A Long-Term, Open-Label, Multicenter, Phase IV Study to Assess Longitudinal Changes on Height and Weight in Patients With MPS II Who Are Receiving Elaprase and Started Treatment With Elaprase at <6 Years of Age
Phase: PHASE4
Conditions: Hunter Syndrome
Sponsor: Shire

For non-commercial use only

Clinical Trial Protocol: Study SHP-ELA-401
Study Title:
A Long-Term, Open-Label, Multicenter, Phase IV Study to Assess 
Longitudinal Changes on Height and Weight in Patients with MPS II 
Who Are Receiving Elaprase and Started Treatment with Elaprase at 
<6 Years of Age
Study Number:
SHP-ELA-401
Study Phase:
Phase IV
Product Name:
Elaprase® for intravenous (IV) infusion
IND Number:
9579
EudraCT 
Number:
2014-004804-31
Indication:
Hunter Syndrome (Mucopolysaccharidosis II, MPS II)
Investigators:
Multicenter
Sponsor:
Shire Human Genetic Therapies, Inc. (Shire)
Sponsor Contact:
300 Shire Way
Lexington, MA  02421 USA
+1-617-349-0200
Medical Monitor:
, MD
Date
Original Protocol:
11 June 2014
Amendment 1
11 November 2015
Amendment 2
05 August 2016
Confidentiality Statement
This document is the proprietary and confidential property of 
Shire, Inc.
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SYNOPSIS
Sponsor:
Shire Human Genetic Therapies, Inc. (Shire)
Name of Finished Product:
Elaprase® for intravenous (IV) infusion
Study Title:
A Long Term, Open Label, Multicenter, Phase IV Study to Assess Longitudinal Changes 
on Height and Weight in Patients with MPS II Who Are Receiving Elaprase and Started 
Treatment with Elaprase at <6 Years of Age
Study Number:  SHP-ELA-401
Study Phase: Phase IV
Product, Dose, and Mode of Administration:  Elaprase for IV infusion 
Comparator, Dose, and Mode of Administration:  Not applicable
Primary Objective(s):  
The primary objectives of this study are to assess longitudinal changes in the following 
parameters in patients with MPS II who began Elaprase treatment at <6 years of age and 
who are receiving treatment with Elaprase:
•
height
•
weight
Secondary Objective(s):
The secondary objectives of this study are to assess longitudinal changes in the following 
parameters in patients with MPS II who began Elaprase treatment at <6 years of age and 
who are receiving treatment with Elaprase:
•
urinary GAG levels (uGAG)
•
liver and spleen volume
•
joint mobility, as measured by Joint Range of Motion (JROM) scores, including
global, upper-limb, and lower-limb joint scores
•
distance walked, as measured by the 6 Minute Walk Test (6MWT)
•
quality of life, as measured by the Hunter-syndrome Functional Outcome in Clinical
Understanding Scale (HS-FOCUS) questionnaire (shortened version)
•
impact of illness on ability to function in daily life as measured by the Childhood
Health Assessment Questionnaire (CHAQ)
•
adaptive behavior as measured by the Vineland Adaptive Behavior Scales (VABS-II)
Tertiary Objective(s):
The tertiary objectives of the study are to evaluate the relationships between:
•
genotype and the following parameters:  residual plasma I2S enzyme activity, cross-
reactive immunologic material (CRIM) status, and antibody status
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•
antibody status and the following parameters:  height, weight, walking, joint mobility, 
and uGAG levels
•
genotype and the following parameters:  height, weight, walking, joint mobility, and 
uGAG levels
•
CRIM status and the following parameters: height, weight, walking, joint mobility, 
uGAG levels, liver and spleen volume
•
CRIM status and the following parameters: safety (adverse events, infusion-related 
adverse reactions [hypersensitivity reactions])
Study Outcome Measures:  
Following are the primary variables to be assessed in this study:
•
height and weight 
•
height and weight Z-scores 
•
safety assessments
Changes in the following additional variables will be assessed in this study:
•
urinary GAG levels normalized to urine creatinine
•
normalized uGAG divided by upper limit of normal for age (uGAG/ULN)
•
liver and spleen volume
•
joint mobility, as measured by Joint Range of Motion (JROM) scores, including 
global, upper-limb, and lower-limb joint scores
•
distance walked, as measured by the Six Minute Walk Test (6MWT)
•
quality of life (QoL), as measured by the Hunter-syndrome Functional Outcome in 
Clinical Understanding Scale (HS-FOCUS shortened form), including individual 
domain scores from the 5 functional domains:  walking/standing, grip/reach, 
schooling/work, activities, and breathing
•
impact of illness on ability to function in daily life, as measured by the Childhood 
Health Assessment Questionnaire (CHAQ Parent Report), including the Disability 
Index (based on 8 subscales:  dressing, hygiene, arising, eating, walking, reach, grip 
and activities), Discomfort Index and Health Status index
•
adaptive behavior, as measured by the Vineland Adaptive Behavior Scales (VABS-II):  
standardized scores for each of 4 domains:  Communication; Daily Living Skills; 
Socialization; Motor Skills; as well as the Adaptive Behavior Composite (ABC) score
•
antibody status
Study Population:  
A minimum of 20 treatment-naive patients with MPS II will be enrolled in this study. 
Additionally, patients enrolled in the Hunter Outcome Survey (HOS) registry will be 
utilized for the analyses of height and weight; approximately 35 patients are planned for 
inclusion in the Primary Growth Analysis. The patient groupings for the study are defined 
as follows:
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Group 1—Prospective Patient Group:  Treatment-naïve patients who are <6 years of 
age at the time of enrollment in this study. At least 20 patients will be enrolled into this 
patient group in this study. A patient is considered included into this patient group if 
informed consent is provided and the patient is treated with Elaprase in Study
SHP-ELA-401.
Group 2—Retrospective Patient Group:  Patients who are not enrolled into Study 
SHP-ELA-401 but are enrolled in the HOS patient registry. While not enrolled in the 
present Study SHP-ELA-401, their height and weight data from HOS will be utilized in 
the Primary Growth Analysis for this study. The data from at least 15 patients in Group 2 
will be utilized in the Primary Growth Analysis for this study. A HOS patient is 
considered included in this patient group if he meets the eligibility requirements described 
below for inclusion in the analysis.
Study Design:
Study SHP-ELA-401 is a long-term, open-label, multicenter, Phase IV study designed to 
assess longitudinal changes in height and weight in patients with MPS II who are 
receiving Elaprase and started Elaprase treatment at <6 years of age. Elaprase for IV 
infusion will be provided to patients enrolled in this study.
The study will enroll at least 20 treatment-naïve patients (Group 1—Prospective Patient 
Group); additionally, height and weight data from patients enrolled in the HOS registry 
will be utilized for the Primary Growth Analysis due to the scarcity of treatment-naïve 
patients (Group 2—Retrospective Patient Group). The Primary Growth Analysis will 
include data on approximately 35 patients with MPS II that cover either 5 years duration 
of treatment with Elaprase, or the time period from initiation of Elaprase treatment until 
the patient reaches his 10th birthday, whichever is longer for each individual patient. 
For enrolled patients (Group 1—Prospective Patient Group only), the study will flow as 
follows:
•
Screening Period:  Day -18 through Day 0
•
Baseline Visit:  Day 0 (may extend to Day 1; however, all Baseline assessments must 
be completed and eligibility confirmed prior to the patient’s first dose of Elaprase)
•
Treatment Period:  As of the first Elaprase infusion in this study until adequate data 
are obtained; specifically, until the patient reaches his 10th birthday or until the patient 
has been in the study for 5 years, whichever is longer. 
•
One Month Study Visit: Day 30 
•
Bi-Annual Study Visit:  Every 6 months
•
Annual Study Visit:  Every 12 months
•
End-of-Study Visit:  After 5 years of treatment observation data are collected or until 
the patient reaches his 10th birthday, whichever is longer.
Note that the Screening Period and Baseline visits may occur on the same day (ie, 
Screening period activities may be completed on Day 0). For all study visits, up to 
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48 hours is allowed for completion of study activities.
The study ends with the last End-of-Study Visit for the last patient.
A minimum number of 20 treatment-naive patients are targeted for enrollment into this 
study (Group 1—Prospective Patient Group). Patients may be invited for entry into the 
study based on their known medical histories or chart reviews. Patients who meet the 
initial eligibility criteria of the study and whose parent(s) and/or legally authorized 
representatives(s) have provided informed consent will be enrolled. Patients will have a 
blood sample drawn for confirmatory MPS II assay. Safety will be monitored throughout 
the study by the assessments of AEs, concomitant medications and surgical procedures, 
vital signs, physical examinations, and clinical laboratory testing (clinical chemistry, 
hematology and urinalysis). Testing for anti-idursulfase antibodies will take place at 
Baseline and every 6 months through the End-of-Study Visit. 
The study will monitor height, weight, joint mobility (measured by JROM), walking 
distance (measured by 6MWT), uGAG levels, liver and spleen volume, QoL (measured by 
HS-FOCUS shortened version), impact of illness on ability to function in daily life 
(measured by CHAQ), adaptive function (measured by VABS-II), and antibody status. 
Genotype and enzymatic activity of iduronate-2-sulfatase (I2S) will be collected at 
Baseline. Additionally, on Day 0, a blood sample for determination of cross-reactive 
immunologic material (CRIM) status will be obtained from Group 1—Prospective Patient 
Group patients for use in the development of an assay to assess CRIM status among 
patients with MPS II. An additional post-treatment sample for CRIM analysis will be 
collected at 12 months.
Study Duration:
The length of on-study follow-up for individual patients in Study SHP-ELA-401 Group 
1—Prospective Patient Group will range from 5 to 10 years, from Screening through the 
End-of-Study Visit.
Study Patient Inclusion and Exclusion Criteria:
Group 1—Prospective Patient Group patients will be enrolled in Study SHP-ELA-401; 
following are the inclusion and exclusion for admission into this study.
Group 1:  Prospective Patient Group Inclusion Criteria
Each patient must meet all inclusion criteria to be enrolled in this study.
1. The patient is male.
2. The patient is Elaprase-naïve at study entry.
3. The patient must have a documented diagnosis of MPS II. Of the 3 criteria below, the 
combinations (3a AND 3b) or (3a AND 3c) will be accepted as diagnostic of MPS II:
a.
The patient has a deficiency in I2S enzyme activity of ≤10% of the lower 
limit of the normal range as measured in plasma, fibroblasts, or leukocytes 
(based on the reference laboratory’s normal range).
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AND
b. The patient has a documented mutation in the I2S gene. 
OR
c. The patient has a normal enzyme activity level of one other sulfatase as 
measured in plasma, fibroblasts, or leukocytes (based on the normal range of 
measuring laboratory).
4. The patient will be <6 years of age at the start of Elaprase treatment.
5. The patient, patient’s parent(s) or legally authorized guardian(s) must have voluntarily 
signed an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
approved informed consent form after all relevant aspects of the study have been 
explained and discussed. Consent of the patient's parent(s) or legally authorized 
guardian(s) and the patient’s assent, as relevant, must be obtained.
Group 1:  Prospective Patient Group Exclusion Criteria
Patients who meet any of the following criteria are not eligible for enrollment into Study 
SHP-ELA-401:
1. The patient has received treatment with any investigational drug or device within the 
30 days prior to study entry. 
2. The patient has received or is receiving treatment with idursulfase-IT.
3. The patient has received growth hormones, a cord blood infusion, or a bone marrow 
transplant at any time.
4. The patient has received blood product transfusions within 90 days prior to Screening.
5. The patient is unable to comply with the protocol as determined by the Investigator.
6. The patient has a history of severe or life-threatening hypersensitivity to the active 
substance or to any of the excipients if hypersensitivity is not controllable.
Retrospective Data Inclusion and Exclusion Criteria:
Group 2—Retrospective Patient Group patients will be enrolled in HOS and not Study 
SHP-ELA-401; however, their growth data may be included in the analysis for Study 
SHP-ELA-401 if the following data inclusion and exclusion criteria are met.
Group 2:  Retrospective Patient Group Data Inclusion Criteria
Patients from Group 2—Retrospective Patient Group must meet the following criteria for 
their data to be included into the Study SHP-ELA-401 Primary Growth Analysis:
1. The patient is male. 
2. The patient is enrolled in HOS. 
3. The patient was <6 years of age at the start of Elaprase treatment. 
4. The patient received Elaprase weekly treatment for at least 5 years.
5. The patient had a height assessment and a weight assessment documented within 
3 months before or after Elaprase treatment start.
6. The patient has had annual height and weight assessments from start of Elaprase 
through age 10 years.
7. The patient, patient's parent(s), or legally authorized guardian(s) agree(s) to data 
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collection. 
8. The patient, patient’s parent(s), or legally authorized guardian(s) must have 
voluntarily signed an IRB/IEC-approved informed consent form after all relevant 
aspects of the HOS study have been explained and discussed. Consent of the patient's 
parent(s) or legally authorized guardian(s) and the patient’s assent, as relevant, must 
be obtained.
Group 2:  Retrospective Patient Group Exclusion Criteria
HOS patients that meet the following criteria are not eligible to be included into the Study 
SHP-ELA-401 Primary Growth Analysis:
1. Patient was treated with growth hormone or other medications or interventions 
intended to promote growth in the time period covered by the analysis.
Pharmacokinetic Variables:
Not applicable.
Pharmacodynamic Assessments:
Not applicable.
Outcome Assessments:
Height and Weight
Height and weight measurements over time will be used to evaluate growth velocity. 
Patient height (centimeters) and weight (kilogram) will be collected and recorded.
Joint Mobility 
Joint mobility will be evaluated and recorded utilizing the JROM, including global, 
upper-limb, and lower-limb joint scores.
Urinary GAG Levels
Urine samples for determination of uGAG levels and urine creatinine will be collected. 
Urinary GAG levels will be normalized to urine creatinine and reported as µg GAG/mg 
creatinine. Additionally, uGAG levels divided by the ULN will also be calculated. 
Liver and spleen volume
Liver and spleen volume will be assessed using abdominal ultrasonography.
Distance Walked
The 6MWT will be conducted according to the American Thoracic Society guidelines for 
the 6MWT in patients who are able to walk. The distance achieved in meters will be 
recorded. 
Analysis of Quality of Life
The patient QoL will be assessed using the HS-FOCUS (shortened version) questionnaire. 
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Childhood Health Assessment
Impact on ability to function in daily life as measured by the CHAQ (Parent Report).
Adaptive Behavior
Adaptive behavior will be measured by the parent reported VABS-II. 
Safety Assessments:
Physical and Neurological Examination
A full physical examination will be performed with a thorough review of body systems.
Physical examinations will include a review of the patient’s general appearance, 
neurological examination, as well as evaluation of the body systems. Any abnormal 
change in findings will be recorded as an adverse event (AE).
Vital Signs
Vital sign assessments will be performed and the results will be recorded. Vital signs data 
will be collected with the patient at rest and in a supine position and will include pulse, 
temperature (using a consistent method), respiration rate, and systolic and diastolic blood 
pressure. 
Clinical Laboratory Tests
Blood and urine samples will be collected for clinical laboratory testing and the results 
will be recorded. All blood samples will be collected via venipuncture. Patients will be in 
a seated or supine position during blood collection. 
Antibody Assessments
Blood samples will be collected and analyzed for determination of anti-idursulfase 
antibodies every 6 months in SHP-ELA-401. Serum samples will be collected for 
evaluation of anti-idursulfase antibodies. Analysis of anti-idursulfase antibodies will be 
conducted using validated 3-tier immunoassay methods (screening, confirmatory, and 
titer) and the anti-idursulfase antibody positive samples will be further tested for the 
presence of neutralizing antibodies (NAb). All blood samples for antibody testing will be 
collected via venipuncture or via an indwelling IV access port. Sample collection, 
processing, and shipping instructions will be provided in the Study Lab Manual to be 
provided by the central laboratory.
Statistical Methods:  
General Methodology
All continuous variables will be summarized using descriptive statistics, including the 
sample size (n), mean, standard deviation (SD), minimum, 25th percentile, median, and 
75th percentile. All categorical variables will be summarized using frequency counts and 
percentages (%). Statistical testing is considered exploratory in this study and no 
adjustment for multiplicity will be performed. 
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Analysis Populations
The following 2 analysis populations will be defined for this study:
Combined Population:  The Combined Population will include data from all patients 
in both patient groups (Group 1—Prospective Patient Group and 
Group 2-Retrospective Patient Group). Selected efficacy analyses will be performed 
using the Combined Population.
Prospective Population:  The Prospective Population will be defined as all patients in
Group 1—Prospective Patient Group. All safety analyses and selected efficacy 
analyses will be performed using the Prospective Population.
Analysis of Safety
Safety will be evaluated through the assessment of AEs, serious adverse events (SAEs) 
(including non-elective hospitalizations), antibody status, concomitant medications, 
therapies, non-elective procedures, vital signs, physical examinations, clinical laboratory 
testing. All summaries will be provided on the Prospective Population using all data from 
Baseline to completion of Study SHP-ELA-401 (ie, prospective data only). All safety 
analyses will be descriptive; no statistical testing will be performed. 
Efficacy Analyses
Descriptive summaries will generally present the data overall and by visit from Baseline 
(defined as Day 0) for the Prospective Population. Retrospective height and weight data 
from start of Elaprase ERT for Group 2—Retrospective Patient Group in the Combined
Population will be used in certain statistical model analyses and figures, as described 
below. No retrospective data will be used in analyses of other endpoints. 
Primary Outcome Measure:  Height and Weight; Z-scores
Height and weight Z-scores will be calculated based on the WHO growth charts normal 
height/weight-for-age data. Descriptive statistics for the Prospective Population at each 
time point for height, weight and Z-scores and for change from baseline will be calculated 
overall and stratified separately by age group at start of Elaprase ERT treatment (<2 years; 
≥2 years), overall antibody status, and genotype class. 
Height, weight, and the corresponding Z-scores from start of ERT will be plotted against 
age for the Combined Population. Analyses using linear mixed models with random 
intercept and slope for age will be fit to the growth data over time from the start of ERT. 
Quadratic and cubic terms for age may be added to the model if significant or necessary to 
better characterize the relationship between physical growth and age over time. Predicted 
growth curves for individuals using the patient specific intercept and slope estimates from 
the model will be plotted. The effect of factors, such as age group at start of ERT and 
genotype class on growth parameters will be explored. The Least Squares means 
(LS-means) and standard errors at various ages estimated from the model will be 
summarized and plotted by factor groups. Similar analyses will be performed on the 
Prospective Population and will assess the effect of antibody status on growth. 
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Analysis of Covariance (ANCOVA) models for the change in uGAG, 6MWT, and JROM 
scores in the Prospective Population will also be used to assess the effects of age group at 
ERT start, antibody status and genotype class. Residual plasma I2S enzyme activity 
results at Baseline will be summarized overall and by antibody status and genotype class.
Interim Analyses
Two interim analyses are planned.
Interim Analysis 1 will examine CRIM assay results with respect to patient genotype and 
I2S enzyme status. This analysis is intended to evaluate suitability of blood samples for 
CRIM testing by confirming that the CRIM status determination is consistent with patient 
genotype. Patients with severe disease presentations, eg, as a result of complete deletion 
or early truncation of I2S enzyme-coding sequence, would be expected to test CRIM-
negative. Interim Analysis 1 will be conducted once the last patient in the Prospective 
Patient Group enrolls in the study and completes baseline assessments. 
Interim Analysis 2 will examine the correlation of CRIM status to prospectively collected 
data on the antibody response, uGAG levels, liver and spleen volume, and clinical 
outcomes. This second analysis will be conducted after the last patient in the Prospective 
Patient Group completes 2-year assessments. 
Date of Amendment:  05 August 2016
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TABLE OF CONTENTS
SYNOPSIS.......................................................................................................................................2
LIST OF IN-TEXT TABLES ........................................................................................................16
LIST OF IN-TEXT FIGURES.......................................................................................................17
LIST OF APPENDICES................................................................................................................18
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................................................19
1
INTRODUCTION..................................................................................................................21
1.1
Disease Overview.....................................................................................................21
1.2
Elaprase ....................................................................................................................21
1.3
Study Overview........................................................................................................22
1.4
Benefit/Risk Assessment..........................................................................................23
1.5
Monitoring of Burden/Risk to Study Participants....................................................24
2
STUDY OBJECTIVES ..........................................................................................................25
2.1
Primary Objective(s) ................................................................................................25
2.2
Secondary Objective(s) ............................................................................................25
2.3
Tertiary Objective(s) ................................................................................................25
3
STUDY OUTCOME MEASURES........................................................................................26
4
INVESTIGATIONAL PLAN.................................................................................................27
4.1
Overall Study Design and Plan ................................................................................27
4.2
Rationale for Study Design ......................................................................................30
4.3
Study Duration .........................................................................................................30
4.4
Primary Growth Analysis.........................................................................................30
5
STUDY POPULATION SELECTION ..................................................................................31
5.1
Study SHP-ELA-401 Population:  Prospective Patients..........................................31
5.1.1
Group 1—Prospective Patient Group Population Inclusion Criteria.....................31
5.1.2
Group 1—Prospective Patient Group Population Exclusion Criteria....................31
5.2
Study SHP-ELA-401 Population:  Retrospective Patients.......................................32
5.2.1
Group 2—Retrospective Patient Group Inclusion Criteria....................................32
5.2.2
Group 2— Retrospective Patient Group Exclusion Criteria..................................32
6
STUDY TREATMENT(S).....................................................................................................33
6.1
Description of Treatment(s) .....................................................................................33
6.1.1
Study Product.........................................................................................................33
6.1.2
Comparator ............................................................................................................33
6.2
Treatment(s) Administered.......................................................................................33
6.3
Selection and Timing of Dose for Each Patient .......................................................33
6.4
Method of Assigning Patients to Treatment Groups................................................33
6.5
Blinding....................................................................................................................33
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6.6
Concomitant Medications, Therapies, and Medical/Surgical Interventions ............33
6.7
Restrictions...............................................................................................................34
6.7.1
Prior Therapy .........................................................................................................34
6.7.2
Fluid and Food Intake............................................................................................34
6.7.3
Patient Activity Restrictions ..................................................................................34
6.8
Treatment Compliance .............................................................................................34
6.9
Packaging and Labeling ...........................................................................................34
6.10
Storage and Accountability ......................................................................................34
6.10.1 Storage ...................................................................................................................34
6.10.2 Investigational Product Retention at Study Site ....................................................34
7
STUDY PROCEDURES........................................................................................................35
7.1
Informed Consent.....................................................................................................35
7.2
Study Entrance Criteria ............................................................................................35
7.3
Confirmation of Study Eligibility ............................................................................35
7.4
Demographics...........................................................................................................35
7.5
Medical History........................................................................................................35
7.6
MPS II Diagnosis and Genotyping...........................................................................36
7.7
Baseline Residual Plasma Residual I2S Enzyme Activity.......................................36
7.8
Cross-Reactive Immunologic Material Blood Samples...........................................36
7.9
Elaprase Administration...........................................................................................36
7.10
Pharmacokinetic Assessments..................................................................................36
7.11
Pharmacodynamic (or Biomarker) Assessments......................................................36
7.12
Outcome Assessments..............................................................................................36
7.12.1 Height and Weight .................................................................................................36
7.12.1.1
Height.....................................................................................................37
7.12.1.2
Weight ....................................................................................................37
7.12.2 Urinary GAG Levels..............................................................................................38
7.12.3 Liver and Spleen Volume ......................................................................................38
7.12.4 Joint Mobility.........................................................................................................38
7.12.5 Distance Walked....................................................................................................38
7.12.6 Analysis of Quality of Life ....................................................................................38
7.12.7 Daily Function .......................................................................................................38
7.12.8 Adaptive Behavior .................................................................................................38
7.13
Safety Assessments ..................................................................................................39
7.13.1 Physical and Neurological Examination................................................................39
7.13.2 Vital Signs..............................................................................................................39
7.13.3 Electrocardiography...............................................................................................39
7.13.3.1
12-Lead Electrocardiogram....................................................................39
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7.13.4 Clinical Laboratory Tests.......................................................................................39
7.13.5 Antibody Assessments...........................................................................................40
7.13.6 Pregnancy Testing..................................................................................................40
7.14
Sample Collection, Storage, and Shipping...............................................................40
7.15
Concomitant Medications, Therapies, and Medical/Surgical Interventions 
Assessments .............................................................................................................41
7.16
Confirmation of Ongoing Elaprase Treatment.........................................................41
7.17
Adverse Events Assessments ...................................................................................41
7.17.1 Definitions of Adverse Events and Serious Adverse Events.................................41
7.17.1.1
Adverse Event ........................................................................................41
7.17.1.2
Serious Adverse Event ...........................................................................42
7.17.1.3
Infusion-Related Adverse Reaction .......................................................42
7.17.2 Classification of Adverse Events and Serious Adverse Events.............................42
7.17.2.1
Clarification between Serious and Severe..............................................43
7.17.3 Procedures for Recording and Reporting Adverse Events ....................................43
7.17.3.1
Adverse Event Monitoring and Period of Observation..........................43
7.17.3.2
Reporting Serious Adverse Events.........................................................43
7.18
Pregnancy.................................................................................................................44
7.19
Abuse, Overdose, and Medication Error..................................................................45
7.20
Removal of Patients from the Trial..........................................................................45
7.21
Other Study Procedures............................................................................................45
7.21.1 Management of Infusion-Related Adverse Events ................................................45
7.21.2 Safety-Related Study Stopping Rules....................................................................46
7.22
Appropriateness of Measurements...........................................................................47
8
STUDY ACTIVITIES............................................................................................................48
8.1
Screening Period (Days -18 to Day 0) .....................................................................48
8.2
Baseline Visit (Day 0)..............................................................................................48
8.3
Treatment Period (Day 1 [or Day 2] to End-of-Study Visit) ...................................49
8.3.1
One Month Visit (Day 30, ±7 days).......................................................................49
8.3.2
Bi-Annual Visits (Every 6 months, ±14 days).......................................................49
8.3.3
Annual Visits (Every 12 months, ±14 days)..........................................................50
8.4
End-of-Study Visit (±14 days) .................................................................................50
9
QUALITY CONTROL AND ASSURANCE ........................................................................52
10 STATISTICAL ANALYSIS ..................................................................................................53
10.1
General Methodology...............................................................................................53
10.2
Determination of Sample Size..................................................................................53
10.3
Analysis Populations................................................................................................53
10.4
Patient Disposition ...................................................................................................53
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10.5
Demographics and Baseline Characteristics ............................................................53
10.6
Elaprase ERT Exposure ...........................................................................................54
10.7
Analysis of Safety ....................................................................................................54
10.7.1 Adverse Events ......................................................................................................54
10.7.2 Immunogenicity.....................................................................................................54
10.7.3 Clinical Laboratory Evaluations ............................................................................54
10.7.4 Vital Signs..............................................................................................................55
10.7.5 Physical Findings...................................................................................................55
10.7.6 Antibody Assessments...........................................................................................55
10.7.7 Concomitant Medications/Therapies .....................................................................55
10.8
Pharmacodynamic and Efficacy Analyses ...............................................................56
10.8.1 Growth Parameters:  Height and Weight...............................................................56
10.8.2 Joint Range of Motion (JROM).............................................................................56
10.8.3 Urinary GAG Levels..............................................................................................58
10.8.4 Liver Volume.........................................................................................................58
10.8.5 Spleen Volume.......................................................................................................59
10.8.6 Distance Walked via Six Minute Walk Test (6MWT) ..........................................59
10.8.7 Analysis of Quality of Life ....................................................................................59
10.8.8 Analysis of Daily Function....................................................................................60
10.8.9 Analysis of Adaptive Behavior..............................................................................61
10.8.10
Analyses of the Relationship between Genotype Class, Residual 
Plasma I2S Enzyme Activity, and Antibody Status...............................................61
10.9
Statistical/Analytical Issues......................................................................................61
10.9.1 Adjustment for Covariates.....................................................................................61
10.9.2 Handling of Drop-outs or Missing Data ................................................................61
10.9.3 Interim Analyses ....................................................................................................61
10.9.4 Multiple Comparisons/Multiplicity .......................................................................62
10.9.5 Sensitivity Analyses...............................................................................................62
11 ADMINISTRATIVE CONSIDERATIONS ..........................................................................63
11.1
Investigators and Study Administrative Structure ...................................................63
11.2
Institutional Review Board or Independent Ethics Committee Approval................63
11.3
Ethical Conduct of the Study ...................................................................................63
11.4
Patient Information and Consent..............................................................................63
11.5
Patient Confidentiality..............................................................................................64
11.6
Study Monitoring .....................................................................................................64
11.7
Case Report Forms and Study Records....................................................................65
11.7.1 Critical Documents ................................................................................................65
11.8
Data Monitoring Committee ....................................................................................65
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11.9
Protocol Violations/Deviations ................................................................................66
11.10
Premature Closure of the Study ...............................................................................66
11.11
Access to Source Documentation.............................................................................66
11.12
Data Generation and Analysis..................................................................................67
11.13
Retention of Data .....................................................................................................67
11.14
Financial Disclosure.................................................................................................67
11.15
Publication and Disclosure Policy............................................................................67
12 LIST OF REFERENCES........................................................................................................69
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LIST OF IN-TEXT TABLES
Table 7-1
Assessments for Physical Examinations .......................................................39
Table 7-2
List of Laboratory Tests ................................................................................39
Table 7-3
Adverse Event Severity.................................................................................42
Table 7-4
Adverse Event Relatedness ...........................................................................43
Table 10-1
Study SHP-ELA-401 Overview of Joints/Motions with Normal Values 
and Clinically Meaningful Changes ..............................................................57
Table 10-2
Upper Limit of Normal for uGAG by Age Ranges.......................................58
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LIST OF IN-TEXT FIGURES
Figure 4-1
Study SHP-ELA-401 Study Flow .................................................................29
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LIST OF APPENDICES
Appendix 1
Group 1—Prospective Patient Group Study Schedule of Events..................71
Appendix 2
Group 2—Retrospective Patient Group Data to be Utilized in Study 
SHP-ELA-401 Final Analysis .......................................................................73
Appendix 3
Protocol Amendment Summary of Changes .................................................74
Appendix 4
Protocol Signature Page ................................................................................83
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Term
Definition
6MWT
six minute walk test
AAOS
American Association of Orthopedic Surgeons
ABC
adaptive behavior composite
AE
adverse event
AMA
American Medical Association
ANCOVA
analysis of covariance
CBC 
complete blood count
CFR
Code of Federal Regulations
CHAQ
Childhood Health Assessment Questionnaire
CNS
central nervous system
CRF
case report form
CRIM
cross-reactive immunologic material
CRO
contract research organization
DNA
deoxyribonucleic
ERT
enzyme replacement therapy
EU
European Union
FDA
United States Food and Drug Administration
GAG
glycosaminoglycans
GCP
Good Clinical Practice
HOS
Hunter Outcome Survey
HRSA
US Health Resources and Services Administration 
HS-FOCUS
Hunter-syndrome Functional Outcome in Clinical Understanding Scale
I2S
iduronate-2-sulfatase
ICH
International Conference on Harmonization
IDS
gene encoding iduronate 2-sulfatase
IEC
independent ethics committee
IND
investigational new drug application
IRB
institutional review board
IV
intravenous(ly)
JROM
joint range of motion
LS-means
least squares means
M6P
mannose-6-phosphate
MedDRA
medical dictionary for regulatory activity 
MPS II
Mucopolysaccharidosis II (Hunter syndrome)
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Term
Definition
PT
preferred term
QoL
quality of life
SAE
serious adverse event
SAS
statistical analysis system©
sBLA
Supplemental Biologics License Application
SD
standard deviation
SOC
system organ class
TEAE
treatment-emergent adverse event
uGAG
urinary glycosaminoglycans
UK
United Kingdom
ULN
Upper limit of normal
US(A)
United States of America
VABS-II
Vineland Adaptive Behavior Scales, Second Edition
WHO-DD
World Health Organization Drug Dictionary
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1
INTRODUCTION
1.1
Disease Overview
Hunter syndrome (Mucopolysaccharidosis II, [MPS II]) is a rare, X-linked lysosomal storage 
disease caused by deficiency of the enzyme, iduronate-2-sulfatase (I2S), which acts to cleave 
O-linked sulfate moieties from 2 glycosaminoglycan (GAG) molecules known as dermatan 
sulfate and heparan sulfate.1, 2 Insufficient levels of I2S lead to excessive accumulation of GAGs 
within lysosomes in nearly all organs and tissues, including the central nervous system (CNS), 
with progressive cellular vacuolization and cell death, urinary excretion of GAGs at high levels, 
and the clinical manifestations of MPS II.2, 3 The currently approved therapy for MPS II is 
intravenous (IV) idursulfase (Elaprase®), a recombinant human I2S for IV administration. 
The incidence rate of MPS II reported from several countries around the world is similar, ranging 
between 0.6 and 2.0 per 100,000 male births.1, 4-9 Although the disease is heterogeneous with 
regard to initial presentation, MPS II is always severe, progressive, and life-limiting, despite the 
use of available therapies.
The central, underlying pathophysiological process leading to the clinical manifestations of 
MPS II is the chronic accumulation of heparan sulfate and dermatan sulfate inside cellular 
lysosomes, resulting in cellular engorgement, organomegaly, tissue destruction, and organ 
system dysfunction. Accumulation of these GAG species 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 CNS. Children with MPS II appear normal at birth. The 
clinical manifestations of MPS II vary considerably from patient to patient with pathology in 
1 organ system presenting the most prominent clinical problem in some patients and impairment 
in other organ systems presenting the biggest challenge in others. 
In the latter stages of the disease, continued accumulation of GAG leads to progressive 
end-organ failure and significantly shortened life span. Although the range of progressive 
physical abnormalities severely curtails the MPS II patient’s quality of life (QoL), approximately 
60% of patients with MPS II also develop global intellectual decline and severe developmental 
delays. Death usually occurs in the second or third decade of life, most often from respiratory 
and/or cardiac failure.2, 10
1.2
Elaprase
Elaprase is a formulation of idursulfase, a purified recombinant form of human I2S, a lysosomal 
enzyme, to be administered weekly as an IV infusion. Idursulfase is produced by recombinant 
deoxyribonucleic (DNA) technology in a human cell line. Idursulfase is an enzyme that 
hydrolyzes the 2-sulfate esters of terminal iduronate sulfate residues from the GAGs dermatan 
sulfate and heparan sulfate in the lysosomes of various cell types. Elaprase is a monomeric 
glycoprotein that is secreted as a 525 amino acid polypeptide having 8 N-linked glycosylation 
sites. Elaprase contains mannose-6-phosphate (M6P) residues that target the enzyme to its site of 
action in the lysosome. The M6P moiety binds to specific M6P receptors in the Golgi and thus 
directs newly synthesized I2S to pre-lysosomal compartments. Enzyme molecules that escape 
this routing system are secreted by the cell, and are often recaptured by cell surface M6P 
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receptors and return I2S to the lysosome by the endocytic pathway.11 Enzyme replacement 
therapy (ERT) with Elaprase in patients with MPS II has been demonstrated to be safe and 
efficacious in clinical studies. 
Elaprase (idursulfase) was approved in the United States (US) on 24 July 2006 and in the 
European Union (EU) on 10 January 2007. Since that time, Elaprase has been approved in 
58 countries and is the only available ERT treatment for MPS II, except for South Korea, where 
Hunterase (idursulfase-beta) is approved. The recommended dose is 0.5 mg of Elaprase per 
kilogram of body weight (0.5 mg/kg).
Please refer to the current edition of the Investigator’s Brochure for further information 
concerning the safety and clinical development of Elaprase.
1.3
Study Overview
This long-term, open-label, multicenter, Phase IV study is proposed to study longitudinal 
changes in height and weight in patients with MPS II who are receiving Elaprase and started 
treatment with Elaprase at <6 years of age. Elaprase for IV infusion will be provided to patients 
enrolled in this study. 
The purpose of Study SHP-ELA-401 is to obtain and evaluate data for patients who initiated and 
continued treatment with Elaprase at <6 years of age. Patients in this study will be followed for a 
minimum of 5 years after initiation of Elaprase treatment, or until their 10th birthday, whichever 
is longer. This study will evaluate various clinical outcome measures. Genotype and enzymatic 
activity of I2S will be collected at Baseline. 
The study will enroll at least 20 treatment-naïve patients and the length of on-study follow-up for 
individual patients in Study SHP-ELA-401 will range from 5 to 10 years, from Screening 
through the End-of-Study. Additionally, due to the scarcity of treatment-naïve patients, height 
and weight data from patients enrolled in the Hunter Outcome Survey (HOS) registry will be 
utilized for the Primary Growth Analysis. 
The Primary Growth Analysis will include data on approximately 35 patients with MPS II that 
cover either 5 years duration of treatment with Elaprase, or the time period from initiation of 
Elaprase treatment until the patient reaches his 10th birthday, whichever is longer for each 
individual patient. The combination of Group 1—Prospective Patient Group data (obtained from 
patients during their participation in the present Study SHP-ELA-401) with Group 2—
Retrospective Patient Group data (obtained from patients during their participation in the HOS 
study) allows for sufficient data to meet the Primary Growth Analysis goals. See Section 4.4 for 
more details on this Primary Growth Analysis.
An additional purpose of Study SHP-ELA-401 is to obtain blood samples from patients to 
determine their cross-reactive immunologic material (CRIM) status, and to correlate CRIM 
status with outcomes data, including anti-idursulfase antibody development, pharmacodynamic 
responses, and clinical outcomes. If a patient’s sample reacts with antibodies against I2S, it is 
concluded that the sample contained this enzyme, and the patient is considered CRIM-positive. If 
a patient’s sample does not react with antibodies against I2S, the patient is considered CRIM-
negative. 
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In the context of MPS II and other lysosomal storage diseases, this means that patients who 
produce some endogenous enzyme, albeit in much reduced quantities or with abnormal amino 
acid sequence, will be CRIM-positive. From a molecular genetic standpoint, this would be 
expected to be the case in patients whose IDS gene mutations include missense mutations, late 
truncations, and late frameshifts. CRIM-negativity, on the other hand, would be expected to be 
seen in patients who produce no enzyme at all; specifically, in patients with complete deletions 
of the IDS gene or mutations resulting in early truncations and frameshifts.
CRIM status has been shown to be a useful predictor of outcomes and immune response to 
enzyme replacement therapy in patients with Pompe disease; CRIM-negative status is associated 
with poorer clinical outcomes in these patients.16 It is unknown whether this is also true for 
patients with MPS II and other diseases being treated with ERT. 
1.4
Benefit/Risk Assessment
In total, 135 individual treatment-naïve male patients have been enrolled and treated with 
Elaprase in completed clinical studies. These patients were representative of the general MPS II 
population as shown by a broad spectrum of disease manifestations. A detailed summary of the 
safety and efficacy of Elaprase is provided in the current edition of the Investigator’s Brochure. 
Across all clinical studies, Elaprase was safe and generally well tolerated. As with other enzyme-
replacement therapies, some patients treated with Elaprase did experience infusion-related
reactions. The infusion-related reactions were generally mild, well tolerated, and treated or 
ameliorated by slowing the infusion rate, interrupting infusion, or by administration of 
medications, such as antihistamines, antipyretics, low-dose corticosteroids or beta-agonist 
nebulization. The most commonly reported infusion-related adverse events included cutaneous 
reactions (rash, pruritus, and urticaria), headache, pyrexia, hypertension, and flushing. 
Additionally, some patients exposed to Elaprase in clinical studies have developed anti-
idursulfase antibodies. Analyses of the immunogenicity reports found no association or increased 
safety risk with the type or magnitude of the immune response to Elaprase, and there have been 
no instances of IgE-associated anaphylaxis. No clinically important changes in laboratory 
profiles, vital signs, or electrocardiogram (ECG) were observed in any of the clinical studies.
Elaprase efficacy is based on results of the pivotal study (TKT024) and several supportive 
studies (TKT008, TKT018, TKT024EXT, and HGT-ELA-038). The greatest benefit observed in 
the pivotal study was one of increased endurance as measured by clinically and statistically 
significant improvements (compared with placebo) in distance walked during the 6-Minute Walk 
Test, as well as clinically relevant improvements in respiratory function as measured by the 
percent predicted and absolute forced vital capacity. Other benefits of Elaprase treatment have 
been demonstrated by statistically and clinically significant reductions in liver and spleen 
volumes and urine glycosaminoglycan levels, as well as clinically significant improvements in 
cardiac function as measured by reductions in left ventricular mass. Improvements in patients’ 
quality of life were also observed after 1 year of treatment in the pivotal study. In a post-hoc 
analysis of immunogenicity, pharmacodynamic and clinical effects of Elaprase treatment were 
observed regardless of the patient’s antibody status.
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Overall, the benefits obtained from Elaprase therapy outweigh the risks, which are, at this point, 
well characterized in clinical studies and in real-life settings. Safety risks related to 
infusion-related reactions are manageable. The cumulative safety data for Elaprase from 
post-marketing sources complements and is consistent with the experience from the clinical 
development program. 
1.5
Monitoring of Burden/Risk to Study Participants
The current study (SHP-ELA-401) is designed to assess longitudinal changes in height and 
weight in patients with MPS II who are receiving Elaprase and who initiated therapy with 
Elaprase below the age of 6 years. The study will cover either 5 years duration of treatment with 
Elaprase, or the time period from initiation of Elaprase treatment until the patient reaches his 10th
birthday, whichever is longer. 
Elaprase will be administered to patients enrolled in this study by trained healthcare providers, 
either in a clinical setting or, if applicable, in an at-home setting. Patients will receive once 
weekly IV infusions of Elaprase at a dose of 0.5 mg/kg; the dose and frequency of Elaprase 
infusions is the same treatment regimen that patients would follow as standard of care per 
approved labeling. The study visits are relatively infrequent (bi-annually after completion of 
Screening/Baseline visits) and up to 48 hours is permitted at each study visit for completion of 
study activities which, in addition to height and weight measurements, include assessments of 
efficacy and quality of life, and standard safety parameters (refer to Appendix 1). The study 
assessments were selected as being minimally invasive and feasible in the patient population, and 
the schedule is typical of that performed in clinical practice for patients receiving Elaprase 
therapy. Permitting the completion of scheduled assessments over 48 hours further reduces the 
burden of study participation for patients. The degree of burden and risk to patients participating 
in this study is, therefore, considered to be low. There is no added burden or risk beyond that 
which patients would expect as standard of care, and no change in burden or risk to participants 
is expected over the duration of the study.
As noted, patients treated with Elaprase may develop infusion-related reactions. In general, such 
reactions are well controlled (refer to Section 7.21.1), and no patient discontinued treatment due 
to an infusion-related reaction during clinical studies of Elaprase. Likewise, potential risk 
associated with severe hypersensitivity reactions should be continually monitored; in particular, 
Elaprase is contraindicated in patients with severe or life-threatening hypersensitivity to the 
active substance or to any of the excipients if hypersensitivity is not controllable (refer to Section 
5.1.2 Group 1—Prospective Patient Group Population Exclusion Criteria). Finally, any serious 
adverse event (SAE) experienced by a patient during the study should be monitored for and be 
reported by the Investigator to the Sponsor (refer to Section 7.17.3), who should apply his/her 
clinical judgment as to whether the reported event alters the threshold of acceptable risk beyond 
that which is expected with Elaprase treatment.
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2
STUDY OBJECTIVES
2.1
Primary Objective(s) 
The primary objectives of this study are to assess longitudinal changes in the following 
parameters in patients with MPS II who began Elaprase treatment at <6 years of age and who are 
receiving treatment with Elaprase:
•
height 
•
weight
2.2
Secondary Objective(s) 
The secondary objectives of this study are to assess longitudinal changes in the following 
parameters in patients with MPS II who began Elaprase treatment at <6 years of age and who are 
receiving treatment with Elaprase:
•
urinary GAG levels 
•
liver and spleen volume
•
joint mobility, as measured by Joint Range of Motion (JROM) scores, including global, 
upper-limb, and lower-limb joint scores 
•
distance walked, as measured by the 6 Minute Walk Test (6MWT)
•
quality of life, as measured by the Hunter-syndrome Functional Outcome in Clinical 
Understanding Scale (HS-FOCUS) questionnaire (shortened version) 
•
impact of illness on ability to function in daily life, as measured by the Childhood Health 
Assessment Questionnaire (CHAQ) 
•
adaptive behavior as measured by the Vineland Adaptive Behavior Scales (VABS-II) 
2.3
Tertiary Objective(s)
The tertiary objectives of the study are to evaluate the relationships between:
•
genotype and the following parameters:  residual plasma I2S enzyme activity, CRIM status, 
and antibody status 
•
antibody status and the following parameters:  height, weight, walking, joint mobility, and 
uGAG levels
•
genotype and the following parameters:  height, weight, walking, joint mobility, and uGAG 
levels
•
CRIM status and the following parameters: height, weight, walking, joint mobility, uGAG 
levels, liver and spleen volume
•
CRIM status and the following parameters: safety (adverse events, infusion-related adverse 
reactions [hypersensitivity reactions])
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3
STUDY OUTCOME MEASURES
Following are the primary variables to be assessed in this study:
•
height and weight 
•
height and weight Z-scores 
•
safety assessments
Changes in the following additional variables will be assessed in this study:
•
urinary GAG levels normalized to urine creatinine
•
normalized uGAG divided by upper limit of normal for age (uGAG/ULN)
•
liver and spleen volume
•
joint mobility, as measured by JROM scores, including global, upper-limb, and lower-limb 
joint scores
•
distance walked, as measured by the 6MWT
•
quality of life, as measured by the HS-FOCUS (shortened version), including individual 
domain scores from the 5 functional domains:  walking/standing, grip/reach, schooling/work, 
activities, and breathing
•
impact of illness on ability to function in daily life, as measured by the CHAQ Parent Report, 
including the Disability Index (based on 8 subscales:  dressing, hygiene, arising, eating, 
walking, reach, grip and activities), Discomfort Index and Health Status index
•
adaptive behavior, as measured by the VABS- II:  standardized scores for each of 4 domains:  
Communication; Daily Living Skills; Socialization; Motor Skills; as well as the Adaptive 
Behavior Composite (ABC) score
•
antibody status
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4
INVESTIGATIONAL PLAN
4.1
Overall Study Design and Plan
Study SHP-ELA-401 is a long-term, open-label, multicenter, Phase IV study proposed to study 
the longitudinal changes in height and weight in patients with MPS II who are receiving 
treatment with Elaprase and started Elaprase treatment at <6 years of age. Elaprase for IV 
infusion will be provided to patients enrolled in this study. 
The purpose of Study SHP-ELA-401 is to obtain and evaluate data for patients who initiated 
Elaprase at <6 years of age and continued treatment with Elaprase. Patients enrolled in this study 
will be followed for a minimum of 5 years after initiation of Elaprase treatment, or until they 
reach their 10th birthday, whichever is longer. This study will evaluate various clinical outcome 
measures. 
Study SHP-ELA-401 will enroll at least 20 treatment-naïve patients and the length of on-study 
follow-up for individual patients in Study SHP-ELA-401 will range from 5 to 10 years, from 
Screening through the End-of-Study. Additionally, due to the scarcity of treatment-naïve 
patients, height and weight data from patients enrolled in the HOS registry will be utilized for the 
Primary Growth Analysis (see Section 4.4 for a description of HOS). 
As described in Section 4.4, the Primary Growth Analysis will include data on approximately 35 
patients with MPS II that cover either 5 years duration of treatment with Elaprase, or the time 
period from initiation of Elaprase treatment until the patient reaches his 10th birthday, whichever 
is longer for each individual patient. The combination of prospective data (obtained from patients 
during their participation in the present Study SHP-ELA-401) with retrospective data (obtained 
from patients during their participation in the HOS study) allows for sufficient data to meet the 
Primary Growth Analysis goals. 
The patient groups are defined as follows:
Group 1—Prospective Patient Group:  Treatment-naïve patients who are <6 years of age at the 
time of enrollment in this study. At least 20 patients will be enrolled into this patient group in 
this study. A patient is considered included into this patient group if informed consent is 
provided and the patient is treated with Elaprase in Study SHP-ELA-401.
Group 2—Retrospective Patient Group:  Patients who are not enrolled into Study 
SHP-ELA-401 but are enrolled in the HOS patient registry. While not enrolled in the present 
Study SHP-ELA-401, their height and weight data from HOS will be utilized in the Primary 
Growth Analysis for this study. A HOS patient is considered included in this patient group if he 
meets the eligibility requirements described below for inclusion in the analysis.
For enrolled patients (Group 1—Prospective Patient Group only), the study will flow as follows:
•
Screening Period:  Day -18 through Day 0
•
Baseline Visit:  Day 0 (may extend to Day 1; however, all Baseline assessments must be 
completed and eligibility confirmed prior to the patient’s first dose of Elaprase)
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•
Treatment Period:  As of the first Elaprase infusion in this study until adequate data are 
obtained; specifically, until the patient reaches his 10th birthday or until the patient has been 
in the study for 5 years, whichever is longer. 
•
One Month Study Visit: Day 30
•
Bi-Annual Study Visit:  Every 6 months
•
Annual Study Visit:  Every 12 months
•
End-of-Study Visit:  After 5 years of treatment observation data are collected or until the 
patient reaches his 10th birthday, whichever is longer.
Note that the Screening Period and Baseline visits may occur on the same day (ie, Screening 
period activities may be completed on Day 0). For all study visits, up to 48 hours is allowed for 
completion of study activities.
A minimum number of 20 treatment-naive patients are targeted for enrollment into this study 
(Group 1—Prospective Patient Group). Patients may be invited for entry into the study based on 
their known medical histories or chart reviews. Patients who meet the initial eligibility criteria of 
the study and whose parent(s) and/or legally authorized representatives(s) have provided 
informed consent will be enrolled. Patients will have a blood sample drawn for confirmatory 
MPS II assay. Safety will be monitored throughout the study by the assessments of AEs, 
concomitant medications and surgical procedures, vital signs, physical examinations, and clinical 
laboratory testing (clinical chemistry, hematology and urinalysis). Testing for anti-idursulfase 
antibodies will take place at Baseline and every 6 months through the End-of-Study Visit. 
The study will monitor height, weight, joint mobility (measured by JROM), walking distance 
(measured by 6MWT), uGAG levels, liver and spleen volume, QoL (measured by HS-FOCUS 
shortened version), impact of illness on ability to function in daily life (measured by CHAQ), 
adaptive function (measured by VABS-II), and antibody status. Genotype and enzymatic activity 
of I2S will be collected at Baseline. Additionally, on Day 0, a blood sample for determination of 
cross-reactive immunologic material (CRIM) status will be obtained from Group 1—Prospective 
Patient Group patients only. An additional post-treatment sample for CRIM analysis will be 
collected at 12 months.
See Figure 4-1 for an overview of the study design and Appendix 1 for the Study Schedule of 
Events Table.
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4.2
Rationale for Study Design 
This study is designed to evaluate growth in patients with MPS II who initiate treatment with 
Elaprase at <6 years of age. All patients enrolled in this study will receive once-weekly IV 
infusions of Elaprase at a dose of 0.5 mg/kg and will be followed for a minimum of 5 years after 
initiation of Elaprase treatment, or until they reach their 10th birthday, whichever is longer. 
As described in Section 7, this study will monitor various clinical outcome assessments, with a 
focus on those that assess growth. Additionally, genotype and enzymatic activity of I2S will be 
collected at Baseline and antibody status will be assessed every 6 months. Blood samples will be 
obtained from patients to determine their CRIM status and to correlate the CRIM status with 
outcomes data. Assessments were selected because they are minimally invasive and are feasible. 
No comparator group is planned. 
4.3
Study Duration
The length of on-study follow-up for individual patients enrolled in Study SHP-ELA-401 will 
range from 5 to 10 years, from Screening through the End-of-Study Visit, since the intention of 
Study SHP-ELA-401 is to obtain and evaluate data for patients who initiated treatment with 
Elaprase at <6 years of age, for a duration of 5 years from initiation of Elaprase treatment or until 
the patient reaches their 10th birthday, whichever is longer. 
4.4
Primary Growth Analysis
To observe longitudinal changes in as many patients as possible with this rare disease, 
retrospective data will be utilized from the HOS registry for the Primary Growth Analysis; these 
patients are referred to in this protocol as Group 2—Retrospective Patient Group. 
The HOS is a long-term, voluntary, observational registry open to all patients with MPS II. This 
registry was developed in conjunction with leading global experts on lysosomal storage disorders 
in general and patients with MPS II in particular to gain a better understanding of the nature of 
the disease, to improve the clinical management of patients affected by MPS II, and to monitor 
the long-term safety and effectiveness of Elaprase in real life.
To be utilized in the Primary Growth Analysis, Group 2—Retrospective Patient Group patient 
data will be used from patients who started treatment with Elaprase at <6 years of age, continued 
treatment with Elaprase for at least 5 years, have height and weight assessments within 3 months 
of the time of start of Elaprase treatment, and will have had annual height and weight 
measurements at the time of data extraction from HOS. See Appendix 2 for a schedule of data to 
be included in the Primary Growth Analysis.
As described in Section 10.3, there will be 2 analysis populations in this study. The Combined
Population is the only analysis population that will utilize both Group 1 and Group 2 patient 
data. The final clinical study report for Study SHP-ELA-401 will also evaluate the Primary 
Growth Analysis results in comparison to existing data about growth in patients with MPS II not 
treated with Elaprase. Potential sources include cross-sectional data in HOS, published literature, 
and any other relevant data available at the time of the development of the final clinical study 
report. 
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5
STUDY POPULATION SELECTION
Study SHP-ELA-401 will enroll at least 20 treatment-naïve patients with MPS II who initiate 
treatment with Elaprase at <6 years of age; these enrolled patients are referred to as Group 1—
Prospective Patient Group. 
Additionally, due to the scarcity of treatment-naïve patients, height and weight data from at least 
15 patients enrolled in the HOS registry will be utilized for the primary growth analyses for 
Study SHP-ELA-401. Therefore, the criteria for inclusion and exclusion of the patient height and 
weight data into the study analyses are described below. These patients are referred to as 
Group-2 Retrospective Patients.
5.1
Study SHP-ELA-401 Population:  Prospective Patients 
Study SHP-ELA-401 will enroll treatment-naïve patients who are <6 years of age at the time of 
enrollment in this study. At least 20 patients will be enrolled into this study. Following are the 
inclusion and exclusion criteria for enrollment into this study.
5.1.1
Group 1—Prospective Patient Group Population Inclusion Criteria
Patients must meet ALL of the inclusion criteria for his group in order to enroll in the trial.
1. The patient is male.
2. The patient is Elaprase-naïve at study entry.
3. The patient must have a documented diagnosis of MPS II. Of the 3 criteria below, the 
combinations (3a AND 3b) or (3a AND 3c) will be accepted as diagnostic of MPS II:
a.
The patient has a deficiency in I2S enzyme activity of ≤10% of the lower limit of 
the normal range as measured in plasma, fibroblasts, or leukocytes (based on the 
reference laboratory’s normal range).
AND
b. The patient has a documented mutation in the I2S gene. 
OR
c. The patient has a normal enzyme activity level of one other sulfatase as measured 
in plasma, fibroblasts, or leukocytes (based on the normal range of measuring 
laboratory).
4. The patient will be <6 years of age at the start of Elaprase treatment.
5. The patient, patient’s parent(s) or legally authorized guardian(s) must have voluntarily signed 
an Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved 
informed consent form after all relevant aspects of the study have been explained and 
discussed. Consent of the patient's parent(s) or legally authorized guardian(s) and the 
patient’s assent, as relevant, must be obtained.
5.1.2
Group 1—Prospective Patient Group Population Exclusion Criteria
Patients who meet any of the following criteria are not eligible for enrollment into this study.
1. The patient has received treatment with any investigational drug or device within the 30 days 
prior to study entry. 
2. The patient has received or is receiving treatment with idursulfase-IT.
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3. The patient has received growth hormones, a cord blood infusion, or a bone marrow 
transplant at any time.
4. The patient has received blood product transfusions within 90 days prior to Screening.
5. The patient is unable to comply with the protocol as determined by the Investigator.
6. The patient has a history of severe or life-threatening hypersensitivity to the active substance 
or to any of the excipients if hypersensitivity is not controllable.
5.2
Study SHP-ELA-401 Population:  Retrospective Patients
Data from at least 15 patients who are not enrolled into Study SHP-ELA-401 but are enrolled in 
the HOS patient registry will be utilized in the Primary Growth Analysis for Study 
SHP-ELA-401. For their height and weight data to be utilized in the Primary Growth Analysis
for Study SHP-ELA-401, the patient data from HOS must meet the following inclusion and 
exclusion criteria.
5.2.1
Group 2—Retrospective Patient Group Inclusion Criteria
The Retrospective HOS patient data must meet ALL of the following criteria to be included into 
the Study SHP-ELA-401 analysis:
1. The patient is male. 
2. The patient is enrolled in HOS. 
3. The patient was <6 years of age at the start of Elaprase treatment. 
4. The patient received Elaprase 0.5 mg/kg IV weekly treatment for at least 5 years.
5. The patient had a height assessment and a weight assessment documented within 3 months 
before or after Elaprase treatment start.
6. The patient has had annual height and weight assessments from start of Elaprase through age 
10 years.
7. The patient, patient's parent(s), or legally authorized guardian(s) agree(s) to data collection. 
8. The patient, patient’s parent(s), or legally authorized guardian(s) must have voluntarily 
signed an IRB/IEC-approved informed consent form after all relevant aspects of the HOS 
study have been explained and discussed. Consent of the patient's parent(s) or legally 
authorized guardian(s) and the patient’s assent, as relevant, must be obtained.
5.2.2
Group 2— Retrospective Patient Group Exclusion Criteria
HOS patients that meet the following criteria are not eligible to be included into the Study 
SHP-ELA-401 Primary Growth Analysis:
1. Patient was treated with growth hormone or other medications or interventions intended to 
promote growth in the time period covered by the analysis.
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6
STUDY TREATMENT(S)
This is an open-label study. All enrolled patients will receive once-weekly IV infusions of 
Elaprase at a dose of 0.5 mg/kg.
Note that the entirety of Section 6 only applies to enrolled patients, Group 1—Prospective 
Patient Group. 
6.1
Description of Treatment(s)
6.1.1
Study Product
After informed consent is signed, all patients who meet the eligibility requirements will be 
enrolled. Enrolled patients will receive their first infusion at Week 1. Thereafter, each enrolled 
patient will receive 1 infusion of Elaprase every week, until which point each individual patient 
completes the study. See Section 4.3 for the duration of the study for each patient.
6.1.2
Comparator
Not applicable.
6.2
Treatment(s) Administered
The dose of Elaprase administered will be calculated based on the patient’s weight at each visit. 
Details on Elaprase storage, preparation, and administration procedures are provided in the
Pharmacy Manual. Refer to country-specific prescribing information for details concerning 
commercially sourced drug.
6.3
Selection and Timing of Dose for Each Patient
All enrolled patients will receive once-weekly IV infusions of Elaprase at a dose of 0.5 mg/kg.
6.4
Method of Assigning Patients to Treatment Groups
Not applicable.
6.5
Blinding
Not applicable.
6.6
Concomitant Medications, Therapies, and Medical/Surgical Interventions
All non-protocol treatments that occur from the time of informed consent through follow-up are 
regarded as concomitant and must be documented. These include medications, therapies and/or 
interventions administered to, and medical/surgical procedures performed on the study patients.
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6.7
Restrictions
6.7.1
Prior Therapy
Please see Section 5.1.2 Exclusion Criteria.
6.7.2
Fluid and Food Intake 
Not applicable.
6.7.3
Patient Activity Restrictions
Patients are restricted from enrolling in another clinical study that involves clinical investigations 
or use of any investigational product (drug or device) within 30 days prior to study enrollment or 
at any time during the study.
6.8
Treatment Compliance
All enrolled patients will receive once weekly treatment with Elaprase under the oversight of the 
Investigator. Elaprase treatment will be administered in a clinical setting or may be administered 
in the patient’s home (with Sponsor approval) after the patient has completed at least 6 months of 
treatment in a hospital setting by appropriately trained and skilled healthcare providers (nurses or 
physicians) with knowledge of the patient’s drug regimen; therefore, full patient compliance with 
treatment is anticipated in this study. The home healthcare provider will record details of 
infusions administered at the patient’s home to ensure treatment compliance and document any 
AEs.
6.9
Packaging and Labeling
All packaging and labeling will be in accordance with applicable regulatory requirements.
6.10
Storage and Accountability
6.10.1
Storage
See the Pharmacy Manual, or approved labeling, as applicable, for details on product storage.
6.10.2
Investigational Product Retention at Study Site
See the Pharmacy Manual for details on product accountability.
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7
STUDY PROCEDURES
Detailed descriptions of evaluations for enrolled patients (Group 1 only) required for this 
protocol are described in this section. These evaluations will be performed during the indicated 
days and weeks of the study (see Schedule of Events Table in Appendix 1). 
All data collected are to be recorded on the appropriate case report form (CRF, paper or 
electronic).
Details for study procedures, including sample collection, are described in the Study Lab 
Manual.
Note that the entirety of Section 7 only applies to enrolled patients, Group 1-Prospective Patient 
Group. 
7.1
Informed Consent
Prior to conducting any study-related procedures, written informed consent must be obtained 
from the patient’s parent(s) or legally authorized representative(s) and assent from the patient (if 
applicable).
The nature, scope, and possible consequences, including risks and benefits, of the study will be 
explained to the patient, the patient’s parent(s), or the patient’s legally authorized 
representative(s) by the Investigator or designee in accordance with the guidelines described in 
Section 11.4. Documentation and filing of informed consent documents should be completed 
according to Section 11.4.
7.2
Study Entrance Criteria
At Screening, each patient will be reviewed for eligibility against the study entrance criteria. 
Patients who do not meet the study entrance criteria will not be allowed to participate in the 
study. The reason(s) for the patient’s ineligibility for the study will be documented.
7.3
Confirmation of Study Eligibility
Patient eligibility according to the study inclusion and exclusion criteria will be confirmed at 
Baseline on the basis of review of the study entrance criteria.
7.4
Demographics
Patient demographic information including gender, age, ethnicity, and race will be collected. 
7.5
Medical History
Medical history will include a review of body systems, documentation of current and prior 
medical procedures, documentation of current concomitant medication usage, documentation of 
the patient’s diagnosis of MPS II.
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7.6
MPS II Diagnosis and Genotyping
Documentation of the diagnosis of MPS II will be collected and is an inclusion criterion for 
enrollment in this study; see Section 5.1.1 for information on acceptable documentation of 
diagnosis of MPS II.
The study will collect genotype information on all patients, to be analyzed by Greenwood 
Medical Laboratory. Patients who have a documented genotype from Greenwood Medical 
Laboratory do not have to have their genotype confirmed. 
The Medical Monitor will review patient genotypes and adjust enrollment, if necessary, to ensure 
representation in the study of patients with a variety of IDS mutations, eg, including patients with 
mutations, such as complete gene deletions or early truncations/frameshifts, which abolish I2S 
expression.
7.7
Baseline Residual Plasma Residual I2S Enzyme Activity
Residual plasma I2S enzyme activity will be collected for enrolled patients prior to the first 
exposure to Elaprase. 
7.8
Cross-Reactive Immunologic Material Blood Samples
Blood samples will be collected for determination of CRIM status and the results will be utilized 
in the analyses. Sample collection, processing, and shipping instructions will be provided in the 
Study Lab Manual.
7.9
Elaprase Administration
Idursulfase will be administered as a continuous IV infusion over a minimum of 3 hours at a 
dose of 0.5 mg/kg. Details on Elaprase administration procedures are provided in the Pharmacy 
Manual. 
Refer to country-specific prescribing information for details concerning administration of 
commercially sourced drug.
7.10
Pharmacokinetic Assessments
Not Applicable.
7.11
Pharmacodynamic (or Biomarker) Assessments
Not Applicable.
7.12
Outcome Assessments
7.12.1
Height and Weight
Height and weight measurements over time will be collected and recorded for all patients. The 
following guidance should be used to obtain height and weight measurements. The procedures 
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are based on the training module available from the US Health Services and Resources 
Administration (HRSA).
7.12.1.1
Height 
•
For patients ≥2 years of age, or for patients who can stand on their own: height should be 
measured using a stadiometer which is calibrated at regular intervals. Two independent 
height measurements should be collected and the results recorded to the nearest 
0.1 centimeter. If the measurements do not agree within 0.5 centimeter, re-measure for a third 
time. The method of collecting height measurements should be standardized across all sites 
(eg, instruction to stand looking straight ahead with the chin parallel to the floor, arms by the 
sides of the trunk with palms facing the thighs, and back of the head, scapulae, buttocks, and 
heels positioned against the vertical backboards of the stadiometer; no shoes or hats are to be 
worn during measurements).
•
For patients <2 years of age, or patients who cannot stand on their own: length should be 
measured using a fixed headboard. Two individuals should conduct the measurement; 
1 person positioning the child and the other collecting the length measurement. Two 
independent length measurements should be collected and the results recorded to the nearest 
0.1 centimeter. If the measurements do not agree within 1 centimeter, re-measure for a third 
time. The method of collecting length measurements should be standardized across all sites 
(eg, placement of the child supine on the measuring board, checking that the child lies
straight on the board and does not change position, shoulders touching the board; spine 
should not be arched. The child’s legs are held down with one hand, applying gentle pressure 
to the knees to straighten the legs without causing injury, while the footboard is moved to a 
position against the child’s feet with the other hand. The soles of the feet should be flat 
against the board with toes pointing upwards).
7.12.1.2
Weight
Weight measurements should be obtained from scales that have been calibrated at regular 
intervals. 
•
For patients ≥2 years of age, or who can stand on their own: weight measurements should be 
collected with the child standing, without assistance, on a calibrated beam balance or 
electronic scale. Two independent weight measurements should be collected and the results 
recorded to the nearest 0.1 kilogram. If the measurements do not agree within 0.3 kilogram, 
re-measure for a third time. The method of collecting weight measurements should be 
standardized across all sites (eg, weight to be collected with the child standing on the center 
of the scale and wearing only lightweight undergarments or a gown).
•
For patients less than <2 years of age, or patients who cannot stand on their own: weight 
measurements should be collected using an infant scale. Two independent weight 
measurements should be collected and the results recorded to the nearest 0.1 kilogram. If the 
measurements do not agree within 0.3 kilogram, re-measure for a third time. The method of 
collecting weight measurements should be standardized across all sites (eg, the child is nude 
or wearing a clean, dry diaper and positioned in the center of the scale tray).
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7.12.2
Urinary GAG Levels
Urine samples for determination of uGAG levels and urine creatinine will be collected.
Urinary GAG levels will be normalized to urine creatinine and reported as mg GAG/ mmol 
creatinine. Additionally, uGAG levels divided by the ULN will be calculated (See Section 
10.8.3). 
Sample collection, processing, and shipping instructions will be described in the Study Lab 
Manual to be provided by the central laboratory.
In the event that a baseline urine sample is unable to be collected successfully, a historical value 
may be used if deemed acceptable by the Sponsor.
7.12.3
Liver and Spleen Volume
Liver and spleen volume will be measured by abdominal ultrasonography. Ultrasound image 
collection, preparation, and transfer procedures will be provided to clinical sites. Patients may 
require sedation or anesthesia for this procedure in accordance with local clinical practice and 
should be recorded appropriately as concomitant medications.
Due to the timing of Protocol Amendment 2, some patients may have enrolled in the study prior 
to the implementation of liver and spleen volume assessments. In these cases, missed 
assessments will not be considered as protocol deviations. Ultrasound imaging should still be 
performed when indicated per protocol, despite the fact that baseline and other visit data points 
may be missing for some patients.
7.12.4
Joint Mobility 
Joint mobility will be evaluated and recorded utilizing the JROM; specifically, global, 
upper-limb, and lower-limb joint scores.
7.12.5
Distance Walked
The 6MWT will be conducted according to the American Thoracic Society guidelines for the 
6MWT for patients who are able to walk. The distance achieved in meters will be recorded. 
7.12.6
Analysis of Quality of Life
Quality of life will be assessed using the HS-FOCUS (shortened version) questionnaire. 
7.12.7
Daily Function
Determination of how illness impacts ability to function in daily life will be assessed using the 
CHAQ.
7.12.8
Adaptive Behavior
Adaptive behavior will be assessed using the VABS-II.
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7.13
Safety Assessments
7.13.1
Physical and Neurological Examination
A full physical examination will be performed with a thorough review of body systems.
Physical examinations will include a review of the patient’s general appearance, neurological 
examination, as well as evaluation of the following body systems (See Table 7-1). Any abnormal 
change in findings will be recorded as an adverse event (AE).
Table 7-1
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
7.13.2
Vital Signs
Vital sign assessments will be performed and the results will be recorded. Vital signs data will be 
collected with the patient at rest and in a supine position and will include pulse, temperature 
(using a consistent method), respiration rate, and systolic and diastolic blood pressure.
7.13.3
Electrocardiography
Not applicable.
7.13.3.1
12-Lead Electrocardiogram
Not applicable.
7.13.4
Clinical Laboratory Tests
Blood and urine samples will be collected as described in this section for clinical laboratory 
testing and recorded. All blood samples will be collected via venipuncture. Patients will be in a 
seated or supine position during blood collection. Laboratory tests will include the following (see 
Table 7-2):
Table 7-2
List of Laboratory Tests
Hematology:
•
Platelet count
•
Complete blood count (CBC) count with 
differential 
Serum Chemistry:
•
Alanine aminotransferase
•
Albumin
•
Alkaline phosphatase
•
Aspartate aminotransferase
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Table 7-2
List of Laboratory Tests
Urinalysis:  
•
Macroscopic evaluation
•
Microscopic evaluation 
•
pH
•
Bicarbonate
•
Chloride
•
Cholesterol
•
Creatine phosphokinase
•
Creatinine
•
Gamma-Glutamyl Transferase
•
Glucose
•
Lactate dehydrogenase
•
Magnesium
•
Phosphorous
•
Potassium (K)
•
Sodium
•
Total and direct bilirubin
•
Total calcium
•
Total carbon dioxide
•
Total protein
•
Triglycerides
•
Urea nitrogen
•
Uric acid
7.13.5
Antibody Assessments
Blood samples will be collected and analyzed for determination of anti-idursulfase antibodies.
Serum samples will be collected for evaluation of anti-idursulfase antibodies. Analysis of 
anti-idursulfase antibodies will be conducted using validated 3-tier immunoassay methods 
(screening, confirmatory, and titer) and the anti-idursulfase antibody positive samples will be 
further tested for the presence of neutralizing antibodies (NAb).
All blood samples for antibody testing will be collected via venipuncture or via an indwelling IV 
access port. Sample collection, processing, and shipping instructions will be provided in the 
Study Lab Manual to be provided by the central laboratory.
7.13.6
Pregnancy Testing
Not applicable.
7.14
Sample Collection, Storage, and Shipping
Sample collection, processing, and shipping instructions will be provided in the Study Lab
Manual.
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7.15
Concomitant Medications, Therapies, and Medical/Surgical Interventions 
Assessments
All medications, therapies/interventions administered to and medical/surgical procedures 
performed on the study patients from the time of informed consent through the follow-up contact 
are regarded as concomitant and will be recorded. 
7.16
Confirmation of Ongoing Elaprase Treatment
Confirmation of ongoing weekly treatment with Elaprase will be recorded.
7.17
Adverse Events Assessments
Adverse events will be collected at weekly Elaprase infusions and at each study visit for enrolled 
patients (Group 1—Prospective Patient Group only). Instructions for recording and reporting 
AEs are provided in Section 7.17.3.
7.17.1
Definitions of Adverse Events and Serious Adverse Events
7.17.1.1
Adverse Event
An AE is any noxious, pathologic, or unintended change in anatomical, physiologic, or 
metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in 
any phase of a clinical study, whether or not considered product-related. This includes an 
exacerbation of a pre-existing condition. 
Adverse events include:
•
Worsening (change in nature, severity, or frequency) of conditions present at the onset of the 
study
•
Intercurrent illnesses
•
Drug interactions
•
Events related to or possibly related to concomitant medications
•
Abnormal laboratory values (this includes significant shifts from Baseline within the range of 
normal that the Investigator considers to be clinically important)
•
Clinically significant abnormalities in physical examination, vital signs, and weight
The Investigator must record all AEs on the AE CRF, regardless of the severity or relationship to 
product. The Investigator should treat patients with AEs appropriately and observe them at 
suitable intervals until the events stabilize or resolve. Adverse events may be discovered through 
observation or examination of the patient, questioning of the patient, complaint by the patient, or 
by abnormal clinical laboratory values.
In addition, AEs may also include laboratory values that become significantly out-of-range. In 
the event of an out-of-range value, the laboratory test should be repeated until it returns to 
normal or can be explained and the patient’s safety is not at risk.
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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 AEs and must be documented as such in the CRF.
7.17.1.2
Serious Adverse Event
An SAE is any AE that results in any of the following outcomes:
•
Death
•
Is life-threatening
•
Requires hospitalization
•
Requires prolongation of existing hospitalization
•
A persistent or significant disability or incapacity 
•
A congenital anomaly or birth defect
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the patient and may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. A life-threatening AE is defined as an AE that placed the 
patient, in the view of the initial reporter, at immediate risk of death from the AE as it occurred 
(ie, it does not include an AE that, had it occurred in a more severe form, might have caused 
death).
7.17.1.3
Infusion-Related Adverse Reaction
An infusion-related adverse reaction (hypersensitivity reaction) will be defined as an AE that 1) 
occurs on the day of the infusion, ie, within 24 hours following the infusion, 2) begins either 
during or after the infusion, and 3) is judged as possibly or probably related to idursulfase 
infusion.
7.17.2
Classification of Adverse Events and Serious Adverse Events
The severity of AEs will be assessed by the Investigator based on the definitions shown in Table 
7-3. The severity of all AEs/SAEs should be recorded on the appropriate CRF page as mild, 
moderate, or severe.
Table 7-3
Adverse Event Severity
Severity
Definition
Mild
No limitation of usual activities.
Moderate
Some limitation of usual activities.
Severe
Inability to carry out usual activities.
Relationship of an adverse event or serious adverse event to the Elaprase is to be determined by
the Investigator based on the following definitions:
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Table 7-4
Adverse Event Relatedness
Relationship to 
Product(s)
Definition
Not Related
Unrelated to investigational product.
Possibly 
Related
A clinical event or laboratory abnormality with a reasonable time sequence to 
administration of investigational product, 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, 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, follows a known or suspected response pattern to the 
investigational product, is confirmed by improvement upon stopping the investigational 
product (de-challenge), and reappears upon repeated exposure (re-challenge). Note that 
this is not to be construed as requiring re-exposure of the patient to investigational 
product; however, the determination of definitely related can only be used when 
recurrence of event is observed.
7.17.2.1
Clarification between Serious and Severe
The term “severe” is often used to describe the intensity (severity) of a specific event (as in mild, 
moderate, or severe myocardial infarction); however, the event itself may be of relatively minor 
medical significance (such as severe headache). This is not the same as “serious,” which is based 
on the outcome or action criteria usually associated with events that pose a threat to life or 
functioning. Seriousness (not severity) and causality serve as a guide for defining regulatory 
reporting obligations.
7.17.3
Procedures for Recording and Reporting Adverse Events
7.17.3.1
Adverse Event Monitoring and Period of Observation
Adverse events will be monitored at weekly Elaprase infusions and at each study visit under the 
oversight of the Investigator.
For the purposes of this study, the period of observation extends from the time at which the 
patient, the patient’s parent(s), or the patient’s legally authorized representative(s) gives 
informed consent until the patient’s final evaluation of the study. For safety purposes, the final 
evaluation will be defined as the End-of-Study Visit.
If the Investigator considers it necessary to report an AE in a study patient after the end of the 
safety observation period, he or she should contact the Sponsor to determine how the AE should 
be documented and reported.
7.17.3.2
Reporting Serious Adverse Events
Any SAE that occurs in a patient after informed consent should be recorded by the clinical site 
on an SAE form. The SAE must be completely described on the patient’s CRF. The Investigator 
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7.19
Abuse, Overdose, and Medication Error
•
Abuse – Persistent or sporadic intentional intake of investigational medicinal product at a 
dose higher than prescribed per protocol (but below the dose defined for overdose) or when 
used for non-medical purpose (eg, altering one’s state of consciousness)
•
Misuse – Intentional or unintentional use of investigational medicinal product other than as 
directed or indicated at any dose, which is at or below the dose defined for overdose (Note:  
This includes a situation where the test article is not used as directed at the dose prescribed 
by the protocol)
•
Overdose – Intentional or unintentional intake of a dose of investigational medicinal product 
higher than the approved dose.
•
Medication Error – A mistake made in prescribing, dispensing, administration and/or use of 
the investigational medicinal product.
All investigational medicinal product provided to pediatrics should be supervised by the 
parent/legally-authorized representative/caregiver.
7.20
Removal of Patients from the Trial
A patient’s participation in the study may be discontinued at any time at the discretion of the 
Investigator. The following may be justifiable reasons for the Investigator to remove a patient 
from the study:
•
Non-compliance, including failure to appear at 1 or more study visits
•
The patient was erroneously included in the study
•
The patient develops an exclusion criterion 
•
The patient suffers an intolerable AE
•
The study is terminated by the Sponsor
The patient, the patient’s parent(s), or the patient’s legally authorized representative(s) acting on 
behalf of the patient is free to withdraw consent and discontinue participation in the study at any 
time without prejudice to further treatment.
If a patient, the patient’s parent(s), or the patient’s legally authorized representative(s) acting on 
behalf of the patient, discontinues participation in the study, or the patient is discontinued by the 
Investigator, reasonable efforts will be made to follow the patient through the end-of-study 
assessments. The reason for refusal will be documented. Any AEs experienced up to the point of 
discontinuation must be recorded. If AEs are present when the patient withdraws from the study, 
the patient will be re-evaluated within 30 days of withdrawal. All ongoing SAEs at the time of 
withdrawal will be followed until resolution.
7.21
Other Study Procedures
7.21.1
Management of Infusion-Related Adverse Events
If a patient develops an infusion-related AE during the infusion, the investigator should decide, 
based on his or her clinical judgment, whether the infusion should be discontinued or not. If the 
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nature and severity of the event requires termination of the infusion, clinical assessment should 
be focused on the determination of whether or not the reaction may be an IgE-mediated process.
If the event is clearly anaphylaxis, then subcutaneous epinephrine should be used. 
An initial study drug infusion causing a severe infusion-related AE should not be restarted.
Patients experiencing a mild infusion-related AE may be premedicated with an anti-pyretic 
and/or an antihistamine (eg, with diphenhydramine) for subsequent infusions. Patients 
experiencing a moderate or severe infusion-related AE may be premedicated with both an 
antihistamine and corticosteroid (eg, with diphenhydramine and hydrocortisone) in addition to 
acetaminophen for subsequent infusions. Premedication with ranitidine (in conjunction with 
hydrocortisone as a protective agent for the intestinal mucosa) may also be considered. If 
subsequent infusions continue without incident, then tapering of medications may also be 
considered.
An anaphylactoid or hypersensitivity reaction may have occurred when any two of the following 
criteria are observed after exposure to idursulfase:
•
Involvement of the skin-mucosal tissue (eg, generalized hives, rash, pruritus, flushing, 
erythema, urticaria, facial edema, swollen lips-tongue-uvula)
•
Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow, hypoxemia [defined as O2 saturation below 88% during the infusion AND 
with corresponding O2 saturation at least above 91% prior to infusion], respiratory, failure, or 
insufficiency, respiratory distress, cyanosis)
•
Reduced blood pressure (systolic blood pressure less than 80 recorded during an infusion 
AND at least 20 points lower than the systolic blood pressure recorded prior to infusion) or 
associated symptoms (eg, hypotonia [collapse], syncope).
For suspected, severe or recurrent hypersensitivity reactions, an anti-idursulfase antibody sample 
should be drawn no sooner than 12 hours after completion of the infusion and no later than 
24 hours after the end of the infusion. A second anti-idursulfase antibody specimen should be 
obtained 1 week (±24 hours) after the hypersensitivity reaction and PRIOR to the next weekly 
idursulfase infusion. 
7.21.2
Safety-Related Study Stopping Rules
This study will be stopped and safety data reviewed if any patient experiences a life-threatening 
SAE or a death occurs, if either is considered possibly or probably related to the product. 
Following the review of safety data, the study will be either:
•
Resumed unchanged
•
Resumed with modifications to the protocol 
•
Terminated
Patient safety will be monitored on a continuous basis during this study until the last patient 
completes his or her last scheduled study visit/assessment. 
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7.22
Appropriateness of Measurements
The measurements utilized in this study are standard, widely used, and generally recognized as 
reliable, accurate, and relevant to the study purpose of studying the longitudinal changes in 
height and weight in patients with MPS II who are receiving treatment with Elaprase and started 
Elaprase treatment at <6 years of age. Patient CRIM status will be determined using a validated 
I2S CRIM assay.17
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8
STUDY ACTIVITIES
Following are all activities to occur for all enrolled patients (Group 1—Prospective Patient 
Group only) within the present study. Please see Appendix 1 for the Schedule of Events and 
Figure 4-1 for the Study Flowchart. 
Note that the entirety of Section 8 only applies to enrolled patients, Group 1—Prospective 
Patient Group. 
8.1
Screening Period (Days -18 to Day 0)
The following procedures and observations* will be performed up to 18 days prior to enrollment:
•
Study informed consent
•
Confirmation of eligibility
•
Demographic information
•
Medical history
•
Physical and neurological examination
•
Concomitant medications, therapies, and procedures
•
Adverse events
*The Screening and Baseline visits may be combined in a single visit.
8.2
Baseline Visit (Day 0)
The following procedures and observations* will be performed on Day 0:
•
Blood sample for CRIM assay**
•
Blood sample for MPS II confirmatory assay 
•
Blood sample for genotype (Patients who have a documented genotype from Greenwood 
Medical Laboratory do not have to have their genotype confirmed.)
•
Blood sample for residual plasma I2S enzyme activity 
•
Blood sample for clinical laboratory tests
•
Blood sample for anti-idursulfase antibody testing
•
Height 
•
Weight
•
Vital signs
•
Collection of urine sample for GAG levels***
•
Ultrasonography of liver****
•
Ultrasonography of spleen****
•
Quality of life (HS-FOCUS shortened version)
•
Joint mobility (JROM upper and lower limbs)
•
Distance walked (6MWT)
•
Childhood health assessment (CHAQ)
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•
Adaptive behavior (VABS-II)
•
Concomitant medications, therapies, and procedures
•
Adverse events
•
Elaprase administration:  First dose of Elaprase to be administered within 1 week of baseline 
assessments and only after all previous assessments have been completed.
*The Screening and Baseline visits may be combined in a single visit. Baseline may last up to 
48 hours (Day 0, Day 1).
8.3
Treatment Period (Day 1 [or Day 2] to End-of-Study Visit)
Elaprase will be administered weekly throughout the study. Details on administration procedures 
are provided in the Pharmacy Manual; refer to country-specific prescribing information for 
details concerning administration of commercially sourced drug. 
Elaprase treatment will be administered under the oversight of the Investigator in a clinical 
setting or may be administered in the patient’s home (with Sponsor approval) after the patient 
has completed at least 6 months of treatment in a hospital setting by appropriately trained and 
skilled healthcare providers (nurses or physicians) with knowledge of the patient’s drug regimen.
8.3.1
One Month Visit (Day 30, ±7 days)
The following procedures and observations will be performed at 1 month, calculated from Day 0:
•
Collection of urine sample for GAG levels***
•
Ultrasonography of liver****
•
Ultrasonography of spleen****
•
Concomitant medications, therapies, and procedures
•
Confirmation of Elaprase administration compliance between visits
•
Adverse events
8.3.2
Bi-Annual Visits (Every 6 months, ±14 days)
The following procedures and observations will be performed every 6 months, calculated from 
Day 0:
•
Height 
•
Weight
•
Blood sample collection for anti-idursulfase antibody testing
•
Collection of urine sample for GAG levels***
•
Ultrasonography of liver****
•
Ultrasonography of spleen****
•
Concomitant medications, therapies, and procedures
•
Confirmation of Elaprase administration compliance between visits
•
Adverse events
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8.3.3
Annual Visits (Every 12 months, ±14 days)
The following procedures and observations will be performed every 12 months, calculated from 
Day 0:
•
Physical and neurological examination
•
Height 
•
Weight
•
Vital signs
•
Blood sample collection for clinical laboratory tests
•
Blood sample for CRIM assay**
•
Collection of urine sample for GAG levels***
•
Ultrasonography of liver****
•
Ultrasonography of spleen****
•
Blood samples collection for anti-idursulfase antibody testing
•
Quality of life (HS-FOCUS shortened version)
•
Joint mobility (JROM upper and lower limbs)
•
Distance walked (6MWT)
•
Childhood health assessment (CHAQ)
•
Adaptive behavior (VABS-II)
•
Concomitant medications, therapies, and procedures
•
Confirmation of Elaprase administration compliance between visits
•
Adverse events
8.4
End-of-Study Visit (±14 days)
The following procedures and observations will be performed at the End-of-Study Visit:
•
Physical and neurological examination
•
Height
•
Weight
•
Vital signs
•
Blood sample collection for clinical laboratory tests
•
Collection of urine sample for GAG levels***
•
Ultrasonography of liver****
•
Ultrasonography of spleen****
•
Blood sample collection for anti-idursulfase antibody testing
•
Quality of life (HS-FOCUS shortened version)
•
Joint mobility (JROM upper and lower limbs)
•
Distance walked (6MWT)
•
Childhood health assessment (CHAQ)
•
Adaptive behavior (VABS-II)
•
Concomitant medications, therapies, and procedures
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•
Confirmation of Elaprase administration compliance between visits
•
Adverse events
Notes
*The Screening Period and Baseline visits may occur on the same day (ie, Screening period 
activities may be completed on Day 0). For all study visits, up to 48 hours is allowed for 
completion of study activities.
**Blood sample collection for the CRIM assay is planned at Baseline and at the 12-Month Study 
Visit. 
***The uGAG assessment is planned at the Baseline, 1-Month, 6-Month, and 12-Month Study 
Visits, and annually thereafter until the End-of-Study Visit. In the event that a baseline urine 
sample is unable to be collected successfully, a historical value may be used if deemed 
acceptable by the Sponsor.
****Liver and spleen ultrasound assessments are planned at the Baseline, 1-Month, 6-Month, 12-
Month, and 24-Month Study Visits, and at the End-of-Study Visit. Due to the timing of Protocol 
Amendment 2, some patients may have enrolled in the study prior to the implementation of liver 
and spleen volume assessments. In these cases, missed assessments will not be considered as 
protocol deviations. Ultrasound imaging should still be performed when indicated per protocol, 
despite the fact that baseline and other visit data points may be missing for some patients.
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9
QUALITY CONTROL AND ASSURANCE
For all study activities that occur within Study SHP-ELA-401 (and not pertaining to HOS data 
collection), 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 Shire or its designee to ensure the accuracy of data against 
source documents. The required data will be captured in a validated clinical data management 
system that is compliant with the Food and Drug Administration (FDA) 21 Code of Federal 
Regulations (CFR) Part 11 Guidance. The clinical trial database will include an audit trail to 
document any evidence of data processing or activity on each data field by each user. Users will 
be trained and given restricted access, based on their role(s) in the study, through a 
password-protected environment.
Data entered in the system will be reviewed manually for validity and completeness against the 
source documents by a clinical monitor from the Sponsor or its designee. If necessary, the study 
site will be contacted for corrections or clarifications; all missing data will be accounted for.
Serious adverse event information captured in the clinical trial database will be reconciled with 
the information captured in the Pharmacovigilance and Risk Management database.
Note that this section only applies to enrolled patients, Group 1—Prospective Patient Group. 
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10
STATISTICAL ANALYSIS
10.1
General Methodology
All statistical analysis will be performed by Shire Biometrics Department using statistical 
analysis system (SAS) software Version 9.3 or higher (SAS Institute, Cary, NC, USA). All 
continuous variables will be summarized using descriptive statistics, including the sample size 
(n), mean, standard deviation (SD), minimum, 25th percentile, median, and 75th percentile. All 
categorical variables will be summarized using frequency counts and percentages (%). Statistical 
testing is considered exploratory in this observational study and no adjustment for multiplicity 
will be performed. 
10.2
Determination of Sample Size
The proposed sample size of at least 20 patients for Group 1—Prospective Patient Group 
represents a number that is feasible to enroll and was determined outside of statistical 
considerations. Patients who withdraw from the study prior to study completion (dropouts) will 
not be replaced. A total sample size of approximately 35 patients is expected for analysis from 
the combination of Group 1—Prospective Patient Group and Group 2—Retrospective Patient 
Group.
10.3
Analysis Populations
The following 2 analysis populations will be defined for this study:
Combined Population:  The Combined Population will include data from all patients in 
both patient groups (Group 1—Prospective Patient Group and Group 2—Retrospective 
Patient Group). Selected efficacy analyses will be performed using the Combined Population.
Prospective Population:  The Prospective Population will be defined as all patients in 
Group 1—Prospective Patient Group. All safety analyses and selected efficacy analyses will 
be performed using the Prospective Population.
10.4
Patient Disposition
The number of patients who were enrolled in Study SHP-ELA-401 and completed the study, the 
number of patients who discontinued the study (and the reason for discontinuation), and the 
number of patients in each patient group and analysis population will be summarized.
10.5
Demographics and Baseline Characteristics
Patient characteristics at the start of Elaprase treatment will be summarized for the Combined 
Population, overall, and by patient group. Continuous variables such as age, weight, and height 
will be summarized using descriptive statistics. Categorical variables, such as age group at start 
of Elaprase ERT (<2 years; ≥2 years) and genotype will be summarized using counts and 
percentages.
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10.6
Elaprase ERT Exposure
The total duration of Elaprase ERT exposure for all patients will be summarized for the 
Combined Population, overall and by patient group.
10.7
Analysis of Safety
Safety will be evaluated through the assessment of AEs, SAEs (including non-elective 
hospitalizations), antibody status, concomitant medications, therapies, non-elective procedures, 
vital signs, physical examinations, clinical laboratory testing. All summaries will be provided on 
the Prospective Population using all data from Study SHP-ELA-401 Baseline to study 
completion. All safety analyses will be descriptive; no statistical testing will be performed.
10.7.1
Adverse Events
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA)
Version 16.0 or higher. Adverse events and SAEs will be summarized according to the Medical 
Dictionary for Regulatory Activities System Organ Class (SOC) and Preferred Term (PT). The 
number and percentage of patients reporting each PT and SOC will be tabulated globally and by 
genotype, baseline CRIM status, and antibody status. A patient experiencing the same AE 
multiple times will only be counted once for the corresponding PT. Similarly, if a patient 
experiences multiple AEs within the same SOC, that patient will be counted only once for that 
SOC. Adverse events will be presented in alphabetical order by SOC. 
Hypersensitivity reactions, treatment-emergent adverse events (TEAEs), and SAEs will each be 
analyzed by baseline CRIM status for both time to first event and number and percentage of 
patients experiencing AEs by SOC and PT. Kaplan-Meier plots of time to first event will be 
graphed by baseline CRIM status and the groups will be compared using the log-rank test.  A 
time-varying proportional hazards (Cox) model will also be used to assess the relationship 
between baseline CRIM status and AEs.
10.7.2
Immunogenicity
The number and percentage of patients who became antibody positive (Ab+) overall (at any time 
during the study) will be tabulated, and the proportion of patients ever developing a positive 
result during the study will be compared between the CRIM-positive and CRIM-negative 
patients using a two-sided Fisher’s Exact test. Additionally, Kaplan-Meier plots for time to 
becoming Ab+ will be provided by baseline CRIM status. The time to first event by CRIM status 
groups will be tested using a log-rank test. A similar analysis may be conducted for PAb+, NAb+ 
and PNAb+ responses. Additionally, immunoglobulin G (IgG) antibody titer at each visit will be 
summarized by baseline CRIM status.
10.7.3
Clinical Laboratory Evaluations
Laboratory values (eg, chemistries, hematology, etc) will be summarized in terms of the absolute 
value and change from baseline at each time point. The number and percentage of patients with 
any clinically significant post-Baseline laboratory result will be presented. 
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10.7.4
Vital Signs 
Vital signs (temperature [C], pulse [bpm], blood pressure [systolic and diastolic, mmHg], 
respiration [per minute], and oxygen saturation [%]) will be summarized by study time point. 
10.7.5
Physical Findings
Abnormal physical examination findings will be recorded and summarized as part of the medical 
history or AE data.
10.7.6
Antibody Assessments
Anti-idursulfase antibody formation will be monitored at Study SHP-ELA 401 Baseline and 
throughout the study. The number and percentage of patients testing anti-idursulfase antibody 
positive and negative at each time point will be summarized overall, by baseline CRIM status,
and by genotype. Titer values will be summarized using box plots over time in patients with 
positive antibodies at or prior to each scheduled visit. The titer values will be plotted similarly 
for patients who developed positive neutralizing antibodies at or prior to each scheduled visit.
Overall antibody status groups will be summarized and are defined as follows:
•
Ab-:  Patients who never had a positive antibody sample
•
Ab+: Patients who had at least 1 positive antibody sample
•
NAb-:  Patients who never had neutralizing antibodies
•
NAb+:  Patients who had at least 1 neutralizing antibody sample
All assessments starting from Baseline in this study will be considered for this determination. If 
sample size permits, the overall Ab+ group will be further divided into:  
•
O-Ab+:  Occasional Ab+ patients:  patients who had antibodies in 25% or less of their blood 
samples
•
I-Ab+:  Intermittent Ab+ patients:  patients who had antibodies in between 25 and 50% of 
their blood samples
•
C-Ab+:  Consistently Ab+ patients:  patients who had antibodies in 50% or more of their 
blood samples
The proportion of patients ever developing a positive result during the study will be compared 
between by baseline CRIM status using a two-sided Fisher’s exact test. Additionally, Kaplan-
Meier plots for time to becoming Ab+ will be provided by baseline CRIM status. The time to 
first event by baseline CRIM status groups will be tested using a log-rank test.
10.7.7
Concomitant Medications/Therapies
Concomitant medications are defined as all medications taken on or after Study SHP-ELA-401 
Baseline. Concomitant medications will be mapped using the World Health Organization Drug 
Dictionary (WHO-DD) and summarized by the therapeutic class and preferred term. 
Concomitant therapies will be mapped using MedDRA Version 16.0 or higher and summarized 
by class and preferred term.
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10.8
Pharmacodynamic and Efficacy Analyses
Descriptive summaries will generally present the data overall and by visit from Study 
SHP-ELA-401 baseline for the Prospective Population. 
Retrospective height and weight data from start of Elaprase ERT for Group 2—Retrospective 
Patient Group in the Combined Population will be used in certain statistical model analyses and 
figures for height and weight, as described below. 
No retrospective data will be used in analyses of all other efficacy endpoints (with exception of 
instances in which historical data may provide missing baseline values); the Prospective 
Population will be utilized only.
10.8.1
Growth Parameters:  Height and Weight 
Height and weight Z-scores will be calculated based on the WHO-DD growth charts normal 
height/weight-for-age data. Descriptive statistics for the Prospective Population at each time 
point for height, weight and Z-scores and for change from baseline will be calculated overall and 
stratified separately by age group at start of Elaprase ERT treatment (<2 years; ≥2 years), overall 
antibody status, baseline CRIM status, and genotype class. 
Height, weight, and the corresponding Z-scores from start of ERT will be plotted against age for 
the Combined Population. Analyses using linear mixed models with random intercept and slope 
for age will be fit to the growth data over time from the start of ERT. Quadratic and cubic terms 
for age may be added to the model if significant or necessary to better characterize the 
relationship between physical growth and age over time. Predicted growth curves for individuals 
using the patient specific intercept and slope estimates from the model will be plotted. The effect 
of factors, such as age group at start of ERT, baseline CRIM status, and genotype class on 
growth parameters will be explored. The Least Squares means (LS-means) and standard errors at 
various ages estimated from the model will be summarized and plotted by factor groups. Similar 
analyses will be performed on the Prospective Population and will assess the effect of baseline 
CRIM status and antibody status on growth.
10.8.2
Joint Range of Motion (JROM)
See Table 10-1 below for a list of the joints/movements that will be assessed in Study 
SHP-ELA-401, as well as normal values and clinically meaningful changes from Baseline. The 
normal values are taken from the paper by Link et al.12 and rely on norms produced by the 
American Medical Association (AMA)13 and the American Association of Orthopedic Surgeons 
(AAOS).14 The clinically meaningful changes (in degrees of joint range) are identical to those 
used in the Study TKT024 Clinical Study Report, the original pivotal study of Elaprase. 
The scoring method for the JROM will use a similar approach as that described in Epps et al.15
The measurement (in degrees) of a given joint motion will be averaged across the right and left 
side, then divided by the normal value and multiplied by 100 to obtain a percent score. The 
percent scores of every motion in a given joint will be averaged to obtain an overall joint score. 
For example, for the knee, the 2 percent scores (representing flexion and extension, respectively) 
will be averaged to produce an overall knee joint score. The Upper Limb score will be the 
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average of the 3 joint scores in the upper limb (shoulder-elbow-wrist) and the Lower Limb Score 
will be the average of the 3 joint scores in the lower limb (hip-knee-ankle).
Two global scores will also be calculated:
•
Key Elements Score:  This score will be the average of the percent scores from the joint 
motions bolded in Table 10-1 . The experience with MPS II patients in HOS has indicated 
that these are the predominantly affected joint movements12
•
Full Score:  This score will be the average of the percent scores from all the joint motions. 
Table 10-1
Study SHP-ELA-401 Overview of Joints/Motions with Normal Values 
and Clinically Meaningful Changes
Joint
Motion Tested
Normal Valuea
Clinically Meaningful Changeb
Lower Limb
Hip
Flexion, Knee Bent
120
≥10
Extension 
30
≥10
Abduction
40
≥5
Adduction
20
Not given
External Rotation
50
≥5
Internal Rotation
45
≥5
Knee
Flexion
150
≥10
Extension
10
≥5
Ankle
Dorsal Extension
20
≥5
Plantar Flexion
50
Not given
Upper Limb
Shoulder
Flexion
180
≥10
Abduction
180
≥10
Internal Rotation
90
≥10
External Rotation
90
≥10
Extension
60
≥10
Elbow
Flexion
150
≥10
Extension
10
≥10
Wrist
Flexion
80
≥10
Extension
70
≥10
a
Link et al. 12
b
As described in the TKT024 CSR.
Scores and changes from baseline in individual joint movements (in degrees) as well as joint, 
upper, lower, and global scores will be summarized descriptively at each time point, overall and 
stratified separately by age group at ERT start, baseline CRIM status, antibody status, and 
genotype class. The proportion of patients with clinically meaningful changes in each joint 
movement will be similarly summarized.
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Analysis of covariance (ANCOVA) will be used to compare the antibody status, baseline CRIM 
status, genotype, and age at ERT start groups with respect to the change from baseline at each 
time point in upper, lower, key elements and full JROM scores. The group indicator (antibody 
status or genotype or age group) and the corresponding baseline JROM score will be included in 
the model as fixed effects. 
10.8.3
Urinary GAG Levels
Urinary GAG levels will be normalized to urine creatinine (normalized uGAG) and normalized 
uGAG divided by the upper limit of normal for age (uGAG/ULN) will be calculated, where the 
ULN for uGAG was obtained from Mayo Clinic as below in Table 10-2.
Table 10-2
Upper Limit of Normal for uGAG by Age Ranges
Age
uGAG ULN
0-4 months
<=53.0 mg/mmol creatinine (468.6 ug/mg)
5-18 months
<=31.0 mg/mmol creatinine (274.1 ug/mg)
19 months-2 years
<=24.0 mg/mmol creatinine (212.2 ug/mg)
3-5 years
<=16.0 mg/mmol creatinine (141.5 ug/mg)
6-10 years
<=12.0 mg/mmol creatinine (106.1 ug/mg)
11-14 years
<=10.0 mg/mmol creatinine (88.4 ug/mg)
>14 years
<=6.5 mg/mmol creatinine (57.5 ug/mg)
Descriptive summaries for the observed values, the change from baseline and the % change from 
baseline in normalized uGAG will be presented for each time point overall and stratified 
separately by age group at ERT start, baseline CRIM status, antibody status, and genotype class. 
Similar tables will be presented for the normalized uGAG/ULN. 
Analysis of covariance will be used to compare the antibody status, genotype, and age at ERT 
start groups with respect to the change from baseline at each time point in uGAG and 
uGAG/ULN. The group indicator (baseline CRIM status, antibody status, genotype, or age 
group) and the corresponding baseline value will be included in the model as fixed effects.
10.8.4
Liver Volume
Abdominal ultrasound examinations will be used to assess the liver volume. The liver volume
will be calculated using the following formula:18
Liver Volume = 0.2618 * (AAL2 + MCL2 + STL2)
The calculation of the upper limit of normal (ULN) for the liver volume will be as follows:
0.53 x height (cm) + 13
Liver volume divided by ULN (liver volume/ULN) will be calculated for each liver volume 
measurement.
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Descriptive summaries for the observed values, the change from baseline and the % change from 
baseline in liver volume will be presented for each time point overall and stratified separately by 
age group at ERT start, baseline CRIM status, antibody status, and genotype class. 
Analysis of covariance will be used to compare the baseline CRIM status, antibody status, 
genotype, and age at ERT start groups with respect to the change from baseline at each time 
point for liver volume. The group indicator (baseline CRIM status, antibody status, genotype, or 
age group at ERT start) and the corresponding baseline value will be included in the model as 
fixed effects.
10.8.5
Spleen Volume
Abdominal ultrasound examinations will be conducted to assess spleen volume. The spleen 
volumes will be calculated using the following formula for an ellipsoid:18
Spleen Volume=0.523 * L * B * (DL + DB)/2
The calculation of the ULN for spleen volume will be as follows:
0.7 + (4.6 x weight [kg]) + 150
Spleen volume divided by ULN (spleen volume/ULN) will be calculated for each spleen volume 
measurement.
Descriptive summaries for the observed values, the change from baseline and the % change from 
baseline in spleen volume will be presented for each time point overall and stratified separately 
by age group at ERT start, baseline CRIM status, antibody status, and genotype class. 
Analysis of covariance will be used to compare the baseline CRIM status, antibody status, 
genotype, and age at ERT start groups with respect to the change from baseline at each time 
point in spleen volume. The group indicator (baseline CRIM status, antibody status, genotype, or 
age group at ERT start) and the corresponding baseline value will be included in the model as 
fixed effects.
10.8.6
Distance Walked via Six Minute Walk Test (6MWT)
Descriptive summaries for the observed values and the change from baseline in distance walked 
as measured by 6MWT will be presented for each time point overall and stratified separately by 
age group at ERT start, baseline CRIM status, antibody status, and genotype class. Analysis of 
covariance will be used to compare the antibody status, baseline CRIM status, genotype, and age 
at ERT start groups with respect to the change from baseline at each time point in distance 
walked. The group indicator (baseline CRIM status, antibody status, genotype, or age group at 
ERT start) and the baseline value will be included in the model as fixed effects.
10.8.7
Analysis of Quality of Life
The analysis of QoL will be performed from study baseline for the Prospective Population 
utilizing the HS-FOCUS (shortened version). 
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The HS-FOCUS (shortened version) questionnaire has 5 function domains (walking/standing, 
grip/reach, schooling/work, activities, and breathing). The scale of the 5 function domains ranges 
from 0 to 3, with a 3 score denoting highest disability:  
0:  With NO difficulty  
1:  With SOME difficulty 
2:  With MUCH difficulty
3:  Unable to do
Missing:  Does not apply
The response option “Does not apply” is treated as “missing” with no score, the same as if the 
item had not been completed in the questionnaire. 
For each of the 5 functional domains, the respective domain scores will be calculated as:  
domain
 within 
completed
items
#
domain
 within 
scores
item
score
Domain 


For both the parent and the child-reported questionnaires, the domain scores and the changes 
from baseline in each of the domains will be summarized descriptively by baseline CRIM status, 
antibody status, genotype, and age at ERT start. 
10.8.8
Analysis of Daily Function
The analysis of impact of illness on ability to function in daily life will be performed from study 
baseline for the Prospective Population utilizing the CHAQ.
The CHAQ includes 30 items measured on a scale of 0 to 3:
0=Without any difficulty
1=With some difficulty
2=With much difficulty
3=Unable to do
Missing:  Does not apply
The highest scoring item in each category determines the score for that category. The mean score 
for the 8 subscales is the Disability Index (dressing, hygiene, arising, eating, walking, reach, grip 
and activities). The Discomfort Index and Health Status Index are measured on separate 15 cm 
scales. The distance from the left end of the scale to the respondent’s mark is measured and 
multiplied by 0.2 to calculate the score.
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The index scores and the changes from baseline will be summarized descriptively by baseline 
CRIM status, antibody status, genotype, and age at ERT start. 
10.8.9
Analysis of Adaptive Behavior
The analysis of adaptive behavior will be performed from study baseline for the Prospective 
Population utilizing the VABS-II. The observed value and change from baseline in the 
standardized scores for each of the 4 domains (communication; daily living skills; socialization; 
motor skills), as well as the adaptive behavior composite score, will be summarized descriptively 
by baseline CRIM status, antibody status, genotype, and age at ERT start. 
10.8.10
Analyses of the Relationship between Genotype Class, Residual Plasma I2S 
Enzyme Activity, and Antibody Status 
Residual plasma I2S enzyme activity results at baseline will be summarized overall and by 
baseline CRIM status, antibody status, and genotype class for the Prospective Population. No 
hypothesis testing will be conducted. 
10.9
Statistical/Analytical Issues
10.9.1
Adjustment for Covariates
Analyses utilizing ANCOVA models as described above will adjust for the baseline value of the 
corresponding outcome of interest as a continuous covariate in the model.
10.9.2
Handling of Drop-outs or Missing Data
Missing growth data will be assumed to be missing at random in statistical analyses and no 
imputation will be performed. Last observation carried forward may be used to impute missing 
data for other efficacy outcomes.
10.9.3
Interim Analyses
Two interim analyses are planned.
Interim Analysis 1 will examine CRIM assay results with respect to patient genotype and I2S 
enzyme status. This analysis is intended to evaluate suitability of blood samples for CRIM 
testing by confirming that the CRIM status determination is consistent with patient genotype. 
Patients with severe disease presentations, eg, as a result of complete deletion or early truncation 
of I2S enzyme-coding sequence, would be expected to test CRIM-negative. Interim Analysis 1 
will be conducted once the last patient in the Prospective Patient Group enrolls in the study and 
completes baseline assessments. 
Interim Analysis 2 will examine the correlation of CRIM status to prospectively collected data 
on the antibody response, uGAG levels, liver and spleen volumes, and clinical outcomes. This 
second analysis will be conducted after the last patient in the Prospective Patient Group 
completes 2-year assessments. 
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10.9.4
Multiple Comparisons/Multiplicity
Statistical testing is considered exploratory and no adjustment for multiplicity will be made. The 
unadjusted p-values will be interpreted descriptively as summarizing the weight of evidence for a 
group difference and may suggest avenues for further exploratory analyses or generate formal 
hypotheses to be tested in future controlled trials.
10.9.5
Sensitivity Analyses
The CRIM status determination at Baseline will be compared to the CRIM status determination 
at the 12-Month Visit to ascertain whether the established in vitro wash-out procedure is 
sufficient to assay I2S CRIM status in patients receiving treatment with Elaprase. 
No additional sensitivity analyses are planned.   
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11
ADMINISTRATIVE CONSIDERATIONS
11.1
Investigators and Study Administrative Structure
Before initiation of the study, the Investigators must provide the Sponsor with a completed Form 
FDA 1572. Curriculum vitae must be provided for the Investigators and sub-investigators listed 
on Form FDA 1572.
The Investigator should ensure that all persons assisting with the study are adequately informed 
about the protocol, any amendments to the protocol, the study treatments, and their study related 
duties and functions. The Investigator must maintain a list of sub-investigators and other 
appropriately qualified persons to whom he or she has delegated significant study related duties.
11.2
Institutional Review Board or Independent Ethics Committee Approval
Before initiation of the study, the Investigator must provide the Sponsor with a copy of the 
written IRB/IEC approval of the protocol and the informed consent form. This approval must 
refer to the informed consent form and to the study title, study number, and version and date of 
issue of the study protocol, as given by the Sponsor on the cover page of the protocol.
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. Unexpected, 
related SAEs which are reported to the US FDA (Investigational New Drug [IND] safety reports) 
or other regulatory agencies must be submitted promptly to the IRB/IEC.
11.3
Ethical Conduct of the Study
The procedures set out in this study protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor and Investigators abide by 
good clinical practice (GCP) as described in the 21 CFR Parts 50, 54, 56, and 312 and the 
International Conference on Harmonisation (ICH) GCP Guidelines Compliance with these 
regulations and guidelines also constitutes compliance with the ethical principles described in the 
Declaration of Helsinki.
11.4
Patient Information and Consent
Before enrolling in the clinical study, the patient’s parent(s) or legally authorized 
representative(s) must consent to participate after the nature, scope, and possible consequences 
of the clinical study have been explained in a form understandable to him or her.
An informed consent form (assent form if applicable) that includes information about the study 
will be prepared and given to the patient or the patient’s parent(s) or legally authorized 
representative(s). This document will contain all FDA and ICH-required elements. The informed 
consent (or assent) form must be in a language understandable to the patient or the patient’s 
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parent(s) or legally authorized representative(s) and must specify who informed the patient, the 
patient’s parent(s), or the patient’s legally authorized representative(s).
After reading the informed consent document, the patient or the patient’s parent(s) or legally 
authorized representative(s) must give consent in writing. Consent must be confirmed at the time 
of consent by the personally dated signature of the patient, the patient’s parent(s) or the patient’s 
legally authorized representative(s) and by the personally dated signature of the person 
conducting the informed consent discussions.
If the patient or the patient’s parent(s) or legally authorized representative(s) is unable to read, 
oral presentation and explanation of the written informed consent form and information to be 
supplied must take place in the presence of an impartial witness. Consent must be confirmed at 
the time of consent orally and by the personally dated signature of the patient or by a local 
legally recognized alternative (eg, the patient’s thumbprint or mark) or by the personally dated 
signature of the patient’s parent(s) or the patient’s legally authorized representative(s). The 
witness and the person conducting the informed consent discussions must also sign and 
personally date the informed consent document. It should also be recorded and dated in the 
source document that consent was given.
A copy of the signed and dated consent document(s) must be given to the patient or the patient’s 
parent(s) or legally authorized representative(s). The original signed and dated consent document 
will be retained by the Investigator.
The Investigator will not undertake any measures specifically required solely for the clinical 
study until valid consent has been obtained.
A model of the informed consent form to be used in this study will be provided to the sites 
separately from this protocol.
11.5
Patient Confidentiality
Patient names will not be supplied to the Sponsor. Only the patient number and patient initials 
will be recorded, and if the patient name appears on any other document, it must be obliterated 
before a copy of the document is supplied to the Sponsor. Study findings stored on a computer 
will be stored in accordance with local data protection laws. The patients will be told that 
representatives of the Sponsor, a designated CRO, the IRB/IEC, or regulatory authorities may 
inspect their medical records to verify the information collected, and that all personal 
information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. The Investigator will maintain a personal patient 
identification list (patient numbers with the corresponding patient names) to enable records to be
identified.
11.6
Study Monitoring
Monitoring procedures that comply with current GCP guidelines will be followed. Review of the 
CRF's for completeness and clarity, cross-checking with source documents, and clarification of 
administrative matters will be performed.
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The study will be monitored by the Sponsor or its designee. Monitoring will be performed by a 
representative of the Sponsor (Clinical Study Monitor) who will review the CRFs and source 
documents. The site monitor will ensure that the investigation is conducted according to protocol 
design and regulatory requirements by frequent site visits and communications (letter, telephone, 
and facsimile).
11.7
Case Report Forms and Study Records
Case report forms (paper or electronic) are provided for each patient. All forms must be filled out 
by authorized study personnel. All corrections to the original CRF entry must indicate the reason 
for change. The Investigator is required to sign the CRF after all data have been captured for 
each patient. If corrections are made after review and signature by the Investigator, he or she 
must be made aware of the changes, and his or her awareness documented by resigning the CRF.
11.7.1
Critical Documents
Before Shire initiates the trial (ie, obtains informed consent from the first patient), it is the 
responsibility of the Investigator to ensure that the following documents are available to Shire or 
their designee:
•
Completed FDA Form 1572 (Statement of Investigator), where applicable, 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, Patient 
Information/Informed Consent Form, and any other written information to be provided 
regarding patient recruitment procedures
•
Copy of IRB/IEC approved Patient Information/Informed Consent Form/any other written 
information/advertisement (with IRB approval stamp and date of approval)
•
Current list of IRB/IEC Committee members/constitution (dated within 12 months prior to 
study initiation)
•
Financial Disclosure Form signed by Investigator and sub-investigator(s)
•
Current laboratory reference ranges (if applicable)
•
Laboratory 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
Not applicable.
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11.9
Protocol Violations/Deviations
The Investigator will conduct the study in compliance with the protocol. The protocol will not be 
initiated until the IRB/IEC and the appropriate regulatory authorities have given 
approval/favorable opinion. Modifications to the protocol will not be made without agreement of 
the Sponsor. Changes to the protocol will require written IRB/IEC approval/favorable opinion 
prior to implementation, except when the modification is needed to eliminate an immediate 
hazard(s) to patients. The IRB/IEC may provide, if applicable regulatory authorities permit, 
expedited review and approval/favorable opinion for minor change(s) in ongoing studies that 
have the approval/favorable opinion of the IRB/IEC. The Sponsor will submit all protocol 
modifications to the regulatory authorities in accordance with the governing regulations.
A record of patients screened, but not entered into the study, is also to be maintained. No 
protocol exemption will be granted for this study.
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
patients, the Investigator will contact the Sponsor or its designee, if circumstances permit, to 
discuss the planned course of action. Any departures from the protocol must be fully documented 
as a protocol deviation. Protocol deviations will need to be reviewed by the medical monitor and 
may also be required to be submitted to the IRB/IEC.
Protocol modifications will only be initiated by the Sponsor and must be approved by the 
IRB/IEC and submitted to the FDA or other applicable international regulatory authority before 
initiation.
11.10 Premature Closure of the Study
If the Sponsor, Investigator, or regulatory authorities discover conditions arising during the study 
which indicate that the clinical investigation should be halted due to an unacceptable patient risk, 
the study may be terminated after appropriate consultation between the Sponsor and the 
Investigator(s). Conditions that may warrant termination of the study or site include, but are not 
limited to:
•
The discovery of an unexpected, significant, or unacceptable risk to the patients enrolled in 
the study
•
Failure of the Investigator to comply with pertinent global regulations
•
Submission of knowingly false information from the study site to the Sponsor or other 
pertinent regulatory authorities
•
Insufficient adherence by the Investigator to protocol requirements
11.11 Access to Source Documentation
Regulatory authorities, the IRB/IEC, or the Sponsor may request access to all source documents, 
CRFs, and other study documentation for onsite audit or inspection. Direct access to these 
documents must be guaranteed by the Investigator, who must provide support at all times for 
these activities. Monitoring and auditing procedures that comply with current GCP guidelines 
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will be followed. On-site review of the CRFs for completeness and clarity, crosschecking with 
source documents, and clarification of administrative matters may be performed.
11.12 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 MedDRA. Concomitant medication will be coded using 
WHO-DD. Centralized laboratories will be employed as described in the Study Lab Manual to 
aid in consistent measurement of efficacy and safety parameters. 
11.13 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 
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. 
11.14 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.
11.15 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 
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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. 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.
3. Burton BK, Giugliani R. Diagnosing Hunter syndrome in pediatric practice: practical 
considerations and common pitfalls. Eur J Pediatr 2012;171:631-9.
4. Baehner F, Schmiedeskamp C, Krummenauer F, et al. Cumulative incidence rates of the 
mucopolysaccharidoses in Germany. J Inherited Metab Dis 2005;28:1011-7.
5. Lin HY, Lin SP, Chuang CK, et al. Incidence of the mucopolysaccharidoses in Taiwan, 
1984-2004. Am J Med Genet 2009;149A:960-4.
6. Lowry RB, Applegarth DA, Toone JR, MacDonald E, Thunem NY. An update on the 
frequency of mucopolysaccharide syndromes in British Columbia. Hum Genet 1990;85:389-
90.
7. Nelson J. Incidence of the mucopolysaccharidoses in Northern Ireland. Hum Genet 
1997;101:355-8.
8. Nelson J, Crowhurst J, Carey B, Greed L. Incidence of the mucopolysaccharidoses in 
Western Australia. Am J Med Genet 2003;123A:310-3.
9. Poorthuis BJ, Wevers RA, Kleijer WJ, et al. The frequency of lysosomal storage diseases in 
The Netherlands. Hum Genet 1999;105:151-6.
10. Young ID, Harper PS. The Natural History of the Severe Form of Hunter's Syndrome: a 
Study Based on 52 cases.  Dev Med Child Neurol1983:481-9.
11. Kornfeld S, Mellman I. The biogenesis of lysosomes. Annu Rev Cell Biol 1989;5:483-525.
12. Link B, de Camargo Pinto LL, Giugliani R, et al. Orthopedic manifestations in patients with 
mucopolysaccharidosis type II (Hunter syndrome) enrolled in the Hunter Outcome Survey. 
Orthopedic reviews 2010;2:e16.
13. Anon. Guides to the Evaluation of Permanent Impairment. 3rd ed: American Medical 
Association; 1990.
14. Bigliani. Joint Motion: Method of Measuring and Recording: American Academy of 
Orthopaedic Surgeons; 1965.
15. Epps H, Hurley M, Utley M. Development and evaluation of a single value score to assess 
global range of motion in juvenile idiopathic arthritis. Arthritis Rheum 2002;47:398-402.
16. Kishnani PS, Goldenberg PC, DeArmey SL, et al. Cross-reactive immunologic material 
status affects treatment outcomes in Pompe disease infants. Mol Genet Metab 2010;99:26-33.
17. A7383M-Elaprase:  CRIM Assay for the Detection of Endogenous I2S by Western Blot in 
Hunter Patients
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18. Dittrich M, Milde S, Dinkel E, Baumann W, Weitzel D. Sonographic biometry of liver and 
spleen size in childhood. Pediatr Radiol 1983;13:206-11.
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Appendix 1
Group 1—Prospective Patient Group Study Schedule of Events
Screeninga
Day -18 to 
Day 0
Baselinea
Day 0
One
Month
(±7
Days)
Bi-Annuala—
Every 6 Months
(±14 Days)
Annuala—
Every 12 
Months
(±14 Days)
End of 
Studya,b
(±14 Days)
Main Site
Main Site
Main Site
Main Site
Main Site
Main Site
Study SHP-ELA-401 
Informed Consentc
●
Confirmation of Eligibility
●
Demographic Information
●
Medical History
●
Blood Sample for 
Confirmation of MPS IId
●
Blood Sample for CRIM 
Assayi
●
●
Blood Sample for Genotypee
●
Sample for Residual Plasma 
I2S Enzyme Activity
●
Physical and Neurological 
Examination
●
●
●
Heightf
●
●
●
●
Weightf
●
●
●
●
Vital Signs
●
●
●
Clinical Laboratory Tests
●
●
●
Urine GAG Levelsj
●
●
●
●
●
Anti-Idursulfase Antibody 
Testing
●
●
●
●
HS-FOCUS (shortened 
version)
●
●
●
JROM
●
●
●
6MWT
●
●
●
CHAQ
●
●
●
VABS-II
●
●
●
Liver ultrasoundk
●
●
●
●
●
Spleen ultrasoundk
●
●
●
●
●
Concomitant Medications, 
Therapies, and Procedures
●
●
●
●
●
●
Elaprase administrationg
●
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Screeninga
Day -18 to 
Day 0
Baselinea
Day 0
One
Month
(±7
Days)
Bi-Annuala—
Every 6 Months
(±14 Days)
Annuala—
Every 12 
Months
(±14 Days)
End of 
Studya,b
(±14 Days)
Main Site
Main Site
Main Site
Main Site
Main Site
Main Site
Confirmation of Elaprase 
administration compliance 
between visits
●
●
●
●
Adverse Eventsh
●
●
●
●
●
●
Abbreviations:  6MWT= 6 minute walk test, CRIM= cross-reactive immunologic material, GAG= 
glycosaminoglycans, HS-FOCUS=Hunter syndrome Functional Outcome in Clinical Standing Scale, I2S=
iduronate-2-sulfatase, JROM= joint range of motion, MPS II= mucopolysaccharidosis II
a
The Screening Period and Baseline visits may occur on the same day (ie, Screening period activities may be 
completed on Day 0). For all study visits, up to 48 hours is allowed for completion of study activities.
b
End of Study Visit is not needed if one of the annual visits took place less than 6 months previously. 
c
Informed consent must be obtained from the patient’s parent(s)/legally authorized representative(s) before 
beginning Screening procedures. 
d
A blood sample will be drawn for confirmatory MPS II assay.
e
Patients who have a documented genotype result from Greenwood Medical Laboratory need not have this 
repeated. 
f
Height and weight assessments must be performed per standardized methodology, described in the protocol
(refer to Section 7.12.1). 
g
The first dose of Elaprase must be administered after all assessments are completed for Baseline at Day 0 and 
within 1 week after the completion of the baseline assessments. Thereafter, Elaprase will be administered 
weekly throughout the study. Details on administration procedures are provided in the Pharmacy Manual; refer 
to country-specific prescribing information for details concerning administration of commercially sourced drug.
Elaprase treatment will be administered under the oversight of the Investigator in a clinical setting or may be 
administered in the patient’s home (with Sponsor approval) after the patient has completed at least 6 months of 
treatment in a hospital setting by appropriately trained and skilled healthcare providers (nurses or physicians) 
with knowledge of the patient’s drug regimen.
h
Adverse events will be collected at weekly Elaprase infusions and at each study visit.
i
Blood sample collection for the CRIM assay is planned at Baseline and at the 12-Month Study Visit.
j
The uGAG assessment is planned at the Baseline, 1-Month, 6-Month, and 12-Month Study Visits, and annually 
thereafter until the End-of-Study Visit. In the event that a baseline urine sample is unable to be collected 
successfully, a historical value may be used if deemed acceptable by the Sponsor.
k
Liver and spleen ultrasound assessments are planned at the Baseline, 1-Month, 6-Month, 12-Month, and 24-
Month Study Visits, and at the End-of-Study Visit. Due to the timing of Protocol Amendment 2, some patients 
may have enrolled in the study prior to the implementation of liver and spleen volume assessments. In these 
cases, missed assessments will not be considered as protocol deviations. Ultrasound imaging should still be 
performed when indicated per protocol, despite the fact that baseline and other visit data points may be missing 
for some patients.
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Appendix 2
Group 2—Retrospective Patient Group Data to be Utilized in Study 
SHP-ELA-401 Final Analysis
Data Used in 
Study SHP-ELA-401 Analysis
Confirmation of HOS informed consenta
●
Demographic Information 
●
Genotype, if available 
●
Date of first dose of Elaprase
●
Annual height assessmentsb
●
Annual weight assessmentsb
●
MPS II= mucopolysaccharidosis II
a
HOS Study informed consent must be confirmed for data to be utilized in the SHP-ELA-401 analysis. 
b
First height and weight assessments must be within 3 months of the first dose of Elaprase. 
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Appendix 3
Protocol Amendment Summary of Changes
AMENDMENT SUMMARY AND RATIONALE 
Clinical protocol SHP-ELA-401 has been amended from the previous version to allow the 
Sponsor to meet postmarketing requirement (PMR) 2792-3 required under 505(o) for sBLA 
125151/184. 
The following major changes will be implemented in this protocol version; a detailed list of 
changes to the text is provided below: 

Five additional patients will be enrolled into the Prospective Patient Cohort of Study 
SHP-ELA-401, for a total of at least 20 prospectively enrolled patients. It is anticipated 
that this patient population will comprise an appropriate mix of genotype and CRIM 
status to allow for evaluation of the impact of CRIM status on clinical outcomes. 

Ultrasonographic measurements of liver and spleen volume will be added to the schedule 
of study assessments at baseline and post-treatment at the 1-Month, 6-Month, 12-Month, 
and 24-Month Study Visits, and at the End-of-Study Visit. CRIM status will be correlated 
to changes in liver and spleen volume. While changes in spleen and/or liver volume are 
not clinical endpoints per se, they are pharmacodynamic biomarkers which may be 
sensitive to change and may aid in correlating changes in outcomes with CRIM status. 

Two interim analyses are planned to satisfy PMR 2792-3. The first will examine CRIM 
assay results with respect to patient genotype and I2S enzyme status and will be 
conducted once the last patient enrolls in the study and completes baseline assessments. 
The second will examine the correlation of CRIM status to prospectively collected data 
on the antibody response, uGAG levels, liver and spleen volume, and clinical outcomes.
Additionally, CRIM status will be correlated with changes in height and weight, 
parameters which are already being assessed in study SHP-ELA-401.
DETAILED SUMMARY OF CHANGES FOR THE AMENDMENT 
This is a section that has been updated to list changes from the previous 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.
Change:  Change to planned enrollment and Primary Growth Analysis
Section impacted by this change:  1.3 Study Overview
Revised Text: 
The study will enroll at least 15 20 treatment-naïve patients and the length of on-study follow-up for 
individual patients in Study SHP-ELA-401 will range from 5 to 10 years, from Screening through the 
End-of-Study. Additionally, due to the scarcity of treatment-naïve patients, height and weight data from 
patients enrolled in the Hunter Outcome Survey (HOS) registry will be utilized for the Primary Growth 
Analysis. 
The Primary Growth Analysis will include data on at least 30 approximately 35 patients with MPS II that 
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cover either 5 years duration of treatment with Elaprase, or the time period from initiation of Elaprase 
treatment until the patient reaches his 10th birthday, whichever is longer for each individual patient. The 
combination of Group 1—Prospective Patient Group data (obtained from patients during their participation 
in the present Study SHP-ELA-401) with Group 2—Retrospective Patient Group data (obtained from 
patients during their participation in the HOS study) allows for sufficient data to meet the Primary Growth 
Analysis goals. See Section 4.4 for more details on this Primary Growth Analysis.
Other sections impacted by this change:  Synopsis; 4.1 Overall Study Design and Plan; 5 Study Population 
Selection; 5.1 Study SHP-ELA-401 Population:  Prospective Patients; 10.2 Determination of Sample Size
Change:  Addition of CRIM status evaluation and interpretation
Section impacted by this change:  1.3 Study Overview
Revised Text: 
An additional purpose of Study SHP-ELA-401 is to obtain blood samples from patients to determine 
their cross-reactive immunologic material (CRIM) status, and to correlate CRIM status with 
outcomes data, including anti-idursulfase antibody development, pharmacodynamic responses, and 
clinical outcomes. If a patient’s sample reacts with antibodies against I2S, it is concluded that the 
sample contained this enzyme, and the patient is considered CRIM-positive. If a patient’s sample does 
not react with antibodies against I2S, the patient is considered CRIM-negative. 
In the context of MPS II and other lysosomal storage diseases, this means that patients who produce 
some endogenous enzyme, albeit in much reduced quantities or with abnormal amino acid sequence, 
will be CRIM-positive. From a molecular genetic standpoint, this would be expected to be the case in 
patients whose IDS gene mutations include missense mutations, late truncations, and late frameshifts. 
CRIM-negativity, on the other hand, would be expected to be seen in patients who produce no enzyme 
at all; specifically, in patients with complete deletions of the IDS gene or mutations resulting in early 
truncations and frameshifts. 
CRIM status has been shown to be a useful predictor of outcomes and immune response to enzyme 
replacement therapy in patients with Pompe disease; CRIM-negative status is associated with poorer 
clinical outcomes in these patients.16 It is unknown whether this is also true for patients with MPS II 
and other diseases being treated with ERT.  
Other sections impacted by this change:  12 List of References
Change:  Change to study objectives
Section impacted by this change:  2.2 Secondary Objective(s) and 2.3Tertiary Objective(s)
Revised Text: 
2.2 Secondary Objective(s) 
•
liver and spleen volume
2.3 Tertiary Objective(s)
•
genotype and the following parameters:  residual plasma I2S enzyme activity, CRIM status, and 
antibody status 
•
CRIM status and the following parameters: height, weight, walking, joint mobility, uGAG levels, 
liver and spleen volume
•
CRIM status and the following parameters: safety (adverse events, infusion-related adverse 
reactions [hypersensitivity reactions])
Other sections impacted by this change:  Synopsis
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Change:  Change to study outcome measures
Section impacted by this change: 3 Study Outcome Measures
Revised Text: 
Changes in the following additional variables will be assessed in this study:
•
liver and spleen volume
Other sections impacted by this change:  Synopsis
Change:  Addition of visit to the study schedule of events
Section impacted by this change: 4.1 Overall Study Design and Plan
Revised Text: 
For enrolled patients (Group 1—Prospective Patient Group only), the study will flow as follows:
•
Screening Period:  Day -18 through Day 0
•
Baseline Visit:  Day 0 (may extend to Day 1; however, all Baseline assessments must be completed and 
eligibility confirmed prior to the patient’s first dose of Elaprase)
•
Treatment Period:  As of the first Elaprase infusion in this study until adequate data are obtained; 
specifically, until the patient reaches his 10th birthday or until the patient has been in the study for 5 
years, whichever is longer. 
•
One Month Study Visit: Day 30
•
Bi-Annual Study Visit:  Every 6 months
•
Annual Study Visit:  Every 12 months
•
End-of-Study Visit:  After 5 years of treatment observation data are collected or until the patient 
reaches his 10th birthday, whichever is longer.
Other sections impacted by this change:  Synopsis; Figure 4-1 Study SHP-ELA-401 Study Flow; 8.3.1 One 
Month Visit (Day 30, ±7 days); Appendix 1 Group 1—Prospective Patient Group Study Schedule of Events
Change:  Clarifications of changes to study plan
Section impacted by this change: 4.1 Overall Study Design and Plan
Revised Text: 
A minimum number of 15 20 treatment-naive patients are targeted for enrollment into this study (Group 1—
Prospective Patient Group). Patients may be invited for entry into the study based on their known medical 
histories or chart reviews. Patients who meet the initial eligibility criteria of the study and whose parent(s) 
and/or legally authorized representatives(s) have provided informed consent will be enrolled. Patients 
without a documented biochemical or genetic diagnosis of MPS II will have blood drawn for confirming 
genetic diagnosis. Patients will have a blood sample drawn for confirmatory MPS II assay. Safety will 
be monitored throughout the study by the assessments of AEs, concomitant medications and surgical 
procedures, vital signs, physical examinations, and clinical laboratory testing (clinical chemistry, 
hematology and urinalysis). Testing for anti-idursulfase antibodies will take place at Baseline and every 6 
months through the End-of-Study Visit.
The study will monitor height, weight, joint mobility (measured by JROM), walking distance (measured by 
6MWT), uGAG levels, liver and spleen volume, QoL (measured by HS-FOCUS shortened version), 
impact of illness on ability to function in daily life (measured by CHAQ), adaptive function (measured by 
VABS-II), and antibody status. Genotype and enzymatic activity of I2S will be collected at Baseline. 
Additionally, on Day 0, a blood sample for determination of cross-reactive immunologic material (CRIM) 
status will be obtained from Group 1—Prospective Patient Group patients only. An additional 
post-treatment sample for CRIM analysis will be collected at 12 months.
Other sections impacted by this change:  Synopsis; 8 Study Activities; Appendix 1 Group 1—Prospective 
Patient Group Study Schedule of Events
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Change:  Expansion of study purpose
Section impacted by this change: 4.2 Rationale for Study Design
Revised Text: 
As described in Section 7, this study will monitor various clinical outcome assessments, with a focus on 
those that assess growth. Additionally, genotype and enzymatic activity of I2S will be collected at Baseline 
and antibody status will be assessed every 6 months. Blood samples will be obtained from patients to 
determine their CRIM status and to correlate the CRIM status with outcomes data. Assessments were 
selected because they are minimally invasive and are feasible. No comparator group is planned.
Other sections impacted by this change:  Synopsis; 1.3 Study Overview;  2.2 Secondary Objective(s) and 2.3
Tertiary Objective(s); 4.1 Overall Study Design and Plan
Change:  Description of plan to monitor enrollment
Section impacted by this change: 7.6 MPS II Diagnosis and Genotyping
Revised Text: 
The Medical Monitor will review patient genotypes and adjust enrollment, if necessary, to ensure 
representation in the study of patients with a variety of IDS mutations, eg, including patients with 
mutations, such as complete gene deletions or early truncations/frameshifts, which abolish I2S 
expression. 
Other sections impacted by this change:  None
Change:  Addition of blood sample collections for CRIM status determination
Section impacted by this change:  7.8 Cross-Reactive Immunologic Material Blood Samples
Revised Text: 
A blood sample for determination of CRIM status will be obtained for assay development and potentially for 
exploratory analyses. Blood samples will be collected for determination of CRIM status and the results 
will be utilized in the analyses. Sample collection, processing, and shipping instructions will be 
provided in the Study Lab Manual.
Other sections impacted by this change:  8 Study Activities; Appendix 1 Group 1—Prospective Patient 
Group Study Schedule of Events
Change:  Clarification to uGAG collection
Section impacted by this change: 7.12.2 Urinary GAG Levels
Revised Text: 
Urine samples for determination of uGAG levels and urine creatinine will be collected. 
Urinary GAG levels will be normalized to urine creatinine and reported as μg mg GAG/mg mmol 
creatinine. Additionally, uGAG levels divided by the ULN will be calculated (See Section 10.8.3). 
Sample collection, processing, and shipping instructions will be described provided in the Study Lab 
Manual to be provided by the central laboratory.
In the event that a baseline urine sample is unable to be collected successfully, a historical value may 
be used if deemed acceptable by the Sponsor.
Other sections impacted by this change:  8 Study Activities; Appendix 1 Group 1—Prospective Patient 
Group Study Schedule of Events (footnote j)
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Change:  Addition of liver and spleen volume assessments
Section impacted by this change:  7.12.3 Liver and Spleen Volume
Revised Text: 
Liver and spleen volume will be measured by abdominal ultrasonography. Ultrasound image 
collection, preparation, and transfer procedures will be provided to clinical sites. Patients may require 
sedation or anesthesia for this procedure in accordance with local clinical practice and should be 
recorded appropriately as concomitant medications.
Due to the timing of Protocol Amendment 2, some patients may have enrolled in the study prior to the 
implementation of liver and spleen volume assessments. In these cases, missed assessments will not be 
considered as protocol deviations. Ultrasound imaging should still be performed when indicated per 
protocol, despite the fact that baseline and other visit data points may be missing for some patients. 
Other sections impacted by this change:  8 Study Activities; Appendix 1 Group 1—Prospective Patient 
Group Study Schedule of Events (footnote k)
Change:  Reference to CRIM assay
Section impacted by this change:  7.22 Appropriateness of Measurements
Revised Text: 
All The measurements utilized in this study are standard, widely used, and generally recognized as reliable, 
accurate, and relevant to the study purpose of studying the longitudinal changes in height and weight in 
patients with MPS II who are receiving treatment with Elaprase and started Elaprase treatment at <6 years of 
age. Patient CRIM status will be determined using a validated I2S CRIM assay.17
Other sections impacted by this change:  12 List of References
Change:  Change to planned assessments
Section impacted by this change:  8 Study Activities
Revised Text: 
8.2 Baseline Visit (Day 0)
The following procedures and observations* will be performed on Day 0:
•
Blood sample for CRIM assay**
•
Blood sample for MPS II confirmatory assay (only for patients without a biochemical diagnosis of MPS 
II) 
•
Blood sample for genotype (Patients who have a documented genotype from Greenwood 
Medical Laboratory do not have to have their genotype confirmed.)
•
Blood sample for residual plasma I2S enzyme activity 
•
Collection of urine sample for GAG levels***
•
Ultrasonography of liver****
•
Ultrasonography of spleen****
8.3.1 One Month Visit (Day 30, ±7 days)
The following procedures and observations will be performed at 1 month, calculated from Day 0:
•
Collection of urine sample for GAG levels***
•
Ultrasonography of liver****
•
Ultrasonography of spleen****
•
Concomitant medications, therapies, and procedures
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•
Confirmation of Elaprase administration compliance between visits
•
Adverse events
8.3.2 Bi-Annual Visits (Every 6 months, ±14 days)
The following procedures and observations will be performed every 6 months, calculated from Day 0:
•
Collection of urine sample for GAG levels***
•
Ultrasonography of liver****
•
Ultrasonography of spleen****
8.3.3 Annual Visits (Every 12 months, ±14 days)
The following procedures and observations will be performed every 12 months, calculated from Day 0:
•
Blood sample for CRIM assay**
•
Collection of urine sample for GAG levels***
•
Ultrasonography of liver**** 
•
Ultrasonography of spleen****
8.4 End-of-Study Visit (±14 days)
The following procedures and observations will be performed at the End-of-Study Visit:
•
Collection of urine sample for GAG levels***
•
Ultrasonography of liver**** 
•
Ultrasonography of spleen****
Notes
*The Screening Period and Baseline visits may occur on the same day (ie, Screening period activities may be 
completed on Day 0). For all study visits, up to 48 hours is allowed for completion of study activities.
**Blood sample collection for the CRIM assay is planned at Baseline and at the 12-Month Study Visit. 
***The uGAG assessment is planned at the Baseline, 1-Month, 6-Month, and 12-Month Study Visits, 
and annually thereafter until the End-of-Study Visit. In the event that a baseline urine sample is 
unable to be collected successfully, a historical value may be used if deemed acceptable by the 
Sponsor.
****Liver and spleen ultrasound assessments are planned at the Baseline, 1-Month, 6-Month, 12-
Month, and 24-Month Study Visits, and at the End-of-Study Visit. Due to the timing of Protocol 
Amendment 2, some patients may have enrolled in the study prior to the implementation of liver and 
spleen volume assessments. In these cases, missed assessments will not be considered as protocol 
deviations. Ultrasound imaging should still be performed when indicated per protocol, despite the fact 
that baseline and other visit data points may be missing for some patients.
Other sections impacted by this change:  8 Study Activities; Appendix 1 Group 1—Prospective Patient 
Group Study Schedule of Events (footnotes d, i, j, k)
Change:  Changes to planned statistical analysis
Section impacted by this change:  10 Statistical Analysis
Revised Text: 
10.7.1 Adverse Events
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) Version 16.0 or 
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higher. Adverse events and SAEs will be summarized according to the Medical Dictionary for Regulatory 
Activities System Organ Class (SOC) and Preferred Term (PT). The number and percentage of patients 
reporting each PT and SOC will be tabulated globally and by genotype, baseline CRIM status, and 
antibody status. A patient experiencing the same AE multiple times will only be counted once for the 
corresponding PT. Similarly, if a patient experiences multiple AEs within the same SOC, that patient will be 
counted only once for that SOC. Adverse events will be presented in alphabetical order by SOC. 
Hypersensitivity reactions, treatment-emergent adverse events (TEAEs), and SAEs will each be 
analyzed by baseline CRIM status for both time to first event and number and percentage of patients 
experiencing AEs by SOC and PT. Kaplan-Meier plots of time to first event will be graphed by 
baseline CRIM status and the groups will be compared using the log-rank test.  A time-varying 
proportional hazards (Cox) model will also be used to assess the relationship between baseline CRIM 
status and AEs.
10.7.2 Immunogenicity
The number and percentage of patients who became antibody positive (Ab+) overall (at any time 
during the study) will be tabulated, and the proportion of patients ever developing a positive result 
during the study will be compared between the CRIM-positive and CRIM-negative patients using a 
two-sided Fisher’s Exact test. Additionally, Kaplan-Meier plots for time to becoming Ab+ will be 
provided by baseline CRIM status. The time to first event by CRIM status groups will be tested using 
a log-rank test. A similar analysis may be conducted for PAb+, NAb+ and PNAb+ responses. 
Additionally, immunoglobulin G (IgG) antibody titer at each visit will be summarized by baseline 
CRIM status.
10.7.6 Antibody Assessments
Anti-idursulfase antibody formation will be monitored at Study SHP-ELA 401 Baseline and throughout the 
study. The number and percentage of patients testing anti-idursulfase antibody positive and negative at each 
time point will be summarized overall, by baseline CRIM status, and by genotype. Titer values will be 
summarized using box plots over time in patients with positive antibodies at or prior to each scheduled visit. 
The titer values will be plotted similarly for patients who developed positive neutralizing antibodies at or 
prior to each scheduled visit.
The proportion of patients ever developing a positive result during the study will be compared 
between by baseline CRIM status using a two-sided Fisher’s exact test. Additionally, Kaplan-Meier 
plots for time to becoming Ab+ will be provided by baseline CRIM status. The time to first event by 
baseline CRIM status groups will be tested using a log-rank test.
10.8 Pharmacodynamic and Efficacy Analyses
No retrospective data will be used in analyses of all other efficacy endpoints (with exception of instances 
in which historical data may provide missing baseline values); the Prospective Population will be 
utilized only.
Other sections impacted by this change:  None
Change:  Changes to planned statistical analysis relating to CRIM status correlations
Section impacted by this change:  10 Statistical Analysis
Revised Text: 
10.8.1 Growth Parameters:  Height and Weight 
Height and weight Z-scores will be calculated based on the WHO-DD growth charts normal 
height/weight-for-age data. Descriptive statistics for the Prospective Population at each time point for 
height, weight and Z-scores and for change from baseline will be calculated overall and stratified separately 
by age group at start of Elaprase ERT treatment (<2 years; ≥2 years), overall antibody status, baseline 
CRIM status, and genotype class. 
Height, weight, and the corresponding Z-scores from start of ERT will be plotted against age for the 
Combined Population. Analyses using linear mixed models with random intercept and slope for age will be 
fit to the growth data over time from the start of ERT. Quadratic and cubic terms for age may be added to 
the model if significant or necessary to better characterize the relationship between physical growth and age 
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over time. Predicted growth curves for individuals using the patient specific intercept and slope estimates 
from the model will be plotted. The effect of factors, such as age group at start of ERT, baseline CRIM 
status, and genotype class on growth parameters will be explored. The Least Squares means (LS-means) and 
standard errors at various ages estimated from the model will be summarized and plotted by factor groups. 
Similar analyses will be performed on the Prospective Population and will assess the effect of baseline 
CRIM status and antibody status on growth.
Other sections impacted by this change: 10.8.2 Joint Range of Motion (JROM); 10.8.3 Urinary GAG 
Levels; 10.8.6 Distance Walked via Six Minute Walk Test (6MWT); 10.8.7 Analysis of Quality of Life; 
10.8.8 Analysis of Daily Function; 10.8.9 Analysis of Adaptive Behavior; 10.8.10 Analyses of the 
Relationship between Genotype Class, Residual Plasma I2S Enzyme Activity, and Antibody Status
Change:  Addition of analyses of liver and spleen volumes
Section impacted by this change: 10 Statistical Analysis
Revised Text: 
10.8.4 Liver Volume
Abdominal ultrasound examinations will be used to assess the liver volume. The liver volume will be 
calculated using the following formula:18
Liver Volume = 0.2618 * (AAL2 + MCL2 + STL2)
The calculation of the upper limit of normal (ULN) for the liver volume will be as follows:
0.53 x height (cm) + 13
Liver volume divided by ULN (liver volume/ULN) will be calculated for each liver volume 
measurement.
Descriptive summaries for the observed values, the change from baseline and the % change from 
baseline in liver volume will be presented for each time point overall and stratified separately by age 
group at ERT start, baseline CRIM status, antibody status, and genotype class. 
Analysis of covariance will be used to compare the baseline CRIM status, antibody status, genotype, 
and age at ERT start groups with respect to the change from baseline at each time point for liver 
volume. The group indicator (baseline CRIM status, antibody status, genotype, or age group at ERT 
start) and the corresponding baseline value will be included in the model as fixed effects.
10.8.5 Spleen Volume
Abdominal ultrasound examinations will be conducted to assess spleen volume. The spleen volumes 
will be calculated using the following formula for an ellipsoid:18
Spleen Volume=0.523 * L * B * (DL + DB)/2
The calculation of the ULN for spleen volume will be as follows:
0.7 + (4.6 x weight [kg]) + 150
Spleen volume divided by ULN (spleen volume/ULN) will be calculated for each spleen volume 
measurement.
Descriptive summaries for the observed values, the change from baseline and the % change from 
baseline in spleen volume will be presented for each time point overall and stratified separately by age 
group at ERT start, baseline CRIM status, antibody status, and genotype class. 
Analysis of covariance will be used to compare the baseline CRIM status, antibody status, genotype, 
and age at ERT start groups with respect to the change from baseline at each time point in spleen 
volume. The group indicator (baseline CRIM status, antibody status, genotype, or age group at ERT 
start) and the corresponding baseline value will be included in the model as fixed effects.
Other sections impacted by this change:  12 List of References
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Change:  Addition of interim analyses to support completion of PMR 2792-3
Section impacted by this change: 10.9.3 Interim Analyses
Revised Text: 
No interim analysis is planned during the course of the study. 
Two interim analyses are planned.
Interim Analysis 1 will examine CRIM assay results with respect to patient genotype and I2S enzyme 
status. This analysis is intended to evaluate suitability of blood samples for CRIM testing by 
confirming that the CRIM status determination is consistent with patient genotype. Patients with 
severe disease presentations, eg, as a result of complete deletion or early truncation of I2S enzyme-
coding sequence, would be expected to test CRIM-negative. Interim Analysis 1 will be conducted once 
the last patient in the Prospective Patient Group enrolls in the study and completes baseline 
assessments. 
Interim Analysis 2 will examine the correlation of CRIM status to prospectively collected data on the 
antibody response, uGAG levels, liver and spleen volumes, and clinical outcomes. This second analysis 
will be conducted after the last patient in the Prospective Patient Group completes 2-year 
assessments. 
Following the completion of the study and collection and verification of all final data, the database will be 
locked and the results of the planned statistical analysis will be described in a final study report.
Other sections impacted by this change:  Synopsis
Change:  Addition of sensitivity analysis comparing CRIM assay results at baseline and post treatment
Section impacted by this change:  10.9.5 Sensitivity Analysis
Revised Text: 
The CRIM status determination at Baseline will be compared to the CRIM status determination at 
the 12-Month Visit to ascertain whether the established in vitro wash-out procedure is sufficient to 
assay I2S CRIM status in patients receiving treatment with Elaprase. 
No additional sensitivity analyses are planned.   
Other sections impacted by this change:  None
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Appendix 3
Protocol Amendment Summary of Changes
AMENDMENT SUMMARY AND RATIONALE 
Clinical protocol SHP-ELA-401 has been amended from the previous version as follows. The 
changes are intended to incorporate feedback obtained from participating clinical sites and to 
implement regulatory authority recommendations.
•
Clarification to the instructions for obtaining height and weight measurements.
•
Permitting a visit window of 48 hours for sites to complete scheduled procedures.
•
With Sponsor approval, allowing home infusion of Elaprase by a trained healthcare provider.
•
Per BfArM (Germany), addition of an assessment of the risk and burden of study 
participation to patients; addition of contraindications to the study exclusion criteria per 
Elaprase labeling.
•
Notification of a change in Medical Monitor contact information
•
Clarification to instructions for AE collection and the AE severity scale; inclusion of 
definitions for AE relatedness terms and infusion-related adverse reactions; addition of 
instructions for management of infusion-related adverse events.
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.
Change:  Addition of section regarding benefit/risk assessment of patients treated with Elaprase in 
completed clinical studies
Section impacted by this change:  Section 1, Introduction
Revised Text: 
Section 1.4 Benefit/Risk Assessment
In total, 135 individual treatment-naïve male patients have been enrolled and treated with Elaprase in 
completed clinical studies. These patients were representative of the general MPS II population as 
shown by a broad spectrum of disease manifestations. A detailed summary of the safety and efficacy 
of Elaprase is provided in the current edition of the Investigator’s Brochure. 
Across all clinical studies, Elaprase was safe and generally well tolerated. As with other enzyme-
replacement therapies, some patients treated with Elaprase did experience infusion-related reactions. 
The infusion-related reactions were generally mild, well tolerated, and treated or ameliorated by 
slowing the infusion rate, interrupting infusion, or by administration of medications, such as 
antihistamines, antipyretics, low-dose corticosteroids or beta-agonist nebulization. The most 
commonly reported infusion-related adverse events included cutaneous reactions (rash, pruritus, and 
urticaria), headache, pyrexia, hypertension, and flushing. Additionally, some patients exposed to 
Elaprase in clinical studies have developed anti-idursulfase antibodies. Analyses of the 
immunogenicity reports found no association or increased safety risk with the type or magnitude of 
the immune response to Elaprase, and there have been no instances of IgE-associated anaphylaxis. No 
clinically important changes in laboratory profiles, vital signs, or ECG were observed in any of the 
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clinical studies.
Elaprase efficacy is based on results of the pivotal study (TKT024) and several supportive studies 
(TKT008, TKT018, TKT024EXT, and HGT-ELA-038). The greatest benefit observed in the pivotal 
study was one of increased endurance as measured by clinically and statistically significant 
improvements (compared with placebo) in distance walked during the 6-Minute Walk Test, as well as 
clinically relevant improvements in respiratory function as measured by the percent predicted and 
absolute forced vital capacity. Other benefits of Elaprase treatment have been demonstrated by 
statistically and clinically significant reductions in liver and spleen volumes and urine 
glycosaminoglycan levels, as well as clinically significant improvements in cardiac function as 
measured by reductions in left ventricular mass. Improvements in patients’ quality of life were also 
observed after 1 year of treatment in the pivotal study. In a post-hoc analysis of immunogenicity, 
pharmacodynamic and clinical effects of Elaprase treatment were observed regardless of the patient’s 
antibody status.
Overall, the benefits obtained from Elaprase therapy outweigh the risks, which are, at this point, well 
characterized in clinical studies and in real-life settings. Safety risks related to infusion-related 
reactions are manageable. The cumulative safety data for Elaprase from post-marketing sources 
complements and is consistent with the experience from the clinical development program. 
Other sections impacted by this change:  Not applicable
Change:  Addition of a section regarding monitoring of burden/risk to participants in this study (SHP-ELA-
401)
Section impacted by this change:  Section 1, Introduction
Revised Text: 
Section 1.5 Monitoring of Burden/Risk to Study Participants
The current study (SHP-ELA-401) is designed to assess longitudinal changes in height and weight in 
patients with MPS II who are receiving Elaprase and who initiated therapy with Elaprase below the 
age of 6 years. The study will cover either 5 years duration of treatment with Elaprase, or the time 
period from initiation of Elaprase treatment until the patient reaches his 10th birthday, whichever is 
longer. 
Elaprase will be administered to patients enrolled in this study by trained healthcare providers, either 
in a clinical setting or, if applicable, in an at-home setting. Patients will receive once weekly IV 
infusions of Elaprase at a dose of 0.5 mg/kg; the dose and frequency of Elaprase infusions is the same 
treatment regimen that patients would follow as standard of care per approved labeling. The study 
visits are relatively infrequent (bi-annually after completion of Screening/Baseline visits) and up to 48 
hours is permitted at each study visit for completion of study activities which, in addition to height 
and weight measurements, include assessments of efficacy and quality of life, and standard safety 
parameters (refer to Appendix 1). The study assessments were selected as being minimally invasive 
and feasible in the patient population, and the schedule is typical of that performed in clinical practice 
for patients receiving Elaprase therapy. Permitting the completion of scheduled assessments over 48 
hours further reduces the burden of study participation for patients. The degree of burden and risk to 
patients participating in this study is, therefore, considered to be low. There is no added burden or 
risk beyond that which patients would expect as standard of care, and no change in burden or risk to 
participants is expected over the duration of the study. 
As noted, patients treated with Elaprase may develop infusion-related reactions. In general, such 
reactions are well controlled (refer to Section 7.21.1), and no patient discontinued treatment due to an 
infusion-related reaction during clinical studies of Elaprase. Likewise, potential risk associated with 
severe hypersensitivity reactions should be continually monitored; in particular, Elaprase is 
contraindicated in patients with severe or life-threatening hypersensitivity to the active substance or 
to any of the excipients if hypersensitivity is not controllable (refer to Section 5.1.2 Group 1—
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Prospective Patient Group Population Exclusion Criteria). Finally, any serious adverse event (SAE) 
experienced by a patient during the study should be monitored for and be reported by the 
Investigator to the Sponsor (refer to Section 7.17.3), who should apply his/her clinical judgment as to 
whether the reported event alters the threshold of acceptable risk beyond that which is expected with 
Elaprase treatment.
Other sections impacted by this change:  Not applicable
Change:  Baseline Visit (Day 0) may also extend to Day 1; however all assessments must be performed and 
eligibility confirmed prior to first dose of Elaprase
Section impacted by this change:  Section 4.1, Overall Study Design and Plan
Revised Text: 
•
Baseline Visit:  Day 0 (may extend to Day 1; however, all Baseline assessments must be completed 
and eligibility confirmed prior to the patient’s first dose of Elaprase)
Other sections impacted by this change:  Synopsis, Study Design; Section 8.2, Baseline Visit; Section 10, 
Statistical Analysis
Change:  Visit window of 48 hours for completion of study activities for all visits
Section impacted by this change:  Section 4.1, Overall Study Design and Plan
Revised Text: 
Note that the Screening Period and Baseline visits may occur on the same day (ie, Screening period
activities may be completed on Day 0). For all study visits, up to 48 hours is allowed for completion of 
study activities.
Footnote to Figure 4-1, Study SHP-ELA-401 Study Flow added:
Note that the Screening Period and Baseline visits may occur on the same day (ie, Screening period 
activities may be completed on Day 0). For all study visits, up to 48 hours is allowed for completion of 
study activities.
Other sections impacted by this change:  Synopsis, Study Design; Section 8, Study Activities; Section 8.2, 
Baseline Visit; Appendix 1, Group 1—Prospective Patient Group Study Schedule of Events
Change:  Exclusion criterion regarding hypersensitivity to active substance or excipients added for Group 1:  
Prospective Patient Group
Section impacted by this change:  Section 5.1.2, Group 1—Prospective Patient Group Population Exclusion 
Criteria
Revised Text: 
6.
The patient has a history of severe or life-threatening hypersensitivity to the active substance or 
to any of the excipients if hypersensitivity is not controllable.
Other sections impacted by this change:  Synopsis, Study Patient Inclusion and Exclusion Criteria
Change:  Clarification concerning treatment
Section impacted by this change:  Section 6.2, Treatment(s) Administered
Revised Text: 
The dose of Elaprase administered will be calculated based on the patient’s weight at each visit. Details on 
Elaprase storage, preparation, and administration procedures are provided outlined in the Pharmacy Study 
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Operations Manual. Refer to country-specific prescribing information for details concerning 
commercially sourced drug.
Other sections impacted by this change:  Not applicable
Change:  Clarification concerning restrictions
Section impacted by this change:  Section 6.7.2, Fluid and Food Intake
Revised Text: 
Not applicable. Patients are to follow Elaprase current country specific prescribing information throughout 
the course of this study.
Other sections impacted by this change:  Not applicable
Change:  Home infusion of Elaprase by a trained healthcare provider allowed, with Sponsor approval
Section impacted by this change:  Section 6.8, Treatment Compliance
Revised Text: 
All enrolled patients will receive once weekly treatment with Elaprase under the oversight of the 
Investigator. Treatment with Elaprase treatment will be administered in a clinical setting or may be 
administered in the patient’s home (with Sponsor approval) after the patient has completed at least 6 
months of treatment in a hospital setting by appropriately trained and skilled healthcare providers (nurses 
or physicians) with knowledge of the patient’s drug regimen and in the controlled environment of a clinical 
center; therefore, full patient compliance with treatment is anticipated in this study. The home healthcare 
provider will record details of infusions administered at the patient’s home to ensure treatment 
compliance and document any AEs.
Other sections impacted by this change:  Section 8.3, Treatment Period (Day 1 [or Day 2] to End of Study 
Visit); Appendix 1, Group 1—Prospective Patient Group Study Schedule of Events
Change:  Clarification concerning storage and accountability
Section impacted by this change:  Section 6.10, Storage and Accountability
Revised Text: 
6.10 Storage and Accountability
See the Pharmacy Study Operations Manual, or approved labeling, as applicable, for details on product
storage and accountability.
6.10.2 Investigational Product  Retention at Study Site
See the Pharmacy Study Operations Manual for details on product storage and accountability.
Other sections impacted by this change:  Not applicable
Change:  Clarification to product administration
Section impacted by this change:  Section 7.9, Elaprase Administration
Revised Text: 
Not applicable. Idursulfase will be administered as a continuous IV infusion over a minimum of 3 
hours at a dose of 0.5 mg/kg. Details on Elaprase administration procedures are provided in the 
Pharmacy Manual. 
Refer to country-specific prescribing information for details concerning administration of 
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commercially sourced drug.
Other sections impacted by this change:  Appendix 1, Group 1—Prospective Patient Group Study Schedule 
of Events
Change:  Clarification to the instructions for obtaining height measurements
Section impacted by this change:  Section 7.12.1, Height and Weight
Revised Text: 
7.12.1 Height and Weight
Height and weight measurements over time will be collected and recorded for all patients. The following 
specific guidance should be used to for obtaining height and weight measurements. The procedures are 
based on the training module available from the US Health Services and Resources Administration 
(HRSA).
7.12.1.1 Height 
•
For patients ≥2 years of age, or for patients who can stand on their own: height measurements should 
be collected measured using a calibrated stadiometer which is calibrated at regular intervals. Two 
independent height measurements should be collected and the results recorded to the nearest 0.1 
centimeter. If the measurements do not agree within 0.5 centimeter, re-measure for a third time.
The method of collecting height measurements should be standardized across all sites (eg, instruction to 
stand looking straight ahead with the chin parallel to the floor, arms by the sides of the trunk with palms 
facing the thighs, and back of the head, scapulae, buttocks, and heels positioned against the vertical 
backboards of the stadiometer; no socks shoes or hats are to be worn during measurements; collection 
of 3 reproducible measurements; same calibration frequency).
•
For patients less than <2 years of age, or patients who cannot stand on their own: length should have 
their lengths be measured using a fixed headboard. Two individuals should conduct the 
measurement; 1 person positioning the child and the other collecting the length measurement. 
Two independent length measurements should be collected and the results recorded to the nearest 
0.1 centimeter. If the measurements do not agree within 1 centimeter, re-measure for a third time. 
The method of collecting length measurements should be standardized across all sites (eg, 
placement of the child supine on the measuring board, checking that the child lies straight on the 
board and does not change position, shoulders touching the board; spine should not be arched. 
The child’s legs are held down with 1 hand, applying gentle pressure to the knees to straighten the 
legs without causing injury, while the footboard is moved to a position against the child’s feet with 
the other hand. The soles of the feet should be flat against the board with toes pointing upwards).
7.12.1.2 Weight
Weight measurements should be obtained from scales that have been calibrated at regular intervals. 
•
For patients ≥2 years of age, or who can stand on their own: weight measurements should be 
collected with the child standing, without assistance, on a calibrated beam balance or electronic 
scale. Two independent weight measurements should be collected and the results recorded to the 
nearest 0.1 kilogram. If the measurements do not agree within 0.3 kilogram, re-measure for a 
third time. The method of collecting weight measurements should be standardized across all sites 
(eg, weight to be collected with the child standing on the center of the scale and wearing only 
lightweight undergarments or a gown).
•
For patients less than <2 years of age, or patients who cannot stand on their own: weight 
measurements should be collected using an infant scale. Two independent weight measurements 
should be collected and the results recorded to the nearest 0.1 kilogram. If the measurements do 
not agree within 0.3 kilogram, re-measure for a third time. The method of collecting weight 
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measurements should be standardized across all sites (eg, the child is nude or wearing a clean, dry 
diaper and positioned in the center of the scale tray).
Other sections impacted by this change:  Not applicable
Change:  Clarification that the 6MWT will be conducted in patients able to walk
Section impacted by this change:  Section 7.12.4, Distance Walked
Revised Text: 
Distance Walked
The 6MWT will be conducted according to the American Thoracic Society guidelines for the 6MWT for 
patients who are able to comply with this assessment walk. 
Other sections impacted by this change:  Synopsis, Outcome Assessments
Change:  Clarification to adverse events assessments
Section impacted by this change:  Section 7.17 Adverse Events Assessments
Revised Text: 
Adverse events will be collected at weekly Elaprase infusions and at each study visit for enrolled patients 
(Group 1—Prospective Patient Group only). Instructions for recording and reporting AEs are provided in 
Section 7.17.3. 
Other sections impacted by this change:  Section 7.17.3.1, Adverse Event Monitoring and Period of 
Observation; Appendix 1, Group 1—Prospective Patient Group Study Schedule of Events
Change:  Addition of section to define infusion-related adverse reactions
Section impacted by this change:  Section 7.17.1, Definitions of Adverse Events and Serious Adverse 
Events
Revised Text: 
Section 7.17.1.3 Infusion-Related Adverse Reaction
An infusion-related adverse reaction will be defined as an AE that 1) occurs on the day of the infusion, 
ie, within 24 hours following the infusion, 2) begins either during or after the infusion, and 3) is 
judged as possibly or probably related to idursulfase infusion.
Other sections impacted by this change:  Not applicable
Change:  Clarification to the AE severity scale and inclusion of definitions for AE relatedness terms
Section impacted by this change:  Section 7.17.2, Classification of Adverse Events and Serious Adverse 
Events
Revised Text: 
The severity of AEs will be assessed by the Investigator based on the definitions shown in using the 
National Cancer Institute Common Toxicity Criteria (NCI CTC) grading scale (provided in the Study 
Operations Manual). If an AE is not described in the NCI CTC, the severity should be recorded based on the 
scale in Table 7-3. The severity of all AEs/SAEs should be recorded on the appropriate CRF page as Grade 
1, 2, or 3 corresponding, respectively, to a severity of mild, moderate, or severe.
Table 7-3
Adverse Event Severity
Severity
Definition
Grade 1 (Mild) Mild
No limitation of usual activities.
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Change:  Clarification that Baseline is not defined strictly as Day 0
Section impacted by this change:  Section 10.8, Efficacy Analyses
Revised Text: 
Descriptive summaries will generally present the data overall and by visit from Study SHP-ELA-401 
Baseline (defined as Day 0) for the Prospective Population. 
Other sections impacted by this change:  Section 4.1, Overall Study Design and Plan; Section 10.7, Analysis 
of Safety
Change:  Removal of footnote pertaining to first height and weight measurements within 3 months of first 
dose of Elaprase
Section impacted by this change:  Appendix 1, Group 1—Prospective Patient Group Study Schedule of 
Events
Revised Text: 
Footnote f modified:
f
First height and weight assessments must be within 3 months of the first dose of Elaprase. Height and 
weight assessments must be performed per standardized methodology, described in the protocol (refer 
to Section 7.12.1). 
Other sections impacted by this change:  Not applicable
Change:  Clarification to footnote concerning Elaprase administration
Section impacted by this change:  Appendix 1, Group 1—Prospective Patient Group Study Schedule of 
Events
Revised Text: 
Footnote g modified:
g
The first dose of Elaprase must be administered after all assessments are completed for Baseline at Day 
0 and within 1 week after the completion of the baseline assessments. Thereafter, Elaprase will be 
administered weekly throughout the study. Details on administration procedures are provided in the 
Pharmacy Manual; refer to country-specific prescribing information for details concerning 
administration of commercially sourced drug. Elaprase treatment will be administered under the 
oversight of the Investigator in a clinical setting or may be administered in the patient’s home 
(with Sponsor approval) after the patient has completed at least 6 months of treatment in a 
hospital setting, by appropriately trained and skilled healthcare providers (nurses or physicians) with 
knowledge of the patient’s drug regimen and in the controlled environment of a clinical center.
Other sections impacted by this change:  Section 6.8, Treatment Compliance, Section 7.9 Elaprase 
Administration; Section 8.3 Treatment Period (Day 1 [or Day 2] to End of Study Visit)
Change:  addition of footnote clarifying AE collection
Section impacted by this change:  Appendix 1, Group 1—Prospective Patient Group Study Schedule of 
Events
Revised Text: 
Footnote h added:
h
Adverse events will be collected at weekly Elaprase infusions and at each study visit.
Other sections impacted by this change: Section 7.17, Adverse Events Assessments; Section 7.17.3.1, 
Adverse Event Monitoring and Period of Observation
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