
a
Informed consent (and patient assent, if applicable) must be obtained from the patient’s parent(s)/legally 
authorized guardian(s) before beginning Screening procedures.
b
Patients will be randomized after they have completed Screening assessments and met all eligibility 
criteria.  The day of randomization is Day 0.
c
The CSF sample will be obtained via lumbar puncture and while the patient is under general anesthesia. 
The samples will be used to analyze standard laboratory parameters (chemistries, cell counts), as well as
concentration of idursulfase enzyme, GAG, albumin, and presence of idursulfase-specific antibodies. 
d
This assessment will not need to be performed if an echocardiogram taken within 3 months of study start 
is available and deemed satisfactory for evaluation of anesthesia risk. 
e
These neurodevelopmental and hearing assessments will be performed at Weeks 16, 28, 40 (±7 days).
f
The results of patients’ genotype analyses must be known prior to randomization (see Section 7.3.1).
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Appendix 4
Expected Adverse Device Effects
A list of the adverse effects expected with the SOPH-A-PORT Mini S is reproduced below from 
the device’s IFU.
Procedure-Related Complications

Components handled improperly before, during, or after implantation 

Access port implanted incorrectly

Catheter positioned improperly

Injection through septum performed incorrectly

Injection of incorrect medication through access port

Injection outside the access port into pocket or subcutaneous tissue or extravasation

Pocket seroma, hematoma, erosion, or infection
Intrathecal Access Complications

Surgical complications such as hemorrhage or hematoma

Infection of the implant site or catheter track

Radiculitis or arachnoiditis

Intrathecal space infection resulting in meningitis or encephalitis

Bleeding 

Spinal cord damage or trauma to the spinal cord or nerve roots

Post-lumbar puncture, cerebrospinal fluid (CSF) leak, leading to headache, or 
subcutaneous CSF collection

Epidural instead of intrathecal placement of catheter

Inflammatory mass resulting in neurological impairment, including paralysis

Pain on injection

Complications of anesthesia

Pseudomeningocele
System-Related Complications

Improperly positioned access port

Erosion of the skin because of the underlying access port or the catheter

Wound dehiscence

Access port migration, fracture, breakage or occlusion

Catheter damage, dislodgement, migration, disconnection, kinking or occlusion, fibrosis, 
or hygroma, resulting in tissue damage or a loss of or change in therapy, or other 
potentially serious adverse health consequences

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
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
Component failure, resulting in loss of therapy

Access port inversion (“flipping”), rotation, or extrusion

Access port or catheter rejection 

Fibrin sheath formation around catheter tip
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Appendix 5
Protocol Amendment Summary of Changes
AMENDMENT SUMMARY AND RATIONALE 
Clinical protocol HGT-HIT-094 has been amended from the previous version as follows:

To allow for the enrollment of approximately 48 patients based on a blinded variability 
assessment (BVA). In accordance with the study protocol, after 35 patients were 
randomized, and prior to enrollment closure, a blinded assessment of overall variability 
for the primary and key secondary endpoints was made by estimating the pooled standard 
deviation (SD) for each endpoint. The BVA was performed by an external, independent 
statistician who is not involved in the final analysis of this study. Based on this 
assessment, it did not appear that the variability was consistent with the original 
assumption used in the sample size calculation; therefore, the sample size was increased 
from 42 to approximately 48 patients. The sample size re-calculation was identical to the 
original calculation except that the estimate of the common standard deviation used for 
the primary and/or key secondary endpoint was revised upward based on the pooled SD 
assessment. As there was no treatment comparison involved, no inflation of the type-I 
error from this procedure was expected, and no adjustment to the significance levels for 
the final analysis was necessary. The results of the BVA support the increase in sample 
size being implemented by this amendment. However, given that uncertainty around the 
variance estimate remains, a second BVA using the same approach as specified above is 
planned to confirm it after approximately 27 patients complete the Week 52 primary 
endpoint assessment. Based on this second blinded assessment, the sample size may be 
increased to a maximum of 54 patients while maintaining the 2:1 allocation ratio.

To remove the portion of inclusion criterion #1 requiring that Spanish-speaking patients 
who are to be assessed using the Spanish version of the DAS-II be <7 years 8 months of 
age at the time of informed consent. Because a Spanish version of the DAS-II School 
Age Years instrument has become available for use in the study, this restriction is no 
longer necessary. 

To align the protocol text with changes (clarification concerning conduct of the follow-up 
contact by telephone and change to medical monitor contact information) which were 
implemented previously by administrative memo.

To modify the planned statistical analysis to allow for the exploratory subgroup analyses 
of efficacy by language and geographic region requested by the FDA.

To update text pertaining to the SOPH-A-PORT Mini S IDDD for consistency with other 
Shire protocols utilizing this device for intrathecal drug delivery.

To clarify aspects of the study schedule pertaining to analysis of CSF and serum samples

To clarify text concerning the management of infusion-related reactions.

To include the EudraCT number on the protocol cover page.
.
DETAILED SUMMARY OF CHANGES FOR THE AMENDMENT 4
This is a section that has been updated to describe significant changes from the original protocol 
version.  Noteworthy changes and additions to the protocol text are captured below. Bold text 
indicates new 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), and refinements to the introductory text, list of abbreviations and 
cross references are not reflected in this change summary.
Change:  addition of EudraCT number
Section impacted by this change:  Cover page
Revised Text: 
EudraCT Number: 2013-002885-38
Other sections impacted by this change:  None
Change:  change to medical monitor contact
Section impacted by this change:  Cover page
Revised Text: 
Medical Monitor: 
, MD, PhD
, DO
Other sections impacted by this change:  7.14.5.2 Reporting Serious Adverse Events
Change:  clarification concerning study population
Section impacted by this change:  Synopsis
Revised Text: 
Pivotal study – approximately 48 42 male patients (about 28 32 treated, 14 16 untreated) are planned.
Substudy - enrollment of patients below 3 years of age into the separate substudy will be considered 
additional to the 42 number of patients planned for the pivotal study, and will conclude when enrollment of 
patients in the pivotal study closes. 
Other sections impacted by this change:  5.1 Study Population
Change:  clarification to study design
Section impacted by this change:  Synopsis
Revised Text: 
The pivotal study design is “no IT treatment-controlled”. Approximately 48 patients will be randomized in 
a 2:1 ratio to IT treatment or no IT treatment arms. in that 28 patients are assigned randomly to receive IT 
treatment and 14 patients are assigned randomly to participate without receiving IT treatment. 
Other sections impacted by this change:  4.1 Overall Study Design and Plan
Change:  clarification concerning performance of follow-up telephone contact
Section impacted by this change:  Synopsis
Revised Text: 
All Patients will complete EOS assessments at Week 52 (Visit Month 13) and will participate in a follow-up 
contact (by telephone) approximately 7 days after the EOS visit. (Note that for those patients who enroll 
in extension study SHP-609-302 within the 7 ±2 day window of the EOS visit the follow-up contact is 
not required. If, however, a patient is not enrolled in the SHP-609-302 study within the 7 ±2 day 
window of the EOS visit, then the follow-up contact should be completed.)
Other sections impacted by this change:  7 Study Procedures, 8.5.1 Patients in the Pivotal Study and 
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Substudy
Change:  Elimination of age restriction for inclusion of Spanish-speaking patients
Section impacted by this change:  Synopsis
Revised Text: 
1.
The patient is male and is ≥3 and <18 years of age at the time of informed consent. Spanish
speaking patients who are to be assessed using the Spanish version of the DAS II Early Years must 
be <7 years 8 months of age at the time of informed consent.
Other sections impacted by this change:  5.2.1 Inclusion Criteria for the Pivotal Study
Change:  Change in cognitive testing of Spanish-speaking patients
Section impacted by this change:  Synopsis
Revised Text: 
Efficacy Assessments:
Neurodevelopmental status will be assessed over time by measuring cognitive and adaptive functions as 
follows:
Cognition: the Differential Ability Scales, Second Edition (DAS-II) will be used to assess all patients 
randomized in the pivotal study. Only the DAS II Early Years (Spanish version) will be used for assessment 
of eligible Spanish speaking patients.
Other sections impacted by this change:  7.9.1 Neurodevelopmental assessment Tools
Change:  Clarification concerning the IDDD
Section impacted by this change:  6.1.2 Intrathecal Drug Delivery Device
Revised Text: 
The investigational product will be administered via the SOPH-A-PORT Mini S Implantable Access Port. 
The SOPH A PORT Mini S is intended for long term, intermittent access to the IT space for delivery of 
investigational product. The device is CE marked in the European Union (EU). 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.
Other sections impacted by this change:  None
Change:  Clarification concerning infusion-related reactions
Section impacted by this change:  6.6.1 Infusion Reactions and Management
Revised Text: 
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 
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or develop post-injection over time.
The management of infusion reactions and hypersensitivity reactions is similar. The following steps 
may be taken, at the discretion of the Investigator, in the event of a suspected infusion 
related/hypersensitivity reaction and the management of such reactions should be based on the 
severity of the reaction:

Treatment with medications such as antihistamines, antipyretics, and/or corticosteroids

Stopping and resuming treatment

Pretreatment with antihistamines and/or corticosteroids may prevent subsequent reactions in 
those cases where symptomatic treatment was required
Infusion-related reactions have been observed in patients receiving IV enzyme replacement therapy (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). Pretreatment 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 pre-treatment with low-dose corticosteroids 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. 
Because idursulfase IT is administered intrathecally, it is not expected that systemic blood levels will be 
high enough to cause an infusion related reaction. 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. 
Other sections impacted by this change:  None
Change:  Clarification to activity restrictions for patients with an implanted IDDD
Section impacted by this change:  6.7.3 Patient Activity Restrictions
Revised Text: 
Please refer to the SOPH-A-PORT Mini S IFU for details regarding patient activity restrictions for patients 
to be implanted with this device. Activities that may include sudden, excessive, or repetitive bending, 
twisting, bouncing, or stretching can damage or dislodge IDDD components and should be avoided.
Other sections impacted by this change:  None
Change:  Clarification concerning treatment compliance
Section impacted by this change:  6.8 Treatment Compliance
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Revised Text: 
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 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 IFU for further details.
Other sections impacted by this change:  None
Change:  Clarification concerning serum albumin  assessment
Section impacted by this change:  7.8.2 CSF and Serum Albumin
Revised Text: 
Albumin levels will be measured in samples of CSF and serum (refer to the SOE for the pivotal study 
(Appendix 1 and Appendix 2) and separate substudy (Appendix 3) to monitor the permeability of the blood-
brain barrier. Measurement of albumin levels in serum is included in the panel of clinical laboratory 
tests (Table 7-2).
Other sections impacted by this change:  Appendix 1 Schedule of Events for Patients Randomized to 
Treatment in the Pivotal Study, Appendix 2 Schedule of Events for Patients Randomized to No Treatment 
in the Pivotal Study, Appendix 3
Schedule of Events for Patients Enrolled in the Substudy
Change:  Clarification to CSF assessment
Section impacted by this change:  7.11.10 Cerebrospinal Fluid Assessments
Revised Text: 
Cerebrospinal fluid samples will be collected via the IDDD or lumbar puncture and used to analyze standard 
safety laboratory parameters (chemistries [including protein, glucose], cell counts), albumin, GAG, and 
concentration of idursulfase enzyme.
Other sections impacted by this change:  None
Change:  Clarification to study activities
Section impacted by this change:  8.1.1 All Patients in the Pivotal Study and Substudy
Revised Text: 

CSF sample collection (by lumbar puncture). CSF samples will be used to analyze standard 
laboratory parameters (chemistries, cell counts), as well as GAG, concentration of idursulfase 
enzyme, albumin, and presence of idursulfase-specific antibodies.

Albumin (serum and CSF) 
Other sections impacted by this change:  8.3.2.1 Pre-treatment 8.4.1
Patients in the IT Treatment Group 
of the Pivotal Study and All Patients in the Substudy, 8.4.2
Patients in the No IT Treatment Group of the 
Pivotal Study
Change:  Change on sample size based on results of a planned blinded variability assessment
Section impacted by this change:  10.2 Determination of Sample Size
Revised Text: 
Using a 2:1 allocation ratio, a sample size of 42 approximately 48 randomized patients (about 28 32 IT 
treated patients, 14 16 no IT control patients) will yield 80% power to detect a clinically meaningful mean 
treatment difference of 11 points in the primary endpoint, GCA change from baseline to Visit Week 52. This 
calculation further assumes a common standard deviation for the change from baseline of 10 11.6 points, a 
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type-I error rate of 0.05 for a two-sided two-sample t-test, with approximately up to 20 10% missing an 
assessment at Visit Week 52. Given this sample size, and conditional on rejection of the null hypothesis for 
the primary endpoint, the power would be 80% to detect a clinically meaningful mean difference of 14.5 10
points in the key secondary endpoint, assuming a common standard deviation for the change from baseline 
of 13.5 10.5 points for a two-sided two-sample t-test with a significance level of 5% and 20 10% missing an 
assessment at Visit Week 52. The variance estimate for this sample size was determined based on a 
blinded variability assessment (BVA) performed as specified in the prior protocol version 
(Amendment 3); refer to Appendix 5 for details. Given that uncertainty around this variability 
estimate remains, a second BVA using the same approach as specified in Appendix 5 is planned to 
confirm the estimate after approximately 27 patients complete the Week 52 primary endpoint 
assessment. Based on this second blinded assessment, the sample size may be increased to a maximum 
of 54 patients while maintaining the 2:1 allocation ratio.
After approximately 36 patients have been randomized, and prior to enrollment closure, a blinded 
assessment of overall variability for the primary and key secondary endpoints will be made by estimating 
the pooled standard deviation (SD) for each endpoint. The blinded variability assessment will be performed 
by an external, independent statistician who is not involved in the final analysis of this study. If it does not 
appear that the variability is consistent with the assumptions used in the sample size calculation, the Sponsor 
may consider increasing the sample size by amending the protocol. The sample size re calculation in this 
case would be identical to the original calculation except that the estimate of the common standard deviation 
used for the primary and/or key secondary endpoint would be revised upward based on the pooled SD 
assessment. As there is no treatment comparison involved, no inflation of the type I error from this 
procedure is expected, and no adjustment to the significance levels for the final analysis is necessary.
Other sections impacted by this change:  None
Change:  Clarifications to exploratory analyses
Section impacted by this change:  10.5.4 Exploratory Analyses
Revised Text: 
A subgroup analysis will be performed for baseline GCA groups. For this analysis, patients with a baseline 
GCA score of greater than 70 will be classified as having “Moderate” cognitive impairment, while patients 
with a baseline GCA score equal to or below 70 will be classified as having “Severe” cognitive impairment. 
The randomization is stratified by this classification variable to ensure treatment group balance within these 
subgroups. Similar exploratory subgroup analyses may be performed for age group (either ≤6 years or >6 
years), native language, geographic region (Spanish versus English speaking region) or other baseline 
factors using MMRM.
A linear random coefficients model (ie, random slope and intercept for continuous time) will be fit for 
the primary and key secondary endpoints if appropriate. The average of the subject-specific slope 
estimates from the model will be compared between treatment groups using the two-sample t-test. To 
explore the relationship between composite scores and their components, correlations between the GCA and 
ABC scores (absolute value and change from baseline) and their respective domain scores will be estimated. 
Scatter plots will also be presented.
Other sections impacted by this change:  None
Change:  Clarification to analysis of IDDD performance
Section impacted by this change:  10.7.7.3 Device Performance
Revised Text: 
The number and proportion of patients for whom a successful first injection of study drug occurred will be 
summarized among those for whom a first injection was attempted (ie, those who had an apparently 
successful implantation and did not suffer a device removal or revision prior to first scheduled injection). 
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The number and proportion of patients who had no failed injection attempts during the study and the total 
number of successful injections will also be summarized. Injections not given for patient reasons (eg, patient 
uncooperative, competing medical issue, etc) will not be included in the determination of these estimates.
The rate of successful IDDD injections will be calculated for each patient and summarized 
descriptively. The IDDD 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. 
Other sections impacted by this change:  None
Change:  Clarification concerning serum albumin assessment
Section impacted by this change: Appendix 1
Schedule of Events for Patients Randomized to Treatment 
in the Pivotal Study
Revised Text: 
Serum albumin
Other sections impacted by this change:  Appendix 2 Schedule of Events for Patients Randomized to No 
Treatment in the Pivotal Study, Appendix 3 Schedule of Events for Patients Enrolled in the Substudy
Change:  Change to footnote
Section impacted by this change:  Appendix 1
Schedule of Events for Patients Randomized to Treatment 
in the Pivotal Study
Revised Text: 
Cerebrospinal fluid samples will be collected via the IDDD or lumbar puncture and used to analyze standard 
laboratory parameters (chemistries, cell counts), as well as albumin, GAG, concentration of idursulfase 
enzyme, GAG, albumin, and presence of idursulfase-specific antibodies. Analyses of CSF samples for 
antibodies and albumin will be performed at Screening, IT Dosing Weeks 4, 16, 28, and 40, and at 
Week 52 (EOS).
Other sections impacted by this change:  Appendix 3 Schedule of Events for Patients Enrolled in the 
Substudy
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