VPRIV Drug Use-Result Survey (Japan)
Conditions: Gaucher Disease
Sponsor: Takeda

Clinical Study Protocol 
NCT Number: NCT03625882 
Title: Drug Use-results Survey for VPRIV® for I.V. Infusion 400 Units 
Study Number: SHP-GCB-401 
Document Version and Date: Amendment 9 / 15-Sep-2023 
Certain information within this document has been redacted (ie, specific content is 
masked irreversibly from view) to protect either personally identifiable information or 
company confidential information. 

Reexamination 
VPRIV 
Protocol of use-result survey  
Takeda Pharmacutical Company Limited 
Amendment 9 
Document Date: 15 September 2023 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

VPRIV® (velaglucerase alfa) 
Clinical Study SHP-GCB-401 Protocol Amendment 9 
15 September 2023 
Takeda 
2 
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................. 2 
1 
PURPOSE OF THE SURVEY .................................................................................................. 3 
2 
ESTIMATED NUMBER OF PATIENTS AND RATIONALE ............................................... 3 
2.1 
Target Number of Cases and Rationale ............................................................................. 3 
3 
TARGET PATIENT POPULATION ........................................................................................ 3 
4 
PLANNED NUMBER OF CENTERS (DEPARTMENTS) WHICH WILL TAKE PART IN 
THE SURVEY............................................................................................................................ 3 
5 
SURVEYING METHOD .......................................................................................................... 3 
6 
ESTIMATED DURATION OF THE SURVEY ....................................................................... 4 
7 
WHAT IS INVESTIGATED IN THE SURVEY ...................................................................... 4 
7.1 
Items for Investigation....................................................................................................... 4 
7.2 
Important Items for Investigation ...................................................................................... 6 
8 
ITEMS FOR ANALYSIS AND THE ANALYSIS METHOD ................................................ 7 
9 
ORGANIZATION FOR IMPLEMENTING THE SURVEY ................................................... 8 
10   OUTSOURCE DETAILS .......................................................................................................... 8 
11   ADDITIONAL MEASURES WHICH MAY BE TAKEN DEPENDING ON THE 
OUTCOME OF THE SURVEY AND THE DECISION CRITERIA FOR INITIATING THE 
MEASURES ............................................................................................................................... 8 
12   MILESTONES FOR THE IMPLEMENTATION OF THE SURVEY AND THE 
ASSESSMENT OF THE RESULTS, OR REPORTING TO THE PMDA, AND THE 
JUSTIFICATION ....................................................................................................................... 8 
13   OTHER NECESSARY ITEMS ................................................................................................. 8 
14   SUMMARY OF CHANGES ................................................................................................... 10 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

VPRIV® (velaglucerase alfa) 
Clinical Study SHP-GCB-401 Protocol Amendment 9 
15 September 2023 
Takeda 
3 
1 PURPOSE OF THE SURVEY 
The objectives of this survey are to collect data to evaluate the safety and efficacy of 
velaglucerase alfa (VPRIV) in the post-marketing phase in patients with Gaucher disease who 
are new to therapy or have been switched from another therapeutic agent for Gaucher disease. 
Data will be collected to address the following specifications: 
•
Incidence of infusion reactions [Preferred Term (PT): Infusion-related reaction]
•
Lack of safety data in treatment-naïve Japanese patients
•
Limited safety data for patients with type 2 and 3 Gaucher disease
•
Additional long term efficacy data in Japanese patients
•
Limited safety data of Japanese pediatric patients
•
Lack of safety data of Japanese elderly patients
2 ESTIMATED NUMBER OF PATIENTS AND RATIONALE 
2.1 
Target Number of Cases and Rationale 
Target number of cases: All patients treated with this product. 
Rationale: We plan to enroll all patients who start VPRIV treatment or transition from VPRIV 
clinical studies during the enrollment period of the DURS. Considering the estimated number of 
patients with Gaucher disease in Japan, 30 patients is a reasonable estimate of the patients who 
would be available for enrollment. 
3 TARGET PATIENT POPULATION 
Patients of any age or gender with confirmed diagnosis of Gaucher disease (types 1, 2, or 3) who 
are either naïve to treatment or patients that have been treated with another therapeutic agent for 
Gaucher disease. 
The scope of patients is defined as patients who are treated with VPRIV. 
4 PLANNED NUMBER OF CENTERS (DEPARTMENTS) WHICH WILL TAKE 
PART IN THE SURVEY 
All treatment centers are in the scope of the survey. 
5 SURVEYING METHOD 
Survey methods employ a central enrollment system. The following steps will be completed: 
1) Request Informed Consent. The purpose is to obtain and document permission from the
patient for the use of patient data by the Sponsor company and other agencies. The informed
consent process involves both a conversation between the patient and the site staff and the
signing of the informed consent form to document the procedure.
2) Conduct patient registration by completing the patient registration form.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

VPRIV® (velaglucerase alfa) 
Clinical Study SHP-GCB-401 Protocol Amendment 9 
15 September 2023 
Takeda 
4 
3) Conduct the assessments, as described in Section 7 and complete relevant case report forms
(CRFs).
6 ESTIMATED DURATION OF THE SURVEY 
Eight years after launch. Please see below for details regarding the specific period durations: 
Enrollment period: Launch date to December 2021 (until nine months before the scheduled 
completion of observation period. 
Observation period: Launch date to September 2022 (until 8 years after launch)  
Survey Completion date (Estimated completion date of Statistical Analysis): January 2024 (plan) 
The maximum observation period in this survey for an individual patient is 8 years. 
7 WHAT IS INVESTIGATED IN THE SURVEY 
Safety and efficacy data that are available as part of routine clinical practices related to Gaucher 
disease and the treatment with VPRIV will be collected. 
7.1 
Items for Investigation 
a.
Information for patient identification
•
Patient initials
•
Information that can identify the specific patient (e.g., Medical Record Number)
b. Patient background
•
Date of birth
•
Sex
•
Race
•
Diagnosis information including time point of definitive diagnosis of Gaucher disease, type
of Gaucher disease, and method of Gaucher disease diagnosis including enzyme activity
measurement.
•
Genotype
•
Height
•
Weight
•
Family history of Gaucher disease
•
Clinical symptoms of Gaucher disease
•
Complications not related to Gaucher disease
•
Past medical and allergic history
•
Prior treatments for Gaucher disease (other therapeutic agents, splenectomy, others).
c.
Administration status
Details to be collected for each administration: 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

VPRIV® (velaglucerase alfa) 
Clinical Study SHP-GCB-401 Protocol Amendment 9 
15 September 2023 
Takeda 
5 
•
Date of administration, time of infusion, dosage, body weight
•
Rationale of selected dosage
•
Whether pretreatment is used for the prevention or management of infusion reactions
•
Status of administration: completed infusion or discontinuation (in the case of
discontinuation, the date of the last infusion and the reason for discontinuation)
d. Concomitant therapy
•
Presence or absence of concomitant therapy
•
Names of concomitant drugs, administration route, start date, continuous use/end date,
indication/purpose of use
e.
Safety
Collected safety assessments include all adverse events (AEs) occurring following initiation of 
treatment with VPRIV regardless of the seriousness or relationship to VPRIV, and 
absence/presence of anti-velaglucerase antibodies. Please note the following definitions related 
to safety information: 
Adverse event: An adverse event is any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with 
the use of a medicinal product, whether or not considered related to the medicinal product. 
Adverse reaction: An adverse reaction is an untoward medical occurrence in a patient 
administered a pharmaceutical product and which does not necessarily have to have a causal 
relationship with this treatment. 
Seriousness criteria: An adverse reaction or adverse event is a serious adverse reaction or 
serious adverse event, respectively, if the reaction or event results in any of the following 
seriousness criteria: 
•
results in death
•
life-threatening (NOTE: The term “life-threatening” in the definition of “serious” refers to
an event/reaction in which the patient was at risk of death at the time of the event/reaction;
it does not refer to an event/ reaction which hypothetically might have caused death if it
were more severe)
•
requires inpatient hospitalization or results in prolongation of existing hospitalization
•
results in persistent or significant disability/incapacity
•
a congenital anomaly/birth defect
•
a medically important event or reaction
Causal Relationship: The relationship between VPRIV and the adverse event may be 
categorized as follows: 
•
Not Related
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

VPRIV® (velaglucerase alfa) 
Clinical Study SHP-GCB-401 Protocol Amendment 9 
15 September 2023 
Takeda 
6 
•
Possibly Related
•
Probably Related
•
Definitely Related
Laboratory assessment may include; RBC, Hb, Ht, WBC, PLT, Total protein, AST, ALT, total 
bilirubin, BUN, creatinine, Na, K, Cl, angiotensin-converting enzyme (ACE), and acid 
phosphatase. These assessments will be performed at the physician’s discretion per standard 
clinical practice. (approximately every 12 weeks as a guide). 
Hypersensitivity reactions are defined as events of drug allergy, angioedema, anaphylactic 
reaction, anaphylactic shock, anaphylactoid reaction, anaphylaxis prophylaxis, anaphylaxis 
treatment, drug reaction with eosinophilia and systemic symptoms. 
Data about pregnancy testing for women of child-bearing potential will be collected throughout 
the survey. Data regarding occurrences of pregnancies/breastfeeding during the survey will also 
be collected. 
f.
Testing of anti-velaglucerase alfa antibodies (including IgGs) will be performed at the
physician’s discretion per standard clinical practice. IgE isotype-specific antibodies could
also be measured when clinically indicated (e.g., AE, SAE or possible of lack of
efficacy).
g. Efficacy
Data from the following assessments are be made at the physician’s discretion per standard 
clinical practice: 
•
Hemoglobin concentration (approximately every 12 weeks as a guide)
•
Platelet count (approximately every 12 weeks as a guide)
•
Liver and spleen volume (approximately every 24 weeks as a guide)
•
Bone density (approximately every 52 weeks as a guide)
•
Evaluation of effects of anti-velaglucerase alfa antibody
•
Potential for reduced efficacy due to development of neutralizing antibodies to velaglucerase
alfa
7.2 
Important Items for Investigation 
Infusion reactions:  Infusion reactions are defined as reactions occurring up to  24 hours after 
the start of the infusion. The most commonly observed symptoms of infusion- related reactions 
were: headache, dizziness, hypotension, hypertension, nausea, fatigue/asthenia, and 
pyrexia/body temperature increased. 
Laboratory assessment may include: RBC, Hb, Ht, WBC, PLT, Total protein, AST, ALT, total 
bilirubin, BUN, creatinine, Na, K, Cl, ACE, and acid phosphatase. These assessments will be 
performed at the physician’s discretion per standard clinical practice (approximately every 12 
weeks as a guide). 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

VPRIV® (velaglucerase alfa) 
Clinical Study SHP-GCB-401 Protocol Amendment 9 
15 September 2023 
Takeda 
7 
8 ITEMS FOR ANALYSIS AND THE ANALYSIS METHOD 
1) Items for analyses
a.
Items on patient constitution
•
Number of cases enrolled, Number of cases collected CRF,
•
Number of cases evaluable for safety, Number of cases evaluable for efficacy,
•
Evaluation of antibody effect on the efficacy and safety
•
Number of cases excluded from the survey with reason
b. Safety issues
•
Adverse reactions/infections (including unknown events), events, severity, incidence, etc.
•
Adverse reactions/infections according to the background factor
•
Serious adverse events by type of event
•
Fetal/infant exposure via pregnancies and breastfeeding
c.
Efficacy issues
•
Assessment of related factors affecting on the efficacy in case of refractory
•
Items on patients with special backgrounds
•
Incidence ratio of adverse reactions/infections and clinical efficacy in patients with special
backgrounds; pediatric, elderly, pregnant, treatment-naïve (ERT-naïve), and Gaucher type 2
or 3 patients
d. Items on important items for investigation
•
Infusion reactions
2) Analysis method
Continuous variables (e.g., change from baseline in hemoglobin over time) will be summarized 
using descriptive statistics (N, mean, standard deviation, minimum, median, and maximum). 
Categorical variables (e.g., number and proportion of patients with infusion reactions over time) 
will be summarized using the number and percentage of patients in each category. In addition, 
the two-sided 95% confidence intervals (CIs) for the parameters of interest will be estimated as 
appropriate. No formal statistical tests will be performed. Safety and efficacy data will be 
presented for the enrolled patients overall, by previous treatment status (treatment-naïve versus 
patients who previously received ERT for Gaucher disease, e.g., imiglucerase or velaglucerase 
alfa) and by type of Gaucher disease as appropriate. 
The safety data will be presented periodically for regulatory submissions per the regulation of the 
Safety Periodic Reporting System. In addition, summaries of the accumulating data including 
efficacy data may be assessed during the conduct of the survey for exploratory and administrative 
purposes, if deemed necessary. The statistical analysis methods will be prospectively specified in 
detail in the statistical analysis plan. 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

VPRIV® (velaglucerase alfa) 
Clinical Study SHP-GCB-401 Protocol Amendment 9 
15 September 2023 
Takeda 
8 
9 ORGANIZATION FOR IMPLEMENTING THE SURVEY 
Same as described in the Risk Management Plan. 
10 OUTSOURCE DETAILS 
Contractor for the operations 1 
 
 
Anticipated scope of services: Request the site to conduct the survey, Contract with the site, 
Status management of the survey, AE information collection, CRF and/or DCF collection  
Operation of specified use-result survey (Request to hospitals/clinics, making contracts with 
hospitals/clinics, enrollment of patients, collection of CRFs and review/follow-up, progress 
management, information collection of adverse reactions/infections, data 
compilation/analyses and medical writing). 
Contractor for the operations 2 
 
Anticipated scope of services: Receipt of paper CRFs, etc. sent from sites, confirmation of 
presence/absence of adverse event descriptions, transfer of original CRFs, etc. to contractor 1 and storage 
of site contract, etc. 
Contractor for the operations 3 
 
Anticipated scope of services: Monitoring 
11 ADDITIONAL MEASURES WHICH MAY BE TAKEN DEPENDING ON THE 
OUTCOME OF THE SURVEY AND THE DECISION CRITERIA FOR INITIATING 
THE MEASURES 
Depending on the outcomes of DURS, if new safety issues or risks are identified the additional 
pharmacovigilance and risk minimization measures will be planned. 
12 MILESTONES FOR THE IMPLEMENTATION OF THE SURVEY AND THE 
ASSESSMENT OF THE RESULTS, OR REPORTING TO THE PMDA, AND 
THE JUSTIFICATION 
Enrollment Completion: December 2021 (~about 7 years after launch) 
Data collection: CRFs should be collected every 6 months for 2 years then yearly thereafter; 
CRF collection is anticipated to be completed within 6 months after the end of the survey. 
Final Report: Within 6 months after data collection completion 
13 OTHER NECESSARY ITEMS 
a. Required/recommended reference materials.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

VPRIV® (velaglucerase alfa) 
Clinical Study SHP-GCB-401 Protocol Amendment 9 
15 September 2023 
Takeda 
9 
•
Contract
•
Guideline for implementation of the survey
•
Registration form for the survey
•
CRF
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

VPRIV® (velaglucerase alfa) 
Clinical Study SHP-GCB-401 Protocol Amendment 9 
15 September 2023 
Takeda 
10 
14 SUMMARY OF CHANGES 
Original Protocol: 26 June 2014 
Amendment 1: 
10 July 2014 
Amendment 2: 
14 August 2014 
Amendment 3: 
01 April 2018 
Amendment 4: 
01 April 2019 
Amendment 5: 
01 October 2020 
Amendment 6: 
01 November 2020 
Amendment 7: 
21 December 2020 
Amendment 8: 
19 August 2021 
Amendment 9: 
15 September 2023 
Rationale for Amendment 2: Guidance for the frequency of assessment of safety laboratory 
assessments (Section 7.1e and Section 7.2) and efficacy assessments (Section 7.1g) was added. 
The major changes are noted below. The deleted text is noted by strikethrough and the new text 
is bolded. 
Summary of Changes for Amendment 2: 
Section 7.1 Items for Investigation 
Subsection e. Safety 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

VPRIV® (velaglucerase alfa) 
Clinical Study SHP-GCB-401 Protocol Amendment 9 
15 September 2023 
Takeda 
11 
Laboratory assessment may include ; RBC, Hb, Ht, WBC, PLT, Total protein, AST, ALT, 
total bilirubin, BUN, creatinine, Na, K, Cl, angiotensin-converting enzyme (ACE), and acid 
phosphatase. These assessments will be performed at the physician’s discretion per standard 
clinical practice (approximately every 12 weeks as a guide). 
Subsection g. Efficacy 
Data from the following assessments are be made at the physician’s discretion per standard 
clinical practice: 
•
Hemoglobin concentration (approximately every 12 weeks as a guide)
•
Platelet count (approximately every 12 weeks as a guide)
•
Liver and spleen volume (approximately every 24 weeks as a guide)
•
Bone density (approximately every 52 weeks as a guide)
•
Evaluation of effects of anti-velaglucerase alfa antibody
•
Potential for reduced efficacy due to development of neutralizing antibodies to velaglucerase
alfa
Section 7.2 Important Items for Investigation 
Laboratory assessment may include; RBC, Hb, Ht, WBC, PLT, Total protein, AST, ALT, total 
bilirubin, BUN, creatinine, Na, K, Cl, ACE, and acid phosphatase. These assessments will be 
performed at the physician’s discretion per standard clinical practice (approximately every 12 
weeks as a guide). 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use

VPRIV® (velaglucerase alfa) 
Clinical Study SHP-GCB-401 Protocol Amendment 9 
15 September 2023 
Takeda 
12 
Rationale for Amendment 3: Organization for Implementing the Survey (Section 9) was revised. 
The major changes are noted below. The deleted text is noted by strikethrough and the new text is 
bolded. 
The name of trustee is changed. 
 
 
Rationale for Amendment 4: Organization for Implementing the Survey (Section 9) was revised. 
Rationale for Amendment 5: Changes in Marketing Authorization Holder. 
Outsource Details (Section 10) was revised. 
Rationale for Amendment 6: Outsource Details (Section 10) was revised. 
Rationale for Amendment 7: Outsource Details (Section 10) was revised. 
Rationale for Amendment 8: Estimated Duration of the Survey & Milestones for the 
Implementation of the Survey (Section 6 & 12) was revised. 
Rationale for Amendment 9: According to the change of term in the Risk Management  Plan, 
‘Infusion-related reaction’ was modified to ‘Infusion reaction’. [Section 1, 7.1c, 7.2, 8.1)d and 8.2)] 
‘Survey Completion date’ was added in Section 6. 
The ‘Medical writing’ was added in the Anticipated scope services to Contractor for the operation 1: 
 
[Section 10] 
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use