Conditions: Gaucher Disease
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 21
Healthy volunteers: no

Brief summary:
The primary purpose of this study is to evaluate the effect of VPRIV therapy (60 units per kilogram \[U/kg\] every other week \[EOW\]) in treatment-naive participants with type 1 Gaucher disease on change from baseline in lumbar spine (LS) bone mineral density (BMD) Z-score as measured by dual energy x-ray absorptiometry (DXA) after 24 months of treatment.

Detailed description:

Arms:
arm 1: Participants will receive 60-minute intravenous infusion of 60 units per kilogram (U/kg) velaglucerase alfa every other week (EOW) and an oral daily dose of 800 IU vitamin D for 24 months (101 weeks).

Interventions: intervention 1: Velaglucerase alfa intervention 2: Vitamin D
Intervention descriptions: intervention 1: Participants will receive 60-minute intravenous infusion of 60 U/kg velaglucerase alfa EOW. intervention 2: Participants will receive 800 IU vitamin D orally daily.

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
NCT Number: 
NCT02574286 
Study Title: 
An Open-label, Multicenter, Single-arm, Phase 4 Study of the Effect of 
Treatment with Velaglucerase alfa on Bone-related Pathology in 
Treatment-naïve Patients with Type 1 Gaucher Disease 
Study Number: 
SHP-GCB-402 
Protocol Version and Date: 
Original Protocol: 
30 Apr 2015 
Amendment 1: 
14 Sep 2015 
Amendment 2: 
02 Jun 2016 
Amendment 3: 
06 Jul 2016 
Amendment 4: 
04 May 2017 
Amendment 5: 
26 Jul 2018 
Amendment 6: 
02 Nov 2020 


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SYNOPSIS
Sponsor:
Shire Human Genetic Therapies, Inc. (Shire), a wholly owned subsidiary of Takeda 
Pharmaceuticals Company Limited
Name of Finished Product: velaglucerase alfa (VPRIV®)
Study Title:
An Open-label, Multicenter, Single-arm, Phase 4 Study of the Effect of Treatment with 
Velaglucerase Alfa on Bone-related Pathology in Treatment-naïve Patients with Type 1 
Gaucher Disease
Study Number: SHP-GCB-402
Study Phase: 4
Investigational Product, Dose, and Mode of Administration: 
Velaglucerase alfa 60 U/kg every other week (EOW) by a minimum 60-minute intravenous 
infusion
Concomitant Medication, Dose, and Mode of Administration:
All patients will also receive 800 IU vitamin D (oral) daily starting at the week 1 visit
Comparator, Dose, and Mode of Administration: Not applicable
Primary Objective: 
The primary objective is: To evaluate the effect of VPRIV therapy (60 U/kg EOW) in 
treatment-naïve patients with type 1 Gaucher disease on change from baseline in lumbar spine 
(LS) bone mineral density (BMD) Z-score as measured by dual energy x-ray absorptiometry 
(DXA) after 24 months of treatment 
Secondary Objectives:
The secondary objectives are to evaluate the effect of VPRIV therapy (60 U/kg EOW) over 
time in treatment-naïve patients with type 1 Gaucher disease on:

BMD as measured by the change from baseline in LS BMD Z-score after 12 months of 
treatment

BMD as measured by the change from baseline in g/cm2 after 12 months and after 
24 months of treatment

Bone marrow burden (BMB) as measured by magnetic resonance imaging (MRI) of the LS 
and femur after 12 and 24 months of treatment

Hemoglobin concentration after 12 and 24 months of treatment 

Platelet count after 12 and 24 months of treatment

Liver volume measured by abdominal MRI after 12 and 24 months of treatment

Spleen volume measured by MRI after 12 and 24 months of treatment

Bone pain as measured by questions taken from the Brief Pain Inventory-Short Form©
(BPI-SF) after 12 and 24 months of treatment

Fatigue measured by the Brief Fatigue Inventory (BFI) after 12 and 24 months of treatment

World Health Organization (WHO) BMD classification (normal bone density, osteopenia, 
osteoporosis) based on LS T-scores after 12 and 24 months of treatment

Safety
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Study Duration:
Patients will be dosed for 101 weeks (51 infusions), preceded by a Screening/baseline period 
of up to 28 days and followed by a 30-day Safety Follow-up Period.
Study Inclusion and Exclusion Criteria:
Inclusion criteria
Each patient must meet all the following criteria to be enrolled in this study:
1. The patient has a documented diagnosis of type 1 Gaucher disease, as documented by 
deficient glucocerebrosidase (GCB) activity in leukocytes (whole blood only) or cultured 
skin fibroblasts. Diagnosis by only dry blood spot test is insufficient. Diagnosis may be 
based on results obtained prior to Screening if documented in the patient’s medical history. 
2. Patients must have a LS BMD Z-score <-1 or BMD T-score of <-1 as measured by DXA 
during the screening phase.
3. Patient is treatment-naïve, ie, should not have received ERT or SRT in the 12 months prior 
to enrollment.
4. The patient is ≥18 and ≤70 years of age. 
5. Female patients of childbearing potential must agree to use a medically acceptable method 
of contraception at all times during the study. (See Section 6.8.3 for acceptable methods of 
contraception).
6. The patient, or patient’s legally authorized representative(s), if applicable, understands the 
nature, scope, and possible consequences of the study and has provided written informed 
consent that has been approved by the Institutional Review Board/Independent Ethics 
Committee (IRB/IEC).
7. The patient must be sufficiently cooperative to participate in this clinical study as judged 
by the investigator.
Exclusion criteria
Patients who meet any of the following criteria will be excluded from the study:
1. Neurological symptoms indicating that the patient may have type 3 Gaucher disease.
2. A significant comorbidity, which, as determined by the investigator, might compromise 
study assessment, affect study data or confound the study results (eg, malignancies, 
primary biliary cirrhosis, autoimmune liver disease, etc).
3. Any osteoporosis-specific treatment (eg, bisphosphonates) or treatment with erythropoietin 
(or erythropoietin-like substances) during the past year.
4. Structural, joint-associated bone damage of such extent and severity that the investigator 
deems it could impact participation in the study and assessment of relevant study endpoints 
(eg, pain).
5. The patient is pregnant or lactating.
6. The patient has had a splenectomy. (This criterion is not meant to exclude subjects who 
have accessory spleens.)
7. The patient is enrolled in another clinical study that involves clinical investigations or use 
of any investigational product (drug or device) within 30 days prior to study enrollment or 
at any time during the study. 
8. Severe vitamin D deficiency to the level that would be expected to result in osteomalacia 
(vitamin D <10 ng/mL [25 nmol/L]). If there is mild vitamin D insufficiency at screening 
(vitamin D >10 and <30 ng/mL) treat with 4000 IU vitamin D per day for 1 month and 
rescreen. 
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Statistical Methods: 
Statistical analyses will be based on the intent-to-treat (ITT) principle for all efficacy 
variables. The ITT analysis will be based on all enrolled patients who received at least 1 study
drug infusion (full or partial). Summary statistics will be provided for the changes and 
percent changes from baseline for each parameter. Two-sided 95% confidence intervals in 
the mean changes and mean percent changes from baseline will be presented for each 
endpoint.
Continuous data collected at baseline and subsequent study visits will be summarized, and the 
mean, standard deviation, minimum, maximum, and median values for each variable will be 
tabulated to facilitate the search for trends over time that may be attributable to study drug. 
Categorical variables will be presented in terms of frequencies and percent. Within patient 
changes from baseline will be examined using 1 sample t-test or Wilcoxon signed rank test. 
Statistical significance will be defined at the 0.05 level. 
Demographic and baseline characteristics will be summarized as frequencies and percentages, 
and data will be presented using descriptive statistics. 
In general, descriptive statistics and graphs will be used for the presentation of study results 
including, if relevant, graphs showing the treatment effect over time for patients individually 
and overall. 
The safety population will be used for all safety analyses and is defined as all enrolled patients 
who received at least 1 study drug infusion (full or partial). Safety will be evaluated on the 
basis of AEs reported, clinical laboratory data, use of concomitant medications, vital signs, and 
physical examinations. In addition, blood samples will be analyzed for determination of the 
presence of anti-velaglucerase alfa antibodies.
Sample Size Determination
In a previous protocol version (Amendment 4), approximately 40 patients were planned for 
enrollment in order to achieve a total of 34 evaluable patients (driven by the key secondary 
efficacy endpoint), assuming a 15 % drop-out rate. A total of 34 evaluable patients provided 
99% power to detect a significant change in LS BMD Z-score from baseline after 24 months of 
treatment (primary efficacy endpoint) when in fact there is a +0.6 change (improvement) in 
Z-score. The calculation assumed an alpha of 0.05 2-sided t-test) and a standard deviation of 
change of 0.6 based on data from study HGT-GCB-044. The 34 evaluable patients also 
conferred 80% power to detect a significant change in one of the key secondary endpoints, 
namely the change from baseline in LS BMD Z-score after 12 months of treatment. 
Assumptions for the key secondary endpoint power calculation were also based on study 
HGT-GCB-044 in which a +0.25 change in in Z-score at 12 months was reported with a 
standard deviation of 0.5. 
In the previous amendment (Amendment 5), the number of patients planned for enrolment was 
revised based on the patient recruitment and retention experience to date to allow for a more 
realistic and achievable recruitment target. Cumulative enrollment data collected from study 
initiation to date indicate a suboptimal enrollment rate of 0.5 patient per month. 
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Study enrollment is hindered by the considerable prevalence of screen failures (approximately 
50%) resulting from the limited global pool of naïve patients with Gaucher disease who 
demonstrate bone involvement at baseline and who meet the eligibility criteria of this study.
Based on this information, the number of patients planned for enrollment was reduced to at 
least 19 patients in order to yield 13 evaluable patients. To be considered evaluable, a patient 
must have an eligible DXA score at Baseline and at 24 months (Week 103 [end of study]). The 
number of evaluable patients was determined assuming a drop-out rate of 30% based on the 
rate of early discontinuations reported during the first 2 years of the study. With 13 evaluable 
patients and assuming the same effect size (increase in LS BMD Z-score of +0.6) and standard 
deviation (0.6) values at 24 months from study HGT-GCB-044, the study will be 90% powered 
to detect significant changes (alpha 0.05) in LS BMD Z-score at 24 months (primary efficacy 
endpoint). As the revised sample size no longer provides adequate statistical power for the
detection of significant changes in the key secondary endpoints defined in the previous 
protocol version, those were demoted to secondary endpoints in the current amendment.
Date of Original Protocol: 30 April 2015
Date of Amendment 1: 14 September 2015
Date of Amendment 2: 02 June 2016
Date of Amendment 3: 06 July 2016 
Date of Amendment 4: 04 May 2017
Date of Amendment 5: 26 July 2018
Date of Amendment 6: 02 November 2020
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EMERGENCY CONTACT INFORMATION
In the event of an SAE, the investigator must fax or e-mail the Shire Clinical Study Serious 
Adverse Event and Non-serious AEs Required by the Protocol Form within 24 hours to the Shire 
Global Patient Safety Evaluation Department. Applicable fax numbers and e-mail address can be 
found on the form (sent under separate cover). A copy of this form must also be sent to the Shire 
Medical Monitor by fax or e-mail using the details below.
Fax: 
Email: 
For protocol- or safety-related issues the investigator must contact the Shire Medical 
Monitor:
, DDS, PhD
Telephone: 
Fax: N/A
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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................3
SYNOPSIS.......................................................................................................................................6
EMERGENCY CONTACT INFORMATION..............................................................................12
TABLE OF CONTENTS...............................................................................................................13
LIST OF IN-TEXT TABLES ........................................................................................................18
LIST OF APPENDICES................................................................................................................18
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................................................19
1
INTRODUCTION..................................................................................................................20
1.1
Bone Pathology in Gaucher Disease - An Unmet Medical Need.............................20
1.2
Experience with ERT for Bone-related Complications of Gaucher Disease ...........20
2
STUDY OBJECTIVES ..........................................................................................................23
2.1
Primary Objective ....................................................................................................23
2.2
Secondary Objectives...............................................................................................23
2.3
Exploratory Objectives.............................................................................................23
3
STUDY ENDPOINTS............................................................................................................24
3.1
Primary Endpoint .....................................................................................................24
3.2
Secondary Endpoints................................................................................................24
3.2.1
Secondary Efficacy Endpoints...............................................................................24
3.2.2
Safety Endpoints....................................................................................................25
3.3
Exploratory Endpoints..............................................................................................25
4
INVESTIGATIONAL PLAN.................................................................................................26
4.1
Overall Study Design and Plan ................................................................................26
4.2
Rationale for Study Design and Comparator Group ................................................26
4.3
Study Duration .........................................................................................................26
5
STUDY POPULATION SELECTION ..................................................................................27
5.1
Study Population ......................................................................................................27
5.2
Inclusion Criteria......................................................................................................27
5.3
Exclusion Criteria.....................................................................................................27
6
STUDY TREATMENT..........................................................................................................29
6.1
Description of Treatment .........................................................................................29
6.1.1
Investigational Product ..........................................................................................29
6.1.2
Comparator ............................................................................................................29
6.2
Treatment Administered...........................................................................................29
6.3
Selection and Timing of Dose for Each Patient .......................................................29
6.4
Method of Assigning Patients to Treatment Groups................................................30
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6.5
Blinding....................................................................................................................30
6.6
Home Infusion of Velaglucerase alfa.......................................................................30
6.7
Infusion Reactions and Management .......................................................................31
6.8
Restrictions...............................................................................................................31
6.8.1
Prior Therapy .........................................................................................................31
6.8.2
Concomitant Therapy.............................................................................................31
6.8.3
Contraception.........................................................................................................32
6.8.4
Fluid and Food Intake............................................................................................32
6.8.5
Patient Activity Restrictions ..................................................................................32
6.9
Treatment Compliance .............................................................................................32
6.10
Packaging and Labeling ...........................................................................................32
6.11
Storage and Accountability ......................................................................................33
6.12
Investigational Product Retention at Study Site.......................................................33
7
STUDY PROCEDURES........................................................................................................34
7.1
Informed Consent.....................................................................................................34
7.2
Study Entrance Criteria ............................................................................................34
7.3
Confirmation of Study Eligibility ............................................................................34
7.4
Demographics...........................................................................................................34
7.5
Medical History........................................................................................................34
7.6
Glucocerebrosidase Genotype Analysis...................................................................35
7.7
Height and Weight ...................................................................................................35
7.8
Investigational Product Administration ...................................................................35
7.9
Pharmacokinetic Assessments..................................................................................35
7.10
Pharmacodynamic (
) Assessments......................................................36
7.11
Efficacy Assessments...............................................................................................36
7.11.1 Bone Mineral Density............................................................................................36
7.11.2 Bone Marrow Burden ............................................................................................36
7.11.3 Bone Pain...............................................................................................................36
7.11.4 Overall Fatigue.......................................................................................................36
7.11.5 Hemoglobin Concentration....................................................................................36
7.11.6 Platelet Count.........................................................................................................36
7.11.7 Liver and Spleen Volume ......................................................................................36
7.11.8 Exploratory Measures of Potential Relevance in Gaucher Disease.......................36
7.11.8.1
.............................................................................................37
7.11.9 Concomitant Medications, Therapies, and Medical/Surgical Interventions 
Assessments...........................................................................................................37
7.11.10
Physical Examination.............................................................................37
7.11.11
Adverse Event Collection.......................................................................37
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7.11.12
Vital Signs..............................................................................................38
7.11.13
Electrocardiography ...............................................................................38
7.11.14
Clinical Laboratory Tests.......................................................................38
7.11.15
Antibody Assessments ...........................................................................40
7.11.16
Pregnancy Testing..................................................................................40
7.12
Sample Collection, Storage, and Shipping...............................................................40
7.13
....................41
7.14
Adverse Events Assessments ...................................................................................41
7.14.1 Definitions of Adverse Events, Period of Observation, Recording of 
Adverse Events ......................................................................................................41
7.14.1.1
Severity Categorization..........................................................................41
7.14.1.2
Relationship Categorization ...................................................................42
7.14.1.3
Outcome Categorization.........................................................................42
7.14.1.4
Symptoms of the Disease under Study...................................................43
7.14.1.5
Clinical Laboratory and Other Safety Evaluations.................................43
7.14.1.6
Pregnancy...............................................................................................43
7.14.1.7
Infusion-related Adverse Event Definition ............................................44
7.14.1.8
Abuse, Misuse, Overdose, and Medication Error ..................................44
7.15
Serious Adverse Event Procedures ..........................................................................45
7.15.1 Reference Safety Information................................................................................45
7.15.2 Reporting Procedures.............................................................................................45
7.15.3 Serious Adverse Event Definition .........................................................................45
7.15.4 Serious Adverse Event Collection Time Frame.....................................................46
7.15.5 Serious Adverse Event Onset and Resolution Dates .............................................46
7.15.6 Fatal Outcome........................................................................................................46
7.15.7 Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................46
7.16
Removal of Patients from the Trial or Investigational Product ...............................47
7.17
Other Study Procedures............................................................................................47
7.17.1 Safety-related Study Stopping Rules .....................................................................47
7.18
Appropriateness of Measurements...........................................................................48
8
STUDY ACTIVITIES............................................................................................................49
8.1
Screening Visit (Days -28 to -4) ..............................................................................49
8.2
Baseline (Days -3 to 0).............................................................................................49
8.3
Treatment Period (Week 1 to Week 101).................................................................50
8.3.1
Weeks 1, 3, 5, 7, 9, 11, 15, 17, 19, 21, 23, 27, 29, 31, 33, 35, 39, 41, 45, 43, 
47, 49, 53, 55, 57, 59, 61, 63, 67, 69, 71, 73, 75, 79, 81, 83, 85, 87, 91, 93, 
95, 97, 99, and 101.................................................................................................50
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8.3.2
Weeks 13, 37, 65, and 89.......................................................................................50
8.3.3
Weeks 25 and 77....................................................................................................50
8.3.4
Week 51 .................................................................................................................51
8.4
End of Study (Week 103)/Early Termination Procedures........................................52
8.5
30-day Safety Follow-up Visit .................................................................................52
9
QUALITY CONTROL AND ASSURANCE ........................................................................53
10 PLANNED STATISTICAL METHODS...............................................................................54
10.1
General Considerations ............................................................................................54
10.2
Determination of Sample Size..................................................................................54
10.3
Analysis Populations................................................................................................55
10.4
Patient Disposition ...................................................................................................55
10.5
Demographics and Baseline Characteristics ............................................................55
10.6
Primary Endpoint .....................................................................................................56
10.6.1 Primary Efficacy Endpoint ....................................................................................56
10.7
Secondary Endpoints................................................................................................56
10.7.1 Safety Endpoints....................................................................................................56
10.7.2 Secondary Efficacy Endpoints...............................................................................57
10.7.3 Other Secondary Efficacy Endpoints (Health Economics and Outcomes 
Research Endpoints) ..............................................................................................58
10.8
Other Assessments or Analyses (Exploratory Measures Research).........................59
10.9
Interim Analysis .......................................................................................................59
11 ADMINISTRATIVE CONSIDERATIONS ..........................................................................60
11.1
Investigators and Study Administrative Structure ...................................................60
11.2
Institutional Review Board or Independent Ethics Committee Approval................60
11.3
Ethical Conduct of the Study ...................................................................................60
11.4
Patient Information and Consent..............................................................................60
11.5
Patient Confidentiality..............................................................................................61
11.6
Study Monitoring .....................................................................................................62
11.7
Case Report Forms and Study Records....................................................................62
11.7.1 Critical Documents ................................................................................................62
11.8
Data Monitoring Committee ....................................................................................63
11.9
Protocol Violations/Deviations ................................................................................63
11.10
Premature Closure of the Study ...............................................................................63
11.11
Access to Source Documentation.............................................................................64
11.12
Data Generation and Analysis..................................................................................64
11.13
Retention of Data .....................................................................................................64
11.14
Financial Disclosure.................................................................................................64
11.15
Publication and Disclosure Policy............................................................................64
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12 LIST OF REFERENCES........................................................................................................66
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LIST OF IN-TEXT TABLES
Table 7-1
Assessments for Physical Examinations .......................................................37
Table 7-2
Schedule for Recording of Vital Signs at Infusion........................................38
Table 7-3
List of Laboratory Tests ................................................................................39
LIST OF APPENDICES
Appendix 1
Study Schedule of Events..............................................................................68
Appendix 2
Protocol Amendment 5 Summary of Changes ..............................................74
Appendix 3
Protocol Amendment 4 Summary of Changes ..............................................78
Appendix 4
Protocol Amendment 3 Summary of Changes ..............................................89
Appendix 5
Protocol Amendment 2 Summary of Changes ..............................................94
Appendix 6
Protocol Amendment 1 Summary of Changes ............................................101
Appendix 7
Questions taken from the BPI-SF©..............................................................113
Appendix 8
Brief Fatigue Inventory ...............................................................................116
Appendix 9
Protocol Addendum – COVID-19...............................................................117
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Term
Definition
1, 25 OH vitamin D
1, 25 dihydroxycholecalciferol
25 OH vitamin D
25 hydroxycholecalciferol
AE
adverse event
BFI
Brief Fatigue Inventory
BMB
bone marrow burden
BMD
bone mineral density 
BMP-2
bone morphogenic protein-2
CFR
Code of Federal Regulations
CNS
central nervous system
CRP
c-reactive protein
DXA
dual energy x-ray absorptiometry
eCRF
electronic case report form
ECG
electrocardiogram
EOW
every other week
ERT
enzyme replacement therapy
FDA
Food and Drug Administration
FDP
fibrinogen degradation product
GCB
glucocerebrosidase
GCP
Good Clinical Practice
GSL
glycosphingolipid 
β-hCG
human chorionic gonadotropin
ICGG
International Collaborative Gaucher Group
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IND
Investigational New Drug
IRB
Institutional Review Board
IRR
infusion-related reactions
ITT
intent-to-treat
LOCF
last observation carried forward
LS
lumbar spine
MedDRA
Medical Dictionary for Regulatory Activities
 
MRI
magnetic resonance imaging
PT
preferred term
QoL
quality of life
Questions taken from 
the BPI-SF©
Questions taken from the Brief Pain Inventory-Short Form©
SAE
serious adverse event
SOC
system organ class
SRT
substrate reduction therapy
TEAE
treatment-emergent adverse event
VPRIV
velaglucerase alfa
WHO
World Health Organization
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1
INTRODUCTION
1.1
Bone Pathology in Gaucher Disease - An Unmet Medical Need
Gaucher disease, a pan-ethnic, autosomal, recessive disease with an estimated 30,000 persons 
with type 1 disease worldwide (Cox and Schofield, 1997), is the most common 
glycosphingolipid (GSL) storage disorder (Cox et al., 2003). Despite the pan-ethnicity of the 
disorder, there is a particularly high prevalence in the Ashkenazi Jewish population. The disease 
occurs when an inherited deficiency of the lysosomal enzyme glucocerebrosidase (GCB) leads to 
progressive accumulation of glucocerebroside within macrophages and subsequent tissue and 
organ damage. Glucocerebrosidase is required for hydrolysis of glucocerebroside to glucose and 
cerebroside. 
Gaucher disease is a multisystem disorder with clinical features reflective of the distribution of 
abnormal macrophages (Gaucher cells) in the liver, spleen, bone marrow, skeleton, lungs, and 
occasionally, lymph nodes (Beutler and Grabowski, 2001). Accumulation of 
glucocerebroside-containing cells (mainly macrophages or macrophage-like cells) in the liver
and spleen leads to secondary changes, including organomegaly, which can be massive, 
particularly in the case of the spleen. Bone involvement results in skeletal abnormalities and 
deformities as well as bone pain and bone crises. Deposits in the bone marrow and splenic 
sequestration lead to dysfunction with clinically significant anemia and thrombocytopenia. 
The disease has been classified into 3 clinical subtypes based on the presence or absence of 
neurological symptoms and severity of neurological symptoms (Beutler and Grabowski, 2001).
Type 1 Gaucher disease, the most common form accounting for more than 90% of all cases,
(Pastores et al., 2004) does not involve the CNS; typical manifestations include hepatomegaly, 
splenomegaly, thrombocytopenia, bleeding tendencies, anemia, hypermetabolism, skeletal 
pathology, growth retardation, pulmonary disease, and decreased quality of life (QoL) (Pastores 
et al., 2004). Patients with type 2 Gaucher disease present with acute neurological deterioration, 
and those with type 3 disease typically display a more subacute neurological course. 
Most research effort to date has focused on strategies for augmenting enzyme levels to 
compensate for the underlying defect; enzyme replacement therapy (ERT) has been the 
cornerstone of treatment for Gaucher disease since the early 1990s and is highly effective in 
improving many of the clinical manifestations (Cox et al., 2003).
1.2
Experience with ERT for Bone-related Complications of Gaucher Disease 
Data from the International Collaborative Gaucher Group (ICGG) demonstrate that 
approximately 90% of all patients with Gaucher disease should achieve normal hemoglobin 
concentration within 2 years of initiation of treatment (Cox et al., 2003). Enzyme replacement 
therapy reduces organomegaly, improves hematological parameters, and positively impacts
health-related QoL (Weinreb et al., 2002; Masek et al., 1999).
Despite the availability since 1991 of the first ERT for Gaucher disease, the management of the 
skeletal manifestations of the disease remains a significant unmet medical need. Skeletal 
complications are a frequent occurrence in patients with Gaucher disease. 
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3
STUDY ENDPOINTS
3.1
Primary Endpoint 
The primary endpoint is:
Change from baseline to 24 months (Week 103 [end of study]) in LS BMD Z-score as measured 
by DXA.
3.2
Secondary Endpoints 
3.2.1
Secondary Efficacy Endpoints
The secondary efficacy endpoints are:

Change from baseline to 12 months (Week 51) in LS BMD Z-score. Assessments will be 
performed at the screening visit and Weeks 51 and 103 (end of study).

Change from baseline to 12 months (Week 51) and 24 months (Week 103, end of study) in 
LS BMD in g/cm2.

Change from baseline to 12 months (Week 51) and 24 months (Week 103 [end of study]) in 
BMB score (MRI of lumbar spine and femur). Assessments will be performed at the baseline 
visit and Weeks 51 and 103 (end of study).

Change from baseline over time in hemoglobin concentration. Assessments will be 
performed at baseline and Weeks 13, 25, 37, 51, 65, 77, 89, and 103 (end of study).

Change from baseline over time in platelet count. Assessments will be performed at baseline 
and Weeks 13, 25, 37, 51, 65, 77, 89, and 103 (end of study).

Change from baseline to 12 months (Week 51) and 24 months (Week 103 [end of study]) in 
normalized liver volume as measured by abdominal MRI. Assessments will be performed at 
the baseline visit and Weeks 51 and 103 (end of study).

Change from baseline to 12 months (Week 51) and 24 months (Week 103 [end of study]) in 
normalized spleen volume as measured by MRI. Assessments will be performed at the 
baseline visit and Weeks 51 and 103 (end of study).

Change from baseline to 12 months (Week 51) and 24 months (Week 103 [end of study]) in 
bone pain as measured by questions taken from the BPI-SF©. Assessments will be performed 
at the baseline visit and Weeks 13, 25, 37, 51, 65, 77, 89, and 103 (end of study).

Change from baseline to 12 months (Week 51) and 24 months (Week 103 [end of study]) in 
overall fatigue as measured by the BFI. Assessments will be performed at the baseline visit 
and Weeks 13, 25, 37, 51, 65, 77, 89, and 103 (end of study).

Shifts in WHO BMD classifications (normal bone density, osteopenia, and osteoporosis) 
based on LS T-scores. Assessments will be performed at baseline (screening visit) and 
Weeks 51 and 103 (end of study).
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4
INVESTIGATIONAL PLAN
4.1
Overall Study Design and Plan
This is a multicenter, open-label, single-arm, Phase 4 study to prospectively evaluate the effect 
of VPRIV on bone-related pathology in treatment-naïve patients with type 1 Gaucher disease. In 
order to yield 13 evaluable patients, at least 19 patients will be enrolled to receive VPRIV at the 
recommended starting dose for treatment-naïve patients of 60 U/kg EOW by a minimum 
60-minute intravenous infusion. To be considered evaluable, a patient must have an eligible 
DXA score at Baseline and at 24 months (Week 103 [end of study]).
The primary endpoint is the change from baseline to 24 months (Week 103 [end of study]) in LS 
BMD Z-score. Bone mineral density will be measured using DXA, and the results will be 
converted to Z-scores appropriate for the patient’s age, sex, and race. 
See Appendix 1 for the Study Schedule of Events table.
4.2
Rationale for Study Design and Comparator Group
Bone-related problems are a critical unmet medical need in Gaucher disease and there is reason 
to believe that treatment with VPRIV may lead to significant bone and bone-related effects as 
early as 12 months after initiation of treatment in ERT-naïve patients. Twenty-one 
treatment-naïve patients received initial VPRIV therapy at a dose of 60 U/kg in Study TKT032 
or HGT-GCB-039 and showed a mean increase in LS BMD Z-score that was statistically 
significant at the first post-baseline assessment (9 months for those patients in 
Study HGT-GCB-039 and 12 months for those patients in Study TKT032). 
In consideration of the rarity of Gaucher disease, a single-arm study was chosen because a 
placebo-controlled trial would not be feasible or ethical for the proposed indication. 
4.3
Study Duration
It is expected that the duration of study participation for each subject will be approximately 
110 weeks, including 101 weeks of treatment (51 infusions), additional screening/baseline 
assessments taking up to 4 weeks, and 4 weeks of safety follow up after treatment is completed. 
It is expected that 24 months of treatment is sufficient to observe statistically significant changes 
in lumbar spine BMD, based on previous experience in Study TKT025EXT and 
Study HGT-GCB-044. 
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5
STUDY POPULATION SELECTION
5.1
Study Population
It is planned that at least 19 patients with type 1 Gaucher disease who are at least 18 years of age 
but no more than 70 years of age and who are naïve to ERT/substrate reduction therapy (SRT) 
will be enrolled. Patients will have a documented diagnosis of type 1 Gaucher disease, as 
documented by deficient GCB activity in leukocytes (whole blood only) or cultured skin 
fibroblasts and a LS BMD Z-score <-1 or BMD T-score of < -1 as measured by DXA during the 
screening phase.
5.2
Inclusion Criteria
Each patient must meet the following criteria to be enrolled in this study.
1. The patient has a documented diagnosis of type 1 Gaucher disease, as documented by 
deficient GCB activity in leukocytes (whole blood only) or cultured skin fibroblasts. 
Diagnosis by only dry blood spot test is insufficient. Diagnosis may be based on results 
obtained prior to screening if documented in the patient’s medical history. 
2. Patients must have a LS BMD Z-score <-1 or BMD T-score of <-1 as measured by DXA 
during the screening phase.
3. Patient is treatment-naïve, ie, has not received ERT or SRT in the 12 months prior to 
enrollment.
4. The patient is ≥18 and ≤70 years of age. 
5. Female patients of childbearing potential must agree to use a medically acceptable method of 
contraception at all times during the study. (See Section 6.8.3 for acceptable methods of 
contraception).
6. The patient, or patient’s legally authorized representative(s), if applicable, understands the 
nature, scope, and possible consequences of the study and has provided written informed 
consent that has been approved by the Institutional Review Board/Independent Ethics 
Committee (IRB/IEC).
7. The patient must be sufficiently cooperative to participate in this clinical study as judged by 
the investigator.
5.3
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from the study.
1. Neurological symptoms indicating that the patient may have type 3 Gaucher disease.
2. A significant comorbidity, which, as determined by the investigator, might affect study data 
or confound the study results (eg, malignancies, primary biliary cirrhosis, autoimmune liver 
disease, etc).
3. Any osteoporosis-specific treatment (eg, bisphosphonates) or treatment with erythropoietin 
(or erythropoietin-like substances) during the past year.
4. Structural, joint-associated bone damage of such extent and severity that the investigator 
deems it could impact participation in the study and assessment of relevant study endpoints 
(eg, pain).
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5. The patient is pregnant or lactating.
6. The patient has had a splenectomy. (This criterion is not meant to exclude subjects who have 
accessory spleens.)
7. The patient is enrolled in another clinical study that involves clinical investigations or use of 
any investigational product (drug or device) within 30 days prior to study enrollment or at 
any time during the study.
8. Severe vitamin D deficiency to the level that would be expected to result in osteomalacia 
(vitamin D <10 ng/mL [25 nmol/L]). If there is mild vitamin D insufficiency at screening 
(vitamin D >10 and <30 ng/mL) treat with 4000 IU vitamin D per day for 1 month and 
rescreen.
9. The patient has previously interrupted ERT for safety reasons.
10. The patient has had hypersensitivity to the active substance or to any of the excipients.
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6
STUDY TREATMENT
6.1
Description of Treatment
6.1.1
Investigational Product
The investigational product to be used in this study is VPRIV for intravenous infusion. 
Velaglucerase alfa is supplied as a sterile, preservative-free, lyophilized powder in single-use 
vials.
6.1.2
Comparator
Not applicable.
6.2
Treatment Administered
All enrolled patients will receive VPRIV by a minimum 60-minute intravenous infusion at the 
recommended approved starting dose for treatment-naïve patients of 60 U/kg EOW. Patients will 
continue to receive 60 U/kg EOW for 24 months (101 weeks). A 30-day follow-up period is 
planned after the final dose. 
6.3
Selection and Timing of Dose for Each Patient
All enrolled patients will receive VPRIV at the same dose, ie, 60 U/kg EOW, which is the 
recommended approved starting dose for patients who are naïve to ERT and SRT for Gaucher 
disease. The first dose of VPRIV will be based on the patient’s weight at screening (Days -28 to 
Day -4). A change in patient weight of ±5% from screening or the last weight used to recalculate 
the dose will require a new dose recalculation by the clinical site. Weight will be measured every 
12 weeks throughout the study, with any dosing adjustment to be completed prior to the next 
dose. When a weight change of ±5% is identified, the dose should be adjusted as soon as 
possible, but no later than the next bi-weekly study visit. If the dose can be adjusted prior to the 
infusion on the same day, this adjustment should be performed; however, if the dose cannot be 
adjusted on the same day, the dose must be adjusted prior to the next bi-weekly infusion. It is 
acceptable for the dose adjustment to occur at either of the following times in the study:
1) The dose adjustment to occur on the same day a weight change of ±5% from the 
screening weight or weight at last dose adjustment is identified at the clinic site 
(Weeks 13, 25, 37, 51, 65, 77, 89); or
2) The dose adjustment to occur at the next bi-weekly study visit after a weight change of 
±5% from the screening weight or weight at last dose adjustment is identified at the clinic 
site (Weeks 13, 25, 37, 51, 65, 77, 89).
For dosing calculations, patient weight can be rounded to the nearest 0.5 kg, VPRIV dose to the 
nearest Unit, and dose volume to the nearest 0.1 mL
Study drug infusions are to occur on approximately the same day of the week, but may occur 
every 14 days (± 7 days) of the target day in order to facilitate patient scheduling. If at all 
possible, missed infusions should be avoided. 
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If a patient is not dosed within 21 days from their scheduled dose, the patient should receive the 
next infusion as soon as possible. It may be acceptable to give the next infusion as early as 
7 days after the previous infusion. Subsequent infusions will return to the original schedule. 
6.4
Method of Assigning Patients to Treatment Groups
Not applicable; single-armed study, all enrolled patients are to receive the same dose of VPRIV.
6.5
Blinding
Not applicable; this is an open-label study.
6.6
Home Infusion of Velaglucerase alfa
The first three velaglucerase alfa infusions are to be administered at the clinical site. After the
first 3 doses, patients who have not experienced a treatment-related serious adverse event or an 
infusion-related adverse event of more than mild severity may receive their subsequent infusions 
at home by qualified and trained medical personnel, per the discretion and direction of the 
Investigator. Patients who have experienced an infusion-related adverse event of more than mild 
severity may be re-evaluated at a later time point during the study for consideration to transition 
to home infusions. Patients receiving velaglucerase alfa as home therapy will be required to 
return to the clinical site at Weeks 13, 25, 37, 51, 65, 77, 89, and 103. Please refer to Appendix 9
for information on transferring visits at Weeks 77 and 89 to home therapy and the addition of 
dose continuation infusions due to the COVID-19 pandemic.
The qualified, trained medical personnel will follow the instruction manual provided separately 
from this protocol that outlines all operating procedures to be followed for this study including 
drug transport, reconstitution and the required patient assessments before, during, and after 
infusion of study drug. Clinical evaluations will remain under the medical supervision of the 
Investigator. Appropriate medical support including adequately trained personnel in emergency 
measures, should be readily available when velaglucerase alfa is administered. If anaphylactic or 
other acute severe reactions occur, immediately discontinue the infusion and initiate appropriate 
medical treatment.
In the home setting, vital signs and documentation of adverse events will be collected at each 
visit. The qualified, trained medical personnel will evaluate and report to the study site the 
occurrence of adverse events. Study site personnel will report SAEs as described in 
Section 7.15.2. In addition, a urine pregnancy test will be conducted at each home infusion visit 
for women of childbearing potential. If the result is positive, the infusion will not be 
administered, and a blood sample will be collected for serum pregnancy testing. The next 
infusion of velaglucerase alfa will not be administered until the results of the serum pregnancy 
test are received. If the serum human chorionic gonadotropin (β -hCG) result is also positive, the 
Investigator is to contact the Shire Medical Monitor to determine the appropriate course of 
action.
If there are no infusion-related reactions (IRRs) during the first 3 infusions the observation and 
vital signs post-infusion can be omitted at the discretion of the investigator.
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If an infusion-related adverse event of more than mild severity occurs while a patient is receiving 
treatment at home, the qualified, trained medical personnel will maintain contact with the 
investigator for treatment advice. The infusion should not be restarted in the home setting after 
an infusion-related adverse event of more than mild severity. Home therapy can only then 
resume at subsequent infusions after agreement is reached by the investigator and the Shire 
Medical Monitor.
6.7
Infusion Reactions and Management
Infusions of proteins can be associated with reactions to the infusion that may or may not be 
immune mediated. Thus, potential reactions to the infusion of the investigational drug are 
unpredictable. Symptoms suggestive of hypersensitivity, including anaphylaxis, have been 
observed in patients receiving ERT. Symptoms included pruritus, flushing, urticaria, 
angioedema, chest discomfort, dyspnea, coughing, cyanosis, and hypotension.
The management of IRRs should be based on the severity of the reaction. Such management may 
include, at the discretion of the investigator, slowing the infusion rate, treatment with 
medications such as antihistamines, antipyretics, and/or corticosteroids and/or stopping and 
resuming treatment with prolonged infusion duration.
Pretreatment with antihistamines and/or corticosteroids may prevent subsequent reactions in 
those cases where symptomatic treatment was previously required. Pretreatment of infusion 
reactions is left to the clinical judgment of the investigator.
In cases when required and at the discretion of the study site, additional clinical laboratory 
samples may be collected for further analysis of IRRs. Suggested laboratory evaluation includes 
complete blood count, complete metabolic panel including liver and renal function tests, CH50, 
C3, C4, C1 inhibitor, C3a and C5a, total tryptase, histamine, immune complex and serum IgE 
levels.
6.8
Restrictions
6.8.1
Prior Therapy
The use of any osteoporosis-specific treatment (eg, bisphosphonates) or treatment with 
erythropoietin within the past year is an exclusion criterion. To be eligible for the study, patients 
are to be treatment-naïve (ie, have not received ERT or SRT in the 12 months prior to study 
enrollment).
6.8.2
Concomitant Therapy
Patients who enter the study receiving supplemental therapy (eg, supplemental iron, calcium) 
must remain on a constant dose and regimen throughout the study. All patients will receive 
800 IU vitamin D (oral) daily starting at the week 1 visit for the duration of the study. Initiation 
of osteoporosis-specific therapy or treatment with erythropoietin during the trial is prohibited. 
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6.8.3
Contraception
Female patients of childbearing potential must agree to use a medically acceptable method of 
contraception at all times during the study. 
One of the following methods would be acceptable:
1. Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation:
•
Oral
•
Intravaginal
•
Transdermal
2. Progestogen-only hormonal contraception associated with inhibition of ovulation:
•
Oral
•
Injectable
•
Implantable
3. Intrauterine device (IUD)
4. Intrauterine hormone-releasing system (IUS)
5. Bilateral tubal occlusion
6. Vasectomized partner
7. Sexual abstinence
6.8.4
Fluid and Food Intake 
No restrictions or requirements.
6.8.5
Patient Activity Restrictions
The patient is restricted from enrolling in another clinical study that involves clinical 
investigations or use of any investigational product (drug or device) within 30 days prior to study 
enrollment or at any time during the study.
6.9
Treatment Compliance
During this study, VPRIV will be administered under controlled conditions; therefore, full 
patient compliance with study treatment is anticipated to be high.
6.10
Packaging and Labeling
Velaglucerase alfa is a sterile, preservative-free, lyophilized powder requiring reconstitution and 
further dilution prior to use. It is supplied in individually packaged glass vials, which are closed 
with a butyl rubber stopper with a fluororesin coating and are sealed with an aluminum overseal 
with a flip-off plastic cap. The vials are intended for single use only. Velaglucerase alfa is 
available as 400 U/vial.
All packaging and labeling will be in accordance with applicable regulatory requirements.
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6.11
Storage and Accountability
The following information should be considered when storing and using the investigational 
product.
Velaglucerase alfa should be stored in a refrigerator at 2ºC to 8ºC (36ºF to 46ºF). The shelf life is 
36 months. Do not use velaglucerase alfa after the expiration date on the vial. Do not freeze. 
Protect the vials from light.
The disposition of all investigational product delivered to a principal investigator must be 
recorded on a patient-by-patient basis by completing the Clinical Trial Material Accountability 
Log or local accountability log. The date and time of administration of the investigational 
product must be documented on the appropriate eCRF.
The principal investigator, clinical research coordinator, or designee (eg, pharmacist, third party 
vendor, etc.) must ensure that all documentation regarding investigational product receipt, 
storage, dispensing, loss/damaged and return of used/unused product is complete, accurate, and 
ready for review at each monitoring visit and/or audit. The sites must ensure that the unused 
investigational product is available for the monitor to inventory and prepare for return shipment 
to the Sponsor or designee, if required. 
6.12
Investigational Product Retention at Study Site
The process for return and destruction of investigational product must be determined and 
documented during the study start-up phase. If the sites do not have an Investigational Product 
Returns Process/Policy, the Sponsor or designee must provide guidelines to the sites. Sites must 
retain copies of these documents within the Site Regulatory Binder.
If the investigational product is to be destroyed by the sites or a third party vendor, the sites or 
third party vendor must follow their own process/policy that describes such activities. The site or 
third party vendor must retain copies of these documents within the Site Regulatory Binder. The 
site or third party vendor must ensure that the Clinical Trial Material Accountability and 
Destruction Log is complete, accurate, and ready for review and/or audit at each monitoring 
visit. 
All manifests documenting shipments of investigational product must be retained as well as 
copies of any investigational product return forms.
See the Pharmacy Manual for additional details.
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7
STUDY PROCEDURES
Detailed descriptions of patient evaluations required for this protocol are described in this 
section. These evaluations will be performed during the indicated days and weeks (±7 days) of 
the study (Study Schedule of Events table in Appendix 1). 
All data collected are to be recorded on the appropriate electronic case report form (eCRF).
7.1
Informed Consent
Prior to conducting any study-related procedures, written informed consent must be obtained 
from the patient, or the patient’s legally authorized representative(s) and assent from the patient 
(if applicable).
The nature, scope, and possible consequences, including risks and benefits, of the study will be 
explained to the patient, or the patient’s legally authorized representative(s) by the investigator or 
designee in accordance with the guidelines described in Section 11.4. Documentation and filing 
of informed consent documents should be completed according to Section 11.4.
7.2
Study Entrance Criteria
At screening, each patient will be reviewed for eligibility against the study entrance criteria 
(Section 5.2 and Section 5.3). Patients who do not meet the study entrance criteria will not be 
allowed to participate in the study. The reason(s) for the patient’s ineligibility for the study will 
be documented.
7.3
Confirmation of Study Eligibility
Patient eligibility according to the study inclusion and exclusion criteria will be confirmed at the 
baseline visit on the basis of review of the study entrance criteria.
7.4
Demographics
Patient demographic information including sex, age, and race will be collected prior to the 
patient receiving the first dose of investigational product.
7.5
Medical History
Medical history will include a review of the patient’s medical status, documentation of current 
and prior medical procedures, documentation of current and prior medication usage (including 
non-Gaucher disease-related investigational drugs or devices, if any), and Gaucher disease 
diagnosis (including documentation of deficient GCB activity in leukocytes relative to normal 
[as measured in whole blood only] or cultured skin fibroblast).
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7.6
Glucocerebrosidase Genotype Analysis
At screening, all patients will have a blood sample collected for Gaucher disease (GBA) gene 
sequencing; however, GBA sequencing is not required at screening if documented results are 
available in the medical history. The sample will be sent to a central laboratory for analyzing and
reporting. The results will be used for statistical analysis purposes. 
7.7
Height and Weight
Height and weight will be recorded for all patients.
The measurements for height will be collected by way of a calibrated stadiometer. Height 
measurements will be collected 3 times for each patient at the specified study visits, and the 
average of the 3 measurements will be determined and recorded at the site.
The clinical site staff will be instructed to use calibrated scales for weight measurement.
7.8
Investigational Product Administration
All doses of VPRIV will be administered by continuous intravenous infusion. Study drug 
infusions are to occur on approximately the same day of the week but may occur every 14 days 
(±7 days of the target day) in order to facilitate patient scheduling. If at all possible, missed 
infusions should be avoided. If a patient is not dosed within 21 days from their scheduled dose, 
the patient should receive the next infusion as soon as possible. It may be acceptable to give the 
next infusion as early as 7 days after the previous infusion. Subsequent infusions will return to 
the original schedule.
The infusion time will be at least 60 minutes (1 hour). For example, a 60 U/kg dose will be 
delivered at a rate of at least 1 U/kg/minute. The infusion of VPRIV will be delivered 
intravenously with an in-line sterilizing filter (0.2 micron or 0.22 micron).
The dose of VPRIV will be calculated based on the patient’s weight determined at screening. A 
change in weight of ±5% from screening or the previous weight assessment in the study will 
require recalculation of the dose.
If a patient experiences an infusion-related AE (as defined in Section 7.14.1.7) during the 
infusion of investigational product, the investigator should decide, based on his or her clinical 
judgment, whether the infusion should be slowed or temporarily or permanently discontinued.
Patients experiencing recurrent infusion-related AEs may be pre-medicated, as described in 
Section 6.6. If infusions continue without incident, then tapering of medications can be 
considered.
7.9
Pharmacokinetic Assessments
Not applicable.
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7.11.12
Vital Signs
Vital signs are to be recorded for all patients and will include pulse, blood pressure, respiration 
rate, temperature, and pulse oxygen measurement.
The schedule included in Table 7-2 will be followed for recording vital signs at home or clinic 
infusion visits.
Table 7-2
Schedule for Recording of Vital Signs at Infusion
Timing Relative to Infusion
Schedule of Assessments
Start of Infusion
Within 10 minutes prior to start of infusion
During Infusion
30 minutes (±5 minutes)
After Infusiona
Within 5 minutes after completing the infusion
30 minutes (±5 minutes) after completing the infusion
60 minutes (±5 minutes) after completing the infusion
a If there are no infusion-related reactions during the first 3 infusions, the observation and vital signs post-infusion 
can be omitted at the discretion of the investigator.
7.11.13
Electrocardiography
Twelve-lead ECGs will be performed in accordance with the clinical site’s standard practice(s). 
ECG recordings will be read locally at the clinical site by the investigator or a qualified designee. 
ECGs will include assessment of heart rate, sinus rhythm, atrial or ventricular hypertrophy, and 
assessment of PR, QRS, QT, and corrected QT intervals. Identification of any clinically 
significant findings and/or conduction abnormalities will be recorded on the eCRF.
7.11.14
Clinical Laboratory Tests
Blood and urine samples will be collected as described in this section for clinical laboratory 
testing. All blood samples will be collected via venipuncture. Patients will be in a seated or 
supine position during blood collection.
Clinical laboratory tests will include the following (Table 7-3). Any clinically significant finding 
as determined by the investigator will be recorded as an AE on the appropriate eCRF.
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Table 7-3
List of Laboratory Tests
Hematology:
-
Hematocrit (Hct)
-
Hemoglobin (Hgb)
-
Mean corpuscular hemoglobin (MCH)
-
Mean corpuscular hemoglobin 
concentration (MCHC)
-
Mean corpuscular volume (MCV)
-
Platelet count
-
Red blood cell (RBC) count 
-
White blood cell (WBC) count with 
differentials
-
Neutrophils
-
Basophils
-
Lymphocytes
-
Monocytes
-
Eosinophils
Urinalysis: 
-
Appearance
-
Bilirubin
-
Color
-
Glucose
-
Ketones
-
Microscopic examination of sediment 
-
Nitrite 
-
Occult blood
-
pH
-
Protein
-
Specific gravity
-
Urobilinogen
Urine human chorionic gonadotropin (hCG) (only 
for females who are not diagnosed as 
postmenopausal)
Serum Chemistry:
-
Vitamin D (screening and Weeks 51 and 
103 only)

25-hydroxycholecalciferol 

1, 25-dihydroxycholecalciferol
-
Albumin (ALB)
-
Alkaline phosphatase (ALK-P)
-
Alanine aminotransferase (ALT; SGPT)
-
Aspartate aminotransferase (AST; SGOT)
-
Blood urea nitrogen (BUN)
-
Calcium 
-
C-reactive protein (CRP)
-
Creatinine
-
Creatine kinase 
-
Ferritin
-
Gamma-glutamyl transferase (GGT)
-
Glucose
-
Iron binding capacity
-
Lactate dehydrogenase (LDH)
-
Phosphorus
-
Potassium (K)
-
Serum iron
-
Sodium (Na)
-
Total bilirubin
-
Total protein
-
Transferrin saturation
-
Unsaturated IBC
Coagulation: 
-
Prothrombin time 
-
Activated partial thromboplastin time 
(aPTT)
-
D-dimer
The following safety laboratory tests will be performed at Screening:

Vitamin D blood test
The following laboratory tests will be performed at baseline and Weeks 13, 25, 37, 51, 65, 77, 
89, and 103:

Coagulation

Prothrombin time
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
Activated partial thromboplastin time (aPTT)

D-dimer
The laboratory tests for Hematology, Serum Chemistry, and Urinalysis are to be performed as 
indicated in Section 7.11.5 and Section 7.11.6 and the Appendix 1 Schedule of Events (at 
Baseline and Weeks 13, 25, 37, 51, 65, 77, 89, and 103).
7.11.15
Antibody Assessments
Blood samples will be collected for all patients for the determination of anti-velaglucerase alfa 
antibodies prior to the patient receiving the first dose of VPRIV at the baseline visit and at 
specified time points throughout the study (Weeks 13, 25, 37, 51, 65, 77, 89 and 103). 
Blood samples collected for anti-velaglucerase alfa antibody determination will be evaluated at 
Shire Bioanalytical and Biomarker Development or a contract research laboratory designated by 
the Sponsor. These samples will be analyzed for anti-therapeutic protein binding antibodies. 
Confirmed positive samples will undergo assessment of neutralizing activity.
7.11.16
Pregnancy Testing
Female patients of childbearing potential will have a pregnancy test at each study visit.
At screening, pregnancy testing will be conducted using a urine test and a serum human 
chorionic gonadotropin (β-hCG) test. Patients with a positive result for either test will not be 
eligible for this study. The screening urine pregnancy test will be performed locally, and the 
screening serum pregnancy test will be analyzed at the central laboratory responsible for this 
study.
At all other visits, pregnancy testing will be performed with a urine test. If the urine test is 
positive, a blood sample will be collected for serum β-hCG testing. The clinical site’s local 
laboratory will analyze and report all subsequent urine and serum pregnancy testing results.
If, during the Treatment Period (Week 1 to Week 103), a urine pregnancy test result is positive, 
the patient will not receive the planned infusion(s) until the result of the serum test is available. If 
the serum β-hCG result is also positive, no additional doses of the investigational product are to 
be administered and the investigator must contact the Shire Medical Monitor. Any report of 
pregnancy for any female study participant must be reported within 1 business day.
7.12
Sample Collection, Storage, and Shipping
All samples will be stored and secured in a way that ensures that unauthorized access is 
prohibited, and the samples are not lost, allowed to deteriorate, or are accidentally or illegally 
destroyed. Detailed sample collection, processing and shipping, and storage procedures will be 
provided in the Study Operations and/or Laboratory Manuals.
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The medical assessment of severity is determined by using the following definitions:
Mild:    A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of daily 
living.
Moderate:    A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses no significant 
or permanent risk of harm to the research subject.
Severe:    A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
7.14.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected response 
pattern to that product, and the event cannot be explained by the subject’s medical 
condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s underlying 
medical condition, concomitant therapy, or accident and no plausible temporal or 
biologic relationship exists between the investigational product and the event.
7.14.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the CRF. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved with Sequelae

Recovering/Resolving

Unknown
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7.14.1.4
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE.
7.14.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory, vital sign, or ECG assessment can represent an AE 
if the change is clinically relevant or if, during treatment with the investigational product, a shift 
of a parameter is observed from a normal value to an abnormal value, or a further worsening of 
an already abnormal value. When evaluating such changes, the extent of deviation from the 
reference range, the duration until return to the reference range, either while continuing treatment 
or after the end of treatment with the investigational product, and the range of variation of the 
respective parameter within its reference range, must be taken into consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or ECG 
values which were not present at the pre-treatment value observed closest to the start of study 
treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (eg, concomitant disease) is found for the 
abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically 
significant and whether it represents an AE.
7.14.1.6
Pregnancy
Any report of pregnancy for a female study participant or the partner of a male study participant 
must be reported within 24 hours to the Shire Global Drug Safety Department using the Shire 
Investigational and Marketed Products Pregnancy Report Form. A copy of the Shire 
Investigational and Marketed Products Pregnancy Report Form (and any applicable follow-up 
reports) must also be sent to the/Shire Medical Monitor using the details specified in the 
emergency contact information section of the protocol.
The pregnant female study participant must be withdrawn from the study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant for every pregnant female study participant withdrawn from the study and 
for pregnant partners of male study participants. It is the responsibility of the investigator to 
obtain this information within 30 calendar days after the initial notification and approximately 30 
calendar days post partum.
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form. Note: An elective abortion is not 
considered an SAE.
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In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Study Serious Adverse Event and 
Non-serious AEs Required by the Protocol Form as well as the Shire Investigational and 
Marketed Products Pregnancy Report Form. The test date of the first positive serum/urine 
-HCG test or ultrasound result will determine the pregnancy onset date.
Pregnancy and lactation are exclusion criteria for this study. Any report of pregnancy for a 
female study participant or the partner of a male study participant during the course of the study 
and through 30 days after the patient’s last dose of VPRIV must be reported to the Sponsor. 
Pregnancy is not to be reported as an AE; the Investigational and Marketed Products Pregnancy 
Report Form should be used to report the pregnancy. The pregnancy will be followed up through 
delivery or final outcome. 
7.14.1.7
Infusion-related Adverse Event Definition
An IRR will be defined as an AE that 1) begins either during or within 24 hours after the start of 
the infusion and 2) is judged as related to study drug. 
Other AEs that occur prior to the infusion, along with AEs associated with protocol-defined 
testing and assessments (laboratory testing and physical examinations) that were performed prior 
to the infusion will not be defined as IRRs. All AEs should be recorded together with a causality 
assessment.
7.14.1.8
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 7.15.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.
•
Abuse – Persistent or sporadic intentional intake of investigational product when used for a 
non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner that 
may be detrimental to the individual and/or society
•
Misuse – Intentional use of investigational product other than as directed or indicated at any 
dose (Note: this includes a situation where the investigational product is not used as directed 
at the dose prescribed by the protocol)
•
Overdose – Intentional or unintentional intake of a dose of investigational medicinal product 
10% higher than the protocol-specified dose. 
•
Medication Error – A mistake made in prescribing, dispensing, administration, and/or use 
of the investigational medicinal product
•
Cases of subjects missing doses of the investigational product are not considered 
reportable as medication errors.
•
Medication errors should be collected/reported for all products under investigation.
•
The administration and/or use of an expired investigational product should be considered 
as a reportable medication error.
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7.15
Serious Adverse Event Procedures
7.15.1
Reference Safety Information
The reference for safety information for this study is the investigator’s brochure for US 
investigator sites and the Summary of Product Characteristics for European investigator sites, 
which the sponsor has provided under separate cover to all investigators.
7.15.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Drug Safety Department and the Shire Medical Monitor within 24 hours of the first awareness 
of the event. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors (see Section 7.14.1.8) unless they result in an 
SAE.
The investigator must complete, sign, and date the Shire Clinical Study Serious Adverse Event 
and Non-serious AEs Required by the Protocol Form and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested) and fax or e-mail the form to the Shire Global Drug Safety
Department. A copy of the Shire Clinical Study Serious Adverse Event and Non-serious AEs 
Required by the Protocol Form (and any applicable follow-up reports) must also be sent to the 
Shire Medical Monitor using the details specified in the emergency contact information section 
of the protocol.
7.15.3
Serious Adverse Event Definition
A Serious Adverse Event (SAE) is any untoward medical occurrence (whether considered to be 
related to investigational product or not) that at any dose:
•
Results in death.
•
Is life-threatening. Note: The term ‘life-threatening’ in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to 
an event which hypothetically might have caused death if it was more severe.
•
Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should not 
be classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).
•
Results in persistent or significant disability/incapacity.
•
Is a congenital abnormality/birth defect.
•
Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. 
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Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home; blood dyscrasias or convulsions that do not 
result in inpatient hospitalization; or the development of drug dependency or drug abuse.
7.15.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 8.5 and must be reported to 
the Shire Global Drug Safety Department and the CRO/Shire Medical Monitor within 24 hours 
of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Drug Safety Department within 24 hours of the first awareness of the event.
7.15.5
Serious Adverse Event Onset and Resolution Dates
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 8.5 and must be reported to 
the Shire Global Drug Safety Department and the Shire Medical Monitor within 24 hours of the 
first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Drug Safety Department within 24 hours of the first awareness of the event.
7.15.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
Action taken with the investigational product should be an active decision by the investigator. 
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another study drug action was previously taken (eg, drug interrupted, reduced, withdrawn), the 
action taken with the investigational product should be recorded as “dose not changed” or “not 
applicable” (if the subject never received investigational product). The study drug action of 
withdrawn should not be selected solely as a result of the subject’s death.
7.15.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The sponsor or sponsor designee is responsible for notifying the relevant regulatory 
authorities/US central IRBs/EU central ECs of related, unexpected SAEs.
In addition, the sponsor or the sponsor’s designee is responsible for notifying active sites of all 
related, unexpected SAEs occurring during all interventional studies across the velaglucerase alfa 
program.
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The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
7.16
Removal of Patients from the Trial or Investigational Product
A patient’s participation in the study may be discontinued at any time at the discretion of the 
investigator. The following may be justifiable reasons for the investigator to remove a patient 
from the study:
•
Non-compliance, including failure to appear at 1 or more study visits
•
The patient was erroneously included in the study
•
The patient develops an exclusion criterion 
•
The patient suffers an intolerable AE
•
The patient requests to be discontinued from the study
•
The study is terminated by the Sponsor
•
Pregnancy
The patient, or the patient’s legally authorized representative(s), acting on behalf of the patient is 
free to withdraw consent and discontinue participation in the study at any time without prejudice 
to further treatment.
If a patient, or the patient’s legally authorized representative(s) acting on behalf of the patient, 
discontinues participation in the study or the patient is discontinued by the investigator,
reasonable efforts will be made to follow the patient through the end of study assessments. The 
reason for refusal will be documented on the eCRF. Any AEs experienced up to the point of 
discontinuation must be documented on the AE eCRF. If AEs are present when the patient 
withdraws from the study, the patient will be re-evaluated within 30 days of withdrawal. All 
ongoing SAEs at the time of withdrawal will be followed until resolution.
7.17
Other Study Procedures
7.17.1
Safety-related Study Stopping Rules
This study will be stopped and safety data reviewed if any patient experiences a life-threatening 
SAE or a death occurs, if either is considered related to the investigational product.
Following the review of safety data, the study will be either:
•
Resumed unchanged
•
Resumed with modifications to the protocol 
•
Terminated
Patient safety will be monitored on a continuous basis during this study until the last patient 
completes his or her last scheduled study visit/assessment. For patients who discontinue or are 
withdrawn prior to the Week 103 end of study visit, a follow-up assessment for safety will occur 
30 (±7) days after their last infusion. This follow-up assessment may be conducted over the 
telephone.
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7.18
Appropriateness of Measurements
Standard assessments will be used to monitor safety in the study. The efficacy measures are well 
established in the general Gaucher disease patient population.
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8
STUDY ACTIVITIES
Study procedures will be conducted only after patients have provided written informed consent 
to participate in the study.
Detailed descriptions of patient evaluations required for this protocol are described below. The 
Study Schedule of Events is provided in Appendix 1.
All data collected are to be recorded on the appropriate eCRF page. Complete instructions for 
eCRF completion will be provided separately from this protocol. 
8.1
Screening Visit (Days -28 to -4)
•
Informed consent (prior to any study-related procedures)
•
Study entrance criteria
•
Medical history
•
Concomitant medications
•
AEs
•
SAEs
•
Vital signs
•
Height
•
Weight
•
Vitamin D blood test
•
Pregnancy test
•
DXA of lumbar spine
8.2
Baseline (Days -3 to 0)
Note: The baseline visit may be combined with the Week 1 (within 7 days after baseline) 
Treatment Period visit.
•
Confirmation of study eligibility
•
Neurological assessment
•
Concomitant medications
•
AEs
•
SAE and IRRs
•
Physical examination 
•
Vital signs
•
Pregnancy test
•
ECG
•
Serum chemistry
•
Hematology/Coagulation
•
Urinalysis
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•
Serum anti-velaglucerase alfa antibody
•
MRI to determine liver and spleen volume
•
MRI of the lumbar spine and whole femur
•
•
Questions taken from the BPI-SF©
•
BFI
8.3
Treatment Period (Week 1 to Week 101)
8.3.1
Weeks 1, 3, 5, 7, 9, 11, 15, 17, 19, 21, 23, 27, 29, 31, 33, 35, 39, 41, 45, 43, 47, 
49, 53, 55, 57, 59, 61, 63, 67, 69, 71, 73, 75, 79, 81, 83, 85, 87, 91, 93, 95, 97, 
99, and 101
•
VPRIV infusion
•
Concomitant medications
•
AEs
•
SAE and IRRs
•
Vital signs
•
Pregnancy test
8.3.2
Weeks 13, 37, 65, and 89
•
VPRIV infusion
•
Concomitant medications
•
AEs
•
SAE and IRRs
•
Physical examination
•
Vital signs
•
Pregnancy test
•
Height
•
Weight
•
Serum chemistry
•
Hematology/Coagulation
•
Urinalysis
•
Serum anti-velaglucerase alfa antibody
•
•
Questions taken from the BPI-SF©
•
BFI
8.3.3
Weeks 25 and 77
•
VPRIV infusion
•
Concomitant medications
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•
AEs
•
SAE and IRRs
•
Physical examination
•
Vital signs
•
Pregnancy test
•
Height
•
Weight
•
ECG
•
Serum chemistry
•
Hematology/Coagulation
•
Urinalysis
•
Serum anti-velaglucerase alfa antibody
•
•
Questions taken from the BPI-SF©
•
BFI
8.3.4
Week 51
•
Neurological assessment
•
VPRIV infusion
•
Concomitant medications
•
AEs
•
SAE and IRRs
•
Physical examination
•
Vital signs
•
Pregnancy test
•
Height
•
Weight
•
Vitamin D blood test
•
ECG
•
Serum chemistry
•
Hematology/Coagulation
•
Urinalysis
•
Serum anti-velaglucerase alfa antibody
•
MRI to determine liver and spleen volume
•
MRI of the LS and whole femur
•
DXA of LS
•
•
Questions taken from the BPI-SF©
•
BFI
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8.4
End of Study (Week 103)/Early Termination Procedures
•
Neurological assessment
•
Concomitant medications
•
AEs
•
SAE and IRRs
•
Physical examination
•
Vital signs
•
Pregnancy test
•
Height
•
Weight
•
Vitamin D blood test
•
ECG
•
Serum chemistry
•
Hematology/Coagulation
•
Urinalysis
•
Serum anti-velaglucerase alfa antibody
•
MRI to determine liver and spleen volume
•
MRI of the LS and whole femur
•
DXA of LS
•
•
Questions taken from the BPI-SF©
•
BFI
8.5
30-day Safety Follow-up Visit
•
AEs
•
SAEs and IRRs
•
Concomitant medications
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9
QUALITY CONTROL AND ASSURANCE
Training will occur at an investigator meeting or at the site initiation visit or both, and instruction 
manuals will be provided to aid consistency in data collection and reporting across sites.
Clinical sites will be monitored by the Sponsor or its designee to ensure the accuracy of data 
against source documents. The required data will be captured in a validated clinical data 
management system that is compliant with the FDA 21 CFR Part 11 Guidance. The clinical trial 
database will include an audit trail to document any evidence of data processing or activity on 
each data field by each user. Users will be trained and given restricted access, based on their 
role(s) in the study, through a password-protected environment.
Data entered in the system will be reviewed manually for validity and completeness against the 
source documents by a clinical monitor from the Sponsor or its designee. If necessary, the study 
site will be contacted for corrections or clarifications; all missing data will be accounted for.
SAE information captured in the clinical trial database will be reconciled with the information 
captured in the Pharmacovigilance and Risk Management database.
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10 PLANNED STATISTICAL METHODS
10.1
General Considerations
This is a multicenter, open-label study designed to evaluate the effect of VPRIV on bone-related 
pathology in adult treatment-naïve patients with Type 1 Gaucher disease. 
Statistical analyses will be based on the intent-to-treat (ITT) principle for all efficacy 
variables. The ITT analysis will be based on all enrolled patients who received at least 
1 study drug infusion (full or partial). Summary statistics will be provided for the changes 
and percent changes from baseline for each parameter. Two-sided 95% confidence intervals 
in the mean changes and mean percent changes from baseline will be presented for each 
endpoint.
Continuous data collected at baseline and subsequent study visits will be summarized, and the 
mean, standard deviation, minimum, maximum, and median values for each variable will be 
tabulated to facilitate the search for trends over time which may be attributable to study drug. 
Categorical variables will be presented in terms of frequencies and percent. Within patient 
changes from baseline will be examined using 1 sample t-test or Wilcoxon signed rank test. 
Statistical significance will be defined at the 0.05 level. 
Demographic and baseline characteristics will be summarized as frequencies and percentages, 
and data will be presented using descriptive statistics. 
In general, descriptive statistics and graphs will be used for the presentation of study results 
including, if relevant, graphs showing the treatment effect over time for patients individually and 
overall. 
Safety will be evaluated on the basis of AEs reported, clinical laboratory data, use of 
concomitant medications, vital signs, and physical examinations. In addition, blood samples will 
be analyzed for determination of the presence of anti-velaglucerase alfa antibodies. 
All statistical analyses will be performed using SAS® software. Any changes to the analyses 
proposed in this protocol will be described in the statistical analysis plan and/or the clinical study 
report. 
10.2
Determination of Sample Size
In a previous protocol version (Amendment 4), approximately 40 patients were planned for 
enrollment in order to achieve a total of 34 evaluable patients (driven by the key secondary 
efficacy endpoint), assuming a 15 % drop-out rate. A total of 34 evaluable patients provided
99% power to detect a significant change in LS BMD Z-score from baseline after 24 months of 
treatment (primary efficacy endpoint) when in fact there is a +0.6 change (improvement) in 
Z-score. The calculation assumed an alpha of 0.05 (2-sided t-test) and a standard deviation of 
change of 0.6 based on data from study HGT-GCB-044. The 34 evaluable patients also conferred 
80% power to detect a significant change in one of the key secondary endpoints, namely the 
change from baseline in LS BMD Z-score after 12 months of treatment. 
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Assumptions for the key secondary endpoint power calculation were also based on study 
HGT-GCB-044 in which a +0.25 change in in Z-score at 12 months was reported with a standard 
deviation of 0.5. 
In the previous amendment (Amendment 5), the number of patients planned for enrolment was 
revised based on the patient recruitment and retention experience to date to allow for a more 
realistic and achievable recruitment target. Cumulative enrollment data collected from study 
initiation to date indicate a suboptimal enrollment rate of 0.5 patient per month. Study enrollment 
is hindered by the considerable prevalence of screen failures (approximately 50%) resulting from 
the limited global pool of naïve patients with Gaucher disease who demonstrate bone 
involvement at baseline and who meet the eligibility criteria of this study. Based on this 
information, the number of patients planned for enrollment was reduced to at least 19 patients in 
order to yield 13 evaluable patients. To be considered evaluable, a patient must have an eligible 
DXA score at Baseline and at 24 months (Week 103 [end of study]). The number of evaluable 
patients was determined assuming a drop-out rate of 30% based on the rate of early 
discontinuations reported during the first 2 years of the study. With 13 evaluable patients and 
assuming the same effect size (increase in LS BMD Z-score of +0.6) and standard deviation (0.6)
values at 24 months from study HGT-GCB-044, the study will be 90% powered to detect 
significant changes (alpha 0.05) in LS BMD Z-score at 24 months (primary efficacy endpoint).
As the revised sample size no longer provides adequate statistical power for the detection of
significant changes in the key secondary endpoints defined in the previous protocol version, 
those were demoted to secondary endpoints in the current amendment.
10.3
Analysis Populations
The ITT population will be used for all efficacy analyses and is defined as all enrolled patients 
who received at least 1 study drug infusion (full or partial). The safety population will be used 
for all safety analyses and is defined as all enrolled patients who received at least 1 study drug 
infusion (full or partial). 
10.4
Patient Disposition
Patient disposition for those enrolled, treated, completed, or discontinued/withdrew will be 
presented in summary tables using number and percentage of patients per category; reasons for 
discontinuation/withdrawal will be presented. 
10.5
Demographics and Baseline Characteristics
Demographic (eg, age, sex, and race) and baseline characteristics (eg, medical history, disease 
history, and bone pathology) will be analyzed using the safety population. Demographic and 
baseline characteristics will be summarized using either descriptive statistics or frequency 
distributions, as appropriate.
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10.6
Primary Endpoint
10.6.1
Primary Efficacy Endpoint
The primary efficacy endpoint is the change from baseline to 24 months (Week 103 [end of 
study]) in LS BMD Z-score as measured by DXA. The null hypothesis is that there is no change 
from baseline to 24 months in LS BMD Z-scores. A statistically significant change in BMD after 
24 months of treatment is highly clinically relevant in this patient population. One sample t-test 
or Wilcoxon signed rank test will be applied for the change from baseline of LS BMD Z-scores 
with patients whose LS BMD scores are collected after 24 months of treatment. A 95% 
confidence interval for the mean of the change from baseline will also be presented. 
As a sensitivity analysis, the primary efficacy analysis will be repeated by applying last 
observation carried forward (LOCF) method. That is, if the LS BMD score is missing at 
24 months (Week 103 [end of study]), the last non-missing score before 24 months will be 
carried forward, and the score at baseline will not be carried forward for the analysis.
The descriptive summary statistics of the percentage of change from baseline of the LS BMD 
Z-score will also be generated. 
10.7
Secondary Endpoints
10.7.1
Safety Endpoints
All patients who receive at least 1 study drug infusion (full or partial) will be assessed for 
clinical safety and tolerability. The safety population will be used for the analyses of the safety 
endpoints. No formal statistical tests will be performed on the safety parameters.
The number and proportion of patients for the following parameters will be descriptively 
summarized:
•
Study drug-related AEs
•
Infusion-related AEs
•
Serious AEs
•
Use of concomitant medication
•
Clinically abnormal laboratory tests (hematology, serum chemistry, and urinalysis)
•
Positive anti-velaglucerase alfa antibody test
AEs will be coded using the MedDRA, and tabular summaries of AEs will be based on all 
TEAEs recorded. A TEAE is defined as any AE that occurred on or after the time of the first 
infusion of study drug until 30 days after the last infusion of study drug. 
The number and proportion of patients experiencing an AE will be tabulated for the following:
•
Overall summary of AEs: Recurrent AEs observed within a patient will be counted once.
•
AEs by system organ class (SOC) and preferred term (PT).
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•
AEs by SOC, PT, and severity: In the case of multiple occurrences of the same AEs (at the 
PT level) in an individual patient, the AE that is classified as the most severe (ie, maximum 
severity) will be identified.
•
AEs by SOC, PT, and relationship: The AE with the closest relationship to the study drug in 
the same PT level will be reported.
•
SAEs, infusion-related AEs, and AEs that led to permanent discontinuation, by SOC and PT. 
Furthermore, an SAE listing and a listing of all patients who permanently discontinued due to an 
AE(s) will be provided. An infusion-related AE is defined as an AE that begins either during or 
within 24 hours after the start of the infusion and is judged as related to the investigational 
product.
Anti-velaglucerase alfa antibody results will also be summarized. For this study, once the patient 
becomes antibody positive to velaglucerase alfa, they will be considered positive for the 
remainder of the study. 
Any newly occurring abnormalities or worsening from baseline in vital signs, ECG, physical 
examination, or clinical laboratory test data will be flagged. In addition, the number and 
proportion of patients with any shifts in vital signs from normal before infusion to abnormal after 
infusion will be presented. Changes in laboratory parameters will also be summarized using shift 
tables based on a classification of values as low, normal, or high with respect to the reference 
range.
10.7.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints include the following evaluations: 
•
Change from baseline to 12 months (Week 51) in LS BMD Z-score. Assessments will be 
performed at the screening visit and Weeks 51 and 103 (end of study).
•
Change from baseline to 12 months (Week 51) and 24 months (Week 103, end of study) in 
LS BMD in g/cm2.
•
Change from baseline to 12 months (Week 51) and 24 months (Week 103 [end of study]) in 
BMB score (MRI of LS and femur). Assessments will be performed at the baseline visit and 
Weeks 51 and 103 (end of study).
•
Change from baseline over time in hemoglobin concentration. Assessments will be 
performed at baseline and Weeks 13, 25, 37, 51, 65, 77, 89, and 103 (end of study).
•
Change from baseline over time in platelet count. Assessments will be performed at baseline 
and Weeks 13, 25, 37, 51, 65, 77, 89, and 103 (end of study).
•
Change from baseline to 12 months (Week 51) and 24 months (Week 103 [end of study]) in 
normalized liver volume as measured by abdominal MRI. Assessments will be performed at 
the baseline visit and Weeks 51 and 103 (end of study).
•
Change from baseline to 12 months (Week 51) and 24 months (Week 103 [end of study]) in 
normalized spleen volume as measured by MRI. Assessments will be performed at the 
baseline visit and Weeks 51 and 103 (end of study).
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•
Shifts in WHO BMD classification (normal bone density, osteopenia, osteoporosis), based on 
LS T-scores. Assessments will be performed at the baseline visit and Weeks 51 and 103 (end 
of study).
For WHO BMD classification based on LS T-score endpoint, the number and proportion of 
patients classified as having normal (T-score ≥-1), osteopenia (-2.5< T-score <-1), or 
osteoporosis(T-score ≤-2.5) BMD will be captured; patient shifts in BMD classification based on 
T-score will be reported. 
For the remaining secondary efficacy parameters, 1 sample t-test or Wilcoxon signed rank 
test will be applied for the change from baseline of each endpoint at each time point. In this 
analysis, the LOCF method for missing values will be applied. As an additional analysis, a 
linear mixed-effects model will be used as a repeated measures analysis to investigate the 
improvement of efficacy over time. This model uses all the clinical information obtained on a 
patient while allowing for the repeated measurements to exhibit correlation between 
observations within the same patient. Estimates for the clinical parameters obtained over time 
will account for the baseline measurements and will be adjusted for demographic and baseline 
factors. This linear mixed-effects model will be described in more detail in a statistical analysis 
plan. 
The descriptive summary statistics of the percentage of change from baseline for the quantitative 
efficacy endpoints will also be generated. 
10.7.3
Other Secondary Efficacy Endpoints (Health Economics and Outcomes 
Research Endpoints)
Health economic and outcomes research endpoints are secondary endpoints. These include the 
following:
•
Change from baseline to 12 months (Week 51) and 24 months (Week 103 [end of study]) in 
overall fatigue as measured by the BFI. Assessments will be performed at the baseline visit 
and Weeks 13, 25, 37, 51, 65, 77, 89, and 103 (end of study).
•
Change from baseline to 12 months (Week 51) and 24 months (Week 103 [end of study]) in 
bone pain as measured by questions taken from the BPI-SF©.
•
Assessments will be performed at the baseline visit and Weeks 13, 25, 37, 51, 65, 77, 89, and 
103 (end of study).
For the health economics and outcomes parameters, 1 sample t-test or Wilcoxon signed rank test 
will be applied for the change from baseline of each endpoint at each time point. In this analysis, 
the LOCF method for missing values will be applied. 
The descriptive summary statistics of the percentage of change from baseline for the quantitative 
efficacy endpoints will also be generated.
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11 ADMINISTRATIVE CONSIDERATIONS
11.1
Investigators and Study Administrative Structure
Before initiation of the study, the investigators must provide the Sponsor with a completed form 
FDA 1572, Investigator Agreement, or other applicable regulatory documentation. 
Investigational product may be administered only under the supervision of the investigators 
listed on these forms. Curriculum vitae must be provided for the investigators and 
sub-investigators listed on form FDA 1572 or other regulatory documentation, as applicable.
The investigator should ensure that all persons assisting with the study are adequately 
informed about the protocol, any amendments to the protocol, the study treatments, and their 
study-related duties and functions. The investigator must maintain a list of sub-investigators and 
other appropriately qualified persons to whom he or she has delegated significant study-related 
duties. 
11.2
Institutional Review Board or Independent Ethics Committee Approval
Before initiation of the study, the investigator must provide the Sponsor with a copy of the 
written IRB/IEC approval of the protocol and the informed consent form. This approval must 
refer to the informed consent form and the study title, study number, and version and date of 
issue of the study protocol, as given by the Sponsor on the cover page of the protocol.
Status reports must be submitted to the IRB/IEC at least once per year. The IRB/IEC must be 
notified of completion of the study. Within 3 months of study completion or termination, a final 
report must be provided to the IRB/IEC. A copy of these reports will be sent to the study clinical 
monitor. The investigators must maintain an accurate and complete record of all submissions 
made to the IRB/IEC, including a list of all reports and documents submitted. AEs which are 
reported to the US FDA or other regulatory agencies (IND safety reports) must be submitted 
promptly to the IRB/IEC.
11.3
Ethical Conduct of the Study
The procedures set out in this study protocol pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor and investigators abide by 
GCP as described in the 21 CFR Parts 50, 56, and 312 and the ICH GCP Guidelines. Compliance 
with these regulations and guidelines also constitutes compliance with the ethical principles 
described in the Declaration of Helsinki.
11.4
Patient Information and Consent
Before enrolling in the clinical study, the patient or legally authorized representative(s) must 
consent to participate after the nature, scope, and possible consequences of the clinical study 
have been explained in a form understandable to him or her. Only informed consent forms 
approved by an IRB or IEC may be used.
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An informed consent form that includes information about the study will be prepared and given 
to the patient or legally authorized representative(s). This document will contain all FDA and 
ICH-required elements. The informed consent form must be in a language understandable to the 
patient or legally authorized representative(s) and must specify who informed the patient, or the 
patient’s legally authorized representative(s).
After reading the informed consent document, the patient or legally authorized representative(s) 
must give consent in writing. Consent must be confirmed at the time of consent by the personally 
dated signature of the patient, or the patient’s legally authorized representative(s) and by the 
personally dated signature of the person conducting the informed consent discussions.
If the patient or legally authorized representative(s) is unable to read, oral presentation and 
explanation of the written informed consent form and information to be supplied must take place 
in the presence of an impartial witness. Consent must be confirmed at the time of consent orally 
and by the personally dated signature of the patient or by a local legally recognized alternative 
(eg, the patient’s thumbprint or mark) or by the personally dated signature of the patient’s legally 
authorized representative. The witness and the person conducting the informed consent 
discussions must also sign and personally date the informed consent document. It should also be 
recorded and dated in the source document that consent was given.
A copy of the signed and dated consent document(s) must be given to the patient or legal 
representative(s). The original signed and dated consent document will be retained by the 
investigator.
The investigator will not undertake any measures specifically required solely for the clinical 
study until valid consent has been obtained.
A model of the informed consent form to be used in this study will be provided to the sites 
separately from this protocol.
11.5
Patient Confidentiality
Patient names will not be supplied to the Sponsor. The patient number will be recorded in the 
eCRF, and if the patient name appears on any other document, it must be obliterated before a 
copy of the document is supplied to the Sponsor. Study findings stored on a computer will be 
stored in accordance with local data protection laws. The patients or patient’s legally authorized 
representative(s), will be told that representatives of the Sponsor, a designated contract research 
organization, the IRB/IEC, or regulatory authorities may inspect their medical records to verify 
the information collected, and that all personal information made available for inspection will be 
handled in strictest confidence and in accordance with local data protection laws. The 
investigator will maintain a personal patient identification list (patient numbers with the 
corresponding patient names) to enable records to be identified.
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11.6
Study Monitoring
Monitoring procedures that comply with current GCP guidelines will be followed. Review of the 
eCRFs for completeness and clarity, cross-checking with source documents, and clarification of 
administrative matters will be performed.
The study will be monitored by the Sponsor or its designee. Monitoring will be performed by a 
representative of the Sponsor (clinical study monitor) who will review the eCRFs and source 
documents. The site monitor will ensure that the investigation is conducted according to protocol 
design and regulatory requirements by frequent site visits and communications (letter, telephone, 
and facsimile).
11.7
Case Report Forms and Study Records
Case report forms (paper or electronic) are provided for each patient. All forms must be filled out 
by authorized study personnel. All corrections to the original eCRF entry must indicate the 
reason for change. The investigator is required to sign the eCRF after all data have been captured 
for each patient. If corrections are made after review and signature by the investigator, he or she 
must be made aware of the changes, and his or her awareness documented by re-signing the 
eCRF.
11.7.1
Critical Documents
Before Shire initiates the trial (ie, obtains informed consent from the first patient), it is the 
responsibility of the investigator to ensure that the following documents are available to Shire or 
its designee:
•
Applicable local regulatory documentation (eg, completed FDA form 1572 [statement of 
Investigator]), signed, dated, and accurate
•
Curricula vitae of investigator and sub-investigator(s) (current, dated and signed within 
24 months of study initiation)
•
Copy of investigator and sub-investigator(s) current medical license (indicating license 
number and expiration date)
•
Signed and dated agreement of the final protocol
•
Signed and dated agreement of any amendment(s), if applicable 
•
Approval/favorable opinion from the IRB/IEC clearly identifying the documents reviewed by 
name, number, and date of approval or re-approval: protocol, any amendments, subject 
information/informed consent form, and any other written information to be provided 
regarding patient recruitment procedures
•
Copy of IRB/IEC-approved subject information/informed consent form, any other written 
information, advertisement (with IRB approval stamp and date of approval)
•
Current list of IRB/IEC members/constitution (dated within 12 months prior to study 
initiation)
•
Financial disclosure form signed by investigator and sub-investigator(s)
•
Current laboratory reference ranges (if applicable)
•
Certification/Quality Assurance scheme/other documentation (if applicable)
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Regulatory approval and notification as required must also be available; these are the 
responsibility of Shire or their designee.
11.8
Data Monitoring Committee
There will be no data monitoring committee.
11.9
Protocol Violations/Deviations
The investigator will conduct the study in compliance with the protocol. The protocol will not be 
initiated until the IRB/IEC and the appropriate regulatory authorities have given 
approval/favorable opinion. Modifications to the protocol will not be made without agreement of 
the Sponsor. Changes to the protocol will require written IRB/IEC approval/favorable opinion 
prior to implementation, except when the modification is needed to eliminate an immediate 
hazard(s) to patients. The IRB/IEC may provide, if applicable regulatory authorities permit, 
expedited review and approval/favorable opinion for minor change(s) in ongoing studies that 
have the approval/favorable opinion of the IRB/IEC. The Sponsor will submit all protocol 
modifications to the regulatory authorities in accordance with the governing regulations.
A record of patients screened, but not entered into the study, is also to be maintained. No 
protocol exemption will be granted for this study.
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
patients, the investigator will contact the Sponsor or its designee, if circumstances permit, to 
discuss the planned course of action. Any departures from the protocol must be fully documented 
as a protocol deviation. Protocol deviations will need to be reviewed by the medical monitor and 
may also be required to be submitted to the IRB/IEC.
Protocol modifications will only be initiated by the Sponsor and must be approved by the 
IRB/IEC and submitted to the FDA or other applicable international regulatory authority before 
initiation.
11.10 Premature Closure of the Study
If the Sponsor, investigator, or regulatory authorities discover conditions arising during the study 
which indicate that the clinical investigation should be halted due to an unacceptable patient risk, 
the study may be terminated after appropriate consultation between the Sponsor and the 
investigator(s). In addition, a decision on the part of the Sponsor to suspend or discontinue 
development of the investigational product may be made at any time. Conditions that may 
warrant termination of the study or site include, but are not limited to:
•
The discovery of an unexpected, significant, or unacceptable risk to the patients enrolled in 
the study
•
Failure of the investigator to comply with pertinent global regulations
•
Submission of knowingly false information from the study site to the Sponsor or other 
pertinent regulatory authorities
•
Insufficient adherence by the investigator to protocol requirements
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11.11 Access to Source Documentation
Regulatory authorities, the IRB/IEC, or the Sponsor may request access to all source documents, 
eCRFs, and other study documentation for on-site audit or inspection. Direct access to these 
documents must be guaranteed by the investigator, who must provide support at all times for 
these activities. Monitoring and auditing procedures that comply with current GCP guidelines 
will be followed. On-site review of the eCRFs for completeness and clarity, cross-checking with 
source documents, and clarification of administrative matters may be performed.
11.12 Data Generation and Analysis
The clinical database will be developed and maintained by a contract research organization or an 
electronic data capture technology provider as designated by Shire. Shire or its designee will be 
responsible for performing study data management activities. 
Adverse events will be coded using the MedDRA. Concomitant medication will be coded using 
the WHO-Drug Dictionary. Centralized laboratories will be employed as described in the study 
manual to aid in consistent measurement of efficacy and safety parameters.
11.13 Retention of Data
Essential documents should be retained until at least 2 years after the last approval of a 
marketing application and until there are no pending or contemplated marketing applications or 
at least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product. The Sponsor will notify the investigator if these documents must be 
retained for a longer period of time. It is the responsibility of the Sponsor to inform the 
investigator or institution as to when these documents no longer need to be retained.
11.14 Financial Disclosure
The investigator should disclose any financial interests in the Sponsor as described in 21 CFR 
Part 54 prior to beginning this study. The appropriate form will be provided to the investigator 
by the Sponsor, which will be signed and dated by the investigator prior to the start of the study. 
The investigator should promptly update this information if any relevant changes occur in the 
course of the investigation or for 1 year following completion of the study. 
11.15 Publication and Disclosure Policy
All information concerning the study material, such as patent applications, manufacturing 
processes, basic scientific data, and formulation information supplied by the Sponsor and not 
previously published are considered confidential and will remain the sole property of the 
Sponsor. The investigator agrees to use this information only in accomplishing this study and 
will not use it for other purposes.
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It is understood by the investigator that the information developed in the clinical study may be 
disclosed as required to the authorized regulatory authorities and governmental agencies. In 
order to allow for the use of the information derived from the clinical studies, it is understood 
that there is an obligation to provide the Sponsor with complete test results and all data 
developed in the study in a timely manner.
The investigator and any other clinical personnel associated with this study will not publish the 
results of the study, in whole or in part, at any time, unless they have consulted with Shire, 
provided Shire a copy of the draft document intended for publication, and obtained Shire’s 
written consent for such publication. All information obtained during the conduct of this study 
will be regarded as confidential.
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12 LIST OF REFERENCES
Beutler, E. & Grabowski, G. 2001. Gaucher Disease. In: Scriver CR, B. A., Sly WS, Valle D 
(ed.) The Metabolic and Molecular Basis of Inherited Disease, 8th Edition. New York: 
McGraw-Hill.
Charrow, J., Andersson, H. C., Kaplan, P., Kolodny, E. H., Mistry, P., Pastores, G., Rosenbloom, 
B. E., Scott, C. R., Wappner, R. S., Weinreb, N. J. & Zimran, A. 2000. The Gaucher 
registry: demographics and disease characteristics of 1698 patients with Gaucher disease. 
Arch Intern Med, 160, 2835-43.
Charrow, J., Dulisse, B., Grabowski, G. A., Weinreb, N. J. C. I. N. C. G. A. & author reply, P. 
2007. The effect of enzyme replacement therapy on bone crisis and bone pain in patients 
with type 1 Gaucher disease. Clinical genetics, 71, 205-11.
Cleeland, C. S. 2002. Pain assessment: the advantages of using pain scales in lysosomal storage 
diseases. Acta Paediatr Suppl, 91, 43-7.
Cox, T. M., Aerts, J. M., Andria, G., Beck, M., Belmatoug, N., Bembi, B., Chertkoff, R., Vom 
Dahl, S., Elstein, D., Erikson, A., Giralt, M., Heitner, R., Hollak, C., Hrebicek, M., 
Lewis, S., Mehta, A., Pastores, G. M., Rolfs, A., Miranda, M. C. & Zimran, A. 2003. The 
role of the iminosugar N-butyldeoxynojirimycin (miglustat) in the management of type I 
(non-neuronopathic) Gaucher disease: a position statement. J Inherit Metab Dis, 26, 513-
26.
Cox, T. M. & Schofield, J. P. 1997. Gaucher's disease: clinical features and natural history.
Baillieres Clin Haematol, 10, 657-89.
Deegan, P. B. & Cox, T. M. 2005. Clinical evaluation of biomarkers in Gaucher disease. Acta 
paediatr (Oslo, Norway: 1992). Suppl, 94, 47-50; discussion 37-8.
Deegan, P. B., Pavlova, E., Tindall, J., Stein, P. E., Bearcroft, P., Mehta, A., Hughes, D., Wraith, 
J. E. & Cox, T. M. 2011. Osseous manifestations of adult Gaucher disease in the era of 
enzyme replacement therapy. Medicine, 90, 52-60.
DeMayo, R. F., Haims, A. H., McRae, M. C., Yang, R. & Mistry, P. K. 2008. Correlations of 
MRI-based bone marrow burden score with genotype and spleen status in Gaucher's 
Disease. Am J Roentgenol, 191, 115-123.
Goker-Alpan, O. 2011. Therapeutic approaches to bone pathology in Gaucher disease: past, 
present and future. Molecular genetics and metabolism, 104, 438-47.
Hoffmann, B., Garcia de Lorenzo, A., Mehta, A., Beck, M., Widmer, U. & Ricci, R. 2005. 
Effects of enzyme replacement therapy on pain and health related quality of life in 
patients with Fabry disease: data from FOS (Fabry Outcome Survey). J Med Genet, 42, 
247-52.
Maas, M., van Kuijk, C., Stoker, J., Hollak, C. E., Akkerman, E. M., Aerts, J. F. & den Heeten, 
G. J. 2003. Quantification of bone involvement in Gaucher disease: MR imaging bone 
marrow burden score as an alternative to Dixon quantitative chemical shift MR imaging--
initial experience. Radiology, 229, 554-61.
Masek, B. J., Sims, K. B., Bove, C. M., Korson, M. S., Short, P. & Norman, D. K. 1999. Quality 
of life assessment in adults with type 1 Gaucher disease. Qual Life Res, 8, 263-8.
Mikosch, P. & Hughes, D. 2010. An overview on bone manifestations in Gaucher disease. Wien 
Med Wochenschr, 160, 609-24.
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Pastores, G. M., Weinreb, N. J., Aerts, H., Andria, G., Cox, T. M., Giralt, M., Grabowski, G. A., 
Mistry, P. K. & Tylki-Szymanska, A. 2004. Therapeutic goals in the treatment of 
Gaucher disease. Semin Hematol, 41, 4-14.
Pavlova, E. V., Deegan, P. B., Tindall, J., McFarlane, I., Mehta, A., Hughes, D., Wraith, J. E. & 
Cox, T. M. 2011. Potential biomarkers of osteonecrosis in Gaucher disease. Blood Cells 
Mol Dis, 46, 27-33.
Ries, M., Mengel, E., Kutschke, G., Kim, K. S., Birklein, F., Krummenauer, F. & Beck, M. 
2003. Use of gabapentin to reduce chronic neuropathic pain in Fabry disease. J Inherit 
Metab Dis, 26, 413-4.
Rosenbloom, B. & Weinreb, N. 2014. Bone disease in patients with Gaucher disease. Expert Rev 
Endocrinol Metab, 9, 153-162.
Schiffmann, R., Kopp, J. B., Austin, H. A., Sabnis, S., Moore, D. F., Weibel, T., Balow, J. E. & 
Brady, R. O. 2001. Enzyme replacement therapy in Fabry disease: a randomized 
controlled trial. JAMA, 285, 2743-9.
Weinreb, Charrow, Andersson, Kaplan, Kolodny, Mistry, Pastores, Rosenbloom, Scott, Wappner 
& Zimran 2002. Effectiveness of enzyme replacement therapy in 1028 patients with type 
1 Gaucher disease after 2 to 5 years of treatment: a report from the Gaucher Registry. 
American Journal of Medicine, The, 113, 112-119.
Weinreb, N., Taylor, J., Cox, T. M., Yee, J. & vom Dahl, S. 2008. A benchmark analysis of the 
achievement of therapeutic goals for type 1 Gaucher disease patients treated with 
imiglucerase. AM J Hematol, 83, 890-5.
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Appendix 1
Study Schedule of Events
Study Schedule of Events: Screening to Study Week 39
Procedure
Screening
Baseline
Treatment Period
Study Week (±7 days)
Day –28 
to
Day –4
Day –3 
to
Day 0a
1a
3 
5
7 
9 
11
13
15
17
19
21
23
25
27
29
31
33
35
37
39
Informed consentb
•
Study entrance criteria
•
Confirmation of study 
eligibility
•
Medical history
•
Glucocerebrosidase 
Genotype Analysisc
•
Neurological assessment
•
VPRIV infusion
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Vitamin D blood testd
•
Concomitant 
medicationse
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Adverse events
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
SAE and IRRs
•f
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Physical examination
•
•
•
•
Vital signs
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Urine pregnancy testg
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Serum β-hCG
•
Height
•
•
•
•
Weight
•
•
•
•
ECG
•
•
Serum chemistry
•
•
•
•
Hematology/Coagulation
•
•
•
•
Urinalysis
•
•
•
•
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02 Nov 2020
Study Schedule of Events: Study Week 41 to Study Week 89
Procedure
Treatment Period
Study Week (±7 days)
41 
43 
45
47 
49 
51
53
55
57
59
61
63
65
67
69
71
73
75
77d
79
81
83
85
87
89d
DXA=dual energy x-ray absorptiometry; ECG=electrocardiogram; β-hCG=human chorionic gonadotropin; IRRs=infusion-related reactions; MRI=magnetic 
resonance imaging; SAE=serious adverse event; VPRIV=velaglucerase alfa
a
Vitamin D testing includes analysis for both 25-hydroxycholecalciferol and 1, 25-dihydroxycholecalciferol.
b
All patients will receive 800 IU vitamin D (oral) daily starting at the week 1 visit for the duration of the study.
c
Pregnancy testing for female patients of childbearing potential will be done with a urine test. If a patient has a positive urine test result, the infusion will be 
held and a serum (β-hCG) test is to be conducted at the local laboratory responsible for the study.
d
Please refer to Appendix 9 for information on transferring visits at Weeks 77 and 89 to home therapy and the addition of dose continuation infusions due to 
the COVID-19 pandemic.
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02 Nov 2020
Study Schedule of Events: Study Week 91 to End of Study (Week 103)/Early Termination and the 30-day Safety Follow-up
Procedure
Study Week (±7 days)
Treatment Period
End of Study (Week 103)/
Early Termination
30-day Safety 
Follow-upa
91
93
95
97
99
101
Neurological assessment
•
VPRIV infusion
•
•
•
•
•
•
Vitamin D Blood Testb
•
Concomitant medicationsc
•
•
•
•
•
•
•
•
Adverse events
•
•
•
•
•
•
•
•
SAE and IRRs
•
•
•
•
•
•
•
•
Physical examination
•
Vital signs
•
•
•
•
•
•
•
Urine pregnancy testd
•
•
•
•
•
•
•
Height
•
Weight
•
ECG
•
Serum chemistry
•
Hematology/Coagulation
•
Urinalysis
•
Serum anti-velaglucerase alfa antibody
•
MRI to determine liver and spleen volume
•
MRI of the lumbar spine and whole femur
•
DXA of lumbar spine
•
•
Questions taken from the BPI-SF©
•
Brief Fatigue Inventory
•
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Page 73
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velaglucerase alfa (VPRIV®)
02 Nov 2020
Study Schedule of Events: Study Week 91 to End of Study (Week 103)/Early Termination and the 30-day Safety Follow-up
Procedure
Study Week (±7 days)
Treatment Period
End of Study (Week 103)/
Early Termination
30-day Safety 
Follow-upa
91
93
95
97
99
101
DXA=dual energy x-ray absorptiometry; ECG=electrocardiogram; β-hCG=human chorionic gonadotropin; IRRs=infusion-related reactions; MRI=magnetic 
resonance imaging; SAE=serious adverse event; VPRIV=velaglucerase alfa
a
The 30-day safety follow-up is to occur 30 (±7) days after the last infusion (Week 101) for patients who complete the study (Section 7.17) and 30 (±7) days 
after the last infusion for patients who discontinue or are withdrawn prior to Week 103. This follow-up assessment may be conducted over the telephone.
b
Vitamin D testing includes analysis for both 25-hydroxycholecalciferol and 1, 25-dihydroxycholecalciferol.
c
All patients will receive 800 IU vitamin D (oral) daily for the duration of the study
d
Pregnancy testing for female patients of childbearing potential will be done with a urine test. If a patient has a positive urine test result, the infusion will be 
held and a serum (β-hCG) test is to be conducted at the local laboratory responsible for the study.
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velaglucerase alfa (VPRIV®)
02 Nov 2020
Section
Summary of Changes
Rationale for change
Synopsis Study 
Endpoints
Section 3.1
Primary 
Endpoint
Section 3.2.1
Key Secondary 
Endpoints
Section 3.2.2
Other 
Secondary 
Endpoints
The primary endpoint of this study is:
•
Change from baseline to 24 months (Week 103 [end of 
study]) in LS BMD Z-score as measured by DXA. Assessments 
will be performed at the screening visit and Weeks 25, 51, 77, 
and 103 (end of study).
The key secondary endpoints of this study are:
•
Change from baseline to 12 months (Week 51) and 24 
months (Week 103 [end of study]) in BMB score (MRI of LS 
and femur). Assessments will be performed at the baseline visit 
and Weeks 25 5177 and 103 (end of study).
•
Change from baseline to 12 months (Week 51) in LS BMD 
Z-score. Assessments will be performed at the screening visit 
and Weeks 25 5177 and 103 (end of study).
Other secondary efficacy endpoints of this study are:
•
Change from baseline to 12 months (Week 51) and 24 
months (Week 103 [end of study]) in normalized liver volume 
as measured by abdominal MRI. Assessments will be performed 
at the baseline visit and Weeks 25 5177 and 103 (end of study).
•
Change from baseline to 12 months (Week 51) and 24 
months (Week 103 [end of study]) in normalized spleen volume 
as measured by MRI. Assessments will be performed at the 
baseline visit and Weeks 25 5177 and 103 (end of study).
Shifts in WHO BMD classifications (normal bone density, 
osteopenia, and osteoporosis) based on LS T-scores. 
Assessments will be performed at baseline (screening visit) and 
Weeks 25 5177 and 103 (end of study)
Revised text to improve 
clarity.
Revised text to improve 
clarity.
Eliminated assessments at 
Weeks 25 and 77 to ease 
subject burden as data 
from these visits will not 
be used in the 
determination of any 
endpoints.
Synopsis Study 
Duration
Patients will be dosed for 102 101 weeks (51 infusions), 
preceded by a Screening/baseline period of up to 28 days and 
followed by a 30-day Safety Follow-up Period.
Corrected an error.
Synopsis Study 
Population
Approximately Up to 40 patients (≥18 and ≤65 70 years of age) 
with type 1 Gaucher disease who are naïve to enzyme 
replacement therapy (ERT)/substrate reduction therapy (SRT) 
are planned to be recruited to achieve 34 evaluable patients.
Revised text to improve 
clarity; increased the 
upper limit of enrolment 
age to 70 years to 
facilitate enrolment.
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Page 82
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velaglucerase alfa (VPRIV®)
02 Nov 2020
Section
Summary of Changes
Rationale for change
Section 6.3
Selection and 
Timing of Dose 
for Each patient
The first dose of VPRIV will be based on the patient’s weight at 
baseline screening (Days 3 -28 to Day -4 0). A change in 
patient weight of ±5% from baseline screening or the last 
weight used to recalculate the dose will require a new dose 
recalculation by the clinical site.
Study drug infusions are to occur on approximately the same 
day of the week, but may occur every 14 days (±3 7 days) of the 
target day in order to facilitate patient scheduling. If at all 
possible, missed infusions should be avoided. If a patient is not 
dosed within 17 21 days from their scheduled dose, the patient 
should receive the next infusion as soon as possible.
Weight measurement will 
be performed at screening 
to allow for calculation of 
patient doses before 
baseline/Week 1 visit.
The window was changed 
to ±7 days to allow for 
patient rescheduling and 
to facilitate protocol 
execution.
Section 6.6
Home Infusion 
of 
Velaglucerase 
alfa
In addition, a urine pregnancy test will be conducted at each 
home infusion visit for women of childbearing potential.
Added text to improve 
clarity.
Section 6.7 
Infusion 
Reactions and 
Management
The management of infusion-related reactions (IRRs) should be 
based on the severity of the reaction. Such management may 
include, at the discretion of the investigator, eg, slowing the 
infusion rate, treatment with medications such as antihistamines, 
antipyretics, and/or corticosteroids and/or stopping and 
resuming treatment with increased prolonged infusion time
duration.
In cases when required and at site’s discretion, additional 
clinical laboratory samples can be collected for further 
analysis of IRRs. Suggested laboratory evaluation includes 
complete blood count, complete metabolic panel including 
liver and renal function tests, CH50, C3, C4, C1 inhibitor,
C3a and C5a, total tryptase, histamine, immune complex 
and IgE levels.
Added or modified text to 
improve clarity. 
Added a description of 
suggested lab testing for 
further evaluation of IRRs 
according to recent expert 
review of the study 
protocol.
Section 6.8.3
Contraception 
8.
Double barrier methods (eg, condoms and diaphragms with 
spermicidal gel or foam)
Removed this method as it 
is not considered a highly 
effective method of 
contraception (<1% 
failure rate per year) by 
Clinical Trial Facilitation 
Group guidance (2014).
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velaglucerase alfa (VPRIV®)
02 Nov 2020
Section
Summary of Changes
Rationale for change
Section 7.11.10
Physical 
Examination
A full physical examination will be performed by the 
investigator with a thorough review of body systems on 
specified study visits.
Added text for clarity.
Section 7.11.13
Electrocardiogr
aphy
… ECG recordings will be read locally at the clinical site by a
qualified cardiologistthe investigator or a qualified designee.
For the purpose of this 
assessment, evaluation by 
a qualified cardiologist is 
not deemed necessary.
Section 7.11.14
Clinical 
Laboratory Test
Clinical laboratory tests will include the following (Table 7-3). 
Any clinically significant findings as determined by the 
investigator will be recorded as an AE on the appropriate 
eCRF.
Text added for further 
details on AE reporting.
Section 7.11.14
Clinical 
Laboratory Test
Table 7-3
Serum Chemistry:
-
Vitamin D (screening and Weeks 51 and 103 only)

25-hydroxycholecalciferol 

1, 25-dihydroxycholecalciferol
Hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV), 
and human immunodeficiency virus (HIV)
The following safety laboratory tests will be performed at 
Screening:
•
Hepatitis B surface antigen (HBsAg)
•
Hepatitis C virus (HCV)
•
Human immunodeficiency virus (HIV)
•
25 hydroxyvitamin Vitamin D blood test
Added text (Vitamin D) 
for clarity.
Removed information on 
screening test for HBV, 
HCV and HIV as these are 
not being performed and 
are not part of the 
evaluation of the 
inclusion/ exclusion 
criteria.
Revised text (Vitamin D) 
for simplicity.
Section 7.14.1.7
Infusion-related 
Adverse Event 
Definition
An IRR will be defined as an AE that 1) begins either during or 
within 12 24 hours after the start of the infusion and 2) is judged 
as related to study drug.
The definition of IRRs has 
been updated for 
alignment with global 
labeling; also, widening 
the timeframe will ensure 
IRRs are not 
underreported.
Section 7.17.1
Safety-related 
Study Stopping 
Rules
For patients who discontinue or are withdrawn prior to the 
Week 103 end of study visit, a follow-up assessment for safety 
will occur 30 (±7) days after their last infusion. This follow-up 
assessment may be conducted over the telephone.
The safety follow-up 
collects information on 
AE/SAEs, IRRs and 
concomitant medications, 
which can be performed 
over the phone.
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02 Nov 2020
Section
Summary of Changes
Rationale for change
Section 8.1
Screening Visit 
(Days -28 to -4)
Height
Weight
25 hydroxyvitaminVitamin D blood test
Weight 
measurement will 
be performed at 
screening visit to 
allow for 
calculation of 
patient doses 
before 
baseline/Week 1 
visit; height and 
weight are 
measured together.
Revised text 
(Vitamin D) for 
simplicity.
Section 8.2
Baseline 
(Days -3 to 0)
Height
Weight
Weight 
measurement will 
be performed at 
screening visit to 
allow for 
calculation of 
patient doses 
before 
baseline/Week 1 
visit; height and 
weight are 
measured together.
Section 8.3.3
Weeks 25 and 
77
MRI to determine liver and spleen volume
MRI of the LS and whole femur
DXA of LS
Eliminated assessments at 
Weeks 25 and 77 to ease 
subject burden as data 
from these visits will not 
be used in the 
determination of any 
endpoints.
Section 8.3.4 
Week 51
Section 8.4 End 
of Study (Week 
103)/Early 
Termination 
Procedures
Vitamin D blood test
Added this text to 
conform with the schedule 
of activities.
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02 Nov 2020
Section
Summary of Changes
Rationale for change
Section 10.2
Determination 
of Sample Size
A total of 34 evaluable patients will provide at least 9099% 
power to detect a significant change in LS BMD Z-score from 
baseline after 24 months of treatment (primary efficacy 
endpoint) when in fact there is a +0.6 change (improvement) in 
Z-score.
A total of 34 evaluable patients will also provide 80% power to 
detect significant change in LS BMD Z-score from baseline 
after 12 months of treatment (one of key secondary efficacy 
endpoint). With consideration of 15% early discontinuation up 
to endpoints), when there is a +0.25 change in Z-score and a 
standard deviation of the change is 0.5 based on the data 
from the Study HGT-GCB-044.
Considering the potential for appreciable numbers of early 
discontinuations before 24 months, up to it is planned that 
approximately 40 patients will be enrolled and needed for the 
primary efficacy analysis.
Revised text to improve
clarity.
Section 10.6.1
Primary 
Efficacy 
Endpoint
…Assessments will be performed at screening and Weeks 
25,51,77, and 103 (end of study).
Revised text to improve 
clarity.
Section 10.7.1
Safety 
Endpoints
… An infusion-related AE is defined as an AE that begins either 
during or within 12 24 hours after the start of the infusion and is 
judged as related to the investigational product.
The definition of IRRs has 
been updated for 
alignment with global 
labeling; also, widening 
the timeframe will ensure 
IRRs are not 
underreported.
Section 10.7.2
Secondary 
Efficacy 
Endpoints
The key secondary endpoints are:
•
Change from baseline to 12 months (Week 51) and 24 
months (Week 103 [end of study]) in BMB score (MRI of LS 
and femur). Assessments will be performed at the baseline visit 
and Weeks 25 5177 and 103 (end of study).
•
Change from baseline to 12 months (Week 51) in LS BMD 
Z-score. Assessments will be performed at the screening visit 
and Weeks 25 5177 and 103 (end of study).
Other secondary efficacy endpoints include the following 
evaluations:
……
•
Change from baseline to 12 months (Week 51) and 24 
months (Week 103 [end of study]) in normalized liver volume 
as measured by abdominal MRI. Assessments will be performed 
at the baseline visit and Weeks 25 5177 and 103 (end of study). 
•
Change from baseline to 12 months (Week 51) and 24 
months (Week 103 [end of study]) in normalized spleen volume 
as measured by MRI. Assessments will be performed at the 
Eliminated assessments at 
Weeks 25 and 77 to ease 
subject burden as data 
from these visits will not 
be used in the 
determination of any 
endpoints.
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velaglucerase alfa (VPRIV®)
02 Nov 2020
Section
Summary of Changes
Rationale for change
a
Vitamin D testing includes analysis for both 25-
hydroxycholecalciferol and 1, 25-
dihydroxycholecalciferol.
b All patients will received 600 800 IU 25 hydroxyvitamin 
vitamin D (oral) daily starting at the week 1 visit for the 
duration of the study.
Study Schedule of Events: Study Week 91 to End of Study 
(Week 103)/Early Termination and the 30-day Safety Follow-up
Study Week (±3 7 Days)
Procedure
Study Week (± 7 days)
Treatment 
Period
End of Study 
(Week 103)/
Early 
Termination
Vitamin D Blood 
Test
•
a
The 30-day safety follow-up is to occur 30 days after the 
last infusion (Week 101) for patients who complete the study 
(Section 7.18) and 30 (±7) days after the last infusion for 
patients who discontinue or are withdrawn prior to Week 103.
This follow-up assessment may be conducted over the 
telephone.
b
Vitamin D testing includes analysis for both 25-
hydroxycholecalciferol and 1, 25-
dihydroxycholecalciferol.
c All patients will received 600 800 IU 25 hydroxyvitamin 
vitamin D (oral) daily for the duration of the study.
Vitamin D testing.
Switched to 800 IU to 
facilitate sourcing of 
vitamin D.
The window was changed 
to ±7 days to allow for 
patient rescheduling and 
to facilitate protocol 
execution.
The safety follow-up 
collects information on 
AE/SAEs, IRRs and 
concomitant medications, 
which can be performed 
over the phone.
Text added for clarity on 
Vitamin D testing.
Switched to 800 IU to 
facilitate sourcing of 
vitamin D.
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02 Nov 2020
Appendix 4
Protocol Amendment 3 Summary of Changes
Previous Version: Protocol Amendment 2 (02 June 2016)
Clinical Protocol SHP-GCB-402 Amendment 3 clarifies administrative changes made to protocol 
SHP-GCB-402, Amendment 2 dated 02 Jun 2016. Clarifications provided in administrative 
change memo dated 27 Jan 2016 were not included in protocol amendment 2 as an oversight. 
The minimum age for inclusion has changed to 18; therefore, informed consent by parents has 
been eliminated. 
Changes in grammar, spelling, punctuation, format, minor editorial changes (including changes 
for consistency and clarity), and updates to the list of abbreviations and cross-references are not 
enumerated in this summary of changes. The text solely deleted is presented as strikethrough and 
the text revised or added is presented in bold font.
The significant changes and additions to Protocol Amendment 3 from Protocol Amendment 2 are 
captured in the table below. 
Section
Summary of Changes
Synopsis
Concomitant 
Medication, Dose, 
and Mode of 
Administration
Section 6.8.2
Concomitant 
Therapy
All patients will also receive 600 IU 25-hydroxyvitamin D (oral) daily starting at the week 1 
visit…
Synopsis
Secondary 
Objectives
…and bone marrow burden (BMB) as measured
Synopsis Study 
Inclusion and 
Exclusion Criteria
1. The patient has a …blood spot test is not sufficient. Diagnosis may be based on results 
obtained prior to Screening if documented in the patient’s medical history.
Synopsis Study 
Inclusion and 
Exclusion Criteria
Section 5.2
Inclusion Criteria
Section 6.8.3
Contraception
5. Female and male patients (with partners) patients of childbearing potential must agree to 
use a medically acceptable method of contraception at all times during the study.
Synopsis Study 
Inclusion and 
Exclusion Criteria
Section 5.2
Inclusion Criteria
6. The patient, and the patient’s parent(s) or patient’s legally authorized representative legal 
guardian(s), if applicable, understands the nature, scope, and…
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02 Nov 2020
Section
Summary of Changes
Section 7.12.8
Pregnancy Testing
...Patients with a positive result for either test will not be eligible for this study. The 
screening urine pregnancy test will be performed locally and the screening serum 
pregnancy test will be analyzed at the central laboratory responsible for this study.
…local laboratory will analyze and report all subsequent urine and serum pregnancy 
testing results.
…If the serum β-hCG result is also positive…
Section 7.17
Removal of 
Patients from the 
Trial or 
Investigational 
Product
…The patient, the patient’s parent(s), or the patient’s legally authorized representative…
…If a patient, the patient’s parent(s), or the patient’s legally authorized…
Section 8 Study 
Activities
Study procedures will be conducted only after patients (or parent/legal guardian) have 
provided written informed consent to participate in the study….
Section 8.1
Screening Visit 
(Days -28 to -4)
…
•
SAEs
•
Vital signs
•
Hemoglobin concentration
•
Platelet count
•
25-hydroxyvitamin D blood test
•
HBsAg, HCV, HIV
Section 8.2
Baseline (Days -3 
to 0)
Note: The baseline visit may be combined with the Week 1 (within 7 days after baseline) 
Treatment Period visit.
…
•
Hematology/Coagulation
Section 8.3.1
Section 8.3.2
Section 8.3.3
Section 8.3.4
8.3.1 Weeks 1, 3, 5, 7, 9, 11, 15, 17, 19, 21, 23, 27, 29, 31, 33, 35, 39, 41, 45, 43, 47, 
49, 53, 55, 57, 59, 61, 63, 67, 69, 71, 73, 75, 79, 81, 83, 85, 87, 91, 93, 95, 97, 99, and 
101
8.3.2 Weeks 7, 19, 31, 45, 57, 71, 83, and 95 (merged above)
•
VPRIV infusion
•
Concomitant medication
•
AEs
•
SAE and IRRs
•
Vital signs
•
Pregnancy test
8.3.3 8.3.2 Weeks 13, 37, 65, and 89
•
Hematology/Coagulation
8.3.4 8.3.3 Weeks 25 and 77
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Section
Summary of Changes
•
Hematology/Coagulation
8.3.5 8.3.4 Week 51
•
Hematology/Coagulation
8.4 End of Study (Week 103)/Early Termination Procedures
•
Hematology/Coagulation
Section 10.6.1
Primary Efficacy 
Endpoint
The primary efficacy endpoint is the change from baseline to 24 months (Week 103 [end of 
study]) in LS BMD Z score as measured by DXA. Assessments will be performed at baseline
screening and Weeks 25, 51, 77, and 103 (end of study). 
Section 11.4 Patient 
Information and 
Consent
Before enrolling in the clinical study, the patient or the patient’s parent(s) or legally 
authorized representative(s) …
… and given to the patient or the patient’s parent(s) or legally authorized representative(s). 
… understandable to the patient or the patient’s parent(s) or legally authorized 
representative(s) and must specify who informed the patient, the patient’s parent(s), or the 
patient’s legally authorized representative(s).
After reading the informed consent document, the patient or the patient’s parent(s) or … by 
the personally dated signature of the patient, the patient’s parent(s), or the patient’s legally 
authorized representative(s) …
If the patient or the patient’s parent(s) or legally authorized representative(s) is unable to 
read… dated signature of the patient’s parent(s) or the patient’s legally authorized 
representative. …
A copy of the signed and dated consent document(s) must be given to the patient or the 
patient’s parent(s) or legal representative(s). …
13 Study Schedule 
of Events
Study Schedule of Events: Screening to Study Week 39
Procedure
Screening
Day –28 
to
Day –4
HBsAg, HCV, HIV
•
25-hydroxyvitamin D blood test
•
Serum β-hCG
•
Hematology/Coagulation
Abbreviations: DXA=dual energy x-ray absorptiometry; ECG=electrocardiogram; 
HBsAg=hepatitis B surface antigen; HCV=hepatitis C virus; HIV=human 
immunodeficiency virus;
a The baseline visit may be combined with the Week 1 (within 7 days after baseline)
Treatment Period visit….
d All patients will receive 600 IU 25-hydroxyvitamin D (oral) daily starting at the week 1 
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Section
Summary of Changes
visit for the duration of the study….
f At the screening visit both urine (local) and serum pregnancy tests (sent to central 
laboratory) will be performed. Patients with a positive result for either test at screening 
will not be eligible. Pregnancy testing at subsequent visits for female patients of 
childbearing potential will be done with a urine test (local). If a patient has a positive urine 
test result, the infusion will be held and a serum (β-hCG) test is to be conducted at the local 
laboratory responsible for the study. At the screening visit both urine and serum pregnancy 
tests will be performed. Patients with a positive result for either test at screening will not be 
eligible.
Study Schedule of Events: Study Week 41 to Study Week 89
Hematology/Coagulation
a All patients will receive 600 IU 25-hydroxyvitamin D (oral) daily starting at the week 1 
visit for the duration of the study….
b Pregnancy testing for female patients of childbearing potential will be done with a urine 
test. If a patient has a positive urine test result, the infusion will be held and a serum (β-hCG) 
test is to be conducted at the local laboratory responsible for the study.
Study Schedule of Events: Study Week 91 to End of Study (Week 103)/Early 
Termination and the 30-day Safety Follow-up
Hematology/Coagulation
a Pregnancy testing for female patients of childbearing potential will be done with a urine 
test. If a patient has a positive urine test result, the infusion will be held and a serum (β-hCG) 
test is to be conducted at the local laboratory responsible for the study.
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Appendix 5
Protocol Amendment 2 Summary of Changes
Previous Version: Protocol Amendment 1 (14 September 2015)
Clinical Protocol SHP-GCB-402 Amendment 2 has been amended to extend evaluation of the 
primary endpoint from 12 to 24 months and secondary endpoints from 24 to 12 months, add
specific guidance for contraception, update emergency contact information, add concomitant 
dosing of 600 IU 25-hydroxyvitatmin D daily, 
, and revise age 
range to ≥18 and ≤65 years of age.
NOTE: Changing the IRR definition timeframe from 12 hours to 24 hours was considered in 
order to align with the post-marketing definition; however, the consensus of the clinical trial 
team was to remain consistent with the definition used in the most recent clinical studies.
Changes in grammar, spelling, punctuation, format, minor editorial changes (including changes 
for consistency and clarity), and updates to the list of abbreviations and cross-references are not 
enumerated in this summary of changes. The text solely deleted is presented as strikethrough and 
the text revised or added is presented in bold font.
The significant changes and additions to Protocol Amendment 2 from Protocol Amendment 1 are 
captured in the table below. 
Section
Summary of Changes
Title Page 
Appendix 6
Protocol Signature 
Page
Medical Monitor: 
, MD, PhD
Medical Monitor: 
, MD
Synopsis 
Concomitant 
Medication, Dose 
and Mode of 
Administration
Section 6.8.2 
Concomitant 
Therapy
Appendix 1 Study 
Schedule of Events 
Footnotes
All patients will also receive 600 IU 25-hydroxyvitamin D (oral) daily
Synopsis
Primary Objective
Section 2.1 Primary 
Objective
The primary objective is:
To evaluate the effect of VPRIV therapy (60 U/kg EOW) in treatment-naïve patients with 
type 1 Gaucher disease on change from baseline in lumbar spine (LS) bone mineral density 
(BMD) Z-score as measured by dual energy x-ray absorptiometry (DXA) after 12 24 months 
of treatment 
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Section
Summary of Changes
Measures of 
Potential Relevance 
in Gaucher Disease
Section 10.8 Other 
Assessments or 
Analyses 
(Exploratory 
Measures Research)
Synopsis Efficacy 
Assessments
Synopsis Inclusion 
Criteria
Section 5.1 Study 
Population 
Section 5.2 
Inclusion Criteria
4.
The patient is ≥16 and ≤65 years of age. For patients ≥16 and <18 years of age a Tanner 
stage of ≥4 must be established.
4.
The patient is ≥18 and ≤65 years of age.
5.
Female and male patients (with partners) of childbearing potential must agree to use a 
medically acceptable method of contraception at all times during the study.
Synopsis Exclusion 
Criteria
Section 5.3 
Exclusion Criteria
8.
Severe vitamin D deficiency to the level that would be expected to result in 
osteomalacia (25-hydroxyvitamin D < 10 ng/mL [25 nmol/L]). If there is mild 
vitamin D insufficiency at screening (25-hydroxyvitamin D > 10 and < 30 ng/mL) 
treat with 4000 IU 25-hydroxyvitamin D per day for 1 month and rescreen.
9.
The patient has previously interrupted ERT for safety reasons.
10. The patient has had hypersensitivity to the active substance or to any of the 
excipients.
Emergency Contact 
Information Page
EMERGENCY CONTACT INFORMATION
Email: 
For protocol or safety related issues the investigator must contact the Shire Medical 
Monitor: 
, MD, 
Telephone: 
Mobile:
 
Email: 
For protocol- or safety-related issues the investigator must contact the Shire Medical 
Monitor:
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Section
Summary of Changes
, MD 
Telephone:
Mobile:
List of 
Abbreviations and 
Definitions of 
Terms
Throughout 
amendment
IRR
infusion-related reactions
Section 6.6 Home 
Infusion of 
Velaglucerase alfa
Appendix 1 Study 
Schedule of Events 
Footnote
Study site personnel will report SAEs as described in Section 7.16.2.
Section 6.6 Home 
Infusion of 
Velaglucerase alfa
Table 7-2 Footnote
If there are no infusion-related reactions during the first 3 home infusions the 
observation and vital signs post-infusion can be omitted at the discretion of the 
investigator.
The qualified, trained medical personnel will leave the patient’s home no sooner than 1 hour 
after completion of the infusion.
Synopsis 
Concomitant 
Medication
Section 6.8.2 
Concomitant 
Therapy
Appendix 1 Study 
Schedule of Events 
Footnote
Patients who enter the study receiving supplemental therapy (eg, supplemental iron, calcium) 
must remain on a constant dose and regimen throughout the study. All patients will receive 
600 IU 25-hydroxyvitamin D (oral) daily for the duration of the study.
Section 6.8.3 
Contraception
One of the following methods would be acceptable:
1.
Combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation:
•
Oral
•
Intravaginal
•
Transdermal
2.
Progestogen-only hormonal contraception associated with inhibition of ovulation:
•
Oral
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Section
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•
Injectable
•
Implantable
3.
Intrauterine device (IUD)
4.
Intrauterine hormone-releasing system (IUS)
5.
Bilateral tubal occlusion
6.
Vasectomized partner
7.
Sexual abstinence
8.
Double barrier methods (eg, condoms and diaphragms with spermicidal gel or 
foam)
Section 7.6 
Glucocerebro-
sidase Genotype 
Analysis
Appendix 1 
Schedule of Events 
Footnote
At screening, all patients will have a blood sample collected for Gaucher disease (GBA) gene 
sequencing; however, GBA sequencing is not required at screening if documented 
results are available in the medical history.
Section 7.11.5 
Hemoglobin 
Concentration
Section 7.11.6 
Platelet Count
Blood samples will be collected for measurement of hemoglobin concentration. Note: The 
measurement of hemoglobin concentration is included as a component of hematology 
laboratory testing at the baseline visit and Weeks 13, 25, 37, 51, 65, 77, 89, and 103 and 
hemoglobin concentration and platelet count are assessed separately at the screening visit and 
Weeks 7, 19, 31, 45, 57, 71, 83, and 95.
Blood samples will be collected for measurement of platelet count. Note: The measurement 
of platelet count is included as a component of hematology laboratory testing at baseline and 
Weeks 13, 25, 37, 51, 65, 77, 89, and 103. , and hemoglobin concentration and platelet count 
are assessed separately at screening and Weeks 7, 19, 31, 45, 57, 71, 83, and 95.
Section 8.1
Appendix 1, 
Schedule of Events 
Table
25-hydroxyvitamin D blood test
Section 8.2
Appendix 1 
Schedule of Events 
Footnote
Note: The baseline visit may be combined with the Week 1 Treatment Period visit.
Section 8.3.2 
Weeks 7, 19, 31, 
45, 57, 71, 83, and 
95
•
VPRIV infusion
•
Concomitant medication
•
AEs
•
SAE and IRRs
•
Vital signs
•
Pregnancy test
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Section
Summary of Changes
•
Hemoglobin concentration
•
Platelet count
Section 7.15.1.7 
Infusion-related 
Adverse Event 
Definition
Section 7.18.1 
Safety-related 
Study Stopping 
Rules
Section 10.7.1 
Safety Endpoints
…An infusion-related AE is defined as an AE that begins either during or within 12 hours 
after the start of the infusion and is judged as possibly or probably related to the 
investigational product.
Section 10.2
Determination of 
Sample Size
A total of 34 evaluable patients will provide at least 80%90% power to detect a significant 
change in LS BMD Z-score from baseline after 12 months of treatment when in fact there is a 
+0.2 +0.6 change (improvement) in Z-score. The calculation was based on the following 
assumptions:
A total of 34 patients will also provide 80% power to detect significant change in LS 
BMD Z-score from baseline after 12 months of treatment. 
With consideration of 5% 15% early discontinuation up to 24 months, up to 40 planned 
patients will be enrolled and needed for the primary efficacy analysis
Section 10.6.1 
Primary Efficacy 
Endpoint
The primary efficacy endpoint is the change from baseline to 12 months (Week 51) 24 
months (Week 103 [end of study]) in LS BMD Z-score as measured by DXA. Assessments 
will be performed at baseline and Weeks 25, 51, 77, and 103 (end of study). The null 
hypothesis is that there is no change from baseline to 12 months 24 months in LS BMD Z-
scores. A statistically significant change in BMD after 1 year 24 months of treatment is 
highly clinically relevant in this patient population. One sample t-test or Wilcoxon signed 
rank test will be applied for the change from baseline of LS BMD Z-scores with patients 
whose LS BMD scores are collected after 1 year 24 months of treatment. A 95% confidence 
interval for the mean of the change from baseline will also be presented. 
As a sensitivity analysis, the primary efficacy analysis will be repeated by applying last 
observation carried forward (LOCF) method. That is, if the LS BMD score is missing at 12 
months (Week 51) 24 months (Week 103 [end of study]), the non-missing score at 6 months 
(Week 25) 12 months (Week 51) will be carried forward, and the score at baseline will not 
be carried forward for the analysis.
Appendix 1 
Schedule of Events
Treatment Period
Study Week (± 3 days)
Section 6.3 
Selection and 
Timing of Dose for 
Each Patient
Section 7 Study 
study visits (± 3 days)
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Section
Summary of Changes
Procedures
Section 7.8 
Investigational 
Product 
Administration
Section 6.3 
Selection and 
Timing of dose for 
Each Patient
For dosing calculations, patient weight can be rounded to the nearest 0.5 kg, VPRIV 
dose to the nearest Unit, and dose volume to the nearest 0.1 mL. 
Section 7.16.1 
Reference Safety 
Information
The reference for safety information for this study is the investigator’s brochure
Investigator’s Brochure for US investigator sites and the Summary of Product 
Characteristics for European investigator sites, which the sponsor has provided under 
separate cover to all investigators.
Appendix 1 Study 
Schedule of Events 
and Footnotes
…Events: Screening to Study Week 39
…Events: Study Week 41 to Study Week 89
…Events: Study Week 91 to End of Study (Week 103)/Early Termination and the 30-day 
Safety Follow-up
Hemoglobin 
concentrationd
•
•
•
•
Platelet countd
•
•
•
•
a
Hemoglobin concentration and platelet count are included as part of the hematology 
panel but are assessed more frequently (approximately every 6 weeks) than the hematology 
panel (quarterly); therefore, at some visits, only hemoglobin concentration and platelet count 
rather than the full hematology panel are assessed (eg, Week 95). For patients receiving home 
therapy on weeks 7, 19, 31, 45, 57, 71, 83 or 95 samples for hemoglobin concentration and 
platelet count will not be collected.
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Section 7.15.1 
Definitions of Adverse 
Events Assessment, 
Period of Observation 
and Recording of 
Adverse Events
All AEs are collected from the time the informed consent is signed until the defined 
follow-up period stated in Section 8.5. This includes events occurring during the 
screening phase of the study, regardless of whether or not investigational product is 
administered. Where possible, a diagnosis rather than a list of symptoms should be 
recorded. If a diagnosis has not been made, then each symptom should be listed 
individually. All AEs should be captured on the appropriate AE pages in the CRF 
and in source documents. In addition to untoward AEs, unexpected benefits outside 
the investigational product indication should also be captured on the AE CRF.
All AEs must be followed to closure (the subject’s health has returned to his/her 
baseline status or all variables have returned to normal), regardless of whether the 
subject is still participating in the study. Closure indicates that an outcome is 
reached, stabilization achieved (the investigator does not expect any further 
improvement or worsening of the event), or the event is otherwise explained. When 
appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
Section 7.15.1.1 
Severity 
Categorization
Mild
no limitation of usual activities
Moderate
some limitations of usual activities
Severe
Inability to carry out usual activities
:
Mild:
A type of AE that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally 
interfere with usual activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm 
to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic 
intervention
Section 7.15.1.2 
Relationship 
Categorization
Table 7-4
Adverse Event Relatedness
Relationship 
to Product
Definition
Not Related
Unrelated to the investigational product
Possibly 
Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of the investigational product, but which 
could also be explained by concurrent disease or other drugs or 
chemicals.
Probably 
Related
A clinical event or laboratory abnormality with a reasonable time 
sequence to administration of the investigational product, unlikely to 
be attributable to concurrent disease or other drugs and chemicals 
and which follows a clinically reasonable response on de challenge. 
The association of the clinical event or laboratory abnormality must 
also have some biologic plausibility, at least on theoretical grounds.
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Definitely 
related
The event follows a reasonable temporal sequence from 
administration of the investigational product, follows a known or 
suspected response pattern to the investigational product, is 
confirmed by improvement upon stopping the investigational 
product (de challenge), and reappears upon repeated exposure (re
challenge). Note that this is not to be construed as requiring re
exposure of the patient to the investigational product; however, the 
determination of definitely related can only be used when recurrence 
of the event is observed.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the 
administration of the investigational product is compelling 
and/or follows a known or suspected response pattern to 
that product, and the event cannot be explained by the 
subject’s medical condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as 
the subject’s underlying medical condition, concomitant 
therapy, or accident and no plausible temporal or biologic 
relationship exists between the investigational product and 
the event.
Section 7.15.1.3 
Outcome 
Categorization
The outcome of AEs must be recorded during the course of the study on the CRF. 
Outcomes are as follows:
•
Fatal
•
Not Recovered/Not Resolved
•
Recovered/Resolved
•
Recovered/Resolved With Sequelae
•
Recovering/Resolving
•
Unknown.
Section 7.15.1.4 
Symptoms of the 
Disease Under Study
Symptoms of the disease under study should not be classed as AEs as long as they 
are within the normal day-to-day fluctuation or expected progression of the disease 
and are part of the efficacy data to be collected in the study; however, significant 
worsening of the symptoms should be recorded as an AE.
Section 7.15.1.5 
Clinical Laboratory 
and Other Safety 
Evaluations
A change in the value of a clinical laboratory, vital sign, or ECG assessment can 
represent an AE if the change is clinically relevant or if, during treatment with the 
investigational product, a shift of a parameter is observed from a normal value to an 
abnormal value, or a further worsening of an already abnormal value. When evaluating 
such changes, the extent of deviation from the reference range, the duration until return 
to the reference range, either while continuing treatment or after the end of treatment 
with the investigational product, and the range of variation of the respective parameter 
within its reference range, must be taken into consideration.
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If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or 
ECG values which were not present at the pre-treatment value observed closest to the 
start of study treatment, further investigations should be performed until the values return 
to within the reference range or until a plausible explanation (e.g., concomitant disease) 
is found for the abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is 
clinically significant and whether it therefore represents an AE.
Section 7.15.1.6 
Pregnancy
Any report of pregnancy must be reported within 24 hours to the Shire Global 
Pharmacovigilance and Risk Management Department using the Shire 
Investigational and Marketed Products Pregnancy Report Form. A copy of the 
Shire Investigational and Marketed Products Pregnancy Report Form (and any 
applicable follow-up reports) must also be sent to the/Shire Medical Monitor using 
the details specified in the emergency contact information section of the protocol.
The pregnant female study participant must be withdrawn from the study.
Every effort should be made to gather information regarding the pregnancy 
outcome and condition of the infant. It is the responsibility of the investigator to 
obtain this information within 30 calendar days after the initial notification and 
approximately 30 calendar days post partum.
Pregnancy complications such as spontaneous abortion/miscarriage or congenital
abnormality are considered SAEs and must be reported using the Shire Clinical 
Study Serious Adverse Event and Non-serious AEs Required by the Protocol Form. 
Note: An elective abortion is not considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets 
serious criteria, it must be reported as an SAE using the Shire Clinical Study 
Serious Adverse Event and Non-serious AEs Required by the Protocol Form as well 
as the Shire Investigational and Marketed Products Pregnancy Report Form. The 
test date of the first positive serum/urine -hCG test or ultrasound result will 
determine the pregnancy onset date.
Pregnancy and lactation are exclusion criteria for this study. Any report of pregnancy for 
a female study participant or the partner of a male study participant during the course of 
the study and through 30 days after the patient’s last dose of VPRIV must be reported to 
the Sponsor. Pregnancy is not to be reported as an AE; the Investigational and Marketed 
Products Pregnancy Report Form should be used to report the pregnancy. The pregnancy 
will be followed up through delivery or final outcome. 
Section 7.15.1.8 
Abuse, Misuse, 
overdose, and 
Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported 
to the sponsor according to the SAE reporting procedure whether or not they result 
in an AE/SAE as described in Section Note: The 24-hour reporting requirement for 
SAEs does not apply to reports of abuse, misuse, overdose, or medication errors 
unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 
category.
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Abuse – Persistent or sporadic intentional intake of investigational medicinal
product at a dose higher than prescribed per protocol (but below the dose defined for 
overdose) or when used for a non-medical purpose (eg, altering.eg, to alter one’s 
state of consciousness or get high) in a manner that may be detrimental to the 
individual and/or society
•
Misuse – Intentional or unintentional use of investigational medicinal product other 
than as directed or indicated at any dose, which is at or below the dose defined for 
overdose (Note: this includes a situation where the test articleinvestigational 
product is not used as directed at the dose prescribed by the protocol)
•
Overdose – Intentional or unintentional intake of a dose of investigational medicinal 
product 10% higher than the protocol-specified dose. 
•
Medication Error – A mistake made in prescribing, dispensing, administration, 
and/or use of the investigational medicinal product
•
Cases of subjects missing doses of the investigational product are not 
considered reportable as medication errors.
•
Medication errors should be collected/reported for all products under 
investigation.
•
The administration and/or use of an expired investigational product should 
be considered as a reportable medication error.
Section 7.16.1 
Reference Safety 
Information
The reference for safety information for this study is the investigator’s brochure, 
which the sponsor has provided under separate cover to all investigators.
Section 7.16.2 
Reporting Procedures
Any SAE, regardless of relationship to the investigational product, which occurs in a 
patient after informed consent should be recorded by the clinical site on an SAE form. 
The SAE must be completely described on the patient’s eCRF, including the judgment of 
the investigator as to the relationship of the SAE to the investigational product. The 
investigator will promptly supply all information identified and requested by the Sponsor 
(or contract research organization) regarding the SAE.
The investigator must report the SAE to the Shire Pharmacovigilance and Risk 
Management Department AND to the Shire Medical Monitor on an SAE form. This form 
must be completed and FAXED or EMAILED within 24 hours of the investigator’s 
learning of the event to:
All initial and follow-up SAE reports must be reported by the investigator must 
report to the Shire Global Pharmacovigilance and Risk Management Department 
and the Shire Medical Monitor within 24 hours of the first awareness of the event. 
Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, and or medication errors according to the SAE reporting 
procedure (see Section 7.15.4.3) unless they result in an SAE.
The investigator must complete, sign, and date the Shire Clinical Study Serious 
Adverse Event and Non-serious AEs Required by the Protocol Form and verify the 
accuracy of the information recorded on the form with the corresponding source 
documents (Note: Source documents are not to be sent unless requested) and fax or 
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e-mail the form to the Shire Global Pharmacovigilance and Risk Management 
Department. A copy of the Shire Clinical Study Serious Adverse Event and Non-
serious AEs Required by the Protocol Form (and any applicable follow-up reports) 
must also be sent to the Shire Medical Monitor using the details specified in the 
emergency contact information section of the protocol.
Section 7.16.3 Serious 
Adverse Event 
Definition
An SAE is any AE occurring at any dose that results in any of the following outcomes:
•
Death
•
Is life threatening
•
Requires hospitalization
•
Requires prolongation of existing hospitalization
•
A persistent or significant disability or incapacity 
•
A congenital anomaly or birth defect
Important medical events that might not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent 1 of the outcomes listed in this definition. A life threatening AE 
is defined as an AE that placed the patient, in the view of the initial reporter, at 
immediate risk of death from the AE as it occurred (ie, it does not include an AE that, 
had it occurred in a more severe form, might have caused death).
Hospitalization, which is the result of elective or previously scheduled surgery for a pre
existing condition that has not worsened after initiation of treatment, should not result in 
an SAE designation. For example, an admission for a previously scheduled ventral 
hernia repair would not be classified as an SAE; however, complication(s) resulting from 
a hospitalization for an elective or previously scheduled surgery that meet(s) serious 
criteria must be reported as SAEs. Furthermore, this does not apply to device failures 
resulting in scheduled surgical revisions, which should be reported as SAEs.
A Serious Adverse Event (SAE) is any untoward medical occurrence (whether 
considered to be related to investigational product or not) that at any dose:
•
Results in death
•
Is life-threatening. Note: The term ‘life-threatening’ in the definition of 
“serious” refers to an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might 
have caused death if it was more severe.
•
Requires inpatient hospitalization or prolongation of existing hospitalization. 
Note: Hospitalizations, which are the result of elective or previously 
scheduled surgery for pre-existing conditions, which have not worsened after 
initiation of treatment, should not be classified as SAEs. For example, an 
admission for a previously scheduled ventral hernia repair would not be 
classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) 
serious criteria must be reported as SAE(s).
•
Results in persistent or significant disability/incapacity
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•
Is a congenital abnormality/birth defect
•
Is an important medical event. Note: Important medical events that may not 
result in death, be life-threatening, or require hospitalization may be 
considered an SAE when, based upon appropriate medical judgment, they 
may jeopardize the subject and may require medical or surgical intervention 
to prevent 1 of the outcomes listed in this definition. Examples of such 
medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home; blood dyscrasias or convulsions that do 
not result in inpatient hospitalization; or the development of drug 
dependency or drug abuse.
Section 7.16.4 Serious 
Adverse Event 
Collection Time Frame
Any SAE, regardless of relationship to the investigational product, which occurs in a 
patient after informed consent should be recorded by the clinical site on an SAE form. 
The SAE must be completely described on the patient’s eCRF, including the judgment of 
the investigator as to the relationship of the SAE to the investigational product. The 
investigator will promptly supply all information identified and requested by the Sponsor 
(or contract research organization) regarding the SAE.
All SAEs (regardless of relationship to study) are collected from the time the 
subject signs the informed consent until the defined follow-up period stated in 
Section 8.5 and must be reported to the Shire Global Pharmacovigilance and Risk 
Management Department and the CRO/Shire Medical Monitor within 24 hours of 
the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and 
discovered by the investigator at any interval after the study has completed must be 
reported to the Shire Global Pharmacovigilance and Risk Management Department 
within 24 hours of the first awareness of the event.
Section 7.16.5 Serious 
Adverse Event Onset 
and Resolution Dates
All SAEs (regardless of relationship to study) are collected from the time the 
subject signs the informed consent until the defined follow-up period stated in 
Section 8.5 and must be reported to the Shire Global Pharmacovigilance and Risk 
Management Department and the Shire Medical Monitor within 24 hours of the 
first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and 
discovered by the investigator at any interval after the study has completed must be 
reported to the Shire Global Pharmacovigilance and Risk Management Department 
within 24 hours of the first awareness of the event.
Section 7.16.6 Fatal 
Outcome
In the event of a severe and unexpected, fatal, or life threatening SAE, the clinical site 
must contact the Shire Medical Monitor by telephone; this is in addition to completing 
and transmitting the SAE form as stated above. The following provides contact 
information for the Shire Medical Monitor. 
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary 
cause of death) must have fatal checked as an outcome with the date of death 
recorded as the resolution date. For all other events ongoing at the time of death 
that did not contribute to the subject’s death, the outcome should be considered not 
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resolved, without a resolution date recorded.
Action taken with the investigational product should be an active decision by the 
investigator. For any SAE that results in the subject’s death or any ongoing events 
at the time of death, unless another study drug action was previously taken (eg, 
drug interrupted, reduced, withdrawn), the action taken with the investigational 
product should be recorded as “dose not changed” or “not applicable” (if the 
subject never received investigational product). The study drug action of 
withdrawn should not be selected solely as a result of the subject’s death. 
Section 7.16.7 
Regulatory Agency, 
Institutional Review 
Board, Ethics 
Committee, and Site 
Reporting
The investigator must promptly report all required information to the IRB/IEC. It is the 
responsibility of the Sponsor to ensure that each investigator receives a copy of any 
CIOMS I/MedWatch report that has been submitted to the appropriate regulatory 
agencies notifying them of an unexpected related SAE. The investigator or Sponsor must 
ensure that the IRB/IEC receives a copy of the report and that a copy is also filed within 
their study files.
The sponsor or sponsor designee is responsible for notifying the relevant regulatory 
authorities/US central IRBs/EU central ECs of related, unexpected SAEs.
In addition the sponsor or the sponsor’s designee is responsible for notifying active 
sites of all related, unexpected SAEs occurring during all interventional studies 
across the velaglucerase alfa program.
The investigator is responsible for notifying the local IRB, local EC, or the relevant 
local regulatory authority of all SAEs that occur at his or her site as required.
Section 7.17 Removal 
of Patients from the 
Trial or Investigational 
Product
A patient’s participation in the study may be discontinued at any time at the discretion of 
the investigator. The following may be justifiable reasons for the investigator to remove 
a patient from the study:
•
Non-compliance, including failure to appear at 1 or more study visits
•
The patient was erroneously included in the study
•
The patient develops an exclusion criterion 
•
The patient suffers an intolerable AE
•
The patient requests to be discontinued from the study
•
The study is terminated by the Sponsor
•
Pregnancy
The patient, the patient’s parent(s), or the patient’s legally authorized representative 
acting on behalf of the patient is free to withdraw consent and discontinue participation 
in the study at any time without prejudice to further treatment.
If a patient, the patient’s parent(s), or the patient’s legally authorized representative(s) 
acting on behalf of the patient, discontinues participation in the study or the patient is 
discontinued by the investigator, reasonable efforts will be made to follow the patient 
through the end of study assessments. The reason for refusal will be documented on the 
eCRF. Any AEs experienced up to the point of discontinuation must be documented on 
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CONFIDENTIAL
Page 112
SHP-GCB-402 Protocol Amendment 6
velaglucerase alfa (VPRIV®)
02 Nov 2020
Changes to Update Safety Language
Section
Summary of Changes
the AE eCRF. If AEs are present when the patient withdraws from the study, the patient 
will be re-evaluated within 30 days of withdrawal. All ongoing SAEs at the time of 
withdrawal will be followed until resolution.
Deleted Sections
The following sections of the original protocol were deleted as the information contained 
was redundant with updated text:

Section 7.15.1.1 Adverse Events

Section 7.15.1.3 Serious Adverse Events

Section 7.15.2.1 Classification of Adverse Events and Serious Adverse Events

Section 7.15.2.1 Clarification between Serious and Severe

Section 15.3 Relatedness of Adverse Events and Serious Adverse Events

Section 7.15.4 Procedures for Recording and Reporting Adverse Events

Section 7.15.4.1 Adverse Event Monitoring and Period of Observation

Section 7.15.4.2 Reporting Serious Adverse Events to the Sponsor and Medical 
Monitor
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CONFIDENTIAL
Page 113
SHP-GCB-402 Protocol Amendment 6
velaglucerase alfa (VPRIV®)
02 Nov 2020
Appendix 7
Questions taken from the BPI-SF©
The graphic below depicts the full Brief Pain Inventory Short Form (BPI-SF©). A subset of 
questions are taken from this form for use in Study SHP-GCB-402. Questions 2, 7, and 8 are not 
used.
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CONFIDENTIAL
Page 116
SHP-GCB-402 Protocol Amendment 6
velaglucerase alfa (VPRIV®)
02 Nov 2020
Appendix 8
Brief Fatigue Inventory
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SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
NCT Number: 
NCT02574286 
Study Title: 
An Open-label, Multicenter, Single-arm, Phase 4 Study of the Effect of 
Treatment with Velaglucerase alfa on Bone-related Pathology in 
Treatment-naïve Patients with Type 1 Gaucher Disease 
Study Number: 
SHP-GCB-402 
SAP Version and Date: 
Version 1.3: 
 
30 Aug 2021 


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Page 2 of 42 
Approved by:  
 
 
 
 
 
 
     
 
 
Data Science Institute 
Thurgauerstrasse 130,  
Glattpark-Opfikon (Zürich)  
8152 
Switzerland 
 
Date:  
 
 
 
 SQS Safety and Health Value 
350 Massachusetts Avenue 
Cambridge, MA 02139 
USA 
 
 
Date:  
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Page 3 of 42 
Table of Contents 
LIST OF ABBREVIATIONS ...................................................................................................... 5 
1. 
INTRODUCTION................................................................................................................ 7 
1.1. 
BACKGROUND AND STUDY RATIONALE ............................................................................. 7 
2. 
INVESTIGATIONAL PLAN ............................................................................................. 8 
2.1. 
OVERALL STUDY DESIGN AND PLAN .................................................................................. 8 
2.2. 
STUDY ENDPOINTS ............................................................................................................. 8 
2.2.1. 
Primary Endpoint ..................................................................................................... 8 
2.2.2. 
Secondary Endpoints ................................................................................................ 8 
2.2.3. 
Exploratory Endpoints ............................................................................................ 10 
2.3. 
TREATMENTS .................................................................................................................... 10 
3. 
GENERAL STATISTICAL CONSIDERATIONS ........................................................ 10 
3.1. 
SAMPLE SIZE .................................................................................................................... 11 
3.2. 
RANDOMIZATION AND BLINDING ..................................................................................... 11 
3.3. 
ANALYSIS POPULATIONS .................................................................................................. 11 
3.3.1. 
All Enrolled Population .......................................................................................... 11 
3.3.2. 
Intent-to-Treat (ITT) Population ............................................................................ 11 
3.3.3. 
Safety Population ................................................................................................... 11 
3.3.4. 
 ............................................................................................. 11 
4. 
PATIENT DISPOSITION................................................................................................. 12 
5. 
PROTOCOL VIOLATIONS AND DEVIATIONS ........................................................ 12 
6. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ..................................... 12 
7. 
MEDICAL HISTORY ....................................................................................................... 13 
8. 
CONCOMITANT MEDICATIONS, THERAPIES, MEDICAL/SURGICAL 
PROCEDURES HISTORY............................................................................................... 13 
9. 
TREATMENT COMPLIANCE AND EXTENT OF EXPOSURE............................... 13 
10. EFFICACY ANALYSIS .................................................................................................... 14 
10.1. PRIMARY EFFICACY ENDPOINT ........................................................................................ 14 
10.1.1. 
Primary Analysis .................................................................................................... 14 
10.2. SECONDARY EFFICACY ENDPOINTS .................................................................................. 15 
10.2.1. 
LS BMD Z-scores .................................................................................................. 15 
10.2.2. 
BMD (g/cm2) .......................................................................................................... 15 
10.2.3. 
BMB score .............................................................................................................. 16 
10.2.4. 
Hemoglobin concentration (g/dL) and Platelet count (x109/L) .............................. 16 
10.2.5. 
Normalized liver volume and Normalized spleen volume ..................................... 17 
10.2.6. 
WHO BMD classification ...................................................................................... 17 
10.2.7. 
Additional Analysis for Secondary Efficacy Endpoints ......................................... 18 
10.2.8. 
Health Economics and Outcomes Research Endpoints .......................................... 18 
10.3. OTHER ASSESSMENTS OR ANALYSES (
) .............. 19 
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11. SAFETY ANALYSIS......................................................................................................... 19 
11.1. ADVERSE EVENTS ............................................................................................................ 19 
11.1.1. 
Treatment-emergent Adverse Events ..................................................................... 19 
11.1.2. 
Serious Adverse Events .......................................................................................... 20 
11.1.3. 
Relationship of Treatment-emergent Adverse Events to Study Drug .................... 21 
11.1.4. 
Infusion-related (IRR) Adverse Events .................................................................. 21 
11.1.5. 
Severity of Treatment-emergent Adverse Event .................................................... 21 
11.2. CLINICAL LABORATORY EVALUATIONS ........................................................................... 21 
11.3. VITAL SIGN MEASUREMENTS ........................................................................................... 23 
11.4. PHYSICAL EXAMINATION ................................................................................................. 24 
11.5. 12-LEAD ELECTROCARDIOGRAM ...................................................................................... 24 
11.6. ANTIBODY ASSESSMENTS ................................................................................................ 24 
11.7. PREGNANCY TESTING ....................................................................................................... 25 
12. STATISTICAL/ANALYTIC ISSUES ............................................................................. 25 
12.1. INTERIM ANALYSES AND DATA MONITORING .................................................................. 25 
12.2. ADJUSTMENT FOR COVARIATES ....................................................................................... 25 
12.3. MULTI-CENTER STUDIES .................................................................................................. 25 
12.4. STATISTICAL ASSUMPTIONS ............................................................................................. 25 
12.5. MULTIPLE COMPARISONS/MULTIPLICITY ......................................................................... 25 
12.6. EXAMINATION OF SUBGROUPS AND INTERACTIONS ......................................................... 26 
12.7. SENSITIVITY ANALYSIS .................................................................................................... 26 
12.7.1. 
Last Observation Carried Forward (LOCF) Method .............................................. 26 
12.7.2. 
COVID-19 Sensitivity Analysis ............................................................................. 26 
12.7.3. 
Sensitivity Analysis for MRI Results ..................................................................... 26 
12.7.4. 
Statistical Methods and Sensitivity Analyses for Estimand ................................... 27 
12.7.5. 
Sensitivity Analysis for Brief Fatigue Inventory© (BFI) and bone pain as 
measured by the questions that were taken from Brief Pain Inventory (Short Form)© (BPI-
SF) Results ............................................................................................................................. 27 
12.8. HANDLING OF MISSING DATA .......................................................................................... 27 
12.9. DEFINITIONS ..................................................................................................................... 27 
13. REFERENCES ................................................................................................................... 29 
14. APPENDICES .................................................................................................................... 30 
14.1. APPENDICES I - LIST OF STATISTICAL TABLES .................................................................. 30 
14.2. APPENDICES II - LIST OF STATISTICAL FIGURES ............................................................... 37 
14.3. APPENDICES III - LIST OF STATISTICAL LISTINGS ............................................................. 38 
14.4. APPENDICES IV - SCHEDULE OF STUDY PROCEDURES ...................................................... 40 
14.5. APPENDICES V - PROGRAMMING CONVENTIONS .............................................................. 40 
14.6. APPENDICES VI- ALGORITHM TO HANDLE END OF STUDY AND UNSCHEDULED VISITS ... 41 
14.7. APPENDICES VII – ESTIMAND AND INTERCURRENT EVENTS ............................................ 42 
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List of Abbreviations 
AE 
Adverse Event 
ALB 
Albumin  
ALK-P 
Alkaline phosphatase 
ALT 
Alanine aminotransferase  
aPTT 
Activated partial thromboplastin time  
AR(1) 
First order autoregressive  
AST 
Aspartate aminotransferase  
BFI 
Brief Fatigue Inventory© 
BMB 
Bone marrow burden 
BMD 
Bone mineral density 
BPI-SF 
Brief Pain Inventory-Short Form© 
BUN 
Blood urea nitrogen  
 
 
CRP 
C-reactive protein  
CSR 
Clinical Study Report 
DXA 
Dual energy x-ray absorptiometry 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EOS 
End of Study 
EOW 
Every other week 
GCB 
Glucocerebrosidase 
GGT 
Gamma-glutamyl transferase  
HCT 
Hematocrit  
HGT 
Human Genetic Therapies 
 
 
IRR 
Infusion-related reactions 
ITT 
Intent-to-treat 
LDH 
Lactate dehydrogenase  
LOCF 
Last observation carried forward 
LS 
Lumbar spine 
 
 
MCH 
Mean corpuscular hemoglobin  
MCHC 
Mean corpuscular hemoglobin concentration  
MCV 
Mean corpuscular volume  
MedDRA 
Medical Dictionary for Regulatory Activities 
 
 
MMRM 
Mixed model repeated measures  
MRI 
Magnetic resonance imaging 
NHANES 
National Health and Examination Survey 
OC 
Observed case 
PT 
Preferred term 
 
 
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RBC 
Red blood cell  
REML 
Restricted maximum likelihood estimation 
SAE 
Serious adverse event 
 
 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
 
 
US(A) 
United States of America 
VPRIV 
Velaglucerase alfa 
WBC 
White blood cell  
WHO 
World Health Organization 
β-hCG 
Human chorionic gonadotropin 
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• Change from baseline to 12 months (Week 51) in LS BMD Z-score. Assessments will be 
performed at the screening visit and Weeks 51 and 103 (end of study). 
• Change from baseline to 12 months (Week 51) in BMD reported as g/cm2. Assessments 
will be performed at the screening visit and Weeks 51 and 103 (end of study). 
• Change from baseline to 24 months (Week 103 [end of study]) in BMD reported as g/cm2. 
Assessments will be performed at the screening visit and Week 103 (end of study). 
• Change from baseline to 12 months (Week 51) and 24 months (Week 103 [end of study]) 
in BMB score (MRI of lumbar spine and femur). Assessments will be performed at the 
baseline visit and Weeks 51 and 103 (end of study). 
• Change from baseline over time in hemoglobin concentration. Assessments will be 
performed at baseline visit and Weeks 13, 25, 37, 51, 65, 77, 89, and 103 (end of study). 
• Change from baseline over time in platelet count. Assessments will be performed at 
baseline and Weeks 13, 25, 37, 51, 65, 77, 89, and 103 (end of study). 
• Change from baseline to 12 months (Week 51) and 24 months (Week 103 [end of study]) 
in normalized liver volume as measured by abdominal MRI. Assessments will be 
performed at the baseline visit and Weeks 51 and 103 (end of study). 
• Change from baseline to 12 months (Week 51) and 24 months (Week 103 [end of study]) 
in normalized spleen volume as measured by MRI. Assessments will be performed at the 
baseline visit and Weeks 51 and 103 (end of study). 
• Change from baseline to 12 months (Week 51) and 24 months (Week 103 [end of study]) 
in bone pain as measured by the questions taken from the BPI-SF©. Assessments will be 
performed at the baseline visit and Weeks 13, 25, 37, 51, 65, 77, 89, and 103 (end of 
study). 
• Change from baseline to 12 months (Week 51) and 24 months (Week 103 [end of study]) 
in overall fatigue as measured by the BFI©. Assessments will be performed at the baseline 
visit and Weeks 13, 25, 37, 51, 65, 77, 89, and 103 (end of study). 
• Shifts in WHO BMD classifications (normal bone density, osteopenia, and osteoporosis) 
based on LS T-scores. Assessments will be performed at baseline (assessed on screening 
visit) and Weeks 51 and 103 (end of study). 
• Safety Endpoints: 
• Adverse events (AE) 
• Use of concomitant medications 
• Clinically abnormal laboratory tests (hematology, serum chemistry, coagulation, and 
urinalysis) 
• Positive anti-velaglucerase alfa antibody status, including assessment of neutralizing 
activity for confirmed antibody positive samples 
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4. Patient Disposition 
Patient disposition for those enrolled, treated, completed, or discontinued/withdrew will be 
presented in summary tables using the number and percentage of patients per category; reasons 
for discontinuation/withdrawal will be presented. The number of patients who completed study 
per protocol and the number of patients who have extended treatment period due to COVID-19 
will be summarized. In addition, the start and end dates of COVID-19 impact of each country 
will be presented. The start date of COVID pandemic is defined as the  date of first case that was 
reported in a specific country: 
Country 
Start Date of COVID Pandemic 
Spain 
N.A. Last subject from Spain completed study in Oct 
2019. 
United Kingdom 
30th Jan 2020 (Lillie PJ, et al, 2020) 
Israel 
21st Feb 2020 (Last M, 2020) 
United States of America 
20th Jan 2020 (Holshue, et al, 2020) 
Patient disposition, patients completing and prematurely discontinued during the study, and 
study analysis sets will be listed by patient for All Enrolled Population.  
5. Protocol Violations and Deviations 
An incident involving noncompliance with the protocol, but one which typically does not have 
significant effects on the patient’s rights, safety, or welfare, or the integrity of the resultant data 
will be considered a protocol deviation. An incident involving noncompliance with the protocol 
which may affect the patient’s rights, safety, or welfare, or the integrity of the resultant data will 
be considered a protocol violation. In particular, any serious deviation that affects the collection 
of data for the primary endpoints will be considered a protocol violation. A record of patients 
screened, but not entered into the study, is also to be maintained. No protocol exemption will be 
granted for this study. 
Patients will be examined on a case-by-case basis to determine if conditions set forth in the study 
protocol have been violated. The complete list of the protocol deviations will not be summarized; 
however, the protocol violations identified will be tabulated and listed. 
6. Demographics and Baseline Characteristics 
Demographic and Baseline characteristics will be summarized using either descriptive statistics 
or frequency distributions, as appropriate.  
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The following baseline demographics will be summarized: age (at time of consent) in years, 
weight (kg) and height (cm) at baseline, race, ethnicity and sex. 
The following clinical characteristics will be summarized: time from diagnosis of type 1 Gaucher 
disease to first treatment, age at diagnosis of type 1 Gaucher disease in years (estimated as age at 
time of consent - time from diagnosis of type 1 Gaucher disease to first treatment, as date of birth 
is not collected in the CRF), method of Gaucher disease diagnosis, main presenting features at 
diagnosis, glucocerebrosidase genotype, LS BMD Z-score at baseline, BMD (g/cm2) at baseline, 
BMB at baseline, normalized liver and spleen volumes (%Body Weight) at baseline and the 
centrally analyzed Screening and Baseline values for hemoglobin concentrations (g/dL) and 
platelet counts (x10^9/L). 
The following laboratory tests will be summarized: Vitamin D blood test at screening visit (or 
baseline, as applicable). 
Baseline height and weight are defined as the last assessment prior to the first VPRIV treatment 
in the study. 
A listing will be created to show all the demographics and baseline characteristics for each 
patient in the Safety Set. 
7. Medical History 
Medical history will be listed by patient. 
8. Concomitant Medications, Therapies, Medical/Surgical Procedures History 
All non-protocol treatments, including medications, therapies/interventions administered to 
patients, and medical/surgical procedures performed on the patients, on entry into the study (at the 
time of informed consent), or at any time during the study are regarded as concomitant. 
The number and percentage of patients who reported use of at least one concomitant medication 
will be summarized by Therapeutic Class and Preferred Term (Concomitant medications will be 
mapped using the WHO-Drug Dictionary version 3, 2015).  
Patients who took concomitant medication and concomitant therapies will be presented in 
listings separately. A listing of all patients who required a medical or surgical procedure will 
also be generated. 
9. Treatment Compliance and Extent of Exposure 
Treatment compliance and exposure summaries will be presented. For each patient, the patient’s 
percent of compliance, reflecting the patient’s willingness to accept the intravenous infusion at 
each infusion visit, will be calculated as follows for up to 24 months (Week 103 [end of study]) 
and for up to the end of COVID-19 extended treatment period.: 
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Page 15 of 42 
test or Wilcoxon signed rank test will be applied for the change from baseline of observed LS 
BMD Z-scores with patients whose LS BMD scores are collected after 24 months of treatment. 
A 95% confidence interval for the mean and median of the change from baseline will also be 
presented. In this analysis, no data imputation will be used. 
Example SAS code for the 95% CI of Median 
proc univariate data=dataset cipctldf cibasic; 
                  var aval; 
run; 
The pattern of LS BMD Z-scores over time, baseline value and change from baseline over time 
will be evaluated both descriptively using summary statistics and graphically using line graph 
and box plots at the screening visit, Week 51 and 103 (end of study) using observed data. 
The descriptive summary statistics of the percentage of change from baseline of the LS BMD Z-
score will also be generated. 
All observed LS BMD Z-score data will be provided in a by-patient listing. 
A sensitivity analysis will be performed for primary endpoint. Details are described in section 
12.7.1. 
10.2. Secondary Efficacy Endpoints  
Secondary efficacy endpoints will include evaluations of change in BMB score and LS BMD Z-
score, as well as change in hemoglobin concentration and platelet count, and changes in organ 
volume (liver and spleen). 
10.2.1. LS BMD Z-scores 
Changes in LS BMD Z-score from baseline to 12 months (Week 51) will be descriptively 
summarized and tested using one sample t-test or Wilcoxon signed rank test in the same manner 
as described above for the primary endpoint. A 95% confidence interval for the mean and 
median of the change from baseline will also be presented.  
10.2.2. BMD (g/cm2) 
Changes in BMD (g/cm2) from baseline to 12 months (Week 51) and 24 months (Week 103 [end 
of study]) will be descriptively summarized and tested using one sample t-test or Wilcoxon 
signed rank test in the same manner as described above for the primary endpoint using observed 
data. A 95% confidence interval for the mean and median of the change from baseline will also 
be presented. In addition, this analysis will be repeated using last observation carried forward 
(LOCF) method. 
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The change and percentage of change from baseline in BMD will be evaluated both descriptively 
using summary statistics and graphically using line graphs at the baseline visit and Weeks 51 and 
103 (end of study) using OC and LOCF data.  
All observed BMD data will be provided in a by-patient listing. 
10.2.3. BMB score 
Bone marrow burden raw scores will be entered into eCRF by two independent radiologists, after 
reviewing MRIs of the LS and femurs. In the event of the sufficient discrepancy is found in the 
analysis (defined as a difference in the total sum of BMB scores between readers being ≥3), the 
independent radiologists will proceed with consensus adjudication process and discuss the data 
together. The mutually agreed upon BMB scores will be entered by one radiologist, and signed 
off by the other. If adjudication is not needed, the scores entered by reader 1 will be used in 
BMB score calculation. The BMB scores range between 1 and 8 for each location and total BMB 
range between 2 and 16, based on the method of DeMayo et al (DeMayo et al., 2008). The total 
lumbar spine score (1-8) is the sum of signal intensity score (0,1,2), T1 signal intensity score 
(0,1,2,3), infiltration pattern (1,2) and absence of fat in basivertebral vein region (0,1). The total 
femora score (1-8) is the sum of signal intensity score (0,1,2,3), T1 signal intensity score (0,1,2), 
site of involvement (1,2,3). Total BMB score is calculated as total lumbar spine score and total 
femora score.  
Changes in BMB score (MRI of LS and femur) from baseline to 12 months (Week 51) and 24 
months (Week 103 [end of study]) will be descriptively summarized and tested using one sample 
t-test or Wilcoxon signed rank test in the same manner as described above for the primary 
endpoint. A 95% confidence interval for the mean and median of the change from baseline will 
also be presented. In this analysis, missing post-baseline data will be imputed using last 
observation carried forward (LOCF) method. 
The change and percentage of change from baseline in BMB score will be evaluated both 
descriptively using summary statistics and graphically using line graphs at the baseline visit and 
Weeks 51 and 103 (end of study) using OC and LOCF data.  
All observed BMB score data will be provided in a by-patient listing. 
10.2.4. Hemoglobin concentration (g/dL) and Platelet count (x109/L) 
Changes from baseline over time in hemoglobin concentration and platelet count will be 
descriptively summarized and tested using one sample t-test or Wilcoxon signed rank test at each 
time point in the same manner as described above for the primary endpoint. For calculating 
changes from baseline for each patient, the patient’s centrally performed hemoglobin 
concentration and platelet count collected at screening and baseline will be averaged to represent 
the patient’s baseline value. If a baseline result is unavailable, the screening result will be used 
(or vice versa). A 95% confidence interval for the mean and median of the change from baseline 
will also be presented. Missing post-baseline data will be imputed using last observation 
carried forward (LOCF) method. 
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In addition to changes from baseline, the pattern of hemoglobin concentration and platelet count 
over time, and the percentage of change from baseline in hemoglobin concentration and platelet 
count will be evaluated descriptively using summary statistics at the baseline visit and 13, 25, 37, 
51, 65, 77, 89, and 103 (end of study) using OC and LOCF data. Line graphs over time will also 
be provided to summarize the hemoglobin concentration and platelet count over time, changes 
from baseline and percentages from baseline using OC and LOCF data.  
All hemoglobin concentration and platelet count data will be listed separately for each patient. 
10.2.5. Normalized liver volume and Normalized spleen volume 
Change from baseline to 12 months (Week 51) and 24 months (Week 103 [end of study]) in 
normalized liver volume and normalized spleen volume as measured by abdominal MRI will be 
descriptively summarized and tested using one sample t-test or Wilcoxon signed rank test in the 
same manner as described above for the primary endpoint. A 95% confidence interval for the 
mean and median of the change from baseline will also be presented. Missing post-baseline data 
will be imputed using last observation carried forward (LOCF) method. 
The MRIs for measurement of liver and spleen volume are only collected at baseline and 
Weeks 51 and 103 (end of the study). Liver and spleen volumes will be normalized to body 
weight measured at baseline and Weeks 51 and 103 (end of the study). 
Liver/Spleen size relative to body weight = (Liver/Spleen volume [cc]/Body weight [g])*100 
Note: Corresponding body weight for a particular visit will be obtained from the Height/Weight 
eCRF page and should be from the same visit as liver and spleen measurements; last 
observation carried forward (LOCF) will be applied for body weight measurement. 
The pattern of normalized liver volume and normalized spleen volume over time, the change 
from baseline over time and the percentage of change from baseline will be evaluated both 
descriptively using summary statistics and graphically using line graphs at the screening visit and 
Weeks 51 and 103 (end of study) using OC and LOCF data.  
All normalized liver volume and normalized spleen volume data will be listed separately for each 
patient. 
10.2.6. WHO BMD classification  
Patients’ WHO BMD classification based on LS T-score will be captured and classified as 
having normal (T-score ≥-1), osteopenia (-2.5< T-score <-1), or osteoporosis (T-score ≤-2.5) 
BMD. The number and proportion of patients who have shifts in BMD classification based on T-
score will be summarized at the baseline visit and Weeks 51 and 103 (end of study). 
A listing of the patients who changed BMD WHO classification based on T-score within the first 
2 years and beyond will be provided. 
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10.2.7. Additional Analysis for Secondary Efficacy Endpoints 
As an additional analysis, a linear mixed model repeated measures (MMRM) will be used as a 
repeated measures analysis to investigate the improvement of efficacy over time. The model will 
include fixed categorical effects for visit week and baseline value of each endpoint, age at 
baseline and age at diagnosis of type 1 Gaucher disease as continuous covariates. All the non-
missing result of each secondary endpoints will be included in the model. SAS Proc Mixed with 
restricted maximum likelihood estimation (REML) and an unstructured within-patient 
covariance structure will be used. The MMRM analysis will be performed using OC and LOCF 
data. If this model fails to converge, a first order autoregressive (AR(1)) covariance structure will 
be used. From this model, change from baseline in least squares means, p-values and 95% 
confidence intervals will be estimated for quantitative secondary efficacy endpoints at each time 
point.  
Example SAS code for the MMRM analysis (all post-baseline results will be used).  
proc mixed data=dataset; 
 class avisitn usubjid; 
 model chg= avisitn base age adiaggau/s cl;  
*avisitn is the analysis visit; usubjid is subject ID; chg is the change from baseline result of each 
endpoint; base is baseline value;; age is age at baseline; adiaggau is age at diagnosis of type 1 
Gaucher disease. 
 repeated avisitn/type=un subject=usubjid r rcorr;  
 lsmeans avisitn/pdiff cl alpha=0.05; 
run; 
10.2.8.  Health Economics and Outcomes Research Endpoints 
Change from baseline to 12 months (Week 51) and 24 months (Week 103 [end of study]) in 
overall fatigue as measured by the Brief Fatigue Inventory© (BFI) and bone pain as measured by 
the questions that were taken from Brief Pain Inventory (Short Form)© (BPI-SF) will be 
evaluated as health economic and outcomes research endpoints.  
The first three questions of BFI evaluate patient fatigue on a 11-point scale ranging from 0 (No 
fatigue) to 10 (As bad as you can imagine). The last six questions in BFI rate how fatigue has 
interfered patient’s activities on a 11-point scale ranging from 0 (Does not interfere) to 10 
(Completely interferes). The global fatigue score will be calculated as average score of all the 9 
items on the BFI. Patients must have at least five of nine items in order to calculate the global 
fatigue score. 
Questions from BPI-SF include 2 subscales: pain severity [Item 3-6, score range 0 (No pain) - 10 
(As bad as you can image)] and pain interference [Item 9A-9G, score range 0 (Does not 
interfere) to 10 (Completely interferes)]. The two subscale scores will be computed as the 
average score of all the items from that subscale. Patients must have non-missing responses to all 
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In summary, imputation of the AE onset date is not needed to deem an AE as 
treatment-emergent or not. Based on the information available, one can compare the 
components (day, month, year) of the AE onset date (and of the AE resolution date if needed) 
with the date of the first infusion. In the end, if an AE cannot be conclusively categorized as a 
pre-treatment AE, then it must be categorized as a treatment-emergent AE. 
AE tabular summaries will be based on all treatment-emergent AEs. AEs will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA) coding dictionary version 18.1 or 
later. 
An overall safety summary of treatment-emergent AEs will be presented. This summary table 
will display the number of patients and associated percentage in each of the following 
categories: 
• 
Patients who experienced no AEs 
• 
Patients who experienced at least one AE 
• 
Patients who experienced at least one drug- related AE 
• Patients who experienced at least one infusion-related AE 
• 
Patients who experienced at least one severe AE 
• 
Patients who experienced at least one drug-related severe AE 
• 
Patients who experienced at least one life-threatening AE 
• 
Patients who experienced at least one drug-related life-threatening AE 
• 
Patients who experienced at least one serious AE (SAE) 
• 
Patients who experienced at least one drug-related SAE 
• 
Patient discontinuation from the study due to an AE(s) 
• 
Patient deaths. 
AEs will be summarized by system organ class (SOC) and preferred term (PT). The number 
and proportion of patients experiencing an AE will be tabulated overall; recurrent AEs 
observed within a patient will be counted once. Within each SOC, the PT will be sorted in 
descending frequency by the overall number of patients experiencing an AE. All AEs will be 
listed. 
AEs that led to permanent discontinuation from the study will be summarized by SOC and PT. 
A listing of all patients who permanently discontinued due to an AE(s) will be provided and 
given a table number. 
11.1.2. Serious Adverse Events 
A SAE is any AE that results in any of the following outcomes: death, is life-threatening, 
requires inpatient hospitalization or prolongation of existing hospitalization, a persistent or 
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significant disability/incapacity, or a congenital anomaly/birth defect. Important medical events 
that may not result in death, be life-threatening, or require hospitalization may be considered as 
SAE when, based upon appropriate medical judgment, they may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the outcomes listed in this definition. 
The number and percentage of patients reporting treatment-emergent SAEs will be presented by 
SOC and PT. In addition, all SAEs will be presented in a by-patient listing and given a table 
number. A listing of all patients who died during the study will also be provided and given a 
table number. 
11.1.3. Relationship of Treatment-emergent Adverse Events to Study Drug 
The investigator should report on the AE eCRF if the AE is a study drug-related AE. If the 
relationship is missing, it will be imputed as “Related”. The relationship will be determined by 
the investigator. The investigator should decide whether, in his or her medical judgment, there is 
a reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”. The number and percentage of patients 
reporting a study drug-related AE will be presented by SOC and PT. In addition, AEs by SOC 
and PT will be tabulated by relationship to study drug by reporting the episode with the closest 
relationship to study drug.  
11.1.4. Infusion-related (IRR) Adverse Events  
An infusion-related reaction (IRR) will be defined as an AE that 1) begins either during or within 
24 hours after the start of the infusion and 2) is judged by the investigator as related to study 
drug. Infusion-related Adverse Events will be presented by SOC and PT. 
11.1.5. Severity of Treatment-emergent Adverse Event 
AEs by SOC and PT will be tabulated by severity. In the case of multiple occurrences of the 
same AE (at the PT level) in an individual patient, the AE that is classified as the most severe 
(i.e., maximum severity) will be identified for the analysis by severity.  
11.2. Clinical Laboratory Evaluations 
The continuous laboratory data (serum chemistry, hematology, urinalysis and coagulation) 
will be descriptively summarized at the baseline visit and at Weeks 13, 25, 37, 51, 65, 77, 
89, and 103 (end of study). In addition, the change from baseline to Weeks 13, 25, 37, 51, 
65, 77, 89, and 103 (end of study) will be descriptively summarized. A laboratory retest, if 
available, that was performed at a scheduled visit, will be used in the analysis. If a baseline 
laboratory result is unavailable and a retest was not performed, the result will be replaced by 
the screening result if available.  
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The change from baseline to the end of study (EOS) measurement will be summarized using 
a shift table presented in terms of Normal (N), Out of Range and Not Clinically Significant 
(NCS), Out of Range and Clinically Significant (CS), or Missing (not done or not 
applicable). Clinical significance is based on the investigator’s assessment and captured on 
the electronic case report form. If a patient prematurely discontinues the study, then all 
subsequent measurements will be marked as not applicable. The summary will be based on 
all available data. All the laboratory data (serum chemistry, hematology, urinalysis and 
coagulation) will be listed by patient. 
Serum Chemistry: 
• 25-hydroxycholecalciferol 
• 1, 25-dihydroxycholecalciferol 
• Albumin (ALB) 
• Alkaline phosphatase (ALK-P) 
• Alanine aminotransferase (ALT; SGPT) 
• Aspartate aminotransferase (AST; SGOT) 
• Blood urea nitrogen (BUN) 
• Calcium 
• C-reactive protein (CRP) 
• Creatinine 
• Creatine kinase 
• Ferritin 
• Gamma-glutamyl transferase (GGT) 
• Glucose 
• Iron binding capacity 
• Lactate dehydrogenase (LDH) 
• Phosphorus 
• Potassium (K) 
• Serum iron 
• Sodium (Na) 
• Total bilirubin 
• Total protein 
• Transferrin saturation 
• Unsaturated IBC 
Hematology: 
• Hematocrit (Hct) 
• Hemoglobin (Hgb) 
• Mean corpuscular hemoglobin (MCH) 
• Mean corpuscular hemoglobin concentration (MCHC) 
• Mean corpuscular volume (MCV) 
• Platelet count 
• Red blood cell (RBC) count 
• White blood cell (WBC) count with differentials 
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• Neutrophils 
• Basophils 
• Lymphocytes 
• Monocytes 
• Eosinophils 
Urinalysis: 
• Appearance 
• Bilirubin 
• Color 
• Glucose 
• Ketones 
• Microscopic examination of sediment 
• Nitrite 
• Occult blood 
• pH  
• Protein 
• Specific gravity 
• Urobilinogen 
Coagulation 
• Prothrombin time 
• Activated partial thromboplastin time (aPTT) 
• D-dimer 
 
Hemoglobin concentration and platelet count will be reported as secondary endpoints and they 
will not be included in the summary of laboratory assessments. 
 
11.3. Vital Sign Measurements 
Infusion vital signs will be recorded at every visit when an infusion is given. Vital signs 
parameters include pulse (bpm), blood pressure (systolic [mmHg] / diastolic [mmHg]), 
respiration rate (breaths per min), temperature (ºC) and pulse oxygen measurement (%). 
For each infusion, the vital signs parameters will be recorded at the following time points: start 
of infusion (within 10 minutes prior to start of infusion), during the infusion (30 minutes after the 
start of infusion, plus or minus 5 minutes), after infusion (within 5 minutes after completing the 
infusion; 30 minutes after completing the infusion plus or minus 5 minutes; and 60 minutes after 
completing the infusion plus or minus 5 minutes). If there are no infusion-related reactions 
during the first 3 home infusions, the observation and vital signs post-infusion can be omitted at 
the discretion of the investigator. 
The infusion vital sign parameters will be summarized by reporting the number and proportion of 
patients experiencing at least one above normal (and at least one below normal) change during 
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transient positive and persistent positive during the study period, and by treatment-induced 
positive and treatment-boosted positive at each post baseline visits. The anti-velaglucerase 
antibody titer will be summarized as continuous variable at baseline, and by any positive, by 
treatment-induced positive and treatment-boosted positive each post baseline visits.  
Treatment-induced positive is defined as subject was positive for ADA or NAb at a study visit 
post baseline in a subject who is negative for ADA, NAb at baseline; Treatment-boosted positive 
is defined as subject’s ADA or NAb titer was boosted to a higher level post baseline (greater than 
or equal to the baseline titer by fourfolds or more) at a study visit in a subject who is ADA or 
NAb positive at baseline; Transient positive is defined as subject tested positive for ADA or NAb 
once during treatment period (excluding last test), or positive for ADA or NAb two times or more 
where the first and last time points for ADA or NAb positive are separated by a period less than 
16 weeks and the subject’s last test is negative; Persistent positive is defined as subject tested 
ADA or NAb positive two times or more (more than 16 weeks apart) during study period 
including last time point tested. Antibody assessments will also be provided in a by-patient listing. 
11.7. Pregnancy Testing 
Female patients’ pregnancy test results will be listed by patient for the safety population. 
12. Statistical/Analytic Issues 
12.1. Interim Analyses and Data Monitoring 
Not applicable. 
12.2. Adjustment for Covariates 
Prognostic and predictive demographic and baseline factors may be incorporated in the repeated 
measures analyses. Unless otherwise specified, all repeated measures models that model the 
change from baseline over time will include baseline age, age at diagnosis of type 1 Gaucher 
disease in years,  and the corresponding baseline value of the outcome parameter of interest as a 
factor. Tabular and graphical summaries obtained from the repeated measures models will 
identify the factors included in the statistical models. 
12.3. Multi-center Studies 
The summary results will not be presented by individual centers due to a small number of patients 
at each center. 
12.4. Statistical Assumptions 
No test will be performed for statistical assumptions. 
12.5. Multiple Comparisons/Multiplicity 
Not applicable. 
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12.6. Examination of Subgroups and Interactions 
A COVID-19 subgroup analyses is planned for the outcome measurements per section 12.7.2. 
12.7. Sensitivity Analysis 
The following sensitivity analyses will be performed: 
12.7.1. Last Observation Carried Forward (LOCF) Method 
As a sensitivity analysis, the primary and secondary efficacy analysis will be repeated by 
applying last observation carried forward (LOCF) method. That is, if the LS BMD score is 
missing at 24 months (Week 103 [end of study]), the last non-missing score before 24 months 
will be carried forward. If all post-baseline assessments are missing, the assessment at baseline 
will not be carried forward for the analysis. 
12.7.2. COVID-19 Sensitivity Analysis 
A subgroup analysis for patients who completed study per protocol and patients who have 
extended treatment period due to COVID-19 will be performed for the following summaries and 
figures to assess the impact of COVID-19 pandemic:  
• Protocol violations 
• Treatment compliance and extent of exposure 
• Primary efficacy endpoint,  
• Secondary efficacy endpoints, excluding BMD scores at month 12 (Week 51) 
• 
 
For the summaries of adverse events, the subgroup analyses will be repeated for pre- and during 
COVID-19 pandemic phases. For any AE that occurred on or after the start of the pandemic, it 
will be considered as the event during COVID-19 pandemic phases. If the AE started before the 
start of the pandemic, it will be considered as pre-COVID-19 pandemic event. The protocol 
violations, patient exposure, Brief Pain Inventory outcomes and 
measurements will be 
listed by patients who completed study per protocol and patients who have extended treatment 
period due to COVID-19. 
12.7.3. Sensitivity Analysis for MRI Results 
Site 
 has changed the MRI machine during the study, resulting in subject 
 having 
the baseline MRI performed on the old machine, and post-baseline MRI performed on the new 
machine. To evaluate the impact of MRI machine on the test results, the summaries of BMB 
score, normalized liver volume and normalized spleen volume will be repeated excluding subject 
. 
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12.7.4. Statistical Methods and Sensitivity Analyses for Estimand 
For subjects who discontinued from the study due to treatment emergent adverse event (TEAE) 
or lack of efficacy (LOE), the missing data following discontinuation will be imputed under the 
hypothetical strategy using multiple imputation (MI) method, assuming discontinuation due to 
TEAE or LOE would not occur. 
Multiple imputation (MI) method will utilize the SAS procedures PROC MI and PROC 
MIANALYZE, based on the assumption of missing at random (MAR) to assign missing LS 
BMD scores. Missing LS BMD Z-score as measured by DXA at Week 103 will be imputed 
using MI. The imputation model by FCS regression method will include age at baseline, age at 
diagnosis of type 1 Gaucher disease, LS BMD Z-score at baseline and at Week 51 as effect. 
 
 and number of imputations will be set as 50. The change from 
baseline in LS BMD Z scores at Week 103 will be calculated from the imputed 50 datasets. The 
50 imputed datasets will be analyzed using the primary analysis methods.  Results from analysis 
of each imputed dataset will be combined using Rubin’s imputation rules to produce a pooled 
estimate of mean change from baseline. PROC MIANALYZE will be used to combine the 
results from each imputed dataset.  
12.7.5. Sensitivity Analysis for Brief Fatigue Inventory© (BFI) and bone pain as measured 
by the questions that were taken from Brief Pain Inventory (Short Form)© (BPI-
SF) Results 
For Brief Fatigue Inventory© (BFI) and questions that were taken from Brief Pain Inventory 
(Short Form)© (BPI-SF), some of the Week 0 assessments were collected after the first infusion. 
A sensitivity analysis will be performed to include these post-infusion results as baseline and 
repeat for the analysis in section 10.2.8. 
12.8. Handling of Missing Data 
Imputation of missing data post-baseline will be employed using last observation carried forward 
(LOCF) for the endpoints of the change from baseline to subsequent time points in LS BMD Z-
score as measured by DXA, BMB score, hemoglobin concentration, platelet count, normalized 
liver volume and normalized spleen volume. No data imputation will be used for the categorical 
analyses of WHO BMD classification based on LS T-scores, bone pain as measured by the 
questions from BPI-SF, and overall fatigue as measured by the BFI. 
Patients who discontinue the study prematurely will be asked to undergo all safety and efficacy 
evaluations required for the end of study visit. If these data meet the algorithm outlined in 
Appendix VI, Algorithm to Handle End of Study and Unscheduled Visits, efficacy data collected 
at these visits will be incorporated in the analyses. 
12.9. Definitions 
 
Term 
Definition 
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Term 
Definition 
Baseline 
Data collected prior to the first administration of 
study drug (Day -3 through Day 0, where Day 0 is 
the day prior to first infusion) 
Modified baseline 
The average of data collected at screening and 
baseline. The non-missing values will be used to 
average. 
Change from baseline 
Post-baseline visit value minus baseline visit value 
or Modified baseline value 
Percent Change from Baseline (Change from baseline * 100) ÷ baseline or Modified 
baseline 
Follow-up 
30 days after the final infusion 
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13. References 
Beutler E, Grabowski G. Gaucher Disease. In: Scriver CR BA, Sly WS, Valle D, ed. The 
Metabolic and Molecular Basis of Inherited Disease, 8th Edition. New York: McGraw-Hill. 
2001; 3635-68. 
Pastores GM, Weinreb NJ, Aerts H, et al. Therapeutic goals in the treatment of Gaucher 
disease. Semin Hematol. 2004; 41:4-14. 
Lillie PJ, Samson A, Li A, et al. Novel coronavirus disease (Covid-19): The first two 
patients in the UK with person to person transmission. J Infect. 2020 May; 80(5):578–
606.  
Last M. The first wave of COVID-19 in Israel—Initial analysis of publicly available data. 
Plos One. 2020 Oct.; https://doi.org/10.1371/journal.pone.0240393. 
Holshue ML, DeBolt C, Lindquist S, et al. First Case of 2019 Novel Coronavirus in the 
United States. N Engl J Med. 2020 March; 382:929-936. 
A C Looker 1, H W Wahner, W L Dunn, M S Calvo, T B Harris, S P Heyse, C C 
Johnston Jr, R L Lindsay. Osteoporos Int. 1995;5(5):389-409. 
A. C. Looker, H. W. Wahner, W. L. Dunn, M. S. Calvo, T. B. Harris, S. P. Heyse, 
C. C. Johnston Jr  and R. Lindsay. Osteoporos Int. 1998; 8:468–489 
DeMayo, R. F., Haims, A. H., McRae, M. C., Yang, R. & Mistry, P. K. Correlations of 
MRI-based bone marrow burden score with genotype and spleen status in Gaucher's 
Disease. Am J Roentgenol. 2008; 191:115-123. 
 
 
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14.6. Appendices VI- Algorithm to Handle End of Study and Unscheduled Visits 
End of Study (EOS) Visits 
For the efficacy analysis, if the EOS visit date for patients who discontinue the study early is on 
or within 17 days after the last infusion date then we will derive the visit number for the EOS 
visit as last infusion week plus 2 weeks. 
Unscheduled Visits 
For the efficacy analysis, compare the unscheduled visit date to the closest infusion date; if the 
unscheduled visit occurred on or within +/- 7 days of that infusion date then we assign the 
infusion week as the visit week for the unscheduled visit. If the unscheduled visit was completed 
between two infusion weeks and the distances are same, the visit week will be assigned as the 
infusion week before unscheduled visit. The assessment result from the unscheduled visit will be 
used to replace the missing result for that visit week. If using the algorithm, multiple 
unscheduled visits fall into the same visit then the one closest to the infusion date will be used to 
replace the missing result for the visit week. If the multiple unscheduled visits that fall into the 
same visit are equal distant from the infusion date then the one before the infusion date will be 
used. 
For vital sign measurements, physical examination, 12-lead ECG and antibody assessments, 
compare the unscheduled visit date to the infusion date of the closest safety assessment visit. If 
the unscheduled visit occurred within +/- 30 days of that infusion date then we assign the 
infusion week as the visit week for the unscheduled visit. The assessment result from the 
unscheduled visit will be used to replace the missing result for that visit week. If using the 
algorithm, multiple unscheduled visits fall into the same visit then the one closest to the infusion 
date will be used to replace the missing result for the visit week. If the multiple unscheduled 
visits that fall into the same visit are equal distant from the infusion date then the one before the 
infusion date will be used. 
Based on the algorithms above, for the efficacy parameters only, the EOS and unscheduled visits 
that fall into the visit window will be carried forward when LOCF analysis is performed. 
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14.7. Appendices VII – Estimand and Intercurrent Events 
Possible intercurrent events are presented below: 
Label 
Intercurrent Event Type 
IcEv1 (Discontinue TEAE) 
Discontinuation from study due to treatment emergent adverse event 
(TEAE). 
IcEv2 (Discontinue LOE) 
Discontinuation from study due to lack of efficacy (LOE). 
IcEv3 (Prohibited medications) 
Use of prohibited medications.  
IcEv4 (Compliance) 
Poor compliance (>=3 consecutively missing dose, or 5 total).  
Primary efficacy estimand with rationale and strategies to address intercurrent events are 
presented below: 
Estimand Label 
Estimand (Primary) 
Estimand Description 
Mean change in LS BMD Z-score as measured by DXA 
from baseline to 24 months (Week 103 [end of study]) in 
treatment-naïve  patients with type 1 Gaucher disease 
irrespective of using prohibited medication or poor 
compliance and assuming patients did not discontinue 
treatment due to TEAE or LOE. 
A hypothetical strategy is used to estimate the change of LS 
BMD Z-score assuming discontinuation due to TEAE or 
LOE would not occur.  
A treatment policy strategy is used for assessing change of 
LS BMD Z-score irrespective of using prohibited 
medication or poor compliance. 
Target Population 
Treatment-naïve Patients with Type 1 Gaucher Disease 
patients who received at least one study drug infusion (full 
or partial). 
Endpoint 
The change from baseline to 24 months (Week 103 [end of 
study]) in LS BMD Z-score as measured by DXA. 
Treatment Condition(s) 
Velaglucerase alfa 60 U/kg every other week (EOW) by a 
minimum 60-minute intravenous infusion 
Population-Level Summary 
Change in means 
Intercurrent Event Strategy  
IcEv1 (Discontinue TEAE) 
Hypothetical strategy 
IcEv2 (Discontinue LOE) 
Hypothetical strategy 
IcEv3 (Prohibited medications) 
Treatment Policy Strategy 
IcEv4 (Compliance) 
Treatment Policy Strategy 
Rationale for Strategies 
A hypothetical strategy for discontinuation due to TEAE or 
LOE to ascertain the efficacy prior to treatment 
discontinuation. 
A treatment policy strategy for use of prohibited medication 
or poor compliance as this is relevant to clinical practice 
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