A Prospective, Multicenter, Single-arm, Open-label, Interventional Phase IV Study to Evaluate the Safety and Efficacy of Idursulfase (r-DNA Origin) (Elaprase™) in Indian Pediatric and Adult Population With Hunter Syndrome (Mucopolysaccharidosis II)
Phase: PHASE4
Conditions: Hunter Syndrome
Sponsor: Takeda

NCT Number: NCT05058391
Title: A Prospective, Multicenter, Single-arm, Open-label, Interventional Phase IV 
Study to Evaluate the Safety and Efficacy of  Idursulfase (r-DNA origin) 
(Elaprase™)  in Indian Pediatric and Adult Population With Hunter Syndrome 
(Mucopolysaccharidosis II) 
Study Number: TAK-665-4001
Document Version and Date: Version 3.0, 27 October 2022
Certain information within this document has been redacted (ie, specific content is masked 
irreversibly from view) to protect either personally identifiable information or company 
confidential information. 
Clinical Study Protocol 
For non-commercial use only

Elaprase 
Study No.  TAK-665-4001 
Page 1 of 87 
Protocol Version 3.0 
  27 October 2022 
CONFIDENTIAL 
PROTOCOL 
A Prospective, Multicenter, Single-arm, Open-label, Interventional Phase IV Study to 
Evaluate the Safety and Efficacy of Idursulfase (r-DNA origin) (Elaprase™) in Indian 
Pediatric and Adult Population with Hunter Syndrome (Mucopolysaccharidosis II) 
Sponsor: 
Takeda Biopharmaceuticals India Pvt. Ltd. 
Building No. 8, 6th Floor, Tower C 
DLF Cyber City 
Gurgaon 122002 
Haryana, India 
Study Number: 
TAK-665-4001 
IND Number: 
Not Applicable 
EudraCT Number: 
Not Applicable 
Compound: 
Idursulfase (r-DNA origin) (Elaprase™) 
Date: 
  27 October 2022 
Version: 
3.0 
CONFIDENTIAL PROPERTY OF TAKEDA 
This document is a confidential communication of Takeda. Acceptance of this document constitutes the 
agreement by the recipient that no information contained herein will be published or disclosed without written 
authorization from Takeda except to the extent necessary to obtain informed consent from those persons to 
whom the drug may be administered. Furthermore, the information is only meant for review and compliance by 
For non-commercial use only

Elaprase 
Study No.  TAK-665-4001 
Page 2 of 87 
Protocol Version 3.0 
  27 October 2022 
CONFIDENTIAL 
the recipient, his or her staff, and applicable institutional review committee and regulatory agencies to enable 
conduct of the study. 
For non-commercial use only

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Elaprase 
 
Study No.  TAK-665-4001 
Page 4 of 87 
Protocol Version 3.0 
  27 October 2022 
 
CONFIDENTIAL 
1.2 
Approval  
REPRESENTATIVES OF TAKEDA  
This study will be conducted with the highest respect for the individual subjects in accordance 
with the requirements of this study protocol and also in accordance with the following: 
• 
The ethical principles that have their origin in the Declaration of Helsinki. 
• 
International Conference on Harmonisation E6 Good Clinical Practice: Consolidated 
Guideline. 
• 
All applicable laws and regulations, including, without limitation, data privacy laws, 
clinical trial disclosure laws, and regulations. 
SIGNATURES 
The signature of the responsible Takeda medical officer and other signatories can be found on 
the signature page. 
Dr 
 
-India, Takeda Date 
 
 
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Elaprase 
 
Study No.  TAK-665-4001 
Page 5 of 87 
Protocol Version 3.0 
  27 October 2022 
 
CONFIDENTIAL 
INVESTIGATOR AGREEMENT  
I confirm that I have read and that I understand this protocol, package insert and any other 
product information provided by the sponsor. I agree to conduct this study in accordance with 
the requirements of this protocol and also to protect the rights, safety, privacy, and well-being 
of study subjects in accordance with the following: 
• 
The ethical principles that have their origin in the Declaration of Helsinki. 
• 
International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline. 
• 
All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations. 
• 
Regulatory requirements for reporting serious adverse events defined in Section 10.2 of 
this protocol. 
• 
Terms outlined in the study site agreement. 
• 
Responsibilities of the Investigator. (Appendix B) 
I further authorize that my personal information may be processed and transferred in 
accordance with the uses contemplated in Error! Reference source not found. of this 
protocol. 
 
Signature of Investigator 
Date 
Investigator Name (print or type) 
 
 
Investigator’s Title 
 
 
Location of Facility (City, State/Provence) 
 
 
Location of Facility (Country) 
 
 
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Study No.  TAK-665-4001 
Page 6 of 87 
Protocol Version 3.0 
  27 October 2022 
 
CONFIDENTIAL 
TABLE OF CONTENTS 
1.0 
ADMINISTRATIVE INFORMATION ............................................................... 3 
1.1 
Contacts........................................................................................................ 3 
1.2 
Approval ...................................................................................................... 4 
1.3 
Protocol version Summary of Changes......................................................... 11 
2.0 
STUDY SUMMARY........................................................................................ 14 
3.0 
STUDY REFERENCE INFORMATION .......................................................... 19 
3.1 
Study-Related Responsibilities .................................................................... 19 
3.2 
Principal Investigator/Coordinating Investigator........................................... 19 
3.3 
List of Abbreviations................................................................................... 20 
3.4 
Corporate Identification .............................................................................. 21 
4.0 
INTRODUCTION ............................................................................................ 22 
4.1 
Background ................................................................................................ 22 
4.1.1 
Elaprase .............................................................................................. 23 
4.2 
Rationale for the Proposed Study ................................................................. 23 
4.3 
Benefit/Risk Profile..................................................................................... 23 
5.0 
STUDY OBJECTIVES AND ENDPOINTS ...................................................... 23 
5.1 
Objectives................................................................................................... 23 
5.1.1 
Primary Objective ............................................................................... 23 
5.1.2 
Secondary Objective............................................................................ 24 
5.2 
Endpoints ................................................................................................... 24 
5.2.1 
Primary Endpoint ................................................................................ 24 
5.2.2 
Secondary Endpoints ........................................................................... 24 
6.0 
STUDY DESIGN AND DESCRIPTION ........................................................... 24 
6.1 
Study Design .............................................................................................. 24 
6.2 
Justification for Study Design, Dose, and Endpoints..................................... 26 
6.3 
Premature Termination or Suspension of Study or Study Site ....................... 27 
6.3.1 
Criteria for Premature Termination or Suspension of the Study ............. 27 
6.3.2 
Criteria for Premature Termination or Suspension of Study Sites .......... 27 
6.3.3 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Sites.................................................................. 27 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS.... 27 
7.1 
Inclusion Criteria ........................................................................................ 27 
7.2 
Exclusion Criteria ....................................................................................... 28 
7.3 
Excluded Medications ................................................................................. 29 
7.4 
Criteria for Discontinuation or Withdrawal of a Subject ............................... 29 
7.5 
Procedures for Discontinuation or Withdrawal of a Subject .......................... 30 
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Protocol Version 3.0 
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CONFIDENTIAL 
8.0 
CLINICAL STUDY MATERIAL MANAGEMENT ......................................... 30 
8.1 
Study Drug and Materials ............................................................................ 31 
8.1.1 
Dosage Form, Manufacturing, Packaging, and Labeling ....................... 31 
8.1.1.1 
Study Drug.................................................................................. 31 
8.1.1.2 
Packaging and Labelling .............................................................. 32 
8.1.2 
Storage ............................................................................................... 32 
8.1.3 
Dose and Regimen .............................................................................. 33 
8.1.4 
Overdose............................................................................................. 33 
8.2 
Study Drug Assignment and Dispensing Procedures..................................... 33 
8.3 
Accountability and Destruction of Sponsor-Supplied Drugs.......................... 33 
9.0 
STUDY PLAN ................................................................................................. 35 
9.1 
Study Procedures ........................................................................................ 35 
9.1.1 
Informed Consent Procedure................................................................ 35 
9.1.2 
Demographics, Medical History, and Medication History Procedure ..... 35 
9.1.3 
Physical Examination Procedure .......................................................... 35 
9.1.4 
Weight, Height .................................................................................... 35 
9.1.5 
Vital Sign Procedure ........................................................................... 36 
9.1.6 
Documentation of Concomitant Medications ........................................ 36 
9.1.7 
Documentation of Concurrent Medical Conditions ............................... 36 
9.1.8 
Primary Efficacy Measurement ............................................................ 36 
9.1.8.1 
Percentage Forced Vital Capacity (% FVC) .................................. 36 
9.1.8.2 
6 Minute Walk Test (6MWT)....................................................... 36 
9.1.8.3 
Cardiac Left Ventricular Mass Index (LVMI) and Ejection Fraction
 ................................................................................................... 37 
9.1.8.4 
Liver Volume .............................................................................. 37 
9.1.8.5 
Spleen Volume ............................................................................ 37 
9.1.8.6 
Glycosaminoglycan ..................................................................... 37 
9.1.8.7 
Global Joint Range of Motion (JROM)......................................... 37 
9.1.8.8 
Anthropometric Parameters.......................................................... 38 
9.1.9 
Health-related Quality of Life (HRQoL) Measures ............................... 38 
9.1.9.1 
Hunter Syndrome-Functional Outcomes for Clinical Understanding 
Scale (HS-FOCUS) ..................................................................... 38 
9.1.9.2 
Childhood Health Assessment Questionnaire (CHAQ).................. 39 
9.1.10 Procedures for Clinical Laboratory Samples ......................................... 39 
9.1.11 Contraception and Pregnancy Avoidance Procedure ............................. 40 
9.1.11.1 Male Subjects and Their Female Partners ..................................... 40 
9.1.11.2 Female Subjects and Their Male Partners ..................................... 40 
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Study No.  TAK-665-4001 
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Protocol Version 3.0 
  27 October 2022 
 
CONFIDENTIAL 
9.1.11.3 Definitions and Procedures for Contraception and Pregnancy 
Avoidance ................................................................................... 40 
9.1.11.4 General Guidance With Respect to the Avoidance of Pregnancy ... 42 
9.1.12 Pregnancy ........................................................................................... 43 
9.1.13 ECG Procedure ................................................................................... 43 
9.1.14 Documentation of Screen Failure ......................................................... 43 
9.1.15 Documentation of Study Entrance........................................................ 44 
9.2 
Monitoring Subject Treatment Compliance .................................................. 44 
9.3 
Schedule of Observations and Procedures .................................................... 44 
9.3.1 
Screening/Visit 1/Days -14 to -1 .......................................................... 44 
9.3.2 
Study Enrollment/Treatment Phase ...................................................... 45 
9.3.2.1 
Baseline Visit/Week 1, Day 1/Visit 2 ........................................... 45 
9.3.2.2 
Visit 3 (Week 2, Day 8) through Visit 53 (Week 52, Day 358) ...... 46 
9.3.2.3 
Efficacy Assessment Visit 28 (Week 27, Day 183) ....................... 46 
9.3.3 
Final Visit/Early Termination/End of Study/Visit 54/Week 53/Day 365 47 
9.3.4 
Unscheduled Visit ............................................................................... 47 
9.3.5 
Post Study Care................................................................................... 48 
10.0 
PRETREATMENT EVENTS AND ADVERSE EVENTS ................................. 48 
10.1 
Definitions .................................................................................................. 48 
10.1.1 PTEs................................................................................................... 48 
10.1.2 AEs .................................................................................................... 48 
10.1.3 Additional Points to Consider for PTEs and AEs .................................. 48 
10.1.4 SAEs .................................................................................................. 50 
10.1.5 ADRs ................................................................................................. 51 
10.1.6 Intensity of PTEs and AEs ................................................................... 52 
10.1.7 Causality of AEs ................................................................................. 52 
10.1.8 Relationship to Study Procedures ......................................................... 52 
10.1.9 Start Date ............................................................................................ 52 
10.1.10 Stop Date ............................................................................................ 53 
10.1.11 Frequency ........................................................................................... 53 
10.1.12 Action Concerning Study Drug ............................................................ 53 
10.1.13 Outcome ............................................................................................. 54 
10.2 
Procedures .................................................................................................. 54 
10.2.1 Collection and Reporting of AEs.......................................................... 54 
10.2.1.1 PTE and AE Collection Period ..................................................... 54 
10.2.1.2 PTE and AE Reporting ................................................................ 54 
10.2.2 Collection and Reporting of SAEs ....................................................... 55 
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Study No.  TAK-665-4001 
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Protocol Version 3.0 
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CONFIDENTIAL 
10.3 
Follow-up of SAEs ..................................................................................... 56 
10.3.1 Safety Reporting to Investigators, IRBs or IECs, and Regulatory 
Authorities .......................................................................................... 56 
11.0 
STUDY-SPECIFIC COMMITTEES ................................................................. 57 
12.0 
DATA HANDLING AND RECORDKEEPING ................................................ 58 
12.1 
CRFs (Electronic) ....................................................................................... 58 
12.2 
Record Retention ........................................................................................ 58 
13.0 
STATISTICAL METHODS.............................................................................. 59 
13.1 
Statistical and Analytical Plans .................................................................... 59 
13.1.1 Analysis Sets....................................................................................... 59 
13.1.2 Analysis of Demographics and Other Baseline Characteristics .............. 60 
13.1.3 Efficacy Analysis ................................................................................ 60 
13.1.4 Safety Analysis ................................................................................... 60 
13.1.4.1 Physical Examination .................................................................. 61 
13.1.4.2 Vital Signs .................................................................................. 61 
13.1.4.3 Laboratory assessments ............................................................... 61 
13.1.4.4 12-Lead ECG .............................................................................. 61 
13.1.4.5 Individual data listings of 12-lead ECG will be presented.Urine 
Pregnancy Test ............................................................................ 62 
13.2 
Interim Analysis and Criteria for Early Termination ..................................... 62 
13.3 
Determination of Sample Size ..................................................................... 62 
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE ................................... 62 
14.1 
Study-Site Monitoring Visits ....................................................................... 62 
14.2 
Protocol Deviations..................................................................................... 62 
14.3 
Quality Assurance Audits and Regulatory Agency Inspections ..................... 63 
15.0 
ETHICAL ASPECTS OF THE STUDY ............................................................ 63 
15.1 
IRB/IEC Approval ...................................................................................... 63 
15.2 
Subject Information, Informed Consent, and Subject Authorization .............. 64 
15.3 
Subject Confidentiality................................................................................ 65 
15.4 
Publication, Disclosure, and Clinical Trial Registration Policy...................... 66 
15.4.1 Publication and Disclosure .................................................................. 66 
15.4.2 Clinical Trial Registration.................................................................... 66 
15.4.3 Clinical Trial Results Disclosure .......................................................... 66 
15.5 
Insurance and Compensation for Injury........................................................ 67 
16.0 
REFERENCES ................................................................................................. 67 
 
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Study No.  TAK-665-4001 
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Protocol Version 3.0 
  27 October 2022 
 
CONFIDENTIAL 
LIST OF IN-TEXT TABLES 
Table 9-a: Clinical Laboratory Tests ............................................................................. 39 
 
LIST OF IN-TEXT FIGURES 
Figure 6.a 
Schematic of Study Design .................................................................... 26 
 
LIST OF APPENDICES 
Appendix A Schedule of Study Procedures ................................................................ 70 
Appendix B Responsibilities of the Investigator......................................................... 75 
Appendix C Elements of the Subject Informed Consent ............................................. 76 
Appendix D Investigator Consent to Use of Personal Information............................... 78 
Appendix E 
Hunter Syndrome – Functional Outcomes For Clinical Understanding Scale 
(HS-FOCUS); Parent Completed Questionnaire (Shortened version) ....... 79 
Appendix F 
Childhood Health Assessment Questionniare (CHAQ)............................ 83 
Appendix G Elaprase Package Insert for India ........................................................... 86 
Appendix H Detailed Description of Amendments to Text ......................................... 87 
 
 
 
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Study No.  TAK-665-4001 
Page 11 of 87 
Protocol Version 3.0 
  27 October 2022 
 
CONFIDENTIAL 
 
1.3 
Protocol version Summary of Changes 
Applicable Sections 
Original text from 
the study protocol  
Protocol version 2.0, 
dated 22 February 
2021 
(Struck-out text is 
text deleted) 
Amended text 
Protocol version 3.0, 
dated 27 October 
2022 
(Bold underlined text 
is the new text added) 
Justification 
Sponsor Name 
Shire Biotech India 
Pvt. Ltd. 
Plot No. 70, A-26, 
Second Floor, Rama 
Road, Industrial 
Area, 
New Delhi – 
110015, India 
Takeda 
Biopharmaceuticals 
India Pvt. Ltd. 
Floor 6th, Building 
No.8, Tower C, 
Cyber City, 
Gurgaon-122002, 
India 
Change in entity 
name 
Section 1.1 - 
Contacts 
TDC sponsored 
investigators per 
individual country 
requirements will be 
provided with 
emergency medical 
contact information 
cards to be carried 
by each subject. 
 
Change in entity 
name & study is 
India specific 
Section 3.4 – 
Corporate 
Identification 
TDC Asia – Takeda 
Development Centre 
Asia Pte Ltd. 
Takeda India – 
Takeda 
Biopharmaceuticals 
India Pvt. Ltd. 
Change in entity 
name 
 
 
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Elaprase 
 
Study No.  TAK-665-4001 
Page 12 of 87 
Protocol Version 3.0 
  27 October 2022 
 
CONFIDENTIAL 
Applicable 
Sections 
Original text from the 
study protocol  
Protocol version 1.0, 
dated 08 September 
2020 
(Struck-out text is text 
deleted) 
Amended text 
Protocol version 2.0, dated 24 February 
2021 
(Bold underlined text is the new text 
added) 
Justification 
Study Title 
and Section 
2 
A Prospective, 
Multicenter, Single-arm, 
Open-label, 
Interventional Phase IV 
Study to Evaluate the 
Safety and Efficacy of 
Elaprase in Indian 
Pediatric and Adult 
Population with Hunter 
Syndrome 
(Mucopolysaccharidosis 
II) 
 
A Prospective, Multicenter, Single-
arm, Open-label, Interventional Phase 
IV Study to Evaluate the Safety and 
Efficacy of Idursulfase (r-DNA 
origin) (Elaprase™)  in Indian 
Pediatric and Adult Population with 
Hunter Syndrome 
(Mucopolysaccharidosis II) 
 
Title updated 
to include the 
product INN 
name. 
Section 2 
Study 
Summary 
and 
Section 7.1  
Male or female* 
Elaprase naïve subjects 
of any age with 
confirmed diagnosis of 
Hunter syndrome based 
on the following 
documented 
biochemical and 
genetic criteria: 
 
Male or female* Elaprase naïve subjects 
(and who are not part of any other 
program at the time of study 
enrollment and during the study 
period) of any age with confirmed 
diagnosis of Hunter syndrome based on 
the following documented biochemical 
and genetic criteria: 
 
Recommendat
ions from 
SEC (meeting 
held on 19th 
January 2021) 
Section 2 
Study 
Summary 
and 
Section 7.2 
The subject has a chronic 
kidney disease and is on 
dialysis  
 
The subject has a chronic kidney 
disease with estimated Glomerular 
Filtration rate less than 15 
mL/min/1.73 m2  and/or is on dialysis  
 
Recommendat
ions from 
SEC (meeting 
held on 19th 
January 2021) 
 
 
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Study No.  TAK-665-4001 
Page 13 of 87 
Protocol Version 3.0 
  27 October 2022 
 
CONFIDENTIAL 
Section 7.4 7. Lack of efficacy. The 
investigator has 
determined that the 
subject is not 
benefiting from study 
treatment; and, 
continued 
participation would 
pose an unacceptable 
risk to the subject 
7. Lack of efficacy. The investigator has 
determined that the subject is not 
benefiting from study treatment; and, 
continued participation would pose 
an unacceptable risk to the subject.  
Lack of efficacy shall be defined 
as below: 
Patients fulfilling all of the below 
criteria should be evaluated by 
the 
treating 
investigators to 
withdraw the patient from further 
continuing Elaprase 
1. No change in normalized urine 
GAG (uGAG) from baseline at 
week 27 
2. No change or increase in liver 
and spleen volumes from baseline 
at week 27 
3. No improvement or decline in 
cardiac function as assessed by 
left ventricular mass index and 
ejection fraction from baseline at 
week 27  
4. No improvement or decline in 
6 Minute Walk Test (6MWT)  and 
percentage Forced Vital Capacity 
(%FVC)  from baseline at week 27 
(Change 
in 
anthropometric 
measurements 
can 
also 
be 
considered for patients with age 
less than 18 years) 
5. No improvement or decline in 
health-related quality 
of life 
(HRQoL)  from baseline at week 
27 
Recommendat
ions from 
SEC (meeting 
held on 19th 
January 2021) 
For non-commercial use only

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D

Elaprase 
Study No.  TAK-665-4001 
Page 16 of 87 
Protocol Version 3.0 
  27 October 2022 
CONFIDENTIAL 
2.0 
STUDY SUMMARY 
Name of Sponsor(s): 
Takeda Biopharmaceuticals India Pvt. Ltd. 
Compound: 
Idursulfase (r-DNA origin) (Elaprase™) 
Title of Protocol: A Prospective, Multicenter, Single-
arm, Open-label, Interventional Phase IV Study to 
Evaluate the Safety and Efficacy of  Idursulfase (r-
DNA origin) (Elaprase™)  in Indian Pediatric and 
Adult Population With Hunter Syndrome 
(Mucopolysaccharidosis II) 
IND No.: Not 
Applicable 
EudraCT No.: 
Not Applicable 
Study Number: TAK-665-4001 
Phase: 4 
Study Design: 
This is a prospective, open-label, multicenter, interventional single-arm Phase IV study to be conducted at 
multiple sites in India to evaluate the safety and efficacy of Elaprase in Indian pediatric and adult population 
with Hunter syndrome (Mucopolysaccharidosis II [MPS II]).  
A total of 5 subjects with Hunter syndrome (MPS II) will be enrolled in this study. The total duration of the 
study for each subject will be up to 55 weeks, consisting of 14 days screening period (Days -14 to -1), a 52-
weeks treatment period (Week 1 to Week 52), followed by 1 week follow-up period after the last dose of 
Elaprase (Week 53). At Week 53, the subject will be assessed for safety and efficacy which will also be 
considered the end of study (EOS). The total duration of the study will be approximately 3 years, based on the 
anticipated recruitment rate, however the study duration may get extended beyond 3 years until the last enrolled 
subject completes the EOS visit. 
After obtaining written informed consent from the subjects or their parents/guardians/legally authorized 
representatives (LARs), the subjects will be screened. An assent form will be provided and should be signed by 
subjects of ≥7 to <18 years of age. Subjects who meet all the inclusion criteria and none of the exclusion criteria 
will be administered Elaprase at the site. Subjects will visit the site for dosing on Week 1, Day 1 followed by 
every week till Week 52, Day 358. The visit on Week 52, Day 358 will be considered as end of treatment 
(EOT). The study drug will be administered as 0.5 mg/kg given intravenously every week. The intravenous 
infusion will be administered over a 3 hour period, which may be gradually reduced to 1 hour if no 
infusion-associated reactions are observed. 
Efficacy assessments will be done at Week 27, Day 183 and Week 53, Day 365. Urine glycosaminoglycan 
(uGAG) and clinical laboratory assessments will also be done at at Week 14, Day 92 and Week 40, Day 27. If 
the subject discontinues study treatment, the subject will have to complete assessments done at Week 53, Day 
365 (Visit 54/EOS). Subjects will be evaluated for safety from initiation of Elaprase treatment until 53 weeks 
(EOS), or for at least 1 week following discontinuation of Elaprase, whichever occurs earlier.  
A subject diary will be provided to the subjects/subject’s parents/guardians/LAR to be filled at home. The diary 
will be used to capture information of any concomitant medications taken, and other adverse events (AEs) that 
may occur in between visits.  
Apart from that, an unscheduled visit can be performed at investigator’s discretion or if the trial subject 
experiences safety concerns. 
Primary Objectives: 
•
To evaluate the safety of Elaprase in pediatric and adult subjects with Hunter syndrome during
53 weeks of study duration.
Secondary Objectives: 
For non-commercial use only

Elaprase 
Study No.  TAK-665-4001 
Page 17 of 87 
Protocol Version 3.0 
  27 October 2022 
CONFIDENTIAL 
•
To evaluate the efficacy of Elaprase in pediatric and adult subjects with Hunter syndrome during
53 weeks of study duration.
Subject Population:  
Male or female subjects of any age with confirmed diagnosis of Hunter syndrome. 
Number of Subjects: 
5 subjects will be enrolled in this study 
Number of Sites:  
Approximately 4-5 Sites in India 
Dose Level: 
Elaprase is administered at a dose of 0.5 mg/kg body 
weight every week by intravenous infusion over a 3 hour 
period, which may be gradually reduced to 1 hour if no 
infusion-associated reactions are observed. 
Route of Administration: 
Intravenous 
Duration of Treatment: 
52 weeks 
Period of Evaluation: 
The study duration for each subject will be 
approximately 55 weeks, which will include 14 days 
of screening, 52 weeks of treatment, and 1 week 
follow-up after the last dose of Elaprase (Week 53). 
At Week 53, the subject will be assessed for safety 
and efficacy which will also be considered as the 
EOS. The total duration of the study will be 
approximately 3 years, based on the anticipated 
recruitment rate, however the study duration may 
get extended beyond 3 years until the last enrolled 
subject completes the EOS visit. 
Main Criteria for Inclusion: 
•
Male or female* Elaprase naïve subjects (and who are not part of any other program at the time of
study enrollment and during the study period) of any age with confirmed diagnosis of Hunter syndrome 
based on the following documented biochemical and genetic criteria:
-
Documented deficiency in iduronate 2-sulfatase (IDS [12S]) enzyme activity of less than or
equal to 10% of the lower limit of the normal range as measured in plasma, fibroblasts, or
leukocytes (based on normal range of measuring laboratory).
-
A normal enzyme activity level of one other sulfatase as measured in plasma, fibroblasts, or
leukocytes (based on normal range of measuring laboratory).
-
The patient has a documented mutation in the IDS gene.
*It is known that Hunter syndrome almost exclusively affects males and it is highly unlikely that females will
be affected by Hunter syndrome.
Main Criteria for Exclusion: 
•
Subject has received hematopoietic stem cell transplantation or a bone marrow transplant at any time.
•
Subject is suffering from any comorbid conditions (including hepatic impairment, acute or chronic) or
having any other clinical observation or history during the screening examination, which would
interfere with the objectives of the study as per investigators judgement.
•
The subject has a chronic kidney disease with estimated Glomerular Filtration rate less than 15
mL/min/1.73 m2 and/or is on dialysis.
For non-commercial use only

Elaprase 
 
Study No.  TAK-665-4001 
Page 18 of 87 
Protocol Version 3.0 
  27 October 2022 
 
CONFIDENTIAL 
• 
Subject has participated in any other clinical study or received any investigational compound or non-
investigational idursulfase beta within the past 30 days before informed consent. 
Main Criteria for Evaluation and Analyses: 
Primary endpoint 
The primary endpoint includes: 
• 
Incidence of AEs, serious AEs (SAEs), treatment emergent AEs, treatment emergent SAEs, adverse 
drug reactions (ADRs), discontinuation due to AEs, infusion-related reactions, and death. 
Secondary endpoints  
The secondary endpoints include: 
• 
Change from baseline in percentage Forced Vital Capacity (%FVC) as a measure of respiratory 
function at Weeks 27 and 53. 
• 
Change from baseline in 6 Minute Walk Test (6MWT) as a measure of physical functional capacity at 
Weeks 27 and 53.  
• 
Change from baseline in Cardiac Left Ventricular Mass Index (LVMI) and Ejection Fraction at Weeks 
27 and 53. 
• 
Change from baseline in liver volume at Weeks 27 and 53. 
• 
Change from baseline in spleen volume at Weeks 27 and 53. 
• 
Change from baseline in uGAG levels at Weeks 14, 27, 40, and 53. 
• 
Change from baseline in Global Joint Range of Motion (JROM) score at Weeks 27 and 53  
• 
Changes from baseline in anthropometric parameters including height in subjects <18 years at baseline 
and weight in all subjects at Weeks 27 and 53. 
• 
Changes from baseline in the health-related quality of life based on Hunter Syndrome-Functional 
Outcomes for Clinical Understanding Scale (HS-FOCUS) (shortened version) and Childhood Health 
Assessment Questionnaire (CHAQ) in subjects between age of ≥1 year to ≤18 years at Weeks 27 and 
53. 
Statistical Considerations: 
The statistical analysis will be carried out using available data from all subjects to be enrolled. The statistical 
analysis for this study will be descriptive in nature. Data on continuous and categorical scale will be expressed 
with appropriate descriptive statistics. It will include number of observations, mean, standard deviation, median, 
10th and 90th percentiles, minimum, maximum for continuous parameters, and proportions, frequency counts 
for categorical parameters, and 90% confidence intervals of point estimates as appropriate. Complete details of 
the statistical methodology will be described in a separate statistical analysis plan, to be finalized before 
database lock. 
Sample Size Justification: 
According to the observed recruitment trend from other published trial results on clinicalTrials.gov and 
considering the rarity of the disease (based on rare disease epidemiology with the estimated incidence of 0.6-1.3 
in 100,000 live male births) and the low availability of subjects, 5 Elaprase naive subjects whose disease 
condition is clinically confirmed will be enrolled. No formal sample size calculation is performed. 
For non-commercial use only

Elaprase 
 
Study No.  TAK-665-4001 
Page 19 of 87 
Protocol Version 3.0 
  27 October 2022 
 
CONFIDENTIAL 
3.0 
STUDY REFERENCE INFORMATION 
3.1 
Study-Related Responsibilities  
The sponsor will perform all study-related activities with the exception of those identified in 
the Study-Related Responsibilities template. The identified vendors for specific study-related 
activities will perform these activities in full or in partnership with the sponsor. 
3.2 
Principal Investigator/Coordinating Investigator 
Takeda will select a Signatory Coordinating Investigator from the investigators who participate 
in the study. Selection criteria for this investigator will include significant knowledge of the 
study protocol, the study drug, their expertise in the therapeutic area and the conduct of clinical 
research as well as study participation. The Signatory Coordinating Investigator will be required 
to review and sign the clinical study report and by doing so agrees that it accurately describes 
the results of the study. 
For non-commercial use only

Elaprase 
Study No.  TAK-665-4001 
Page 20 of 87 
Protocol Version 3.0 
  27 October 2022 
CONFIDENTIAL 
3.3 
List of Abbreviations 
Abbreviation 
Definition 
6MWT 
6 Minute Walk Test 
ADR 
adverse drug reaction 
AE 
adverse event 
ALP 
alanine phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
BPI 
Brief Pain Inventory 
CHAQ 
Childhood Health Assessment Questionnaire 
CRA 
clinical research associate 
CRO 
Contract Research Organization 
DCGI 
Drug Controller General of India 
DOH 
Declaration of Helsinki 
ECG 
Electrocardiogram 
Ecrf 
electronic case report form 
EOT 
end-of-treatment 
EOS 
end-of-study 
ERT 
enzyme replacement therapy  
FAS 
full analysis set 
FVC 
Forced vital capacity 
GCP 
Good Clinical Practice 
GGT 
gamma-glutamyl transferase 
hCG 
human chorionic gonadotropin 
HRQoL 
health related quality of life 
HSCT 
hematopoietic stem cell transplant 
HS-FOCUS 
Hunter Syndrome-Functional Outcomes for Clinical Understanding Scale 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IDS 
iduronate-2-sulfatase 
IEC 
Independent Ethics Committee  
IRB 
Institutional Review Board 
GAG 
Glycosaminoglycans 
JROM 
Joint Range of Motion 
LAR 
legal authorized representative 
LVMI 
Left ventricular mass index 
M6P 
mannose-6-phosphate 
MedDRA 
Medical Dictionary for Regulatory Activities 
PT 
preferred term 
PTE 
pretreatment event 
RBC 
red blood cell 
For non-commercial use only

Elaprase 
Study No.  TAK-665-4001 
Page 21 of 87 
Protocol Version 3.0 
  27 October 2022 
CONFIDENTIAL 
SAE 
serious adverse event 
SOC 
System Organ Class 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
USG 
Ultrasonography 
uGAG 
urine glycosaminoglycan 
WBC 
white blood cell 
3.4 
Corporate Identification 
Takeda India 
Takeda Biopharmaceuticals India Pvt. Ltd. 
For non-commercial use only

Elaprase 
Study No.  TAK-665-4001 
Page 22 of 87 
Protocol Version 3.0 
  27 October 2022 
CONFIDENTIAL 
4.0 
INTRODUCTION 
4.1 
Background 
Hunter syndrome (Mucopolysaccharidosis II) 
Hunter syndrome (Mucopolysaccharidosis II [MPS II]), is a rare X-linked lysosomal storage 
disorder caused by a deficiency of iduronate-2-sulfatase (IDS), involved in the catabolism of 
glycosaminoglycans (GAG) (1). Mutations in the IDS gene located at Xq28 are responsible for 
Hunter syndrome (2-5). Affected patients show a progressive accumulation of GAG in the 
lysosomes of many organs and tissues, which contribute to the clinical manifestations of Hunter 
syndrome. In Hunter syndrome, multiple organ systems are affected, with signs and symptoms 
usually emerging in the first few years of life. Disease presentation and rate of progression vary 
greatly, and the few manifestations of Hunter syndrome typically include recurrent respiratory 
infections, coarse facial features, joint stiffness, otitis media, umbilical/inguinal hernias, 
cardiomyopathies and hepatosplenomegaly (6,7); the characteristic short stature is usually 
apparent by ~8 years of age (8,9). Patients may also develop neurological symptoms, such as 
carpal tunnel syndrome, communicating hydrocephalus, spinal cord compression and hearing 
loss. For clinical purposes, patients are generally considered to fall into one of two categories 
according to the presence or absence of progressive central nervous system (CNS) involvement 
(typified by cognitive impairment, with behavioral difficulties and regression in developmental 
milestones), which occurs in as many as two-thirds of patients (10-14). The phenotypical 
spectrum of Hunter syndrome is variable: In patients with the neuronopathic (severe) form, the 
onset of clinical symptoms is usually between 2 and 4 years of age, with progressive neurologic 
symptoms that lead to cognitive impairment (1). This group of patients die in the first or second 
decade, usually due to obstructive airway disease and/or cardiac failure associated with 
progressive neurologic deterioration (1). On the other hand, patients with the non-neuronopathic 
(attenuated) form show milder somatic symptoms and minimal neurological involvement. 
These patients have normal intelligence and survive until their fifth or sixth decade (15,16). The 
disease is inherited in an X-linked manner and primarily affects males, although a small number 
of female patients have been described (17,18). 
The treatment of Hunter syndrome was palliative prior to the introduction of enzyme 
replacement therapy (ERT). Hematopoietic stem cell transplant (HSCT)/bone marrow 
transplant (BMT) for the treatment of patients with Hunter syndrome is not supported by 
consistent evidence of somatic or neurological symptom improvements (19)(20). In contrast, 
successful clinical trials (21,22) have led to the approval of ERT with human recombinant 
idursulfase (Elaprase, Takeda Human Genetic Therapies, Lexington, MA) by the United States 
Food and Drug Administration (FDA) in 2006 and European Medical Evaluation Agency 
(EMEA) and Japan in 2007.  
For non-commercial use only

Elaprase 
Study No.  TAK-665-4001 
Page 23 of 87 
Protocol Version 3.0 
  27 October 2022 
CONFIDENTIAL 
4.1.1 
Elaprase 
Elaprase is a formulation of idursulfase, a purified form of human IDS, a lysosomal enzyme 
produced by recombinant deoxyribonucleic acid (DNA) technology in a human cell line. 
Idursulfase is an enzyme that hydrolyzes the 2-sulfate esters of terminal iduronate sulfate 
residues from the glycosaminoglycans dermatan sulfate and heparan sulfate in the lysosomes 
of various cell types (1).  
Due to the missing or defective IDS (12S) enzyme in patients with Hunter syndrome, GAG 
progressively accumulate in the lysosomes of a variety of cells, leading to cellular engorgement, 
organomegaly, tissue destruction, and organ system dysfunction (1).  
Elaprase is intended to provide exogenous enzyme for uptake into cellular lysosomes. Mannose-
6-phosphate (M6P) residues on the oligosaccharide chains allow binding of the enzyme to the
M6P receptors on the cell surface, leading to cellular internalization of the enzyme, targeting to
intracellular lysosomes and subsequent catabolism of accumulated GAG.
4.2 
Rationale for the Proposed Study 
The current study will be conducted to generate the safety and efficacy data of Elaprase in 
Indian population to meet the regulatory requirements of Drug Controller General of India 
(DCGI). Considering this to be a rare disease, and based on the rare epidemiology of Hunter 
syndrome with the estimated incidence of 0.6–1.3 in 100,000 live male births (23-25), the 
approximate number of subjects enrolled in this study will be 5 (23-25). 
4.3 
Benefit/Risk Profile 
Data on the safety and efficacy profile of Elaprase is not available in India. This Phase 4 study 
is designed to gather important information on the safety and efficacy of Elaprase in subjects 
with Hunter syndrome. The dosing and administration regimen and study population in this 
study are consistent with the approved Elaprase label. Overall, Elaprase has been well tolerated 
in clinical studies. The procedures performed during the study are part of usual clinical practice. 
Taking into account the risks associated with procedures and the disease worsening in this 
population, the benefit-risk profile is anticipated to remain positive for Elaprase in this study. 
5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Objectives 
5.1.1 
Primary Objective 
•
To evaluate the safety of Elaprase in pediatric and adult subjects with Hunter syndrome
during 53 weeks of study duration.
For non-commercial use only

Elaprase 
 
Study No.  TAK-665-4001 
Page 24 of 87 
Protocol Version 3.0 
  27 October 2022 
 
CONFIDENTIAL 
5.1.2 
Secondary Objective 
• To evaluate the efficacy of Elaprase in pediatric and adult subjects with 
Hunter syndrome during 53 weeks of study duration.  
5.2 
Endpoints 
5.2.1 
Primary Endpoint 
• Incidence of adverse events (AEs), serious AEs (SAEs), treatment emergent AEs, 
treatment emergent SAEs, adverse drug reactions (ADRs), discontinuations due to AEs, 
infusion-related reactions, and death. 
5.2.2 
Secondary Endpoints 
• Change from baseline in percentage Forced Vital Capacity (%FVC) as a measure of 
respiratory function at Weeks 27 and 53  
• Change from baseline in 6 Minute Walk Test (6MWT) as a measure of physical 
functional capacity at Weeks 27 and 53  
•  Change from baseline in Cardiac Left Ventricular Mass Index (LVMI) and Ejection 
Fraction at Weeks 27 and 53. 
• Change from baseline in liver volume at Weeks 27 and 53. 
• Change from baseline in spleen volume at Weeks 27 and 53. 
• Change from baseline in normalized urine GAG (uGAG) levels at Weeks 14, 27, 40, 
and 53. 
• Change from baseline in Global Joint Range of Motion (JROM) score at Weeks 27 and 
53  
• Changes from baseline in anthropometric parameters including height in subjects 
<18 years at baseline and weight in all subjects at Weeks 27 and 53. 
• Change from baseline in the health-related quality of life (HRQoL) based on 
Hunter Syndrome-Functional Outcomes for Clinical Understanding Scale (HS-FOCUS) 
(shortened version) in all subjects and Childhood Health Assessment Questionnaire 
(CHAQ) in subjects between age of ≥1 year to ≤18 years at Weeks 27 and 53. 
6.0 
STUDY DESIGN AND DESCRIPTION 
6.1 
Study Design 
This is prospective, open-label, multicenter, interventional single-arm Phase IV study to be 
conducted at multiple sites in India to evaluate the safety and efficacy of Elaprase in Indian 
pediatric and adult population with Hunter syndrome (MPS II).  
A total of 5 subjects with Hunter syndrome will be enrolled in this study. The total duration of 
the study for each subject will be up to 55 weeks, consisting of 14 days screening period (Days 
For non-commercial use only

Elaprase 
 
Study No.  TAK-665-4001 
Page 25 of 87 
Protocol Version 3.0 
  27 October 2022 
 
CONFIDENTIAL 
-14 to -1), a 52-weeks treatment period (Week 1 to Week 52), followed by 1 week follow-up 
period after the last dose of Elaprase (Week 53). At Week 53, the subject will be assessed for 
safety and efficacy which will also be considered the end of study (EOS). The total duration of 
the study will be approximately 3 years, based on the anticipated recruitment rate, however the 
study duration may get extended beyond 3 years until the last enrolled subject completes the 
EOS visit. 
After obtaining written informed consent from the subjects or their parents/guardians/legally 
authorized representatives (LARs), the subjects will be screened. An assent form will be 
provided and should be signed by subjects of ≥7 to <18 years of age. Subjects who meet all the 
inclusion criteria and none of the exclusion criteria will be administered Elaprase at the site. 
Subjects will visit the site for dosing from Week 1, Day 1 followed by every week till 
Week 52, Day 358. The visit on Week 52, Day 358 will 
be considered as 
end of treatment (EOT) visit. The study drug will be administered as 0.5 mg/kg given 
intravenously every week. The intravenous infusion will be administered over a 3 hour period, 
which may be gradually reduced to 1 hour if no infusion-associated reactions are observed. 
Efficacy assessments will be done at Week 27, Day 183 and Week 53, Day 365. Urine 
glycosaminoglycan (uGAG) and clinical laboratory assessments will also be done at Week 14, 
Day 92 and Week 40, Day 27. If the subject discontinues study treatment, the subject will have 
to complete assessments done at Week 53, Day 365 (EOS). Subjects will be evaluated for safety 
from initiation of Elaprase treatment until 53 weeks (EOS), or for at least 1 week following 
discontinuation of Elaprase, whichever occurs earlier. 
A subject diary will be provided to the subjects/subject’s parents/guardians to be filled at home. 
The diary will be used to capture information of any concomitant medications taken, and other 
AEs that occur in between visits. 
Apart from that, an unscheduled visit can be performed at investigator’s discretion or if the trial 
subject experience safety concerns. 
A schematic of the study design is included as Figure 6.a. A schedule of assessments is listed 
in Appendix A.
For non-commercial use only

Elaprase 
 
Study No.  TAK-665-4001 
Page 26 of 87 
Protocol Version 3.0 
  27 October 2022 
 
CONFIDENTIAL 
Figure 6.a 
Schematic of Study Design 
 
6.2 
Justification for Study Design, Dose, and Endpoints 
The study is being undertaken to collect data on the safety and efficacy of Elaprase in Indian 
subjects with Hunter syndrome for regulatory submission. DCGI has granted marketing 
authorization for Elaprase in India based on efficacy studies of Elaprase in Hunter syndrome 
conducted across the globe; and so, safety data of Elaprase in Indian subjects needs to be 
submitted to DCGI. Considering rare disease, a single-arm, open-label design is the most 
appropriate design to generate such data, as the focus of the study is primarily to collect 
information on safety and to additionally explore the clinical efficacy of the study drug.  
V1 
Day -14 to Day -1 
Screening Visit 
V2 
Week 1, Day 1 
V3 
to 
V53 
Week 2 to Week 52 
(Day 8 to Day 358) 
V54 
Week 53 (EOS) 
(Day 365) 
Informed Consent 
Medical History 
Clinical Examinations 
Laboratory Investigations 
Assessment of Inclusion/Exclusion 
Start Treatment with Elaprase 0.5 mg/kg IV 
(Dose 1) 
Weight-based Elaprase Administration Every 
Week 
(Efficacy Assessments at Week 27, Day 183) 
Efficacy Assessments and Safety Follow up after 
the Last Dose Administration of Elaprase 
For non-commercial use only

Elaprase 
 
Study No.  TAK-665-4001 
Page 27 of 87 
Protocol Version 3.0 
  27 October 2022 
 
CONFIDENTIAL 
Elaprase 0.5 mg/kg IV infusion is approved for the indications planned to be studied. The safety 
and treatment efficacy endpoints are similar to those used in other outcome studies in Hunter 
syndrome. The study period of 55 weeks includes 14 days of screening period, 52 weeks 
treatment period and 1 week follow-up after the last dose of Elaprase (Week 53). This study 
duration will help us in reporting safety endpoints of interest including AEs, SAEs, and ADRs. 
6.3 
Premature Termination or Suspension of Study or Study Site 
6.3.1 
Criteria for Premature Termination or Suspension of the Study 
The study will be completed as planned unless 1 or more of the following criteria are satisfied 
that require temporary suspension or early termination of the study. 
• New information or other evaluation regarding the safety or efficacy of the study drug 
that indicates a change in the known risk/benefit profile for the Elaprase, such that the 
risk/benefit is no longer acceptable for subjects participating in the study. 
• Significant violation of Good Clinical Practice (GCP) that compromises the ability to 
achieve the primary study objectives or compromises subject safety. 
6.3.2 
Criteria for Premature Termination or Suspension of Study Sites 
A study site may be terminated prematurely or suspended if the site (including the investigator) 
is found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure 
adequate performance of the study, or as otherwise permitted by the contractual agreement. 
6.3.3 
Procedures for Premature Termination or Suspension of the Study or the 
Participation of Study Sites 
In the event that the sponsor, an institutional review board (IRB)/independent ethics committee 
(IEC) or regulatory authority elects to terminate or suspend the study or the participation of a 
study site, a study-specific procedure for early termination or suspension will be provided by 
the sponsor; the procedure will be followed by applicable study sites during the course of 
termination or study suspension. 
7.0 
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS 
All entry criteria, including test results, need to be confirmed prior to first dose administration.  
7.1 
Inclusion Criteria 
Subject eligibility is determined according to the following criteria prior to entry into the study:  
1. Male or female# Elaprase naive subjects (and who are not part of any other program at the 
time of study enrollment and during the study period) of any age with confirmed diagnosis 
of Hunter syndrome based on the following documented biochemical and genetic criteria: 
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• Documented deficiency in IDS (12S) enzyme activity of less than or equal to 10% of 
the lower limit of the normal range as measured in plasma, fibroblasts, or leukocytes 
(based on normal range of measuring laboratory). 
• A normal enzyme activity level of one other sulfatase as measured in plasma, fibroblasts, 
or leukocytes (based on normal range of measuring laboratory). 
• The patient has a documented mutation in the IDS gene. 
2. In the opinion of the investigator, the subject or the subject’s parents/guardians are capable 
of understanding and complying with protocol requirements. 
3. The subject or, when applicable, the subject’s parents/guardians/LAR signs and dates a 
written, informed consent form and any required privacy authorization prior to the initiation 
of any study procedures. If the subject participating in this study is ≥7 and <18 years of age 
signs and dates an assent form. 
4. A male subject who is nonsterilized* and sexually active with a female partner of 
childbearing potential#* agrees to use barrier method of contraception (eg, condom with or 
without spermicide)* from signing of informed consent throughout the duration of the 
study. The female partner of a male subject should also be advised to use a highly 
effective/effective method of contraception.*  
5. A female subject of childbearing potential#* who is sexually active with a nonsterilized* 
male partner agrees to use a highly effective method of contraception* from signing of 
informed consent throughout the duration of the study.  
*Definitions and highly effective methods of contraception are defined in Section 9.1.11 and 
reporting responsibilities are defined in Section 9.1.12. 
#It is known that Hunter syndrome almost exclusively affects males and it is highly unlikely 
that females will be affected by Hunter syndrome.  
7.2 
Exclusion Criteria 
Any subject who meets any of the following criteria will not qualify for entry into the study:  
1. Subject has received HSCT or a bone marrow transplant at any time. 
2. Subject is unable to comply with the protocol, eg, uncooperative with protocol schedule, 
refusal to agree to all of the study procedures, inability to return for safety evaluations, or is 
otherwise unlikely to complete the study, as determined by the investigator. 
3. Subject is suffering from any comorbid conditions (including hepatic impairment, acute or 
chronic) or having any other clinical observation or history during the screening 
examination, which would interfere with the objectives of the study as per investigators 
judgement. 
4. The subject has a chronic kidney disease with estimated Glomerular Filtration rate less than 
15 mL/min/1.73 m2 and/or is on dialysis.  
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5. The subject is an immediate family member, study site employee, or is in a dependent 
relationship with a study site employee who is involved in conduct of this study (eg, spouse, 
parent, child, sibling) or may consent under duress. 
6. The subject has a history of hypersensitivity or allergies to related compounds including any 
associated excipients. 
7. If female, the subject is pregnant or lactating or intending to become pregnant before 
participating in this study, during the study; or intending to donate ova during such time 
period.  
8. If male, the subject intends to donate sperm during the course of this study.  
9. The subject has participated in another clinical study or received any investigational 
compound or non-investigational idursulfase beta within the past 30 days before informed 
consent. 
7.3 
Excluded Medications  
No formal medicinal product interaction studies have been conducted with Elaprase (Refer 
Appendix F). 
7.4 
Criteria for Discontinuation or Withdrawal of a Subject 
The primary reason for discontinuation or withdrawal of the subject from the study or study 
drug should be recorded in the case report form (eCRF) using the following categories. For 
screen failure subjects, refer to Section 9.1.14. 
1. Pretreatment event (PTE) or AE: The subject has experienced a PTE or AE that requires 
early termination because continued participation imposes an unacceptable risk to the 
subject’s health or the subject is unwilling to continue because of the PTE or AE. 
2. Significant protocol deviation: The discovery after the first dose of study drug that the 
subject failed to meet protocol entry criteria or did not adhere to protocol requirements, and 
continued participation poses an unacceptable risk to the subject’s health. 
3. Lost to follow-up: The subject did not return to the clinic and attempts to contact the subject 
were unsuccessful. Attempts to contact the subject must be documented in the subject’s 
source documents.  
4. Voluntary withdrawal: The subject (or subject’s parents/guardian/ LAR) wishes to withdraw 
from the study. The reason for withdrawal, if provided, should be recorded in the eCRF. 
Note: All attempts should be made to determine the underlying reason for the withdrawal and, where possible, 
the primary underlying reason should be recorded (ie, withdrawal due to an AE or lack of efficacy should not 
be recorded in the “voluntary withdrawal” category). 
5. Study termination: The sponsor, IRB/IEC or regulatory agency terminates the study. 
6. Pregnancy: The subject is found to be pregnant.  
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. The procedure is 
described in Section 9.1.12. 
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7. Lack of efficacy. The investigator has determined that the subject is not benefiting from 
study treatment; and, continued participation would pose an unacceptable risk to the subject.  
Lack of efficacy shall be defined as below: 
Patients fulfilling all of the below criteria should be evaluated by the treating investigators 
to withdraw the patient from further continuing Elaprase 
1. No change in normalized urine GAG (uGAG) from baseline at week 27 
2. No change or increase in liver and spleen volumes from baseline at week 27 
3. No improvement or decline in cardiac function as assessed by left ventricular mass index 
and ejection fraction from baseline at week 27  
4. No improvement or decline in 6 Minute Walk Test (6MWT) and percentage Forced 
Vital Capacity (%FVC)  from baseline at week 27 
(Change in anthropometric measurements can also be considered for patients with age 
less than 18 years) 
5. No improvement or decline in health-related quality of life (HRQoL) from baseline at 
week 27 
8. Other. 
Note: The specific reasons should be recorded in the “specify” field of the eCRF. 
7.5 
Procedures for Discontinuation or Withdrawal of a Subject 
The investigator may discontinue a subject’s study participation at any time during the study 
when the subject meets the study termination criteria described in Section 7.4. In addition, a 
subject may discontinue his or her participation without giving a reason at any time during the 
study. If subject discontinues the treatment early, an early termination visit should be scheduled 
at 7 days after the last dose. Should a subject’s participation be discontinued, the primary 
criterion for termination must be recorded by the investigator. The assessments and procedures 
for the early termination visit will be the same as for the Visit 54/EOS Visit. If the subject 
withdraws from the study, then efforts should be made to perform all the assessments scheduled 
on early termination as early as possible. Discontinued or withdrawn subjects will not be 
replaced. 
8.0 
CLINICAL STUDY MATERIAL MANAGEMENT 
This section contains information regarding all medications and materials provided directly by 
the sponsor, and/or sourced by other means, that are required by the study protocol, including 
important sections describing the management of study material. 
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8.1 
Study Drug and Materials 
8.1.1 
Dosage Form, Manufacturing, Packaging, and Labeling 
8.1.1.1 
Study Drug 
The Elaprase supplied for this study is a clear to slightly opalescent, colourless solution of 1 mL 
concentrate for solution for infusion containing 2 mg of Elaprase. The content of Elaprase is 
provided in 5 mL vial containing 3.0 mL concentrate corresponding to 6 mg Elaprase. 
The ingredients of 1 mL concentrate are described below.  
Ingredient 
Quantity per mL 
Grade 
Elaprase 
2.0 mg 
In-house monograph 
Sodium phosphate, monobasic, 
monohydrate 
2.25 mg 
USP 
Polysorbate 20 
0.0002 mL 
NF, EP 
Sodium chloride  
8.0 mg 
USP, EP, JP 
Sodium hydroxide 
Qs 
USP, EP, JP 
Water for Injection 
Qs 
USP, EP, JP 
Abbreviations: EP=European Pharmacopoeia; JP=Japanese Pharmacopoeia; NF=National Formulary; 
Qs=quantity sufficient; USP=United States Pharmacopoeia 
Each vial of Elaprase is intended for single use only and contains 6 mg of idursulfase in 3 mL 
of solution. Elaprase is for intravenous infusion and must be diluted in sodium chloride 
9 mg/mL (0.9%) solution for infusion prior to use. Elaprase is administered using a 
low-protein-binding infusion set equipped with a low-protein-binding 0.2 μm in-line filter.  
Since the drug is given as weight-based regimen, weight of participant will be recorded prior to 
dose calculation which is to be administered. After recording the weight of participant, the dose 
and number of Elaprase vials needed will be calculated. The total volume of Elaprase 
concentrate required will be diluted in 100 mL of 9 mg/mL (0.9%) sodium chloride solution for 
infusion. Care must be taken to ensure the sterility of the prepared solutions since Elaprase does 
not contain any preservative or bacteriostatic agent; aseptic technique must be observed. Once 
diluted, the solution should be mixed gently but not shaken. The solution should be inspected 
visually for particulate matter and discolouration prior to administration. Since no preservative 
is present, it is recommended that infusion should be started as soon as possible after dilution.  
Elaprase 0.5 mg/kg is given every week as intravenous infusion over a 3 hours period, which 
may be gradually reduced to 1 hour if no infusion-associated reactions are observed. 
Participants may require longer infusion times if hypersensitivity reactions occur; however, 
infusion times should not exceed 8 hours. The initial infusion rate should be 8 mL per hour for 
the first 15 minutes. If the infusion is well tolerated, the rate of infusion may be increased by 
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8 mL per hour increments every 15 minutes. The infusion rate should not exceed 
100 mL per hour. 
The solution for infusion is for single use only therefore any unused product or waste material 
should be disposed of in accordance with local requirements. Elaprase should not be infused 
with other medicinal products in the infusion tubing. 
8.1.1.2 
Packaging and Labelling 
Packaging and labelling will be controlled by Clinical Trial Supply Management Team of 
sponsor/Contract Research Organization (CRO). 
All packaging and labelling as well as the production of study drug will be in compliance with 
Good Manufacturing Practices (GMP) specifications, as per applicable Indian laws and 
regulations. 
A sponsor Qualified Person/Representative will release all the clinical supplies prior to 
shipment to investigational sites. A Certificate of Compliance will be issued stating the expiry 
date of the clinical supplies. 
The contents of the label will be in accordance with DCGI requirements. 
The labels will show the following information: 
• Name of the drug or code number 
• Batch number/lot number 
• Date of manufacture 
• Expiry date/use before date 
• Storage conditions 
• Name of the institute/organization/centre where clinical trial is being conducted 
• Name and address of the manufacturer 
• “For clinical trial use only” 
8.1.2 
Storage 
The vials should be stored in a refrigerator at 2 to 8 °C. Vials should be kept with outer carton 
in order to protect from light.  
Study drug must be kept in an appropriate, limited-access, secure place until it is used or 
returned to the sponsor or designee for destruction. Study drug must be stored under the 
conditions specified on the label, and remain in the original container until dispensed. A daily 
temperature log of the drug storage area must be maintained every working day. 
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8.1.3 
Dose and Regimen 
The dose and dosing regimen for all subjects is provided below. 
Treatment Group 
Dose 
Treatment Description 
All subjects 
Elaprase 0.5 mg/kg IV 
Week 1, Day 1 and every week thereafter 
till Week 52, Day 358. 
No dose modifications will be allowed during the study. 
8.1.4 
Overdose 
An overdose is defined as a known deliberate or accidental administration of study drug, to or 
by a study subject, at a dose above that which is assigned to that individual subject according 
to the study protocol. 
All cases of overdose (with or without associated AEs) will be documented on an overdose page 
of the eCRF, in order to capture this important safety information consistently in the database. 
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs 
associated with an overdose will be documented on AE page of eCRFs according to 
Section 10.0. 
SAEs associated with overdose should be reported according to the procedure outlined in 
Section 10.2.2. 
In the event of drug overdose, the subject should be treated symptomatically. 
8.2 
Study Drug Assignment and Dispensing Procedures 
Since this is an open-label single-arm study, randomization procedures will not be applicable 
for this study. Subjects will receive treatment sequentially as they enter the study and according 
to the study schedule. The subject identification number will be entered in to the eCRF. 
8.3 
Accountability and Destruction of Sponsor-Supplied Drugs 
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee. The investigator or designee must ensure that the sponsor-supplied drug is used in 
accordance with the protocol and is dispensed only to subjects enrolled in the study. To 
document appropriate use of sponsor-supplied drug, the investigator or designee must maintain 
records of all sponsor-supplied drug delivery to the site, site inventory, dispensation and use by 
each subject, and return to the sponsor or designee. 
Upon receipt of sponsor-supplied drug, the investigator or designee must verify the contents of 
the shipments against the packing list. The verifier should ensure that the quantity is correct, 
and the medication is in good condition. If quantity and conditions are acceptable, investigator 
or designee should acknowledge the receipt of the shipment. If there are any discrepancies 
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between the packing list versus the actual product received, Takeda must be contacted to resolve 
the issue. The packing list should be filed in the investigator’s essential document file. 
The investigator or designee must maintain 100% accountability for all sponsor-supplied drugs 
received and dispensed during his or her entire participation in the study. Proper drug 
accountability includes, but is not limited to: 
• Continuously monitoring expiration dates if expiry date is provided to the investigator 
or designee.  
• Frequently verifying that actual inventory matches documented inventory. 
• Verifying that the log is completed for the drug lot/medication ID used to prepare each 
dose. 
• Verifying that all containers used are documented accurately on the log. 
• Verifying that required fields are completed accurately and legibly. 
If any dispensing errors or discrepancies are discovered, the sponsor must be notified 
immediately. 
The investigator or designee must record the current inventory of all sponsor-supplied drugs on 
a sponsor-approved drug accountability log. The following information will be recorded at a 
minimum: protocol number and title, name of investigator, site identifier and number, 
description of sponsor-supplied drugs, date and amount dispensed including initials, seal, or 
signature of the person dispensing the drug, and the date and amount returned to the site by the 
subject, including the initials, seal, or signature of the person receiving the sponsor-supplied 
drug. The log should include all required information as a separate entry for each subject to 
whom sponsor-supplied drug is dispensed.  
Prior to site closure or at appropriate intervals, a representative from the sponsor or its designee 
will perform sponsor-supplied drug accountability and reconciliation before sponsor-supplied 
drugs are returned to the sponsor or its designee for destruction. The investigator or designee 
will retain a copy of the documentation regarding sponsor-supplied drug accountability, return, 
and/or destruction, and originals will be sent to the sponsor or designee. 
The investigator will be notified of any expiry date or retest date extension of sponsor-supplied 
drug during the study conduct. On expiry date notification from the sponsor or designee, the 
site must complete all instructions outlined in the notification, including segregation of expired 
sponsor-supplied drug for return to the sponsor or its designee for destruction. 
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9.0 
STUDY PLAN 
9.1 
Study Procedures 
The following sections describe the study procedures and data to be collected. For each 
procedure, subjects are to be assessed by the same investigator or site personnel whenever 
possible. The Schedule of Study Procedures is located in Appendix A. 
9.1.1 
Informed Consent Procedure 
The requirements of the informed consent are described in Section 15.2. 
Informed consent must be obtained prior to the subject entering into the study, and before any 
protocol-directed procedures are performed. 
A unique subject identification number (subject number) will be assigned to each subject at the 
time when informed consent is obtained; this subject number will be used throughout the study. 
9.1.2 
Demographics, Medical History, and Medication History Procedure 
Demographic information to be obtained will include age, sex, height, weight, and smoking 
status of the subject at Screening.  
Medical history to be obtained will include determining whether the subject has any significant 
conditions or diseases relevant to the disease under study that resolved at or prior to signing of 
informed consent. Ongoing conditions are considered concurrent medical conditions (see 
Section 9.1.7). 
Medication history information to be obtained includes any medication relevant to eligibility 
criteria stopped at or within 30 days prior to signing of informed consent. 
9.1.3 
Physical Examination Procedure 
A baseline physical examination (defined as the assessment prior to first dose of study drug) 
will be performed on Week 1, Day 1. Physical examination includes general appearance; 
assessments of head, neck, and thyroid; eyes, ears, nose, and throat; chest and lungs; heart; 
lymph nodes; abdomen; anorectal; genitourinary; skin; musculoskeletal; endocrine; 
neurological; and other. 
All subsequent physical examinations should assess clinically significant changes from the 
assessment prior to first dose examination. 
9.1.4 
Weight, Height  
A subject should have weight and height measured while wearing indoor clothing and with 
shoes off. Height is recorded in centimeters without decimal places. Weight is collected in 
kilograms (kg) with 1 decimal place.  
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9.1.5 
Vital Sign Procedure 
Vital signs will include body temperature, respiratory rate, blood pressure, and pulse (beats per 
minute). Blood pressure will be measured when subjects are in the supine position.  
If the vital signs are scheduled at the same time as blood draws, the blood draw will take priority 
and vital signs will be obtained within 0.5 hours before or after the scheduled blood draw. On 
dosing days, vitals are taken predose. 
The investigator will assess whether a change from baseline in vital signs may be deemed within 
normal limits, abnormal but not clinically significant, or abnormal and clinically significant. 
9.1.6 
Documentation of Concomitant Medications 
Concomitant medication is any drug given in addition to the study drug. These may be 
prescribed by a physician or obtained by the subject over the counter. Concomitant medication 
is not provided by the sponsor. At each visit, subjects will be asked whether they have taken 
any medication other than the study drug (used from signing of informed consent through the 
end of the study), and all medication including vitamin supplements, over-the-counter 
medications, and oral herbal preparations, must be recorded in the eCRF. 
9.1.7 
Documentation of Concurrent Medical Conditions 
Concurrent medical conditions are those significant ongoing conditions or diseases that are 
present at signing of informed consent. This includes clinically significant laboratory, 
electrocardiogram (ECG), or physical examination abnormalities noted at screening/baseline 
examination, according the judgment of the investigator. The condition (ie, diagnosis) should 
be described. 
9.1.8 
Primary Efficacy Measurement  
9.1.8.1 
Percentage Forced Vital Capacity (% FVC) 
Pulmonary function will be assessed by spirometry to measure FVC (26, 27).  
Change from baseline will be measured at Weeks 27 and 53 to evaluate the efficacy of Elaprase.. 
Feasibility of Pulmonary function assessment  in subjects <5 years can be assessed by the 
Investigator prior to performing the procedure if the subject is not found to be fit for the 
procedure, testing procedure can be deffered/avoided. 
9.1.8.2 
6 Minute Walk Test (6MWT) 
6 Minute Walk Test will be conducted as per standard practice for patients with delayed 
development (28). The 6MWT will be conducted by a single specialist. 
Change from baseline will be measured at Weeks 27 and 53 to evaluate the efficacy of Elaprase.  
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Feasibility of 6 Minute Walk Test  in subjects <5 years can be assessed by the Investigator prior 
to performing the procedure , if the subject is not found to be fit for the procedure, testing 
procedure can be deffered/avoided 
9.1.8.3 
Cardiac Left Ventricular Mass Index (LVMI) and Ejection Fraction 
Cardiac LVMI and Ejection Fraction will be determined by 2D echocardiography. Cardiac 
LVMI is the left ventricular mass (LVM, in g) indexed to body surface area (BSA), in 
square meter (m2). Cardiac LVMI (in gram per square meter [g/m2])=LVM divided by BSA. 
Change from baseline will be measured at Weeks 27 and 53 to evaluate the efficacy of Elaprase.  
9.1.8.4 
Liver Volume  
Liver volume will be determined by USG. Hepatomegaly is defined as a liver volume (L) >3.5% 
of body weight (kg) in subjects aged 5-12 years, 2.2% of body weight in subjects aged 
13-17 years, and >2.6% in subjects more than 18 years old (30).  
Change from baseline will be measured at Weeks 27 and 53 to evaluate the efficacy of Elaprase.  
9.1.8.5 
Spleen Volume 
Spleen volume will be determined by USG. Splenomegaly is defined as having a splenic volume 
greater than the 95th percentile of the normal distribution in children (31).  
Change from baseline will be measured at Weeks 27 and 53 to evaluate the efficacy of Elaprase.  
9.1.8.6 
Glycosaminoglycan 
Normalized uGAG will be analyzed using urine testing (32). The uGAG levels will be 
normalized to urine creatinine and will be reported as microgram GAG per milligram creatinine 
(µg GAG/mg creatinine). 
Change from baseline will be measured at Weeks 14, 27, 40, and 53 to evaluate the efficacy of 
Elaprase. Urine GAG may also be analysed at Weeks 14 and/or 40 at investigator’s discretion. 
9.1.8.7 
Global Joint Range of Motion (JROM) 
Passive joint mobility is defined as the range of motion of the shoulder, elbow, wrist, hip, knee, 
and ankle joints, as assessed by one expert physician using universal goniometry method. 
Global JROM (% of normal range of motion) is the average of 11 ratios multiplied by 100. 
Ratios are left/right means of passive range of motion in shoulder (flexion/extension, abduction, 
internal/external rotation), elbow (flexion/extension), wrist (flexion/extension), index finger 
(flexion/extension [combined metacarpophalangeal joint, proximal interphalangeal joint, distal 
interphalangeal joint motion]), hip (flexion/extension, abduction, internal/external rotation), 
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knee (flexion/extension), and ankle (dorsiflexion) divided by the normal range 
(American Academy of Orthopedic Surgeons and American Medical Association) (33). 
Change from baseline will be measured at Weeks 27 and 53 to evaluate the efficacy of Elaprase.  
 
9.1.8.8 
Anthropometric Parameters 
Change from baseline in anthropometric parameters including height and weight will be 
assessed at Weeks 27 and 53 to evaluate the efficacy of Elaprase. 
Change in height will be assessed in subjects <18 years and weight will be assessed in all 
subjects. 
9.1.9 
Health-related Quality of Life (HRQoL) Measures 
The HRQoL measures of this study includes one disease-specific and one generic questionnaire. 
9.1.9.1 
Hunter Syndrome-Functional Outcomes for Clinical Understanding Scale 
(HS-FOCUS) 
The HS-FOCUS was developed as a disease-specific measure of the impact of Hunter syndrome 
on HRQoL. The HS-FOCUS is designed to gather information on the patient’s daily life and 
wellbeing, satisfaction with treatment, and hospitalizations, as well as on how Hunter syndrome 
impacts the patient’s general quality of life. The HS-FOCUS includes 2 validated components: 
a parent version and a patient self -reported version for those over age 12 years. To increase the 
validity and efficiency of completion of HS-FOCUS, some items were removed from the 
original questionnaire (Version 1.0) to produce a shorter version (Version 2.0). 
The HS-FOCUS (shortened version) questionnaire has 5 function domains (walking/standing, 
grip/reach, school/work, activities, and breathing). (34). The scale of the 5 function domains 
ranges from 0 to 3, with 0 signifying an ability to complete the activity-related functions 
‘without any difficulty’ and 3 score denoting highest disability. Complete item responses are 
averaged to calculate the six individual function domain scores and the overall function score, 
with higher scores representing a higher degree of incapacity. If more than half of the items for 
a function domain are missing or marked ‘not applicable’, that domain score is deemed to be 
‘missing’ and not included in the analysis (35). 
For each of the 5 functional domains, the respective domain scores will be calculated as follows: 
Domain score =
∑
𝑖𝑡𝑒𝑚 𝑠𝑐𝑜𝑟𝑒𝑠 𝑤𝑖𝑡ℎ𝑖𝑛 𝑑𝑜𝑚𝑎𝑖𝑛
𝑁𝑜.𝑜𝑓 𝑖𝑡𝑒𝑚𝑠 𝑐𝑜𝑚𝑝𝑙𝑒𝑡𝑒𝑑 𝑤𝑖𝑡ℎ𝑖𝑛 𝑑𝑜𝑚𝑎𝑖𝑛 
The HRQoL assessment based on HS-FOCUS will be performed in all subjects at screening, 
Weeks 27 and 53 and the changes from baseline will be measured and reported (Appendix E).  
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9.1.9.2 
Childhood Health Assessment Questionnaire (CHAQ) 
The CHAQ was initially developed for assessing juvenile idiopathic arthritis, from the 
perspective of the parent or patient, and has been previously applied to other chronic disabling 
conditions such as Hunter syndrome (36). It is a 30-item instrument that measures functional 
capacity and independence in activities of daily life across eight domains: dressing and 
grooming, arising, eating, walking, reach, grip, hygiene, and activities. For each domain, there 
is a 4-level difficulty scale that is scored from 0 to 3, with 0 corresponding to ‘without any 
difficulty’ and 3 to ‘unable to do’. An additional question asks for any aids or devices children 
usually use for any of the above activities, which is used to adjust the scores of the domains into 
the CHAQ disability index score (CHAQ DIS). This is used as the outcome measure of 
functional disabilities in severely disabled patients, with a scale from 0 to 3, where 3 represents 
the worst functions. CHAQ also presents two visual analogue scales for pain evaluation and 
overall well-being evaluation, where 0 represents ‘no pain’ and ‘doing very well’ and 100 
represents ‘very severe pain’ and feeling ‘very poor’ (35). 
The HRQoL assessment based on CHAQ will be performed in subjects between age of 
≥1 year to ≤18 years at screening, Weeks 27 and 53 and the changes from baseline will be 
measured and reported (Appendix F).  
9.1.10 
Procedures for Clinical Laboratory Samples 
All samples will be collected in accordance with acceptable laboratory procedures. The 
approximate total volume of blood for the study is 28 mL. Details of these procedures and 
required safety monitoring will be given in the laboratory manual. 
Table 9-a lists the tests that will be obtained for each laboratory specimen. 
Table 9-a: Clinical Laboratory Tests 
Hematology 
Serum Chemistry 
Urinalysis 
Red blood cells (RBCs) 
White blood cells (WBCs) 
with differential (ie, 
basophils, eosinophils, 
lymphocytes, monocytes, 
and neutrophils)  
Hemoglobin 
Hematocrit 
Mean corpuscular volume 
(MCV) 
Mean corpuscular 
haemoglobin concentration 
(MCHC) 
Platelets 
ALT 
Albumin 
Globulin 
Alkaline phosphatase 
AST  
Total bilirubin 
Total protein 
Creatinine 
Blood urea nitrogen 
γ-Glutamyl transferase (GGT) 
Potassium 
Sodium 
Chloride 
Bicarbonate 
Glucose 
Urea 
Specific gravity  
pH  
Glucose 
Protein blood 
Ketones  
Bilirubin 
Urobilinogen  
Nitrite  
RBCs 
WBCs  
Epithelial cells  
Crystals 
Casts 
Bacteria. 
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High-density lipoprotein  
Low-density lipoprotein  
Triglycerides 
Total cholesterol 
Other: 
Urine 
Urine pregnancy test (Female subjects of childbearing potential) 
The local laboratory will perform laboratory tests for hematology, serum chemistries, and 
urinalysis. The results of laboratory tests will be returned to the investigator, who is responsible 
for reviewing and filing these results. 
The clinical laboratory tests will be performed at screening, Weeks 14, 27, 40, and 53, and the 
changes from baseline will be measured and reported. 
9.1.11 
Contraception and Pregnancy Avoidance Procedure 
9.1.11.1 
Male Subjects and Their Female Partners 
From signing of informed consent, throughout the duration of the study, nonsterilized** male 
subjects who are sexually active with a female partner of childbearing potential* must use 
barrier contraception (eg, condom with or without spermicidal cream or jelly). In addition, they 
must be advised not to donate sperm during this period. Females of childbearing potential who 
are partners of male subjects are also advised to use additional contraception as shown in the 
list containing highly effective contraception below. 
9.1.11.2 
Female Subjects and Their Male Partners 
From signing of informed consent, throughout the duration of the study, female subjects of 
childbearing potential* who are sexually active with a nonsterilized male partner** must use a 
two highly effective methods/one highly effective and one effective method of contraception 
(from the list below).  
In addition they must be advised not to donate ova during this period. 
9.1.11.3 
Definitions and Procedures for Contraception and Pregnancy Avoidance 
The following definitions apply for contraception and pregnancy avoidance procedures. 
*A woman is considered a woman of childbearing potential (WOCBP), ie, fertile, following 
menarche and until becoming postmenopausal unless permanently sterile. Permanent 
sterilization methods include hysterectomy, and bilateral oophorectomy. A postmenopausal 
state is defined as no menses for 12 months without an alternative medical cause. A high follicle 
stimulating hormone (FSH) level in the postmenopausal range (FSH >40 IU/L) may be used to 
confirm a postmenopausal state in younger women (eg, those <45 year old) or women who are 
not using hormonal contraception or hormonal replacement therapy. However, in the absence 
of 12 months of amenorrhea, a single FSH measurement is insufficient. 
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**Sterilized males should be at least 1 year postbilateral vasectomy and have confirmed that 
they have obtained documentation of the absence of sperm in the ejaculate or have had bilateral 
orchidectomy. 
The following procedures apply for contraception and pregnancy avoidance. 
1. Highly effective methods of contraception are defined as “those, alone or in combination, 
that result in a low failure rate (ie, less than 1% failure rate per year when used consistently 
and correctly). In this study, where medications and devices containing hormones are 
included, the only acceptable methods of contraception are:  
• Non-hormonal methods:  
- 
Intrauterine device (IUD)  
- 
Bilateral tubal occlusion  
- 
Vasectomised partner (provided that partner is the sole sexual partner of the trial 
subject and that the vasectomised partner has received medical assessment of the 
surgical success  
• Hormonal methods:  
- 
Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation initiated at least 3 months prior to the first dose of study 
drug OR combined with a barrier method (male condom, female condom or 
diaphragm) if for shorter duration until she has been on contraceptive for 3 months; 
o Oral  
o Intravaginal (eg, ring) 
o Transdermal  
- 
Progestogen-only hormonal contraception associated with inhibition of ovulation1 
initiated at least 3 months prior to the first dose of study drug OR combined with a 
barrier method (male condom, female condom or diaphragm) if shorter till she has 
been on contraceptive for 3 months; 
o oral  
o Injectable 
o Implantable 
2. Unacceptable methods of contraception are: 
• Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods). 
• Spermicides only. 
• Withdrawal. 
• No method at all. 
• Use of female and male condoms together. 
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• Cap/diaphragm/sponge without spermicide and without condom. 
• Sexual abstinence is not an acceptable method of contraception. 
3. Subjects will be provided with information on highly effective/effective methods of 
contraception as part of the subject informed consent process and will be asked to sign a 
consent form stating that they understand the requirements for avoidance of pregnancy, 
donation of ova, and sperm donation during the course of the study. 
4. During the course of the study, regular urine human chorionic gonadotropin (hCG) 
pregnancy tests will be performed only for women of childbearing potential and all subjects 
(male and female) will receive continued guidance with respect to the avoidance of 
pregnancy and sperm donation as part of the study procedures. Such guidance should 
include a reminder of the following: 
a) contraceptive requirements of the study 
b) reasons for use of barrier methods (ie, condom) in males with pregnant partners 
c) assessment of subject compliance through questions such as 
i. Have you used the contraception consistently and correctly since the last visit? 
ii. Have you forgotten to use contraception since the last visit?  
iii. Are your menses late (even in women with irregular or infrequent menstrual cycles 
a pregnancy test must be performed if the answer is “yes”) 
iv. Is there a chance you could be pregnant? 
5. In addition to a negative urine hCG pregnancy test at Screening, female subjects of 
childbearing potential must also have confirmed menses in the month before first dosing 
(no delayed menses), a negative urine hCG pregnancy test prior to first dose of study 
medication on Week 1, Day 1 and every week before dosing till Week 52.  
9.1.11.4 
General Guidance With Respect to the Avoidance of Pregnancy 
Such guidance should include a reminder of the following: 
• Contraceptive requirements of the study. 
• Reasons for use of barrier methods (ie, condom) in males with pregnant partners. 
• Assessment of subject compliance through questions such as: 
- 
Have you used the contraception consistently and correctly since the last visit? 
- 
Have you forgotten to use contraception since the last visit?  
- 
Are your menses late (even in women with irregular or infrequent menstrual cycles 
a pregnancy test must be performed if the answer is “yes”) 
- 
Is there a chance you could be pregnant? 
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9.1.12 
Pregnancy 
If any subject is found to be pregnant during the study, she should be withdrawn and any 
sponsor-supplied drug should be immediately discontinued. In addition, any pregnancies in the 
partner of a male subject during the study, should also be recorded following authorization from 
the subject’s partner.  
Note 1: Pregnancies during pretreatment phase need not be reported to regulatory authorities. Therefore, please 
enter the correct visit number above for when first sponsor-supplied drug is administered. 
Note 2: The period for reporting pregnancies following last dose of study drug is same as the period for AE 
reporting.  
If the female subject and/or female partner of a male subject agrees to the primary care physician 
being informed, the investigator should notify the primary care physician that the female 
subject/female partner of the subject was participating in a clinical study at the time she became 
pregnant and provide details of the study drug the subject received. 
All pregnancies, including female partners of male subjects, in subjects on active study drug 
will be followed up to final outcome, using the pregnancy form. Pregnancies will remain 
blinded to the study team. The outcome, including any premature termination, must be reported 
to the sponsor. An evaluation after the birth of the child will also be conducted. 
9.1.13 
ECG Procedure 
The triplicate 12-lead ECG (each taken about 1 minute apart within a 5-minute window per 
timepoint) safety evaluation will be performed at screening/baseline, Weeks 27 and 53, and the 
changes from baseline will be measured and reported. The ECG can also be performed at 
Weeks 14 and/or 40, or any visit at investigator’s discretion. The investigator (or a qualified 
observer at the study site) will interpret the ECG using 1 of the following categories: within 
normal limits, abnormal but not clinically significant, or abnormal and clinically significant. 
When blood sampling, vital signs, and ECG are scheduled on same day, the blood sampling 
should be done last and sequence should be ECG, vital signs, and blood sampling.  
9.1.14 
Documentation of Screen Failure 
Investigators must account for all subjects who sign informed consent. 
If the subject is withdrawn at the screening visit, the investigator should complete the eCRF. 
The primary reason for screen failure is recorded in the eCRF using the following categories: 
• PTE/AE 
• Did not meet inclusion criteria or did meet exclusion criteria  
• Lost to follow-up 
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• Voluntary withdrawal 
• Study termination 
• Other study-specific (specify reasons) 
Subject identification numbers assigned to subjects who fail screening should not be reused. 
9.1.15 
Documentation of Study Entrance 
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible 
for enrolment into the treatment phase. 
If the subject is found to be not eligible for treatment phase, the investigator should record the 
primary reason for failure on the applicable eCRF. 
9.2 
Monitoring Subject Treatment Compliance 
All supplies used to administer study drug to the subject will be recorded on the eCRFs.  
If a subject is persistently noncompliant with the study drug, it may be appropriate to withdraw 
the subject from the study. All subjects should be reinstructed about the dosing requirement 
during study contacts. The authorized study personnel conducting the re-education must 
document the process in the subject source records. 
9.3 
Schedule of Observations and Procedures 
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time points. 
9.3.1 
Screening/Visit 1/Days -14 to -1 
Subjects will be screened within 14 days prior to baseline. Subjects will be screened in 
accordance with predefined inclusion and exclusion criteria as described in Section 7.0. See 
Section 9.1.14 for procedures for documenting screening failures. 
Procedures to be completed at Screening (Visit 1) include: 
• Informed consent 
• Demographics, medical history, and medication history 
• Physical examination 
• Vital signs 
• Weight, height 
• Concomitant medications 
• Concurrent medical conditions 
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• Screening clinical laboratory tests 
• 12-Lead ECG 
• Urine pregnancy test for females* of childbearing potential 
• Efficacy measures: 
- 
Percentage FVC based on spirometry** 
- 
 6MWT based on the standard method used for patients with developmental delay 
- 
JROM using universal goniometry method 
- 
Cardiac LVMI and Ejection Fraction using 2D echocardiography** 
- 
Liver and spleen volume using Ultrasonography (USG)** 
- 
Urine GAG by urine test 
- 
HRQoL based on HS-FOCUS and CHAQ  
Note: *It is known that Hunter syndrome almost exclusively affects males and it is highly unlikely that females 
will be affected by Hunter syndrome. 
Note: **2D echocardiography, USG (liver and spleen volume), and spirometry tests should have been performed 
within 30 days of subject’s enrolment or at the time of screening. 
The laboratory and efficacy evaluations done at screening will be considered as baseline for 
study evaluations. After meeting the eligibility criteria, the investigator or his/her designee will 
instruct subjects to come for the next visit at the study site. 
9.3.2 
Study Enrollment/Treatment Phase 
The study drug administration during the treatment phase will be done weekly starting from 
Visit 2 (Week 1, Day 1) till Visit 53 (Week 52, Day 358). The subjects must attend visits as 
close as possible to the planned day, and ideally within ±3 days. 
9.3.2.1 
Baseline Visit/Week 1, Day 1/Visit 2 
Study enrollment will take place on Week 1, Day 1. If the subject has satisfied all of the 
inclusion criteria and none of the exclusion criteria, the subject should be enrolled in the study. 
The following procedures will be performed and documented at study entrance: 
• Physical examination  
• Height and weight 
• Vital signs  
• 12-Lead ECG at investigator’s discretion or if not performed at screening visit 
• Urine pregnancy test for females of childbearing potential 
• Documentation of AEs and concomitant medications 
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The procedure for documenting Screening failures is provided in Section 9.1.14. 
9.3.2.2 
Visit 3 (Week 2, Day 8) through Visit 53 (Week 52, Day 358) 
The following assessments will be performed at these visits:  
• Physical examination  
• Vital signs  
• Urine pregnancy test for females of childbearing potential 
• Study diary will be checked 
• Documentation of AEs and concomitant medications 
9.3.2.3 
Efficacy Assessment Visit 28 (Week 27, Day 183) 
The mandatory scheduled assessments during the treatment phase will be done at 
Visit 28 (Week 27, Day 183). The subject will receive the routine dose of study drug on these 
days. In addition to the assessments done at drug administration visits, the following 
assessments will be performed at this visit:  
• Height and weight 
• 12-Lead ECG  
• Efficacy measures:  
- 
Percentage FVC based on spirometry  
- 
6MWT based on the standard method used for patients with developmental delay 
- 
JROM using universal goniometry method  
- 
Cardiac LVMI and Ejection Fraction using 2D echocardiography  
- 
Liver and spleen volume using USG  
- 
Urine GAG by urine test (will be done at Week 14, Day 92 and Week 40, Day 274 
also) 
- 
HRQoL assessments based on HS-FOCUS and CHAQ 
• Samples will be collected to assess the clinical laboratory parameters including 
haematology, urinalysis, and clinical chemistry (will be done at Week 14, Day 92 and 
Week 40, Day 274 also). Additional tests may be performed at investigator’s discretion. 
Please refer to Appendix A for list of assessments to be performed from Visit 3 (Week 2, Day 8) 
to Visit 53 (Week 52, Day 358). 
 
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9.3.3 
Final Visit/Early Termination/End of Study/Visit 54/Week 53/Day 365  
The 
last 
scheduled 
efficacy 
assessment 
and 
safety 
follow-up 
visit 
is 
Visit 54 (Week 53, Day 365). The following assessments will be performed at this visit:  
• Physical examination  
• Height and weight 
• Vital signs  
• Urine pregnancy test for females of childbearing potential 
• Efficacy measures:  
- 
Percentage FVC based on spirometry 
- 
6MWT based on the standard method used for patients with developmental delay 
- 
JROM using universal goniometry method 
- 
Cardiac LVMI and Ejection Fraction using 2D echocardiography  
- 
Liver and spleen volume using USG 
- 
Urine GAG by urine test 
- 
HRQoL assessments based on HS-FOCUS and CHAQ 
• Samples will be collected to assess the clinical laboratory parameters including 
haematology, urinalysis, and clinical chemistry. Additional test may be performed at 
investigator’s discretion.  
• Study diary will be checked and retrieved 
• Documentation of AEs and concomitant medications 
The study doctor will enquire about any AEs, and any concomitant medications that may have 
started after the last dose of Elaprase. All AEs/SAEs must be followed to closure (the subject’s 
health has returned to his/her baseline status or all variables have returned to baseline), 
regardless of whether the subject is still participating in the study. Closure indicates that an 
outcome is reached, stabilization achieved (the Investigator does not expect any further 
improvement or worsening of the event), or the event is otherwise explained. 
9.3.4 
Unscheduled Visit 
An unscheduled visit can be performed at investigator’s discretion or if the trial subject 
experiences safety concerns. The assessments at unscheduled visits will be performed at 
investigator’s discretion as clinically indicated.  
Please refer Appendix A for detailed list of assessments to be performed throughout the study 
period. 
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9.3.5 
Post Study Care 
Study drug will not be available upon completion of the subject’s participation in the study. The 
subject should be returned to the care of a physician and standard therapies as required. 
10.0 
PRETREATMENT EVENTS AND ADVERSE EVENTS 
10.1 
Definitions 
10.1.1 
PTEs 
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who 
has signed informed consent to participate in a study but prior to administration of any study 
drug; it does not necessarily have to have a causal relationship with study participation. 
10.1.2 
AEs 
An AE is defined as any untoward medical occurrence in a clinical investigation subject 
administered a drug; it does not necessarily have to have a causal relationship with this 
treatment. 
An AE can therefore be any unfavorable and unintended sign (eg, a clinically significant 
abnormal laboratory value), symptom, or disease temporally associated with the use of a drug 
whether or not it is considered related to the drug. 
10.1.3 
Additional Points to Consider for PTEs and AEs 
An untoward finding generally may: 
• Indicate a new diagnosis or unexpected worsening of a preexisting condition. 
(Intermittent events for preexisting conditions or underlying disease should not be 
considered PTEs or AEs). 
• Necessitate therapeutic intervention. 
• Require an invasive diagnostic procedure. 
• Require discontinuation or a change in infusion or a concomitant medication. 
• Be considered unfavorable by the investigator for any reason. 
PTEs/AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as a 
PTE/AE. 
Diagnoses vs signs and symptoms: 
• Each event should be recorded to represent a single diagnosis. Accompanying signs 
(including abnormal laboratory values or ECG findings) or symptoms should not be 
recorded as additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be 
recorded appropriately as a PTE(s) or as an AE(s). 
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Laboratory values and ECG findings: 
• Changes in laboratory values or ECG findings are only considered to be PTEs or AEs if 
they are judged to be clinically significant (ie, if some action or intervention is required 
or if the investigator judges the change to be beyond the range of normal physiologic 
fluctuation). A laboratory or ECG re-test and/or continued monitoring of an abnormal 
value or finding are not considered an intervention. In addition, repeated or additional 
noninvasive testing for verification, evaluation or monitoring of an abnormality is not 
considered an intervention. 
• If abnormal laboratory values or ECG findings are the result of pathology for which 
there is an overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only 
should be reported appropriately as a PTE or as an AE. 
Preexisting conditions: 
• Preexisting conditions (present at the time of signing of informed consent) are 
considered concurrent medical conditions and should not be recorded as PTEs or AEs. 
Baseline evaluations (eg, laboratory tests, ECG, X-rays etc.) should not be recorded as 
PTEs unless related to study procedures. However, if the subject experiences a 
worsening or complication of such a concurrent medical condition, the worsening or 
complication should be recorded appropriately as a PTE (worsening or complication 
occurs before start of study drug) or an AE (worsening or complication occurs after start 
of study drug). Investigators should ensure that the event term recorded captures the 
change in the condition (eg, “worsening of…”). 
• If a subject has a preexisting episodic concurrent medical condition (eg, asthma, 
epilepsy) any occurrence of an episode should only be captured as a PTE/AE if the 
condition becomes more frequent, serious or severe in nature. Investigators should 
ensure that the AE term recorded captures the change in the condition from baseline (eg, 
“worsening of…”). 
• If a subject has a degenerative concurrent medical condition (eg, cataracts, rheumatoid 
arthritis), worsening of the condition should only be recorded as a PTE/AE if occurring 
to a greater extent to that which would be expected. Investigators should ensure that the 
AE term recorded captures the change in the condition (eg, “worsening of…”). 
Worsening of PTEs or AEs: 
• If the subject experiences a worsening or complication of a PTE after the start of study 
drug, the worsening or complication should be recorded as an AE. Investigators should 
ensure that the AE term recorded captures the change in the PTE (eg, “worsening of…”). 
• If the subject experiences a worsening or complication of an AE after any change in 
study drug, the worsening or complication should be recorded as a new AE. 
Investigators should ensure that the AE term recorded captures the change in the 
condition (eg, “worsening of…”). 
Changes in intensity of AEs /Serious PTEs: 
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• If the subject experiences changes in intensity of an AE/serious PTE, the event should 
be captured once with the maximum intensity recorded. 
Preplanned procedures (surgeries or interventions): 
• Preplanned procedures (surgeries or therapies) that were scheduled prior to signing of 
informed consent are not considered PTEs or AEs. However, if a preplanned procedure 
is performed early (eg, as an emergency) due to a worsening of the preexisting condition, 
the worsening of the condition should be recorded as a PTE or an AE. Complications 
resulting from any planned surgery should be reported as AEs. 
Elective surgeries or procedures: 
• Elective procedures performed where there is no change in the subject’s medical 
condition should not be recorded as PTEs or AEs, but should be documented in the 
subject’s source documents. Complications resulting from an elective surgery should be 
reported as AEs. 
Insufficient clinical response (lack of efficacy): 
• Insufficient clinical response, efficacy, or pharmacologic action, should not be recorded 
as an AE. The investigator must make the distinction between exacerbation of 
preexisting illness and lack of therapeutic efficacy. 
Overdose: 
• Cases of overdose with any medication without manifested side effects are not 
considered PTEs or AEs, but instead will be documented on an overdose page of the 
eCRF. Any manifested side effects will be considered PTEs or AEs and will be recorded 
on the AE page of the eCRF. 
10.1.4 
SAEs 
An SAE is defined as any untoward medical occurrence that at any dose: 
1. Results in DEATH. 
2. Is LIFE THREATENING. 
• The term “life threatening” refers to an event in which the subject was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if it were more severe. 
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization. 
4. Results in persistent or significant DISABILITY/INCAPACITY. 
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT. 
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following: 
• May require intervention to prevent items 1 through 5 above. 
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• May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization. 
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and 
should be reported and followed up in the same manner (see Sections 10.2.2 and 10.3). 
10.1.5 
ADRs 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered ADRs. The phrase “responses to a medicinal product” means that a causal 
relationship between a medicinal product and an AE is at least a reasonable possibility ie, the 
relationship cannot be ruled out. 
The ADRs associated with Elaprase noted during pre- and postmarketing evaluation for Hunter 
syndrome, are summarized in Tabel 10 a. 
Tabel 10 a : Adverse drug reactions associated with use of Elaprase  
 
System organ 
class 
Adverse reaction (preferred term) 
Very common  
Common 
Uncommon 
Not known 
Immune system 
disorders 
Anaphylactoid/anaphylactic 
reaction 
Nervous system 
disorders 
Headache 
Dizziness, tremor 
 
 
Cardiac disorders 
Cyanosis, arrhythmia, 
tachycardia 
Vascular disorders Flushing 
Hypertension, 
Hypotension 
Respiratory, 
thoracic and 
mediastinal 
disorders 
Wheezing, dyspnoea Hypoxia, 
bronchospasm, cough 
Tachypnoea 
Gastrointestinal 
disorders 
Abdominal pain, 
nausea, diarrhoea, 
vomiting 
Swollen tongue, 
dyspepsia 
 
 
Skin and 
subcutaneous 
tissue disorders 
Urticaria, rash, 
pruritus, erythema 
Musculoskeletal 
and connective 
disorders 
Arthralgia 
General disorders 
and administration 
site conditions 
Pyrexia, chest pain 
Infusion-site swelling, 
face oedema, oedema 
peripheral 
Injury, poisoning Infusion-related 
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and procedural 
complications 
reaction 
10.1.6 
Intensity of PTEs and AEs 
The different categories of intensity (severity) are characterized as follows: 
Mild: 
The event is transient and easily tolerated by the subject. 
Moderate: 
The event causes the subject discomfort and interrupts the subject’s usual activities. 
Severe: 
The event causes considerable interference with the subject’s usual activities. 
10.1.7 
Causality of AEs 
The relationship of each AE to study drug will be assessed using the following categories: 
Related: 
An AE that follows a reasonable temporal sequence from administration of a drug (including 
the course after withdrawal of the drug), or for which possible involvement of the drug cannot 
be ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant medications and concurrent treatments, may also be responsible. 
Not Related: 
An AE that does not follow a reasonable temporal sequence from administration of a drug 
and/or that can reasonably be explained by other factors, such as underlying diseases, 
complications, concomitant medications and concurrent treatments. 
10.1.8 
Relationship to Study Procedures 
Relationship (causality) to study procedures should be determined for all PTEs and AEs. 
The relationship should be assessed as related if the investigator considers that there is 
reasonable possibility that an event is due to a study procedure. Otherwise, the relationship 
should be assessed as not related. All cases judged by either the reporting health care 
professional or the sponsor as having a reasonable suspected causal relationship to the study 
drug qualify as ADRs. 
10.1.9 
Start Date 
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject 
and/or investigator. 
The start date of PTEs/AEs will be determined using the following criteria: 
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PTEs/AEs 
Start Date 
Any 
signs/symptoms/diseases 
(diagnosis) 
The date that the first signs/symptoms/diseases were noted by the subject 
and/or the investigator should be recorded. 
Asymptomatic diseases 
The date when examination was performed for diagnosis and diagnosis 
was confirmed should be recorded. 
The date when diagnosis was confirmed should also be recorded even 
when values or findings showed previous values or findings or the onset 
time can be estimated. 
Worsening or complication of 
concurrent medical conditions or 
any signs/symptoms/diseases before 
treatment 
The date that a worsening or complication of the condition was noted 
first by the subject and/or the investigator should be recorded. 
The examination after start of the 
study drug 
showed abnormal 
values/findings. 
The date of examination when an abnormal value or findings that was 
judged to be clinically significant was noted should be recorded. 
The examination at the start of the 
study drug 
showed abnormal 
values/findings and the subsequent 
examinations showed worsening of 
the symptoms. 
The date of examination when apparent elevation, reduction, increase or 
decrease was confirmed in judgment according to the trends in those 
values or findings should be recorded. 
 
10.1.10 Stop Date  
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved but 
with sequelae or the subject died. 
10.1.11 Frequency  
Episodic AEs/PTE (eg, vomiting) or those which occur repeatedly over a period of consecutive 
days are intermittent. All other events are continuous. 
10.1.12 Action Concerning Study Drug  
• Drug withdrawn – a study drug is stopped due to the particular AE. 
• Dose not changed – the particular AE did not require stopping a study drug. 
• Unknown – only to be used if it has not been possible to determine what action has been 
taken. 
• Not applicable – a study drug was stopped for a reason other than the particular AE eg, 
the study has been terminated, the subject died, dosing with study drug was already 
stopped before the onset of the AE. 
• Dose reduced – the dose was reduced due to the particular AE. 
• Dose increased – the dose was increased due to the particular AE. 
• Dose interrupted – the dose was interrupted due to the particular AE. 
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10.1.13 Outcome 
• Recovered/Resolved – subject returned to first assessment status with respect to the 
AE/PTE. 
• Recovering/Resolving – the intensity is lowered by 1 or more stages: the diagnosis or 
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but 
has not returned to the normal range or to baseline; the subject died from a cause other 
than the particular AE/PTE with the condition remaining “recovering/resolving”. 
• Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the 
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the 
observed study period has got worse than when it started; is an irreversible congenital 
anomaly; the subject died from another cause with the particular AE/PTE state 
remaining “Not recovered/not resolved”. 
• Resolved with sequelae – the subject recovered from an acute AE/PTE but was left with 
permanent/significant impairment (eg, recovered from a cardiovascular accident but 
with some persisting paresis. 
• Fatal – the AEs/PTEs which are considered as the cause of death.  
• Unknown – the course of the AE/PTE cannot be followed up due to hospital change or 
residence change at the end of the subject’s participation in the study. 
10.2 
Procedures 
10.2.1 
Collection and Reporting of AEs 
10.2.1.1 
PTE and AE Collection Period 
Collection of PTEs will commence from the time the subject signs the informed consent to 
participate in the study and continue until the subject is first administered study drug 
(Week1, Day 1) or until screen failure. For subjects who discontinue prior to study drug 
administration, PTEs are collected until the subject discontinues study participation. 
Collection of AEs will commence from the time the subject signs the ICF and will continue 
until Week 53, Day 365.  
10.2.1.2 
PTE and AE Reporting 
At each study visit, the investigator will assess whether any AEs have occurred. A neutral 
question, such as “How have you been feeling since your last visit?” may be asked. Subjects 
may report AEs occurring at any other time during the study. Subjects experiencing a serious 
PTE must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or there is a satisfactory explanation for the change. 
Non-serious PTEs, related or unrelated to the study procedure, need not to be followed-up for 
the purposes of the protocol. 
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All subjects experiencing AEs, whether considered associated with the use of the study drug or 
not, must be monitored until the symptoms subside and any clinically relevant changes in 
laboratory values have returned to baseline or until there is a satisfactory explanation for the 
changes observed. All PTEs and AEs will be documented in the PTE/AE page of the eCRF, 
whether or not the investigator concludes that the event is related to the drug treatment. The 
following information will be documented for each event: 
1. Event term 
2. Start and stop date and time. 
3. Frequency. 
4. Intensity. 
5. Investigator’s opinion of the causal relationship between the event and administration of 
study drug (related or not related) (not completed for PTEs). 
6. Investigator’s opinion of the causal relationship to study procedures, including the details 
of the suspected procedure. 
7. Action concerning study drug (not applicable for PTEs). 
8. Outcome of event. 
9. Seriousness. 
PRO and subject diary will not be used as a primary means to collect AEs. However, should the 
investigator become aware of a potential AE through the information collected with this 
instrument, proper follow-up with the subject for medical evaluation should be undertaken. 
Through this follow-up if it is determined that an AE not previously reported has been 
identified, normal reporting requirements should be applied. 
10.2.2 
Collection and Reporting of SAEs 
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure: 
A Takeda SAE form must be completed, in English, and signed by the investigator immediately 
or within 24 hours of first onset or notification of the event. The information should be 
completed as fully as possible but contain, at a minimum: 
A short description of the event and the reason why the event is categorized as serious. 
• Subject identification number. 
• Investigator’s name. 
• Name of the study drug 
• Causality assessment. 
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The SAE form should be transmitted within 24 hours to the attention of the contact listed in 
Section 1.1.  
Any SAE spontaneously reported to the investigator following the AE collection period should 
be reported to the sponsor if considered related to study participation. 
Reporting of serious PTEs will follow the procedure described for SAEs. 
10.3 
Follow-up of SAEs 
If information not available at the time of the first report becomes available at a later date, the 
investigator should complete a follow-up SAE form or provide other written documentation and 
fax it immediately within 24 hours of receipt. Copies of any relevant data from the hospital 
notes (eg, ECGs, laboratory tests, discharge summary, postmortem results) should be sent to 
the addressee, if requested. 
All SAEs should be followed up until resolution or permanent outcome of the event. The 
timelines and procedure for follow-up reports are the same as those for the initial report. 
10.3.1 
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities 
The sponsor or its designate will be responsible for reporting all suspected unexpected serious 
adverse reactions (SUSARs) and any other applicable SAEs to regulatory authorities, 
investigators and IRBs or IECs, as applicable. Relative to the first awareness of the event by/or 
further provision to the sponsor or sponsor’s designee, SUSARs will be submitted to the 
regulatory authorities as expedited report within 7 days for fatal and life-threatening events and 
15 days for other serious events, unless otherwise required by national regulations. The sponsor 
or its designate will also prepare an expedited report for other safety issues where these might 
materially alter the current benefit-risk assessment of a study drug/sponsor supplied drug or that 
would be sufficient to consider changes in the study drug/sponsor supplied drug administration 
or in the overall conduct of the trial. The study site also will forward a copy of all expedited 
reports to his or her IRB or IEC in accordance with local regulations. 
 
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11.0 
STUDY-SPECIFIC COMMITTEES 
No steering committee, data safety monitoring committee, or clinical endpoint committee will 
be used in this study. 
 
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12.0 
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data Management 
Plan. AEs, PTEs, medical history, and concurrent medical conditions will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the World 
Health Organization drug dictionary. 
12.1 
CRFs (Electronic) 
Completed eCRFs are required for each subject who signs an informed consent. 
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor 
will make arrangements to train appropriate site staff in the use of the eCRFs. These forms are 
used to transmit the information collected in the performance of this study to the sponsor and 
regulatory authorities. eCRFs must be completed in English. Data are transcribed directly onto 
eCRFs. 
After completion of the entry process, computer logic checks will be run to identify items, such 
as inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
The investigator must review the eCRFs for completeness and accuracy and must sign and date 
the appropriate eCRFs as indicated. Furthermore, the investigator must retain full responsibility 
for the accuracy and authenticity of all data entered on the eCRFs. 
After the lock of the study database, any change of, modification of or addition to the data on 
the eCRFs should be made by the investigator with use of change and modification records of 
the eCRFs. The investigator must review the data change for completeness and accuracy, and 
must sign, or sign and seal, and date. 
Electronic CRFs will be reviewed for completeness and acceptability at the study site during 
periodic visits by the sponsor or its designee. The sponsor or its designee will be permitted to 
review the subject’s medical and hospital records pertinent to the study to ensure accuracy of 
the eCRFs. The completed eCRFs are the sole property of the sponsor and should not be made 
available in any form to third parties, except for authorized representatives of appropriate 
governmental health or regulatory authorities, without written permission of the sponsor.  
12.2 
Record Retention 
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
and detailed records of drug disposition to enable evaluations or audits from regulatory 
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authorities, the sponsor or its designees. Any source documentation printed on degradable 
thermal sensitive paper should be photocopied by the site and filed with the original in the 
subject’s chart to ensure long term legibility. Furthermore, International Conference on 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) E6 
Section 4.9.5 requires the investigator to retain essential documents specified in ICH E6 
(Section 8) until at least 2 years after the last approval of a marketing application for a specified 
drug indication being investigated or, if an application is not approved, until at least 2 years 
after the investigation is discontinued and regulatory authorities are notified. In addition, 
ICH E6 Section 4.9.5 states that the study records should be retained until an amount of time 
specified by applicable regulatory requirements or for a time specified in the study site 
agreement between the investigator and sponsor. 
Refer to the study site agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of 
any such documents. 
13.0 
STATISTICAL METHODS 
13.1 
Statistical and Analytical Plans 
A statistical analysis plan (SAP) will be prepared and finalized prior to database lock. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives. 
The SAP will also include a description of how missing, unused and spurious data will be 
addressed. All statistical analyses will be performed using SAS® (SAS Institute Inc., NC, USA). 
13.1.1 
Analysis Sets 
Full analysis set (FAS): FAS will comprise all enrolled subjects who received at least one dose 
of study drug and with at least one post-baseline evaluation of any of the efficacy endpoints. 
This analysis set will be used for the efficacy analyses. 
Safety analysis set (SAF): SAF will comprise all subjects who received at least one dose of 
study drug at any time during trial. 
The definition of each analysis set will be described in the Handling Rules for Analysis Data. 
The sponsor or its designate will verify the validity of the definitions of the analysis sets as well 
as the rules for handling data, with consulting a medical expert as needed. If necessary, the 
Handling Rules for Analysis Data will be supplemented with new handling rules that were not 
discussed at the planning stage. The Handling Rules for Analysis Data must be finalized prior 
to database lock. 
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13.1.2 
Analysis of Demographics and Other Baseline Characteristics 
The number and percentage of all the subjects entering, completing the study, discontinued from 
study along with primary reasons for discontinuation will be provided. The listing of subjects 
who discontinued from the study along with reason of discontinuation will be presented. 
Descriptive statistics for various continuous demographic variables: age (in years), height (in 
cm), and weight (in kg) will be provided. The frequency count (n) and percentages (%) for 
categorical variables: sex, ethnic origin, and race will be provided. Other baseline data will be 
summarized and listed appropriately. 
Medical history will be coded using the latest available version of MedDRA. The frequency 
count (n) and percentage (%) of subjects will be summarized according to the coded terms of 
system organ class (SOC) and preferred term (PT). 
13.1.3 
Efficacy Analysis 
The efficacy analysis will be performed on all the subjects in the FAS.  
Efficacy Endpoint Analysis 
All secondary efficacy endpoints will be analysed using the FAS population who received at 
least one dose of study drug.  
Descriptive summary of the secondary efficacy endpoints, ie, baseline,post-baseline, and 
change from baseline will be provided along with 90% CI.  
Health-related quality of life measured using HS-FOCUS and CHAQ will be summarised 
descriptively. 
13.1.4 
Safety Analysis 
Adverse events will be summarized by SOC and PT. Adverse events will be coded using the 
most recent version of MedDRA. A subject will only be counted once per system organ class 
and once per PT.  
Treatment-emergent AEs will be summarized for all subjects in SAF by SOC and PT. Each 
TEAE will be counted only once for a given subject. If the same TEAE occurs on multiple 
occasions, the highest severity and relationship will be considered for analysis. Summary of 
serious TEAEs will be presented separately. All other TEAEs will be summarized in similar 
manner. 
The counts and percentage of subjects will be presented for the following summaries: 
a) All AEs 
b) All TEAEs 
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c) All serious TEAEs 
d) All TEAEs by severity 
e) All TEAEs by relationship to study treatment 
f) All TEAEs related to study treatment 
g) All TEAEs related to study treatment by severity 
h) All serious TEAEs by relatedness and severity 
i) All TEAEs leading to death 
j) All TEAEs leading to discontinuation from study 
k) Infusion-related reactions 
l) ADRs (refer to Tabel 10 a) 
m) Unexpected ADRs 
No statistical inference will be performed on AEs. Listings will be presented for all AEs and 
TEAEs listed above.  
13.1.4.1 
Physical Examination 
Counts (and percentages) plus shift-changes from baseline data in the physical exam will be 
summarized. 
Individual data listings of change from baseline data in the physical exam will be presented. 
13.1.4.2 
Vital Signs 
The observed and change from baseline data of vital signs: blood pressure and pulse rate will 
be summarized descriptively. 
Individual data listings of each vital sign parameter will be presented. 
13.1.4.3 
Laboratory assessments 
The observed data of clinical laboratory assessments will be summarized and presented 
descriptively as appropriate. Clinical significant changes will be summarized categorically 
(normal, clinically significant and clinically not significant). 
Individual data listings of each laboratory parameter will be presented. 
13.1.4.4 
12-Lead ECG 
The observed data of 12-lead ECG will be summarized and presented descriptively as 
appropriate. Clinically significant changes will be summarized categorically (normal, clinically 
significant, and clinically not significant). 
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13.1.4.5 
Individual data listings of 12-lead ECG will be presented.Urine Pregnancy Test 
Individual data listings of urine pregnancy test will be presented for each subject (if any).  
13.2 
Interim Analysis and Criteria for Early Termination 
No interim analysis is planned. 
13.3 
Determination of Sample Size 
A total of 5 subjects will be enrolled in this study. According to the observed recruitment trend 
from other published trial results on clinicalTrials.gov and considering the rarity of the disease 
(based on rare disease epidemiology in India and poor diagnostic rate of ~0.1%) and the low 
availability of subjects, 5 Elaprase naive subjects whose disease condition is clinically 
diagnosed and confirmed will be enrolled.  
14.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
14.1 
Study-Site Monitoring Visits 
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and the study site guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC. 
All aspects of the study and its documentation will be subject to review by the sponsor or 
designee, including but not limited to the investigator’s binder, study drug, subject medical 
records, informed consent documentation, documentation of subject authorization to use 
personal health information (if separate from the ICFs), and review of eCRFs and associated 
source documents. It is important that the investigator and other study personnel are available 
during the monitoring visits and that sufficient time is devoted to the process. 
14.2 
Protocol Deviations 
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will 
require deviation from protocol-specified procedures, the investigator should consult with the 
sponsor or designee (and IRB or IEC, as required) to determine the appropriate course of action. 
There will be no exemptions (a prospectively approved deviation) from the inclusion or 
exclusion criteria. 
The site should document all protocol deviations in the subject’s source documents. In the event 
of a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
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assessment. A Deviation Form should be completed by the site clinical research associate and 
signed/approved by the project manager/clinical team lead for any significant deviation from 
the protocol.  
14.3 
Quality Assurance Audits and Regulatory Agency Inspections 
The study site also may be subject to quality assurance audits by the sponsor or designees. In 
this circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the drug is stored and prepared, and any other facility used during the study. If the study 
site is contacted for an inspection by a regulatory body, the sponsor should be notified 
immediately. The investigator and institution guarantee access for quality assurance auditors to 
all study documents as described in Section 14.1. 
15.0 
ETHICAL ASPECTS OF THE STUDY 
This study will be conducted with the highest respect for the individual subjects (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in 
Appendix B. The principles of Helsinki are addressed through the protocol and through 
appendices containing requirements for informed consent and investigator responsibilities. 
15.1 
IRB/IEC Approval 
IRBs and IECs must be constituted according to the applicable requirements of each 
participating region. The sponsor or designee will require documentation noting all names and 
titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC 
has direct participation in this study, written notification regarding his or her abstinence from 
voting must also be obtained. 
The sponsor or designee will supply relevant documents for submission to the respective IRB 
or IEC for the protocol’s review and approval. This protocol, the package insert, a copy of the 
informed consent form, and, if applicable, subject recruitment materials and/or advertisements 
and other documents required by all applicable laws and regulations, must be submitted to a 
central or local IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol 
and subject informed consent must be obtained and submitted to the sponsor or designee before 
commencement of the study. The IRB or IEC approval must refer to the study by exact protocol 
title, number, and version date; identify versions of other documents (eg, informed consent 
form) reviewed; and state the approval date. The sponsor will ship drug once the sponsor has 
confirmed the adequacy of site regulatory documentation and, when applicable, the sponsor has 
received permission from competent authority to begin the study. Until the site receives 
notification, no protocol activities including screening may occur. 
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Study sites must adhere to all requirements stipulated by their respective IRB or IEC. This may 
include notification to the IRB or IEC regarding protocol amendments, updates to the informed 
consent form, recruitment materials intended for viewing by subjects, local safety reporting 
requirements, reports and updates regarding the ongoing review of the study at intervals 
specified by the respective IRB or IEC, and submission of the investigator’s final status report 
to IRB or IEC. All IRB and IEC approvals and relevant documentation for these items must be 
provided to the sponsor or its designee. 
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor. 
15.2 
Subject Information, Informed Consent, and Subject Authorization 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form, subject authorization form (if 
applicable), and subject information sheet (if applicable) describe the planned and permitted 
uses, transfers, and disclosures of the subject’s personal and personal health information for 
purposes of conducting the study. The informed consent form and the subject information sheet 
(if applicable) further explain the nature of the study, its objectives, and potential risks and 
benefits, as well as the date informed consent is given. The informed consent form will detail 
the requirements of the subject and the fact that he or she is free to withdraw at any time without 
giving a reason and without prejudice to his or her further medical care. 
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent form and if applicable, the subject authorization form. The informed consent 
form, subject authorization form (if applicable), and subject information sheet (if applicable) 
must be approved by both the IRB or IEC and the sponsor prior to use. 
The informed consent form, subject authorization form (if applicable), and subject information 
sheet (if applicable) must be written in a language fully comprehensible to the prospective 
subject. It is the responsibility of the investigator to explain the detailed elements of the 
informed consent form, subject authorization form (if applicable), and subject information sheet 
(if applicable) to the subject. Information should be given in both oral and written form 
whenever possible and in the manner deemed appropriate by the IRB or IEC. In the event the 
subject is not capable of rendering adequate written informed consent, then the subject’s 
parents/guardian/LAR may provide such consent for the subject in accordance with applicable 
laws and regulations. 
The subject, or the subject’s parents/guardian/LAR, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If 
the subject, or the subject’s parents/guardian/LAR, determines he or she will participate in the 
study, then the informed consent form and subject authorization form (if applicable) must be 
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signed and dated by the subject, or the subject’s parents/guardian/LAR, at the time of consent 
and prior to the subject entering into the study. The subject or the subject’s 
parents/guardian/LAR should be instructed to sign using their legal names, not nicknames, 
using blue or black ballpoint ink. An assent form must be signed by participants of 
≥7 to <18 years of age The investigator must also sign and date the informed consent form and 
subject authorization (if applicable) at the time of consent and prior to subject entering into the 
study; however, the sponsor may allow a designee of the investigator to sign to the extent 
permitted by applicable law. 
Once signed, the original informed consent form, subject authorization form (if applicable), and 
subject information sheet (if applicable) will be stored in the investigator’s site file. The 
investigator must document the date the subject signs the informed consent in the subject’s 
medical record. Copies of the signed informed consent form, the signed subject authorization 
form (if applicable), and subject information sheet (if applicable) shall be given to the subject. 
All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s parents/guardian/LAR in the same manner as the original informed consent. 
The date the revised consent was obtained should be recorded in the subject’s medical record, 
and the subject should receive a copy of the revised informed consent form. 
15.3 
Subject Confidentiality 
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked 
to the sponsor’s clinical trial database or documentation via a subject identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth, and subject initials may be used to verify the subject and accuracy of the subject’s 
unique identification number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
sponsor requires the investigator to permit the monitor or the sponsor’s designee, 
representatives from any regulatory authority (eg, FDA, Medicines and Healthcare products 
Regulatory Agency, Pharmaceuticals and Medical Devices Agency), the sponsor’s designated 
auditors, and the appropriate IRBs and IECs to review the subject’s original medical records 
(source data or documents), including, but not limited to, laboratory test result reports, ECG 
reports, admission and discharge summaries for hospital admissions occurring during a 
subject’s study participation, and autopsy reports. Access to a subject’s original medical records 
requires the specific authorization of the subject as part of the informed consent process (see 
Section 15.2). 
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier 
fields not collected on the subject’s eCRF). 
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15.4 
Publication, Disclosure, and Clinical Trial Registration Policy 
15.4.1 
Publication and Disclosure 
The investigator is obliged to provide the sponsor with complete test results and all data derived 
by the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required 
by law or regulation. Except as otherwise allowable in the study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor. 
The sponsor may publish any data and information from the study (including data and 
information generated by the investigator) without the consent of the investigator. Manuscript 
authorship for any peer-reviewed publication will appropriately reflect contributions to the 
production and review of the document as per ICMJE guidelines. All publications and 
presentations must be prepared in accordance with this section and the study site agreement. In 
the event of any discrepancy between the protocol and the study site agreement, the study site 
agreement will prevail. 
15.4.2 
Clinical Trial Registration 
In order to ensure that information on clinical trials reaches the public in a timely manner and 
to comply with applicable laws, regulations and guidance, Takeda will, at a minimum register 
all interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov and/or 
other publicly accessible websites before start of study, as defined in Takeda Policy/Standard. 
Takeda contact information, along with investigator’s city, state (for Americas investigators), 
country, and recruiting status will be registered and available for public viewing.  
For some registries, Takeda will assist callers in locating study sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor. 
Any investigator who objects to the sponsor providing this information to callers must provide 
the sponsor with a written notice requesting that their information not be listed on the registry 
site. 
15.4.3 
Clinical Trial Results Disclosure 
Takeda will post the results of clinical trials on ClinicalTrials.gov and/or other publicly 
accessible websites, as required by Takeda Policy/Standard, applicable laws and/or regulations. 
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15.5 
Insurance and Compensation for Injury 
Each subject in the study must be insured in accordance with the regulations applicable to the 
site where the subject is participating. If a local underwriter is required, then the sponsor or 
sponsor’s designee will obtain clinical study insurance against the risk of injury to study 
subjects. Refer to the study site agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, 
he or she should contact the sponsor or sponsor’s designee. 
16.0 
REFERENCES 
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2. Lissens W, Seneca S, Liebaers I. Molecular analysis in 23 Hunter disease families. J Inherit 
Metab Dis 1997;20:453–6. 
3. Timms KM, Bondeson ML, Ansari-Lari MA, et al. Molecular and phenotypic variation in 
patients with severe Hunter syndrome. Hum Mol Genet 1997;6:479–86. 
4. Kim CH, Hwang HZ, Song SM, et al. Mutational spectrum of the iduronate 2 sulfatase gene 
in 25 unrelated Korean Hunter syndrome patients: identification of 13 novel mutations. 
Hum Mutat 2003;21:449–50. 
5. Sohn YB, Ki CS, Kim CH, et al. Identification of 11 novel mutations in 49 Korean patients 
with mucopolysaccharidosis type II. Clin Genet 2012;81:185–90. 
6. Martin R, Beck M, Eng C, Giugliani R, Harmatz P, Muñoz V, Muenzer J. Recognition and 
diagnosis of mucopolysaccharidosis II (Hunter syndrome). Pediatr 2008;121(2):e377–e86.  
7. Burton BK, Giugliani R. Diagnosing Hunter syndrome in pediatric practice: practical 
considerations and common pitfalls. Eur J Pediatr 2012;171(4):631–9.  
8. Rozdzynska A, Tylki-Szymanska A, Jurecka A, Cieslik J. Growth pattern and growth 
prediction of body height in children with mucopolysaccharidosis type II. Acta Paediatr 
2011;100(3):456–60.  
9. Parini R, Jones SA, Harmatz PR, Giugliani R, Mendelsohn NJ. The natural history of growth 
in patients with Hunter syndrome: data from the Hunter Outcome Survey (HOS). Mol Genet 
Metab 2016;117(4):438–46.  
10. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, 
et al, editors. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: 
McGraw-Hill 2001;3421–52. 
11. Schwartz IV, Ribeiro MG, Mota JG, et al. A clinical study of 77 patients with 
mucopolysaccharidosis type II. Acta Paediatr Suppl 2007;96(455):63–70.  
12. Tylki-Szymańska A. Mucopolysaccharidosis type II, Hunter’s syndrome. Pediatr 
Endocrinol Rev 2014;12(1):107–13.  
13. Young ID, Harper PS. Mild form of Hunter’s syndrome: clinical delineation based on 31 
cases. Arch Dis Child 1982;57(11):828–36.  
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14. Young ID, Harper PS. The natural history of the severe form of Hunter’s syndrome: a study 
based on 52 cases. Dev Med Child Neurol 1983;25(4):481–9. 
15. Neufeld EF, Muenzer J. The mucopolysaccharidoses. In: Scriver CR, Beaudet AL, Sly WS, 
et al, editors. The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: 
McGraw-Hill. 2001;3421–3452. 
16. Jones SA, Almassy Z, Beck M, et al. Mortality and cause of death in mucopolysaccharidosis 
type II-a historical review based on data from the Hunter Outcome Survey (HOS). J Inherit 
Metab Dis 2009;32(4):534–43.  
17. Pinto LL, Vieira TA, Giugliani R, Schwartz IV. Expression of the disease on female carriers 
of X-linked lysosomal disorders: a brief review. Orphanet J Rare Dis 2010;14(5):1-10.  
18. Tuschl K, Gal A, Paschke E, Kircher S, Bodamer OA. Mucopolysaccharidosis type II in 
females: case report and review of literature. Pediatr Neurol 2005;32(4):270–2. 
19. Malm G, Gustafsson B, Berglund G, et al. Outcome in six children with 
mucopolysaccharidosis type IH, Hurler syndrome, after haematopoietic stem cell 
transplantation (HSCT). Acta paediatrica 2008;97:1108–12. 
20. Vellodi A, Young E, Cooper A, Lidchi V, Winchester B, Wraith JE. Long-term follow-up 
following bone marrow transplantation for Hunter disease. J Inherit Metab Dis 
1999;22:638–48. 
21. Muenzer J, Gucsavas-Calikoglu M, McCandless SE, Schuetz TJ, Kimura A. A phase I/II 
clinical trial of enzyme replacement therapy in mucopolysaccharidosis II (Hunter 
syndrome). Mol Genet Metab 2007;90:329–37. 
22. Muenzer J, Wraith JE, Beck M, et al: A phase II/III clinical study of enzyme replacement 
therapy with idursulfase in mucopolysaccharidosis II (Hunter syndrome). Genet Med 
2006;8:465–73. 
23. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. 
JAMA. 1999;281(3):249–54. 
24. Tylki-Szymanska A. Mucopolysaccharidosis type II, Hunter’s syndrome. Pediatr 
Endocrinol Rev. 2014;12(1):107–13. 
25. Baehner F, Schmiedeskamp C, Krummenauer F, Miebach E, Bajbouj M, Whybra C, 
Kohlschutter A, Kampmann C, Beck M. Cumulative incidence rates of the 
mucopolysaccharidoses in Germany. J Inherit Metab Dis. 2005;28(6):1011–7. 
26. American Thoracic Society. Standardization of Spirometry, 1994 Update. Am J Respir Crit 
Care Med 1995;152:1107–36. 
27. Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC. Lung volumes 
and forced ventilatory flows. Report Working Party Standardization of Lung Function 
Tests, European Community for Steel and Coal. Official Statement of the European 
Respiratory Society. Eur Respir J Suppl 1993;16:5–40. 
28. American Thoracic Society. ATS statement: guidelines for the six-minute walk test. Am J 
Respir Crit Care Med 2002;166:111–7. 
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29. Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, Reichek N. 
Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy 
findings. Am J Cardiol 1986;57:450–8. 
30. Kakkis ED, Muenzer J, Tiller GE, et al. Enzyme-replacement therapy in 
mucopolysaccharidosis I. N Engl J Med 2001;344:182–8. 
31. Schlesinger AE, Edgar KA, Boxer LA. Volume of the spleen in children as measured on 
CT scans: normal standards as a function of body weight. AJR Am J Roentgenol 
1993;160:1107–9. 
32. de Jong JGN, Wevers RA, Laarakkers C, Poorthuis BJ. Dimethylmethylene blue based 
spectrophotometry of glycosaminoglycans in untreated urine: a rapid screening procedure 
for mucopolysaccharidoses. Clin Chem 1989;35:1472–7. 
33. Norkin CC, White DD. Measurement of joint motion; a guide to goniometry. 3rd edition. 
Philadelphia: F.A. Davis Company; 2003. 
34. Wiklund I, Raluy-Callado M, Stull DE, Jangelind Y, Whiteman DA, Chen WH. The Hunter 
syndrome-functional outcomes for 
clinical 
understanding scale 
(HS-FOCUS) 
questionnaire: evaluation of measurement properties. Qual Life Res. 2013;22(4):875-884.  
35. Raluy-Callado M, Chen WH, Whiteman DAH, Fang J, Wiklund I. The impact of Hunter 
syndrome (mucopolysaccharidosis type II) on health-related quality of life. Orphanet J Rare 
Dis. 2013;8:101. 
36. Giannini EH, Ruperto N, Ravelli A, Lovell DJ, Felson DT, Martini A. Preliminary 
definition of improvement in juvenile arthritis. Arthritis Rheum. 1997;40(7):1202-1209. 
 
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Appendix A Schedule of Study Procedures 
Visits 
V1 
V2 
V3 to V14 
V15 
V16 to V27 
28 
V29 to V40 
V41 
V42 to V53 
(EOT) 
V54 
Unschedul
ed visit 
  
Screening 
Baseline 
Treatment and Assessments 
EOS/ET 
Assessmentsc  
 
Weeks (W) 
/Days(D) 
Day -14 to 
Day -1 
W1D1  
(Day 1)a 
 
 
W2 D1 to 
W13D1 
(Day 8 
to 
Day 85)b 
W14 D1 
(Day 92) b  
 
W15 D1 to 
W26 D1 
(Day 99 
to 
Day 176)b  
W27 D1 
(Day 183) b 
 
 
W28 D1 to 
W39 D1 
(Day 190 to 
Day 267) b 
 
 
 
 
W40 D1 
(Day 274)b  
 
 
 
W41 D1 to 
W52 D1 
(Day 281 to 
Day 358)b 
 
 
 
 
W53 D1 
 (Day 365)b 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Demographics (Age and Sex) 
X 
 
 
 
 
 
 
 
 
 
 
Anthropometry (Height, 
Weight)d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Diagnosis and Baseline 
Disease Characteristicse 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Prior Medications 
X 
 
 
 
 
 
 
 
 
 
 
Prior Disease-Specific 
Therapies/ Medications 
X 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Examinationf 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Visits 
V1 
V2 
V3 to V14 
V15 
V16 to V27 
28 
V29 to V40 
V41 
V42 to V53 
(EOT) 
V54 
Unschedul
ed visit 
  
Screening 
Baseline 
Treatment and Assessments 
EOS/ET 
Assessmentsc  
 
Weeks (W) 
/Days(D) 
Day -14 to 
Day -1 
W1D1  
(Day 1)a 
 
 
W2 D1 to 
W13D1 
(Day 8 
to 
Day 85)b 
W14 D1 
(Day 92) b  
 
W15 D1 to 
W26 D1 
(Day 99 
to 
Day 176)b  
W27 D1 
(Day 183) b 
 
 
W28 D1 to 
W39 D1 
(Day 190 to 
Day 267) b 
 
 
 
 
W40 D1 
(Day 274)b  
 
 
 
W41 D1 to 
W52 D1 
(Day 281 to 
Day 358)b 
 
 
 
 
W53 D1 
 (Day 365)b 
 
 
 
 
Vital Signs g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Inclusion and Exclusion 
Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
12-Lead ECG h,i 
X 
 
 
 
 
X 
 
 
 
X 
 
Subject Diary Dispensed 
 
X 
 
 
 
 
 
 
 
 
 
Subject Diary Retrieved and 
Reviewed 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study Drug Administration 
 
                                0.5 mg/kg IV infusion every week 
 
 
 
FVC, percent predicted/ FVC 
absolutej,i (Spirometry) 
Xk 
 
 
 
 
X 
 
 
 
X 
 
6MWTl,i 
X 
 
 
 
 
X 
 
 
 
X 
 
Cardiac LVMI & Ejection 
Fractionm,i (2D 
echocardiography) 
Xk 
 
 
 
 
X 
 
 
 
X 
 
Liver and spleen volumen,i 
(USG)  
Xk 
 
 
 
 
X 
 
 
 
X 
 
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Visits 
V1 
V2 
V3 to V14 
V15 
V16 to V27 
28 
V29 to V40 
V41 
V42 to V53 
(EOT) 
V54 
Unschedul
ed visit 
  
Screening 
Baseline 
Treatment and Assessments 
EOS/ET 
Assessmentsc  
 
Weeks (W) 
/Days(D) 
Day -14 to 
Day -1 
W1D1  
(Day 1)a 
 
 
W2 D1 to 
W13D1 
(Day 8 
to 
Day 85)b 
W14 D1 
(Day 92) b  
 
W15 D1 to 
W26 D1 
(Day 99 
to 
Day 176)b  
W27 D1 
(Day 183) b 
 
 
W28 D1 to 
W39 D1 
(Day 190 to 
Day 267) b 
 
 
 
 
W40 D1 
(Day 274)b  
 
 
 
W41 D1 to 
W52 D1 
(Day 281 to 
Day 358)b 
 
 
 
 
W53 D1 
 (Day 365)b 
 
 
 
 
Global Joint Range of Motion 
(JROM) Score,i 
X 
X 
 
 
 
X 
 
 
 
X 
 
HRQoL (HS-FOCUS and 
CHAQ)o,i 
X 
 
 
 
 
X 
 
 
 
X 
 
Sample Collection 
 
 
 
 
 
 
 
 
 
 
 
Urinalysisp,i 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Clinical chemistryq,i 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Hematologyr,i 
X 
 
 
X 
 
X 
 
X 
 
X 
 
Urine GAG, µg GAG/mg 
creatinines,i 
X 
      
 
X 
 
X 
 
X 
 
X* 
 
Urine Pregnancy Test for 
Female of Childbearing 
Potential t  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
AEs collection 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
Abbreviations: 6WMT=6 Minute Walk Test, AE=Adverse event, ALP=Alkaline phosphatase, ALT=Alanine aminotransferase, AST=Aspartate aminotransferase, 
BUN=Blood urea nitrogen, CHAQ=Childhood Health Assessment Questionnaire, D=Day, ECG=Electrocardiogram, ET=Early termination, FVC=Forced vital capacity, 
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GAG=Glycosaminoglycan, GGT=Gamma-glutamyltransferase, HRQoL=health related quality of life, HS-FOCUS=Hunter Syndrome-Functional Outcomes for Clinical 
Understanding Scale; IV=intravenous; JROM=Joint Range of Motion, LVMI=Left Ventricular Mass Index, USG=Ultrasonography, V=Visit, W=Week. 
a. 
 The day of first study drug administration for treatment period is Day 1. The day before first study drug administration for treatment period is 
Day -1.  
b. The subjects must attend visits as close as possible to the planned day, and ideally within ±3 days. 
c. The end of study visit is defined as the date of the last visit (Week 53) of the subject or until discontinuation of study drug. 
d. Height will be measured at baseline for all subjects; for subjects <18 years at baseline, height will also be measured at the assessment visits 
(Week 27, Day 183 and Week 53, Day 365). Height can also be optionally measured at Visit 15 (Week 14, Day 92) and Visit 41 (Week 40, Day 
274) at investigator’s discretion, and if measured the data will be recorded in eCRF. Weight will be measured for all the subjects at all the visits.  
e. Including date of diagnosis, past and present illnesses/complications due to Hunter syndrome. 
f. 
Physical examination includes general appearance; assessments of head, neck, and thyroid; eyes, ears, nose, and throat; chest and lungs; heart; 
lymph nodes; abdomen; anorectal; genitourinary; skin; musculoskeletal; endocrine; neurological; and other (at investigator’s discretion). 
g. Include blood pressure, pulse, respiratory rate, and temperature. Vital signs are taken immediately before and after every infusion (within 10 
minutes). 
h. Can be performed at Visit 2 if not done at screening and repeated at other visits at investigator’s discretion.  
i. 
All these assessments can also be performed at unscheduled visit at investigator’s discretion. If these assessments are done at investigator’s 
discretion at any unscheduled visit, the data will be recorded in eCRF. 
j. 
As the trial includes pediatric population also, feasibility of FVC procedure  in subjects < 5 years of age can be performed  by the investigator 
prior to performing the procedure. 
k. 2D echocardiography, USG (Liver and spleen volume), and spirometry tests should have been performed within 30 days of subject’s enrolment 
or at the time of screening. 
l. 
As the trial includes pediatric population also, feasibility of 6MWT procedure  in subjects < 5 years of age can be performed  by the investigator 
prior to performing the procedure. 
m. Cardiac LVMI and Ejection Fraction will be determined by 2D echocardiography. 
n. Liver and spleen volumes will be determined by Ultrasonography. 
o. HRQoL assessment based on HS-FOCUS will be done in all subjects and CHAQ will be done in subjects between age of ≥6 months to ≤18 years. 
p. Includes specific gravity, pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, red blood cells, white blood cells, epithelial cells, 
crystals, casts, and bacteria. 
q. Includes glucose, urea, potassium, sodium, chloride, total bilirubin, total protein, albumin, globulin, ALP, ALT, AST, BUN, a nd GGT and fasting 
lipids profile (high-density lipoprotein [HDL], low-density lipoprotein [LDL], triglycerides, and total cholesterol). 
r. 
Includes haemoglobin, haematocrit, red blood cell count, and white blood cell count with differential (ie, basophils, eosinophils, lymphocytes, 
monocytes, and neutrophils), mean corpuscular volume (MCV), mean corpuscular haemoglobin concentration (MCHC), and platelet count. 
s. Mean normalized urine GAG will be analyzed using urine testing. The urine GAG levels will be normalized to urine creatinine a nd will be reported 
as microgram GAG per milligram creatinine (µg GAG/mg creatinine). 
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t. 
It is known that Hunter syndrome almost exclusively affects males and it is highly unlikely that females will be affected by Hunter syndrome. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix B Responsibilities of the Investigator 
Clinical research studies sponsored by the sponsor are subject to International Conference on 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use E6 Good Clinical 
Practice (ICH GCP) and all the applicable local laws and regulations.  
The investigator agrees to assume the following responsibilities: 
1. Conduct the study in accordance with the protocol. 
2. Personally conduct or supervise the staff who will assist in the protocol. 
3. Ensure that study related procedures, including study specific (non routine/non standard panel) 
screening assessments are not performed on potential subjects, prior to the receipt of written approval 
from relevant governing bodies/authorities. 
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed of these 
obligations. 
5. Secure prior approval of the study and any changes by an appropriate Institutional Review Board 
(IRB)/Independent Ethics Committee (IEC) that conform to ICH, and local regulatory requirements. 
6. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval of the 
protocol. Promptly report to the IRB/IEC all changes in research activity and all anticipated risks to 
subjects. Make at least yearly reports on the progress of the study to the IRB/IEC, and issue a final 
report within 3 months of study completion. 
7. Ensure that requirements for informed consent, as outlined in ICH and local regulations, are met. 
8. Obtain valid informed consent from each subject who participates in the study, and document the 
date of consent in the subject’s medical chart. Valid informed consent is the most current version 
approved by the IRB/IEC. Each informed consent form should contain a subject authorization section 
that describes the uses and disclosures of a subject’s personal information (including personal health 
information) that will take place in connection with the study. If an informed consent form does not 
include such a subject authorization, then the investigator must obtain a separate subject authorization 
form from each subject or the subject’s parents/guardian/LAR. 
9. Prepare and maintain adequate case histories of all persons entered into the study, including eCRFs, 
hospital records, laboratory results, etc, and maintain these data for a minimum of 2 years following 
notification by the sponsor that all investigations have been discontinued or that the regulatory 
authority has approved the marketing application. The investigator should contact and receive written 
approval from the sponsor before disposing of any such documents. 
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents. 
11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied drugs, 
and return all unused sponsor-supplied drugs to the sponsor.  
12. Report adverse reactions to the sponsor promptly. In the event of an serious adverse event (SAE), 
notify the sponsor within 24 hours. 
 
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Appendix C Elements of the Subject Informed Consent  
In seeking informed consent, the following information shall be provided to each subject: 
1. A statement that the study involves research. 
2. An explanation of the purposes of the research. 
3. The expected duration of the subject’s participation. 
4. A description of the procedures to be followed, including invasive procedures. 
5. The identification of any procedures that are experimental. 
6. The estimated number of subjects involved in the study. 
7. A description of the subject’s responsibilities. 
8. A description of the conduct of the study. 
9. A statement describing the treatment. 
10. A description of the possible side effects of the treatment that the subject may receive. 
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when applicable, 
to an embryo, fetus, or nursing infant. 
12. A description of any benefits to the subject or to others that reasonably may be expected from the 
research. When there is no intended clinical benefit to the subject, the subject should be made aware 
of this. 
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be 
advantageous to the subject and their important potential risks and benefits. 
14. A statement describing the extent to which confidentiality of records identifying the subject will be 
maintained, and a note of the possibility that regulatory agencies, auditor(s), Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC), and the monitor may inspect the records. By 
signing a written informed consent form, the subject or the subject’s parents/guardian/LAR is 
authorizing such access. 
15. For research involving more than minimal risk, an explanation as to whether any compensation and 
an explanation as to whether any medical treatments are available if injury occurs and, if so, what 
they consist of or where further information may be obtained. 
16. The anticipated prorated payment(s), if any, to the subject for participating in the study. 
17. The anticipated expenses, if any, to the subject for participating in the study. 
18. An explanation of whom to contact for answers to pertinent questions about the research 
(investigator), subject’s rights, and IRB/IEC and whom to contact in the event of a research-related 
injury to the subject. 
19. A statement that participation is voluntary, that refusal to participate will involve no penalty or loss 
of benefits to which the subject otherwise is entitled, and that the subject or the subject’s 
parents/guardian/LAR may discontinue participation at any time without penalty or loss of benefits 
to which the subject is otherwise entitled. 
20. The consequences of a subject’s decision to withdraw from the research and procedures for orderly 
termination of participation by the subject. 
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21. A statement that the subject or the subject’s parents/guardian/LAR will be informed in a timely 
manner if information becomes available that may be relevant to the subject’s willingness to continue 
participation in the study. 
22. A statement that results of pharmacogenomic analysis will not be disclosed to an individual, unless 
prevailing laws require the sponsor to do so. 
23. The foreseeable circumstances or reasons under which the subject’s participation in the study may be 
terminated. 
24. A written subject authorization (either contained within the informed consent form or provided as a 
separate document) describing to the subject the contemplated and permissible uses and disclosures 
of the subject’s personal information (including personal health information) for purposes of 
conducting the study. The subject authorization must contain the following statements regarding the 
uses and disclosures of the subject’s personal information: 
a) that personal information (including personal health information) may be processed by or 
transferred to other parties in other countries for clinical research and safety reporting purposes, 
including, without limitation, to the following: (1) Takeda, its affiliates, and licensing partners; 
(2) business partners assisting Takeda, its affiliates, and licensing partners; (3) regulatory 
agencies and other health authorities; and (4) IRBs/IECs; 
b) it is possible that personal information (including personal health information) may be processed 
and transferred to countries that do not have data protection laws that offer subjects the same level 
of protection as the data protection laws within this country; however, Takeda will make every 
effort to keep your personal information confidential, and your name will not be disclosed outside 
the clinic unless required by law; 
c) that personal information (including personal health information) may be added to Takeda’s 
research databases for purposes of developing a better understanding of the safety and 
effectiveness of the study drug(s), studying other therapies for patients, developing a better 
understanding of disease, and improving the efficiency of future clinical studies; 
d) that subjects agree not to restrict the use and disclosure of their personal information (including 
personal health information) upon withdrawal from the study to the extent that the restricted use 
or disclosure of such information may impact the scientific integrity of the research; and 
e) that the subject’s identity will remain confidential in the event that study results are published. 
25. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) who are 
sexually active must use highly effective contraception (as defined in the informed consent) from 
Screening throughout the duration of the study. Regular pregnancy tests will be performed throughout 
the study for all female subjects of childbearing potential. If a subject is found to be pregnant during 
study, study drug will be discontinued and the investigator will offer the subject the choice to receive 
unblinded treatment information. 
26. Male subjects must use highly effective contraception (as defined in the informed consent) from 
signing the informed consent throughout the duration of the study. If the partner or wife of the subject 
is found to be pregnant during the study, the investigator will offer the subject the choice to receive 
unblinded treatment information. 
27. A statement that clinical trial information from this trial will be publicly disclosed in a publicly 
accessible website, such as ClinicalTrials.gov. 
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Appendix D Investigator Consent to Use of Personal Information  
Takeda will collect and retain personal information of investigator, including his or her name, address, 
and other personally identifiable information. In addition, investigator’s personal information may be 
transferred to other parties located in countries throughout the world (eg, the United Kingdom, United 
States, and Japan), including the following: 
• Takeda, its affiliates, and licensing partners. 
• Business partners assisting Takeda, its affiliates, and licensing partners. 
• Regulatory agencies and other health authorities. 
• IRBs and IECs. 
• Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following: 
• Assessment of the suitability of investigator for the study and/or other clinical studies. 
• Management, monitoring, inspection, and audit of the study. 
• Analysis, review, and verification of the study results. 
• Safety reporting and pharmacovigilance relating to the study. 
• Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study. 
• Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study drug. 
• Inspections and investigations by regulatory authorities relating to the study. 
• Self-inspection and internal audit within Takeda, its affiliates, and licensing partners. 
• Archiving and audit of study records. 
• Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites. 
Investigator’s personal information may be transferred to other countries that do not have data protection 
laws that offer the same level of protection as data protection laws in investigator’s own country. 
Investigator acknowledges and consents to the use of his or her personal information by Takeda and other 
parties for the purposes described above. 
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Appendix E Hunter Syndrome – Functional Outcomes For Clinical Understanding Scale 
(HS-FOCUS); Parent Completed Questionnaire (Shortened version) 
For non-commercial use only

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Elaprase 
 
Study No. TAK-665-4001 
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Protocol Final 
                        24 February 2021 
 
CONFIDENTIAL 
 
 
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1.0 TITL 
E PAGE 
Elaprase 
 
Study No. TAK-665-4001 
               Page 86 of 87 
Protocol Final 
        24 February 2021 
 
 
Appendix G Elaprase Package Insert for India 
 
 
For non-commercial use only

Elaprase 
 
Study No. TAK-665-4001 
                               Page 87 of 87 
Protocol Final 
                        24 February 2021 
 
CONFIDENTIAL 
 
Appendix H Detailed Description of Amendments to Text 
This is an original protocol. 
For non-commercial use only