Retrospective and Prospective Observational Study of MRI Changes in Bone and Visceral Lesions of Patients With Type 1 Gaucher Disease Treated With VPRIV® (Velaglucerase Alfa)
Conditions: Gaucher Disease, Type 1, MRI
Sponsor: CEN Biotech

 
 
Retrospective and prospective observational study of MRI changes 
in bone and visceral lesions of patients with type 1 Gaucher disease 
treated with VPRIV® (velaglucerase alfa) 
 
Study Title: 
Retrospective and prospective observational study of MRI changes in bone and 
visceral lesions of patients with type 1 Gaucher disease treated with VPRIV® 
(velaglucerase alfa) 
Study Number: RMGF - SHPGCB-703 
Study Phase: 
Retrospective and prospective observational study 
 
 
Principal 
Investigator 
Nadia Belmatoug MD, Service de Médecine Interne - Centre de Référence des  
maladies lysosomales, Hôpital Beaujon, Clichy, France   
 
Scientific 
Coordinators: 
    
- David Petrover MD, hôpital Lariboisière, Clinique Bachaumont, Paris, 
France 
- Luc Bracoud, Bioclinica, Lyon, France 
- François-André Allaert, MD, PhD, CHRU Bocage, Dijon, France 
 
 
Sponsor: 
Shire France 
Sponsor 
Contact: 
Dr El Hadi Bessa  
Email:  ebessa0@shire.com 
 
 
 
 
  
Original Protocol Version 
15th of September 2015 
 
Modified 05 april  2016 
 
 
 
 
Confidentiality Statement 
This document is the proprietary and confidential property of  
Shire Rare diseases  

Retrospective and prospective observational study of MRI changes in bone and visceral lesions of patients with type 1 
Gaucher disease treated with VPRIV® (velaglucerase alfa) 
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SYNOPSIS 
Sponsor : Shire France 
 
Study Title: Retrospective and prospective observational study of MRI changes in bone and 
visceral lesions of patients with type 1 Gaucher disease treated with VPRIV® (velaglucerase 
alfa) 
 
Study Number: RMGF - SHPGCB-703 
Study Phase:   
Non-Interventional, retro-prospective observational study 
 
Rationale and background: 
Gaucher’s disease (GD) is a rare autosomal recessive disorder caused by the deficiency of 
the lysosomal glucocerebrosidase. This enzyme is required for the hydrolysis of 
glucosylceramide (or glucocerebroside) derived from degradation of the cell membrane of 
the formed elements of the blood. In GD, non-degraded glucosylceramide accumulates in 
lysosomes of the cells of the reticuloendothelial system and especially in macrophages.  
The prevalence of MG is about 1/136 000 in the general population in France. Three main 
phenotypes (clinical forms) are traditionally distinguished: 
- Type 1 accounts for 95% of cases. Its clinical expression is very heterogeneous ranging 
from asymptomatic throughout life to severe forms as soon childhood. 
- Type 2 is an exceptional form (less than 1% of cases), with a very early expression (before 
the age of 1 year), and a very poor prognosis (death before the age of 2 years). 
- Type 3 is a rare (less than 5% of cases) involving progressive encephalopathy of varying 
severity (oculomotor apraxia, epilepsy, ataxia) beginning before age 20 with similar forms 
than type 1 (1). 
The study will focus on the phenotype 1. The diagnosis of type 1 GD can be done at any age 
and its main manifestations are hepatosplenomegaly, thrombocytopenia, anemia, asthenia 
and occasionally incapacitating bone involvement (infarction, osteonecrosis, fractures, 
decreased bone density) causing acute and / or chronic pain. Bone involvement is the major 
complication of Gaucher disease whose manifestations are the leading cause of morbidity 
and disability (1, 2, 3). 
Velaglucerase alfa in Gaucher’s disease 
VPRIV® is a long term enzyme replacement therapy in patients with Type 1 Gaucher 
disease. 
The active substance of VPRIV, velaglucerase alfa is a glycoprotein made up of 497 amino 
acids and presents an amino acid sequence identical to the naturally occurring enzyme 

Retrospective and prospective observational study of MRI changes in bone and visceral lesions of patients with type 1 
Gaucher disease treated with VPRIV® (velaglucerase alfa) 
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glucocerebrosidase. There are five potential N-glycosylation sites, four of which are 
occupied. Velaglucerase alfa offsets or replaces beta-glucocerebrosidase (the natural enzyme 
responsible for the hydrolysis of glucocerebroside to glucose and ceramide in the lysosome) 
thus reducing the quantity of glucocerebrosides accumulated and correcting the 
physiopathology of Gaucher disease.  
Justification of the study 
Velaglucerase alfa increases the level of haemoglobin and the platelets count and reduces 
hepatic and splenic volumes in patients with type 1 Gaucher disease (4); promising results 
have also been observed in the domain of bone disorders (5-10). However, to date, the only 
MRI data available in French Gaucher patient’s dossiers are qualitative data. This study with 
standardized reading MRIs, will provide for the first time objective and quantified data on 
organomegaly (liver and spleen volumes) as well as bone alteration (Bone Marrow Burden11) 
of French patients treated with VPRIV®. These data will help to better assess the impact of 
this treatment on these parameters. 
The result of this study will also answer in part to the request of the French Transparency 
Commission (CT: Commission de Transparence) of the French National Health Authority 
(HAS: Haute Autorité de Santé) to provide them with data of French patients treated with 
VPRIV®. 
Objectives: 
Primary Objective:  
• 
To describe the changes of bone disease in femur and lumbar spine 
 
Secondary Objectives:  
• 
To describe the socio-demographic status of patients 
• 
To describe the clinical evolution of patients (asthenia, abdominal pain, chronic bone 
pain, bone crises, hemorrhagic syndrome, hepatosplenomegaly, pulmonary, 
neurological) 
• 
To describe the evolution of the parameters measured by MRI 
- Bone alterations (spine, pelvis, femurs, tibias and other symptomatic localization) 
- Visceral involvement (liver, spleen) 
• 
To describe the evolution of biological parameters 
 
If possible, to compare the evolution of MRI parameters between treatment-naive patients 
and patients previously treated with another specific treatment for Gaucher disease at the 
baseline MRI. 
 
Study Endpoints:  
• Primary Endpoint 

Retrospective and prospective observational study of MRI changes in bone and visceral lesions of patients with type 1 
Gaucher disease treated with VPRIV® (velaglucerase alfa) 
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The primary endpoint is the change over time between the baseline MRI and the 
follow-up MRIs, of the BMB score weighted at T1 and T2 and measured at the femur 
and lumbar spine 
• Secondary and exploratory endpoints 
The secondary and exploratory endpoints of this study are: 
• socio-demographic characteristics: age, sex, occupation 
• history of the disease and context of diagnosis: age at diagnosis, type of symptoms, 
exams that allowed the diagnosis and its confirmation, enzymatic assay value 
genotype and presence or absence of family history 
• medical history 
• clinical evaluation criteria: weight (kg), height (cm), absence or presence (mild, 
moderate or severe) asthenia, abdominal pain, chronic bone pain, bone crises, 
bleeding syndrome, pulmonary impairment, neurological impairment 
• clinical endpoints for liver and spleen 
- absence or presence of hepatomegaly, with the extent of the arrow (medio-clavicular 
line) (cm) 
- absence or presence of splenomegaly, with the extent of the costal overhang (cm).- 
• liver evaluation criteria and spleen MRI 
- absence or presence of hepatomegaly, with the extent of the arrow (medio-clavicular 
line) (cm) 
- absence or presence of splenomegaly, with the extent of the costal overhang (cm) 
- liver volume (m3) 
- spleen volume (m3) 
- presence or absence of myocardial, nodules, fibrosis, vesicular stones or other 
alterations 
• evaluation criteria of bone lesions by MRI (spine, pelvis, femurs, tibias and other 
symptomatic localization) 
Absence or presence of bone lesions and their locations: bone infiltration, cortical 
thinning, osteonecrosis, bone infarction, stroke sequelae, vertebral compression, 
fracture or other bone disease 
• evaluation criteria of the biological parameters: 
hemoglobin (g/dl); leukocytes (cells/mm3); platelets (mm3); ACE (angiotensin 
converting enzyme (U/l); ferritin (mg/l); chitotriosidase (nmol/h/ml); CCL18 
(ng/ml), vitamin D (nmol/L), vitamin B12 (pmol/l); SGOT/AST (U/l), SGPT/ ALT 
(U/l), GGT (U/l), alkaline phosphatase (U/l), triglycerides (mmol/l), total cholesterol 
(mmol/l) gamma globulin (g/l) serum calcium (mmol/l) presence or absence of a 
monoclonal peak and the type if any. 
 
Study Population  

Retrospective and prospective observational study of MRI changes in bone and visceral lesions of patients with type 1 
Gaucher disease treated with VPRIV® (velaglucerase alfa) 
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To reflect the daily practices, this study includes all patients with a confirmed diagnosis of 
Type 1 Gaucher disease treated with VPRIV® at the date of beginning of the study and who 
meet the selection criteria of the study. 
 
 
 
 
Study Inclusion and Exclusion Criteria 
Inclusion Criteria 
1. Patients of any age or gender with confirmed diagnosis of type 1 Gaucher disease, 
2. Patients treated with VPRIV® at the beginning of the study.  Prior starting VPRIV® 
patients could be either treatment naïve or previously treated with any other Gaucher 
treatment than VPRIV® 
3. Patients should have one MRI data in the 5 previous years before starting VPRIV®  
  Treatment (up to 3 months after initiation of VPRIV® 
4. Informed written consent obtained from the patient, and/or patient’s parent(s), and/or  
  legal representative. Assent, if old enough to grant, will be obtained from all patients  
  under the age of 18 years 
 
Exclusion Criteria 
1. Patients for whom MRI is contra-indicated 
2. Patients who did not had an MRI during the five years prior to the initiation of 
treatment with VPRIV® or within three months after initiation of VPRIV®. 
3. Patients included in an ongoing clinical trial where the product is blinded  
 
Study Design and duration 
The study developed in conjunction with the French Referral Centers of Lysosomal Diseases 
and French Gaucher Treatment and Evaluation Committee (CETG: Comité d'Evaluation du 
Traitement de la Maladie de Gaucher) is a retro-prospective observational study of the French 
cohort of patients with type 1 Gaucher disease treated with VPRIV® in everyday clinical 
practice. 
 
It consists of two phases:  a retrospective and a prospective one with an inclusion period of 
1 year. 
Phase I: retrospective phase 
The retrospective period includes the period between the date of the baseline MRI to the 
patient's date of inclusion in the study. The reference MRI is defined as the closest MRI to 
the initiation of VPRIV®, within the past five years, or within three months after initiation 
of VPRIV®. 
Phase II: prospective phase 
Prospective period will be one year from the date of patient inclusion in the study. 
 
The final MRI 
MRI being performed in current practice every 2 years, the final MRI follow-up performed 
corresponds to those in the previous year or in the year following the patient's inclusion.

Retrospective and prospective observational study of MRI changes in bone and visceral lesions of patients with type 1 
Gaucher disease treated with VPRIV® (velaglucerase alfa) 
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The duration of the study will be 2 years,1-year inclusion period to be sure to include all 
patients VPRIV® (reviewed annually in consultation each year) and a prospective follow-up 
period of 1 year. 
 
Provisional timetable for the study: 
 
 
 
 
 
 
 
 
Data collection and transmission 
 
All data entered will be used for analysis purposes and results will be submitted to inform 
regulatory agencies. Patient care and management is freely determined by the participating 
physician, in the framework of an observational study reflecting the daily medical practice. 
The clinical data, the results of routine clinical and laboratory testing that are part of standard 
medical care for patients with Gaucher disease will be collected from the medical record of 
the patient : 
- 
Socio-demographic characteristics  
- 
History of the disease and context of diagnosis 
- 
Medical background 
- 
MRI: abdominal and bone, as defined below 
- 
Clinical data available in the range from 3 months before or after each MRI 
- 
Biological data available in the range from 3 months before or after each MRI 
- 
Treatment with VPRIV® (velaglucerase alfa), including the doses and regimens. 
 
The MRI images collected during the study: 
 
The MRIs performed in the patient's usual medical follow-up for its Gaucher disease     
(abdominal MRI (liver and spleen) and bone MRI (back injury pelvis, lower limbs) and / 
or whole-body MRI) will be collected. Among the MRIs available in the patient's medical 
records, MRIs will be collected as following: 
 
- Reference MRI: MRI closest to the date of initiation of VPRIV® in the five years 
preceding the start of treatment or within three months after initiation of VPRIV®. 
- MRIs of the retrospective phase of the study: All MRIs available between the reference 
MRI and the inclusion date of the patient. 
- MRIs of the prospective phase of the study: all the MRIs that will be realized during the 
prospective phase of the study, that is to say during  the year following the date patient 
inclusion in the study  
 
CCTIRS / CNIL authorisation
October 23, 2015
Inclusion of the first patient in the study
September 30, 2016 
Inclusion of the last patient in the study
September 30, 2017
Last visit of the last patient
September 30, 2018
Study clinical report 
January 31, 2019

Retrospective and prospective observational study of MRI changes in bone and visceral lesions of patients with type 1 
Gaucher disease treated with VPRIV® (velaglucerase alfa) 
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Second reading of the MRI 
The collected MRIs will be subject to a second reading, which will be conducted centrally 
by a medical image processing center (BioClinica). 
This second reading of MRIs will particularly provide quantitative data not available initially 
in the patient records, such as BMB score at the lumbar spine and femur, and liver and spleen 
volumes. 
In case the second reading provides additional data to the first reading, as any new comments 
or discordant diagnosis, the investigating doctor will integrate these data as soon as he has 
knowledge of them in the medical care of the patient. 
 
MRI collection and transmission 
 
Except the data from the second reading of MRIs by BioClinica, all data defined above, will 
be collected in the case report of the study, from the patient's medical record. 
For the second centralized reading of the MRIs, the MRIs will be transmitted as follows: the 
investigation center will make a copy on CD-ROM of each MRI collected for the study 
needs, and will replace the identity the patient by an identification number whose 
correspondence with the patient's identity is only known by the investigation center. This 
patient identification number will be predefined and attributed to the patient’s MRI when  the 
patient is included in the study. 
Copies of MRIs and coded will be sent securely at BioClinica center for analysis. In case of 
connection failure from the participating centers, MRI scans will be sent by post. 
Data from this second reading by BioClinica will be retrieved for analysis. The results of the 
second reading by BioClinica will be forwarded to investigation center, which will include 
them in the patient's record. 
Statistical analysis 
Primary endpoint: 
The values observed at the different follow up times and the variations between the reference 
MRI and the follow-up MRI, of the BMB weighted score at T1 and T2 measured at the femur 
and lumbar spine, are described by mean and standard deviation and the 95% confidence 
interval will be calculated. These values will be compared at the different follow up times by 
test on repeated data: ANOVA on repeated series or Wilcoxon rank test, depending on the 
nature and distributions of the studied variables. 
Secondary endpoints: 

Retrospective and prospective observational study of MRI changes in bone and visceral lesions of patients with type 1 
Gaucher disease treated with VPRIV® (velaglucerase alfa) 
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Socio-demographic characteristics of the patients, history of their disease, context of 
diagnosis, medical history, clinical evaluation criteria of liver and spleen, MRI evaluation 
criteria of the liver and spleen,  MRI evaluation criteria of bone lesions and the biological 
evaluation criteria are described by mean and standard deviation for quantitative variables, 
by frequency and percentage for categorical and ordinal variables. The 95% confidence 
intervals will be calculated. The evolutions of these criteria at the different periods when they 
are collected will be described by mean and standard deviation or percentage changes. They 
will be compared between the different times of the study by test on repeated data: ANOVA 
on repeated series or Wilcoxon rank test, depending on the nature and distributions of the 
studied variables. 
 
 
Software 
Data will be entered on CLINSIGHT and analysed with SAS 9.3. 
 
Indirectly personal character of data 
The patient information is sent to the radiological analysis centre in an indirectly personal 
form comparable to that used in therapeutic trials, namely the patient’s initials and a file 
number. Only the practitioner at the Gaucher Disease Reference Centre knows the 
correspondence between this number attributed to the patient and the patient’s identity. 
 
Justification of indirectly personal character 
This indirectly personal character (initials and file number which only the practitioner can 
match with the patient’s identity) allows the practitioner to record successive follow-ups of 
the patient without any risk of mistaking files. 
Patients’ rights protection 
It is the responsibility of the Investigator to obtain written Informed Consent and assent, 
where applicable from study patients. All consent and assent documentation must be in 
accordance with applicable regulations and GCP. Each patient or the patient’s legally 
authorised representative as applicable is requested to sign the Patient Informed Consent. 
Form or a certified translation, if applicable after the patient has received and read (or been 
read) the written patient information and received an explanation of what the study involves, 
including but not limited to: the objectives, potential benefits and risk, inconveniences and 
the patient’s rights and responsibilities. A copy of the informed consent and assent 
documentation (i.e., a complete set of patient information sheets and fully executed signature 
pages) must be given to the patient or the patient’s legally authorised representative. If 
applicable, it is provided in a certified translation of the local language. Signed consent forms 
must remain in each patient’s study file and must be available for verification at any time. 
Patients shall also be informed that they may decline to participate in the study without that 
being detrimental to the quality of care dispensed to them by their practitioner and that they 
have a right of access to this information through their Gaucher Referent Center. 

Retrospective and prospective observational study of MRI changes in bone and visceral lesions of patients with type 1 
Gaucher disease treated with VPRIV® (velaglucerase alfa) 
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Figure 1. Study flowchart 
 
0. Eligible patients (n= 40-50)  
 
 
1. Patient inclusion (Written Informed Consent 
obtained)
 
Retrospective data collection 
2. Retrospective data collection 
 
The closest MRI conducted during the 5 years before the 
initiation of VPRIV® treatment or in the 3 months after the 
Vpriv  initiation  is collected and corresponds to the reference 
MRI. 
Clinical and biological data available 3 months before or 
after the reference MRI are collected  
Medical history and clinical and biological data available, 
when VPRIV® treatment is initiated , are collected 
Each MRI available since Vpriv treatment initiation and 
patients inclusion is collected as well as clinical and 
biological data available 3 months before or after it 
 ......................................................................................... 
MRI collected are anonymously  sent to a central lab reading: 
MRI results data collection 
 
Medical history  
Clinical data  
Laboratory data 
VPRIV® treatment 
MRI  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 ............. VPRIV treatment  
Centralized MRI reading: 
- Liver and spleen 
volumes 
- BMB score of  the spine 
and femur
Prospective data collection 
3. Prospective follow-up:  
For each MRI that will be conducted from the patient 
inclusion until the end of the one year follow up study, 
clinical and laboratory data available within the 3 months 
before the MRI and the 3 months after MRI are collected. 
 
 ......................................................................................... 
 ......................................................................................... 
MRI collected are anonymously  sent to a central lab reading: 
MRI results data collection 
 
 
Clinical data  
Laboratory data 
VPRIV® treatment  
MRI 
 
 
 .........................................  
Centralized MRI reading: 
- Liver and spleen 
volumes 
- BMB score of  the spine 
and femur
 

Retrospective and prospective observational study of MRI changes in bone and visceral lesions of patients with type 1 
Gaucher disease treated with VPRIV® (velaglucerase alfa) 
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TABLE OF CONTENTS 
SYNOPSIS .................................................................................................................................2 
TABLE OF CONTENTS .........................................................................................................10 
LIST OF APPENDICES ..........................................................................................................12 
1 
INTRODUCTION ...........................................................................................................13 
1.1 
Gaucher disease .....................................................................................................13 
1.2 
Velaglucerase alfa in type 1 Gaucher disease ........................................................13 
1.3 
Justification of the study ........................................................................................13 
2 
STUDY OBJECTIVES ....................................................................................................15 
2.1 
Primary Objective(s) ..............................................................................................15 
2.2 
Secondary Objective(s) ..........................................................................................15 
3 
STUDY ENDPOINT .......................................................................................................16 
3.1 
Primary Endpoint(s) ...............................................................................................16 
3.2 
Secondary Endpoint(s) ...........................................................................................16 
4 
STUDY PLAN .................................................................................................................17 
4.1 
Data collection and transmission ...........................................................................17 
4.2 
The MRI images collected during the study: .........................................................17 
4.3 
Second lecture of the MRI .....................................................................................17 
4.4 
MRI collection and transmission ...........................................................................18 
4.5 
Data collection and transmission ...........................................................................18 
4.6 
Indirectly personal character of data ......................................................................19 
4.7 
Justification of indirectly personal character .........................................................19 
4.8 
Patients’ rights protection ......................................................................................19 
4.9 
Overall Study Design and Plan ..............................................................................20 
4.10 
Rationale for Study Design ....................................................................................21 
4.11 
Rationale for centralized MRI measurements ........................................................21 
4.12 
Study Duration .......................................................................................................21 
5 
STUDY POPULATION ..................................................................................................22 
5.1 
Inclusion Criteria ...................................................................................................22 
5.2 
Exclusion Criteria ..................................................................................................22 
5.3 
Withdrawal of Patients from the Study ..................................................................22 
6 
STUDY PROCEDURES .................................................................................................23 
6.1 
Informed Consent...................................................................................................23 
6.2 
Institutional Review Board or Independent Ethics Committee .............................23 
6.3 
Study Entrance Criteria ..........................................................................................24 
6.4 
Confirmation of Study Eligibility ..........................................................................24 
6.5 
Demographics ........................................................................................................24 
6.6 
Medical History .....................................................................................................24 

Retrospective and prospective observational study of MRI changes in bone and visceral lesions of patients with type 1 
Gaucher disease treated with VPRIV® (velaglucerase alfa) 
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6.7 
Efficacy and Effectiveness Assessments ...............................................................26 
6.8 
Safety Assessments ................................................................................................29 
6.9 
Concomitant Medications, Therapies, and Medical/Surgical Interventions 
Assessments ...........................................................................................................29 
6.10 
Adverse Events Assessments .................................................................................29 
6.11 
Serious Adverse Drug Reactions ...........................................................................32 
6.12 
Removal of Patients from the Study ......................................................................34 
7 
QUALITY CONTROL AND ASSURANCE .................................................................36 
7.1 
Appropriateness of Measurements .........................................................................36 
7.2 
Monitoring .............................................................................................................36 
8 
PLANNED STATISTICAL METHODS ........................................................................37 
8.1 
General Considerations ..........................................................................................37 
8.2 
Determination of Sample Size ...............................................................................37 
8.3 
Analysis Populations ..............................................................................................37 
8.4 
Demographics and Baseline Characteristics ..........................................................37 
8.5 
Primary Endpoint(s) or Assessments .....................................................................37 
Primary Safety Endpoint(s)................................................................................................37 
Primary Efficacy/Effectiveness Endpoint(s)................................................................37 
8.6 
Secondary Endpoint(s) ...........................................................................................38 
8.7 
Interim Analysis .....................................................................................................38 
9 
ADMINISTRATIVE CONSIDERATIONS ....................................................................39 
9.1 
Investigators and Study Administrative Structure .................................................39 
9.2 
Institutional Review Board or Independent Ethics Committee Approval and Other 
Governing Regulatory Bodies................................................................................39 
9.3 
Study Monitoring ...................................................................................................39 
9.4 
Case Report Forms and Study Records .................................................................39 
9.5 
Critical Documents ................................................................................................40 
9.6 
Data Monitoring Committee and/or Adjudication Committee ..............................40 
9.7 
Protocol Violations/Deviations ..............................................................................40 
9.8 
Premature Closure of the Study .............................................................................41 
9.9 
Access to Source Documentation ..........................................................................41 
9.10 
Data Generation and Analysis ...............................................................................41 
9.11 
Retention of Data ...................................................................................................41 
10 
REFERENCE LIST .........................................................................................................42 
 
 
 

Retrospective and prospective observational study of MRI changes in bone and visceral lesions of patients with type 1 
Gaucher disease treated with VPRIV® (velaglucerase alfa) 
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LIST OF APPENDICES 
Appendix 1 
Protocol Amendment Summary of Changes......................................43 
Appendix 2 
Overview of the Study Design ...........................................................44 
Appendix 3 
Protocol Signature Page .....................................................................45 
 
Abbreviations 
Definition 
AE 
Adverse Event 
CHMP 
Committee for Medicinal Products for Human Use 
CNS 
Central Nervous System 
CRO 
Contract Research Organization 
CSF 
Cerebrospinal Fluid 
CSR 
Clinical Sudy Report 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
EMA 
European Medicines Agency 
EOS 
End Of Study 
EOW 
Every Other Week 
ERT 
Ezyme Replacement Ttherapy 
FDA 
United States Food and Drug Administration 
GCP 
Good Cinical Practice 
GGT 
Gamma Glutamyl Transferase 
GPP 
Good Pharmacoepidemiological Practices 
GVP 
Good Pharmacovigilance Practice Guidelines 
Hb 
Hemoglobin 
Hct 
Hematocrit 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
SOE 
Schedule Of Events 
WHO-DD 
World Health Organization Drug Dictionary 

Retrospective and prospective observational study of MRI changes in bone and visceral lesions of patients with type 1 
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1 
INTRODUCTION 
1.1 
Gaucher disease 
 
Gaucher disease (GD) is a rare autosomal recessive disorder caused by the deficiency of the 
lysosomal glucocerebrosidase. This enzyme is required for the hydrolysis of glucosylceramide (or 
glucocerebroside) derived from degradation of the cell membrane of the formed elements of the 
blood. In GD, non-degraded glucosylceramide accumulates in lysosomes of the cells of the 
reticuloendothelial system and especially in macrophages.  
The prevalence of MG in France is about 1/136 000 in the general population. Three main 
phenotypes (clinical forms) are traditionally distinguished: 
- Type 1 accounts for 95% of cases. Its clinical expression is very heterogeneous ranging from 
asymptomatic throughout life to severe forms as soon childhood. 
- Type 2 is an exceptional form (less than 1% of cases), with a very early expression (before the 
age of 1 year), and a very poor prognosis (death before the age of 2 years). 
- Type 3 is a rare (less than 5% of cases) involving progressive encephalopathy of varying severity 
(oculomotor apraxia, epilepsy, ataxia) beginning before age 20 with similar forms than type 1 (1). 
The study will focus on the type phenotype 1. The diagnosis of type 1 GD can be done at any age 
and its main manifestations are hepatosplenomegaly, thrombocytopenia, anemia, asthenia and 
occasionally incapacitating bone involvement (infarction, osteonecrosis, fractures, decreased bone 
density) causing acute and / or chronic pain. Bone involvement is the major complication of 
Gaucher disease whose manifestations are the leading cause of morbidity and disability (1,2,3). 
 
1.2 
Velaglucerase alfa in type 1 Gaucher disease 
 
VPRIV® is a long term enzyme replacement therapy in patients with Type 1 Gaucher disease. The 
active substance of VPRIV, velaglucérase alfa is a glycoprotein made up of 497 amino acids and 
presents an amino acid sequence identical to the naturally occurring enzyme glucocerebrosidase. 
There are five potential N-glycosylation sites, four of which are occupied. Velaglucerase alfa 
offsets or replaces beta-glucocerebrosidase (the enzyme responsible for the hydrolysis of 
glucocerebroside to glucose and ceramide in the lysosome) thus reducing the quantity of 
glucocerebosides accumulated and correcting the physiopathology of Gaucher’s disease.  
1.3 
Justification of the study 
 
Velaglucerase alfa increases the level of haemoglobin and the platelet count and reduces hepatic 
and splenic volumes in patients with type 1 Gaucher disease (4), promising results have also been 
observed in the domain of bone disorders (5-10). However, to date, the only MRI data available in 
French Gaucher patients’s dossiers are qualitative data. This study with standardized reading 
MRIs, will provide for the first time objective and quantified data on organomegaly (liver and 
spleen volumes) as well as bone alteration  (score BMB) of French patients treated with VPRIV®. 
These data will help to better assess the impact of the treatment on these parameters. The result of 
this study will also answer in part to the request of the French Transparency Commission (CT: 

Retrospective and prospective observational study of MRI changes in bone and visceral lesions of patients with type 1 
Gaucher disease treated with VPRIV® (velaglucerase alfa) 
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14 
Commission de Transparence) of the French National Health Authority (HAS: Haute Autorité de 
Santé) to provide them with data of French patients treated with Vpriv®. 

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2 
STUDY OBJECTIVES  
2.1 
Primary Objective(s)  
To describe changes in bone disease in femur and lumbar spine in Gaucher’s disease 
patients treated with Velaglucerase alfa measured by MRI. 
 
2.2 
Secondary Objective(s)  
• To describe the socio-demographic of patients; 
• To describe the clinical evolution of patients (asthenia, abdominal pain, chronic bone pain, 
bone crises, hemorrhagic syndrome, hepatosplenomegaly,  pulmonary, neurological,) 
• To describe the evolution of the parameters measured by MRI 
- 
Bone alterations  (spine, pelvis, femurs, tibias and other symptomatic localization) 
- 
Visceral involvement (liver, spleen) 
• To describe the evolution of biological parameters 
 
If possible, compare the evolution of MRI parameters between treatment-naive patients and 
patients previously treated with another specific treatment for Gaucher disease at the baseline MRI. 
 

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3 
 STUDY ENDPOINT 
3.1 
Primary Endpoint(s)  
The primary endpoint is the change over time between the baseline MRI and the follow-up MRIs, 
of the BMB score (11) weighted at T1 and T2 and measured at the femur and lumbar spine .  
 
3.2 
Secondary Endpoint(s)  
The secondary and exploratory endpoint(s) of this study are: 
• socio-demographic characteristics: age, sex, occupation 
• history of the disease and context of diagnosis: age at diagnosis, type of symptoms, exams 
that allowed the diagnosis and its confirmation, enzymatic assay value, genotype and 
presence or absence of family history 
• medical history 
• clinical evaluation criteria: weight (kg), height (cm), absence or presence (mild, moderate 
or severe) asthenia, abdominal pain, chronic bone pain, bone crises, syndrome bleeding, 
pulmonary impairment, neurological impairment 
• clinical endpoints of liver and spleen: 
- Absence or presence of hepatomegaly, with the extent of the arrow (medio-clavicular 
line) (cm) 
- Absence or presence of splenomegaly, with the extent of the costal overhang (cm).-  
• liver evaluation criteria and spleen MRI: 
- Absence or presence of hepatomegaly, with the extent of the arrow (medio-clavicular 
line) (cm) 
- Absence or presence of splenomegaly, with the extent of the costal overhang (cm) 
- Liver volume (m3) 
- Spleen volume (m3) 
- Presence or absence of myocardial, nodules, fibrosis, vesicular stones or other alterations. 
• evaluation criteria of bone lesions by MRI (spine, pelvis, femurs, tibias and other 
symptomatic localization) 
Absence or presence of bone lesions and their locations: bone infiltration, cortical thinning, 
osteonecrosis, bone infarction, stroke sequelae, vertebral compression fracture or other 
bone disease 
• evaluation criteria of the biological parameters: hemoglobin (g/dl); leukocytes 
(cells/mm3); platelets (mm3); ACE (angiotensin converting enzyme (U/l); ferritin (mg/l); 
chitotriosidase (nmol/ h/ ml); CCL18 (ng/ml), vitamin D (nmol/L), vitamin B12 (pmol / l); 
SGOT / AST (U/l), SGPT / ALT (U/l), GGT (U/l), alkaline phosphatase (U/l), triglycerides 
(mmol/l), total cholesterol (mmol/l) gamma globulin (g/l) serum calcium (mmol/l) 
presence or absence of a monoclonal peak and the type if any 

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4 
STUDY PLAN 
 
4.1 
Data collection and transmission 
 
All data entered will be used for analysis purposes and results will be submitted to inform 
regulatory agencies. Patient care and management is freely determined by the participating 
physician, in the framework of an observational study reflecting the daily medical practice. 
The clinical data, the results of routine clinical and laboratory testing that are part of standard 
medical care for patients with Gaucher disease will be collected from the medical record of 
the patient : 
- 
Socio-demographic characteristics  
- 
History of the disease and context of diagnosis 
- 
Medical background 
- 
MRI: abdominal and bone, as defined below 
- 
Clinical data available in the range from 3 months before or after each MRI 
- 
Biological data available in the range from 3 months before or after each MRI 
- 
Treatment with VPRIV® (velaglucerase alfa), including the doses and regimens 
 
4.2 
The MRI images collected during the study: 
The MRIs performed in the patient's usual medical follow-up for its Gaucher disease     
(abdominal MRI (liver and spleen) and bone MRI (back injury pelvis, lower limbs) and / 
or whole-body MRI) will be collected. Among the MRIs available in the patient's medical 
records, MRIs will be collected the following: 
 
- Reference MRI: MRI closest to the date of initiation of VPRIV® in the five years 
preceding the start of treatment or within three months after initiation of VPRIV®. 
- MRIs of the retrospective phase of the study: All MRIs available between the reference 
MRI and the inclusion date of the patient. 
- MRIs of the prospective phase of the study: all the MRIs that will be realized during the 
prospective phase of the study, that is to say, during the year following the date patient 
inclusion in the study. 
 
4.3 
Second lecture of the MRI 
The collected MRIs will be subject to a second reading, which will be conducted centrally 
by a medical image processing center (BioClinica). 
This second reading of MRIs will particularly provide quantitative data not available initially 
in the patient records, such as BMB score at the lumbar spine and femur, and liver and spleen 
volumes. 
In case the second reading provides additional data to the first reading, as any new comments 
or discordant diagnosis, the investigating doctor will integrate these data as soon as it has 
knowledge of them in the medical care of the patient. 

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4.4 
MRI collection and transmission 
Except the data from the second reading of MRIs by BioClinica, all data defined above, will 
be collected in the case report of the study, from the patient's medical record. 
For the second centralized reading of the MRIs, the MRIs will be transmitted as follows: the 
investigation center will make a copy on CD-ROM of each MRI collected for the study 
needs, and will replace the identity the patient by an identification number whose 
correspondence with the patient's identity is only known by the investigation center. This 
patient identification number will be predefined and attributed to the patient’s MRI the 
patient is included in the study. 
Copies of MRIs and coded will be sent securely at BioClinica center for analysis. In case of 
connection failure from the participating centers, MRI scans will be sent by post. 
Data from this second reading by BioClinica will be retrieved for analysis. The results of the 
second reading by BioClinica will be forwarded to investigation center, which includes them 
the patient's record. 
 
4.5 
Data collection and transmission 
As part of their routine practice, the practitioners working at the Gaucher Referent Centers 
in France collect a basic information form regarding the management of their Gaucher 
patients as well as the MRI data of these patients followed in these referent centers. 
For the needs of the study, the Gaucher Referent Centers make a copy of the MRI Cd-Roms 
and and replace the person’s identity on the copy by a code for which the Reference Centre 
alone has the chart for cross-referencing with the patient’s identity. This code is made up of 
the first two letters of the surname and the first letter of the first name and a file number.  
The imaging data thus made anonymous with respect to third parties are then transmitted to 
French Gaucher Treatment and Evaluation Committee “CETG” which in turn transfer them 
to BIOCLINICA, the radiological analysis centre. The latter is in charge of conducting 
standardised measurements of the volume of their hepatosplenomegaly as well as the 
characteristics of their bone disorders. 
The resulting data are then sent to the CETG which in turn transfer these data to the Referent 
Gaucher Centers (practitioner) which includes them in the patient’s monitoring file. 
 
 
 
 
 
 

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4.6 
Indirectly personal character of data 
The patient information is sent to the radiological analysis centre in an indirectly personal form 
comparable to that used in therapeutic trials, namely the patient’s initials and a file number. Only 
the practitioner at the Gaucher Disease Reference Centre knows the correspondence between this 
number attributed to the patient and the patient’s identity. 
4.7 
Justification of indirectly personal character 
This indirectly personal character (initials and file number which only the practitioner can match 
with the patient’s identity) allows the practitioner to record successive follow-ups of the patient 
without any risk of mistaking files. 
4.8 
Patients’ rights protection 
It is the responsibility of the Investigator to obtain written Informed Consent and assent, where 
applicable from study patients. All consent and assent documentation must be in accordance with 
applicable regulations and GCP. Each patient or the patient’s legally authorised representative as 
applicable is requested to sign the Patient Informed Consent. 
Form or a certified translation, if applicable after the patient has received and read (or been read) 
the written patient information and received an explanation of what the study involves, including 
but not limited to: the objectives, potential benefits and risk, inconveniences and the patient’s 
rights and responsibilities. A copy of the informed consent and assent documentation (i.e., a 
complete set of patient information sheets and fully executed signature pages) must be given to 
the patient or the patient’s legally authorised representative. If applicable, it is provided in a 
certified translation of the local language. Signed consent forms must remain in each patient’s 
study file and must be available for verification at any time. 
 
 
 
 
 
 
 
 

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4.9 
Overall Study Design and Plan 
Figure 1. Overview of the Study Design 
 
 
 
0. Eligible patients (n= 40-50)  
 
 
1. Patient inclusion (Written informed consent 
obtained) 
 
Retrospective data collection 
2. Retrospective data collection 
 
The closest MRI conducted during the 5 years before the 
initiation of VPRIV® treatment or in the 3 months after the 
VPRIV® initiation  is collected and corresponds to the 
reference MRI. 
Clinical and biological data available 3 months before or 
after the reference MRI are collected  
Medical history and clinical and biological data available, 
when VPRIV® treatment is initiated , are collected 
Each MRI available since VPRIV® treatment initiation and 
patients inclusion is collected as well as clinical and 
biological data available 3 months before or after it 
 ......................................................................................... 
MRI collected are anonymously  sent to a central lab reading: 
MRI results data collection 
 
Medical history  
Clinical data  
Laboratory data 
VPRIV® treatment 
MRI  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 ............. VPRIV treatment  
Centralized MRI reading: 
- Liver and spleen 
volumes 
- BMB score of  the spine 
and femur
Prospective data collection 
3. Prospective follow-up:  
For each MRI that will be conducted from the patient 
inclusion until the end of the one year follow up study, 
clinical and laboratory data available within the 3 months 
before the MRI and the 3 months after MRI are collected. 
 
 .........................................................................................
 ......................................................................................... 
MRI collected are anonymously  sent to a central lab reading: 
MRI results data collection 
 
 
Clinical data  
Laboratory data 
VPRIV® treatment  
MRI 
 
 
 .........................................  
Centralized MRI reading: 
- Liver and spleen 
volumes 
- BMB score of  the spine 
and femur
The study will last for one year from the date of the patient inclusion 
The study is constituted of 2 phases: a retrospective and a prospective period 
Phase I: Retrospective period 
The retrospective period includes the period before VPRIV® treatment initiation until the 
beginning of this study..  
Phase II: Prospective period 
The prospective period will last for one year from the date of the patients inclusion 
 

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4.10 Rationale for Study Design  
Retrospective-observational studies are required to describe population treated in the daily practice, the use 
of the drug and its effect and safety in real life conditions. 
4.11 Rationale for centralized MRI measurements 
It is customary for any multi-center clinical trial to collect MRI scans from various scanner manufacturers 
(General Electric, Siemens and Philips mainly), as is also the rule in the clinical practice. Although there 
are subtle technical differences in the implementation of each MRI pulse sequence, the outcome (e.g. the 
MR images) is extremely similar from a visual standpoint whatever the origin. This would therefore not 
introduce a bias in the analysis for qualitative assessments (bone disease scoring). For quantitative 
assessments (organ volumes), specific efforts are made when setting up the MRI protocol at each site in 
order to minimize the variability across sites, and allow accurate measurements. 
When it comes to assessing longitudinal changes (either qualitatively or quantitatively), it is highly 
preferable to impose that the exact same scanner and scanning parameters be used from one visit to the 
other at a given site. Such requirement is reminded to the MRI facilities within the study imaging guidelines, 
and verified upon image QC at BioClinica. 
 
4.12  Study Duration 
The study is developed in conjunction with the French Referral Centers of Lysosomal Diseases, and the 
French Gaucher Treatment and Evaluation Committee (CETG: Comité d'Evaluation du Traitement de la 
maladie de Gaucher). It is a retro prospective observational study of the French cohort of patients with type 
1 Gaucher disease treated with VPRIV® in everyday clinical practice. 
 
It consists of two phases:  a retrospective and a prospective phase with a 1 year inclusion period. 
 
Phase I: retrospective phase  
The retrospective period includes the period between the date of the baseline MRI to the patient's date of 
inclusion in the study. The reference MRI is defined as the closest MRI to the initiation of VPRIV®, within 
the past five years, or within three months after initiation of VPRIV®. 
 
Phase II: prospective phase 
Prospective period will be one year from the date of patient inclusion in the study. 
 
The final MRI 
MRI being performed in current practice every 2 years, the final MRI follow-up performed corresponds to 
those in the previous year or in the year following the patient's inclusion. 
The duration of the study will be 2 years: a 1-year inclusion period to be sure to include all patients treated 
with VPRIV® (reviewed annually in consultation each year) and a prospective follow-up period of 1 year. 
Provisional timetable for the study: 
 
 
 
 
 
 
CCTIRS / CNIL authorization
October 23, 2015
Inclusion of the first patient in the study
September 30, 2016 
Inclusion of the last patient in the study
September 30, 2017
Last visit of the last patient
September 30, 2018
Study clinical report 
January 31, 2019

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STUDY POPULATION  
To reflect the daily practices, this study includes all patients with a confirmed diagnosis of Type 1 Gaucher 
disease treated with VPRIV® at the date of beginning of the study and who meet the selection criteria of the 
study. 
 
5.1 
 Inclusion Criteria 
1. Patients of any age or gender with confirmed diagnosis of type 1 Gaucher disease, 
2. Patients treated with VPRIV® at the beginning of the study.  Prior starting VPRIV® patients could be 
either treatment naïve or previously treated with any other Gaucher treatment than VPRIV®. 
3. Patients should have one MRI data in the 5 previous years before starting VPRIV® treatment 
4. Informed written consent obtained from the patient, and/or patient’s parent(s), and/or legal representative. 
Assent, if old enough to grant, will be obtained from all patients under the age of 18 years. 
5.2 
Exclusion Criteria 
1. Patients for whom MRI is contra-indicated 
2. Patients who did not had an MRI during the five years prior to the initiation of treatment with VPRIV® 
or within three months after initiation of VPRIV® 
3. Patients included in an ongoing clinical trial where the product is blinded  
 
5.3 
Withdrawal of Patients from the Study 
Patients are free to withdraw from the study at any time without having to justify their decision and without 
any consequences for their quality of care and the quality of their relation with their treating physician. 
However, if possible the reason of the withdrawal will be asked and recorded. 

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6 
STUDY PROCEDURES 
6.1 
Informed Consent 
It is the responsibility of the Investigator to obtain written Informed Consent and assent, where 
applicable from study patients. All consent and assent documentation must be in accordance with 
applicable regulations and GCP. Each patient or the patient’s legally authorised representative as 
applicable is requested to sign the Patient Informed Consent 
Form or a certified translation, if applicable after the patient has received and read (or been read) 
the written patient information and received an explanation of what the study involves, including 
but not limited to: the objectives, potential benefits and risk, inconveniences and the patient’s 
rights and responsibilities. A copy of the informed consent and assent documentation (i.e., a 
complete set of patient information sheets and fully executed signature pages) must be given to 
the patient or the patient’s legally authorised representative. If applicable, it is provided in a 
certified translation of the local language. Signed consent forms must remain in each patient’s 
study file and must be available for verification at any time. 
The Principal Investigator provides the Sponsor with a copy of the consent form (and assent form 
where applicable) which was reviewed by the IRB/IEC and which received their favourable 
opinion/approval. A copy of the IRB/IEC’s written favourable opinion/approval of these 
documents must be provided to the Sponsor, prior to the start of the study unless it is agreed to and 
documented (abiding by regulatory guidelines and national provisions) prior to study start that 
another party (i.e., sponsor or Coordinating Principal Investigator) is responsible for this action. 
Additionally, if the IRB/IEC requires modification of the sample, Patient Information and Consent 
document provided by the Sponsor, the documentation supporting this requirement must be 
provided to the Sponsor. 
 
6.2 
Institutional Review Board or Independent Ethics Committee 
For investigator sites outside the EU, it is the responsibility of the Investigator to submit this 
protocol, the informed consent document (approved by the Sponsor or their designee), relevant 
supporting information and all types of patient recruitment information to the IRB/IEC for review, 
and all must be approved prior to site initiation. 
For investigator sites within the EU and if applicable within a given region the applicant for an 
IEC opinion can be the Sponsor, the Investigator, or for multicentre studies the Coordinating 
Principal Investigator or Sponsor, according to national provisions. 
Responsibility for coordinating with IRBs/IECs is defined in the Investigator/Sponsor (CRO) 
Contract. 
Prior to implementing changes in the study, the Sponsor and the IRB/IEC must approve any 
revisions of any revised informed consent documents and amendments to the protocol 
unless there is a patient safety issue. 
For investigator sites outside the EU, the Investigator is responsible for keeping the IRB/IEC 
appraised of the progress of the study and of any changes made to the protocol, but in any case at 
least once a year. For investigator sites within the EU and if applicable within a given region, this 
can be done by the Sponsor, the Investigator or for multicentre studies the Coordinating Principal 
Investigator, according to national provisions. The Investigator must also keep the local IRB/IEC 
informed of any serious and significant AEs. 

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6.3 
 Study Entrance Criteria 
At screening, each patient will be reviewed for eligibility against the study entrance criteria. 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 reviewed during remote and/or on-site monitoring visits 
(investigating the number of patients expected at the site vs. the number observed in the database).  
6.4 
Confirmation of Study Eligibility 
Patient eligibility according to the study inclusion and exclusion criteria will be confirmed at Baseline on 
the basis of review of the study entrance criteria. 
6.5 
Demographics 
Patient demographic information including gender, age, and professional status will be collected as soon 
as the patient is included in the observational study. The age that will be collected is the age of patient at 
VPRIV® treatment initiation.  
6.6 
Medical History 
 For the retrospective part of the study, medical past history are collected by the physician from 
the medical record of the patient. On the CRF are reported: 
• Socio-demographic and clinical characteristics of patients with Gaucher’s disease 
• All medical past history of the patient: nature, beginning date, end date or ongoing and 
relationship  to Gaucher disease 
• Family past history : nature and family link 
• The description of the history of the disease : year of first symptoms, nature of the first 
symptoms, diagnostic year, nature of the laboratory examination which has confirmed the 
diagnosis (enzyme assay, molecular biology (genotyping), bone marrow, bone marrow 
biopsy, liver biopsy, histology of the spleen, other), value of the enzyme assay, phenotype 
and genotype 
• The clinical and biological status within the 6 months period : 3 months before the MRI - 
3 months after the selected MRI which is the closest available one to the VPRIV®initiation 
• The clinical and biological status of the patients when the VPRIV® treatment was initiated 
• The standardized measures issued from the standardized review of the MRI by Bioclinica 
centralized laboratory. The review is conducted on the MRI that the treating physician 
addresses via the CETG to a central review radiological center after anonymisation of the 
documents  
 
The quality of the MRI is evaluated and classified in three categories: Optimal, sub optimal and 
not assessable according the following definition: 
- 
Optimal: Sufficient anatomical coverage, good image quality with no to minimal image 
artifacts and compliance with the imaging protocol 
- 
Suboptimal: Sufficient anatomical coverage, presence of moderate image artifacts 
and/or minor deviations to the imaging protocol, with minimal impact on the analysis  

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- 
Not assessable: Insufficient anatomical coverage and/or presence of strong image 
artifacts and/or severe deviations to the imaging protocol, which would lead to an 
unreliable analysis. 
 
 
Spleen/Liver:  
 
TEST 
DESCRIPTION 
FORMAT/VALUES 
ABDO_TECH_AD 
Technical Adequacy for Abdominal 
MR data 
0 = Optimal 
1 = sub optimal 
2 = Not assessable 
ABDO_TECH_REASONS
Reasons for Abdominal MR images 
not being optimal 
List of reasons separated by a | 
SPLEEN_VOL 
Spleen Volume (mm3) 
FLOAT 
LIVER_VOL 
Liver Volume (mm3) 
FLOAT 
SPLEEN_COV 
Full Spleen Coverage achieved 
Y/N 
LIVER_COV 
Full Liver Coverage achieved 
Y/N 
SPLEEN_INF 
Presence of Infarcts 
Y/N 
SPLEEN_FD 
Presence of Filling Defects 
Y/N 
LIVER_INF 
Presence of Infarcts 
Y/N 
LIVER_FD 
Presence of Filling Defects 
Y/N 
 
 
 
 
Spine/Femur: 
 
TEST 
DESCRIPTION 
FORMAT/VALUES 
SPINE_TECH_AD 
Technical Adequacy for Spine MR data 
0 = Optimal 
1 = sub optimal 
2 = Not assessable 
SPINE_TECH_REASONS 
Reasons for Spine MR images not being 
optimal 
List of reasons separated by a | 
SPINE_BMB_T1 
Spine BMB score of T1-weighted 
0 = Slightly hyper intense 
1 = Isointense 
2 = Slightly hypo intense 
3 = Hypo intense 
4 = N/A 
SPINE_BMB_T2 
Spine BMB score of T2-weighted 
0 = Iso intense 
1 = Slightly hypo intense 
2 = Slightly hyper intense 
3 = Hypo intense 
4 = Hyper intense 
5 = N/A 

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SPINE_BMB_INFILTR 
Spine BMB score for Infiltration Pattern 
0 = None 
1 = Patchy 
2 = Diffuse 
5 = N/A 
SPINE_BMB_FAT 
Assessment of Spinal Fat in Basivertebral 
Region 
3 = Preservation of fat 
4 = Absence of fat 
5 = N/A 
SPINE_COMMENTS 
Free Comments on Spine Scoring 
 
FEMUR_TECH_AD 
Technical Adequacy For Femur MR Data 
0 = Optimal 
1 = Readable, but not optimal 
2 = Not readable 
FEMUR_TECH_REASONS 
Reasons for Femur MR images not being 
Optimal 
List of reasons separated by a | 
FEMUR_BMB_T1 
Femur BMB Score of T1-weighted 
0 = Slightly hyper intense or 
isointense 
1 = Slightly hypo intense 
2 = Hypo intense 
3 = N/A 
FEMUR_BMB_T2 
Femur BMB Score of T2-weighted 
0 = Isointense 
1 = Slightly hypo intense 
2 = Slightly hyper intense 
3 = Hypo intense 
4 = Hyper intense 
5 = Mixed type 
6 = N/A 
FEMUR_BMB_SITE 
Femur BMB Score for sites of involvement 
0 = No site of involvement 
1 = Diaphysis 
2 = Proximal epiphysis / apophysis 
3 = Distal epiphysis 
4 = N/A 
FEMUR_COMMENTS 
Free comments on Femur scoring 
 
 
 
Posology at initiation: UI/kg/2 weeks, UI/kg/3 weeks, UI/kg/1month 
 
6.7 
Efficacy and Effectiveness Assessments  
For the closest MRI realized before the initiation of VPRIV® treatment and for each MRI which will be 
conducted during the prospective one year period, the following information will be recorded whenever 
they are available in patient’s dossiers. Clinical and biological status will also be recorded when treatment 
was started and the patient included in the study. 
- 
Spine and femur BMB score of T1 and T2 weighted,  
- 
Marrow infiltration, bone infarction, osteonecrosis, pathological fractures (vertebral) 
 
 
 
 
The clinical status:  

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- 
Height, weight 
- 
Asthenia (absent / present : mild , moderate or severe), abdominal pain (absent / present 
: mild , moderate or severe), chronic pain in bone (absent / present : mild , moderate or 
severe), hemorrhagic syndrome (epistaxis, gingival bleeding, bruising, other rated : 
absent / present : mild , moderate or severe), lung disease, neurological disease  
 
The biological status: 
hemoglobin (g/dl); leukocytes (cells/mm3); platelets (mm3); ACE (angiotensin converting 
enzyme (U/l); ferritin (mg/l); chitotriosidase (nmol / h / ml); CCL18 (ng/ml), vitamin D 
(nmol/l), vitamin B12 (pmol/l); SGOT/AST (U/l), SGPT/ALT (U/l), GGT (U/l), alkaline 
phosphatase (U/l), triglycerides (mmol / l), total cholesterol (mmol/l) gamma globulin (g/l) 
serum calcium (mmol/l) presence or absence of a monoclonal peak and type if any. 
 
The review will be done on the MRI that the treating physician has addressed for a central 
review radiological center via the CETG after blinding of the documents.  
 
As previously, the quality of the MRI is evaluated and classified in three categories: Optimal, 
sub optimal and not assessable according the following definition: 
- 
Optimal: Sufficient anatomical coverage, good image quality with no to minimal image 
artifacts and compliance with the imaging protocol 
- 
Suboptimal: Sufficient anatomical coverage, presence of moderate image artifacts 
and/or minor deviations to the imaging protocol, with minimal impact on the analysis  
- 
Not assessable: Insufficient anatomical coverage and/or presence of strong image 
artifacts and/or severe deviations to the imaging protocol, which would lead to an 
unreliable analysis. 
 
 
 
 
 
 
Spleen/Liver:  
 
TEST 
DESCRIPTION 
FORMAT/VALUES 
ABDO_TECH_AD 
Technical Adequacy for Abdominal 
MRI data 
0 = Optimal 
1 = Sub optimal 
2 = Not assessable 
ABDO_TECH_REASONS
Reasons for Abdominal MR images 
not being optimal 
List of reasons separated by a | 
SPLEEN_VOL 
Spleen volume (mm3) 
FLOAT 
LIVER_VOL 
Liver Volume (mm3) 
FLOAT 
SPLEEN_COV 
Full Spleen Coverage achieved 
Y/N 
LIVER_COV 
Full Liver Coverage achieved 
Y/N 
SPLEEN_INF 
Presence of Infarcts 
Y/N 

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TEST 
DESCRIPTION 
FORMAT/VALUES 
SPLEEN_FD 
Presence of Filling Defects 
Y/N 
LIVER_INF 
Presence of Infarcts 
Y/N 
LIVER_FD 
Presence of Filling Defects 
Y/N 
 
Spine/Femur: 
 
TEST 
DESCRIPTION 
FORMAT/VALUES 
SPINE_TECH_AD 
Technical Adequacy for Spine MR data
0 = Optimal 
1 = sub optimal 
2 = Not assessable 
SPINE_TECH_REASONS 
Reasons for spine MR images not 
being optimal 
List of reasons separated by a | 
SPINE_BMB_T1 
Spine BMB score of T1-weighted 
0 = Slightly hyper intense 
1 = Iso intense 
2 = Slightly hypo intense 
3 = Hypo intense 
4 = N/A 
SPINE_BMB_T2 
Spine BMB score of T2-weighted 
0 = Isointense 
1 = Slightly hypo intense 
2 = Slightly hyper intense 
3 = Hypo intense 
4 = Hyper intense 
5 = N/A 
SPINE_BMB_INFILTR 
Spine BMB score for Infiltration Pattern
0 = None 
1 = Patchy 
2 = Diffuse 
5 = N/A 
SPINE_BMB_FAT 
Assessment of Spinal Fat in Basi 
vertebral Region 
3 = Preservation of fat 
4 = Absence of fat 
5 = N/A 
SPINE_COMMENTS 
Free Comments on Spine Scoring 
 
FEMUR_TECH_AD 
Technical Adequacy for Femur MR 
data 
0 = Optimal 
1 = Readable, but not optimal 
2 = Not readable 
FEMUR_TECH_REASONS Reasons for Femur MR images not 
being optimal 
List of reasons separated by a | 
FEMUR_BMB_T1 
Femur BMB score of T1-weighted 
0 = Slightly hyper intense or 
isointense 
1 = Slightly hypo intense 
2 = Hypo intense 
3 = N/A 
FEMUR_BMB_T2 
Femur BMB score of T2-weighted 
0 = Isointense 
1 = Slightly hypo intense 

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2 = Slightly hyper intense 
3 = Hypo intense 
4 = Hyper intense 
5 = Mixed type 
6 = N/A 
FEMUR_BMB_SITE 
Femur BMB score for sites of 
involvement 
0 = No site of involvement 
1 = Diaphysis 
2 = Proximal epiphysis / 
apophysis 
3 = Distal epiphysis 
4 = N/A 
FEMUR_COMMENTS 
Free comments on femur scoring 
 
 
6.8 
Safety Assessments 
Safety of VPRIV® will be assessed according to ADRs, safety reporting associated with any 
medication given according to clinical routine. It should also be done according to local 
applicable drug law and using the procedures of the respective pharmaceutical manufacture. 
 
6.9 
Concomitant Medications, Therapies, and Medical/Surgical Interventions 
Assessments 
All medications, therapies/interventions administered to and medical/surgical procedures 
performed on the study subjects from the time of informed consent through the follow-up 
contact are regarded as concomitant and will be documented on the CRF.  
 
6.10 Adverse Events Assessments 
Definition of Adverse Events/Adverse Drug Reactions, Period of Observation, Recording of 
Adverse Events/Adverse Drug Reactions 
An Adverse Event (AE) is any untoward medical occurrence in a clinical investigation patient 
administered a product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, disease or exacerbation of a pre-existing condition temporally 
associated with the use of a medicinal product. 
Only AEs that will appear only in the prospective part of this observational study and which 
are considered to be related to Velaglucerase alpha are considered as ADRs, will be collected 
during this study, ADRs that will be related to the  retrospective part of this study will not be 
collected. (See Section 7.1.2 for further guidance). An ADR is a response to a medicinal 
product which is noxious and unintended and which occurs at doses normally used in man for 
prophylaxis, diagnosis, and therapy of disease or for the restoration, correction, or modification 
of physiological function. Response in this context means that a causal relationship between a 
medicinal product and an AE is at least a reasonable possibility. Each ADR requires a complete 
and thorough description on the CRF.  
All ADRS, including those associated with the protocol are collected from the time the 
informed consent is signed until the end of the study duration, are to be recorded on the 

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appropriate CRF and in source documents. 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 ADRs (serious and non-serious) must be followed until closure (the patient’s health has 
returned to his/her baseline status or all variables have returned to normal), an outcome is 
reached, stabilization (the Investigator does not expect any further improvement or worsening 
of the event), or the event is otherwise explained regardless of whether or not the patient is still 
participating in the study. When appropriate, medical tests and examinations are performed so 
that resolution of event(s) can be documented. 
 
Severity Categorisation 
The severity of AEs must be recorded during the course of the event including the start and 
stop dates for each severity. An event that changes in intensity should be captured as a new 
event. Worsening of pre-treatment events, must be recorded as new AEs (for example if a 
patient experiences mild intermittent dyspepsia prior to dosing, but the dyspepsia becomes 
severe and more frequent after first dose of product administration, a new AE of severe 
dyspepsia (with the appropriate date of onset) is recorded on the appropriate CRF). 
 
The medical assessment of intensity 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 patient. 
Severe: A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
 
Relationship Categorisation 
An Investigator who is qualified in medicine must make the assessment of relationship to product 
for each AE. The Investigator should decide whether, in his or her medical judgement, there is a 
reasonable possibility that the event may have been caused by the 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 product and the occurrence of the AE, then the AE should be 
considered ‘related’. 
 
 
 
 
The following additional guidance may be helpful: 

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Term 
Relationship 
Definition 
Related 
Yes 
The temporal relationship between the event and the administration 
of the product is compelling and/or follows a known or suspected 
response pattern to that product, and the event cannot be explained by 
the patient’s medical condition, other therapies, or accident. 
Not Related 
No 
The event can be readily explained by other factors such as the 
patient’s underlying medical condition, concomitant therapy or 
accident and no obvious temporal or biologic relationship exists 
between the product and the event. 
 
 
Outcome Categorisation 
The outcome of AEs must be recorded during the course of the study in the CRF. Outcomes are as follows: 
• Fatal 
• Not Recovered/Not Resolved 
• Recovered/Resolved 
• Recovered/Resolved With Sequelae 
• Recovering/Resolving 
• Unknown 
Symptoms of the Disease under Study 
Symptoms of the disease under study should not be classed as ADRs as long as they are within the normal 
day-to-day fluctuation or expected progression of the disease. However, significant worsening of the 
symptoms should be recorded as an ADR.  
Clinical Laboratory Evaluations 
A change in the value of a safety laboratory investigation can represent an ADR if the change is clinically 
relevant or if, during treatment with the 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 which is assessed to be associated 
with the use of VPRIV® .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 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 observation period, there are abnormal laboratory values which were not present at the 
time of informed consent/patient enrolment, further clinical or laboratory investigations should be 

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performed until the values return to within reference range or until a plausible explanation (e.g., 
concomitant disease) is found for the pathological laboratory values. 
The Investigator should decide, based on the above criteria and the clinical condition of a patient, whether 
a change in a laboratory parameter is clinically significant and therefore represents an AE. 
Pregnancy 
All pregnancies are to be reported from the time informed consent is signed until the end of the study 
duration, as applicable. 
Any report of pregnancy for any female study participant must be reported within one business day to Shire 
Pharmacovigilance Department using the Shire Pharmaceuticals Investigational and Marketed Products 
Pregnancy Form. 
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. If no information is received, 1 
additional documented follow-up attempt will be made approximately 30 calendar days after the 30-day 
post-partum contact. 
Pregnancy complications such as miscarriage or congenital abnormality are considered SAEs and must be 
reported using the Shire Pharmaceuticals Clinical Trial Serious Adverse Event Report Form. An elective 
abortion, which is not associated with any complications, in itself, does not meet the criteria of an SAE. 
If the Investigator determines that the pregnancy meets serious criteria, it must be reported as an SAE using 
the Shire Pharmaceuticals Clinical Trial Serious Adverse Event Report Form. The test date of the first 
positive serum/UA HCG test or ultrasound result will determine the pregnancy onset date. 
Abuse, Misuse, Overdose and Medication Errors 
Abuse, misuse, overdose or medication error must be reported to the Sponsor according to the SAE 
reporting procedure whether or not they result in an AE/SAE as defined in Section 7.2. 
• Abuse – Persistent or sporadic intentional intake of a product at higher dose than prescribed per protocol 
(but below the dose defined for overdose) or when used for non-medical purpose (e.g. altering one’s state 
of consciousness). 
• Misuse – Intentional or un-intentional use of a 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 article is 
not used as directed at the dose prescribed by the protocol). 
• Overdose – Intentional or un-intentional intake of a dose of a product higher than dosage levels described 
in the label for VPRIV®. 
• Medication Error – A mistake made in prescribing, dispensing, administration, and/or use of the product. 
6.11 Serious Adverse Drug Reactions 
All SADRs are collected and reported to Shire Pharmacovigilance. 

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The reference for safety information for this study is available in the French VPRIV® SmPC. 
A Serious Adverse Drug Reaction (SADR)) is any untoward medical occurrence considered to be related 
to VPRIV® 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 hospitalisation or prolongation of existing hospitalisation 
• 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 hospitalisation may be considered an SADR when, based upon appropriate medical 
judgment, they may jeopardise the patient or may require medical or surgical intervention to prevent one 
of the other outcomes listed in this definition. In addition, suspected transmission (via marketed medicinal 
product) of any infectious agent is reportable to the Sponsor. 
Examples of important 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 hospitalisation; 
or development of drug dependency or drug abuse. 
Hospitalisations, 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 classed as SADRs. For 
example, an admission for a previously scheduled ventral hernia repair would not be classed as SADRs; 
however, complication(s) resulting from a hospitalisation for an elective or previously scheduled surgery 
that meets the serious criteria must be reported if it qualifies as an SADR. 
All SADRs are to be collected from the time the patient signs informed consent until the end of the 6-month 
study duration and it must be reported to the Sponsor/designee within 1 business day of the first awareness 
of the event. 
The onset date of the SADR is defined as the date the event met serious criteria and the resolution date is 
defined as the date the event no longer met serious criteria, when the symptoms resolve, or the event is 
considered chronic or closed (i.e., when no further information is expected). In the case of hospitalisations, 
the hospital admission and discharge dates would be considered the onset and resolution dates, respectively. 
Additionally, any signs or symptoms experienced by the patient prior to admission into the hospital or 
leading up to the onset date of the SADR and following the resolution date of the SADR, must be recorded 
as an ADR as appropriate, to identify individual seriousness and intensities. 
Any SAE that results in the patient’s death (i.e., the SAE was noted as the primary cause of death) must 
have fatal checked as an outcome and the resolution date for that event is the date of death. For all other 

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events ongoing at time of death that did not contribute to the patient’s death, the outcome should be 
considered not resolved, without a resolution date recorded. 
The physician/investigator is responsible to: 
• Report all SADRs to Shire Pharmacovigilance department within one business day of the first awareness 
of the event. 
• Complete, sign and date the Shire Clinical Trial Serious Adverse Event Form, verify the accuracy of the 
information recorded on the Shire Clinical Trial SAE Form with the corresponding source documents, and 
send a copy by fax to: (+44 (0)1256 894715 or+33 (0) 1 46 08 21 49) or email 
(globalpharmacovigilance@shire.com) to the Shire Pharmacovigilance department. 
• Notify, according to the local laws and requirements, any ethics committees (as applicable) and/or 
regulatory agencies, of: 
- SADRs that occur at his or her site, as required 
- All unexpected SADRs (15 Day Safety Reports) that occur during clinical trials with VPRIV®. 
The physician/investigator is encouraged to discuss with Shire’s Medical Monitor any ADRs for which the 
issue of relationship is unclear or questioned. Multiple inquiries between the Sponsor and/or the CRO and 
the study site may be necessary for report preparation. 
The Sponsor must: 
• Notify the relevant regulatory authorities/EU central Independent Ethics Committees (IEC) of unexpected 
SADRs 
• Notify investigators of new relevant safety information that becomes available during any studies with 
VPRIV®  
6.12 Removal of Patients from the Study 
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 one or more visits (or standard of care) 
• The patient was erroneously included in the study 
• The patient develops an exclusion criterion  
• The patient suffers an intolerable adverse event 
• The study is terminated by the Sponsor 
 
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 by the physician or at the institution. Discontinued patients should be followed 
according to medical practice standards.  
If a patient or 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, 

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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 adverse events (AE’s) 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 thetime of 
withdrawal will be followed until resolution. 

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7 
QUALITY CONTROL AND ASSURANCE 
7.1 
Appropriateness of Measurements 
• MRI is a standard method to study the evolution of the bones, liver and spleen impairment, the 
only difference with the standard practice is that a second review of all document will be 
conducted in a central review center in order to have standardized measurement. Patients for 
whom MRI is contraindicated are excluded from the study. 
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. 
7.2 
 Monitoring  
 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 and other global guidances as required. The clinical 
study 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. 
Serious adverse event information captured in the clinical study database will be reconciled with the 
information captured in the Pharmacovigilance and Risk Management database. 

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8 
PLANNED STATISTICAL METHODS 
8.1 
General Considerations 
Statistical plan will be written and Statistical analysis will be conducted by CenBiotech using SAS 
9.3 and under the authority of Pr Francois-André Allaert, Public health specialist and 
biostatistician, head of the medical evaluation Chair of the Business school of Dijon. A detailed 
analysis plan will be secondary provided and validated by Shire. 
8.2 
Determination of Sample Size 
There is no predefined sample size but in order to reflect daily practices, the study may include 
all patients presenting type 1 Gaucher disease and treated with VPRIV® in France. 
 So, based on data from the CETG, a sample size from 40 to 50 patients could be expected. 
 
8.3 
Analysis Populations 
All patients included in the study will be included in the statistical analysis 
 
8.4 
Demographics and Baseline Characteristics 
The socio-demographic and clinical characteristics of the cohort of patients with type 1 Gaucher’s 
disease and the arrangements for their care are described by the usual parameters, mean and 
standard deviation for quantitative variables, frequencies and percentages for qualitative variables. 
 
8.5 
Primary Endpoint(s) or Assessments 
The changes pre and post treatment with velaglucerase alfa of the spine and femur BMB score will 
be described and compared using Wilcoxon signed-rank test. The analysis will be conducted 
successively on all MRI assessable and on optimal quality MRI only. 
 
Primary Safety Endpoint(s) 
Adverse events will be coded using MedDRA and described as recommended in ECH 
procedures as far as possible due in particular to retrospective conditions..  
 
Primary Efficacy/Effectiveness Endpoint(s) 
The values observed at the different follow up times and the variations between the reference MRI 
and the follow-up MRI, of the BMB weighted score at T1 and T2 measured at the femur and 
lumbar spine, are described by mean and standard deviation and the 95% confidence interval will 
be calculated. These values will be compared at the different follow up times with test on repeated 
data: ANOVA on repeated series or Wilcoxon rank test, depending on the nature and distributions 
of the studied variables. 

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8.6 
Secondary Endpoint(s) 
The socio-demographic characteristics of the patients, the history of their disease, the context of 
the diagnosis, the medical history, the clinical evaluation criteria of liver and spleen, the MRI 
evaluation criteria of the liver and spleen,  the MRI evaluation criteria of bone lesions and the  
biological evaluation criteria are described by mean and standard deviation for quantitative 
variables, by frequency and percentage for categorical and ordinal variables. The 95% confidence 
intervals will be calculated. The evolutions of these criteria at the different periods when they are 
collected are described by mean and standard deviation or percentage changes. They are compared 
between the different times of the study by test on repeated data: ANOVA on repeated series or 
Wilcoxon rank test, depending on the nature and distributions of the studied variables 
The analysis will describe and analyze the evolution of bone disease on the basis of the MRI’s 
measures. It will describe and analyzes also the evolution of patients on the basis of their other 
MRI measures, clinical and laboratory data. It will describe also the incidence of spleen infarcts, 
fibrosis, liver nodules and their evolution under treatment by velaglucerase alfa.  
Comparisons shall be made by analysis of variance on repeated series for quantitative variables or 
by Wilcoxon signed rank tests is normality is not demonstrated and by McNemar tests or rank tests 
on repeated series for quantitative or ordinal criteria 
Changes over time in hepatomegaly, presence of lithiasis, nodules or infarct will be analysed using 
macNemar test and changes in liver measurements will be compare using analysis of variance on 
repeated series,  
Changes over time in splenomegaly, presence of nodules or infarct will be analysed using Mac 
Nemar test and changes in spleen measurements will be compare using analysis of variance on 
repeated series,  
Change in marrow infiltration, bone infarction, osteonecrosis, pathological fractures vertebral will 
be analysed using Mac Nemar test or Wilcoxon rank test. 
Changes in fatigue, abdominal pain, bone pain: hemorrhagic syndrome, lung disease and 
neurological disease will be analysed using Mac Nemar test or wilcoxon rank test 
Changes over time of biological parameters ( hemoglobinemia, leucocytes, platelets count, SGOT, 
SGPT, Gamma GT, alkalin phosphatases, converting enzyme angiotensin, ferritin, chitriosidase, 
gamma globulins, IgG, IgA, IgM, calcium level, D vitamin, B12 vitamin, triglycerides, cholesterol, 
monoclonal peak) will be analysed using variance analysis on repeated series. 
Logistic regression type shall be used to determine criteria influencing positive or negative 
evolutions. The analysis on MRI parameters will be conducted successively on all MRI assessable and on 
optimal quality MRI only. 
8.7 
Interim Analysis  
All data analysis previously described will be conducted at the end of the study scheduled on February 
2018. 

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9 
ADMINISTRATIVE CONSIDERATIONS 
9.1 
Investigators and Study Administrative Structure 
All the financial convention between Shire and the medical practitioners will be submitted for approval to 
the National Board of Medical Professional and declare to the French administrative authorities according 
the reference procedure. 
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. 
9.2 
Institutional Review Board or Independent Ethics Committee Approval and 
Other Governing Regulatory Bodies 
The protocol, the CRF and the informed consent of this observational study have be approved by 
the CCTIRS. 
 
9.3 
Study Monitoring 
Good Pharmacoepidemiological (GPPs) guidelines for observational studies will be followed. Review of 
the eCRF's 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) and in accordance 
with current GPPs and the respective local and French government regulations and guidelines. Records and 
data may additionally be reviewed by auditors or by regulatory authorities. 
The Sponsor ensures that Local Regulatory Authority requirements are met before the start of the study. 
The Sponsor (or a nominated designee) is responsible for the preparation, submission, and confirmation of 
receipt of any Regulatory Authority approvals required. 
9.4 
Case Report Forms and Study Records 
The clinical data are extracted from the medical record of the patients and are reported on the paper 
form. Forms are then transmitted by mail to the CRO which records it (double entry) on a 
computerized CRF developed on capture system. Automatic control of data entry and automatic 
request on missing data or data not fulfilling the control quality previously described in accordance 
with the laboratory are issued and transmitted to the medical practitioner 
 
Case report forms (paper) are provided for each patient. All forms must be filled out by authorized 
study personnel. All corrections to the original CRF entry must indicate the reason for change. The 
Investigator is required to sign the CRF after all data have been captured for each patient. If 

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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 resigning the CRF. 
 
9.5 
Critical Documents 
Before Shire Rare diseases initiates the study (ie, obtains written informed consent from the first patient), 
it is the responsibility of the Investigator to ensure that all required documents are available to Shire Rare 
diseases or their designee. Examples include: 
• Curricula vitae of Investigator and sub-investigator(s) (current, dated and signed within 
12 months of study initiation) 
• Signed and dated agreement of the final protocol 
• Signed and dated agreement of any amendment(s), if applicable 
• Approval/favorable opinion from the CCTIRS and by the National Board of Medical 
Practitioner 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 subjects recruitment procedures 
• Copy of CCTIRS approved Subject Information/Written Informed Consent Form/any other 
written information 
 
Regulatory approval and notification as required must also be available; these are the responsibility of 
Shire Rare diseases. 
9.6 
Data Monitoring Committee and/or Adjudication Committee 
Nadia Belmatoug MD, Service de Médecine Interne- Centre de Référence des maladies 
lysosomales, Hôpital Beaujon, Clichy, France            
- David Petrover MD, hôpital Lariboisière, Clinique Bachaumont, Paris, France 
- Luc Bracoud, Centre Bioclinica, Lyon, France 
- François-André Allaert, MD, PhD, CHRU Bocage, Dijon, France 
 
9.7 
Protocol Violations/Deviations 
The Investigator will conduct the study in compliance with the protocol. The protocol will not be initiated 
until the CCTIRS 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 CCTIRS 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 CCTIRS. The Sponsor will submit all protocol modifications to the regulatory authorities in 
accordance with the governing regulations. 
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. 

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Protocol deviations will need to be reviewed by the medical monitor and may also be required to be 
submitted to the CCTIRS. 
Protocol modifications will only be initiated by the Sponsor and must be approved by the CCTIRS or other 
applicable international regulatory authority before initiation. 
9.8 
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 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 
 
9.9 
Access to Source Documentation 
Regulatory authorities, the IRB/IEC, or the Sponsor may request access to all source documents, CRFs, and 
other study documentation for onsite 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 or GPP (where relevant) guidelines will be followed. 
On-site review of the CRFs for completeness and clarity, crosschecking with source documents, and 
clarification of administrative matters may be performed. 
9.10 Data Generation and Analysis 
The clinical database will be developed and maintained by Cenbiotech (a contract research organization) 
or an electronic data capture technology provider as designated by Shire Rare diseases. Cenbiotech will be 
responsible for performing study data management activities. Data will be recorded using double entry 
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA). Concomitant 
medication will be coded using WHO-Drug Dictionary (WHO-DD). Centralized laboratories will be 
employed as described in the study manual to aid in consistent measurement of efficacy and safety 
parameters.  
9.11 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. 

Retrospective and prospective observational study of MRI changes in bone and visceral lesions of patients with type 1 
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42 
10 REFERENCE LIST 
 
1) Maladie de gaucher. Protocole national de diagnostic et de soins, Haute Autorité de Santé, 
décembre 2015 
2) Stirnemann J, et al, The French Gaucher's disease registry: clinical characteristics, 
complications and treatment of 562 patients,  Orphanet J Rare Dis. 2012 Oct 9;7:77.  
3) Javier RM, Hachulla E, Osteoarticular manifestations of Gaucher disease in adults: 
pathophysiology and treatment, 2007, Dec;36 (12 Pt 3):1971-84. Epub 2007 May 10 
4) VPRIV Summary of Product Characteristics – Résumé des Caractéristiques Produit, 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/00124
9/human_med_001381.jsp&mid=WC0b01ac058001d124  
5) Ben Turkia H, et al., Velaglucerase alfa enzyme replacement therapy compared with 
imiglucerase in patients with Gaucher disease, Am J Hematol 2013  
6) Gonzalez DE et al. Enzyme replacement therapy with velaglucerase alfa in Gaucher 
disease: Results from a randomized, double-blind, multinational, Phase 3 study. Am J 
Hematol 2013;88:166–171 
7) Zimran A, et al., therapy in adults with type 1 Gaucher disease: 48-month experience Phase 
1/2 and extension study of velaglucerase alfa replacement, Blood 2010;115:4651–6 
8) Zimran A et al. Safety and efficacy of velaglucerase alfa in Gaucher disease type 1 
patients previously treated with imiglucerase. Am J Hematol 2013; 88: 172–178. 
9) Elstein D, et al., Significant and continuous improvement in bone mineral density among 
type 1 Gaucher disease patients treated with velaglucerase alfa: 69-month experience, 
including dose reduction Blood Cells Mol Dis 2011; 47: 56–61. 
10) Hughes DA, et al., Velaglucerase alfa (VPRIV) enzyme replacement therapy in patients 
with Gaucher disease: long-term data from phase III clinical trials, Am J Hematol 2015; 
90: 584–91 
11) Maas M, et al, 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. 2003 Nov; 229(2): 554-61. Epub 2003 Oct 2. 

Retrospective and prospective observational study of MRI changes in bone and visceral lesions of patients with type 1 
Gaucher disease treated with VPRIV® (velaglucerase alfa) 
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43 
Appendix 1 
Protocol Amendment Summary of Changes 
No amendment was made  

Retrospective and prospective observational study of MRI changes in bone and visceral lesions of patients with type 1 
Gaucher disease treated with VPRIV® (velaglucerase alfa) 
Shire Rare Diseases – version 5 – 05/04/2016 Confidential 
44 
Appendix 2 
Overview of the Study Design 
 
 
0. Eligible patients (n= 40-50)  
 
 
1. Patient inclusion (Written informed consent 
obtained)
 
Retrospective data collection 
2. Retrospective data collection 
 
The closest MRI conducted during the 5 years before the 
initiation of VPRIV® treatment or in the 3 months after the 
VPRIV® initiation  is collected  and defined as  the reference 
MRI. 
Clinical and biological data available 3 months before or 
after the reference MRI are collected  
Medical history and clinical and biological data available, 
when VPRIV® treatment is initiated , are collected 
Each MRI available since VPRIV® treatment initiation and 
patients inclusion is collected as well as clinical and 
biological data available 3 months before or after it 
 ......................................................................................... 
MRI collected are anonymously  sent to a central lab reading: 
MRI results data collection 
Medical history  
Clinical data  
Laboratory data 
VPRIV® treatment 
MRI  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 ............. VPRIV treatment  
Centralized MRI reading: 
- Liver and spleen 
volumes 
- BMB score of  the spine 
and femur 
Prospective data collection 
3. Prospective follow-up:  
For each MRI that will be conducted from the patient 
inclusion until the end of the one year follow up study , 
clinical and laboratory data available within the 3 months 
before the MRI and the 3 months after MRI are collected. 
 
 .........................................................................................
 ......................................................................................... 
MRI collected are anonymously  sent to a central lab reading: 
MRI results data collection 
 
 
Clinical data  
Laboratory data 
VPRIV® treatment  
MRI 
 
 
 .........................................  
Centralized MRI reading: 
- Liver and spleen 
volumes 
- BMB score of  the spine 
and femur
 
 

Retrospective and prospective observational study of MRI changes in bone and visceral lesions of patients with type 1 
Gaucher disease treated with VPRIV® (velaglucerase alfa) 
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Appendix 3 
Protocol Signature Page 
Study Title: 
Retrospective and prospective observational study of patients 
with type 1 Gaucher disease treated with VPRIV® (velaglucerase 
alfa) 
 
Study Number: 
RMGF - SHPGCB-703 
Final Date: 
05/04/2016 
Amendment Date: 
 
Sponsor’s Approval 
This study has been approved by Shire Rare diseases. 
Signatory: 
Sponsor 
 
25/04/2016 
Signature 
Date 
 
BESSA El Hadi 
 
 
Printed Name 
 
 
 
Investigator’s Acknowledgement 
I have read the protocol described above. I agree to comply with all applicable regulations and to conduct 
the study as described in the protocol.  
Signatory: 
 
 
Investigator 
Name Title 
Signature 
Date 
Institution
 
Printed Name 
 
 
 
 
 
 
 

Retrospective and prospective observational study of MRI changes in bone and visceral lesions of patients with type 1 
Gaucher disease treated with VPRIV® (velaglucerase alfa) 
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List of centers that will be involved in this study  
 
Investigators/ 
centers 
CENTRE DE COMPÉTENCE DES MALADIES HÉRÉDITAIRES DU MÉTABOLISME DU 
GRAND OUEST (Tours 1-2 - Angers - Poitiers) 
CENTRE DE PÉDIATRIE GATIEN DE CLOCHEVILLE 
49 boulevard Béranger - 37044 Tours Cedex 09 
CHU TOURS - HÔPITAL BRETONNEAU 
2 boulevard Tonnellé - 37044 Tours Cedex 09 
HÔPITAL JEANNE DE FLANDRE - CHRU DE LILLE 
Rue Eugène Avinée - 59037 Lille cedex 
HÔPITAL JEANNE DE FLANDRE Correspondant extra-hospitalier 
Hôpital Saint-Vincent 
Boulevard de Bellefort - 59020 Lille cedex 
HÔPITAL HURIEZ Correspondant extra-hospitalier 
Hôpital Huriez 
rue Michel Polonovski - 59100 Lille cedex 
HÔPITAL D’ENFANTS LA TIMONE 
264 rue Saint Pierre - 13005 Marseille 
CHU DE REIMS - HÔPITAL ROBERT DEBRÉ 
Avenue du Général Koening - 51092 Reims 
HÔPITAL HAUTEPIERRE 
1 avenue Molière - 67098 Strasbourg 
HÔPITAL AUGUSTIN MORVAN 
5 avenue Hoche - BP 824 - 29609 Brest Cedex 
CHU DE NANTES 
38 boulevard Jean Monnet - 44093 Nantes 
HÔPITAL ARNAUD DE VILLENEUVE 
371 avenue du Doyen Gaston Giraud - 34295 Montpellier cedex 05 
HÔPITAL LAPEYRONIE 
371 avenue du Doyen Gaston Giraud - 34295 Montpellier cedex 
HÔPITAL GUI DE CHAULIAC 
Avenue Augustin Fliche - 34295 Montpellier cedex 
HÔPITAL FEMME-MÈRE-ENFANT/GROUPEMENT HOSPITALIER EST 
59 boulevard Pinel - 69677 Bron cedex 
HÔPITAL D’ENFANTS LA TIMONE 
264 rue Saint Pierre - 13005 Marseille 
HÔPITAL D’ENFANTS 
Rue du Morvan - 54511 Vandoeuvre-les-Nancy cedex 
HÔPITAL DE BRABOIS 
Allée du Morvan - 54511 Vandoeuvre-les-Nancy cedex 
HÔPITAL PELLEGRIN - CHU BORDEAUX 
Place Amélie Raba Léon - 33076 Bordeaux Cedex 
CHU LE BOCAGE 
Boulevard Maréchal De Lattre de Tassigny 
Centre national de référence de la maladie de Fabry et des maladies 
héréditaires du tissu conjonctif 
104 boulevard Raymond Poincaré - 92380 Garches 
CHU SAINT-JACQUES ET JEAN MINJOZ 
2 place Saint-Jacques 
et 1 boulevard Flemming - 25000 Besançon 
HÔPITAL BICHAT 
46 rue Henri Huchard - 75018 Paris 
HÔPITAL COCHIN 

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27 rue du Faubourg Saint-Jacques - 75679 Paris cedex 14 
GROUPE HOSPITALIER LA PITIÉ SALPÊTRIÈRE 
47-83 boulevard de l’Hôpital - 75651 Paris cedex 13 
HÔPITAL JEAN VERDIER 
Avenue du 14 juillet - 93140 Bondy cedex 
HÔPITAL TROUSSEAU 
26 avenue du Docteur Arnold Netter - 75571 Paris cedex 12 
HÔPITAL ROBERT DEBRÉ 
48 boulevard Sérurier - 75019 Paris 
HÔPITAL NECKER ENFANTS MALADES 
149 rue de Sèvres - 75743 Paris cedex 15 
GROUPE HOSPITALIER LA PITIÉ SALPÊTRIÈRE 
47-83 boulevard de l’Hôpital - 75651 Paris cedex 13 
HÔPITAL KREMLIN BICÊTRE 
78 avenue du Général Leclerc - 94275 Le Kremlin Bicêtre 
CHU DE REIMS - HÔPITAL ROBERT DEBRÉ 
Avenue du Général Koening - 51092 Reims