Conditions: Gaucher Disease
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 31
Healthy volunteers: no

Brief summary:
Primary Objective:

Evaluate long term skeletal response to eliglustat in adult participants who successfully completed one of the Phase 2 or Phase 3 eliglustat studies.

Secondary Objective:

Evaluate the safety of eliglustat (by serious adverse event continuous monitoring), the quality of life (Short Form-36 Health Survey \[SF-36\]) and biomarkers of Gaucher disease type 1 (GD1) (chitotriosidase, plasma glucosylceramide \[GL-1\] and lyso glucosylceramide \[lyso-GL-1\]) in adult participants who successfully completed one of the Phase 2 or Phase 3 studies.

Detailed description:
Study duration for individual participants was to be of minimum 2 years and up to 4 years, or until commercial eliglustat was available to participants through reimbursement. If after 4 years since the beginning of the study eliglustat was not approved and available to participants in participating country, participants in this country might continue to receive study treatment until eliglustat was available to participants through the compassionate use (expanded access) program or was approved and available through reimbursement, whichever came first.

Arms:
arm 1: Participants who completed one of the Phase 2 (GZGD00304 \[NCT00358150\]) or Phase 3 studies (GZGD02507 \[NCT00891202\], GZGD02607 \[NCT00943111\], or GZGD03109 \[NCT01074944\]) were enrolled in this current (EFC13781) study. Participants who were cytochrome P450 (CYP) 2D6 intermediate metabolizer (IM), extensive metabolizer (EM) and ultra-rapid metabolizers (URM) received eliglustat 84 milligrams (mg) twice daily and participants who were CYP2D6 poor metabolizer (PM) received eliglustat 84 mg once daily, for duration of minimum 2 years (unless early discontinuation occurred) and up to 4 years, or until commercial eliglustat was available to participants through reimbursement or through the compassionate use (expanded access) program.

Interventions: intervention 1: Eliglustat, GZ385660
Intervention descriptions: intervention 1: Pharmaceutical form: capsule

Route of administration: oral

Protocol document:
Prot_000.pdf: 


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NAMES AND ADDRESSES OF 
COORDINATING 
INVESTIGATOR 
 
Name: 
Address: 
 
 
Tel: 
Fax: 
E-mail: 
 
 
MONITORING TEAM’S 
REPRESENTATIVE 
 
Name: 
Address: 
 
 
 
Tel: 
Fax: 
E-mail: 
 
 
SPONSOR 
 
Company: 
Address: 
 
 
 
 
Sanofi Genzyme Corporation 
500 Kendall Street 
Cambridge, MA 02142 
USA 
 
OTHER EMERGENCY 
TELEPHONE NUMBERS 
 
 
 
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CLINICAL TRIAL SUMMARY 
 
COMPOUND: GZ385660 
STUDY No: EFC13781  
STUDY NAME: EXOSKEL 
TITLE 
Open Label Interventional Multicenter Phase 3b Study to Evaluate Skeletal 
Response to Eliglustat in Adult Patients Who Successfully Completed the 
Phase 2 or Phase 3 Studies 
INVESTIGATOR/TRIAL LOCATION 
The study centers that participated in the eliglustat Phase 2 or Phase 3 
studies are eligible to participate in this study.   
PHASE OF DEVELOPMENT 
Phase 3b 
STUDY OBJECTIVE(S) 
 
Primary objective 
Evaluate long term skeletal response to eliglustat in adult patients who 
successfully completed one of the Phase 2 or Phase 3 eliglustat studies. 
Secondary objective(s)  
Evaluate the safety of eliglustat (by (serious) adverse event (AE) continuous 
monitoring), the quality of life (Short Form-36 Health Survey (SF-36)) and 
biomarkers of Gaucher disease type 1 (GD1) (chitotriosidase, plasma 
glucosylceramide (GL-1) and lyso glucosylceramide (lyso-GL-1)) in adult 
patients who successfully completed one of the Phase 2 or Phase 3 studies. 
STUDY DESIGN 
This is an open label, interventional, non-comparative, multicenter, 
multinational Phase 3b study to evaluate long term skeletal response to 
eliglustat and eliglustat safety and effect on quality of life in adult patients who 
successfully completed one of the Phase 2 or Phase 3 studies in the eliglustat 
program. This study is considered an extension of these previous studies and 
will continue to evaluate the safety of eliglustat and patients’ quality of life 
(SF-36).  
Participating investigators will enroll patients who successfully completed one 
of the Phase 2 or Phase 3 studies. Patients will be treated for a minimum of 
2 years and up to 4 years, or until eliglustat is approved and available to 
patients through reimbursement.  If after 4 years since the beginning of the 
study eliglustat is not approved and available to patients in participating 
country, patients in this country may continue to receive study treatment until 
eliglustat is available to patients through the compassionate use (expanded 
access) program or is approved and available through reimbursement, 
whichever comes first. 
STUDY POPULATION  
Main selection criteria 
Adult patients who completed successfully the Phase 2 (GZGD00304) or a 
Phase 3 study (GZGD02507, GZGD02607 or GZGD03109). 
 
Inclusion criteria  
I 01. 
The patient must have successfully* completed the Phase 2 
(GZGD00304) or a Phase 3 study (GZGD02507, GZGD02607 or 
GZGD03109). 
* Successful completion is defined as patients enrolled in one of the 
above mentioned studies who received eliglustat through the end of 
the study and completed the end of study visit without having 
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discontinued or been withdrawn prematurely. 
I 02. 
The patient is willing and able to provide signed informed consent 
prior to any protocol required procedures being performed. 
I 03. 
Female patients of childbearing potential must have a documented 
negative pregnancy test prior to enrollment and while they are 
receiving eliglustat treatment. 
I 04. 
Female patients of childbearing potential must be willing to practice 
true abstinence in line with their preferred and usual lifestyle, or use 
a medically accepted form of contraception (either a barrier method, 
such as condom or diaphragm + spermicide, or a non-barrier 
method such as oral, injected, or implanted hormonal methods, or 
an intra-uterine device or system) while receiving eliglustat. 
 
Exclusion criteria 
E 01. 
The patient is unwilling to comply with the requirements of the 
protocol. 
E 02. 
The patient has received an investigational product (other than 
eliglustat) within 30 days prior to enrollment. 
E 03. 
The patient has received miglustat within the 6 months prior to 
enrollment. 
E 04. 
The patient has documented prior esophageal varices or liver 
infarction or current liver enzymes (alanine transaminase 
[ALT]/aspartate aminotransferase [AST]) or Total Bilirubin >2 times 
the upper limit of normal (ULN), unless the patient has a diagnosis 
of Gilbert Syndrome. 
E 05. 
The patient has any clinically significant disease, other than 
Gaucher disease, including cardiovascular, renal, hepatic, 
gastrointestinal, pulmonary, neurologic, endocrine, metabolic (eg, 
hypokalemia, hypomagnesemia), psychiatric disease, other medical 
conditions, or serious intercurrent illnesses that may preclude 
participation in the study. 
E 06. 
The patient is known to have any of the following: cardiac disease 
(congestive heart failure, recent acute myocardial infarction, 
bradycardia, heart block, ventricular arrhythmia), long QT syndrome, 
or current treatment with Class IA or Class III antiarrhythmic 
medicinal products. 
E 07. 
The patient has tested positive for the human immunodeficiency 
virus (HIV) antibody, hepatitis C antibody, or hepatitis B surface 
antigen. 
E 08. 
The patient has a history of cancer within 6 months of enrolment, 
with the exception of basal cell carcinoma. 
E 09. 
The patient is cytochrome P450 (CYP) 2D6 intermediate (IMs), 
extensive (EMs) or ultra-rapid (URM) metabolizer and taking a 
strong or moderate CYP2D6 inhibitor concomitantly with a strong or 
moderate CYP3A inhibitor 
E 10. 
The patient is CYP2D6 poor metabolizer (PMs) having taken a 
strong CYP3A inhibitor within 2 weeks prior to enrolment. 
E 11. 
If a female patient of childbearing potential has a positive pregnancy 
test blood β-Human Chorionic Gonadotropin (β-HCG) or is 
breastfeeding prior to first dosing of eliglustat in this study, the 
patient cannot enroll in the study at this time, but may be rescreened 
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after the end of the pregnancy, and/or when she is no longer breast 
feeding, provided rescreening takes place before the end of the 
enrollment period. 
E 12. 
Women of childbearing potential who are unwilling or unable to be 
tested for pregnancy. 
 
Total expected number of patients 
Approximately 32 patients 
Expected number of sites:  
Approximately 4 sites 
STUDY TREATMENT(s) 
 
Investigational medicinal 
product(s) 
 
Formulation 
Eliglustat 
 
Eliglustat is supplied as 84 mg hard gelatin capsules. Each 84 mg capsule 
contains 100 mg eliglustat tartrate, which is equivalent to 84 mg  eliglustat 
free base 
Route(s) of administration 
Oral 
Dose regimen 
Cytochrome P450 2D6 (CYP2D6) IMs, EMs and URMs will be treated with 84 
mg twice daily (BID). 
CYP2D6 PMs will be treated with 84 mg once daily (QD). 
Noninvestigational medicinal 
product(s) (if applicable) 
 
Formulation 
N/A 
Route(s) of administration 
N/A 
Dose regimen 
N/A 
ENDPOINT(S) 
 
Primary endpoint 
The main purpose in this extension study is to evaluate long term skeletal 
response to eliglustat, i.e., change in bone disease after 2 years of additional 
treatment with eliglustat. The elements of bone disease to be evaluated 
include bone pain, bone crisis, mobility, bone marrow infiltration,  bone 
mineral density (BMD), lytic lesions, infarcts, fractures, osteonecrosis, and 
bone biomarkers (Procollagen type I N-terminal propeptide (P1NP; bone 
formation) and C- terminal telopeptide (CTX; bone resorption), and 
macrophage inflammatory protein-1 beta (MIP-1 β). These efficacy 
assessments will be collected at baseline and thereafter at twice-yearly (bone 
biomarkers) or yearly (pain, crisis, mobility, bone marrow infiltration, bone 
mineral density, lytic lesions, infarcts, fractures) intervals. 
Secondary endpoint(s) 
Evaluation of patients’ quality of life (Short Form-36 Health Survey) and 
biomarkers of GD1 (chitotriosidase, plasma GL-1 and lyso-GL-1). Quality of 
Life (QOL) and biomarkers of GD1 will be performed at baseline and twice 
yearly.  
The safety of eliglustat (i.e., incidence of (S)AEs, concomitant medications, 
changes from study baseline in physical examinations, routine laboratory 
assessments (hematology) and pregnancy testing for female patients of 
childbearing potential). Safety assessments will be performed at baseline and 
twice yearly. Continuous monitoring will be performed for (S)AEs and 
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concomitant medications.   
ASSESSMENT SCHEDULE 
V1-2 (Day -45 to -1): screening 
V3 (D1): baseline, 1st  eliglustat administration in this study  
From V3 onwards, at 6 month intervals up to 4 years or until eliglustat is 
approved and available to patients through reimbursement or through the 
compassionate use (expanded access) program: efficacy, safety and general 
patient condition assessment parameters 
Last visit: last dose of IMP; efficacy, safety and general patient condition 
assessment parameters. 
For all visits, a time frame of ± 14 days is acceptable, using Day 1 as 
reference (If one visit date is changed, the next visit should take place 
according to the original schedule). 
Note: patients who prematurely discontinue treatment have to perform the 
discontinuation visit. 
STATISTICAL CONSIDERATIONS 
 
Sample size determination: 
This study will enroll all eligible patients having successfully completed one of 
the Phase 2 or Phase 3 trials (approximately 32 patients). 
Analysis population: 
Efficacy analyses will be performed on the Full Analysis Set (FAS) population, 
defined as all patients who enroll in this study and who received at least 
1 dose of eliglustat treatment in this study.  
Safety analyses will be performed on the Safety Set, which is equivalent to 
the FAS for this study. 
Primary analysis: 
Analysis will be performed at two time points in this study. The main analysis 
will be performed after all patients have completed the 2 year assessments 
(two-year analysis period). An additional analysis will be performed upon 
study completion. For both efficacy and safety outcomes summary statistics 
will be calculated and presented. Hypothesis testing will not be performed.  
For bone disease outcomes, summary statistics as well as cumulative 
incidence and incidence rates will be calculated, as appropriate. For 
continuous variables, change from study baseline as well as change from 
eliglustat baseline, defined as the change from first dose of eliglustat in the 
Phase 2 or 3 study, will be presented. Incidence and incidence rates will also 
be calculated separately, from study baseline and eliglustat baseline. 
Analysis of secondary endpoints: 
Quality of Life assessments, physical examinations, hematology, biomarkers 
and pregnancy testing for female patients of childbearing potential will be 
summarized at each time point.  Additionally, the change from study baseline 
and eliglustat baseline (1st dose received in the previous study) will be 
summarized, as appropriate. Adverse experience will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) Version 18.0 or higher. 
All adverse experiences will be summarized by body system and MedDRA 
preferred term (PT) overall, by relationship and severity and seriousness. All 
deaths will be summarized. Concomitant medications will be reported. 
 
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DURATION OF STUDY PERIOD (per 
patient)  
The study will include a screening period (Day -45 to -1) and a long-term 
treatment period up to 4 years, or until eliglustat is approved and available to 
patients through reimbursement with minimum duration of treatment of 
2 years. If after 4 years since the beginning of the study eliglustat is not 
approved and available to patients in participating country, patients in this 
country may continue to receive study treatment until eliglustat is available to 
patients through the compassionate use (expanded access) program or is 
approved and available through reimbursement, whichever comes first. 
Enrollment: up to 20 months. 
After study completion, patients will be encouraged to enroll in the 
International Collaborative Gaucher Group (ICGG) Gaucher Registry. 
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Screening 
(Day -45 
to -1)a 
Treatment Observations 
VISIT 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Assessments after Week 
208 
Study completion or Patient 
Discontinuation/Withdrawal
b 
WEEKS 
 
 
Da
y 1 
Wk 26 
(±14 
days 
Wk 
52 
(±14 
days) 
Wk 
78 
(±14 
days) 
Wk 
104 
(±14 
days) 
Wk 
130 
(±14 
days) 
Wk 
156 
(±14 
days) 
Wk 
182 
(±14 
days) 
Wk 
208 
(±14 
days) 
Every 6 
months 
(±14 
days) 
Every 
12 
Months 
(±14 
days 
Every 
24 
months 
(±14 
days) 
 
Human 
immunodeficiency 
virus (HIV) antibody, 
Hepatitis C antibody, 
or Hepatitis B 
surface antigen. 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
(including 
hemoglobin, platelet) 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum Chemistry 
(AST, ALT, AP, 
Total bilirubin, 
albumin, GGT)  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomarkers: serum 
chitotriosidase,  
plasma MIP- 1 β, 
serum P1NP, serum 
CTX h, plasma GL-1  
and lyso-GL-1 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood pregnancy 
test (for women of 
childbearing 
potential) i 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Screening 
(Day -45 
to -1)a 
Treatment Observations 
VISIT 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
Assessments after Week 
208 
Study completion or Patient 
Discontinuation/Withdrawal
b 
WEEKS 
 
 
Da
y 1 
Wk 26 
(±14 
days 
Wk 
52 
(±14 
days) 
Wk 
78 
(±14 
days) 
Wk 
104 
(±14 
days) 
Wk 
130 
(±14 
days) 
Wk 
156 
(±14 
days) 
Wk 
182 
(±14 
days) 
Wk 
208 
(±14 
days) 
Every 6 
months 
(±14 
days) 
Every 
12 
Months 
(±14 
days 
Every 
24 
months 
(±14 
days) 
 
a Final GZGD00304, GZGD02507, GZGD02607 and GZGD03109 study assessments may serve as entry evaluation for this study if performed less than 3 month for laboratory testing, 1 year for bone imaging (X-ray 
femur and lumbar spine, dual-energy X-ray absorptiometry (DXA) hips and lumbar spine, Magnetic Resonance Imaging (MRI) femur and lumbar spine) and 6 months for other assessments. 
However, safety (S)AE, concomitant medication and prior medication history, physical examinations, human immunodeficiency virus (HIV) antibody, hepatitis C antibody, or hepatitis B surface antigen, blood pregnancy 
test for female of childbearing potential, height, will have to be performed in all cases. 
The screening procedures do not have to be performed over 2 visits. Scheduling will be based on investigator, patient and resources availability. Screening can be performed at the same time as the end-of-study visit 
of the previous study the patient was enrolled in. 
b Study duration will be up to 4 years, or until eliglustat is approved and available to patients through reimbursement with minimum duration of 2 years. If after 4 years since the beginning of the study eliglustat is not 
approved and available to patients in participating country, patients in this country may continue to receive study treatment until eliglustat is available to patients through the compassionate use (expanded access) 
program or is approved and available through reimbursement, whichever comes first.  At study completion or patient discontinuation/withdrawal certain radiological assessments will not be repeated (bone X-Ray if 
performed less than 2 years prior; DXA, bone MRI and liver and spleen MRI if performed less than 1 year prior). 
c A unique patient ID number will be assigned. The ID of the previous study the patient was enrolled in and the patient’s ID in that study will be collected in the new clinical database. 
d Medico-surgical history already collected in the previous study database should not be re-entered. Should be entered in the Medical/surgical history CRF 1/ adverse events (AEs) started during the previous study, 
which are closed at the time of the screening visit and are still considered clinically significant by the investigator at the time of the screening visit; 2/ medical/surgical events started after the follow-up phone call of the 
previous study and before the ICF signing in the current study, whether ongoing or closed, if they are considered clinically significant by the investigator.  
e Prior medications are all ongoing medications at the time of screening, and medications received during the 30 day period prior to screening even if no longer taken at the time of screening, including eliglustat and 
enzyme replacement therapy (ERT). 
f 
Only at Study completion visit and not at Patient discontinuation/withdrawal visit. 
g Patients will be contacted approximately every 4 weeks for safety monitoring and will be asked if they have had any significant experiences, begun taking any new medications, changed the dose of any medications 
they are taking. In addition patients of child bearing potential will be asked about the result of the urine pregnancy test performed every 4 weeks at home.  
h Serum samples for CTX should be collected after overnight fasting. 
i 
Urine pregnancy test must be performed before radiological assessments and the result provided to the personnel performing the assessment so that he/she can verify the result is negative and sign off on it before 
performing the exam. All positive urine pregnancy tests will be verified with a blood pregnancy test. 
Note:  
Central reading will be set up for liver and spleen MRI and bone imaging. All laboratory tests will be done at the local laboratories at the exception of the biomarkers, which will be done in central laboratories. 
Cytochrome P450 2D6 URM patients will have liver and spleen MRI and hematology performed every 6 month till week 52. However, the frequency of liver and spleen MRI and hematology can be increased to every 3 
month till week 52 at the discretion of the Investigator. After week 52 CYP2D6 URM patients will follow the standard schedule. 
Although pharmacokinetic (PK) samples are not scheduled, unscheduled PK samples may be collected after discussion between PI and Genzyme. 
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2 
TABLE OF CONTENTS 
1 
FLOW CHARTS...............................................................................................................................8 
1.1 
GRAPHICAL STUDY DESIGN ........................................................................................................8 
1.2 
STUDY FLOW CHART ....................................................................................................................9 
2 
TABLE OF CONTENTS ................................................................................................................13 
3 
LIST OF ABBREVIATIONS ..........................................................................................................18 
4 
INTRODUCTION AND RATIONALE.............................................................................................20 
5 
STUDY OBJECTIVES ...................................................................................................................26 
5.1 
PRIMARY.......................................................................................................................................26 
5.2 
SECONDARY ................................................................................................................................26 
6 
STUDY DESIGN ............................................................................................................................27 
6.1 
DESCRIPTION OF THE PROTOCOL...........................................................................................27 
6.2 
DURATION OF STUDY PARTICIPATION ....................................................................................27 
6.2.1 
Duration of study participation for each patient .............................................................................27 
6.2.2 
Determination of end of clinical trial (all patients) ..........................................................................27 
6.3 
INTERIM ANALYSIS......................................................................................................................27 
6.4 
STUDY COMMITTEES..................................................................................................................27 
7 
SELECTION OF PATIENTS..........................................................................................................29 
7.1 
INCLUSION CRITERIA..................................................................................................................29 
7.2 
EXCLUSION CRITERIA ................................................................................................................29 
7.2.1 
Exclusion criteria related to study methodology ............................................................................29 
7.2.2 
Exclusion criteria related to eliglustat.............................................................................................30 
7.2.3 
Exclusion criteria related to the current knowledge of eliglustat....................................................30 
7.3 
PATIENT DISCONTINUATION/WITHDRAWAL CRITERIA..........................................................31 
8 
STUDY TREATMENTS .................................................................................................................33 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT ...............................................................................33 
8.1.1 
IMP dose reduction ........................................................................................................................33 
8.1.2 
IMP temporary suspension ............................................................................................................33 
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8.2 
PACKAGING AND LABELING ......................................................................................................34 
8.3 
STORAGE CONDITIONS AND SHELF LIFE................................................................................34 
8.4 
RESPONSIBILITIES ......................................................................................................................34 
8.4.1 
Treatment accountability and compliance......................................................................................35 
8.4.2 
Return and/or destruction of treatments ........................................................................................35 
8.5 
CONCOMITANT MEDICATION.....................................................................................................35 
8.5.1 
INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF 
INTERACTION...............................................................................................................................36 
8.5.1.1 
ANTIARRHYTHMICS.....................................................................................................................36 
8.5.1.2 
EFFECT OF OTHER DRUGS ON ELIGLUSTAT..........................................................................36 
8.5.1.3 
EFFECT OF ELIGLUSTAT ON OTHER DRUGS..........................................................................37 
9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT ..............................................38 
9.1 
PRIMARY ENDPOINT ...................................................................................................................38 
9.1.1 
Gaucher disease clinical assessments (mobility, bone pain, bone crisis).....................................38 
9.1.2 
Bone marrow infiltration .................................................................................................................39 
9.1.3 
Bone mineral density (BMD)..........................................................................................................39 
9.1.4 
Lytic lesions, osteonecrosis, fractures and infarcts .......................................................................39 
9.1.5 
Bone biomarkers............................................................................................................................39 
9.2 
SECONDARY ENDPOINT(S)........................................................................................................39 
9.2.1 
Efficacy endpoints..........................................................................................................................39 
9.2.2 
Safety endpoints ............................................................................................................................40 
9.2.2.1 
Adverse events ..............................................................................................................................40 
9.2.2.2 
Laboratory safety variables............................................................................................................40 
9.2.2.3 
Physical examination .....................................................................................................................40 
9.2.3 
Patient Reported Outcomes...........................................................................................................40 
9.3 
PHARMACOKINETICS..................................................................................................................40 
9.3.1 
Sampling time ................................................................................................................................40 
9.3.2 
Pharmacokinetics handling procedure...........................................................................................41 
9.3.3 
Bioanalytical method......................................................................................................................41 
9.3.4 
Pharmacokinetics parameters .......................................................................................................41 
9.4 
FUTURE USE OF SAMPLES ........................................................................................................41 
9.5 
APPROPRIATENESS OF MEASUREMENTS ..............................................................................41 
9.5.1 
Primary endpoint............................................................................................................................41 
9.5.2 
Secondary endpoints .....................................................................................................................42 
10 
STUDY PROCEDURES ................................................................................................................43 
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10.1 
GENERAL CONSIDERATIONS ....................................................................................................43 
10.2 
VISIT SCHEDULE..........................................................................................................................43 
10.2.1 
Screening period............................................................................................................................43 
10.2.1.1 Clinical information.........................................................................................................................44 
10.2.1.2 Imaging ..........................................................................................................................................45 
10.2.1.3 Laboratory tests .............................................................................................................................45 
10.2.2 
Day 1 visit.......................................................................................................................................45 
10.2.3 
Semiannual visits ...........................................................................................................................46 
10.2.3.1 Clinical assessments......................................................................................................................46 
10.2.3.2 Laboratory tests .............................................................................................................................46 
10.2.3.3 Special provision for URM patients................................................................................................46 
10.2.4 
Annual visits ...................................................................................................................................46 
10.2.4.1 Clinical assessments......................................................................................................................46 
10.2.4.2 Imaging ..........................................................................................................................................46 
10.2.5 
Study completion or patient discontinuation/withdrawal ................................................................47 
10.2.5.1 Clinical assessments......................................................................................................................47 
10.2.5.2 Laboratory assessments................................................................................................................47 
10.2.5.3 Imaging ..........................................................................................................................................47 
10.3 
DEFINITION OF SOURCE DATA..................................................................................................47 
10.4 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION.......................................47 
10.4.1 
Temporary treatment discontinuation with investigational medicinal product(s) ...........................48 
10.4.2 
Permanent treatment discontinuation with investigational medicinal product(s) ...........................48 
10.4.3 
Criteria for permanent treatment discontinuation...........................................................................48 
10.4.4 
Procedure and consequence for patient withdrawal from study....................................................49 
The patients may withdraw from the study before study completion if they decide to do so, at any time and 
irrespective of the reason...................................................................................................................49 
10.5 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING ..........................49 
10.5.1 
Definitions of adverse events.........................................................................................................49 
10.5.1.1 Adverse event ................................................................................................................................49 
10.5.1.2 Serious adverse event ...................................................................................................................49 
10.5.1.3 Adverse event of special interest...................................................................................................50 
10.5.2 
General guidelines for reporting adverse events ...........................................................................51 
10.5.3 
Instructions for reporting serious adverse events ..........................................................................52 
10.5.4 
Guidelines for reporting adverse events of special interest...........................................................53 
10.6 
OBLIGATIONS OF THE SPONSOR .............................................................................................53 
10.7 
ADVERSE EVENTS MONITORING..............................................................................................54 
11 
STATISTICAL CONSIDERATIONS..............................................................................................55 
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11.1 
DETERMINATION OF SAMPLE SIZE...........................................................................................55 
11.2 
DISPOSITION OF PATIENTS .......................................................................................................55 
11.3 
ANALYSIS POPULATIONS...........................................................................................................55 
11.3.1 
Efficacy populations .......................................................................................................................55 
11.3.2 
Safety population ...........................................................................................................................55 
11.3.3 
Pharmacokinetic population...........................................................................................................55 
11.4 
STATISTICAL METHODS .............................................................................................................55 
11.4.1 
Extent of study treatment exposure and compliance.....................................................................56 
11.4.2 
Analyses of efficacy endpoints.......................................................................................................57 
11.4.2.1 Analysis of primary efficacy endpoint(s) ........................................................................................57 
11.4.2.2 Analyses of secondary efficacy endpoints.....................................................................................57 
11.4.3 
Analyses of safety data..................................................................................................................57 
11.4.4 
Analyses of pharmacokinetic and pharmacodynamic variables ....................................................58 
11.4.5 
Analyses of Patient Reported Outcomes (Health-related Quality of Life/health economics 
variables.........................................................................................................................................59 
12 
ETHICAL AND REGULATORY CONSIDERATIONS...................................................................60 
12.1 
ETHICAL AND REGULATORY STANDARDS ..............................................................................60 
12.2 
INFORMED CONSENT .................................................................................................................60 
12.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) ..............61 
13 
STUDY MONITORING...................................................................................................................62 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S).......................................................................62 
13.2 
RESPONSIBILITIES OF THE SPONSOR.....................................................................................62 
13.3 
SOURCE DOCUMENT REQUIREMENTS....................................................................................62 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST......................................................................................................................................63 
13.5 
USE OF COMPUTERIZED SYSTEMS..........................................................................................63 
14 
ADDITIONAL REQUIREMENTS...................................................................................................64 
14.1 
CURRICULUM VITAE....................................................................................................................64 
14.2 
RECORD RETENTION IN STUDY SITES ....................................................................................64 
14.3 
CONFIDENTIALITY .......................................................................................................................64 
14.4 
PROPERTY RIGHTS.....................................................................................................................65 
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14.5 
DATA PROTECTION.....................................................................................................................65 
14.6 
INSURANCE COMPENSATION....................................................................................................66 
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES .................................66 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE............................................................................................................................................66 
14.8.1 
By the Sponsor...............................................................................................................................66 
14.8.2 
By the Investigator .........................................................................................................................67 
14.9 
CLINICAL TRIAL RESULTS ..........................................................................................................67 
14.10 
PUBLICATIONS AND COMMUNICATIONS .................................................................................67 
15 
CLINICAL TRIAL PROTOCOL AMENDMENTS ..........................................................................69 
16 
BIBLIOGRAPHIC REFERENCES.................................................................................................70 
17 
APPENDICES................................................................................................................................72 
APPENDIX A 
CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION..............................................................................................................................73 
APPENDIX B 
DOCUMENT(S) RELATED TO THE ASSESSMENT OF 1 (OR MORE) 
ENDPOINT(S)..................................................................................................................................2 
APPENDIX C GENERAL GUIDANCE FOR THE FOLLOW-UP OF LABORATORY 
ABNORMALITIES BY SANOFI........................................................................................................8 
 
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3 
LIST OF ABBREVIATIONS 
 
AE: 
adverse event 
ALT: 
alanine transaminase 
AP: 
alkaline phosphatase 
AST: 
aspartate aminotransferase 
AUC: 
area under the concentration-time curve 
AUClast: 
area under the concentration-time curve from time zero to the last measurable 
concentration 
BID: 
twice daily 
BMD: 
bone mineral density 
CFDA: 
China Food and drug administration 
CRF.: 
Case Report Form 
CTX: 
C-terminal telopeptide 
CV: 
curriculum vitae 
CYP2D6: 
cytochrome P450 2D6, cytochrome P450 2D6 
CYP3A: 
cytochrome P450 3A 
CYP3A4: 
cytochrome P450 3A4 
DRF: 
discrepancy resolution form 
DXA: 
dual-energy X-ray absorptiometry 
EM: 
extensive metaboliser 
EOS: 
end of study 
ERT: 
enzyme replacement therapy 
FAS: 
Full Analysis Set  
FDA: 
US Food and Drug Administration 
GCP: 
good clinical practice 
GD1: 
Gaucher disease type 1 
GL-1: 
glucosylceramide 
HIV: 
human immunodeficiency virus 
ICGG: 
International Collaborative Gaucher Group 
IM: 
intermediate metaboliser 
IRB/IEC: 
Institutional Review Board/Independent Ethics Committee 
LC/MS/MS: 
liquid chromatography coupled to tandem mass spectrometry 
LS: 
least squares 
lyso-Gl-1: 
lyso glucosylceramide 
MCS: 
mental component summary 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MIP1-β: 
macrophage inflammatory protein-1 beta 
MRI: 
Magnetic Resonance Imaging 
P1NP: 
Procollagen type I N-terminal propeptide 
PAP: 
primary analsyis period 
PCS: 
physical component summary 
PK: 
Pharmacokinetic 
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PM: 
poor metaboliser 
PMDA: 
Pharmaceuticals Medical Devices Agency 
PT: 
preferred term 
QD: 
once daily 
QOL: 
Quality of Life 
SAE: 
serious adverse event 
SD: 
standard deviation 
SF-36: 
Short Form-36 Health Survey 
SOC: 
system organ class 
TGA: 
Therapeutic Goods Administration 
ULN: 
upper limit of normal 
URM: 
ultra-rapid metabolizer  
β-hCG: 
β-Human Chorionic Gonadotrophin 
 
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4 
INTRODUCTION AND RATIONALE 
Sanofi Genzyme has developed Cerdelga® (International Nonproprietary Name: eliglustat) as an 
oral therapy for Gaucher disease type 1.  Eliglustat is a member of a class of glucosylceramide 
(GL-1) synthase inhibitors that resemble the substrate (ceramide). 
Gaucher disease is an autosomal recessive lysosomal glycolipid storage disease that results from a 
deficiency of acid β-glucosidase. The major natural substrate for this enzyme is GL-1, an 
intermediate metabolite in the synthesis and catabolism of more complex glycosphingolipids. 
Gaucher disease is characterized by lysosomal accumulation of GL-1 due to impaired GL-1 
hydrolysis secondary to the deficiency of the enzyme acid β-glucosidase. In patients with Gaucher 
disease, different tissues show increases in GL-1 concentration, leading to the main 
manifestations of the disease: anemia, thrombocytopenia, hepatosplenomegaly, skeletal disease, 
and neurological disease (1)(2)(3)(4)(5). 
The hallmark of Gaucher disease is the presence of lipid-engorged cells derived from the 
monocyte/macrophage lineage (Gaucher cell), which show a characteristic histological 
appearance and are distributed in tissues where macrophages reside (eg, liver, spleen, lung, and 
bone marrow). It is believed that the storage material within these Gaucher cells originates from 
phagocytosis of blood cells, while in neurons, the storage material is believed to originate from 
endogenous synthesis (5). 
Gaucher disease type 1 is rare, with an estimated frequency of 1 in 60,000 births in the general 
population (6). Although it is pan-ethnic, it is most commonly seen in the Ashkenazi Jewish 
population. Based on results of gene frequency for the two most common Ashkenazi Jewish 
mutations, the incidence of Gaucher disease in this population has been estimated to be 1 in 855 
births (5). 
Gaucher disease type 1 has a broad spectrum of severity (5). Thrombocytopenia is the most 
common hematological abnormality. Anemia is frequently mild, but occasionally quite severe. 
Some patients with severe enlargement of the spleen and liver have minimal skeletal involvement, 
while others with severe bone disease have minimal visceral disease. In other patients, visceral 
involvement and skeletal involvement are approximately equal in severity. The degree and type of 
bone involvement is markedly variable; however, loss of bone mass is very common, irrespective 
of the severity of the other manifestations of the disease. 
The accumulation of GL-1 and the more common clinical manifestations of the disease including 
anemia, thrombocytopenia, hepatosplenomegaly, and bone disease, can be treated by enzyme 
replacement therapy (ERT) with recombinant acid β-glucosidase (Cerezyme®, Genzyme, and 
VPRIV™, Shire) (7)(8)(9)(10)(11)(12). Elelyso (Pfizer, New York) was approved in the United 
States on 01 May 2012 as an ERT for the treatment of GD1. An alternative approach is the use of 
substrate reduction therapy using eliglustat, which acts by partially inhibiting the enzyme GL-1 
synthase. The goal of this approach is to reduce the synthesis of GL-1 to a level where the residual 
enzymatic activity of the mutant acid β-glucosidase, the enzyme deficient in Gaucher disease, can 
degrade GL-1, thus preventing its accumulation. 
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Certain disease affected tissues such as bone marrow and cortical bone are not optimally targeted 
with existing treatments (13). Because the biodistribution of a small molecule drug is likely to be 
more extensive than that of an enzyme, the substrate reduction therapy (SRT) approach is 
expected to provide benefit in tissues that are less accessible to ERT (14) and in cells that lack 
mannose receptors (15). In fact, preclinical studies with eliglustat demonstrated a wide 
distribution to tissues, including bone marrow. 
Bone involvement is a nearly universal and clinically relevant aspect of Gaucher disease, which 
affects both the osseous tissue and the bone marrow. As skeletal involvement can be severe and 
lead to significant morbidity, improvement in bone disease is important to patients as well as 
expert physicians (16) as evidenced by its inclusion as a key therapeutic goal for ERT (9) and in 
the schedule of recommended assessments in the ICGG Registry irrespective of treatment status. 
Some experts consider skeletal disease to be the most challenging aspect of the disease to treat. 
For example, Deegan et al. argue, having studied 100 patients with GD1 from 3 major referral 
centers in the United Kingdom, who had been treated with ERT, that Gaucher disease should no 
longer be viewed as a disorder with cytopenia causing bleeding, anemia and susceptibility to 
infection due to bone marrow infiltration and splenomegaly, but rather as a principally skeletal 
disorder with disabling effects on bone structure and metabolism, which once established are 
refractory to therapy (17). 
Eliglustat was approved by the US Food and Drug Administration (FDA) on 19 August 2014, the 
European Commission on 19 January 2015, the Health Canada on 21 April 2017, and the 
Australian Therapeutic Goods Administration (TGA) on 10 February 2015. Eliglustat marketing 
authorization applications are being assessed by other health authorities. 
 The efficacy of eliglustat in the treatment of adult patients with GD1 and posology in 
intermediate metabolizers (IMs) and extensive metabolizers (EMs) with a dose of 100 mg BID 
and poor metabolizers (PMs) with a dose of 100 mg QD is based on an extensive clinical 
development program and robust clinical results from 2 adequate, well controlled Phase 3 studies 
(ENGAGE and ENCORE), with supportive long term data from the Phase 2 study and ENGAGE 
and ENCORE extension periods (comprising data from 225 treated adult patients with GD1), and 
from extensive population based pharmacokinetic (PBPK) simulations.  
The benefits of eliglustat treatment include clinically meaningful reductions in organ volumes in 
treatment naïve patients and maintenance of organ volume stability in patients switching from 
ERT; increases in hematological values in treatment naïve patients and maintenance of 
hematological stability in patients switching from ERT (hemoglobin level and platelet count; 
improvement of bone disease in treatment naïve patients and maintenance of bone disease 
stability in patients switching from ERT (bone marrow infiltration and bone mineral density 
(BMD); a well defined mechanism of action and clinical pharmacology profile, and limited safety 
risk. These benefits have been demonstrated across a wide range of GD1 severity. 
The efficacy of eliglustat compares favorably to those of other marketed products for GD1. 
Eliglustat's safety profile is distinct from ERTs, with different common TEAEs, and is unlike 
miglustat, wherein high incidences of diarrhea, weight loss, and tremor result in a therapy with 
limited tolerability and acceptance by treating physicians and patients with GD patients. In 
addition to comparable efficacy to other approved ERTs and a favorable safety profile, eliglustat 
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has certain advantages over ERTs. Enzyme replacement therapy requires regular intravenous (IV) 
infusions (generally every 2 weeks) for the duration of a patient's lifetime, and some patients are 
unable or unwilling to receive ERT. 
Overall, eliglustat shows a favorable safety profile. Based on review of all available safety data, 
the adverse drug reaction profile of eliglustat is characterized by diarrhea, headache, arthralgia, 
flatulence, abdominal pain, fatigue, and nausea, each occurring in <6% of the treated population. 
Most reported adverse events (AEs) were mild in severity, and few patients discontinued due to 
AEs. The risks of greatest concern with eliglustat treatment have not been observed in clinical 
trials, but modeling suggests the possibility for clinically significant electrocardiogram (ECG) 
interval increases, which are mild in scope, in the setting of high eliglustat exposure. Also, since 
eliglustat is extensively metabolized by CYP2D6 and to a lesser extent by CYP3A4, the potential 
for drug-drug interactions that could lead to increases in eliglustat exposure exists.CYP2D6 
phenotype based dosing regimen allows managing potential for drug-drug interactions by 
restricting the patient population to PM, IM, and EM patients only, to ensure that patient exposure 
to eliglustat will remain within the therapeutic range.  
As seen in the Phase 2 study, ENGAGE, and ENCORE, and commensurate with the general 
population, more than 90% of GD1 patients are CYP2D6 PMs, IMs, or EMs, can be safely and 
effectively dosed at 100 mg daily (QD) (PMs) or 100 mg BID (IMs and EMs). The sufficiency of 
the IM and EM proposed dose is supported in particular by the Phase 2 study and ENGAGE, 
where most treatment naïve patients with IM and EM phenotypes were successfully treated at the 
100 mg BID dose.  
While patients of all phenotypes were successfully treated in clinical trials using dose titration, 
Sanofi Genzyme recommends an eliglustat dosing regimen comprised of 100 mg BID for IM and 
EM patients and 100 mg QD for PM patients in the post approval setting. 
During the clinical development program, a limited number of GD1 patients who were ultra rapid 
metabolizers (URMs) (1 in ENGAGE and 4 in ENCORE) were treated with eliglustat. The single 
URM patient in ENGAGE who received 100 mg BID was a nonresponder, suggesting that the 
100 mg dose may result in a maximum concentration (Cmax) too low to be effective for URMs. 
For indeterminate metabolizers, a phenotype cannot be predicted based on genotype, and 
therefore a dose cannot be recommended. Other treatment options are available for this minority 
of patients who would be ineligible for treatment with eliglustat. 
In vitro, eliglustat is a substrate of the efflux transporter P glycoprotein (P-gp). In addition, 
CYP2D6 and to a lesser degree cytochrome P450 3A4 (CYP3A4) are involved in eliglustat 
metabolism in vitro. Consequently, moderate and strong inhibitors of CYP2D6 and CYP3A 
increase its exposure, and potent cytochrome P450 3A (CYP3A) inducers decrease it. In addition, 
mild QTc interval prolongation is predicted to occur in a dose proportional fashion at eliglustat 
plasma concentrations beyond the therapeutic range. For these reasons, the restrictions on 
concomitant medications shown in Table 1 (Concomitant Medications Recommendations for Use 
with Eliglustat) have been proposed in product labeling for eliglustat. These restrictions will help 
ensure that exposure to eliglustat will remain within the range shown to be safe and effective in 
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Previous clinical studies of eliglustat have provided evidence of its efficacy on bone 
manifestations. In Study GZGD00304, a Phase 2 open label study, 56% (n = 10) of the patients 
had reduced bone marrow infiltration of the femur as assessed by MRI after 4 years of treatment 
with eliglustat, and the mean lumbar spine BMD (g/cm2) increased by 9.9% (n = 15, p = 0.0176). 
The mean standard deviation (SD) lumbar spine BMD T-score was in the osteopenic range at 
baseline, -1.63 (1.07), and reached the normal range, -0.88 (1.26), after 4 years of treatment (p = 
0.0139). The mean (SD) lumbar spine BMD Z-score was -1.17 (0.92) at baseline and increased to 
-0.48 (1.07) after 4 years of treatment (p = 0.0044) ( GZGD00304: 48-month period clinical study 
report). 
In the Pivotal Phase 3 Study GZGD02507 where patients were randomized to eliglustat or 
placebo, the total bone marrow infiltration score, as assessed by MRI in lumbar spine and femur, 
decreased by a mean of 1.1 point after 9 months (n = 20) and 2.15 points after 18 months (n = 18) 
in the eliglustat group. The percentage of eliglustat treated patients with a clinically significant 
reduction of at least 2 points in the total bone marrow infiltration score increased from 26% 
(n = 5) after 9 months to 44% (n = 8) after 18 months. After 18 months of eliglustat treatment the 
mean (SD) lumbar spine BMD T score increased from -1.06 (0.82) (n = 17), within the osteopenic 
range, to -0.91 (0.88) (n = 15), within the normal range. Statistically significant reductions in 
plasma MIP-1 β, which is considered to be a biomarker of active bone disease, were observed 
with eliglustat compared with placebo (least squares [LS] mean treatment difference = -43.5%, 
p<0.0001). After 18 months and 30 months of treatment, BMB score had decreased by a mean of 
2.2 points (n=18) and 2.7 (n=15) points, respectively, for the patients originally randomized to 
eliglustat, compared to a mean decrease of 1 point (n=20) and 0.8 (n=16) in those originally 
randomized to placebo, and the percentage of eliglustat-treated patients with a significant 
reduction of at least 2 points in the total BMB score increased to 44% (n=8). After 18 and 30 
months of treatment with eliglustat in an open-label extension phase, the mean lumbar spine Z-
score in all patients increased from -1.208 (1.0546) at Baseline (n=38) to -0.949 (1.1447) (n=31). 
After 30 months and 4.5 years, the Z score further increased to -0.761 (1.0760) (n=31) and -0.478 
(0.7870) (n=9), respectively ( GZGD02507: 39-week [primary analysis period] and 78-week 
clinical study reports). 
In the Pivotal Phase 3 Study GZGD02607 where patients who had reached the Gaucher disease 
therapeutic goals (9) on ERT were randomized to eliglustat or ERT, lumbar spine BMD and total 
bone marrow infiltration score remained stable after 12 months, with similar mean changes in 
both treatment arms. Bone parameters remained stable after 24 months of eliglustat treatment. 
After completion of the primary analysis period (PAP), all patients who transitioned to the long-
term treatment period were treated with eliglustat. Individual disease parameters of spleen 
volume, liver volume, hemoglobin levels and platelet count remained stable through 4 years. With 
regard to BMD, lumbar spine and femur BMD T- and Z-scores were maintained within the 
normal range in patients treated with eliglustat for up to 4 years  (GZGD02607: 52-week [primary 
analysis period] and 104-week clinical study reports). 
In the 3rd Phase 3 study, EDGE GZGD03109, which evaluated the efficacy, safety, and 
pharmacokinetics (PK) of QD versus BID eliglustat in patients with GD1 who have demonstrated 
clinical stability on BID dosing of eliglustat, the majority of patients (83%) reached or maintained 
all 5 therapeutic goals (bone crises, hemoglobin, platelet count, spleen, and liver volume). Marked 
reductions in MIP1 β concentrations assessed as investigational biomarker of active bone disease 
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were observed after eliglustat treatment between 6 and 18 months (GZGD03109: 78-week clinical 
study report). 
More detailed efficacy and safety information is provided in the Investigator Brochure. 
The current study is an open label, interventional multicenter Phase 3b study to evaluate long term 
skeletal response to eliglustat in adult patients who successfully completed the Phase 2 or one of 
the Phase 3 studies (GZGD02507, GZGD02607, or GZGD03109). This study is considered an 
extension of these previous studies and will continue to evaluate long term safety of eliglustat and 
patients quality of life (SF-36).  
The main purpose of this extended treatment study is to evaluate long term skeletal response to 
eliglustat, i.e., change in bone disease after 2 additional years of treatment with eliglustat. The 
elements of bone disease to be evaluated include bone marrow infiltration,  BMD, lytic lesions, 
incidence of fractures and infarcts, bone biomarker levels (P1NP [bone formation], CTX and 
MIP1-β) and Gaucher disease assessments (mobility, bone crisis, and bone pain). These efficacy 
assessments will be collected at baseline and thereafter at twice-yearly (bone biomarkers, Gaucher 
disease assessments) and yearly (bone marrow infiltration, bone mineral density, lytic lesions, 
infarcts, osteonecrosis, fractures) intervals. 
As secondary endpoints the study will continue to evaluate patients’ quality of life (SF-36) and 
biomarkers of GD1 (chitotriosidase, plasma GL-1 and lyso-GL-1). Quality of life questionnaires 
will be administered and biomarkers of GD1 will be measured at baseline and twice-yearly 
thereafter. The safety of eliglustat (ie, incidence of [S]AEs), concomitant medications, changes 
from baseline in physical examinations, hematology will be monitored. Results of pregnancy 
testing for female patients of childbearing potential will be collected. Safety assessments will be 
performed at baseline and twice yearly. Continuous monitoring will be performed for (S)AEs and 
concomitant medications. 
Approximately four of the study centers that participated in the eliglustat Phase 2 or Phase 3 
studies will participate in this study. Participating physicians will enroll patients who successfully 
completed the Phase 2 or Phase 3 studies. The study will run for a minimum of 2 years and up to 
4 years, or until eliglustat is approved and available to patients through reimbursement or through 
the compassionate use (expanded access) program, whichever comes first. 
The study will enroll approximately 32 patients who will be treated with eliglustat and who have 
provided a signed informed consent. 
The study will include a screening period (Day -45 to -1) and a long-term treatment period up to 
4 years or until eliglustat is available to patients through reimbursement or through the 
compassionate use (expanded access) program, whichever comes first. After study completion 
patients will be encouraged to enroll in the ICGG Gaucher Registry. 
Cytochrome P450 (CYP) 2D6 IM, EM and URM patients will be treated with eliglustat 84 mg 
twice daily (BID). Cytochrome P450 (CYP) 2D6 PM patients will be treated with eliglustat 84 mg 
once daily (QD). Doses may have to be decreased when certain concomitant medications are 
administered (see Section 8.5.1.2). 
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Eliglustat tartrate (the drug substance) is an L tartaric acid salt, and exists in plasma as a free base, 
Genz-99067, which is the active moiety. Throughout this document, Genz-99067 is used when 
referring to drug exposure (eg, plasma concentrations), and eliglustat is used in all other instances 
with doses reflecting the tartrate form. 
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5 
STUDY OBJECTIVES 
5.1 
PRIMARY 
To evaluate the long term skeletal response to eliglustat in adult patients who successfully 
completed one of the Phase 2 or Phase 3 studies of eliglustat.  
5.2 
SECONDARY 
The secondary objectives are to evaluate: 
• The safety of eliglustat by (S)AE continuous monitoring,  
• The quality of life by Short Form-36 Health Survey and  
• Biomarkers of GD1 (chitotriosidase, plasma GL-1 and lyso-GL-1). 
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6 
STUDY DESIGN 
6.1 
DESCRIPTION OF THE PROTOCOL 
This is an open label, interventional, non-comparative, multicenter, multinational Phase 3b study 
to evaluate long term skeletal responses to eliglustat, eliglustat safety and effect on quality of life 
in adult patients who successfully completed one of the Phase 2 or Phase 3 studies in the eliglustat 
program. This study is considered an extension of these previous studies with the goal of 
obtaining longer term data. 
6.2 
DURATION OF STUDY PARTICIPATION 
6.2.1 Duration of study participation for each patient 
The duration of study participation for individual patients will be at least 2 years (unless early 
discontinuation occurs) and up to 4 years, or until commercial eliglustat is available to patients 
through reimbursement.  If after 4 years since the beginning of the study eliglustat is not approved 
and available to patients in participating country, patients in this country may continue to receive 
study treatment until eliglustat is available to patients through the compassionate use (expanded 
access) program or is approved and available through reimbursement, whichever comes first. 
The study will include  
• A screening period that can extend from Day -45 to Day-1,  
• A long-term treatment period  up to 4 years or until eliglustat is available to patients 
through reimbursement or through the compassionate use (expanded access) program, 
starting on Day 1 
After study completion, patients will be encouraged to enroll in the ICGG Gaucher Registry. 
6.2.2 Determination of end of clinical trial (all patients) 
The end of the study is defined as the last visit for the last patient. 
6.3 
INTERIM ANALYSIS 
No interim analysis is planned. 
6.4 
STUDY COMMITTEES 
The study data will not be reviewed by a Data Monitoring Committee. The IMP is approved for 
the treatment of Gaucher disease type 1 patients, the study population, by the FDA, EMA and 
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TGA. This is an extension study for patients who have been receiving the IMP for 4-8 years prior 
to enrollment in the study. 
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7 
SELECTION OF PATIENTS 
The patients who have completed successfully the Phase 2 study (GZGD00304) or one of the 
Phase 3 studies (GZGD02507, GZGD02607 or GZGD03109) in the eliglustat program will be 
invited to participate in this study.  
7.1 
INCLUSION CRITERIA 
I 01. The patient must have successfully* completed the Phase 2 (GZGD00304) or a Phase 3 
study (GZGD02507, GZGD02607 or GZGD03109). 
* Successful completion is defined as patients enrolled in one of the above mentioned 
studies who received eliglustat through the end of the study and completed the end of 
study (EOS) visit without having discontinued or being withdrawn prematurely. 
I 02. The patient is willing and able to provide signed informed consent prior to any protocol 
required procedures being performed. 
I 03. Female patients of childbearing potential must have a documented negative pregnancy test 
prior to enrollment and  while they are receiving eliglustat treatment 
I 04. Female patients of childbearing potential must be willing to practice true abstinence in line 
with their preferred and usual lifestyle, or use a medically accepted form of contraception 
(either a barrier method, such as condom or diaphragm + spermicide, or a non-barrier 
method such as oral, injected, or implanted hormonal methods, or an intra-uterine device 
or system ) while receiving eliglustat. 
7.2 
EXCLUSION CRITERIA 
Patients who have met all the inclusion criteria listed in Section 7.1 will be screened for the 
following exclusion criteria that are sorted and numbered in the following 4 subsections:  
7.2.1 Exclusion criteria related to study methodology 
E 01. The patient is unwilling to comply with the requirements of the protocol.   
E 02. The patient has received an investigational product (other than eliglustat) within 30 days 
prior to enrollment. 
E 03. The patient has received miglustat within the 6 months prior to enrollment. 
E 04. The patient has documented prior esophageal varices or liver infarction or current liver 
enzymes (alanine transaminase [ALT]/aspartate aminotransferase [AST]) or Total 
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Bilirubin >2 times the upper limit of normal (ULN), unless the patient has a diagnosis of 
Gilbert Syndrome. 
E 05. The patient has any clinically significant disease other than Gaucher disease, including 
cardiovascular, renal, hepatic, gastrointestinal, pulmonary, neurologic, endocrine, 
metabolic (eg, hypokalemia, hypomagnesemia), psychiatric disease, other medical 
conditions, or serious intercurrent illnesses that may preclude participation in the study. 
E 06. The patient is known to have any of the following: cardiac disease (congestive heart 
failure, recent acute myocardial infarction, bradycardia, heart block, ventricular 
arrhythmia), long QT syndrome, or current treatment with Class IA or Class III 
antiarrhythmic medicinal products. 
E 07. The patient has tested positive for the human immunodeficiency virus (HIV) antibody, 
hepatitis C antibody, or hepatitis B surface antigen. 
E 08. The patient has a history of cancer within 6 months of enrolment, with the exception of 
basal cell carcinoma. 
7.2.2 Exclusion criteria related to eliglustat 
E 09. The patient is a CYP2D6 IM, EM and URM and is taking a strong or moderate CYP2D6 
inhibitor concomitantly with a strong or moderate CYP3A inhibitor. 
E 10. The patient is a CYP2D6 PM having taken a strong CYP3A inhibitor within 2 weeks prior 
to enrolment. 
7.2.3 Exclusion criteria related to the current knowledge of eliglustat 
E 11. If a female patient of childbearing potential has a positive pregnancy test blood β-Human 
Chorionic Gonadotropin  (blood β-hCG) or is breastfeeding prior to first dosing of 
eliglustat in this study, the patient cannot enroll in the study at this time, but may be 
rescreened after the end of the pregnancy, and/or when she is no longer breast feeding, 
provided rescreening takes place before the end of the enrollment period. 
E 12. Women of childbearing potential who are unwilling or unable to be tested for pregnancy.  
Rescreening will be allowed for patients who have failed screening because they met a temporary 
exclusion criterion such as concomitant medication. Patients will be allowed to rescreen only once 
and within 2 weeks of the 1st screening, except for pregnant or breast feeding patients who may be 
rescreened later, as described in E11 above. 
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7.3 
PATIENT DISCONTINUATION/WITHDRAWAL CRITERIA   
Patients are free to discontinue participation or withdraw consent from the study at any time, for 
any reason, and without prejudice to further treatment.  Patients who discontinue/withdraw from 
this study will receive treatment as deemed appropriate by their treating physician. 
A patient's participation in the study also may be discontinued at any time at the discretion of the 
Investigator or Sanofi Genzyme.  The Investigator will contact Sanofi Genzyme Clinical Study 
Director if a patient meets any of the withdrawal criteria.  The following may be justifiable 
reasons for the Investigator or Sanofi Genzyme to remove a patient from the study: 
• The patient was erroneously included in the study. 
• The patient is uncooperative, including failure to appear at one or more study visits, or is 
not compliant with taking study medication. 
• The patient develops an exclusion criterion or concurrent disease. 
• The patient receives other investigational product(s) during the course of this study. 
• The patient experiences an AE that is considered intolerable by the patient or investigator. 
• Sanofi Genzyme terminates the study. 
• If a female patient of childbearing potential has a positive pregnancy test  blood β-hCG or 
is lactating after first dosing with eliglustat in this study, the patient may remain in the 
study, but must suspend eliglustat till delivery and while breast feeding. The maximum 
duration of such an IMP suspension is 12 months. During the IMP suspension the patient 
must maintain compliance with all the other study requirements, except for the 
radiological examinations that are prohibited in pregnant women. 
If a patient meets at least 1 of the following criteria, the Investigator must notify the Sanofi 
Genzyme Clinical Study Director.  The Investigator and Sanofi Genzyme will review the clinical 
status of the patient and will determine if the patient should be withdrawn from the study.   
• The patient’s hemoglobin level falls below 80 g/L and remains below 80 g/L when the test 
is repeated within approximately 2 weeks. 
• The patient’s platelet count falls below 50 x 109/L and remains below 50 x 109/L when the 
test is repeated within approximately 2 weeks,  
• The patient experiences a clinically significant bleeding episode assessed by the 
Investigator as related to a low platelet count. 
• The patient experiences a decline in Gaucher disease status that, in the opinion of the 
Investigator, warrants discontinuation from the study (eg, repeated bone crises, clinically 
significant increases in liver or spleen volumes). 
Patient who discontinue or withdraw from participation in the study will be contacted in order to 
obtain information about the reason(s) for discontinuation/withdrawal and for collection of AEs, if 
any. The patient will be asked to return to the clinic to complete all study 
discontinuation/withdrawal assessments. The Investigator will describe the reason for 
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discontinuation on the Completion/Discontinuation case report form. Patients who 
discontinue/withdraw participation from the study will not be replaced. A summary of all 
discontinuations will be included in the final study report. 
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8 
STUDY TREATMENTS 
8.1 
INVESTIGATIONAL MEDICINAL PRODUCT 
Eliglustat is supplied as 84 mg hard gelatin capsules for oral administration. Each 84 mg capsule 
contains 100 mg of eliglustat tartrate, which is equivalent to 84 mg of eliglustat free base. 
CYP2D6 IM, EM and URM patients will receive 84 mg BID. CYP2D6 PM will receive 84 mg 
QD. 
Given the rarity of the CYP2D6 URM phenotype, experience on treating these patients is limited. 
To make sure they are properly treated, additional monitoring will be performed in this patients 
(see Section 10.2.3.3). 
Eliglustat will be taken orally with water. 
For patients on BID dosing regimen, doses should be taken roughly every 12 hours (one capsule 
in the morning and one capsule in the evening). For patients on QD dosing regimen, doses should 
be taken at about the same time every day. 
Eliglustat absorption is not affected by food. Therefore, it can be taken with or without food at the 
convenience of the patient. 
8.1.1 IMP dose reduction 
Certain concomitant medications require a reduction in the dose of eliglustat (see Section 8.5.1.2). 
8.1.2 IMP temporary suspension 
Treatment with eliglustat should be suspended in patients who require short-term treatment with 
• A strong or moderate CYP2D6 inhibitor with a strong or moderate CYP3A inhibitor in 
CYP2D6 EMs and IMs. 
• A strong or moderate CYP3A inhibitor in CYP2D6 PMs. 
These medications can be used for up to 2 weeks at a time.  
All IMP temporary suspension should be documented in the IMP distribution CRF. 
Up to 2 episodes of eliglustat suspension are allowed per year. 
If these medications are required for longer treatment periods, the investigator should consult with 
the Clinical Study Director. 
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If a patient becomes pregnant during her participation in the study she may remain in the study, 
but must suspend eliglustat until delivery and while breast feeding. The maximum duration of 
such an IMP suspension is 12 months. During the IMP suspension the patient must maintain 
compliance with all the other study requirements, except for the radiological examinations that are 
prohibited in pregnant women. 
8.2 
PACKAGING AND LABELING 
Each bottle of IMP 84 mg capsules will contain 60 capsules and will be labeled with a single 
panel label. This will be provided in induction-sealed, high density polyethylene bottles with child 
resistant closure caps. Label text will include, at a minimum, the study protocol number, the 
contents of the bottle, lot number, use-by date, storage conditions and Genzyme name and 
address. Also included on the label will be any required cautionary statements and any other 
requirements, in accordance with regulations specific to each country where this study is 
conducted. 
Packaging is in accordance with the administration schedule. The content of the labeling is in 
accordance with the local regulatory specifications and requirements. 
8.3 
STORAGE CONDITIONS AND SHELF LIFE 
The IMP must be stored at a controlled room temperature of 20°C-25°C, with excursions 
permitted from 15°C - 30°C, in a secured location.  
Investigators or other authorized persons (eg, pharmacists) are responsible for storing the IMP in a 
secure and safe place in accordance with local regulations, labeling specifications, policies, and 
procedures.  
Control of IMP storage conditions, especially control of temperature (eg, controlled room 
temperature storage) and information on in-use stability and instructions for handling the IMP 
should be managed according to the rules provided by Sanofi Genzyme. 
8.4 
RESPONSIBILITIES 
The Investigator, the hospital pharmacist, or other personnel allowed to store and dispense the 
IMP will be responsible for ensuring that the IMP used in the clinical trial is securely maintained 
as specified by the Sponsor and in accordance with applicable regulatory requirements. 
All IMP will be dispensed in accordance with the Investigator's prescription and it is the 
Investigator's responsibility to ensure that an accurate record of IMP issued and returned is 
maintained. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc.) should be promptly notified to 
Genzyme. Some deficiencies may be recorded through a complaint procedure. 
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A potential defect in the quality of IMP may be subject to initiation of a recall procedure by 
Genzyme. In this case, the Investigator will be responsible for promptly addressing any request 
made by Genzyme, in order to recall IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party, allow the IMP to be 
used other than as directed by this clinical trial protocol, or dispose of IMP in any other manner. 
8.4.1 Treatment accountability and compliance 
At each visit the Investigator or his/her delegate will question patients to assess treatment 
compliance and will remind patient of the importance of excellent treatment compliance. 
IMP accountability: 
• Treatment units are returned by the patient at each visit; 
• The Investigator or delegate records the dosing information on the appropriate page(s) of 
the CRF; 
• The monitor in charge of the study then checks the CRF data by comparing them with the 
IMP that he/she has retrieved and the treatment log forms. 
8.4.2 Return and/or destruction of treatments 
All used, partially-used or unused treatment bottles will be retrieved from each patient at each site 
visit. A detailed treatment log of the patient returned bottles (used, partially used, or unused) to 
the site will be established.  Any IMP destroyed on site or returned to Genzyme will be 
documented in the treatment log and associated Sponsor form(s).  The Investigator will not 
destroy any IMP unless Genzyme provides written authorization. Please refer to the study 
Pharmacy Manual for further details.   
8.5 
CONCOMITANT MEDICATION 
Patients will be monitored continuously for changes in the use of concomitant medications 
(introduction of new medications and changes in the dose or regimen of preexisting medications).  
Patients will be instructed to report to the Investigator any changes in concomitant medications 
before these changes are made, or, in the case of changes made in emergency situations, as soon 
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8.5.1 INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF 
INTERACTION  
8.5.1.1 ANTIARRHYTHMICS 
Because eliglustat is predicted to cause mild increases in ECG intervals (PR, QTc, and QRS) at 
substantially elevated eliglustat plasma concentrations, use of eliglustat is prohibited in 
combination with Class IA and Class III antiarrhythmic medications. Patients who require long 
term treatment with any of these medications should be removed from the study. 
8.5.1.2 EFFECT OF OTHER DRUGS ON ELIGLUSTAT 
Eliglustat is metabolized primarily by CYP2D6 and to a lesser extent by CYP3A4. Concomitant 
administration of substances affecting CYP2D6 or CYP3A4 activity (ie, CYP2D6/CYP3A 
inhibitors and CYP3A strong inducer) may alter Genz-99067 plasma concentrations. Grapefruit 
products contain one or more components that inhibit CYP3A and can increase plasma 
concentrations of eliglustat. Grapefruit and grapefruit products including grapefruit juice, but not 
grapefruit seeds, are prohibited at any time during the study.  
Table 1 provides an overview of allowed and prohibited inhibitors and inducers for chronic use, 
as determined by the patient’s CYP2D6 phenotype.  
Table 1 - Concomitant Medications Recommendations for Use with Eliglustat 
Category of Inducer / Inhibitor 
CYP2D6 
Phenotype 
Strong 
CYP3A 
Inducer 
Weak 
CYP3A 
Inhibitor 
ALONE 
Moderate 
CYP3A 
Inhibitor 
ALONE 
Strong CYP3A 
Inhibitor 
ALONE 
Moderate 
CYP2D6 
Inhibitor 
ALONE 
Strong 
CYP2D6 
Inhibitor 
ALONE 
Moderate or Strong CYP3A Inhibitor 
and Moderate or Strong CYP2D6 
Inhibitor COMBINED 
Poor 
Metabolizer 
Not 
recommended 
Use 
with 
caution 
Not 
recommended 
Contraindicated 
Allowed 
Allowed 
Moderate 
CYP3A 
Inhibitor and 
Moderate or 
Strong 
CYP2D6 
Inhibitor 
COMBINED 
As moderate 
CYP3A 
inhibitor alone 
(Not 
recommended) 
Strong CYP3A 
Inhibitor and 
Moderate or 
Strong CYP2D6 
Inhibitor 
COMBINED 
As Strong 
CYP3A alone 
(Contraindicated) 
Intermediate 
and 
Extensive 
Metabolizer 
Not 
recommended 
Allowed 
at usual 
dose of 
84 mg 
BID 
Use with 
caution 
Use with 
caution 
Use with 
caution 
84 mg 
once 
daily 
Contraindicated 
Ultra-Rapid 
Metabolizer 
Not 
recommended 
Allowed 
Allowed 
Allowed 
84 mg 
once 
daily 
84 mg 
once 
daily 
Contraindicated 
 
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8.5.1.3 EFFECT OF ELIGLUSTAT ON OTHER DRUGS 
In vivo eliglustat was found to be an inhibitor of P-glycoprotein (P-gp; 1.5-fold increase in 
digoxin area under the plasma concentration versus time curve from 0 to the real time 
corresponding to the last concentration above the lower limit of quantification) and an inhibitor of 
CYP2D6 (2.1-fold in metoprolol area under the plasma concentration versus time curve 
extrapolated to infinity [area under the concentration-time curve (AUC)]), consistent with in vitro 
data showing eliglustat to be an inhibitor of CYP2D6 and of P-gp. Eliglustat may increase the 
plasma concentration of those substances and should be used with caution in combination with a 
P-gp or a CYP2D6 substrate. Lower doses of such drugs may be required. 
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9 
ASSESSMENT OF INVESTIGATIONAL MEDICINAL PRODUCT 
9.1 
PRIMARY ENDPOINT 
The main purpose of this extended treatment study is to evaluate long term skeletal responses to 
eliglustat after 2 additional years of treatment with eliglustat.  Five common skeletal 
manifestations of Gaucher disease will be assessed:  
1) Mobility, bone pain and bone crisis, as assessed by the Gaucher Disease clinical assessments; 
2) bone marrow infiltration; 3) BMD; 4) Lytic lesions, osteonecrosis, fractures and infarcts; 5) 
bone biomarkers  
9.1.1 Gaucher disease clinical assessments (mobility, bone pain, bone crisis). 
Patients will be asked to rate  
• Current mobility  
- 
Unrestricted mobility 
- 
Walks with difficulty 
- 
Walks with orthopedic aid 
- 
Requires wheelchair 
- 
Bedridden  
• Level of bone pain during the last 4 weeks as 
- 
None 
- 
Very mild 
- 
Mild 
- 
Moderate 
- 
Severe 
- 
Extreme 
• In addition, investigators will report the number of bone crisis since the previous 
assessment. Bone crisis is defined as pain with acute onset, which requires immobilization 
of the affected area, narcotics for relief of pain, and may be accompanied by one or more 
of the following: periosteal elevation, elevated white blood cell count, fever, or 
debilitation of >3 days.   
Gaucher disease clinical assessments will be performed at screening and then yearly. 
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9.1.2 Bone marrow infiltration  
Will be assessed on sagittal T1 and T2 weighted MRI views of the lumbar spine and coronal T1 
and T2 weighted MRI views of the entire bilateral femurs. A categorical bone marrow infiltration 
score will be calculated based on the amount of fat in the basivertebral vein region and the T1 and 
the T2 signals (18).  
Bone marrow infiltration will be measured at screening and then yearly. 
Bone MRI will be read locally and centrally. The central reads will be used for analysis. 
9.1.3 Bone mineral density (BMD)  
Will be measured by DXA of both hips and the lumbar spine. T and Z scores, and bone mineral 
densities will be provided by the DXA report. 
Bone mineral density will be measured at screening and then yearly. 
9.1.4 Lytic lesions, osteonecrosis, fractures and infarcts 
Lytic lesions, osteonecrosis, infarcts and fractures will be assessed on bone MRI and bone X-Ray.  
9.1.5 Bone biomarkers 
Will include 
• Total procollagen type 1 N-terminal propeptide (P1NP), a marker of bone formation 
• C-terminal telopeptide of type 1 collagen (CTx), a marker of bone resorption  
• MIP 1 β 
These biomarkers will be measured at baseline and then every 6 months. 
These markers will be measured by a central laboratory. 
Results of centrally read assessments will be available to Investigators during or after the study 
depending on the assessment. 
9.2 
SECONDARY ENDPOINT(S) 
9.2.1 Efficacy endpoints 
Blood levels of biomarkers of GD1 (chitotriosidase, plasma GL-1 and lyso-GL-1) will be 
evaluated at baseline and twice yearly. These markers will be measured in a central laboratory. 
Measured values as well as absolute and percent changes from study baseline and eliglustat 
baseline will be summarized. 
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9.2.2 Safety endpoints 
9.2.2.1 Adverse events 
Refer to Section 10.5 to 10.7 for details. 
Continuous monitoring will be performed for (S)AEs and concomitant medications.  
Results of pregnancy testing for female patients of childbearing potential will be collected. 
9.2.2.2 Laboratory safety variables 
The clinical laboratory data consist of hematology analyses. These analyses will be conducted by 
local laboratories at each site. Clinical laboratory values will be analyzed after conversion into 
standard international units. International units will be used in all listings and tables. 
9.2.2.3 Physical examination 
Complete physical exam will be performed including complete neurological exam with ocular 
motility test. 
9.2.3 Patient Reported Outcomes  
Patients’ quality of life (Short Form-36 Health survey) will be evaluated at baseline and twice-
yearly.  
The SF-36 survey is a self-reported questionnaire used to measure a patient’s profile of functional 
health and well-being as well as psychometrically-based physical and mental health summary 
measures. The SF-36 is a multi-purpose, short-form health survey with 36 questions. Accordingly, 
the SF-36 has proven useful in surveys of general and specific populations, comparing the relative 
burden of diseases, and in differentiating the health benefits produced by a wide range of different 
treatments (19). A recall period of 1 week will be used. 
9.3 
PHARMACOKINETICS 
Although PK samples are not scheduled, unscheduled PK samples may be collected in individual 
cases after discussion between the investigator and Genzyme. 
9.3.1 Sampling time 
Sampling times will be decided in each case after discussion between the investigator and 
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9.3.2 Pharmacokinetics handling procedure 
Special procedures for collection, storage and shipping of plasma will be described in the 
operational manual for handling samples. 
9.3.3  Bioanalytical method 
Plasma Genz-99067 will be measured with a validated liquid chromatography coupled to tandem 
mass spectrometry method with a lower limit of quantification of 0.2 ng/mL.  
9.3.4 Pharmacokinetics parameters 
Not applicable. 
9.4 
FUTURE USE OF SAMPLES 
Not all of the samples collected during this study may be required for the tests planned in this 
clinical trial. For subjects who have consented to it, the samples that are unused or left over after 
testing  may be used for other research purposes (excluding genetic analysis) related to lysosomal 
storage disorders  than those defined in the present protocol.  
These other research analyses will help to understand either disease subtypes or drug response, or 
to develop and/or validate a bioassay method, or to identify new drug targets or biomarkers.  
These samples will remain labelled with the same identifiers than the one used during the study 
(ie, subject ID). They will be transferred to a Sponsor site (or a subcontractor site), which can be 
located outside of the country where the study is conducted. Genzyme has included safeguards for 
protecting subject confidentiality and personal data (see Section 14.3 and Section 14.5). 
9.5 
APPROPRIATENESS OF MEASUREMENTS  
9.5.1 Primary endpoint 
The primary endpoint, bone disease, will be assessed using measurements that have been 
validated for Gaucher disease or for other more common bone conditions. 
Gaucher disease clinical assessments (mobility, bone pain and bone crisis) are established clinical 
parameters of bone lesions in Gaucher disease (8). 
Magnetic Resonance Imaging is an established procedure to evaluate bone marrow not only for 
Gaucher disease, but also in oncology (20). It avoids the exposure to ionizing radiations observed 
with computerized tomography. A semi-quantitative method of measuring bone marrow 
infiltration by MRI has been developed and validated (18). It requires only standard equipment. 
Therefore, it can be implemented in study sites worldwide. Central reading of the images by 
trained readers will increase the quality and decrease the variability of the results. 
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Bone MRI also allows detecting lytic lesions, osteonecrosis, infarction and fractures. 
Bone MRI will be performed yearly, a standard frequency in patients who are expected to be 
stable after multiple years of eliglustat treatment. 
Dual-energy X-ray absorptiometry is the gold standard to measure BMD. A yearly frequency has 
been established as the time necessary to see significant changes in BMD. 
Femur and spine X-Ray will serve mainly as references for additional follow up of the patients 
once they have left the study, when MRI may not been widely available or traditionally used to 
follow patients. 
Bone biomarkers 
Total procollagen type 1 N-terminal propeptide (P1NP), a marker of bone formation, and 
C-terminal telopeptide of type 1 collagen (CTx), a marker of bone resorption, have been 
recommended as reference markers of fracture risk assessment in age related osteoporosis by a 
working group of the International Osteoporosis Foundation and the International Federation of 
Clinical Chemistry and Laboratory Medicine (21). 
MIP1β has been shown to display moderate sensitivity and specificity to detect osteonecrosis in 
Gaucher disease (22). 
9.5.2 Secondary endpoints 
The use of patient reported outcomes as provided by quality of life questionnaires is encouraged 
by health authorities and entities paying for health care. In the absence of a validated tool to 
specifically assess disease burden in Gaucher disease type I patients, SF-36 has been selected 
because it is validated in multiple diseases and is available in multiple languages. 
Chitotriosidase is an established biomarker in Gaucher disease and is thought to reflect the total 
body burden in Gaucher cells, except in patients who carry 1 or 2 null allele. Its level is related to 
the amount of GL-1, the substrate that accumulates as a result of the decreased activity of mutated 
acid β-glucosidase. Its level is elevated in untreated patients, especially the more severely affected 
ones, and decreases when patients improve on ERT or SRT (see for example (23)(24). 
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10 
STUDY PROCEDURES 
10.1 
GENERAL CONSIDERATIONS  
Imaging: 
Central reading will be set up for liver and spleen MRI and bone imaging. All imaging procedures 
will be performed locally and the images copied onto an electronic support and shipped to a 
central facility for interpretation. Interpretation by local specialists will be used for the usual care 
of the patients, but its results will not be entered in the clinical database. 
Urine Pregnancy test: 
In addition to the blood pregnancy tests performed at every visit, prior to performing any 
radiologic study assessment (imaging), a urine pregnancy test must be performed and the result 
reviewed by the radiologist/technician who will document that the patient has a negative 
pregnancy test result by signing, dating, and noting the time of the review on the pregnancy result 
report. In case of a positive pregnancy test, radiologic study assessments will not be performed.  
In addition female patients must perform a urine pregnancy test at home every 4 weeks while 
receiving eliglustat treatment. 
Any positive urine pregnancy test will be verified with a blood pregnancy test. All pregnancy tests 
results must be documented in the patient file. 
Laboratory tests: 
All laboratory tests will be done at the local laboratory at the exception of those for biomarkers, 
which will be done in central laboratories. 
10.2 
VISIT SCHEDULE 
All visits will be outpatient visits. However, for patients who have to travel long distances to 
come to a site, overnight stay in the hospital or in a lodging facility nearby may be used. 
10.2.1 Screening period 
Screening will be performed between 45 and 1 day before Day 1 of the study. Screening can be 
performed at the time of the EOS visit of the previous study the patient was enrolled in. 
Final GZGD00304, GZGD02507, GZGD02607 and GZGD03109 study assessments may serve as 
entry evaluation for this study if performed less than 3 month for laboratory testing, 1 year for 
bone imaging and 6 months for other assessments. 
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However, safety (S)AE, concomitant medication and prior medication history, physical 
examinations, HIV antibody, hepatitis C antibody, or hepatitis B surface antigen, blood pregnancy 
test, height will have to be performed in all cases.  
Patients will be assigned a unique ID number. This new ID number as well as the number of the 
previous study the patient was enrolled in and his/her ID number in that study will appear in the 
clinical database. 
For some assessments it will be possible to use results from the end of study visit of the previous 
eliglustat study the patient was enrolled in. For others they will need to be performed anew. See 
detail below. 
The screening procedures do not have to be performed over 2 visits. Scheduling will be based on 
investigator, patient and resources availability. 
After completion of all the screening assessments, the investigator will review their results to 
confirm that each patient meets all the inclusion criteria and none of the exclusion criteria before 
scheduling the patient for the Day 1 visit. 
10.2.1.1 Clinical information 
• Demographic data will be entered in the corresponding CRF. 
• Previous medical/surgical history entered in the CRF of the previous study should not be 
re-entered in the Medical history CRF of this study, but will be used in the analysis of this 
study.  
• The following categories of medico/surgical events are considered part of the 
medical/surgical history of the patient and should be entered in the Medical/surgical 
history CRF: 
- 
AEs started during the previous study, which are closed at the time of the screening 
visit and are still considered clinically significant by the investigator at the time of the 
screening visit. 
- 
Medical/surgical events started after the follow-up phone call of the previous study 
and before the ICF signing in the current study, whether ongoing or closed, if they are 
considered clinically significant by the investigator.  
- 
Clinically significant abnormal laboratory test results at Visits 1 and 2 (Screening 
period) 
• AEs started during the previous study, which are ongoing at the time of the screening visit 
should be entered in the AE CRF regardless of whether the patient had a gap in eliglustat 
treatment after the end of the previous study, or the end of study visit of the previous study 
and the screening visit of this study are concomitant. 
• Concomitant medications: Any concomitant medication the patient is taking at the time of 
screening or took during the previous 30 days. This should include eliglustat if the last 
dose of eliglustat in the previous study was taken 30 days or less prior to the screening 
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visit. ERT should be included if the patient was on ERT during the period between the end 
of the previous study and the screening visit.  
• Complete physical exam including weight and height 
• Gaucher disease clinical assessments 
• SF-36, to be completed at the study site by the patient before any other study assessment. 
10.2.1.2 Imaging 
• X-Rays of both femurs and lumbar spine, unless the same exams were performed as part 
of the previous study 1 year or less prior. 
• DXA of both hips and the lumbar spine, unless the same exams were performed as part of 
the previous study 1 year or less prior. 
• MRI of both femurs and lumbar spine, unless the same exams were performed as part of 
the previous study 1 year or less prior,  
• Spleen and liver MRI, unless the same exams were performed as part of the previous study 
6 months or less prior. 
Details on technical specifications and quality control for these procedures will be provided in the 
vendor manual and must be strictly followed. 
10.2.1.3 Laboratory tests 
To be collected only if there were performed more than 3 months ago as part of the previous study 
the patient was enrolled in and the results are available, except for the viral serologies and the 
blood pregnancy test (only for female of child bearing potential), which will need to be performed 
in all cases. 
• Viral serologies: human immunodeficiency virus antibody, and hepatitis C antibody or 
hepatitis B surface antigen. 
• Complete blood count (hemoglobin, hematocrit, red blood cell count, white blood cell 
count and differential, platelet count, red blood cell parameters, reticulocytes) 
• Liver functions tests: AST, ALT, Alkaline phosphatase (AP), total bilirubin, albumin, 
GGT. 
• Biomarkers: serum chitotriosidase; plasma MIP1-β; serum P1NP; serum CTX that must be 
collected after overnight fasting; plasma GL-1; plasma lyso-GL-1. 
• For women of child bearing potential: blood pregnancy test.  
10.2.2 Day 1 visit 
• Complete physical exam 
• For women of child bearing potential: blood pregnancy test 
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10.2.3 Semiannual visits 
Semiannual visits will be performed at 6 month intervals (+/-14 days) in reference to the Day 1 
visit. 
10.2.3.1 Clinical assessments 
• Complete physical exam. 
• IMP compliance. 
• AE 
• Concomitant medications 
• SF-36 
10.2.3.2 Laboratory tests 
• CBC (includes red blood cell count, hemoglobin, hematocrit, mean corpuscular volume, 
mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, reticulocyte 
count, white blood cell count and differential, platelet count). 
• Biomarkers: serum chitotriosidase; plasma MIP1-β; serum P1NP; serum CTX that must be 
collected after overnight fasting; plasma GL-1; plasma lyso-GL-1. 
• For women of child bearing potential: blood pregnancy test 
10.2.3.3 Special provision for URM patients 
CYP2D6 URM patients will have liver and spleen MRI and hematology performed every 6 month 
till week 52. However, the frequency of liver and spleen MRI and hematology can be increased to 
every 3 month till week 52 at the discretion of the Investigator. After week 52 CYP2D6 URMs 
patients will follow the standard schedule. 
10.2.4 Annual visits 
Annual visits will be performed once a year (+/-14 days) in reference to the Day 1 visit. 
In addition to the assessments of the semiannual visits the following assessments will be 
performed. 
10.2.4.1 Clinical assessments 
• Gaucher assessments 
10.2.4.2 Imaging 
• DXA of both hips and the lumbar spine 
• MRI of entire bilateral femur and lumbar spine 
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• Liver and spleen MRI 
• At the 2nd and 4th anniversaries only, X-Ray of femur and lumbar spine. 
10.2.5 Study completion or patient discontinuation/withdrawal 
10.2.5.1 Clinical assessments 
• Complete physical exam including weight 
• Gaucher disease clinical assessments 
• SF-36 
• IMP compliance. 
• AE 
• Concomitant medications 
10.2.5.2 Laboratory assessments 
• CBC 
• Biomarkers 
10.2.5.3 Imaging 
• X-Ray femur and spine, unless it was performed less than 2 years prior 
• DXA hip and spine, unless it was performed less than 1 year prior 
• Bone MRI, unless it was performed less than 1 year prior 
• Liver and spleen MRI, unless it was performed less than 1 year prior 
10.3 
DEFINITION OF SOURCE DATA 
Source Data are defined as original documents, data and records. This includes but is not limited 
to hospital records, clinic and office charts, study-specific source document worksheets, phone 
logs, memoranda, evaluation checklists, laboratory requisitions and reports, MRI, DXA, X-Ray 
reports, local laboratory reports, medication dispensing reports and any other documents 
regarding the patient.  
10.4 
HANDLING OF PATIENT TEMPORARY OR PERMANENT TREATMENT 
DISCONTINUATION AND OF PATIENT STUDY DISCONTINUATION  
The IMP should be continued whenever possible. In case the IMP is discontinued, it should be 
determined whether the discontinuation can be made temporarily; permanent IMP discontinuation 
should be a last resort. Any IMP discontinuation should be fully documented in the patient’s 
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medical file and the IMP Accountability CRF. In any case, the patient should remain in the study 
as long as possible. 
10.4.1 Temporary treatment discontinuation with investigational medicinal product(s) 
Temporary treatment discontinuation may be considered by the Investigator because of suspected 
AEs. Reinitiating of treatment with the IMP will be done under close and appropriate clinical/and 
or laboratory monitoring once the Investigator will have considered according to his/her best 
medical judgment that the responsibility of the IMP(s) in the occurrence of the concerned event 
was unlikely and if the selection criteria for the study are still met, and after discussion with 
Genzyme (refer to Section 7.1  and 7.2). 
For all temporary treatment discontinuations, duration should be recorded by the Investigator in 
the IMP administration CRF.  
If a patient becomes pregnant during her participation in the study she may remain in the study, 
but must suspend the IMP till delivery and while breast feeding. The maximum duration of such 
an IMP suspension is 12 months. During the IMP suspension the patient must maintain 
compliance with all the other study requirements, except for the radiological examinations that are 
prohibited in pregnant women. 
10.4.2 Permanent treatment discontinuation with investigational medicinal product(s) 
Permanent treatment discontinuation is any treatment discontinuation associated with the 
definitive decision from the Investigator or the patient not to re-expose the patient to the IMP 
during the duration of the study. 
10.4.3 Criteria for permanent treatment discontinuation 
The patients may withdraw from treatment with the IMP if they decide to do so, at any time and 
irrespective of the reason, or this may be the Investigator’s decision. All efforts should be made to 
document the reasons for treatment discontinuation and this should be documented in the e-CRF. 
The use of eliglustat is prohibited in combination with Class IA and Class III antiarrhythmic 
medications. See Section 8.5.1.1 for detail. 
Patients requiring medications incompatible with eliglustat because of drug-drug interaction for 
longer than 2 weeks should be discontinued from the study. See Section 8.5.1.2 for detail. 
Handling of patients after permanent treatment discontinuation 
Patients will be followed-up according to the study procedures as specified in this protocol up to 
the scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up, whichever comes last, unless the patient is lost to follow up. 
If possible, and after the permanent discontinuation of treatment, the patients will be assessed 
using the procedure normally planned for the last visit at study completion or patient 
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All cases of permanent treatment discontinuation should be recorded by the Investigator in the 
appropriate pages of the CRF when considered as confirmed. 
10.4.4 Procedure and consequence for patient withdrawal from study. 
The patients may withdraw from the study before study completion if they decide to do so, at any 
time and irrespective of the reason. 
If possible, the patients are assessed using the procedure normally planned for the visit at study 
completion or patient discontinuation/withdrawal. 
For patients who fail to return to the site, the Investigator should make the best effort to recontact 
the patient, and to determine his/her health status, including at least his/her vital status. Attempts 
to contact such patients must be documented in the patient’s records (eg, times and dates of 
attempted telephone contact, receipt for sending a registered letter). 
The statistical analysis plan will specify how these patients lost to follow-up for their primary 
endpoints will be considered. 
Patients who have withdrawn from the study cannot be enrolled again in the study. Their 
inclusion and treatment numbers must not be reused.  
10.5 
OBLIGATION OF THE INVESTIGATOR REGARDING SAFETY REPORTING 
10.5.1 Definitions of adverse events  
10.5.1.1 Adverse event 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and which does not necessarily have to have a 
causal relationship with this treatment. 
10.5.1.2 Serious adverse event 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• Results in death, or 
• Is life-threatening, or 
 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which 
 
the patient 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 were more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, or 
• Results in persistent or significant disability/incapacity, or 
• Is a congenital anomaly/birth defect 
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• Is a medically important event 
Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations, such as important medical events that may not 
be immediately life-threatening or result in death or hospitalization but may jeopardize the 
patient or may require medical or surgical intervention (ie, specific measures or corrective 
treatment) to prevent one of the other outcomes listed in the definition above. 
Note: The following list of medically important events is intended to serve as a guideline for 
determining which condition has to be considered as a medically important event. The list is 
not intended to be exhaustive nor indicative of expected AEs: 
• Any reason for intensive treatment in an emergency room or at home 
• Cancers diagnosed during the study or aggravated during the study (only if judged 
unusual/significant by the Investigators in oncology studies) 
• Chronic neurodegenerative diseases (newly diagnosed) or aggravated during the study 
(only if judged unusual/significant by the Investigators in studies assessing specifically the 
effect of a study drug on these diseases). 
10.5.1.3 Adverse event of special interest 
An adverse event of special interest (AESI) is an AE (serious or non-serious) of scientific and 
medical concern specific to Genzyme product or program, for which ongoing monitoring and 
immediate notification by the Investigator to Genzyme is required. Such events may require 
further investigation in order to characterize and understand them. Adverse events of special 
interest may be added or removed during a study by protocol amendment. 
For this study the following AEs will be considered as AESI and should be reported as such to 
GPE: 
• Clinically significant cardiac arrhythmias detected by ECG or Holter monitoring that do 
not meet criteria for an SAE. 
• Syncope from any cause.  
• Pregnancy of a female patient as well as pregnancy occurring in a female partner of a male 
patient. 
• Pregnancy will be qualified as an SAE only if it fulfills one of the seriousness criteria (see 
Section 10.5.1.2). 
In the event of pregnancy in a female patient, IMP should be suspended. See Section 10.4.3 for 
detail. 
Female patients will be instructed to notify the investigator immediately if they discover they are 
pregnant. Pregnant female patients will be discontinued from the study.  
Male patients will be instructed to notify the investigator immediately if they discover that their 
sexual partner is pregnant. 
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If the investigator learns of a report of pregnancy at any time after signing the informed consent, 
the investigator should follow the instructions in Section 10.5.4 to contact the sponsor within 
24 hours; however, the investigator will be asked to complete the Pregnancy forms rather than 
SAE forms. The patient will be followed until the outcome of the pregnancy is known (eg, live 
birth or stillbirth). The investigator will be responsible for this follow-up. 
Follow-up of the pregnancy in a female patient or in a female partner of a male patient is 
mandatory until the pregnancy outcome has been determined, unless prohibited by local 
regulations. 
• Symptomatic overdose (serious or non-serious) with IMP 
- 
A symptomatic overdose (accidental or intentional) with the IMP is an event suspected 
by the Investigator or spontaneously notified by the patient (not based on systematic 
pills count) and defined as administration of a quantity of IMP per administration or 
per day, which is above the maximum recommended dose according to the authorized 
product information  
If overdose is suspected, the patient will be asked to suspend the IMP immediately and 
come back to the site for appropriate monitoring. 
Asymptomatic overdose has to be reported as a standard AE. 
10.5.2 General guidelines for reporting adverse events 
• Patients for whom the screening visit of this study is done at the same time as the EOS 
visit of the previous eliglustat study they were enrolled in, the safety follow-up phone 
scheduled 30-37 days after the EOS visit of the previous study will not be done. Instead, 
these patients will be monitored according to the standard safety procedures of this study. 
The Ethics Committees (and Local Health Autority, if required) at the affected sites will 
be notified.  
• All AEs, regardless of seriousness or relationship to IMP, spanning from the signature of 
the informed consent form until the end of study visit, or the last IMP administration for 
patient with early termination, are to be recorded on the corresponding page(s) or screen(s) 
of the CRF.  
• The following categories of medico/surgical events are considered part of the 
medical/surgical history of the patient and should be entered in the Medical/surgical 
history CRF: 
- 
AEs started during the previous study, which are closed at the time of the screening 
visit and are still considered clinically significant by the investigator at the time of the 
screening visit. 
- 
Medical/surgical events started after the follow-up phone call of the previous study 
and before the ICF signing in the current study, whether ongoing or closed, if they are 
considered clinically significant by the investigator.  
• AEs started during the previous study, which are ongoing at the time of the screening visit 
should be entered in the AE CRF regardless of whether the patient had a gap in eliglustat 
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treatment after the end of the previous study, or the end of study visit of the previous study 
and the screening visit of this study are concomitant. 
• Whenever possible, diagnosis or single syndrome should be reported instead of symptoms. 
The Investigator should specify the date of onset, intensity, action taken with respect to 
IMP, corrective treatment/therapy given, additional investigations performed, outcome, 
and his/her opinion as to whether there is a reasonable possibility that the AE was caused 
by the IMP or by the study procedure(s).  
• The Investigator should take appropriate measures to follow all AEs until clinical recovery 
is complete and laboratory results have returned to normal, or until progression has been 
stabilized, or until death, in order to ensure the safety of the patients. This may imply that 
observations will continue beyond the last planned visit per protocol, and that additional 
investigations may be requested by the monitoring team up to as noticed by Genzyme. 
Patients who experience an ongoing SAE or an AESI at the prespecified study end-date, 
should be monitored until follow-up is no longer considered medically necessary or the 
patient is lost to follow-up.  
• When treatment is prematurely discontinued, the patient’s observations will continue until 
the end of the study visit as defined by the protocol for that patient, unless the patient is 
lost to follow up. 
• Clinically significant laboratory abnormalities after Visit 3 (Day 1) are to be recorded as 
AEs only if:  
- 
Symptomatic and/or  
- 
Requiring either corrective treatment or consultation, and/or  
- 
Leading to IMP discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or  
- 
Defined as an AESI 
10.5.3 Instructions for reporting serious adverse events 
In the case of occurrence of an SAE, the Investigator must immediately: 
• ENTER (within 24 hours) the information related to the SAE in the appropriate screens of 
the e-CRF; the system will automatically send a notification to the monitoring team after 
approval of the Investigator within the e-CRF or after a standard delay. 
• SEND (preferably by fax or e-mail) a photocopy of all examinations carried out and the 
dates on which these examinations were performed, to the representative of the monitoring 
team whose name, fax number, and email address appear on the clinical trial protocol. 
Care should be taken to ensure that the patient's identity is protected and the patient's 
identifiers in the clinical trial are properly mentioned on any copy of a source document 
provided to Genzyme. For laboratory results, include the laboratory normal ranges. 
• All further data updates should be recorded in the e-CRF as appropriate, and further 
documentation as well as additional information (for laboratory data, concomitant 
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medications, patient status, etc.) should be sent (by fax or e-mail) to the monitoring team 
within 24 hours of knowledge of the SAE. In addition, every effort should be made to 
further document any SAE that is fatal or life threatening within a week (7 days) of the 
initial notification. 
• A back-up plan (using a paper CRF process) is available and should be used when the 
e-CRF system does not work. 
Any SAE brought to the attention of the Investigator at any time after the end of the study for the 
patient and considered by him/her to be caused by the IMP with a reasonable possibility, should 
be reported to GPE. 
10.5.4 Guidelines for reporting adverse events of special interest   
For AESIs, Genzyme must be informed immediately (ie, within 24 hours), as per SAE notification 
guidelines described in Section 10.5.3, even if not fulfilling a seriousness criterion, using the 
corresponding pages of the CRF (to be sent) or screens in the e-CRF. Instructions for AE 
reporting are summarized in Table 2. 
Table 2 - Summary of adverse event reporting instructions 
Case Report Form completion 
Event category 
Reporting 
timeframe 
Specific events in this 
category 
AE 
form 
Safety 
Complementary 
Form 
Other 
specific 
forms 
Adverse Event (non-
SAE, non-AESI) 
Routine 
Any AE that is not SAE or AESI 
Yes 
No 
No 
Serious Adverse Event 
(non-AESI or AESI) 
Expedited (within 
24 hours) 
Any AE meeting seriousness 
criterion per Section 10.5.1.2 
Yes 
Yes 
No 
Adverse Event of 
Special Interest  
Expedited (within 
24 hours) 
 Pregnancy and any AE listed in 
Section 10.5.1.3 
Yes 
Yes 
Yes 
10.6 
OBLIGATIONS OF THE SPONSOR 
During the course of the study, Genzyme will report in an expedited manner: 
• All SAEs that are both unexpected and at least reasonably related to the IMP (SUSAR), to 
the regulatory authorities, IECs/IRBs as appropriate and to the Investigators.    
• All SAEs that are expected and at least reasonably related to the IMPs to the regulatory 
authorities, according to local regulations. 
Any other AE not listed as an expected event in the Investigator’s Brochure will be considered 
unexpected. 
Genzyme will report all safety observations made during the conduct of the trial in the clinical 
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10.7 
ADVERSE EVENTS MONITORING 
All events will be managed and reported in compliance with all applicable regulations, and 
included in the final clinical study report. 
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11 
STATISTICAL CONSIDERATIONS 
11.1 
DETERMINATION OF SAMPLE SIZE 
This study will enroll all eligible patients having completed one of the Phase 2 or Phase 3 trials 
(approximately 32 patients). 
This is an extension study. No sample size calculation has been performed. The patients who will 
be enrolled have already been receiving the IMP for approximately 4 to 8 years prior to the start 
of the study. The aim of the study is to continue collecting long term data on the efficacy and 
safety of the IMP. 
11.2 
DISPOSITION OF PATIENTS 
Screened patients are defined as any patient who met the study criteria and signed the informed 
consent.  
11.3 
ANALYSIS POPULATIONS 
11.3.1 Efficacy populations 
Primary and secondary efficacy will be evaluated in the Full Analysis Set population (FAS) 
defined as all patients enrolled who receive at least 1 dose of eliglustat treatment in this study. 
11.3.2 Safety population 
Safety analyses will be performed on the Safety Set, which is equivalent to the FAS for this study. 
11.3.3 Pharmacokinetic population 
Pharmacokinetic (PK) population: a subset of safety population containing patients who have at 
least one PK sample taken. Patients will be analyzed in the treatment group corresponding to 
those defined in the safety population. 
11.4 
STATISTICAL METHODS 
All endpoints will be summarized descriptively; no hypothesis testing will be performed. 
Descriptive statistics include those for continuous (n, mean, median, minimum, maximum), 
categorical (n, percent), cumulative incidence (n, percent) or incidence rate (n/year) outcomes, as 
appropriate. Calculations and summaries will include all non-missing data at a given time point, 
imputation will not be performed. 
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Analysis will be performed on safety and efficacy endpoints at 2 points in this study: 
• After the last patient enrolled has completed 2 years of treatment (two-year analysis 
period)  
• When the study is complete    
For the PAP, response will be calculated both in reference to study entry (study period) and to 
first eliglustat treatment (eliglustat treatment period).  Because patients will enter this study 
having been treated with eliglustat for various durations, two baselines will be used:  
• Study baseline, defined as status at study entry; and  
• Eliglustat baseline, defined at status at first dose of eliglustat in the previous Phase 2 or 
Phase 3 study.   
In reference to the study period, skeletal response will be evaluated for all patients at the 2 year 
point by measured values (eg, category of bone pain, or bone density value in g/cm2) and changes 
from baseline (eg, shift in category of bone pain or absolute and percent change from baseline in 
BMD g/cm2 or incidence over 2 years, as appropriate).   
In reference to the period of eliglustat treatment, skeletal response will be evaluated 2 years after 
study entry, but results will be grouped by duration of eliglustat treatment at the time of analysis.  
The actual groupings will depend on the distribution of treatment duration at the time of analysis, 
eg, 6 yr., 7 yr., 8 yr. or 6-8 yr., 8-10 yr. 
When the study has completed, summaries will be performed for both the total on-study period, 
and the eliglustat treatment period, as described above.   
11.4.1 Extent of study treatment exposure and compliance 
The extent of study treatment exposure and compliance will be assessed and summarized by 
actual treatment received within the safety population. 
Duration of IMP exposure is defined as:  last dose date – first dose date + 1 day, regardless of 
unplanned intermittent discontinuations.   
A given period of administration will be considered noncompliant if the patient takes less than 
90% or more than 105% of the planned dose of treatment as required by the protocol.  No 
imputation will be made for patients with missing or incomplete data. Treatment compliance, 
above-planned and under-planned dosing percentages will be summarized descriptively (N, Mean, 
SD, Median, Min, and Max). The percentage of patients with compliance categorized as <80%, 
80%-90%, 90%-105%, >105% will be summarized. 
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11.4.2 Analyses of efficacy endpoints 
11.4.2.1 Analysis of primary efficacy endpoint(s) 
Five common skeletal manifestations of Gaucher disease will be summarized separately. A single 
composite endpoint will not be constructed.   
1. Mobility, bone crisis and pain: Category of mobility status and bone pain, as well as 
number of new bone crises, will be summarized. Additionally shifts in category of 
mobility and pain from study and eliglustat baseline will be presented. 
2. Bone marrow infiltration:  Bone marrow infiltration score will be summarized both 
continuously and categorically. Reported values and changes from study and eliglustat 
baseline will be summarized as data is available.   
Category of infiltration score will be constructed and summarized:   
Mild: 0 to 4 
Moderate: 5 to 8 
Severe: 9-16 
Shifts in category from study and eliglustat baseline will be summarized.  
1. BMD: Bone mineral density in (g/cm2), as well as T and Z scores, will be summarized by 
time point as well as absolute and percent changes from study and eliglustat baseline.  
2. Lytic lesions, fractures, infarctions and osteonecrosis. Incidence of new or worsening lytic 
lesions, new or worsening AVN, new or worsening infarctions and new fractures will be 
summarized at the 2 year and end of study time points. Annual incidence rates may also be 
calculated and summarized.   
3. Bone biomarkers: Levels of P1NP, CTx and MIP 1 β, as well as absolute and percent 
changes from study or eliglustat baseline will be summarized.  
11.4.2.2 Analyses of secondary efficacy endpoints 
Biomarker: Biomarkers will be summarized as measured values, absolute and percent change 
from eliglustat and study baseline. 
11.4.3 Analyses of safety data 
Adverse experience will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) Version 18.0 or higher; all adverse experiences will be summarized by body system 
and MedDRA preferred term overall, by relationship and severity and seriousness. All deaths will 
be summarized. 
Physical examinations, routine laboratory assessments (chemistry and hematology), biomarkers 
and pregnancy testing for female patients of childbearing potential will be summarized at each 
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time point.  Additionally, the change from study baseline and/or eliglustat baseline, as 
appropriate, may be summarized. Concomitant medications will be reported. 
Observation period  
The observation of safety data will be as follows:  
• Screening is from signed informed consent to the day before the 1st dose of IMP is 
administered.     
• TEAE observation period is from first to last dose of IMP in this study. Patients with an 
SAE or AESI should be followed until resolution or when follow-up is no longer 
considered medically necessary, or the patient is lost to follow-up. 
All safety analyses will be performed on the Safety population using the following common rules: 
The baseline value is defined generally as the last available value before first dose of IMP in this 
study.   
Adverse event incidence tables will present by system organ class (SOC) (sorted by 
internationally agreed order), preferred term (PT) sorted by decreasing frequency for each 
treatment group, the number (n) and percentage (%) of patients experiencing an AE.  Multiple 
occurrences of the same event in the same patient will be counted only once in the tables within a 
treatment Phase. The denominator for computation of percentages is the safety population within 
each treatment group. 
AE incidence tables for the AESIs below will be generated. 
• Clinically significant cardiac arrhythmias detected by ECG or Holter monitoring that do 
not meet criteria for an SAE. 
• Syncope from any cause. 
Death: The following deaths summaries will be generated: 
• Number (%) of patients who died and reasons for death if collected in death report form 
summarized on the safety population 
• All AEs leading to death (death as an outcome on the AE CRF page as reported by the 
Investigator), by primary SOC and PT, showing number (%) of patients sorted by 
internationally agreed order of SOC and alphabetic order of PT  
• TEAE leading to death (death as an outcome on the AE CRF page as reported by the 
Investigator) by primary SOC and PT showing number (%) of patients sorted by 
internationally agreed order of SOC and alphabetic order of PT.  
11.4.4 Analyses of pharmacokinetic and pharmacodynamic variables 
A listing of Genz-99067 plasma concentrations will be provided. 
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11.4.5 Analyses of Patient Reported Outcomes (Health-related Quality of Life/health 
economics variables 
The SF-36 Health Status Survey Version 2 is made up of 36 questions, each of which has a 
weighted response associated with it.  The 36 questions are combined into various groupings to 
form eight scales, which are then further combined to form two overall summary measures, the 
Physical Component Summary (PCS) and Mental Component Summary (MCS).  These will be 
generated and summarized at each visit, as well as changes from eliglustat and study baseline, as 
described in the statistical analysis plan.  
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12 
ETHICAL AND REGULATORY CONSIDERATIONS 
12.1 
ETHICAL AND REGULATORY STANDARDS 
This clinical trial will be conducted by Genzyme, the Investigator, delegated Investigator staff and 
Sub investigator, in accordance with the principles laid down by the 18th World Medical 
Assembly (Helsinki, 1964) and all applicable amendments laid down by the World Medical 
Assemblies, and the ICH guidelines for good clinical practice (GCP), all applicable laws, rules 
and regulations. 
This clinical trial will be recorded in a free, publicly accessible, internet-based registry, no later 
than 21 days after the first patient enrollment, in compliance with applicable regulatory 
requirements and with Sponsor public disclosure commitments.  
12.2 
INFORMED CONSENT 
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, and under the Investigator's responsibility, should fully inform the patient of all 
pertinent aspects of the clinical trial including the written information giving approval/favorable 
opinion by the Ethics Committee (Institutional Review Board/Independent Ethics Committee 
(IRB/IEC)). All participants should be informed to the fullest extent possible about the study, in 
language and terms they are able to understand. 
Prior to a patient’s participation in the clinical trial, the written informed consent form should be 
signed, name filled in and personally dated by the patient or by the patient’s legally acceptable 
representative, and by the person who conducted the informed consent discussion. A copy of the 
signed and dated written informed consent form will be provided to the patient.  
The informed consent form used by the Investigator for obtaining the patient's informed consent 
must be reviewed and approved by Genzyme prior to submission to the appropriate Ethics 
Committee (IRB/IEC) for approval/favorable opinion. 
The Investigator (according to applicable regulatory requirements), or a person designated by the 
Investigator, should fully inform the patient (and the parent[s] or guardian[s]) of all pertinent 
aspects of the clinical trial including the written information given approval/favorable opinion by 
the ethics committee (IRB/IEC). All participants should be informed to the fullest extent possible 
about the study in language and terms they are able to understand. 
Prior to a patient’s participation in the clinical trial, the informed consent form should be signed, 
name filled in and personally dated by the patient, and by the person who conducted the informed 
consent discussion.   
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The informed consent form and the assent form used by the Investigator for obtaining the 
Patient’s Informed Consent must be reviewed and approved by the Sponsor prior to submission to 
the appropriate Ethics Committee (IRB/IEC) for approval/favorable opinion. 
12.3 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) 
As required by local regulation, the Investigator or Genzyme must submit this clinical trial 
protocol to the appropriate IRB/IEC, and is required to forward to the respective other party  a 
copy of the written and dated approval/favorable opinion signed by the Chairman with  IRB/IEC 
composition. 
The clinical trial (study number, clinical trial protocol title and version number), the documents 
reviewed (clinical trial protocol, informed consent form, Investigator’s Brochure, Investigator’s 
curriculum vitae [CV], etc.) and the date of the review should be clearly stated on the written 
(IRB/IEC) approval/favorable opinion. 
IMP will not be released at the study site and the Investigator will not start the study before the 
written and dated approval/favorable opinion is received by the Investigator and Genzyme. 
During the clinical trial, any amendment or modification to the clinical trial protocol should be 
submitted to the IRB/IEC before implementation, unless the change is necessary to eliminate an 
immediate hazard to the patients, in which case the IRB/IEC should be informed as soon as 
possible. It should also be informed of any event likely to affect the safety of patients or the 
continued conduct of the clinical trial, in particular any change in safety. All updates to the 
Investigator’s Brochure will be sent to the IRB/IEC. 
A progress report is sent to the IRB/IEC at least annually and a summary of the clinical trial’s 
outcome at the end of the clinical trial.  
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13 
STUDY MONITORING 
13.1 
RESPONSIBILITIES OF THE INVESTIGATOR(S) 
The Investigator is required to ensure compliance with all procedures required by the clinical trial 
protocol and with all study procedures provided by Genzyme (including security rules). The 
Investigator agrees to provide reliable data and all information requested by the clinical trial 
protocol (with the help of the CRF, Discrepancy Resolution Form [DRF] or other appropriate 
instrument) in an accurate and legible manner according to the instructions provided and to ensure 
direct access to source documents by Sponsor representatives. 
If any circuit includes transfer of data particular attention should be paid to the confidentiality of 
the patient's data to be transferred. 
The Investigator may appoint such other individuals as he/she may deem appropriate as Sub 
investigators to assist in the conduct of the clinical trial in accordance with the clinical trial 
protocol. All Sub investigators shall be appointed and listed in a timely manner. The Sub 
investigators will be supervised by and work under the responsibility of the Investigator. The 
Investigator will provide them with a copy of the clinical trial protocol and all necessary 
information. 
13.2 
RESPONSIBILITIES OF THE SPONSOR 
Genzyme of this clinical trial is responsible to regulatory authorities for taking all reasonable 
steps to ensure the proper conduct of the clinical trial as regards ethics, clinical trial protocol 
compliance, and integrity and validity of the data recorded on the CRFs. Thus, the main duty of 
the monitoring team is to help the Investigator and Genzyme maintain a high level of ethical, 
scientific, technical and regulatory quality in all aspects of the clinical trial. 
At regular intervals during the clinical trial, the site will be contacted, through monitoring visits, 
letters or telephone calls, by a representative of the monitoring team to review study progress, 
Investigator and patient compliance with clinical trial protocol requirements and any emergent 
problems. These monitoring visits will include but not be limited to review of the following 
aspects: patient informed consent, patient recruitment and follow-up, SAE documentation and 
reporting, AESI documentation and reporting, AE documentation, IMP allocation, patient 
compliance with the IMP regimen, IMP accountability, concomitant therapy use and quality of 
data. 
13.3 
SOURCE DOCUMENT REQUIREMENTS 
According to the ICH GCP, the monitoring team must check the CRF entries against the source 
documents. The informed consent form will include a statement by which the patient allows the 
Sponsor’s duly authorized personnel, the Ethics Committee (IRB/IEC), and the regulatory 
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authorities to have direct access to original medical records  which support the data on the CRFs 
(eg, patient's medical file, appointment books, original laboratory records, etc.). These personnel, 
bound by professional secrecy, must maintain the confidentiality of all personal identity or 
personal medical information (according to confidentiality and personal data protection rules). 
13.4 
USE AND COMPLETION OF CASE REPORT FORMS (CRFS) AND ADDITIONAL 
REQUEST 
It is the responsibility of the Investigator to maintain adequate and accurate CRFs (according to 
the technology used) designed by the Sponsor to record (according to Sponsor instructions) all 
observations and other data pertinent to the clinical investigation in a timely manner. All CRFs 
should be completed in their entirety to ensure accurate interpretation of data. 
Should a correction be made, the corrected information will be entered in the e-CRF overwriting 
the initial information. An audit trail allows identifying the modification.  
Data are available within the system to the Sponsor as soon as they are entered in the e-CRF. 
The computerized handling of the data by the Sponsor may generate additional requests (DRF) to 
which the Investigator is obliged to respond by confirming or modifying the data questioned. The 
requests with their responses will be managed through the e-CRF. 
13.5 
USE OF COMPUTERIZED SYSTEMS 
The complete list of computerized systems used for the study is provided in a separate document 
which is maintained in the Sponsor and Investigator study files. 
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14 
ADDITIONAL REQUIREMENTS 
14.1 
CURRICULUM VITAE 
A current copy of the CV describing the experience, qualification and training of each 
Investigator and Sub investigator will be signed, dated and provided to the Sponsor prior to the 
beginning of the clinical trial. 
14.2 
RECORD RETENTION IN STUDY SITES 
The Investigator must maintain confidential all study documentation, and take measures to 
prevent accidental or premature destruction of these documents. 
The Investigator should retain the study documents at least 15 years after the completion or 
discontinuation of the clinical trial. 
However, applicable regulatory requirements should be taken into account in the event that a 
longer period is required. 
The Investigator must notify the Sponsor prior to destroying any study essential documents 
following the clinical trial completion or discontinuation. 
If the Investigator's personal situation is such that archiving can no longer be ensured by him/her, 
the Investigator shall inform the Sponsor and the relevant records shall be transferred to a 
mutually agreed upon designee.  
14.3 
CONFIDENTIALITY 
All information disclosed or provided by the Sponsor (or any company/institution acting on their 
behalf), or produced during the clinical trial, including, but not limited to, the clinical trial 
protocol, personal data in relation to the patients, the CRFs, the Investigator's Brochure and the 
results obtained during the course of the clinical trial, is confidential, prior to the publication of 
results. The Investigator and any person under his/her authority agree to undertake to keep 
confidential and not to disclose the information to any third party without the prior written 
approval of the Sponsor. 
However, the submission of this clinical trial protocol and other necessary documentation to the 
Ethics committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same 
obligation of confidentiality. 
The Sub investigators shall be bound by the same obligation as the Investigator. The Investigator 
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The Investigator and the Sub investigators shall use the information solely for the purposes of the 
clinical trial, to the exclusion of any use for their own or for a third party's account. 
14.4 
PROPERTY RIGHTS 
All information, documents and IMP provided by the Sponsor or its designee are and remain the 
sole property of the Sponsor. 
The Investigator shall not and shall cause the delegated Investigator staff /Sub investigator not to 
mention any information or the Product in any application for a patent or for any other intellectual 
property rights. 
All the results, data, documents and inventions, which arise directly or indirectly from the clinical 
trial in any form, shall be the immediate and exclusive property of the Sponsor. 
The Sponsor may use or exploit all the results at its own discretion, without any limitation to its 
property right (territory, field, continuance). The Sponsor shall be under no obligation to patent, 
develop, market or otherwise use the results of the clinical trial. 
As the case may be, the Investigator and/or the Sub investigators shall provide all assistance 
required by the Sponsor, at the Sponsor's expense, for obtaining and defending any patent, 
including signature of legal documents. 
14.5 
DATA PROTECTION 
• The patient's personal data, which are included in the Sponsor database shall be treated in 
compliance with all applicable laws and regulations; 
• When archiving or processing personal data pertaining to the Investigator and/or to the 
patients, the Sponsor shall take all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party. 
• The Sponsor also collects specific data regarding Investigator as well as personal data 
from any person involved in the study which may be included in the Sponsor’s databases, 
shall be treated by both the Sponsor and the Investigator in compliance with all applicable 
laws and regulations. 
Subject race or ethnicity (White, Black, Asian, American Indian or Alaska native, Native 
Hawaiian or Other Pacific Islander, Hispanic or Latino, Jewish descent –Ashkenazi or Sephardic, 
Japanese descent, Chinese descent) will be collected in this study because these data are required 
by several regulatory authorities (eg, on Japanese population for the Pharmaceuticals Medical 
Devices Agency (PMDA) in Japan, or on Chinese population for the China Food and drug 
administration (CFDA) in China). 
Analyses of Subject genetic data will be conducted as described in the protocol as this is needed 
for pharmacogenetic analyses required for the purpose of the study or by regulatory authorities. 
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The data collected in this study will only be used for the purpose(s) of the study and to document 
the evaluation of the benefit/ risk ratio, efficacy and safety of the product(s). They may be further 
processed if they have been anonymized. 
14.6 
INSURANCE COMPENSATION 
The Sponsor certifies that it has taken out a liability insurance policy covering all clinical trials 
under its sponsorship.  This insurance policy is in accordance with local laws and requirements. 
The insurance of the Sponsor does not relieve the Investigator and the collaborators from any 
obligation to maintain their own liability insurance policy. An insurance certificate will be 
provided to the IECs/IRBs or regulatory authorities in countries requiring this document.  
14.7 
SPONSOR AUDITS AND INSPECTIONS BY REGULATORY AGENCIES 
For the purpose of ensuring compliance with the clinical trial protocol, GCP and applicable 
regulatory requirements, the Investigator should permit auditing by or on the behalf of the 
Sponsor and inspection by regulatory authorities. 
The Investigator agrees to allow the auditors/inspectors to have direct access to his/her study 
records for review, being understood that these personnel is bound by professional secrecy, and as 
such will not disclose any personal identity or personal medical information. 
The Investigator will make every effort to help with the performance of the audits and 
inspections, giving access to all necessary facilities, data, and documents. 
As soon as the Investigator is notified of a planned inspection by the authorities, he will inform 
the Sponsor and authorize the Sponsor to participate in this inspection. 
The confidentiality of the data verified and the protection of the patients should be respected 
during these inspections. 
Any result and information arising from the inspections by the regulatory authorities will be 
immediately communicated by the Investigator to the Sponsor. 
The Investigator shall take appropriate measures required by the Sponsor to take corrective 
actions for all problems found during the audit or inspections. 
14.8 
PREMATURE DISCONTINUATION OF THE STUDY OR PREMATURE CLOSE-OUT OF 
A SITE 
14.8.1 By the Sponsor  
The Sponsor has the right to terminate the participation of either an individual site or the study at 
any time, for any reason, including but not limited to the following:  
• The information on the product leads to doubt as to the benefit/risk ratio; 
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• Patient enrollment is unsatisfactory; 
• The Investigator has received from the Sponsor all IMP, means and information necessary 
to perform the clinical trial and has not included any patient after a reasonable period of 
time mutually agreed upon; 
• Non-compliance of the Investigator or Sub investigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP; 
• The total number of patients are included earlier than expected; 
In any case the Sponsor will notify the Investigator of its decision by written notice. 
14.8.2 By the Investigator 
The Investigator may terminate his/her participation upon thirty (30) days' prior written notice if 
the study site or the Investigator for any reason becomes unable to perform or complete the 
clinical trial.  
In the event of premature discontinuation of the study or premature close-out of a site, for any 
reason whatsoever, the appropriate IRB/IEC and regulatory authorities should be informed 
according to applicable regulatory requirements. 
14.9 
CLINICAL TRIAL RESULTS 
The Sponsor will be responsible for preparing a clinical study report and to provide a summary of 
study results to the Investigator. 
14.10 PUBLICATIONS AND COMMUNICATIONS  
It is anticipated that publications may result from this study. This will be specified at an 
appropriate time. 
The Investigator undertakes not to make any publication or release pertaining to the study and/or 
results of the study prior to the Sponsor’s written consent, being understood that the Sponsor will 
not unreasonably withhold its approval. 
As the study is being conducted at multiple sites, the Sponsor agrees that, consistent with 
scientific standards, a primary presentation or publication of the study results based on global 
study outcomes shall be sought. However, if no multicenter publication is submitted, underway or 
planned within twelve (12) months of the completion of this study at all sites, the Investigator 
shall have the right to publish or present independently the results of this study in agreement with 
other Investigators and stakeholders. The Investigator shall provide the Sponsor with a copy of 
any such presentation or publication for review and comment at least 30 days in advance of any 
presentation or submission for publication.  In addition, if requested by the Sponsor, any 
presentation or submission for publication shall be delayed for a limited time, not to exceed 
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90 days, to allow for filing of a patent application or such other justified measures as the Sponsor 
deems appropriate to establish and preserve its proprietary rights.  
The Investigator shall not use the name(s) of the Sponsor and/or its employees in advertising or 
promotional material or publication without the prior written consent of the Sponsor. The Sponsor 
shall not use the name(s) of the Investigator and/or the collaborators in advertising or promotional 
material or publication without having received his/her and/or their prior written consent(s). 
The Sponsor has the right at any time to publish the results of the study. 
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15 
CLINICAL TRIAL PROTOCOL AMENDMENTS 
All appendices attached hereto and referred to herein are made part of this clinical trial protocol. 
The Investigator should not implement any deviation from, or changes of the clinical trial protocol 
without agreement by the Sponsor and prior review and documented approval/favorable opinion 
from the IRB/IEC of an amendment, except where necessary to eliminate an immediate hazard(s) 
to clinical trial patients, or when the change(s) involves only logistical or administrative aspects of 
the trial. Any change agreed upon will be recorded in writing, the written amendment will be 
signed by the Investigator and by the Sponsor and the signed amendment will be filed with this 
clinical trial protocol. 
Any amendment to the clinical trial protocol requires written approval/favorable opinion by the 
IRB/IEC prior to its implementation, unless there are overriding safety reasons. 
In some instances, an amendment may require a change to the informed consent form. The 
Investigator must receive an IRB/IEC approval/favorable opinion concerning the revised 
informed consent form prior to implementation of the change and patient signature should be re-
collected if necessary. 
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16 
BIBLIOGRAPHIC REFERENCES 
1. 
Brady RO. Gaucher's disease: past, present and future. Baillieres Clin Haematol. 
1997;10(4):621-634. 
2. 
Charrow J, Andersson HC, Kaplan P, Kolodny EH, Mistry P, Pastores G, et al. The 
Gaucher registry: demographics and disease characteristics of 1698 patients with Gaucher disease. 
Arch Intern Med. 2000;160(18):2835-43. 
3. 
Cox TM. Gaucher disease: understanding the molecular pathogenesis of sphingolipidoses. 
J Inherit Metab Dis. 2001;24 (Suppl 2):106-121;discussion 87-8. 
4. 
Elstein D, Abrahamov A, Dweck A, Hadas-Halpern I, Zimran A. Gaucher disease: 
pediatric concerns. Paediatr Drugs. 2002;4(7):417-426. 
5. 
Grabowski GA, Petsko GA, Kolodny EH. Gaucher Disease. In: Valle D. et al, eds. The 
Online Metabolic and Molecular Bases of Inherited Disease. New York: NY: McGraw-Hill; 2010: 
Chapter 146.  DOI Reference Number: http://dx.doi.org/10.1036/ommbid.176. Accessed June 
2013. 
6. 
Grabowski GA. Gaucher disease: gene frequencies and genotype/phenotype correlations. 
Genet Test. 1997;1(1):5-12. 
7. 
Altarescu G, Schiffmann R, Parker CC, Moore DF, Kreps C, Brady RO, et al. 
Comparative efficacy of dose regimens in enzyme replacement therapy of type I Gaucher disease. 
Blood Cells Mol Dis. 2000; 26(4):285-290. 
8. 
Barranger JA, O’Rourke E.  Lessons learned from the development of enzyme therapy for 
Gaucher disease.  J. Inherit  Metab Dis. 2001;24 (Suppl. 2):89-96;discussion 87-8. 
9. 
Pastores GM, Weinreb NJ, Aerts H, Andria G, Cox TM, Giralt M et al.  Therapeutic goals 
in the treatment of Gaucher disease. Semin Hematol.  2004;41(4 Suppl 5):4-14. 
10. 
Vellodi A, Bembi B, de Villemeur TB, Collin-Histed T, Erikson A, Mengel E et al.  
Management of neuronopathic Gaucher disease: a European consensus.  J Inhert Metab Dis.  
2001;24(3):319-27. 
11. 
Weinreb NJ, Charrow J, Andersson HC, Kaplan P, Kolodny EH, Mistry P et al. 
Effectiveness of enzyme replacement therapy in 1028 patients with type 1 Gaucher disease after 2 
to 5 years of treatment: a report from the Gaucher Registry. Am J Med. 2002;113(2):112-9. 
12. 
Aerts JMFG, Yasothan U, Kirkpatrick P.  Velaglucerase alfa. Nat Rev Drug Discov. 
2010;9(11):837-838. 
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13. 
Cox TM. Eliglustat tartrate, an orally active glucocerebroside synthase inhibitor for the 
potential treatment of Gaucher disease and other lysosomal storage diseases. Curr Opin Investig 
Drugs. 2010;11(10):1169-81. 
14. 
Marshall J, Ashe KM, Bangari D, McEachern KA, Chuang WL, Pacheco J, et al. Substrate 
reduction augments the efficacy of enzyme therapy in a mouse model of Fabry disease. PLoS 
One. 2010;5(11);e15033. 
15. 
Mistry PK, Liu J, Yang M, Nottoli T, McGrath J, Jain D, et al. Glucocerebrosidase gene-
deficient mouse recapitulates Gaucher disease displaying cellular and molecular dysregulation 
beyond the macrophage. Proc Natl Acad Sci. 2010:107(45):19473-8. 
16. 
Rosenbloom BE, Weinreb NJ. Bone disease in patients with Gaucher disease Expert Rev. 
Endocrinol. Metab. 2014;9(2):153–162. 
17. 
Deegan PB, Pavlova E, Tindall J, Stein PE, Bearcroft P, Mehta A, et al. Osseous 
manifestations of adult Gaucher disease in the era of enzyme replacement therapy. Medicine 
(Baltimore) 2011;90 (1):52-60. 
18. 
Maas M, van Kuijk C, Stoker J, Hollak CE, Akkerman EM, Aerts JF, 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;229(2):554-61. 
19. 
Rogers WH, Wittink H, Wagner A, Cynn D, Carr DB. Assessing individual outcomes 
during outpatient multidisciplinary chronic pain treatment by means of an augmented SF-36. Pain 
Med. 2000;1(1):44-54. 
20. 
Hwang S, Panicek DM. Magnetic resonance imaging of bone marrow in oncology, Part 2. 
Skeletal Radiol. 2007;36(11):1017-27. 
21. 
Vasikaran S, Eastell R, Bruyère O, Foldes AJ, Garnero P, Griesmacher A, et al. Markers 
of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a 
need for international reference standards. Kanis JA: IOF-IFCC Bone Marker Standards Working 
Group. Osteoporos Int. 2011; Feb 22(2):391–420. 
22. 
Pavlova EV, Deegan PB & Cox TM. Biomarkers for osteonecrosis in Gaucher disease. 
Expert Opin. Med. Diagn. 2012;6(1):1-13. 
23. 
van Dussen L, Hendriks EJ, Groener JE, Boot RG, Hollak CE, Aerts JM. Value of plasma 
chitotriosidase to assess non-neuronopathic Gaucher disease severity and progression in the era of 
enzyme replacement therapy. J Inherit Metab Dis. 2014;37(6):991–1001. 
24. 
Lukina E, Watman N, Dragosky M, Pastores GM, Arreguin EA, Rosenbaum H, et al. 
Eliglustat, an investigational oral therapy for Gaucher disease type 1: Phase 2 trial results after 4 
years of treatment. Blood Cells Mol Dis. 2014; Dec;53(4):274-6.  
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Appendix A 
Contraceptive guidance and collection of pregnancy information 
DEFINITIONS 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy. 
3. Postmenopausal female 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). However, in the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient. 
- 
Females on hormone replacement therapy (HRT) and whose menopausal status is in 
doubt will be required to use one of the non-hormonal highly effective contraception 
methods if they wish to continue their HRT during the study. Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment. 
CONTRACEPTION GUIDANCE 
Male participants 
No contraception requirements. 
Female participants 
Female patients of childbearing potential are eligible to participate if they are willing to practice 
true abstinence in line with their preferred and usual lifestyle, or if they agree to use a medically 
accepted form of contraception (either a barrier method, such as condom or diaphragm + 
spermicide, or a non-barrier method such as oral, injected, or implanted hormonal methods, or an 
intra-uterine device or system ) consistently and correctly while receiving eliglustat. 
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COLLECTION OF PREGNANCY INFORMATION 
Male participants with partners who become pregnant 
• The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study treatment. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for procedure. 
Female participants who become pregnant 
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on the 
appropriate form and submitted to the Sponsor within 24 hours of learning of a 
participant's pregnancy. The participant will be followed to determine the outcome of the 
pregnancy. The Investigator will collect follow-up information on the participant and the 
neonate, and the information will be forwarded to the Sponsor. Generally, follow-up will 
not be required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or absence 
of anomalies) or indication for procedure. 
• Any pregnancy complication or elective termination of a pregnancy will be reported as an 
AE or SAE. A spontaneous abortion is always considered to be an SAE and will be 
reported as such.  While the Investigator is not obligated to actively seek this information 
in former study participants, he or she may learn of an SAE through spontaneous 
reporting. 
• Any female participant who becomes pregnant while participating in the study must stop 
study treatment as soon as a pregnancy is confirmed and will be either withdrawn from the 
study or remain in the study. If a pregnant patient decides to remain in the study she must 
suspend the IMP till delivery and while breast feeding. The maximum duration of such an 
IMP suspension is 12 months. During the IMP suspension the patient must maintain 
compliance with all the other study requirements, except for the radiological examinations 
that are prohibited during pregnancy. 
(electronic 
 
 
 
2.0)


AMENDED CLINICAL TRIAL PROTOCOL 02  
31-Jul-2017 
EFC13781 
Version number: 1 
 
SF-36v2® Health Survey © 1992, 2002 QualityMetric Incorporated and Medical Outcomes Trust.  All rights reserved. 
SF-36® is a registered trademark of Medical Outcomes Trust. 
 
(SF-36v2® Health Survey Standard, Canada (English)) 
Appendix B 
Document(s) related to the assessment of 1 (or more) endpoint(s) 
Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) Questionnaire 
(electronic 
 
 
 
2.0)


AMENDED CLINICAL TRIAL PROTOCOL 02  
31-Jul-2017 
EFC13781 
Version number: 1 
(electronic 
 
 
2.0)


AMENDED CLINICAL TRIAL PROTOCOL 02  
31-Jul-2017 
EFC13781 
Version number: 1 
(electronic 
 
 
2.0)


AMENDED CLINICAL TRIAL PROTOCOL 02  
31-Jul-2017 
EFC13781 
Version number: 1 
(electronic 
 
 
2.0)


AMENDED CLINICAL TRIAL PROTOCOL 02  
31-Jul-2017 
EFC13781 
Version number: 1 
(electronic 
 
 
2.0)


AMENDED CLINICAL TRIAL PROTOCOL 02  
31-Jul-2017 
EFC13781 
Version number: 1 
(electronic 
 
 
2.0)


AMENDED CLINICAL TRIAL PROTOCOL 02  
31-Jul-2017 
EFC13781 
Version number: 1 
 
 
Appendix C 
General guidance for the follow-up of laboratory abnormalities by 
Sanofi 
Not applicable. 
(electronic 
 
 
 
2.0)



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Statistical Analysis Plan  
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................................................................... 5 
1 
OVERVIEW AND INVESTIGATIONAL PLAN ................................................................................ 6 
1.1 
STUDY DESIGN AND RANDOMIZATION ...................................................................................... 6 
1.2 
OBJECTIVES ................................................................................................................................... 6 
1.2.1 
Primary objectives ............................................................................................................................ 6 
1.2.2 
Secondary objectives ....................................................................................................................... 6 
1.3 
DETERMINATION OF SAMPLE SIZE ............................................................................................. 7 
1.4 
STUDY PLAN ................................................................................................................................... 7 
1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL .................................. 8 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN ....................... 8 
2 
STATISTICAL AND ANALYTICAL PROCEDURES ...................................................................... 9 
2.1 
ANALYSIS ENDPOINTS ................................................................................................................. 9 
2.1.1 
Demographic and baseline characteristics ...................................................................................... 9 
2.1.2 
Prior or concomitant medications ................................................................................................... 10 
2.1.3 
Efficacy endpoints .......................................................................................................................... 10 
2.1.3.1 
Primary efficacy endpoint(s) .......................................................................................................... 10 
2.1.3.2 
Secondary efficacy endpoint(s) ...................................................................................................... 14 
2.1.3.3 
Additional efficacy endpoint(s) ....................................................................................................... 14 
2.1.4 
Safety endpoints ............................................................................................................................ 15 
2.1.4.1 
Adverse events variables ............................................................................................................... 15 
2.1.4.2 
Deaths ............................................................................................................................................ 16 
2.1.4.3 
Laboratory safety variables ............................................................................................................ 16 
2.1.4.4 
Vital signs variables ....................................................................................................................... 17 
2.1.4.5 
Electrocardiogram variables .......................................................................................................... 17 
2.1.4.6 
Other safety endpoints ................................................................................................................... 17 
2.1.5 
Pharmacokinetic variables ............................................................................................................. 17 
2.1.6 
Quality-of-life endpoints ................................................................................................................. 17 
2.2 
DISPOSITION OF PATIENTS ....................................................................................................... 17 
2.2.1 
Randomization and drug dispensing irregularities ......................................................................... 18 
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2.3 
ANALYSIS POPULATIONS ........................................................................................................... 18 
2.3.1 
Efficacy populations ....................................................................................................................... 18 
2.3.2 
Safety population ........................................................................................................................... 19 
2.3.3 
Pharmacokinetic population ........................................................................................................... 19 
2.4 
STATISTICAL METHODS ............................................................................................................. 19 
2.4.1 
Demographics and baseline characteristics .................................................................................. 19 
2.4.2 
Prior or concomitant medications ................................................................................................... 20 
2.4.3 
Extent of investigational medicinal product exposure and compliance ......................................... 20 
2.4.3.1 
Extent of investigational medicinal product exposure .................................................................... 20 
2.4.3.2 
Compliance .................................................................................................................................... 21 
2.4.4 
Analyses of efficacy endpoints ....................................................................................................... 21 
2.4.4.1 
Analysis of primary efficacy endpoint(s) ........................................................................................ 22 
2.4.4.2 
Analyses of secondary efficacy endpoints ..................................................................................... 23 
2.4.4.3 
Multiplicity issues ........................................................................................................................... 23 
2.4.4.4 
Additional efficacy analysis(es) ...................................................................................................... 23 
2.4.5 
Analyses of safety data .................................................................................................................. 24 
2.4.5.1 
Analyses of adverse events ........................................................................................................... 24 
2.4.5.2 
Deaths ............................................................................................................................................ 27 
2.4.5.3 
Analyses of laboratory variables .................................................................................................... 27 
2.4.5.4 
Analyses of vital sign variables ...................................................................................................... 27 
2.4.5.5 
Analyses of electrocardiogram variables ....................................................................................... 27 
2.4.5.6 
Analyses of other safety endpoints ................................................................................................ 27 
2.4.6 
Analyses of pharmacokinetic and pharmacodynamic variables .................................................... 28 
2.4.7 
Analyses of quality of life/health economics variables ................................................................... 28 
2.5 
DATA HANDLING CONVENTIONS .............................................................................................. 28 
2.5.1 
General conventions ...................................................................................................................... 28 
2.5.2 
Data handling conventions for secondary efficacy variables ......................................................... 29 
2.5.3 
Missing data ................................................................................................................................... 30 
2.5.4 
Windows for time points ................................................................................................................. 31 
2.5.5 
Unscheduled visits ......................................................................................................................... 32 
2.5.6 
Pooling of centers for statistical analyses ...................................................................................... 32 
2.5.7 
Statistical technical issues ............................................................................................................. 32 
3 
INTERIM ANALYSIS ..................................................................................................................... 33 
4 
DATABASE LOCK ........................................................................................................................ 34 
5 
SOFTWARE DOCUMENTATION ................................................................................................. 35 
6 
REFERENCES ............................................................................................................................... 36 
7 
LIST OF APPENDICES ................................................................................................................. 37 
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APPENDIX A 
SF-36 HEALTH SURVEY .................................................................................................... 38 
APPENDIX B 
SUMMARY OF STATISTICAL ANALYSES ........................................................................ 41 
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ATC: 
anatomic category 
BMD: 
bone mineral density 
BMI: 
body mass index 
BQL: 
below quantification level 
CRF: 
case report form 
CTx: 
C-telopeptide-bone resorption 
CYP2D6: 
Cytochrome P450 2D6 
DXA: 
dual-energy X-ray absorptiometry 
ECG: 
electrocardiogram 
ERT: 
enzyme replacement treatment 
FAS: 
full analysis set 
GD1: 
Gaucher disease type 1 
GL-1: 
Glucosylceramide 
HIV: 
human immunodeficiency virus 
HLGT: 
high-level group term 
HLT: 
high-level term 
LLOQ: 
lower limit of quantification 
LLT: 
lower-level term 
lyso-GL-1: 
lyso glucosylceramide 
MCS: 
mental component scale 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MIP 1 β: 
Macrophage inflammatory protein-1 beta 
MN: 
multiples of normal 
MRI: 
Megnetic Resonance Imaging 
P1NP: 
Procollagen type I N-terminal propeptide 
PCS: 
physical component scale 
PK: 
pharmacokinetic 
PT: 
preferred term 
QOL: 
quality of life 
SAE: 
serious adverse event 
SD: 
standard deviation 
SOC: 
system organ class 
TEAE: 
treatment emergent adverse event 
URM: 
ultra-rapid metabolizer 
WHO-DD: 
World Health Organization-Drug dictionary 
 
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1 
OVERVIEW AND INVESTIGATIONAL PLAN  
1.1 
STUDY DESIGN AND RANDOMIZATION  
This is an open label, interventional, non-comparative, multicenter, multinational Phase 3b study 
to evaluate long term skeletal response to eliglustat and eliglustat safety and effect on quality of 
life in adult patients who successfully completed one of the Phase 2 (GZGD00304) or Phase 3 
studies (GZGD02507, GZGD02607, GZGD03109) in the eliglustat program. This study is 
considered an extension of these previous studies and will continue to evaluate the safety of 
eliglustat and patients’ quality of life (SF-36).  
Participating investigators will enroll patients who successfully completed one of the Phase 2 or 
Phase 3 studies. Patients will be treated for a minimum of 2 years and up to 4 years, or until 
eliglustat is approved and available to patients through reimbursement. If after 4 years since the 
beginning of the study eliglustat is not approved and available to patients in participating country, 
patients in this country may continue to receive study treatment until eliglustat is available to 
patients through the compassionate use (expanded access) program or is approved and available 
through reimbursement, whichever comes first. 
Note: Eliglustat (United States Adopted Name [USAN]: eliglustat tartrate, previously 
Genz-112638) is an L-tartaric acid salt, and exists in plasma as a free base, Genz-99067, which is 
the active moiety. Throughout this SAP, Genz-99067 is used when referring to drug exposure 
(eg, plasma concentrations), and eliglustat is used in all other instances.  
1.2 
OBJECTIVES  
1.2.1 Primary objectives  
The primary objective of this study is to evaluate long term skeletal response to eliglustat in adult 
patients who successfully completed one of the Phase 2 or Phase 3 studies.  
1.2.2 Secondary objectives  
The secondary objectives are to evaluate: 
• The safety of eliglustat by (S)AE continuous monitoring, 
• The quality of life by Short Form-36 Health Survey and 
• Biomarkers of GD1 (chitotriosidase, plasma GL-1 and lyso-GL-1). 
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1.3 
DETERMINATION OF SAMPLE SIZE  
This study will enroll all eligible patients having completed one of the Phase 2 or Phase 3 trials 
(approximately 32 patients). 
This is a long term extension study. No sample size calculation has been performed. The patients 
who will be enrolled have already been receiving the IMP for approximately 4 to 8 years prior to 
the start of the study. The aim of the study is to continue collecting long term data on the efficacy 
and safety of the IMP. 
1.4 
STUDY PLAN  
This is an open label, interventional, non-comparative, multicenter, multinational Phase 3b study 
to evaluate long term skeletal responses to eliglustat, eliglustat safety and effect on quality of life 
in adult patients who successfully completed one of the Phase 2 or Phase 3 studies in the eliglustat 
program. 
The study includes a screening period from Day -45 to Day -1 and a long-term treatment period 
from Day 1 to the end of study. The duration of study participation for individual patients will be 
at least 2 years (unless early discontinuation occurs) and up to 4 years, or until commercial 
eliglustat is available to patients through reimbursement.  
Analysis will be performed on safety and efficacy endpoints at 2 points in this study: 
• After the last patient enrolled has completed 2 years of treatment (two-year analysis 
period) 
• At the study completion 
Table 1 - Study schedule  
Variable 
Visit schedule 
Gaucher disease clinical assessment (mobility, bone crisis 
and bone pain) 
Screening, every 52 weeks (yearly) until end of study visit 
X-ray femurs and lumbar spine 
Screening, every 104 weeks (every 2 years) until end of study 
visit 
DXA (hip and lumbar spine) 
Screening, every 52 weeks (yearly) until end of study visit 
MRI (entire bilateral femur and lumbar spine, Spleen and liver 
volume) 
Screening, every 52 weeks (yearly) until end of study visit 
QOL questionnaire (SF36) 
Screening, every 26 weeks (every half year) until end of study 
visit 
Hematology (including HGB and PLAT) 
Screening, every 26 weeks (every half year) until end of study 
visit 
Serum chemistry (AST, ALT, AP, Total bilirubin, albumin, 
GGT) 
Screening 
 
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1.5 
MODIFICATIONS TO THE STATISTICAL SECTION OF THE PROTOCOL  
Not applicable. 
1.6 
STATISTICAL MODIFICATIONS MADE IN THE STATISTICAL ANALYSIS PLAN  
The definition for treatment-emergent period was added for clarification, specifying the on-
treatment period and residual treatment periods, respectively in Section 2.1.4. 
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2 
STATISTICAL AND ANALYTICAL PROCEDURES  
2.1 
ANALYSIS ENDPOINTS  
2.1.1 Demographic and baseline characteristics  
The baseline is referred to study baseline, which is defined as available assessment result or status 
before the first dose of eliglustat in this study.  
All baseline safety and efficacy parameters are presented along with the on-treatment summary 
statistics in the safety and efficacy sections (Section 2.4.5 and Section 2.4.4). 
Demographic characteristics 
Demographic variables are gender (Male, Female), race (Caucasian/white, Black, Asian/Oriental, 
American Indian or Alaska Native, Native Hawaiian or other Pacific Island, other), Jewish 
Descent (Jewish Ashkenazi, Jewish Sephardic, Non-Jewish), age at study entry in years 
(quantitative), ethnicity (Hispanic/Latino, non-Hispanic/Latino). 
Medical or surgical history 
Medical (or surgical) history will be completed according to the protocol.  
This information will be coded using the version of Medical Dictionary for Regulatory Activities 
(MedDRA) currently in effect at Sanofi at the time of database.  
Medical (or surgical) history recorded in the previous study will not be re-entered as medical 
(or surgical) history in this study, but will be used in the analysis of this study. 
Disease characteristics at baseline 
Specific disease history includes the following: 
• Time since initial Gaucher diagnosis relative to enrollment (in years)  
• Time since first symptoms of Gaucher relative to enrollment (in years)  
• CYP2D6 metabolizer status (poor, intermediate, extensive, ultra-rapid) 
Vital signs  
Vital signs at baseline are height at study entry (quantitative), weight at study entry (quantitative) 
and BMI at study entry (quantitative). 
Any technical details related to computation, dates, and imputation for missing dates are described 
in Section 2.5.  
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2.1.2 Prior or concomitant medications  
All medications taken within 30 days prior to patient providing written, informed consent to the 
study until the end of the study, including eliglustat if the last dose of eliglustat in the previous 
study happened in this period of time, are to be reported in the case report form pages. Enzyme 
replacement treatment (ERT) should also be included if the patient was on ERT during the period 
between the end of the previous study and the screening visit. 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version currently in effect at Sanofi at the time of database lock. 
• Prior medications are all ongoing medications at the time of screening, and medications 
received during the 30 day period prior to screening even if no longer taken at the time of 
screening, including eliglustat and enzyme replacement therapy (ERT). Prior medications 
can be discontinued before first administration or can be ongoing during treatment phase.  
• Concomitant medications are any treatments received by the patient concomitantly with 
eliglustat, during the on-treatment period. A given medication can be classified both as a 
prior medication and as a concomitant medication. Concomitant medications do not 
include medications started after the on-treatment period (as defined in the observation 
period in Section 2.1.4).  
Any technical details related to computation, dates, imputation for missing dates are described in 
Section 2.5. 
2.1.3 Efficacy endpoints  
The detailed assessment schedule refers to Table 1 in Section 1.4. No imputation will be conduct 
for all the endpoints.  
2.1.3.1 Primary efficacy endpoint(s)  
Five common skeletal manifestations of Gaucher disease will be assessed: 
• Mobility, bone pain and bone crisis, as assessed by the Gaucher Disease clinical 
assessments; 
• Bone marrow infiltration;  
• BMD;  
• Lytic lesions, osteonecrosis, fractures and infarcts;  
• Bone biomarkers. 
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2.1.3.1.1 Gaucher disease clinical assessments (mobility, bone pain, bone crisis)  
Patients will be asked to rate mobility and bone pain as below: 
• Current mobility 
- 
Unrestricted mobility 
- 
Walks with difficulty 
- 
Walks with orthopedic aid 
- 
Requires wheelchair 
- 
Bedridden 
• Level of bone pain during the last 4 weeks as 
- 
None 
- 
Very mild 
- 
Mild 
- 
Moderate 
- 
Severe 
- 
Extreme 
In addition, investigators will report the number of bone crisis since the previous assessment. 
Bone crisis is defined as pain with acute onset, which requires immobilization of the affected area, 
narcotics for relief of pain, and may be accompanied by one or more of the following: periosteal 
elevation, elevated white blood cell count, fever, or debilitation of >3 days. Category of number 
of bone crisis defined as: 
- 
No bone crisis 
- 
1 – 2 bone crisis 
- 
>2 bone crisis 
Gaucher disease clinical assessments will be performed at screening and then yearly. 
2.1.3.1.2 Bone marrow infiltration  
The assessment of bone marrow infiltration is based on the sum of seven bone marrow burden 
scores for spine (T1-weighted, T2-weighted, infiltration pattern and fat in basivertebral region) 
and femur (T1-weighted, T2-weighted, and sites of involvement) assessed by MRI views. BMB 
scores range from 0 to 16 and will only be calculated for patients who have non-missing values 
for all seven scores. 
The BMB score for this study will be assessed by two readers. The primary readers will read in 
pairs, blinded to patient, treatment, and time point. If readers differ by a score of one or more, for 
each of the questions, for the femur subtotal, for the spine subtotal and for the overall score, a 
third reader will serve as the adjudicator and will provide a third read. The average of the three 
reader results will be used in the analysis. Bone marrow infiltration will be measured at screening 
and then yearly. 
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Bone MRI will be read locally and centrally. The central reads will be used for analysis. 
 
Lumbar Spine: 
Femur: 
 
T1-weighted:  
0 = Slightly hyperintense 
1 = Isointense 
2 = Slightly hypointense 
3 = Hypointense 
NA = Not assessable 
 
T2-weighted: 
0 = Isointense 
1 = Slightly hypointense 
1 = Slightly hyperintense 
2 = Hypointense 
2 = Hyperintense 
NA = Not assessable 
 
Infiltration Pattern: 
0 = None 
1 = Patchy 
2 = Diffuse 
 
Fat in basivertebral vein region 
0 = Preservation of fat 
1 = Absence of fat 
NA = Not assessable 
 
T1-weighted: 
0 = Slightly hyperintense or isointense 
1 = Slightly hypointense 
2= Hypointense 
NA = Not assessable 
 
 
T2-weighted: 
0 = Isointense 
1= Slightly hypointense 
1= Slightly hyperintense 
2= Hypointense 
2= Hyperintense 
3= Mixed type 
NA = Not assessable 
 
Sites of Involvement:  
0 = No site involvement 
1 = Diaphysis 
2 = Proximal epiphysis / apophysis 
3 = Distal epiphysis 
NA = Not assessable 
 
2.1.3.1.3 Bone mineral density (BMD)  
BMD will be measured by DXA of both hips and the lumbar spine. T and Z scores, and bone 
mineral densities will be provided by the DXA report. 
Centrally reviewed DXA data will be used to determine each patient’s bone density category:  
T-score Bone Density Categories: 
• Normal: T-score > -1 
• Osteopenia: -2.5 < T-score ≤ -1 
• Osteoporosis: T-score ≤2.5  
Z-score Bone Density Categories: 
• Normal: Z-score > -2 
• Below Normal: Z-score ≤ -2 
Bone mineral density will be measured at screening and then yearly. 
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2.1.3.1.4 Lytic lesions, osteonecrosis, fractures and infarcts  
Lytic lesions, osteonecrosis, infarcts and fractures will be assessed on bone MRI and bone X-Ray. 
Bone MRI will be assessed at screening and then yearly. Bone X-Ray will be collected at 
screening and every 2 years. 
 
Spine: 
Femur: 
Infarction: 
0 = Not Present 
1 = Present 
2 = Present, Unchanged 
3 = Present, Larger 
4 = Present, Smaller 
NA = Not Available 
NV = Not Viewable 
 
Avascular Necrosis: 
0 = Not Present 
1 = Present 
2 = Present, Unchanged 
3 = Present, Larger 
4 = Present, Smaller 
NA = Not Available 
NV = Not Viewable 
 
Lytic lesion: 
0 = Not Present 
1 = Present 
2 = Present, Unchanged 
3 = Present, Larger 
4 = Present, Smaller 
NA = Not Available 
NV = Not Viewable 
 
Fracture: 
0 = Not Present 
1 = Present 
2 = Present, Unchanged 
3 = Present, Larger 
NA = Not Available 
NV = Not Viewable 
 
Infarction: 
0 = Not Present 
1 = Present 
2 = Present, Unchanged 
3 = Present, Larger 
4 = Present, Smaller 
NA = Not Available 
NV = Not Viewable 
 
Avascular Necrosis (represents infarction in 
the subchondral bone of the epiphysis): 
0 = Not Present 
1 = Present 
2 = Present, Unchanged 
3 = Present, Larger 
4 = Present, Smaller 
NA = Not Available 
NV = Not Viewable 
 
Dark Marrow (Bone Infiltration) 
0 = Not Present 
1 = Present 
2 = Present, Unchanged 
3 = Present, Larger 
4 = Present, Smaller 
NA = Not Available 
NV = Not Viewable 
 
Fracture 
0 = Not Present 
1 = Present 
NA = Not Available 
NV = Not Viewable 
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2.1.3.1.5 Bone biomarkers  
Bone biomarkers include: 
• Total procollagen type 1 N-terminal propeptide (P1NP), a marker of bone formation. 
• C-terminal telopeptide of type 1 collagen (CTx), a marker of bone resorption. 
• MIP 1 β 
These biomarkers will be measured at baseline and then every 6 months. 
These markers will be measured by a central laboratory. 
Results of centrally read assessments will be available to Investigators during or after the study 
depending on the assessment. 
2.1.3.2 Secondary efficacy endpoint(s)  
Blood levels of biomarkers of GD1 (chitotriosidase, plasma GL-1 and lyso-GL-1) will be 
evaluated at baseline and twice yearly. These markers will be measured in a central laboratory. 
Measured values as well as absolute and percent changes from study baseline and eliglustat 
baseline will be summarized. 
2.1.3.2.1 Chitotriosidase Values  
Prior to being used in analyses, chitotriosidase values will be normalized using chitotriosidase 
genotyping information. 
Chitotriosidase Genotype 
Chitotriosidase value used in analyses 
Normal 
Value reported from the lab 
Heterozygous 
Value reported from the lab, multiplied by 2 Homozygous 
Mutation 
BQL, set to missing (see Section 2.5.1) 
2.1.3.3 Additional efficacy endpoint(s)  
Spleen volume and liver volume for non-URM patients will be evaluated at screening and 
every year by MRI. Hemoglobin and platelet results of non-URM patients will be assessed at 
screening and every half-year along with hematology laboratory test.  
For URM patients, the frequency of spleen and liver volume MRI scan can be increased to 
every 3 months till Week 52. And the frequency of hematology and platelet test can be 
performed every 6 months till Week 52.  
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2.1.4 Safety endpoints  
The safety analysis will be based on the reported adverse events (AEs) and other safety 
information, such as clinical laboratory data. The safety endpoints to be analyzed include: 
Observation period  
The observation period will be divided into 4 periods: 
• The pre-treatment period is defined as the time from the signed informed consent to first 
dose of IMP administration in this study.  
• The treatment-emergent period is defined as the time from the first administration of the 
IMP to the last administration of the IMP + 5 days. The treatment-emergent period 
includes the following 2 periods: 
- 
The on-treatment period is defined as the period from the first IMP administration to 
the last administration of the IMP + 1 day. 
- 
The residual treatment period is defined as the time from the last administration of 
IMP to the end of the treatment-emergent period. 
• The post-treatment period is defined as the period from the end of treatment-emergent 
period. 
The treatment-emergent adverse event (TEAE) observation period includes both on-treatment and 
residual treatment periods.  
The on-study observation period is defined as the time from screening until the end of the study 
(defined as last protocol planned visit or the resolution/stabilization of all serious adverse events 
[SAEs] and adverse events of special interest [AESIs]).  
2.1.4.1 Adverse events variables  
Adverse event observation period  
• Pre-treatment adverse events are adverse events that developed or worsened or became 
serious during the pre-treatment period. 
• Treatment-emergent adverse events (TEAEs) are adverse events that developed or 
worsened or became serious during the treatment-emergent period (treatment-emergent 
adverse event observation period). 
• Post-treatment adverse events are adverse events that developed or worsened or became 
serious during the post-treatment period.  
Continuous monitoring will be performed for (S)AEs and concomitant medications. Results of 
pregnancy testing for female patients of childbearing potential will be collected. Patients with an 
SAE or AESI should be followed until event resolution or when follow-up is no longer considered 
medically necessary, or the patient is lost to follow-up. 
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All adverse events (including SAEs and AESIs) will be will be coded to a lower-level term (LLT), 
preferred term (PT), high-level term (HLT), high-level group term (HLGT), and associated 
primary system organ class (SOC) using the version of Medical Dictionary for Regulatory 
Activities (MedDRA) currently in effect at Sanofi at the time of database lock. 
Adverse events (including serious adverse events and adverse event of special interest) will be 
recorded from the time of signed informed consent until the end of the study.  
Any SAE (including death) brought to the attention of the Investigator at any time after the end of 
the study for the patient and considered by him/her to be caused by the IMP with a reasonable 
possibility, should be reported to Global Pharmacovigilance department and will not be recorded 
in the clinical database.  
Serious adverse events and adverse events of special interest (AESI) are defined in the protocol 
(refer to protocol Section 10.5.1.2 and 10.5.1.3). AESI will be identified and summarized based 
on CRF information, not standardized or customized MedDRA queries.  
2.1.4.2 Deaths  
The deaths observation period are per the observation periods defined above.  
• Death on-study: deaths occurring during the on-study observation period 
• Death on-treatment: deaths occurring during the treatment-emergent adverse event period  
2.1.4.3 Laboratory safety variables  
Clinical laboratory data consists of blood analysis, including hematology, clinical chemistry, and 
urinalysis. Clinical laboratory values after conversion will be analyzed into standard international 
units and international units will be used in all listings and tables. 
Blood samples for clinical laboratories will be taken at visits described in the protocol or early 
termination unless otherwise specified. The laboratory parameters will be classified as follows:  
• Hematology  
- 
Red blood cells and platelets and coagulation: Red Blood Cells (RBC), 
Hemoglobin, Hematocrit, Platelet Count 
- 
White blood cells: White Blood Cells (WBC), Neutrophils, Eosinophils, Basophils, 
Lymphocytes, Monocytes 
• Clinical chemistry  
- 
Markers of liver synthetic function: Albumin, Total Bilirubin 
- 
Markers of hepatocellular damage and cholestasis: alanine aminotransferase, 
aspartate aminotransferase, alkaline phosphatase, gamma glutamyl transferase 
- 
Pregnancy test: Serum β-human chorionic gonadotropin for all female patients of 
childbearing potential  
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- 
HIV and Hepatitis screen: Human immunodeficiency virus (HIV) , hepatitis B 
surface antigen, anti-hepatitis-C antibody  
• Urine samples will be collected as follows: 
- 
Urinalysis: Urine pregnancy test.  
Technical formulas are described in Section 2.5.1. 
2.1.4.4 Vital signs variables  
No vital sign variables are collected in this study.  
2.1.4.5 Electrocardiogram variables  
No electrocardiogram and Holter assessment variables are collected in this study. 
2.1.4.6 Other safety endpoints  
Complete physical exam and complete neurological exam with ocular motility test will be 
performed. Height and weight will be monitored as well. 
2.1.5 Pharmacokinetic variables  
Although PK samples are not scheduled, unscheduled PK samples may be collected in individual. 
There is no planned analysis for these PK samples. 
2.1.6 Quality-of-life endpoints  
Patients’ quality of life (Short Form-36 Health survey) will be evaluated at baseline and 
twice yearly. Total 8 scales including physical functioning, role-physical, bodily pain, general 
health, vitality, social functioning, role-emotional and mental health will be assessed based on 
SF-36. The two overall summary measures, physical component scale (PCS) and mental 
component scale (MCS), will be summarized from the 8 scales for quality of life assessment as 
well. SF-36 health survey is presented in Appendix A. 
2.2 
DISPOSITION OF PATIENTS  
This section describes patient disposition for both patient study status and the patient analysis 
populations. 
Screened patients are defined as any patient who met the study criteria and signed the informed 
consent. 
For patient study status, the total number of patients in each of the following categories will be 
presented in the clinical study report using a flowchart diagram or summary table: 
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• Screened patients 
• Screen failure patients and reasons for screen failure 
• Treated patients 
• Patients who completed the 2-year study period 
• Patients who did not complete the 2-year study treatment period as per protocol 
• Patients who completed the whole study period as per protocol 
• Patients who did not complete study treatment period as per protocol 
• Patients who discontinued study treatment by main reason for permanent treatment 
discontinuation 
For all categories of patients, percentages will be calculated using the number of screened patients 
as the denominator. Reasons for treatment discontinuation will be supplied in tables giving 
numbers and percentages overall. Listing of permanent and temporary treatment discontinuation 
reasons by site and by patient will be provided respectively. 
A patient is considered lost to follow-up at the end of the study if he/she is not assessed at the last 
protocol planned visit and failed to response to 3 attempts of contact via phone or registered letter.  
All critical or major deviations potentially impacting efficacy analyses, inclusion, and 
drug-dispensing irregularities, and other major or critical deviations will be summarized in tables 
giving numbers and percentages overall and by site. 
Additionally, the analysis populations for safety and efficacy will be summarized in a table by 
number of patients included in the study. 
• Efficacy population  
• Safety population 
• Pharmacokinetics population 
2.2.1 Randomization and drug dispensing irregularities  
Since the study is an open-label follow-up study and IVRS was not implemented, the 
randomization and drug dispending irregularities is not applicable.  
2.3 
ANALYSIS POPULATIONS  
2.3.1 Efficacy populations  
Primary and secondary efficacy will be evaluated in the Full Analysis Set population (FAS) 
defined as all patients enrolled who receive at least 1 dose of eliglustat treatment in this study. 
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2.3.2 Safety population  
Safety analyses will be performed on the Safety Set, which is equivalent to the FAS for this study. 
2.3.3 Pharmacokinetic population  
Pharmacokinetic (PK) population: a subset of safety population containing patients who have at 
least one PK sample taken. Patients will be analyzed in the treatment group corresponding to 
those defined in the safety population. 
2.4 
STATISTICAL METHODS  
Analysis will be performed on safety and efficacy endpoints at 2 points in this study: 
• After the last patient enrolled has completed 2 years of treatment (two-year analysis 
period) 
• At the study completion 
Both efficacy and safety results will be calculated both in reference to study entry (study period) 
and to first eliglustat treatment (eliglustat treatment period). Because patients will enter this study 
having been treated with eliglustat for various durations, two baselines will be used: 
• Study baseline, defined as status at study entry, which is the last non-missing value before 
the first dose of eliglustat of this study; and 
• Eliglustat baseline, defined as status at first dose of eliglustat in the previous Phase 2 or 
Phase 3 studies. The definition of eliglustat baseline should be the last non-missing value 
prior to first dose of eliglustat in prior studies. 
The eliglustat baseline can only be obtained if the assessments in EFC13781 study and the 
previous studies are comparable. Assessment method, location, parameters, result evaluation, etc 
should be considered for comparability check if applicable. In addition, eliglustat baseline 
definition of hemoglobin and platelet for Phase 2 and ENCORE study were defined separately in 
Section 2.5.2.  
2.4.1 Demographics and baseline characteristics  
Continuous data will be summarized using the number of available data, mean, standard 
deviation (SD), median, minimum and maximum in overall group. Categorical and ordinal data 
will be summarized using the number and percentage of patients in overall group.  
Parameters will be summarized on the full analysis population analyzed in the overall group to 
which they were enrolled.  
Parameters described in Section 2.1.1 will be summarized in overall treatment groups using 
descriptive statistics.  
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Medical and surgical history 
Medical and surgical history will be summarized by primary SOC and PT in overall group. The 
table will be sorted by SOC internationally agreed order and decreasing frequency of PT based on 
the overall incidence in the overall treatment group. No specific description of the safety 
parameters will be provided at baseline. If relevant, the baseline values will be described along 
with each safety analysis. 
No specific description of the efficacy parameters will be provided at baseline. If relevant, the 
baseline values will be described along with each efficacy analysis. 
2.4.2 Prior or concomitant medications  
The prior and concomitant medications will be presented for the full analysis population.  
Medications will be summarized in overall group according to the WHO-DD dictionary, 
considering the first digit of the anatomic category (ATC) class (anatomic category) and the 
first 3 digits of the ATC class (therapeutic category). All ATC codes corresponding to a 
medication will be summarized, and patients will be counted once in each ATC category 
(anatomic or therapeutic) linked to the medication. Therefore patients may be counted several 
times for the same medication.  
The table for prior medications will be sorted by decreasing frequency of ATC followed by all 
other therapeutic classes based on the overall incidence. In case of equal frequency regarding 
ATCs (anatomic or therapeutic categories), alphabetical order will be used. 
The tables for concomitant medications will be sorted by decreasing frequency of ATC followed 
by all other therapeutic classes based on the overall group. In case of equal frequency regarding 
ATCs (anatomic or therapeutic categories), alphabetical order will be used.  
2.4.3 Extent of investigational medicinal product exposure and compliance  
The extent of eliglustat exposure and compliance will be assessed and summarized for the safety 
population (Section 2.3.2). 
2.4.3.1 Extent of investigational medicinal product exposure  
The extent of eliglustat exposure will be assessed by the duration of eliglustat exposure over the 
course of the study.  
Duration of eliglustat exposure is defined as last dose date – first dose date + 1 day, regardless of 
unplanned intermittent discontinuations (see Section 2.5.3 for calculation in case of missing or 
incomplete data).  
Duration of eliglustat exposure will be summarized descriptively as a quantitative variable 
(number, mean, SD, median, minimum, and maximum). In addition, duration of treatment 
exposure will also be summarized categorically by numbers and percentages for each of the 
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following categories and cumulatively according to these categories: ≤1 year, 1 to ≤2 years,  
2 to ≤3 years, 3 to ≤4 years, 4 to ≤5 years, and >5 years.  
Additionally, the cumulative duration of eliglustat treatment exposure will be provided, defined as the 
sum of the duration of treatment exposure for all patients, and will be expressed in patient years. A 
listing of exposure will be produced. 
2.4.3.2 Compliance  
A given administration will be considered noncompliant if the patient did not take the planned 
dose of treatment as required by the protocol over the course of the study period. No imputation 
will be made for patients with missing or incomplete data. 
Percentage of compliance for a patient will be defined as the number of capsules taken from 
Day 1 to end of treatment divided by the total number of capsules that the patient should have 
taken from Day 1 to end of treatment as per the protocol (BID = 2 capsules per day,  
QD = 1 capsule per day). 
Above-planned dosing percentage for a patient is defined as the number of administrations that 
the patient took more than 105% of planned dose during the on-treatment period.  
Under-planned dosing percentage for a patient is defined as the number of administrations that 
the patient took less than 90% of planned dose during the on-treatment period. Treatment 
compliance, above-planned, and under-planned dosing percentages will be summarized 
descriptively as quantitative variables (number, mean, SD, median, minimum, and maximum).  
The overall compliance will be summarized in categories (<80%, 80% - 90%, 90% - 105%, >105%). 
In addition, numbers and percentages of patients with at least 1 above-planned dose 
administration will also be provided, as well as numbers and percentages of patients with 0,  
(0, 20%], and >20% under-planned dose administrations. 
Cases of overdose (defined as actual IMP dose administration is greater than planned dose 
administration per day) will constitute by protocol as an adverse event of special interest and will 
be listed as such. More generally, dosing irregularities will be listed in Section 2.2.1. 
2.4.4 Analyses of efficacy endpoints  
In reference to the study period, efficacy result will be evaluated for all patients at the 2 year point 
by measured values (eg, category of bone pain, or bone density value in g/cm2) and changes from 
baseline (eg, shift in category of bone pain or absolute and percent change from baseline in BMD 
g/cm2 or incidence over 2 years, as appropriate). 
In reference to the period of eliglustat treatment, efficacy result will be evaluated 2 years after 
study entry, but results will be grouped by duration of eliglustat treatment at the time of analysis. 
The actual groupings will depend on the distribution of treatment duration at the time of analysis 
(eg, ≤5 years verses >5 years). 
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When the study has completed, summaries will be performed comparing to the 2 baselines as 
described above if applicable. 
All efficacy endpoints will be summarized descriptively; no hypothesis testing will be performed. 
In general, descriptive statistics (number, mean, standard deviation, minimum and maximum) of 
the absolute value, change from baseline and/or percentage change from baseline for continuous 
endpoints will be analyzed. Summary statistics (count, percentage) will be summarized for the 
categorical endpoints. Cumulative incidence (n, percentage), incidence rate (n/year), or other 
descriptive statistics will also be displayed as appropriate. Calculations and summaries will 
include all non-missing data at a given time point, imputation will not be performed. 
By-patient data listings containing efficacy endpoints will be produced if necessary.  
All the below mentioned other efficacy endpoint analyses will be produced for the full analysis 
population. Refer to Section 2.5.3 for details on handling dropouts, missing data, and patients who 
have more than one value assessed within the same time frame. 
2.4.4.1 Analysis of primary efficacy endpoint(s)  
The main efficacy endpoints of interest are five common manifestations of Gaucher’s disease 
summarized separately which includes:  
• Mobility, bone pain and bone crisis, as assessed by the Gaucher Disease clinical 
assessments; 
• Bone marrow infiltration;  
• BMD;  
• Lytic lesions, osteonecrosis, fractures and infarcts;  
• Bone biomarkers. 
2.4.4.1.1 Mobility, bone pain and bone crisis  
Category of mobility status and bone pain, as well as number of new bone crises, will be 
summarized by visit. Absolute value, change from baseline and percent change from baseline of 
bone crisis over time will be summarized using descriptive statistics by visit using two baselines 
(study baseline and eliglustat baseline). Additionally, shifts in category of mobility and pain from 
study and eliglustat baseline by each post-baseline visit will be presented. 
2.4.4.1.2 Bone marrow infiltration  
Bone marrow infiltration score by location and total bone marrow infiltration score will be 
summarized both continuously and categorically. Absolute values, change and percent change 
from baseline (study baseline and eliglustat baseline) will be summarized by visit. Category of 
total infiltration score (Mild: 0 to 4; Moderate: 5 to 8; Severe: 9-16) will be constructed and 
summarized by visit. Shifts in category of infiltration from study and eliglustat baseline will be 
summarized by each post-baseline visit. 
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2.4.4.1.3 BMD  
Absolute value, change and percent change from baseline (study baseline and eliglustat baseline) 
for bone mineral density in (g/cm2), T and Z scores by location will be summarized by visit. Shift 
in bone density categories of T and Z scores will be summarized by visit. In addition, mean plots 
of absolute values and percent change from baseline for total BMD, T-scores, and Z-scores for all 
patients with standard deviation will be provided. 
2.4.4.1.4 Lytic lesions, osteonecrosis, fractures and infarcts  
Total incidence of new or worsening lytic lesions, new or worsening AVN, new or worsening 
infarctions and new fractures among all locations will be summarized since study entry until all 
the patients completed their 2-year follow-up period and at end of study. Summary statistics 
(N, mean, standard deviation, median, minimum and maximum) will be displayed by visit. 
Annual incidence rates and will also be calculated as total number of incidence divided by the 
total number of person-years. MRI and X-ray assessment result will be summarized separately.  
2.4.4.1.5 Bone biomarkers  
Absolute values, change and percent change from baseline (study baseline and eliglustat baseline) 
for levels of P1NP, CTx and MIP 1 β will be summarized by visit. 
2.4.4.2 Analyses of secondary efficacy endpoints  
For secondary analysis blood levels of biomarkers of GD1 (chitotriosidase, GL-1 and lyso-Gl-1), 
for all patients and separately for CYP2D6 URMs patients will be evaluated at baseline (study 
baseline and eliglustat baseline) by visits. Measured values as well as absolute and percent 
changes from study baseline and eliglustat baseline will be summarized. Analysis similar to those 
described in Section 2.4.4.1 will be conducted and reproduced. 
For lyso-GL-1, analyses will include all available data. 
Refer to Section 2.1.3.2.1 for details on how chitotriosidase values will be normalized prior to 
being used in analyses and for definitions of bone density categories. 
2.4.4.3 Multiplicity issues  
Not applicable. 
2.4.4.4 Additional efficacy analysis(es)  
Summary statistics (including number, mean, median, standard deviation, minimum and 
maximum) of the absolute value, change and percentage change from baseline (study baseline and 
eliglustat baseline) for spleen volume, liver volume, hemoglobin and platelet results will be 
presented by visit. Descriptive statistics for CYP2D6 URMs patients will be analyzed separately. 
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2.4.5 Analyses of safety data  
The summary of safety results will be presented for data from the 2-year eliglustat treatment period as 
well as at study completion by overall. Descriptive summaries will be produced as described below. 
General common rules 
All safety analyses will be performed on the safety population as defined in Section 2.3.2, unless 
otherwise specified, using the following common rules: 
• Safety data in patients who do not belong to the safety population (eg, exposed but not 
included) will be listed separately. 
• The study baseline value is defined as the last available value before the first dose of 
eliglustat of this study. The eliglustat baseline value is defined as the last available value 
before the first dose of eliglustat of corresponding initial study.  
• For quantitative safety parameters based on central laboratory/reading measurements, 
descriptive statistics will be used to summarize results and change from baseline values by 
visit and overall group.  
• The analysis of the safety variables will be essentially descriptive and no systematic 
testing is planned.  
2.4.5.1 Analyses of adverse events  
Generalities 
The primary focus of adverse event reporting will be on treatment-emergent adverse events 
(TEAEs). Pre-treatment adverse events and post-treatment adverse events will be described 
separately, if applicable.  
If an adverse event date/time of onset (occurrence, worsening, or becoming serious) is incomplete, 
the undetermined adverse event should be treated as treatment-emergent adverse event. Details on 
classification of adverse events with missing or partial onset dates are provided in Section 2.5.3. 
Adverse event incidence tables will present by SOC, HLGT, HLT, and PT, sorted in alphabetical 
order for overall group, the number (n) and percentage (%) of patients experiencing an adverse 
event. Multiple occurrences of the same event in the same patient will be counted only once in the 
tables within a treatment phase. The denominator for computation of percentages is the safety 
population. 
Sorting within tables ensures the same presentation for the set of all adverse events within the 
observation period (pre-treatment and treatment-emergent). For that purpose, the table of all 
treatment-emergent adverse events presented by SOC and PT sorted by the internationally agreed 
SOC order and decreasing frequency of PTs within SOCs will define the presentation order for all 
other tables unless otherwise specified. Sorting will be based on results for the overall group.  
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Analysis of all pre-treatment adverse events 
• Overview of pre-treatment adverse events, summarizing number (%) of patients with any 
- 
Adverse event 
- 
Serious adverse event 
- 
Adverse event with special interest (AESI) 
- 
Adverse event leading to death 
- 
Severe adverse event 
By-patient listing of all pre-treatment adverse event  
Analysis of all treatment-emergent adverse events 
The following treatment-emergent adverse event summaries will be generated for the safety 
population. 
• Overview of treatment-emergent adverse events, summarizing number (%) of patients 
with any 
- 
Treatment-emergent adverse event 
- 
Treatment-emergent serious adverse event 
- 
Treatment-emergent adverse event of special interest (AESI) 
- 
Treatment-emergent adverse event leading to death 
- 
Treatment-emergent adverse event leading to permanent treatment discontinuation 
- 
Treatment- related treatment-emergent adverse event 
- 
Severe treatment-emergent adverse event 
• All treatment-emergent adverse event by primary SOC, HLGT, HLT, and PT, showing 
number (%) of patients with at least 1 treatment-emergent adverse event sorted by the 
SOC internationally agreed order. The other levels (HLGT, HLT, PT) will be presented in 
alphabetical order 
• All treatment-emergent adverse events by primary SOC and PT, showing the number (%) 
of patients with at least 1 treatment-emergent adverse event, sorted by the internationally 
agreed SOC order and by decreasing incidence of PTs within each SOC. This sorting order 
will be applied to all other tables, unless otherwise specified 
• All treatment-emergent adverse events regardless of relationship and related by primary 
SOC and PT, showing the number (%) of patients with at least 1 treatment-emergent 
adverse event, sorted by the internationally agreed SOC order and by decreasing incidence 
of PTs within each SOC 
• All treatment-emergent adverse events by maximal severity, presented by primary SOC 
and PT, showing the number (%) of patients with at least 1 treatment-emergent adverse 
event by severity (ie, mild, moderate, or severe), sorted by the sorting order defined above 
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• By-patient listing of all treatment-emergent adverse events 
• By-patient listing of all severe treatment-emergent adverse event  
Analysis of all treatment emergent serious adverse event(s) 
• All treatment-emergent serious adverse events by primary SOC and PT, showing the 
number (%) of patients with at least 1 treatment-emergent serious adverse event, sorted by 
the internationally agreed SOC order and by decreasing incidence of PTs within each SOC  
• All treatment-emergent serious adverse events regardless of relationship and related to 
IMP, by primary SOC and PT, showing the number (%) of patients with at least 
1 treatment-emergent serious adverse event, sorted by the internationally agreed SOC 
order. 
• By-patient listing of all serious treatment-emergent adverse events  
Analysis of all treatment-emergent adverse event(s) leading to permanent treatment 
discontinuation 
• All treatment-emergent adverse events leading to permanent treatment discontinuation, by 
primary SOC, HLGT, HLT, and PT, showing the number (%) of patients sorted by the 
internationally agreed SOC order. The other levels (HLGT, HLT, PT) will be presented in 
alphabetical order 
• By-patient listing of all treatment-emergent adverse events leading to permanent treatment 
discontinuation 
Analysis of treatment-emergent adverse events of special interest 
• All pre-specified treatment-emergent adverse events of special interest, by primary SOC 
and PT, showing the number (%) of patients, sorted by the internationally agreed SOC 
order and by decreasing incidence of PTs within each SOC 
• By-patient listing of all treatment-emergent adverse events of special interest  
Analysis of all post-treatment adverse events 
• Overview of post-treatment adverse events, summarizing number (%) of patients with any 
- 
Adverse event 
- 
Serious adverse event 
- 
Adverse event of special interest (AESI) 
- 
Adverse event leading to death 
- 
Severe adverse event 
• By-patient listing of all post-treatment adverse events 
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2.4.5.2 Deaths  
The following summaries of deaths will be generated for the safety population. 
• All adverse events leading to death (death as an outcome on the adverse event case report 
form page as reported by the Investigator) by primary SOC and PT showing the number 
(%) of patients sorted by the internationally agreed SOC order and by decreasing 
incidence of PTs within each SOC 
• Treatment-emergent adverse events leading to death (death as an outcome on the adverse 
event case report form page as reported by the Investigator) by primary SOC and PT 
showing the number (%) of patients sorted by the internationally agreed SOC order and by 
decreasing incidence of PTs within each SOC  
• Number (%) of patients who died by study period (on-study, on-treatment) 
• By-patient listing of all AE leading to death  
2.4.5.3 Analyses of laboratory variables  
The summary statistics (including number, mean, median, standard deviation, minimum and 
maximum) of all laboratory variables (central and local laboratory values and changes from 
baseline, percentage change from baseline) will be calculated for each visit or study assessment 
(baseline, each postbaseline time point) in overall group. Both study baseline and eliglustat 
baseline will be applied to the summary statistics.  
By-patient listings for those patients with abnormal laboratory values will be provided by 
category of laboratory tests. Hemoglobin and platelet test result will be analyzed as above 
separately. A by-patient data listing of all pregnancy testing for female patients will be 
produced. 
2.4.5.4 Analyses of vital sign variables  
No vital sign variables are collected in this study. 
2.4.5.5 Analyses of electrocardiogram variables  
No electrocardiogram variables are collected in this study. 
2.4.5.6 Analyses of other safety endpoints  
2.4.5.6.1 Physical examinations  
A summary statistics of physical exam findings interpretations will be presented by visit for each 
body system. 
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2.4.5.6.2 Weight, height and BMI  
A summary statistics of absolute value, changes from baseline and percentage change from 
baseline (study baseline as well as Eliglustat baseline) in height, weight and BMI will be analyzed 
by visit. 
2.4.5.6.3 Complete neurological examination  
A summary statistics of quantitative neurological examinations findings will be presented by visit. 
2.4.6 Analyses of pharmacokinetic and pharmacodynamic variables  
No scheduled PK data are collected in this study. But unscheduled PK samples may be collected 
in individual cases after discussion between the investigator and Genzyme. By-patient listing may 
be provided if necessary. 
2.4.7 Analyses of quality of life/health economics variables  
The score for each scale will be estimated from the Short Form-36 Health survey [SF-36]. The 
overall physical component scale (PCS) and mental component scale (MCS) will be computed. 
Summary statistics as well as change and percentage change from baseline (study and eliglustat) 
by visit by all SF-36 QOL variables will be presented. 
2.5 
DATA HANDLING CONVENTIONS  
2.5.1 General conventions  
The following formulas will be used for computation of parameters. 
For all safety and efficacy parameters, values that are reported as BQL (below quantification 
level) or LLOQ (lower limit of quantification) will have numeric values set equal to the BQL or 
LLOQ lower limit (eg, if BQL < 2, then value will be set equal to 2). However, the original value 
will be displayed in by-patient data listings. 
The only exception is for chitotriosidase values. Patients who have a chitotriosidase genotyping 
category of “Homozygous Mutation” have no expected chitotriosidase activity. Therefore, 
patients who have a value of BQL reported will have numeric values set equal to missing. 
Demographic formulas 
Age will be presented as the number of years between date of birth and the reference date. The 
following ages (in years) may be computed using the formula [(Study (EXOSKEL) reference date 
– date of birth) + 1 day]/365.25, with reference dates indicated as follows: 
 
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Statistical Analysis Plan  
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Age 
Reference Date 
Age at study informed consent 
Date of study informed consent 
Age at Day 1 study dose 
Date of first Eliglustat dose of the study  
Age at Gaucher disease diagnosis 
Date of Gaucher Disease Diagnosis 
Age at first Gaucher disease symptom onset 
Date of First Gaucher Disease Symptom Onset 
If the date of diagnosis is not complete or date of symptom onset is not complete then age at 
diagnosis or symptom onset will be determined by the month and/or year of date of birth and 
diagnosis or symptom onset. 
Certain assessments may be summarized by age categories which will be determined prior to 
database lock based on the frequency of ages reported (eg, ≤ median age for all patients,  
> median age for all patients). 
Vital signs formulas 
Weight in pounds will be multiplied by 0.4536 to be converted to kilograms (kg); and height in 
inches will be multiplied by 2.54 to be converted to centimeters (cm). 
BMI (kg/ m2) will be calculated using the following formula:  
 
2.5.2 Data handling conventions for secondary efficacy variables  
Eliglustat baseline for hemoglobin and platelet count for patients originated from Phase 2 and 
Encore study 
To obtain a single Study Baseline value for Hemoglobin and Platelet Count, the average of the 
last two measurements prior to receiving Day 1 dose of Eliglustat in the study will be 
calculated. This average value will be referred to as the Baseline value. If either of the 
2 measurements is missing, the Study Baseline value will refer to the non-missing value. 
To obtain a single Eliglustat Baseline value for Hemoglobin and Platelet Count, the average of 
the last two measurements prior to receiving Day 1 dose of Eliglustat in the previous Phase 2 
or Phase 3 trials will be calculated. This average value will be referred to as the Eliglustat 
Baseline value. If either of the 2 measurements is missing, the Eliglustat Baseline value will 
refer to the non-missing value. 
Formulas for calculation of organ Multiples of Normal (MN) 
The following equations will be used to calculate multiples of normal (MN) values for spleen and 
liver volume. If a patient does not have weight assessed on the same date as the spleen/liver 
volume assessment, the weight having the closest date to the spleen/liver assessment will be used.  
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Statistical Analysis Plan  
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2.5.3 Missing data  
For categorical variables, patients with missing data are not included in calculations of 
percentages unless otherwise specified. When relevant, the number of patients with missing data 
is presented. 
Handling of computation of treatment duration if investigational medicinal product end of 
treatment date is missing For the calculation of the treatment duration, the date of the last dose of 
IMP is equal to the date of last administration reported on the end-of-treatment case report form 
page. If this date is missing, the exposure duration should be left as missing.  
The last dose intake should be clearly identified in the case report form and should not be 
approximated by the last returned package date. 
Handling of medication missing/partial dates 
No imputation of medication start/end dates or times will be performed. If a medication date or 
time is missing or partially missing and it cannot be determined whether it was taken prior or 
concomitantly, it will be considered a prior, concomitant, and posttreatment medication. 
Handling of adverse events with missing or partial date/time of onset 
In case of missing or inconsistent information, an adverse event (AE) will be counted as a 
treatment-emergent adverse event (TEAE), unless it can clearly be ruled out that it is not a TEAE 
(eg, by partial dates or other information). 
If the start date of an AE is incomplete or missing, it will be counted as TEAE except if an 
incomplete date indicates that the AE started prior to treatment. 
No imputation of adverse event end dates/times will be performed. These data imputations are for 
categorization purpose only and will not be used in listings. No imputation is planned for 
date/time of adverse event resolution. 
Handling of adverse events when date and time of first investigational medicinal product 
administration is missing 
When the date and time of the first IMP administration is missing, all adverse events that occurred 
on or after the day of enrollment should be considered as treatment-emergent adverse events. The 
exposure duration should be kept as missing. 
The last dose intake should be clearly identified in the case report form and should not be 
approximated by the last returned package date. 
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Handling of missing assessment of relationship of adverse events to investigational medicinal 
product  
If the assessment of the relationship to IMP is missing, then the relationship to IMP has to be 
assumed and the adverse event considered as such in the frequency tables of possibly related 
adverse events, but no imputation should be done at the data level. 
Handling of missing severity of adverse events 
No imputation of the severity of AEs will be performed. 
2.5.4 Windows for time points  
The time window is defined as below to create analysis visit. The relative day below is referred to 
the first dose intake in the EFC13781 study. The end of study is defined as patient completed at 
least 2 years of follow-up (unless early discontinuation) up to 4 years or early discontinued from 
the study or until commercial eliglustat is available to the patients. Thus, the analysis visit list may 
be longer than the list below. The same algorithm will be applied to the trailing visits after the 
Week 416 if applicable. 
Table 2 - Analysis visit schedule  
Analysis visit 
Target day 
Schedule A 
Schedule B 
Schedule C 
Schedule D 
Baseline 
1 
[-45, 1] 
[-45, 1] 
[-45, 1] 
[-45, 1] 
Week 26 
182 
[2, 272] 
 
[2, 272] 
 
Week 52 
364 
[273, 454] 
[2, 545] 
[273, 454] 
 
Week 78 
546 
[455, 636] 
 
[455, 636] 
 
Week 104 
728 
[637, 818] 
[546, 909] 
[637, 818] 
[2, 1091] 
Week 130 
910 
[819, 1000] 
 
[819, 1000] 
 
Week 156 
1092 
[1001, 1182] 
[910, 1273] 
[1001, 1182] 
 
Week 182 
1274 
[1183, 1364] 
 
[1183, 1364] 
 
Week 208 
1456 
[1365, 1546] 
[1274, 1637] 
[1365, 1546] 
[1092, 1819] 
Week 234 
1638 
[1547, 1728] 
 
[1547, 1728] 
 
Week 260 
1820 
[1729, 1910] 
[1638, 2001] 
[1729, 1910] 
 
Week 286 
2002 
[1911, 2092] 
 
[1911, 2092] 
 
Week 312 
2184 
[2093, 2274] 
[2002, 2365] 
[2093, 2274] 
[1820, 2547] 
Week 338 
2366 
[2275, 2456] 
 
[2275, 2456] 
 
Week 364 
2548 
[2457, 2638] 
[2366, 2729] 
[2457, 2638] 
 
Week 390 
2730 
[2639, 2820] 
 
[2639, 2820] 
 
Week 416 
2912 
[2821, 3002] 
[2730, 3093] 
[2821, 3002] 
[2548, 3275] 
Note: Target day is calculated as number of week times 7 days.  
The relative day is calculated as date of assessment - first eliglustat administration date in EFC13781 + 1. 
Schedule A should be applied to complete physical examination and blood pregnancy test. 
Schedule B should be applied to Gaucher disease clinical assessment, DXA, MRI (femur, lumbar, spleen, liver) assessment. 
Scheduled C should be applied to QOL (SF36), Biomarkers and Hematology assessment. 
Scheduled D should be applied to X-ray (femurs, lumbar spine) assessment. 
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Analysis flag will be generated to ensure only one assessment per parameter per analysis visit 
time window can be included in the analysis. The assessment closest to the targeted visit date will 
be used in the presence of multiple measurements within the same time window. When there are 
multiple measurements have the same distance compare to the target day, then scheduled visit 
should be selected first, than unscheduled visit can be considered. If there is still “tie” situation, 
we will choose the later one.  
2.5.5 Unscheduled visits  
Unscheduled visit measurements of laboratory data, vital signs, and ECG will not be included in 
the by-visit summaries (unless it is for repeat liver or spleen volume assessment), but will be used 
for computation of baseline and/or worst values. 
2.5.6 Pooling of centers for statistical analyses  
None planned. 
2.5.7 Statistical technical issues  
Not applicable. 
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Statistical Analysis Plan  
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3 
INTERIM ANALYSIS  
There is no interim analysis planned. However, early analysis, including major efficacy and safety 
endpoints, will be performed after the last patient enrolled and completed 2 years of treatment 
(two-year analysis period). 
Only data collected up to the date of all patients completed 2-year analysis period will be used for 
this early analysis.  
Summary of patient disposition, demographics and key baseline characteristics, prior and 
concomitant medications, extent of IMP exposure and compliance will be provided, as described 
in Section 2.2, Section 2.4.1, Section 2.4.2, and Section 2.4.3, respectively, in the analysis report. 
For efficacy endpoints, the 2-year analysis will be performed for the following efficacy endpoints 
in which details are provided in Section 2.4.4. 
• Mobility, bone pain and bone crisis, as assessed by the Gaucher Disease clinical 
assessments 
• Bone marrow infiltration 
• BMD 
• Lytic lesions, osteonecrosis, fractures and infarcts 
• Bone biomarkers 
• Blood levels of biomarkers of GD1 (chitotriosidase, plasma GL-1 and lyso-GL-1) 
• Gaucher disease related hematology assessment (hemoglobin, platelet) 
• Spleen volume and liver volume 
For safety endpoints, key safety results including TEAE, SAE, AESI, death, AEs leading to 
treatment discontinuation along with related laboratory values, in which details are provided in 
Section 2.4.5 will be provided in the 2-year analysis report. 
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Statistical Analysis Plan  
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4 
DATABASE LOCK  
The 2-year analysis is planned to be locked approximately 28 days after last patient completed 
2-year follow-up. The final database is planned to be locked at approximately 28 days after 
last patient last visit.  
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Statistical Analysis Plan  
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5 
SOFTWARE DOCUMENTATION  
All tables, listings, and figures will be generated in a validated environment using SAS® 
version 9 or higher. 
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Statistical Analysis Plan  
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6 
REFERENCES  
 
1. Ware JE, Kosinski M, Bjorner JB, Turner-Bowker DM, Gandek B, Maruish MW. User’s 
Manual for the SF-36v2 Health Survey, 2nd ed. QualityMetric Incorporated, Lincoln, RI; 
2007.  
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7 
LIST OF APPENDICES  
 
Appendix A
SF-36 health survey 
Appendix B 
Summary of statistical analyses 
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Appendix A 
SF-36 health survey  
A number of computations must be carried out to go from SF-36 questionnaire responses to 
summary scores. These computations are described in this section.  
Each questionnaire item has a final item value, which will be used in the computation of the raw 
score for each of the eight scales. Many questionnaire items have a final item value that is 
equivalent to its pre-coded item value. Prior to any summary scores being calculated, ten items in 
the questionnaire will be re-coded according to the developer’s instructions as follows: 
Item 7 
 
Response Choices 
Pre-coded Item Value 
Final Item Value 
None 
1 
6.0 
Very Mild 
2 
5.4 
Mild 
3 
4.2 
Moderate 
4 
3.1 
Severe 
5 
2.2 
Very Severe 
6 
1.0 
Item 8 – if both Items 7 and 8 are answered. 
 
Response Choices 
Item 8 Pre-coded Item 
Value 
Item 7 Pre-coded 
Item Value 
Final Item Value 
Not At All 
1 
1 
6 
Not At All 
1 
2 through 6 
5 
A Little Bit 
2 
1 through 6 
4 
Moderately 
3 
1 through 6 
3 
Quite A Bit 
4 
1 through 6 
2 
Extremely 
5 
1 through 6 
1 
Item 8 – if Item 7 is not answered. 
 
Response Choices 
Pre-coded Item Value 
Final Item Value 
Not At All 
1 
6.0 
A Little Bit 
2 
4.75 
Moderately 
3 
3.5 
Quite A Bit 
4 
2.25 
Extremely 
5 
1.0 
Item 1 
 
Response Choices 
Pre-coded Item Value 
Final Item Value 
Excellent 
1 
5.0 
Very Good 
2 
4.4 
Good 
3 
3.4 
Fair 
4 
2.0 
Poor 
5 
1.0 
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Items 11b and 11d 
 
Response Choices 
Pre-coded Item Value 
Final Item Value 
Definitely True 
1 
5 
Mostly True 
2 
4 
Don’t Know 
3 
3 
Mostly False 
4 
2 
Definitely False 
5 
1 
Items 9a, 9d, 9e and 9h 
 
Response Choices 
Pre-coded Item Value 
Final Item Value 
All of the Time 
1 
5 
Most of the Time 
2 
4 
Some of the Time 
3 
3 
A Little of the Time 
4 
2 
None of the Time 
5 
1 
Item 6 
 
Response Choices 
Pre-coded Item Value 
Final Item Value 
Not At All 
1 
5 
Slightly 
2 
4 
Moderately 
3 
3 
Quite A Bit 
4 
2 
Extremely 
5 
1 
Item 2 
 
Response Choices 
Pre-coded Item Value 
Final Item Value 
Much Better 
1 
5 
Somewhat Better 
2 
4 
About the Same 
3 
3 
Somewhat worse 
4 
2 
Much worse 
5 
1 
Raw scale scores are calculated using final item values. The raw scale scores will be computed by 
taking the sum of the items for that particular scale (see Table below). A respondent has to have 
answered at least 50% of the items contributing to a particular scale for a raw scale score to be 
computed. If the respondent did not answer at least 50% of the items contributing to a particular 
scale at a particular time point, the raw scale score will be set to missing for that scale for that 
respondent for that particular time point. If a respondent has answered at least 50% of the items 
contributing to a particular scale but some of the items were not answered, the missing items will 
be estimated by the average score across the items that were answered. 
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Each raw scale score will then be transformed to a 0 to 100 scale using the following formula: 
 
Lowest possible raw score and possible raw score range values are:  
 
SF-36 Raw and Transformed Scale Score Specifications 
Scale 
Sum of Final Item Values for 
Raw Scale Score 
Lowest And Highest 
Possible Raw Scores 
Possible Raw Score Range 
Physical Functioning (PF) 
3a + 3b + 3c + 3d + 3e + 3f + 3g + 
3h + 3i + 3j 
10, 30 
20 
Role-Physical (RP) 
4a + 4b + 4c + 4d 
4, 20 
16 
Bodily Pain (BP) 
7 + 8 
2, 12 
10 
General Health (GH) 
1 + 11a + 11b + 11c + 11d 
5, 25 
20 
Vitality (VT) 
9a + 9e + 9g + 9i 
4, 20 
16 
Social Functioning (SF) 
6 + 10 
2, 10 
8 
Role-Emotional (RE) 
5a + 5b + 5c 
3, 15 
12 
Mental Health (MH) 
9b + 9c + 9d + 9f + 9h 
5, 25 
20 
The two overall summary scores will be calculated by first determining the Z-scores for the eight 
scales as follows: 
 
where mean and SD are the appropriate mean and standard deviation of the 1998 general U.S. 
population (1). Z-scores are in standard deviation units. 
The raw PCS and MCS summary scores will be computed by multiplying the z scores for the raw 
component scores (PCS: PF, RP, BP, GH, VT, SF, RE, MH; MCS: PF, RP, BP, GH, VT, SF, RE, 
MH) by the corresponding scoring coefficients (from the general U.S. population [1]) and taking 
the sum of those values. Finally, the PCS and MCS will be standardized as follows: 
PCS = (raw PCS x 10) + 50 
MCS = (raw MCS x 10) + 50 
 
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Appendix B 
Summary of statistical analyses  
EFFICACY ANALYSIS 
 
Endpoint 
Analysis 
population 
Primary 
analysis 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
Primary endpoints 
Gaucher Disease clinical 
assessments: Mobility, 
bone pain, bone crisis 
FAS 
Descriptive statistics 
No 
No 
No 
Bone marrow infiltration 
FAS 
Descriptive statistics 
No 
No 
No 
Bone mineral density 
(BMD) 
FAS 
Descriptive statistics 
No 
No 
No 
Lytic lesions, osteonecrosis, 
fractures and infarcts 
FAS 
Descriptive statistics 
Annual incidence 
rate 
No 
No 
Bone biomarker 
FAS 
Descriptive statistics 
No 
No 
No 
Secondary endpoints 
GD-1 biomarker 
FAS 
Descriptive statistics 
No 
No 
No 
SAFETY ANALYSES 
 
Endpoint 
Analysis 
population 
Primary analysis 
Supportive 
analysis 
Subgroup 
analysis 
Other 
analyses 
Adverse events 
Safety 
Descriptive statistics 
No 
No 
No 
Laboratory, other safety  
Safety 
Descriptive statistics 
No 
No 
No 
 
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