Conditions: Gaucher Disease
Keywords: VPRIV Gaucher Disease
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 20
Healthy volunteers: no

Brief summary:
The main purpose of this study is to observe the side effects of VPRIV in participants with type 1 Gaucher disease who are either treatment-naïve (newly diagnosed) or who are currently being treated with enzyme replacement therapy (ERT).

Participants will receive VPRIV intravenously during the treatment period (up to 51 weeks), followed by the end-of-treatment (EOT) visit after 2 weeks.

Detailed description:
The drug being tested in this study is called Velaglucerase Alfa (VPRIV). VPRIV will be tested to treat participants with type 1 Gaucher disease. This study will look at the safety, efficacy and pharmacokinetics of VPRIV in the treatment of type 1 Gaucher disease.

The study will enroll approximately 20 participants with Gaucher disease. The study comprises a screening period (Day -21 through Day -4), baseline period (Day -3 through Day 0), treatment period (Week 1 to Week 51), and safety follow-up period. Participants will be assigned to the following drug administration:

• Velaglucerase Alfa (VPRIV)

Participants will receive VPRIV as intravenous (IV) infusion every other week from Week 1 through Week 51 during the Treatment Period. Percentage of participants with at least one serious treatment-emergent adverse event (TEAE) will be evaluated throughout the study.

This multi-center trial will be conducted in China. The overall time to participate in this study is approximately 59 weeks. Participants will make a safety follow-up telephone call or visit to the site after 30 (±7) days of the last infusion of the study drug.

Arms:
arm 1: Participants received VPRIV IV infusion at 60 units per kilogram (U/kg) body weight once every other week (EOW) for 60 (+10) minutes for up to 51 weeks.

Interventions: intervention 1: Velaglucerase Alfa
Intervention descriptions: intervention 1: VPRIV intravenous infusion every other week for 60 minutes.

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


TAKEDA PHARMACEUTICALS 
Protocol: 
TAK-669-3001 
Title: 
A Multicenter, Open-label Study to Evaluate the Safety, Efficacy, and 
Pharmacokinetics of Velaglucerase alfa in Chinese Subjects With 
Type 1 Gaucher Disease 
Short Title: 
Safety, Efficacy, and Pharmacokinetics of Velaglucerase alfa in 
Chinese Subjects With Type 1 Gaucher Disease 
Study Phase: 
Phase 3b 
Drug: 
Velaglucerase alfa (VPRIV) 
IND Number: 
Non-IND 
EUDRACT 
Number: 
Non-EUDRACT 
Sponsor: 
Takeda Development Center Americas, Inc. 
95 Hayden Ave, Lexington, MA 02421, USA 
Principal/ 
Coordinating 
Investigator: 
 
 
Protocol History: 
Original Protocol: 22 Nov 2021 
Protocol Amendment 1: 02 Aug 2022 
Confidentiality Statement 
This document contains confidential and proprietary information of Takeda and is disclosed pursuant to 
confidentiality and nondisclosure obligations. This information should be used solely for the purposes for which 
it was provided and should not be copied, shared with, or disclosed to any third party without the express written 
consent of Takeda. 
For non-commercial use only


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CONFIDENTIAL 
Page 3 
Velaglucerase alfa (VPRIV) 
Clinical Study Protocol Amendment 1: TAK-669-3001  
02 Aug 2022 
 
 
 
SUMMARY OF CHANGES FROM PREVIOUS PROTOCOL VERSION 
A summary of the changes incorporated into Amendment 1 is provided in the table below. Any 
minor revisions in grammar, spelling, punctuation, and format are not reflected in the summary 
of changes. 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
1 
Amendment Date 
02 Aug 2022 
China 
Description of Each Change and Rationale  
Section(s) Affected by Change 
Added details regarding contact information cards and changed the 
section heading as per the updated protocol template. 
Contacts  
 
Increased the frequency of the body weight test as body weight changes 
requires to recalculate the dose of investigational product. 
Section 1.1 Synopsis 
Table 1 Schedule of Activities 
Section 6.2.3 Dosing 
Added a window duration for the infusion to +10 minutes over a period 
of 60 minutes to provide the additional operational flexibility.  
The window duration of infusion should not be applicable on Day 1 
(Week 1) and Week 37 as the PK sample collection are scheduled during 
these visits and the PK sampling timepoints are the nominal timepoints 
based on a 60-minute infusion. 
Section 1.1 Synopsis 
Table 1 Schedule of Activities, 
footnote ‘l’ 
Section 6.2 Administration of 
Investigational Product 
Added the sentence that QoL assessment is not applicable for subjects 
<5 years of age for clarification. 
Section 1.1 Synopsis 
Table 1 Schedule of Activities, 
footnote ‘x’ 
Section 4.1 Overall Design 
Section 8.2.4.3 Quality of Life 
Specified the minimum number of enrolled subjects in the study who 
should be <18 and ≥18 years old for better clarification. 
Section 1.1 Synopsis 
Table 2 Pharmacokinetic Sampling 
Time Points 
Section 4.1 Overall Design 
Removed the dose of VPRIV as the switch subjects may use different 
dose in the study than already defined (60 U/kg body weight). 
 
Section 1.1 Synopsis 
Section 3.1.1 Primary Objective 
Section 4.1 Overall Design 
Section 4.2 Scientific Rationale for 
Study Design 
Section 6.2.3 Dosing 
Increased the number of clinical sites from ‘5 to 6’ to ‘at least 8’ to 
increase the recruitment capability. 
Section 1.1 Synopsis 
Section 4.5 Sites and Regions 
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CONFIDENTIAL 
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Velaglucerase alfa (VPRIV) 
Clinical Study Protocol Amendment 1: TAK-669-3001  
02 Aug 2022 
 
 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
1 
Amendment Date 
02 Aug 2022 
China 
Description of Each Change and Rationale  
Section(s) Affected by Change 
Updated the previous inclusion criterion#3 and #4 as the subject needs to 
meet any 1 criterion to be eligible for the study and merged it as inclusion 
criterion#3. 
Reported the details of previous inclusion criterion#3 (b and c) as 
inclusion criterion#4 and #5 for better clarity and to specify how to assess 
splenomegaly and hepatomegaly. 
Section 1.1 Synopsis 
Section 5.1 Inclusion Criteria 
 
Changed the size of in-line sterilizing filter from ‘0.2 μm’ through 
‘0.22 μm’ in consistent with the China label. 
Section 1.1 Synopsis 
Section 6.2 Administration of 
Investigational Product 
Added the body weight test during the screening period as it is used for 
normalized liver and spleen volume calculation measured by abdominal 
radiology scan (MRI or CT scan). 
Updated the frequency of height to match with the frequency of 
abdominal radiology scan (MRI or CT scan) which will be used for 
normalized liver and spleen volume calculation. 
Table 1 Schedule of Activities 
Added the details for the initial dose calculation for subject who received 
Imiglucerase ERT within the 12 months prior to screening for 
consistency with other sections of the protocol. 
Table 1 Schedule of Activities, 
footnote ‘l’ 
Clarified that vital signs and 12-lead ECG will be measured/collected 
prior to blood draw and/or initiation of infusion following 5 minutes of 
rest as per the standard operational requirements. 
Table 1 Schedule of Activities, 
footnote ‘m’ 
Table 1 Schedule of Activities, 
footnote ‘o’ 
Section 8.2.3.3 Vital Signs 
Section 8.2.3.6 12-lead 
Electrocardiogram 
Removed the test ‘subtypes for creatine kinase’ as some sites could not 
perform this test and based on the previous results, it is not critical to 
evaluate the safety of VPRIV. 
Specified the name of ‘blood urea nitrogen’ as ‘(blood) urea nitrogen or 
(blood) urea’ to allow flexibility at sites. 
Removed the tests of ‘iron-binding capacity, transferrin saturation, and 
unsaturated iron-binding capacity’ as some sites could not perform this 
test and these tests are not critical tests to distinguish 
iron-deficiency-related anemia and Gaucher disease-related anemia. 
Table 1 Schedule of Activities, 
footnote ‘r’ 
Appendix 2 
 
Added criteria for defining hepatomegaly and moderate splenomegaly 
and to enable eligibility at local clinical site. 
Table 1 Schedule of Activities, 
footnote ‘v’ 
Section 8.2.2.2 Liver and Spleen 
Magnetic Resonance Imaging or 
Computed Tomography Scan 
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CONFIDENTIAL 
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Velaglucerase alfa (VPRIV) 
Clinical Study Protocol Amendment 1: TAK-669-3001  
02 Aug 2022 
 
 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
1 
Amendment Date 
02 Aug 2022 
China 
Description of Each Change and Rationale  
Section(s) Affected by Change 
Widen the allowed PK sample collection window to facilitate the study 
execution without impacting the integrity of the PK assessment. 
Removed the predose PK sample in 4 through 11 years old subject to 
reduce the blood collection times/volume. 
Changed the PK sample collection window for the start of infusion to 0 (-
30 minutes) and end of infusion to 60 (-3 minutes) and added footnotes 
‘a’ and ‘b’ that ‘a PK sample should be collected within 30 min prior to 
the start of 60 minutes infusion’ and ‘a PK sample should be collected 
within 3 minutes prior to the end of 60 minutes infusion’, respectively for 
better clarification. 
Added a footnote “the PK sampling timepoints are the nominal 
timepoints based on a 60-minute infusion” to clarify the PK sample 
collections relative to the infusion duration. 
Table 2 Pharmacokinetic Sampling 
Time Points 
Added the details of restricted items of which female and male subjects 
should refrain from for the duration of the study and for 30 days after the 
last dose of study treatment per the study requirements. 
Section 5.4.1 Female Contraception 
Section 5.4.2 Male Contraception 
Added the details to clarify the responsibility of an investigator if a 
subject experiences an infusion-related AEs. 
Added the sentence that “site specific discharge requirements should be 
followed if any” to increase the operational flexibility. 
Section 6.2 Administration of 
Investigational Product 
Removed the term ‘destruction at site tracking’ as the study drug will be 
destructed at the central depot designated by sponsor. 
Section 6.2.1 Interactive Response 
Technology for Investigational 
Product Management 
Added a sentence “A daily temperature log of the drug storage area must 
be maintained every working day” to clearly define the requirement of 
study drug temperature record. 
Section 6.3.3 Storage 
Added additional details for review of subject eligibility at baseline visit 
due to the complex inclusion criteria and reduce screening failure rate. 
Section 8.1.2 Baseline Visit (Day –3 
Through Day 0) 
Updated the number of blood samples for children (4 through 11 years 
old) from ‘7 blood samples’ to ‘6 blood samples’ as predose PK sample 
has been removed to reduce the blood collection times/volume. 
Specified that listed PK parameters are only for Day 1 (Week 1) based on 
serial PK sampling. 
Section 8.2.4.1 Pharmacokinetics 
Added a sentence that alternative approaches such as remote source data 
review via phone or video could be used for monitoring purpose per the 
updated protocol template. 
Appendix 1.3 
Updated the existing questionnaire with the standard questionnaires from 
the license holder. 
Appendix 5 Scales and Assessments 
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CONFIDENTIAL 
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Velaglucerase alfa (VPRIV) 
Clinical Study Protocol Amendment 1: TAK-669-3001  
02 Aug 2022 
 
 
 
Protocol Amendment 
Summary of Change(s) Since the Last Version of the Approved Protocol 
Amendment Number 
1 
Amendment Date 
02 Aug 2022 
China 
Description of Each Change and Rationale  
Section(s) Affected by Change 
Minor grammatical and administrative changes, rewording and updates 
have been made for consistency, to remove redundancies, and to improve 
readability, and clarity of the protocol. 
Throughout the document 
AE=adverse event; CT=computed tomography; ECG=electrocardiogram; ERT=enzyme replacement therapy; 
PK=pharmacokinetic; QoL=quality of life; MRI=magnetic resonance imaging; SAE=serious adverse event; 
VPRIV=velaglucerase alfa. 
See Appendix 7 for protocol history, including all previous amendments. 
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CONTACTS  
Contacts 
Certain events and study-related activities will require the investigator and/or subject to have 
appropriate contact information. The sponsor or contract research organization (CRO) will 
provide investigators with emergency medical contact information cards to be carried by each 
subject. 
SAE Reporting 
In the event of a serious adverse event (SAE), the investigator should complete an SAE 
electronic Case Report Form (eCRF) in English or report via the paper safety report form (as 
backup) within 24 hours of becoming aware of any SAE. The fax number and email address are 
provided in the Form Completion Instruction. 
Protocol and Safety-Related Questions or Concerns 
For protocol- or safety-related questions or concerns, the investigator must contact PPD medical 
monitor: 
Hotline number (24 hours a day/7 days a week): + 44 1223 374 240 
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PRODUCT QUALITY COMPLAINTS 
Investigators are required to report investigational product quality complaints or nonmedical 
complaints to Takeda within 1 business day. If requested, the defective product(s) will be 
returned to the sponsor for inspection and analysis. 
A product quality complaint includes any instances where there is an allegation or report relating 
to Takeda licensed or investigational products, received in writing, electronically, or orally, 
which indicates an impact to a product’s strength, identity, safety, purity, or quality, or which 
suggests that the product did not meet the criteria defined in the regulatory applications, licenses, 
or marketing authorizations for the product. Examples of investigational product quality 
complaints include, but are not limited to, the following: 
Unit issues 
• Capsule fill empty or overage 
• Bottle/vial fill shortage or overage 
• Capsule/tablet damaged/broken 
• Syringe/vial cracked/broken 
• Syringe leakage 
• Missing components 
• Product discoloration 
• Device malfunction 
Labeling 
• Label missing 
• Leaflet or Instructions For Use 
missing  
• Label illegible 
• Incomplete, inaccurate, or 
misleading labeling 
• Lot number or serial number missing 
Packaging 
• Damaged packaging (eg, secondary, 
primary, bag/pouch) 
• Tampered seals 
• Inadequate or faulty closure 
• Missing components within package 
Foreign 
material 
• Contaminated product 
• Particulate in bottle/vial 
• Particulate in packaging 
 
Please report the product quality complaint using Clinical Trial Material Compliant Form via the 
email address:  
ctmcomplaint@takeda.com 
For instructions on reporting adverse events related to product complaints, see Appendix 3.4. 
 
 
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TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE ........................................................................................2 
SUMMARY OF CHANGES FROM PREVIOUS PROTOCOL VERSION .....................3 
CONTACTS .............................................................................................................................7 
PRODUCT QUALITY COMPLAINTS ................................................................................8 
TABLE OF CONTENTS ........................................................................................................9 
LIST OF IN-TEXT TABLES ...............................................................................................13 
LIST OF IN-TEXT FIGURES .............................................................................................13 
LIST OF APPENDICES .......................................................................................................13 
1. PROTOCOL SUMMARY ................................................................................................14 
1.1 Synopsis ........................................................................................................................14 
1.2 Schema .........................................................................................................................21 
1.3 Schedule of Activities ..................................................................................................22 
2. INTRODUCTION..............................................................................................................27 
2.1 Indication and Current Treatment Options .............................................................27 
2.2 Product Background and Clinical Information .......................................................28 
2.3 Study Rationale ...........................................................................................................29 
2.4 Benefit/Risk Assessment .............................................................................................29 
2.5 Compliance Statement ................................................................................................31 
3. OBJECTIVES AND ENDPOINTS ..................................................................................32 
3.1 Study Objectives ..........................................................................................................32 
3.1.1 Primary Objective ................................................................................................32 
3.1.2 Secondary Objectives ...........................................................................................32 
3.2 Study Endpoints ..........................................................................................................32 
4. STUDY DESIGN ................................................................................................................34 
4.1 Overall Design .............................................................................................................34 
4.2 Scientific Rationale for Study Design ........................................................................35 
4.3 Justification for Dose ..................................................................................................35 
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4.4 Duration of Subject Participation .............................................................................35 
4.5 Sites and Regions .........................................................................................................35 
5. STUDY POPULATION ....................................................................................................36 
5.1 Inclusion Criteria ........................................................................................................36 
5.2 Exclusion Criteria .......................................................................................................37 
5.3 Restrictions ..................................................................................................................38 
5.4 Reproductive Potential ...............................................................................................38 
5.4.1 Female Contraception ..........................................................................................38 
5.4.2 Male Contraception ..............................................................................................39 
6. STUDY INTERVENTION ................................................................................................40 
6.1 Investigational Product ...............................................................................................40 
6.1.1 Identity of Investigational Product .....................................................................40 
6.1.2 Blinding the Treatment Assignment ...................................................................40 
6.2 Administration of Investigational Product ...............................................................40 
6.2.1 Interactive Response Technology for Investigational Product Management .41 
6.2.2 Allocation of Subjects to Treatment ...................................................................41 
6.2.3 Dosing ....................................................................................................................41 
6.2.4 Unblinding the Treatment Assignment ..............................................................41 
6.2.5 Dose Modification .................................................................................................41 
6.3 Labeling, Packaging, Storage, and Handling of Investigational Product ..............42 
6.3.1 Labeling .................................................................................................................42 
6.3.2 Packaging ..............................................................................................................42 
6.3.3 Storage ...................................................................................................................42 
6.4 Drug Accountability ....................................................................................................43 
6.5 Subject Compliance ....................................................................................................44 
6.6 Permitted and Prohibited Treatment ........................................................................44 
6.6.1 Permitted Treatment ............................................................................................44 
6.6.2 Prohibited Treatment ...........................................................................................44 
7. DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL .......................................................................45 
7.1 Discontinuation of Study Treatment .........................................................................45 
7.1.1 Reasons for Discontinuation ................................................................................45 
7.2 Withdrawal From the Study ......................................................................................45 
7.3 Subjects “Lost to Follow-up” Prior to the Last Scheduled Visit ............................46 
8. STUDY ASSESSMENTS AND PROCEDURES ............................................................47 
8.1 Study Periods ...............................................................................................................47 
8.1.1 Screening Period (Day –21 Through Day –4) ....................................................47 
8.1.2 Baseline Visit (Day –3 Through Day 0) ..............................................................47 
8.1.3 Treatment Period (Week 1 Through 51) ............................................................48 
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8.1.4 End-of-Treatment Visit (Week 53) or Early Withdrawal Visit .......................48 
8.1.5 Safety Follow-up Period .......................................................................................49 
8.1.6 Additional Care of Subjects After the Study .....................................................49 
8.1.7 COVID-19–related Protocol Considerations .....................................................49 
8.2 Study Assessments .......................................................................................................50 
8.2.1 Demographic and Other Baseline Characteristics ............................................50 
8.2.1.1 Medical History ..............................................................................................50 
8.2.1.2 Prior and Concomitant Treatments .............................................................50 
8.2.1.3 Immunology ....................................................................................................50 
8.2.1.4 Electroencephalogram ...................................................................................51 
8.2.2 Efficacy Assessments ............................................................................................51 
8.2.2.1 Hemoglobin Concentration and Platelet Count ..........................................51 
8.2.2.2 Liver and Spleen Magnetic Resonance Imaging or Computed 
Tomography Scan ..........................................................................................51 
8.2.3 Safety Assessments ...............................................................................................51 
8.2.3.1 Physical Examination ....................................................................................51 
8.2.3.2 Adverse Events ...............................................................................................52 
8.2.3.3 Vital Signs .......................................................................................................52 
8.2.3.4 Clinical Laboratory Tests ..............................................................................52 
8.2.3.5 Pregnancy Test ...............................................................................................53 
8.2.3.6 12-lead Electrocardiogram ............................................................................53 
8.2.3.7 Serum Anti-velaglucerase Alfa Antibody ....................................................53 
8.2.3.8 X-ray of Bilateral Femoral Neck and Distal Femur (Procedural Imaging)54 
8.2.4 Other Assessments ................................................................................................54 
8.2.4.1 Pharmacokinetics ...........................................................................................54 
8.2.4.2 Circulating Biomarkers .................................................................................55 
8.2.4.3 Quality of Life ................................................................................................55 
8.2.5 Volume of Blood to Be Drawn From Each Subject ...........................................55 
9. STATISTICAL CONSIDERATIONS .............................................................................57 
9.1 Statistical Analysis Process ........................................................................................57 
9.2 Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee ...57 
9.3 Sample Size and Power Considerations ....................................................................57 
9.4 Statistical Analysis Sets ..............................................................................................57 
9.5 Analysis of Disposition ................................................................................................58 
9.6 Medical History ...........................................................................................................58 
9.7 Demographics and Baseline Characteristics Analyses ............................................58 
9.8 Treatment Compliance and Extent of Exposure ......................................................58 
9.9 Efficacy Analyses .........................................................................................................58 
9.10 Safety Analyses ..........................................................................................................59 
9.11 Other Analyses ..........................................................................................................60 
9.11.1 Pharmacokinetic Analyses .................................................................................60 
9.11.2 Health-related Quality-of-Life Analyses ..........................................................60 
9.11.3 Biomarker Analyses ...........................................................................................60 
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10. REFERENCES .................................................................................................................61 
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LIST OF IN-TEXT TABLES 
Table 1. Schedule of Activities ..............................................................................................22 
Table 2. Pharmacokinetic Sampling Time Points ...............................................................26 
Table 3. Objectives and Endpoints .......................................................................................32 
Table 4. Schedule for Recording of Vital Signs on Infusion Days .....................................52 
 
LIST OF IN-TEXT FIGURES 
Figure 1. Study Schematic Diagram.....................................................................................21 
 
LIST OF APPENDICES 
Appendix 1 
Regulatory, Ethical, and Study Oversight Considerations ........................62 
Appendix 2 
Clinical Laboratory Tests..............................................................................70 
Appendix 3 
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-Up, and Reporting ................................................................................................71 
Appendix 4 
Contraceptive Guidance ................................................................................80 
Appendix 5 
Scales and Assessments .................................................................................82 
Appendix 6 
Abbreviations .................................................................................................96 
Appendix 7 
Protocol History .............................................................................................98 
 
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1. PROTOCOL SUMMARY 
1.1 Synopsis 
Protocol number: TAK-669-3001 
Drug: Velaglucerase alfa (VPRIV)  
Title of the study: A Multicenter, Open-label Study to Evaluate the Safety, Efficacy, and Pharmacokinetics of 
Velaglucerase alfa in Chinese Subjects With Type 1 Gaucher Disease 
Short title: Safety, Efficacy, and Pharmacokinetics of Velaglucerase alfa in Chinese Subjects With Type 1 
Gaucher Disease 
Study phase: Phase 3b 
Number of subjects (total): The study is anticipated to enroll a total of 20 subjects. 
Investigator:  
 
 
Sites and region:  
The study is planned to be conducted in at least 8 clinical sites in China. 
Study period (planned): 2022 to 2025 
Clinical phase: 
3b 
Objectives: 
Primary: 
The primary objective of the study is to evaluate the safety of VPRIV by assessing the incidence of serious 
treatment-emergent adverse events (TEAEs) when administered every other week (EOW) up to 51 weeks by 
intravenous (IV) infusion in Chinese subjects with type 1 Gaucher disease. 
Secondary:  
The secondary objectives of the study are to assess: 
• 
Other safety parameters of VPRIV (including the incidence of TEAEs and infusion-related reactions 
[IRRs] and rates of antibody formation) 
• 
The effect of VPRIV on hematologic manifestations 
• 
The effect of VPRIV on the liver and spleen volume 
• 
The effect of VPRIV on quality of life (QoL) 
• 
The pharmacokinetics (PK) of VPRIV 
• 
The effect of VPRIV on disease biomarkers 
Rationale: 
On 27 Apr 2021, VPRIV received approval of its New Drug Application from China’s National Medical Products 
Administration for the treatment of type 1 Gaucher disease. As part of the approval requirements of China’s 
Health Authority, this Phase 3b interventional post approval commitment study is planned to evaluate the safety, 
efficacy, and PK of VPRIV in Chinese subjects with type 1 Gaucher disease. 
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Investigational product, dose, and mode of administration: 
Investigation product 
The investigational product, VPRIV, will be provided in single-use, 4-mL vials containing 11 mg or 440 U 
velaglucerase alfa after reconstitution and provides 10 mg or 400 U for infusion use, and the solution should be 
clear to slightly opalescent and colorless for IV infusion. 
Dose 
Velaglucerase alfa (VPRIV) infusions will occur at the clinical site. Subjects will receive VPRIV as an IV 
infusion EOW (±3 days). For treatment-naive subjects, the initial dose of VPRIV will be calculated based on the 
subject’s body weight determined at baseline. For subjects who received Imiglucerase enzyme replacement 
therapy (ERT) within the 12 months prior to screening, the initial dose will be determined by the investigator 
after discussing with the sponsor and recording in appropriate document based on the subject’s specific treatment 
and situation at the time of enrollment, according to the subject’s benefit and risk assessment. Weight will be 
measured every 6 weeks (Weeks 7, 13, 19, 25, 31, 37, 43, and 49) throughout the study before starting the study 
drug infusion. For all dosed subjects, a change in body weight of ±5% from baseline or the previous body weight 
used to recalculate the dose will require a new dose recalculation by the clinical site. 
Mode of administration 
Velaglucerase alfa should be administered through a 0.22 μm in-line sterilizing filter over a period of 60 (+10) 
minutes; on Day 1 (Week 1) and Week 37, the infusion should be administered over a period of 60 minutes. The 
infusion should be completed within 24 hours of reconstitution of the vials. Velaglucerase alfa should not be 
infused with other products in the same infusion tubing, as the compatibility in solution with other products has 
not been evaluated. 
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Methodology: 
This is a China only, Phase 3b, multicenter, nonrandomized, open-label, single-arm study to evaluate the safety, 
efficacy, and PK of VPRIV in Chinese subjects who have confirmed diagnosis of type 1 Gaucher disease. The 
study is anticipated to enroll a total of 20 subjects with a documented diagnosis of type 1 Gaucher disease, 
including at least 12 subjects who have not received any Gaucher disease treatment within 12 months prior to 
enrollment and up to 8 subjects who have been treated with Imiglucerase for Gaucher disease within 12 months 
prior to enrollment. The study is eligible for subjects aged 2 years and above, and the attempts should be made to 
enroll at least 3 subjects who are <18 years old and at least 3 subjects who are ≥18 years old in the naive subjects 
group. 
After signing the informed consent form (ICF), subjects will have the study procedures required during the 
screening period (Day –21 through Day –4). After completion of the baseline procedures and assessments during 
the baseline visit period (Day –3 through Day 0), eligible subjects will receive IV infusions of VPRIV EOW 
(±3 days) from Week 1 through Week 51 during the treatment period (except at Week 1 where the time window 
is +3 days [Day 1 through Day 3]), followed by the end-of-treatment (EOT) visit at Week 53. 
Additionally, for subjects ≥4 years old, PK assessments and sample collections will occur on Day 1 (Week 1) and 
Week 37 (±3 days) at the required timepoints. Pharmacokinetic samples will be collected only for the naive 
subjects who have not received any Gaucher disease treatment within the 12 months prior to enrollment. 
Pharmacokinetic parameters, including the maximum serum concentration (Cmax [ng/mL]), time to maximum 
concentration (Tmax [min]), area under the curve from time 0 to infinity (AUCinf [ng•min/mL]), half-life (T1/2 
[min]), clearance (CL [mL/min/kg]), and apparent steady-state volume of distribution (Vss [mL/kg]), will be 
determined, where appropriate, from individual serum-concentration time data using noncompartmental methods 
and actual sampling times. 
All subjects will undergo safety assessments throughout the study until completion of the follow-up period of 
approximately 30 days (±7 days) from completion of the treatment infusion (or the last infusion for early 
treatment discontinued subjects). Safety assessments will include monitoring of AEs, use of concomitant 
treatment(s), clinical laboratory values, antibody formation, vital signs, physical examinations, and 
electrocardiogram (ECG) results.  
Efficacy assessments in terms of hemoglobin concentration and platelet count will be required at baseline and 
every 6 weeks from Week 7 during the study treatment period and EOT visit. Liver and spleen volume evaluation 
will be performed at screening, Week 25, and the EOT visit. A questionnaire on QoL will be performed at 
baseline, Week 25, and the EOT visit. Quality-of-life assessment will include Short Form-36, version 2 (SF-36; 
for subjects ≥18 years of age) or Childhood Health Questionnaire-Parent Form 50 (CHQ-PF50; for subjects ≥5 
and <18 years of age); QoL assessment is not applicable for subjects <5 years of age. Biomarker assessments, 
such as chemokine (C-C motif) ligand 18 (CCL18) and glucosylsphingosine (Lyso-Gb1), may be assessed from 
samples collected at the baseline, Week 13, Week 25, Week 37, and EOT visits. 
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Inclusion and exclusion criteria:  
Inclusion criteria: 
Each subject has to meet the following criteria to be eligible for the study: 
1. Has a documented, confirmed diagnosis of type 1 Gaucher disease based on the following, as 
determined by the investigator: 
a. 
Decreased glucocerebrosidase (GCB) activity level that is ≤30% of normal or 
b. Decreased GCB activity level that is >30% of normal, but with confirmation of genetic mutation 
test 
2. Is at least 2 years of age, inclusive, at screening 
3. Is naive to treatment for Gaucher disease (Has not received treatment for Gaucher disease 
[investigational or approved products] within the 12 months prior to screening) 
OR 
Is receiving or has recently received Imiglucerase ERT (Has received Imiglucerase treatment within the 
12 months prior to screening and not within the 14 days prior to screening) 
4. Has Gaucher disease-related hematological abnormalities, defined as  
• 
Hemoglobin levels of ≥1 g/dL below the lower limit of normal for their age and gender  
AND/OR  
• 
A platelet count of <90 × 109/L below the lower limit of normal for their age and gender 
5. Has Gaucher disease-related viscera abnormalities, defined as the following:  
• 
Subject has at least moderate splenomegaly, assessed by palpation (2 to 3 cm below the left 
costal margin), or by abdominal radiology scan (magnetic resonance imaging [MRI] or 
computed tomography [CT] scan, with spleen volume >5 times normal) 
AND/OR 
• 
Subject has hepatomegaly, assessed by palpation or by abdominal radiology scan (MRI or 
CT scan); subjects who have undergone splenectomy must have satisfied these criteria for 
this study. 
6. If a female of childbearing potential, must agree to use a medically acceptable method of contraception 
at all times during the study and for 30 days following the last dose of the investigational product and 
must have a negative pregnancy test result at the time of screening and throughout their participation in 
the study. Male subjects must agree to use a medically acceptable method of birth control at all times 
during the study and for 30 days following the last dose of the investigational product and are required 
to report the pregnancy of a partner. 
7. The subject (and/or their legally authorized representative) must voluntarily sign an Institutional Review 
Board-/Ethics Committee-approved written ICF after all relevant aspects of the study have been 
explained and discussed with the subject. Subjects who are <18 years old must provide assent AND their 
parents/legally authorized representative should sign the ICF accordingly. 
8. Must be sufficiently cooperative to participate in the study as judged by the investigator 
Exclusion criteria: 
The subject will be excluded from the study if any of the following exclusion criteria are met. 
1. Has type 2 or 3 Gaucher disease or is suspected of having type 3 Gaucher disease as assessed by the 
investigator (eg, subject has Gaucher disease-related central nervous system manifestations or abnormal 
electroencephalogram [EEG] examinations). 
2. Has had a splenectomy or an active, clinically significant spleen infarction within the 12 months prior to 
screening. 
3. Has received treatment with any investigational drug or device within 30 days prior to screening or 
within 5 half-lives of that investigational product, whichever is greater; such treatment during the study 
will not be permitted. 
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4. Is currently receiving red blood cell growth factor (eg, erythropoietin), chronic systemic corticosteroids, 
or has been on such treatment within the 6 months prior to screening. 
5. Has a positive test result at screening for hepatitis B surface antigen (HBsAg) with detectable hepatitis B 
viral DNA load, hepatitis C virus (HCV) antibody with confirmation by HCV RNA polymerase chain 
reaction testing, and HIV antibody. 
6. Presents with non-Gaucher disease-related exacerbated anemia at screening (eg, due to iron, folic acid, 
and/or vitamin B12 deficiency or infectious/immune-mediated causes). Subjects who have a folic acid 
deficiency, vitamin B12-deficiency–related anemia, or iron-deficiency–related anemia during screening 
do not meet the study entry criteria and will be considered a screening failure. Subjects may be treated 
for the underlying disease and be rescreened as judged by investigator. Rescreening will be permitted 
once only. 
7. Subject, subject’s parent(s), or subject’s legal guardian(s) is/are unable to understand the nature, scope, 
and possible consequences of the study. 
8. Has a significant comorbidity, in the opinion of the investigator, that might affect the study data or 
confound the study results (eg, malignancies, primary biliary cirrhosis, or autoimmune liver disease) 
9. Is unable to comply with the protocol (eg, has a clinically relevant medical condition making 
implementation of the protocol difficult, an uncooperative attitude, is unable to return to the site for 
safety evaluations, or is otherwise unlikely to complete the study), as determined by the investigator 
10. Is a pregnant and/or lactating female 
11. Has experienced a severe (grade 3 or higher) infusion-related hypersensitivity reaction (anaphylactic or 
anaphylactoid reaction) to any ERT (approved or investigational) 
Note: Subjects with a historical positive antibody result to Imiglucerase but without a severe 
infusion-related hypersensitivity reaction will not be excluded. 
Maximum duration of subject participation in the study: The maximum duration of participation is expected 
to be 59 weeks: 
• 
Screening period: Day –21 through Day –4 
• 
Baseline: Day –3 through Day 0 (prior to the first dose) 
• 
Treatment period: Week 1 (Day 1; first dose) through Week 51 (a total of 26 infusions will be 
administered per subject) 
• 
End-of-treatment visit: Week 53 or 2 weeks (±7 days) after the last infusion for early withdrawal or 
discontinuation of subjects 
• 
Safety follow-up period: 30 days (±7 days) after the last infusion 
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Statistical analysis: 
Analysis sets 
• 
The intent-to-treat (ITT) set will include all subjects who sign the ICF (and assent form if applicable) 
and are eligible for the study based on the defined inclusion/exclusion criteria. The ITT set will be used 
for efficacy analyses. 
• 
The safety set will include all subjects in the ITT set who receive at least 1 dose of VPRIV. The safety 
set will be used for analysis of the safety endpoints.  
• 
The per-protocol (PP) set will include all subjects in the ITT set excluding subjects with major protocol 
deviations. The PP set will be identified by a team consisting of, at a minimum, a physician and 
statistician from Takeda. The PP set will be used for an efficacy sensitivity analysis. 
• 
The PK set will include all subjects in the ITT set who receive at least 1 dose of VPRIV and provide 
evaluable PK concentration data. 
Sample size and power considerations 
A sample size of 20 safety evaluable subjects is planned to be enrolled in the study to descriptively provide an 
estimate of the serious TEAE rate. No formal sample size calculations have been done, and the sample size is 
based on feasibility. 
Study endpoints 
Primary: 
• 
Incidence rate of serious TEAEs throughout the study 
Secondary: 
• 
Incidence rate of other safety parameters of VPRIV throughout the study: 
a) 
TEAEs 
b) 
IRRs  
c) 
Development of anti-VPRIV antibodies, including neutralizing antibodies  
• 
Other safety aspects measured by laboratory assessments, vital signs, and ECG results 
• 
Change from baseline to Week 53 in hemoglobin concentration and platelet count (time frame: 53 weeks) 
• 
Change from baseline to Week 53 in normalized liver and spleen volume (percent of body weight) (time 
frame: 53 weeks) 
• 
Change from baseline to Week 53 in the QoL questionnaire assessment (including SF-36, version 2 for 
subjects ≥18 years of age or CHQ-PF50 for subjects ≥5 and <18 years of age) (time frame: 53 weeks) 
• 
The PK parameters of VPRIV at Week 1 and single serumdrug concentration at the end of the infusion at 
Week 37 
• 
Percentage change from baseline to Week 53 in biomarkers (such as plasma CCL18 and Lyso-Gb1) (time 
frame: 53 weeks) 
Efficacy analyses 
Continuous variables will be summarized with descriptive statistics including the mean, standard deviation (SD), 
median, first quartile (Q1), third quartile (Q3), minimum and maximum. Categorical data will be summarized 
with the frequency and percentage of subjects falling within each category. 
The observed values, change from baseline, change over time, and percentage change from baseline for the 
efficacy measurements (hematologic manifestations and liver and spleen volume) will be summarized by sex and 
visit. Subject listings will be provided for the clinical outcomes from the QoL questionnaires. 
Efficacy analyses will be based on the ITT set, with the PP set as a sensitivity analysis. Data from the subjects 
who previously received Imiglucerase ERT and treatment-naive populations will be analyzed separately, as well 
as pooled. 
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Safety analyses 
Adverse events will be coded using the most recent version of MedDRA. Treatment-emergent AEs will be 
summarized overall and by system organ class (SOC) and preferred term (PT). Analysis of AEs will be 
performed at both the subject and AE levels. Similar displays will be provided for IRRs. The AEs will be 
summarized by severity, seriousness, and relation to the investigational product. 
Subjects will be counted once per SOC and once per PT. Multiple events of the same type will be combined for 
each subject and the worst severity or outcome for each event type will be presented for the analysis. When 
calculating the event rates, the denominator will be the total population size, irrespective of dropouts over the 
course of follow-up.  
Tabular summaries of other safety parameters (eg, vital signs, blood tests, concomitant treatments [coded using 
WHODrug Global], anti-VPRIV antibody status, and infusion information) will be produced at baseline and, if 
applicable, for each postbaseline evaluation visit. 
Changes in the results of physical examinations from baseline will be presented by visit and body system in the 
form of a shift table. 
The observed values and change from baseline for ECG parameters (PR, QRS, QT, and corrected QT intervals 
and heart rate) will be summarized by visit. The number of subjects with normal and abnormal ECG results 
during the study will be summarized by visit in the form of a shift table. 
Laboratory data will be listed by subject. Subjects with newly occurring abnormalities outside the normal range 
will be flagged, listed separately, and summarized. The mean change from baseline in laboratory values or a shift 
table will be provided for each visit. The change from baseline will be calculated by subtracting the baseline 
value from the postbaseline value. 
Vital sign data will be listed by subject, and any newly occurring changes outside the reference range from 
baseline will be flagged. The mean changes from baseline for vital sign data will be summarized. Subjects with 
notable abnormal values will be identified and listed separately along with their values. 
The number and percentage of subjects reporting at least 1 use of concomitant treatment during the study will be 
reported. Subject listings will be provided describing the reason(s) for study discontinuation. 
Antibody data, including neutralizing antibodies, will also be presented in the form of individual subject listings. 
Safety data will be analyzed using the safety set. Safety data will be analyzed separately for subjects who 
previously received Imiglucerase ERT and treatment-naive populations, as well as pooled. 
Other analyses 
Pharmacokinetic analyses: 
Statistical analysis of PK data will be based on the PK set. 
For the PK set, individual concentrations will be listed and summarized by visit and scheduled time points for 
naive subjects with PK assessments and by age (eg, ≥18 years vs 12 through 17 years vs 4 through 11 years). 
Individual PK parameters of VPRIV at Week 1 will be listed and summarized by treatment for all PK subjects, as 
well as by age, with descriptive statistics (number, arithmetic mean, SD, coefficient of variation [CV], median, 
minimum, maximum, geometric mean, and CV [95% CI] of the geometric mean). Pharmacokinetic parameter 
estimates will be computed, where appropriate, from individual serum-concentration time data using 
noncompartmental methods and actual times. Figures of individual and mean (SD) concentration-time profiles of 
VPRIV will be generated based on nominal time points. 
Health-related quality-of-life analyses: 
The change over time in subject rating of QoL will be analyzed using the SF-36, version 2 for subjects ≥18 years 
of age and CHQ-PF50 for subjects ≥5 and <18 years of age. 
Initially, simple summary statistics will be produced for the overall score and (if available) any subscale score of 
each patient-reported outcome measure. Continuous variables will be summarized using the following descriptive 
statistics: mean, SD, median, Q1, Q3, minimum, and maximum. The number and percentage of observed levels 
will be reported for all categorical measures. 
Biomarker analyses: 
Circulating biomarker data will be summarized using descriptive statistics. 
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1.2 Schema 
Figure 1. Study Schematic Diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
Enrollment 
SCREENING  
(Day -21 through Day -4)  
BASELINE 
(Day -3 through Day 0)  
TREATMENT PERIOD 
Velaglucerase alfa  
60 U/kg intravenously every 
other week 
(Week 1 to Week 51)  
END-OF-TREATMENT 
VISIT 
(Week 53)  
OR  
EARLY WITHDRAWAL 
VISIT 
(2 weeks [±7 days] after the 
last infusion)  
SAFETY FOLLOW-UP 
PERIOD 
(30 days [±7 days] after the 
last infusion)  
Pharmacokinetics 
Assessments 
(Day 1 [Week 1] and 
Week 37 visits)  
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k Prior treatments received within the 30 days prior to signing the ICF will be collected and recorded in the subject’s source documents and on the appropriate 
eCRF page. 
l The VPRIV infusions will be administered at the clinical site. For treatment-naive subjects, the initial dose of VPRIV will be calculated based on the subject’s 
body weight determined at baseline. For subjects who received Imiglucerase ERT within the 12 months prior to screening, the initial dose will be determined by 
the investigator after discussing with the sponsor and recording in appropriate document based on the subject’s specific treatment and situation at the time of 
enrollment, according to the subject’s benefit and risk assessment. For all dosed subjects, a change in body weight of ±5% from baseline or the previous body 
weight assessment at Weeks 7, 13, 19, 25, 31, 37, 43, or 49 used to recalculate the dose will require a new dose recalculation by the clinical site. Velaglucerase 
alfa should be administered over a period of 60 (+10) minutes; on Day 1 (Week 1) and Week 37, the infusion should be administered over a period of 60 
minutes. 
m Vital signs include pulse rate, blood pressure, respiratory rate, temperature, body weight, and height. Measurement of pulse rate, blood pressure, respiratory 
rate, and temperature will be taken prior to blood draw and/or initiation of infusion following 5 minutes of rest. Vital signs should be recorded as outlined in 
Table 4 and will be recorded in the subject’s source documents and on the appropriate eCRF page. If there are no infusion-related reactions observed during the 
first 3 infusions, vital signs assessment for the subsequent infusions can be omitted at the discretion of the investigator.  
n Height will be measured as part of the vital sign assessments and for calculation of normalized liver and spleen volume which will be measured by abdominal 
radiology scan (MRI or CT scan) at screening, at Week 25, and the EOT visit. 
o Electrocardiogram parameters (PR, QRS, QT, and corrected QT intervals and heart rate) will be collected prior to blood draw and/or initiation of infusion 
following 5 minutes of rest. 
p Female subjects of childbearing potential will have a pregnancy test. Pregnancy testing will be performed using a urine sample and, if needed, a serum β-hCG 
sample. If the urine pregnancy test is negative, the study assessments and procedures will be completed; serum β-hCG testing will not be required. If the urine 
test is positive, a blood sample will be collected for serum β-hCG testing and sent to either the local laboratory or Takeda-designated laboratory for analysis. No 
additional study assessments or procedures should be completed until the result of the serum pregnancy test is available. Female subjects of childbearing 
potential must have a negative serum β-hCG test to be eligible for the study. A positive serum β-hCG test would result in the subject being a screen failure or 
discontinued from the study. The pregnancy test at the baseline visit can be waived if it had been performed within 7 days of the previous test during the 
screening visit. 
q Urinalysis parameters include bilirubin, color, glucose, ketones, nitrite, occult blood, pH, protein, specific gravity, and urobilinogen. 
r Serum chemistry laboratory tests include albumin, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, (blood) urea nitrogen or (blood) 
urea, calcium, creatinine, creatine kinase, ferritin, γ-glutamyl transferase glucose, lactate dehydrogenase, potassium, serum iron, sodium, total bilirubin, and 
total protein. Subjects who have folic acid deficiency, vitamin B12-deficiency–related anemia, or iron-deficiency–related anemia at screening do not meet the 
study entry criteria and will be considered a screening failure. Subjects may be treated for the underlying disease and be rescreened as judged by the 
investigator. Rescreening will be permitted once only. Subjects who enter the study receiving iron supplement therapy will continue receiving iron supplement 
therapy throughout their participation in the study. 
s Hematology laboratory tests for safety include hematocrit, hemoglobin, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, mean 
corpuscular volume, platelet count, red blood cell count, white blood cell count with differential, neutrophils, basophils, lymphocytes, monocytes, and 
eosinophils. Assessments of hemoglobin concentration and platelet count are included as components of the hematology laboratory panel at screening, baseline 
(Day –3 through Day 0) and Weeks 13, 25, 37, and 53 (EOT). For statistical analysis purposes, an additional blood sample will be collected and sent to a central 
laboratory for evaluation of hemoglobin concentration and platelet count at baseline (Day –3 through Day 0) and Weeks 7, 13, 19, 25, 31, 37, 43, 49, and 53 
(EOT). 
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t The sample will be collected before the VPRIV infusion and evaluated at a Takeda-designated laboratory. 
u Circulating biomarkers include glucosylsphingosine and chemokine (C-C motif) ligand 18. 
v Liver and spleen volume will be confirmed by an abdominal MRI or CT scan. All imaging modalities should remain consistent for all subject at all timepoints 
throughout the study. Investigator is responsible to perform eligibility check for presence of at least hepatomegaly and/or moderate splenomegaly (spleen 
volume >5 times normal). The multiples of normal (MN) for splenomegaly is given by spleen volume (MN) = spleen volume (cm3) / 2 x subject’s weight (kg). 
The multiples of normal for hepatomegaly is given by liver volume (MN) = liver volume (cm3) / 25 x subject’s weight (kg). To evaluate VPRIV efficacy, the 
volumes of liver and spleen will be analyzed and calculated centrally by sending the MRI/CT images to a Takeda-designated imaging vendor.  
w  X-ray test can be waived if it has been performed within the 30 days prior to the baseline visit.  
x Quality-of-life assessments include Short Form-36, version 2 (for subjects ≥18 years of age) or Childhood Health Questionnaire-Patient Form 50 (for subjects 
≥5 and <18 years of age); QoL assessment is not applicable for subjects <5 years of age.  
y The PK sampling schedule is specified in Table 2. Pharmacokinetic samples will be evaluated at a Takeda-designated laboratory. 
Table 2. Pharmacokinetic Sampling Time Points 
 
Day 1 (Week 1) 
Week 37 
Age Group 
Before the 
infusion 
During the Infusion End of the 
Infusion 
After the infusion 
End of the 
Infusion 
 
0 (-30) mina 
20 (±1) 
min 
40 (±2) 
min 
60 (-3) 
minb 
65 (±3) 
min 
70 (±3) 
min 
80 (±4) 
min 
90 (±4) 
min 
105 (±5) 
min 
120 (±6) 
min 
60 (-3) 
minb 
≥18 years old 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12 through 17 years 
old 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
4 through 11 years old 
 
X 
 
X 
 
X 
X 
X 
 
 
X 
min=minute(s). 
Notes: The study is anticipated to enroll 12 naive subjects (attempts should be made to enroll at least 3 subjects who are <18 years old and at least 3 subjects who 
are ≥18 years old) for pharmacokinetic assessment. Pharmacokinetic assessments will occur for subjects ≥4 years old. Pharmacokinetic samples will be collected 
only for the naive subjects who have not received any Gaucher disease treatment within the 12 months prior to enrollment. Pharmacokinetic blood samples must 
not be drawn from the arm being used for the infusion. 
The PK sampling timepoints are the nominal timepoints based on a 60-minute infusion. 
a A PK sample should be collected within 30 min prior to the start of 60-min infusion. 
b A PK sample should be collected within 3 min prior to the end of 60-min infusion.
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2. INTRODUCTION 
2.1 Indication and Current Treatment Options  
Gaucher disease, a panethnic, autosomal, recessive disease (Cox and Schofield 1997) is the most 
common glycosphingolipid storage disorder (Cox et al. 2003). The disease occurs when an 
inherited deficiency of the lysosomal enzyme glucocerebrosidase (GCB) leads to progressive 
accumulation of glucocerebroside within macrophages and subsequent tissue and organ damage. 
In China, domestic experts estimate that the prevalence rate of Gaucher disease in the Chinese 
population is lower than the global average, with only 0.2 to 0.5 cases per 100,000 people 
(prevalence is approximately 1/500,000 to 1/200,000), speculated from neonatal prevalence 
(Zhang 2020). In 2018, Gaucher disease had been listed in the Catalogue of Rare Diseases in 
China (http://www.gov.cn/zhengce/zhengceku/2018-12/31/content_5435167.htm, Notice of 
Releasing First Batch of Rare Disease List, Accessed 11 Nov 2021).  
Gaucher disease is a multisystem disorder, with clinical features reflective of the distribution of 
abnormal macrophages (Gaucher cells) in the liver, spleen, bone marrow, skeleton, lungs, and 
occasionally, lymph nodes (Beutler and Grabowski 2001). Accumulation of 
glucocerebroside-containing cells (mainly macrophages or macrophage-like cells) in the liver 
and spleen leads to secondary changes, including organomegaly, which can be massive, 
particularly in the case of the spleen. Bone involvement results in skeletal abnormalities and 
deformities, as well as bone pain and crises. Deposits in the bone marrow and splenic 
sequestration lead to dysfunction with clinically significant anemia and thrombocytopenia. 
The disease has been classified into 3 clinical subtypes based on the presence or absence of 
neurological symptoms and severity of neurological symptoms (Beutler and Grabowski 2001). 
Global statistics show that type 1 patients account for about 95%, type 2 patients account for 1%, 
and type 3 patients account for approximately 2% to 3%. Type 1 Gaucher disease, the most 
common form, does not involve the central nervous system; typical manifestations include 
hepatomegaly, splenomegaly, thrombocytopenia, bleeding tendencies, anemia, hypermetabolism, 
skeletal pathology, growth retardation, pulmonary disease, and decreased quality of life (QoL) 
(Pastores et al. 2004). Patients with type 2 Gaucher disease present with acute neurological 
deterioration, and those with type 3 disease typically display a more subacute neurological 
course. In Northeast Asia, including China, Japan, and South Korea, the proportion of type 2 and 
type 3 is relatively high and, according to expert predictions, may reach approximately 30% to 
50%, mainly related to gene mutations (Zhang 2020). 
Most of the research effort to date has focused on strategies for augmenting enzyme levels to 
compensate for the underlying defect; enzyme replacement therapy (ERT) has remained the 
cornerstone of treatment for Gaucher disease since the early 1990s and is highly effective in 
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improving many of the clinical manifestations of this disease (Cox et al. 2003). Data from the 
International Collaborative Gaucher Group show that approximately 90% of all patients with 
Gaucher disease who have anemia should achieve normal hemoglobin concentrations within 
2 years of initiation of ERT (Weinreb et al. 2002). Enzyme replacement therapy reduces 
organomegaly, improves hematological parameters, and positively affects health-related QoL 
(Barton et al. 1991, Masek et al. 1999, Weinreb et al. 2002). In China, the use of ERT has more 
than 20 years of real-world experience. Enzyme replacement therapy specifically supplements 
the lack of enzymes in the patient’s body, reduces the accumulation of glucocerebrosides in the 
body, and is a specific treatment for Gaucher disease. 
2.2 Product Background and Clinical Information 
Velaglucerase alfa (VPRIV) is a human GCB that catalyzes the hydrolysis of glucocerebroside, 
reducing the amount of accumulated glucocerebroside and correcting the pathophysiology of 
Gaucher disease. It is produced by gene activation in a human cell line. In order to produce an 
enzyme that is readily taken up by the mannose receptors of phagocytic cells, VPRIV is 
manufactured to contain predominantly high-mannose type N-linked glycans.  
Velaglucerase alfa is approved as a long-term ERT for the treatment of type 1 Gaucher disease in 
pediatric and adult subjects. The initial approval was on 26 Feb 2010 in the United States (US), 
and approval in the European Union (EU) was granted on 26 Aug 2010 under the trade name 
VPRIV. Global commercialization is ongoing with approval in 66 countries as of 27 Jul 2021. 
Orphan drug designation has been received in the US, the EU, Switzerland, Australia, Japan, 
South Korea, Mexico, and Taiwan. In China, VPRIV was listed as the First List of Overseas 
New Drugs in Urgent Clinical Need in 2018 and was given conditional approval in Apr 2021. 
As of 25 Feb 2020, a total of 355 subjects have received VPRIV in the clinical studies. Clinical 
safety, efficacy, and pharmacokinetic (PK) data from 4 core Phase 1/2 to 3 studies (TKT025, 
TKT032, TKT034, and HGT-GCB-039) supported the global commercialization of VPRIV. 
Three of the core studies (TKT025, TKT032, and HGT-GCB-039) were conducted in 
treatment-naive subjects; the fourth core study (TKT034) was performed in subjects previously 
treated with Imiglucerase and then switched to VPRIV at the same dose. The core studies were 
extended via 2 extension studies (TKT025EXT and HGT-GCB-044) to evaluate long-term 
safety and efficacy. In the core studies, VPRIV was administered intravenously (IV) over 
60 minutes at doses ranging from 15 to 60 U/kg every other week (EOW). The youngest subject 
receiving VPRIV in these studies was 4 years of age. 
Overall data from the studies to date support the finding that long-term ERT with VPRIV is 
generally well tolerated at all doses tested in adult or pediatric, male or female subjects with 
type 1 Gaucher disease. Adverse event (AE) profiles are consistent between treatment-naive 
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subjects and subjects who switch from prior treatment with Imiglucerase. Very common adverse 
drug reactions (ADRs), defined as those occurring at a frequency of at least 1 in 10 subjects, 
comprised headache, dizziness, abdominal pain/upper abdominal pain, bone pain, arthralgia, 
back pain, infusion-related reactions (IRRs), asthenia/fatigue, and pyrexia/body temperature 
increased.  
2.3 Study Rationale 
On 27 Apr 2021, VPRIV received approval of its New Drug Application from China’s National 
Medical Products Administration for the treatment of type 1 Gaucher disease. As part of the 
approval requirements of China’s Health Authority, this Phase 3b interventional post approval 
commitment study is planned to evaluate the safety, efficacy, and PK of VPRIV in Chinese 
subjects with type 1 Gaucher disease. 
2.4 Benefit/Risk Assessment 
Velaglucerase alfa is a protein for which the expected metabolic pathway is degradation to small 
peptides and individual amino acids by widely distributed proteolytic enzymes. Therefore, no 
studies have been conducted to evaluate the metabolism of VPRIV. Efficacy data from previous 
core studies demonstrated that increases in hemoglobin concentration and platelet count and 
decreases in normalized liver and spleen volume were seen in treatment-naive adult and pediatric 
subjects with type 1 Gaucher disease. Response based on increases in hemoglobin concentration 
for VPRIV treatment was shown to be noninferior to that of Imiglucerase, and no statistically 
significant treatment difference was seen between VPRIV and Imiglucerase for the increase in 
platelet count or decrease in liver or spleen volumes. An exploratory analysis showed an increase 
in the bone mineral density of the lumbar spine in adult subjects following treatment with 
VPRIV and suggested a beneficial effect on the linear growth of children with Gaucher disease. 
Hemoglobin concentration, platelet count, and liver and spleen volumes observed after long-term 
treatment with Imiglucerase were maintained in adult and pediatric subjects when these subjects 
were switched from Imiglucerase to VPRIV at the same dose. Similar improvements in visceral 
manifestations to those seen in subjects with type 1 Gaucher disease were also observed in 
treatment-naive pediatric subjects with type 3 Gaucher disease. 
To date, VPRIV has shown an overall favorable safety profile in the clinical studies in a total of 
355 subjects. Infusion-related reactions were the most commonly observed adverse reactions in 
subjects treated with VPRIV in the clinical studies. Most of the IRRs were mild in severity. The 
management of IRRs is based on the severity of the reaction, and may include slowing the 
infusion rate, treatment with medications such as antipyretics and/or corticosteroids, and/or 
stopping and resuming treatment with an increased infusion time. Subjects were not routinely 
premedicated prior to infusion of VPRIV during the clinical studies. 
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The most serious adverse reactions in subjects treated with VPRIV were hypersensitivity 
reactions. As with any IV protein product, hypersensitivity reactions, including symptoms 
consistent with anaphylaxis, are possible. Treatment with VPRIV should be approached with 
caution in subjects who have exhibited symptoms of hypersensitivity to the active ingredient, 
excipients in the drug product, or other ERT. Appropriate medical support should be readily 
available when VPRIV is administered. If a severe reaction occurs, current medical standards for 
emergency treatment are to be followed. 
In the clinical studies, 4 serious AEs (SAEs) were reported that were considered to be related to 
VPRIV. These SAEs included 1 subject with grade 3 allergic dermatitis that resolved during the 
9-month study (HGT-GCB-039). This subject continued treatment with VPRIV in the extension 
study (HGT-GCB-044) with no recurrence. One switched subject experienced an SAE of an 
anaphylactoid reaction: this subject permanently discontinued treatment with VPRIV in 
Study TKT034. One subject in Study HGT-GCB-058 had an SAE of a migraine, which was 
considered mild in severity. One subject in Study HGT-GCB-087, conducted in Japan, had an 
SAE of retinal detachment. This subject had 2 nonrelated SAEs of vitreous opacities and 
2 nonrelated SAEs of retinal detachment during participation in the Extension Study HGT-GCB-
091, continued to receive treatment, and completed the study. 
There have been no deaths considered related to VPRIV. One pediatric subject with a history of 
seizures died during participation in a clinical study following extended treatment with VPRIV. 
The cause of death was convulsions and considered by the investigator as not related to VPRIV. 
A tiered approach was used for immunogenicity monitoring. In the core studies (TKT025, 
TKT032, TKT034, and HGT-GCB-039), 1 of 94 subjects (1.1%) who received VPRIV 
developed antibodies. The neutralizing antibodies were detected by an enzymatic activity assay. 
No IRRs were reported for this subject. In the extension studies (TKT025EXT and 
HGT-GCB-044), 1 of 105 subjects (1.0%) developed anti-VPRIV antibodies. In Study 
HGT-GCB-058, 1 of 167 assessable subjects (0.6%) in the treatment protocol developed 
antibodies. In Study HGT-GCB-068, 1 of 6 assessable subjects developed anti-VPRIV 
antibodies that were not neutralizing. In the core studies, extension studies, and Study HGT-
GCB-058, positive subject samples were also tested for the presence of immunoglobulin (Ig)E 
anti-VPRIV antibodies. No subjects in these studies developed IgE anti-VPRIV antibodies. No 
subjects in the Japanese studies (HGT-GCB-087 and HGT-GCB-091) developed anti-VPRIV 
antibodies. In the ongoing study (SHP-GCB-402), 3 subjects developed anti-VPRIV antibodies. 
One of the subjects showed a persistent anti-VPRIV antibody response from Week 25 onwards 
with low antibody titers. The second subject had positive results for anti-VPRIV antibodies at 
baseline and all time points tested; antibody titers were within a 2-step dilution of the baseline 
titer of 80. For this subject, neutralizing antibodies were transiently seen at Week 51. The third 
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subject developed anti-VPRIV antibody response at Week 25 through Week 51 and again at 
Week 77 through the end of the study. No SAEs were reported for these subjects, and the AEs 
reported were in alignment with the known safety profile of VPRIV. 
The safety profile of VPRIV in the postmarketing setting is consistent with that seen in the 
clinical development program. No new safety concerns have been identified. 
Always refer to the latest version of the VPRIV investigator’s brochure (IB) for the overall 
benefit/risk assessment and most accurate and current information regarding drug metabolism, 
PK, efficacy, and safety of VPRIV. 
2.5 Compliance Statement 
The study will be conducted in accordance with this protocol, the International Council for 
Harmonization Guideline for Good Clinical Practice E6 (ICH GCP, 1996; ICH E6 R2, 2016), 
and applicable national and local regulatory requirements. 
The responsibilities of the study sponsor and investigator are described fully in Appendix 1. 
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3. OBJECTIVES AND ENDPOINTS 
3.1 Study Objectives 
3.1.1 Primary Objective 
The primary objective of the study is to evaluate the safety of VPRIV by assessing the incidence 
of serious treatment-emergent AEs (TEAEs) when administered EOW up to 51 weeks by IV 
infusion in Chinese subjects with type 1 Gaucher disease. 
3.1.2 Secondary Objectives 
The secondary objectives of the study are to assess: 
• Other safety parameters of VPRIV (including the incidence of TEAEs and IRRs and rates 
of antibody formation) 
• The effect of VPRIV on hematologic manifestations 
• The effect of VPRIV on the liver and spleen volume 
• The effect of VPRIV on QoL  
• The PK of VPRIV 
• The effect of VPRIV on disease biomarkers 
 
3.2 Study Endpoints 
Table 3. Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• 
To evaluate the safety of 
VPRIV by assessing the 
incidence of serious TEAEs 
• 
Incidence rate of serious TEAEs throughout the study 
Secondary 
 
• 
To assess other safety 
parameters of VPRIV 
• 
Incidence rate of other safety parameters of VPRIV throughout the 
study: 
a) 
TEAEs 
b) 
Infusion-related reactions 
c) 
Development of anti-VPRIV antibodies, including neutralizing 
antibodies  
• 
Other safety aspects measured by laboratory assessments, vital 
signs, and electrocardiogram results 
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Table 3. Objectives and Endpoints 
Objectives 
Endpoints 
• 
To assess the effect of 
VPRIV on hematologic 
manifestations 
• 
Change from baseline to Week 53 in hemoglobin concentration and 
platelet count (time frame: 53 weeks) 
• 
To assess the effect of 
VPRIV on the liver and 
spleen volume 
• 
Change from baseline to Week 53 in normalized liver and spleen 
volume (percent of body weight) (time frame: 53 weeks) 
• 
To assess the effect of 
VPRIV on QoL 
• 
Change from baseline to Week 53 in the QoL questionnaire 
assessment (including Short Form-36, version 2 for subjects 
≥18 years of age or Childhood Health Questionnaire-Parent Form 
50 for subjects ≥5 and <18 years of age) (time frame: 53 weeks) 
• 
To assess the PK of VPRIV 
• 
The PK parameters of VPRIV at Week 1 and single serum drug 
concentration at the end of the infusion at Week 37 
• 
To assess the effect of 
VPRIV on disease 
biomarkers 
• 
Percentage change from baseline to Week 53 in biomarkers (such as 
plasma chemokine [C-C motif] ligand 18 and glucosylsphingosine) 
(time frame: 53 weeks) 
PK=pharmacokinetic(s); QoL=quality of life; TEAE=treatment-emergent adverse event; VPRIV=velaglucerase alfa. 
 
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4. STUDY DESIGN 
4.1 Overall Design 
This is a China only, Phase 3b, multicenter, nonrandomized, open-label, single-arm study to 
evaluate the safety, efficacy, and PK of VPRIV in Chinese subjects who have confirmed 
diagnosis of type 1 Gaucher disease. The study is anticipated to enroll a total of 20 subjects with 
a documented diagnosis of type 1 Gaucher disease, including at least 12 subjects who have not 
received any Gaucher disease treatment within 12 months prior to enrollment and up to 
8 subjects who have been treated with Imiglucerase for Gaucher disease within 12 months prior 
to enrollment. The study is eligible for subjects aged 2 years and above, and the attempts should 
be made to enroll at least 3 subjects who are <18 years old and at least 3 subjects who are ≥18 
years old in the naive subjects group. 
After signing the informed consent form (ICF), subjects will have the study procedures required 
during the screening period (Day –21 through Day –4). After completion of the baseline 
procedures and assessments during the baseline visit period (Day –3 through Day 0), eligible 
subjects will receive IV infusions of VPRIV EOW (±3 days) from Week 1 through Week 51 
during the treatment period (except at Week 1 where the time window is +3 days [Day 1 through 
Day 3]), followed by the end-of-treatment (EOT) visit at Week 53. 
Additionally, for subjects ≥4 years old, PK assessments and sample collections will occur on 
Day 1 (Week 1) and Week 37 (±3 days) at the required timepoints (Table 2). Pharmacokinetic 
samples will be collected only for the naive subjects who have not received any Gaucher disease 
treatment within the 12 months prior to enrollment. Pharmacokinetic parameters, including 
maximum serum concentration (Cmax [ng/mL]), time to maximum concentration (Tmax [min]), 
area under the curve from time 0 to infinity (AUCinf [ng•min/mL]), half-life (T1/2 [min]), 
clearance (CL [mL/min/kg]), and apparent steady-state volume of distribution (Vss [mL/kg]), will 
be determined, where appropriate, from individual serum-concentration time data using 
noncompartmental methods and actual sampling times. 
All subjects will undergo safety assessments throughout the study until completion of the 
follow-up period of approximately 30 days (±7 days) from completion of the treatment infusion 
(or the last infusion for early treatment discontinued subjects). Safety assessments will include 
monitoring of AEs, use of concomitant treatment(s), clinical laboratory values, antibody 
formation, vital signs, physical examinations, and electrocardiogram (ECG) results.  
Efficacy assessments in terms of hemoglobin concentration and platelet count will be required at 
baseline and every 6 weeks from Week 7 during the study treatment period and EOT visit. Liver 
and spleen volume evaluation will be performed at screening, Week 25, and the EOT visit. A 
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questionnaire on QoL will be performed at baseline, Week 25, and the EOT visit. Quality-of-life 
assessment will include Short Form-36, version 2 (SF-36; for subjects ≥18 years of age) or 
Childhood Health Questionnaire-Parent Form 50 (CHQ-PF50; for subjects ≥5 and <18 years of 
age); quality-of-life assessment is not applicable for subjects <5 years of age. Biomarker 
assessments, such as chemokine (C-C motif) ligand 18 (CCL18) and glucosylsphingosine 
(lyso-Gb1), may be assessed from samples collected at the baseline, Week 13, Week 25, Week 
37, and EOT visits. 
4.2 Scientific Rationale for Study Design 
In order to facilitate the broadest evaluation of the efficacy and safety of VPRIV, the enrolled 
patient population will be as diverse as possible. In this nonrandomized, open-label, multicenter, 
China only study, both treatment-naive patients (untreated within the 12 months prior to 
screening) and patients switched from Imiglucerase ERT (treated within the 12 months prior to 
screening and not within the 14 days prior to screening) will be enrolled. Clinical activity of 
gene-activated human GCB will be measured by measuring the change in hemoglobin 
concentration and platelet count, along with reduction in the liver and spleen volume. 
Biomarkers will also be measured. 
4.3 Justification for Dose 
Velaglucerase alfa has been approved in 60 countries as of 25 Feb 2020 for the treatment of 
type 1 Gaucher disease in pediatric and adult subjects. Velaglucerase alfa will be administered at 
the globally approved dose of 60 U/kg body weight EOW as a 60-minute IV infusion. 
4.4 Duration of Subject Participation 
The maximum duration of participation is expected to be 59 weeks: 
• Screening period: Day –21 through Day –4 
• Baseline: Day –3 through Day 0 (prior to the first dose) 
• Treatment period: Week 1 (Day 1; first dose) through Week 51 (a total of 26 
infusions will be administered per subject)  
• End-of-treatment visit: Week 53 or 2 weeks (±7 days) after the last infusion 
for early withdrawal or discontinuation of subjects 
• Safety follow-up period: 30 (±7) days after the last infusion 
 
4.5 Sites and Regions 
The study is planned to be conducted in at least 8 clinical sites in China. 
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5. STUDY POPULATION 
Each subject must participate in the informed consent process and provide written informed 
consent/assent before any assessments and procedures specified in the protocol are performed. 
5.1 Inclusion Criteria 
Each subject has to meet the following criteria to be eligible for the study: 
1. Has a documented, confirmed diagnosis of type 1 Gaucher disease based on the 
following, as determined by the investigator: 
a. Decreased GCB activity level that is ≤30% of normal or 
b. Decreased GCB activity level that is >30% of normal, but with confirmation of 
genetic mutation test 
2. Is at least 2 years of age, inclusive, at screening 
3. Is naive to treatment for Gaucher disease (Has not received treatment for Gaucher disease 
[investigational or approved products] within the 12 months prior to screening 
OR 
Is receiving or has recently received Imiglucerase ERT (Has received Imiglucerase 
treatment within the 12 months prior to screening and not within the 14 days prior to 
screening) 
4. Has Gaucher disease-related hematological abnormalities, defined as  
• Hemoglobin levels of ≥1 g/dL below the lower limit of normal for their 
age and gender  
AND/OR  
• A platelet count of <90 × 109/L below the lower limit of normal for their 
age and gender 
5. Has Gaucher disease-related viscera abnormalities, defined as the following:  
• Subject has at least moderate splenomegaly, assessed by palpation (2 to 
3 cm below the left costal margin), or by abdominal radiology scan 
(magnetic resonance imaging [MRI] or computed tomography [CT] scan, 
with spleen volume >5 times normal) 
AND/OR 
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• Subject has hepatomegaly, assessed by palpation or by abdominal 
radiology scan (MRI or CT scan); Subjects who have undergone 
splenectomy must have satisfied these criteria for this study. 
6. If a female of childbearing potential, must agree to use a medically acceptable method of 
contraception at all times during the study and for 30 days following the last dose of the 
investigational product and must have a negative pregnancy test result at the time of 
screening and throughout their participation in the study. Male subjects must agree to use 
a medically acceptable method of birth control at all times during the study and for 
30 days following the last dose of the investigational product and are required to report 
the pregnancy of a partner. 
7. The subject (and/or their legally authorized representative) must voluntarily sign an 
Institutional Review Board (IRB)/Ethics Committee (EC)-approved written ICF after all 
relevant aspects of the study have been explained and discussed with the subject. Subjects 
who are <18 years old must provide assent AND their parents/legally authorized 
representative should sign the ICF accordingly. 
8. Must be sufficiently cooperative to participate in the study as judged by the investigator 
5.2 Exclusion Criteria 
The subject will be excluded from the study if any of the following exclusion criteria are met. 
Has type 2 or 3 Gaucher disease or is suspected of having type 3 Gaucher disease as assessed by 
the investigator (eg, subject has Gaucher disease-related central nervous system manifestations 
or abnormal electroencephalogram [EEG] examinations). 
2. Has had a splenectomy or an active, clinically significant spleen infarction within the 
12 months prior to screening 
3. Has received treatment with any investigational drug or device within 30 days prior to 
screening, or within 5 half-lives of that investigational product, whichever is greater; such 
treatment during the study will not be permitted. 
4. Is currently receiving red blood cell growth factor (eg, erythropoietin), chronic systemic 
corticosteroids, or has been on such treatment within the 6 months prior to screening 
5. Has a positive test result at screening for hepatitis B surface antigen (HBsAg) with 
detectable hepatitis B viral DNA load, hepatitis C virus (HCV) antibody with 
confirmation by HCV RNA polymerase chain reaction testing, and HIV antibody 
6. Presents with non-Gaucher disease-related exacerbated anemia at screening (eg, due to 
iron, folic acid, and/or vitamin B12 deficiency or infectious/immune-mediated causes). 
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Subjects who have a folic acid deficiency, vitamin B12-deficiency–related anemia, or 
iron-deficiency–related anemia during screening do not meet the study entry criteria and 
will be considered a screening failure. Subjects may be treated for the underlying disease 
and be rescreened as judged by investigator. Rescreening will be permitted once only. 
7. Subject, subject’s parent(s), or subject’s legal guardian(s) is/are unable to understand the 
nature, scope, and possible consequences of the study 
8. Has a significant comorbidity, in the opinion of the investigator, that might affect the 
study data or confound the study results (eg, malignancies, primary biliary cirrhosis, or 
autoimmune liver disease) 
9. Is unable to comply with the protocol (eg, has a clinically relevant medical condition 
making implementation of the protocol difficult, an uncooperative attitude, is unable to 
return to the site for safety evaluations, or is otherwise unlikely to complete the study), as 
determined by the investigator 
10. Is a pregnant and/or lactating female 
11. Has experienced a severe (grade 3 or higher) infusion-related hypersensitivity reaction 
(anaphylactic or anaphylactoid reaction) to any ERT (approved or investigational). Note: 
Subjects with a historical positive antibody result to Imiglucerase but without a severe 
infusion-related hypersensitivity reaction will not be excluded. 
5.3 Restrictions  
Not applicable. 
5.4 Reproductive Potential 
5.4.1 Female Contraception 
Sexually active females of childbearing potential should use an acceptable form of contraception. 
Females of childbearing potential must be advised to use acceptable contraceptives throughout 
the study period and for 30 days following the last dose of the investigational product. If used, 
hormonal contraceptives should be administered according to the package insert. Any female of 
childbearing potential who is not currently sexually active must agree to use acceptable 
contraception, as defined below, if she becomes sexually active during the study and for 30 days 
following the last dose of the investigational product. Female children and adolescent subjects 
should be either: 
• Premenarchal and either Tanner stage 1 or less than age 9 years or 
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• Of childbearing potential with a negative urine and/or serum β-human chorionic 
gonadotropin (β-hCG) pregnancy test at screening. Females of childbearing potential 
must agree to abstain from sexual activity that could result in pregnancy or agree to use 
the acceptable methods of contraception. 
Female adult subjects should be either: 
• Postmenopausal (12 consecutive months of spontaneous amenorrhea and age ≥51 years), 
• Surgically sterile (having undergone one of the following surgical acts: hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy, or bilateral salpingectomy) and at least 
6 weeks have passed since sterilization, or 
• Of childbearing potential with a negative urine and/or serum β-hCG pregnancy test at 
screening. Females of childbearing potential must agree to abstain from sexual activity 
that could result in pregnancy or agree to use the acceptable methods of contraception. 
 
Acceptable methods of contraception (see Appendix 4 for guidance) include the following: 
• Intrauterine devices plus condoms 
• Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam) 
• Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), stabilized for at 
least 30 days prior to the screening visit, plus condoms. 
Note: If the subject becomes sexually active during the study, she should use one of the 
other acceptable methods of contraception noted above in addition to the hormonal 
contraceptive until it has been stabilized for 30 days. 
 
Female subjects must agree not to become pregnant, breastfeed a baby or donate an egg or eggs 
(ova) for the duration of the study and for 30 days after the last dose of study treatment. 
5.4.2 Male Contraception 
Males, including males who are surgically sterile (vasectomy), with female partners of 
childbearing potential must agree to be abstinent or use a medically acceptable form of 
contraception (see Appendix 4 for guidance) from screening through 30 days after the last dose 
of the investigational product. 
Male subjects must refrain from donating sperm for the duration of the study and for 30 days 
after the last dose of study treatment. 
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6. STUDY INTERVENTION 
6.1 Investigational Product 
6.1.1 Identity of Investigational Product 
The investigational product, VPRIV, will be provided in single-use, 4-mL vials containing 11 mg 
or 440 U velaglucerase alfa after reconstitution and provides 10 mg or 400 U for infusion use, 
and the solution should be clear to slightly opalescent and colorless for IV infusion.  
Additional information is provided in the VPRIV IB. 
6.1.2 Blinding the Treatment Assignment 
Not applicable. 
6.2 Administration of Investigational Product 
Velaglucerase alfa is a sterile lyophilized powder that requires reconstitution and dilution and is 
intended for IV infusion only. Velaglucerase alfa contains no preservatives, and vials are for 
single use only; once reconstituted, the product should be used immediately. Refer to the VPRIV 
IB for reconstitution instructions. If immediate use is not possible, the reconstituted or diluted 
product may be stored for up to 24 hours at 2 to 8 ºC (36 to 46 ºF); it should be protected from 
light and should not be frozen. Any unused solution should be discarded in accordance with local 
regulations. 
Velaglucerase alfa should be administered through a 0.22 μm in-line sterilizing filter over a 
period of 60 (+10) minutes; on Day 1 (Week 1) and Week 37, the infusion should be 
administered over a period of 60 minutes. The infusion should be completed within 24 hours of 
reconstitution of the vials. Velaglucerase alfa should not be infused with other products in the 
same infusion tubing, as the compatibility in solution with other products has not been evaluated. 
If a subject experiences an infusion-related AE (as defined in Appendix 3.1) during the infusion 
of investigational product, the investigator should decide, based on his or her clinical judgment, 
whether the infusion should be slowed or temporarily or permanently discontinued. 
Investigational product infusions are to occur on approximately the same day of the week but 
may occur every 14 (±3) days in order to facilitate subject scheduling. If at all possible, missed 
infusions should be avoided. If a subject is not dosed within 17 days from their scheduled dose, 
the subject should receive the next infusion as soon as possible after approval from the medical 
monitor for the subject to continue in the study. It may be acceptable to give the next infusion as 
early as 11 days after the previous infusion. Subsequent infusions will return to the original 
schedule.  
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Subjects will be discharged from the clinic 1 hour following completion of the infusion if they 
are clinically stable. However, on infusion days when PK assessments are scheduled, subjects 
will be discharged from the clinic approximately 3 hours after completion of the infusion if they 
are clinically stable. Site specific discharging requirement should be followed if any. 
6.2.1 Interactive Response Technology for Investigational Product Management 
An interactive response technology (IRT) will be used for investigational product management 
tasks, including investigational product supply management, inventory management and supply 
ordering, investigational product expiration tracking, and return of the investigational product. 
Please refer to the separate instruction manual that outlines the operating procedures regarding 
the IRT.  
6.2.2 Allocation of Subjects to Treatment  
This is an open-label, nonrandomized study, where all subjects will be enrolled to receive 
VPRIV. Subject numbers are assigned to all subjects as they consent to take part in the study. At 
each site, the subject number will be assigned to subjects according to the sequence of 
presentation for study participation.  
6.2.3 Dosing 
Velaglucerase alfa (VPRIV) infusions will occur at the clinical site. Subjects will receive VPRIV 
as an IV infusion EOW (±3 days). For treatment-naive subjects, the initial dose of VPRIV will 
be calculated based on the subject’s body weight determined at baseline. For subjects who 
received Imiglucerase ERT within the 12 months prior to screening, the initial dose will be 
determined by the investigator after discussing with the sponsor and recording in appropriate 
document based on the subject’s specific treatment and the situation at the time of enrollment, 
according to the subject’s benefit and risk assessment. Weight will be measured every 6 weeks 
(Weeks 7, 13, 19, 25, 31, 37, 43, and 49) throughout the study before starting the study drug 
infusion. For all dosed subjects, a change in body weight of ±5% from baseline or the previous 
body weight used to recalculate the dose will require a new dose recalculation by the clinical 
site.  
6.2.4 Unblinding the Treatment Assignment 
Not applicable. 
6.2.5 Dose Modification 
Not applicable. 
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6.3 Labeling, Packaging, Storage, and Handling of Investigational Product 
Velaglucerase alfa (VPRIV) is supplied in individually packaged borosilicate glass vials, which 
are closed with a butyl rubber stopper with a fluorescein coating and an aluminum overseal with 
a flip-off plastic cap. Each vial contains 11 mg or 440 U velaglucerase alfa after reconstitution 
and provides 10 mg or 400 U for infusion use. Velaglucerase alfa will be supplied by Takeda and 
shipped by a qualified distributor to the clinical site. 
6.3.1 Labeling 
Investigational product labels will contain the information necessary to meet the applicable 
regulatory requirements. 
6.3.2 Packaging 
The investigational product is packaged according to applicable local and regulatory 
requirements for investigational studies. 
Changes to the Takeda-supplied packaging prior to dosing may not occur without full agreement 
in advance by the sponsor. 
6.3.3 Storage 
Velaglucerase alfa should be stored in a refrigerator at 2 to 8 °C (36 to 46 °F) and should not be 
frozen. The vial should be protected from light. Velaglucerase alfa should not be used beyond 
the expiration date on the vial. 
The investigator has overall responsibility for ensuring that the investigational product is stored 
in a secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
a member of the study team, but this delegation must be documented. 
The investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range.  
The investigator is responsible for ensuring that the temperature is monitored throughout the 
duration of the study and that records are maintained. A daily temperature log of the drug storage 
area must be maintained every working day; the temperature should be monitored continuously 
by using either an in-house system, a mechanical recording device such as a calibrated chart 
recorder, or by manual means, such that both minimum and maximum thermometric values over 
a specific time period can be recorded and retrieved as required. Such a device (ie, certified 
minimum/maximum thermometer) would require manual resetting upon each recording. The 
sponsor must be notified immediately upon discovery of any excursion from the established 
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range, and the temperature excursion must be recorded in IRT immediately. Temperature 
excursions will require site investigation as to cause and remediation. The sponsor will determine 
the ultimate impact of excursions on the investigational product and provide supportive 
documentation as necessary. Under no circumstances should the product be dispensed to subjects 
until the impact has been determined and investigational product is deemed appropriate for use 
by the sponsor. 
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the investigational product, eg, 
fumigation of a storage room. 
6.4 Drug Accountability 
Investigators will be provided with sufficient amounts of the investigational product to carry out 
the study for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product received, dispensed, used, returned, and/or destroyed must 
be maintained as detailed further in this section.The investigator has the overall responsibility for 
administering/dispensing the investigational product. Where permissible, tasks may be delegated 
to a qualified designee (eg, a pharmacist) who is adequately trained on the protocol and works 
under the direct supervision of the investigator. This delegation must be documented in the 
applicable study delegation of authority form. 
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense and administer the investigational product only to the 
subjects included in the study following the procedures set out in the study protocol. Each 
subject will be given only the investigational product carrying his/her treatment dose assignment. 
All administered and dispensed medication will be documented in the subject’s source 
documents and/or other investigational product record.  
No investigational product stock or returned inventory from a Takeda-sponsored study may be 
removed from the site where it was originally shipped without prior knowledge and consent by 
the sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer. 
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records. 
With the written agreement of the sponsor, at the end of the study, all unused stock, and 
empty/used investigational product packaging will be destroyed centrally by a 
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Takeda-designated supplier. In this case, destruction records identifying what was destroyed, 
when, and how must be obtained, with copies provided to the sponsor. Destruction of the 
investigational product must be in accordance with local, state, and national laws. 
Based on entries on the site drug accountability forms, it must be possible to reconcile the 
investigational products delivered with those used and returned. All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction. 
6.5 Subject Compliance 
In this study, VPRIV will be administered only to eligible subjects under the supervision of the 
investigator or identified subinvestigator(s) at a clinical site. 
6.6 Permitted and Prohibited Treatment 
6.6.1 Permitted Treatment 
Treatments for the common ailments (eg, common cold and allergy remedies) or medications 
that are considered necessary for the welfare of the subject are permissible, provided they are not 
included in the list of prohibited treatments (see Section 6.6.2). 
Every effort should be made to keep supportive Gaucher’s disease treatment (ie, treatments for 
bone disease and hematologic symptoms) constant throughout the study; however, changes in 
these medications are acceptable if necessary, according to clinical judgment. Any change(s) 
must be recorded on the appropriate electronic Case Report Form (eCRF) page. 
Subjects may receive iron supplement therapy. The treatment regimen for iron supplement 
therapy will be based on the investigator’s assessment on a per-subject basis. Subjects who enter 
the study receiving iron supplement therapy will continue receiving iron supplement therapy 
throughout their participation in the study. 
6.6.2 Prohibited Treatment 
The following medications and treatments are prohibited throughout the course of the study: 
• Drugs that are indicated to treat anemia or thrombocytopenia (such as red blood cell 
growth factor or proprietary Chinese medicine) 
• Any other investigational drug or device 
• Any additional treatment for type 1 Gaucher disease 
• Chronic systemic corticosteroids
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7. DISCONTINUATION OF STUDY INTERVENTION AND SUBJECT 
DISCONTINUATION/WITHDRAWAL 
7.1 Discontinuation of Study Treatment 
If study treatment is discontinued, regardless of the reason, the assessments and procedures listed 
for the EOT visit will be performed as completely as possible. Whenever possible, all 
discontinued subjects should also undergo the protocol-specified assessments and procedures at 
the safety follow-up visit. Comments (spontaneous or elicited) or complaints made by the subject 
must be recorded in the source documents. The reason for discontinuation, date of 
discontinuation of the investigational product, and total amount of investigational product 
administered must be recorded in the source documents. 
7.1.1 Reasons for Discontinuation 
The primary reason for discontinuation must be determined by the investigator and recorded in 
the subject’s source documents.  
Reasons for discontinuation include, but are not limited to, the following:  
• Adverse event 
• Protocol deviation 
• Withdrawal by subject (by a parent or both parents/legal guardian for pediatric subjects) 
• Lost to follow-up 
• Lack of efficacy 
• Pregnancy in female subjects 
• Study termination 
• Other (if “Other” is selected, the investigator must specify the reason on the eCRF) 
7.2 Withdrawal From the Study 
A subject may withdraw from the study at any time and for any reason without prejudice to 
his/her future medical care by the physician or at the institution or may be withdrawn at any time 
at the discretion of the investigator or sponsor (eg, in the interest of subject safety). The 
investigator is encouraged to discuss withdrawal of a subject with the medical monitor when 
possible. 
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7.3 Subjects “Lost to Follow-up” Prior to the Last Scheduled Visit 
A minimum of 3 documented attempts must be made to contact any subject who is lost to 
follow-up at any time point prior to the last scheduled contact (site visit or telephone contact).  
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8. STUDY ASSESSMENTS AND PROCEDURES 
See Table 1 for the schedule of activities. Study assessments are detailed in Section 8.2. 
8.1 Study Periods 
The study schedule includes a screening period, baseline visit, treatment period, end-of-treatment 
visit, and safety follow-up period. 
The study completion date is defined as the date on which the last subject in the study completes 
the final protocol-defined assessments. This includes the safety follow-up visit or contact, 
whichever is later (see Section 8.1.5). 
8.1.1 Screening Period (Day –21 Through Day –4) 
Informed consent and assent (when applicable) must be obtained for all subjects participating in 
the study prior to performing any study-related assessments and procedures. Subjects may 
withdraw their consent at any time and for any reason. Participation in the study may be 
terminated at any time without the subject’s consent as determined by the investigator. The 
screening assessments and procedures can be performed over multiple days within a period of up 
to 18 days following the subject’s signature of the ICF. 
The investigator or qualified site personnel will confirm that all of the inclusion criteria 
(Section 5.1) and none of the exclusion criteria (Section 5.2) have been met. 
Subjects who fail screening due to a single laboratory test result that does not meet the eligibility 
criteria may have that laboratory test repeated at the discretion of the investigator. This includes 
a repeat of only the failed assessment (retesting) rather than a repeat of all screening assessments, 
which is allowed only once within 2 weeks of the initial screening.  
Subjects who fail screening will be permitted rescreening once only; they must sign the new ICF 
and will be assigned a new subject number. 
Subjects who have folic acid deficiency, vitamin B12-deficiency–related anemia, or 
iron-deficiency–related anemia during screening do not meet study entry criteria and will be 
considered a screening failure. Subjects may be treated for the underlying disease and be 
rescreened as judged by investigator. Rescreening will be permitted once only. 
8.1.2 Baseline Visit (Day –3 Through Day 0) 
All assessments and procedures listed for the baseline visit in Table 1 must be completed prior to 
the first VPRIV infusion and will be performed at the clinical site. Subject eligibility will be 
reconfirmed at baseline on the basis of review of the study entrance criteria. Subjects should not 
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proceed to the treatment period unless they continue to meet all inclusion/exclusion criteria. 
Subjects who do not meet all eligibility criteria at the baseline visit can be retested once only. 
The reason(s) for the subject’s ineligibility for the study will be documented. Takeda and/or its 
delegates will review subject eligibility remotely before first infusion. The investigator sites will 
provide summary information on the subject's eligibility, which is consistent with the required 
information on the eCRF (see Appendix 1.3). Source documents will be shared only in 
accordance with local regulations and subject to confidentially measures.  
All medical decisions are the responsibility of the investigator and Takeda and/or its delegates 
cannot in any way influence such medical decisions. 
8.1.3 Treatment Period (Week 1 Through 51) 
The treatment period will be up to 51 weeks, during which time the subjects will receive an IV 
infusion of VPRIV EOW at the clinical site.  A window of ±3 days is allowed around the infusion 
interval to facilitate subject scheduling, except at Week 1 where the time window is +3 days 
(Day 1 through Day 3). For treatment-naive subjects, the first dose of VPRIV will be based on 
the subject’s body weight determined at baseline. For subjects who received Imiglucerase 
treatment within the 12 months prior to screening, the initial dose will be determined by the 
investigator after discussing with the sponsor and recording in appropriate document based on 
the subject’s specific treatment and situation at the time of enrollment, according to the subject’s 
benefit and risk assessment. 
During the treatment period, safety assessments, including monitoring of AEs, use of prior and 
concomitant treatments, clinical laboratory values, antibody formation, vital signs, physical 
examinations, ECGs, and pregnancy tests will be conducted at visits as outlined in Table 1. 
Efficacy assessments in terms of hemoglobin concentration and platelet count will performed 
every 6 weeks starting from Week 7. The evaluation for circulating biomarker, liver and spleen 
volume (MRI or CT scan), QoL assessments, and PK assessments will be conducted at visits as 
outlined in Table 1. 
8.1.4 End-of-Treatment Visit (Week 53) or Early Withdrawal Visit 
After completion of the treatment period, the subject will return to the site at Week 53 for the 
EOT visit assessments and procedures. If VPRIV treatment is discontinued early or the subject is 
withdrawn from the study, regardless of the reason, the assessments and procedures listed for 
Week 53 will be performed as completely as possible within 2 weeks (±7 days) after the last 
infusion (early withdrawal visit). 
The subject may visit the clinical site at visits other than those scheduled for assessments and 
procedures as clinically warranted; these will be recorded as unscheduled visits. 
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8.1.5 Safety Follow-up Period 
The safety follow-up period for the study is 30 (±7) days after the last infusion at Week 51 (or 
the last infusion for early discontinued subjects). During this period, there will be a telephone 
call or scheduled visit to the site to query for AEs, SAEs, and concomitant treatments. All AEs 
and SAEs that are not resolved at the time of this contact will be followed to closure or return to 
baseline level or explained by the investigator if the AE and/or SAE will not be resolved as 
documented in the subject’s source documents (see Appendix 3.2). 
8.1.6 Additional Care of Subjects After the Study 
No aftercare is planned for this study. 
8.1.7 COVID-19–related Protocol Considerations 
On a temporary basis, in order to maintain subject safety, confidentiality, and study integrity in 
the context of health care delivery challenges presented by the COVID-19 pandemic, subjects 
who may be impacted should contact clinical sites and investigators to determine the best course 
of action. Depending on the impact, in some cases, it may be possible to arrange for alternative 
solutions as permitted by local regulations. Any decision on procedural changes should be made 
on a case-by-case basis by the principal investigator in consultation with the study team and 
medical monitor while maintaining subject safety and confidentiality as the priority. 
Missing data, remote visits, changes to assessment approaches, and altered visit windows during 
the COVID-19 public health emergency may affect the study results. Thus, it is important to 
identify all protocol deviations and altered data collection or assessment methods. It is crucial 
that any deviations related to COVID-19 be clearly identified as such in the eCRF. 
The following procedural changes may be considered: 
• If necessary, informed consent from a potential or current trial subject may be obtained 
via electronic informed consent capabilities or an electronic face-to-face consent 
interview when potential subjects are unable to travel to the site. 
• Subjects who discontinued from screening due to COVID-19–related factors but were 
otherwise qualified to participate in the trial may be rescreened if the medical monitor 
agrees. 
• Remote checks instead of site visits (if appropriate) may be performed as a safety check 
on subject well-being. 
• The subject may be transferred to an investigational site away from the risk zones to 
complete the required visits. 
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• If the screening period exceeds 18 days due to COVID-19–related factors, the subject 
may be rescreened. 
8.2 Study Assessments 
Detailed descriptions of the study assessments and procedures required are described in this 
section. The timing for the performance of these assessments and procedures is presented in the 
schedule of activities (Table 1). 
8.2.1 Demographic and Other Baseline Characteristics 
Subject demographic information, including gender, age, and race, will be collected prior to the 
subject receiving the first dose of the investigational product.  
8.2.1.1 Medical History 
At screening, the subject’s complete medical history, including surgical procedures within the 
30 days prior to signing the ICF, will be collected and recorded in the subject’s source 
documents and on the appropriate eCRF page. This will include a review of body systems and 
documentation of current and prior medical procedures. 
8.2.1.2 Prior and Concomitant Treatments 
All nonstudy treatment including, but not limited to, herbal treatments, vitamins, behavioral 
treatment, or nonpharmacological treatment, such as psychotherapy, received within the 30 days 
prior to signing ICF through the end of the safety follow-up period must be recorded in the 
subject’s source documents and on the appropriate eCRF page. For the subjects who have not 
been treated for Gaucher disease within the 12 months prior to screening, verification for 
treatment will be conducted; for the subjects who have received Imiglucerase ERT within the 
12 months prior to screening, the dose and frequency must be recorded. 
Concomitant treatment refers to all treatment received between the date of signing the ICF and 
the end of the safety follow-up period, inclusive. Concomitant treatment information must be 
recorded in the subject’s source documents and on the appropriate eCRF page. 
8.2.1.3 Immunology 
Immunology testing will be performed at screening to ensure that subjects do not present with 
viral infections that might compromise their ability to safely complete the study and confound 
later interpretation of the study findings. 
Immunology tests include HBsAg, HCV, and HIV. Tests for HBsAg with detectable hepatitis B 
viral DNA load, HCV antibody with confirmation by HCV RNA polymerase chain reaction 
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testing, and HIV antibody will be performed at the local laboratory or Takeda-designated 
laboratory. 
Subjects with a positive result are to be excluded from the study. 
8.2.1.4 Electroencephalogram 
The EEG will be performed at screening at the local laboratory to exclude subjects who are at the 
early stage of type 3 Gaucher disease. Subjects with abnormal EEG examinations will be 
excluded from the study. 
8.2.2 Efficacy Assessments 
8.2.2.1 Hemoglobin Concentration and Platelet Count 
Efficacy assessments in terms of hemoglobin concentration and platelet count will be required at 
baseline and every 6 weeks starting from Week 7 during the study treatment period through 
Week 53. These assessments are included as components of the hematology laboratory panel. 
Hemoglobin concentration and platelet count will be evaluated at a Takeda-designated 
laboratory.  
8.2.2.2 Liver and Spleen Magnetic Resonance Imaging or Computed Tomography Scan 
Subjects will have an MRI or CT scan of the liver and spleen at screening, Week 25, and 
Week 53. All imaging modalities should remain consistent for all subject at all timepoints 
throughout the study. The MRI or CT scan will be performed at local laboratory. Investigator is 
responsible to perform the eligibility check for presence of at least of hepatomegaly and/or 
moderate splenomegaly. To evaluate VPRIV efficacy, the volumes of liver and spleen will be 
analyzed and calculated centrally by sending the MRI/CT images to a Takeda-designated 
imaging vendor. Image collection and preparation procedures are provided in the imaging 
manual. 
8.2.3 Safety Assessments 
8.2.3.1 Physical Examination 
A complete physical examination will be performed. A complete physical examination will 
include, at a minimum, assessments of the following organs and systems: eyes, ears, nose, throat, 
cardiovascular, respiratory, gastrointestinal, dermatologic, musculoskeletal, extremities, lymph 
nodes, nervous system (eg, eye movement disorder), and other. 
Any abnormal change in the physical findings will be recorded as an AE in the subject’s source 
documents and on the appropriate eCRF page.  
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8.2.3.2 Adverse Events 
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”). 
Adverse events will be collected from the time the ICF is signed.  
See Appendix 3 for definitions; assessments; collection time frames; and reporting procedures of 
AEs, TEAEs, serious TEAEs, and other events.  
8.2.3.3 Vital Signs 
Vital signs include pulse rate, blood pressure, respiratory rate, temperature, body weight, and 
height. Measurement of pulse rate, blood pressure, respiratory rate, and temperature will be taken 
prior to blood draw or initiation of infusion following 5 minutes of rest. Vital signs should be 
recorded as outlined in Table 4 and will be recorded in the subject’s source documents and on 
the appropriate eCRF page. 
If there are no IRRs observed during the first 3 infusions, vital signs assessment for the 
subsequent infusions can be omitted at the discretion of the investigator.  
The investigator will assess whether a change from baseline in vital signs is clinically significant 
and whether the change should be considered and recorded as an AE. 
Table 4. Schedule for Recording of Vital Signs on Infusion Days 
Timing Relative to the Infusion 
Schedule of Activities 
Start of the Infusion 
Within 10 minutes prior to the start of the infusion 
During the Infusion 
30 (±5) minutes after the start of the infusion 
After the Infusiona 
Within 10 minutes after completing the infusion, 
30 (±5) minutes after completing the infusion, and 
60 (±5) minutes after completing the infusion 
a If there are no infusion-related reactions during the first 3 infusions, the vital signs assessment for the 
subsequent infusions can be omitted at the discretion of the investigator. 
8.2.3.3.1 Body Weight and Height 
Body weight and height will be measured as part of vital signs assessments at the time points 
presented in the schedule of activities (Table 1). 
8.2.3.4 Clinical Laboratory Tests 
All clinical laboratory tests will be performed according to the laboratory’s standard procedures. 
Reference ranges will be supplied by the laboratory and used to assess the results for clinical 
significance and out-of-range changes that may be associated with, or constitute, an AE. The 
investigator should assess out-of-range clinical laboratory values for clinical significance, 
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indicating if the value is or is not clinically significant. Abnormal clinical laboratory values that 
are unexpected or not explained by the subject’s clinical condition may, at the discretion of the 
investigator or sponsor, be repeated as soon as possible until confirmed, explained, or resolved. 
Hemoglobin concentration and platelet count tests for efficacy assessment will be performed at a 
Takeda-designated laboratory. Serum chemistry tests, hematology tests for safety assessment, 
and urinalysis tests will be performed at the local laboratory. See Section 8.1.1 for rescreening of 
subjects who have folic acid deficiency, vitamin B12-deficiency–related anemia, or 
iron-deficiency–related anemia at screening. 
A complete list of the clinical laboratory tests (serum chemistry, hematology, urinalysis, and 
other tests) to be performed is provided in Appendix 2. 
8.2.3.5 Pregnancy Test 
Female subjects of childbearing potential must have a negative pregnancy test at all visits 
indicated in Table 1 to be eligible for the study.  
Pregnancy testing will be performed using a urine sample and, if needed, a serum β-hCG sample. 
If the urine pregnancy test is negative, the study assessments and procedures will be completed; 
serum β-hCG testing will not be required. If the urine test is positive, a blood sample will be 
collected for serum β-hCG testing and sent to either the local laboratory or Takeda-designated 
laboratory for analysis. No additional study assessments or procedures should be completed until 
the result of the serum pregnancy test is available. A positive serum β-hCG test would result in 
the subject being a screen failure or discontinued from the study. 
The pregnancy test at the baseline visit can be waived if it had been performed within 7 days of 
the previous test during the screening visit. 
8.2.3.6 12-lead Electrocardiogram 
12-lead ECGs will be performed prior to blood draw and/or initiation of infusion following 
5 minutes of rest and in accordance with the clinical site’s standard practice(s) at visits specified 
in the schedule of activities (Table 1). The ECG recordings will be read locally at the clinical site 
by the investigator or a qualified designee. Electrocardiogram parameters (PR, QRS, QT, and 
corrected QT intervals and heart rate) will be collected following 5 minutes of rest. Identification 
of any clinically significant findings and/or conduction abnormalities will be recorded as an AE 
in the subject’s source documents and on the appropriate eCRF page. 
8.2.3.7 Serum Anti-velaglucerase Alfa Antibody 
All subjects will have a blood sample collected at the visits specified in the schedule of activities 
(Table 1) for determination of serum anti-VPRIV antibodies. During the treatment period, these 
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blood samples will be collected prior to the VPRIV infusion and evaluated at a 
Takeda-designated laboratory. Sample collection, preparation, and shipping procedures are 
provided in the laboratory manual. 
8.2.3.8 X-ray of Bilateral Femoral Neck and Distal Femur (Procedural Imaging) 
X-ray images of the bilateral femoral neck and distal femur will be taken at baseline to test the 
bone density and determine the severity of the bone disease. X-ray test can be waived if it has 
been performed within the 30 days prior to the baseline visit. If any bone pain or damage occurs 
during the study, X-rays will be used to judge the relevance of AEs. 
8.2.4 Other Assessments 
8.2.4.1 Pharmacokinetics 
Blood samples for PK analysis will be collected on Day 1 (Week 1) and at Week 37; the PK 
sampling time points are specified in Table 2. Pharmacokinetic samples will be collected only 
for the naive subjects who have not received any Gaucher disease treatment within the 
12 months prior to enrollment. A total of 11 blood samples will be collected from adult subjects 
(≥18 years old). A total of 9 blood samples will be collected from adolescent subjects 
(12 through 17 years old). A total of 6 blood samples will be collected from children (4 through 
11 years old). Pharmacokinetic blood samples must not be drawn from the arm being used for 
the infusion. Sample collection, processing, and shipping information is provided in the 
laboratory manual. Serum samples will be analyzed for VPRIV using a validated analytical 
method (eg, enzyme-linked immunosorbent assay) at a Takeda-designated laboratory.  
The PK parameters on Day 1 (week 1) will include:  
• Cmax (ng/mL) 
• Tmax (min) 
• AUCinf (ng•min/mL) 
• T1/2 (min) 
• CL (mL/min/kg) 
• Vss (mL/kg) 
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8.2.4.2 Circulating Biomarkers  
Plasma lyso-Gb1 and serum CCL18 will be assessed at baseline, Weeks 13, 25, and 37 and EOT 
visits specified in the schedule of activities (Table 1). The sample will be collected before the 
VPRIV infusion and evaluated at a Takeda-designated laboratory. 
8.2.4.3 Quality of Life 
At baseline, Week 25, and Week 53 visits, subject’s QoL will be assessed using validated, 
Chinese versions of SF-36, version 2 (for subjects ≥18 years of age) and CHQ-PF50 (for subjects 
≥5 and <18 years of age); QoL assessment is not applicable for subjects <5 years of age. The SF-
36, version 2 will be completed by the subject, while the CHQ-PF50 will be completed by the 
subject’s parent or caregiver.  
During treatment period, the SF-36, version 2 and CHQ-PF50 questionnaires should be 
completed prior to any testing or discussion with the investigator. The subject and/or subject’s 
parent or caregiver should be given sufficient space and time to complete the questionnaires. The 
questionnaires are intended to be self-reported and should not be interviewer-administered. 
The SF-36, version 2 is a self-administered, validated questionnaire designed to measure generic 
health-related QoL. This 36-item questionnaire measures 8 domains, including physical 
functioning, role-physical, bodily pain, general health, vitality, social functioning, role 
emotional, and mental health. Two summary scores, including the Physical Component Score 
and Mental Component Score, will be calculated. Additionally, the scores can be calculated 
based on each of the 8 domains. Higher scores indicate better health status. The subject should 
complete the questionnaire on their own without any assistance from the study staff or a 
caregiver. 
The CHQ-PF50 will assess the parent(s) or caregiver’s impression of the following scales: global 
health, physical functioning, role/social limitations (emotional/behavioral and physical), bodily 
pain/discomfort, behavior, global behavior, mental health, self-esteem, general health 
perceptions, change in health, parental impact (emotional and time), family activities, and family 
cohesion. An increase in the CHQ-PF50 score indicates a more favorable assessment by the 
proxy of the child’s health and/or well-being. The subject’s parent or caregiver should complete 
the questionnaire on their own without any assistance from the study staff. 
Sample questionnaires for QoL assessments included in the study are provided in Appendix 5. 
8.2.5 Volume of Blood to Be Drawn From Each Subject 
The amount of blood to be collected for each assessment tested at the Takeda-designated 
laboratory is provided in the central laboratory manual. The amount of blood to be collected for 
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each assessment tested at the local laboratory follows each selected site’s requirement. The 
amount of blood to be collected may vary according to the instructions provided by the 
manufacturer or laboratory for an individual assessment. When more than 1 blood assessment is 
to be done at the time point/period, the assessments may be combined if they require the same 
type of tube.  
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9. STATISTICAL CONSIDERATIONS 
9.1 Statistical Analysis Process 
The study will be analyzed by the sponsor or its agent.  
A statistical analysis plan (SAP) will provide the statistical methods and definitions for analysis 
of the efficacy and safety data, as well as describe the approaches to be taken for summarizing 
other study information, such as subject disposition, demographics and baseline characteristics, 
investigational product exposure, and prior and concomitant treatments. The SAP will also 
include a description of how missing, unused, and spurious data will be addressed. 
To preserve the integrity of the statistical analysis and study conclusions, the SAP will be 
finalized prior to database lock. 
All statistical analyses will be performed using SAS statistical software, version 9.4 or higher 
(SAS Institute). 
9.2 Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee 
No interim analysis, adaptive design, or data monitoring committee is planned for the study. 
9.3 Sample Size and Power Considerations 
A sample size of 20 safety evaluable subjects is planned to be enrolled in the study to 
descriptively provide an estimate of the serious TEAE rate. No formal sample size calculations 
have been done, and the sample size is based on feasibility. 
9.4 Statistical Analysis Sets 
The statistical analysis will include the following analysis sets: 
• The intent-to-treat (ITT) set will include all subjects who sign the ICF (and assent form, 
if applicable) and are eligible for the study based on the defined inclusion/exclusion 
criteria. The ITT set will be used for efficacy analyses. 
• The safety set will include all subjects in the ITT set who receive at least 1 dose of 
VPRIV. The safety set will be used for analysis of the safety endpoints.  
• The per-protocol (PP) set will include all subjects in the ITT set excluding subjects with 
major protocol deviations. The PP set will be identified by a team consisting of, at a 
minimum, a physician and statistician from Takeda. The PP set will be used for an 
efficacy sensitivity analysis. 
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• The PK set will include all subjects in the ITT set who receive at least 1 dose of VPRIV 
and provide evaluable PK concentration data. 
9.5 Analysis of Disposition 
The number of subjects enrolled, completing, or withdrawing from the study, along with the 
reasons for withdrawal, will be tabulated for the ITT set. 
9.6 Medical History 
Medical history will be coded using the most recent version of the Medical Dictionary for 
Regulatory Activities (MedDRA) and summarized by system organ class (SOC) and preferred 
term (PT) for the ITT set. 
9.7 Demographics and Baseline Characteristics Analyses 
Baseline and demographic variables will be descriptively summarized for the ITT set. 
9.8 Treatment Compliance and Extent of Exposure 
Treatment compliance and the extent of exposure will be described by calculating the percentage 
of planned doses and total number of actual doses received by the subject and summarized for 
the ITT set. 
9.9 Efficacy Analyses 
The efficacy endpoints are described in Table 3. 
Continuous variables will be summarized with descriptive statistics including the mean, standard 
deviation (SD), median, first quartile (Q1), third quartile (Q3), minimum, and maximum. 
Categorical data will be summarized with the frequency and percentage of subjects falling within 
each category. 
The observed values, change from baseline, change over time, and percentage change from 
baseline for the efficacy measurements (hematologic manifestations and liver and spleen 
volume) will be summarized by sex and visit. Subject listings will be provided for the clinical 
outcomes from the QoL questionnaires. 
Efficacy analyses will be based on the ITT set, with the PP set as a sensitivity analysis. Data 
from subjects who previously received Imiglucerase ERT and treatment-naive populations will 
be analyzed separately, as well as pooled. 
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9.10 Safety Analyses 
The safety endpoints are described in Table 3. 
Adverse events will be coded using the most recent version of MedDRA. Treatment-emergent 
AEs will be summarized overall and by SOC and PT. Analysis of AEs will be performed at both 
the subject and AE levels. Similar displays will be provided for IRRs. The AEs will be 
summarized by severity, seriousness, and relation to the investigational product. 
Subjects will be counted once per SOC and once per PT. Multiple events of the same type will 
be combined for each subject and the worst severity or outcome for each event type will be 
presented for the analysis. When calculating the event rates, the denominator will be the total 
population size, irrespective of dropouts over the course of follow-up.  
Tabular summaries of other safety parameters (eg, vital signs, blood tests, concomitant 
treatments [coded using WHODrug Global], anti-VPRIV antibody status, and infusion 
information) will be produced at baseline and, if applicable, for each postbaseline evaluation 
visit. 
Changes in the results of physical examinations from baseline will be presented by visit and 
body system in the form of a shift table. 
The observed values and change from baseline for ECG parameters (PR, QRS, QT, and 
corrected QT intervals and heart rate) will be summarized by visit. The number of subjects with 
normal and abnormal ECG results during the study will be summarized by visit in the form of a 
shift table. 
Laboratory data will be listed by subject. Subjects with newly occurring abnormalities outside 
the normal range will be flagged, listed separately, and summarized. The mean change from 
baseline in laboratory values or a shift table will be provided for each visit. The change from 
baseline will be calculated by subtracting the baseline value from the postbaseline value. 
Vital sign data will be listed by subject, and any newly occurring changes outside the reference 
range from baseline will be flagged. The mean changes from baseline for vital sign data will be 
summarized. Subjects with notable abnormal values will be identified and listed separately along 
with their values. 
The number and percentage of subjects reporting at least 1 use of concomitant treatment during 
the study will be reported. Subject listings will be provided describing the reason(s) for study 
discontinuation. 
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Antibody data, including neutralizing antibodies, will also be presented in the form of individual 
subject listings. 
Safety data will be analyzed using the safety set. Safety data will be analyzed separately for 
subjects who previously received Imiglucerase ERT and treatment-naive populations, as well as 
pooled. 
9.11 Other Analyses 
The PK, QoL, and biomarker endpoints are described in Table 3. 
9.11.1 Pharmacokinetic Analyses 
Statistical analysis of PK data will be based on the PK set. 
For the PK set, individual concentrations will be listed and summarized by visit and scheduled 
time points for naive subjects with PK assessments and by age (eg, ≥18 years vs 12 through 
17 years vs 4 through 11 years). Individual PK parameters of VPRIV at Week 1 will be listed 
and summarized by treatment for all PK subjects, as well as by age, with descriptive statistics 
(number, arithmetic mean, SD, coefficient of variation [CV], median, minimum, maximum, 
geometric mean, and CV [95% CI] of the geometric mean). Pharmacokinetic parameter estimates 
will be computed, where appropriate, from individual serum-concentration time data using 
noncompartmental methods and actual times. Figures of individual and mean (SD) 
concentration-time profiles of VPRIV will be generated based on nominal time points. 
9.11.2 Health-related Quality-of-Life Analyses 
The change over time in subject rating of QoL will be analyzed using the SF-36, version 2 for 
subjects ≥18 years of age and CHQ-PF50 for subjects ≥5 and <18 years of age. 
Initially, simple summary statistics will be produced for the overall score and (if available) any 
subscale score of each patient-reported outcome measure. Continuous variables will be 
summarized using the following descriptive statistics: mean, SD, median, Q1, Q3, minimum, and 
maximum. The number and percentage of observed levels will be reported for all categorical 
measures. 
9.11.3 Biomarker Analyses 
Circulating biomarker data will be summarized using descriptive statistics. 
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10. REFERENCES 
Barton, N. W., Brady, R. O., Dambrosia, J. M., Di Bisceglie, A. M., Doppelt, S. H., Hill, S. C., et 
al. 1991. Replacement therapy for inherited enzyme deficiency--macrophage-targeted 
glucocerebrosidase for Gaucher's disease. N Engl J Med, 324, 1464-70. 
Beutler, E.and Grabowski, G. A. 2001. Gaucher Disease. In: Scriver CR, B. A., Sly WS, Valle D 
(ed.) The Metabolic and Molecular Basis of Inherited Disease, 8th Edition. New York: 
McGraw-Hill. 
Cox, T. M., Aerts, J. M., Andria, G., Beck, M., Belmatoug, N., Bembi, B., et al. 2003. The role 
of the iminosugar N-butyldeoxynojirimycin (miglustat) in the management of type I 
(non-neuronopathic) Gaucher disease: a position statement. J Inherit Metab Dis, 26, 513-
26. 
Cox, T. M.and Schofield, J. P. 1997. Gaucher's disease: clinical features and natural history. 
Baillieres Clin Haematol, 10, 657-89. 
Masek, B. J., Sims, K. B., Bove, C. M., Korson, M. S., Short, P., Norman, D. K. 1999. Quality of 
life assessment in adults with type 1 Gaucher disease. Qual Life Res, 8, 263-8. 
Pastores, G. M., Weinreb, N. J., Aerts, H., Andria, G., Cox, T. M., Giralt, M., et al. 2004. 
Therapeutic goals in the treatment of Gaucher disease. Semin Hematol, 41, 4-14. 
Weinreb, N. J., Charrow, J., Andersson, H. C., Kaplan, P., Kolodny, E. H., Mistry, P., et al. 
2002. Effectiveness of enzyme replacement therapy in 1028 patients with type 1 Gaucher 
disease after 2 to 5 years of treatment: a report from the Gaucher Registry. Am J Med, 
113, 112-9. 
Zhang, L. 2020. Expert consensus on the diagnosis and treatment of Gaucher disease in adults in 
China. Natl Med J China, 100, 1841-9. 
 
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Appendix 1 
 REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS 
Appendix 1.1   Regulatory and Ethical Considerations 
This study is conducted in accordance with current applicable regulations, including ICH E6 and 
all updates, as well as local ethical and legal requirements.  
Compliance with these regulations and guidelines also constitutes compliance with the ethical 
principles described in the Declaration of Helsinki. 
The name and address of each third-party vendor (eg, contract research organization [CRO]) 
used in this study will be maintained in the investigator and sponsor files, as appropriate. 
Appendix 1.2   Sponsor’s Responsibilities 
Good Clinical Practice Compliance 
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations and current ICH GCP guidelines, as well as all applicable 
national and local laws and regulations. 
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and eCRFs in accordance with current GCP guidelines and the respective local 
and (inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities. 
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to the release of the 
investigational product for shipment to the site. 
Indemnity/Liability and Insurance 
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator prior to study initiation per local country guidelines. 
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied to the CRO as necessary. 
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Public Posting of Study Information 
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.The timing for study registration and results summary posting must be in 
accordance with applicable local and national requirements. 
Submission of Summary of Clinical Study Report to Competent Authorities of Member 
States Concerned and Ethics Committees 
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
community guideline on GCP. This requirement will be fulfilled within 6 months of the study 
completion date for pediatric studies and 1 year for nonpediatric studies as per guidance. 
Study Suspension, Termination, and Completion 
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that the applicable sites, 
regulatory agencies, and IRBs/ECs are notified as appropriate. Additionally, the discontinuation 
of a registered clinical study that has been posted to a designated public website will be updated 
accordingly. 
Appendix 1.3   Investigator’s Responsibilities 
Good Clinical Practice Compliance 
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996) and E6 R2 (2017) and applicable regulatory requirements and guidelines. 
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period. 
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and subinvestigators are provided to the study 
sponsor (or designee) before starting the study. 
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If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study. 
A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies. Agreement with the final clinical study report is documented by the signed 
and dated signature of the coordinating principal investigator (multicenter study), in compliance 
with ICH Guidance E3 (1995).  
Protocol Adherence and Investigator Agreement 
The investigator and any subinvestigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met the 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol. 
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations. 
Communication with local IRBs/ECs to ensure accurate and timely information is provided at all 
phases during the study may be done by the sponsor, applicable CRO, or coordinating principal 
investigator according to national provisions and will be documented in the investigator 
agreement. 
Documentation and Retention of Records 
Electronic Case Report Forms 
Electronic Case Report Forms are supplied by theCRO and should be handled in accordance with 
instructions from the sponsor. 
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded on the eCRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Electronic Case Report Forms 
must be completed by the investigator or designee as stated in the site delegation log. 
All data will have separate source documentation; no data will be recorded directly onto the 
eCRF. 
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The clinical research associate/study monitor will verify the contents against the source data per 
the monitoring plan. If the data are unclear or contradictory, queries will be sent for corrections 
or verification of data. Alternative approaches may be used to ensure data quality, data integrity, 
and subject safety (eg, remote source data review via phone or video) as permitted by regional 
and local regulations. Additional details are in the monitoring plan. 
Recording, Access, and Retention of Source Data and Study Documents 
Original source data to be reviewed during this study will include, but are not limited to, the 
subject’s medical file and original clinical laboratory reports. 
All key data must be recorded in the subject’s source documents. 
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities; the IRB/EC; and auditors to inspect facilities and have 
direct access to original source records relevant to this study, regardless of media. 
The clinical research associate/study monitor (and auditors and IRB/EC or regulatory inspectors) 
may check the eCRF entries against the source documents. The consent form includes a 
statement by which the subject agrees to the monitor/auditor from the sponsor or its 
representatives, national or local regulatory authorities, or the IRB/EC having access to source 
data (eg, subject’s medical file, appointment books, original laboratory reports, and X-rays). 
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US Food and 
Drug Administration [FDA], European Medicines Agency (EMA), and United Kingdom 
Medicines and Healthcare Products Regulatory Agency) or an auditor. 
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor. 
Audit/Inspection 
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the EMA, the Medicines and Healthcare Products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site. 
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Financial Disclosure 
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries, 
such as a grant to fund ongoing research; compensation in the form of equipment; retainer for 
ongoing consultation or honoraria; any proprietary interest in the investigational product; or any 
significant equity interest in the sponsor or subsidiaries as defined in 21 Code of Federal 
Regulations 54 2(b) (1998). 
Appendix 1.4   Data Management Considerations 
Data Collection 
The investigators’ authorized site personnel must enter the information required by the study 
eCRF completion guidelines or similar for all data requiring transcription of the source. A study 
monitor will visit each site in accordance with the monitoring plan and review the eCRF data 
against the source data for completeness and accuracy. Discrepancies between the source data 
and data entered on the eCRF will be addressed by qualified site personnel. When a data 
discrepancy warrants correction, the correction will be made by authorized site personnel. Data 
collection procedures will be discussed with the site at the site initiation visit and/or at the 
investigator’s meeting.  
Data Management 
Data are to be entered into a clinical database as specified in the sponsor’s data management plan 
or similar. Quality control and data validation procedures are applied to ensure the validity and 
accuracy of the clinical database. 
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.  
Appendix 1.5   Ethical Considerations 
Informed Consent 
It is the responsibility of the investigator to obtain written informed consent and assent, where 
applicable, from all study subjects prior to any study-related assessments and procedures, 
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including screening. All consent and assent documentation must be in accordance with 
applicable regulations and GCP. Each subject or the subject’s parent/legally authorized 
representative, as applicable, is requested to sign and date the ICF or a certified translation, if 
applicable, after the subject has received and read (or been read) the written subject information 
and received an explanation of what the study involves, including, but not limited to, the 
objectives, potential benefits and risk, inconveniences, and subject’s rights and responsibilities. 
A copy of the ICF and assent documentation (ie, a complete set of subject information sheets and 
fully executed signature pages) must be given to the subject or subject’s legally authorized 
representative and/or parent(s) or caregiver, as applicable. This document may require translation 
into the local language. Signed ICFs must remain in each subject’s study file and be available for 
verification at any time. 
The principal investigator will provide the sponsor with a copy of the ICF and assent form that 
was reviewed by the IRB/EC and received their favorable opinion/approval. A copy of the 
IRB/EC’s written favorable opinion/approval of these documents must be provided to the 
sponsor prior to the start of the study unless it is agreed to and documented (abiding by 
regulatory guidelines and national provisions) prior to the study start that another party (ie, the 
sponsor or coordinating principal investigator) is responsible for this action. Additionally, if the 
IRB/EC requires modification of the sample subject information and consent document provided 
by the sponsor, the documentation supporting this requirement must be provided to the sponsor. 
Institutional Review Board or Ethics Committee 
It is the responsibility of the investigator to submit this protocol, the ICF (approved by the 
sponsor or their designee), relevant supporting information, and all types of subject recruitment 
information to the IRB/EC for review, and all documents must be approved prior to site 
initiation. 
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement. 
Investigational product supplies will not be released until the sponsor has received written 
IRB/EC approval. 
Prior to implementing changes in the study, the sponsor and IRB/EC must approve any revisions 
of all informed consent/assent documents and amendments to the protocol unless there is a 
subject safety issue. If required by local law, substantial amendments to the protocol must also 
be approved by the appropriate regulatory agency prior to implementation. 
The investigator is responsible for keeping the IRB/EC apprised of the progress of the study and 
of any changes made to the protocol at least annually or more frequently in accordance with the 
requirements, policies, and procedures established by the IRB/EC. The investigator must also 
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keep the local IRB/EC informed of any serious and significant AEs as required by IRB/EC 
procedures. 
Privacy and Confidentiality 
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines. 
After subjects have consented to take part in the study, the sponsor and/or its representatives will 
review their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market VPRIV; national or local regulatory authorities; and the IRB/EC that gave approval for 
the study to proceed. The sponsor and/or its representatives accessing the records and data will 
take all reasonable precautions in accordance with applicable laws, regulations, and guidelines to 
maintain the confidentiality of subjects’ identities. Subjects are assigned a unique identifying 
number; however, their initials and date of birth may also be collected, if permitted under local 
laws governing privacy.  
The results of studies containing subjects’ unique identifying number, relevant medical records, 
and possibly initials and dates of birth, where allowed per local law, may be transferred to, and 
used in, other countries that may not afford the same level of protection that applies within the 
country where this study is conducted. The purpose of any such transfer would include to support 
regulatory submissions, conduct new data analyses to publish or present the study results, or 
answer questions asked by regulatory or health authorities. 
Study Results/Publication Policy 
The term “publication” shall mean any paper, article, manuscript, report, poster, internet posting, 
presentation slides, abstract, outline, video, instructional material, presentation (in the form of a 
written summary), or other public disclosure of the study results in printed, electronic, oral, or 
other form. The parties understand and agree that participation in the study may involve a 
commitment to publish the data from all sites participating in the study in a cooperative 
publication with other investigators prior to publication or oral presentations of the study results 
on an individual basis. The site agrees not to publish or present the site’s study results until such 
time as either the aggregate multisite study results are published in a cooperative publication or 
for a period of 1 year after termination or completion of the study at all participating sites, 
whichever occurs first. After that time, the site may publish the site’s study results in scientific 
journals or present the study results at a symposia or other professional meetings in accordance 
with the following provisions. 
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If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single site data being presented. 
At least 60 days prior to submitting an abstract, manuscript, or other document for publication, a 
copy of the proposed publication must be provided to the sponsor by the site for review. Upon 
the sponsor’s request, the site agrees to remove any and all confidential information (expressly 
excluding study results) identified in the publication and to delay such submission or 
presentation for an additional 60-day period in order to allow the sponsor time to file any patent 
application(s). All publications of the study results shall appropriately reference the multisite 
study publication, if any, or the fact that the study results are a subset of data resulting from a 
larger multisite study. 
The sponsor is committed to transparent dissemination of all scientific, technical, and medical 
manuscripts generated from Takeda-supported research. Therefore, after 01 Jan 2018, the 
sponsor will require the submission of all Takeda-supported research manuscripts to journals that 
offer public availability via open access (including publisher platforms/repositories and 
self-archiving). Open access refers to the free point of entry, online availability of published 
research output with, where available, rights of reuse according to an end-user license. 
Unless otherwise required by the journal in which the publication appears or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
Recommendation for the Conduct, Reporting, Editing and Publication of Scholarly Work in 
Medical journals. Participation as an investigator does not confer any rights to authorship of 
publications. 
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Appendix 2 
 CLINICAL LABORATORY TESTS 
The following clinical laboratory assessments will be performed:
Serum chemistry: 
 
• 
Albumin 
• 
Alkaline phosphatase 
• 
Alanine aminotransferase 
• 
Aspartate aminotransferase 
• 
(Blood) Urea nitrogen or (blood) urea 
• 
Calcium 
• 
Creatinine 
• 
Creatine kinase 
• 
Ferritin 
• 
γ-glutamyl transferase glucose  
• 
Lactate dehydrogenase 
• 
Potassium 
• 
Serum iron 
• 
Sodium  
• 
Total bilirubin 
• 
Total protein 
• 
 
Hematology: 
 
• 
Hematocrit 
• 
Hemoglobin 
• 
Mean corpuscular hemoglobin 
• 
Mean corpuscular hemoglobin concentration 
• 
Mean corpuscular volume 
• 
Platelet count 
• 
Red blood cell count 
• 
White blood cell count with differential 
• 
Neutrophils 
• 
Basophils 
• 
Lymphocytes 
• 
Monocytes 
• 
Eosinophils 
 
Urinalysis: 
 
• 
Bilirubin 
• 
Color 
• 
Glucose 
• 
Ketones 
• 
Nitrite 
• 
Occult blood 
• 
pH 
• 
Protein 
• 
Specific gravity 
• 
Urobilinogen 
Others: 
 
• 
HIV and hepatitis (B surface antigen and C 
antibody) 
• 
Pregnancy test 
• 
Serum anti-velaglucerase alfa antibody 
• 
Plasma chemokine (C-C motif) ligand 18 
• 
Glucosylsphingosine 
• 
Pharmacokinetic test (velaglucerase assay) 
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Appendix 3 
 ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING 
Appendix 3.1  Adverse Event Definitions 
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with the 
investigational product. An AE can therefore be any unfavorable and unintended sign (including 
a clinically significant laboratory finding), symptom, or disease temporally associated with the 
use of the investigational product, whether or not causality is suspected (ICH Guidance E2A 
1995). 
Treatment-emergent Adverse Event 
A TEAE is defined as any event emerging or manifesting at or after the initiation of the 
investigational product or any existing event that worsens in either intensity or frequency 
following exposure to the investigational product. 
Serious Adverse Event 
An SAE is any untoward clinical manifestation of signs, symptoms, or outcomes (whether 
considered related to the investigational product or not) and at any dose: 
• Results in death 
• Is life-threatening. Note: The term “life-threatening” in the definition of “serious” 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 was more severe. 
• Requires in-patient hospitalization or prolongation of hospitalization. Note: 
Hospitalizations that are the result of elective or previously scheduled investigations 
procedures or surgery for preexisting conditions and have not worsened after initiation of 
treatment should not be classified as SAEs.  
- 
For example, an admission for a previously scheduled ventral hernia repair would not 
be classified as an SAE; however, complication(s) resulting from hospitalization for 
an elective or previously scheduled surgery that meets serious criteria must be 
reported as an SAE. 
• Results in persistent or significant disability/incapacity 
• Results in a congenital abnormality/birth defect 
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• Is an important medical event. Note: Important medical events that may not result in 
death, be life-threatening, or require hospitalization may be considered an SAE when, 
based upon appropriate medical judgment, they may jeopardize the subject and require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include: 
- 
Bronchospasm associated with anaphylaxis requiring intensive treatment at an 
emergency department or home; blood dyscrasias or convulsions that do not result in 
in-patient hospitalization; or the development of drug dependency or abuse. 
- 
Reviewed and confirmed seroconversion for HIV, hepatitis A virus, hepatitis B virus, 
HCV, hepatitis E virus, or parvovirus B19  
Infusion-related Adverse Event 
An infusion-related AE will be defined as an AE that 1) begins either during or within 12 hours 
after the start of the infusion and 2) is judged as possibly or probably related to the study 
treatment. 
If a subject has an infusion-related AE during the infusion of the study medication, the 
investigator should decide, based on his/her clinical judgment, whether the infusion should be 
slowed or temporarily or permanently discontinued. Infusion-related AEs that occur after the 
infusion should be assessed and treated in a similar manner. 
Subjects experiencing recurrent infusion-related AEs may be premedicated. If infusions continue 
without incident, then tapering of medications may be considered. The investigator and medical 
monitor will evaluate reduction or discontinuation of premedications after the first 3 months of 
treatment. 
For severe infusion-related AEs, the investigator should consult with the medical monitor prior 
to the subject’s next dose to determine the appropriate course of action for future infusions. 
Unexpected Adverse Event 
An unexpected adverse event is an AE that’s nature, severity, specificity, or outcome is not 
consistent with the term, representation, or description used in the reference safety information 
(RSI). “Unexpected” also refers to the AEs that are mentioned in the IB as occurring with a class 
of drugs or as anticipated from the pharmacological properties of the product but are not 
specifically mentioned as occurring with the particular product under investigation.  
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The expectedness of AEs will be determined by the sponsor using the IB as the RSI. This 
determination will include considerations such as the number of AEs previously observed but not 
on the basis of what might be anticipated from the pharmacological properties of a product. 
Suspected Unexpected Serious Adverse Reaction  
A suspected unexpected serious adverse reaction (SUSAR) is defined as any suspected adverse 
reaction to the study treatment that is both serious and unexpected.  
The event must meet all of the following: 
• Suspected adverse reaction 
• Serious 
• Unexpected 
• Assessed as related to the study treatment 
Symptoms of the Disease Under Study 
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected disease progression and are part of the efficacy or 
effectiveness data collected in the study. Significant worsening of symptoms should be recorded 
as an AE. 
Preexisting conditions prior to screening or initiation of study medication are described in the 
medical history and those that manifest with the same severity, frequency, or duration after drug 
exposure are not be recorded as AEs. However, when there is an increase in the severity, 
duration, or frequency of a preexisting condition, the event must be described on the AE eCRF. 
Clinical Laboratory and Other Safety Assessment 
A change in the value of a clinical laboratory parameter, vital sign, or ECG assessment can 
represent an AE if the change is clinically relevant or if, during administration of the 
investigational product, a shift of a parameter is observed from a value in the normal range to a 
value that is outside the normal range and considered clinically significant or a further waning of 
an already clinically significant value. When evaluating such changes, the extent of deviation 
from the reference range; duration until return to the reference range, either while continuing 
administration or after the end of administration with the investigational product; and range of 
variation of the respective parameter within its reference range should also be considered. 
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If, at the end of the treatment period, there are abnormal clinical laboratory (such as hematology 
panel or clinical chemistry panel), vital sign, or ECG values that were not present at baseline, 
further investigations should be performed until the values return to within the reference range or 
until a plausible explanation (eg, concomitant disease or expected disease evolution) is found for 
the abnormal values. 
The investigator should assess, based on the above criteria and clinical condition of the subject, 
whether a change in a clinical laboratory value, vital sign, or ECG parameter is clinically 
significant and represents an AE. 
Appendix 3.2   Collection of Adverse Events 
All AEs/SAEs will be collected from the time the informed consent document is signed until the 
safety follow-up period (Section 8.1.5). This includes events occurring during screening, 
regardless of whether or not the investigational product has been administered.  
All AEs/SAEs must be followed to closure (when 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 is achieved 
(the investigator does not expect any further improvement or worsening of the event), or the 
event is otherwise explained. 
Appendix 3.3   Assessment of Adverse Events 
Severity Categorization 
The severity of AEs must be recorded during the course of the event, including the start and stop 
dates for each change in severity. An event that changes in severity is captured as a new event. 
Worsening medical conditions, signs, or symptoms present prior to the initiation of the 
investigational product must be recorded as new AEs. For example, if a subject reports mild 
intermittent dyspepsia prior to initiation of dosing with the investigational product and the 
dyspepsia becomes severe and more frequent after the first dose, a new AE of severe dyspepsia 
(with the appropriate date of onset) should be documented in the source. 
The medical assessment of severity is determined by using the following definitions: 
• Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living. 
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• Moderate: A type of AE that is usually alleviated with specific therapeutic intervention. 
The event interferes with usual activities of daily living, causing discomfort, but poses no 
significant or permanent risk of harm to the research subject. 
• Severe: A type of AE that interrupts usual activities of daily living, significantly affects 
clinical status, or may require intensive therapeutic intervention. 
Relationship Categorization 
A physician/investigator must make the assessment of the relationship to the investigational 
product for each AE. The investigator should decide whether, in his/her medical judgment, there 
is a reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and occurrence of 
the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source. 
The following additional guidance may be helpful: 
Table A1. Adverse Event Relationship Categorization 
Related 
The temporal relationship between the event and administration of the investigational 
product is compelling enough and/or follows a known or suspected response pattern to that 
product, and the event cannot be explained by the subject’s medical condition, other 
therapies, or an accident. 
Not related 
The event can be readily explained by other factors, such as the subject’s underlying medical 
condition, concomitant therapy, or an accident, and no plausible temporal or biologic 
relationship exists between the investigational product and event. 
Outcome Categorization 
The outcome of AEs must be documented in the source during the course of the study. Outcomes 
are as follows: 
• Fatal 
• Not recovered/not resolved 
• Recovered/Resolved 
• Recovered/Resolved with sequelae 
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• Recovering/Resolving 
• Unknown 
Appendix 3.4   Safety Reporting 
Reference Safety Information 
The RSI for this study is the IB, which the sponsor has provided under separate cover to all 
investigators. 
Reporting Procedures 
The investigator should complete an SAE eCRF in English or report via the paper SAE report 
form (as a backup) within 24 hours of becoming aware of any SAE. It is applicable to all initial 
and follow-up SAE reports. Note: The 24-hour reporting requirement for SAEs does not apply to 
reports of abuse, misuse, overdose, or medication errors (see Appendix 3.9) unless they result in 
an SAE. 
Appendix 3.5   Serious Adverse Event Collection Time Frame 
All SAEs (regardless of the relationship to the investigational product) are collected from the 
time the subject signs the ICF until the safety follow-up period (Section 8.1.5) and must be 
reported to the Takeda Global Patient Safety Evaluation (GPSE) and CRO/Takeda medical 
monitor within 24 hours of the first awareness of the event. 
In addition, any SAE considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Takeda GPSE 
Department within 24 hours of the first awareness of the event. 
Appendix 3.6   Serious Adverse Event Onset and Resolution Dates 
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, date the symptoms resolve, or event is 
considered chronic. In the case of hospitalizations, the hospital admission and discharge dates are 
considered the onset and resolution dates, respectively. 
In addition, any signs or symptoms reported by the subject after signing the ICF, leading up to 
the onset date of the SAE or following the resolution date of the SAE, must be recorded as an 
AE, if appropriate. 
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Appendix 3.7   Fatal Outcome 
Any SAE that results in the subject’s death (eg, the SAE was noted as the primary cause of 
death) must have fatal checked as an outcome, with the date of death recorded as the resolution 
date. For all other events ongoing at the time of death that did not contribute to the subject’s 
death, the outcome should be considered not resolved, without a resolution date recorded. 
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received the investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death. 
Appendix 3.8   Pregnancy 
All pregnancies are reported from the time of signing the ICF until the safety follow-up period 
(Section 8.1.5). 
Any report of pregnancy in any female subject or the female partner of a male subject must be 
reported within 24 hours of the first awareness of the pregnancy to the Takeda GPSE using the 
paper Pregnancy Report Form. The fax number and email address are provided in the Form 
Completion Instruction. 
A copy of the Takeda Pregnancy Report Form (and any applicable follow-up reports) must also 
be sent to the CRO/Takeda medical monitor using the details specified in the emergency contact 
information section of the protocol. The pregnant female subject must be withdrawn from the 
study. 
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days and 1 year 
postpartum. 
Pregnancy complications, such as abortion/miscarriage, or congenital abnormality are considered 
SAEs and must be reported using the same procedure as describing the SAE reporting. 
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the same procedure as describing the SAE reporting, as well 
as the Takeda Pregnancy Report Form. The test date of the first positive serum/urine β-hCG test 
or ultrasound result will determine the pregnancy onset date.  
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Appendix 3.9   Abuse, Misuse, Overdose, and Medication Error 
Abuse, misuse, overdose, or medication error must be reported to the sponsor according to the 
SAE reporting procedure, whether or not they result in an AE/SAE as described in Appendix 3.1.  
Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, misuse, 
overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category. 
• Abuse: Persistent or sporadic intentional intake of the investigational product when used 
for a nonmedical purpose (eg, to alter one’s state of consciousness or get high) in a 
manner that may be detrimental to the individual and/or society 
• Misuse: Intentional use of the investigational product other than as directed or indicated 
at any dose. (Note: This includes a situation where the investigational product is not used 
as directed at the dose prescribed by the protocol.) 
• Overdose: Intentional or unintentional intake of a dose of the investigational product 
higher than the protocol-prescribed dose 
• Medication error: An error made in prescribing, dispensing, administration, and/or use of 
the investigational product. For studies, medication errors are reportable to the sponsor 
only as defined below. 
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors. 
Medication errors should be collected/reported for all products under investigation. 
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error. 
All investigational product provided to pediatric subjects should be supervised by the 
parent/legally authorized representative/caregiver. 
Appendix 3.10   Urgent Safety Measures 
An urgent safety measure is an immediate action taken, which is not defined by the protocol, in 
order to protect subjects participating in a clinical trial from immediate harm; these do not 
constitute de facto deviation from the protocol. Urgent safety measures may be taken by the 
sponsor or clinical investigator and may include any of the following: 
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• Immediate change to the study design or study procedures 
• Temporary or permanent halt of a given clinical trial or trials 
• Any other immediate action taken in order to protect subjects from an immediate hazard 
to their health and safety 
The investigator may implement urgent safety measures to protect subjects from immediate 
hazard to their health or safety. The measures should be implemented immediately and do not 
require prior authorization from the sponsor. In the event of an apparent direct hazard to the 
subject, the investigator will notify the sponsor immediately by phone and confirm notification to 
the sponsor in writing as soon as possible and within 1 calendar day after the change is 
implemented. The sponsor will also ensure the responsible IRB/EC(s) and relevant competent 
authority(s) are notified of the urgent safety measures taken in such cases according to local 
regulations. 
Appendix 3.11   Regulatory Agency, Institutional Review Board, Ethics Committee, and 
Site Reporting 
The sponsor/CRO is responsible for reporting all SUSARs and any other applicable (serious) 
ADRs to regulatory authorities, investigators, and ECs/institutions, as applicable, in accordance 
with safety regulations in the countries where the study is conducted. The sponsor/CRO will also 
prepare an expedited report for other safety issues where these might materially alter the current 
benefit-risk assessment of an investigational product or would be sufficient to consider changes 
to the investigational product administration or overall conduct of the trial. 
In addition, the sponsor is responsible for notifying active sites of all related, unexpected SAEs 
occurring during all interventional studies across the VPRIV program. 
The investigator is responsible for notifying the local IRB/EC of all safety reports or significant 
safety findings that occur at his/her site as required by IRB/EC procedures and applicable safety 
regulations (see Appendix 1.5). 
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Appendix 4 
 CONTRACEPTIVE GUIDANCE  
Female subjects: 
Female subjects of childbearing potential are eligible to participate in the study if they are not 
pregnant or lactating and agree to use a highly effective method of contraception consistently and 
correctly as described in the following table: 
Highly Effective Contraceptive Methods That Are User Dependenta 
With a failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of 
ovulation  
• 
Oral  
• 
Intravaginal  
• 
Transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation: 
• 
Oral  
• 
Injectable  
Highly Effective Contraceptive Methods That Are User Independenta 
Implantable progestogen-only hormonal contraception associated with inhibition of ovulationb: 
• 
Intrauterine device 
• 
Intrauterine hormone-releasing system 
Bilateral tubal occlusion 
Vasectomized partnerc 
Sexual abstinenced 
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for subjects participating in clinical studies.  
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the 
efficacy of the contraceptive method. In this case, 2 highly effective methods of contraception should be 
utilized during the treatment period and for at least 30 days after the last dose of the study treatment. 
c A vasectomized partner is a highly effective contraception method provided that the partner is the sole male 
sexual partner of the female of childbearing potential and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used. 
d Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study treatment. The reliability of sexual 
abstinence needs to be evaluated in relation to the duration of the study and preferred and usual lifestyle of the 
subject. 
 
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Male subjects: 
Male subjects with female partners of childbearing potential are eligible to participate if they 
agree to use one of the following:  
• Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent 
• Agree to use a male condom plus partner use of a contraceptive method with a failure rate 
of <1% per year when having penile-vaginal intercourse with a female of childbearing 
potential who is not currently pregnant 
Male subjects with a pregnant or lactating partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom during each episode of penile-vaginal 
penetration during the protocol-defined time frame (from screening through 30 days after the last 
dose of the investigational product).  
Male subjects must refrain from donating sperm for the duration of the study and for 30 days 
after the last dose of study treatment. 
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Appendix 5 
 SCALES AND ASSESSMENTS 
The following scales/assessments in the Chinese language (ie, validated, Chinese version of QoL 
instruments) will be utilized in this study: 
Full Title of Scale/Assessment 
Age 
Short Form 36 Version 2 
≥18 years 
Child Health Questionnaire-Parent Form 50 
≥5 to <18 years  
A separate master file containing each scale/assessment will be provided to the site. Updates to 
the scales/assessments during the study (if applicable) will be documented in the table above, 
and a new master file containing the revised scale/assessment will be provided to the site. 
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Child Health Questionnaire-Parent Form 50 
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Appendix 6 
 ABBREVIATIONS 
Abbreviation 
Definition 
ADR 
adverse drug reaction 
AE  
adverse event 
AUCinf 
area under the curve from time 0 to infinity 
β-hCG 
β-human chorionic gonadotropin 
CCL18 
chemokine (C-C motif) ligand 18 
CHQ-PF50 
Childhood Health Questionnaire-Parent Form 50 
CL 
clearance 
Cmax 
maximum serum concentration 
CRO 
contract research organization 
CT 
computed tomography  
CV 
coefficient of variation 
EC 
Ethics Committee 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form  
EEG 
electroencephalogram 
EMA 
European Medicines Agency 
EOT 
end of treatment 
EOW 
every other week 
ERT 
enzyme replacement therapy 
EU 
European Union 
FDA 
Food and Drug Administration  
GCB 
glucocerebrosidase 
GCP 
Good Clinical Practice 
GPSE 
Global Patient Safety Evaluation 
HBsAg 
hepatitis B surface antigen 
HCV 
hepatitis C virus 
IB 
investigator’s brochure 
ICF 
informed consent form 
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Abbreviation 
Definition 
ICH 
International Council for Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human 
Use 
Ig 
immunoglobulin 
IRB 
Institutional Review Board 
IRR 
infusion-related reaction 
IRT 
interactive response technology 
ITT 
intent-to-treat 
IV 
intravenous(ly)  
lyso-Gb1 
glucosylsphingosine 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
PK 
pharmacokinetic(s) 
PP 
per-protocol 
PT 
preferred term 
QoL 
quality of life 
Q1 
first quartile 
Q3 
third quartile 
RSI 
reference safety information 
SAE 
serious adverse event  
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
system organ class 
SUSAR 
suspected unexpected serious adverse reaction 
T1/2 
half-life 
TEAE 
treatment-emergent adverse event 
Tmax 
time to maximum concentration 
US 
United States 
VPRIV 
velaglucerase alfa 
Vss 
apparent steady-state volume of distribution  
 
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Appendix 7 
 PROTOCOL HISTORY  
Document 
Date 
Global/Country/Site Specific 
Original Protocol 
22 Nov 2021 
China 
Protocol Amendment 1 
02 Aug 2022 
China 
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SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN 
Study Number:  TAK-669-3001 
Study Title:  A Multicenter, Open-Label Study to Evaluate the Safety, Efficacy and 
Pharmacokinetics of Velaglucerase alfa in Chinese Subjects With Type I Gaucher Disease 
Phase:  3b 
Version:  3.0 
Date:  13-Sep-2024 
Prepared by:  
 
Based on: 
Protocol Version:  Protocol Amendment 1 
Protocol Date:  02-Aug-2022 
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. 
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Statistical Analysis Plan Final 
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CONFIDENTIAL 
REVISION HISTORY 
Version  
Approval Date 
Primary Rationale for Revision 
Original version 
03-Oct-2022 
Not Applicable 
Version 2.0 
26-Apr-2024 
Update for analysis clarifications and additions. 
Version 3.0 
13-Sep-2024 
Update for clarifications and additions, see section 9.1. 
 
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CONFIDENTIAL 
TABLE OF CONTENTS 
1.0 
OBJECTIVES, ENDPOINTS AND ESTIMANDS ............................................................8 
1.1 
Objectives ......................................................................................................................8 
1.1.1 
Primary Objective ..................................................................................................8 
1.1.2 
Secondary Objective(s) .........................................................................................8 
1.1.3 
Additional Objective(s) .........................................................................................8 
1.2 
Endpoints .......................................................................................................................8 
1.2.1 
Primary Endpoint(s) ..............................................................................................8 
1.2.2 
Secondary Endpoint(s) ..........................................................................................9 
1.2.2.1 
Key Secondary Endpoints(s) .........................................................................9 
1.2.2.2 
Other Secondary Endpoint(s) ......................................................................10 
1.2.3 
Exploratory Endpoint(s) ......................................................................................10 
1.2.4 
Safety Endpoints ..................................................................................................10 
1.2.5 
Other Endpoints ...................................................................................................11 
1.3 
Estimands .....................................................................................................................11 
2.0 
STUDY DESIGN...............................................................................................................11 
3.0 
STATISTICAL HYPOTHESES AND DECISION RULES .............................................12 
3.1 
Statistical Hypotheses ..................................................................................................12 
3.2 
Statistical Decision Rules ............................................................................................12 
3.3 
Multiplicity Adjustment ...............................................................................................12 
4.0 
SAMPLE-SIZE DETERMINATION ................................................................................12 
5.0 
ANALYSIS SETS .............................................................................................................12 
5.1 
Intent-to-Treat Set ........................................................................................................12 
5.2 
Per-Protocol Analysis Set ............................................................................................12 
5.3 
Safety Analysis Set ......................................................................................................12 
5.4 
Pharmacokinetic Set.....................................................................................................13 
6.0 
STATISTICAL ANALYSIS .............................................................................................13 
6.1 
General Considerations ................................................................................................13 
6.1.1 
Handling of Treatment Misallocations ................................................................13 
6.1.2 
Analysis Approach for Continuous Variables .....................................................13 
6.1.3 
Analysis Approach for Binary Variables ............................................................13 
6.1.4 
Analysis Approach for Time-to-Event Variables ................................................14 
6.2 
Disposition of Subjects ................................................................................................14 
6.3 
Demographic and Other Baseline Characteristics .......................................................14 
6.3.1 
Demographics ......................................................................................................14 
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6.3.2 
Medical History and Concurrent Medical Conditions .........................................14 
6.3.3 
Baseline Characteristics .......................................................................................14 
6.4 
Medication History and Concomitant Medications .....................................................15 
6.4.1 
Prior Medications ................................................................................................15 
6.4.2 
Concomitant Medications ....................................................................................15 
6.5 
Efficacy Analysis .........................................................................................................15 
6.5.1 
Primary Endpoint(s) Analysis .............................................................................15 
6.5.1.1 
Derivation of Endpoint(s) ...........................................................................15 
6.5.1.2 
Main Analytical Approach ..........................................................................15 
6.5.1.3 
Sensitivity Analysis .....................................................................................15 
6.5.1.4 
Supplementary Analyses .............................................................................16 
6.5.2 
Secondary Endpoint(s) Analysis .........................................................................16 
6.5.2.1 
Key Secondary Endpoint(s) Analysis (if applicable) ..................................16 
6.5.2.2 
Derivation of Endpoint(s) ...........................................................................16 
6.5.2.3 
Main Analytical Approach ..........................................................................16 
6.5.2.4 
Sensitivity Analysis .....................................................................................16 
6.5.2.5 
Supplementary Analyses .............................................................................17 
6.5.3 
Other Secondary Endpoints Analysis (if applicable) ..........................................17 
6.5.4 
Subgroup Analyses (if applicable) ......................................................................17 
6.6 
Safety Analysis ............................................................................................................17 
6.6.1 
Adverse Events ....................................................................................................17 
6.6.2 
Adverse Events of Special Interest (if applicable) ..............................................18 
6.6.3 
Other Safety Analysis (if applicable) ..................................................................18 
6.6.4 
Extent of Exposure and Compliance ...................................................................20 
6.7 
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses .................................21 
6.7.1 
Pharmacokinetic Analysis ...................................................................................21 
6.7.2 
Pharmacodynamic Analysis ................................................................................22 
6.7.3 
Biomarker Analysis .............................................................................................22 
6.8 
Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints 
Analysis........................................................................................................................22 
6.8.1 
PRO Analysis ......................................................................................................22 
6.8.2 
Health Care Utilization Analysis .........................................................................23 
6.9 
Other Analyses .............................................................................................................23 
6.10 
Interim Analyses ..........................................................................................................23 
6.11 
Data Monitoring Committee/Internal Review Committee/ [Other Data Review 
Committees] .................................................................................................................23 
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7.0 
REFERENCES ..................................................................................................................23 
8.0 
CHANGES TO PROTOCOL PLANNED ANALYSES ...................................................23 
9.0 
APPENDIX ........................................................................................................................23 
9.1 
Changes From the Previous Version of the SAP .........................................................23 
9.2 
Data Handling Conventions .........................................................................................24 
9.2.1 
General Data Reporting Conventions ..................................................................24 
9.2.2 
Imputation of missing dates .................................................................................24 
9.2.3 
Definition of Baseline ..........................................................................................24 
9.2.4 
Definition of Visit Windows ...............................................................................25 
9.3 
Analysis Software ........................................................................................................25 
 
 
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ABBREVIATIONS 
 
ADA 
antidrug antibody 
AE 
adverse event 
AESI 
adverse event of special interest 
AUC 
area under the curve 
BMI 
body mass index 
CHQ-PF50 
Childhood Health Questionnaire-Parent Form 50  
CI 
confidence interval 
eCRF 
electronic case report form 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EOT 
end-of-treatment 
EOW 
every other week 
ERT 
enzyme replacement therapy 
ICF 
informed consent form 
IRR 
infusion-related reaction 
ITT 
intention-to-treat 
IV 
intravenous 
MedDRA 
Medical Dictionary for Regulatory Activities 
Nab 
neutralizing antibody 
PK 
pharmacokinetic 
PP 
per-protocol  
PRO 
patient-reported outcomes 
PT 
Preferred Term (MedDRA) 
Q1 
25th percentile 
Q3 
75th percentile 
QoL 
quality of life 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
System Organ Class 
SD 
standard deviation 
SF-36 
Short Form-36 
TEAE  
treatment-emergent adverse event 
 
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1.0 
OBJECTIVES, ENDPOINTS AND ESTIMANDS 
1.1 
Objectives 
1.1.1 
Primary Objective 
The primary objective of the study is to evaluate the safety of VPRIV by assessing the incidence 
of serious treatment-emergent AEs (TEAEs) when administered every other week (EOW) up to 
51 weeks by intravenous (IV) infusion to Chinese subjects with type 1 Gaucher disease. 
1.1.2 
Secondary Objective(s) 
The secondary objectives of the study are to assess:  
 
Other safety parameters of VPRIV (including the incidence of TEAEs and infusion-related 
reactions (IRRs) and rate of antibody formation)  
 
The effect of VPRIV on hematologic manifestations  
 
The effect of VPRIV on the liver and spleen volume  
 
The effect of VPRIV on quality of life (QoL)  
 
The PK of VPRIV  
 
The effect of VPRIV on disease biomarkers  
1.1.3 
Additional Objective(s) 
Not applicable. 
1.2 
Endpoints 
1.2.1 
Primary Endpoint(s) 
 
Primary objective 
Primary Endpoint 
 
 
To evaluate the safety of VPRIV by 
assessing the incidence of serious TEAEs  
 
 
 
Incidence 
rate 
of 
serious 
TEAEs 
throughout the study  
 
 
 
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6.1.4 
Analysis Approach for Time-to-Event Variables 
Not applicable. 
6.2 
Disposition of Subjects 
The number of subjects enrolled, completing, or withdrawing from the study, along with the 
reasons for withdrawal, will be tabulated for the ITT Set. 
Protocol deviations will be summarized for the ITT set, as well as listed for each subject. 
6.3 
Demographic and Other Baseline Characteristics 
6.3.1 
Demographics 
Baseline and demographic variables will be descriptively summarized by age groups for the ITT 
Set. 
Demographic and Baseline characteristics will be summarized using either descriptive statistics 
or frequency distributions, as appropriate.  
The following baseline demographics will be summarized:  
 
age (years) at Informed Consent 
 
weight (kg) and height (cm)  
 
BMI (kg/m2) 
 
Sex 
 
Hemoglobin (g/dL) 
 
Platelet count (x109/L) 
 
Normalized liver size (as %BW) 
 
Normalized spleen size (as %BW) 
 
6.3.2 
Medical History and Concurrent Medical Conditions 
Medical history will be coded using the most recent version of the Medical Dictionary for 
Regulatory Activities (MedDRA) and summarized by system organ class (SOC) and preferred 
term (PT) for the ITT Set. 
6.3.3 
Baseline Characteristics 
Refer to Section 6.3.1. 
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6.4 
Medication History and Concomitant Medications  
6.4.1 
Prior Medications 
All non-study treatment including, but not limited to, herbal treatments, vitamins, behavioral 
treatment, or nonpharmacological treatment, such as psychotherapy, received within the 30 days 
prior to signing ICF through the end of the safety follow-up period must be recorded in the 
 For the subjects who have not 
been treated for Gaucher disease within the 12 months prior to screening, verification for 
treatment will be conducted; for the subjects who have received Imiglucerase ERT within the 12 
months prior to screening, the dose and frequency must be recorded. 
Prior treatment (medication or procedure) refers to all treatments (medications or procedures) 
received and discontinued prior to signing the ICF. 
Prior medication will be listed by subject for the Safety Set. 
6.4.2 
Concomitant Medications 
Concomitant treatment refers to all treatment received between the date of signing the ICF and 
the end of the safety follow-up period, inclusive.  Concomitant treatment information must be 
CRF page. 
The number and percentage of subjects who reported use of at least one concomitant medication 
will be summarized by Therapeutic Class and Preferred Term (Concomitant medications will be 
mapped using the most recent WHO-Drug Dictionary version). 
Concomitant medication will be summarized and listed by subject for the Safety Set. 
Prior and concomitant treatment (medication or procedure) refers to all treatments (medications 
or procedures) received prior to signing the ICF, and continued to be taken during the study 
period, that is, after signing the ICF. 
6.5 
Efficacy Analysis 
6.5.1 
Primary Endpoint(s) Analysis 
6.5.1.1 
Derivation of Endpoint(s) 
The primary analysis will be the incidence of serious TEAEs and is discussed in Section 6.6 
below. 
6.5.1.2 
Main Analytical Approach 
Not applicable. 
6.5.1.3 
Sensitivity Analysis 
Not applicable. 
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6.5.1.4 
Supplementary Analyses 
Not applicable. 
6.5.2 
Secondary Endpoint(s) Analysis 
Efficacy analysis 
The observed values, the change from baseline, the change over time, and the percentage change 
from baseline for the efficacy measurements (hemoglobin, platelet count, liver and spleen size), 
will be summarized by visit and sex for the ITT set.  
Additionally, the observed values, the change from baseline and the percentage change from 
baseline in multiples of normal (MN) for liver and spleen volume will be summarized by visit 
and sex for the ITT set. 
If applicable, mean (±SE) efficacy measurements (hemoglobin, platelet count, liver and spleen 
size) will be plotted by visit for the ITT set. 
6.5.2.1 
Key Secondary Endpoint(s) Analysis (if applicable) 
No secondary endpoint has been identified as key. 
6.5.2.2 
Derivation of Endpoint(s) 
BMI will be derived as follows: 
BMI (kg/m2) = weight (kg) / [height (m)] 2. 
 
Normalized liver and spleen volumes (as percentage of body weight) will be derived as follows: 
Normalized liver/spleen volume (%BW) = [liver/spleen size (mL) / body weight (g)] * 100. 
 
The multiples of normal for spleen volume is given by 
Spleen volume (MN) = spleen volume (cm3) / [2* 
]. 
 
The multiples of normal for liver volume is given by  
Liver volume (MN) = liver volume (cm3) / [25* 
]. 
6.5.2.3 
Main Analytical Approach 
Not applicable. 
6.5.2.4 
Sensitivity Analysis 
Not applicable. 
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6.5.2.5 
Supplementary Analyses 
Not applicable. 
6.5.3 
Other Secondary Endpoints Analysis (if applicable) 
Not applicable. 
6.5.4 
Subgroup Analyses (if applicable) 
Efficacy analyses will be analyzed by age group (<18 [<12 / 12 to <18] 
informed 
consent) and sex.  Treatment naïve subjects (at enrolment) and subjects who switched from 
Imiglucerase will also be summarized separately. 
6.6 
Safety Analysis 
The primary analysis will be the incidence of serious TEAEs. 
A TEAE is defined as any event emerging or manifesting at or after the initiation of the 
investigational product or any existing event that worsens in either intensity or frequency 
following exposure to the investigational product. 
Serious adverse events will be coded using the most recent version of Medical Dictionary for 
Regulatory Activities (MedDRA) coding dictionary.  Serious treatment-emergent adverse events 
(TEAEs) will be summarized for overall and by system organ class (SOC) and preferred term 
(PT).  Furthermore, serious TEAEs will be summarized by maximum severity, by age groups 
and by relationship to investigational product.   
Analysis of AEs will be performed at both subject level and AE level.   
Subjects will be counted once per SOC and once per PT.  Multiple events of the same type will 
be combined for each subject and, when doing this, the worst severity or outcome for each event 
type will be presented for the analysis.  When calculating event rates, the denominator will be the 
total population size, irrespective of dropouts over the course of follow-up.  
The Safety Set will be used. 
6.6.1 
Adverse Events 
Secondary safety analysis 
The secondary safety analyses will be based on the Safety Set. 
Adverse events will be coded using the most recent version of Medical Dictionary for Regulatory 
Activities (MedDRA) coding dictionary.    Treatment-emergent adverse events (TEAEs) will be 
summarized for overall and by system organ class (SOC) and preferred term (PT).  Analysis of 
AEs will be performed at both subject level and AE level, i.e., summarized by number (%) of 
subjects who reported at least one AE, as well as the number of AEs reported.  Similar displays 
will be provided for IRRs.   
An IRR will be defined as an AE that  
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1) begins either during or within 12 hours after the start of the infusion, and  
2) is judged as related to study drug.   
The AEs will be summarized by severity, seriousness, age groups, and relation to investigational 
product.  
Subjects will be counted once per SOC and once per PT.  Multiple events of the same type will 
be combined for each subject and, when doing this, the worst severity or outcome for each event 
type will be presented for the analysis. When calculating event rates, the denominator will be the 
total population size, irrespective of dropouts over the course of follow-up. 
All fatal AEs will be listed by subject.   
6.6.2 
Adverse Events of Special Interest (if applicable) 
Infusion-related reactions (IRRs) will be summarized in a similar fashion than overall TEAEs  
see Section 6.6.1 above.  An additional summary table will be provided for the potential 
relationship between IRRs and anti-VPRIV antibody status.  This summary table will include the 
specific IRR, the outcome of the IRR, and the antibody status (positive / negative).  This 
summary will be done at a visit level (i.e., at Week 13, 25 and 37) where infusions and antibody 
samples collected are done at the same visit. 
6.6.3 
Other Safety Analysis (if applicable) 
Tabular summaries of other safety parameters (eg, vital signs, blood tests, concomitant 
treatments [coded using WHODrug Global], anti-VPRIV antibody status, and infusion 
information) will be produced at baseline and, if applicable, for each postbaseline evaluation 
visit.  
Changes in the results of physical examinations from baseline will be presented by visit and 
body system in the form of a shift table.  
The observed values and change from baseline for ECG parameters (PR, QRS, QT, and 
corrected QT intervals and heart rate) will be summarized by visit.  The number of subjects with 
normal and abnormal ECG results during the study will be summarized by visit in the form of a 
shift table.  
Laboratory data will be listed by subject.  Subjects with newly occurring abnormalities outside 
the normal range will be flagged, listed separately, and summarized.  The mean change from 
baseline in laboratory values or a shift table will be provided for each visit.  The change from 
baseline will be calculated by subtracting the baseline value from the postbaseline value. If 
needed, the white blood cell differential count will be calculated by multiplying the white blood 
cell count by the percentage of each type of white cell. 
Vital sign data will be listed by subject, and any newly occurring changes outside the reference 
range from baseline will be flagged.  The mean changes from baseline for vital sign data will be 
summarized.  Subjects with notable abnormal values will be identified and listed separately 
along with their values. 
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 Persistent positive:  the duration between first and last post-treatment positive > 16 weeks.  
The last post-treatment will be the last time point tested and the result of last time point 
tested should be positive. 
 Persistent positive:  This also include only if the last time point tested positive, regardless 
of outcome of previous tests. 
 Transient positive:  at least one post-treatment positive, but last time point tested is 
negative 
 Transient positive:  exclude the subjects that fulfilled the condition of persistent positive. 
 
Safety data will be analyzed using the Safety Set.  Safety data will be analyzed separately for 
subjects who previously received Imiglucerase ERT and treatment-naive populations, as well as 
pooled. 
Immunology data will be listed for each subject, using the Safety Set. 
6.6.4 
Extent of Exposure and Compliance 
Treatment compliance and exposure summaries will be presented.  For each subject, the 
infusion at each infusion visit, will be calculated as follows for up to 51 weeks: 
 
Compliance = [(Number of Complete Infusions Received) / (Expected Number of 
Infusions)]*100 
 
Note:  Expected number of infusions is defined as the number of infusions that the subject would 
ompletion from the study. 
The number and percentage of subjects who received 
80% of scheduled infusions (not 
including partial infusions) will be reported.  In addition, the total number of missed infusions 
will be categorized as 0, 1, 2 to 5, and >5 and summarized by n and the percentage in each 
category.  The number of subjects with missed infusions will also be summarized. 
The duration (in weeks) of drug exposure to VPRIV will be calculated as follows: 
 
Exposure (weeks) = [(Date of the last dose  Date of first dose) + 1]/7 
 
The exposure data and the total number of infusions received will be summarized by descriptive 
statistics.  The actual dose and per protocol dose amount (U/kg) are defined as the weight 
adjusted actual dose.  For actual dose amount, weight is the last available measurement on or 
prior to each infusion date.  The per-protocol dose amount for naïve subjects is 60 U/kg.  The 
actual and per protocol dose amounts (U/kg) and durations of infusion (minutes) will be 
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averaged across the non-missing infusions for each subject and then summarized by the 
descriptive statistics across all subjects.  All exposure data will be presented in a by-subject 
listing. 
For subjects who received Imiglucerase ERT within the 12 months prior to screening, the initial 
dose will be determined by the investigator after discussing with the sponsor and recording in 
appropriate document based on the subject s specific treatment and the situation at the time of 
enrollment, according to the subject s benefit and risk assessment. 
Duration of infusion (minutes) will be derived as follows: 
 
Duration (min) = infusion stop time  infusion start time. 
 
6.7 
Pharmacokinetic, Pharmacodynamic, and Biomarker Analyses 
6.7.1 
Pharmacokinetic Analysis 
Individual pharmacokinetic concentrations will be listed and summarized for the PK Analysis 
Set by age (e.g., 
18 years vs 12 through 17 years vs 4 through 11 years), visit and scheduled 
time points for naive subjects with PK assessments with descriptive statistics (number, arithmetic 
mean, SD, coefficient of variation [CV], median, minimum, maximum, geometric mean, and CV 
[95% CI] of the geometric mean). Individual concentration-time profiles of VPRIV will be 
generated based on actual time, and mean (± SD) concentration-time profiles of VPRIV will be 
generated based on scheduled time. 
Pharmacokinetic parameter estimates will be computed with Phoenix® WinNonlin® software 
Version 8.3 using noncompartmental methods from individual serum-concentration time data 
and actual times and dosing, where appropriate. 
PK parameters include, but are not limited to, the following:  
 
Cmax:  Maximum concentration observed  
 
Tmax (min):  Time of maximum observed concentration sampled post-dose  
 
AUCinf (ng min/mL):  Area under the concentration-time curve from time zero 
extrapolated to infinity  
 
T1/2 (min):  Terminal elimination half-life, defined as the natural log of 2 divided by the 
terminal rate constant ( z)  
 
CL (mL/min/kg):  Total body clearance of the drug from serum, normalized for body 
weight  
 
Vss (mL/kg):  Volume of distribution at steady state, normalized for body weight 
Individual PK parameters of VPRIV at Week 1 will be listed and summarized for the PK 
Analysis Set by treatment as well as by age group, with descriptive statistics (number, arithmetic 
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mean, SD, coefficient of variation [CV], median, minimum, maximum, geometric mean, and CV 
and 95% CI of the geometric mean).   
6.7.2 
Pharmacodynamic Analysis 
Not applicable. 
6.7.3 
Biomarker Analysis 
The observed values, the change from baseline, the change over time, and the percentage change 
from baseline for biomarkers will be summarized by visit.  Furthermore, the percentage change 
from baseline for biomarker will be summarized by anti-VPRIV antibody status at Week 13, 25, 
37 and 53.  These will be shown for the ITT set.  A by-subject listing will also be provided for 
the ITT set. 
If applicable, individual biomarker measurements and the percentage change from baseline will 
be plotted by visit for the ITT set. 
6.8 
Patient Reported Outcomes (PROs) and Health Care Utilization Endpoints 
Analysis 
6.8.1 
PRO Analysis 
The change over time in subject rating of QoL will be analyzed using the SF-36v2 for subjects 
-PF50 for subjects 
5 and <18 years of age.  Quality of life 
assessments are not applicable for subjects <5 years of age. 
The SF-36v2 comprises 36 items across eight domains (subscales).  The eight SF-36v2 subscales 
will be aggregated using weight to calculate Physical Component Summary (PCS) and Mental 
Component Summary (MCS) scores.  The CHQ-PF50 consists of 50 items on 14 unique 
concepts to measure physical vs. psychosocial aspects of general health.  The domains can be 
further combined to derive overall physical and psychosocial scores:  the Physical Component 
Summary and Psychosocial Component Summary scores. 
Following the scoring instructions of the instruments, the scale item scores for the SF-36v2 and 
CHQ-PF50 will be summed and directly transformed into a 0-100 scale, with a mean of 50 and 
SD of 10, on the assumption that each item carries equal weight.  The higher the scale score, the 
better the health state (i.e., a score of 0 is equivalent to worst possible health state and a score of 
100 is equivalent to best possible health).  Some specific items will be re-coded to ensure that all 
items are positively scored and that higher scores indicate better health.  
Descriptive summary statistics will be produced for the overall component summary scores and 
(if available) any subscale score of SF-36v2 and CHQ-PF50, respectively, by presenting the 
mean, SD, median, Q1, Q3, minimum, and maximum at each time point and also the score 
change from baseline to Week 53. All available QoL assessments will be used in summary. 
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6.8.2 
Health Care Utilization Analysis 
Not applicable. 
6.9 
Other Analyses 
Further by-subject listings will be provided for pregnancy tests (female subjects), and 
electroencephalogram, using the Safety Set. 
6.10 
Interim Analyses 
Not applicable. 
6.11 
Data Monitoring Committee/Internal Review Committee/ [Other Data Review 
Committees] 
Not applicable. 
7.0 
REFERENCES 
Not applicable. 
8.0 
CHANGES TO PROTOCOL PLANNED ANALYSES 
Not applicable. 
9.0 
APPENDIX  
9.1 
Changes From the Previous Version of the SAP 
 
SAP Section  
Impacted Text (shown in 
bold) 
Change  
Rationale for Change 
6.5.2 Secondary 
Endpoint(s) Analysis 
 
Add multiples of normal 
(MN) for hepatomegaly 
and splenomegaly 
summary. 
Update. 
6.5.2.2 Derivation of 
Endpoint(s) 
 
Add the multiples of 
normal calculation 
formula. 
Update. 
6.6.1 Adverse Events 
begins either during or 
within 24 hours after the 
start of the infusion, and 
Update IRR definition. 
Keep consistent with 
protocol. 
6.6.3 Other Safety 
Analysis 
 
Update vital sign 
parameter normal ranges. 
Update. 
 
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9.2 
Data Handling Conventions   
9.2.1 
General Data Reporting Conventions  
Means and medians (and Q1/Q3) will be presented to 1 more decimal place than the recorded 
data.  The standard deviations (SDs) will be presented to 2 more decimal places than the 
recorded data.  CIs intervals will be presented using the same number of decimal places as the 
parameter estimate. 
For categorical variables, the count (n) and percent (%) will be displayed.  Unless otherwise 
stated in table shells, the denominator for percentages is N (the number of subjects in the 
treatment group within that analysis set). For any summary by subgroups (e.g. by sex), the 
denominator is the number of subjects in that subgroup/treatment group within that analysis set.  
Percentages will be reported to 1 decimal place, except when the percentage equals exactly 100 
where it will be displayed as an integer (100).  For zero, only count and no percentage will be 
displayed.  
For summaries of categorical variables percentages are usually based on N as stated above. 
However, if missing is not a category then the denominator is the number of subjects with non-
missing values. Any exceptions to the denominator should be explained in the footnotes. 
9.2.2 
Imputation of missing dates 
Any date that is collected only as MONTH / YEAR, e.g, date of birth, the 15th of the month will 
be imputed. 
If AE start date is partial, the following imputation will be done: 
 If day is missing, impute 1st of the month 
 If day and month are missing, impute 01 July.  However, this should be checked not to be 
later than the AE stop date.  If AE stop date is available, the 1st of the month of the AE 
stop month should be imputed. 
If AE stop date is partial, the following imputation will be done: 
 If day is missing, impute end of the month (30th or 31st) 
 If day and month are missing, impute 31 Dec. 
The same rules above (for AE date imputation) will be followed for medical history and prior / 
concomitant medications. 
9.2.3 
Definition of Baseline  
Baseline will be defined as the data collected prior to or on the first administration of study drug 
(for measurements on the same day as first dose, but with no time collected, it will be assumed as 
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prior to first dose).  If the value prior to first administration is not available, the screening value 
will be used. 
9.2.4 
Definition of Visit Windows  
For the efficacy analysis, we will take the closest scheduled visit week as the visit week for the 
unscheduled visit. The assessment result from the unscheduled visit will be used to replace the 
missing result for that visit week.   If both unscheduled and scheduled visits exist for the same 
visit, then the scheduled visit will be used. 
9.3 
Analysis Software  
All statistical analyses will be performed using SAS® (SAS Institute, Cary, NC 27513) version 
9.4 or higher. 
 
 
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