Clinical trial NCT02412787
Conditions: Hunter Syndrome
Sponsor: Shire
Start date: 2015-04-14; Completion date: 2024-04-18
Enrollment: 56 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This extension study will allow participants that completed Study HGT-HIT-094 to continue receiving Elaprase treatment in conjunction with idursulfase IT or to continue receiving Elaprase treatment and begin concurrent IT treatment for those that did not receive idursulfase IT treatment in Study HGT-HIT-094.

Detailed description:

Arms: arm 1: Participants received 10 milligrams (mg) of idursulfase-IT intrathecally via intrathecal drug delivery device (IDDD) or lumbar puncture (LP) once every 28 days along with standard-of-care therapy with Elaprase, for 470 weeks (for participants who began intrathecal \[IT\] treatment in this study) and 480 weeks (for participants who began IT treatment in HGT-HIT-094 and continued to receive IT treatment in this study). Participants who were younger than 3 years of age received an adjusted dose of 7.5 mg (\>8 months to 30 months of age) or 10 mg (\>30 months to 3years of age) of idursulfase-IT.
Interventions: intervention 1: Idursulfase-IT intervention 2: Elaprase
Intervention descriptions: intervention 1: Participants received 10 mg of idursulfase-IT intrathecally via IDDD or LP once every 28 days. Participants who were younger than 3 years of age received an adjusted dose of 7.5 mg (\>8 months to 30 months of age) and 10 mg (\>30 months to 3 years of age). intervention 2: Participants received intravenous (IV) Elaprase infusions at a minimum of 48 hours after IT administration of idursulfase-IT.

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


Clinical Trial Protocol: SHP609-302
Study Title:
An Open Label Extension of Study HGT-HIT-094 Evaluating Long 
Term Safety and Clinical Outcomes of Intrathecal Idursulfase 
Administered in Conjunction with Elaprase® in Patients with Hunter 
Syndrome and Cognitive Impairment
Study Number:
SHP609-302
Study Phase:
II/III
Product Name:
Idursulfase for intrathecal use (idursulfase-IT [HGT-2310])
Device Name:
SOPH-A-PORT® Mini S, Implantable Access Port, Spinal, Mini 
Unattached, with Guidewire 
IND Number:
100,610
EUDRACT Number
2014-004143-13
Indication:
Long-term treatment of Hunter syndrome in patients with cognitive 
impairment to slow progression of cognitive and functional 
impairment
Investigators:
Multicenter
Sponsor:
Shire Human Genetic Therapies, Inc. (Shire)
Sponsor Contact:
300 Shire Way
Lexington, MA  02421 USA
+1-617-349-0200
Medical Monitor:
, DO
Date
Original Protocol:
02 October 2014
Administrative Change 1
25 November 2014
Administrative Change 2
13 January 2015
Amendment 1
09 March 2015 
Administrative Change 3
05 May 2015
Administrative Change 4
02 November 2015
Amendment 2
25 May 2016
Administrative Change 5
03 August 2016
Amendment 3
28 February 2017
Amendment 4
09 October 2018
Confidentiality Statement
This document is the proprietary and confidential property of Shire.
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SYNOPSIS
Sponsor:
Shire Human Genetic Therapies, Inc. (Shire)
Name of Investigational Product:
Idursulfase for intrathecal use (idursulfase-IT [HGT-2310])
Name of Device:
SOPH-A-PORT® Mini S, Implantable Access Port, Spinal, Mini Unattached, with 
Guidewire (SOPH-A-PORT Mini S)
Study Title:
An Open Label Extension of Study HGT-HIT-094 Evaluating Long Term Safety and 
Clinical Outcomes of Intrathecal Idursulfase Administered in Conjunction with Elaprase®
in Patients with Hunter Syndrome and Cognitive Impairment
Study Number:
SHP609-302
Study Phase: II/III
Investigational Product, Dose, and Mode of Administration: 
idursulfase-IT, 10 mg, intrathecal (IT)
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 indicated for intrathecal delivery intermittently over a long period of time.
Comparator, Dose, and Mode of Administration:
Not applicable.
Primary Objective: 
The primary objective of this study is to evaluate long-term safety in subjects with Hunter 
syndrome and cognitive impairment who are receiving intrathecal idursulfase-IT and 
intravenous (IV) Elaprase® enzyme replacement therapy (ERT).
Secondary Objectives:
The secondary objectives of this study are to evaluate long-term clinical efficacy 
outcomes in subjects with Hunter syndrome and cognitive impairment who are treated 
with idursulfase-IT in conjunction with Elaprase therapy with respect to the following:
•
Cognitive function as measured by General Conceptual Ability (GCA), the cluster
areas and subtests of the Differential Abilities Scale, Second Edition (DAS-II), or
domains of the Bayley Scales of Infant Development, Third Edition (BSID-III)
•
Adaptive behavior as measured by the Adaptive Behavior Composite (ABC) score
and standard domain scores of the Vineland Adaptive Behavior Scales, Second
Edition (VABS-II)
•
Brain structure volume as measured by magnetic resonance imaging (MRI)
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Pharmacokinetic and Pharmacodynamic Objectives:
•
To evaluate the concentration of idursulfase and determine PK parameters in serum 
after IT administration in subjects with Hunter syndrome and cognitive impairment 
who are treated with idursulfase-IT in conjunction with Elaprase therapy
•
To evaluate the concentration of idursulfase in CSF in subjects with Hunter syndrome 
and cognitive impairment who are treated with idursulfase-IT in conjunction with 
Elaprase therapy
•
To evaluate the concentration of glycosaminoglycan (GAG) in CSF in subjects with 
Hunter syndrome and cognitive impairment who are treated with idursulfase-IT in 
conjunction with Elaprase therapy
•
To evaluate the concentration of GAG in urine in subjects with Hunter syndrome and 
cognitive impairment who are treated with idursulfase-IT in conjunction with Elaprase 
therapy
Health Economics and Outcomes Research Objectives:
•
To evaluate health status as measured by the EuroQol-5D-5L (EQ-5D-5L) instrument, 
in subjects with Hunter syndrome and cognitive impairment who are treated with 
idursulfase IT in conjunction with Elaprase therapy
•
To evaluate healthcare resource utilization, as measured by the Healthcare Utilization
Questionnaire (HCUQ) in subjects with Hunter syndrome and cognitive impairment 
who are treated with idursulfase IT in conjunction with Elaprase therapy
•
To evaluate the social/emotional, physical, daily activities and financial impact on 
caregivers and families of subjects with Hunter syndrome and cognitive impairment as 
measured by Caregiver Impact Questionnaire (CIQ)
•
To evaluate functional status as measured by the HS-FOCUS (Hunter Syndrome 
Functional Outcomes for Clinical Understanding Scale) instrument, in subjects with 
Hunter syndrome and cognitive impairment who are treated with idursulfase-IT in 
conjunction with Elaprase therapy
SOPH-A-PORT Mini S Objective:
•
To evaluate the safety and performance of the SOPH-A-PORT Mini S
Study Endpoints: 
The primary safety endpoints of this study are the following:

Adverse events (AEs; by type, severity, and relationship to treatment [idursulfase-
IT, the intrathecal drug delivery device (IDDD), device surgical procedure, or IT 
administration process] and IV Elaprase infusion)

Changes in clinical laboratory testing (serum chemistry, hematology, urinalysis)

Vital signs

Twelve-lead ECG recordings

CSF laboratory parameters (chemistries, cell counts)

Anti-idursulfase antibodies in CSF and serum, including determination of 
anti-idursulfase antibodies having enzyme neutralizing activity
The secondary efficacy endpoints of this study are the following:

Change from baseline in DAS-II standard scores: GCA, Special Nonverbal 
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Composite (SNC); and cluster scores:  Verbal, Nonverbal, Spatial; and/or the age 
equivalents and Development Quotient (DQ) from the BSID-III domains: 
Cognitive and Language

Change from baseline in standard composite scores of the VABS-II: ABC and 
domain standard scores: Communication, Daily Living Skills, Socialization, and 
Motor Skills

Change from baseline in age equivalents, developmental quotients, and T-scores 
for the core 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 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 in the v-Scale scores and observed maladaptive levels of the 
VABS-II Maladaptive Behavior Index and its subscales (Internalizing, 
Externalizing)

Change from baseline in Brain Total Intracranial Volume, Brain Total Tissue 
Volume, Brain Total White Matter, Brain Total Gray Matter, and Total CSF 
Volume
The exploratory efficacy endpoints of this study are the following:

Change from Visit Month 13/baseline to Visit Month 25/Week 52 in study 
SHP609-302 as estimated by linear regression in:
o
DAS-II GCA scores from Early Years battery
o
DAS-II Early Years core subtests T scores: Verbal Comprehension, Picture 
Similarities, Naming Vocabulary, Pattern Construction, Matrices, and 
Copying
o
DAS-II Early Years battery standard cluster scores: Verbal, Nonverbal, 
Spatial, and SNC composite scores
o
DAS-II GCA scores including both Early Years and School Age batteries
o
VABS-II ABC scores
Note that the interval from Visit Month 13/baseline to Visit Month 25/Week 52 in 
study SHP609-302 is defined as from Visit Month 13 to Visit Month 25 in SHP609-
302 Extended Treatment Phase for subjects in the Early IT group, and from baseline 
in study SHP609-302 to Visit Week 52 in SHP609-302 Initial Treatment Phase for 
subjects in the Delayed IT group. The Early IT group and Delayed IT group 
designations are based on the treatment regimen (idursulfase-IT or No IT treatment) in 
the antecedent study (HGT-HIT-094).

Ordered categorical outcome for each subject at study SHP609-302 Visit Month 
25/Week 52
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
Binary unreversed floor effect outcome for each subject
The health economics and outcomes research endpoints of this study are the following:

Health status dimensions as obtained by the EQ-5D-5L questionnaire

Health care resource utilization will be assessed using the HCUQ

Health-related quality of life for caregivers will be assessed using the CIQ

Functional status as obtained by the HS-FOCUS form
The pharmacokinetic and pharmacodynamic endpoints of this study are the following:

Serum concentration of idursulfase and serum PK parameters after IT 
administration

CSF concentration of idursulfase 

Change from baseline in the concentration of GAG in CSF

Change from baseline in the concentration of GAG in urine
Study Population: 
Pediatric subjects (plus potentially any pediatric subjects younger than 3 years of age in 
the antecedent substudy) who completed Study HGT-HIT-094, and meet the eligibility 
criteria may enroll in this study.
Study Design:
This is an open-label, non-randomized study for subjects who completed Study 
HGT-HIT-094; all subjects in this study will be treated with intrathecal idursulfase-IT in 
conjunction with Elaprase therapy. 
Subjects who complete Visit Week 52 assessments of Study HGT-HIT-094 and who meet 
the eligibility criteria and for whom informed consent is provided will be enrolled in this 
extension study. 
All subjects will receive idursulfase-IT at the same dose and frequency (10 mg once every 
28 days) as selected for the HGT-HIT-094 study. Subjects who are younger than 3 years 
of age will continue to receive an adjusted dose. 
The assessments in this study are similar to those performed in Study HGT-HIT-094 and 
will be performed at regular intervals; the frequency of assessments will vary depending 
on the treatment phase of the study (Initial Treatment Phase or Extended Treatment 
Phase). 
Subjects who participated in the control arm (no treatment with idursulfase-IT) in 
Study HGT-HIT-094 will begin this study in the Initial Treatment Phase. These subjects 
will have the IDDD implanted following enrollment in order to begin treatment with 
idursulfase-IT. These subjects will, during the Initial Treatment Phase of this study (ie, the 
first 12 months), undergo treatment and assessments similar to those performed for 
subjects who were treated with idursulfase-IT in Study HGT-HIT-094. After completion 
of the Initial Treatment Phase and if there are no safety concerns, subjects may continue 
receiving monthly idursulfase-IT in the Extended Treatment Phase of this study.
Subjects who received treatment in the HGT-HIT-094 study will begin this study in the 
Extended Treatment Phase, which reflects a reduced frequency of assessments compared 
with the schedule of assessments in Study HGT-HIT-094. Standardized 
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neurodevelopmental assessments and health economic and outcomes research assessments 
will be performed every 24 weeks and CSF assessments (other than standard chemistry) 
and clinical laboratory tests of blood and urine will be performed every 12 weeks. Brain 
MRI and 12-lead ECG will be performed every 48 weeks. A pharmacokinetic assessment 
will be performed once during this phase of the study. All subjects in the study will 
undergo EOS procedures approximately 28 days following their last administration of 
idursulfase-IT.
It is anticipated that the IDDD will be used to obtain cerebrospinal fluid (CSF) samples 
and to deliver all intrathecal (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(s), which provides details on the investigation and management 
of any IDDD-related issues. This includes possible partial revision or complete 
replacement of the IDDD as indicated. If the IT space is not accessible via the IDDD, 
study drug may be administered and CSF sampled by lumbar puncture (LP). General 
anesthesia or sedation may be required for injections of study drug and some evaluations, 
and can be used at the discretion of the Investigator as indicated in the study manuals. 
Subjects will have the IDDD removed when they discontinue from or complete the study, 
unless the subject is continuing to receive treatment through another mechanism (eg,
extension study, expanded access program).
Study Duration:
Subjects will participate in this extension study for a duration of 10 years of treatment, 
unless they discontinue the study or Shire discontinues the study.
Study Inclusion and Exclusion Criteria:
Each subject must meet the following criteria to be enrolled in this study:
1. Subjects must have completed Visit Week 52 assessments in Study HGT-HIT-094.
2. The subject’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 subject’s parent(s) or legally authorized guardian(s) and the 
subject’s consent/assent, as relevant, must be obtained.
3. The subject has continued to receive Elaprase on a regular basis in Study 
HGT-HIT-094.
Subjects who meet any of the following criteria will be excluded from the study:
1. The subject has experienced, in the opinion of the Investigator, a safety or medical 
issue that contraindicates treatment with idursulfase-IT, including, but not limited to, 
uncontrolled seizure disorder, bleeding disorder, and clinically relevant hypertension
2. The subject has a known hypersensitivity to any of the components of idursulfase-IT
3. The subject has clinically relevant intracranial hypertension
4. The subject is enrolled in another clinical study, other than HGT-HIT-094, that 
involves clinical investigations or use of any investigational product (drug or 
[intrathecal/spinal] device) within 30 days prior to study enrollment or at any time 
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during the study
5. The subject 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.
6. The subject has a condition that is contraindicated as described in the SOPH-A-PORT 
Mini S IDDD Instructions for Use, including:
a.
The subject has had, or may have, an allergic reaction to the materials of 
construction of the SOPH-A-PORT Mini S device
b. The subject’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 subject’s drug therapy requires substances known to be incompatible with the 
materials of construction 
d. The subject has a known or suspected local or general infection
e.
The subject is at risk of abnormal bleeding due to a medical condition or therapy
f.
The subject has 1 or more spinal abnormalities that could complicate safe 
implantation or fixation
g. The subject has a functioning CSF shunt device
h. The subject has shown an intolerance to an implanted device
Pharmacokinetic Variables:
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 
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 and urine samples.
Efficacy Assessments:
Neurodevelopmental status will be assessed over time by measuring cognitive and 
adaptive functions as follows:
•
The DAS-II will be used to assess all subjects of age 2 years, 6 months or older. 
•
Any subjects who cannot be assessed with the DAS-II due to a deteriorating condition 
or who are younger than 2 years, 6 months of age, will be assessed with the BSID-III. 
Spanish-speaking subjects will be assessed using the Spanish version of the DAS-II 
Early Years or DAS-II School Age. 
•
The VABS-II will be used to assess adaptive behavior.
Brain structure volumes will be measured by brain MRI.
SOPH-A-PORT Mini S Device Assessments:
The SOPH-A-PORT Mini S will be evaluated using assessments of device implantation, 
device function, device longevity, and AEs associated with the implant surgery or device. 
This data will be collected on the subject’s eCRF from the time of initial implantation.
Safety Assessments:
Safety will be assessed by AEs (by type, severity, and relationship to treatment 
[idursulfase-IT, IDDD, device surgical procedure, IT administration process], IV Elaprase 
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infusion, IV Elaprase and/or idursulfase-IT), changes in clinical laboratory testing (serum 
chemistry, hematology, urinalysis), AEs determined from physical and neurological 
examination, vital signs, 12-lead ECG recordings, CSF laboratory parameters 
(chemistries, cell counts), anti-idursulfase antibodies in CSF and serum (including 
determination of antibodies having enzyme neutralizing activity).
Statistical Methods: 
Statistical analyses will be performed by the Biostatistics and Statistical Programming 
Department of Shire or its designee using SAS statistical software (SAS Institute, Cary, 
NC, USA), unless otherwise specified. Analysis methods will be detailed in the statistical 
analysis plan (SAP). 
Data from studies SHP609-302 and HGT-HIT-094 will be integrated for efficacy and 
safety analyses. Baseline for the subjects previously treated in HGT-HIT-094 will be the 
same as the baseline defined in HGT-HIT-094. Baseline for the previously untreated 
subjects (ie, No IT treatment) in HGT-HIT-094 will be the closest available assessment 
prior to the initial IDDD implant date, which takes place in Study SHP609-302, unless 
otherwise specified. This could potentially include EOS visit data from Study 
HGT-HIT-094. The analyses presented here will include the data measured at and after 
baseline. 
Safety data descriptive summaries will be presented for the Early IT group, Delayed IT 
group, and overall. The Early IT group and Delayed IT group designations are based on 
the treatment regimen (idursulfase-IT or No IT treatment) in the antecedent study
(HGT-HIT-094). The Early IT group is defined as subjects who were randomized to the
idursulfase-IT treatment cohort in study HGT-HIT-094 and continued IT treatment in 
study SHP609-302. The Delayed IT group is defined as subjects who were randomized to 
the control cohort (No IT treatment) in study HGT-HIT-094 and began IT treatment in 
study SHP609-302. Subjects who participated in the HGT-HIT-094 substudy will be 
included in the Early IT group.
Efficacy data descriptive summaries will be presented separately for subjects who 
enrolled from the pivotal study or substudy of HGT HIT 094. For subjects enrolled from 
the pivotal study, descriptive statistics will be presented by the Early IT group, the 
Delayed IT group and overall. For secondary efficacy endpoints, the mean difference in 
the change at each time point between the 2 treatment groups (Early IT group and 
Delayed IT group) and the corresponding 90% confidence interval of the mean difference 
will be presented where appropriate. The mean values (±SD) for all efficacy endpoints 
will be graphed over time where appropriate.
Inferential testing is planned for some exploratory efficacy endpoints. The  main 
exploratory efficacy analysis to examine the IT treatment effect will be rate of change 
(weighted) analyses of the exploratory efficacy endpoints from Visit Month 13/baseline in 
study SHP609-302 to Visit Month 25/Week 52 as estimated by linear regression for DAS-
II Early Years GCA scores and selected neurodevelopment assessment scores.
Summary statistics for continuous variables will include the n, mean, standard deviation, 
median, minimum and maximum. Categorical variables will be summarized in a 
contingency table by the frequency and percentage of subjects in each category.
Date of Protocol Amendment: 09 Oct 2018
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TABLE OF CONTENTS
SYNOPSIS.......................................................................................................................................2
LIST OF IN-TEXT TABLES ........................................................................................................19
LIST OF IN-TEXT FIGURES.......................................................................................................19
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
Pharmacokinetic and Pharmacodynamic Objectives ...............................................27
2.4
Health Economics and Outcomes Research Objectives...........................................27
2.5
SOPH-A-PORT Mini S Device Objective...............................................................28
3
STUDY ENDPOINTS............................................................................................................29
3.1
Primary Safety Endpoints.........................................................................................29
3.2
Secondary Efficacy Endpoints .................................................................................29
3.3
Exploratory Efficacy Endpoints...............................................................................29
3.4
Health Economics and Outcomes Research Endpoints............................................31
3.5
Pharmacokinetic and Pharmacodynamic Endpoints ................................................31
3.6
SOPH-A-PORT Mini S Assessments ......................................................................31
4
INVESTIGATIONAL PLAN.................................................................................................32
4.1
Overall Study Design and Plan ................................................................................32
4.1.1
Initial Treatment Phase – Only Subjects Not Treated with Idursulfase-IT 
in Study HGT-HIT-094.....................................................................................33
4.1.2
Extended Treatment Phase – All Subjects ........................................................33
4.1.3
Treatment Schedule...........................................................................................33
4.2
Intrathecal Drug Delivery.........................................................................................34
4.3
Rationale for Study Design and Comparator Group ................................................34
4.4
Study Duration .........................................................................................................35
5
STUDY POPULATION SELECTION ..................................................................................36
5.1
Study Population ......................................................................................................36
5.2
Inclusion Criteria......................................................................................................36
5.3
Exclusion Criteria.....................................................................................................36
6
STUDY TREATMENTS........................................................................................................37
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6.1
Description of Treatments........................................................................................37
6.1.1
Investigational Product......................................................................................37
6.1.2
Intrathecal Drug Delivery Device.....................................................................37
6.1.3
Comparator Product ..........................................................................................37
6.2
Treatments Administered .........................................................................................38
6.3
Selection and Timing of Dose for Each Subject ......................................................38
6.4
Method of Assigning Subjects to Treatment Groups...............................................39
6.5
Blinding....................................................................................................................39
6.6
Concomitant Medications, Therapies, and Medical/Surgical Interventions ............39
6.6.1
Infusion Reactions and Management................................................................39
6.7
Restrictions...............................................................................................................40
6.7.1
Prior Therapy ....................................................................................................40
6.7.2
Fluid and Food Intake .......................................................................................41
6.7.3
Subject Activity Restrictions ............................................................................41
6.8
Treatment Compliance .............................................................................................41
6.9
Packaging and Labeling ...........................................................................................41
6.9.1
Investigational Product......................................................................................41
6.9.2
Intrathecal Drug Delivery Device.....................................................................41
6.10
Storage and Accountability......................................................................................41
6.10.1
Investigational Product......................................................................................41
6.10.2
Intrathecal Drug Delivery Device.....................................................................42
6.10.3
Comparator Product ..........................................................................................43
7
STUDY PROCEDURES........................................................................................................44
7.1
Informed Consent.....................................................................................................45
7.2
Study Entrance Criteria ............................................................................................45
7.3
Confirmation of Study Eligibility ............................................................................45
7.4
Medical History........................................................................................................45
7.5
Echocardiogram .......................................................................................................46
7.6
Device-Related Procedures ......................................................................................46
7.6.1
Intrathecal Drug Delivery Device Implantation and Revision..........................46
7.6.2
X-ray Verification of Intrathecal Drug Delivery Device Placement ................46
7.6.3
Cerebrospinal Fluid Sampling Procedure .........................................................47
7.6.4
Device Revision or Removal ............................................................................47
7.7
Investigational Product Administration ...................................................................47
7.7.1
Same-Day Investigational Administration with Elaprase Infusion...................48
7.8
Pharmacokinetic Assessments..................................................................................48
7.9
Pharmacodynamic/Biomarker Assessments ............................................................49
7.9.1
Cerebrospinal Fluid Glycosaminoglycan..........................................................49
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7.9.2
Cerebrospinal Fluid and Serum Albumin .........................................................49
7.10
Efficacy Assessments...............................................................................................49
7.10.1
Neurodevelopmental Assessment Tools ...........................................................49
7.10.1.1
Cognition................................................................................................49
7.10.1.2
Adaptive Behavior..................................................................................50
7.10.2
Brain Magnetic Resonance Imaging.................................................................50
7.11
Health Economics and Outcomes Research Assessments .......................................51
7.11.1
Health Status Assessment .................................................................................51
7.11.2
Healthcare Resource Utilization and Impact Questionnaires ...........................51
7.11.3
Functional Outcomes for Clinical Understanding Scale...................................51
7.12
Safety Assessments ..................................................................................................52
7.12.1
Physical and Neurological Examination...........................................................52
7.12.2
Height and Weight ............................................................................................52
7.12.3
Head Circumference..........................................................................................52
7.12.4
Hearing Assessment..........................................................................................52
7.12.5
Vital Signs.........................................................................................................53
7.12.6
Electrocardiography..........................................................................................53
7.12.7
Clinical and Other Laboratory Tests.................................................................53
7.12.8
Cerebrospinal Fluid Assessments .....................................................................54
7.12.9
Antibody Assessments ......................................................................................55
7.12.10
Device Assessments..........................................................................................55
7.12.11
Leachable/Extractable Assessment...................................................................55
7.12.12
Pregnancy Testing.............................................................................................55
7.13
Sample Collection, Storage, and Shipping...............................................................55
7.14
Concomitant Medications, Therapies, and Medical/Surgical Interventions 
Assessments .............................................................................................................56
7.15
Adverse Events Assessments ...................................................................................56
7.15.1
Definitions of Adverse Events and Serious Adverse Events ............................56
7.15.1.1
Adverse Event ........................................................................................56
7.15.1.2
Elaprase-related Adverse Event .............................................................57
7.15.1.3
Elaprase and/or idursulfase-IT-related Adverse Event ..........................57
7.15.1.4
Intrathecal Drug Delivery Device-related Adverse Events....................57
7.15.1.5
Device Surgical Procedure-related Adverse Events...............................57
7.15.1.6
Intrathecal Administration Process Adverse Events ..............................58
7.15.1.7
Serious Adverse Event ...........................................................................58
7.15.1.8
Unanticipated Adverse Device Effect ....................................................58
7.15.2
Device-associated Definitions...........................................................................59
7.15.2.1
Device Revision (Partial and Full).........................................................59
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7.15.2.2
Device Malfunction................................................................................59
7.15.2.3
Device Failure ........................................................................................59
7.15.2.4
Device Adjustment.................................................................................59
7.15.3
Classification of Adverse Events and Serious Adverse Events ........................59
7.15.4
Clarification between Serious and Severe.........................................................59
7.15.5
Relatedness of Adverse Events and Serious Adverse Events...........................60
7.15.6
Procedures for Recording and Reporting Adverse Events................................61
7.15.6.1
Adverse Event Monitoring and Period of Observation..........................61
7.15.6.2
Reporting Serious Adverse Events.........................................................62
7.16
Pregnancy.................................................................................................................63
7.17
Abuse, Misuse, Overdose, and Medication Error ....................................................63
7.18
Removal of Subjects from the Trial or Investigational Product...............................63
7.19
Other Study Procedures............................................................................................64
7.19.1
Safety-related Study Stopping Rules ................................................................64
7.20
Appropriateness of Measurements...........................................................................64
8
STUDY ACTIVITIES............................................................................................................66
8.1
Initial Treatment Phase (Subjects Who Were Not Treated with Idursulfase-IT 
in Study HGT-HIT-094 Only)..................................................................................66
8.1.1
Baseline (Month -1, Week -1, Days -7 to Day -1) – Initial Treatment 
Phase .................................................................................................................66
8.1.2
Confirmation of Study Eligibility (Month 0, Week 0) – Initial Treatment 
Phase .................................................................................................................67
8.1.3
Intrathecal Drug Delivery Device Implantation (Week 2 [-14, +7 Days]) 
– Initial Treatment Phase ..................................................................................67
8.1.3.1
Prior to Surgery for Intrathecal Drug Delivery Device Implantation 
– Initial Treatment Phase........................................................................67
8.1.3.2
Surgery to Implant Intrathecal Drug Delivery Device – Initial 
Treatment Phase .....................................................................................67
8.1.3.3
Follow-up to Surgery to Implant Intrathecal Drug Delivery Device –
Initial Treatment Phase...........................................................................68
8.1.4
Treatment and Assessments (Months 1-12, Weeks 4-48 [±7 Days]) –
Initial Treatment Phase .....................................................................................68
8.1.4.1
Months 1-12 (Weeks 4-48 [±7 Days]) – Prior to Intrathecal Injection 
–Initial Treatment Phase.........................................................................68
8.1.4.2
Months 1-12 (Weeks 4-48 [±7 Days]) – Intrathecal Injection – Initial 
Treatment Phase .....................................................................................69
8.1.4.3
Months 1-12 (Weeks 4-48 [±7 Days]) – Safety Follow-up for 
Intrathecal Injection – Initial Treatment Phase ......................................69
8.2
Extended Treatment Phase (All Subjects)................................................................70
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8.2.1
Month 13 (Week 52 [±7 Days]) – Extended Treatment Phase– All 
Subjects .............................................................................................................70
8.2.1.1
Month 13 (Week 52 [±7 Days]) – Prior to Intrathecal Injection –
Extended Treatment Phase – All Subjects .............................................70
8.2.1.2
Month 13 (Week 52 [±7 Days]) – Intrathecal Injection – Extended 
Treatment Phase – All Subjects .............................................................71
8.2.1.3
Month 13 (Week 52 [±7 Days]) – Safety Follow-up for Intrathecal 
Injection – Extended Treatment Phase – All Subjects ...........................71
8.2.2
Months 14, 15, 17, 18, 20, 21, 23, 24, 26, 27, 29, 30, 32, 33, 35, 36, 38, 
39, 41, 42, 44, 45, 47, 48, 50, 51, 53, 54, 56, 57, 59, 60, 62, 63, 65, 66, 
68, 69, 71, 72, 74, 75, 77, 78, 80, 81, 83, 84, 86, 87, 89, 90, 92, 93, 95, 
96, 98, 99, 101, 102, 104, 105, 107, 108, 110, 111, 113, 114, 116, 117, 
119, 120 (Weeks 56, 60, 68, 72, 80, 84, 92, 96, 104, 108, 116, 120, 128, 
132, 140, 144, 152, 156, 164, 168, 176, 180, 188, 192, 200, 204, 212, 
216, 224, 228, 236, 240, 248, 252, 260, 264, 272, 276, 284, 288, 296, 
300, 308, 312, 320, 324, 332, 336, 344, 348, 356, 360, 368, 372, 380, 
384, 392, 396, 404, 408, 416, 420, 428, 432, 440, 444, 452, 456, 464, 
468, 476, 480 [±7 Days]) – Extended Treatment Phase – All Subjects............72
8.2.2.1
Months 14, 15, 17, 18, 20, 21, 23, 24, 26, 27, 29, 30, 32, 33, 35, 36, 
38, 39, 41, 42, 44, 45, 47, 48, 50, 51, 53, 54, 56, 57, 59, 60, 62, 63, 
65, 66, 68, 69, 71, 72, 74, 75, 77, 78, 80, 81, 83, 84, 86, 87, 89, 90, 
92, 93, 95, 96, 98, 99, 101, 102, 104, 105, 107, 108, 110, 111, 113, 
114, 116, 117, 119, 120 (Weeks 56, 60, 68, 72, 80, 84, 92, 96, 104, 
108, 116, 120, 128, 132, 140, 144, 152, 156, 164, 168, 176, 180, 
188, 192, 200, 204, 212, 216, 224, 228, 236, 240, 248, 252, 260, 
264, 272, 276, 284, 288, 296, 300, 308, 312, 320, 324, 332, 336, 
344, 348, 356, 360, 368, 372, 380, 384, 392, 396, 404, 408, 416, 
420, 428, 432, 440, 444, 452, 456, 464, 468, 476, 480 [±7 Days]) –
Prior to Intrathecal Injection – Extended Treatment Phase – All 
Subjects ..................................................................................................72
8.2.2.2
Months 14, 15, 17, 18, 20, 21, 23, 24, 26, 27, 29, 30, 32, 33, 35, 36, 
38, 39, 41, 42, 44, 45, 47, 48, 50, 51, 53, 54, 56, 57, 59, 60, 62, 63, 
65, 66, 68, 69, 71, 72, 74, 75, 77, 78, 80, 81, 83, 84, 86, 87, 89, 90, 
92, 93, 95, 96, 98, 99, 101, 102, 104, 105, 107, 108, 110, 111, 113, 
114, 116, 117, 119, 120 (Weeks 56, 60, 68, 72, 80, 84, 92, 96, 104, 
108, 116, 120, 128, 132, 140, 144, 152, 156, 164, 168, 176, 180, 
188, 192, 200, 204, 212, 216, 224, 228, 236, 240, 248, 252, 260, 
264, 272, 276, 284, 288, 296, 300, 308, 312, 320, 324, 332, 336, 
344, 348, 356, 360, 368, 372, 380, 384, 392, 396, 404, 408, 416, 
420, 428, 432, 440, 444, 452, 456, 464, 468, 476, 480 [±7 Days]) –
Intrathecal Injection – Extended Treatment Phase – All Subjects.........72
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8.2.2.3
Months 14, 15, 17, 18, 20, 21, 23, 24, 26, 27, 29, 30, 32, 33, 35, 36, 
38, 39, 41, 42, 44, 45, 47, 48, 50, 51, 53, 54, 56, 57, 59, 60, 62, 63, 
65, 66, 68, 69, 71, 72, 74, 75, 77, 78, 80, 81, 83, 84, 86, 87, 89, 90, 
92, 93, 95, 96, 98, 99, 101, 102, 104, 105, 107, 108, 110, 111, 113, 
114, 116, 117, 119, 120 (Weeks 56, 60, 68, 72, 80, 84, 92, 96, 104, 
108, 116, 120, 128, 132, 140, 144, 152, 156, 164, 168, 176, 180, 
188, 192, 200, 204, 212, 216, 224, 228, 236, 240, 248, 252, 260, 
264, 272, 276, 284, 288, 296, 300, 308, 312, 320, 324, 332, 336, 
344, 348, 356, 360, 368, 372, 380, 384, 392, 396, 404, 408, 416, 
420, 428, 432, 440, 444, 452, 456, 464, 468, 476, 480 [±7 Days]) 
Safety Follow-up for Intrathecal Injection – Extended Treatment 
Phase – All Subjects...............................................................................73
8.2.3
Months 16, 22, 28, 34, 40, 43, 46, 52, 55, 58, 64, 70, 76, 82, 88, 94, 100, 
103, 106, 112, 115, 118 (Weeks 64, 88, 112, 136, 160, 172, 184, 208, 
220, 232, 256, 280, 304, 328, 352, 376, 400, 412, 424, 448, 460, 472 [±7 
Days]) – Extended Treatment Phase – All Subjects .........................................74
8.2.3.1
Months 16, 22, 28, 34, 40, 43, 46, 52, 55, 58, 64, 70, 76, 82, 88, 94, 
100, 103, 106, 112, 115, 118 (Weeks 64, 88, 112, 136, 160, 172, 
184, 208, 220, 232, 256, 280, 304, 328, 352, 376, 400, 412, 424, 
448, 460, 472 [±7 Days]) – Prior to Intrathecal Injection – Extended 
Treatment Phase – All Subjects .............................................................74
8.2.3.2
Months 16, 22, 28, 34, 40, 43, 46, 52, 55, 58, 64, 70, 76, 82, 88, 94, 
100, 103, 106, 112, 115, 118 (Weeks 64, 88, 112, 136, 160, 172, 
184, 208, 220, 232, 256, 280, 304, 328, 352, 376, 400, 412, 424, 
448, 460, 472 [±7 Days]) – Intrathecal Injection – Extended 
Treatment Phase – All Subjects .............................................................74
8.2.3.3
Months 16, 22, 28, 34, 40, 43, 46, 52, 55, 58, 64, 70, 76, 82, 88, 94, 
100, 103, 106, 112, 115, 118 (Weeks 64, 88, 112, 136, 160, 172, 
184, 208, 220, 232, 256, 280, 304, 328, 352, 376, 400, 412, 424, 
448, 460, 472  [±7 Days]) – Safety Follow-up for Intrathecal 
Injection – Extended Treatment Phase – All Subjects ...........................75
8.2.4
Months 19, 25, 31, 37, 43, 49, 55, 61, 67, 73, 79, 85, 91, 97, 103, 109, 
115 (Weeks 76, 100, 124, 148, 172, 196, 220, 244, 268, 292, 316, 340, 
364, 388, 412, 436, 460 [±7 Days]) – Extended Treatment Phase – All 
Subjects .............................................................................................................75
8.2.4.1
Months 19, 25, 31, 37, 43, 49, 55, 61, 67, 73, 79, 85, 91, 97, 103,
109, 115 (Weeks 76, 100, 124, 148, 172, 196, 220, 244, 268, 292, 
316, 340, 364, 388, 412, 436, 460 [±7 Days]) – Prior to Intrathecal 
Injection – Extended Treatment Phase – All Subjects ...........................75
8.2.4.2
Months 19, 25, 31, 37, 43, 49, 55, 61, 67, 73, 79, 85, 91, 97, 103, 
109, 115 (Weeks 76, 100, 124, 148, 172, 196, 220, 244, 268, 292, 
316, 340, 364, 388, 412, 436, 460 [±7 Days]) – Intrathecal Injection 
– Extended Treatment Phase – All Subjects ..........................................76
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8.2.4.3
Months 19, 25, 31, 37, 43, 49, 55, 61, 67, 73, 79, 85, 91, 97, 103, 
109, 115 (Weeks 76, 100, 124, 148, 172, 196, 220, 244, 268, 292, 
316, 340, 364, 388, 412, 436, 460 [±7 Days]) – Safety Follow-up for 
Intrathecal Injection – Extended Treatment Phase – All Subjects.........77
8.3
End-of-study (Month 121, Week 484 [±7 Days]) – Extended Treatment Phase 
– All Subjects ...........................................................................................................77
9
QUALITY CONTROL AND ASSURANCE ........................................................................78
10 STATISTICAL ANALYSES.................................................................................................79
10.1
General Methodology...............................................................................................79
10.2
Determination of Sample Size..................................................................................79
10.3
Method of Assigning Study Subjects to Treatment Groups.....................................80
10.4
Population Description and Exposure......................................................................80
10.4.1
Data Integration Strategy ..................................................................................80
10.4.2
Analysis Populations.........................................................................................81
10.4.3
Subject Disposition ...........................................................................................82
10.4.4
Protocol Deviations...........................................................................................83
10.4.5
Demographics and Baseline Characteristics.....................................................83
10.4.6
Treatment Compliance......................................................................................83
10.4.7
Extent of Exposure............................................................................................83
10.5
Analysis of Efficacy.................................................................................................83
10.5.1
Primary Efficacy Analysis ................................................................................83
10.5.2
Key Secondary Efficacy Analysis.....................................................................83
10.5.3
Other Secondary Efficacy Analysis ..................................................................83
10.5.4
Subgroup Analyses ...........................................................................................84
10.5.5
Exploratory Analyses........................................................................................84
10.5.6
Health Economics and Outcomes Research Endpoint Analyses ......................85
10.6
Analysis of Pharmacokinetic and Pharmacodynamic Data......................................85
10.6.1
Pharmacokinetic Measurement and Parameters................................................85
10.6.2
Pharmacodynamic Analyses .............................................................................86
10.7
Analysis of Safety ....................................................................................................86
10.7.1
Adverse Events..................................................................................................86
10.7.1.1
Investigational Product...........................................................................87
10.7.1.2
Intrathecal Drug Delivery Device and Surgical Procedure-related 
AEs.........................................................................................................87
10.7.2
Clinical Laboratory Evaluation.........................................................................87
10.7.3
Electrocardiogram Evaluation...........................................................................87
10.7.4
Vital Signs.........................................................................................................87
10.7.5
Physical Findings ..............................................................................................88
10.7.6
Other Observations Related to Safety...............................................................88
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10.7.6.1
Intrathecal Drug Delivery Device Performance.....................................88
10.7.6.2
Immunogenicity .....................................................................................88
10.7.7
Hearing Assessment..........................................................................................88
10.7.8
Concomitant Medications .................................................................................88
10.8
Statistical/Analytical Issues......................................................................................89
10.8.1
Adjustment for Covariates ................................................................................89
10.8.2
Handling of Dropouts or Missing Data.............................................................89
10.8.3
Interim Analyses and Data Monitoring.............................................................89
10.8.4
Multicenter Studies ...........................................................................................89
10.8.5
Multiple Comparisons/Multiplicity...................................................................89
10.8.6
Sensitivity Analyses..........................................................................................89
11 ADMINISTRATIVE CONSIDERATIONS ..........................................................................90
11.1
Investigators and Study Administrative Structure ...................................................90
11.2
Institutional Review Board or Independent Ethics Committee Approval................90
11.3
Ethical Conduct of the Study ...................................................................................90
11.4
Subject Information and Consent.............................................................................90
11.5
Subject Confidentiality.............................................................................................91
11.6
Study Monitoring .....................................................................................................92
11.7
Case Report Forms and Study Records....................................................................92
11.7.1
Case Report Forms............................................................................................92
11.7.2
Critical Documents............................................................................................92
11.8
Data Monitoring Committee ....................................................................................93
11.9
Device Failure Review Process................................................................................93
11.10
Protocol Violations/Deviations ................................................................................93
11.11
Premature Closure of the Study ...............................................................................94
11.12
Access to Source Documentation.............................................................................94
11.13
Data Generation and Analysis..................................................................................95
11.14
Retention of Data .....................................................................................................95
11.15
Financial Disclosure.................................................................................................95
11.16
Publication and Disclosure Policy............................................................................95
12 LIST OF REFERENCES........................................................................................................96
13 APPENDICES ........................................................................................................................98
Appendix 1
Initial Treatment Phase Schedule of Events: For Subjects Who 
Did Not Receive Intrathecal Idursulfase-IT in Study HGT-HIT-094...............99
Appendix 2
Extended Treatment Phase Schedule of Events – Months 13-15 
(Weeks 52-60).................................................................................................103
Appendix 3
Extended Treatment Phase Schedule of Events – Months 16-20 
(Weeks 64-80).................................................................................................106
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Appendix 4
Extended Treatment Phase Schedule of Events – Months 21-25 
(Weeks 84-100)...............................................................................................109
Appendix 5
Extended Treatment Phase Schedule of Events – Months 26-30 
(Weeks 104–120) ............................................................................................112
Appendix 6
Extended Treatment Phase Schedule of Events – Months 31-34 
(Weeks 124-136).............................................................................................115
Appendix 7
Extended Treatment Phase Schedule of Events – Months 35-37 
(Weeks 140-148).............................................................................................118
Appendix 8
Extended Treatment Phase Schedule of Events – Months 38-42 
(Weeks 152-168).............................................................................................121
Appendix 9
Extended Treatment Phase Schedule of Events – Months 43-47 
(Weeks 172-188).............................................................................................124
Appendix 10
Extended Treatment Phase Schedule of Events – Months 48-112 
(Weeks 192-448).............................................................................................127
Appendix 11
Extended Treatment Phase Schedule of Events – Months 53-117 
(Weeks 212-468).............................................................................................130
Appendix 12
Extended Treatment Phase Schedule of Events – Month 58 (Week 
232) – End-of-study (Month 121, Week 484).................................................133
Appendix 13
Pharmacokinetic Sample Collection for Same-Day Investigational 
Product Administration with Elaprase Infusion..............................................136
Appendix 14
Maximum Blood Volume Collection by Study Visit 
(Months/Weeks) for the Initial Treatment Phase (Subjects Who Did Not 
Receive Intrathecal Idursulfase-IT in Study HGT-HIT-094)..........................137
Appendix 15
Maximum Blood Volume Collection by Study Visit 
(Months/Weeks) for the Extended Treatment Phase (Months 13-27 -
Weeks 52-108) ................................................................................................138
Appendix 16
Maximum Blood Volume Collection by Study Visit 
(Months/Weeks) for the Extended Treatment Phase (Months 28-42 -
Weeks 112-168) ..............................................................................................139
Appendix 17
Maximum Blood Volume Collection by Study Visit 
(Months/Weeks) for the Extended Treatment Phase (Months 43-60 -
Weeks 172-240................................................................................................140
Appendix 18
Maximum Blood Volume Collection by Study Visit 
(Months/Weeks) for the Extended Treatment Phase (Months 61-72 -
Weeks 244-288................................................................................................141
Appendix 19
Maximum Blood Volume Collection by Study Visit 
(Months/Weeks) for the Extended Treatment Phase (Months 73-87 -
Weeks 292-348................................................................................................142
Appendix 20
Maximum Blood Volume Collection by Study Visit 
(Months/Weeks) for the Extended Treatment Phase (Months 88-102 -
Weeks 352-408................................................................................................143
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Appendix 21
Maximum Blood Volume Collection by Study Visit 
(Months/Weeks) for the Extended Treatment Phase (Months 103-121 -
Weeks 412-484................................................................................................144
Appendix 22
Cumulative Maximum Blood Volume Collection for Subjects in 
the Initial Treatment and Extended Treatment Phases (Months -1-121) 
and Subjects Only in the Extended Treatment Phase (Months 13-121) .........145
Appendix 23
Neurodevelopmental Assessments in Study SHP609-302...................146
Appendix 24
Expected SOPH-A-PORT Mini S Adverse Device Effects.................147
Appendix 25
Protocol Amendment Summary of Changes........................................148
Appendix 26
Protocol Signature Page .......................................................................159
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LIST OF IN-TEXT TABLES
Table 1
Neurodevelopmental Assessments in Study SHP609-302............................50
Table 2
Assessments for Physical Examinations .......................................................52
Table 3
List of Laboratory Tests ................................................................................54
Table 4
Adverse Event Severity.................................................................................59
Table 5
Adverse Event Relatedness ...........................................................................61
LIST OF IN-TEXT FIGURES
Figure 1
Planned Duration of Treatment (Study HGT-HIT-094 and/or SHP609-
302)................................................................................................................35
Figure 2
Conceptual Plot of Treatment Periods in Early IT and Delayed IT 
Groups in Studies HGT-HIT-094 and SHP609-302 .....................................82
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ABC
adaptive behavior composite
AE
adverse event
ALK
alkaline phosphatase
ALT
alanine aminotransferase (SGPT)
AST
aspartate aminotransferase
AUC
area under the serum concentration-time curve
BSID-III
Bayley Scales of Infant Development, Third Edition
BUN
blood urea nitrogen
CFR
Code of Federal Regulations
CIOMS
Council for International Organizations of Medical Sciences
CIQ
Caregiver Impact Questionnaire
CL/f
clearance for IT-L administration
Cmax
maximal concentration
CNS
central nervous system
CO2
carbon dioxide
CRF
case report form (paper or electronic)
CRO
contract research organization
CS
clinically significant
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-5L
EuroQol-5D-5L instrument for use as a measure of health outcome
ERT
enzyme replacement therapy
EU
European Union
FDA
United States Food and Drug Administration
FT
full time
GAG
glycosaminoglycan
GCA
general conceptual ability
GCP
Good Clinical Practice
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Abbreviation
Definition
GGT
gamma glutamyl transferase
Hct
hematocrit
HCUQ
Healthcare Utilization Questionnaire
Hgb
hemoglobin
HGT-2310
drug code name for formulation of recombinant iduronate-2-sulfatase (idursulfase) 
for intrathecal administration 
HS
heparan sulfate
HS-FOCUS
Hunter Syndrome Functional Outcomes for Clinical Understanding Scale
ICH
International Conference on Harmonisation
IDS
iduronate-2-sulfatase
IDDD
intrathecal drug delivery device
IEC
Independent Ethics Committee
IFU
Instructions for Use
IND
Investigational New Drug application
IRB
Institutional Review Board
IT
intrathecal
IV
intravenous(ly)
LDH
lactate dehydrogenase
LP
lumbar puncture
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MDR
medical device report
MedDRA
Medical Dictionary for Regulatory Activities 
MPS II
Mucopolysaccharidosis II (Hunter syndrome)
MRI
magnetic resonance imaging
MRT
mean residence time
N or n
number of observations
NCS
not clinically significant 
NW
not working
PACU
post-anesthesia care unit
PD
pharmacodynamic(s)
PK
pharmacokinetic(s)
PORT-A-CATH
PORT-A-CATH® II Low Profile™ Intrathecal Implantable Access System
PRO
patient reported outcome
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Abbreviation
Definition
PT
part time
PT
prothrombin time
PTT
partial thromboplastin time
QTc
corrected QT interval
RBC
red blood cell(s)
SAE
serious adverse event
SAP
statistical analysis plan
SAS
Statistical Analysis System©
SEM
standard error of measurement
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
SOPH-A-PORT 
Mini S
SOPH-A-PORT® Mini S, Implantable Access Port, Spinal, Mini Unattached, with 
Guidewire 
t1/2
terminal half-life
T4
thyroxine
Tmax
time of maximal concentration
TSH
thyroid-stimulating hormone
Tx
treatment
UK
United Kingdom
US
United States
VAS
visual analog scale
VABS-II
Vineland Adaptive Behavior Scales, Second Edition
Vz/F
volume of distribution based on terminal phase
WBC
white blood cell(s)
WHO-DD
World Health Organization Drug Dictionary
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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.1, 2 Though 
typically appearing normal at birth, all MPS II patients suffer from a progressive, serious, life 
limiting disease.3, 4
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).4 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).5 Clinical manifestations include 
severe airway obstruction, skeletal deformities, cardiomyopathy and, in most patients, 
neurological decline.6 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.4
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.4, 7 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.”7 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.5-8 An earlier appearance of clinical 
symptoms generally, but not always, predicts a more severe clinical course.4, 5, 9, 10 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 (IDS) gene, who manifest 
severe neurodevelopmental impairment.11, 12
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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,13-15 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 it is not intended for direct injection into 
the CNS. Thus, no approved therapy exists for the CNS pathologies of Hunter syndrome. 
Because intravenously administered idursulfase is unlikely 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. 
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 the CSF since it is isotonic and contains excipients suitable for IT use.
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 subjects 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 subjects 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 
investigational product. There have been no deaths or discontinuations due to adverse events 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 the device because of mechanical failures, primarily connector pin 
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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 investigational product 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 is being used in the 
antecedent Phase II/III study (HGT-HIT-094). 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 subjects in studies 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 subjects 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 slowing of cognitive decline.
1.3.1
Rationale for Current Phase II/III Study
The current study is an extension study to the pivotal Phase II/III study, HGT-HIT-094. Study 
HGT-HIT-094 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 subjects with Hunter syndrome and 
early cognitive impairment who have previously received and tolerated a minimum of 4 months 
of therapy with Elaprase. Subjects are randomized to idursulfase-IT treatment or no 
idursulfase-IT treatment. All subjects continue to receive Elaprase therapy.
The therapeutic strategy in the ongoing, antecedent study (HGT-HIT-094) and this extension 
study, consisting of idursulfase-IT administered intrathecally while the subject continues to 
receive Elaprase as standard of care, 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 subjects with cognitive impairment to slow progression of cognitive and functional 
impairment. 
This study serves to extend the treatment, as well as safety and efficacy monitoring, for subjects 
who completed study HGT-HIT-094, which is designed to include the 42 pediatric subjects 
randomized to receive idursulfase-IT monthly, or no IT treatment, plus potentially a number of 
pediatric subjects younger than 3 years old in the open-label, single-arm substudy also included 
in HGT-HIT-094. Subjects in the substudy follow a similar schedule of study visits as subjects in 
the main study receiving idursulfase-IT.
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The design of the antecedent study (HGT-HIT-094), including the neurodevelopmental 
assessment tools and endpoints, and the selection of idursulfase-IT 10 mg dose, were informed 
by the results of Phase I/II studies HGT-HIT-045 and HGT-HIT-046. Similar assessment tools 
and endpoints are employed in this study.
It is planned that the SOPH-A-PORT Mini S delivery device will be used for IT administration 
of idursulfase-IT to MPS II subjects in this study. In contrast to IT administration via lumbar 
puncture (LP), the use of an IDDD does not always require full anesthesia; in many cases, 
sedation or local topical anesthetic 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 subject 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 subjects, 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. 
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
2.1
Primary Objective 
The primary objective of this study is to evaluate long-term safety in subjects with Hunter 
syndrome and cognitive impairment who are receiving intrathecal idursulfase-IT and IV 
Elaprase® enzyme replacement therapy (ERT).
2.2
Secondary Objectives 
The secondary objectives of this study are to evaluate long-term clinical efficacy outcomes in 
subjects with Hunter syndrome and cognitive impairment who are treated with idursulfase-IT, in 
conjunction with Elaprase therapy with respect to the following:
•
Cognitive function as measured by General Conceptual Ability (GCA),  the cluster areas and 
subtests of the Differential Abilities Scale, Second Edition (DAS-II), or domains of the 
Bayley Scales of Infant Development, Third Edition (BSID-III)
•
Adaptive behavior as measured by the Adaptive Behavior Composite (ABC) score and 
standard domain scores of the Vineland Adaptive Behavior Scales, Second Edition 
(VABS-II)
•
Brain structure volume as measured by magnetic resonance imaging (MRI)
2.3
Pharmacokinetic and Pharmacodynamic Objectives
•
To evaluate the concentration of idursulfase and determine PK parameters in serum after IT 
administration in subjects with Hunter syndrome and cognitive impairment who are treated 
with idursulfase-IT in conjunction with Elaprase therapy
•
To evaluate the concentration of idursulfase in CSF in subjects with Hunter syndrome and 
cognitive impairment who are treated with idursulfase-IT in conjunction with Elaprase 
therapy
•
To evaluate the concentration of GAG in CSF in subjects with Hunter syndrome and 
cognitive impairment who are treated with idursulfase-IT in conjunction with Elaprase 
therapy
•
To evaluate the concentration of GAG in urine in subjects with Hunter syndrome and 
cognitive impairment who are treated with idursulfase-IT in conjunction with Elaprase 
therapy
2.4
Health Economics and Outcomes Research Objectives
•
To evaluate health status as measured by the EuroQol-5D-5L (EQ-5D-5L) instrument, in 
subjects with Hunter syndrome and cognitive impairment who are treated with idursulfase-IT 
in conjunction with Elaprase therapy
•
To evaluate healthcare resource utilization, as measured by the Healthcare Utilization 
Questionnaire (HCUQ) in subjects with Hunter syndrome and cognitive impairment who are 
treated with idursulfase IT in conjunction with Elaprase therapy
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•
To evaluate the social/emotional, physical, daily activities and financial impact on caregivers 
and families of subjects with Hunter syndrome and cognitive impairment as measured by 
Caregiver Impact Questionnaire (CIQ)
•
To evaluate functional status as measured by the HS-FOCUS (Hunter Syndrome Functional 
Outcomes for Clinical Understanding Scale) instrument, in subjects with Hunter syndrome 
and cognitive impairment who are treated with idursulfase-IT in conjunction with Elaprase 
therapy
2.5
SOPH-A-PORT Mini S Device Objective
•
To evaluate the safety and performance of the SOPH-A-PORT Mini S
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3
STUDY ENDPOINTS
3.1
Primary Safety Endpoints
Safety will be assessed during the study by the following:
•
Adverse events (AEs) (by type, severity, and relationship to treatment [idursulfase-IT, the 
IDDD, device surgical procedure, or IT administration process], IV Elaprase infusion, IV 
Elaprase and/or idursulfase-IT)
•
Changes in clinical laboratory testing (serum chemistry, hematology, urinalysis)
•
Vital signs
•
Twelve-lead ECG recordings
•
CSF laboratory parameters (chemistries, cell counts)
•
Anti-idursulfase antibodies in CSF and serum, including determination of anti-idursulfase 
antibodies having enzyme neutralizing activity
3.2
Secondary Efficacy Endpoints 
The secondary efficacy endpoints of this study are the following:
•
Change from baseline in DAS-II standard scores: GCA, Special Nonverbal Composite 
(SNC); and standard cluster scores: Verbal, Nonverbal, Spatial; and/or the age equivalents 
and Development Quotient (DQ) from the BSID-III domains: Cognitive and Language
•
Change from baseline in standard composite scores of the VABS-II: ABC and domain 
standard scores: Communication, Daily Living Skills, Socialization, and Motor Skills
•
Change from baseline in age equivalents, developmental quotients, and T-scores for the core 
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 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 in the v-Scale scores and observed maladaptive levels of the VABS-II 
Maladaptive Behavior Index and its subscales (Internalizing, Externalizing)
•
Change from baseline in Brain Total Intracranial Volume, Brain Total Tissue Volume, Brain 
Total White Matter, Brain Total Gray Matter, and Total CSF Volume
3.3
Exploratory Efficacy Endpoints
The exploratory efficacy endpoints of this study are the following:
•
Change from Visit Month 13/baseline to Visit Month 25/Week 52 in study SHP609-302 as 
estimated by linear regression in:
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•
DAS-II GCA scores from Early Years battery
•
DAS-II Early Years battery core subtests T scores: Verbal Comprehension, Picture 
Similarities, Naming Vocabulary, Pattern Construction, Matrices, and Copying
•
DAS-II Early Years battery standard cluster scores: Verbal, Nonverbal, Spatial, and 
SNC composite score
•
DAS-II GCA scores including both Early Years and School Age batteries
•
VABS-II ABC scores
Note that the interval from Visit Month 13/baseline to Visit Month 25/Week 52 in study 
SHP609-302 is defined as from Visit Month 13 to Visit Month 25 in SHP609-302 Extended 
Treatment Phase for subjects in the Early IT group (defined in Section 10.4.1), and from 
baseline in study SHP609-302 to Visit Week 52 in SHP609-302 Initial Treatment Phase for 
subjects in the Delayed IT group (defined in Section 10.4.1). The Early IT group and 
Delayed IT group designations are based on the treatment regimen (idursulfase-IT or No IT 
treatment) in the antecedent study (HGT-HIT-094).
•
Ordered categorical outcomes for each subject at study SHP609-302 Visit Month 25/Week 
52 are defined below. The definition for each response category threshold is based on the 
standard error of measurement (SEM) for the DAS-II. The SEM for the GCA, based on test-
retest reliability of the DAS-II,17 is approximately ±5 points. The ordered categorical 
outcomes will be defined for both DAS-II GCA scores from Early Years battery and GCA 
scores.
•
Above average cognitive development (Category 1) is defined as a subject with an 
observed GCA score at Visit Month 25/Week 52 which is more than 10 points (2 
SEM) higher than the observed GCA score at Visit Month 13/baseline in study 
SHP609-302; ie, 

GCA (Visit Month 25/Week 52) > GCA (Visit Month 13/baseline) +
10 points
•
Average cognitive development (Category 2) is defined as a subject with an observed 
GCA score at Visit Month 25/Week 52 which is within a range of ±10 points, 
inclusive (2 SEM), of the observed GCA score at Visit Month 13/baseline in study 
SHP609-302; ie,

GCA (Visit Month 13/baseline) - 10 points ≤ GCA (Visit Month 
25/Week 52) ≤ GCA (Visit Month 13/baseline) + 10 points
•
Below average cognitive development (Category 3) is defined as a subject with an 
observed GCA score at Visit Month 25/Week 52 which is more than 10 points (2 
SEM) below the observed GCA score at Visit Month 13/baseline in study 
SHP609-302; ie, 

GCA (Visit Month 25/Week 52) <GCA (Visit Month 13/baseline) –
10 points
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•
Binary unreversed floor effect outcome for each subject
3.4
Health Economics and Outcomes Research Endpoints 
The health economics and outcomes research endpoints of this study are the following:
•
Health status dimensions as obtained by the EQ-5D-5L questionnaire
•
Health care resource utilization will be assessed using the HCUQ
•
Health-related quality of life for caregivers will be assessed using the CIQ
•
Functional status as obtained by the HS-FOCUS form
3.5
Pharmacokinetic and Pharmacodynamic Endpoints 
The pharmacokinetic and pharmacodynamic endpoints of this study are the following:
•
Serum concentration of idursulfase and serum PK parameters after IT administration
•
CSF concentration of idursulfase 
•
Change from baseline in the concentration of GAG in CSF
•
Change from baseline in the concentration of GAG in urine
3.6
SOPH-A-PORT Mini S Assessments
The SOPH-A-PORT Mini S device will be evaluated using assessments of device implantation, 
device function, device longevity, and AEs associated with the implant surgery or device. These
data will be collected on the subject’s eCRF from the time of initial implantation.
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4
INVESTIGATIONAL PLAN
4.1
Overall Study Design and Plan
This is an open-label, non-randomized study for subjects who completed Study HGT-HIT-094; 
all subjects in this study will be treated with intrathecal idursulfase-IT in conjunction with 
Elaprase therapy. 
Subjects who complete Visit Week 52 assessments of Study HGT-HIT-094 and who meet the 
eligibility criteria and for whom informed consent is provided will be enrolled in this extension 
study. Subjects planning to continue in this extension study will have written informed consent 
provided prior to completing the HGT-HIT-094 EOS assessments. The Visit Week-52 
HGT-HIT-094 assessments must be completed prior to the first idursulfase-IT injection in this 
study.
Prior to conducting any study-related procedures, written informed consent (signed and dated) 
must be obtained from the subject’s parent(s) or legally authorized guardian(s) (and 
consent/assent from the subject, 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.
During Study SHP609-302, subjects who exceed the age of enrollment eligibility for Study 
HGT-HIT-094 and/or have reached the applicable legal age of consent to participate in a clinical 
study will be allowed to continue participation in Study SHP609-302 until the end of the study.
The HGT-HIT-094 EOS visit is intended to be the same as the first visit for subjects enrolled in 
this study. Subjects enrolling in this study are not required to participate in the safety follow-up 
visit of HGT-HIT-094. For subjects who were treated with idursulfase-IT in Study 
HGT-HIT-094, the visit weeks in this study are numbered continuously with visit weeks in Study 
HGT-HIT-094. 
All subjects will receive idursulfase-IT at the same dose and frequency (10 mg once every 
28 days) as selected for the HGT-HIT-094 study. Subjects who are younger than 3 years of age 
will continue to receive an adjusted dose as specified in Section 6.3. As in Study HGT-HIT-094, 
subjects will undergo pre-treatment and safety assessments on Day 1 and will receive an IT 
injection of idursulfase-IT on Day 2 of each IT Dosing Week, followed by a safety follow-up 
visit. From Week 28 onward, pre-treatment assessments may be performed on the same day as 
IT administration of idursulfase-IT, if the subject can arrive at the study site early in the day and 
if the investigator deems this clinically appropriate. In addition (from Week 28 onward), and in 
the absence of any safety concerns, subjects may complete the safety follow-up visit on the same 
day as IT administration prior to discharge.
The assessments in this study are similar to those performed in Study HGT-HIT-094 and will be 
performed at regular intervals; the frequency of assessments will vary depending on the 
treatment phase of the study as described in Sections 4.1.1 and 4.1.2 for the Initial Treatment 
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Phase and Extended Treatment Phase, respectively. All subjects in the study will undergo EOS 
procedures approximately 28 days following their last administration of idursulfase-IT.
4.1.1
Initial Treatment Phase – Only Subjects Not Treated with Idursulfase-IT in 
Study HGT-HIT-094
Subjects who participated in the control arm (no treatment with idursulfase-IT) in Study 
HGT-HIT-094 will begin this study in the Initial Treatment Phase. These subjects will have the 
IDDD implanted following enrollment in order to begin treatment with idursulfase-IT. These 
subjects will, during the Initial Treatment Phase of this study (ie, the first 12 months), undergo 
treatment and assessments similar to those performed for subjects who were treated in Study 
HGT-HIT-094. After completion of the Initial Treatment Phase and if there are no safety 
concerns, subjects may continue receiving monthly idursulfase-IT in the Extended Treatment 
Phase of this study (Section 4.1.2).
The Schedule of Events for the Initial Treatment Phase is provided in Appendix 1. 
4.1.2
Extended Treatment Phase – All Subjects
Subjects who received treatment with idursulfase-IT in the HGT-HIT-094 study will begin this 
study in the Extended Treatment Phase, which reflects a reduced frequency of assessments 
compared with the schedule of assessments in Study HGT-HIT-094. Standardized 
neurodevelopmental assessments and health economic and outcomes research assessments will 
be performed every 24 weeks and CSF assessments (other than standard chemistry) and clinical 
laboratory tests of blood and urine will be performed every 12 weeks. Brain MRI and 12-lead 
ECG will be performed every 48 weeks. A PK assessment will be performed once during this 
phase of the study.
The Study Schedule of Events for the Extended Treatment Phase is provided in Appendix 2, 
Appendix 3, Appendix 4, Appendix 5, Appendix 6, Appendix 7, Appendix 8, Appendix 9, 
Appendix 10, Appendix 11, and Appendix 12.
4.1.3
Treatment Schedule
When a subject has received and tolerated a total of 12 monthly doses of idursulfase-IT across 
studies HGT-HIT-094 and SHP609-302, the sponsor and principal investigator will consider the 
feasibility of transitioning the subject’s monthly IT dosing to local sites to reduce the burden 
imposed by monthly travel. The local sites will be selected and approved by the Sponsor, and the 
subject must have no safety or medical issues that would preclude transitioning to a local site 
(Note: the main site may serve as a local site as needed; and in this case, the main site will follow 
the assessment schedule for a local site). Exceptions include study visits at which PK, MRI, and
neurodevelopmental assessments are scheduled; these will take place at the main site. Subjects 
must provide a separate written informed consent/assent to participate in study procedures to be 
conducted at the local site prior to the conduct of any procedures.
Subjects will receive their monthly doses of intrathecal idursulfase-IT at the main study site or at 
a local site. All subjects will receive their weekly IV infusions of Elaprase throughout the study. 
Elaprase infusions may be administered at the main study site, at a local site, or at a site 
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determined by the subject’s physician or at the subject’s home depending upon the standard 
location as determined for each subject (at the discretion of local laws and the treating 
physician).
4.2
Intrathecal Drug Delivery
It is anticipated that the IDDD will be used to collect CSF samples and to deliver IT injections of 
idursulfase-IT and preservative-free saline flushes. No other medication will be administered 
through the device. If the IDDD appears to be non-functional, or if its use is precluded on a 
scheduled day of dosing, site personnel will refer to the IDDD Manual, which provides details on 
the investigation and management of any IDDD-related issues. This includes possible partial 
revision or complete replacement of the IDDD as indicated. If the IT space is not accessible via 
the IDDD, investigational product may be administered by LP. Should the IDDD become 
clogged, undergo mechanical complications or otherwise not be accessible, the CSF sample may 
also be obtained by LP.
If there are medical contra-indications to the re-implantation of a new device, or if the subject so 
desires, repeat monthly lumbar punctures may be considered as an alternative way of delivering 
the study drug and obtaining CSF samples under limited circumstances. If no safety risks are 
identified by the investigator, up to 12 consecutive LPs may be performed across studies 
HGT-HIT-094 and SHP609-302. Once a subject has reached the maximum of 12 consecutive 
lumbar punctures, a new IDDD may be re-implanted for subsequent dosing, unless, in the 
opinion of the investigator and medical monitor, assessment of risk/benefit favors continued 
dosing via lumbar puncture.
Continued treatment via repeat LP beyond the stipulated 12 consecutive monthly doses can be 
considered only in individual cases of subjects where this treatment is very well tolerated and the 
investigator has not identified any safety concerns associated with repeat lumbar puncture and 
repeat sedation/anesthesia.
General anesthesia or sedation may be required for injections of investigational product and 
some evaluations, and can be used at the discretion of the investigator as indicated in the study 
manuals. It is anticipated that study procedures such as LP and MRI will have to be performed 
with sedation/anesthesiology support.
A Data Monitoring Committee (DMC) will oversee both idursulfase-IT and device safety. The 
DMC will be notified of all IDDD failures and IDDD-related complications at times defined in 
the DMC charter (Section 11.8).
Subjects will have the IDDD removed when they discontinue from or complete the study unless 
the subject is continuing to receive product or treatment through another mechanism (eg, 
extension study, expanded access program).
4.3
Rationale for Study Design and Comparator Group
The study design is intended to provide ongoing treatment with idursulfase-IT to subjects who 
received idursulfase-IT in study HGT-HIT-094 and to initiate treatment in subjects who received 
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5
STUDY POPULATION SELECTION
5.1
Study Population
Pediatric subjects (plus potentially any pediatric subjects younger than 3 years of age in the 
antecedent substudy) who completed Study HGT-HIT-094, and meet the eligibility criteria may
enroll in this study.
5.2
Inclusion Criteria
Each subject must meet the following criteria to be enrolled in this study.
1. Subjects must have completed Visit Week 52 assessments in Study HGT-HIT-094
2. The subject’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 subject’s parent(s) or legally authorized guardian(s) and the subject’s 
consent/assent, as relevant, must be obtained
3. The subject has continued to receive Elaprase on a regular basis in Study HGT-HIT-094
5.3
Exclusion Criteria
Subjects who meet any of the following criteria will be excluded from the study.
1. The subject has experienced, in the opinion of the investigator , a safety or medical issue that 
contraindicates treatment with idursulfase-IT, including, but not limited to, uncontrolled 
seizure disorder, bleeding disorder, and clinically relevant hypertension
2. The subject has a known hypersensitivity to any of the components of idursulfase-IT
3. The subject has clinically relevant intracranial hypertension
4. The subject is enrolled in another clinical study, other than HGT-HIT-094, that involves 
clinical investigations or use of any investigational product (drug or [intrathecal/spinal] 
device) within 30 days prior to study enrollment or at any time during the study
5. The subject 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
6. The subject has a condition that is contraindicated as described in the SOPH-A-PORT Mini S 
IDDD Instructions for Use, including:
a.
The subject has had, or may have, an allergic reaction to the materials of construction of 
the SOPH-A-PORT Mini S device
b. The subject’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 subject’s drug therapy requires substances known to be incompatible with the 
materials of construction 
d. The subject has a known or suspected local or general infection
e.
The subject is at risk of abnormal bleeding due to a medical condition or therapy
f.
The subject has 1 or more spinal abnormalities that could complicate safe implantation or 
fixation
g. The subject has a functioning CSF shunt device
h. The subject has shown an intolerance to an implanted device
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6
STUDY TREATMENTS
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 drug 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 considered investigational in non-EU countries.
The SOPH-A-PORT Mini S comprises the following 7 components:
•
One SOPH-A-PORT Mini S Access Port
•
One intrathecal port closed-tip catheter
•
One guidewire
•
Two suture wings
•
One 14-gauge Tuohy needle
•
One 22-gauge non-coring Huber needle
•
One Luer lock Connector
Further details are provided in the SOPH-A-PORT Mini S Instructions for Use.
6.1.3
Comparator Product
There is no comparator product in this study.
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6.2
Treatments Administered
All subjects in this study will receive idursulfase-IT and standard-of-care therapy with Elaprase 
during the study. Elaprase will not be provided by the sponsor, but rather will be prescribed by 
the subject’s physician in accordance with local prescribing information.
Subjects who did not receive treatment with idursulfase-IT in the antecedent study 
(HGT-HIT-094) 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 subject 
will receive standard perioperative care. 
The investigational product (idursulfase-IT) will be administered through an IDDD. Refer to 
Section 4.2 for further details.
The initial implantation and any revision and/or explantation of the SOPH-A-PORT Mini S will 
be performed by pediatric or general neurosurgeons or anesthesiologists who have experience in 
port and catheter implant procedures and intrathecal-access procedures and have completed 
training for the SOPH-A-PORT Mini S. Please refer to the Instructions for Use (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 subject’s 
drug regimen and experienced in accessing vascular or CNS ports or CNS infusion pumps. 
Subjects’ and subjects’ 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.
The investigational product may be administered on the same day (ie, the same calendar day or 
within a 24-hour period) as the Elaprase IV infusion. However, this can only occur for subjects 
participating in the Extended Treatment Phase who have already completed at least 12 months of 
idursulfase-IT treatment in studies HGT-HIT-094 or SHP609-302. If same-day dosing is elected, 
idursulfase-IT will be administered first and the Elaprase IV infusion will be administered 
second. Please refer to Section 7.7.1 for details.
6.3
Selection and Timing of Dose for Each Subject
The doses (1 mg, 10 mg, and 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 
subjects with MPS II indicated that the 10 mg dose provides a maximum pharmacologic 
response. The 10 mg dose of idursulfase-IT was therefore selected for the pivotal Phase II/III
study, HGT-HIT-094; the dose will remain the same in this extension study. 
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Subjects who are younger than 3 years of age will continue to receive an adjusted dose as 
follows based on reference brain weight16:
•
>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
All subjects will receive idursulfase-IT monthly (every 28 days) via a surgically implanted 
IDDD (SOPH-A-PORT® Mini S, Implantable Access Port, Spinal, Mini Unattached, with 
Guidewire).
All subjects will also 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 subject’s physician in 
accordance with local prescribing information.
6.4
Method of Assigning Subjects to Treatment Groups
All subjects will receive investigational product (idursulfase-IT).
6.5
Blinding
This is an open-label study in which all subjects receive investigational product (idursulfase-IT).
6.6
Concomitant Medications, Therapies, and Medical/Surgical Interventions
Treatment with any other investigational therapies at any time during this study is prohibited.
All subjects are to receive Elaprase therapy throughout this study. Elaprase will be prescribed by 
the subject’s physician and will be administered in accordance with local prescribing 
information. Elaprase will not be provided by the study sponsor.
All medications, therapies/interventions administered to and medical/surgical procedures 
performed on subjects will be regarded as concomitant and recorded on the subject’s eCRF as 
described in Section 7.14. 
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.
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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 subjects receiving IV ERT with Elaprase, with 
symptoms including cutaneous reactions (rash, pruritus, and urticaria), pyrexia, headache, 
hypertension, and flushing. Previous experience with Elaprase is fully described in the Elaprase 
US Package Insert and the EU Summary of Product Characteristics (SmPC). 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 subjects 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. As of the date of this protocol, there have been no significant concerns regarding 
infusion-related immune reactions following IT administration in studies HGT-HIT-045 and 
HGT-HIT-046. Additionally, safety assessments in the present study will evaluate the effect of 
same-day IV and IT regime on the incidence and/or severity of infusion-related adverse 
reactions, even if the subject had no prior such reactions on Elaprase alone. 
Note that any subjects with prior experience of infusion-related anaphylactoid event(s) or 
evidence of consistent severe adverse events related to treatment with Elaprase were excluded 
from participating in the antecedent study.
6.7
Restrictions
6.7.1
Prior Therapy
All subjects must have received and tolerated treatment with idursulfase IV (Elaprase) therapy 
on a regular basis in the antecedent study and have no safety or medical issue that contraindicates 
treatment with idursulfase-IT.
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Treatment with another investigational product (drug or [intrathecal/spinal] device) within the 
30 days prior to study enrollment is prohibited according to the exclusion criteria (Section 5.3).
6.7.2
Fluid and Food Intake 
Not applicable.
6.7.3
Subject Activity Restrictions
Please refer to the SOPH-A-PORTMini S IFU for details regarding subject activity restrictions 
for subjects 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 (idursulfase-IT) will be administered via an IDDD (or 
LP) under the supervision of the investigator and in the controlled environment of a clinical 
center; therefore, full subject compliance with treatment is anticipated in this study.
6.9
Packaging and Labeling
All packaging and labeling will be in accordance with applicable regulatory requirements.
6.9.1
Investigational Product
Idursulfase-IT drug product is a sterile liquid formulation of recombinant idursulfase for monthly 
IT administration using a medical device, and that is packaged in 2-mL type-I borosilicate glass 
vials that are single-use. 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. The 
idursulfase-IT must be used as soon as possible after it is prepared because it does not contain 
preservatives.
6.9.2
Intrathecal Drug Delivery Device
The SOPH-A-PORT Mini S Access Port is available in 1 size, individually packaged, with other 
SOPH-A-PORT Mini S components in double peel-off, sterile, pyrogen-free packaging, 
sterilized with Ethylene Oxide. Instructions for use are also included in the packaging. A 
guidewire is provided in separate double pouch, sterile, pyrogen-free packaging.
Labels are provided on the outer carton, and on both the SOPH-A-PORT Mini S box and 
guidewire/cannula package inside and will be in accordance with local regulatory requirements.
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 
2-8°C (36-46°F). The investigational product should be handled as follows:
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•
Idursulfase-IT vials should be stored at 2-8ºC (36-46°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 subject-by-subject basis by completing the accountability log. The date and time of 
administration of the investigational product and use of the device must be documented on the 
subject’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 subject-by-subject 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 subject’s appropriate eCRF.
The principal investigator, clinical research coordinator, or designee (eg, pharmacist) must 
ensure that all documentation regarding receipt, storage, dispensing, loss/damaged 
SOPH-A-PORT Mini S devices and return of used/unused SOPH-A-PORT Mini S device(s) is 
complete, accurate, and ready for review at each monitoring visit and/or audit. The sites must 
ensure that the SOPH-A-PORT Mini S devices are available for the monitor to inventory and 
prepare for product destruction or return shipment to the sponsor or designee.
The SOPH-A-PORT Mini S and its components are sterile, single-use devices.
Please refer to the IDDD Manual for device destruction or return instructions.
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6.10.3
Comparator Product
Not applicable to this study.
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7
STUDY PROCEDURES
Descriptions of subject procedures and evaluations required for this protocol are provided in this 
section. These evaluations will be performed during the days and weeks of the study as indicated
in the Schedule of Events (Appendix 1, Appendix 2, Appendix 3, Appendix 4, Appendix 5,
Appendix 6, Appendix 7, Appendix 8, Appendix 9, Appendix 10, Appendix 11, and Appendix 
12).
All subjects will receive weekly IV Elaprase infusions as prescribed throughout the study. 
During the Initial Treatment Phase, 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. 
During the Extended Treatment Phase only, the investigator will have the option of 
administering the Elaprase IV infusion and idursulfase-IT on the same day. Please refer to 
Section 7.7.1 for details.
Subjects who were not previously treated with idursulfase-IT in Study HGT-HIT-094 will begin 
participation in this study (if confirmed eligible) at the start of the Initial Treatment Phase (ie, the 
first 12 months) of this study, which is similar in schedule of assessments for subjects who were 
treated with intrathecal idursulfase-IT in Study HGT-HIT-094. At completion of these 
procedures and if there are no safety concerns, subjects may continue into the Extended 
Treatment Phase of this study.
Subjects who were previously treated with idursulfase-IT in Study HGT-HIT-094 will begin 
participation in this study (if confirmed eligible) at the start of the Extended Treatment Phase (ie, 
from Week 52 [Month 13] onward). 
The Initial Treatment Phase (subjects who were not treated with idursulfase-IT in Study 
HGT-HIT-094) will be conducted according to the following schedule: 
•
Informed Consent and Review of Study Entry Criteria (Weeks -1 [Day -7 to Day -1])
•
Pre-surgery, Surgery, Follow-up, and Post-operative Recovery (Week 2 [-14, +7 days])
•
Treatment and Assessments (Week 4 through Week 48 [±7 days])
•
If no safety concerns, subjects continue into Extended Treatment Phase.
The Extended Treatment Phase (all subjects) will be conducted according to the following 
schedule:
•
Informed Consent and Review of Study Entry Criteria (Week 52 [±7 days], only for those 
subjects previously treated in HGT-HIT-094)
•
Treatment and Assessments (Week 52 through Week 480 [±7 days], all subjects)
•
End of Study (EOS, Week 484 [±7 days], all subjects)
Refer to Appendix 1 for the Schedule of Events for the Initial Treatment Phase (subjects who did 
not receive treatment with idursulfase-IT in Study HGT-HIT-094).
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Refer to Appendix 2, Appendix 3, Appendix 4, Appendix 5, Appendix 6, Appendix 7, Appendix 
8, Appendix 9, Appendix 10, Appendix 11, and Appendix 12 for the Schedule of Events for the 
Extended Treatment Phase (continued treatment for subjects who did not receive treatment with 
idursulfase-IT and beginning of participation for subjects originally enrolled in the substudy in 
HGT-HIT-094 and subjects who received treatment with idursulfase-IT in Study HGT-HIT-094). 
All data collected are to be recorded on the subject’s appropriate eCRF.
Details for study procedures including sample collection are described in the Operations Manual 
for this study.
7.1
Informed Consent
Prior to conducting any study-related procedures, written informed consent (signed and dated) 
must be obtained from the subject’s parent(s) or legally authorized guardian(s) (and 
consent/assent from the subject, 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.
During Study SHP609-302, subjects who exceed the age of enrollment eligibility for Study 
HGT-HIT-094 and/or have reached the applicable legal age of consent to participate in a clinical 
study will be allowed to continue participation in Study SHP609-302 until the end of the study.
7.2
Study Entrance Criteria
Each subject will be reviewed for eligibility against the study entrance criteria. Subjects who do 
not meet the study entrance criteria will not be allowed to participate in the study. The reason(s) 
for the subject’s ineligibility for the study will be documented. No protocol exemptions will be 
permitted. 
7.3
Confirmation of Study Eligibility
Subject eligibility according to the study inclusion and exclusion criteria will be confirmed on 
the basis of review of the study entrance criteria.
7.4
Medical History
A standard medical history assessment will be performed. Medical and surgical history reflecting 
the period of time since the subject completed the antecedent study (HGT-HIT-094) will be 
recorded. 
Medical history will include 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. Surgical history will also be recorded.
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7.5
Echocardiogram
An echocardiogram will be performed as part of the study entry assessments. This procedure will 
not be necessary if the subject has had an echocardiogram performed within 3 months of study 
entry, the data are available, and deemed satisfactory for evaluation of anesthesia risk.
7.6
Device-Related Procedures
7.6.1
Intrathecal Drug Delivery Device 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 subject 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.
Details of the implantation/revision and malfunctions/failure will be documented on the subject’s 
eCRF.
If at the time of a scheduled dosing, due to a device-related issue it is not possible to aspirate 
CSF prior to dose administration, administer a full medication dosage using the standard 
administration steps detailed in the device’s IFU, or flush the system following dose 
administration, the IDDD will be declared a device malfunction. If the device malfunction is 
irreversible and cannot be corrected without a partial or full device revision or removal, the 
IDDD will be declared a device failure, starting from the date of the initial malfunction.
The IDDD will then be surgically removed or revised and a new device and/or device 
components will be re-implanted at the earliest possible opportunity, preferably at the same time.
7.6.2
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 
subject’s eCRF. If the device requires revision or replacement during the study, additional X-
rays will be taken to document proper positioning of the device. If an IDDD malfunctions, an X-
ray will be performed to assess the potential cause of malfunction. Fluoroscopy should be used 
during device implantation procedures.
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7.6.3
Cerebrospinal Fluid Sampling Procedure
Cerebrospinal fluid will be sampled via the IDDD. If this is not possible, and if CSF sampling is 
necessary, either for adherence to the protocol, or to investigate clinical concerns, an LP may be 
performed to sample CSF, either with or without administration of drug afterwards.
7.6.4
Device Revision or Removal
If at the time of a scheduled dosing it is not possible to administer a full medication dosage using 
the standard administration steps detailed in the device’s IFU due to a device related issue, the 
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.
Subjects will have the IDDD removed when they discontinue from or complete the study, unless 
the subject is continuing to receive treatment through another mechanism (eg, extension study, 
expanded access program, commercially available).
Details of the device removal will be recorded in the subject’s CRF.
7.7
Investigational Product Administration
It is planned that idursulfase-IT will be administered every 28 days by means of the IDDD (or 
LP, refer to Section 4.2). A visual examination of both the port and catheter track will be 
performed before each IT injection. If the IT space is not accessible via the IDDD, study drug 
may be administered by LP.
A 22-gauge Huber non-coring needle is to be used for access to the implanted port; standard 
hypodermic needles would damage the septum and may cause leakage. If no needle-free 
connector is present, a stopcock or the Huber needle infusion set’s clamp is to be used to prevent 
CSF backflow and to mitigate the risk of air entering the system. It is possible to use other 
brands of Huber non-coring needles, provided that their specifications are identical to that of the 
Huber needle supplied by Sophysa in a SOPH-A-PORT Mini S (22G).
The injection date, injection start/stop time, planned dose, injection volume, and flush volume 
will be recorded on the subject’s eCRF. 
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.
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Specifically, the investigational product will be administered in a volume of 1 mL (1 mL of a 
10 mg/mL solution) (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.
Subjects will remain under the observation of study personnel 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 administration of investigational product for safety 
assessments. Thereafter, if deemed clinically stable by the investigator, subjects 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 in the Initial Treatment Phase, subjects 
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 subject overnight for convenience, this hospitalization should not 
initiate a serious adverse event report. For the latter 6 months of treatment with idursulfase-IT in 
the Initial Treatment Phase and onward (ie, from Week 28 onward), and in the absence of any 
safety concerns, subjects may complete the safety follow-up visit on the same day as IT 
administration prior to discharge.
7.7.1
Same-Day Investigational Administration with Elaprase Infusion
During the Initial Treatment Phase, 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. 
During the Extended Treatment Phase only, the investigator will have the option of 
administering the IV Elaprase infusion and idursulfase-IT on the same day. If same-day dosing is 
elected, idursulfase-IT will be administered first and the Elaprase infusion will be administered 
second. Pharmacokinetic assessments are to occur at the first study visit at which same-day 
dosing is elected. At this visit, administration of the Elaprase infusion should start within 
approximately 90 minutes of completion of idursulfase-IT administration.
Note that on the occasion of the first same-day administration, the duration of IV Elaprase 
infusion is to be standardized to 3 hours. Thereafter, at subsequent visits on which the Elaprase 
infusion and idursulfase-IT are administered on the same day, the investigator may use discretion 
in deciding the appropriate Elaprase infusion rate based on past experience with the subject, and 
the subject’s prior response to the same-day regime.
7.8
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 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 
Schedule of Events (Appendix 1, Appendix 2, Appendix 3, Appendix 4, Appendix 5, Appendix 
6, Appendix 7, Appendix 8, Appendix 9, Appendix 10, Appendix 11, and Appendix 12).
During the Extended Treatment Phase, blood samples for pharmacokinetic assessments will be 
collected on the occasion of the first same-day administration of idursulfase-IT and Elaprase. 
This pharmacokinetic sampling need only be scheduled once, and may occur at Month 25 or at 
an alternative visit during the Extended Treatment Phase (see Appendix 13 for PK sampling time 
points associated with same-day administration).
7.9
Pharmacodynamic/Biomarker Assessments
7.9.1
Cerebrospinal Fluid Glycosaminoglycan
Cerebrospinal fluid will be collected for measurement of the concentration of GAG.
7.9.2
Cerebrospinal Fluid and Serum Albumin
Albumin levels will be measured in samples of CSF and serum. The relative permeability of the 
blood-brain barrier will be monitored by the CSF/serum albumin ratio.
7.10
Efficacy Assessments
The efficacy endpoints are specified in Section 3.2.
7.10.1
Neurodevelopmental Assessment Tools
The study methodology will include standardized neurodevelopmental assessments to 
provide a quantifiable measure of subject neurodevelopmental status.5
Neurodevelopmental status will be assessed over time by measuring cognitive and 
adaptive functions as follows and as summarized in Appendix 23.
7.10.1.1
Cognition
The Differential Ability Scales, Second Edition (DAS-II),17 will be used to assess all subjects of 
age 2 years, 6 months or older, including Spanish-speaking subjects who will be assessed with 
the Spanish version of the DAS-II. 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 
Early Years battery is further divided into the Lower Level for children ages 2 years, 6 months 
through 3 years, 5 months and Upper Level for children ages 3 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. 
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Any subjects who cannot be assessed with the DAS-II due to a deteriorating condition or who are 
younger than 2 years, 6 months, will be assessed with the BSID-III.18
7.10.1.2
Adaptive Behavior
The Vineland Adaptive Behavioral Scales, Second Edition (VABS-II)19 will be used to assess all 
subjects. The VABS-II Expanded Interview Form will be used to measure the personal and 
social skills of subjects serially over time; these scales are organized within a 3-domain structure: 
Communication, Daily Living, and Socialization. In addition, the VABS-II offers a Motor Skills 
Domain and an optional Maladaptive Behavior Index. The VABS-II Expanded Interview Form 
assesses what a subject actually does, rather than what the subject is able to do.
Table 1
Neurodevelopmental Assessments in Study SHP609-302
Assessment
Intended Study Population
Applicable Age
DAS-II
Subjects 2 years, 6 months of 
age and oldera
Early Years Batterya, b
2 years 6 months through 6 years 11 months
(extended norms: up to 8 years, 11 months)
Early Years Lower Level:  2 years 6 months through 3 years 5 
months; Early Years Upper Level:  3 years 6 months through 
6 years 11 months
School Age Battery
7 years 0 months through 17 years 11 months
BSID-III
Subjects younger than 2 years, 
6 months of age and older 
children who cannot perform the 
DAS-II
1 to 42 months
VABS-II
All subjects
Birth to 90 years
Abbreviations: BSID-III=Bayley Scales of Infant and Toddler Development, Third Edition; DAS-II=Differential 
Ability Scales, Second Edition; VABS-II=Vineland Adaptive Behavioral Scales, Second Edition
a For the DAS-II, Spanish-speaking subjects will be assessed using the Spanish versions of the DAS-II (Early Years
and School Age). 
b Extended norms may be used.
It is intended that full neurodevelopmental assessments be conducted for all subjects; however, it 
is recognized that the feasibility of conducting these assessments may be dependent on the 
subject’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.
7.10.2
Brain Magnetic Resonance Imaging
Subjects will undergo 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. 
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7.11
Health Economics and Outcomes Research Assessments
7.11.1
Health Status Assessment
The health status of subjects will be assessed using the EuroQol-5D-5L (EQ-5D-5L) 
questionnaire, a standardized instrument for use as a measure of health status which is applicable
to a wide range of health conditions and treatments.20, 21 The EQ-5D-5L provides a descriptive 
profile and index value for health status.
Applicable to a wide range of health conditions and treatments, the EQ-5D-5L provides a 
descriptive profile and a single index value for health status which can be used in the clinical and 
economic evaluation of health care, as well as in population health surveys.
The EQ-5D-5L is designed for self-completion by respondents and is suited for use in clinics and 
in face-to-face interviews. The questionnaire takes only a few minutes to complete. Instructions 
to respondents are included in the questionnaire.
7.11.2
Healthcare Resource Utilization and Impact Questionnaires
Two questionnaires assessing healthcare resource utilization and caregiver impact (the HCUQ 
and CIQ), developed specifically for subjects with Hunter syndrome, will be administered. These
measures will focus on collecting self-reported direct and indirect costs of care for subjects with 
MPS II. The health economic and outcome research endpoints evaluate the key healthcare 
resource utilization and impact variables, such as the number of emergency room visits, 
caregiver employment status (full time [FT], part time [PT], and not working [NW]), and the 
number of hours of additional paid help needed by caregivers, over the course of the study.
7.11.3
Functional Outcomes for Clinical Understanding Scale
The functional status of subjects will be assessed using the HS-FOCUS. The parent version of
HS-FOCUS will be administered.
The HS-FOCUS evaluates functional status in 5 domains (walking/standing, grip/reach, 
school/work, activities, and breathing) using a parent-completed form. The individual items 
within each function domain are scored using the following response scale:
•
0 = With NO difficulty
•
1 = With SOME difficulty
•
2 = With MUCH difficulty
•
3 = UNABLE to do
Higher scores thus correspond to a higher degree of incapacity and available items are averaged 
within each domain to derive the 5 domain scores. If more than half of the items within a domain 
are missing or marked as “Does not apply to me,” the domain score is missing.
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7.12
Safety Assessments
Safety will be assessed by AEs (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), AEs determined 
from physical and neurological examination, vital signs, 12-lead ECG recordings, CSF 
laboratory parameters (chemistries, cell counts), anti-idursulfase antibodies in CSF and serum 
(including determination of antibodies having enzyme neutralizing activity).
7.12.1
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 subject’s general appearance, neurological 
examination, as well as evaluation of the body systems and the device port and catheter track as 
listed in Table 2. Any abnormal change in findings will be recorded as an AE on the appropriate 
CRF.
Table 2
Assessments for Physical Examinations
Assessment
Assessment
General appearance
Endocrine
Head and neck
Cardiovascular
Eyes
Abdomen
Ears
Genitourinary
Nose
Skin
Throat
Musculoskeletal
Chest and lungs
Neurological
Port and catheter track
7.12.2
Height and Weight
Height (cm) and weight (kg) will be recorded. The clinical site staff will be instructed to use a 
calibrated scale for weight measurement.
7.12.3
Head Circumference
Head circumference (cm) will be measured in a uniform manner for all subjects. 
7.12.4
Hearing Assessment
Each subject 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 subject has 
sufficient understanding to participate in study assessments.
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7.12.5
Vital Signs
Vital signs are to be recorded and will include pulse, blood pressure, respiration rate, oxygen 
saturation, and temperature.
7.12.6
Electrocardiography
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. 
7.12.7
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. The maximum 
volume of blood collected is presented by study visit in Appendix 14, Appendix 15, Appendix 
16, Appendix 17, Appendix 18, Appendix 19, Appendix 20, Appendix 21, and Appendix 22.
Clinical laboratory tests will include those listed in Table 3.
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Table 3
List of Laboratory Tests
Hematology:
-
Hematocrit (Hct)
-
Hemoglobin (Hgb)
-
Mean corpuscular hemoglobin (MCH)
-
Mean corpuscular hemoglobin concentration 
(MCHC)
-
Mean corpuscular volume (MCV)
-
Platelet count
-
Red blood cell (RBC) count 
-
White blood cell (WBC) count with differential 
Urinalysis: 
-
Appearance (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 albumin
Serum Chemistry:
-
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 creatinine will be 
analyzed in the collected samples. Urine GAG and urine creatinine will be analyzed and reported 
by separate sponsor-designated laboratories. Urine GAG concentration will be normalized to 
urine creatinine and reported as mg GAG/mmol creatinine. 
7.12.8
Cerebrospinal Fluid Assessments
Cerebrospinal fluid samples will be collected via the IDDD or LP prior to idursulfase-IT
administration 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 
(Section 7.12.9).
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Cerebrospinal fluid will be obtained during the days and weeks of the study as indicated in the 
Schedule of Events (Appendix 1, Appendix 2, Appendix 3, Appendix 4, Appendix 5, Appendix 
6, Appendix 7, Appendix 8, Appendix 9, Appendix 10, Appendix 11, and Appendix 12). Should 
the IDDD become clogged or undergo mechanical complications, the CSF sample will be 
obtained via LP until the subject had a functional IDDD.
7.12.9
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.
7.12.10
Device Assessments
The SOPH-A-PORT Mini S device will be evaluated using assessments of device implantation, 
device function, device longevity, and AEs associated with the implant surgery or device. These
data will be collected on the subject’s eCRF from the time of initial implantation.
7.12.11
Leachable/Extractable Assessment
As part of the assessment of the SOPH-A-PORT Mini S, the levels of leachables from the device 
into the CSF and blood may be determined. The subject and/or subject’s parent(s) or legal 
representative(s) has the option to allow testing of residual CSF and serum samples to determine 
the levels of leachable materials related to the IDDD.
7.12.12
Pregnancy Testing
Not applicable. 
7.13
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 subjects at the intervals indicated in the 
schedule of events. Until analyzed, these will be stored securely in a way that ensures subject 
confidentiality and that ensures unauthorized access is prohibited and the samples are not lost, 
deteriorated, or accidentally or illegally destroyed.
Testing of residual blood, urine, and CSF samples for additional scientific research is optional. 
The subject and/or subject’s parent(s) or legal representative(s) has the option to allow this 
testing for additional research assessments.
Samples will be stored until used up or for a maximum of 10 years after the last subject visit in 
this study, after which any residual material will be destroyed.
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7.14
Concomitant Medications, Therapies, and Medical/Surgical Interventions 
Assessments
All medications, therapies/interventions administered to and medical/surgical procedures 
performed on subjects from the time of informed consent through the follow-up contact are 
regarded as concomitant and will be recorded on the subject’s eCRF. 
Concomitant therapies such as speech therapy, ergotherapy, music therapy, and physical therapy 
are permitted, and will also be recorded on the subject’s eCRF during the study.
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.
7.15
Adverse Events Assessments
7.15.1
Definitions of Adverse Events and Serious Adverse Events
7.15.1.1
Adverse Event
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 case report form 
(CRF), regardless of the severity or relationship to investigational product. The investigator
should treat subjects 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 subject, questioning of the subject or his parent(s)/legally authorized 
guardian(s), complaint by the subject 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 subject’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.
7.15.1.2
Elaprase-related Adverse Event 
All subjects 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 
subjects with Hunter syndrome are listed in Section 6.6.1. Note that, during weeks of IT dose 
administration in the Initial Treatment Phase, 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. 
7.15.1.3
Elaprase and/or idursulfase-IT-related Adverse Event
During the Extended Treatment Phase, the investigator will have the option of administering the 
IV Elaprase infusion and idursulfase-IT on the same day. With same-day dosing, it may not be 
possible to distinguish idursulfase of IV-administered origin from that of IT-administered origin. 
Therefore, adverse events that are potentially related to IV Elaprase infusion and/or 
idursulfase-IT administration will be captured.
7.15.1.4
Intrathecal Drug Delivery Device-related Adverse Events 
Examples of AEs related to use of the IDDD include, but are not limited to, the following: device 
failure, device malfunction, incorrect connection of IDDD components, erosion of the 
portal/catheter through the skin, fibrin sheath formation around the catheter tip, hematoma, 
implant rejection, migration of the portal/catheter, occlusion of the portal/catheter, portal site or 
subcutaneous tract infection. A malfunction of the device (defined in Section 7.15.2.2) should 
not be entered as an adverse event unless it has physiological consequences. In the event of a 
device failure (defined in Section 7.15.2.3), the device may need to be replaced or repaired. If 
overnight hospitalization is required for such a procedure (or the device failure meets any other 
serious criteria, eg, medically important), the device failure will be reported as a serious adverse 
event. Details of the cause of the IDDD malfunction or failure will be recorded on the device
malfunction and failure eCRF, and the serious adverse event (SAE) form (where applicable). A 
list of the most common IDDD AEs is included in Appendix 24.
7.15.1.5
Device Surgical Procedure-related Adverse Events 
Examples of AEs related to device surgical procedures include, but are not limited to, the 
following: events that occur during or shortly following IDDD implant/explant, IDDD 
adjustment, full revision, partial revision, IDDD removal, and delayed re-implantation after 
previous IDDD removal (such as complications of anesthesia, excessive bleeding, wound 
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hematoma), and post-operative complications (such as post-operative infection). These events 
are related to the surgical procedure itself.
7.15.1.6
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 Huber needle), or complications of lumbar puncture.
7.15.1.7
Serious Adverse Event
An SAE is any AE 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 [refer to Section 7.7])
•
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 subject 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 subject, 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.
7.15.1.8
Unanticipated Adverse Device Effect 
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 subjects (21CFR812.3[s] or other regulatory 
requirements, as applicable). 
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7.15.2
Device-associated Definitions
7.15.2.1
Device Revision (Partial and Full)
Partial device revision: surgical revision/replacement of 1 or more component(s) of the device; 
other component(s) of the original device remain implanted and are not affected (eg, port 
revision).
Full device revision: the device is removed (explanted) in its entirety and a completely new 
device is implanted.
7.15.2.2
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.
7.15.2.3
Device Failure
The device irreversibly fails to perform as intended and requires either a partial or full device 
revision or removal.
7.15.2.4
Device Adjustment
Device adjustment is surgery of the device which does not result in partial or complete revision 
or removal (eg, surgical exploration only or placement of additional sutures, tissue glue, and/or 
fascial repair).
7.15.3
Classification of Adverse Events and Serious Adverse Events
The severity of AEs will be assessed by the investigator based on the definition indicated in
Table 4. The severity of all AEs and SAEs should be recorded on the appropriate eCRF page to a 
severity of mild, moderate, or severe.
Table 4
Adverse Event Severity
Severity
Definition
Mild
No limitation of usual activities.
Moderate
Some limitation of usual activities.
Severe
Inability to carry out usual activities.
7.15.4
Clarification between Serious and Severe
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache). This is not the same as “serious,” which is based 
on the outcome or action criteria usually associated with events that pose a threat to life or 
functioning (refer to Section 7.15.1.7). Seriousness (not severity) and causality serve as a guide 
for defining regulatory reporting obligations.
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7.15.5
Relatedness of Adverse Events and Serious Adverse Events
Relationship of an AE or SAE to investigational product, IDDD, device surgical procedure, or IT 
administration process will be assessed by the investigator as follows:
•
Relationship to idursulfase-IT
•
Relationship to IV Elaprase infusion will be assessed by the investigator as described in 
Section 7.15.1.2
•
Relationship to IV Elaprase infusion and/or idursulfase-IT as described in Section 7.15.1.3
•
Relationship to the IDDD (examples of IDDD-related adverse events are listed in 
Section 7.15.1.4)
•
Relationship to a device surgical procedure (surgical implantation of the IDDD, partial or full 
device revision as described in Section 7.15.1.5)
•
Relationship to the IT administration process (examples of IT administration process-related 
adverse events are listed in Section 7.15.1.6)
The relationship to study treatment will be categorized based on the definitions provided in Table 
5.
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Table 5
Adverse Event Relatedness
Relationship
Definition
Not Related
Unrelated to investigational product, device, device surgical 
procedure, or IT administration process.
Possibly Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of investigational product, the presence of 
the device, device surgical procedure, or IT administration process 
but which could also be explained by concurrent disease or other 
drugs or chemicals.
Probably Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of investigational product, the presence of 
the device, device surgical procedure, or IT administration process
unlikely to be attributable to concurrent disease or other drugs and 
chemicals and which follows a clinically reasonable response on de-
challenge. The association of the clinical event or laboratory 
abnormality must also have some biologic plausibility, at least on 
theoretical grounds.
Definitely related
The event follows a reasonable temporal sequence from 
administration of the investigational product, the presence of the 
device, device surgical procedure, or IT administration process 
follows a known or suspected response pattern to the investigational 
product, is confirmed by improvement upon stopping the 
investigational product (de-challenge), and reappears upon repeated 
exposure (re-challenge). Note that this is not to be construed as 
requiring re-exposure of the subject to investigational product; 
however, the determination of definitely related can only be used 
when recurrence of event is observed.
7.15.6
Procedures for Recording and Reporting Adverse Events
7.15.6.1
Adverse Event Monitoring and Period of Observation
Adverse events will be monitored continuously throughout the study.
For the purposes of this study, the period of observation extends from the time at which the 
subject, the subject’s parent(s), or the subject’s legally authorized representative gives informed 
consent until the subject’s final evaluation of the study. For safety purposes, the final evaluation 
will be defined as the follow-up (EOS) evaluation performed approximately 28 days after the last 
dose for subjects who complete the study.
If the investigator considers it necessary to report an AE in a study subject after the end of the 
safety observation period, he or she should contact the sponsor to determine how the AE should 
be documented and reported.
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The device manufacturer will submit mandatory medical device reports (MDRs) (ie, 
unanticipated adverse device effects) to the relevant regulatory agencies consistent with 
applicable regulations and Shire will submit MDRs to the Investigational New Drug application 
(IND). Shire will report expedited drug related events (serious, unexpected/unlisted, causally 
related) to the relevant regulatory agencies consistent with applicable regulations.
It is the responsibility of the sponsor to ensure that each investigator receives a copy of any 
CIOMS I/MDR report that has been submitted to the appropriate regulatory agencies notifying 
them of an unexpected drug-related serious adverse event or unanticipated adverse device effect 
(submitted by the sponsor or manufacturer, respectively). The investigator must ensure that the 
IRB/IEC receives a copy of the report and that a copy is also filed within their study files.
7.16
Pregnancy
Not applicable.
7.17
Abuse, Misuse, Overdose, and Medication Error
Abuse – Persistent or sporadic intentional intake of investigational product at a dose higher than 
prescribed per protocol (but below the dose defined for overdose) or when used for non-medical 
purpose (eg, altering one’s state of consciousness).
Misuse – Intentional or unintentional use of investigational product other than as directed or 
indicated at any dose, which is at or below the dose defined for overdose (Note: This includes a 
situation where the investigational product is not used as directed at the dose prescribed by the 
protocol).
Overdose – Intentional or unintentional intake of a dose of investigational product higher than 
the protocol-mandated dose. No clinical information on overdose is available. Idursulfase-IT has 
been well tolerated at the highest once monthly dose (30 mg) administered intrathecally to 
pediatric subjects in clinical trials.
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 Global 
Drug Safety Department AND to the Shire medical monitor on the SAE form. This form must be 
completed and FAXED or EMAILED within 24 hours of the investigator’s learning of the event 
(refer to the contact information for reporting of SAEs provided in Section 7.15.6.2).
7.18
Removal of Subjects from the Trial or Investigational Product
A subject’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 subject from the study:
•
The subject exhibits non-compliance with the study protocol that is considered disruptive to 
study conduct.
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•
The subject was erroneously included in the study.
•
The subject develops an exclusion criterion.
•
The subject suffers an intolerable adverse event.
•
The study is terminated by the sponsor.
The subject or the subject’s parent(s) or legally authorized guardian(s) acting on behalf of the 
subject is free to withdraw consent and discontinue participation in the study at any time without 
prejudice to further treatment.
If the subject or the subject’s parent(s) or legally authorized guardian(s) acting on behalf of the 
subject discontinues participation in the study, or the subject is discontinued by the investigator,
reasonable efforts will be made to follow the subject 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 subject withdraws from the study, the subject 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.
7.19
Other Study Procedures
7.19.1
Safety-related Study Stopping Rules
This study will be stopped and the safety data reviewed if any subject experiences a 
life-threatening serious adverse event or a death occurs, if either is considered possibly, 
probably, or definitely 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:
•
Resumed unchanged
•
Resumed with modifications to the protocol 
•
Terminated
Subject safety in this study will be monitored by an independent DMC until the last subject
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 (refer to Section 11.8 for additional details).
7.20
Appropriateness of Measurements
The measures of safety to be used in the study are appropriate for a long-term follow-up 
interventional study in MPS II subjects. These include, but are not limited to, monitoring of 
adverse events and medication use, both standard parameters for the assessment of safety.
Secondary efficacy endpoints have been included for the purposes of providing additional data to 
support a long-term evaluation of efficacy in follow-up to the antecedent study. 
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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 continue to assess cognitive and adaptive functions in children with MPS II. These 
assessment tools (DAS-II [BSID-III] and 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. For the DAS-II, 
Spanish-speaking subjects will be assessed using the Spanish version of the DAS II-Early Years 
and the DAS-II School Year. The BSID-III will be used to assess subjects who cannot be 
assessed with the DAS-II. 
As in the antecedent study, any subjects who cannot be assessed with the DAS-II due to a 
deteriorating condition or who are too young (younger than 2 years, 6 months of age) will be 
assessed with the BSID-III. The BSID-III measures the mental and motor development and test 
the behavior of infants from 1 to 42 months of age and has been used extensively worldwide. 
The BSID-III consists of a core battery of scales and is suitable for use in children from 1 to 
42 months of age. Three scales (Motor [Fine, Gross], Language [Receptive, Expressive], and 
Cognitive) are administered with child interaction. The first item set of the 3 main subtests of the 
DAS-II (Verbal comprehension, Naming Vocabulary and Pattern Construction) will be 
administered initially. If the subject cannot complete these, the BSID-III will be used to assess 
cognition. The BSID-III scale is recommended for low-functioning and nonverbal or preverbal 
children, and as such, is used primarily during the study to assess the neurodevelopmental status 
of subjects who are unable to complete the DAS-II.
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 
(or BSID-III) and VABS-II will be utilized as the primary and secondary assessment tools for 
efficacy. 
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8
STUDY ACTIVITIES
The schedule for each study activity is specified in the Schedule of Events. The Schedule of 
Events for the Initial Treatment Phase is in Appendix 1 and the Schedule of Events for the 
Extended Treatment Phase is in Appendix 2, Appendix 3, Appendix 4, Appendix 5, Appendix 6, 
Appendix 7, Appendix 8, Appendix 9, Appendix 10, Appendix 11, and Appendix 12.
As described in Section 4.1.3, when a subject has received and tolerated a total of 12 monthly 
doses of intrathecal idursulfase-IT across studies HGT-HIT-094 and SHP609-302, the sponsor 
and principal investigator will consider the feasibility of transitioning the subject’s monthly IT 
dosing to local sites to reduce the burden imposed by monthly travel. Exceptions include study 
visits at which PK, MRI, and neurodevelopmental assessments are scheduled; these will take 
place at the main site.
General anesthesia or sedation may be required for injections of investigational product and 
some evaluations, and can be used at the discretion of the investigator as indicated in the study 
manuals. It is anticipated that study procedures such as lumbar puncture and MRI will have to be 
performed with sedation/anesthesiology support.
8.1
Initial Treatment Phase (Subjects Who Were Not Treated with Idursulfase-IT in 
Study HGT-HIT-094 Only)
8.1.1
Baseline (Month -1, Week -1, Days -7 to Day -1) – Initial Treatment Phase
The following procedures will be performed up to 7 days prior to enrollment (ie, Day -7 to 
Day -1): 
•
Written informed consent (assent if applicable) by subject’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 (since EOS in Study HGT-HIT-094)
•
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.)
•
HCUQ and CIQ
•
HS-FOCUS
•
Concomitant medications, therapies/interventions, and medical/surgical procedures
•
Adverse events
Any data from HGT-HIT-094 EOS assessments may be carried over to baseline in this study, as 
necessary for analysis.
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8.1.2
Confirmation of Study Eligibility (Month 0, Week 0) – Initial Treatment 
Phase
Enrollment will be confirmed with a confirmation of study eligibility. An assessment of AEs and 
concomitant medications, therapies/interventions, and medical/surgical procedures will also be 
performed.
8.1.3
Intrathecal Drug Delivery Device Implantation (Week 2 [-14, +7 Days]) –
Initial Treatment Phase
Subjects who did not receive treatment with idursulfase-IT in Study HGT-HIT-094 will undergo 
surgical implantation of the IDDD. Surgical implantation of the IDDD includes surgical 
implantation of the IDDD, and a post-surgical assessment. IDDD placement will require 
anesthesia. At least 14 days will be allowed for recovery following the placement of the IDDD 
before the administration of the first IT dose.
This Week 2 visit may occur as early as Week 0, as soon as the subject has been enrolled (ie, 
study eligibility has been confirmed).
8.1.3.1
Prior to Surgery for Intrathecal Drug Delivery Device Implantation –
Initial Treatment Phase
•
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
8.1.3.2
Surgery to Implant Intrathecal Drug Delivery Device – Initial Treatment 
Phase
•
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
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8.1.3.3
Follow-up to Surgery to Implant Intrathecal Drug Delivery Device –
Initial Treatment Phase
The following assessments will be performed after surgery and prior to discharge. It is expected 
that, for most subjects, 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
8.1.4
Treatment and Assessments (Months 1-12, Weeks 4-48 [±7 Days]) – Initial 
Treatment Phase
8.1.4.1
Months 1-12 (Weeks 4-48 [±7 Days]) – Prior to Intrathecal Injection –
Initial Treatment Phase
•
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)
•
DAS-II 
•
BSID-III for subjects unable to complete the DAS-II
•
VABS-II
•
Twelve-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, and 40)
•
Anti-idursulfase antibody testing (serum and CSF, performed at Weeks 4, 16, 28, and 40)
•
Serum albumin (performed at Weeks 4, 16, 28, and 40)
•
CSF GAG and idursulfase (performed at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48) 
•
EQ-5D-5L (performed at Weeks 4, 16, 28, and 40)
•
HCUQ and CIQ (performed at Weeks 4, 16, 28, and 40)
•
HS-FOCUS (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 subject can arrive at the study site early in the day and if 
the investigator deems this clinically appropriate.
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8.1.4.2
Months 1-12 (Weeks 4-48 [±7 Days]) – Intrathecal Injection – Initial 
Treatment Phase
Subjects will remain under observation in the hospital setting (eg, may include infusion center, 
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, 
subjects may leave the hospital setting (with exception of Visit Weeks 4 and 48 at which serial 
blood sampling for PK evaluation is planned). The subject may need to be examined the 
following day (see follow-up, Section 8.1.4.3) 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.
•
Twelve-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), GAG, albumin, 
concentration of idursulfase enzyme, 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 and 48). Samples will be collected 
within 30 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
8.1.4.3
Months 1-12 (Weeks 4-48 [±7 Days]) – Safety Follow-up for Intrathecal 
Injection – Initial Treatment Phase
For the first 6 months of treatment with idursulfase-IT (ie, Weeks 4, 8, 12, 16, 20, 24), subjects 
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 subject 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, subjects may complete the 
safety follow-up visit on the same day as IT administration prior to discharge.
•
Physical and neurological examination
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•
Concomitant medications, therapies/interventions, and medical/surgical procedures
•
Adverse events
8.2
Extended Treatment Phase (All Subjects)
For subjects entering this extension study who previously received 12 months of treatment with 
intrathecal idursulfase-IT in Study HGT-HIT-094, results of Study HGT-HIT-094 EOS 
assessments may provide Month 13 values for this study, if necessary.
8.2.1
Month 13 (Week 52 [±7 Days]) – Extended Treatment Phase– All Subjects
8.2.1.1
Month 13 (Week 52 [±7 Days]) – Prior to Intrathecal Injection – Extended 
Treatment Phase – All Subjects
Pre-treatment assessments may be performed on the same day as IT administration of 
idursulfase-IT, if the subject can arrive at the study site early in the day and if the investigator
deems this clinically appropriate.
Only Subjects Who Were Previously Treated with Idursulfase-IT in Study 
HGT-HIT-094
•
Written informed consent (assent if applicable) by subject’s parent(s) or legally authorized 
guardian(s) prior to any study-related procedures 
•
Assessment of eligibility according to review of study entry criteria
•
Enrollment
Only Subjects Continuing from the Initial Treatment Phase
•
Physical and neurological examination
•
Height and weight
•
Head circumference
•
Hearing assessment
•
Neurodevelopmental assessment
•
Twelve-lead ECG
•
Vital signs
•
Clinical laboratory tests
•
Urine GAG and creatinine
•
Anti-idursulfase antibody testing (serum)
•
General anesthesia
•
Brain MRI
•
Serum albumin
•
EQ-5D-5L
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All Subjects
•
HCUQ and CIQ
•
HS-FOCUS
•
Concomitant medications, therapies/interventions, and medical/surgical procedures
•
Adverse events
8.2.1.2
Month 13 (Week 52 [±7 Days]) – Intrathecal Injection – Extended 
Treatment Phase – All Subjects
Subjects will remain under observation in the hospital setting (eg, may include infusion center, 
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, 
subjects may leave the hospital setting. The subject may need to be examined the following day 
(see Follow-up, Section 8.1.4.3) by the investigator; however, there is no requirement for an 
overnight hospital stay. Note that, on IT Dosing Weeks during the Initial Treatment Phase, the 
IV infusion of Elaprase should be scheduled to occur a minimum of 48 hours after IT 
administration of idursulfase-IT. However, during the Extended Treatment Phase only, the 
investigator will have the option of administering the IV Elaprase infusion and idursulfase-IT on 
the same day. Please refer to Section 7.7.1 for details.
Only Subjects Continuing from the Initial Treatment Phase
•
CSF sample collection (performed prior to idursulfase-IT injection). Cerebrospinal fluid 
samples will be collected via the IDDD or lumbar puncture and used to analyze GAG, 
albumin, concentration of idursulfase enzyme, and presence of idursulfase-specific 
antibodies. 
All Subjects
•
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 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)
•
Idursulfase-IT injection  
•
Concomitant medications, therapies/interventions, and medical/surgical procedures
•
Adverse events
8.2.1.3
Month 13 (Week 52 [±7 Days]) – Safety Follow-up for Intrathecal 
Injection – Extended Treatment Phase – All Subjects
•
Concomitant medications, therapies/interventions, and medical/surgical procedures
•
Adverse events
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In the absence of any safety concerns, subjects may complete this safety follow-up visit on the 
same day as IT administration prior to discharge.
8.2.2
Months 14, 15, 17, 18, 20, 21, 23, 24, 26, 27, 29, 30, 32, 33, 35, 36, 38, 39, 41, 
42, 44, 45, 47, 48, 50, 51, 53, 54, 56, 57, 59, 60, 62, 63, 65, 66, 68, 69, 71, 72, 
74, 75, 77, 78, 80, 81, 83, 84, 86, 87, 89, 90, 92, 93, 95, 96, 98, 99, 101, 102, 
104, 105, 107, 108, 110, 111, 113, 114, 116, 117, 119, 120 (Weeks 56, 60, 68, 
72, 80, 84, 92, 96, 104, 108, 116, 120, 128, 132, 140, 144, 152, 156, 164, 168, 
176, 180, 188, 192, 200, 204, 212, 216, 224, 228, 236, 240, 248, 252, 260, 264, 
272, 276, 284, 288, 296, 300, 308, 312, 320, 324, 332, 336, 344, 348, 356, 360, 
368, 372, 380, 384, 392, 396, 404, 408, 416, 420, 428, 432, 440, 444, 452, 456, 
464, 468, 476, 480 [±7 Days]) – Extended Treatment Phase – All Subjects 
8.2.2.1
Months 14, 15, 17, 18, 20, 21, 23, 24, 26, 27, 29, 30, 32, 33, 35, 36, 38, 39, 41, 
42, 44, 45, 47, 48, 50, 51, 53, 54, 56, 57, 59, 60, 62, 63, 65, 66, 68, 69, 71, 72, 
74, 75, 77, 78, 80, 81, 83, 84, 86, 87, 89, 90, 92, 93, 95, 96, 98, 99, 101, 102, 
104, 105, 107, 108, 110, 111, 113, 114, 116, 117, 119, 120 (Weeks 56, 60, 68, 
72, 80, 84, 92, 96, 104, 108, 116, 120, 128, 132, 140, 144, 152, 156, 164, 168, 
176, 180, 188, 192, 200, 204, 212, 216, 224, 228, 236, 240, 248, 252, 260, 264, 
272, 276, 284, 288, 296, 300, 308, 312, 320, 324, 332, 336, 344, 348, 356, 360, 
368, 372, 380, 384, 392, 396, 404, 408, 416, 420, 428, 432, 440, 444, 452, 456, 
464, 468, 476, 480 [±7 Days]) – Prior to Intrathecal Injection – Extended
Treatment Phase – All Subjects 
•
Physical and neurological examination 
•
Vital signs
•
Concomitant medications, therapies/interventions, and medical/surgical procedures
•
Adverse events
Pre-treatment assessments may be performed on the same day as IT administration of 
idursulfase-IT, if the subject can arrive at the study site early in the day and if the investigator
deems this clinically appropriate.
8.2.2.2
Months 14, 15, 17, 18, 20, 21, 23, 24, 26, 27, 29, 30, 32, 33, 35, 36, 38, 39, 41, 
42, 44, 45, 47, 48, 50, 51, 53, 54, 56, 57, 59, 60, 62, 63, 65, 66, 68, 69, 71, 72, 
74, 75, 77, 78, 80, 81, 83, 84, 86, 87, 89, 90, 92, 93, 95, 96, 98, 99, 101, 102, 
104, 105, 107, 108, 110, 111, 113, 114, 116, 117, 119, 120 (Weeks 56, 60, 68, 
72, 80, 84, 92, 96, 104, 108, 116, 120, 128, 132, 140, 144, 152, 156, 164, 168, 
176, 180, 188, 192, 200, 204, 212, 216, 224, 228, 236, 240, 248, 252, 260, 264, 
272, 276, 284, 288, 296, 300, 308, 312, 320, 324, 332, 336, 344, 348, 356, 360, 
368, 372, 380, 384, 392, 396, 404, 408, 416, 420, 428, 432, 440, 444, 452, 456, 
464, 468, 476, 480 [±7 Days]) – Intrathecal Injection – Extended 
Treatment Phase – All Subjects
Subjects will remain under observation in the hospital setting (eg, may include infusion center, 
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, 
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subjects may leave the hospital setting. The subject may need to be examined the following day
(see Follow-up, Section 8.1.4.3) by the investigator; however, there is no requirement for an 
overnight hospital stay. Note that, on IT Dosing Weeks during the Initial Treatment Phase, the 
IV infusion of Elaprase should be scheduled to occur a minimum of 48 hours after IT 
administration of idursulfase-IT. However, during the Extended Treatment Phase only, the 
investigator will have the option of administering the IV Elaprase infusion and idursulfase-IT on 
the same day. Please refer to Section 7.7.1 for details.
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 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)
•
Idursulfase-IT injection  
•
Concomitant medications, therapies/interventions, and medical/surgical procedures
•
Adverse events
8.2.2.3
Months 14, 15, 17, 18, 20, 21, 23, 24, 26, 27, 29, 30, 32, 33, 35, 36, 38, 39, 41, 
42, 44, 45, 47, 48, 50, 51, 53, 54, 56, 57, 59, 60, 62, 63, 65, 66, 68, 69, 71, 72, 
74, 75, 77, 78, 80, 81, 83, 84, 86, 87, 89, 90, 92, 93, 95, 96, 98, 99, 101, 102, 
104, 105, 107, 108, 110, 111, 113, 114, 116, 117, 119, 120 (Weeks 56, 60, 68, 
72, 80, 84, 92, 96, 104, 108, 116, 120, 128, 132, 140, 144, 152, 156, 164, 168, 
176, 180, 188, 192, 200, 204, 212, 216, 224, 228, 236, 240, 248, 252, 260, 264, 
272, 276, 284, 288, 296, 300, 308, 312, 320, 324, 332, 336, 344, 348, 356, 360, 
368, 372, 380, 384, 392, 396, 404, 408, 416, 420, 428, 432, 440, 444, 452, 456, 
464, 468, 476, 480 [±7 Days]) Safety Follow-up for Intrathecal Injection –
Extended Treatment Phase – All Subjects
•
Concomitant medications, therapies/interventions, and medical/surgical procedures
•
Adverse events
In the absence of any safety concerns, subjects may complete the safety follow-up visit on the 
same day as IT administration prior to discharge.
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8.2.3
Months 16, 22, 28, 34, 40, 43, 46, 52, 55, 58, 64, 70, 76, 82, 88, 94, 100, 103, 
106, 112, 115, 118 (Weeks 64, 88, 112, 136, 160, 172, 184, 208, 220, 232, 256, 
280, 304, 328, 352, 376, 400, 412, 424, 448, 460, 472 [±7 Days]) – Extended 
Treatment Phase – All Subjects
8.2.3.1
Months 16, 22, 28, 34, 40, 43, 46, 52, 55, 58, 64, 70, 76, 82, 88, 94, 100, 103, 
106, 112, 115, 118 (Weeks 64, 88, 112, 136, 160, 172, 184, 208, 220, 232, 
256, 280, 304, 328, 352, 376, 400, 412, 424, 448, 460, 472 [±7 Days]) – Prior 
to Intrathecal Injection – Extended Treatment Phase – All Subjects
•
Physical and neurological examination 
•
Height and weight 
•
Vital signs
•
Clinical laboratory tests (hematology, serum chemistry, urinalysis)
•
Urine GAG and creatinine 
•
Anti-idursulfase antibody testing (serum)
•
Serum albumin
•
Concomitant medications, therapies/interventions, and medical/surgical procedures
•
Adverse events
Pre-treatment assessments may be performed on the same day as IT administration of 
idursulfase-IT, if the subject can arrive at the study site early in the day and if the investigator 
deems this clinically appropriate.
8.2.3.2
Months 16, 22, 28, 34, 40, 43, 46, 52, 55, 58, 64, 70, 76, 82, 88, 94, 100, 103, 
106, 112, 115, 118 (Weeks 64, 88, 112, 136, 160, 172, 184, 208, 220, 232, 
256, 280, 304, 328, 352, 376, 400, 412, 424, 448, 460, 472 [±7 Days]) –
Intrathecal Injection – Extended Treatment Phase – All Subjects
Subjects will remain under observation in the hospital setting (eg, may include infusion center, 
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, 
subjects may leave the hospital setting. The subject may need to be examined the following day 
(see Follow-up, Section 8.1.4.3) by the investigator; however, there is no requirement for an 
overnight hospital stay. Note that, on IT Dosing Weeks during the Initial Treatment Phase, the 
IV infusion of Elaprase should be scheduled to occur a minimum of 48 hours after IT 
administration of idursulfase-IT. However, during the Extended Treatment Phase only, the 
investigator will have the option of administering the IV Elaprase infusion and idursulfase-IT on 
the same day. Please refer to Section 7.7.1 for details.
•
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 prior to idursulfase-IT injection). Cerebrospinal fluid 
samples will be collected via the IDDD or lumbar puncture and used to analyze standard 
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laboratory parameters (chemistries, cell counts), GAG, albumin, concentration of idursulfase 
enzyme, and presence of idursulfase-specific antibodies. 
•
Idursulfase-IT injection  
•
Concomitant medications, therapies/interventions, and medical/surgical procedures
•
Adverse events
8.2.3.3
Months 16, 22, 28, 34, 40, 43, 46, 52, 55, 58, 64, 70, 76, 82, 88, 94, 100, 103, 
106, 112, 115, 118 (Weeks 64, 88, 112, 136, 160, 172, 184, 208, 220, 232, 
256, 280, 304, 328, 352, 376, 400, 412, 424, 448, 460, 472 [±7 Days]) –
Safety Follow-up for Intrathecal Injection – Extended Treatment Phase –
All Subjects
•
Concomitant medications, therapies/interventions, and medical/surgical procedures
•
Adverse events
In the absence of any safety concerns, subjects may complete the safety follow-up visit on the 
same day as IT administration prior to discharge.
8.2.4
Months 19, 25, 31, 37, 43, 49, 55, 61, 67, 73, 79, 85, 91, 97, 103, 109, 115
(Weeks 76, 100, 124, 148, 172, 196, 220, 244, 268, 292, 316, 340, 364, 388, 412, 
436, 460 [±7 Days]) – Extended Treatment Phase – All Subjects
8.2.4.1
Months 19, 25, 31, 37, 43, 49, 55, 61, 67, 73, 79, 85, 91, 97, 103, 109, 115 
(Weeks 76, 100, 124, 148, 172, 196, 220, 244, 268, 292, 316, 340, 364, 388, 
412, 436, 460 [±7 Days]) – Prior to Intrathecal Injection – Extended 
Treatment Phase – All Subjects
•
Physical and neurological examination 
•
Height and weight
•
Head circumference (Months 25, 37, and 49 only)
•
Hearing assessment
•
Neurodevelopmental assessments
•
DAS-II
•
BSID-III for subjects unable to complete the DAS-II  
•
VABS-II
•
Vital signs
•
Clinical laboratory tests (hematology, serum chemistry, urinalysis)
•
Urine GAG and creatinine 
•
Anti-idursulfase antibody testing (serum)
•
General anesthesia
•
Brain MRI (Months 25, 37, and 49 only)
•
Serum albumin
•
EQ-5D-5L
•
HCUQ and CIQ
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•
HS-FOCUS
•
Concomitant medications, therapies/interventions, and medical/surgical procedures
•
Adverse events
Pre-treatment assessments may be performed on the same day as IT administration of 
idursulfase-IT, if the subject can arrive at the study site early in the day and if the investigator
deems this clinically appropriate.
8.2.4.2
Months 19, 25, 31, 37, 43, 49, 55, 61, 67, 73, 79, 85, 91, 97, 103, 109, 115
(Weeks 76, 100, 124, 148, 172, 196, 220, 244, 268, 292, 316, 340, 364, 388, 
412, 436, 460 [±7 Days]) – Intrathecal Injection – Extended Treatment 
Phase – All Subjects
Subjects will remain under observation in the hospital setting (eg, may include infusion center, 
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, 
subjects may leave the hospital setting. The subject may need to be examined the following day 
(see Follow-up, Section 8.1.4.3) by the investigator; however, there is no requirement for an 
overnight hospital stay. Note that, on IT Dosing Weeks during the Initial Treatment Phase, the 
IV infusion of Elaprase should be scheduled to occur a minimum of 48 hours after IT 
administration of idursulfase-IT. However, during the Extended Treatment Phase only, the 
investigator will have the option of administering the IV Elaprase infusion and idursulfase-IT on 
the same day. Please refer to Section 7.7.1 for details.
•
Twelve-lead ECG (Months 25, 37, and 49 only)
•
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 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), GAG, albumin, concentration of idursulfase 
enzyme, and presence of idursulfase-specific antibodies. 
•
Idursulfase-IT injection
•
Serum sampling for PK analysis will be collected at Month 25 only and within 30 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
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8.2.4.3
Months 19, 25, 31, 37, 43, 49, 55, 61, 67, 73, 79, 85, 91, 97, 103, 109, 115
(Weeks 76, 100, 124, 148, 172, 196, 220, 244, 268, 292, 316, 340, 364, 388, 
412, 436, 460 [±7 Days]) – Safety Follow-up for Intrathecal Injection –
Extended Treatment Phase – All Subjects
•
Concomitant medications, therapies/interventions, and medical/surgical procedures
•
Adverse events
In the absence of any safety concerns, subjects may complete the safety follow-up visit on the 
same day as IT administration prior to discharge.
8.3
End-of-study (Month 121, Week 484 [±7 Days]) – Extended Treatment Phase – All 
Subjects
•
Physical and neurological examination 
•
Height and weight
•
Head circumference
•
Hearing assessment
•
Neurodevelopmental assessments
•
DAS-II 
•
BSID-III for subjects unable to complete the DAS-II
•
VABS-II
•
Twelve-lead ECG
•
Vital signs
•
Clinical laboratory tests (hematology, serum chemistry, urinalysis)
•
Urine GAG and creatinine 
•
Anti-idursulfase antibody testing (serum)
•
General anesthesia
•
Brain MRI
•
X-ray
•
CSF sample collection. Cerebrospinal fluid samples will be collected via the IDDD or lumbar 
puncture and used to analyze standard laboratory parameters (chemistries, cell counts), GAG, 
albumin, concentration of idursulfase enzyme, and presence of idursulfase-specific 
antibodies. 
•
Serum albumin
•
EQ-5D-5L
•
HCUQ and CIQ
•
Concomitant medications, therapies/interventions, and medical/surgical procedures
•
Adverse events
Subjects who do not continue treatment with idursulfase-IT will have the IDDD removed.
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9
QUALITY CONTROL AND ASSURANCE
Training will occur at an investigator meeting or at the site initiation visit or both, and instruction 
manuals will be provided to aid consistency in data collection and reporting across sites.
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 and applicable 
local requirements. 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 Global Drug Safety database.
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10
STATISTICAL ANALYSES
10.1
General Methodology
Statistical analyses will be performed by the Biostatistics and Statistical Programming 
Department of Shire or its designee using SAS statistical software (SAS Institute, Cary, NC, 
USA), unless otherwise specified. Analysis methods will be detailed in the statistical analysis 
plan (SAP). 
Data from studies SHP609-302 and HGT-HIT-094 will be integrated for efficacy and safety 
analyses. Baseline for the subjects previously treated in HGT-HIT-094 will be the same as the 
baseline defined in HGT-HIT-094. Baseline for the previously untreated subjects (ie, No IT 
treatment) in HGT-HIT-094 will be the closest available assessment prior to the initial IDDD 
implant date, which takes place in Study SHP609-302, unless otherwise specified. This could 
potentially include EOS visit data from Study HGT-HIT-094. The analyses presented here will 
include the data measured at and after baseline. 
Safety data descriptive summaries will be presented for the Early IT group, Delayed IT group, 
and overall. The Early IT group and Delayed IT group designations are based on the treatment 
regimen (idursulfase-IT or No IT treatment) in the antecedent study (HGT-HIT-094). Subjects 
who participated in the HGT-HIT-094 substudy will be included in the Early IT group.
Efficacy data descriptive summaries will be presented separately for subjects who enrolled from 
the pivotal study or substudy of HGT-HIT-094. For subjects enrolled from the pivotal study, 
descriptive statistics will be presented by the Early IT group, the Delayed IT group, and overall. 
For secondary efficacy endpoints, the mean difference in the change at each time point between 
the 2 treatment groups (Early IT group and Delayed IT group) and the corresponding 90% 
confidence interval of the mean difference will be presented where appropriate. The mean values 
(±SD) for all efficacy endpoints will be graphed over time where appropriate.
Inferential testing is planned for some exploratory efficacy endpoints. The main exploratory 
efficacy analyses to examine the IT treatment effect will be rate of change (weighted) analyses of 
the exploratory efficacy endpoints from Visit Month 13/baseline to Visit Month 25/Week 52 as 
estimated by linear regression for DAS-II Early Years GCA scores and selected 
neurodevelopment assessment scores.
Summary statistics for continuous variables will include the n, mean, standard deviation, median, 
minimum, and maximum. Categorical variables will be summarized in a contingency table by 
the frequency and percentage of subjects in each category.
Efficacy data for subjects enrolled from the HGT-HIT-094 substudy will be presented in listings.
10.2
Determination of Sample Size
This is an open-label extension trial of Study HGT-HIT-094. Only eligible subjects who 
participated in Study HGT-HIT-094 may enroll in SHP609-302, and therefore no sample size 
calculation was performed.
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10.3
Method of Assigning Study Subjects to Treatment Groups
SHP609-302 is a non-randomized extension study in which all enrolled subjects receive 
idursulfase-IT treatment.
10.4
Population Description and Exposure
10.4.1
Data Integration Strategy
Data from studies SHP609-302 and HGT-HIT-094 will be integrated for data analyses. 
For safety and efficacy descriptive summary analyses using integrated data, the 2 treatment 
groups are the Early IT group and Delayed IT group based on HGT-HIT-094 treatment regimen 
(idursulfase-IT or No IT Treatment), defined as follows:

The Early IT group is defined as subjects who were randomized to the idursulfase-IT 
treatment cohort in study HGT-HIT-094 and continued IT treatment in study 
SHP609-302. HGT-HIT-094 substudy will be included in the Early IT group.

The Delayed IT group is defined as subjects who were randomized to the control cohort 
(No IT treatment) in study HGT-HIT-094 and began IT treatment in study SHP609-302. 
For exploratory efficacy analyses, only data collected in study SHP609-302 will be used; the
2 treatment groups are the Early IT group and Delayed IT group. 
Visit Month 13 of the SHP609-302 Extended Treatment Phase corresponds to the scheduled visit 
at which subjects in the Early IT group have completed 12 months of IT treatment in antecedent 
study HGT-HIT-094. The treatment regimen in HGT-HIT-094 comprised 1 month for surgical 
IDDD implantation at the beginning of the study followed by 12 months of IT treatment during 
HGT-HIT-094.
Likewise, Visit Month 25 of the SHP609-302 Extended Treatment Phase corresponds to the 
scheduled visit at which subjects in the Early IT group have completed two 12-month periods of 
IT treatment, and comprises 1 month for surgical IDDD implantation at the beginning of HGT-
HIT-094, 12 months of IT treatment during HGT-HIT-094, and a continued 12 months of IT 
treatment in the Extended Treatment Phase of SHP609-302. 
Visit Week 52 of the SHP609-302 Initial Treatment Phase is the scheduled visit at which 
subjects in the Delayed IT group have completed 12 months of IT treatment in study 
SHP609-302, and comprises 12 months of No IT treatment during HGT-HIT-094, 1 month for 
surgical IDDD implantation at the beginning of SHP609-302, and 12 months of IT treatment in 
the Initial Treatment Phase of SHP609-302. 
It is noted that Visit Month 25 and Visit Week 52 of SHP609-302 are 4 weeks apart for the Early 
IT and Delayed IT groups. This difference is accounted for by the need for subjects in the 
Delayed IT group, who enrolled into the Initial Treatment Phase of SHP609-302 from the 
HGT-HIT-094 No IT treatment group, to undergo surgical implantation of the device at the 
beginning of study SHP609-302. Therefore, the first dose of SHP609 was administered 4 weeks 
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later to these subjects compared with subjects in the Early IT group who were randomized to IT 
treatment and underwent IDDD implantation in HGT-HIT-094 prior to enrolling in the Extended 
Treatment Phase of SHP609-302. For evaluation of the long-term efficacy of IT treatment in 
SHP609-302, this 4-week difference is considered to have minimal impact on 
neurodevelopmental assessment scores.
10.4.2
Analysis Populations
All descriptive summary analyses of safety and efficacy data will be based on the Safety 
Population, which is defined as all subjects in study SHP609-302 who underwent IDDD 
implantation or received at least 1 dose of study drug (full or partial). 
The following nomenclature will be used to identify “A”, “B”, “C”, and “D” in Figure 2.

Observation Groups A and C identify the period of observation during study 
HGT-HIT-094, for subjects randomized to IT treatment and No IT treatment,
respectively. 

Observation Groups B and D identify the period of observation during study SHP609-302
up to completion of 1 year, for subjects who were randomized in HGT-HIT-094 to 
receive IT treatment and No IT treatment, respectively, noting that all subjects in 
SHP609-302 received IT treatment. 
The subjects in “B” are the same subjects as in “A” with periods of observation from studies 
SHP609-302 and HGT-HIT-094, respectively, as we can view “B” as a continuation of “A”. The 
subjects in “D” are the same subjects as in “C” with periods of observation from studies 
SHP609-302 and HGT-HIT-094, respectively, as we can view “D” as a continuation of “C”.
“D” subjects are therefore similar to “A” subjects since these subjects all transitioned from 
receiving weekly IV infusion of Elaprase, to also receive monthly IT idursulfase. More 
generally, because study SHP609-302 did not have baseline GCA inclusion criteria, such as that 
employed for study HGT-HIT-094, “B” and “D” subjects could differ with regard to their 
baseline GCA score at the beginning of the observation period. Therefore, for consideration of 
“B” and “D”, only subjects meeting the key inclusion criteria to HGT-HIT-094 will be included 
in inferential efficacy analyses, ie, with GCA scores between 55 and 85 inclusive at the 
enrollment of SHP609-302.
The exploratory efficacy analyses will be conducted on “HGT-HIT-094 Comparable Set,”
“HGT-HIT-094 Comparable Set 1”, and “HGT-HIT-094 Comparable Set 2”. The primary 
analysis population is HGT-HIT-094 Comparable Subset 1, which may be the subject population 
with the most potential to benefit from the idursulfase-IT treatment.

HGT-HIT-094 Comparable Set: subjects in the Safety Population who met the key HGT-
HIT-094 inclusion criterion (baseline GCA scores between 55 and 85 inclusive) at 
enrollment in SHP609-302 (Visit Month 13/baseline), ie, Safety Population subjects with 
GCA scores between 55 and 85 inclusive at enrollment in SHP609-302

HGT-HIT-094 Comparable Subset 1 (primary analysis population): subjects in the 
HGT-HIT-094 Comparable Set with age <6 years at enrollment in SHP609-302 (Visit 
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Month 13/baseline), ie, Safety Population subjects with GCA scores between 55 and 85 
inclusive and age <6 years at enrollment in SHP609-302

HGT-HIT-094 Comparable Subset 2: subjects in the HGT-HIT-094 Comparable Set with 
age <55 months at the enrollment of SHP609-302 (Visit Month 13/baseline), ie, Safety 
Population subjects with GCA scores between 55 and 85 inclusive and age <55 months at 
enrollment in SHP609-302
Figure 2
Conceptual Plot of Treatment Periods in Early IT and Delayed IT Groups in 
Studies HGT-HIT-094 and SHP609-302
Device-related analyses will be conducted in the subset of subjects in the Safety Population who 
had the device implanted.
All pharmacokinetic data analyses will be performed using the PK population. The PK 
population will be defined as all subjects who received study drug and had sufficient serum 
samples collected to derive pharmacokinetic parameters.
10.4.3
Subject Disposition
The number of subjects screened, included in the Safety Population, completed the study, and 
discontinued prematurely will be presented in a summary table by the Early IT group, the 
Delayed IT group, and overall; reasons for discontinuation/withdrawal will also be summarized.
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10.4.4
Protocol Deviations
Reported protocol deviations and subject data will be examined prior to database lock to 
determine if conditions set forth in the study protocol have been violated. The complete list of 
protocol deviations will not be summarized; however, if applicable, protocol violations identified 
will be listed for the Safety Population.
10.4.5
Demographics and Baseline Characteristics
Demographic data and baseline characteristics will be summarized by the Early IT group, the 
Delayed IT group, and overall for the Safety Population. 
Medical history will be coded by the Medical Dictionary for Regulatory Activities (MedDRA) 
version 16.0 or higher and will be similarly summarized.
10.4.6
Treatment Compliance
Treatment compliance will be summarized by the Early IT group, the Delayed IT group, and 
overall for the Safety Population. Treatment compliance is defined as: [(Number of Complete IT 
administrations) ÷ (Expected Number of IT administrations)] * 100.
10.4.7
Extent of Exposure
The total number of doses of study drug, the number of doses received via IDDD, the number of 
doses received via LP and the average duration of IT administration will be summarized by the 
Early IT group, the Delayed IT group, and overall for the Safety Population. The duration of IT 
administration is calculated by subtracting the IT administration start time from the IT 
administration end time.
10.5
Analysis of Efficacy
10.5.1
Primary Efficacy Analysis
Not applicable.
10.5.2
Key Secondary Efficacy Analysis
Not applicable.
10.5.3
Other Secondary Efficacy Analysis
For all other efficacy endpoints described in Section 3.2, the observed values and change from 
baseline will be summarized descriptively for each assessment time point by the Early IT group, 
the Delayed IT group, and overall. Any HGT-HIT-094 substudy subjects will be included in the
Early IT group for analysis. The mean difference in the change at each time point between the 
two HGT-HIT-094 treatment groups and the corresponding 90% confidence interval of the mean 
difference will be presented. The BSID-III endpoints will be listed only. Graphical plots of the 
mean value for each endpoint over time will be presented. A spaghetti plot of the age equivalent 
scores for individual subjects will be plotted against chronological age.
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10.5.4
Subgroup Analyses
Subgroup descriptive summary analyses of the secondary efficacy endpoints, change from 
baseline in GCA and ABC scores will be performed for baseline GCA groups (either ≤70 or >70) 
and baseline age groups (either <6 years or ≥6 years; <55 months or ≥55 months). Descriptive 
summaries within these subgroups and plots of mean values (±SD) over time will be presented.
The baseline is defined in Section 10.1.
Subgroup analyses are planned for the rate of change (weighted) analyses in GCA scores from 
the Early Years battery, GCA scores and ABC scores for GCA classification groups at Visit 
Month 13/baseline (either ≤70 or >70), age groups at Visit Month 13/baseline (either <6 years or 
≥6 years), and age groups at Visit Month 13/baseline (either <55 months or ≥55 months).
10.5.5
Exploratory Analyses
The main exploratory efficacy analyses to examine the IT treatment effect will be rate of change 
(weighted) analyses of the exploratory efficacy endpoints from Visit Month 13/baseline to Visit 
Month 25/Week 52 in study SHP609-302 as estimated by linear regression for the following 
neurodevelopmental assessment scores:
•
DAS-II GCA scores from Early Years battery
•
DAS-II Early Years core subtests T scores: Verbal Comprehension, Picture Similarities, 
Naming Vocabulary, Pattern Construction, Matrices, and Copying
•
DAS-II Early Years battery standard cluster scores: Verbal, Nonverbal, Spatial, and SNC 
composite scores
•
DAS-II GCA scores including both Early Years and School Age batteries
•
VABS-II ABC scores
Complete details of the rate of change (weighted) analysis, including examination of premises of 
the rate of change (weighted) analysis, model diagnostics, and estimation and comparison of the 
treatment effects during observation periods “B” and “D” will be described in the SAP.
The descriptive summary of ordered categorical outcomes will be presented at Month 25/Week 
52 by the Early IT group, the Delayed IT group, and overall using the SHP609-302 data “B” and 
“D”. The definitions of ordered categorical outcomes for each subject are described in 
Section 3.3.
For each of the neurodevelopmental assessments, there may be a “floor effect”, ie, the lower 
limitation of the assessment tool, below which the assessment may not be reliable or meaningful.
Refer to the SAP for complete details.
Other exploratory analyses may include assessment of the correlation between PD and efficacy 
endpoints; and between composite scores and their components (ie, correlations between the 
GCA and ABC scores and their respective cluster/domain scores). Scatter plots may be presented 
to explore the relationships among variables.
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10.5.6
Health Economics and Outcomes Research Endpoint Analyses
The EQ-5D-5L 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 subjects with each response will be presented by dimension at each visit. 
The visual analog scale (VAS) records the subject’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 will be 
summarized as each time point. 
HCUQ variables include the number of emergency room visits, caregiver employment status 
(full time [FT], part time [PT], and not working [NW]), and the number of hours of additional 
paid help needed by caregivers, over the course of the study. The CIQ question items measure 
social, emotional, physical, and financial impacts on the caregiver. Descriptive statistics, 
including n, mean, median, and range (for continuous variables), and n and proportions (for 
categorical variables), for these key HCUQ and CIQ variables will be presented.
The HS-FOCUS shortened form will be used to assess subjects. Domain scores from the 
5 functional domains (walking/standing, grip/reach, schooling/work, activities, and breathing) 
will be summarized.
Additional 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 in a separate document.
10.6
Analysis of Pharmacokinetic and Pharmacodynamic Data
10.6.1
Pharmacokinetic Measurement and Parameters
The PK population will be used to perform the analysis of pharmacokinetic data. Idursulfase 
concentrations in all collected serum samples will be measured and reported. Individual subject 
idursulfase serum concentration-time profiles will be presented. Individual PK parameters will 
be derived by a noncompartmental analysis and reported. The actual PK blood sample collection 
times will be used to determine the individual subject idursulfase serum concentration-time 
profiles. Pharmacokinetic parameters will be calculated if sufficient idursulfase 
concentration-time points exist to derive values. Individual subject CSF idursulfase 
concentrations at each collection time point will be reported.
Pharmacokinetic parameters calculated will include:
•
Maximum observed serum concentration (Cmax)
•
Time of Cmax (Tmax)
•
Area under the serum concentration-time curve from time zero to the last sampling time at 
which serum concentrations were measurable (AUC0-last)
•
Area under the serum concentration-time curve extrapolated to infinity (AUC0-∞)
•
Apparent terminal rate constant (λz) derived from the slope of the log-linear regression of the 
log-linear terminal portion of the serum concentration-time curve.
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•
Terminal half-life (t1/2) calculated as 0.693/ λz
•
Mean residence time (MRT0-∞), calculated as AUMC0-∞/AUC0-∞
•
Clearance for IT-L administration (CL/F)
•
Volume of distribution based on the terminal phase for IT-L administration (Vz/F)  
The analysis of PK parameter data will be performed by the Shire Clinical Pharmacology and 
Pharmacokinetics department or its designee.
10.6.2
Pharmacodynamic Analyses 
The levels of GAG in CSF and urine are PD endpoints. Analyses of PD endpoints will be 
performed in the Safety Population. The observed values and changes from baseline in CSF 
GAG levels will be summarized for each assessment time by the Early IT group, Delayed IT 
group, and overall. A graphical plot of mean CSF GAG levels across time will be presented. The 
urine GAG levels will be analyzed in a manner similar to that described for CSF data.
10.7
Analysis of Safety
All analyses of safety data will be descriptive and presented by the Early IT group, Delayed IT 
group, and overall. The analysis of safety will be based on the Safety Population.
10.7.1
Adverse Events
Adverse events will be recorded throughout the study. Adverse events will be coded using the 
MedDRA dictionary, version 16.0 or higher.
Treatment-emergent AEs, defined as all AEs from the time of initial intervention (first surgery 
for IDDD implantation, including failed surgeries, or first dose if before first IDDD implantation 
surgery) to the EOS visit, will be summarized by the Early IT group, Delayed IT group, and 
overall. 
The number and percentage of subjects having an AE and the number of events, by system organ 
class (SOC) and preferred term will be presented. Treatment-emergent AEs will also be 
summarized by severity and degree of relationship to study drug. An adverse event will be 
considered related if indicated to be “possibly,” “probably,” or “definitely” related. In the case of 
multiple occurrences of the same AE (at the preferred term level) in an individual subject, the 
AE that is classified as the most severe (ie, maximum severity) will be identified for the analysis 
by severity and the AE that has the closest relationship to study drug/procedure will be identified 
for the analysis by relationship. In general, an AE will be considered a treatment-emergent AE if 
it cannot be definitively categorized otherwise by documentation that its onset preceded either 
IDDD surgery or first dose.
Serious adverse events will be similarly tabulated according to SOC and preferred term and 
presented in a separate listing.
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10.7.1.1
Investigational Product
Treatment-emergent AEs deemed by the investigator to be related to idursulfase-IT study drug 
will be summarized by presenting the number and percentage of subjects having an AE and the 
number of events, by SOC and preferred term. Separate tabulations of IV Elaprase 
infusion-related adverse events and IV Elaprase infusion and/or idursulfase-IT-related AEs will 
also be presented.
10.7.1.2
Intrathecal Drug Delivery Device and Surgical Procedure-related AEs 
IDDD and procedure-related AEs will be summarized within MedDRA system organ class 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 1 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 subjects in the Safety Population with the IDDD implanted.
10.7.2
Clinical Laboratory Evaluation
Observed values and changes from baseline for continuous laboratory test results will be 
summarized for each assessment time by the Early IT group, Delayed IT group, and overall. 
Each laboratory result will be categorized as a subject having had (1) an abnormal and clinically 
significant (CS) value at any time post-baseline, (2) no CS values at any time post-baseline, but 
had at least 1 Abnormal and not CS (NCS) value, and (3) no CS or NCS values at any time post-
baseline; the number and percentage in each category will be presented. For any subject who 
experiences a CS laboratory result at any time post-baseline that was not CS at baseline (or the 
most recent non-missing value prior to the start of the treatment), their entire profile for that 
particular laboratory parameter will be presented in a listing. 
10.7.3
Electrocardiogram Evaluation
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 subjects with ECG abnormalities will be presented.
10.7.4
Vital Signs
The observed values and changes from baseline for IT-administration vital sign parameters will 
be summarized. The IT vital signs will be graphed as box plots over the time from the start of the 
IT injection for each IT injection.
Height (cm), weight (kg), and head circumference (cm) and the change from baseline will be 
summarized for each assessment time point.
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10.7.5
Physical Findings
Clinically significant physical and neurological examination findings will be recorded and 
summarized as part of the medical history or adverse event data.
10.7.6
Other Observations Related to Safety
10.7.6.1
Intrathecal Drug Delivery Device Performance
Safety and performance data for the SOPH-A-PORT Mini S IDDD will be analyzed and 
summaries will be provided for implanted subjects. Difficulties associated with the implant 
procedure (eg, excessive bleeding, CSF leakage, etc.) will be summarized. A summary of 
abnormal findings from the device radiological assessments will also be presented. 
The proportion of subjects with at least 1 device failure and/or malfunction, as well as the 
number of and reasons for device failures/malfunctions will be summarized. The rate of device 
failures/malfunctions and 90% confidence interval will also be estimated. The time from initial 
implant surgery to first device failure and/or malfunction will be summarized. Subjects without a 
device failure/malfunction will be censored at their last study drug injection date. A by-subject 
listing of the device failure/malfunction data will be displayed.
The rate of successful IDDD injections will be calculated for each subject and summarized 
descriptively. The success rate will be calculated as the number of IDDD injections given as a 
percentage of IDDD injections given plus any malfunctions reported for inability to dose. The 
corresponding 90% confidence interval for the mean rate will be estimated, where appropriate. 
Injections that are not administered for subject-related reasons (eg, subject uncooperative, 
competing medical issue, etc.) will not be included in the determination of the injection success 
rate.
10.7.6.2
Immunogenicity
Anti-idursulfase antibody formation will be monitored throughout the study for both serum and 
CSF. The number and percentage of subjects testing anti idursulfase antibody positive and 
negative at each scheduled time point from baseline will be summarized by the Early IT group, 
Delayed IT group, and overall. Titer values will be summarized as box plots over time in 
subjects with positive antibodies at or prior to each scheduled visit by treatment group. Similar 
summaries will be presented for subjects who developed positive neutralizing antibodies.
10.7.7
Hearing Assessment
Any hearing assessment data will be summarized or listed as appropriate.
10.7.8
Concomitant Medications
Concomitant medications will be coded using the World Health Organization-Drug Dictionary 
(WHO-DD). The concomitant medications that occur from the time of the surgery for IDDD 
implantation to the last subject visit in the study, will be summarized by therapeutic class and 
preferred term. Concomitant therapies will be mapped using the MedDRA Version 16.0 or 
higher and will be similarly summarized by the SOC and preferred term.
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10.8
Statistical/Analytical Issues
10.8.1
Adjustment for Covariates
The rate of change (weighted) analysis will adjust for GCA classification (either ≤70 or >70) at 
enrollment of SHP609-302 in the weighted generalized linear model.
10.8.2
Handling of Dropouts or Missing Data
In general, no imputation will be performed and analyses will be based on available data. 
Missing or partial AE dates will not be imputed. However, a conservative approach will be 
adopted in such cases so that the AE will be deemed to be treatment emergent if it cannot be 
definitively categorized to have occurred prior to surgery for IDDD implantation. Similar logic 
will be applied to deal with missing and partial date for concomitant medications.
10.8.3
Interim Analyses and Data Monitoring
Interim analyses may be conducted before trial completion for safety monitoring, regulatory 
reporting or general planning purposes. Analyses will be descriptive in nature, with no formal 
comparisons planned and no hypotheses tested formally. An independent DMC will be 
established to provide an ongoing, independent review and assessment of subject safety data 
(refer to Section 11.8). An analysis of the data for DMC review will occur at specific times 
during the study as specified in the DMC charter.
10.8.4
Multicenter Studies
It is planned that the data from all centers that participate in this protocol will be combined so 
that an adequate number of subjects will be available for analysis. Because of the potential for a 
relatively large number of centers, and small numbers of subjects at some centers, no subset 
analyses by center are planned.
10.8.5
Multiple Comparisons/Multiplicity
No multiple comparison procedure or multiplicity adjustment will be performed.
10.8.6
Sensitivity Analyses
Given the design and objectives of the study, no sensitivity analyses are planned.
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11
ADMINISTRATIVE CONSIDERATIONS
11.1
Investigators and Study Administrative Structure
Before initiation of the study, the investigator must provide the sponsor with a completed Form 
FDA 1572, Investigator Agreement, or other applicable regulatory documentation. 
Investigational product may be administered only under the supervision of the investigator(s)
listed on these forms. 
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.
Curriculum vitae must be provided for the investigators and sub-investigators listed on Form 
FDA 1572 or other regulatory documentation, as applicable. 
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. Within 3 months of study completion or termination, a final 
report must be provided to the IRB/IEC. A copy of these reports will be sent to the study clinical 
monitor. The investigators must maintain an accurate and complete record of all submissions 
made to the IRB/IEC, including a list of all reports and documents submitted. Adverse events 
which are reported to the US FDA or other Regulatory agencies (safety reports) must be 
submitted promptly to the IRB/IEC.
11.3
Ethical Conduct of the Study
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the sponsor and investigators abide by 
good clinical practice (GCP) as described in the 21 CFR Parts 50, 56, and 312 and the 
International Conference on Harmonization (ICH) GCP Guidelines Compliance with these 
regulations and guidelines also constitutes compliance with the ethical principles described in the 
Declaration of Helsinki.
11.4
Subject Information and Consent
Before enrolling in the clinical study, the subject or the subject’s parent(s), guardian, or legally 
authorized representative(s) must consent to participate after the nature, scope, and possible 
consequences of the clinical study have been explained in a form understandable to him or her.
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An informed consent form (assent form if applicable) that includes information about the study 
will be prepared and given to the subject or the subject’s parent(s), guardian, or legally 
authorized representative(s). This document will contain all FDA and ICH-required elements. 
The informed consent (or assent) form must be in a language understandable to the subject or the 
subject’s parent(s) or legally authorized representative(s) and must specify who informed the
subject, the subject’s parent(s), or the subject’s legally authorized representative(s).
Note: When a subject has reached the legal age of consent to participate in a clinical study, but 
has been deemed by the investigator, in accordance with applicable law and IRB/IEC guidelines,
as lacking mental capacity to provide informed consent, the subject’s parent(s), guardian, or 
legally authorized representative(s) will be asked to provide informed consent on behalf of the 
subject to allow for continued participation in the trial.
After reading the informed consent document, the subject or the subject’s parent(s), guardian, or 
legally authorized representative(s) must give consent in writing. Consent must be confirmed at 
the time of consent by the personally dated signature of the subject, the subject’s parent(s) or the 
subject’s legally authorized representative(s) and by the personally dated signature of the person 
conducting the informed consent discussions.
If the subject or the subject’s parent(s) or legally authorized representative(s) is unable to read, 
oral presentation and explanation of the written informed consent form and information to be 
supplied must take place in the presence of an impartial witness. Consent must be confirmed at 
the time of consent orally and by the personally dated signature of the subject or by a local 
legally recognized alternative (eg, the subject’s thumbprint or mark) or by the personally dated 
signature of the subject’s parent(s) or the subject’s legally authorized representative. The witness 
and the person conducting the informed consent discussions must also sign and personally date 
the informed consent document. It should also be recorded and dated in the source document that 
consent was given.
A copy of the signed and dated consent document(s) must be given to the subject or the subject’s 
parent(s) or legal representative(s). The original signed and dated consent document will be 
retained by the investigator.
The investigator will not undertake any measures specifically required solely for the clinical 
study until valid consent has been obtained.
A model of the informed consent form(s) to be used in this study will be provided to the sites 
separately from this protocol.
11.5
Subject Confidentiality
Subject names will not be supplied to the sponsor. Only the subject number will be recorded in 
the eCRF, and if the subject 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 subjects will be told that 
representatives of the sponsor, a designated CRO, the IRB/IEC, or regulatory authorities may 
inspect their medical records to verify the information collected, and that all personal 
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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 subject
identification list (subject numbers with the corresponding subject 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 
eCRFs for completeness and clarity, cross-checking with source documents, and clarification of 
administrative matters will be performed.
The study will be monitored by the sponsor or its designee. Monitoring will be performed by a 
representative of the sponsor (clinical study monitor) who will review the eCRFs and source 
documents. The site monitor will ensure that the investigation is conducted according to protocol 
design and regulatory requirements by frequent site visits and communications (letter, telephone, 
and facsimile).
11.7
Case Report Forms and Study Records
11.7.1
Case Report Forms
Case report forms (paper or electronic) are provided for each subject. All forms must be filled 
out by authorized study personnel. All corrections to the original eCRF entry must indicate the 
reason for change. The investigator is required to sign the eCRF after all data have been captured 
for each subject. If corrections are made after review and signature by the investigator, he or she 
must be made aware of the changes, and his or her awareness documented by resigning the 
eCRF.
11.7.2
Critical Documents
Before Shire initiates the trial at a clinical site (ie, obtains informed consent from the first 
subject), it is the responsibility of the investigator to ensure that the following documents are 
available to Shire or its designee:
•
Applicable local regulatory documentation (eg, completed FDA Form 1572 [Statement of 
Investigator], 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 
regarding subject 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)
•
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; these are the 
responsibility of Shire.
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 
subjects 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 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
The investigator will conduct the study in compliance with the protocol. The protocol will not be 
initiated until the IRB/IEC and the appropriate regulatory authorities have given 
approval/favorable opinion. Modifications to the protocol will not be made without agreement of 
the sponsor. Changes to the protocol will require written IRB/IEC approval/favorable opinion 
prior to implementation, except when the modification is needed to eliminate an immediate 
hazard(s) to subjects. The IRB/IEC may provide, if applicable regulatory authorities permit, 
expedited review and approval/favorable opinion for minor change(s) in ongoing studies that 
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have the approval/favorable opinion of the IRB/IEC. The sponsor will submit all protocol 
modifications to the regulatory authorities in accordance with the governing regulations.
A record of subjects 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 
subjects, 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, or regulatory authorities discover conditions arising during the study 
which indicate that the clinical investigation should be halted due to an unacceptable subject risk, 
the study may be terminated after appropriate consultation between the sponsor and the 
investigator(s). In addition, a decision on the part of the sponsor to suspend or discontinue 
development of the investigational product may be made at any time. Conditions that may 
warrant termination of the study or site include, but are not limited to:
•
The discovery of an unexpected, significant, or unacceptable risk to the subjects enrolled in 
the study
•
Failure of the investigator to comply with pertinent global regulations
•
Submission of knowingly false information from the study site to the sponsor or other 
pertinent regulatory authorities
•
Insufficient adherence by the investigator to protocol requirements
11.12 Access to Source Documentation
Regulatory authorities, the IRB/IEC, or the sponsor (or their designee) may request access to all 
source documents, eCRFs, and other study documentation for onsite audit or inspection. Direct 
access to these documents must be guaranteed by the investigator, who must provide support at 
all times for these activities. Monitoring and auditing procedures that comply with current GCP 
guidelines will be followed. On-site review of the eCRFs for completeness and clarity, 
crosschecking with source documents, and clarification of administrative matters may be 
performed.
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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 Shire. Shire or its designee will be
responsible for performing study data management activities. 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA). 
Concomitant medication will be coded using WHO-DD. Centralized laboratories will be 
employed as described in the study manual to aid in consistent measurement of efficacy and 
safety parameters. 
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. 
The investigator should promptly update this information if any relevant changes occur in the 
course of the investigation or for 1 year following completion of the study.
11.16 Publication and Disclosure Policy
All information concerning the study material, such as patent applications, manufacturing 
processes, basic scientific data, and formulation information supplied by the sponsor and not 
previously published are considered confidential and will remain the sole property of the 
sponsor. The investigator agrees to use this information only in accomplishing this study and will 
not use it for other purposes.
It is understood by the investigator that the information developed in the clinical study may be 
disclosed as required to the authorized regulatory authorities and governmental agencies. In 
order to allow for the use of the information derived from the clinical studies, it is understood 
that there is an obligation to provide the sponsor with complete test results and all data developed 
in the study in a timely manner.
The investigator and any other clinical personnel associated with this study will not publish the 
results of the study, in whole or in part, at any time, unless they have consulted with Shire, 
provided Shire a copy of the draft document intended for publication, and obtained Shire’s 
written consent for such publication. All information obtained during the conduct of this study 
will be regarded as confidential. 
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12
LIST OF REFERENCES
1. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. 
JAMA 1999;281:249-54.
2. Young ID, Harper PS. Incidence of Hunter's syndrome. Hum Genet 1982;60:391-2.
3. Beck M. Mucopolysaccharidosis type II (Hunter syndrome): clinical picture and treatment. 
Curr Pharm Biotechnol 2011.
4. Martin R, Beck M, Eng C, et al. Recognition and diagnosis of mucopolysaccharidosis II 
(Hunter syndrome). Pediatr 2008;121:e377-86.
5. 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.
6. 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.
7. Young ID, Harper PS, Newcombe RG, Archer IM. A clinical and genetic study of Hunter's 
syndrome. 2. Differences between the mild and severe forms. J Med Genet 1982;19:408-11.
8. Holt JB, Poe MD, Escolar ML. Natural progression of neurological disease in 
mucopolysaccharidosis type II. Pediatr 2011;127:e1258-65.
9. 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.
10. 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; 2001:3421-52.
11. 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.
12. 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.
13. Muenzer J, Beck M, Eng CM, et al. Multidisciplinary management of Hunter syndrome. 
Pediatr 2009;124:e1228-39.
14. 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.
15. Wraith JE, Scarpa M, Beck M, et al. Mucopolysaccharidosis 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.
16. 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.
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17. Elliott, CD. Differential Ability Scales (Second Edition). San Antonio, TX: The 
Psychological Corporation; 2007.
18. Bayley N. Bayley Scales of Infant and Toddler Development (Third Edition). San Antonio, 
TX. The Psychological Corporation; 2005.
19. Sparrow S, Balla D, Cicchetti D. Vineland Adaptive Behavior Scales (Second Edition). 4201 
Woodland Road Circle Pines, MN 55014-1796: American Guidance Service, Inc; 2005.
20. Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQol Group. Annals of 
medicine 2001;33:337-43.
21. EuroQol--a new facility for the measurement of health-related quality of life. The EuroQol 
Group. Health Policy 1990;16:199-208.
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APPENDICES
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Appendix 13 Pharmacokinetic Sample Collection for Same-Day Investigational Product Administration with Elaprase 
Infusion
Assessment
Monthly Visits 13-120a
IT Dosing Week: Main Site only
Pre-Tx Day 1
IT Inj Day
Days 3-7
Serum Sample for PKb,c
●
Same-day Elaprase IV infusion and 
idursulfase-IT administrationc
●
Abbreviations: Inj=injection; IT=intrathecal; IV=intravenous; PK=pharmacokinetic; Tx=treatment
a
Same-day administration of the IV Elaprase infusion and idursulfase-IT can only occur during the Extended Treatment Phase, ie Months 13-120.
b
Samples for PK assessments are to be collected on the occasion of the first same-day administration. This pharmacokinetic sampling need only be scheduled 
once, and may occur at Month 25 or at an alternative visit during the Extended Treatment Phase.
c
Serum samples for PK analysis will be collected within 30 minutes (±5 minutes) prior to intrathecal administration of idursulfase-IT, within 30 minutes prior 
to the start of Elaprase infusion, and at 30 minutes (±5 minutes), 60 minutes (±5 minutes), 120 minutes (±5 minutes), 3 hours (±5 minutes; ie, the end of  
Elaprase infusion), 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 Elaprase Infusion.
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Appendix 14 Maximum Blood Volume Collection by Study Visit (Months/Weeks) for the Initial Treatment Phase (Subjects 
Who Did Not Receive Intrathecal Idursulfase-IT in Study HGT-HIT-094)
Procedure
Baseline
IDDD Implantation Period
Initial Treatment Phase
TOTAL
Months
-1
0
1
1
1
2
3
4
5
6
7
8
9
10
11
12
Weeks
-1
0
2 - Pre-
surgery
2- Surgery
2 -
Post-
op
4
8
12
16
20
24
28
32
36
40
48
BLOOD (mL)
Hematology 
1.2
1.2
1.2
1.2
1.2
102.3
Serum Chemistry 
2.5
2.5
2.5
2.5
2.5
Anti-idursulfase 
Antibody Testing
4
4
4
4
Serum Sample 
for PK
33
33
Coagulation
1.8
Total Blood 
Volume
0
0
5.5
0
0
40.7
0
0
7.7
0
0
7.7
0
0
7.7
33
Abbreviations: IDDD=intrathecal drug delivery device; mL=milliliter; PK=pharmacokinetics
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Appendix 15 Maximum Blood Volume Collection by Study Visit (Months/Weeks) for the Extended Treatment Phase (Months 
13-27 - Weeks 52-108)
Procedure
Extended Treatment Phase
TOTAL
Months
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
13-120a
Weeks
52
56
60
64
68
72
76
80
84
88
92
96
100
104
108
52-480a
BLOOD (mL)
Hematology 
1.2
1.2
1.2
1.2
1.2
108.5
Serum Chemistry 
2.5
2.5
2.5
2.5
2.5
Anti-idursulfase Antibody Testing
4
4
4
4
4
Serum Sample for PK
33
37
Coagulation
Total Blood Volume
7.7
0
0.0
7.7
0
0.0
7.7
0
0.0
7.7
0
0.0
40.7
0.0
0
37
Abbreviations: IDDD=intrathecal drug delivery device; mL=milliliter; PK=pharmacokinetics
•
To be collected only once at any study visit during Months 13-120 (Weeks 52-480).
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Appendix 16 Maximum Blood Volume Collection by Study Visit (Months/Weeks) for the Extended Treatment Phase (Months 
28-42 - Weeks 112-168)
Procedure
Extended Treatment Phase
TOTAL
Months
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
Weeks
112
116
120
124
128
132
136
140
144
148
152
156
160
164
168
BLOOD (mL)
Hematology 
1.2
1.2
1.2
1.2
1.2
38.5
Serum Chemistry 
2.5
2.5
2.5
2.5
2.5
Anti-idursulfase Antibody Testing
4
4
4
4
4
Serum Sample for PK
Coagulation
Total Blood Volume
7.7
0
0.0
7.7
0
0.0
7.7
0
0.0
7.7
0
0.0
7.7
0.0
0
Abbreviations: IDDD=intrathecal drug delivery device; mL=milliliter; PK=pharmacokinetics
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Appendix 17 Maximum Blood Volume Collection by Study Visit (Months/Weeks) for the Extended Treatment Phase (Months 
43-60 - Weeks 172-240
Procedure
Extended Treatment Phase
TOTAL
Months
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Weeks
172
176
180
184
188
192
196
200
204
208
212
216
220
224
228
232
236
240
BLOOD (mL)
Hematology 
1.2
1.2
1.2
1.2
1.2
1.2
46.2
Serum Chemistry 
2.5
2.5
2.5
2.5
2.5
2.5
Anti-idursulfase Antibody Testing
4
4
4
4
4
4
Serum Sample for PK
Coagulation
Total Blood Volume
7.7
0
0.0
7.7
0
0.0
7.7
0
0.0
7.7
0
0.0
7.7
0.0
0.0
7.7
0.0
0.0
Abbreviations: EOS=End of Study; IDDD=intrathecal drug delivery device; mL=milliliter; PK=pharmacokinetics
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Appendix 18 Maximum Blood Volume Collection by Study Visit (Months/Weeks) for the Extended Treatment Phase (Months 
61-72 - Weeks 244-288
Procedure
Extended Treatment Phase
TOTAL
Months
61
62
63
64
65
66
67
68
69
70
71
72
244
248
252
256
260
264
268
272
276
280
284
288
BLOOD (mL)
Hematology 
1.2
1.2
1.2
1.2
30.8
Serum Chemistry 
2.5
2.5
2.5
2.5
Anti-idursulfase Antibody Testing
4
4
4
4
Serum Sample for PK
Coagulation
Total Blood Volume
7.7
0
0.0
7.7
0
0.0
7.7
0
0.0
7.7
0
0.0
Abbreviations: IDDD=intrathecal drug delivery device; mL=milliliter; PK=pharmacokinetics
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Appendix 19 Maximum Blood Volume Collection by Study Visit (Months/Weeks) for the Extended Treatment Phase (Months 
73-87 - Weeks 292-348
Procedure
Extended Treatment Phase
TOTAL
Months
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
Weeks
292
296
300
304
308
312
316
320
324
328
332
336
340
344
348
BLOOD (mL)
Hematology 
1.2
1.2
1.2
1.2
1.2
38.5
Serum Chemistry 
2.5
2.5
2.5
2.5
2.5
Anti-idursulfase Antibody Testing
4
4
4
4
4
Serum Sample for PK
Coagulation
Total Blood Volume
7.7
0
0.0
7.7
0
0.0
7.7
0
0.0
7.7
0
0.0
7.7
0.0
0
Abbreviations: IDDD=intrathecal drug delivery device; mL=milliliter; PK=pharmacokinetics
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Appendix 20 Maximum Blood Volume Collection by Study Visit (Months/Weeks) for the Extended Treatment Phase (Months 
88-102 - Weeks 352-408
Procedure
Extended Treatment Phase
TOTAL
Months
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
Weeks
352
356
360
364
368
372
376
380
384
388
392
396
400
404
408
BLOOD (mL)
Hematology 
1.2
1.2
1.2
1.2
1.2
38.5
Serum Chemistry 
2.5
2.5
2.5
2.5
2.5
Anti-idursulfase Antibody Testing
4
4
4
4
4
Serum Sample for PK
Coagulation
Total Blood Volume
7.7
0
0.0
7.7
0
0.0
7.7
0
0.0
7.7
0
0.0
7.7
0.0
0
Abbreviations: IDDD=intrathecal drug delivery device; mL=milliliter; PK=pharmacokinetics
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Appendix 21 Maximum Blood Volume Collection by Study Visit (Months/Weeks) for the Extended Treatment Phase (Months 
103-121 - Weeks 412-484
Procedure
Extended Treatment Phase
EOS 
TOTAL
Months
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
Weeks
412
416
420
424
428
432
436
440
444
448
452
456
460
464
468
472
476
480
BLOOD (mL)
Hematology 
1.2
1.2
1.2
1.2
1.2
1.2
1.2
53.9
Serum Chemistry 
2.5
2.5
2.5
2.5
2.5
2.5
2.5
Anti-idursulfase Antibody Testing
4
4
4
4
4
4
4
Serum Sample for PK
Coagulation
Total Blood Volume
7.7
0
0.0
7.7
0
0.0
7.7
0
0.0
7.7
0
0.0
7.7
0.0
0.0
7.7
0.0
0.0
7.7
Abbreviations: EOS=End of Study; IDDD=intrathecal drug delivery device; mL=milliliter; PK=pharmacokinetics
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Appendix 22 Cumulative Maximum Blood Volume Collection for Subjects in the Initial Treatment and Extended Treatment 
Phases (Months -1-121) and Subjects Only in the Extended Treatment Phase (Months 13-121)
Months
Initial and Extended Treatment
Phase
Extended Treatment
Phase
Blood Volume (mL)
1-12
102.3
0
13-27
108.5
108.5
28-42
38.5
38.5
43-60
46.2
46.2
61-72
30.8
30.8
73-87
38.5
38.5
88-102
38.5
38.5
103-121
53.9
53.9
Total
457.2
354.9
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Appendix 23 Neurodevelopmental Assessments in Study SHP609-302
Assessment
Intended Study 
Population
Applicable Age
DAS-II
Subjects 2 years, 
6 months of age and 
oldera
Early Years Batterya, b
2 years 6 months through 6 years 11 months
(extended norms: up to 8 years, 11 months);
Early Years Lower Level:  2 years 6 months through 3 years 
5 months; Early Years Upper Level:  3 years 6 months 
through 6 years 11 months
School Age Battery
7 years 0 months through 17 years 11 months
BSID-III
Subjects younger than 
2 years, 6 months of age 
and older children who 
cannot perform the 
DAS-II
1 to 42 months
VABS-II
All subjects
Birth to 90 years
Abbreviations: BSID-III=Bayley Scales of Infant and Toddler Development, Third Edition; DAS-II=Differential 
Ability Scales, Second Edition; VABS-II=Vineland Adaptive Behavioral Scales, Second Edition
a
For the DAS-II, Spanish-speaking subjects will be assessed using the Spanish version of the DAS-II Early 
Years and the DAS-II School Years. 
b
Extended norms may be used.
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Appendix 24 Expected SOPH-A-PORT Mini S Adverse Device Effects
Procedure-related Complications
•
Components handled improperly before, during, or after implantation 
•
Access port implanted incorrectly
•
Catheter positioned improperly
•
Injection through septum performed incorrectly
•
Injection of incorrect medication through access port
•
Injection outside the access port into pocket or subcutaneous tissue or extravasation
•
Pocket seroma, hematoma, erosion, or infection
Procedure-related 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
•
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 25 Protocol Amendment Summary of Changes
Amendment Summary and Rationale 
Amendment 4 (applicable to all countries): 
On 05 Mar 2018, Shire met with members of the FDA Division of Gastroenterology and Inborn 
Errors Products (DGIEP). Shire proposed to amend the study SHP609-302 protocol to include 
statistical testing of efficacy data to provide a self-contained data set from 12-24 months 
collected as part of the SHP609-302 study. The Agency recommended Shire to submit a formal 
Meeting Request and to submit the draft SHP609-302 protocol amendment, draft SHP609-302 
SAP and draft ISE SAP as briefing documentation for written FDA feedback. Based on this 
feedback, clinical protocol SHP609-302 was amended from the previous version to add the 
following:
•
Exploratory efficacy endpoints to evaluate change from Visit Month 13/baseline to Visit 
Month 25/Week 52 as estimated by linear regression for DAS-II Early Years GCA and
selected neurodevelopmental assessment scores
•
Other exploratory efficacy endpoints to evaluate change from Visit Month 13/baseline to 
Visit Month 25/Week 52 as estimated by ordered categorical outcomes
•
Clarification regarding statistical methods and addition of inferential testing for the 
exploratory efficacy endpoints
•
Strategy for data integration
•
Language regarding planned subgroup analyses
•
Description of lower and upper levels of the Early Years battery for DAS-II
•
Extension of the duration of treatment from a maximum of 5 years to a maximum of 10 years
•
Clarifications to language regarding operational aspects of the study
Detailed Summary of Changes for the Amendment 4:
This is a section that has been updated to describe significant changes from the previous protocol 
version (Amendment 3). Noteworthy changes and additions to the protocol text are captured 
below. Bold text indicates new text. Strikethrough text indicates deleted text.
Changes in grammar, spelling, punctuation, format, minor editorial changes (including changes 
for consistency and clarity), and any refinements to the introductory text, list of abbreviations 
and cross references are not reflected in this change summary.
Change: Update of “patient” to “subject”
Rationale:  To align with Shire submission standards for clinical trials
Section impacted by this change: Entire protocol except for study title and Section 1, Introduction
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Change: Clarification of health economics and outcomes research objectives
Rationale:  To enable statistical analysis of outcomes
Section impacted by this change: Section 2.4, Health Economics and Outcomes Research Objectives
Revised Text: 

To evaluate healthcare resource utilization, as measured by the Healthcare Utilization Questionnaire 
(HCUQ) in subjects with Hunter syndrome and cognitive impairment who are treated with 
idursulfase IT in conjunction with Elaprase therapy

To evaluate the social/emotional, physical, daily activities and financial impact on caregivers and 
families of subjects with Hunter syndrome and cognitive impairment as measured by Caregiver 
Impact Questionnaire (CIQ)

To evaluate healthcare resource utilization, as measured by 2 questionnaires consisting of the Healthcare 
Utilization Questionnaire (HCUQ) and Caregiver Impact Questionnaire (CIQ), in patients with Hunter 
syndrome and cognitive impairment who are treated with idursulfase- IT in conjunction with Elaprase 
therapy
Other sections impacted by this change: Synopsis, Section 3 Study Endpoints
Change: Clarification of secondary efficacy endpoints
Rationale:  To enable statistical analysis of efficacy
Section impacted by this change: Section 3.2, Secondary Efficacy Endpoints
Revised Text: 
The secondary efficacy endpoints of this study are the following:

Change from baseline in DAS-II standard scores in cluster areas of the DAS-II:  GCA, Verbal, Nonverbal, 
Spatial, and Special Nonverbal Composite (SNC), ); and standard cluster scores:  Verbal, Nonverbal, 
Spatial; and/or the age equivalents and Development Quotient (DQ) from the BSID-III domains: 
Cognitive and Language

Change from baseline in standard composite scores of the VABS-II domains: ABC, and domain standard 
scores:  Communication, Daily Living Skills, Socialization, and Motor Skills

Change from baseline in age equivalents, developmental quotients, and T-scores for the core 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
Other sections impacted by this change: Synopsis, Study Endpoints
Change: Addition of exploratory efficacy endpoints to evaluate change from Visit Month 13/baseline to Visit Month 
25/Week 52, ordered categorical outcomes and binary outcomes for each subject
Rationale:  To enable statistical analysis of efficacy
Section impacted by this change: Section 3.3, Exploratory Efficacy Endpoints
New Text: 
The exploratory efficacy endpoints of this study are the following:
•
Change from Visit Month 13/baseline to Visit Month 25/Week 52 in study SHP609-302 as estimated by 
linear regression in:
•
DAS-II GCA scores from Early Years battery
•
DAS-II Early Years core subtests T scores: Verbal Comprehension, Picture Similarities, Naming 
Vocabulary, Pattern Construction, Matrices, and Copying
•
DAS-II Early Years battery standard cluster scores: Verbal, Nonverbal, Spatial, and SNC 
composite scores
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•
DAS-II GCA scores including both Early Years and School Age batteries
•
VABS-II ABC scores
Note that the interval from Visit Month 13/baseline to Visit Month 25/Week 52 in study SHP609-302 is 
defined as from Visit Month 13 to Visit Month 25 in SHP609-302 Extended Treatment Phase for subjects in 
the Early IT group (defined in Section 10.4.1), and from baseline in study SHP609-302 to Visit Week 52 in 
SHP609-302 Initial Treatment Phase for subjects in the Delayed IT group (defined in Section 10.4.1). The 
Early IT group and Delayed IT group designations are based on the treatment regimen (idursulfase-IT or No 
IT treatment) in the antecedent study (HGT-HIT-094).
•
Ordered categorical outcomes for each subject at study SHP609-302 Visit Month 25/Week 52 are defined 
below. The definition for each response category threshold is based on the standard error of 
measurement (SEM) for the DAS-II. The SEM for the GCA, based on test-retest reliability of the DAS-
II,17 is approximately ±5 points. The ordered categorical outcomes will be defined for both DAS-II GCA 
scores from Early Years battery and GCA scores.
•
Above average cognitive development (Category 1) is defined as a subject with an observed GCA 
score at Visit Month 25/Week 52 which is more than 10 points (2 SEM) higher than the observed 
GCA score at Visit Month 13/baseline in study SHP609-302; ie, 

GCA (Visit Month 25/Week 52) > GCA (Visit Month 13/baseline) + 10 points
•
Average cognitive development (Category 2) is defined as a subject with an observed GCA score 
at Visit Month 25/Week 52 which is within a range of ±10 points, inclusive (2 SEM), of the 
observed GCA score at Visit Month 13/baseline in study SHP609-302; ie,

GCA (Visit Month 13/baseline) - 10 points ≤ GCA (Visit Month 25/Week 52) ≤ 
GCA (Visit Month 13/baseline) + 10 points
•
Below average cognitive development (Category 3) is defined as a subject with an observed GCA 
score at Visit Month 25/Week 52 which is more than 10 points (2 SEM) below the observed GCA 
score at Visit Month 13/baseline in study SHP609-302; ie, 

GCA (Visit Month 25/Week 52) < GCA (Visit Month 13/baseline) – 10 points
•
Binary unreversed floor effect outcome for each subject
Other sections impacted by this change:  Synopsis, Study Endpoints
Change: Clarification that the health-related quality of life for caregivers will be assessed using the CIQ
Rationale:  Clarification of an operational aspect of the study
Section impacted by this change: Section 3.4, Health Economics and Outcomes Research Endpoints
Revised Text:
•
Health care resource utilization will be assessed using the HCUQ and CIQ
•
Health-related quality of life for caregivers will be assessed using the CIQ
Other sections impacted by this change: Synopsis, Study Endpoints
Change: Addition of language clarifying that consent may be obtained from a subject, such as when they reach the 
legal age of consent
Rationale: Clarification of an operational aspect of the study
Section impacted by this change: Section 4.1, Overall Study Design and Plan
New Text:
Prior to conducting any study-related procedures, written informed consent (signed and dated) must be 
obtained from the subject’s parent(s) or legally authorized guardian(s) (and consent/assent from the subject, 
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Change: Change Pharmacovigilance and Risk Management department name to Global Drug Safety, with update to 
e-mail address
Rationale:  Clarification of an operational aspect of the study
Section impacted by this change: Section 7.15.6.2, Reporting Serious Adverse Events
Updated Text:
The investigator must report the serious adverse event to the Shire Pharmacovigilance and Risk ManagementGlobal 
Drug Safety Department AND to the Shire medical monitor on the SAE form. This form must be completed and 
FAXED or EMAILED within 24 hours of the investigator’s learning of the event to:
Shire Global Drug Safety Pharmacovigilance and Risk Management Department:
International FAX: +44-1256-894715 (UK) OR United States FAX: +1-866-557-4473
Email: drugsafetyglobalpharmacovigilance@shire.com
Other sections impacted by this change: Section 7.17, Abuse, Misuse, Overdose, and Medication Error; Section 9, 
Quality Control and Assurance
Change: Addition of language clarifying that the subject is free to withdraw consent and discontinue participation in 
the study
Rationale: Clarification of an operational aspect of the study
Section impacted by this change: Section 7.18, Removal of Subjects from the Trial or Investigational Product
Revised Text:
The subject or the subject’s parent(s) or legally authorized guardian(s) acting on behalf of the subject is free to 
withdraw consent and discontinue participation in the study at any time without prejudice to further treatment.
If the subject or the subject’s parent(s) or legally authorized guardian(s) acting on behalf of the subject discontinues 
participation in the study, or the subject is discontinued by the investigator , reasonable efforts will be made to 
follow the subject through the end of study assessments. 
Other sections impacted by this change: Not applicable
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Change: Addition of months and weeks extending the study to a duration of 10 years
Rationale: Clarification of an operational aspect of the study
Sections impacted by this change: Sections 8.2.2, 8.2.3, and 8.2.4
Revised Text:
8.2.2     Months 14, 15, 17, 18, 20, 21, 23, 24, 26, 27, 29, 30, 32, 33, 35, 36, 38, 39, 41, 42, 44, 45, 47, 48, 50, 51, 
53, 54, 56, 57, 59, 60, 62, 63, 65, 66, 68, 69, 71, 72, 74, 75, 77, 78, 80, 81, 83, 84, 86, 87, 89, 90, 92, 93, 
95, 96, 98, 99, 101, 102, 104, 105, 107, 108, 110, 111, 113, 114, 116, 117, 119, 120 (Weeks 56, 60, 68, 72, 
80, 84, 92, 96, 104, 108, 116, 120, 128, 132, 140, 144, 152, 156, 164, 168, 176, 180, 188, 192, 200, 204, 
212, 216, 224, 228, 236, 240, 248, 252, 260, 264, 272, 276, 284, 288, 296, 300, 308, 312, 320, 324, 332, 
336, 344, 348, 356, 360, 368, 372, 380, 384, 392, 396, 404, 408, 416, 420, 428, 432, 440, 444, 452, 456, 
464, 468, 476, 480 [±7 Days]) – Extended Treatment Phase – All Subjects
8.2.3     Months 16, 22, 28, 34, 40, 43, 46, 52, 55, 58, 64, 70, 76, 82, 88, 94, 100, 103, 106, 112, 115, 118 (Weeks 
64, 88, 112, 136, 160, 172, 184, 208, 220, 232, 256, 280, 304, 328, 352, 376, 400, 412, 424, 448, 460, 472
[±7 Days]) – Extended Treatment Phase – All Subjects
8.2.4     Months 19, 25, 31, 37, 43, 49, 55, 61, 67, 73, 79, 85, 91, 97, 103, 109, 115 (Weeks 76, 100, 124, 148, 172, 
196, 220, 244, 268, 292, 316, 340, 364, 388, 412, 436, 460 [±7 Days]) – Extended Treatment Phase – All 
Subject
Other sections impacted by this change: Appendix 10; Appendix 11; Appendix 12; Appendix 13; Appendix 15; 
Appendix 18; Appendix 19; Appendix 20; Appendix 21; Appendix 22
Change: Clarification regarding statistical methods for efficacy and safety combined analyses for SHP609-302 and 
HGT-HIT-094 studies, including descriptive summaries presentation (Early IT group, Delayed IT group and overall) 
and the addition of inferential testing for the primary efficacy endpoints and one of the secondary endpoints.
Rationale:  To enable statistical analysis of efficacy
Section impacted by this change: Section 10.1, General Methodology
Revised Text:
Statistical analyses will be performed by the BiometricsBiostatistics and Statistical Programming Department of 
Shire or its designee using SAS statistical software (SAS Institute, Cary, NC, USA), unless otherwise specified. 
Analysis methods will be detailed in the statistical analysis plan (SAP).
Data from studies SHP609-302 data and HGT-HIT-094 will be combined with that of Study HGT HIT 094
integrated for efficacy and safety analyses. Baseline for the subjects  previously treated in HGT-HIT-094 will be 
the same as the baseline defined in HGT-HIT-094. Baseline for the previously untreated subjects (ie, No IT 
treatment) in HGT-HIT-094 is will be the closest available assessment prior to the initial IDDD implant date, 
which takes place in Study SHP609-302, unless otherwise specified. This could potentially include EOS visit data 
from Study HGT-HIT-094. The analyses presented here will include the data measured at and after baseline. 
Safety and efficacy data descriptive summaries will be presented by the antecedent study, HGT HIT 094, treatment 
regimen (idursulfase IT or No Treatment) and overall. for the Early IT group, Delayed IT group, and overall. 
The Early IT group and Delayed IT group designations are based on the treatment regimen (idursulfase-IT 
or No IT treatment) in the antecedent study (HGT-HIT-094).Any former HGT-HIT-094 Substudy patients will 
be included in the idursulfase-IT treated group. Subjects who participated in the HGT-HIT-094 substudy will be 
included in the Early IT group.
Efficacy data descriptive summaries will be presented separately for subjects who enrolled from the pivotal 
study or substudy of HGT-HIT-094. For subjects enrolled from the pivotal study, descriptive statistics will be 
presented by the Early IT group, the Delayed IT group, and overall. For secondary efficacy endpoints, the 
mean difference in the change at each time point between the 2 treatment groups (Early IT group and 
Delayed IT group) and the corresponding 90% confidence interval of the mean difference will be presented 
where appropriate. The mean values (±SD) for all efficacy endpoints will be graphed over time where 
appropriate.
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Inferential testing is planned for some exploratory efficacy endpoints. The main exploratory efficacy analyses 
to examine the IT treatment effect will be rate of change (weighted) analyses of the  exploratory efficacy 
endpoints from Visit Month 13/baseline to Visit Month 25/Week 52 as estimated by linear regression for 
DAS-II Early Years GCA scores and selected neurodevelopment assessment scores.
Summary statistics for continuous variables will include the n, mean, standard deviation, median, minimum, and 
maximum. Categorical variables will be summarized in a contingency table by the frequency and percentage of 
subjects in each category.
The statistical methodology supporting the trial will focus on descriptive rather than inferential approaches, given 
the design and objectives of this trial. Summary statistics for continuous variables will include the n, mean, standard 
deviation, median, minimum and maximum. Categorical variables will be summarized in a contingency table by the 
frequency and percentage of patientssubjects in each category.
All safety and efficacy data will be summarized descriptively at scheduled visits. For efficacy endpoints, the mean 
difference in the change at each time point between the 2 HGT HIT 094 treatment groups and the corresponding 
95% confidence interval of the mean difference will be presented where appropriate. The mean values for all 
efficacy endpoints will be graphed over time where appropriate.
Efficacy data for subjects enrolled from the HGT-HIT-094 substudy will be presented in listings.
Other sections impacted by this change: Synopsis, Statistical Methods; Section 10.4.3, Subject Disposition; Section 
10.4.5, Demographics and Baseline Characteristics; Section 10.4.6, Treatment Compliance; Section 10.4.7, Extent 
of Exposure; Section 10.6.2, Pharmacodynamic Analyses; Section 10.7, Analysis of Safety; Section 10.7.1, Adverse 
Events; Section 10.7.2, Clinical Laboratory Evaluation; Section 10.7.6.2, Immunogenicity
Change: Addition of strategy regarding data integration
Rationale:  To enable statistical analysis of integrated safety and efficacy data
Section impacted by this change: Section 10.4.1, Data Integration Strategy
New Text:
Data from studies SHP609-302 and HGT-HIT-094 will be integrated for data analyses. 
For safety and efficacy descriptive summary analyses using integrated data, the 2 treatment groups are the 
Early IT group and Delayed IT group based on HGT-HIT-094 treatment regimen (idursulfase-IT or No IT 
Treatment), defined as follows:

The Early IT group is defined as subjects who were randomized to the idursulfase-IT treatment 
cohort in study HGT-HIT-094 and continued IT treatment in study SHP609-302. HGT-HIT-094 
substudy will be included in the Early IT group.

The Delayed IT group is defined as subjects who were randomized to the control cohort (No IT 
treatment) in study HGT-HIT-094 and began IT treatment in study SHP609-302.
For exploratory efficacy analyses, only data collected in study SHP609-302 will be used; the 2 treatment 
groups are the Early IT group and Delayed IT group. 
Visit Month 13 of the SHP609-302 Extended Treatment Phase corresponds to the scheduled visit at which 
subjects in the Early IT group have completed 12 months of IT treatment in antecedent study HGT-HIT-094. 
The treatment regimen in HGT-HIT-094 comprised 1 month for surgical IDDD implantation at the beginning 
of the study followed by 12 months of IT treatment during HGT-HIT-094.
Likewise, Visit Month 25 of the SHP609-302 Extended Treatment Phase corresponds to the scheduled visit at 
which subjects in the Early IT group have completed two 12-month periods of IT treatment, and comprises 1 
month for surgical IDDD implantation at the beginning of HGT-HIT-094, 12 months of IT treatment during 
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HGT-HIT-094, and a continued 12 months of IT treatment in the Extended Treatment Phase of SHP609-302. 
Visit Week 52 of the SHP609-302 Initial Treatment Phase is the scheduled visit at which subjects in the 
Delayed IT group have completed 12 months of IT treatment in study SHP609-302, and comprises 12 months 
of No IT treatment during HGT-HIT-094, 1 month for surgical IDDD implantation at the beginning of 
SHP609-302, and 12 months of IT treatment in the Initial Treatment Phase of SHP609-302. 
It is noted that Visit Month 25 and Visit Week 52 of SHP609-302 are 4 weeks apart for the Early IT and 
Delayed IT groups. This difference is accounted for by the need for subjects in the Delayed IT group, who 
enrolled into the Initial Treatment Phase of SHP609-302 from the HGT-HIT-094 No IT treatment group, to 
undergo surgical implantation of the device at the beginning of study SHP609-302. Therefore, the first dose of 
SHP609 was administered 4 weeks later to these subjects compared with subjects in the Early IT group who 
were randomized to IT treatment and underwent IDDD implantation in HGT-HIT-094 prior to enrolling in 
the Extended Treatment Phase of SHP609-302. For evaluation of the long-term efficacy of IT treatment in 
SHP609-302, this 4-week difference is considered to have minimal impact on neurodevelopmental assessment 
scores.
Other sections impacted by this change: Not applicable
Change: Text and figure added to describe the conceptual plot of treatment periods in Early IT and Delayed IT 
Groups in Studies HGT-HIT-094 and SHP609-302
Rationale:  To enable statistical analysis of efficacy
Section impacted by this change: Section 10.4.2, Analysis Populations
Revised Text:
All data descriptive summary analyses of safety and efficacy data will be based on the Safety Population, which 
is defined as all patientssubjects in Study SHP609-302 who underwent IDDD implantation or received at least 1 
dose of study drug (full or partial). 
The following nomenclature will be used to identify “A”, “B”, “C”, and “D” in Figure 2.

Observation Groups A and C identify the period of observation during study HGT-HIT-094, for 
subjects randomized to IT treatment and No IT treatment, respectively. 

Observation Groups B and D identify the period of observation during study SHP609-302 up to 
completion of 1 year, for subjects who were randomized in HGT-HIT-094 to receive IT treatment 
and No IT treatment respectively, noting that all subjects in SHP609-302 received IT treatment.
The subjects in “B” are the same subjects as in “A” with periods of observation from studies SHP609-302 and 
HGT-HIT-094, respectively as we can view “B” as a continuation of “A”. The subjects in “D” are the same 
subjects as in “C” with periods of observation from studies SHP609-302 and HGT-HIT-094, respectively as 
we can view “D” as a continuation of “C”.
“D” subjects are therefore similar to “A” subjects since these subjects all transitioned from receiving weekly 
IV infusion of Elaprase, to also receive monthly IT idursulfase. More generally, because study SHP609-302 
did not have baseline GCA inclusion criteria, such as that employed for Study HGT-HIT-094, “B” and “D” 
subjects could differ with regard to their baseline GCA score at the beginning of the observation period. 
Therefore, for consideration of “B” and “D”, only subjects meeting the key inclusion criteria to HGT-HIT-
094 will be included in inferential efficacy analyses, ie, with GCA scores between 55 and 85 inclusive at the 
enrollment of SHP609-302.
The exploratory efficacy analyses will be conducted on “HGT-HIT-094 Comparable Set”, “HGT-HIT-094 
Comparable Subset 1”, and “HGT-HIT-094 Comparable Subset 2”. The primary analysis population is 
HGT-HIT-094 Comparable Subset 1, which may be the subject population with the most potential to benefit 
from the idursulfase-IT treatment.

HGT-HIT-094 Comparable Set: subjects in the Safety Population who met the key HGT-HIT-094 
inclusion criterion (baseline GCA scores between 55 and 85 inclusive) at enrollment in SHP609-302
(Visit Month 13/baseline), ie, Safety Population subjects with GCA scores between 55 and 85 
inclusive at enrollment in SHP609-302
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
HGT-HIT-094 Comparable Subset 1 (primary analysis population): subjects in the HGT-HIT-094 
Comparable Set with age <6 years at enrollment in SHP609-302 (Visit Month 13/baseline), ie, Safety 
Population subjects with GCA scores between 55 and 85 inclusive and age <6 years at enrollment in 
SHP609-302

HGT-HIT-094 Comparable Subset 2: subjects in the HGT-HIT-094 Comparable Set with age <55 
months at the enrollment of SHP609-302 (Visit Month 13/baseline), ie, Safety Population subjects 
with GCA scores between 55 and 85 inclusive and age <55 months at enrollment in SHP609-302
Other sections impacted by this change: Figure 2, Conceptual Plot of Treatment Periods in Early IT and Delayed IT 
Groups in Studies HGT-HIT-094 and SHP609-302
Change: Clarification regarding other efficacy endpoints (analysis groups and confidence interval)
Rationale:  To clarify statistical analysis of efficacy
Section impacted by this change: Section 10.5.3, Other Secondary Efficacy Analysis
Revised Text:
For eachall other efficacy endpoints described in Section 3.2, the observed values and change from baseline will be 
summarized descriptively for each assessment time point by the Early IT group, the Delayed IT group the 
HGT-HIT-094 treatment regimen (idursulfase-IT or No Treatment) and overall. Any HGT-HIT-094 Substudy 
patients subjects will be included in the idursulfase-IT treated group Early IT group for analysis. The mean 
difference in the change at each time point between the two HGT-HIT-094 treatment groups and the corresponding 
950% confidence interval of the mean difference will be presented. The BSID-III endpoints will be listed only. 
Graphical plots of the mean value for each endpoint over time will be presented. A spaghetti plot of the age 
equivalent scores for individual patientssubjects will be plotted against chronological age.
Other sections impacted by this change: Not applicable
Change: Addition of language regarding planned subgroup analyses
Rationale:  To enable statistical analysis of efficacy for the subgroups
Section impacted by this change: Section 10.5.4, Subgroup Analyses
Revised Text:
Section 10.5.4, Subsetgroup Analyses
Subgroup descriptive summary analyses of the secondary efficacy endpoints, change from baseline in GCA and 
ABC scores will be performed for baseline GCA groups (either ≤70 or >70) and baseline age groups (either ≤<6 
years or ≥>6 years; <55 months or ≥55 months). Descriptive summaries within these subgroups and plots of mean 
values (±SD) over time will be presented. The baseline is defined in Section 10.1.
Subgroup analyses are planned for the rate of change (weighted) analyses in GCA scores from Early Years 
battery, GCA scores and ABC scores for GCA classification groups at Visit Month 13/baseline (either ≤70 or 
>70), age groups at Visit Month 13/baseline (either <6 years or ≥6 years), and age groups at Visit Month 
13/baseline (either <55 months or ≥ 55 months).
Other sections impacted by this change: Not applicable
Change: Addition of language regarding exploratory analyses, including text regarding the possible floor effector for 
neurodevelopmental assessments
Rationale:  To enable statistical analysis of efficacy
Section impacted by this change: Section 10.5.5, Exploratory Analyses
New Text:
The main exploratory efficacy analyses to examine the IT treatment effect will be rate of change (weighted) 
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analyses of the exploratory efficacy endpoints from Visit Month 13/baseline to Visit Month 25/Week 52 in 
study SHP609-302 as estimated by linear regression for the following neurodevelopmental assessment scores:

DAS-II GCA scores from Early Years battery

DAS-II Early Years core subtests T scores: Verbal Comprehension, Picture Similarities, Naming 
Vocabulary, Pattern Construction, Matrices, and Copying

DAS-II Early Years battery standard cluster scores: Verbal, Nonverbal, Spatial, and SNC composite 
scores

DAS-II GCA scores including both Early Years and School Age batteries

VABS-II ABC scores
Complete details of the rate of change (weighted) analysis, including examination of premises of the rate of 
change (weighted) analysis, model diagnostics for the 2 analysis stages, and estimation and comparison of the 
treatment effects during observation periods “B” and “D” will be described in the SAP.
The descriptive summary of ordered categorical outcomes will be presented at Month 25/Week 52 by the 
Early IT group, the Delayed IT group, and overall using the SHP609-302 data “B” and “D”. The definitions 
of ordered categorical outcomes for each subject are described in Section 3.3.
For each of the neurodevelopmental assessments, there may be a “floor effect”, ie, the lower limitation of the 
assessment tool, below which the assessment may not be reliable or meaningful. Refer to the SAP for 
complete details.
Other eExploratory analyses may include assessment of the correlation between PD and efficacy endpoints; and 
between composite scores and their components (ie, correlations between the GCA and ABC scores and their 
respective cluster/domain scores). Scatter plots may be presented to explore the relationships among variables.
Other sections impacted by this change: Not applicable
Change: Language added regarding the CIQ question items for clarification
Rationale:  Clarification of an operational aspect of the study
Section impacted by this change: Section 10.5.6, Health Economics and Outcomes Research Endpoint Analyses
New Text:
HCUQ and CIQ variables include the number of emergency room visits, caregiver employment status (full time 
[FT], part time [PT], and not working [NW]), and the number of hours of additional paid help needed by caregivers, 
over the course of the study. The CIQ question items measure social, emotional, physical and financial impacts 
on the caregiver. Descriptive statistics, including n, mean, median, and range (for continuous variables), and n and 
proportions (for categorical variables), for these key HCUQ and CIQ variables will be presented.
Other sections impacted by this change: Study Endpoints
Change: Clarification that 90% rather than 95% confidence interval will be estimated.
Rationale:  Clarification of statistical analysis of IDDD performance
Section impacted by this change: Section 10.7.6.1, IDDD Performance
New Text:
The proportion of subjects with at least one1 device failure and/or malfunction, as well as the number of and reasons 
for device failures/malfunctions will be summarized. The rate of device failures/malfunctions and 950% confidence 
interval will also be estimated. The time from initial implant surgery to first device failure and/or malfunction will 
be summarized. Subjects without a device failure/malfunction will be censored at their last study drug injection date. 
A by-subject listing of the device failure/malfunction data will be displayed.
The rate of successful IDDD injections will be calculated for each subject and summarized descriptively. The 
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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 950% confidence interval for the mean rate 
will be estimated, where appropriate. Injections that are not administered for subject-related reasons (eg, subject
uncooperative, competing medical issue, etc.) will not be included in the determination of the injection success rate.
Other sections impacted by this change: Not applicable
Change: Addition of new language for adjustment for covariates
Section impacted by this change: Section 10.8.1, Adjustment for Covariates
Revised Text:
Given the design of this study, no statistical modeling or covariate adjustment is planned. The rate of change 
(weighted) analysis will adjust for GCA classification (either ≤70 or >70) at enrollment of SHP609-302 in the 
weighted generalized linear model.
Other sections impacted by this change: Not applicable
Change: Addition of new language indicating no multiple comparisons or multiplicity adjustments to be made
Section impacted by this change: Section 10.8.5, Multiple Comparisons/Multiplicity
Revised Text:
Statistical analyses are descriptive and no adjustment for No multiple comparison procedure or multiplicity
adjustment will be performed.
Other sections impacted by this change: Not applicable
Change: Clarification that when a subject is the legal age of majority but lacking mental capacity to provide 
informed consent, the subject’s parent or legally authorized representative will provide informed consent
Rationale:  Clarification of an operational aspect of the study
Section impacted by this change: Section 11.4, Subject Information and Consent
New Text:
When a subject has reached the legal age of consent to participate in a clinical study, but has been deemed by 
the investigator, in accordance with applicable law, as lacking mental capacity to provide informed consent, 
the subject’s parent(s) or legally authorized representative(s) will be asked to provide informed consent on 
behalf of the subject to allow for continued participation in the trial.
Other sections impacted by this change: Appendix 1, Initial Treatment Phase Schedule of Events: For Subjects Who 
Did Not Receive Intrathecal Idursulfase IT in Study HGT-HIT-094; Appendix 2, Extended Treatment Phase 
Schedule of Events – Months 13-15 (Weeks 52-60)
Change: Clarifications to List of References
Rationale: Clarification to literature cited
Section impacted by this change: Section 12, List of References
New Text:
17. Elliott, CD 2007. Differential Ability Scales (2nd ed Second Edition). San
Antonio, TX: Harcourt Assessment The Psychological Corporation; 2007.
18. Bayley N. Bayley Scales of Infant and Toddler Development. 3 ed (Third Edition). San
Antonio, TX. The Psychological Corporation; 2005.
Other sections impacted by this change: Not Applicable
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Appendix 21
Protocol Amendment Summary of Changes
Amendment Summary and Rationale 
Amendment 3 (applicable to all countries): 
Clinical protocol SHP-609-302 was amended from the previous version to introduce the option 
of same-day administration of IV Elaprase and idursulfase-IT for patients who have already 
completed at least 12 months of idursulfase-IT treatment in studies HGT-HIT-094 or SHP-609-
302, ie, those patients participating in the Extended Treatment Phase of the present study. Same-
day administration may be elected at the investigator’s discretion and is intended to offer 
convenience to patients participating in the Extended Treatment Phase, who otherwise would be 
required to schedule an extra clinic visit in order to receive Elaprase at least 48 hours after their 
monthly IT dose.
If same-day dosing is elected, idursulfase-IT is to be administered first and the IV Elaprase 
infusion will be administered second. Per this protocol amendment, additional pharmacokinetic 
assessments will be implemented to measure any increase in total systemic exposure to 
idursulfase under the same-day administration regime. While, with same-day dosing, it will not 
be possible to distinguish idursulfase of IV-administered origin from that of IT-administered 
origin, pharmacokinetic and safety assessments will evaluate the effect of the same-day IV and 
IT regime on total idursulfase exposure and on safety parameters such as the incidence and/or 
severity of infusion-related reactions, even if the patient had no prior such reactions on Elaprase 
alone. The clinical safety profile of Elaprase is well understood. Based on the known 
pharmacokinetic properties and safety profile of idursulfase-IT in pediatric MPS II patients also 
receiving Elaprase therapy, the contribution to total systemic exposure of IT-administered 
idursulfase in the setting of same-day IV Elaprase infusion is not expected to detrimentally 
impact patient safety. With this amendment, a new category of adverse event relatedness, related 
to IV Elaprase and/or idursulfase-IT, will be incorporated into the protocol to facilitate the 
collection and analysis of adverse events observed with same-day administration.
Note that, on the occasion of the first same-day administration, the duration of IV Elaprase 
infusion is to be standardized to 3 hours, corresponding to the recommended infusion rate for 
new Elaprase patients per product labeling. This cautious approach is in the interest of patient 
safety, as well as to promote the homogeneity in data collection needed for the interpretation of 
pharmacokinetic data. Thereafter, at subsequent monthly visits at which same-day administration 
of IV Elaprase infusion and idursulfase-IT are elected, the investigator may use discretion in 
deciding the appropriate Elaprase infusion rate based on past experience with the patient, and the 
patient’s prior response to the same-day administration regime.
Detailed Summary of Changes for the Amendment 3
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 adverse event relationship category
Section impacted by this change: 3.1 Primary Endpoints
Revised Text: 
Safety will be assessed during the study by the following:
•
Adverse events (AEs) (by type, severity, and relationship to treatment [idursulfase-IT, the IDDD, 
device surgical procedure, or IT administration process], IV Elaprase infusion, IV Elaprase and/or 
idursulfase-IT)
Other sections impacted by this change: Synopsis; 6.6.1 Infusion Reactions and Management; 7.15.1.3 
Elaprase and/or idursulfase-IT-related Adverse Event; 7.15.5 Relatedness of Adverse Events and Serious 
Adverse Events; 10.7.1.1 Investigational Product
Change: Introduction of same-day dosing regime
Section impacted by this change: 6.2 Treatments Administered
Revised Text: 
The investigational product may be administered on the same day (ie, the same calendar day or 
within a 24-hour period) as the Elaprase IV infusion. However, this can only occur for patients 
participating in the Extended Treatment Phase who have already completed at least 12 months of 
idursulfase-IT treatment in studies HGT-HIT-094 or SHP-609-302. If same-day dosing is elected, 
idursulfase-IT will be administered first and the Elaprase IV infusion will be administered second 
Please refer to Section 7.7.1 for details.
Other sections impacted by this change: 7 Study Procedures
Change: Clarification of safety assessment with same-day dosing
Section impacted by this change: 6.6.1 Infusion Reactions and Management
Revised Text: 
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. As of 
the date of this protocol, there have been no significant concerns regarding infusion-related immune 
reactions following IT administration in studies HGT-HIT-045 and HGT-HIT-046. Additionally, safety 
assessments in the present study will evaluate the effect of same-day IV and IT regime on the 
incidence and/or severity of infusion-related adverse reactions, even if the patient had no prior such 
reactions on Elaprase alone.
Other sections impacted by this change: 7.15.1.3 Elaprase and/or idursulfase-IT-related Adverse Event; 
7.15.5 Relatedness of Adverse Events and Serious Adverse Events; 10.7.1.1 Investigational Product
Change: Introduction of same-day dosing regime
Section impacted by this change: 7 Study Procedures
Revised Text: 
All patients will receive weekly IV Elaprase infusions as prescribed throughout the study. During the 
Initial Treatment Phase, 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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During the Extended Treatment Phase only, the investigator will have the option of administering the 
Elaprase IV infusion and idursulfase-IT on the same day. Please refer to Section 7.7.1 for details.
Other sections impacted by this change: 7.7.1 Same Day Investigational Administration with Elaprase 
Infusion
Change: Description of same-day dosing regime
Section impacted by this change: 7.7.1 Same-Day Investigational Administration with Elaprase Infusion
Revised Text: 
During the Initial Treatment Phase, 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. 
During the Extended Treatment Phase only, the investigator will have the option of administering the 
IV Elaprase infusion and idursulfase-IT on the same day. If same-day dosing is elected, idursulfase-IT 
will be administered first and the Elaprase infusion will be administered second. Pharmacokinetic 
assessments are to occur at the first study visit at which same-day dosing is elected. At this visit, 
administration of the Elaprase infusion should start within approximately 90 minutes of completion of 
idursulfase-IT administration.
Note that on the occasion of the first same-day administration, the duration of IV Elaprase infusion is 
to be standardized to 3 hours. Thereafter, at subsequent visits on which the Elaprase infusion and 
idursulfase-IT are administered on the same day, the investigator may use discretion in deciding the 
appropriate Elaprase infusion rate based on past experience with the patient, and the patient’s prior 
response to the same-day regime.
Other sections impacted by this change: 7.8 Pharmacokinetic Assessments
Change: Timing of CSF sample collection and PK sampling
Section impacted by this change: 7.8 Pharmacokinetic Assessments
Revised Text: 
Blood samples will be collected for determination of idursulfase serum concentration-time profiles and 
serum pharmacokinetic parameters after IT administration.
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 Schedule of 
Events (Appendix 1, Appendix 2, Appendix 3, Appendix 4, Appendix 5, Appendix 6, Appendix 7, 
Appendix 8, Appendix 9, Appendix 10, Appendix 11, and Appendix 12).
During the Extended Treatment Phase, blood samples for pharmacokinetic assessments will be 
collected on the occasion of the first same-day administration of idursulfase-IT and Elaprase. This 
pharmacokinetic sampling need only be scheduled once, and may occur at Month 25 or at an 
alternative visit during the Extended Treatment Phase (see Appendix 13 for PK sampling time points 
associated with same-day administration).
Other sections impacted by this change: Appendix 13 Pharmacokinetic Sample Collection for Same-Day 
Investigational Product Administration with Elaprase Infusion
Change: Addition of adverse event relationship category
Section impacted by this change: 7.15.1.3 Elaprase and/or idursulfase-IT-related Adverse Event
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Revised Text: 
During the Extended Treatment Phase, the investigator will have the option of administering the IV 
Elaprase infusion and idursulfase-IT on the same day. With same-day dosing, it may not be possible 
to distinguish idursulfase of IV-administered origin from that of IT-administered origin. Therefore, 
adverse events that are potentially related to IV Elaprase infusion and/or idursulfase-IT 
administration will be captured.
Other sections impacted by this change: 7.15.5 Relatedness of Adverse Events and Serious Adverse Events; 
10.7.1.1 Investigational Product
Change: Addition of adverse event relationship category
Section impacted by this change: 7.15.5 Relatedness of Adverse Events and Serious Adverse Events
Revised Text: 
Relationship of an AE or SAE to investigational product, IDDD, device surgical procedure, or IT 
administration process will be assessed by the Investigator as follows: 
•
Relationship to idursulfase-IT
•
Relationship to IV Elaprase infusion will be assessed by the Investigator as described in Section 
7.15.1.2
•
Relationship to IV Elaprase infusion and/or idursulfase-IT as described in Section 7.15.1.3
•
Relationship to the IDDD (examples of IDDD-related adverse events are listed in Section 7.15.1.4)
•
Relationship to a device surgical procedure (surgical implantation of the IDDD, partial or full device 
revision as described in Section 7.15.1.5)
•
Relationship to the IT administration process (examples of IT administration process-related adverse 
events are listed in Section 7.15.1.6)
Other sections impacted by this change: Synopsis; 3.1 Primary Endpoints
Change: Clarification to timing of CSF sample collection
Section impacted by this change: 8.1.4.1 Prior to Intrathecal Injection (Months 1-12, Weeks 4-48 [±7 Days]) 
- Initial Treatment Phase
Revised Text: 
•
CSF GAG and idursulfase (performed at Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48) 
Other sections impacted by this change: Appendix 1 Initial Treatment Phase Schedule of Events: For Patients 
Who Did Not Receive Intrathecal Idursulfase IT in Study HGT HIT 094
Change: Clarification to timing of PK sample collection
Section impacted by this change: 8.1.4.2 Intrathecal Injection (Months 1-12, Weeks 4-48 [±7 Days]) –
Initial Treatment Phase
Revised Text: 
•
Serum sampling for PK analysis (performed at Weeks 4 and 48). Samples will be collected within 15 30
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
Other sections impacted by this change: 8.2.4.2 Months 19, 25, 31, 37, and 49 (Weeks 76, 100, 124, 148, 
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and 196 [±7 Days]) – Intrathecal Injection – Extended Treatment Phase – All Patients; Appendix 1 Initial 
Treatment Phase Schedule of Events: For Patients Who Did Not Receive Intrathecal Idursulfase IT in Study 
HGT-HIT-094; Appendix 4 Extended Treatment Phase Schedule of Events – Months 21-25 (Weeks 84-100)
Change: Introduction of same-day dosing regime
Section impacted by this change: 8.2.1.2 Month 13 (Week 52 [±7 Days]) – Intrathecal Injection – Extended 
Treatment Phase – All Patients
Revised Text: 
Patients will remain under observation in the hospital setting (eg, may include infusion center, 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. The patient may need to be examined the following day (see Follow-up, Section 8.1.4.3) by 
the Investigator; however, there is no requirement for an overnight hospital stay. Note that, on IT Dosing 
Weeks during the Initial Treatment Phase, the IV infusion of Elaprase should be scheduled to occur a 
minimum of 48 hours after IT administration of idursulfase-IT. However, during the Extended Treatment 
Phase only, the investigator will have the option of administering the IV Elaprase infusion and 
idursulfase-IT on the same day. Please refer to Section 7.7.1 for details.
Other sections impacted by this change: 8.2.2.2 Months 14, 15, 17, 18, 20, 21, 23, 24, 26, 27, 29, 30, 32, 33, 
35, 36, 38, 39, 41, 42, 44, 45, 47, 48, 50, 51, 53, 54, 56, 57, 59, and 60 (Weeks 56, 60, 68, 72, 80, 84, 92, 96, 
104, 108, 116, 120, 128, 132, 140, 144, 152, 156, 164, 168, 176, 180, 188, 192, 200, 204, 212, 216, 224, 
228, 236, and 240 [±7 Days]) – Intrathecal Injection – Extended Treatment Phase – All Patients; 8.2.3.2 
Months 16, 22, 28, 34, 40, 43, 46, 52, 55, and 58 (Weeks 64, 88, 112, 136, 160, 172, 184, 208, 220, and 232 
[±7 Days]) – Intrathecal Injection – Extended Treatment Phase – All Patients; 8.2.4.2 Months 19, 25, 31, 37, 
and 49 (Weeks 76, 100, 124, 148, and 196 [±7 Days]) – Intrathecal Injection – Extended Treatment Phase –
All Patients; Appendix 2
Extended Treatment Phase Schedule of Events – Months 13-15 (Weeks 52-60); 
Appendix 3 Extended Treatment Phase Schedule of Events – Months 16-20 (Weeks 64-80); Appendix 4 
Extended Treatment Phase Schedule of Events – Months 21-25 (Weeks 84-100); Appendix 5 Extended 
Treatment Phase Schedule of Events – Months 26-30 (Weeks 104–120); Appendix 6 Extended Treatment 
Phase Schedule of Events – Months 31-34 (Weeks 124-136); Appendix 7 Extended Treatment Phase 
Schedule of Events – Months 35-37 (Weeks 140-148); Appendix 8 Extended Treatment Phase Schedule of 
Events – Months 38-42 (Weeks 152-168); Appendix 9 Extended Treatment Phase Schedule of Events –
Months 43-47 (Weeks 172-188); Appendix 10 Extended Treatment Phase Schedule of Events – Months 48-
52 (Weeks 192-208); Appendix 11 Extended Treatment Phase Schedule of Events – Months 53-57 (Weeks 
212-228); Appendix 12 Extended Treatment Phase Schedule of Events – Month 58 (Week 232) – End of 
study (Month 61, Week 244); 
Change: Clarification to PK analysis
Section impacted by this change: 10.6.1 Pharmacokinetic Measurement and Parameters
Revised Text: 
The analysis of PK parameter data will be performed by the Shire Clinical Pharmacology and 
Pharmacokinetics department or its designee.
Other sections impacted by this change: None
Change: Clarification to TEAE definition
Section impacted by this change: 10.7.1 Adverse Events
Revised Text: 
Treatment-emergent AEs, defined as all AEs from the time of initial intervention (first surgery for IDDD 
implantation, including failed surgeries, or first dose if before first IDDD implantation surgery) to the EOS 
visit last patient visit in the study, will be summarized by the HGT-HIT-094 treatment regimen (idursulfase-
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IT or No Treatment) and overall. 
Other sections impacted by this change: 7.15.6.1 Adverse Event Monitoring and Period of Observation
Change: Addition of adverse event relationship category
Section impacted by this change: 10.7.1.1 Investigational Product
Revised Text: 
Treatment-emergent AEs deemed by the investigator to be related to idursulfase-IT study drug will be 
summarized by presenting the number and percentage of patients having an AE and the number of events, 
by SOC and preferred term. A Separate tabulations of IV Elaprase infusion-related adverse events and IV 
Elaprase infusion and/or idursulfase-IT-related adverse events will also be presented. 
Other sections impacted by this change: Synopsis; 3.1 Primary Endpoints
Change: Clarification concerning interim analyses
Section impacted by this change: 10.8.3 Interim Analyses and Data Monitoring
Revised Text: 
No formal interim analysis or statistical testing is planned. Descriptive analyses of the data Interim 
analyses may be conducted before trial completion may be performed for safety monitoring, regulatory 
reporting or general planning purposes. Analyses will be descriptive in nature, with no formal 
comparisons planned and no hypotheses tested formally.
Other sections impacted by this change: None
Change: Addition of PK sampling with same-day IT-IV dosing
Section impacted by this change: Appendix 13 Pharmacokinetic Sample Collection for Same-Day 
Investigational Product Administration with Elaprase Infusion
Revised Text: 
Assessment
Monthly Visits 13-60a
IT Dosing Week: Main Site only
Pre-Tx Day 1
IT Inj Day
Days 3-7
Serum Sample for PKb,c
●
Same-day Elaprase IV 
infusion and idursulfase-
IT administrationc
●
Abbreviations: Inj=injection; IT=intrathecal; IV=intravenous; PK=pharmacokinetic; Tx=treatment
a
Same-day administration of the IV Elaprase infusion and idursulfase-IT can only occur during the 
Extended Treatment Phase, ie, Months 13-60. 
b
Samples for PK assessments are to be collected on the occasion of the first same-day administration. 
This pharmacokinetic sampling need only be scheduled once, and may occur at Month 25 or at an 
alternative visit during the Extended Treatment Phase.
c
Serum samples for PK analysis will be collected within 30 minutes (±5 minutes) prior to intrathecal 
administration of idursulfase-IT, within 30 minutes prior to the start of Elaprase infusion, and at 30 
minutes (±5 minutes), 60 minutes (±5 minutes), 120 minutes (±5 minutes), 3 hours (±5 minutes; ie, the 
end of  Elaprase infusion), 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 
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of Elaprase Infusion. 
Other sections impacted by this change: 7.8 Pharmacokinetic Assessments
Change: Change to blood sample collection volumes
Section impacted by this change: Appendix 14 Maximum Blood Volume Collection by Study Visit 
(Months/Weeks) for the Initial Treatment Phase (Patients Who Did Not Receive Intrathecal Idursulfase-IT 
in Study HGT HIT-094)
Revised Text: 
BLOOD (mL)
TOTAL
Hematology 
1.2
1.2
1.2
1.2
1.2
1.2
102.3
110
Serum Chemistry 
2.5
2.5
2.5
2.5
2.5
2.5
Anti-idursulfase 
Antibody Testing
0
4
4
4
4
Serum Sample for 
PK
33
33
Coagulation
1.8
Total Blood 
Volume
7.7
0
0
5.5
0
0
40.7
0
0
7.7
0
0
7.7
0
0
7.7
33
Other sections impacted by this change: None
Change: Change to blood sample collection volumes
Section impacted by this change: Appendix 15 Maximum Blood Volume Collection by Study Visit 
(Months/Weeks) for the Extended Treatment Phase (Months 13-27 - Weeks 52-108)
Revised Text: 
Procedure
Extended Treatment Phase
TOTAL
Months
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
13-
60a
Weeks
52
56
60
64
68
72
76
80
84
88
92
96
100
104
108
52-
240a
BLOOD (mL)
Hematology 
1.2
1.2
1.2
1.2
1.2
71.5
108.5
Serum 
Chemistry 
2.5
2.5
2.5
2.5
2.5
Anti-
idursulfase 
Antibody 
Testing
4
4
4
4
4
Serum 
Sample for 
PK
33
37
Coagulation
Total Blood 
Volume
7.7
0
0.0
7.7
0
0.0
7.7
0
0.0
7.7
0
0.0
40.7
0.0
0
37
Abbreviations: IDDD=intrathecal drug delivery device; mL=milliliter; PK=pharmacokinetics
a
To be collected only once at any study visit during Months 13-60 (Weeks 52-240).
Other sections impacted by this change: None
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Change: Change to blood sample collection volumes
Section impacted by this change: Appendix 18 Cumulative Maximum Blood Volume Collection for Patients 
in the Initial Treatment and Extended Treatment Phases (Months -1-61) and Patients Only in the Extended 
Treatment Phase (Months 13-61)
Revised Text:
Months
Initial and Extended 
Treatment
Phase
Extended Treatment
Phase
Blood Volume (mL)
1-12
110 102.3
0
13-27
71.5 108.5
71.5 108.5
28-42
38.5
38.5
43-61
53.9
53.9
Total
273.9 303.5
163.9 200.9
Other sections impacted by this change: None
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Appendix 16
Protocol Amendment Summary of Changes
AMENDMENT SUMMARY AND RATIONALE 
Amendment 1 (applicable only to UK): Clinical protocol SHP-609-302 was amended from the 
original version as follows:
•
The original protocol specified a duration of treatment of 3 years, but left open the possibility 
that patients could transition to receiving commercial drug once the product became 
available. At the request of the health authority in the United Kingdom (MHRA), the 
protocol was amended in Amendment 1 to specify a firm commitment on the part of the 
Sponsor to a duration of treatment of 3 years in this study.
•
This amendment also incorporated clarifications to the text which were implemented 
previously under Administrative Change Memo #1 (25 November 2014) and Administrative 
Change Memo #2 (13 January 2015) and the further clarification that a treatment and 
assessment window of ±7 days applies to both the initial and extended treatment phases of 
the study as specified in Section 8 Study Activities and in the Schedules of Events provided 
as appendices.
Amendment 2 (applicable to all countries): Clinical protocol SHP-609-302 was amended from 
the previous version as follows: 
•
To implement Amendment 1 in all countries (this was only implemented in UK initially)
•
To provide clarification concerning study population
•
To extend the treatment duration in the study to 5 years
•
To specify the maximum volume of blood to be collected from a patient by study visit.
•
To remove language requiring Spanish-speaking patients older than 8 years, 11 months, to 
use the BAS-II for cognitive testing, as a Spanish version of the DAS-II School Age Years 
instrument has become available for use in the study
•
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 text concerning the management of infusion-related reactions
•
To clarify that there are 2 questionnaires, the HCUQ and CIQ, to evaluate health resource 
utilization and impact
•
To clarify that the Month 13 (Week 52) infusion must be performed at the main study site
DETAILED SUMMARY OF CHANGES FOR THE AMENDMENT 1
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.
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.
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Change: Change to planned study duration
Section impacted by this change: 4.4 Study Duration
Revised Text: 
Patients will participate in this extension study for a duration of 3 years of treatment unless they 
discontinue the study or Shire discontinues the study, or until they are transitioned onto commercially 
available treatment, for a maximum duration of 3 years of treatment in this study (SHP-609-302).
Other sections impacted by this change: Synopsis
Change: Removal of duplicated text
Section impacted by this change: 7.15.6.2 Reporting Serious Adverse Events
Revised Text: 
The following provides contact information for the Shire Medical Monitor.
Other sections impacted by this change: None
Change: Clarification to study procedure
Section impacted by this change: 8.2.4.1 Months 19, 25, and 31 (Weeks 76, 100, and 124 [±7 days]) – Prior 
to Intrathecal Injection – Extended Treatment Phase - All Patients
Revised Text: 
•
Head circumference (Week Month 25 only)
•
Brain MRI (Week Month 25 only)
Other sections impacted by this change: None
Change: Clarification to study procedure
Section impacted by this change: 8.2.4.2 Months 19, 25, and 31 (Weeks 76, 100, and 124 [±7 days]) –
Intrathecal Injection – Extended Treatment Phase - All Patients
Revised Text: 
•
12-lead ECG (Week Month 25 only)
•
Serum sampling for PK analysis will be collected at Week Month 25 only …
Other sections impacted by this change: None
Change: Clarification to study procedure
Section impacted by this change: 8.1.4Treatment and Assessments (Months 1 – 12, Weeks 4 – 48 [±7 
days]) – Initial Treatment Phase
Revised Text: 
Treatment and Assessments (Months 1 – 12, Weeks 4 – 48 [±7 days]) – Initial Treatment Phase
Other sections impacted by this change: 7 Study Procedures, 8.2.1 Month 13 (Week 52 [±7 days]) –
Extended Treatment Phase – All Patients, 8.2.2 Months 14, 15, 17, 18, 20, 21, 23, 24, 26, 27, 29, 30, 32, 33, 
35, and 36 (Weeks 56, 60, 68, 72, 80, 84, 92, 96, 104, 108, 116, 120, 128, 132, 140, and 144 [±7 days]) –
Extended Treatment Phase - All Patients, 8.2.3 Months 16, 22, 28, and 34 (Weeks 64, 88, 112, and 136 [±7 
days]) –Extended Treatment Phase - All Patients, 8.2.4 Months 19, 25, and 31 (Weeks 76, 100, and 124 [±7 
days]) – Extended Treatment Phase - All Patients, 8.3 End-of-Study (Month 37, Week 148 [±7 days]) –
Extended Treatment Phase - All Patients, Schedules of Events in Appendix 2, Appendix 3, Appendix 4, 
Appendix 5, Appendix 6 and Appendix 7
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Change: Clarification to recording of information
Section impacted by this change: 11.5 Patient Confidentiality
Revised Text: 
Only the patient number and patient initials will be recorded in the eCRF, and if the patient name appears on 
any other document, it must be obliterated before a copy of the document is supplied to the Sponsor.
Other sections impacted by this change: None
Change: Clarification to footnote lettering
Section impacted by this change: Appendix 4 Extended Treatment Phase Schedule of Events - Months 21 -
25 (Weeks 84 - 100)
Revised Text: 
[Due to duplication of footnote a in the list of footnotes shown below the schedule of assessments in 
Appendix 4, the sequential lettering of the listed footnotes should be readjusted to appear as follows:]
a
Neurodevelopmental status will be assessed over time by measuring cognitive and adaptive functions as 
depicted in Appendix 8.
b
The 12-lead ECG is to be performed within 4 hours after IT administration of study drug.
c
General anesthesia or sedation may be required for injections of investigational product and some 
evaluations, and can be used at the discretion of the Investigator as indicated in the Study Manuals. It is 
anticipated that study procedures such as lumbar puncture and MRI will have to be performed with 
sedation/anesthesiology support.
d
X-rays may be performed to check placement of the device, and as needed, throughout the study. An 
X-ray will be performed at the end of the study to verify that the IDDD is in the correct position.
e
Serum samples for PK analysis 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.
f
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.
g
When a patient has received and tolerated a total of 12 monthly doses of intrathecal idursulfase-IT 
across studies HGT-HIT-094 and SHP-609-302, the Sponsor and Principal Investigator will consider 
the feasibility of transitioning the patient’s monthly IT dosing to local sites to reduce the burden 
imposed by monthly travel.
h
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. 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.
i
Patients will remain under observation in the hospital setting (eg, may include infusion center, PACU 
(recovery suite), observation unit, short stay center) for 4 hours post IT injection for vital signs and 
other safety assessments. Vital signs will be 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. Thereafter, if deemed clinically stable 
by the Investigator, patients may leave the hospital setting (with exception of Visits at which serial 
blood sampling for pharmacokinetic evaluation is planned). The patient may need to be examined the 
following day.
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Change: Clarification that 2 questionnaires are used to evaluate healthcare resource utilization
Section impacted by this change: 2.4 Health Economics and Outcomes Research Objectives
Revised Text: 
•
To evaluate healthcare resource utilization, as measured by 2 questionnaires consisting of thea 
Healthcare Resource Utilization Questionnaire (HCUQ) and Caregiver Impact Questionnaire (CIQ), 
in patients with Hunter syndrome and cognitive impairment who are treated with idursulfase-IT in 
conjunction with Elaprase therapy
Other sections impacted by this change: Synopsis; 3.3 Health Economics and Outcomes Research 
Endpoints; 7.11.2 Healthcare Resource Utilization and Impact Questionnaires; 8.1.1 Baseline (Month  1, 
Week  1, Days -7 to Day -1) – Initial Treatment Phase; 8.1.4.1 Prior to Intrathecal Injection (Months 1-12, 
Weeks 4-48 [±7 Days]) – Initial Treatment Phase; 8.2.1.1 Month 13 (Week 52 [±7 Days]) – Prior to 
Intrathecal Injection – Extended Treatment Phase – All Patients; 8.2.4.1 Months 19, 25, 31, 37, 49, and 61 
(Weeks 76, 100, 124, 148, 196, and 244 [±7 Days]) – Prior to Intrathecal Injection – Extended Treatment 
Phase – All Patients; 8.3 End of Study (Month 61, Week 244 [±7 Days]) – Extended Treatment Phase – All 
Patients; 10.5.6 Health Economics and Outcomes Research Endpoint Analyses; Appendix 1, Appendix 2, 
Appendix 3, Appendix 4, Appendix 5, Appendix 6, and Appendix 7
Change: Clarification regarding treatment at home
Section impacted by this change: 4.1.3 Treatment Schedule
Revised Text: 
Patients will receive their monthly doses of intrathecal idursulfase-IT at the main study site or at a local site. 
All patients will receive their weekly IV infusions of Elaprase throughout the study. Elaprase infusions may 
be administered at the main study site, at a local site, or at a site determined by the patient’s physician, or
at the patient’s home depending upon the standard location as determined for each patient (at the discretion 
of local laws and the treating physician).
Other sections impacted by this change: Appendix 2
Change: Change to planned study duration, extended treatment phase increased to 5 years
Section impacted by this change: 4.4 Study Duration
Revised Text: 
Patients will participate in this extension study for a duration of 35 years of treatment unless they 
discontinue the study or Shire discontinues the study.
Other sections impacted by this change: Synopsis; 4.1.2 Extended Treatment Phase – All Patients; Appendix 
1, Appendix 7, Appendix 8, Appendix 9, Appendix 10, Appendix 11, and Appendix 12; 7 Study Procedures; 
7.8 Pharmacokinetic Assessments; 7.12.8 Cerebrospinal Fluid Assessments; 8 Study Activities; 8.2.2
Months 14, 15, 17, 18, 20, 21, 23, 24, 26, 27, 29, 30, 32, 33, 35, 36, 38, 39, 41, 42, 44, 45, 47, 48, 50, 51, 53, 
54, 56, 57, 59, and 60 (Weeks 56, 60, 68, 72, 80, 84, 92, 96, 104, 108, 116, 120, 128, 132, 140, 144, 152, 
156, 164, 168, 176, 180, 188, 192, 200, 204, 212, 216, 224, 228, 236, and 240 [±7 Days]) – Extended 
Treatment Phase – All Patients; 8.2.3 Months 16, 22, 28, 34, 40, 43, 46, 52, 55, and 58 (Weeks 64, 88, 112, 
136, 160, 172, 184, 208, 220, and 232 [±7 Days]) – Extended Treatment Phase – All Patients; 8.2.4 Months 
19, 25, 31, 37, 43, 49, 55, and 61 (Weeks 76, 100, 124, 148, 196, and 244 [±7 Days]) – Extended Treatment 
Phase – All Patients; 8.3 End of Study (Month 61, Week 244 [±7 Days]) – Extended Treatment Phase – All 
Patients
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Change: Clarification concerning study population
Section impacted by this change: 5.1 Study Population
Revised Text: 
Up to42 pPediatric patients (plus potentially any pediatric patients younger than 3 years of age in the 
antecedent substudy) who completed Study HGT-HIT-094, and meet the eligibility criteria may enroll in 
this study.
Other sections impacted by this change: Synopsis; 1.3.1 Rationale for Current Phase II/III Study
Change: Clarification concerning the IDDD
Section impacted by this change: 6.1.2 Intrathecal Drug Delivery Device
Revised Text: 
The drug 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 timedevice is intended for long term, intermittent access to the IT 
space for the delivery of investigational drug. The device is CE Marked in the European Union (EU) and 
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 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 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.
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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. CThe 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. As of the date of this protocol, there have been no 
significant concerns regarding infusion-related immune reactions following IT administration in studies 
HGT-HIT-045 and HGT-HIT-046.
Other sections impacted by this change: None
Change: Guidance concerning IDDD malfunction
Section impacted by this change: 7.6.1 IDDD Implantation and Revision
Revised Text: 
If at the time of a scheduled dosing, due to a device-related issue it is not possible to aspirate CSF 
prior to dose administration, administer a full medication dosage using the standard administration 
steps detailed in the device’s IFU, or flush the system following dose administration, the IDDD will be 
declared a device malfunction. If the device malfunction is irreversible and cannot be corrected 
without a partial or full device revision or removal, the IDDD will be declared a device failure, 
starting from the date of the initial malfunction.
The IDDD will then be surgically removed or revised and a new device and/or device components will 
be re-implanted at the earliest possible opportunity, preferably at the same time.
Other sections impacted by this change: None
Change: Clarification concerning serum albumin  assessment
Section impacted by this change: 7.9.2 Cerebrospinal Fluid and Serum Albumin
Revised Text: 
Albumin levels will be measured in samples of CSF and serum to monitor the permeability of the blood
brain barrier. The relative permeability of the blood-brain barrier will be monitored by the CSF/serum 
albumin ratio.
Other sections impacted by this change: 7.12.7 Clinical and Other Laboratory Tests
Change: Change in cognitive testing of Spanish-speaking patients
Section impacted by this change: 7.10.1 Neurodevelopmental Assessment Tools
Revised Text: 
COGNITION
The Differential Ability Scales, Second Edition (DAS-II),17 will be used to assess all patients of age 2 years, 6 
months or older, including Spanish-speaking patients who will be assessed with the Spanish version of the 
DAS-II. 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 
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months through 17 years 11 months. These batteries are fully co-normed for ages 5 years 0 months through 8 
years 11 months. 
Any patients who cannot be assessed with the DAS-II due to a deteriorating condition or who are younger 
than 2 years, 6 months of age, will be assessed with the BSID-III.18 Spanish-speaking patients will be 
assessed using the Spanish version of the DAS II Early Years only for patients of age 8 years, 11 months 
or younger. Spanish speaking patients older than 8 years, 11 months will be assessed with the Spanish 
version of the BAS II.
Table 7-1    Neurodevelopmental Assessments in Study SHP-609-302
Assessment
Intended Study 
Population
Applicable Age
DAS-II
Patients 2 years, 6 months 
of age and oldera
Early Years Batterya, b
2 years, 6 months through 6 years, 11 months
(extended norms: up to 8 years, 11 months)
School Age Battery
7 years, 0 months through 17 years, 11 months
BSID-III
Patients younger than 
2 years, 6 months of age 
and older children who 
cannot perform the 
DAS-II or BAS-II
1 to 42 months
BAS-IIa
Spanish-speaking patients 
older than 8 years, 11 
months
School Age Scale
6 years 0 months to 17 years 11 months
VABS-II
All patients
Birth to 90 years
Abbreviations: BAS-II=British Abilities Scale, Second Edition; BSID-III=Bayley Scales of Infant and 
Toddler Development, Third Edition; DAS-II=Differential Ability Scales, Second Edition; 
VABS-II=Vineland Adaptive Behavioral Scales, Second Edition
a
For the DAS-II, Spanish-speaking patients will be assessed using the Spanish versions of the DAS-II 
(Early Years and School Age) only. The BAS-II will be used instead of the DAS-II to assess any 
Spanish-speaking patients older than 8 years, 11 months of age
b
Extended norms may be used.
Other sections impacted by this change: Synopsis; 2.2 Secondary Objectives; 3.2 Secondary Efficacy 
Endpoints; 7.20 Appropriateness of Measurements; 8.1.4.1 Prior to Intrathecal Injection (Months 1-12, Weeks 
4-48 [±7 Days]) – Initial Treatment Phase; 8.2.4 Months 19, 25, 31, 37, 43, 49, 55, and 61 (Weeks 76, 100, 
124, 148, 196, and 244 [±7 Days]) – Extended Treatment Phase – All Patients; 8.3 End of Study (Month 61, 
Week 244 [±7 Days]) – Extended Treatment Phase – All Patients; 10.1 General Methodology
Change: Clarification to CSF assessment
Section impacted by this change: 7.12.8 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. The CSF samples will also be analyzed for idursulfase-specific antibodies 
and antibodies with enzyme neutralizing activity (Section 7.12.9).
Cerebrospinal fluid will be obtained during the days and weeks of the study as indicated in the Schedule of 
Events (Appendix 1Appendix 1, Appendix 2, Appendix 3, Appendix 4, Appendix 5, Appendix 6, and Appendix 
7, Appendix 8, Appendix 9, Appendix 10, Appendix 11, and Appendix 12). Should the IDDD become 
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clogged or undergo mechanical complications, the CSF sample will be obtained via LP until the subject had a 
functional IDDD.
Other sections impacted by this change: None
Change: Clarification regarding device adjustment
Section impacted by this change: 7.15.2.4 Device Adjustment
New section:
7.15.2.4 Device Adjustment
Surgery of the device which does not result in partial or complete revision or removal (eg, surgical 
exploration only or placement of additional sutures, tissue glue, and/or fascial repair.
Other sections impacted by this change: None
Change: Clarification regarding statistical methods, details to be included in Statistical Analysis Plan
Section impacted by this change: 10.1 General Methodology
New section:
All safety and efficacy data will be summarized descriptively at scheduled visits. For efficacy endpoints, the 
mean difference in the change at each time point between the 2 HGT-HIT-094 treatment groups and the 
corresponding 95% confidence interval of the mean difference will be presented where appropriate. If the 
parametric assumption for the distribution cannot be justified, a non-parametric approach will be utilized to 
estimate the treatment difference and the corresponding 95% confidence interval (ie, median difference or 
Hodges Lehmann estimator and the corresponding confidence intervals). The mean values for all efficacy 
endpoints will be graphed over time where appropriate.
Other sections impacted by this change: Synopsis
Change: Modification of TEAE definition for statistical analysis
Section impacted by this change: 10.7.1 Adverse Events
Revised Text:
Treatment-emergent AEs, defined as all AEs from the time of initial intervention (first surgery for IDDD 
implantation (including failed surgeries, or first dose if no before first IDDD implantation surgery), to 
the last patient visit in the study, will be summarized by the HGT-HIT-094 treatment regimen (idursulfase-
IT or No Treatment) and overall.
Other sections impacted by this change: None
Change: Clarification to analysis of IDDD performance
Section impacted by this change: 10.7.6.1 IDDD Performance
Revised Text: 
The proportion of patients for whom a successful first injection of study drug occurred will be reported 
among those for whom a first injection was attempted (i.e. those who had an apparently successful 
implantation and did not suffer a device removal or revision prior to first scheduled injection). The 
proportion of patients who had no failed injection attempts during the study will also be summarized. The 
corresponding 95% confidence intervals of the proportion of interest will be estimated, where appropriate. 
Injections that are not administered for patient-related reasons (e.g. patient uncooperative, competing 
medical issue, etc) will not be included in the determination of the success of injection rate. 
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The rate of successful IDDD injections will be calculated for each patient and summarized 
descriptively. The success rate will be calculated as the number of IDDD injections given as a 
percentage of IDDD injections given plus any malfunctions reported for inability to dose. The 
corresponding 95% confidence interval for the mean rate will be estimated, where appropriate. 
Injections that are not administered for patient-related reasons (eg, patient uncooperative, competing 
medical issue, etc.) will not be included in the determination of the injection success rate.
Other sections impacted by this change: None
Change: Addition of tables summarizing maximum blood volume collection by study visit
Section impacted by this change: Appendix 13 Maximum Blood Volume Collected by Study Visit
Revised Text: 
See 4 new tables, as follows:
Maximum Blood Volume Collection by Study Visit (Months/Weeks) for the Initial Treatment Phase 
(Patients Who Did Not Receive Intrathecal Idursulfase-IT in Study HGT-HIT-094)
Maximum Blood Volume Collection by Study Visit (Months/Weeks) for the Extended Treatment 
Phase (Months 13-27 – Weeks 52-108)
Maximum Blood Volume Collection by Study Visit (Months/Weeks) for the Extended Treatment 
Phase (Months 28-42 – Weeks 112-168)
Maximum Blood Volume Collection by Study Visit (Months/Weeks) for the Extended Treatment 
Phase (Months 43-60 – Weeks 172-240)
Other sections impacted by this change: 7.12.7 Clinical and Other Laboratory Tests
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SAP_001.pdf: 
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CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document constitutes the 
agreement by the recipient that no information contained herein will be published or disclosed without 
written authorization from Takeda. 
STATISTICAL ANALYSIS PLAN FOR SHP609-302 Final Abbreviated 
CSR 
Protocol Title:  
An Open-Label Extension of Study HGT-HIT-094 Evaluating Long-Term Safety and 
Clinical Outcomes of Intrathecal Idursulfase Administered in Conjunction with 
Elaprase® in Patients with Hunter Syndrome and Cognitive Impairment 
    Protocol Number: 
     SHP609-302 (Amendment 4) 
    Protocol Date: 
     09 Oct 2018 
     Investigation Product:   idursulfase for intrathecal use (idursulfase-IT [HGT-2310]),  
     Device Name:     
    SOPH-A-PORT® Mini S, Implantable Access Port, Spinal, Mini Unattached, with 
Guidewire (SOPH-A-PORT® Mini S) 
     SAP Version:  
     2.0, an addendum to SAP for interim analysis 1.1 
 Date:
     21 Feb 2023 
 Prepared by: 
  
 
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STATISTICAL ANALYSIS PLAN FOR FINAL ABBREVIATED CSR 
 
CONFIDENTIAL  
 
 
 
 
TABLE OF CONTENTS 
 
TABLE OF CONTENTS ............................................................................................................................. 3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................................. 4 
1. 
INTRODUCTION ............................................................................................................................... 5 
2. 
OBJECTIVES AND ENDPOINTS ...................................................................................................... 5 
2.1 Objectives ............................................................................................................................................ 5 
2.2 Endpoints ............................................................................................................................................. 5 
3. 
ANALYSIS SETS ............................................................................................................................... 6 
4. 
STATISTICAL ANALYSIS ............................................................................................................... 6 
4.1 Patient Disposition ............................................................................................................................... 6 
4.2 Protocol Deviations .............................................................................................................................. 6 
4.3 Demographic and Baseline Characteristics ......................................................................................... 6 
4.4 Treatment Compliance and Extent of Exposure .................................................................................. 6 
4.5 Secondary Pharmacodynamic Analyses .............................................................................................. 7 
4.6 Analysis of Safety ................................................................................................................................ 7 
4.7 SOPH-A-PORT Mini S Device Performance ...................................................................................... 8 
4.8 Concomitant Medications .................................................................................................................... 8 
5. 
STATISTICAL/ANALYTIC ISSUES ................................................................................................ 8 
6. 
REFERENCES .................................................................................................................................... 8 
7. 
APPENDICES ..................................................................................................................................... 8 
 
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STATISTICAL ANALYSIS PLAN FOR FINAL ABBREVIATED CSR 
 
CONFIDENTIAL  
 
 
 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
 
AE 
Adverse Event 
CRF 
case report form 
CRO 
contract research organization 
CSF 
cerebrospinal fluid 
CSR 
clinical study report 
ECG 
electrocardiogram 
GAG 
Glycosaminoglycan(s) 
HEOR 
health economics and outcomes research 
IA 
interim analysis 
IDDD 
intrathecal drug delivery device 
IT 
intrathecal 
IV 
intravenous 
PD 
pharmacodynamic 
PK 
pharmacokinetic 
SAP 
statistical analysis plan 
SAS 
Statistical Analysis System© 
SQS 
 
    Statistical & Quantitative Sciences 
  
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STATISTICAL ANALYSIS PLAN FOR FINAL ABBREVIATED CSR 
 
CONFIDENTIAL  
 
 
 
1. 
INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide specifications for the final 
analysis which will appear in the final abbreviated clinical study report (CSR). 
Unless otherwise specified, the analyses in this SAP will apply the same methodologies as 
specified in the SAP for interim analysis (IA) (v1.1, dated 14 Mar 2019) and addendum 1 for 
interim analysis 2 (dated 26 Mar 2020). All available data in the extended treatment phase will 
be included in the final analyses. Only safety and pharmacodynamic (PD) analyses will be 
presented in the final abbreviated CSR.  
2. 
OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
The primary objective of this study is to evaluate long-term safety in patients with Hunter 
syndrome and cognitive impairment who are receiving intrathecal idursulfase-IT (SHP609) and 
intravenous (IV) Elaprase® enzyme replacement therapy (ERT).  
The secondary and exploratory objectives are as noted in the SAP for IA in section 4.1. The final 
analyses will not address efficacy, exploratory, pharmacokinetic (PK) or health economics and 
outcomes research (HEOR) objectives.  
The device objective is to evaluate the safety and performance of the SOPH-A-PORT Mini S. 
2.2 
Endpoints 
The endpoints are defined in section 4.1 of the SAP for IA. The final analyses will focus on the 
safety and PD related endpoints as stated in section 4.1 of the SAP for IA. The endpoints for the 
final abbreviated CSR are reiterated below. 
The primary endpoint of this study is the safety of intrathecal idursulfase-IT administration. 
Safety will be measured by adverse events (AEs, by type, severity, and relationship to treatment 
[idursulfase-IT, the intrathecal drug delivery device (IDDD), device surgical procedure, or IT 
administration process] and IV Elaprase infusion), changes in clinical laboratory testing (serum 
chemistry, hematology, urinalysis), vital signs, twelve-lead electrocardiogram (ECG) recordings, 
cerebral spinal fluid (CSF) parameters (chemistries, cell counts), anti-idursulfase antibodies in 
CSF and serum, including determination of anti-idursulfase antibodies having enzyme 
neutralizing activity. 
 
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STATISTICAL ANALYSIS PLAN FOR FINAL ABBREVIATED CSR 
 
CONFIDENTIAL  
 
 
 
The secondary PD endpoints include CSF concentration of idursulfase, the change from baseline 
in concentration of glycosaminoglycan (GAG) in CSF and the change from baseline in the 
concentration of GAG in urine. 
The SOPH-A-PORT Mini S device will be evaluated using assessments of device implantation, 
device function, device longevity, and AEs associated with the implant surgery or device. These 
data will be collected on the patient’s eCRF from the time of initial implantation. 
3. 
ANALYSIS SETS 
All PD and safety data analysis will be performed using the Safety Population, which is defined 
as follows: All subjects in study SHP609-302 who underwent IDDD implantation or received at 
least 1 dose of study drug (full or partial). The definitions of each analysis population are stated 
in section 6.2 of the SAP for IA; however, the focus of the final analyses will be safety and PD 
endpoints. 
4. 
STATISTICAL ANALYSIS 
All statistical analyses will be performed by Statistics & Quantitative Sciences (SQS) 
Department at Takeda or its designated contract research organization (CRO) unless otherwise 
specified, using SAS® software version 9.4 or higher (SAS Institute, Cary, N.C., USA). 
Summary tables will be tabulated as noted in section 6.1 of the SAP for IA. The complete results 
from initial and extended treatment phases will be described in the final abbreviated CSR.   
4.1 
Patient Disposition 
Patient disposition will be presented as described in section 6.3 of the SAP for IA. 
4.2 
Protocol Deviations 
Protocol deviations will be presented in a listing as noted in section 6.4 of the SAP for IA. 
4.3 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics (as detailed in section 6.5 of the SAP for IA) will be 
presented in summary using the Safety Population by the Early IT group, the Delayed IT group 
for the antecedent pivotal study, antecedent substudy and overall.  
4.4 
Treatment Compliance and Extent of Exposure 
Treatment compliance and extent of exposure will use the same methodology as in section 6.6 of 
the SAP for IA. These will be summarized by the Early IT group, the Delayed IT group for the 
antecedent pivotal study, antecedent substudy and overall using the Safety Population.  
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STATISTICAL ANALYSIS PLAN FOR FINAL ABBREVIATED CSR 
 
CONFIDENTIAL  
 
 
 
4.5 
Secondary Pharmacodynamic Analyses 
The CSF and urine GAG levels will be presented in graphs (mean observed values and mean 
percent change by visit) and descriptive statistics will be in summary tables (observed values, 
change from baseline and percent change from baseline) as noted in section 6.7.6 of the SAP for 
IA.   
Analysis of both CSF total GAG and CSF heparan sulfate if available will be performed. CFS 
albumin concentrations, CSF/serum albumin quotients observed levels, the change from baseline 
and the percent change from baseline will be summarized as noted in section 6.7.6 of the SAP 
for IA.  
Summaries will be presented by the Early IT group, the Delayed IT group and overall by visit 
using the Safety Population. All available data in the extended treatment phase to the end of 
study will be presented. 
4.6 
Analysis of Safety 
Similar methodology as in the SAP for IA section 6.8 will be used for the Safety Population. All 
summaries will include all available scheduled visits to the end of the study.  
The primary assessments of this study are the safety of idursulfase-IT administration. Safety will 
be measured by AEs, changes in clinical laboratory testing, vital signs, 12-lead ECG, CSF 
chemistries, anti-idursulfase antibodies and antibodies having enzyme neutralizing activity in 
CSF and serum. All analyses of safety data will be descriptive and presented by the Early IT 
group, the Delayed IT group and overall. Any former HGT-HIT-094 Substudy subjects will be 
included in the Early IT group. 
AEs will be presented as detailed in section 6.8.1 of the SAP for IA. The clinical and CSF 
laboratory results will be presented as detailed in section 6.8.2 of the SAP for IA. The 12-lead 
ECG results will be presented as detailed in section 6.8.3 of the SAP for IA. The injection (IT) 
vital signs and regular vital signs will be listed as detailed in section 6.8.4 of the SAP for IA. 
Similar methodology as in SAP for IA section 6.8.6 will be applied to the Safety Population for:  
x Anti-idursulfase antibody formation (specifics in section 6.8.6.1)  
x The Idursulfase enzyme levels in CSF (specifics in section 6.8.6.2) 
x Height (cm), weight (kg), and head circumference (cm) (specifics in section 6.8.6.3) 
x Brain MRI (specifics in section 6.8.6.4) 
x Hearing Assessments (specifics in section 6.5.6.5). 
 
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CONFIDENTIAL 
The details are in sections of the SAP for IA mentioned above and presentations will include all 
available scheduled study visits to the end of study.  
All safety analyses will be descriptive, no statistical testing will be performed. 
4.7 
SOPH-A-PORT Mini S Device Performance  
See section 6.8.6.6 of the SAP for IA for details regarding device-related terminology as well as 
well as device performance analyses to be presented. 
4.8 
Concomitant Medications 
See section 6.8.7 of the SAP for IA regarding presentations relating to concomitant medications.  
5.
STATISTICAL/ANALYTIC ISSUES
See section 8 of the SAP for IA. This section has 9 subsections which give details on adjustment 
for covariates, handling of dropouts/missing data, IA and data monitoring, multicenter studies, 
multiple comparisons/multiplicity, examination of interactions, sensitivity analyses, windowing 
visits, and data listings. 
6.
REFERENCES
1. Statistical Analysis Plan for Interim Analyses (for Protocol SHP609-302, amendment 4).
Version 1.1. 14 March 2019.
7.
APPENDICES
See section 10 of the SAP for IA for the appendix I: list of statistical outputs, and appendix II: 
protocol violations definitions. Other appendices are not applicable for the final CSR. 
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SHP609-302 Statistical Analysis Plan for Interim Analysis 
Idursulfase for Intrathecal Administration
14 Mar 2019
TABLE OF CONTENTS
ABBREVIATIONS AND DEFINITIONS OF TERMS .........................................................5
1.
INTRODUCTION ...................................................................................................................8
2.
Background....................................................................................................................8
2.1
Study Rationale..............................................................................................................8
2.2
PURPOSE OF STATISTICAL ANALYSIS PLAN .............................................................10
3.
SUMMARY OF CLINICAL TRIAL FEATURES ...............................................................11
4.
General Description .....................................................................................................11
4.1
Determination of Sample Size/Randomization............................................................15
4.2
EFFICACY AND SAFETY VARIABLES...........................................................................16
5.
Schedule of Evaluations...............................................................................................16
5.1
Primary Safety Endpoints ............................................................................................16
5.2
Secondary Efficacy Endpoints.....................................................................................16
5.3
Exploratory Efficacy Endpoints...................................................................................16
5.4
5.4.1
Study Visits Used to Define Exploratory Efficacy Endpoints...........................16
5.4.2
Thresholds of Clinically Meaningful Change....................................................19
5.4.3
Change over a 12-Month Period Endpoints.......................................................20
5.4.4
Ordered Categorical Outcomes (3 Categories) Endpoints.................................20
5.4.5
Binary Unreversed Floor Effect Outcomes Endpoints ......................................21
Health Economics and Outcomes Research Endpoints ...............................................22
5.5
Pharmacokinetic and Pharmacodynamic Endpoints ....................................................22
5.6
SOPH-A-PORT Mini S Assessments ..........................................................................22
5.7
STATISTICAL ANALYSIS .................................................................................................23
6.
General Methodology ..................................................................................................23
6.1
Data Integration Strategy and Analysis Populations ...................................................23
6.2
6.2.1
Data Integration Strategy ...................................................................................23
6.2.2
Analysis Populations..........................................................................................25
Patient Disposition.......................................................................................................26
6.3
Protocol Deviations......................................................................................................27
6.4
Demographic and Other Baseline Characteristics .......................................................27
6.5
Treatment Compliance and Extent of Exposure ..........................................................27
6.6
Analysis of Efficacy.....................................................................................................28
6.7
6.7.1
Primary Efficacy Analysis .................................................................................28
6.7.2
Secondary Efficacy Analysis .............................................................................28
6.7.3
Subgroup Analyses ............................................................................................32
6.7.4
Exploratory Efficacy Analyses ..........................................................................32
6.7.5
Health Economics and Outcomes Research Endpoint Analyses .......................42
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6.7.6
Pharmacodynamic Outcome ..............................................................................42
Analysis of Safety........................................................................................................43
6.8
6.8.1
Adverse Events ..................................................................................................43
6.8.2
Clinical and CSF Laboratory Evaluations .........................................................44
6.8.3
12-Lead ECG Evaluations .................................................................................45
6.8.4
Vital Signs..........................................................................................................45
6.8.5
Physical and Neurological Findings ..................................................................46
6.8.6
Other Observations Related to Safety................................................................46
6.8.7
Concomitant Medications ..................................................................................50
6.8.8
Concomitant Therapies ......................................................................................50
Analysis of Pharmacokinetic Data...............................................................................51
6.9
6.9.1
Concentration Data ............................................................................................51
6.9.2
Handling BLQ Values........................................................................................51
6.9.3
Pharmacokinetic Parameters..............................................................................51
Drug-Drug and Drug-Disease Interactions ..................................................................52
6.10
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES.............53
7.
Changes in the Conduct of the Study...........................................................................53
7.1
Changes from the Analyses Planned in the Protocol ...................................................53
7.2
STATISTICAL/ANALYTIC ISSUES ..................................................................................54
8.
Adjustment for Covariates ...........................................................................................54
8.1
Handling of Dropouts or Missing Data........................................................................54
8.2
Interim Analyses and Data Monitoring........................................................................54
8.3
Multicenter Studies ......................................................................................................54
8.4
Multiple Comparisons/Multiplicity .............................................................................54
8.5
Examination of Interactions.........................................................................................54
8.6
Sensitivity Analyses.....................................................................................................54
8.7
Windowing Visits ........................................................................................................55
8.8
Data Listings ................................................................................................................55
8.9
REFERENCES ......................................................................................................................56
9.
APPENDICES .......................................................................................................................57
10.
Appendix I – List of Statistical Outputs ......................................................................57
10.1
Appendix II – Protocol Violations Definitions............................................................57
10.2
Appendix III – Sample SAS Code...............................................................................57
10.3
10.3.1
Sample SAS Code for Rate of Change (Weighted) Analysis ............................57
10.3.2
Sample SAS Code for Correlation Analysis Using Repeated Measures ...........59
10.3.3
Sample SAS Code for James-Stein/Empirical Bayes Estimator........................59
Appendix IV – James-Stein/Empirical Bayes Estimator of Weight ............................59
10.4
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LIST OF TABLES
Table 1
Putatively Clinically Meaningful Change and Floor Effect Threshold 
for DAS-II and VABS-II Assessment Scores ...............................................20
Table 2
Definition of analysis populations in SHP609-302 IA SAP .........................26
Table 3
Summary of Exploratory Efficacy Analysis in the SHP609-302 IA 
SAP................................................................................................................39
LIST OF FIGURES
Figure 1
Scheduled Visits and Duration of Treatment in Studies HGT-HIT-094 
and SHP609-302............................................................................................16
Figure 2
Schematic Relationship in Studies HGT-HIT-094 and SHP609-302 ...........24
Figure 3
Hypothetical Illustration of Comparisons of Analysis 1 on “D”...................36
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Idursulfase for Intrathecal Administration
14 Mar 2019
ABBREVIATIONS AND DEFINITIONS OF TERMS
1.
Abbreviation
Definition
ABR
auditory brainstem response
AE
adverse event
ATC
Anatomic therapeutic class
AUC0-∞
Area under the curve extrapolated to infinity, calculated using the 
observed value of the last non-zero concentration
AUC0-t
Area under the curve from the time of dosing to the last 
measureable concentration
BBB
Blood brain barrier
BLQ
Below the lower limit of quantification
BOT-2
Bruininks-Oseretsky Test of Motor Proficiency, Second Edition
BRI
Behavioral Regulation Index
BRIEF
Behavior Rating Inventory of Executive Function 
BRIEF-P
Behavior Rating Inventory of Executive Function-Preschool
BSID-III
Bayley Scales of Infant Development, Third Edition
CBC
complete blood count
CI
confidence interval
CL
Total body clearance for intravenous administration
CL/F
Total body clearance for extravascular administration divided by 
fraction of dose absorbed
Cmax
Maximum serum concentration at tmax
CNS
central nervous system
CS
clinically significant
CSF
cerebrospinal fluid
CSR
Clinical study report
DAS-II
Differential Ability Scales, Second Edition
DQ
Developmental Quotient
DS
dermatan sulfate
eCRF
Electronic case report form
eCDF
Empirical Cumulative Distribution Function
EC
Emotional Control
ECG
Electrocardiogram
EMI
Emergent Metacognition Index
EOS
end of study
ERT
enzyme replacement therapy
EY
Early Years
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Abbreviation
Definition
FI
Flexibility Index
FMQ
Fine Motor Quotient
GAG
glycosaminoglycan
GCA
General Conceptual Ability
GCA EY
DAS-II GCA standard scores from Early Years battery
GEC
Global Executive Composite
GMQ
Gross Motor Quotient
HS
heparan sulfate
IA
interim analysis
ICP
intracranial pressure
IDDD
intrathecal drug delivery device
ILP
Inter-peak latency
ISCI
Inhibitor Self-Control Index
IT
Intrathecal
IV
Intravenous
KM
Kaplan-Meier
LLOQ
Lower limit of quantification
LP
Lumbar puncture
MedDRA
Medical Dictionary for Regulatory Activities 
mg
milligram(s)
MI
Megacognition Index
Min
Minimum
Max
Maximum
MMRM
Mixed Model for Repeated Measures
MRI
magnetic resonance imaging
MRT
Mean residence time
MSE
Mean squared error
NA
Not applicable
NCS
not clinically significant
PDMS-2
Peabody Developmental Motor Scales-2
PK
pharmacokinetic(s)
PO
Plan/Organize
PORT-A-CATH
PORT-A-CATH® II Low Profile™Intrathecal Implantable Access 
System
PT
prothrombin time
PTA
Pure tone average
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Abbreviation
Definition
PTT
partial thromboplastin time
Q1
25th percentile
Q3
75th percentile
QTc
corrected QT interval
SA
School Age
SAE
serious adverse event
SAP
Statistical Analysis Plan
SIB-R
Scale of Independent Behavior-revised
SNC
Special Nonverbal Composite
SOC
system organ class
SOPH-A-PORT Mini S
SOPH-A-PORT® Mini S, Implantable Access Port, Spinal, Mini
Unattached, with Guidewire
SD
Standard deviation
Std. Err.
Standard error
SS
Standard score
t1/2
Terminal half-life
T4
Thyroxine
tmax
Time to maximum serum concentration during a dosing interval
TEAE
Treatment-emergent adverse event
TMQ
Total Motor Quotient
Vss
Apparent volume of distribution at steady-state
Vss(%BW)
Vss normalized for body weight
Vz
Volume of distribution associated with the terminal slope
Vz/F
Volume of distribution associated with the terminal slope following 
extravascular administration divided by the fraction of dose 
absorbed
WHO
World Health Organization
WM
Working Memory
λz
First order rate constant associated with the terminal (log-linear) 
portion of the curve
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INTRODUCTION
2.
Background
2.1
Hunter syndrome (Mucopolysaccharidosis II; MPS II) is an extremely rare disease with an 
estimated incidence of 1 in 162,000 live births worldwide. 1, 2 It is expected that approximately 
67%-77% of these patients will present with the severe phenotype of the disease that includes 
progressive cognitive impairment (communicating hydrocephalus, increased intracranial 
pressure, seizures and hearing problems) and serious somatic disease.
Study Rationale 
2.2
Elaprase is approved globally including the EU, USA, Canada, and Japan as an intravenously 
(IV) administered enzyme replacement therapy (ERT) for patients with Hunter syndrome. Large
proteins such as Elaprase are not expected to cross the blood brain barrier (BBB) in sufficient
amounts to be therapeutically beneficial. Therefore, it is not possible to treat the progressive
brain disease in severe Hunter syndrome with Elaprase, and direct administration of the active
enzyme to the central nervous system is required. Although idursulfase-IT (SHP609) contains
the same active substance as Elaprase, their respective compositions differ in that idursulfase-IT
(SHP609) contains only three of the five excipients contained in Elaprase. In contrast to
Elaprase, idursulfase-IT (SHP609) is specially formulated for and compatible with direct
introduction into the IT space, since it is isotonic and contains excipients suitable for IT
administration. Note that Elaprase and idursulfase-IT (SHP609) are specifically formulated for
the IV and IT compartments respectively; they must not be interchanged for safety reasons. A
formulation appropriate for intrathecal administration of idursulfase (idursulfase-IT, SHP609,
HGT-2310), using an intrathecal drug delivery device (IDDD) the SOPH-A-PORT® Mini S
(Implantable Access Port, Spinal, Mini Unattached, with Guidewire), has been developed to
address this unmet medical need in an extremely rare population. The advantage of using an
IDDD in a chronic disease such as Hunter syndrome is the potential to obviate the need for
multiple lumbar punctures for drug delivery.
Nonclinical experience with IT administration of idursulfase-IT has demonstrated wide 
distribution of idursulfase-IT 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.
The safety and tolerability of ascending doses (1, 10, or 30 mg) of intrathecally administered 
idursulfase-IT (SHP609) 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 
(SHP609) 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. Based on the 
data available from HGT-HIT-045 and the extension study HGT-HIT-046, idursulfase-IT 
(SHP609) has been found to be well tolerated at all doses administered without safety concerns 
related to the investigational product.
The current study is an extension study to the pivotal Phase II/III study, HGT-HIT-094. Study 
HGT-HIT-094 is a controlled, randomized, two-arm, open-label, assessor-blinded, multicenter 
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study to determine the effect on clinical parameters of neurodevelopmental status of monthly IT 
administration of idursulfase-IT (SHP609) 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 weekly therapy with Elaprase. This study serves to extend the 
treatment, as well as safety and efficacy monitoring, for patients who completed study HGT-
HIT-094, which is designed to include the pediatric patients randomized to receive 
idursulfase-IT (SHP609) monthly, or no IT treatment, plus potentially a number of pediatric 
patients younger than 3 years old in the open-label, single-arm substudy also included in 
HGT-HIT-094.
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PURPOSE OF STATISTICAL ANALYSIS PLAN
3.
The interim analysis (IA) of study data will be conducted when all SHP609-302 subjects 
complete 12 months of idursulfase-IT (SHP609) treatment from the time of enrollment in 
SHP609-302 at visit Month 25/Week 52 or discontinue in study SHP609-302. The visit Month 
25/Week 52 is the Visit Month 25 in the study SHP609-302 Extended Treatment Phase for 
subjects who were randomized to the idursulfase-IT (SHP609) treatment cohort in study HGT-
HIT-094 and continued in study SHP609-302, and the Visit Week 52 in the study SHP609-302 
Initial Treatment Phase for subjects who were randomized to the control cohort (No IT 
treatment) in study HGT-HIT-094 and began IT treatment in study SHP609-302. The purpose of 
this interim analysis statistical analysis plan (SAP) is to document technical and detailed 
specifications for the interim analysis of data collected for protocol SHP609-302 Amendment 4. 
Results of the interim analysis described in this SAP will be included in the interim clinical study 
report (CSR). Additionally, the planned analyses identified in this SAP may be included in 
regulatory submissions or future manuscripts. Any post-hoc, or unplanned analyses performed to 
provide results for inclusion in the interim CSR but not identified in this prospective SAP will be 
clearly identified in the interim CSR.
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SUMMARY OF CLINICAL TRIAL FEATURES
4.
General Description
4.1
Study Objectives
The primary objective of this study is:

To evaluate long-term safety in patients with Hunter syndrome and cognitive
impairment who are receiving intrathecal idursulfase-IT (SHP609) and
intravenous (IV) Elaprase® enzyme replacement therapy (ERT)
The secondary objectives of this study are to evaluate long-term clinical efficacy 
outcomes in patients with Hunter syndrome and cognitive impairment who are treated 
with idursulfase-IT (SHP609), in conjunction with Elaprase therapy with respect to the 
following:

Cognitive function as measured by General Conceptual Ability (GCA),  the
cluster areas and subtests of the Differential Abilities Scale, Second Edition
(DAS-II), or domains of the Bayley Scales of Infant Development, Third Edition
(BSID-III)

Adaptive behavior as measured by the Adaptive Behavior Composite (ABC)
score and standard domain scores of the Vineland Adaptive Behavior Scales,
Second Edition (VABS-II)

Brain structure volume as measured by magnetic resonance imaging (MRI)
The exploratory objectives of this study are:

To evaluate the long-term effects of intrathecal idursulfase-IT (SHP609), given
in conjunction with Elaprase, on clinical parameters (e.g., physiological
assessments, neurocognitive assessments, neurologic function, and brain
structure volumes)

To explore potential relationships between biomarkers and CNS
symptomatology

To determine whether monthly idursulfase-IT (SHP609) administrations results
in accumulation of idursulfase within the CSF compartment by measuring
idursulfase levels in CSF immediately prior to idursulfase-IT (SHP609)
administration

To determine the safety and performance of the SOPH-A-PORT Mini S
The Pharmacokinetic and Pharmacodynamic Objectives are:

To evaluate the concentration of idursulfase and determine PK parameters in
serum after IT administration in patients with Hunter syndrome and cognitive
impairment who are treated with idursulfase-IT (SHP609) in conjunction with
Elaprase therapy

To evaluate the concentration of idursulfase in CSF in patients with Hunter
syndrome and cognitive impairment who are treated with idursulfase-IT
(SHP609) in conjunction with Elaprase therapy

To evaluate the concentration of GAG in CSF in patients with Hunter syndrome
and cognitive impairment who are treated with idursulfase-IT (SHP609) in
conjunction with Elaprase therapy

To evaluate the concentration of GAG in urine in patients with Hunter syndrome
and cognitive impairment who are treated with idursulfase-IT (SHP609) in
conjunction with Elaprase therapy
The Health Economics and Outcomes Research Objectives are:

To evaluate health status as measured by the EuroQol-5D-5L (EQ-5D-5L)
instrument, in patients with Hunter syndrome and cognitive impairment who are
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treated with idursulfase-IT (SHP609) in conjunction with Elaprase therapy

To evaluate healthcare resource utilization, as measured by the Healthcare
Utilization Questionnaire (HCUQ)in patients with Hunter syndrome and
cognitive impairment who are treated with idursulfase-IT (SHP609) in
conjunction with Elaprase therapy

Health Related Quality of Life (HRQoL) for caregivers in the Caregiver Impact
Questionnaire (CIQ), in patients with Hunter syndrome and cognitive
impairment who are treated with idursulfase-IT (SHP609) in conjunction with
Elaprase therapy

To evaluate functional status as measured by the HS-FOCUS (Hunter Syndrome
Functional Outcomes for Clinical Understanding Scale) instrument, in patients
with Hunter syndrome and cognitive impairment who are treated with
idursulfase-IT (SHP609) in conjunction with Elaprase therapy
The SOPH-A-PORT Mini S Device Objective is:

To evaluate the safety and performance of the SOPH-A-PORT Mini S
Study Endpoints
The primary safety endpoints of this study are:

Adverse events (AEs; by type, severity, and relationship to treatment
[idursulfase-IT, the intrathecal drug delivery device (IDDD), device surgical
procedure, or IT administration process] and IV Elaprase infusion)

Changes in clinical laboratory testing (serum chemistry, hematology, urinalysis)

Vital signs

Twelve-lead ECG recordings

CSF laboratory parameters (chemistries, cell counts)

Anti-idursulfase antibodies in CSF and serum, including determination of
anti-idursulfase antibodies having enzyme neutralizing activity
The secondary efficacy endpoints of this study are: 

Change from baseline (simple subtraction) in DAS-II standard scores at
scheduled visits (including both Early Years and School Age batteries): GCA
and Special Nonverbal Composite (SNC); and standard cluster scores: Verbal,
Nonverbal, Spatial; and/or the age equivalents and Development Quotient (DQ)
from the BSID-III domains: Cognitive and Language

Change from baseline (simple subtraction) in standard composite score of the
VABS-II at scheduled visits: ABC; and domain standard scores:
Communication, Daily Living Skills, Socialization, and Motor Skills

Change from baseline (simple subtraction) in age equivalents, developmental
quotients, and T scores for the core subtests of the DAS-II at scheduled visits:
Verbal Comprehension, Picture Similarities, Naming Vocabulary, Pattern
Construction, Matrices, and Copying for the DAS-II Early Years battery and
Recall of Designs, Word Definitions, Pattern Construction, Matrices, Verbal
Similarities, and Sequential and Quantitative Reasoning for the DAS-II School
Age battery

Change from baseline (simple subtraction) in age equivalents, developmental
quotients, and v-scale scores of the VABS-II subdomains at scheduled visits:
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 (simple subtraction) in the v-scale scores and observed
maladaptive levels of the VABS-II Maladaptive Behavior Index and its subscales
(Internalizing, Externalizing) at scheduled visits

Change from baseline (simple subtraction) in Brain Total Intracranial Volume,
Brain Total Tissue Volume, Brain Total White Matter, Brain Total Gray Matter,
and Total CSF Volume at scheduled visits
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The exploratory efficacy endpoints of this study are:

Change in scores from the time of enrollment in SHP609-302 to 12 months 
during study SHP609-302, estimated by linear regression from Visit Month 
13/Baseline to Visit Month 25/Week 52 in study SHP609-302,  for:

DAS-II GCA standard scores from Early Years battery

DAS-II T scores from Early Years battery

DAS-II standard cluster scores and SNC composite scores from Early 
Years battery

DAS-II GCA standard scores (including both Early Years and School 
Age batteries)

VABS-II ABC standard scores

Ordered categorical outcomes for each subject at 12-month visit (i.e., Visit 
Month 25/Week 52)  in study SHP609-302, for:

DAS-II GCA standard scores from Early Years battery

DAS-II GCA standard scores (including both Early Years and School 
Age batteries)

Binary unreversed floor effect outcome for each subject at 12-month visit (i.e., 
Visit Month 25/Week 52) in study SHP609-302, for:

DAS-II GCA standard scores from Early Years battery

DAS-II T scores from Early Years battery

DAS-II standard cluster scores and SNC composite scores from Early 
Years battery

DAS-II GCA standard scores (including both Early Years and School 
Age batteries)

VABS-II standard ABC scores
The pharmacokinetic and pharmacodynamic endpoints of this study are: 

Serum concentration of idursulfase and serum PK parameters after IT 
administration

CSF concentration of idursulfase 

Change from baseline in the concentration of GAG in CSF

Change from baseline in the concentration of GAG in urine
The health economics and outcomes research endpoints for this study are: 

Health status dimensions as obtained by the EQ-5D questionnaire

Health care resource utilization will be assessed using the HCUQ

Health-related quality of life (HRQoL) of the caregiver using CIQ 

Functional status as obtained by the HS-FOCUS form
SOPH-A-PORT Mini S assessments will include: 

The SOPH-A-PORT Mini S device will be evaluated using assessments of 
device implantation, device function, device longevity, and AEs associated with 
the implant surgery or device. These data will be collected on the patient’s eCRF 
from the time of initial implantation.
Study Design
This is an open-label, non-randomized study for patients who completed Study 
HGT-HIT-094; all patients in this study will be treated with intrathecal idursulfase-IT 
(SHP609) in conjunction with Elaprase therapy.  
Patients who complete Visit Week 52 assessments of Study HGT-HIT-094 and who meet 
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the eligibility criteria and for whom informed consent is provided will be enrolled in this 
extension study.  
All patients will receive idursulfase-IT (SHP609) at the same dose and frequency (10 mg 
once every 28 days) as selected for the HGT-HIT-094 study. Patients who are younger 
than 3 years of age will continue to receive an adjusted dose as specified in the protocol 
(Amendment 3) Section 6.3. The assessments in this study are similar to those performed 
in Study HGT-HIT-094 and will be performed at regular intervals; the frequency of 
assessments will vary depending on the treatment phase of the study.
Initial Treatment Phase – Only Patients Not Treated with Idursulfase-IT (SHP609) in 
Study HGT-HIT-094: Patients who participated in the control arm (no treatment with 
idursulfase-IT) in Study HGT-HIT-094 will begin this study in the Initial Treatment 
Phase. These patients will have the intrathecal drug delivery device (IDDD) implanted 
following enrollment in order to begin treatment with idursulfase-IT (SHP609). These 
patients will, during the Initial Treatment Phase of this study (i.e., the first 12 months), 
undergo treatment and assessments similar to those performed for patients who were 
treated in Study HGT-HIT-094. After completion of the Initial Treatment Phase and if 
there are no safety concerns, patients may continue receiving monthly idursulfase-IT 
(SHP609) in the Extended Treatment Phase of this study  
Extended Treatment Phase – All Patients:  Patients who received treatment with 
idursulfase-IT (SHP609) in the HGT-HIT-094 study will begin this study in the Extended 
Treatment Phase, which reflects a reduced frequency of assessments compared with the 
schedule of assessments in Study HGT-HIT-094. Standardized neurodevelopmental 
assessments and health economic and outcomes research assessments will be performed 
every 24 weeks and CSF assessments (other than standard chemistry) and clinical 
laboratory tests of blood and urine will be performed every 12 weeks. Brain MRI and 
12-lead ECG will be performed every 48 weeks. A pharmacokinetic assessment will be
performed once during this phase of the study.
Patients will receive their monthly doses of intrathecal idursulfase-IT (SHP609) at the 
main study site or at a local site. All patients will receive their weekly IV infusions of 
Elaprase throughout the study.
It is anticipated that the IDDD will be used to collect CSF samples and to deliver IT 
injections of idursulfase-IT (SHP609) and preservative-free saline flushes. No other 
medication will be administered through the device. If the IDDD appears to be 
non-functional, or if its use is precluded on a scheduled day of dosing, site personnel will 
refer to the IDDD Manual, which provides details on the investigation and management of 
any IDDD-related issues. This includes possible partial revision or complete replacement 
of the IDDD as indicated. If the IT space is not accessible via the IDDD, investigational 
product may be administered by LP. Should the IDDD become clogged, undergo 
mechanical complications or otherwise not be accessible, the CSF sample may also be 
obtained by LP.
General anesthesia may be required for injections of study drug and some evaluations, and 
can be used at the discretion of the Investigator as indicated in the study manuals. It is 
anticipated that study procedures such as lumbar puncture, MRI, and audiometry will 
have to be performed with sedation/anesthesiology support.
Patients will have the IDDD removed when they discontinue from or complete the study 
unless the patient is continuing to receive product or treatment through another 
mechanism (e.g., extension study, expanded access program).
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Number of 
Patients
Pediatric patients (plus potentially any pediatric patients younger than 3 years of age in 
the antecedent substudy) who completed Study HGT-HIT-094, and meet the eligibility 
criteria may enroll in this study. Up to 49 patients from the HGT-HIT-094 pivotal study 
and 9 patients from the HGT-HIT-094 substudy are expected.  
Study Product
Idursulfase for intrathecal use (idursulfase-IT, SHP609, HGT-2310) 10 mg
Intrathecal drug 
delivery device
SOPH-A-PORT® Mini S, Implantable Access Port, Spinal, Mini Unattached, with 
Guidewire (SOPH-A-PORT® Mini S)
Treatment and 
Study Duration
Patients will participate in this extension study for a maximum duration of 10 years of 
treatment across studies HGT-HIT-094 and SHP609-302, unless they discontinue the 
study or Shire discontinues the study. The study will conclude after the last patient has 
completed his last visit.
Randomization 
and Blinding
This is an open-label, non-randomized study. All patients will receive idursulfase-IT 
(SHP609) at the same dose and frequency (10 mg once every 28 days) as selected for the 
HGT-HIT-094 study.
Determination of Sample Size/Randomization
4.2
This is an open-label extension trial of Study HGT-HIT-094. Only eligible patients who 
participated in Study HGT-HIT-094 may enroll in SHP609-302, and therefore no sample size 
calculation was performed. The number of patients is described above in Section 4.1.
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EFFICACY AND SAFETY VARIABLES
5.
Schedule of Evaluations
5.1
This extension study has 2 phases: an Initial Treatment Phase (only patients not treated with 
idursulfase-it in study HGT-HIT-094) and an Extended Treatment Phase (all patients). The 
detailed schedule of evaluations is located in the SHP609-302 protocol (Amendment 4).
Primary Safety Endpoints
5.2
The primary safety endpoints are described above in Section 4.1. 
Secondary Efficacy Endpoints 
5.3
The secondary efficacy endpoints are described above in Section 4.1.
Exploratory Efficacy Endpoints 
5.4
5.4.1
Study Visits Used to Define Exploratory Efficacy Endpoints 
For exploratory efficacy endpoints described above in Section 4.1, the treatment effect is 
evaluated at the following scheduled study visits in study SHP609-302 Interim Analysis. The 
Early IT and Delayed IT groups are defined in Section 6.2, and their designations are based on 
the treatment regimen (idursulfase-IT or No IT treatment) in the antecedent study HGT-HIT-094.
Figure 1
Scheduled Visits and Duration of Treatment in Studies HGT-HIT-094 and 
SHP609-302
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Scheduled study visits in the Early IT group of study SHP609-302 IA:

Visit Month 13 (Visit Week 52) in the Extended Treatment Phase of study SHP609-302 
for subjects in the Early IT group is the scheduled visit when those subjects have 
completed a 12-month period of IT treatment in the antecedent study HGT-HIT-094, and 
comprises of one month for surgical IDDD implantation at the beginning of the study 
followed by 12 months of IT treatment during HGT-HIT-094.

Visit Month 19 in the Extended Treatment Phase of study SHP609-302 for subjects in the 
Early IT group is the scheduled visit when those subjects have completed a 18-month 
period of IT treatment, and comprises of one month for surgical IDDD implantation at 
the beginning of HGT-HIT-094, 12 months of IT treatment during HGT-HIT-094 and an 
additional 6 months of IT treatment in the Extended Treatment Phase of SHP609-302.

Visit Month 25 in the Extended Treatment Phase of study SHP609-302 for subjects in the 
Early IT group is the scheduled visit when those subjects have completed a 24-month 
period (i.e., two 12-month periods) of IT treatment, and comprises of one month for 
surgical IDDD implantation at the beginning of HGT-HIT-094, 12 months of IT 
treatment during HGT-HIT-094 and an additional 12 months of IT treatment in the 
Extended Treatment Phase of SHP609-302. 
Scheduled study visits in the Delayed IT group of study SHP609-302:

Time of Enrollment (Baseline) in SHP609-302 in delayed IT group is the closest 
available assessment prior to the initial IDDD implant date, which takes place in study 
SHP609-302, for subjects in the Delayed IT group. This could potentially include EOS 
visit data from Study HGT-HIT-094.

Visit Week 16 in SHP609-302 in the Initial Treatment Phase of study SHP609-302 for 
subjects in the Delayed IT group is the scheduled visit when those subjects have 
completed a 15-month period (i.e., 12 months of No IT treatment and 3 months of IT 
treatment), and comprises of 12 months of No IT treatment during HGT-HIT-094, one 
month for surgical IDDD implantation at the beginning of SHP609-302 and 3 months of 
IT treatment in the Initial Treatment Phase of SHP609-302. 

Visit Week 28 in SHP609-302 in the Initial Treatment Phase of study SHP609-302 for 
subjects in the Delayed IT group is the scheduled visit when those subjects have 
completed a 18-month period (i.e., 12 months of No IT treatment and 6 months of IT 
treatment), and comprises of 12 months of No IT treatment during HGT-HIT-094, one 
month for surgical IDDD implantation at the beginning of SHP609-302 and 6 months of 
IT treatment in the Initial Treatment Phase of SHP609-302. 

Visit Week 40 in SHP609-302 in the Initial Treatment Phase of study SHP609-302 for 
subjects in the Delayed IT group is the scheduled visit when those subjects have 
completed a 21-month period (i.e., 12 months of No IT treatment and 9 months of IT 
treatment), and comprises of 12 months of No IT treatment during HGT-HIT-094, one 
month for surgical IDDD implantation at the beginning of SHP609-302 and 9 months of 
IT treatment in the Initial Treatment Phase of SHP609-302. 
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
Visit Week 52 in SHP609-302 in the Initial Treatment Phase of study SHP609-302 for 
subjects in the Delayed IT group is the scheduled visit when those subjects have 
completed a 24-month period (i.e., 12 months of No IT treatment and 12 months of IT 
treatment), and comprises of 12 months of No IT treatment during HGT-HIT-094, one 
month for surgical IDDD implantation at the beginning of SHP609-302 and 12 months of 
IT treatment in the Initial Treatment Phase of SHP609-302.
Matched visits and comparisons between Early IT group and Delayed IT group in study 
SHP609-302 IA:

Visit Month 13 vs. Time of Enrollment in SHP609-302  (12-month comparison in HGT-
HIT-094), black vertical lines in Figure 1, Visit Month 13 in the Extended Treatment 
Phase of study SHP609-302 (i.e., 52 weeks from study HGT-HIT-094 baseline) for 
subjects in the Early IT group versus time of enrollment in SHP609-302 for subjects in 
the Delayed IT group. This is considered as the beginning of study SHP609-302.  For 
simplicity, the visit names will be referred to as ‘Visit Month 13/ Time of Enrollment in 
SHP609-302’ hereafter. 

Visit Month 19 vs. Visit Week 28 in SHP609-302 (18-month comparison), blue vertical 
lines in Figure 1, Visit Month 19 in the Extended Treatment Phase of study SHP609-302 
(i.e., 76 weeks from study HGT-HIT-094 baseline) for subjects in the Early IT group 
versus Visit Week 28 in the Initial Treatment Phase of study SHP609-302 (i.e., 80 weeks 
from study HGT-HIT-094 baseline) for subjects in the Delayed IT group. For simplicity, 
the visit names will be referred to as ‘Visit Month 19/ Week 28 in SHP609-302’ 
hereafter.

Visit Month 25 vs. Visit Week 52 in SHP609-302 (24-month comparison), green vertical 
lines in Figure 1, Visit Month 25 in the Extended Treatment Phase of study SHP609-302 
(i.e., 100 weeks from study HGT-HIT-094 baseline) for subjects in the Early IT group 
versus Visit Week 52 in the Initial Treatment Phase of study SHP609-302 (i.e., 104 
weeks from study HGT-HIT-094 baseline) for subjects in the Delayed IT group.  For 
simplicity, the visit names will be referred to as ‘Visit Month 25/ Week 52 in SHP609-
302’ hereafter. 

Visit Month 19 vs. Visit Week 28 from Visit Month 13/ Time of Enrollment in SHP609-
302   (6-month comparison in SHP609-302), from the black vertical line to the blue 
vertical lines in Figure 1, from Visit Month 13 to Visit Month 19 in the Extended 
Treatment Phase of study SHP609-302 for subjects in the Early IT group versus from 
time of enrollment in study SHP609-302 to Visit Week 28 in SHP609-302 in the Initial 
Treatment Phase of study SHP609-302 for subjects in the Delayed IT group. For 
simplicity, the visit names will be referred to as ‘From Visit Month 13/ Time of 
Enrollment in SHP609-302 to Visit Month 19/ Week 28 in SHP609-302’ hereafter.

Visit Month 25 vs. Visit Week 52 from Visit Month 13/ Time of Enrollment in SHP609-
302   (12-months comparison in SHP609-302), from the black vertical lines to the green 
vertical lines in Figure 1, from Visit Month 13 to Visit Month 25 in the Extended 
Treatment Phase of study SHP609-302 for subjects in the Early IT group versus from 
time of enrollment in study SHP609-302 to Visit Week 52 in SHP609-302 in the Initial 
Treatment Phase of study SHP609-302 for subjects in the Delayed IT group.  For 
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simplicity, the visit names will be referred to as ‘From Visit Month 13/ Time of 
Enrollment in SHP609-302 to Visit Month 25/Week 52 in SHP609-302’ hereafter. 
It is noted that Visit Month 25 vs. Visit Week 52 in SHP609-302 (also Visit Month 19 vs. Visit 
Week 28 in SHP609-302) are 4 weeks apart for the two treatment groups. This difference is due 
to the need for subjects in the Delayed IT group to undergo surgical IDDD implantation of the 
device at the beginning of study SHP609-302. Therefore, the first dose of idursulfase-IT was 
administered 4 weeks later to subjects in the Delayed IT group compared with subjects in the 
Early IT group who were randomized to IT treatment and underwent IDDD implantation in 
HGT-HIT-094 prior to enrolling in the Extended Treatment Phase of SHP609-302. For 
evaluation of the long-term efficacy of IT treatment in SHP609-302, this 4-week difference is 
considered to have minimal impact on neurodevelopmental assessment scores.
5.4.2
Thresholds of Clinically Meaningful Change 
For each of the neurodevelopmental assessment scores, a putatively clinically meaningful change 
threshold is established using standard error of measurement (SEM), based on test-retest 
reliability between the baseline and the first post-baseline visit (Month 3 visit) of all pooled 
SHP609 clinical trial data. The pooled clinical trial data include the natural history study HGT-
HIT-090, the Phase I/II study HGT-HIT-045 and the Phase II/III pivotal study HGT-HIT-094. 
Data from extension studies HGT-HIT-046 and SHP609-302 are not included for establishing 
the SEM since those subjects are the same subjects from the studies HGT-HIT-045 and HGT-
HIT-094, respectively. 
Using 2 SEMs to denote a putatively clinically meaningful change, the threshold for each 
neurodevelopmental assessment score is summarized in Table 1 below. For example, for the 
GCA standard scores, a putatively clinically meaningful change is considered to be 10 points, 
where SEM is calculated as 4.5 (rounded up to 5 points).
These putatively clinically meaningful change thresholds are also applied to define the ordered 
categorical outcomes (3 categories) endpoints in Section 5.4.4 and the binary unreversed floor 
effect outcome endpoints in Section 5.4.5. 
Patient level profile plots of each neurodevelopmental assessment scores will be provided to
assess GCA scores and other neurodevelopmental assessment scores during the 24-month period.
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Table 1
Putatively Clinically Meaningful Change and Floor Effect Threshold for DAS-II 
and VABS-II Assessment Scores
Neurodevelopment Assessment 
Scores
SEM 
(Approximately)
Putatively 
Clinically 
Meaningful 
Change 
Lowest 
Reportable
Score
Floor Effect 
Threshold
DAS-II GCA standard scores from 
Early Years battery 
5
10
30
40
DAS-II T scores from Early Years 
battery
2.5
5
10
15
DAS-II  standard  clusters  scores 
and composite scores from Early 
Years battery
5
10
30
40
DAS-II GCA standard scores 
(including both Early Years and
School Age batteries)
5
10
30
40
VABS-II ABC standard scores 
4
8
20
28
Note: SEM= Standard Error of Measurement
5.4.3
Change over a 12-Month Period Endpoints 
Change in scores from the time of enrollment in SHP609-302 to 12 months during study 
SHP609-302, estimated by linear regression from Visit Month 13/ Time of Enrollment in 
SHP609-302 to Visit Month 25/Week 52 in SHP609-302, for:

DAS-II GCA standard scores from Early Years battery

DAS-II T scores from Early Years battery: Verbal Comprehension, Picture Similarities, 
Naming Vocabulary, Pattern Construction, Matrices, and Copying

DAS-II standard cluster scores and composite scores from Early Years battery: Verbal, 
Nonverbal, Spatial and Special Nonverbal Composite (SNC)

DAS-II GCA standard scores (including both Early Years and School Age batteries)

Vineland Adaptive Behavior Scales, Second Edition (VABS-II) Adaptive Behavior 
Composite (ABC) standard scores
5.4.4
Ordered Categorical Outcomes (3 Categories) Endpoints
The ordered categorical outcomes (3 categories: above average cognitive development, average 
cognitive development, and below average cognitive development) for each subject at 12-month 
visit in SHP609-302 (i.e., Visit Month 25/Week 52 in SHP609-302) from the time of enrollment 
in SHP609-302 are defined for the following assessments

DAS-II GCA standard scores from Early Years battery

DAS-II GCA standard scores (including both Early Years and School Age batteries)
The categorical outcomes will be determined by comparing the baseline values of 
neurodevelopment assessment score from the time of enrollment in SHP609-302 +/- the 
putatively clinical meaningful change thresholds to the 12-month post-baseline values of 
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corresponding neurodevelopment assessment score. For DAS-II GCA standard scores, the 
categorical outcome endpoints are defined below:
o
Above average cognitive development (Category 1) is defined as subjects who had 
the observed GCA at Visit Month 25/Week 52 in SHP609-302 more than 10 points (2 
SEM) higher than observed GCA at Visit Month 13/ Time of Enrollment in SHP609-
302, i.e.,

GCA (Month 25/Week 52) > GCA (Month 13/ Time of Enrollment in 
SHP609-302) + 2 × SEM (10 points for GCA scores)
o
Average cognitive development (Category 2) is defined as subjects who had the 
observed GCA at Visit Month 25/Week 52 in SHP609-302 within the range of ± 10 
points (2 SEM) (inclusive) of the observed GCA at Visit Month 13/ Time of 
Enrollment in SHP609-302, i.e.,

GCA (Month 13/ Time of Enrollment in SHP609-302) -2 × SEM (10 
points for GCA scores) ≤ GCA (Month 25/Week 52 in SHP609-302) ≤ 
GCA (Month 13/ Time of Enrollment in SHP609-302)  +2 × SEM (10 
points for GCA scores)
o
Below average cognitive development (Category 3) is defined as subjects who had 
the observed GCA at Visit Month 25/Week 52 in SHP609-302 more than 10 points (2 
SEM) below the observed GCA at Visit Month 13/ Time of Enrollment in SHP609-
302, i.e.,

GCA (Month 25/Week 52 in SHP609-302) < GCA (Month 13/ Time of 
Enrollment in SHP609-302) – 2 × SEM (10 points for GCA scores)
5.4.5
Binary Unreversed Floor Effect Outcomes Endpoints
For each of the neurodevelopmental assessment scores, there may be a “floor effect”. “Floor 
effect” is considered to be the lower limitation of the assessment tool, below which the 
assessment may not be reliable or meaningful. The term “floor effect” is used to define an 
endpoint, where we classify the status of unreversed neurodevelopment decline. Subjects who 
reach this score are not expected to achieve improvement of neurodevelopment ability.
The binary unreversed floor effect outcome is defined as whether or not a subject has reached an 
unreversed floor effect status by 12 months (assessed in SHP609-302) from the time of 
enrollment in SHP609-302. An unreversed floor effect status for a subject means that the subject 
has achieved a decline in the neurodevelopmental assessment score to below the floor effect 
threshold (Table 1 in Section 5.4.2) and has not reversed to equal or above the threshold as of the 
12-month visit (i.e., Visit Month 25/Week 52 in SHP609-302). Of note, if a subject reached 
below the floor effect threshold at the 12-month visit only, the subject will still be considered as 
having reached the unreversed floor effect by 12 months. For missing data, the last available 
score carried forward approach will be implemented. 
The binary unreversed floor effect outcomes will be defined for the following assessments: 
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
DAS-II GCA standard scores from Early Years battery

DAS-II T scores from Early Years battery

DAS-II standard cluster scores and composite scores from Early Years battery

DAS-II GCA standard scores (including both Early Years and School Age batteries)

VABS-II ABC standard scores
Health Economics and Outcomes Research Endpoints
5.5
The health economics and outcomes research endpoints are described above in Section 4.1.
Pharmacokinetic and Pharmacodynamic Endpoints 
5.6
The pharmacokinetic and pharmacodynamic endpoints are described above in Section 4.1.
SOPH-A-PORT Mini S Assessments
5.7
The SOPH-A-PORT Mini S device will be evaluated using assessments of device implantation, 
device function, device longevity, and AEs associated with the implant surgery or device. These 
data will be collected on the patient’s case report form (CRF) from the time of initial 
implantation.
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STATISTICAL ANALYSIS
6.
General Methodology
6.1
All statistical analyses will be performed by the Biostatistics and Statistical Programming
Department at Shire or its designated CRO unless otherwise specified, using SAS® software 
version 9.3 or higher (SAS Institute, Cary, N.C., USA).
Data from studies SHP609-302 and HGT-HIT-094 will be integrated for efficacy and safety 
analyses. Baseline of study SHP609-302 for the subjects previously IT treated in HGT-HIT-094 
will be the same as the baseline defined in HGT-HIT-094. Baseline of study SHP609-302 for the 
previously IT untreated subjects in HGT-HIT-094 will be the closest available assessment prior 
to the initial IDDD implant date, which takes place in Study SHP609-302, unless otherwise 
specified. This could potentially include EOS visit data from Study HGT-HIT-094. The analyses 
presented here will include the data measured at and after baseline of study SHP609-302 as 
defined above. 
Safety data descriptive summaries will be presented by the Early IT group, the Delayed IT group 
and overall. The Early IT group and Delayed IT group designations are based on the treatment 
regimen (idursulfase-IT or No IT treatment) in the antecedent study (HGT-HIT-094). For 
analysis of safety, medical history, concomitant medications and concomitant therapies, any
former HGT-HIT-094 substudy subjects will be included in the Early IT treated group. 
Efficacy data descriptive summaries will be presented separately for subjects who enrolled from 
the pivotal study or substudy of HGT-HIT-094. For subjects enrolled from the pivotal study, 
descriptive statistics will be presented by the Early IT group, the Delayed IT group and overall. 
For secondary efficacy endpoints, the mean difference in the change at each time point between 
the two treatment groups (Early IT group and Delayed IT group) and the corresponding 90% 
confidence interval of the mean difference will be presented where appropriate. The mean values 
(± SD) for all efficacy endpoints will be graphed over time where appropriate.
Summary statistics for continuous variables will include the n, mean, standard deviation, median, 
minimum and maximum. Categorical variables will be summarized in a contingency table by the 
frequency and percentage of subjects in each category.
For subjects enrolled from HGT-HIT-094 substudy, their efficacy data will be presented in 
listings. 
Listing will be provided as per Shire’s standard recommended listings. Additional listings may 
be produced as deemed appropriate.
An interim clinical study report is planned to describe the results of the interim analysis. 
Data Integration Strategy and Analysis Populations
6.2
6.2.1
Data Integration Strategy
Data from studies SHP609-302 and HGT-HIT-094 will be integrated for data analyses. 
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For safety and efficacy descriptive summary analyses using integrated data, the two treatment 
groups are Early IT group and Delayed IT group based on the HGT-HIT-094 treatment regimen 
(idursulfase-IT or No IT Treatment), defined as follows:

Early IT group: subjects who were randomized to the idursulfase-IT treatment cohort in 
study HGT-HIT-094 and continued in study SHP609-302. HGT-HIT-094 substudy will 
be included in the Early IT group.

Delayed IT group: subjects who were randomized to the control cohort (No IT treatment) 
in study HGT-HIT-094 and began IT treatment in study SHP609-302
Baseline of study SHP609-302 for the subjects in Early IT group will be the same as the baseline 
defined in HGT-HIT-094. Baseline of study SHP609-302 for subjects in Delayed IT group will 
be the closest available assessment prior to the initial IDDD implant date, which takes place in 
study SHP609-302. This could potentially include EOS visit data from Study HGT-HIT-094. 
For exploratory efficacy analyses, only data from the HGT-HIT-094 pivotal study subjects will 
be included because the substudy subjects were evaluated by BSID-III in the 12-month HGT-
HIT-094 substudy and their GCA scores at the HGT-HIT-094 baseline and the time of 
enrollment in SHP609-302 may not available. Only 12-month data collected in study SHP609-
302 from the time of enrollment in SHP609-302 at Visit Month 25/Week 52 in SHP609-302 will 
be used, except the correlation analysis between different neurodevelopmental assessments 
(section 6.7.4.2); the two treatment groups are the Early IT group (excluding substudy subjects) 
and Delayed IT group. The 12-month data from Visit Month 13/Time of Enrollment in SHP609-
302 to Visit Month 25/Week 52 in SHP609-302 will be used for Early IT group and Delayed IT 
group, respectively. 
Figure 2
Schematic Relationship in Studies HGT-HIT-094 and SHP609-302
The following nomenclature will be used to identify “A”, “B”, “C”, and “D” in Figure 2.
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
Observation Groups A and C identify the period of observation during study HGT-HIT-
094, for subjects randomized to IT treatment and No IT treatment, respectively.

Observation Groups B and D identify the period of observation during study SHP609-302 
up to completion of one year, for subjects who were randomized in HGT-HIT-094 to 
receive IT treatment and No IT treatment, respectively, noting that all subjects in 
SHP609-302 received IT treatment.  
The subjects in “B” are the same subjects as in “A” with periods of observation from studies 
SHP609-302 and HGT-HIT-094, respectively, as we can view “B” as a continuation of “A”. 
Subjects in “A” and “B” constitute the Early IT group. The subjects in “D” are the same subjects 
as in “C” with periods of observation from studies SHP609-302 and HGT-HIT-094, respectively, 
as we can view “D” as a continuation of “C”. Subjects in “C” and “D” constitute the Delayed IT 
group.
“D” subjects are therefore similar to “A” subjects since these subjects all transitioned from
receiving weekly IV infusion of Elaprase, to also receive monthly IT idursulfase. Since study 
SHP609-302 did not have baseline GCA inclusion criteria at the time of enrollment in SHP609-
302, such as employed for Study HGT-HIT-094, “B” and “D” subjects could differ with regard 
to their baseline GCA scores at the beginning of the observation period.  Therefore, for 
consideration of “B” and “D”, only subjects meeting the key inclusion criteria to HGT-HIT-094 
will be included in efficacy analyses, i.e., with GCA scores between 55 and 85 inclusive at the 
time of enrollment in SHP609-302 (i.e., Visit Month 13/ Time of Enrollment in SHP609-302).
6.2.2
Analysis Populations
All descriptive summary analyses of safety and efficacy data will be based on the Safety 
Population, which is defined as all subjects in study SHP609-302 who underwent IDDD 
implantation or received at least 1 dose of study drug (full or partial). Device-related analyses 
will be conducted in the set of patients in the Safety Population who had the device implant 
procedure performed. Data from “A”, “B” and “D” will be used.
Descriptive analyses of health economics and outcomes research endpoints and 
pharmacodynamic endpoints will be performed using the Safety Population and presented 
separately for subjects enrolled from the pivotal study or substudy of HGT-HIT-094. Data from 
“A”, “B” and “D” will be used.
All pharmacokinetic data analyses will be performed using the PK population. Data from “A”, 
“B” and “D” will be used.
The exploratory efficacy analyses, i.e., the rate of change (weighted) analysis, the ordered 
categorical outcomes analysis and the floor effect analysis, will be conducted on “HGT-HIT-094 
Comparable Set”, “HGT-HIT-094 Comparable Subset 1” and “HGT-HIT-094 Comparable 
Subset 2”. Data from “B” and “D” will be used. The correlation analysis will be conducted on 
the Safety Population. 
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The primary efficacy analysis population is HGT-HIT-094 Comparable Subset 1, which is the 
most informative patient population (e.g. youngest and least affected patients at baseline) with 
the most potential to benefit from the idursulfase-IT treatment. 
Based on the analysis results from study HGT-HIT-094, we do not expect idursulfase IT to 
provide a treatment benefit for the older subjects (≥6 years) and for those subjects with cognitive 
abilities below a GCA of 55 at baseline. Therefore the efficacy analyses in the ISE will focus on 
the younger subjects (< 6 years) with cognitive abilities above a GCA of 55 at baseline, referred 
to as HGT-HIT-094 Comparable Subset 1. The more general population (subjects with GCA 
scores between 55 and 85 at the time of enrollment in SHP609-302) is defined in the SHP609-
302 IA, the HGT-HIT-094 Comparable Set as an exploratory overall analysis population. The 
primary efficacy analysis population is the HGT-HIT-094 Comparable Subset 1, defined as a 
subgroup of HGT-HIT-094 Comparable Set, limited to subjects of age <6 years old at the time of 
enrollment in SHP609-302.  The HGT-HIT-094 Comparable Subset 2 is a subgroup of even 
younger subjects, i.e., age <55 months old at the time of enrollment in SHP609-302. 
The definition of each analysis populations used in study SHP609-302 IA are listed in Table 2.
Table 2
Definition of analysis populations in SHP609-302 IA SAP
Analysis Population
Definition
Intended Usage
Safety Population
All subjects in study SHP609-302 who underwent IDDD implantation 
or received at least 1 dose of study drug (full or partial)  
Primary safety 
population
HGT-HIT-094 
Comparable Set
“B” and “D” subjects in the Safety Population with GCA scores 
between 55 and 85 inclusive at the time of enrollment in SHP609-302 
(i.e., Visit Month 13/Baseline)
Exploratory overall 
analysis population
HGT-HIT-094 
Comparable Subset 1 
“B” and “D” subjects in the Safety Population with GCA scores 
between 55 and 85 inclusive and age <6 years old at the time of 
enrollment in SHP609-302 (i.e., Visit Month 13/Baseline)
Primary efficacy 
analysis 
population
HGT-HIT-094 
Comparable Subset 2
“B” and “D” subjects in the Safety Population with GCA scores 
between 55 and 85 inclusive and age <55 months old at the time of 
enrollment in SHP609-302 (i.e., Visit Month 13/Baseline)
Subgroup of 
primary efficacy 
analysis population
Pharmacokinetic 
Population
All subjects in SHP609-302 who received study drug and participated 
in the scheduled pharmacokinetic studies, and for whom at least 1 post-
dose PK blood sample was collected
PK population
Patient Disposition
6.3
Patient disposition (signed informed consent, patient population [Safety Population and PK 
Population], treatment status [completed, discontinued/withdrew]) will be presented in summary 
tables using number and percentage of subjects by the Early IT group, the Delayed IT group for 
antecedent pivotal study, antecedent substudy and overall. Reasons for 
discontinuation/withdrawal will be presented.
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Protocol Deviations
6.4
An incident involving noncompliance with the protocol, but one which typically does not have 
significant effects on the patient’s rights, safety, or welfare, or the integrity of the resultant data 
will be considered a protocol deviation.  
Protocol violations will be defined as any major protocol deviation that affects study evaluations.  
Patients will be examined on a case-by-case basis prior to final database lock to determine if 
conditions set forth in the study protocol have been violated. The complete list of protocol 
deviations will not be summarized; however, a list of major protocol deviation will be presented.
Demographic and Other Baseline Characteristics
6.5
Demographic and baseline characteristics (e.g., age [years], race, ethnicity, weight [kg], height 
[cm], and baseline disease status) will be reported in summary tables using the Safety Population 
by the Early IT group, the Delayed IT group for the antecedent pivotal study, antecedent 
substudy and overall.
For patients previously receiving active treatment in study HGT-HIT-094, age (in years) = (date 
of event from study HIT-094 – birth date + 1)/365.25. Date of event is defined as randomization 
date for the antecedent pivotal study patients, and date of eligibility (enrollment date) for the 
antecedent substudy patients. For patients previously receiving no IT treatment in study HIT-
094, age (in years) = (date of informed consent for the Initial Treatment Phase of study SHP609-
302 – birth date + 1)/365.25. When age is presented in the table, it will be rounded down to the 
first decimal point. Since height and weight may be measured for multiple times during a visit, 
the average, if any, of these measurements for the same visit will be used as the value for that 
visit.
Treatment Compliance and Extent of Exposure
6.6
The total number of doses of study drug, the number of doses received via IDDD, the number of 
doses received via LP, the actual average dose, the actual average duration of IT administrations, 
the duration of idursulfase-IT treatment, and the percent doses received will be summarized by 
the Early IT group, the Delayed IT group for the antecedent pivotal study, antecedent substudy 
and overall using the Safety Population. 
The duration of idursulfase-IT treatment, summarized in months, is defined as the time from the 
first IT administration to the last administration.
The duration for each idursulfase-IT administrations (in minutes) is calculated by subtracting the 
administration start time from the administration end time. The actual average duration of 
idursulfase-IT administration (in minutes) will be calculated as an average value of the 
idursulfase-IT administrations across all available administrations for the same subject.
Treatment compliance will be summarized by the Early IT group, the Delayed IT group for the 
antecedent pivotal study, antecedent substudy and overall using the Safety population. Treatment 
compliance is defined as the percent of scheduled doses received for each subject, which is 
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[(Number of Complete IT injections Received) ÷ (Expected Number of IT injections at data 
cutoff date)] * 100.
Analysis of Efficacy
6.7
All efficacy descriptive summaries described below refer to the Safety Population who enrolled 
from the pivotal study of HGT-HIT-094. All exploratory efficacy analyses described below refer 
to the HGT-HIT-094 Comparable Set, HGT-HIT-094 Comparable Subsets 1 and 2, except the 
correlation analysis using the Safety Population (section 6.7.4.2). All efficacy data for subjects 
who enrolled from the antecedent substudy will be listed, including measurements from the 
BSID-III, VABS-II, DAS-II if available, health economics and outcomes research data, and 
pharmacodynamics data. 
6.7.1
Primary Efficacy Analysis
Not applicable.
6.7.2
Secondary Efficacy Analysis 
For the parameters listed in each subsection below except as noted, the following analyses will 
be done:

The observed values and change from baseline will be summarized at the scheduled study 
visits, unless specified otherwise. The mean difference in the change at each time point 
between the two treatment groups (the Early IT group, the Delayed IT group) and the 
corresponding 90% confidence interval of the mean difference will be presented.
o
During the HGT-HIT-094/Initial Treatment Phase, descriptive statistics of 
observed values and changes from baseline will be summarized at 
Screening/Baseline, on Pre-Treatment Day 1 of IT Dosing Week 16, 28 and 40 
visits. 
o
During the Extended Treatment Phase, descriptive statistics of observed values 
and changes from baseline will be summarized on Pre-Treatment of IT Day 1 of 
Month 13 and  at 6-month intervals on the Pre Treatment Day of Monthly IT 
Dosing Weeks (i.e., at Months 19, 25, 31, 37, 43, 49, 55 and 61).

The mean value (± SD) for each endpoint over time will be graphed. 

A spaghetti plot of the age equivalent scores for individual subjects will be plotted 
against chronological age.

A spaghetti plot of each endpoint over time for individual subjects will be plotted.
Chronological age, when presented, is the age of the subject at the time of the test. It will be 
calculated by (test date – birth date + 1)/365.25 and 2 decimals will be kept in the dataset.
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6.7.2.1
Differential Ability Scale, second edition (DAS-II) and Bayley Scales of Infant 
Development (BSID-III) Analyses
DAS-II
Descriptive statistics at observed values and changes from baseline will be summarized at 
scheduled visits for the following:

Standard scores in subjects who had taken DAS-II test (including both Early Years and 
School Age batteries) for each cluster and composite: 
o
Verbal 
o
Nonverbal 
o
Spatial 
o
GCA 
o
SNC

T scores, age equivalents and developmental quotients in subjects who had taken a DAS-
II test for Early Years for each core subtest, where DQ=Age 
equivalent*100/Chronological age: 
o
Verbal Comprehension (Vcom)
o
Picture Similarities (Psim)
o
Naming Vocabulary (Nvoc)
o
Pattern Construction (Pcon) 
o
Matrices (Mat) 
o
Coping (Copy) 

T scores, age equivalents and developmental quotients in subjects who had a DAS-II test 
for School Age for each core subtest: 
o
Recall of Designs (RDes)
o
Word Definitions (WDef)
o
Pattern Construction
o
Matrices (Mat)
o
Verbal Similarities (VSim)
o
Sequential & Quantitative Reasoning (SQR)
A summary table of neurodevelopment assessment type for each subject will be presented.
Mean values (± SD) by the Early IT group and the Delayed IT group will be plotted over time. 
This includes the following endpoints:

The observed values and change from baseline to each scheduled visit in the standard 
scores for GCA, SNC, each cluster, T scores, age equivalents and DQ for the core 
subtests of the DAS-II Early Years and the DAS-II School Years
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The observed values of age equivalents will be plotted for individual subjects against 
chronological age. This includes the following endpoints:

Age equivalents for the core subtests of the DAS-II Early Years and DAS-II/School 
Years
The observed values and change from baseline values of each endpoint for individual subjects 
will be plotted over time. This includes the following endpoints:

Standard scores for each cluster, T scores, age equivalents and DQ for the core subtests 
of the DAS-II/Early Years and the DAS-II/School Years
Empirical cumulative distribution function (eCDF) plots for the change from Visit Month 
13/Time of Enrollment in SHP609-302 at 12 months (Visit Month 25/Week 52 in SHP609-302) 
in DAS-II GCA standard scores from Early Years battery (GCA EY), between the Early IT and 
Delayed IT groups will be provided for each analysis population HGT-HIT-094 Comparable Set, 
Comparable Subset 1 and 2.
Listings will be presented for the above parameters as well as the parameters below:

Standard scores / percentiles in each subject who had taken a DAS-II test for GCA, SNC 
and each cluster

T scores, percentiles of the T scores and age equivalents (directly from eCRF) versus 
chronological age as well as Developmental Quotient (DQ) in each subject who had 
taken a DAS-II test for Early Years for each core subtest 

T scores, percentiles of the T scores and age equivalents versus chronological age as well 
as DQ in each subject who had taken a DAS-II test for School Age for each core subtest
A listing of neurodevelopment assessment type for each subject will be presented. 
BSID-III
A listing for the antecedent substudy population will be presented by subject and visit for the 
following parameters:

Raw score, age equivalents versus chronological age, as well as DQ, composite score and 
percentile for each subject evaluated by the BSID-III test and each domain 

Motor (Fine, Gross)

Language (Receptive, Expressive)

Cognitive 
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6.7.2.2
Vineland Adaptive Behavior Scales, Second Edition (VABS-II)
Descriptive statistics at observed values and changes from baseline will be summarized at 
scheduled visits for the following:

Standard scores of the VABS-II composite and domains: 
o
ABC
o
Communication 
o
Daily Living Skills 
o
Socialization 
o
Motor Skills

Age equivalents, developmental quotients, and v-scale scores of the VABS-II 
subdomains: 
o
Communication (Receptive, Expressive, Written) 
o
Daily Living Skills (Personal, Domestic, Community) 
o
Socialization (Interpersonal Relationships, Play and Leisure Time, Coping Skills) 
o
Motor Skills (Gross, Fine) 

v-scale scores and observed maladaptive levels of the VABS-II Maladaptive Behavior 
Index and its subscales (Internalizing, Externalizing)
Mean values (± SD) by the Early IT group and the Delayed IT group will be plotted over time. 
This includes the following endpoints:

The observed values and change from baseline to each scheduled visit in standard scores 
for ABC, each domain, v-scale scores, age equivalents and DQ for the subdomains of the 
VABS-II

The observed values and change from baseline to each scheduled visit in v-scale scores 
and the observed maladaptive levels of the VABS-II Maladaptive Behavior Index and its 
sub-scales
The observed values of age equivalents for the subdomains of the VABS-II will be plotted for 
individual subjects against chronological age. 
The observed values and change from baseline values of each endpoint for individual subjects 
will be plotted over time. This includes the following endpoints:

Standard scores in subjects evaluated by the VABS-II test for ABC and each domain

v-scale scores, age equivalents, chronological age and DQ for subjects evaluated by the 
VABS-II test for each subdomain
Listings will be presented for the following parameters:

Standard scores and percentile in subjects evaluated by the VABS-II test for ABC and 
each domain 

v-scale scores, age equivalents, chronological age and DQ for subjects evaluated by the 
VABS-II test for each subdomain
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SHP609-302 Statistical Analysis Plan for Interim Analysis 
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
v-scale scores and Maladaptive levels of Maladaptive Behavior Index and its sub-scales 
(Internalizing, Externalizing) in VABS-II
6.7.3
Subgroup Analyses
Subgroup descriptive summary analyses of the secondary efficacy endpoints, change from 
baseline in GCA (including both Early Years and School Age batteries) and ABC scores at 
scheduled visits will be performed for baseline GCA classification groups (either ≤70 or >70), 
baseline age groups (either <6 years or ≥6 years and either <55 months or ≥ 55 months).  
Descriptive summaries within these subgroups and plots of mean values (± SD) over time will be 
presented. The baseline of study SHP609-302 is defined in Section 6.2.1.
Subgroup analyses of the exploratory rate of change (weighted) analyses are planned for the 
following subgroups:

HGT-HIT-094 Comparable Subset 2 (age <55 months old at the time of enrollment in 
SHP609-302), which is a subgroup of primary efficacy analysis population; 

GCA classification groups (either ≤70 or >70) at the time of enrollment in SHP609-302 
(i.e., Visit Month 13/ Baseline) using HGT-HIT-094 Comparable Set (exploratory overall 
analysis population).
HGT-HIT-094 Comparable Subset 1 (age <6 years old at the time of enrollment in SHP609-302) 
is considered as the primary efficacy analysis population. It is a subgroup of HGT-HIT-094 
Comparable Set.
6.7.4
Exploratory Efficacy Analyses
6.7.4.1
Exploratory Ordered Categorical Outcome Analysis
Descriptive summary of ordered categorical outcomes will be provided for the 12-month visit in 
SHP609-302 (i.e., Visit Month 25/Week 52 in SHP609-302) from the time of enrollment in 
SHP609-302 by the observation group (either “B” or “D”) for the HGT-HIT-094 Comparable 
Set, HGT-HIT-094 Comparable Subsets 1 and 2. The definitions of ordered categorical outcomes 
endpoints for each subject are described in Section 5.4.4. Sensitivity analysis using a 5-, 15-, and 
20- point score change to supplement the proposed 10-point change threshold for the Ordered 
Categorical Outcomes for DAS-II GCA standard scores from Early Years battery (GCA EY) will 
be performed as specified below.
For each sensitivity-change threshold (SENS=5, 15 or 20) the categorical outcomes will be 
determined for each subject by comparing the baseline values of GCA EY from study SHP609-
302 +/- SENS to the post-baseline values of GCA EY. The ordered categorical outcomes for 
each SENS are defined as:

Above average cognitive development (Sens-Category 1) is defined for subjects who had 
the observed GCA EY at post baseline visit more than SENS points higher than observed 
study SHP609-302 baseline GCA EY, i.e.,
o
GCA EY (Post-Baseline) > GCA EY (Baseline) +SENS
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
Average cognitive development (Sens-Category 2) is defined for subjects who had the 
observed GCA EY at a post-baseline visit within the range of ± SENS (inclusive) of the 
observed study SHP609-302 baseline GCA EY, i.e.,
o
GCA EY (Baseline) -SENS  ≤ GCA EY (Post-Baseline) ≤ GCA EY (Baseline)  + 
SENS

Below average cognitive development (Sens-Category 3) is defined for subjects who had 
the observed GCA EY at a post-baseline visit more than SENS points below the observed 
study SHP609-302 baseline GCA EY, i.e.,
o
GCA EY (Post-Baseline) < GCA EY (Baseline) – SENS
Descriptive summary of ordered categorical outcomes defined for each SENS value (5-, 15- and 
20-points) will be provided at post-baseline of 12 months (i.e., Month 25/Week 52 in SHP609-
302) by Early IT and Delayed IT groups for the HGT-HIT-094 Comparable Set, Comparable 
Subset 1 and 2.
The 5-point change threshold is approximately 1 SEM and the 15-point change is approximately 
a 90% CI for Sdiff estimates, providing psychometric and clinical meaning for these changes 
scores. Shire is not aware of any statistical, clinical or psychometric evidence to support using a 
20-point change from baseline threshold for the DAS-II GCA scores.  On the contrary, a 20-
point change over this time period is considered by neuropsychologists as a quite extreme change 
in cognitive development. While this SAP is incorporating the suggested sensitivity analyses 
with all of the thresholds proposed by the Agency (5, 15 and 20 points), the limitations of their 
clinical interpretations should be noted.
6.7.4.2
Exploratory Analysis to Assess Floor Effect 
The number and percentage of subjects who reached an unreversed floor effect by 12-month visit 
in SHP609-302 (i.e., Month 25/Week 52 in SHP609-302) from the time of enrollment in 
SHP609-302 will be summarized by the observation group (either “B” or “D”) and overall using 
the 12-month SHP609-302 data “B” and “D” for the HGT-HIT-094 Comparable Set, HGT-HIT-
094 Comparable Subsets 1 and 2. The definitions of binary unreversed floor effect outcomes
endpoints are described in Section 5.4.5.
6.7.4.3
Exploratory Rate of Change (Weighted) Analysis
The main exploratory efficacy analyses to examine the 12-month IT treatment effect in study 
SHP609-302 will be the rate of change (weighted) analyses on the exploratory efficacy 
endpoints, change in scores from the time of enrollment in SHP609-302 to 12 months during 
study SHP609-302, estimated by linear regression from Visit Month 13/Baseline to Visit Month 
25/Week 52 in study SHP609-302, for the select neurodevelopment assessment scores.
The 12-month rate of change (weighted) analysis on DAS-II GCA standard scores from Early 
Years battery can be considered as a two-stage procedure 3 and is described below. For other 
neurodevelopmental assessment scores, a similar two-stage procedure will be followed.
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
The first stage involves estimation of the rate parameter (slope) for each subject 
separately, which is the linear regression slope of GCA scores from Visit Month 13/ 
Time of Enrollment in SHP609-302 to Visit Month 25/Week 52 in SHP609-302  (12-
month SHP609-302 observation period “B” or “D”) for each individual subject.  For “B” 
or “D”, the subjects who meet any criteria below will not be included in the linear 
regression analyses:
o
Have less than 3 available GCA scores in that period. We require 3 or more points 
for the conventional fit of linear regression. A linear regression with only 2 
available scores will result in zero degree of freedom for errors, so we will not 
have a weight estimate.

For sensitivity analysis, subjects with two available GCA scores, at the 
beginning and at the end of the 12-month period, (i.e., Visit Month 13/
Time of Enrollment in SHP609-302 and Visit Month 25/ Week 52 in 
SHP609-302) will be included and assigned the smallest weight observed 
among subjects with at least 3 observations in the second stage.
o
Have missing GCA scores either at the beginning or at the end of the 12-month 
period (i.e., Visit Month 13/ Time of Enrollment in SHP609-302 or Visit Month 
25/Week 52 in SHP609-302). This criterion is used to avoid estimation of 12-
month change using 6-month or 9-month data, essentially extrapolating a 12-
month result..
o
Have reached GCA ‘floor effect’ at the beginning of the 12-month period (i.e., 
Visit Month 13/Baseline for “B” or “D”). The term “floor effect” is for the 
purpose of evaluating the baseline eligibility of subjects entering SHP609-302 for 
inclusion in the analyses for the 12 months endpoints. For example, GCA scores 
below 30 points are not possible and GCA baseline scores below 40 points will 
not lead to a reliable estimate of change from baseline at 12 months in study 
SHP609-302, potentially falsely indicating stability of disease. This subject 
exclusion is for subjects at or near the bottom of the neurodevelopment 
assessment scale at the time of enrollment in SHP609-302. Those subjects have 
little potential to measure further decline using the DAS II, so they would 
inappropriately appear to have stable cognitive ability based on test scores due to 
the inability of the instrument to differentiate scores near the bottom of the scale. 
Including those subjects could potentially lead to analysis bias in favor of 
treatment effect. This is a limitation of all cognitive ability tests, which cannot 
provide meaningful measurement below a floor effect threshold. The exclusion of 
these subjects only impacts the 12 months endpoints.
The GCA score change over a 12-month period from Visit Month 13/ Time of Enrollment in 
SHP609-302 to Visit Month 25/Week 52 in SHP609-302 is estimated by the slope estimate 
multiplied by 52 weeks directly. The slope unit is change in GCA scores per nominal week. 

The second stage uses the individual rate parameter estimates for treatment comparison 
based on weighted generalized linear models. The weights are the inverse of estimated 
variances of GCA score change over a 12-month period  from Visit Month 13/Baseline to 
Visit Month 25/ Week 52, estimated by the inverse of the variance of the slope from each 
For non-commercial use only


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Shire
CONFIDENTIAL
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SHP609-302 Statistical Analysis Plan for Interim Analysis 
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14 Mar 2019
Figure 3
Hypothetical Illustration of Comparisons of Analysis 1 on “D”
Note: The primary comparison based on a 1-sample test is to compare the LL of the 90% CI for the estimated 
change over a 12-month period and the clinically meaningful change (e.g., -10 points for GCA scores). The 
secondary comparison is to compare the estimated mean change over a 12-month period and the same threshold.
Analysis 2 (IT treatment effect in “B”“D”): Compare subjects’ initial 12 months of IT 
treatment with subjects’ second 12 months of IT treatment using the rate of change over a 
12 month period  and examine the overall IT treatment effect in SHP609-302 using 
weighted ANOVA model. The model will include a group indicator of "B" vs "D" as well 
as a fixed categorical effect for GCA classification groups (either ≤70 or >70) at the time 
of enrollment in SHP609-302 (i.e., Visit Month 13/ Time of Enrollment in SHP609-302) 
in the weighted ANOVA model. In this scenario, the treatment by the group interaction 
cannot be included because the treatment (Early IT or Delayed IT) and group indicator 
(“B” or “D”) are identical.
o
Primary comparison: if the LL of 90% CI of estimated change over a 12-month 
period in “B” “D” from Visit Month 13/ Time of Enrollment in SHP609-302 to 
Visit Month 25/Week 52 in SHP609-302 based on weighted ANOVA model is 
greater than the pre-defined clinically meaningful change (Table 1), then the IT 
treatment would be considered showing effect in “B”“D”. 
o
Secondary comparison: in view of the small sample size and wide confidence 
interval, if the estimated mean change over a 12-month period in “B” “D” based 
on weighted ANOVA model is greater than the pre-defined clinically meaningful 
change, then the IT treatment would be considered showing effect in “B”“D”. 
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SHP609-302 Statistical Analysis Plan for Interim Analysis 
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The premises of the rate of change (weighted) analysis will be examined prior to the analysis. 
The premises of the rate of change (weighted) analysis include:

No extreme systematic departure of linearity on residual distribution of overall linear fits 
of GCA scores change over a 12-month period from Visit Month 13/ Time of Enrollment 
in SHP609-302 to Visit Month 25/Week 52 in SHP609-302 for each individual subject 
meeting the first stage criteria 
o
Approximately normally distributed residuals centered near zero at each visit time
o
Variance homogeneity of residuals at each visit time

Overall agreement between the estimated GCA score change over a 12-month period as 
estimated by a linear regression and the observed GCA score change over a 12-month 
period in SHP609-302 as calculated by a simple subtraction

No correlation between weights and estimated GCA score change over a 12-month period 
in SHP609-302
As model diagnostics, the distribution property of linearity, variance homogeneity at each visit 
and approximate normality at each visit will be examined using residual plots, boxplots of 
residuals and normal probability plots of residuals. The overall agreement between estimated 
GCA score change over a 12-month period by a linear regression and observed GCA score 
change over a 12-month period in SHP609-302 by a simple subtraction will be examined using 
scatter plots. The correlation between weights and estimated GCA score change over a 12-month 
period in SHP609-302 (also between weight and slopes) will be examined using scatter plots. 
Linear regression lines for individual subjects will be plotted. For rate of change (weighted) 
analysis on other select neurodevelopmental assessment scores, similar model premises have to 
be examined prior to the analysis.
The rate of change (weighted) analysis will be performed on HGT-HIT-094 Comparable Set, 
HGT-HIT-094 Comparable Subsets 1 and 2. The estimated treatment effect and 90% confidence 
intervals on the treatment effect from the weighted ANOVA model will be reported without 
reporting p-values and presented in Forest plots.
The sample SAS code is presented in. Appendix 10.3.1
6.7.4.4
Correlation between Different Neurodevelopmental Assessment Scores
The correlation analysis between different neurodevelopment assessment scores is a supportive 
exploratory analysis performed on the Safety Population who enrolled from the pivotal study of 
HGT-HIT-094. Data from periods A, B and D in Figure 1 will be used.

The following correlation coefficients for observed values and change from baseline will 
be estimated from a linear mixed effects model that takes into account the repeated 
measures on each subject using the method described by Hamlett et. al.5 SAS Proc Mixed 
with restricted maximum likelihood estimation (REML) and an unstructured between and 
within-subject covariance structure for the random effects will be used for this model. 
Each pair of parameters will also be graphed as scatter plots. DAS-II (including both 
Early Years and School Age batteries) GCA standard score and
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SHP609-302 Statistical Analysis Plan for Interim Analysis 
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o
DAS-II Verbal standard score 
o
DAS-II Nonverbal standard score 
o
DAS-II Spatial standard score 
o
DAS-II SNC standard score 
o
VABS-II ABC standard score 
o
VABS-II Communication standard score 
o
VABS-II Daily Living Skills standard score 
o
VABS-II Socialization standard score 
o
VABS-II Motor Skills standard score 
o
CSF GAG levels (natural log scale)

VABS-II ABC standard score and 
o
VABS-II Communication standard score 
o
VABS-II Daily Living Skills standard score 
o
VABS-II Socialization standard score 
o
VABS-II Motor Skills standard score 
o
CSF GAG levels (natural log scale)
Each pair of parameters will also be graphed as scatter plots. The sample SAS code is presented 
in Appendix 10.3.2.
Other exploratory analyses may include assessment of the correlation between PD and efficacy 
endpoints; and between composite scores and their components (i.e., correlations between the 
GCA and ABC scores and their respective cluster/domain scores). 
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SHP609-302 Statistical Analysis Plan for Interim Analysis 
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Table 3
Summary of Exploratory Efficacy Analysis in the SHP609-302 IA SAP
Analysis
Comparison
/Evaluation
Endpoints
Rationale and Additional Considerations
SAP
Supportive 
Exploratory: 
12-month
Ordered 
Categorical 
Outcome (3 
categories) 
Analysis
“B” and “D” Ordered categorical outcomes (3 categories: above 
average cognitive development, average cognitive 
development, and below average cognitive development) 
at 12 months (assessed in SHP609-302) from the time of 
enrollment in SHP609-302, for:

Main
o
DAS-II GCA scores from Early Years 
battery 

Supportive
o
DAS-II GCA scores (including both 
Early Years and School Age batteries)
Rationale: 

Descriptive summary of subjects change during the 
second 12 months of IT treatment (“B”)

Descriptive summary of subjects change during the 
first 12 months of IT treatment (“D”)
SHP609-
302 IA 
Section 
6.7.4.1
Supportive 
Exploratory: 
12-month
Floor Effect 
Analysis
“B” and “D” Binary outcomes for each subject: whether or not the 
subject reached an unreversed floor effect at 12 months 
(assessed in SHP609-302) from the time of enrollment in 
SHP609-302, for:

Main
o
DAS-II GCA scores from Early Years 
battery 

Supportive
o
DAS-II T scores from Early Years 
battery 
o
DAS-II standard cluster scores and 
composite scores from Early Years 
battery
o
DAS-II GCA scores (including both 
Early Years and School Age batteries)
o
VABS-II ABC scores
Rationale:

Descriptive summary of subjects reaching an 
unreversed floor effect during the second 12 months 
of IT treatment (“B”)

Descriptive summary of subjects reaching an 
unreversed floor effect during the first 12 months of 
IT treatment (“D”)
Additional consideration:

“Floor effect” is considered to be the lower limitation 
of the assessment tool, below which the assessment 
may not be reliable or meaningful.

The summarized number and percentage of subjects 
who reached the unreversed floor effect will be used 
to evaluate the floor effects on the efficacy analyses 
results.
SHP609-
302 IA 
Section 
6.7.4.2
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Table 3
Summary of Exploratory Efficacy Analysis in the SHP609-302 IA SAP
Analysis
Comparison
/Evaluation
Endpoints
Rationale and Additional Considerations
SAP
Main 
Exploratory: 
12-month Rate 
of Change 
(Weighted) 
Analysis
“D”
(Analysis 1 –
Primary 
Comparison)
Change in scores from the time of enrollment in SHP609-
302 to 12 months during SHP609-302 (“D”), estimated 
by linear regression, for:

Main
o
DAS-II GCA scores from Early Years 
battery 

Supportive
o
DAS-II T scores from Early Years 
battery 
o
DAS-II standard cluster scores and 
composite scores from Early Years 
battery
o
DAS-II GCA scores (including both 
Early Years and School Age batteries)
o
VABS-II ABC scores 
Rationale: 

Examine the treatment effect in “D” alone. 
Additional consideration: 

The primary comparison will be based on a 1-sample 
test, i.e., between the lower bound of the 90% CI for 
the weighted mean of change from baseline and a 
clinically meaningful change. 

Due to the very small projected sample size in “D”, 
the CI may be too wide. Therefore, a secondary 
comparison will be made using only a point estimate, 
i.e., the weighted mean of change from baseline, and 
compare it to a clinically meaningful change.

Since study SHP609-302 did not have baseline GCA 
inclusion criteria range at the time of enrollment in 
SHP609-302, such as employed for study HGT-HIT-
094, “D” subjects could differ with regard to their 
baseline GCA scores at the beginning of the 
observation period. Therefore, for consideration of 
“D”, only “D” subjects with GCA scores between 
55 and 85 inclusive at the time of enrollment in 
SHP609-302 will be included.
SHP609-
302 IA 
Section 
6.7.4.3
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Table 3
Summary of Exploratory Efficacy Analysis in the SHP609-302 IA SAP
Analysis
Comparison
/Evaluation
Endpoints
Rationale and Additional Considerations
SAP
Supportive 
Exploratory: 
12-month  
Rate of 
Change 
(Weighted) 
Analysis
“B” “D”
(Analysis 2 –
Supportive 
Comparison)
Change in scores from the time of enrollment in SHP609-
302 to 12 months during SHP609-302 ( “B” and “D”), 
estimated by linear regression, for:

Main
o
DAS-II GCA scores from Early Years 
battery 

Supportive
o
DAS-II T scores from Early Years 
battery 
o
DAS-II standard cluster scores and 
composite scores from Early Years 
battery
o
DAS-II GCA scores (including both 
Early Years and School Age batteries)
o
VABS-II ABC scores
Rationale:

Compare subjects’ initial 12 months of IT treatment 
(“D”) with subjects’ second 12 months of IT 
treatment (“B”) using the rate of change over a 12 
month period. Note: this is a parallel group 
comparison. Within subject comparisons (intra-
subject) will be performed in the ISE. 

Estimate the treatment effect using all IT treatment 
data in SHP609-302 (increased sample size) if “B” 
and “D” appear similar.
Additional consideration: 
Method of analysis will be the same as for the main 
exploratory analysis above.Only “B” and “D” subjects 
with GCA scores between 55 and 85 inclusive at the time 
of enrollment in SHP609-302 will be included.
SHP609-
302 IA 
Section 
6.7.4.3
Note: The exploratory analyses listed in Table 1 will be performed on HGT-HIT-094 Comparable Set, HGT-HIT-094 Comparable Subsets 1 and 2.
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6.7.5
Health Economics and Outcomes Research Endpoint Analyses
The health status of subjects will be assessed using the EQ-5D questionnaire. 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: 

No problems 

Slight problems

Moderate problems

Severe problems

Unable to do / Extreme problems
The number and percent of subjects with each response will be presented by dimension at each 
visit.  The visual analogue scale (VAS) records the subject’s health rated by parent/caregiver on 
a 0 (worst health) to 100 (best health) scale.  The VAS score, as well as the change from baseline 
will be summarized at each time point.
Additional 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 in a separate 
document.
6.7.6
Pharmacodynamic Outcome

CSF and Urine GAG 
CSF and Urine GAG observed levels, the change from baseline and percent change from 
baseline will be summarized by the Early IT group, the Delayed IT group and overall and by 
visit.  Mean observed values (+/- SE) and mean percent change compared to baseline will be 
plotted over time.  The percent change compared to baseline is defined as the value at the 
corresponding visit multiplied by 100 and divided by the baseline value. One decimal will be 
kept for the percent compared to baseline. Analysis of both CSF total GAG and CSF heparan 
sulfate if available will be performed.

Albumin Concentration and Albumin Quotients
CSF albumin concentrations, CSF/serum albumin quotients (QAlb = CSF albumin/serum 
albumin) observed levels, the change and the percent change from baseline will be summarized 
by the Early IT group, the Delayed IT group and overall and by visit and to assess the blood-CSF 
barrier function.

During the HGT-HIT-094/Initial Treatment Phase, descriptive statistics at observed 
values, changes from baseline, and the percent change from baseline will be summarized 
at Screening/Baseline, Week 4, 16, 28, and 40. 

During the Extended Treatment Phase, descriptive statistics at observed values, changes 
from baseline, and the percent change from baseline will be summarized on month 13 
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and at 3-month intervals (i.e., at Months 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 
55, 58 and 61).
Analysis of Safety
6.8
All analyses of safety data will be descriptive and presented by the Early IT group, the Delayed 
IT group and overall. The analysis of safety will be based on the Safety population. Any former 
HGT-HIT-094 Substudy subjects will be included in the Early IT group. 
6.8.1
Adverse Events
AEs will be recorded throughout the study and at early termination.  AEs and medical conditions 
will be coded using the MedDRA version 16.1 or higher.
For IA analysis, treatment-emergent AEs (TEAE) are defined as all AEs occurring on or after the 
date of the first IDDD implant surgery or first dose (whichever is earlier) and on or before the 
EOS visit (+30 days)  or 2 weeks after the removal of the last IDDD if early termination 
(whichever is later). In general, an AE will be deemed TEAE if it cannot be definitively 
categorized by the available components (day, month, year) of the AE onset date with respect to 
the date of  intervention (the date of the first IDDD implant surgery or first dose [whichever is 
earlier]). Summaries for the following TEAE categories will be presented: 
1) Patients who experienced no AEs, 
2) Patients who experienced at least one AE 
3) Patients who discontinued due to an AE(s)
4) Patients who died
5) Patients who experienced at least one serious adverse event (SAE),
6) Patients who experienced at least one severe/life-threatening AE,
7) Patients who experienced at least one IV Elaprase infusion-related adverse event
8) Patients who experienced at least one idursulfase-IT-related adverse event 
9) Patients who experienced at least one idursulfase-IT or IV Elaprase infusion-related 
adverse event
10) Patients who experienced at least one IT Treatment Regimen-related adverse event (i.e., 
related to one or more of the following: study drug, IDDD, device surgical procedure, 
and IT-administration process)
11) Patients who experienced at least one IDDD surgical procedure-related adverse event
12) Patients who experienced at least one IDDD-related adverse event
13) Patients who experienced at least one IT Administration Process-related adverse event
The AE categories 1-13 will be presented by each treatment group and overall, while the AE 
categories 8-13 will be presented for patients in the Safety Population who received idursulfase-
IT. IT administration process-related AEs will be summarized by IT administration method (LP 
or IDDD) as well. The AE categories 11-12 will be presented for patients in the Safety 
Population with the device implanted. 
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The number and percentage of patients, and the number of corresponding AEs will be 
summarized in overall summary tables. In addition, the number and percentage of patients 
having any treatment-emergent AE within the AE categories 2, 5, 7-13 and the number of 
corresponding AEs will be displayed by MedDRA system organ class (SOC), preferred term 
(PT) and treatment group. The most common treatment-emergent AEs which happened in >10% 
patients in either treatment group will also be summarized by SOC and PT. The most common 
non-serious treatment-emergent AEs which happened in >5% patients in either treatment group 
will also be summarized by SOC and PT.
The number and percentage of patients having any treatment-emergent AE, and the number of 
corresponding AEs will be summarized by severity.
The number and percentage of patients having any treatment-emergent AE, and the number of 
corresponding AEs will be summarized by relationship to IV Elaprase, idursulfase-IT, and at 
least one IT treatment regimen, and displayed by MedDRA SOC, PT and treatment dose. 
Furthermore, listings of all the AEs of categories 3-6 will be provided if applicable.
6.8.2
Clinical and CSF Laboratory Evaluations
Chemistry and hematology serum laboratory and CSF (standard chemistries, glucose, protein, 
and cell counts) values will be summarized in terms of the absolute value and change from 
baseline at each scheduled study visit by the Early IT group, the Delayed IT group and overall.

During the HGT-HIT-094/Initial Treatment Phase, descriptive statistics at observed 
values and changes from baseline will be summarized at Screening/Baseline, Pre-Surgery 
Day 1 of Week 2, at Week 4, 16, 28 and 40 visit. 

During the Extended Treatment Phase, descriptive statistics at observed values and 
changes from baseline will be summarized on Pre-Treatment of IT Day 1 of Month 13 
and  at 3-month intervals on the Pre-Treatment Day of Monthly IT Dosing Weeks (i.e., at
Months 16, 19, 22, 25, 28, 31, 34, 37, 40, 43, 46, 49, 52, 55 and 61).
All the laboratory (chemistry, hematology, urinalysis and CSF) values will be categorized as a 
patient having had (1) a Clinically Significant (CS) value at any time during the study post 
baseline, and (2) no CS values at any time during the study post baseline. The number and 
percentage of patients in each category will be presented by the Early IT group, the Delayed IT 
group and overall. Patients with a Normal or non-CS value for a particular laboratory parameter 
at baseline who experience a change to CS for that laboratory parameter post-baseline will be 
identified and listed separately along with the corresponding laboratory values over time. 
Baseline for the patients previously treated in HGT-HIT-094 is defined as the screening 
measurement in HGT-HIT-094; if it is not available, the Pre-Surgery Day 1 of Week 1 
measurement will be used as baseline. Baseline for the untreated patients in HGT-HIT-094 is the 
closest available assessment prior to the initial IDDD implant date, which takes place in Study 
SHP609-302. This could potentially include EOS visit data from Study HGT-HIT-094.
If a particular laboratory measurement has been either repeated or retested, then the repeated or 
retested measurement for that laboratory parameter, with respect to date/time, will be used in the 
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statistical analysis unless this value is invalid/missing. The handling of repeated or retested 
laboratory measurements should only consider the specific laboratory measurement that was 
repeated or retested.
6.8.3
12-Lead ECG Evaluations
The 12-lead ECG parameters (heart rate [bpm], PR interval [msec], QRS interval [msec], QT 
interval [msec] and the corrected QT interval (QTc) [msec]) will be summarized in terms of 
absolute value and change from baseline by the Early IT group, the Delayed IT group and visit. 
The analysis will be based on the Safety population. Any former HGT-HIT-094 Substudy 
patients will be included in the Early IT group. The QTc interval will be calculated using Bazett's 
formula as QT divided by the square root of RR interval. The number and percentage of patients 
with ECG abnormalities post baseline will be presented by the Early IT group and the Delayed 
IT group.

During the HGT-HIT-094/Initial Treatment Phase, descriptive statistics at observed 
values and changes from baseline will be summarized at Screening/Baseline, Pre-Surgery 
Day 1 of Week 2, and at 3-month intervals of after injection of study drug on Week 4, 16, 
28 and 40. 

During the Extended Treatment Phase, descriptive statistics of observed values and 
changes from baseline will be summarized on Pre-Treatment of IT Day 1 of Month 13, 
and at 12-month intervals of after injection of study drug on Monthly IT Dosing Weeks 
(i.e., at Months 25, 37, 49 and 61).
6.8.4
Vital Signs
The injection (IT) vital signs and regular vital signs (temperature [C], pulse [bpm], blood 
pressure [systolic and diastolic, mmHg], oxygen saturation, and respiration rate [per min] will be 
listed.

During the HGT-HIT-094/Initial Treatment Phase, vital signs will be collected at 
Screening/Baseline, during Surgery Week 2 at Day 1, Day 2, Days 3-6 (i.e., during IV 
infusion of Elaprase), Pre-Treatment Day 1 of each IT Dosing Week, Day 2 and Days 3-7
(i.e., during IV infusion of Elaprase) of each IT Dosing Week after injection of the study 
drug.
At a minimum, vital signs will be collected at the following time points on IT administration of 
idursulfase-IT: within 15 minutes prior to IT administration, 30 minutes (±10 minutes) post end 
of IT administration, 60 minutes (±10 minutes) post end of IT administration, 120 minutes (±10 
minutes) post end of IT administration, and 4 hours (±10 minutes) post end of IT administration.

During the Extended Treatment Phase, vital signs will be collected on Pre-Treatment Day 
1 and on the IT Injection Day of Month 13 and on Pre-Treatment Day 1 and on the IT 
Injection Day on Monthly IT Dosing Weeks.
At a minimum, vital signs will be collected at the following time points on IT administration of 
idursulfase-IT: within 15 minutes prior to IT administration, 30 minutes (±10 minutes) post end 
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of IT administration, 60 minutes (±10 minutes) post end of IT administration, 120 minutes (±10 
minutes) post end of IT administration, and 4 hours (±10 minutes) post end of IT administration.
Vital signs will be plotted for individual patients over the time by scheduled study visit. The IT 
vital signs will be plotted for individual patients over the time by scheduled study visit from the 
start of the IT injection for each IT injection.
6.8.5
Physical and Neurological Findings
Clinically significant physical and neurological examination findings will be recorded and 
summarized either as part of the medical history or adverse event data. No additional summary 
or listing will be provided.
6.8.6
Other Observations Related to Safety 
6.8.6.1
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 scheduled time point will be summarized by the Early IT group, the Delayed IT 
group and overall. The analysis will be based on the Safety population. Any former HGT-HIT-
094 Substudy patients will be included in the Early IT group.
Antibody titer values will be plotted for individual patients over time by scheduled study visit in 
patients with positive antibodies at or prior to each scheduled visit.  The neutralizing antibodies 
(NAb) titer will be plotted similarly for patients who developed positive neutralizing antibodies 
at or prior to each scheduled visit. 
6.8.6.2
CSF Enzyme Level
The observed idursulfase enzyme levels in CSF will be plotted for individual patients before 
each IT dose over time by scheduled study visit. If a measurement is less than the lower level of 
quantification (LLOQ), then it will be replaced by zero.
6.8.6.3
Height, Weight, and Head Circumference
Height (cm), weight (kg), and head circumference (cm) observed values, and the change from 
baseline will be summarized by the Early IT group and the Delayed IT group at scheduled study 
visits. The analysis will be based on the Safety population. Any former HGT-HIT-094 Substudy 
patients will be included in the Early IT group. If multiple measurements were taken for the 
same visit, their mean will be the measurement for that visit.
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6.8.6.4
Brain MRI
All patients will have MRI of the brain at Screening and at 12-month intervals, i.e., at months 13, 
25, 37, 49 and 61. The analysis will be based on the Safety population. Any former HGT-HIT-
094 Substudy patients will be included in the idursulfase-IT treated group. Descriptive statistics 
at observed values and changes from baseline will be summarized by the Early IT group, the 
Delayed IT group and overall for the following parameters: 

Brain Total Intracranial Volume (cm3)

Brain Total Tissue Volume (cm3)

Brain Total White Matter (cm3)

Brain Total Gray Matter (cm3)

Total CSF Volume (cm3)
6.8.6.5
Hearing Assessments
The number and percentage of patients in the hearing assessment categories (right ear hearing 
aid, left ear hearing aid, and sufficient hearing for study assessments) will be summarized by the 
Early IT group, the Delayed IT group and visit. The analysis will be based on the Safety 
population. Any former HGT-HIT-094 Substudy patients will be included in the Early IT group.
6.8.6.6
SOPH-A-PORT Mini S Device Performance 
Device-related Terminology

Initial device implant:  The first IDDD implant that a patient ever receives

Partial device revision: Surgical revision/replacement of one or more component(s) of the 
device; other component(s) of the original device remain implanted and are not affected 
(e.g., port revision).

Full device revision: The device is removed (explanted) in its entirety and a completely 
new device is implanted, including complete device removal with immediate replacement 
and delayed device implant after previous removal.

Complete device removal with immediate replacement: Immediately implant of a new 
device after a device had been completely removed.

Delayed device implant after previous removal: Implant of a new device after a previous 
device had been completely removed without immediate replacement on a separate and 
earlier occasion. 

Complete device removal without replacement: All parts of the device (both port and 
catheter) are removed and there is no new device implant. 

Device adjustment: surgical procedure of the device that is not a port replacement or full 
device revision.

Device malfunction: The device does not perform as intended, based on the description in 
the device’s Instructions for Use, but does not require either a partial or full device 
revision. If at the time of a scheduled dosing it is not possible to administer a full 
medication dosage as per the standard administration steps detailed in the device’s 
Instructions for Use due to a device related issue, the IDDD will be declared a device 
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malfunction.  A device malfunction could be resolved without the need for a full or 
partial surgical revision. Programmatically it is when the malfunction date is present and 
outcome of malfunction is resolved.

Device failure: When the device irreversibly fails to perform as intended and cannot be 
corrected without a device surgical intervention of either a partial or full device revision 
or removal. The IDDD will be declared a device failure, starting from the date of the 
initial malfunction that persists leading to the above surgical intervention. IDDDs that are 
considered to be malfunctioning at the end of the study will be categorized as Failures.
For programming purposes, a device failure is when the malfunction date is present and 
outcome of malfunction is either ongoing or device failure (Surgical Procedure). The date 
of the device failure is the date of the initial malfunction.

IDDD longevity: Total number of IDDD failures and explant divided by the total time at 
risk across all subjects in weeks (sum of time to IDDD failure or the last injection if not 
failed at the end of the data cut or explant date, from initial implantation, delayed 
implantation, or revision for all IDDDs).
Device Performance Analyses
SOPH-A-PORT® safety and performance will be summarized for IDDD-implanted patients in 
Safety Population. The number and proportion of patients of the following categories and the 
corresponding event count and event percentage will be summarized. 

Patients who had the initial implant only (i.e., no additional surgeries) 

Patients who had any post-initial implantation device surgeries 

Patients who had any type of difficulty associated with the implant procedure (e.g., 
difficulty accessing spinal canal, etc.)
IDDD-related surgical procedure details for initial implants, complete removal with immediate 
replacement, and delayed implantation across all IDDD implantations for all patients will be 
summarized by failed or not failed IDDDs and overall, including incision region (paramedian vs. 
other), identification of the catheter passer used (Phoenix Neuro vs. other), number of suture 
wings implanted, suture wing configuration,  interspace for catheter insertion into lumbar spine 
(L1-2, L2-3, L3-4, L4-5, L5-S1), spinal vertebral level of catheter tip (cervical, thoracic, lumbar 
and sacral), use of a purse string suture, use of the guidewire, orientation of the Tuohy needle 
and clinical site. 
The number and proportion of patients who had at least one abnormal IDDD radiological 
assessment finding and the number of abnormal findings from the IDDD radiological 
assessments will be also summarized by types of the abnormality. 
The number and proportion of patients and IDDDs with total malfunctions (including failure and 
malfunctions) as well as the corresponding event numbers will be presented. The types of total 
malfunctions and the reasons for IDDD failures reported by the site and the Adjudication 
Committee will be summarized at the patient, IDDD and event level. 
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The annual event rate of IDDD failures and malfunctions will be calculated for each patient and 
the descriptive statistics will be summarized. The overall IDDD failure rate and its 95% CI will 
be presented. The overall IDDD failure rate is calculated as the total number of IDDD failures 
for all patients divided by the total IDDD time at risk, which is defined as the total time to IDDD 
failure or the last injection if IDDD is not failed at the end of the study, from initial implantation, 
or full device revision for all IDDDs.  The overall IDDD malfunction rate is defined in the same 
manner.
The IDDD longevity (time to failure in weeks) and time to first total malfunction, for all 
implanted IDDDs, will be analyzed using the KM method. A new port identifies a new IDDD, 
starting from the date of implantation (either an initial implantation, a partial or full revision, or a 
delayed device implant after previous removal). The time to IDDD failure (weeks) or total 
malfunction will be obtained by subtracting the date of the  IDDD kit implantation from the date 
of IDDD failure (i.e., the initial malfunction date that persists leading to surgical intervention) or 
first total malfunction plus 1, and divided by 7, one decimal will be kept. IDDDs which did not 
fail or malfunction will be censored at the last study drug injection date for each IDDD. The 
number of IDDDs at risk, the cumulative number of IDDDs failed, censored, and the cumulative 
probability of failure with its standard error will be summarized in a table at each event time.  
The proportion of patients for whom a successful first injection of investigational drug product 
occurred will be reported among those for whom a first injection was attempted (i.e., those who 
had an apparently successful implantation and did not suffer a device removal or revision prior to 
first scheduled injection). An injection is defined as study drug administered using IDDD. A 
successful injection is defined as the completion of study drug injection via IDDD without a 
malfunction. The proportion of patients who had no unsuccessful injection attempts during the 
study will also be summarized. Injections that are not successful for patient-related reasons (e.g., 
patient uncooperative, competing medical issue) will not be included in the determination of the 
injection success rate.  The detailed list of the “Other” malfunction types will be reviewed by the 
Shire physician to determine if the injection was not given for patient reasons. If the injection is 
not given for patient reasons then it would not be counted as an unsuccessful injection attempt.
Whether any device component was implanted will be summarized for all IDDD kits which were 
opened. For the implanted IDDDs, their status (i.e., removed or not) at the end of the study will 
be reported. If an IDDD was removed, whether the catheter was removed along with the port will 
also be summarized.
An IDDD timeline of events (in weeks from implantation) including the timing of device 
surgeries (device adjustment, partial or full revision, and complete device removal without 
replacement), and malfunction and failure by IDDDs will be plotted by patient sorted by the 
duration since the initial implantation, longest on top. 
The number of surgeries per patient will be presented by a bar chart. The types of IDDD 
malfunctions and failure per patient, as well as the reasons for the failures for the IDDDs 
reported by the site and the Adjudication Committee will be presented similarly by a bar chart.
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The time from initial implant surgery to first IDDD failure and the time to first malfunction will 
be analyzed using the Kaplan Meier (KM) method for each patient who is in the Safety 
Population with IDDD implanted. The time to first IDDD failure or malfunction will be obtained
by subtracting the date of the first IDDD implantation for the patient from the date of first failure 
or malfunction plus 1, divided by 7, and one decimal will be kept. Patients without an IDDD 
failure or malfunction will be censored at their last study drug injection date. The 25th percentile 
(Q1), median and 75th percentile (Q3) of the time to first failure or malfunction distribution and 
the 95% confidence interval (CI) will be presented together with the KM plots. A by-patient 
listing of the device failure and malfunction data will be displayed. 
The IDDD longevity (time to failure in weeks) and time to first total malfunction, for all 
implanted IDDDs, will be plotted using the KM method. The 25th percentile (Q1), median and 
75th percentile (Q3) of the time to failure or total malfunction distribution and the 95% CI will 
also be presented together with the KM plots.
The time (weeks) from IDDD implantation to failure/continuing function will be plotted as a 
horizontal bar chart for each device sorted by duration of each device implantation (time from 
the implantation of the corresponding IDDD), longest on top.
6.8.7
Concomitant Medications
For IA analysis, concomitant medications are defined as all medications taken on or after the 
date of the first IDDD implant surgery or first dose (whichever is earlier) and on or before the 
EOS visit (+30 days) or 2 weeks after the removal of the last IDDD if early termination 
(whichever is later). 
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Dictionary version March 2013 or higher. Concomitant medication use will be summarized by 
Therapeutic Class and Preferred Term by the Early IT group, the Delayed IT group and overall 
for the Safety Population. Any former HGT-HIT-094 Substudy patients will be included in the 
Early IT group.
6.8.8
Concomitant Therapies
For IA analysis, concomitant therapies are defined as all therapies taken on or after the date of 
the first IDDD implant surgery or first dose (whichever is earlier) and on or before the EOS visit 
(+30 days) or 2 weeks after the removal of the last IDDD if early termination (whichever is 
later). 
Concomitant therapies will be coded using the MedDRA Version 16.1 or higher and summarized 
by Therapeutic Class and Preferred Term by the Early IT group, the Delayed IT group and 
overall for the Safety Population. Any former HGT-HIT-094 Substudy patients will be included 
in the Early IT group.
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Analysis of Pharmacokinetic Data
6.9
All pharmacokinetic analyses will be performed using the PK Population. Serum and CSF 
concentrations as well as pharmacokinetic parameters will be listed and summarized by the Early 
IT group, the Delayed IT group and visit.
6.9.1
Concentration Data
Blood samples will be collected for determination of idursulfase serum concentration-time 
profiles and serum pharmacokinetic parameters after IT administration.  Idursulfase 
concentrations in serum and CSF will be determined using a validated Enzyme-Linked 
Immunosorbent Assay (ELISA) method which was used for the previous idursulfase IT clinical
studies. The idursulfase concentrations in serum will also be determined by a validated liquid 
chromatography tandem mass spectrometry (LC-MS/MS) method.  The LC-MS/MS method is 
expected to be less susceptible to interference by anti-idursulfase antibodies.
6.9.2
Handling BLQ Values
The following procedures will be used for serum concentrations below the lower limit of 
quantification (LLOQ) (reported as BLQ):

Serum samples that are BLQ are reported as zero on the data listings.

Samples that are BLQ are treated as zero in the calculation of summary statistics (e.g., 
mean, SD, etc.) for the serum concentrations at individual time points.

Mean concentrations are reported as zero if all values are BLQ, and no descriptive 
statistics are reported.  If the calculated mean (± SD) concentration is less than the 
LLOQ, the value will be reported as calculated.  The mean values derived using these 
conventions will be used to create the mean serum concentration versus time plots.

For calculation of area under the serum concentration curve (AUC), BLQ values are set 
equal to zero in the dataset loaded into WinNonlin for pharmacokinetic analysis.  
WinNonlin uses the zero values that occur before the first time point with a concentration 
greater than LLOQ, but WinNonlin excludes the zero values from AUC calculation for 
all later time points.
6.9.3
Pharmacokinetic Parameters
The pharmacokinetic analysis will be conducted by the pharmacokinetics CRO for the Clinical 
Pharmacology and Pharmacokinetics Department of Shire Pharmaceuticals using Phoenix 
WinNonlin version 6.2 or higher (Pharsight Corporation, Mountain View, California, USA).
Pharmacokinetic parameters will be determined from serum concentration-time data using 
noncompartmental methods and all calculations will be based on actual sampling times. Serum 
concentration vs. time will be plotted for each patient. Mean serum concentration vs. time curves 
will also be presented by dose (5 mg, 7.5 mg, and 10 mg) and visit (Week 4, Week 48, and Week 
100) with Week 4 and 48 assessments only made for subjects who received no IT treatment in 
HGT-HIT-094 and initiated IT treatment in this study.
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CONFIDENTIAL
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SHP609-302 Statistical Analysis Plan for Interim Analysis 
Idursulfase for Intrathecal Administration
14 Mar 2019
The pharmacokinetic parameters will include, but not be limited to, the following:

AUC0-∞- Area under the curve extrapolated to infinity, calculated using the observed
value of the last non-zero concentration

AUC0-t - Area under the curve from the time of dosing to the last measurable
concentration

Cmax - Maximum concentration occurring at tmax

tmax - Time of maximum observed concentration sampled during a dosing interval

CL/F – Total body clearance for extravascular administration divided by the fraction of
dose absorbed.

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

t½ - Terminal half-life

MRT0-∞- Mean residence time
CL/F and Vz/F will also be normalized for body weight.
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 bioanalytical method (ELISA, LC-MS/MS), dose and visit.  Serum 
and CSF concentrations of idursulfase at each nominal sampling time will also be summarized 
by bioanalytical method, dose and visit using descriptive statistics.
Protocol Amendment 3 provides the investigator with the option of administering the IV 
Elaprase infusion and idursulfase-IT on the same day during the Extended Treatment Phase. If 
same-day dosing is elected, idursulfase-IT will be administered first and the Elaprase infusion 
will be administered second. Pharmacokinetic assessments are to occur at the first study visit at 
which same-day dosing is elected. At this visit, administration of the Elaprase infusion should 
start within approximately 90 minutes of completion of idursulfase-IT administration. Note that 
on the occasion of the first same-day administration, the duration of IV Elaprase infusion is to be 
standardized to 3 hours. The pharmacokinetic assessments for the same-day dosing option will 
be analyzed and summarized separately from the days with IT-only administration.
The association of the presence of anti-idursulfase antibodies and idursulfase concentration-time 
profiles and pharmacokinetic parameters will be evaluated, if applicable.
Drug-Drug and Drug-Disease Interactions
6.10
This study was not designed to evaluate drug-drug or drug-disease interactions and therefore the 
interactions will not be assessed in the study.
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CONFIDENTIAL
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SHP609-302 Statistical Analysis Plan for Interim Analysis 
Idursulfase for Intrathecal Administration
14 Mar 2019
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSES
7.
Changes in the Conduct of the Study
7.1
Please see the amendment summaries in the SHP609-302 protocol Amendment 4.
Changes from the Analyses Planned in the Protocol
7.2
Not applicable
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CONFIDENTIAL
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SHP609-302 Statistical Analysis Plan for Interim Analysis 
Idursulfase for Intrathecal Administration
14 Mar 2019
STATISTICAL/ANALYTIC ISSUES
8.
Adjustment for Covariates
8.1
The rate of change (weighted) analysis will adjust for GCA classification factor (either ≤70 or 
>70) at the time of enrollment in SHP609-302 (i.e., Visit Month 13/Time of Enrollment in 
SHP609-302) in the weighted generalized linear model. 
Handling of Dropouts or Missing Data
8.2
No data imputation will be performed.
Interim Analyses and Data Monitoring
8.3
One interim analysis is planned when all SHP609-302 subjects complete visit Month 25/Week 
52 in SHP609-302 or discontinue. 
Patient safety data 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.
Multicenter Studies
8.4
This is a multicenter study. No subset analyses of center effect will be conducted. No adjustment 
due to multi-centers will be utilized in the analyses.
Multiple Comparisons/Multiplicity
8.5
No multiple comparison procedure or multiplicity adjustment will be performed for the 
secondary and exploratory efficacy endpoints.
Examination of Interactions
8.6
Interaction effects will not be examined for the outcome measurements due to the small sample 
size.
Sensitivity Analyses
8.7
For the exploratory ordered categorical outcome analysis sensitivity analysis will be conducted 
as described in Section 6.7.4.1.
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SHP609-302 Statistical Analysis Plan for Interim Analysis 
Idursulfase for Intrathecal Administration
14 Mar 2019
For the 12-month rate of change (weighted) analysis, the following sensitivity analyses will be 
conducted (see Section 6.7.4.1 for further details):

Subjects with only two available GCA scores, one at the beginning and one at the end of 
the 12-month period

Two shrinkage weights in the form of the James-Stein estimator 
Windowing Visits
8.8
Although there is a visit window of +/- 7 days around the expected visit date, nominal visits will 
be used for the per-visit analyses.  The data obtained outside the scheduled visits for certain 
procedures could be assigned to nominal visits, for instance, CSF GAGs or Neurodevelopment 
assessments. For subjects who withdraw from the study prematurely, if the early termination 
visit falls into the window of a scheduled visit as defined in the protocol, the early termination 
visit is also summarized for that scheduled visit, unless the scheduled visit already took place.
Data Listings
8.9
All data will be presented as SAS datasets in CDISC format.  Unless specifically stated in above 
sections, no other by-subject data listings will be provided.
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SHP609-302 Statistical Analysis Plan for Interim Analysis 
Idursulfase for Intrathecal Administration
14 Mar 2019
REFERENCES
9.
1.
Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. 
JAMA 1999;281:249-54.
2.
Young ID, Harper PS. Incidence of Hunter's syndrome. Hum Genet 1982;60:391-2.
3.
Singer, J. D., & Willett, J. B. (2003). Applied longitudinal data analysis: Modeling change 
and event occurrence. Oxford: Oxford University Press.
4.
Efron, B. & Morris, C.(1977). Stein's paradox in statistics. Scientific American 236 (5), 119-
127.
5.
Hamlett A, Ryan L, Serrano-Trespalacios P, Wolfinger R. Mixed models for assessing 
correlation in the presence of replication. Journal of the Air & Waste Management 
Association (1995) 2003;53:442-50.
For non-commercial use only


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SHP609-302 Statistical Analysis Plan for Interim Analysis 
Idursulfase for Intrathecal Administration
14 Mar 2019
APPENDICES
10.
Appendix I – List of Statistical Outputs
10.1
There is a separate document called “Table Shells” including Tables, Figures and Listings.
Appendix II – Protocol Violations Definitions
10.2
A list of possible protocol violations is given below.  A more comprehensive list will be 
constructed once the review of patient data has been completed, immediately prior to locking the 
database.
Violations

Violation of admission (inclusion/exclusion) criteria (i.e., eligibility violation) for which no 
exemption was obtained

Occurrence of a treatment dispensing error
Appendix III – Sample SAS Code 
10.3
10.3.1
Sample SAS Code for Rate of Change (Weighted) Analysis
/*Linear regression fit for individual subjects*/;
ods output  ANOVA=ANOVA ParameterEstimates=Parms;
proc reg data = subject_data ;
      model GCA = AVISITN ;
run ;
data slope;  /*calculate slope and estimated change from baseline*/;
set parms;
if variable=' AVISITN ';
            CFBL= estimate*52;  /* GCA score change from Visit Month 13/ Time of Enrollment in 
SHP609-302 to Visit Month 25/ Week 52 in SHP609-302*/;
keep usubjid variable estimate CFBL;
run;
/*If subjects have 5 non-missing visits, then n=5, calculate the sum of square (x_i-x_bar) for 
each subject, x_i is 0, 16, 28, 40 and 52. If n=4, x_i is 0, 52 and any two values from 16, 28, and 
40 depends on the missing visit. If n=3, x_i is 0, 52 and any one value from 16, 28, and 40 
depends on the missing visits.*/;
proc univariate data=subqs noprint;
   var avisitn;
   output out=parameters mean=mean;
run;
proc sql noprint;
   select mean
   into : avg_avisitn
   from parameters;
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SHP609-302 Statistical Analysis Plan for Interim Analysis 
Idursulfase for Intrathecal Administration
14 Mar 2019
quit;
data subqs;
   set subqs;
   sqavt = (avisitn - &avg_avisitn)**2;
run;
proc univariate data=subqs noprint;
   var sqavt;
   output out=parameters sum=sum;
run;
proc sql noprint;
   select sum
   into :sum_sqavt
   from parameters;
quit;
data weight; /*calculate weight=inverse of variance of change over 12-month period*/;
   set anova;
   weight = 1/((52**2) * ms/sum_sqavt);  /*mse is unbiased estimator of sigma2*/;
run;
/*Analysis 1 - weighted generalized linear model to test treatment effect in “D” */;
proc glm data=data;
class gcascatn_m13_bl; /* GCA classification factor at Visit Month 13/Baseline (either ≤70 
vs. >70)*/;
model CFBL= gcascatn_m13_bl /solution clparm alpha = 0.1;
weight weight;
       estimate 'Pooled Mean' intercept 1;
run;
/*Analysis 2 - weighted generalized linear model to test treatment effect in “B””D”  */;
proc glm data=data;
  class observation_group gcascatn_m13_bl;
  model CFBL= observation_group gcascatn_m13_bl /solution clparm alpha = 0.1 ;
  weight weight;
        estimate 'Pooled Mean' intercept 1;
        estimate 'Diff between observation group' observation_group 1 -1;
        lsmeans observation_group / stderr pdiff CL alpha = 0.1;
run;
For non-commercial use only


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CONFIDENTIAL
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SHP609-302 Statistical Analysis Plan for Interim Analysis 
Idursulfase for Intrathecal Administration
14 Mar 2019
10.3.2
Sample SAS Code for Correlation Analysis Using Repeated Measures
ods output vcorr=vcorr;
proc mixed;
class usubjid vtype replicate;
      model response = vtype / ddfm=kr;
      random vtype / type=un subject=usubjid v vcorr cl;
repeated vtype / type=un subject=replicate(usubjid) r rcorr;
run;
/*usubjid corresponds to subject number; vtype refers to the two variables assessed, which are 
coded as 1 and 2; Response corresponds to the values of the two variables; and Replicate 
corresponds to the number of repeated measurements for each subject, which need not be the 
same.*/;
10.3.3
Sample SAS Code for James-Stein/Empirical Bayes Estimator
proc univariate data=slope_data noprint;
   var rms;  /* rms = sqrt(ms) positive square root of mse*/;
   output out=parameters mean=mean;
run;
proc sql noprint;
   select mean
   into : avg_rms
   from parameters;
quit;
data weight_js;
   set slope_data;
   c=0.8;     /* using a fixed shrinkage factor c=0.8*/
   z = &avg_rms + (rms - &avg_rms) * c;   /* JS estimator of square root of mse */;
   weight_js = 1/((z**2) / sum_sqavt * (52**2));  /* JS estimator of weight */;
run;
Appendix IV – James-Stein/Empirical Bayes Estimator of Weight
10.4
The James-Stein form estimator is used to construct the shrinkage estimators of variance of GCA 
score change over a 12-month period, and then the shrinkage estimators of weights used in the 
weighted generalized linear model. The James-Stein estimator (a.k.a. empirical Bayes estimator) 
used information from all linear regressions to provide potentially better estimates of variance of 
GCA score change over a 12-month period for each linear regression.
There are three steps to construct James-Stein estimator of weight.
1. Generate James-Stein estimator of square root of mean squared error (MSE), i.e., RMSE
2. Plug the James-Stein estimator of RMSE into the variance of GCA score change over a 
12-month period, which is a function of RMSE
For non-commercial use only


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Addendum to the  
Statistical Analysis Plan for Interim Analysis 2 
Shire
Confidential
PAGE 2 OF 6 
Table of Contents 
1.
ABBREVIATIONS .................................................................................................... 3 
2.
PURPOSE OF THE STATISTICAL ANALYSIS PLAN ADDENDUM ................. 4 
3.
OBJECTIVE AND ENDPOINTS .............................................................................. 4 
3.1 
Objective ............................................................................................................. 4 
3.2 
Efficacy Endpoints .............................................................................................. 4 
4.
STATISTICAL ANALYSIS ...................................................................................... 5 
4.1 
Analysis Populations ........................................................................................... 5 
4.2 
Primary Efficacy Analysis .................................................................................. 5 
4.3 
Secondary Efficacy Analysis .............................................................................. 5 
4.4 
Subgroup Analysis .............................................................................................. 5 
4.5 
Exploratory Efficacy Analyses ........................................................................... 5 
4.6 
Health Economics and Outcomes Research Endpoint Analyses ........................ 6 
4.7 
Pharmacodynamic Outcome ............................................................................... 6 
4.8 
Analysis of Safety ............................................................................................... 6 
4.9 
Analysis of Pharmacokinetic Data ...................................................................... 6 
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Addendum to the  
Statistical Analysis Plan for Interim Analysis 2 
Shire
Confidential
PAGE 3 OF 6 
1.
ABBREVIATIONS
ERT 
enzyme replacement therapy 
IA2 
Interim analysis 2 
IV 
Intravenous 
SAP
statistical analysis plan
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Addendum to the  
Statistical Analysis Plan for Interim Analysis 2 
Shire
Confidential
PAGE 4 OF 6 
2.
PURPOSE OF THE STATISTICAL ANALYSIS PLAN
ADDENDUM
The interim analysis 2 (IA2) of study data will be conducted when all SHP609-302 
subjects complete 24 months of idursulfase-IT (SHP609) treatment from the time of 
enrollment in SHP609-302 (at visit Month 37/Month 25) or discontinue in study 
SHP609-302.  
The purpose of this statistical analysis plan (SAP) addendum for IA2 is to document the 
technical and detailed specifications for the analysis on the 24-month data of study 
SHP609-302 with cut-off date of 30th July 2019 in addition to the SAP for interim 
analysis v1.1 dated on 14 March 2019 (referred to as SHP609-302 IA SAP v1.1 
hereafter) which provided a technical and detailed elaboration of the planned interim 
analysis based on the 12-month data with cut-off date of 6th September 2018 for protocol 
SHP609-302 Amendment 4.0. 
Unless otherwise specified, the analyses in this SAP addendum will apply the same 
methodologies as specified in the SHP609-302 IA SAP v1.1 for 12-month data. Detailed 
methods for additional analyses, if not included in the SHP609-302 IA SAP v1.1, will be 
specified in this SAP addendum. 
3.
OBJECTIVE AND ENDPOINTS
3.1 
Objective 
To evaluate long-term safety in patients with Hunter syndrome and cognitive impairment 
who are receiving intrathecal idursulfase-IT (SHP609) and intravenous (IV) Elaprase® 
enzyme replacement therapy (ERT) as specified in SHP609-302 IA SAP v1.1 Section 
4.1.  
3.2 
Efficacy Endpoints 
Primary, secondary and exploratory efficacy endpoints are defined similarly to those in 
Sections 4.1 of the SHP609-302 IA SAP v1.1, where the duration will be extended by an 
additional 12 months, to a total of at least 24 months for each subject during study 
SHP609-302, with the exception that “Change over a 12-Month Period Endpoints”, 
“Ordered Categorical Outcomes (3 Categories)”, “Binary Unreversed Floor Effect 
Outcomes” (SHP609-302 IA SAP v1.1 Section 5.4.3, 5.4.4 and 5.4.5, respectively) will 
not be included in this SAP addendum because those analyses only pertain to 12-month 
data during study SHP609-302.    
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Addendum to the  
Statistical Analysis Plan for Interim Analysis 2 
Shire
Confidential
PAGE 5 OF 6 
4.
STATISTICAL ANALYSIS
4.1 
Analysis Populations 
Safety Population and Pharmacokinetic Population will be used in SHP609-302 IA2. The 
definition of the populations will be the same as in SHP609-302 IA SAP v1.1. 
Definition of analysis populations in SHP609-302 IA2 SAP Addendum 
Analysis Population 
Definition 
Intended Usage 
Safety Population 
All subjects in study SHP609-302 who underwent IDDD 
implantation or received at least 1 dose of study drug (full or partial)   
Primary safety 
population 
Pharmacokinetic 
Population 
All subjects in SHP609-302 who received study drug and 
participated in the scheduled pharmacokinetic studies, and for whom 
at least 1 post-dose PK blood sample was collected 
PK population 
4.2 
Primary Efficacy Analysis 
Not applicable.  
4.3 
Secondary Efficacy Analysis 
The same methodology as in SHP609-302 IA SAP v1.1 Section 6.7.2 will be used with 
additional data in Extended Treatment Phase included.    
4.4 
Subgroup Analysis 
The same methodology as in SHP609-302 IA SAP v1.1 Section 6.7.3 will be used with 
additional data in Extended Treatment Phase included. 
4.5 
Exploratory Efficacy Analyses 
The same methodology as in SHP609-302 IA SAP v1.1 Section 6.7.4 will be used with 
additional data in Extended Treatment Phase included.  
The following analyses will not be included in this SAP addendum: 
•
Rate of Change (Weighted) Analysis
•
Exploratory Ordered Categorical Outcome Analysis
•
Exploratory Analysis to Assess Floor Effect
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Addendum to the  
Statistical Analysis Plan for Interim Analysis 2 
Shire
Confidential
PAGE 6 OF 6 
4.6 
Health Economics and Outcomes Research Endpoint Analyses 
The same methodology as in SHP609-302 IA SAP v1.1 Section 6.7.5 will be used with 
additional data in Extended Treatment Phase included. 
4.7 
Pharmacodynamic Outcome 
The same methodology as in SHP609-302 IA SAP v1.1 Section 6.7.6 will be used with 
additional data in Extended Treatment Phase included. 
4.8 
Analysis of Safety 
The same methodology as in SHP609-302 IA SAP Section 6.8 will be used with 
additional data in Extended Treatment Phase included. 
4.9 
Analysis of Pharmacokinetic Data 
The same methodology as in SHP609-302 IA SAP Section 6.9 will be used with 
additional data in Extended Treatment Phase included.  
For non-commercial use only