Clinical trial NCT04002830
Conditions: Gaucher Disease, Type 3
Sponsor: Ari Zimran
Start date: 2020-11-20; Completion date: 2023-07-30
Enrollment: 14 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a multicenter study to assess the safety and efficacy of taliglucerase alfa (60 units/kg) in previously untreated subjects of any age with Type 3 GD. Subjects will receive an infusion of taliglucerase alfa every 2 weeks for 12 months. Subjects who tolerate the infusions well, and who are treated in centers where home therapy is the SOC will be allowed to switch from site to home treatment at the discretion of the PI but after no less than 3 uneventful infusions at the site.

Detailed description:
Patients with Type 3 GD exhibit both visceral and neurologic manifestations. In addition to the progressive neurologic involvement, somatic disease manifestations, especially splenomegaly and resulting cytopenia, contribute to significant mortality and morbidity . The effects of enzyme replacement therapy (ERT) on patients with Type 1 GD have been clearly documented and have a beneficial effect on visceral and hematologic disease parameters . It is known that recombinant enzyme does not pass the blood-brain barrier and has no effect on neurologic involvement . Probably due to the rarity of Type 3 GD, information on the somatic effects of ERT is largely limited to case reports or single-center series. There are also few reviews of cohorts but the clinical subtype, age, genotype, ERT dosage, accompanying therapies, and treatment response vary widely among patients in these cohorts. This prospective study aims to objectively evaluate the hematologic and visceral effects of ERT with taliglucerase alfa on a rather clinically and genetically homogenous group of treatment-naïve patients with Type 3 GD . For the purposes of this study, subjects receiving no Gaucher-specific medications for at least 12 months will be considered "untreated". The results of this study are expected to provide a more objective view of the degree of response of this patient type, and potentially create new areas of research.

Arms: arm 1: Intravenous infusion of Taligluucerase alfa (Elelyso) in treatment-naive patients with type 3 Gaucher disease
Interventions: intervention 1: Elelyso
Intervention descriptions: intervention 1: Taliglucerase alfa is currently an approved therapy in the United States and many other countries for adults and children with a confirmed diagnosis of Type 1 GD ,and is also approved for use in Type 3 GD in a small number of countries.

Protocol documents:
Prot_000.pdf: 
Page 1 
 
 
Study Title: 
A Multicenter, Safety and Efficacy Study of Taliglucerase Alfa in Subjects With Type 3 Gaucher 
Disease 
 
 
NCT Number: 
NCT04002830 
 
 
Protocol Date: 
10 December 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Page 2 
 
 
 
CLINICAL STUDY PROTOCOL 
 
Protocol Title:  A Multicenter, Safety and Efficacy Study of 
Taliglucerase Alfa in Subjects with Type 3 Gaucher Disease 
 
 
 
Study Product: 
Taliglucerase alfa (plant cell expressed 
recombinant human glucocerebrosidase) 
Indication: 
Type 3 Gaucher Disease 
Phase: 
3B 
Version and Date: 
Version: 5.0   Date: December 10 2021 
Name and Affiliation of 
Principal Investigators 
A list of the Principal Investigators is 
maintained in the trial master file 
Name and Address of Sponsor 
 Prof. Ari Zimran, MD 
Shaare Zedek Medical Center 
Jerusalem 
Israel 
Good Clinical Compliance (GCP) 
Statement 
This study will be performed in 
compliance with GCP, including the 
archiving of essential documents. 
The information in this document is confidential and is proprietary to the Sponsor. It is understood that information 
in this document shall not be disclosed to any third party, in any form, without prior written consent of the Sponsor. 


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1. 
SYNOPSIS 
TITLE:  A Multicenter, Safety and Efficacy Study of Taliglucerase Alfa in Subjects with 
Type 3 Gaucher Disease  
INVESTIGATIONAL PRODUCT:  Taliglucerase alfa (plant cell expressed recombinant 
human glucocerebrosidase) 
INDICATION:  Gaucher Disease (GD) 
PHASE OF DEVELOPMENT:  3B 
INVESTIGATIONAL SITES/LOCATIONS:  Multicenter, (Israel, India, and Turkey) 
INTERNAL PFIZER STUDY NUMBER:  WI224302 
OBJECTIVES:  To assess the safety and efficacy of taliglucerase alfa in untreated subjects 
(any age) with symptoms and clinical manifestations of Type 3 GD. 
STUDY DESIGN:  This is a multicenter study to assess the safety and efficacy of 
taliglucerase alfa (60 units/kg) in previously untreated subjects of any age with Type 3 GD.  
Subjects will receive an infusion of taliglucerase alfa every 2 weeks for 12 months.  Subjects 
who tolerate the infusions well, and who are treated in centers where home therapy is the SOC 
will be allowed to switch from site to home treatment at the discretion of the PI but after no 
less than 3 uneventful infusions at the site.  
NUMBER OF SUBJECTS (PLANNED): up to 15 
DIAGNOSIS AND MAIN CRITERIA FOR INCLUSION: 
Key inclusion criteria 
Eligible subjects must fulfill the following inclusion criteria: 
1. Male or female of any age; however, if female: 
• must be using contraception if of childbearing potential or must be surgically sterile 
• must not be lactating 
2. Diagnosis of Type 3 GD by enzyme and sequence analysis; and confirmed by the 
Medical Monitor. 
3. Splenomegaly at least 5 x multiples of normal (MN). 
4. Treatment-naïve. 


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Key exclusion criteria 
Eligible subjects may not have any of the following exclusion criteria: 
1. Type 2 GD. 
2. Presence of myoclonic seizures. 
3. At least one allele of: 
• N370S (N409S in recent nomenclature) 
• R496H (R535H in recent nomenclature) 
 
4. Presence of calcification in heart valves or arteries in echocardiography. 
5. Presence of untreated iron, folic acid, vitamin B12 deficiency and/or hypothyroidism.  
(Resolved anemia is not an exclusion criterion.) 
6. Presence of human immunodeficiency virus (HIV), hepatitis B surface antigen 
(HBsAg), and/or hepatitis C infections. 
7. Splenectomy and bone marrow transplantation. 
8. Presence of any medical, emotional, behavioural, or psychological condition that in the 
judgment of the Investigator would interfere with the subject’s compliance with the 
requirements of the study. 
9. Any other disorder that may interfere with the results of the efficacy endpoints. 
10. Pregnancy or breastfeeding. 
11. Currently taking another investigational drug for any condition or any therapeutic drug 
for Gaucher disease. 
12. The subject and/or subject’s parent(s) or legal guardian(s) are unable to understand the 
nature, scope, and possible consequences of the study. 
13. Medical history of any food/drugs allergy. 
TEST PRODUCT(S), DOSE AND MODE OF ADMINISTRATION:  Taliglucerase alfa, 
60 units/kg, intravenously, every 2 weeks 
DURATION OF TREATMENT:  12 months 
DISCONTINUATION FROM THE STUDY:   
Reasons for permanent discontinuation include the following: 
• The subject experiences two or more Grade 3 toxicities or one or more Grade 4 toxicity 
considered by the Investigator associated with taliglucerase alfa treatment 
• A subject who experiences progressive hypersensitivity or severe hypersensitivity will 
be treated appropriately and may be withdrawn from the study, at the discretion of the 
treating Investigator and/or Medical Monitor 


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• The subject, or subject’s parent or guardian, requests to discontinue treatment 
• Investigator feels that it is not in the best interest of the subject to continue treatment 
and/or the Investigator believes that the subject can no longer be compliant with the 
requirements of the study 
• Deteriorating clinical condition, for which the Investigator decides additional 
treatments would be needed 
EFFICACY VARIABLES: 
Primary efficacy variable is: 
• Percent change in spleen volume (expressed in MN) from baseline to Month 12 
Secondary efficacy variables are: 
• Percent change in liver volume (expressed in MN) from baseline to Month 12 
• Percent change in hemoglobin from baseline to Months 3, 6, 9, and 12 
• Percent change in platelet count from baseline to Months 3, 6, 9, and 12 
• Percent change in Lyso-Gb1 from baseline to Months 3, 6, 9, and 12 
• Percent change in Chitotriosidase from baseline to Months 3, 6, 9, and 12 
Other efficacy variables are: 
• Change in height SDS (standard deviation score) from baseline to Months 3, 6, 9, and 
12 
• Change in weight SDS from baseline to Months 3, 6, 9, and 12 
• Change in Tanner Stage from baseline to Month 12 
• Change in bone age (by X-ray of left hand and wrist) from baseline to Month 12 
• Change in bone mineral density (DEXA) from baseline to Month 12 
Exploratory endpoints: 
• Change in mSST from screening, Month 6 and 12. 
SAFETY ENDPOINTS: 
• Adverse events 
• Clinical laboratory tests 
• Vital signs 
• Physical examinations 
IMMUNOGENICITY: 
• Anti-taliglucerase alfa antibodies 


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STATISTICAL ANALYSIS: 
A sample size of 9 subjects is chosen to evaluate the efficacy and safety of taliglucerase alfa in 
subjects with this orphan disease in which recruitment in clinical trials is difficult. This sample 
size of 9 evaluable subjects will provide a power of 80.9% to detect a responder rate of 0.91 
for reduction in spleen volume from baseline to Month 12, with an actual significant level of 
0.04. Up to 15 subjects will be enrolled in order to yield at least 9 subject who will complete 
the study. 
The primary endpoint is the percent change in spleen volume (expressed in MN) from baseline 
to Month 12.  The Wilcoxon signed rank test at 2-sided significance level of 0.05 will be 
performed to analyse this primary efficacy endpoint.  The Wilcox signed rank test will be 
applied for the secondary efficacy endpoints: percent change from baseline to Month 12 in 
liver volume MN, hemoglobin, platelet count, chitotriosidase and Lyso-Gb1 separately.  
The other efficacy endpoints will be primarily summarized using descriptive statistics by visit. 
For example, change in growth and development assessment from baseline to each visit will 
be summarized using descriptive statistics by visit.  Descriptive statistics will also be reported 
for change in Tanner Stage, bone assessment (bone age, bone mineral density and Z-score) and 
modified severity score (mSST) from screening to Month 12. 
The immunogenicity status will be tabulated by frequency and percentage.  Safety data will be 
descriptively summarized. 
 


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DOCUMENT APPROVAL 
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP) and 
applicable regulatory requirements. 
 
 
 
PRINCIPAL INVESTIGATOR 
 
 
Signature: _______________________________ Date: ______________________ 
 
Name (print): _Ari Zimran___________________ 
 
 


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TABLE OF CONTENTS 
1. 
SYNOPSIS ...............................................................................................................................3 
2. 
ABBREVIATIONS ................................................................................................................11 
3. 
ETHICAL CONDUCT OF THE STUDY AND REGULATORY REQUIREMENTS ........12 
3.1 
Institutional Review Board (IRB) ......................................................................................12 
3.2 
Ethical Conduct of the Study .............................................................................................12 
3.3 
Subject Information and Consent.......................................................................................12 
4. 
INTRODUCTION ..................................................................................................................13 
4.1 
Gaucher Disease (GD) .......................................................................................................13 
4.2 
Taliglucerase Alfa ..............................................................................................................13 
4.3 
Overview of Clinical Data .................................................................................................13 
4.3.1 
Study PB-06-001 in Adult GD Patients ......................................................................13 
4.3.2 
Study PB-06-002 in Adult and Pediatric GD Patients Previously Treated with 
Imiglucerase ................................................................................................................14 
4.3.3 
Study PB-06-005 in Pediatric Patients with Type 1 GD or Type 3 GD .....................15 
4.3.4 
Long-term Studies in Adult GD Patients ....................................................................15 
4.3.4.1 
Extension Study PB-06-003 ...................................................................................15 
4.3.4.2 
Extension Study PB-06-007 ...................................................................................16 
4.3.5 
Long-Term Extension Study in Pediatric GD Patients ...............................................16 
4.4 
Rationale for Study ............................................................................................................16 
5. 
STUDY OBJECTIVES ..........................................................................................................17 
6. 
INVESTIGATIONAL PLAN .................................................................................................17 
6.1 
Overall Study Design and Plan – Description ...................................................................17 
6.2 
Discussion of Study Design and Choice of Control Group(s) ...........................................17 
6.3 
Selection of Study Population ............................................................................................18 
6.3.1 
Inclusion Criteria ........................................................................................................18 
6.3.2 
Exclusion Criteria .......................................................................................................18 
6.3.3 
Removal of Subjects from Study ................................................................................19 
6.3.4 
Replacement Policy ....................................................................................................19 
7. 
STUDY PRODUCT ...............................................................................................................19 
7.1 
Study Medication Supply ...................................................................................................19 
7.2 
Description of Study Product .............................................................................................19 
7.3 
Description of Comparator Product ...................................................................................20 
7.4 
Study Drug Administration ................................................................................................20 
7.5 
Packaging and Labeling .....................................................................................................20 
7.6 
Conditions for Storage and Use .........................................................................................20 
7.7 
Method of Assigning Subjects to Treatment Groups .........................................................20 
7.8 
Dispensing, Compliance, and Accountability ....................................................................20 
7.9 
Prior and Concomitant Therapy .........................................................................................20 
8. 
EFFICACY AND SAFETY ASSESSMENTS ......................................................................21 
8.1 
Efficacy Variables ..............................................................................................................21 
8.2 
Safety Variables .................................................................................................................22 
8.2.1 
Adverse Events ...........................................................................................................22 


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8.2.1.1 
Adverse Events (AE) and Serious Adverse Events (SAE) ....................................22 
8.2.1.2 
Procedures for Assessing, Recording, and Reporting Adverse Events and Serious 
Adverse Events ......................................................................................................23 
8.2.2 
Clinical Laboratory .....................................................................................................24 
8.2.3 
Vital Signs ..................................................................................................................25 
8.2.4 
Physical Examination .................................................................................................25 
8.3 
Immunogenicity .................................................................................................................25 
9. 
STUDY PROCEDURES AND FLOW CHART ...................................................................25 
9.1 
Study Flow Chart ...............................................................................................................26 
9.2 
Study Visits ........................................................................................................................28 
9.2.1 
Screening (Visit 0, Day -25 ± 10) ...............................................................................28 
9.2.2 
Visit 1 (Baseline, Day 1) ............................................................................................28 
9.2.3 
Visits 2 – 5 (Weeks 2, 4, 6, and 8 ± 3 Days) ..............................................................29 
9.2.4 
Visit 6 (Week 10 ± 3 Days) ........................................................................................30 
9.2.5 
Visit 7 (Month 3 [Week 12] ± 7 Days) .......................................................................30 
9.2.6 
Visits 8 – 13 (Weeks 14, 16, 18, 20, 22, and 24 ± 3 Days) ........................................30 
9.2.7 
Visit 14 (Month 6 [Week 26] ± 7 Days) .....................................................................31 
9.2.8 
Visits 15 – 19 (Weeks 28, 30, 32, 34, and 36 ± 3 Days) ............................................31 
9.2.9 
Visit 20 (Month 9 [Week 38] ± 7 Days) .....................................................................32 
9.2.10 
Visits 21 – 26 (Weeks 40, 42, 44, 46, 48, and 50 ± 3 Days) ......................................32 
9.2.11 
Visit 27 (Month 12 [Week 52] ± 7 Days) ...................................................................32 
9.2.12 
Early Termination Visit ..............................................................................................33 
10. STATISTICAL METHODS PLANNED AND SAMPLE SIZE ...........................................33 
10.1 Determination of Sample Size ...........................................................................................33 
10.2 Analysis Populations ..........................................................................................................34 
10.3 Analysis..............................................................................................................................34 
10.3.1 
Demographics .............................................................................................................34 
10.3.2 
Medical History ..........................................................................................................34 
10.3.3 
Medications .................................................................................................................34 
10.3.4 
Efficacy Analysis ........................................................................................................34 
10.3.5 
Safety Analysis ...........................................................................................................35 
10.3.5.1 Adverse Events ......................................................................................................35 
10.3.5.2 Clinical Laboratory ................................................................................................35 
10.3.5.3 Vital Signs ..............................................................................................................36 
10.3.5.4 Physical Examinations ...........................................................................................36 
10.3.6 
Immunogenicity ..........................................................................................................36 
11. QUALITY CONTROL AND QUALITY ASSURANCE .....................................................36 
11.1 Source Data Records ..........................................................................................................36 
11.2 Reporting of Results ..........................................................................................................36 
11.3 Confidentiality of Subject Data .........................................................................................37 
12. REPORTING AND PUBLICATION .....................................................................................37 
12.1 Confidentiality of Subject Data .........................................................................................37 
12.2 Publication Policy ..............................................................................................................37 
13. REFERENCES .......................................................................................................................38 


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14. APPENDICES ........................................................................................................................40 
14.1 Appendix 1:  ELELYSO® Prescribing Information (US) ..................................................40 
14.2 Appendix 2:  Infusion Rate Algorithm ..............................................................................44 
14.3 Appendix 3:  Taliglucerase Alfa Hypersensitivity Evaluation and Treatment Algorithm 46 
14.4 Appendix 4:  Magnetic Resonance Imaging (MRI) ...........................................................49 
14.4.1 
Subject and Sites .........................................................................................................49 
14.4.2 
MRI Data ....................................................................................................................49 
14.4.3 
MRI Evaluation Parameters ........................................................................................49 
14.4.4 
Sites and Image Data Management ............................ Error! Bookmark not defined. 
14.4.4.1 Standardization of Image Acquisition, Initial Site Qualification...........................49 
14.4.4.2 Subject Sedation.....................................................................................................49 
14.4.4.3 Quality Control of Image Data and Site Quality Assurance During the Course of 
the Study ................................................................................................................49 
14.4.5 
Image Processing and Centralized Analysis ............... Error! Bookmark not defined. 
14.4.5.1 Spleen and Liver Segmentation ............................. Error! Bookmark not defined. 
14.4.5.2 Centralized Image Review by Independent ReadersError! Bookmark not defined. 
14.4.6 
Data and Report Transfers to Sponsor ........................ Error! Bookmark not defined. 
14.4.7 
Direct Access to Study Data ....................................... Error! Bookmark not defined. 
14.4.8 
Unevaluable MRI ........................................................ Error! Bookmark not defined. 
14.5 Appendix 5:  WHO Common Toxicity Criteria ................................................................51 
 
LIST OF TABLES 
Table 1: 
Study Flow Chart ........................................................................................................26 
 
 
 


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2. 
ABBREVIATIONS 
 
Abbreviation or 
Specialist Term 
 
Definition/Description 
AE(s) 
Adverse Event(s) 
β-GCD 
β-Glucocerebrosidase 
CCL18 
Pulmonary and activation-regulated chemokine 
CDC 
Centers for Disease Control and Prevention 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
DEXA 
Dual-emission X-ray Absorptiometry 
EC 
Ethics Committee 
ERT 
Enzyme Replacement Therapy 
GBA 
Glucoside Beta Acid 
GCP 
Good Clinical Practice 
GD 
Gaucher Disease 
HBsAg 
Hepatitis B Surface Antigen 
HCG 
Human Chorionic Gonadotropin 
HCV 
Hepatitis C Virus 
hGCD 
Human Glucocerebrosidase 
HIV 
Human Immunodeficiency Virus 
ICH 
International Conference on Harmonization 
IR 
Infusion Rate 
IRB 
Institutional Review Board 
IV 
Intravenous 
Lyso-Gb1 
Lyso-glucosylsphingosine 
MedDRA 
Medical Dictionary for Regulatory Activities 
MN 
Multiples of Normal 
MRI 
Magnetic Resonance Imaging 
mSST 
Modified severity scoring tool 
PK 
Pharmacokinetic 
SAE(s) 
Serious Adverse Event(s) 


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Abbreviation or 
Specialist Term 
 
Definition/Description 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
Taliglucerase alfa 
Plant Cell Expressed Recombinant Human Glucocerebrosidase 
TEAE 
Treatment-emergent Adverse Event 
T4 
Free Thyroxine 
TSH 
Thyroid Stimulating Hormone 
WHO 
World Health Organization 
 
3. 
ETHICAL CONDUCT OF THE STUDY AND REGULATORY 
REQUIREMENTS 
3.1 
Institutional Review Board (IRB) 
An Institutional Review Board (IRB) or Ethics Committee (EC) will review the study protocol 
and any amendments. The IRB or EC will also review the informed consent form, their updates 
(if any), and any written materials given to the subjects. A list of all IRBs and ECs and contact 
information will be included in the study report. 
3.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles that have their origins in 
the Declaration of Helsinki, in compliance with the approved protocol, GCP and applicable 
regulatory requirements. 
3.3 
Subject Information and Consent 
The Investigator will obtain a freely given written consent or assent from each subject or parent 
or guardian after an appropriate explanation of the aims, methods, anticipated benefits, potential 
hazards, and any other aspects of the study that are relevant to the subject's decision to 
participate. The consent form must be signed and dated by the subject or parent or guardian 
before the subject is exposed to any protocol-specific procedure. 
The Investigator will explain that the subjects are completely free to refuse to enter the study or 
to withdraw from it at any time, without any consequences for their further care and without the 
need to justify. 
The subject or parent or guardian will receive a copy of the subject information and the signed 
informed consent. 
The subject or parent or guardian will be informed if information becomes available that may be 
relevant to his/her willingness to continue participation in the study. 


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Each subject or parent or guardian will be informed that a monitor or a health authority 
inspector, in accordance with applicable regulatory requirements, may review the portions of 
their source records and source data related to the study.  Data protection and confidentiality will 
be handled in compliance with local laws. 
4. 
INTRODUCTION 
4.1 
Gaucher Disease (GD) 
Gaucher disease is a rare genetic disorder of lipid metabolism 
is the most common inherited 
lysosomal storage disorder, thought to affect around 10,000 people globally [1,2].  The disease 
affects persons of all ages and both sexes and is the result of mutations that affect the GBA gene 
that encodes β-glucocerebrosidase (β-GCD) [3, 4].  The defect results in a deficiency in β-GCD, 
which consequently leads to the build-up of glucocerebroside in macrophages, mostly in the 
spleen, liver, lungs, and bone marrow [5].   
Gaucher disease is classified into 3 major phenotypic subcategories based on the absence 
(Type 1) or presence and severity (Types 2 and 3) of primary central nervous system 
involvement [6].  Gaucher disease Type 3, the population under study in this current protocol, 
affects approximately 5% of documented GD cases [6].  Type 3 GD is associated with 
progressive neurodegenerative disease, with symptom onset usually between infancy and 
adolescence [7].  Manifestations of Type 3 GD vary among patients, ranging from visceral and 
bone disease, cytopenia, hearing impairment, supranuclear gaze palsy, developmental delay, and 
cardiac calcification to myoclonic encephalopathy with seizures and eventual death [8, 9].  
Overall life expectancy is usually dramatically shortened, although there are some documented 
patients now alive in their sixth decade [10]. 
4.2 
Taliglucerase Alfa 
Taliglucerase alfa, a hydrolytic lysosomal glucocerebroside-specific enzyme for intravenous 
infusion, is a recombinant active form of the lysosomal enzyme, β-GCD.  In contrast to other 
β-GCD products for GD therapy, which are produced in mammalian cell culture [11, 12] 
taliglucerase alfa is produced using transgenic [13] carrot plant root cells [14] grown in 
suspension culture with a modified gene sequence encoding human β-GCD [13].  Taliglucerase 
alfa is a glycosylated protein with mannose-terminated oligosaccharide chains that are 
specifically recognized by endocytic carbohydrate receptors on macrophages [14], enabling 
uptake into Gaucher cells [13]. 
Taliglucerase alfa is currently an approved therapy in the United States and many other countries 
for adults and children with a confirmed diagnosis of Type 1 GD [14], and is also approved for 
use in Type 3 GD in a small number of countries. 
4.3 
Overview of Clinical Data 
4.3.1 
Study PB-06-001 in Adult GD Patients 
Study PB-06-001 was a Phase 3, multicenter (11 centers worldwide), double-blind trial in which 
32 adult patients with Type 1 GD randomly received either 30 units/kg or 60 units/kg of 
taliglucerase alfa intravenously every 2 weeks for 38 weeks (20 infusions).  At the end of the 
study, eligible patients were offered enrollment in an open-label extension study (PB-06-003). 


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The primary efficacy analysis demonstrated that taliglucerase alfa treatment significantly 
reduced spleen volume from screening to Month 9 (taliglucerase alfa 30 units/kg, 26.91%, 
p<0.0001; taliglucerase alfa 60 units/kg, 38.01%, p<0.0001) and Month 6 (taliglucerase alfa 
30 units/kg, 22.21%, p<0.0001; taliglucerase alfa 60 units/kg, 29.94%, p<0.0001). 
The secondary efficacy analysis demonstrated that taliglucerase alfa treatment significantly 
increased hemoglobin level from baseline to Month 9 (taliglucerase alfa 30 units/kg, 1.6 g/dL, 
p<0.0001; taliglucerase alfa 60 units/kg, 2.2 g/dL, p<0.0001).  A significant reduction in liver 
volume from screening was also observed in both taliglucerase alfa dose groups at the end of the 
study (taliglucerase alfa 30 units/kg, 10.48%, p=0.0041; taliglucerase alfa 60 units/kg, 11.11%, 
p<0.0001).  In addition, a significant increase in platelet count from baseline was observed in the 
60 units/kg dose group at Month 9 (41,494/mm3, p=0.0031) and an increase in platelet count at 
Month 9 was also observed for the taliglucerase alfa 30 units/kg dose group (11,427/mm3, 
p=0.0460).  Improvements were also observed at the Month 6 visit.   
Overall, 23 patients experienced 137 adverse events (AEs) (12 in the 30 units/kg had 65 AEs and 
11 in the 60 units/kg had 72 AEs).  Eight patients (3 in the 30 units/kg group and 5 in the 
60 units/kg group) experienced 28 events that were considered by the respective investigators to 
be treatment-related.  Of the treatment-related events, none were seen in more than one patient in 
each group.  All AEs were mild or moderate in intensity and the majority of the events resolved 
by the end of the study.  No deaths or serious adverse events (SAEs) occurred during the study.  
Two patients (1 per dose group) discontinued from the study due to a hypersensitivity reaction. 
Pharmacokinetic (PK) analyses showed no tendency for accumulation or change in PK 
parameters with repeated doses of taliglucerase alfa. 
4.3.2 
Study PB-06-002 in Adult and Pediatric GD Patients Previously Treated with 
Imiglucerase 
Study PB-06-002 was a Phase 3, multicenter (11 centers worldwide), open-label study that 
assessed the safety and efficacy of taliglucerase alfa in adult (n=25) and pediatric (n=5) patients 
with Type 1 GD who were switched from treatment with Cerezyme® (imiglucerase) (note: 1 
pediatric patient was subsequently diagnosed with Type 3 GD).  The initial dose of taliglucerase 
alfa was equivalent to the patient’s imiglucerase dose, with subsequent dosage increases allowed 
up to a maximum of 60 units/kg.  Taliglucerase alfa was administered intravenously every 
2 weeks for 9 months.  At the end of the study, eligible patients were offered enrollment in open-
label extension studies (PB-06-003 for adults, PB-06-006 for pediatric patients). 
At the end of 9 months of treatment, all patients main disease parameters remained clinically 
stable.  Mean platelet counts and hemoglobin values were within expected parameters in both 
adult and pediatric patients, and there was also a mean reduction in spleen and liver volumes. 
There was no evidence of increased safety concerns in patients after switching from imiglucerase 
to taliglucerase alfa. 
Comparison between Type 1 GD and Type 3 GD Pediatric Patients 
Pediatric patients showed improvement in the systemic symptoms of Gaucher disease, regardless 
of disease variant.  The absolute mean reductions observed in spleen volume and liver volume in 
the single pediatric patient with Type 3 GD were qualitatively similar, yet quantitatively greater 


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than the change observed in the 4 pediatric patients with Type 1 GD: spleen volume -1.9 MN 
(-9.5%) vs. -0.5 (-23.7%) MN; liver volume 0.1 MN (-6.3%) vs. 0 MN (-3.5%). 
4.3.3 
Study PB-06-005 in Pediatric Patients with Type 1 GD or Type 3 GD 
Study PB-06-005 was a multicenter (11 centers in Israel, Paraguay, and South Africa), double-
blind trial in which 11 untreated pediatric patients (2 to <18 years of age) with a diagnosis of 
Type 1 or Type 3 GD (excluding acute neuropathic GD) were randomized to receive 30 units/kg 
(n=6) or 60 units/kg (n=5) of taliglucerase alfa intravenously every 2 weeks for 12 months.  At 
the end of the study (Month 12) both treatment doses demonstrated the therapeutic efficacy of 
taliglucerase alfa in this pediatric population.  Patients had an increase from baseline in median 
hemoglobin level, decrease in chitotriosidase and CCL18 levels, mean reduction in spleen and 
liver volumes, and mean increase in platelet count, height and weight, and bone age.  
Additionally, the Child Health Questionnaire scores showed that the quality of life of both the 
children and their parents/guardians improved after 12 months of taliglucerase alfa treatment.  
The efficacy results and the observed safety profile in these pediatric patients are consistent with 
previous data of taliglucerase alfa from clinical trials conducted in adult patients.  No new safety 
signals were observed in this study. 
Comparison between Type 1 GD and Type 3 GD in Pediatric Patients 
The 9 patients with Type 1 GD receiving either 30 units/kg or 60 units/kg of taliglucerase alfa 
had improvements in hemoglobin concentration of +2.1 g/dL (20.8%) and 1.6 g/dL (15.8%), 
respectively, from baseline to Month 12, whereas the 2 patients with Type 3 GD had no 
meaningful change in hemoglobin.  The changes from baseline to Month 12 in liver volume, 
spleen volume, and platelet count in the patients with Type 3 GD were qualitatively similar, but 
quantitatively less than the changes observed in patients with Type 1 GD. 
4.3.4 
Long-term Studies in Adult GD Patients 
4.3.4.1 
Extension Study PB-06-003 
This study extended treatment for adult patients who were treatment-naïve (n=26) or previously 
treated with imiglucerase (n=18) and had completed studies PB-06-001 PB-06-002, respectively.  
Thirty-seven patients completed this long-term extension study. 
Long-term data from treatment-naïve adult patients with Type 1 GD who were treated for a total 
of 36 months (9 months in PB-06-001 and 27 months in extension study PB-06-003) support a 
conclusion of continued improvement with both doses of taliglucerase alfa.  After 36 months, 
reductions in spleen volume of 50.1% and 64.6% were observed in the 30 units/kg and 
60 units/kg dose groups, respectively. 
Patients from study PB-06-002 who were switched from imiglucerase to taliglucerase alfa 
maintained stability across efficacy measures, with a reduction in spleen volume of 19.8% after 
36 months of treatment. 
Overall, long-term treatment with taliglucerase alfa was well tolerated and there was no evidence 
of increased safety concerns in patients switched from imiglucerase to taliglucerase alfa. 


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4.3.4.2 
Extension Study PB-06-007 
This study extended treatment for 17 treatment-naïve adult patients (8 at 30 units/kg and 9 at 
60 units/kg) who completed studies PB-06-001 and PB-06-003.  Patients demonstrated 
tolerability and efficacy as determined by organ volume size, hematologic parameters, and 
biomarker measurements.  Taligulcerase alfa was well tolerated during administration for up to 
60 months. 
4.3.5 
Long-Term Extension Study in Pediatric GD Patients 
Study PB-06-006 extended treatment for pediatric patients who were previously treated with 
imiglucerase (n=10) or were treatment-naïve (n=5) and had completed studies PB-06-002 or 
PB-06-005, respectively.  Eleven patients completed this long-term extension study. 
After a total of 36 months of treatment with taliglucerase alfa, treatment-naïve patients showed 
improvements from baseline in organ volumes, hematologic parameters, and biomarkers.  
Patients receiving 60 units/kg of taliglucerase alfa showed greater improvement in most of these 
parameters compared with patients receiving 30 units/kg.  In patients previously treated with 
imiglucerase, disease parameters (spleen volume, liver volume, platelet counts, and hemoglobin 
levels) remained stable through 33 months of treatment. 
Overall, taliglucerase alfa was well tolerated and there was no evidence of increased safety 
concerns in pediatric patients with up to 36 months of treatment. 
Type 3 GD Pediatric Patients 
Two patients with Type 3 GD continued into the PB-06-006 extension study: 1 treatment-naïve 
patient and the 1 previously treated with imiglucerase. 
At 36 months, the treatment-naïve patient showed improvement in hemoglobin (4.9%) and 
platelet count (5.5%), both less than changes observed in patients with Type 1 GD.  For the 
Type 3 GD patient previously treated with imiglucerase, changes in spleen volume and platelet 
count were greater than changes observed in patients with Type 1 GD, whereas changes in liver 
volume and hemoglobin were less in the Type 3 GD patient than in Type 1 GD patients. 
4.4 
Rationale for Study 
Patients with Type 3 GD exhibit both visceral and neurologic manifestations.  In addition to the 
progressive neurologic involvement, somatic disease manifestations, especially splenomegaly 
and resulting cytopenia, contribute to significant mortality and morbidity [15].  The effects of 
enzyme replacement therapy (ERT) on patients with Type 1 GD have been clearly documented 
and have a beneficial effect on visceral and hematologic disease parameters [16].  It is known 
that recombinant enzyme does not pass the blood-brain barrier and has no effect on neurologic 
involvement [17].  Probably due to the rarity of Type 3 GD, information on the somatic effects 
of ERT is largely limited to case reports or single-center series [18].  There are also few reviews 
of cohorts but the clinical subtype, age, genotype, ERT dosage, accompanying therapies, and 
treatment response vary widely among patients in these cohorts [19].  This prospective study 
aims to objectively evaluate the hematologic and visceral effects of ERT with taliglucerase alfa 
on a rather clinically and genetically homogenous group of treatment-naïve patients with Type 3 
GD.  For the purposes of this study, subjects receiving no Gaucher-specific medications for at 


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least 12 months will be considered “untreated”.  The results of this study are expected to provide 
a more objective view of the degree of response of this patient type, and potentially create new 
areas of research. 
5. 
STUDY OBJECTIVES 
The efficacy objectives of this study are to assess the efficacy of taliglucerase alfa in subjects 
with Type 3 GD, as measured by percent change from baseline in spleen and liver volume 
evaluated by magnetic resonance imaging (MRI), hemoglobin, platelet count, and Lyso-
Glucosylsphingosine (Lyso-Gb1); bone mineral density evaluated by dual-emission X-ray 
absorptiometry (DEXA) in all children 9 years of age and above, and evaluation of modified 
severity. 
For children, change from baseline in growth and development (height, weight, sexual 
development by Tanner classification, and bone age by X-ray of left hand and wrist) will be 
measured,   
The safety of taliglucerase alfa will be assessed by adverse events, clinical laboratory tests, vital 
signs, and physical examinations.  Anti-taliglucerase alfa antibodies will also be assessed. 
6. 
INVESTIGATIONAL PLAN 
6.1 
Overall Study Design and Plan – Description 
This is a multicenter study to assess the efficacy and safety of taliglucerase alfa (60 units/kg) in 
previously untreated subjects of any age with Type 3 GD.  For the purposes of this study, 
subjects receiving no Gaucher-specific medications for at least 12 months will be considered 
“untreated”. Subjects will receive an IV infusion of taliglucerase alfa every 2 weeks for 
12 months. Subjects who are treated in centers where home therapy is the SOC will be allowed 
to switch from site to home treatment at the discretion of the PI but after no less than 3 
uneventful infusions at the site. At the end of the 12-month treatment period, eligible subjects 
will be offered enrollment in an open-label extension study if taliglucerase alfa is not 
commercially available. 
6.2 
Discussion of Study Design and Choice of Control Group(s) 
Type 3 GD is a very rare genetic orphan disease.  This study will not have a placebo control 
group because it would be unethical to deny patients the possibility to improve their 
symptomology with an ERT that has been proved efficacious and safe, not only for Type 1 GD 
in many countries but also for Type 3 GD in a small number of countries.  Thus, all subjects will 
receive the investigational product in this study. 
The parameters chosen as endpoints for this study are the most relevant parameters to GD and 
allow a significant and relevant evaluation of improvement as a result of treatment for 
12 months.  Improvement in the clinical manifestations of the disease leads to the achievement of 
the therapeutic goals of GD treatment in the medical community, which are improved fatigue 
and decreased risk for morbidities. 


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6.3 
Selection of Study Population 
6.3.1 
Inclusion Criteria 
For inclusion into the trial, subjects are required to fulfill all of the following criteria: 
1. Male or female of any age; however, if female: 
• must be using contraception if of childbearing potential or must be surgically sterile 
• must not be lactating 
2. Diagnosis of Type 3 GD by enzyme and sequence analysis; and confirmed by the 
Medical Monitor. 
3. Splenomegaly at least 5 x multiples of normal (MN). 
4. Treatment-naïve. 
6.3.2 
Exclusion Criteria 
Any of the following is regarded as a criterion for exclusion from the trial: 
1. Type 2 GD. 
2. Presence of myoclonic seizures. 
3. At least one allele of: 
• N370S (N409S in recent nomenclature) 
• R496H (R535H in recent nomenclature) 
 
4. Presence of calcification in heart valves or arteries in echocardiography. 
5. Presence of untreated iron, folic acid, vitamin B12 deficiency and/or hypothyroidism.  
(Resolved anemia is not an exclusion criterion.) 
6. Presence of human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), 
and/or hepatitis C virus (HCV) infections. 
7. Splenectomy and bone marrow transplantation. 
8. Presence of any medical, emotional, behavioural, or psychological condition that in the 
judgment of the Investigator would interfere with the subject’s compliance with the 
requirements of the study. 
9. Any other disorder that may interfere with the results of the efficacy endpoints. 
10. Pregnancy or breastfeeding. 
11. Currently taking another investigational drug for any condition or any therapeutic drug 
for Gaucher disease. 
12. The subject and/or subject’s parent(s) or legal guardian(s) are unable to understand the 
nature, scope, and possible consequences of the study. 
13. Any medical history of food/drugs allergy. 


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6.3.3 
Removal of Subjects from Study 
Reasons for permanent discontinuation include the following: 
1. The subject experiences two or more Grade 3 toxicities or one or more Grade 4 toxicity 
considered by the Investigator associated with taliglucerase alfa treatment (see Section 
8.2.1: Adverse Events; and Appendix 14.5: WHO Common Toxicity Criteria) 
2. The subject experiences progressive hypersensitivity or severe hypersensitivity will be 
treated appropriately and may be withdrawn from the study, at the discretion of the 
treating Investigator and/or Medical Monitor (see Appendix 14.2: Infusion Rate 
Algorithm; and Appendix 14.3: Taliglucerase Alfa Hypersensitivity Evaluation and 
Treatment Algorithm) 
3. The subject, or subject’s parent or guardian, requests to discontinue treatment 
4. Investigator feels that it is not in the best interest of the subject to continue treatment 
and/or the Investigator believes that the subject can no longer be compliant with the 
requirements of the study 
5. Deteriorating clinical condition, which the Investigator decides additional treatments 
would be needed 
For any discontinuation, the Investigator will obtain all required details and document the date 
and the main reason for the premature discontinuation.  If the reason for discontinuation is an 
adverse event, the specific event or the main laboratory abnormality will be recorded in the case 
report form (CRF).  The Investigator will make thorough efforts to document the outcome.  The 
Investigator will attempt to continue to follow the subject for the full duration of the study or at 
least for 30 days following discontinuation. If circumstances prevent the subject from completing 
all visits, every attempt will be made to complete all procedures listed in Section 9.2.11 for 
Visit 27. 
6.3.4 
Replacement Policy 
Withdrawn subjects will not be replaced. 
7. 
STUDY PRODUCT 
7.1 
Study Medication Supply 
Reconstitution of each taliglucerase alfa vial (212 units) with sterile water for injection (5.1 mL) 
yields a final volume of 5.3 mL human taliglucerase alfa (40 U/mL), which provides a 
withdrawal volume of 5.0 mL (200 units).  The solution must be mixed gently until clear. 
7.2 
Description of Study Product 
Human taliglucerase alfa is a purified recombinant, plant cell-expressed glucocerebrosidase, 
which is described in detail in the taliglucerase alfa Prescribing Information (Appendix 14.1). 
Each 200 unit vial contains the following lyophilized ingredients: 
• 212 units of taliglucerase alfa 


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• 195 mg mannitol 
• 35 mg sodium citrate 
• 0.53 mg polysorbate 80, NF 
7.3 
Description of Comparator Product 
Not applicable. 
7.4 
Study Drug Administration 
Taliglucerase alfa will be administered over 1 to 2 hours (the total volume to be prepared and 
infused is 100-120 mL + 20 mL saline flushing of the system) for initial infusions in all subjects.  
Tolerability will be determined by vital signs taken 30 minutes after starting the infusion and 
symptoms during the infusion and for one hour after the infusion in the clinic and also by 
telephone contact the day after the first infusion.  If this initial rate of infusion is well tolerated, 
the infusion rate may be increased up to 2.0 mL/min (120 mL/hr) to deliver the volume of 
reconstituted enzyme plus 20 mL saline flush over 1 to 2 hours for all subsequent dose 
administrations (see Appendix 14.2: Infusion Rate Algorithm). 
7.5 
Packaging and Labeling 
Lyophilized drug powder is stored in 13.5 mL borosilicate glass (Type 1) bottles (Forma Vitrum 
AG, Hungary).  Lyophilization stoppers (Helvoet Pharma, Belgium) composed of two-leg 
brombutyl rubber are sealed with aluminum Snap Caps and polypropylene discs (Helvoet 
Pharma, Belgium). 
7.6 
Conditions for Storage and Use 
The study product is to be stored at 2°C to 8°C (36°F to 46°F) before reconstitution. 
7.7 
Method of Assigning Subjects to Treatment Groups 
Not applicable. 
7.8 
Dispensing, Compliance, and Accountability 
The Sponsor will provide drug accountability forms to assist the pharmacist in maintaining 
current and accurate inventory records covering receipt, dispensing, and the return of 
investigational drug supplies.  When a shipment is received, the pharmacist will verify the 
quantities received and return the acknowledgment to the study monitor or designee.  The 
pharmacist investigational drug accountability record includes the identification of the person to 
whom the drug is dispensed, the quantity and the date of dispensing and any returned or unused 
drug.  This record is in addition to any drug accountability information recorded on the CRF.  
These records will be readily available for inspection by a monitor or Sponsor audits and are 
open to regulatory authority inspection at any time. 
7.9 
Prior and Concomitant Therapy 
Medications having the potential to interfere with the evaluation of efficacy are excluded 
throughout the trial. 


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The following medications are strictly prohibited during the study: 
• Zavesca® (miglustat) 
• Ceredase® (algucerase) 
• Cerezyme® (imiglucerase) 
• Vpriv® (velaglucerase alfa) 
• Cerdelga® (eliglustat) 
The following medications are allowed and expected during the study: 
• Treatments for hypersensitivity, anaphylaxis, or anaphylactoid reactions, 
e.g., epinephrine, norepinephrine, glucagon, albuterol 
• Treatments for anemia, e.g., iron, folic acid, vitamin B12 
• Treatments for bone disease, e.g., bisphosphonates 
• Analgesics, e.g., nonsteroidal anti-inflammatory drugs (note: aspirin may be 
contraindicated due to its effects on platelets and risk for bleeding) 
8. 
EFFICACY AND SAFETY ASSESSMENTS 
8.1 
Efficacy Variables 
Spleen and liver volumes will be measured by MRI using a standardized protocol (see 
Appendix 14.4).  Hemoglobin and platelet counts will be measured locally by standard 
laboratory procedures, and biomarkers will be analyzed at a central laboratory 
Primary efficacy variable is: 
• Percent change in spleen volume (expressed in MN) from baseline to Month 12 
Secondary efficacy variables are: 
• Percent change in liver volume (expressed in MN) from baseline to Month 12 
• Percent change in hemoglobin from baseline to Months 3, 6, 9, and 12 
• Percent change in platelet count from baseline to Months 3, 6, 9, and 12 
• Percent change in Lyso-Gb1 from baseline to Months 3, 6, 9, and 12 
• Percent change in Chitotriosidase from baseline to Months 3, 6, 9, and 12 
 
Other efficacy variables are: 
• Change in height SDS from baseline to Months 3, 6, 9, and 12 
• Change in weight SDS from baseline to Months 3, 6, 9, and 12 
• Change in Tanner Stage from baseline to Month 12 
• Change in bone age (by X-ray of left hand and wrist) from baseline to Month 12 


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• Change in bone mineral density (DEXA) from baseline to Month 12 
• Change in mSST from screening Month 6 and 12 
8.2 
Safety Variables 
8.2.1 
Adverse Events 
8.2.1.1 
Adverse Events (AE) and Serious Adverse Events (SAE) 
An adverse event is any untoward medical occurrence in a subject participating in a clinical trial.  
An adverse event can be any unfavorable and unintended sign, symptom or disease temporally 
associated with the use of the study medication, whether or not considered related to the study 
medication.  Adverse events will be collected from the start of treatment until 30 days following 
the final visit dose.  Any events occurring prior to treatment will be recorded on the medical 
history page with the event name and onset date and end date if not continuing.  Pre-existing, 
known clinically significant conditions observed at screening should be recorded as medical 
history. 
This definition also includes accidental injuries, reasons for any change in medication (drug 
and/or dose) other than planned titration, reasons for admission to a hospital, or reasons for 
surgical procedures (unless for minor elective surgery for a pre-existing condition).  It also 
includes adverse events commonly observed and adverse events anticipated based on the 
pharmacological effect of the study medication.  Any laboratory abnormality assessed as 
clinically significant by the Investigator must be recorded as an adverse event. 
A treatment-emergent adverse event (TEAE) is any adverse event occurring after start of study 
medication and within the time of residual drug effect, or a pre-treatment adverse event or 
pre-existing medical condition that worsens in intensity after start of study medication and within 
the time of residual drug effect. 
Adverse events should be recorded as diagnoses, if available.  If not, separate sign(s) and 
symptom(s) are to be recorded.  One diagnosis/symptom should be entered per record. 
Note that death is not an event, but the cause of death is.  An exception is the event of sudden 
death of unknown cause.  Note that hospitalization is not an event; however, the reason for 
hospitalization is.  Procedures are not events; the reasons for conducting the procedures are.  In 
general, only the reason for conducting the procedure will be captured as an adverse event.  
However, if deemed necessary by the Investigator, a procedure can be captured along with the 
reason for conducting the procedure. 
An overdose or medication error is not an adverse event unless it is temporally associated with 
an unfavorable or unintended sign or symptom. 
Each adverse event is to be classified by the Investigator as serious or non-serious.  A serious 
adverse event (SAE) is any untoward medical occurrence or effect that occurs at any dose: 
• Results in death 
• Is life-threatening (i.e., an immediate risk of death) 
• Requires in-patient hospitalization or prolongation of existing hospitalization 


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• Results in persistent or significant disability/incapacity 
• Is associated with a congenital anomaly/birth defect 
• Is an important medical event 
An adverse event caused by an overdose or medication error is considered serious if a criterion 
listed in the definition above is fulfilled. 
Important adverse events that may not result in death, may not be life-threatening, or do not 
require hospitalization may be considered serious when, based on appropriate medical judgment, 
they may jeopardize the subject’s safety or may require medical or surgical intervention to 
prevent one of the outcomes listed above. 
Serious adverse events also include any other event that the Investigator or Sponsor judges to be 
serious or which is defined as serious by the regulatory agency. 
The Investigator is to report all directly observed adverse events and all adverse events 
spontaneously reported by the trial subject using concise medical terminology.  In addition, each 
trial subject will be questioned about adverse events.  The question asked will be “Since you 
began taking the study medication, have you had any health problems?” 
8.2.1.2 
Procedures for Assessing, Recording, and Reporting Adverse Events and Serious 
Adverse Events 
Throughout the duration of the study, the Investigator will closely monitor each subject for 
evidence of drug intolerance and for the development of clinical or laboratory evidence of 
adverse events.  All adverse events (expected or unexpected) that occur during the course of  the 
study, whether observed by the Investigator or by the subject, and whether or not thought to be 
drug-related, will be reported and followed until resolution or until they become stable. 
The description of the adverse event will include description of event, start date, stop date, 
intensity, if it was serious, relationship to test drug, change in test drug dosage, if the subject 
died, and if treatment was required. 
Adverse events will be coded to one of the following intensity categories below: 
Severity 
Definition 
Mild 
Awareness of signs or symptoms, but no disruption of usual activity 
Moderate 
Event sufficient to affect usual activity (disturbing) 
Severe 
Event causes inability to work or perform usual activities (unacceptable) 
 


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Adverse events will be coded into one of the following causality categories as defined below: 
Category 
Definition 
Unrelated 
Clearly and incontrovertibly due only to extraneous causes, and does not 
meet criteria listed under possible or probable. 
Unlikely 
Does not follow a reasonable temporal sequence from administration.  May 
have been produced by the subject’s clinical state or by environmental 
factors or other therapies administered. 
Possible 
Follows a reasonable temporal sequence from administration, but may have 
been also produced by the subject’s clinical state, environmental factors, or 
other therapies administered. 
Probable 
Clear-cut temporal association with administration with improvement on 
cessation of investigational medicinal product or reduction in dose.  
Reappears upon rechallenge.  Follows a known pattern of response to the 
investigational medicinal product. 
 
Adverse events with the causality assessed as unrelated or unlikely are categorized as not related 
to study medication. 
Adverse events with the causality assessed as possible or probable are categorized as related to 
study medication and are called adverse drug reactions. 
All SAEs must be reported immediately (no more than 24 hours after becoming aware of the 
event).  The Investigator must complete the eCRF SAE Report according to the Serious Adverse 
Event Report Form Instructions. 
8.2.2 
Clinical Laboratory 
The following laboratory tests will be analyzed locally by standard laboratory procedures: 
• Hematology: complete blood count, total white blood cell count, differential count 
(neutrophils, lymphocytes, monocytes, eosinophils and basophils), red blood cells 
(hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin and 
mean corpuscular hemoglobin concentration), platelets and reticulocytes. 
• Biochemistry: sodium, potassium, glucose, blood urea nitrogen, creatinine, calcium, 
phosphate (inorganic), uric acid, total protein, albumin, bilirubin (total), alkaline 
phosphatase, aspartate transaminase, alanine transaminase, gamma-glutamyl transferase, 
and lactate dehydrogenase, iron, activated AST (GOT), activated ALT(GPT), LDH, 
cholesterol,HDL cholesterol, C-reactive protein, TIBC. 
• Endocrynology: Ferritin, Vitamin D. 
• Urinalysis:  presence of glucose, ketones, protein, and leukocytes 
 
 


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8.2.3 
Vital Signs 
Vital signs measurements will include systolic/diastolic blood pressure, pulse rate, temperature, 
and respiratory rate. 
8.2.4 
Physical Examination 
Physical examination will include assessment of standard body systems. 
8.3 
Immunogenicity 
Anti-taliglucerase alfa antibodies, including neutralizing antibodies in subjects having a positive 
antibody response, will be assessed using a validated analytical method by a central laboratory. 
 
9. 
STUDY PROCEDURES AND FLOW CHART 


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9.1 
Study Flow Chart 
Table 1: 
Study Flow Chart 
Activity 
Visit 0 
Screening 
Visit 1 
Baseline 
Visits 
2-5 
 
Visit 6 
Visit 7 
Month 3 
Visits  
8-13 
Visit 14 
Month 6 
Visits  
15-19 
Visit 20 
Month 9 
Visits  
21-26 
Visit 27 
Month 12 
Day 
-50 ±10 
Day 1 
Weeks 2, 
4, 6, 8, 
(±3 days) 
Week 10 
(±3 days) 
Week 12  
(±7 days) 
Weeks 14, 
16, 18, 20, 
22, 24 
(±3 days) 
Week 26 
(±7 days) 
Weeks 28, 
30, 32,  
34, 36 
(±3 days) 
Week 38 
(±7 days) 
Weeks 40, 
42, 44, 46, 
48, 50 
(±3 days) 
Week 52d 
(±7 days) 
Sign informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Review inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Current/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight/height 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
Physical examination 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
Neurologic assessment 
X 
 
 
 
 
 
X 
 
 
 
X 
Hematology 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
Biochemistryf,g 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
Urinalysis 
X 
X 
 
 
X 
 
X 
 
X 
 
X 
Serology (HIV, HBsAg, HCV) 
X 
 
 
 
 
 
 
 
 
 
 
TSH, free T4, transferrin, B12 and 
folic acid 
X 
 
 
 
 
 
 
 
 
 
 
Beta HCG (post-menarcheal girls) 
X 
 
 
 
 
 
 
 
 
 
 
Vital signsh 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anti-taliglucerase alfa antibodies 
 
X 
 
 
 
 
X 
 
 
 
X 
Organ volumes (MRI) 
X 
 
 
 
 
 
 
 
 
 
X 
Ultrasound (liver and spleen) 
X 
 
 
 
 
 
X 
 
 
 
X 
Echocardiography 
X 
 
 
 
 
 
 
 
 
 
 
Tanner Stage 
 
X 
 
 
 
 
 
 
  
 
X 
X-ray of left hand and wrist 
 
X 
 
 
 
 
 
 
 
 
X 
DEXA 
 
X 
 
 
 
 
 
 
 
 
X 
mSST 
X 
 
 
 
 
 
X 
 
 
 
X 
Molecular analysise 
X 
 
 
 
 
 
 
 
 
 
 
Lyso-Gb1 biomarker 
 
X 
 
 
X 
 
X 
 
X 
 
X 
Chitotriosidase 
 
X 
 
 
X 
 
X 
 
X 
 
X 
IV infusion of taliglucerase alfa 
 
Xa 
Xb 
X 
Xc 
X 
Xc 
X 
Xc 
X 
Xc 
Observe subject clinically 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
Evaluate injection site 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
Adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
DEXA = dual-emission X-ray absorptiometry; HBsAg = hepatitis B surface antigen; HCG = human chorionic gonadotropin; HCV = hepatitis C virus; HIV = human immunodeficiency 
virus, IV = intravenous; MRI = magnetic resonance imaging; T4 = thyroxine; TSH = thyroid stimulating hormone 


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a A follow-up telephone call with the subject and/or parent or guardian will be held the day after the infusion. 
b Subjects who tolerate the infusions will be eligible for transfer to home or infusion center treatment after this visit at the discretion of the Investigator and Medical Monitor. 
c Taliglucerase alfa infusion must be done at the subject’s selected medical center. 
d All Month 12 (Week 52) procedures/assessments are to be done for any subject who withdraws or is discontinued from the study before completion. 
e Molecular  analysis will be done localy (if not done before), and a confirmation from Central Laboratory (Centogene) will be done using the CentoCard. 
f HDL, Phosphate inorganic and cholesterol assessments, which are taken at screening, should not be repeated at baseline, if done within a period of 1 month. 
g  ALT and AST assessments are enough if activated ALT and activated AST are done on site (or the way around). 
h Vital signs to be done once on screening visit, from baseline till visit 27; to be done only pre and post infusion, and as needed  if an AE occurs during infusion.  


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9.2 
Study Visits 
9.2.1 
Screening (Visit 0, Day -50 ± 10) 
The following procedures will be performed: 
1. Obtain written informed consent from the subject and/or parent or guardian 
2. Assign screening number 
3. Record demographic data 
4. Medical history 
5. Current medications 
6. Physical examination, including body weight and height 
7. Neurologic assessment 
8. mSST evaluation 
9. Molecular Analysis; Done locally (if not done before), and a confirmation from Central 
Laboratory (Centogene) will be done using the CentoCard) 
10. Vital signs (systolic/diastolic blood pressure, pulse rate, temperature, and respiration rate) 
11. MRI for spleen and liver volume 
12. Ultrasound for spleen and liver volume. 
 
13. Clinical laboratory tests: 
• Hematology 
• Biochemistry 
• Urinalysis 
• Thyroid stimulating hormone (TSH) 
• Free thyroxine (free T4) 
• Transferrin 
• Folic acid 
• Vitamin B12 
• Blood pregnancy test (beta-HCG) for females of childbearing potential 
• Serology for HIV, HBsAg, HCV 
14. Review all inclusion and exclusion criteria and determine subject’s eligibility 
15. Request for subject and/or parent or guardian approval 
9.2.2 
Visit 1 (Baseline, Day 1) 
The following procedures will be performed: 


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1. Concomitant medications 
2. Physical examination including body weight and height 
3. Clinical laboratory tests: 
• Hematology 
• Biochemistry; 
- 
 (HDL, Phosphate inorganic and cholesterol assessments, which are taken at 
screening, should not be repeated at baseline, if done within a period of 1 
month). 
- 
ALT and AST assessments are enough if activated ALT and activated AST 
are done on site (or the way around). 
• Urinalysis 
• Anti-taliglucerase alfa antibody test 
• Biomarkers: Lyso-Gb1 and Chitotriosidase 
4. Left hand and wrist X-ray for bone age 
5. Tanner Stage 
6. DEXA 
7. Taliglucerase alfa infusion 
8. Adverse event evaluation 
The following procedures will be performed after taliglucerase alfa dosing: 
1. Observe the subject clinically for a minimum of 1 hour post-dosing. 
2. Evaluate vital signs pre and post infusion, and as needed  if an AE occurs during infusion. 
Evaluate the injection site. 
3. A follow up telephone call with the subject and/or parent or guardian will be held the day 
after the infusion. 
The subject and/or parent or guardian will be reminded of the date of the next visit. 
9.2.3 
Visits 2 – 5 (Weeks 2, 4, 6, and 8 ± 3 Days) 
Subjects will receive their taliglucerase alfa infusion at their selected medical center.  The 
following procedures will be performed post-dosing: 
1. Observe the subject clinically for a minimum of 1 hour post-dosing. 
2. Evaluate vital signs pre and post infusion, and as needed  if an AE occurs during infusion.  
3. Evaluate the injection site. 
Adverse events and concomitant medications will be recorded at each visit. 


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Subjects will only receive transfusions at the medical center where they will be followed up and 
treated.  The procedures to be followed will depend on local standards of care and procedures 
established at the medical center Minimally, safety data (vital signs, adverse events, concomitant 
medications) will be recorded at each bi-weekly treatment with taliglucerase alfa administered at 
the medical center. 
The subject and/or parent or guardian will be reminded of the date of the next visit. 
9.2.4 
Visit 6 (Week 10 ± 3 Days) 
Subjects will receive their taliglucerase alfa infusion at their selected medical center.  The 
following procedures will be performed post-dosing: 
1. Adverse event evaluation. 
2. Concomitant medications. 
3. Vital signs pre and post infusion, and as needed  if an AE occurs during infusion.  
The subject and/or parent or guardian will be reminded of the date of the next infusion/visit. 
9.2.5 
Visit 7 (Month 3 [Week 12] ± 7 Days) 
All subjects will receive their taliglucerase alfa infusion at their selected medical center and have 
the following evaluations: 
1. Adverse event evaluation. 
2. Concomitant medications. 
3. Physical examination including body weight and height. 
4. Clinical laboratory tests: 
• Hematology 
• Biochemistry 
• Urinalysis 
• Biomarkers: Lyso-Gb1 and Chitotriosidase 
The following procedures will be performed post-dosing: 
1. Observe subjects clinically for 1 hour post-dosing 
2. Evaluate vital signs pre and post infusion, and as needed  if an AE occurs during infusion.  
3. Evaluate the injection site. 
The subject and/or parent or guardian will be reminded of the date of the next visit. 
9.2.6 
Visits 8 – 13 (Weeks 14, 16, 18, 20, 22, and 24 ± 3 Days) 
Subjects will receive their Taliglucerase alfa infusion at their selected medical center. The 
following procedures will be performed post-dosing: 
4. Adverse event evaluation. 


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5. Concomitant medications. 
6. Vital signs pre and post infusion, and as needed  if an AE occurs during infusion.  
The subject and/or parent or guardian will be reminded of the date of the next infusion/visit. 
9.2.7 
Visit 14 (Month 6 [Week 26] ± 7 Days) 
All subjects are required to return to their selected medical center to receive their taliglucerase 
alfa infusion and have the following evaluations: 
1. Adverse event evaluation 
2. Concomitant medications 
3. Physical examination including body weight and height 
4. Neurologic assessment 
5. Ultrasound for spleen and liver volume. 
6. mSST evaluation. 
7. Clinical laboratory tests: 
• Hematology 
• Biochemistry 
• Urinalysis 
• Biomarkers: Lyso-Gb1 and Chitotriosidase 
• Anti-taliglucerase alfa antibody test 
The following procedures will be performed post-dosing: 
1. Observe the subject clinically for 1 hour post-dosing 
2. Evaluate vital signs pre and post infusion, and as needed  if an AE occurs during infusion.  
3. Evaluate the injection site. 
The subject and/or parent or guardian will be reminded of the date of the next visit. 
9.2.8 
Visits 15 – 19 (Weeks 28, 30, 32, 34, and 36 ± 3 Days) 
Subjects will receive their taliglucerase alfa infusion at their selected medical center.  The 
following procedures will be performed post-dosing: 
1. Adverse event evaluation. 
2. Concomitant medications. 
3. Vital signs pre and post infusion, and as needed beforehence 
The subject and/or parent or guardian will be reminded of the date of the next infusion/visit. 


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9.2.9 
Visit 20 (Month 9 [Week 38] ± 7 Days) 
All subjects are required to return to their selected medical center to receive their taliglucerase 
alfa infusion and have the following evaluations: 
1. Adverse event evaluation. 
2. Concomitant medications. 
3. Physical examination including body weight and height. 
4. Clinical laboratory tests: 
• Hematology 
• Biochemistry 
• Urinalysis 
• Biomarkers: Lyso-Gb1 and Chitotriosidase 
The following procedures will be performed post-dosing: 
1. Observe the subject clinically for 1 hour post-dosing. 
2. Evaluate vital signs pre and post infusion, and as needed  if an AE occurs during infusion.  
3. Evaluate the injection site. 
The subject and/or parent or guardian will be reminded of the date of the next infusion/visit. 
9.2.10 
Visits 21 – 26 (Weeks 40, 42, 44, 46, 48, and 50 ± 3 Days) 
Subjects will receive their aliglucerase alfa infusion at their selected medical center. The 
following procedures will be performed post-dosing: 
1. Adverse event evaluation. 
2. Concomitant medications. 
3. Vital signs pre and post infusion, and as needed  if an AE occurs during infusion.  
The subject and/or parent or guardian will be reminded of the date of their next infusion/visit. 
9.2.11 
Visit 27 (Month 12 [Week 52] ± 7 Days) 
All subjects are required to return to their selected medical center to receive their taliglucerase 
alfa infusion and have the following evaluations: 
1. Physical examination including body weight and height. 
2. Neurologic assessment. 
3. MRI for spleen and liver volume. 
4. Ultrasound for spleen and liver volume. 
 
5. Clinical laboratory tests 


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• Hematology 
• Biochemistry 
• Urinalysis 
• Biomarkers: Lyso-Gb1 and Chitotriosidase 
• Anti-taliglucerase antibody test 
6. Left hand and wrist X-ray for bone age 
7. Tanner Stage 
8. DEXA  
9. mSST evaluation 
10. Adverse event evaluation 
11. Concomitant medications 
The following procedures will be performed post-dosing: 
1. Observe the subject clinically for 1 hour post-dosing. 
2. Evaluate vital signs pre and post infusion, and as needed  if an AE occurs during infusion 
3. Evaluate the injection site. 
9.2.12 
Early Termination Visit 
If the subject withdraws or is discontinued from the study before completion, the reason for 
discontinuation must be documented in the subject’s CRF.  Whenever a subject is discontinued, 
the procedures/assessments listed in Section 9.2.11 should be conducted, unless advised 
otherwise by the Medical Monitor. 
10. STATISTICAL METHODS PLANNED AND SAMPLE SIZE 
Detailed methodology for the summary and statistical analysis of the data collected in this study 
will be documented in a Statistical Analysis Plan (SAP), which will be prepared and finalized 
prior to database lock.  
10.1 Determination of Sample Size 
It is assumed that the Type 3 GD patients and Type 1 GD patients will have similar efficacy 
response to taliglucerase alfa 60 units/kg.  Given the fact that Type 3 GD usually develops at 
younger age and 60 units/kg is the recommended dose, data from the 5 treatment-naïve pediatric 
patients (Type 1 GD) treated with taliglucerase alfa 60 units/kg in Study PB-06-005 are used to 
calculate sample size.  Since the available data are limited and the data distribution is unknown, a 
responder rate is calculated from the percent change from baseline in spleen volume MN in these 
5 patients as a reference.  A subject is considered a responder if the subject has a reduction from 
baseline in spleen volume MN greater than 20%. 


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The sample size and power calculation are then estimated using the exact computation from a 
2-sided sign test for the null hypothesis that the responder rate is equal to 0.5 for this single-
group design.  This null hypothesis is corresponding to a median reduction of 20% in spleen 
volume at Month 12.  A sample size of 9 evaluable subjects will provide a power of 80.9% to 
detect a responder rate of 0.91 with an actual significant level of 0.04.  An actual significant level 
of 0.05 is not available when the data are discrete and the sample size is small.  
10.2 Analysis Populations 
Full analysis population is defined as all subjects who receive at least one complete dose (or 
partial dose if adverse events prevent complete infusion dose) of study medication. 
Per protocol population is defined as subjects who have the primary efficacy data collected at 
Month 12 and baseline, and receive at least one complete dose (or partial dose if adverse events 
prevent complete infusion dose) of study medication. 
The safety analysis population is equivalent to the full analysis population. 
10.3 Analysis 
10.3.1 
Demographics 
Continuous variables will be summarized with descriptive statistics (number, mean, standard 
deviation, median, minimum, and maximum).  For categorical variables, frequency counts and 
percentages will be presented. 
10.3.2 
Medical History 
Frequency counts will be provided for each body system. 
10.3.3 
Medications 
Data listings of the prior, concomitant medication, and class of medication will be provided. 
10.3.4 
Efficacy Analysis 
Efficacy variables are listed in Section 8.1. 
Analysis for the primary efficacy endpoint 
The primary efficacy evaluation will be the median percent change in spleen volume (expressed 
in MN) from baseline to Month 12 measured by MRI.  For the primary efficacy endpoint, a 
Wilcoxon signed rank test at 2-sided significance level of 0.05 will be applied to test the null 
hypothesis that the median percent change from baseline to Month 12 in spleen volume MN is 
equal to -20%.  The median percent change from baseline and the corresponding p-value will be 
reported. 
Frequency and percentage of the responders who have the reduction greater than 20% in spleen 
volume MN will be provided. The 95% confidence interval for the responder rate will be 
provided using Clopper-Pearson method.  
Analysis for the secondary efficacy endpoints 


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The percent change from baseline (Visit 1 or Screening) to each assessment time point will be 
calculated and summarized by visit with descriptive statistics (number, mean, median, standard 
deviation, minimum, and maximum) for spleen and liver volume (MN), hemoglobin, platelet 
count, chitotriosidase and Lyso-Gb1. 
The Wilcoxon signed rank test will be applied for the secondary efficacy endpoints: percent 
change from baseline to Month 12 in liver volume MN measured by MRI, hemoglobin, platelet 
count, and chitotriosidase and Lyso-Gb1 separately.  Though hemoglobin, platelet counts, 
chitotriosidase and Lyso-Gb1 will be collected at Month 3, 6 and 9 as well, no adjustment will be 
made for multiple comparisons, as the changes from baseline to Month 3, 6 and 9 will be 
descriptively summarized only. 
Analysis for other efficacy variables 
For change in growth and development, the height and weight will be assigned to a SDS-scores 
using the World Health Organization (WHO) Child Growth Standards.  The Centers for Disease 
Control and Prevention (CDC) reference standards will be used for the age categories where the 
WHO reference standards are not available.  Change in growth and development assessment 
from baseline to each visit will be summarized using descriptive statistics by visit. 
Descriptive statistics will also be reported for change in Tanner Stage, bone assessment 
(including bone age, bone mineral density and Z-score for each bone area), and mSST from 
screening to Month 6, Month 12. 
10.3.5 
Safety Analysis 
10.3.5.1 Adverse Events 
The Medical Dictionary for Regulatory Activities (MedDRA) (latest version) will be used to 
classify all adverse events to system organ class and preferred term. All adverse events occurring 
after the initiation of the study treatment (TEAEs) will be reported, including events present at 
baseline that worsened during the study. 
Adverse events will be summarized by overall incidence (the number of subjects reporting at 
least one episode of a specific adverse event), incidence of adverse events by severity within 
system organ class, incidence of adverse events by attribution within system organ class, and 
incidence of adverse events causing discontinuation, and incidence of serious adverse events.  
Regarding severity and attribution summaries, the most extreme outcome (highest severity and 
closest to study drug related) will be used for those subjects who experience the same adverse 
event on more than one occasion. 
Written narratives will be provided for all serious, unexpected, or other significant adverse 
events that are judged to be of special interest because of their clinical importance. 
10.3.5.2 Clinical Laboratory 
Lab data will be presented for the value and abnormality of each of the clinical laboratory results 
by visit.   


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10.3.5.3 Vital Signs 
Descriptive statistics will be presented for vital signs (systolic/diastolic blood pressure, pulse, 
temperature, and respiratory rate) at baseline (Visit 1) and Month 3, 6, 9 and 12 visits, including 
absolute values, change from baseline and percent change from baseline.   
10.3.5.4 Physical Examinations 
The physical examination data collected at screening and all post-treatment visits will be 
tabulated by frequency count and percentage of normal or abnormal findings for each body 
system. 
10.3.6 
Immunogenicity 
Antibody status (Positive / Negative) determined at baseline (Visit 1), Month 6, and Month 12 
will be tabulated by frequency count and percentage. 
11. QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 Source Data Records 
Source data are all the information in original records and certified copies of original records of 
clinical findings, observations, laboratory reports, data sheets provided by the Sponsor or other 
activities in the study, which are necessary for the reconstruction and evaluation of the study.  
The Investigator will permit study-related monitoring, audit(s), IRB review(s), and regulatory 
inspection(s), with direct access to all the required source records. 
All study records will be retained for a period of time as defined by the regulatory authority for 
the country in which the investigation is conducted.  Generally, this means at least 2 years 
following the date on which the drug is approved by the regulatory authority for marketing for 
the purposes that were the subject of the investigation.  In other situations (e.g., where the 
investigation is not in support of or as part of an application for a research or marketing permit), 
a period of 2 years following the date on which the entire clinical program is completed, 
terminated or discontinued or the investigational application under which the investigation is 
being conducted is terminated or withdrawn by the regulatory authorities. 
In the event the Investigator retires, relocates, or for any other reason withdraws from the 
responsibility for maintaining records for the period of time required, custody of the records may 
be transferred to any other person who will accept responsibility for the records.  Notice of such 
a transfer must be given in writing to the Sponsor.  The Investigator must contact the Sponsor 
before disposal of any records related to this study. 
11.2 Reporting of Results 
The CRF is an integral part of the study and subsequent reports.  The CRF must be used to 
capture all study data recorded in the subject’s medical record.  The CRF must be kept current to 
reflect subject status during the course of the study.  Only a subject screening number and 
subject initials will be used to identify the subject.  A CRF will be provided for each screened 
subject. 
The monitor is responsible for performing on-site monitoring at regular intervals throughout the 
study to verify adherence to the protocol; verify adherence to local regulations on the conduct of 


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clinical research; and ensure completeness, accuracy, and consistency of the data entered in the 
CRF. 
All protocol-required information collected during the study must be entered by the Investigator, 
or designated representative, in the Target e*CRF™, an Internet-based electronic data collection 
system.  All details of the CRF completion and correction will be explained to the investigator.  
The management module of Target e*CRF™ includes edit check and query systems that 
seamlessly integrate with the data entry system.  All modifications to the data in the eCRF are 
tracked by an electronic audit trail (date and identity of the person making the change are 
instantaneously recorded).  Target e*CRF™ is 21CFR Part 11 compliant. 
If the Investigator authorizes other persons to make entries in the CRF, the names, positions, and 
signatures of these persons must be supplied to the Sponsor. 
The Investigator, or designated representative, should complete the eCRF as soon as possible 
after information is collected, preferably on the same day that a study subject is seen for an 
examination, treatment, or any other study procedure. Any outstanding entries must be 
completed immediately after the final examination.  By design, an explanation must be provided 
for all missing data, altered data, and/or out of range data. 
The completed CRF must be reviewed and signed by the Investigator named in the study 
protocol or by a designated sub-investigator. 
Final monitored and audited eCRFs will be provided by the Sponsor to the sites at the end of the 
study in the format of a PDF file. 
11.3 Confidentiality of Subject Data 
The Investigator will ensure that the confidentiality of the subjects’ data will be preserved.  In 
the CRF or any other documents submitted to the Sponsor, the subjects will not be identified by 
their names, but by an identification system, which consists of their initials and number in the 
study.  The Investigator will maintain documents not meant for submission to the Sponsor, 
e.g., the confidential subject identification code and the signed informed consent forms, in strict 
confidence. 
12. REPORTING AND PUBLICATION 
12.1 Confidentiality of Subject Data 
Any information relating to the study product or the study, including any data and results from 
the study, will be the exclusive property of the Sponsor.  The Investigator and any other persons 
involved in the study will protect the confidentiality of this proprietary information belonging to 
the Sponsor. 
12.2 Publication Policy 
The Sponsor agrees to make the report of the multicenter study results available to Investigators 
for preparing a publication of the results in meeting abstract or medical journal form.  The 
Sponsor will have 30 days to review any proposed publication of the data for accuracy and 
proprietary information. 


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13. REFERENCES 
1. Jmoudiak M, Futerman AH. Gaucher disease: pathological mechanisms and modern 
management. Br J Haematol 2005;129(2):178-188. 
2. Zeller JL, Burke AE, Glass RM. JAMA patient page. Gaucher Disease. JAMA 
2007;298(11):1358. 
3. Amato D, Stachiw T, Clarke JT, Rivard GE. Gaucher disease: variability in phenotype 
among siblings. J Inherit Metab Dis 2004;27(5):659-669. 
4. Sidransky E. Gaucher disease: complexity in a “simple” disorder. Mol Genet Metab 
2004;83(1-2):6-15. 
5. Baris HN, Cohen IJ, Mistry PK. Gaucher disease: the metabolic defect, pathophysiology, 
phenotypes and natural history. Pediatr Endocrinol Rev 2014;12(Suppl 1):72-81. 
6. Charrow J, Andersson HC, Kaplan P, Kolodny EH, Mistry P, Pastores G, et al. The Gaucher 
registry: demographics and disease characteristics of 1698 patients with Gaucher disease. 
Arch Intern Med 2000;160(18):2835-2843. 
7. Biegstraaten M, van Schaik IN, Aerts JM, Hollak CE. “Non-neuronopathic” Gaucher disease 
reconsidered. Prevalence of neurological manifestations in a Dutch cohort of type I Gaucher 
disease patients and a systematic review of the literature. J Inherit Metab Dis 
2008;31(3):337-349. 
8. Lim-Melia ER, Kronn DF. Current enzyme replacement therapy for the treatment of 
lysosomal storage diseases. Pediatric Ann 2009;38(8):448-455. 
9. Cox TM. Gaucher disease: clinical profile and therapeutic developments. Biologics 
2010;4:299-313. 
10. Rosenbloom BE, Weinreb NJ. Bone disease in patients with Gaucher disease. Expert Review 
of Endocrinology & Metabolism 2014;9(2):153-162. 
11. Cerezyme (imiglucerase for injection). Prescribing information. Cambridge, MA: Genzyme 
Corporation; 2009. 
12. VPRIV (velaglucerase alfa for injection). Prescribing information. Cambridge, MA: Shire 
Human Genetic Therapies, Inc.; 2010. 
13. Shaaltiel Y, Bartfeld D, Hashmueli S, et al. Production of glucocerebrosidase with terminal 
mannose glycans for enzyme replacement therapy of Gaucher’s disease using a plant cell 
system. Plant Biotechnol J 2007;5:579-590. 
14. Taliglucerase alfa for injection. Prescribing Information. New York, NY: Pfizer, Inc.; 2016. 
15. Lee NC, Chien YH, Wong SL, Sheen JM, Tsai FJ, Peng SF, et al. Outcome of early-treated 
type III Gaucher disease patients. Blood Cells Mol Dis 2014;53(3):105-109. 


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16. Deegan P, Fernandez-Sasso D, Giraldo P, Lau H, Panahloo Z, Zimran A. Blood Cells Mol 
Dis 2016;S1079-9796(16):30213-3. 
17. Zimran A, Elstein D. Management of Gaucher disease: enzyme replacement therapy. Pediatr 
Endocrinol Rev 2014;12(Suppl 1):82-87. 
18. Kraoua I, Sedel F, Caillaud C, Froissart R, Stirnemann J, Chaurand G, et al. A French 
experience of type 3 Gaucher disease: phenotypic diversity and neurological outcome of 
10 patients. Brain Dev 2011;33(2):131–139. 
19. El-Beshlawy A, Tylki-Szymanska A, Vellodi A, Belmatoug N, Grabowski GA, Kolodny EH, 
et al. Long-term hematological, visceral, and growth outcomes in children with Gaucher disease type 
3 treated with imiglucerase in the International Collaborative Gaucher Group Gaucher Registry. 
Mol Genet Metab 2017;120 (1-2):47–56. 
 


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14. APPENDICES 
14.1 Appendix 1:  ELELYSO® Prescribing Information (US) 
 
 
 


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14.2 Appendix 2:  Infusion Rate Algorithm 
The infusion rate (IR) may be adjusted according to individual subject symptoms and signs.  The 
assumptions with respect to adverse experiences to the infusion are: 
1. Most of the subjects will tolerate the infusion without any special symptom or event.  The 
infusion rate may be increased over time to the maximal rate 2.0 mL/minute (or 
120 mL/hour) only after discussion with the Medical Monitor (an infusion duration of 
1 hour). 
2. Subjects presenting symptoms and signs of severe hypersensitivity will be evaluated 
according to the WHO Drug Toxicity criteria and there may be a discontinuation of 
treatment according to the protocol. 
3. Subjects may present signs and symptoms that will respond to reducing of the infusion 
rate and may not appear at the next infusion. 
4. Tolerability and the subject specific infusion rate will be assessed and decided by the 
Investigator according to vital signs and clinical status of the subject. 
Definitions to be applied regarding tolerability of infusions are as follows: 
Good Tolerability 
Partial Tolerability 
Poor Tolerability 
Infusion was performed 
without signs and symptoms 
(such as burning, pruritus, 
flushing, discomfort, or 
change in vital signs). 
Signs and symptoms 
appeared during the infusion 
and resolved after slowing 
infusion rate or at the end of 
the infusion. 
Signs and symptoms meeting 
the definitions of WHO 
Grade 1 or 2 toxicity 
responding to reduction of 
infusion rate or responding to 
treatment (example, 
antihistamine for urticaria). 
 
The specific algorithm to be followed is below. 
 
 


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Adjust IR 
according to 
protocol 
Adjust IR 
according to 
protocol 
Next infusion at a 
slower IR 
(= 1 treatment) 
<1.3 mL/min 
2.0 to 1.3 mL/min 
2.2 to 1.5 mL/min 
Evaluate 
tolerability and 
decide next IR 
Good 
Tolerability 
Partial 
Tolerability 
Poor 
Tolerability 
Evaluate tolerability of 
the infusion according 
to definitions 


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14.3 Appendix 3:  Taliglucerase Alfa Hypersensitivity Evaluation and 
Treatment Algorithm 
During and after infusion of taliglucerase alfa, the following algorithm will be followed to 
monitor and manage the occurrence of hypersensitivity, anaphylaxis, or anaphylactoid reactions. 
Clinical Signs 
Early 
• Sensations of warmth and itching 
• Feelings of anxiety or panic 
Moderate 
• Pruritus 
• Flushing 
• Urticaria 
• Chest discomfort 
• Mild hypotension 
Progressive 
• Erythematous or massive urticarial rash 
• Edema of face, neck, soft tissues 
Severe 
• Hypotension 
• Bronchospasm (wheezing) 
• Laryngeal edema (dyspnea, stridor, aphonia, drooling) 
• Arrhythmias 
 
Treatment Algorithm 
With the onset of any of the above clinical signs, immediately discontinue study medication 
administration and initiate the following monitoring: 
• Continuous electrocardiographic monitoring 
• Continuous pulse oximetry 
• Measure blood pressure every 5 minutes 
• Perform chest auscultation every 5 minutes 


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• Blood samples need to be collected for Tryptase (29-33) and antibodies.  Tryptase 
samples need to be withdrawn at: 
o 1st sample taken 0.25-3 hours after onset of symptoms 
o 2nd sample taken between 3-6 hours 
o 3rd sample taken 24-48 hours to verify the return to baseline 
In the case of progressive or severe hypersensitivity, treat appropriately and withdraw the subject 
from the study.  Treat as detailed below. 
Urticaria or edema of the face, neck, or soft tissues 
• Epinephrine 1:1000 solution, 0.5 mL subcutaneously, repeat as needed every 5-10 
minutes 
• Antihistamines 
• Corticosteroids 
Hypotension (systolic blood pressure (SBP) ≤90 mmHg) 
• Isotonic sodium chloride solution, 1 L every 30 minutes as needed to maintain SBP 
>90 mmHg 
• Epinephrine 1:10,000 solution given IV at 1 μg/minute initially, then 2-10 μg/minute to 
maintain SBP >90 mmHg 
• Norepinephrine 4 mg in 1 L 5% dextrose in water given IV at 2-12 μg/minute to maintain 
SBP >90 mmHg 
• Glucagon 1 mg in 1 L 5% dextrose in water given IV at 5-15 μg/minute for refractory 
hypotension 
Bronchospasm 
• Oxygen by face mask at 6-8 L/minute to maintain oxygen saturation at >90% 
• Epinephrine 1:1000 solution, 0.5 mL subcutaneously 
• Albuterol 0.5 mL of 0.5% solution in 2.5 mL of sterile saline every 15 minutes  
up to three doses 
• Inhaled beta-agonists 
• Corticosteroids 
Laryngeal edema 
• Epinephrine 1:1000 solution, 0.5 mL subcutaneously, repeat as needed every  
5 to 10 minutes 
• Corticosteroids 
 


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Premedication 
Premedication for subsequent taliglucerase alfa infusions may be considered at the discretion of 
the Investigator and Medical Monitor for subjects experiencing early clinical signs of 
hypersensitivity or rash/urticaria that responds promptly to oral antihistamine administration (see 
also Appendix 14.2 for adjustment of infusion rate).  The premedication will be applied 
according to the following steps as needed to prevent progressive hypersensitivity: 
• Antihistamine (H1 blocker: diphenhydramine, hydroxyzine, cetrizine, loratadine, 
desloratidine) at a standard dose 12 hours and 2 hours before the start of the infusion 
• H1 blocker plus H2 blocker (ranitidine, cimetidine, famotidine) at standard doses 
12 hours and 2 hours before the start of the infusion 
• H1 blocker plus H2 blocker plus prednisone up to 50 mg administered 12 hours and 
2 hours before the start of the infusion 


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14.4 Appendix 4:  Magnetic Resonance Imaging (MRI) 
14.4.1 
Subject and Sites 
Nine subjects will be enrolled in this study by 5 to 10 sites worldwide. 
14.4.2 
MRI Data 
Each subject enrolled in this study will have 2 MRI time points during the course of the trial at 
Baseline and Month 12 (or early termination).  For each time point, the same set of T1 and T2-
weighted MRI sequences will be acquired.  An imaging manual will be shared with sites to 
outline the scanning protocol.  The exact sequence parameters will be defined based on site’s 
equipment and abilities to provide sufficient image quality and contrast for organ (spleen and 
liver) detection and quantification, and full spleen and liver coverage in GD subjects.  No 
contrast agent will be used.   
An MRI of the abdomen containing the entire spleen and liver will be collected at the Screening 
visit (Day -25 ± 10) and Week 52 Visit (± 7 days).  Volumes of liver and spleen will be 
evaluated centrally by an independent radiologist.  All scans should be submitted within 2 days 
of acquisition to allow quality review by the central radiologist. . The MRI site must confirm the 
scan is acceptable prior to sending images for central review.  The inspection by the site will 
include complete anatomic coverage of the liver and spleen.  Scans that are not accepted by the 
central radiologist may result in rescan requests.  The method of evaluation used for each patient 
at baseline should remain consistent for the duration of the study. In instances when the scan 
must be repeated (ie, if upon submission to the central radiologist, quality control issues are 
identified and communicated to the site) the repeated scan must be evaluated.  
14.4.3 
MRI Evaluation Parameters 
The following MRI parameters will be evaluated during this study: 
• Volume of spleen (in cm3) 
• Volume of liver (in cm3) 
14.4.3.1 Standardization of Image Acquisition, Initial Site Qualification 
The image acquisition procedure will be provided to sites in a separate image acquisition 
manual.  The same image acquisition and management procedure will be used by all sites.  All 
images will be anonymized by the sites (in order to remove any subject-related nominative 
information) and provided in digital format (DICOM).  Only digital images will be centrally 
processed by the central radiologist. 
14.4.3.2 Subject Sedation 
Pediatric subjects may require sedation in order to obtain the high quality images required.  Sites 
may use standard sedation protocols approved by the institution. 
14.4.3.3 Quality Control of Image Data and Site Quality Assurance During the Course of 
the Study 
The image data will be collected and quality inspected by the central radiologist for checking the 
technical adequacy, the compliance of data acquisition with the imaging guidelines  and the 


Protocol Number WI224302 
10Dec2021 
 
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diagnostic quality of the images (their appropriateness for centralized evaluations).  If any 
quality-related issue is detected by the central reviewer this will be communicated to the site.  


Protocol Number WI224302 
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14.5 Appendix 5:  WHO Common Toxicity Criteria 
 
Category 
Toxicity 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Hematology 
WBC (x103/L) 
4 
3.0 - 3.9 
2.0 - 2.9 
1.0 - 1.9 
< 1.0 
Hematology 
Platelets (x103/L) 
WNL 
75.0 - normal 
50.0 - 74.9 
25.0 - 49.9 
< 25.0 
Hematology 
Hemoglobin (g/dL) WNL 
10.0 - normal 
8.0 - 9.9 
6.5 - 7.9 
< 6.5 
Hematology 
Granulocytes/ 
Bands 
2 
1.5 - 1.9 
1.0 - 1.4 
0.5 - 0.9 
< 0.5 
Hematology 
Lymphocytes 
(x103/L) 
2 
1.5 - 1.9 
1.0 - 1.4 
0.5 - 0.9 
< 0.5 
Hematology 
Hemorrhage 
none 
mild, no 
gross, 1 - 2 units 
transfusion per episode 
gross, 3 - 4 units 
transfusion per episode 
massive, > 4 units 
transfusion per episode 
Coagulation 
Fibrinogen 
WNL 
0.99 - 0.75 x N 
0.74 - 0.50 x N 
0.49 - 0.25 x N 
< 0.25 x N 
Coagulation 
Prothrombin 
time(Quick) 
WNL 
1.01 - 1.25 x N 
1.26 - 1.50 x N 
1.51 - 2.00 x N 
> 2.00 x N 
Coagulation 
Partial thrombo- 
plastin time 
WNL 
1.01 - 1.66 x N 
1.67 - 2.33 x N 
2.34 - 3.00 x N 
> 3.00 x N 
Metabolic 
Hyperglycemia 
(mg/dL) 
< 116 
116 - 160 
161 - 250 
251 - 500 
> 500 or ketoacidosis 
Metabolic 
Hypoglycemia 
(mg/dL) 
> 64 
55 – 64 
40 - 54 
30 - 39 
< 30 
Metabolic 
Amylase 
WNL 
< 1.5 x N 
1.5 - 2.0 x N 
2.1 - 5.0 N 
> 5.0 x N 
Metabolic 
Hypercalcemia 
(mg/dL) 
< 10.6 
10.6 - 11.5 
11.6 - 12.5 
12.6 - 13.4 
13.5 
Metabolic 
Hypocalcemia 
(mg/dL) 
> 8.4 
8.4 - 7.8 
7.7 - 7.0 
6.9 - 6.1 
6 
Metabolic 
Hypomagnesemia 
(mg/dK) 
> 1.4 
1.4 - 1.2 
1.1 - 0.9 
0.8 - 0.6 
0.5 
 


Protocol Number WI224302 
10Dec2021 
 
Page 52 
 
Category 
Toxicity 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Gastrointestinal Nausea 
none 
able to eat reasonable intake 
intake significantly 
decreased but can eat 
no significant intake 
----- 
Gastrointestinal Vomiting 
none 
1 episode in 24 hrs 
2 - 5 episodes in 24 hrs 
6 - 10 episodes in 24 hrs 
> 10 episodes in 24 hrs 
or requiring parenteral 
support 
Gastrointestinal Diarrhea 
none 
increase of 2 - 3 stools / day 
over pre-Rx 
increase of 4 - 6 stools / 
day, or nocturnal stools, or 
moderate cramping 
increase of 7 - 9 stools / 
day, or incontinence, or 
severe cramping 
increase of > 10 stools 
/ day or grossly bloody 
diarrhea, or need for 
parenteral support 
Gastrointestinal Stomatitis 
none 
painless ulcers, erythema, or 
mild soreness 
painful erythema, edema, 
or ulcers but can eat solids 
painful erythema, 
edema, or ulcers and 
cannot eat solids 
requires parenteral or 
enteral support for 
alimentation 
Liver 
Bilirubin (N = 17 
µmol/L) 
WNL 
----- 
< 1.5 x N 
1.5 - 3.0 x N 
> 3.0 x N 
Liver 
Transaminase 
(SGOT, SGPT) 
WNL 
2.5 x N 
2.6 - 5.0 x N 
5.1 - 20.0 x N 
> 20.0 x N 
Liver 
Alk phos or 5 
nucleotidase 
WNL 
< 2.5 x N 
2.6 - 5.0 x N 
5.1 - 20.0 x N 
> 20.0 x N 
Liver 
Liver- clinical 
No change 
from baseline ----- 
----- 
precoma 
hepatic coma 
Kidney, bladder Creatinine 
WNL 
< 1.5 x N 
1.5 - 3.0 x N 
3.1 - 6.0 x N 
> 6.0 x N 
Kidney, bladder Proteinuria 
No change 
1 (+) or < 0.3 g% or 3 g/L 
2 - 3 (+) or 0.3 - 1.0 g% or 
3 - 10 g/L 
4 (+) or > 1.0 g% or > 
10g/L 
nephrotic syndrome 
Kidney, bladder Hematuria 
Negative 
microscopic only 
gross, no clots no Rx 
needed 
gross and clots bladder 
irrigation 
requires trans fusion 
or cystectomy 
Kidney, bladder Weight gain/ loss 
< 5.0 % 
5.0 - 9.9 % 
10.0 - 19.9 % 
20.00% 
----- 
Pulmonary 
Pulmonary 
none or no 
change 
asymptomatic, with  
abnormality in PFTs 
dyspnea on significant 
exertion 
dyspnea at normal 
level of activity 
dyspnea at rest 
 
 
 


Protocol Number WI224302 
10Dec2021 
 
Page 53 
 
Category 
Toxicity 
Grade 0 
Grade1 
Grade2 
Grade3 
Grade4 
Cardiac 
Cardiac arrhythmias none 
asymptomatic, transient, 
requiring no therapy 
recurrent or persistent, no 
therapy required 
requires treatment 
requires monitoring; or 
hypotension, or 
ventricular tachycardia 
or fibrillation 
Cardiac 
Cardiac function 
none 
asymptomatic, decline of 
resting ejection fraction by less 
than 20 % of baseline value 
asymptomatic, decline of 
resting ejection fraction by 
more than 20 % of baseline 
value 
mild CHF, responsive to 
therapy 
severe of refractory 
CHF 
Cardiac 
Cardiac ischemia 
none 
non-specific T- wave flattening 
asymptomatic, ST and T 
wave changes suggesting 
ischemia 
angina without evidence 
of infraction 
acute myocardial 
infarction 
Cardiac 
Cardiac-pericardial none 
asymptomatic effusion, no 
intervention required 
pericarditis (rub, chest 
pain, ECG changes) 
symptomatic effusion; 
drainage required 
tamponade; drainage 
urgently required 
Cardiac 
Hypertension 
none or no 
change 
asymptomatic, transient 
increase by greater than 20 mm 
Hg (D) or to > 150 / 100 if 
previously WNL. No treatment 
required. 
recurrent or persistent 
increase by greater than 20 
mm HG (D) or to > 150 / 
100 if previously WNL.  
No treatment required. 
requires therapy 
hypertensive crisis 
Cardiac 
Hypotension 
none or no 
change 
changes requiring no therapy 
(including transient orthostatic 
hypotension) 
requires fluid replacement 
or other therapy but not 
hospitalization 
requires therapy and 
hospitalization; resolves 
within 48 hours of 
stopping the agent 
requires therapy and 
hospitalization for 
> 48 hrs after stopping 
the agent 
Neurologic 
Neuro: sensory 
none or no 
change 
mild paresthesia; loss of deep 
tendon reflexes 
mild or moderate objective 
sensory loss moderate 
paresthesia 
severe objective sensory 
loss or paresthesia that 
interfere with function 
----- 
Neurologic 
Neuro: motor 
none or no 
change 
subjective weakness; no 
objective findings 
mild objective weakness 
without significant 
impairment of function 
objective weakness with 
impairment of function 
paralysis 
 
 
 


Protocol Number WI224302 
10Dec2021 
 
Page 54 
 
 
Category 
Toxicity 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Neurologic 
Neuro: cortical 
none 
mild somnolence or agitation 
moderate somnolence or 
agitation 
severe somnolence,  
(>50% waking 
hours), agitation, 
confusion, 
disorientation or 
hallucinations 
coma, seizures, toxic 
psychosis 
Neurologic 
Neuro: cerebellar 
none 
slight incoordination, 
dysdiadochokinesia 
intention tremor, 
dysmetria, slurred speech, 
nystagmus 
locomotor ataxia 
cerebellar necrosis 
Neurologic 
Neuro: mood 
no change 
mild anxiety or depression 
moderate anxiety or 
depression 
severe anxiety or 
depression 
suicidal ideation 
Neurologic 
Neuro: headache 
none 
mild 
moderate or severe but 
transient 
unrelenting and severe 
----- 
Neurologic 
Neuro: constipation none or no 
change 
mild 
moderate 
severe 
ileus > 96 hrs 
Neurologic 
Neuro: hearing 
none or no 
change 
asymptomatic, hearing loss on 
audiometry only 
tinnitus 
hearing loss interfering 
with function but 
correctable with hearing 
aid 
deafness not 
correctable 
Neurologic 
Neuro: vision 
none or no 
change 
----- 
----- 
symptomatic subtotal 
loss of vision 
blindness 
Pain 
Pain 
none 
mild 
moderate 
severe 
requires narcotics 
Skin 
Skin 
none or no 
change 
scattered macular or papular 
eruption or erythema that is 
asymptomatic 
scattered macular or 
papular eruption or 
erythema with pruritus or 
other associated symptoms 
generalized symptomatic 
macular, papular or 
vesicular eruption 
exfoliative dermatitis 
or ulcerating dermatitis 
Alopecia 
Alopecia 
no loss 
mild hair loss 
pronounced or total hair 
loss 
----- 
----- 
 
 


Protocol Number WI224302 
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Page 55 
 
Category 
Toxicity 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Allergy 
Allergy 
none 
transient rash, drug fever 
< 38°C (100.4°F) 
urticaria, drug fever 38°C 
(100.4°F), mild 
bronchospasm 
serum sickness, 
bronchospasm requiring 
parenteral medication 
anaphylaxis 
Local 
Local 
none 
pain 
pain and swelling with 
inflammation or phlebitis 
ulceration 
plastic surgery 
indicated 
Fever of 
unknown origin 
Fever of unknown 
origin 
none 
37.1 - 38.0°C 98.7° - 100.4°F 
38.1 - 40.0°C 100.5 - 
104°F 
> 40.0°C > 104.0°F for 
less than 24hrs 
> 40.0°C (>104°F) for 
more than 24 hrs or 
accompanied by 
hypotension 
Infection 
Infection 
none 
mild 
moderate 
severe 
life-threatening 
Additional 
events 
Asthenia 
analogous to 
Karnofsky 
index (WHO 
grading) 
Additional 
events 
Chills 
Analogous to 
fever 
Additional 
events 
Peripheral edema 
analogous to 
weight gain 
Additional 
events 
Anorexia 
analogous to 
weight loss 
 
 
 

SAP_001.pdf: 
Study Title: 
A Multicenter, Safety and Efficacy Study of Taliglucerase Alfa in Subjects With Type 3 Gaucher 
Disease 
NCT Number: 
NCT04002830 
Statistical Plan Date: 
24 September 2020 
 


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Protocol WI224302
A MULTICENTER, SAFETY AND EFFICACY STUDY OF TALIGLUCERASE 
ALFA IN SUBJECTS WITH TYPE 3 GAUCHER DISEASE
Statistical Analysis Plan 
(SAP)
Version:
1
Date:
24 Sep 2020


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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................4
APPENDICES ...........................................................................................................................4
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................5
2.1. Study Objectives, Endpoints, and Estimands............................................................6
2.1.1. Primary Estimand(s).....................................................................................6
2.1.2. Secondary Estimand(s).................................................................................6
2.1.3. Additional Estimand(s).................................................................................7
2.2. Study Design .............................................................................................................7
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ..................................................................................................................7
3.1. Primary Endpoint ......................................................................................................8
3.2. Secondary Endpoint(s) ..............................................................................................8
3.2.1. Liver Volume by MN ...................................................................................8
3.2.2. Hemoglobin (g/dL).......................................................................................8
3.2.3. Platelet Count (103/uL).................................................................................8
3.2.4. Lyso-Gb1 Biomarker (ng/mL)......................................................................8
3.2.5. Chitotriosidase (nmol/ml/hr) ........................................................................9
3.3. Other Endpoint(s)......................................................................................................9
3.3.1. Height SDS and Weight SDS .......................................................................9
3.3.2. Tanner Stage .................................................................................................9
3.3.3. Bone Measurement.......................................................................................9
3.3.4. Modified Severity Scoring Tool (mSST) ...................................................10
3.3.5. Organ Volumes measured by Ultrasound...................................................10
3.4. Baseline Variables...................................................................................................10
3.5. Safety Endpoints .....................................................................................................10
3.5.1. Adverse Events...........................................................................................10
3.5.2. Laboratory Data..........................................................................................11
3.5.3. Vital Signs ..................................................................................................11
3.5.4. Antibodies...................................................................................................11
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................11


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5. GENERAL METHODOLOGY AND CONVENTIONS....................................................12
5.1. Hypotheses and Decision Rules ..............................................................................12
5.2. General Methods .....................................................................................................12
5.2.1. Analyses for Binary Endpoints...................................................................12
5.2.2. Analyses for Continuous Endpoints ...........................................................12
5.2.3. Analyses for Categorical Endpoints ...........................................................13
5.2.4. Analyses for Time-to-Event Endpoints ......................................................13
5.3. Methods to Manage Missing Data ..........................................................................13
6. ANALYSES AND SUMMARIES ......................................................................................13
6.1. Primary Endpoint ....................................................................................................13
6.1.1. Main Analysis.............................................................................................13
6.1.2. Sensitivity/Supplementary Analyses ..........................................................14
6.2. Key Secondary Endpoints .......................................................................................14
6.2.1. Main Analysis.............................................................................................14
6.2.2. Sensitivity/Supplementary Analysis...........................................................15
6.3. Other Secondary Endpoints.....................................................................................15
6.4. Other Endpoint(s)....................................................................................................16
6.4.1. Immunogenicity (Antibodies).....................................................................16
6.5. Subset Analyses.......................................................................................................16
6.6. Baseline and Other Summaries and Analyses.........................................................16
6.6.1. Baseline Summaries....................................................................................16
6.6.2. Study Conduct and Participant Disposition................................................16
6.6.3. Study Treatment Exposure .........................................................................17
6.6.4. Concomitant Medications and Nondrug Treatments..................................17
6.7. Safety Summaries and Analyses .............................................................................17
6.7.1. Adverse Events...........................................................................................17
6.7.2. Laboratory Data..........................................................................................17
6.7.3. Vital Signs ..................................................................................................17
6.7.4. Physical Examination .................................................................................18
7. INTERIM ANALYSES.......................................................................................................18
8. REFERENCES ....................................................................................................................18
9. APPENDICES .....................................................................................................................19


Protocol WI224302 (Taliglucerase Alfa) Statistical Analysis Plan
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LIST OF TABLES
Table 1.
Summary of Changes..................................................................................5
APPENDICES
Appendix 1. Summary of Efficacy Analyses...........................................................................19
Appendix 2. Data Derivation Details.......................................................................................21
Appendix 2.1. Definition and Use of Visit Windows in Reporting.........................................21
Appendix 2.2. Endpoint Derivations .......................................................................................22
Appendix 2.3. Definition of Protocol Deviations That Relate to Statistical 
Analyses/Populations................................................................................22
Appendix 3. Data Set Descriptions..........................................................................................22
Appendix 4. Statistical Methodology Details..........................................................................23
Appendix 5. List of Abbreviations...........................................................................................24


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1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated 
Protocol 
Amendment
Rationale
Specific Changes
V1
Amendment 4
Original SAP
No
2. INTRODUCTION
Gaucher disease (GD) is a rare genetic disorder of lipid metabolism and is the most common 
inherited lysosomal storage disorder, thought to affect around 10,000 people globally. 
Gaucher disease is classified into 3 major phenotypic subcategories based on the absence 
(Type 1) or presence and severity (Types 2 and 3) of primary central nervous system 
involvement.  Gaucher disease Type 3 (except Type 3c), the population under study in this 
current protocol, affects approximately 5% of documented GD cases.  Type 3 GD is 
associated with progressive neurodegenerative disease, with symptom onset usually between 
infancy and adolescence.  Manifestations of Type 3 GD vary among patients, ranging from 
visceral and bone disease, cytopenia, hearing impairment, supranuclear gaze palsy, 
developmental delay, and cardiac calcification to myoclonic encephalopathy with seizures 
and eventual death.
Taliglucerase alfa, a hydrolytic lysosomal glucocerebroside-specific enzyme for intravenous 
infusion, is a recombinant active form of the lysosomal enzyme, β-GCD
(β-glucocerebrosidase), produced using transgenic carrot plant root cells grown in 
suspension culture with a modified gene sequence encoding human β-GCD.  Taliglucerase 
alfa is currently an approved therapy in the United States and many other countries for 
adults and children with a confirmed diagnosis of Type 1 GD, and is also approved for use in 
Type 3 GD in a small number of countries.
The effects of enzyme replacement therapy (ERT) on patients with Type 1 GD have been 
clearly documented and have a beneficial effect on visceral and hematologic disease 
parameters. It is known that recombinant enzyme does not pass the blood-brain barrier and 
has no effect on neurologic involvement.  This prospective study aims to objectively evaluate 
the hematologic and visceral effects of ERT with taliglucerase alfa on a rather clinically and 
genetically homogenous group of treatment-naïve patients with Type 3 GD.  The results of
this study are expected to provide a more objective view of the degree of response of this 
patient type, and potentially create new areas of research.
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study WI224302.  This document may modify the 
plans outlined in the protocol; however, any major modifications of the primary endpoint 
definition or its analysis will also be reflected in a protocol amendment.


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2.1. Study Objectives, Endpoints, and Estimands
The efficacy objectives of this study are to assess the efficacy of taliglucerase alfa in subjects 
with Type 3 GD, as measured by percent change from baseline in spleen and liver volume 
evaluated by magnetic resonance imaging (MRI), hemoglobin, platelet count, and 
lyso-glucosylsphingosine (Lyso-Gb1); change from baseline in growth and development 
(height, weight, sexual development by Tanner classification, and bone age by X-ray of left 
hand and wrist), bone mineral density evaluated by dual-emission X-ray absorptiometry 
(DEXA), and evaluation of fatigue.
The safety of taliglucerase alfa will be assessed by adverse events, clinical laboratory tests, 
vital signs, and physical examinations.  Anti-taliglucerase alfa antibodies will also be 
assessed.
2.1.1. Primary Estimand(s)
The primary estimand of this study uses the treatment policy strategy and estimates the effect 
for all participants are treated and regardless of whether an intercurrent event occurs.  It 
includes the following 4 attributes: 

Population: All patients who suffer from the Type 3 GD as defined by the inclusion 
and exclusion criteria, and who have received at least one complete dose (or partial 
dose if adverse events prevent completing infusion dose);

Variable: Percent change from baseline to Month 12 in spleen volume expressed in 
MN (Multiples of Normal) and measured by MRI (Magnetic Resonance Imaging);

Intercurrent event: All data after an intercurrent event (discontinuation of treatment, 
discontinuation of study, etc), if collected, will be included;  

Population-level summary: median percent change from baseline to Month 12 and 
p-value from the Wilcoxon signed ranks test.
2.1.2. Secondary Estimand(s)
There are couple of secondary estimands of this study, which estimate the effect for all 
participants treated and regardless of whether an intercurrent event occurs.  Each of them
includes the following 4 attributes: 

Population: All patients who suffer from the Type 3 GD as defined by the inclusion 
and exclusion criteria, and who have received at least one complete dose (or partial 
dose if adverse events prevent completing infusion dose);

Variable: 

Percent change from baseline to Month 12 in liver volume expressed in MN and 
measured by MRI;


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
Percent change from baseline to Month 12 in hemoglobin;

Percent change from baseline to Month 12 in platelet;

Percent change from baseline to Month 12 in Lyso-Gb1
(lyso-glucosylsphingosine);

Percent change from baseline to Month 12 in chitotriosidase.

Intercurrent event: All data after an intercurrent event (discontinuation of treatment, 
discontinuation of study, etc), if collected, will be included;  

Population-level summary: median percent change from baseline to Month 12 and 
p-value from the Wilcoxon signed ranks test. 
2.1.3. Additional Estimand(s)
The responders to the primary efficacy endpoint are defined as participants who had the 
reduction from baseline greater than 20% in spleen volume MN.  The responder rate among 
all patients received at least one complete dose, will be used as the populatin-level summary 
for this alternative estimand. 
2.2. Study Design
This is a multicenter study to assess the safety and efficacy of taliglucerase alfa (60 units/kg) 
in previously untreated subjects of any age with Type 3 GD.  Subjects will receive an infusion 
of taliglucerase alfa every 2 weeks for 12 months.  Subjects who tolerate the infusions well 
for 3 months will be eligible for home therapy based on approval of the Investigator.
Type 3 GD is a very rare genetic orphan disease.  This study will not have a placebo control 
group because it would be unethical to deny patients the possibility to improve their 
symptomology with an ERT that has been proved efficacious and safe, not only for Type 1
GD in many countries but also for Type 3 GD in a small number of countries.  Thus, all 
subjects will receive the investigational product in this study.
The parameters chosen as endpoints for this study are the most relevant parameters to GD 
and allow a significant and relevant evaluation of improvement as a result of treatment for 
12 months.  Improvement in the clinical manifestations of the disease leads to the 
achievement of the therapeutic goals of GD treatment in the medical community, which are 
improved fatigue and decreased risk for morbidities.
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
Percent change from baseline will be calculated at the participant level = [(Post baseline 
value – Baseline)/Baseline] * 100%


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3.1. Primary Endpoint
The primary efficacy evaluation will be the percent change in spleen volume (expressed in 
MN) measured by MRI from baseline to Month 12.  
Spleen volume will be measured at the Screening and Month 12 according to the Schedule of 
Activities in Section 9 of the protocol, measured by MRI by site according to the Appendix 4 
of the protocol. The spleen volume (cm3) will be used for the sponsor to calculate the spleen 
volume by multiples of normal (MN) data applying the formula below:  
weight
body
kg
cm
Volume
Spleen
MN
by
Volume
Spleen
*
/
2
3

When body weight (kg) is not available at a visit, the body weight measured in the previous 
visit will be used to estimate the participant’s expected normal volume at the visit.
3.2. Secondary Endpoint(s)
3.2.1. Liver Volume by MN
The secondary efficacy evaluation will be the percent change in liver volume (expressed in 
MN) measured by MRI from baseline to Month 12.  
Liver volume will be measured at the Screening and Month 12 according to the Schedule of 
Activities in Section 9 of the protocol, measured by MRI by site according to the Appendix 4 
of the protocol. The spleen volume (cm3) will be used for the sponsor to calculate the liver
volume by multiples of normal (MN) data applying the formula below:  
weight
body
kg
cm
Volume
Liver
MN
by
Volume
Liver
*
/
25
3

When body weight (kg) is not available at a visit, the body weight measured in the previous 
visit will be used to estimate the participant’s expected normal volume at the visit.
3.2.2. Hemoglobin (g/dL)
Hemoglobin will be measured at Screening, Baseline, Month 3, Month 6, Month 9 and 
Month 12 according to the Schedule of Activities in Section 9 of the protocol.
3.2.3. Platelet Count (103/uL)
Platelets will be counted at Screening, Baseline, Month 3, Month 6, Month 9 and Month 12 
according to the Schedule of Activities in Section 9 of the protocol.
3.2.4. Lyso-Gb1 Biomarker (ng/mL)
Lyso-Gb1 (lyso-glucosylsphinegosine) will be measured at Baseline, Month 3, Month 6, 
Month 9 and Month 12 according to the Schedule of Activities in Section 9 of the protocol.


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3.2.5. Chitotriosidase (nmol/ml/hr)
Chitotriosidase will be measured at Baseline, Month 3, Month 6, Month 9 and Month 12 at 
the same schedule of the biomarker of Lyso-Gb1 according to the Schedule of Activities in 
Section 9 of the protocol.
3.3. Other Endpoint(s)
3.3.1. Height SDS and Weight SDS
For change in growth and development, the height and weight will be assigned to a 
SDS/Z-scores using the World Health Organization (WHO) Child Growth Standards.  The 
Center for Disease Control and Prevention (CDC) reference standards will be used for the 
age categories where the WHO reference standards are not available.
Height and weight will be collected at Screening, Baseline, Month 3, Month 6, Month 9 and 
Month 12 according to the Schedule of Activities in Section 9 of the protocol.
Z-scores include height standard deviation score (SDS) by chronologic age, height SDS by 
bone age, weight SDS by chronologic age, weight SDS by bone age.  Z-scores will be 
calculated by the sponsor using SAS macros following World Health Organization (WHO) 
reference standards.  The input variable of age will be repeatedly applied using chronologic 
age and bone age in order to derive the above four SDS.  Detailed documents on how the 
physical growth curves and motor milestone windows of achievement were developed as 
well as application tools to support implementation of the standards is publicly available at
WHO website1 for children ages 0-5 years and for children ages 5-19 years separately.  
Height SDS and Weight SDS should be calculated using the Statistical Analysis System
(SAS) macros available at the same website.1
There are no WHO reference standards for weight SDS for pediatric participants >10 years of 
age.  Therefore, as an alternative, weight SDS for all pediatric participants will be also 
calculated using the CDC reference standards2 and SAS programs.  
In calculation of the percentage change from baseline for SDS, the absolute value of the 
baseline will be used as the denominator to address the situation where the value is negative.
3.3.2. Tanner Stage
Tanner stage of development will be collected at Baseline and Month 12 according to the 
Schedule of Activities in Section 9 of the protocol, including pubic hair stage (stage 1 to 5), 
genitalia stage (stage 1 to 5) and testis volume (mL).
3.3.3. Bone Measurement
Bone age assessed by X-ray of left hand and wrist will be collected at Baseline and Month 12 
according to the Schedule of Activities in Section 9 of the protocol.


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Bone mineral density (BMD) and Z-score assessed by dual-emission X-ray absorptiometry 
(DEXA) for L femoral neck, total left hip, R femoral neck, total right hip, lumbar spine, 
cortical bone and total body will be collected at baseline and Month 12 according to the 
Schedule of Activities in Section 9 of the protocol. The DEXA will be done in children 
9 years of age and above.
3.3.4. Modified Severity Scoring Tool (mSST)
Modified Severity Scoring Tool (mSST) will be collected at Screening, Month 6 and 
Month 12 according to the Schedule of Activities in Section 9 of the protocol.  The total 
score is a sum of the single scores from gaze palsy, ophthalmology, epilepsy, age at first 
epilepsy, cognitive ability, ataxia of gait, cerebellar tremor, pyramidal, extrapyramidal, 
swallowing difficulties/oral bulbar function, speech and spinal alignment. It ranges from 0 to 
36, while 0 indicating normal and 36 indicating severe symptom.
3.3.5. Organ Volumes measured by Ultrasound
Spleen volume and liver volume will be also measured by ultrasound at the Screening, 
Month 6 and Month 12 according to the Schedule of Activities in Section 9 of the protocol.  
If collected, the spleen volume and liver volume will be calculated as the product of 
craniocaudal dimension (cm), anteroposterior dimension (cm) and longitudinal dimension 
(cm) from ultrasound measurement.
The spleen volume by MN will be calculated by sponsor applying the formula in Section 3.1
based on the spleen volume (cm3) measurement by ultrasound and body weight.  The liver 
volume by MN will be calculated by sponsor applying the formula in Section 3.2.1 based on 
the liver volume (cm3) measurement by ultrasound and body weight.
3.4. Baseline Variables
Baseline is defined as Screening visit (Visit 0) for spleen volume defined in Section 3.1, liver 
volume defined in Section 3.2.1 and mSST defined in Section 3.3.4.  Baseline is defined as 
Day 1 (or Visit 1) for the endpoints specified in Sections 3.2.2 to 3.3, which are 
corresponding to the secondary efficacy assessment, growth development, biomarker 
measurement, as well as the adverse events in Section 3.5 for the safety assessment.
3.5. Safety Endpoints
3.5.1. Adverse Events
The adverse event (AE) including time of the onset, severity, action/treatment and outcome 
of the AE resolution, related to taliglucerase alfa treatment or not, will be collected at each 
scheduled visit with the visit window specified in the Schedule of Activities in Section 9 of 
the protocol.
An AE is considered as a treatment emergent adverse event (TEAE), if the event occurring or 
worsening on or after the first dose of taliglucerase alfa in the study. The AE reporting 
period for this study will be defined as the duration from the first dose of taliglucerase alfa in 
the study until 30 calendar days following the final visit dose.


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3.5.2. Laboratory Data
Lab data other than hemoglobin and platelet counts will be collected at Screening, baseline, 
Month 3, Month 6, Month 9 and Month 12 according to the Schedule of Activities in 
Section 9 of the protocol, including hematology, biochemistry and urinalysis lab tests.
3.5.3. Vital Signs
Vital sign data will be collected during each bi-weekly Taliglucerase alfa infusion. It will be 
evaluated every 30 minutes if the participant tolerates the previous infusions; otherwise, 
every 15 minutes for the first hour.
3.5.4. Antibodies
Anti-taliglucerase alfa antibodies will be collected at baseline, Month 6 and Month 12 
according to the Schedule of Activities in Section 9 of the protocol, including the status 
(positive, negative, not done) for IgG, in-vitro neutralizing, cell based neutralizing, and IgE 
anti-taliglucerase alfa antibodies.
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to releasing the database and classifications will 
be documented per standard operating procedures.
The analysis populations for reporting are defined in the following table. 
Population
Description
Enrolled
All participants who sign the informed consent document.
Evaluable or Full Analysis 
Set (FAS)
All enrolled participants to the study who take at least 
1 complete dose of taliglucerase alfa (or partial dose if adverse 
events prevent completing infusion dose). Participants will be 
collected according to the study drug actually received for this 
non-randomized study.
Safety
All participants who receive at least 1 dose of study drug. 
Participants will be analyzed according to the study drug they 
actually received. An enrolled but not treated participant will 
be excluded from the safety analyses.  
Per Protocol set (PP)
All participants who complete the primary efficacy data 
collection at Month 12 and baseline assessment, and receive at 
least 1 complete dose of taliglucerase alfa (or partial dose if 
adverse events prevent completing infusion dose).


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5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
For the primary efficacy endpoint, a Wilcoxon signed rank test at 2-sided significance level 
of 0.05 will be applied to test the null hypothesis that the median percent change from 
baseline to Month 12 in spleen volume MN is equal to -20%.  The corresponding p-value will 
be reported.
The primary null hypothesis is:
H0: λ = -20%
and the primary alternative hypotheses are:
Ha1: λ < -20% and Ha2: λ > -20%,
where λ is the common median of the observed percent difference from the paired data.
Taliglucerase alfa will be considered efficacious with respect to the spleen volume MN, if the 
median percent change from baseline to Month 12 is significantly less than -20% (or the 
median precent reduction is greater than 20%) at the 2-sided 0.05 level, ie, p-value from 
Wilcoxon signed rank test less than 0.05.
For the secondary efficacy endpoints, such as hemoglobin, platelet counts and Lyso-Gb1, the 
same Wilcoxon signed rank test will be applied for the percent change from baseline to
Month 12. No adjustment for multiple comparisons will be made.  Though hemoglobin, 
platelet counts, chitotriosidase and Lyso-Gb1 will be collected at Month 3, 6 and 9 as well, 
changes from baseline to Months 3, 6 and 9 will be descriptively summarized only.
5.2. General Methods
5.2.1. Analyses for Binary Endpoints
Frequency and percentage of the responders defined in Section 2.1.3, will be provided as a 
descriptive type of summary. The 95% confidence interval for the responder rate will be 
provided using exact Clopper-Pearson method via one sample procedure in SAS Proc Freq. 
The sample code is provided in Appendix 4.
5.2.2. Analyses for Continuous Endpoints
The Wilcoxon signed rank test will be performed for the percent change from baseline to
Month 12 in primary and secondary efficacy endpoints due to the possible skewed 
distribution for the efficacy data. 
The rank with positive and negative signs will be assigned to the percent difference (Di) 
between baseline and Month 12 values. Di are a random variable, which are mutually 
independent from each participant and have the same median. All the zero differences are 
ignored in the analysis. The Wilcoxon signed rank test inference is based on permutational 
distribution of its test statistics. This test will be implemented and exact p-values will be 
produced via  SAS Proc Univariate.  The Proc Univariate excludes missing values for an 
analysis variable before calculating statistics.  The sample code is provided in Appendix 4.


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5.2.3. Analyses for Categorical Endpoints
Frequency and percentage for each category of the variable will be provided as a descriptive 
summary for each visit. For example, the frequency and percentage of the stage 1 to 5 for 
tanner stage will be presented at Baseline and Month 12.
5.2.4. Analyses for Time-to-Event Endpoints
Not applicable.
5.3. Methods to Manage Missing Data
The missing data for the primary and secondary efficacy endpoints analyzed by the Wilcoxon
signed rank test will be imputed using last observation carried forward (LOCF) method in 
FAS, ie, the measurement obtained at the early termination visit will be used to impute the 
Month 12 data.  
For imaging-based endpoints, the spleen volume and liver volume measured by the MRI at 
the early termination visit will be taken as the Month 12 measurement, if the Month 12 visit 
is missing. If there is no post-baseline MRI measurement, the percentage change from 
baseline to Month 12 in organ volumes by ultrasound can be used to impute the missing 
percentage change from baseline in organ volumes by MRI per clinical judgment.  The 
percentage change from baseline needs to be derived within the same imaging test, ie, based 
on post-baseline organ volume measured by ultrasound and baseline organ volume measured 
by ultrasound. If there is no post-baseline imaging measurement, the baseline observation 
carried forward (BOCF) will be applied for missing data, ie, the baseline volume measured 
by MRI will be used to impute Month 12 MRI data.
Missing safety data will be handled according to the Pfizer Clinical Data Interchange 
Standards Consortium (CDISC) safety rulebook and data standard rules for imputation,
including missing dates (when the date is required for a calculation) and missing severity of 
adverse events.
6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint
6.1.1. Main Analysis

Estimand strategy: Treatment policy strategy for percent change from baseline to 
Month 12 in spleen volume MN measured by MRI.

Analysis set: FAS (defined in Section 4).  All participants assigned to study drug and 
received at least 1 complete dose of taliglucerase alfa (or partial dose if adverse events 
prevent completing infusion dose) will be included.

Analysis methodology: Percent change from baseline to Month 12 will be analyzed using 
Wilcoxon signed rank test detailed in Section 5.2.2.  In order to judge whether this
primary efficacy endpoint meets the 20% reduction from baseline, a 20% shift will be 
added on the percent change from baseline for each participant in the analysis set before 
the procedure of Proc Univariate (Appendix 4).


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
Intercurrent events and missing data: Data after study drug discontinuation will be 
included. Missing values will be imputed using LOCF and other methods specified in
Section 5.3 and be included in calculating percent change from baseline.

Summary of statistical comparison: The 2-sided p-value from the exact inference for 
Wilcoxon signed rank statistics for comparing Month 12 to baseline value, as well as the 
median percent change from baseline, will be presented and used to judge whether 
efficacious criteria is met.  The n, minimum and maximum for the observed percent 
change from baseline will be presented together as well.

Descriptive summary including n, mean, SD, median, minimum, and maximum for
absolute value, change from baseline and percent change from baseline in spleen volume 
and spleen volume MN measured by MRI at each visit will be presented.
6.1.2. Sensitivity/Supplementary Analyses
Sensitivity analyses

To assess the impact of early discontinuation, the same Wilcoxon signed rank test 
will be repeated in the PP set (Section 4) among those who have the primary efficacy 
data collected by MRI at Month 12 and Baseline.

Descriptive summary for absolute value, change from baseline and percent change 
from baseline in spleen volume and spleen volume MN measured by MRI at each 
visit will be repeated in the PP set.
Supplementary analysis

In addition to the main analysis on the primary estimand, the supportive analysis on 
the alternative estimand of the binary responder rate based on spleen volume MN 
reduction measured by MRI will be provided in FAS.  This includes the frequency 
and percentage of the responders, as well as the 95% confidence interval (CI) for the 
responder rate using exact Clopper-Pearson method. The supportive evidence can be 
obtained, if the lower bound of the 95% CI excludes the responder rate of 50%.
6.2. Key Secondary Endpoints
6.2.1. Main Analysis

Estimand strategy: Treatment policy strategy for percent change from baseline to 
Month 12 in liver volume MN measured by MRI, hemoglobin, platelet and Lyso-Gb1
(lyso-glucosylsphingosine), chitotriosidase.

Analysis set: FAS (defined in Section 4).  All participants assigned to study drug and 
received at least 1 complete dose of taliglucerase alfa (or partial dose if adverse events 
prevent completing infusion dose) will be included.


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
Analysis methodology: Percent change from baseline to Month 12 will be analyzed using 
Wilcoxon signed rank test detailed in Section 5.2.2.  

Intercurrent events and missing data: Data after study drug discontinuation will be 
included; Missing values will be imputed using LOCF, and other methods specified in
Section 5.3, and included in calculating percent change from baseline.

Summary of statistical comparison: The 2-sided p-value from the exact inference for 
Wilcoxon signed rank statistics for comparing Month 12 to baseline value, as well as 
median percent change from baseline, will be presented.  The n, minimum and maximum 
for observed percent change from baseline will be presented together as well.

Descriptive summary including n, mean, SD, median, minimum, and maximum for 
absolute value, change from baseline and percent change from baseline at each visit will 
be presented.  The visit includes baseline and Month 12 for liver volume and liver 
volume MN measured by MRI, and baseline, Month 3, 6, 9 and 12 for hemoglobin, 
platelet, chitotriosidase and Lyso-Gb1.
6.2.2. Sensitivity/Supplementary Analysis
There are no sensitivity and supplementary analyses planned for these endpoints.
6.3. Other Secondary Endpoints

Estimand strategy: Treatment policy strategy for change from baseline in height SDS, 
weight SDS, tanner stage, bone age, BMD and Z-score for bone assessment, total score 
from mSST, as well as change from baseline in organ volume measured by ultrasound if 
available.

Analysis set: FAS (defined in Section 4).  All participants assigned to study drug and who 
take at least 1 complete dose of taliglucerase alfa (or partial dose if adverse events 
prevent completing infusion dose).

Intercurrent events and missing data: Data after study drug discontinuation will be 
excluded; Missing values won’t be included in calculating change from baseline and will 
not be imputed.

Descriptive statistics including n, mean, SD, median, minimum, and maximum will be 
presented for observed continuous variables at each visit. This includes the absolute 
values, change from baseline and percent change from baseline in height SDS by 
chronologic age, height SDS by bone age, weight SDS by chronologic age, weight SDS 
by bone age, bone age, BMD and Z-score for bone assessment, right and left testis 
volume, total score from mSST, and spleen volume, spleen volume MN, liver volume, 
liver volume MN measured by ultrasound.


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
BDM and Z-score for bone assessment will be descriptively summarized by each 
bone area, such as L femoral neck, total left hip, total body, etc. that listed in
Section 3.3.3.

Frequency and percentage will be provided for categorical variables at each visit, such as 
tanner stage.  
6.4. Other Endpoint(s)
6.4.1. Immunogenicity (Antibodies)
Frequency and percentage of anti-taliglucerase alfa antibodies in FAS will be reported at 
baseline, Month 6 and Month 12, if adequate data are collected.
6.5. Subset Analyses
There is no planned subset analysis for this study.
6.6. Baseline and Other Summaries and Analyses
6.6.1. Baseline Summaries
Descriptive summary including n, mean, SD, median, minimum, and maximum will be 
presented for continuous baseline variables.  Frequency and percentage will be provided for 
categorical baseline variables. The following baseline data and disease characteristics will be 
summarized, if data permits.

Demographic data: Age, race, ethnicity, proportion of Ashkenazi Jewish descent (via 
number of grandparents) will be summarized by gender at birth and ‘All Participants’ 
in accordance with the Pfizer reporting standards.

Primary diagnosis: Type of GD, method of diagnosis and symptoms presented at the 
diagnosis will be summarized.

Medical history: Genarl MH will be summarized by SOC and PT according to 
MedDRA dictionary in the latest available version.  
6.6.2. Study Conduct and Participant Disposition
Participant evaluation groups will show end of study participant disposition and will show 
which participants were analyzed for efficacy and safety (adverse events and laboratory 
data).  
Frequency counts and percentage will be reported for participant discontinuation(s), 
temporary discontinuation(s) or dose reduction due to adverse events and reasons for 
discontinuation.
Data will be reported in accordance with the Pfizer reporting standards.


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6.6.3. Study Treatment Exposure
Taliglucerase dosing (study drug administration schedule) will be listed for each participant. 
Dose will be descriptively summarized as n, median, minimum, maximum, mean and SD.
6.6.4. Concomitant Medications and Nondrug Treatments
The concomitant medication(s) and non-drug treatment(s) will be provided in the listings.
6.7. Safety Summaries and Analyses
All the safety data will be summarized descriptively through the appropriate data tablulations 
in safety population (defined in Section 4) according to Pfizer Safety Rulebook and CDISC 
standards analyses, to evaluate any potential risk associated with the safety and toleration of 
administering taliglucerase alfa in Type 3 GD patients.
6.7.1. Adverse Events
Treatment-emergent adverse events (TEAE) will be summarized with counts and percentage 
for safety population (defined in Section 4) according to Pfizer CDISC standard. All adverse 
events will be reported in a data listing.
In addition to the system organ class (SOC) and preferred term (PT) defined in the live 
MedDRA version at the final reporting stage, an additional SOC of hypersensitivity reactions
will be summarized using frequency and percentage for each preferred term, including but 
not limited to:

Early clinical signs: sensation of warmth and itching, feelings of anxiety or panic;

Moderate clincal signs: pruritus, flushing, urticaria, chest discomfort, mild 
hypotension;

Progressive clinical signs: erythematous or massive urticarial rash;

Severe clinical signs: hypotension, bronchospasm (wheezing), laryngeal edema 
(dyspnea, stridor, aphonia, drooling), arrhythmias.
6.7.2. Laboratory Data
Laboratory data will be presented in accordance with the Pfizer CDISC reporting standards.
6.7.3. Vital Signs
All vital sign data will be listed by participant and visit.
Though vital signs will be collected during each infusion visit per standard of care, only vital 
sign collected at the baseline, Month 3, 6, 9 and 12 will be summarized descriptively.  
Absolute values, change from baseline and percent change from baseline for vital sign data 
will be summarized using n, mean, SD, median and range.


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6.7.4. Physical Examination
Physical examination and neurologic assessment data will be listed only by participant and 
visit.
7. INTERIM ANALYSES
There is no planned interim analysis in this study.
8. REFERENCES
1.
WHO reference standards and SAS programs for child growth at the WHO website 
(http://www.who.int/childgrowth/software/en/) for children ages 0-5 years and
(http://www.who.int/growthref/en/) for children ages 5-19 years. 
2.
CDC reference standards for 2000 CDC growth charts and SAS programs at the CDC 
website (http://www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas.htm).


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9. APPENDICES
Appendix 1. Summary of Efficacy Analyses
Endpoint
Analysis Type
Population
Data Inclusion and 
Rules for Handling 
Intercurrent Events 
and Missing Data 
Analysis Model
Percent change from 
baseline to Month 12 in 
spleen volume MN 
measured by MRI
Summary
Evaluable 
(FAS), PP
observed data at each 
visit
N/A
Main analysis
Evaluable 
(FAS)
Month 12 or data from 
early termination 
assessment and baseline 
Wilcoxon signed 
rank test (exact 
p-value), median 
%change 
Sensitivity 
analysis
PP
completed both Month 
12 and baseline without 
missing data imputation
Wilcoxon signed 
rank test (exact 
p-value), median 
%change
Responder rate in spleen 
volume reduction measured 
by MRI
Supplementary 
analysis
Evaluable 
(FAS)
Month 12 or data from 
early termination 
assessment and baseline
Clopper-Pearson 
CI 
Percent change from 
baseline to Month 12 in 
liver volume MN measured 
by MRI
Summary
Evaluable 
(FAS)
observed data at each 
visit
N/A
Main analysis
Evaluable 
(FAS)
Month 12 or data from 
early termination 
assessment and baseline
Wilcoxon signed 
rank test (exact 
p-value), median 
%change
Percent change from 
baseline in hemoglobin
Summary
Evaluable 
(FAS)
observed data at each 
visit (baseline, Month 3, 
6, 9, 12)
N/A
Main analysis
Evaluable 
(FAS)
Month 12 or data from 
early termination 
assessment and baseline
Wilcoxon signed 
rank test (exact 
p-value), median 
%change
Percent change from 
baseline in platelet
Summary
Evaluable 
(FAS)
observed data at each 
visit (baseline, Month 3, 
6, 9, 12)
N/A
Main analysis
Evaluable 
(FAS)
Month 12 or data from 
early termination 
assessment and baseline
Wilcoxon signed 
rank test (exact 
p-value), median 
%change
Percent change from 
baseline in Lyso-Gb1
Summary
Evaluable 
(FAS)
observed data at each 
visit (baseline, Month 3, 
6, 9, 12)
N/A
Main analysis
Evaluable 
(FAS)
Month 12 or data from 
early termination 
assessment and baseline
Wilcoxon signed 
rank test (exact 
p-value), median 
%change


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Endpoint
Analysis Type
Population
Data Inclusion and 
Rules for Handling 
Intercurrent Events 
and Missing Data 
Analysis Model
Percent change from 
baseline in chitotriosidase
Summary
Evaluable 
(FAS)
observed data at each 
visit (baseline, Month 3, 
6, 9, 12)
N/A
Main analysis
Evaluable 
(FAS)
Month 12 or data from 
early termination 
assessment and baseline
Wilcoxon signed 
rank test (exact 
p-value), median 
%change
Change from baseline in 
height SDS
Summary
Evaluable 
(FAS)
observed data at each 
visit 
N/A
Change from baseline in 
weight SDS
Summary
Evaluable 
(FAS)
observed data at each 
visit 
N/A
Change from baseline in 
bone assessment
Summary
Evaluable 
(FAS)
observed data at each 
visit 
N/A
Percent change from 
baseline to Month 12 in 
spleen volume MN 
measured by ultrasound
Summary
Evaluable 
(FAS)
observed data at each 
visit 
N/A
Percent change from 
baseline to Month 12 in 
liver volume MN measured 
by ultrasound
Summary
Evaluable 
(FAS)
observed data at each 
visit 
N/A
Change from baseline in 
VAS fatigue score
Summary
Evaluable 
(FAS)
observed data at each 
visit 
N/A
Tanner stage
Summary
Evaluable 
(FAS)
observed data at each 
visit 
N/A
Change from baseline in 
total score from mSST
Summary
Evaluable 
(FAS)
observed data at each 
visit 
N/A
Anti-taliglucerase 
antibodies
Summary
Evaluable 
(FAS)
observed data at each 
visit 
N/A


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Appendix 2. Data Derivation Details
Appendix 2.1. Definition and Use of Visit Windows in Reporting
The following table provides the windows categorizing dated assessments under nominal 
visits for the purpose of reporting.
Nominal
Visit 
Visit window for clinical-based 
assessment
Visit window for imaging-based assessment
Baseline  
Day 1
date of the first MRI or ultrasound for organ 
volumes at Screening visit; date of the first 
assessment around Day 1 (Baseline visit) for 
other imaging-based measurement.
Month 3  
12 weeks -7 days < Visit date1 – Day 1
+1 <= 12 weeks + 7 days
NA
Month 6
26 weeks -7 days < Visit date – Day 1
+1 <= 26 weeks  + 7 days
26 weeks -42 days < Assessment date2 – Baseline 
assessment date +1 <= 26 weeks +42 days
Month 9  
38 weeks -7 days < Visit date – Day 1 
+1 <= 38 weeks + 7 days
NA
Month 12  
52 weeks -7 days < Visit date – Day 1 
+1 <= 52 weeks + 7 days
52 weeks -42 days < Assessment date2 – Baseline 
assessment date +1 <= 52 weeks +42 days
1 visit date is the date collected on the top of the pages for each visit.
2 assessment date for organ volume (ie, spleen and liver) and skeletal assessment (eg, skeletal age and 
bone mineral density) are collected as the “Date of assessment ” on the corresponding eCRF modules.
Handling Missing Dates
Missing visit dates will be handled according to Pfizer CDISC data standard for imputation.
Missing day in assessment date will be imputed as the first day of each month. If the month 
is missing for assessment date, the visit date collected at the same visit  will be used.  
Handling Multiple Observations in the Same Visit Window
If there are multiple observations in one participant falling into one single visit window, the 
worst assessment will be used for summary. The imaging-based assessment will less likely 
have multiple observations in the same visit window.  The clinical lab-based test, such as 
hemoglobin and platelet, may have this situation. Since increase from baseline in 
hemoglobin and platelet indicating clinical improvement, then the least increase from 
baseline or most decrease from baseline will be considered as the worst assessment in 
handling multiple observations in the same visit window.
The definition of the worst assessment for some of the biomarkers or measurements may 
involve other considerations.  For example, the worst assessment for bone age estimation  
needs to be compared to the chronological age.  For tanner stage and testis volume, it will be 
assessed at individual case though lower categorical number or lower volume usually 
indicates as the worse assessment. In such cases and any parameters not specified above, the 
definition of the worst assessment will be decided case by case and will be documented in the 
programming document, such as analysis datasets specification. 


Protocol WI224302 (Taliglucerase Alfa) Statistical Analysis Plan
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TMF Doc ID: 98.03
Appendix 2.2. Endpoint Derivations
Not applicable.
Appendix 2.3. Definition of Protocol Deviations That Relate to Statistical 
Analyses/Populations
Not applicable.
Appendix 3. Data Set Descriptions
Not applicable.


Protocol WI224302 (Taliglucerase Alfa) Statistical Analysis Plan
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TMF Doc ID: 98.03
Appendix 4. Statistical Methodology Details
1. Sample code for Wilcoxon signed rank test:
data one;
      input id $ pre post;
      label pre=’Baseline’ post=’Mon12’;
      cards;
      1
8.74
4.22
2
6.77
4
1.34
1.95
5
4.52
3.76
6
6.72
5.85
7
2.37
2.74
8
3.69
2.93
9
4.55
3.62
10
17.12 16.84
11
14.93 18.07
;run;
data two;
set one;
pctch=((post-pre)/pre)*100;
adjpctch=pctch + 20;  ** for primary efficacy endpoint **;
run;
** Wilcoxon signed rank test for primary efficacy endpoint with decision 
criteria;
proc univariate data=two;
   var adjpctch;
   output out=rankpct SIGNRANK=statistics PROBS=p median=median; 
run;
** Wilcoxon signed rank test for secondary efficacy endpoints;
proc univariate data=two;
   var pctch;
   output out=rankpct SIGNRANK=statistics PROBS=p median=median; 
run;
2. Sample code for Clopper-Pearson exact test and CI for the responder rate: 
data three;
      input status $ count;
cards;
respond 8
nonresp 1;
run;
proc freq data=three;
table status/binomial (exact p=0.5) alpha=0.05;
weight count;
run;


Protocol WI224302 (Taliglucerase Alfa) Statistical Analysis Plan
DMB02-GSOP-RF02 5.0 Statistical Analysis Plan Template 05-Dec-2019
PFIZER CONFIDENTIAL 
Page 24
TMF Doc ID: 98.03
Appendix 5. List of Abbreviations
Abbreviation
Term
Abs
absolute
AE
adverse event
TEAE
Treatment emergent adverse event
BOCF
baseline observation carried forward
BP
blood pressure
CDISC
Clinical Data Interchange Standards Consortium
CDC
Center of Disease Control and Prevention
CI
confidence interval
CRF
case report form
CSR
clinical study report
ECG
electrocardiogram
FAS
full analysis set
FDA
Food and Drug Administration (United States)
ICD
informed consent document
ICH
International Council for Harmonisation
Lyso-Gb1
Lyso-glucosylsphingosine
LOCF
last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
MN
Multiples of Normal
MRI
Magnetic Resonance Imaging
mSST
modified Severity Scoring Tool 
N/A
not applicable
PP
per-protocol
PPAS
per-protocol analysis set
PT
preferred term
QTc
corrected QT
QTcF
corrected QT (Fridericia method)
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reaction
TA
therapeutic area
ULN
upper limit of normal
VAS
visual analog scale
WHO 
World Health Organization
WHODD
World Health Organization Drug Dictionary