Clinical trial NCT04705051
Conditions: Congenital Cystic Kidney Disease
Sponsor: Sanofi
Start date: 2021-02-09; Completion date: 2021-07-13
Enrollment: 24 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Primary Objective:

-To determine the effect of early versus delayed treatment with venglustat on the total kidney volume (TKV) in participants at risk of rapidly progressive autosomal dominant polycystic kidney disease (ADPKD).

Secondary Objective:

* To determine the effect of early versus delayed treatment with venglustat on the renal function (estimated glomerular filtration rate \[eGFR\] \[Chronic Kidney Disease Epidemiology Collaboration {CKD-EPI} equation\]).
* To characterize the safety profile of venglustat.
* To evaluate the effect of venglustat on the lens by ophthalmological examination.
* To evaluate the effect of venglustat on mood using Beck Depression Inventory-II (BDI-II).

Detailed description:
The planned study duration per participant was 25.5 months (maximal). Screening period (when applicable): up to 2 weeks. Core treatment period: 24 months. Follow-up: 30 days after final dose of the investigational medicinal product (IMP) (venglustat).

Arms: arm 1: Participants were to be treated with venglustat 15 milligrams once daily orally for 24 months or until venglustat was commercially available, whichever came first.
Interventions: intervention 1: Venglustat GZ402671
Intervention descriptions: intervention 1: Pharmaceutical form: capsule Route of administration: oral

Protocol documents:
Prot_000.pdf: 


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 2 
PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY  
 
Document 
Country/countries impacted 
by amendment 
Date, version 
Amended Clinical Trial Protocol 01  
Belgium, Czech Republic, Denmark, 
Germany, Italy, Poland, Portugal, 
Romania, and Spain 
16 March 2021, version 1 (electronic 1.0) 
Original Protocol 
All 
28 September 2020, version 1 (electronic 2.0) 
Amended protocol 01 (16 March 2021) 
This amended protocol (amendment 01) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT  
The protocol is being amended to include country-specific requirements for patients in countries 
participating in the Voluntary Harmonisation Procedure (VHP) for multinational clinical trials in 
Europe (Belgium, Czech Republic, Denmark, Germany, Italy, Poland, Portugal, Romania, and 
Spain). 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis, Overall Design; 
Section 4.1 Overall Design 
Added reference for country-specific requirements 
for patients participating in Belgium, Czech 
Republic, Denmark, Germany, Italy, Poland, 
Portugal, Romania, and Spain. These countries 
will follow instructions provided in Section 10.8.2. 
To comply with the request 
raised during the European 
(EU) VHP review phase. 
Section 10.8 (Appendix 8), 
Country-specific requirements 
Inserted section heading 10.8.1 for Germany 
country-specific requirements. Inserted new 
Section 10.8.2 for Belgium, Czech Republic, 
Denmark, Germany, Italy, Poland, Portugal, 
Romania, and Spain with country-specific 
requirements. All participants will be treated for 
the duration of 24 months. The protocol instruction 
“or until venglustat is commercially available for 
patients, whichever comes first” is not applicable 
to the countries listed above. 
To comply with the request 
raised during the EU VHP 
review phase, study 
participants in these countries 
will receive venglustat (15 mg 
once daily) for the duration of 
24 months. 
 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 3 
TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 01 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
DOCUMENT HISTORY ................................................................................................................................... 2 
OVERALL RATIONALE FOR THE AMENDMENT ........................................................................................ 2 
TABLE OF CONTENTS .................................................................................................................................. 3 
LIST OF TABLES ........................................................................................................................................... 7 
LIST OF FIGURES .......................................................................................................................................... 8 
1 
PROTOCOL SUMMARY ................................................................................................................. 9 
1.1 
SYNOPSIS ....................................................................................................................................... 9 
1.2 
SCHEMA ........................................................................................................................................ 12 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 13 
1.3.1 
Study flowchart for participants enrolled in LTS15823 study at Visit 12 (Month 24) of the 
EFC15392 study ............................................................................................................................ 13 
1.3.2 
Study flowchart for participants enrolled in LTS15823 study after the end-of-treatment visit 
of the EFC15392 study .................................................................................................................. 17 
2 
INTRODUCTION  .......................................................................................................................... 22 
2.1 
STUDY RATIONALE ..................................................................................................................... 22 
2.2 
BACKGROUND ............................................................................................................................. 22 
2.2.1 
Venglustat ...................................................................................................................................... 22 
2.2.2 
Autosomal dominant polycystic kidney disease ............................................................................. 23 
2.2.3 
Autosomal dominant polycystic kidney disease and venglustat .................................................... 24 
2.2.4 
Clinical trials of venglustat in humans ............................................................................................ 25 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 26 
2.3.1 
Risk assessment ............................................................................................................................ 27 
2.3.2 
Benefit assessment ........................................................................................................................ 28 
2.3.3 
Overall benefit-risk conclusion ....................................................................................................... 29 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 30 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 31 
4 
STUDY DESIGN ............................................................................................................................ 32 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 4 
4.1 
OVERALL DESIGN ........................................................................................................................ 32 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 32 
4.2.1 
Participant input into design ........................................................................................................... 32 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 33 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 33 
5 
STUDY POPULATION .................................................................................................................. 34 
5.1 
INCLUSION CRITERIA .................................................................................................................. 34 
5.2 
EXCLUSION CRITERIA  ............................................................................................................... 35 
5.3 
LIFESTYLE CONSIDERATIONS................................................................................................... 37 
5.3.1 
Meals and dietary restrictions ........................................................................................................ 37 
5.3.2 
Caffeine, alcohol, and tobacco....................................................................................................... 37 
5.3.3 
Activity ............................................................................................................................................ 37 
5.4 
SCREEN FAILURES ..................................................................................................................... 38 
5.5 
CRITERIA FOR TEMPORARILY DELAYING ENROLLMENT OR ADMINISTRATION OF 
STUDY INTERVENTION ADMINISTRATION ............................................................................... 38 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................................... 39 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 39 
6.1.1 
Devices .......................................................................................................................................... 40 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY ...................................................... 40 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 40 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 40 
6.5 
DOSE MODIFICATION .................................................................................................................. 41 
6.5.1 
Retreatment criteria ....................................................................................................................... 41 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY ...................... 41 
6.7 
TREATMENT OF OVERDOSE ...................................................................................................... 41 
6.8 
CONCOMITANT THERAPY .......................................................................................................... 42 
6.8.1 
List of forbidden concomitant medication ...................................................................................... 42 
6.8.2 
Rescue medicine............................................................................................................................ 43 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL   ......................................................................................... 44 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 5 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  ..................................................................... 44 
7.1.1 
Permanent discontinuation ............................................................................................................ 44 
7.1.2 
Liver chemistry stopping criteria .................................................................................................... 45 
7.1.3 
QTc stopping criteria ...................................................................................................................... 45 
7.1.4 
Temporary discontinuation ............................................................................................................. 46 
7.1.5 
Rechallenge ................................................................................................................................... 46 
7.1.5.1 
Study intervention restart or rechallenge after liver stopping criteria met...................................... 46 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 46 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 47 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 48 
8.1 
EFFICACY ASSESSMENTS  ........................................................................................................ 48 
8.1.1 
Magnetic resonance imaging ......................................................................................................... 48 
8.1.2 
Estimated glomerular filtration rate ................................................................................................ 48 
8.2 
SAFETY ASSESSMENTS  ............................................................................................................ 49 
8.2.1 
Physical examinations ................................................................................................................... 49 
8.2.2 
Vital signs ....................................................................................................................................... 50 
8.2.3 
Electrocardiograms ........................................................................................................................ 50 
8.2.4 
Clinical safety laboratory assessments .......................................................................................... 51 
8.2.5 
Pregnancy testing .......................................................................................................................... 51 
8.2.6 
Suicidal ideation and behavior risk monitoring .............................................................................. 51 
8.2.6.1 
Beck Depression Inventory, second edition ................................................................................... 52 
8.2.7 
Ophthalmological examination ....................................................................................................... 53 
8.2.8 
Participant reported outcomes ....................................................................................................... 54 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING ................................................................................................................... 55 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 55 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 55 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 55 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 56 
8.3.5 
Pregnancy ...................................................................................................................................... 56 
8.3.6 
Cardiovascular and death events .................................................................................................. 57 
8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 57 
8.3.8 
Adverse event of special interest ................................................................................................... 57 
8.3.9 
Guidelines for reporting product complaints .................................................................................. 58 
8.3.9.1 
Medical device deficiencies ........................................................................................................... 58 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 6 
8.4 
PHARMACOKINETICS .................................................................................................................. 58 
8.5 
GENETICS AND/OR PHARMACOGENOMICS ............................................................................ 58 
8.6 
BIOMARKERS ............................................................................................................................... 58 
8.7 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 59 
8.8 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS ................................................................................................................................. 59 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 59 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 61 
9.1 
SAMPLE SIZE DETERMINATION................................................................................................. 61 
9.2 
POPULATIONS FOR ANALYSES ................................................................................................. 61 
9.3 
STATISTICAL ANALYSES ............................................................................................................ 62 
9.3.1 
General considerations .................................................................................................................. 62 
9.3.2 
Primary endpoint ............................................................................................................................ 64 
9.3.3 
Secondary endpoints ..................................................................................................................... 65 
9.3.4 
Tertiary/exploratory endpoint(s) ..................................................................................................... 66 
9.3.5 
Safety analysis ............................................................................................................................... 66 
9.3.5.1 
Adverse events .............................................................................................................................. 66 
9.3.5.2 
Laboratory variables, vital signs, and electrocardiograms (ECGs) ................................................ 67 
9.3.6 
Other analysis ................................................................................................................................ 68 
9.4 
INTERIM ANALYSES  ................................................................................................................... 68 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 69 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 69 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 69 
10.1.2 
Financial disclosure ....................................................................................................................... 70 
10.1.3 
Informed consent process .............................................................................................................. 70 
10.1.4 
Data protection ............................................................................................................................... 71 
10.1.5 
Committees structure ..................................................................................................................... 73 
10.1.5.1 Data Monitoring Committee ........................................................................................................... 73 
10.1.5.2 Steering committee ........................................................................................................................ 73 
10.1.6 
Dissemination of clinical study data ............................................................................................... 74 
10.1.7 
Data quality assurance .................................................................................................................. 74 
10.1.8 
Source documents ......................................................................................................................... 75 
10.1.9 
Study and site start and closure ..................................................................................................... 75 
10.1.10 Publication policy ........................................................................................................................... 76 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 7 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 77 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING ......................................................................... 78 
10.3.1 
Definition of AE .............................................................................................................................. 78 
10.3.2 
Definition of SAE ............................................................................................................................ 80 
10.3.3 
Recording and follow-up of AE and/or SAE ................................................................................... 81 
10.3.4 
Reporting of SAEs ......................................................................................................................... 83 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE ................................................... 84 
10.4.1 
Definitions ...................................................................................................................................... 84 
10.4.2 
Contraception guidance ................................................................................................................. 84 
10.5 
APPENDIX 5: GENETICS ............................................................................................................. 87 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS ............................................................................................................................ 88 
10.7 
APPENDIX 7: AES, ADES, SAES, SADES, USADES AND DEVICE DEFICIENCIES: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, FOLLOW-UP, 
AND REPORTING IN MEDICAL DEVICE STUDIES .................................................................... 89 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 89 
10.8.1 
Germany ........................................................................................................................................ 89 
10.8.2 
Belgium, Czech Republic, Denmark, Germany, Italy, Poland, Portugal, Romania, Spain ............ 89 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................... 89 
10.10 
APPENDIX 10: BECK DEPRESSION INVENTORY II .................................................................. 93 
10.11 
APPENDIX 11: BRIEF PAIN INVENTORY (SHORT FORM) (BPI-SF) ......................................... 95 
10.12 
APPENDIX 12: BRIEF FATIGUE INVENTORY (BFI) ................................................................... 97 
10.13 
APPENDIX 13: EUROQOL (EQ-5D-5L) ........................................................................................ 98 
10.14 
APPENDIX 14: ABBREVIATIONS ................................................................................................. 99 
10.15 
APPENDIX 15: PROTOCOL AMENDMENT HISTORY .............................................................. 100 
11 
REFERENCES............................................................................................................................. 101 
 
LIST OF TABLES  
Table 1 - Risk assessment ............................................................................................................................ 28 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 8 
Table 2 - Objectives and endpoints ............................................................................................................... 30 
Table 3 - Overview of study interventions administered ............................................................................... 39 
Table 4 - Arms and associated interventions ................................................................................................ 39 
Table 5 - Participant reported outcome (PRO) concepts and questionnaires .............................................. 54 
Table 6 - Populations for analyses ................................................................................................................ 61 
Table 7 - Protocol-required laboratory tests .................................................................................................. 77 
Table 8 - Highly effective contraceptive methods ......................................................................................... 86 
 
LIST OF FIGURES  
Figure 1 - Graphical study design including the EFC15392 study ................................................................ 12 
Figure 2 - Dose-dependent glucosylceramide synthase lowering and efficacy in the jck mouse model of 
polycystic kidney disease .............................................................................................................................. 24 
 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 9 
1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title:  
Multicenter, open-label, extension study to characterize the long-term efficacy and safety of early 
versus delayed treatment with venglustat (GZ/SAR402671) in patients at risk of rapidly 
progressive autosomal dominant polycystic kidney disease (ADPKD) 
Brief title: Long-term treatment of autosomal dominant polycystic kidney disease (ADPKD) with 
venglustat 
Rationale: 
To obtain the long-term efficacy and safety of additional 24-month treatment with venglustat in 
patients with ADPKD who completed Study EFC15392. 
Objectives and endpoints  
 
 
 
Objectives 
Endpoints 
Primary 
• 
To determine the effect of early versus delayed 
treatment with venglustat on the total kidney volume 
(TKV) in participants at risk of rapidly progressive 
ADPKD. 
• 
Percent change in TKV based on magnetic 
resonance imaging (MRI) from the EFC15392 study 
baseline to 24 months of open-label extension 
study, in early-treated and delayed-treated 
participants. 
Secondary 
• 
To determine the effect of early versus delayed 
treatment with venglustat on the renal function 
(estimated glomerular filtration rate [eGFR]). 
• 
Change in eGFR (Chronic Kidney Disease 
Epidemiology Collaboration [CKD-EPI] equation) 
from the EFC15392 study baseline to 24 months of 
open-label extension study, in early-treated and 
delayed-treated participants. 
• 
To characterize the safety profile of venglustat. 
• 
Safety in terms of treatment-emergent adverse 
events (TEAEs), adverse events (AEs), serious 
adverse events (SAEs), laboratory parameters, vital 
signs, electrocardiogram and findings from physical 
examination will be assessed through the study and 
will be reported in the electronic case report form 
(eCRF). 
• 
To evaluate the effect of venglustat on the lens by 
ophthalmological examination. 
• 
Change from EFC15392 study baseline in the lens 
clarity by ophthalmological examination during the 
open-label extension treatment-emergent period. 
• 
To evaluate the effect of venglustat on mood using 
Beck Depression Inventory-II (BDI-II). 
• 
Change from EFC15392 study baseline in BDI-II 
score during the open-label extension 
treatment-emergent period. 
 
 
 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 10 
Overall design: 
This will be an international, multicenter, open-label extension study rolling over adult 
participants at risk of rapidly progressive ADPKD who have previously completed Stage 1 or 
Stage 2 of Study EFC15392. All participants will be treated with venglustat 15 mg once daily 
(QD) for 24 months or until venglustat is commercially available for patients, whichever comes 
first. See Appendix 8 (Section 10.8) for definition applicable for patients participating in Belgium, 
Czech Republic, Denmark, Germany, Italy, Poland, Portugal, Romania, and Spain 
(Section 10.8.2). 
Brief summary:  
This is a single group, treatment, Phase 3, open-label study to evaluate the efficacy and safety of 
venglustat in male and female participants at risk of rapidly progressive Autosomal Dominant 
Polycystic Kidney Disease (ADPKD). 
Number of participants: 
It is anticipated that a maximum of 640 participants who completed Stage 1 or Stage 2 of the 
EFC15392 study could be enrolled to participate in this study. 
Intervention groups and duration: 
This will be an interventional single arm study.  
Duration period: 25.5 months at the maximum. Screening period (when applicable): up to 
2 weeks. Core treatment period: 24 months. Follow-up: 30 days after final dose of the 
investigational medicinal product (IMP) (venglustat). 
Enrollment in LTS15823 study must coincide with Visit 12 (Month 24; end-of-treatment visit) of 
the EFC15392 study. Patients who cannot be included in the extension study at the time of 
Visit 12 for administrative or logistical reasons, and provided they agree to participate in the 
LTS15823 study, will have a separate Screening visit (Visit 0) performed and must be enrolled in 
the LTS15823 within 2 months of the last dose of IMP (Visit 12 [Month 24]) administered in the 
EFC15392 study. This 2-month window can be further extended up to 6 months following review 
and approval from the Sponsor. 
Study intervention(s) 
Investigational medicinal product(s) 
• Formulation: venglustat is provided in capsule formulation containing 15 mg of venglustat 
(active moiety). Venglustat is not approved in any territory. 
• Route(s) of administration: oral. 
• Dose regimen: 15 mg once daily. 
  
Devices 
Not applicable. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 11 
Posttrial access to study medication 
Not applicable. 
Statistical considerations: 
• Primary endpoint: Percent change in TKV based on magnetic resonance imaging (MRI) 
from the EFC15392 study baseline to 24 months of open-label extension study, in 
early-treated and delayed-treated participants. 
The primary estimand will be the difference (early venglustat versus delayed venglustat) in mean 
percent change in TKV from the EFC15392 study baseline to 24 months in the LTS15823 study, 
in all participants from the primary efficacy population, regardless of whether or not participants 
completed the LTS15823 study treatment period (treatment policy strategy). 
Percent change from the EFC15392 study baseline in TKV will be analyzed using a mixed effect 
model with repeated measures (MMRM). The MMRM will include percent change in TKV at the 
following time points:  
• Month 18 in the EFC15392 study. 
• Baseline in the LTS15823 study. 
• Month 24 in the LTS15823 study. 
The MMRM will include fix effect of treatment group (early venglustat versus delayed 
venglustat), Mayo Imaging Classification (as per randomization stratification factor in the 
EFC15392 study: Class 1C versus 1D versus 1E), time point (as a categorical variable), 
treatment*time point interaction, Mayo Imaging Classification*time point interaction as well as 
the continuous fixed covariates of baseline TKV and the baseline-by-time point interaction. 
The difference in baseline adjusted least-squares means will be used to compare the early 
venglustat group to the delayed venglustat group, at the 2-sided 0.05 level. 
The primary analysis will include all observed TKV data in participants from the primary efficacy 
population, regardless of whether or not participants completed the treatment period. Participants 
who prematurely and permanently discontinue IMP in the LTS15823 study will be requested to 
obtain an MRI scan at 24-month visit and their data collected after treatment discontinuation will 
be included in the primary analysis. All efforts will be made to minimize the amount of missing 
data. 
• Main secondary endpoints: Change in eGFR (Chronic Kidney Disease Epidemiology 
Collaboration [CKD-EPI] equation) from the EFC15392 study baseline to 24 months of 
open-label extension study, in early-treated and delayed-treated participants 
Change from the EFC15392 study baseline in eGFR will be analyzed using a MMRM similar to 
those used to analyze percent change in TKV. The MMRM will include change in eGFR at all 
time points in the EFC15392 and LTS15823 studies (change at Months 1, 3, 6, 9, 12, 15, 18, 21, 
and 24 in the EFC15392 study and at Baseline, Months 1, 6, 12, 18, and 24 in the 
LTS15823 study). 
Data Monitoring/Other committee: Yes 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 12 
1.2 
SCHEMA  
Figure 1 - Graphical study design including the EFC15392 study  
 
In the open-label extension LTS15823 study:  
• Early venglustat: participants who were randomized to venglustat (8 mg or 15 mg) in Stage 1 or Stage 2 of the EFC15392 study. 
• Delayed venglustat: participants who were randomized to placebo in Stage 1 or Stage 2 of the EFC15392 study. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 13 
1.3 
SCHEDULE OF ACTIVITIES (SOA)  
1.3.1 Study flowchart for participants enrolled in LTS15823 study at Visit 12 (Month 24) of the EFC15392 study  
 
Visit 
1a, b 
Baseline 
2 
3 
4 
5 
6 
7 
8 
9 
10c 
(EOT)  
11d 
(Follow-
up) 
Month 
0 
1 
3 
6 
9 
12 
15 
18 
21 
24 
25 
Day (window [days]) 
1 
 
30 
(±7) 
90  
(±7) 
180  
(±7) 
270  
(±7) 
360 
(±7) 
450  
(±7) 
540 
(±7) 
630  
(±7) 
720 
(±7) 
750 
(±7) 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
Inclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
Exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
 
Body weight, heighte 
X 
 
 
 
 
X 
 
 
 
X 
  
Vital signsf 
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination - Complete 
(including full neurological 
examination)  
Xb 
 
 
 
 
X 
 
 
 
X 
 
Physical examination - 
Abbreviatedg 
 
X 
 
X 
 
 
 
X 
 
  
Xh 
Chemistryi 
Xb 
X 
 
X 
 
X 
 
X 
 
X 
Xh 
Blood creatinine only (for eGFR 
calculation)i 
 
 
X 
 
X 
 
X 
 
X 
 
 
Hematology 
Xb 
X 
 
X 
 
X 
 
X 
 
X 
 
Urine pregnancy test (WOCBP)j  
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 14 
Visit 
1a, b 
Baseline 
2 
3 
4 
5 
6 
7 
8 
9 
10c 
(EOT)  
11d 
(Follow-
up) 
Month 
0 
1 
3 
6 
9 
12 
15 
18 
21 
24 
25 
Day (window [days]) 
1 
 
30 
(±7) 
90  
(±7) 
180  
(±7) 
270  
(±7) 
360 
(±7) 
450  
(±7) 
540 
(±7) 
630  
(±7) 
720 
(±7) 
750 
(±7) 
Urinalysis with microscopyk 
Xb 
X 
 
X 
 
X 
 
X 
 
X 
X 
GSL markersl 
Xb 
 
 
X 
 
X 
 
X 
 
X 
 
Serum/plasma biomarkersh, l 
Xb 
 
 
X 
 
X 
 
X 
 
X 
 
Urinary markers (24-hour)m  
Xb 
X 
 
X 
 
X 
 
X 
 
X 
 
12-lead ECGn 
Xb 
 
 
X 
 
 
 
 
 
X 
 
MRIo 
Xa 
 
 
 
 
 
 
 
 
X 
 
BDI-II 
Xb 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ophthalmological examinationp 
Xb 
 
 
X 
 
X 
 
X 
 
X 
 
BPI-SFq 
Xb 
X 
 
X 
 
X 
 
X 
 
X 
 
BFIq 
Xb 
X 
 
X 
 
X 
 
X 
 
X 
 
EQ-5D-5Lq 
Xb 
X 
  
X 
 
X  
 
X 
 
X  
 
Call IxRS 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense IMP 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
 
IMP accounting and compliance 
  
X 
X 
X 
X 
X 
X  
X  
X  
X 
  
Biobankingl, r 
Xb 
 
 
 
 
X 
 
 
 
X 
 
Concomitant medications 
Xb 
X 
X 
X 
X 
X 
X 
X  
X 
X 
X 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 15 
Visit 
1a, b 
Baseline 
2 
3 
4 
5 
6 
7 
8 
9 
10c 
(EOT)  
11d 
(Follow-
up) 
Month 
0 
1 
3 
6 
9 
12 
15 
18 
21 
24 
25 
Day (window [days]) 
1 
 
30 
(±7) 
90  
(±7) 
180  
(±7) 
270  
(±7) 
360 
(±7) 
450  
(±7) 
540 
(±7) 
630  
(±7) 
720 
(±7) 
750 
(±7) 
AEs/SAEt 
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs = adverse events; AESIs = adverse events of special interest; BDI-II = Beck Depression Inventory II; BFI = Brief Fatigue Inventory; BP = blood pressure;  
BPI-SF = Brief Pain Inventory short form; eGFR = estimated glomerular filtration rate; ECG = electrocardiogram; EOT= end-of-treatment; EQ-5D-5L = EuroQoL 
5 dimension 5 level; EW = early withdrawal; GSL = glycosphingolipid; IMP = investigational medicinal product; IxRS = interactive voice/web response system;  
MRI = magnetic resonance imaging; PRO = participant reported outcome; SAEs = serious AEs; WHO = World Health Organization; WOCBP = women of 
childbearing potential. 
a Visit 12 (the end-of treatment, Month 24) of the EFC15392 study will correspond to Visit 1 (Day 1) of the LTS15823 study with all evaluations of Visit 12 of 
EFC15392 study and an additional MRI that will be performed in the time frame of Visit 1 of the LTS15823 study. Every effort shall be made to have MRI 
performed at Visit 1 of the LTS15823 study prior to the start of IMP. If for technical reasons MRI examination cannot be performed at Visit 1, it should be 
performed as soon as possible, within next 7 days. 
b Clinical and instrumental assessments obtained at Visit 12 (Month 24) of the EFC15392 study will be used for both Visit 12 (Month 24) of EFC15392 study and 
Visit 1 of the LTS15823 study. 
c If a participant discontinues treatment with IMP early during the core treatment period, the participant will have an end-of-treatment/early withdrawal (EOT/EW) 
Visit within 7 days and a Follow-up Visit 30 days after the last dose of IMP. Early EOT/EW visit will be performed without MRI. Participants who prematurely 
and permanently discontinue study medication in the LTS15823 study will be requested to obtain an MRI scan at Month 24 Visit.  
d Follow-up assessments will be evaluated 30 days after the last dose of IMP. 
e Height measured in the EFC15392 study will be recorded only at Visit 1. 
f Vital sign measurements (sitting BP and heart rate): For all measurements, 3 separate seated BP measurements should be taken with at least 1 minute 
between readings, following at least 10-minute rest period and prior to phlebotomy. The arm with the higher pressure at the initial Screening visit of the 
EFC15392 study should be used for all subsequent BP measurements.   
g The abbreviated physical examination should focus on areas important for assessment of AEs if necessary. 
h Only for participants with abnormal laboratory results and/or AEs that will require follow up after Visit 10. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 16 
i Samples should be collected in fasting conditions.  
j Any positive urine pregnancy test result must be confirmed based on serum pregnancy test. The Investigator may perform additional tests at their discretion or 
as required by local regulations. Participants will perform monthly urine pregnancy test at home and report to the site. 
k Urinalysis includes urine dipstick and microscopy. Dipstick includes assessment of specific gravity, pH, protein, glucose, blood, ketones, bilirubin, urobilinogen, 
nitrite, and leukocyte esterase. Microscopy (central laboratory) includes detection of formed cellular elements, casts, bacteria, yeast, parasites, and crystals in 
centrifuged urine sediment. Dipstick will be done locally; if any parameter on the dipstick is abnormal, a urine sample should be sent to the central laboratory 
for quantitative measurement.  
l Not applicable for Chinese participants. 
m A 24-hour urine sample will be collected to evaluate exploratory biomarkers (not applicable for Chinese participants), albumin, total protein, creatinine, 
electrolytes, and osmolality. At the end of on-site visit, the participant should be given suitable containers in which to collect the 24-hour urine, required prior to 
the next on-site visit and to be returned at that visit. 
n The 12-lead ECG recordings should be performed before blood samplings. The ECG will be evaluated as “normal” or “abnormal”. 
o Using a central reader, liver volume and combined renal volume of both kidneys will be measured. Combined renal cyst volume and renal parenchyma may be 
determined at a later date for a subset of participants. 
p The participant is required to have full ophthalmological examination at Visit 1, at Month 12 (Visit 6), and at Month 24 (Visit 10) (or upon withdrawal or 
discontinuation) with pupil dilation and WHO simplified cataract grading system evaluation of lens opacities. Best corrected visual acuity (BCVA) examination 
will be additionally performed at Month 6 (Visit 4) and Month 18 (Visit 8). If at any time during study participation, the participant experiences a decrease  
≥2 lines in BCVA compared to baseline or previous assessment, full ophthalmological examination with pupil dilation and WHO simplified cataract grading 
system evaluation should be performed. If a new or worsening lens abnormality is found, documentation of finding with lens photography is recommended. 
Pupil dilation and full eye examination can be performed at any time if deemed medically necessary; WHO simplified cataract grading system evaluation should 
be performed if a change from baseline is observed during slit-lamp examination. 
q The PROs will be administered to participants at study visit according to the listed schedule before dosing and before clinical assessments. 
r Prior to the start of IMP at Baseline Visit. In participants who have consented to it, samples of serum will be collected and archived for future analysis. 
s All ongoing or new medications from the end of the EFC15392 study should be reported in the LTS15823 study, even if reported prior to informed consent. 
t All SAEs, AEs, and AEs of special interest (AESIs) will be collected starting with signing the informed consent and will continue until 30 days after the last dose 
of IMP or study end, whichever comes later. All AEs that occurred during treatment should be followed for at least 30 days following the last dose of IMP or 
until the event has resolved, the condition has stabilized, the etiology of the event is determined to be not related to IMP, or the participant is lost to follow-up. 
All participants will have a Follow-up visit 30 days after the last dose of IMP to collect safety information. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 17 
1.3.2 Study flowchart for participants enrolled in LTS15823 study after the end-of-treatment visit of the EFC15392 study  
 
Visit 
0a, b 
Screening 
1b, c 
Baseline 
2 
3 
4 
5 
6 
7 
8 
9 
10d 
(EOT) 
11e 
(Follow-
up) 
Month 
 
0 
1 
3 
6 
9 
12 
15 
18 
21 
24 
25 
Day (window [days]) 
-7 daysf 
(+3) 
1 
(+3) 
30  
(±7) 
90 
(±7) 
180 
(±7) 
270 
(±7) 
360 
(±7) 
450 
(±7) 
540 
(±7) 
630 
(±7) 
720  
(±7) 
750 
(±7) 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
Medical/surgical historyg 
X 
 
 
 
 
 
 
 
 
 
 
 
Medication historyg 
X 
 
 
 
 
 
 
 
 
 
 
 
Body weight, heighth 
X 
 
 
 
 
 
X 
 
 
 
X 
  
Vital signsi 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination - 
Complete (including full 
neurological examination)  
X 
 
 
 
 
 
X 
 
 
 
X 
 
Physical examination - 
Abbreviatedj 
 
 
X 
 
X 
 
 
 
X 
 
  
Xk 
Chemistryl 
X  
 
X 
 
X 
 
X 
 
X 
 
X 
Xk 
Blood creatinine only (for 
eGFR calculation)l 
 
 
 
X 
 
X 
 
X 
 
X 
 
 
Hematology 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Serum pregnancy test 
(WOCBP)m  
X 
 
 
 
 
 
 
 
 
 
 
 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 18 
Visit 
0a, b 
Screening 
1b, c 
Baseline 
2 
3 
4 
5 
6 
7 
8 
9 
10d 
(EOT) 
11e 
(Follow-
up) 
Month 
 
0 
1 
3 
6 
9 
12 
15 
18 
21 
24 
25 
Day (window [days]) 
-7 daysf 
(+3) 
1 
(+3) 
30  
(±7) 
90 
(±7) 
180 
(±7) 
270 
(±7) 
360 
(±7) 
450 
(±7) 
540 
(±7) 
630 
(±7) 
720  
(±7) 
750 
(±7) 
FSH and/or estradiol as 
neededn 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test 
(WOCBP)o  
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis with microscopyp 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
GSL markersq 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
Serum/plasma biomarkersk, q 
X 
 
 
 
X 
 
X 
 
X 
 
X 
 
Urinary markers (24-hour)r 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Viral serology 
Xs 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECGt 
X 
 
 
 
X 
 
 
 
 
 
X 
 
MRIu 
X 
 
 
 
 
 
 
 
 
X 
 
BDI-II 
X 
  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ophthalmological 
examinationv 
X 
 
 
X 
 
X 
 
X 
 
X 
 
BPI-SFw 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
BFIw 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
EQ-5D-5Lw 
 
X 
X 
  
X 
 
X  
 
X 
 
X 
 
Call IxRS 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense IMP 
 
Xb, c 
X 
X 
X 
X 
X 
X 
X 
X 
  
 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 19 
Visit 
0a, b 
Screening 
1b, c 
Baseline 
2 
3 
4 
5 
6 
7 
8 
9 
10d 
(EOT) 
11e 
(Follow-
up) 
Month 
 
0 
1 
3 
6 
9 
12 
15 
18 
21 
24 
25 
Day (window [days]) 
-7 daysf 
(+3) 
1 
(+3) 
30  
(±7) 
90 
(±7) 
180 
(±7) 
270 
(±7) 
360 
(±7) 
450 
(±7) 
540 
(±7) 
630 
(±7) 
720  
(±7) 
750 
(±7) 
IMP accounting and 
compliance 
  
 
X 
X 
X 
X  
X 
X 
X 
X 
X 
  
Biobankingq, x  
X 
 
 
 
 
 
X 
 
 
 
X 
 
Concomitant medicationy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AEs/SAEz 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AB = antibody; AEs = adverse events; AESI = adverse events of special interest; BCVA = best corrected visual acuity; BDI-II = Beck Depression Inventory II;  
BFI = Brief Fatigue Inventory; BP = blood pressure; BPI-SF = Brief Pain Inventory short form; DNA = deoxyribonucleic acid; eCRF = electronic case report form; 
eGFR = estimated glomerular filtration rate; ECG = electrocardiogram; EOT= end-of-treatment; EQ-5D-5L = EuroQoL 5 dimension 5 level; EW = early withdrawal; 
FSH = follicle-stimulating hormone; GSL = glycosphingolipid; HBV = hepatitis B virus; IMP = investigational medicinal product; IxRS = interactive voice/web 
response system; MRI = magnetic resonance imaging; PRO = participant reported outcome; SAEs = serious AEs; WHO = World Health Organization;  
WOCBP = women of childbearing potential. 
a Patients  who cannot be included in the extension study at the time of the end-of-treatment visit of the EFC15392 study for administrative or logistical reasons 
must have a separate Screening visit (Visit 0) in the LTS15823 study. Neurological and ophthalmic examination results obtained at Visit 12 (Month 24) of the 
EFC15392 study can be used for Visit 1 of the LTS15823 study in these participants if Visit 0 of LTS15823 is performed within 2 months after the Visit 12 in the 
EFC15392 study. All other assessments required at Visit 0 of LTS15823 study must be performed in the time frame of the LTS15823 study. Patients screened 
in more than 2 months after Visit 12 of the EFC15392 study will have as well as a separate Screening visit (Visit 0) and all Visit 0 assessments performed. 
b All Visit 0 and Visit 1 assessments, including MRI, must be performed prior to the first IMP administration in the LTS15823 study. 
c The IMP will be dispensed at Visit 1 after confirmation of Visit 0 eGFR >30 mL/min/1.73 m2, after review of Visit 0 blood chemistry and hematology results,  
Visit 0 ECG central reading, blood pregnancy test (if done at Visit 0) and Visit 1 urinary pregnancy test. 
d If a participant discontinues treatment with IMP early during the core treatment period, the participant will have an end-of-treatment/Early Withdrawal (EOT/EW) 
Visit within 7 days and a Follow-up Visit 30 days after the last dose of IMP. Early EOT/EW visit will be performed without MRI. Participants who prematurely 
and permanently discontinue IMP in the LTS15823 study will be requested to obtain an MRI scan at the Month 24 Visit. 
e Follow-up assessments will be evaluated 30 days after the last dose of IMP.  
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 20 
f If necessary, a second pretreatment eGFR value can be obtained for confirmation of eligibility to account for potential eGFR variability. Duration of screening 
period can be increased up to 2 weeks if a second pretreatment eGFR value will be required or if any test has to be repeated due to indeterminate result or 
technical issue. Other reasons have to be discussed with the Sponsor. 
g Only medical events that occurred between the end-of-study visit of the EFC15392 study and Visit 1 in LTS15823 study. Ongoing medications at the time of the 
end-of-study visit of the EFC15392 or new medications and changes in dose of ongoing medications that occurred between the end-of-treatment visit of the 
EFC15392 study and Visit 0 in LTS15823 study. All medical events will be reported in AE eCRF forms. 
h Height measured in the EFC15392 study will be recorded only at Visit 0. 
i Vital sign measurements (sitting BP and heart rate): For all measurements 3 separate seated BP measurements should be taken with at least 1 minute 
between readings, following at least 10-minute rest period and prior to phlebotomy. The arm with the higher pressure at the Screening visit (Visit 0) should be 
used for all subsequent BP measurements.   
j The abbreviated physical examination should focus on areas important for assessment of AEs if necessary. 
k Only for participants with abnormal laboratory results and/or AEs that will require follow up after Visit 10. 
l Samples should be collected in fasting conditions. 
m Serum pregnancy testing at Visit 0 only for female participants who stopped using contraception after the end of the EFC15392 study (no urine pregnancy test 
will be required at Visit 0 for these participants). If serum pregnancy test was performed at Visit 0, test result must be reviewed prior to the start of IMP  
at Visit 1. 
n FSH and estradiol will be tested at screening at the discretion of Investigator if participant progressed into menopause and will require confirmation of 
menopause status. 
o No urine pregnancy test will be required at Visit 0 for participants who will have a blood urine pregnancy test performed at Visit 0. Any positive urine pregnancy 
test result must be confirmed based on serum pregnancy test. The Investigator may perform additional tests at their discretion or as required by local 
regulations. Participants will perform monthly urine pregnancy test at home and report to the site. 
p Urinalysis includes urine dipstick and microscopy. Dipstick includes assessment of specific gravity, pH, protein, glucose, blood, ketones, bilirubin, urobilinogen, 
nitrite, and leukocyte esterase. Microscopy (central laboratory) includes detection of formed cellular elements, casts, bacteria, yeast, parasites, and crystals in 
centrifuged urine sediment. Dipstick will be done locally, if any parameter on the dipstick is abnormal, a urine sample should be sent to the central laboratory 
for quantitative measurement.  
q Not applicable for Chinese participants. 
r 24-hour urine sample will be collected to evaluate exploratory biomarkers (not applicable for Chinese participants), albumin, total protein, creatinine, 
electrolytes, and osmolality. At the end of Visit 1 and other on-site visits, the participant should be given suitable containers in which to collect the 24-hour 
urine, required prior to the next on-site visit and to be returned at that visit. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 21 
s At the discretion of Investigator if a new medical (viral hepatitis or HIV infection) condition is suspected. If Investigator will decide that viral serology test is 
warranted at Visit 1, patient will be excluded in case of positive result of any of the following tests: hepatitis B surface antigen (HBsAg), anti-hepatitis C virus 
(anti HCV) antibodies, anti-human immunodeficiency virus 1 and 2 antibodies (anti HIV 1 and anti HIV 2 Ab). Patients with a positive hepatitis B surface 
antibody (HBsAb) test are eligible if other criteria are met (ie, negative tests for: HBsAg, hepatitis B core antibody [HBcAb]). Patients who are immune due to 
natural infection (positive HBsAb, negative HBsAg, and positive HBcAb) are eligible if they have a negative HBV DNA test. 
t The 12-lead ECG recordings should be performed before blood samplings. Visit 0 ECG central reader assessment should be evaluated prior to IMP 
administration at Visit 1. The ECG will be evaluated as “normal” or “abnormal”. 
u Baseline MRI should be performed prior to first IMP administration in the LTS15823 study. Using a central reader, liver volume and combined renal volume of 
both kidneys will be measured. Combined renal cyst volume and renal parenchyma may be determined at a later date for a subset of participants. 
v The participant is required to have full ophthalmological examination at Visit 0 or Visit 1, at Month 12 (Visit 6), and at Month 24 (Visit 10) (or upon withdrawal or 
discontinuation) with pupil dilation and WHO simplified cataract grading system evaluation of lens opacities. Best corrected visual acuity (BCVA) examination 
will be additionally performed at visits Month 6 (Visit 4) and Month 18 (Visit 8). If at any time during study participation, the participant experiences a decrease 
≥2 lines in BCVA compared to baseline or previous assessment, full ophthalmological examination with pupil dilation and WHO simplified cataract grading 
system evaluation should be performed. If a new or worsening lens abnormality is found, documentation of finding with lens photography is recommended. 
Pupil dilation and full eye examination can be performed at any time if deemed medically necessary; WHO simplified cataract grading system evaluation should 
be performed if a change from baseline is observed during slit-lamp examination. 
w The PROs will be administered to participants at study visit according to the listed schedule before dosing and before clinical assessments. 
x Prior to the start of IMP at Baseline visit. In participants who have consented to it, samples of serum will be collected and archived for future analysis. 
y All ongoing or new medications from the end of the EFC15392 study should be reported in the LTS15823 study, even if reported prior to informed consent. 
z All SAEs, AEs and AESIs will be collected starting from the end of the study visit in EFC15392 (including those prior to informed consent) and will continue until 
30 days after the last dose of IMP or study end, whichever comes later. All AEs that occurred during treatment should be followed for at least 30 days following 
the last dose of IMP or until the event has resolved, the condition has stabilized, the etiology of the event is determined to be not related to IMP, or the 
participant is lost to follow-up. All participants will have a Follow-up visit 30 days after the last dose of IMP to collect safety information. 
 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 22 
2 
INTRODUCTION   
2.1 
STUDY RATIONALE  
To evaluate the long-term efficacy and safety of venglustat in patients with autosomal dominant 
polycystic kidney disease (ADPKD) who have previously completed Stage 1 or Stage 2 of the 
EFC15392 study. 
2.2 
BACKGROUND  
2.2.1 Venglustat  
GZ402671, also referred to as venglustat, SAR402671 is a GCS inhibitor that decreases the 
synthesis of glucosylceramide (GL-1), a central building block for more complex 
glycosphingolipids (GSLs). Substrate reduction therapy (SRT) with GCS inhibitors is expected to 
have broad therapeutic applicability across a number of disorders, including lysosomal storage 
diseases, as well as other disorders associated with increased GL-1 or increased levels of GSLs 
that contain GL-1 at their core. 
Sanofi is investigating venglustat as a potential SRT for treating patients with Fabry disease (FD), 
Gaucher disease Type 3 (GD3), Parkinson’s disease patients with a confirmed acid-β-glucosidase 
(glucocerebrosidase gene [GBA]) mutation (GBA-PD), GM2 gangliosidosis and ADPKD. A 
novel GCS inhibitor, venglustat inhibits the enzymatic conversion of ceramide to GL-1, the first 
step in glycosphingolipid biosynthesis. By reducing the production of GL-1, the central building 
block for the synthesis of more complex GSLs (including globotriaosylceramide [GL-3], GM1, 
GM2, and monosialodihexosylganglioside [GM3]), SRT with venglustat offers a potential 
therapeutic strategy for FD, GD, GBA-PD, and ADPKD.  
Venglustat is a potent and selective inhibitor of murine and human GCS in biochemical and 
cell-based in vitro assays. In vivo pharmacology studies in rodents and dogs showed reduction in 
plasma GL-1 concentrations as a pharmacodynamic (PD) marker of GCS inhibition. Reductions 
of GL-1 concentrations in plasma (rodents and dogs) and tissue (rodents only) were observed 
following oral venglustat administration. In both species, the effects of venglustat on plasma GL-1 
were dose-dependent and correlated with plasma concentrations of the compound. Based on 
multiple preclinical studies following a single oral administration to rats, venglustat distributed 
extensively in kidney, liver, lung, spleen, intestine, and heart tissues and crossed the blood brain 
barrier.  
In safety studies performed in adult mouse, rat and dog, the gastrointestinal tract, testes and lens 
of the eye have been identified as target organs of toxicity. A safety margin was established of 
approximately 4- to 15-fold based on the exposures at the no observed adverse effect level 
(NOAEL) in 26-week rat and 39-week dog safety studies. Also, there is approximately a 60-fold 
safety margin for human ether-a-go-go-related gene (hERG) ion channel in vitro activity and 
approximately a 35-fold safety margin for cardiac parameters evaluated in dogs compared with 
the exposure observed at the highest administered dose in Study TDR12768, a Phase 1, 14-day 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 23 
repeat-dose study in humans with 20 mg malate salt capsule corresponding to 14.9 mg venglustat 
active moiety. 
In a juvenile toxicology study (but not in 7 different adult toxicology studies), in rats given 
venglustat, unilateral/bilateral degeneration of germinal epithelium in the testes of males and 
lenticular (eye lenses) degeneration in both sexes was observed. The NOAEL for development 
endpoints was 45 mg/kg. The NOAEL for all anatomic findings was 15 mg/kg with the exception 
of findings in the lens. For this finding, the NOAEL was 5 mg/kg in females and 15 mg/kg in 
males. 
2.2.2 Autosomal dominant polycystic kidney disease  
Autosomal dominant polycystic kidney disease (ADPKD) is a life-threatening genetic disease 
caused by mutations in PKD1 and PKD2 genes characterized by the formation of multiple kidney 
cysts that enlarge with disease progression to result in end-stage renal disease and dialysis in 
~50% of patients (1). Cysts may also develop in liver and other organs (eg, seminal vesicle, 
pancreas). At least 60% of ADPKD patients report pain (back pain and abdominal pain) and up to 
one third of patients report severe symptoms. The target population is those patients with ADPKD 
at high risk of progressing to end-stage renal disease (1C, 1D, and 1E of the Mayo Imaging 
Classification). Classes 1C, 1D, and 1E represent 30% to 40% of the diagnosed ADPKD 
population who can be identified by imaging measures of kidney size (2, 3). In the United States 
of America (USA), the diagnosed patient population is estimated to be between 1 in 2500 to 1 in 
3000 or roughly 120 000 people which qualifies for an orphan designation (prevalence of less 
than 200 000). In the European Union (EU), the population is estimated to be approximately 
170 000 people or 4.7 in 10 000 people. This is below the EU ceiling for orphan designation 5 in 
10 000 (1). 
Tolvaptan is approved in Japan, EU, USA, and Canada to slow the progression of cyst 
development and renal insufficiency. The liver toxicity led to the requirement in the EU for a risk 
management plan which includes 18 months of monthly monitoring of the liver function (4). 
Tolvaptan safety (risk of idiosyncratic liver toxicity) and tolerability (eg, thirst, polyuria, and 
nocturia in ~55%, 38%, and 29% of patients, respectively) make it a suboptimal chronic 
treatment. In clinical studies, treatment discontinuation rates were 23% for tolvaptan and 14% for 
placebo, primarily due to AEs.  
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 24 
2.2.3 Autosomal dominant polycystic kidney disease and venglustat  
Human and murine ADPKD is associated with increased GCS activity, leading to a pathogenic 
accumulation of GSLs such as GL-1, lactosylceramide (GL-2), and GM3 (8, 9). Several 
structurally distinct GCS inhibitors have significantly reduced cyst growth and preserved renal 
function in 3 different preclinical ADPKD models: the orthologous model with conditionally 
inactivated PKD1 gene (aggressive course of ADPKD), the jck mouse model (moderately 
progressive phenocopy of human disease), and the pcy mouse model (slowly progressive disease) 
(10) (and unpublished data). Efficacy is consistently observed when kidney GL-1 lowering 
exceeds 70% (10). Kidney and serum GL-1 lowering is well-correlated in the mouse, suggesting 
that either can be used as a PD marker. 
Efficacy of venglustat has been confirmed in the jck mouse model of ADPKD 
 
Treatment with venglustat (and the related molecule, Genz-667161) significantly reduced 
cystogenesis, as demonstrated by the decreased kidney to body weight ratio and cyst volume. 
Reduced blood urea nitrogen measurements suggest preserved kidney function, since the 
experiment was not sufficiently powered to achieve statistical significance for this disease 
parameter. Kidney and serum GL-1 measurements show a strong correspondence between serum 
and kidney GL-1 lowering.  
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 25 
2.2.4 Clinical trials of venglustat in humans  
The clinical program for venglustat includes 4 completed Phase 1 studies in adult healthy 
volunteer participants and 2 completed studies in participants with FD, 1 ongoing study in 
participants with GD3, 1 ongoing study in participants with GBA-PD, and 1 ongoing study in 
participants with late-onset GM2 gangliosidosis. Doses administered refer to the malate salt of the 
compound for the Phase 1 studies and to the active moiety for the Phase 2 study. 
Completed studies of venglustat include the following: 
• TDU12766 was a Phase 1, double-blind, randomized, placebo-controlled, sequential, 
ascending single oral dose study designed to assess the tolerability, safety, and 
pharmacokinetics (PK) of venglustat in healthy adult male participants. 
• TDR12768 was a Phase 1, double-blind, randomized, placebo-controlled, sequential, 
ascending repeated oral dose study in healthy male and female participants. It was 
designed to assess the tolerability, safety, PK, and PD of 14-day ascending, repeated, oral 
doses of venglustat. 
• FED12767 was a Phase 1, open-label, randomized, 2-sequence, 2-treatment crossover 
study designed to obtain information on the effect of a high fat meal on the PK of 
venglustat in healthy adult male participants. Additional objectives for Study FED12767 
included assessing the tolerability and safety of venglustat after single oral doses in both 
fed and fasted conditions. 
• ACT13739 was a Phase 2, multicenter, open-label, single-arm uncontrolled, once daily 
(QD), repeat-dose, 26-week clinical study. The study was designed to evaluate the safety, 
PD, PK, and exploratory efficacy of venglustat in enzyme replacement therapy 
treatment-naïve adult male participants with FD.  
• LTS14116 was an open-label Phase 2 extension study that assessed the long-term safety, 
PD, and exploratory efficacy of venglustat in FD participants who completed the 
ACT13739 study. 
• INT14339 was a Phase 1, single-center, open-label, 2-period single-sequence, 
non-randomized, drug-drug interaction  study to assess the effect of multiple doses of the 
potent cytochrome P450 3A4 (CYP3A4) inhibitor itraconazole 100 mg capsule twice daily 
on the PK of single dose venglustat under fed conditions with washout duration of exactly 
7 days between treatment periods.  
• POP14499 was a Phase 1, single-center, open-label, single dose study in participants with 
mild, moderate and severe renal impairment, and in matched participants with normal 
renal function, to study the effect of renal impairment on venglustat PK and tolerability 
following a single dose of 15 mg venglustat given under fasted conditions on Day 1 of a 
10-day PK sampling and observation period.  
• ACC15856 was a palatability study in 12 healthy volunteers who tested the organoleptic 
characteristics of 5 different chewable tablet formulations of venglustat (different 
percentages of apricot flavor and sucralose as sweetener) compared with a reference 
formulation (without flavor or sweetener). 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 26 
In completed clinical studies in healthy participants, venglustat was observed to be safe and 
well-tolerated. Overall, the AE profile of participants in the venglustat dosing groups was similar 
to that observed in the placebo groups. 
PDY13949 is an ongoing 3-part study with: Part 1 evaluating biomarkers in GD1 and GD3, Part 2 
for obtaining treatment efficacy first in an open-label setting followed by cohort expansion in a 
randomized, placebo-controlled manner in adult and pediatric participants with GD3 and finally 
Part 3 which is an open-label long-term treatment for Part 2 participants.  
ACT14820 is an ongoing double-blind, randomized, placebo-controlled Phase 2 study to assess 
the efficacy, safety, PK, and PD of QD dosing of venglustat in participants with GBA-PD. Part 1 
of the study will last up to 9 months, and Part 2 will last up to approximately 3 years. 
EFC15299 is an ongoing multicenter, multinational, randomized, double-blind, 
placebo-controlled, 110 weeks Phase 3 study to assess the efficacy, PD, PK, safety, and 
tolerability of QD dosing of venglustat in late-onset GM2 gangliosidosis (Tay-Sachs disease and 
Sandhoff disease) together with a separate basket for juvenile/adolescent late-onset GM2 
gangliosidosis and ultra‑rare diseases within the same and similar glucosylceramide-based 
sphingolipid pathway.  
EFC15392 is a seamless Phase 2/3 multicenter, randomized, double-blind, placebo-controlled 
2-stage study to characterize the efficacy, safety, tolerability and PK of venglustat in adult male 
and female participants at risk of rapidly progressive ADPKD. Two-stage study is as follows: 
• Stage 1 (24 months of treatment): Randomized, double-blind, placebo-controlled, 3-arm 
study with primary objective to determine the effect of venglustat on the rate of TKV 
growth as compared to placebo in participants with eGFR between 45 and 
89.9 mL/min/1.73 m2 who are at risk of rapidly progressive ADPKD. 
• Stage 2 (24 months of treatment): Randomized, double-blind, placebo-controlled, 2-arm 
study, with primary objective to determine the effect of venglustat on rate of renal function 
(eGFR) decline as compared to placebo in participants with eGFR between 30 and 
89.9 mL/min/1.73 m2 who are at risk of rapidly progressive ADPKD. 
The seamless design of this 2-stage study is based on the similarities of the endpoints of the 
2 stages and overlapping but not identical inclusion/exclusion criteria of the 2 stages. 
More information on the safety of venglustat and on the clinical program can be found in the 
Investigator’s Brochure (IB). 
2.3 
BENEFIT/RISK ASSESSMENT  
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 27 
2.3.1 Risk assessment  
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 28 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 29 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 30 
3 
OBJECTIVES AND ENDPOINTS  
Table 2 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
• 
To determine the effect of early versus delayed 
treatment with venglustat on the total kidney volume 
(TKV) in participants at risk of rapidly progressive 
ADPKD. 
• 
Percent change in TKV based on magnetic 
resonance imaging (MRI) from the EFC15392 study 
baseline to 24 months of open-label extension 
study, in early-treated and delayed-treated 
participants. 
Secondary 
• 
To determine the effect of early versus delayed 
treatment with venglustat on the renal function 
(estimated glomerular filtration rate [eGFR]). 
• 
Change in eGFR (Chronic Kidney Disease 
Epidemiology Collaboration [CKD-EPI] equation) 
from the EFC15392 study baseline to 24 months of 
open-label extension study, in early-treated and 
delayed-treated participants. 
• 
To characterize the safety profile of venglustat. 
• 
Safety in terms of treatment-emergent adverse 
events (TEAEs), adverse events (AEs), serious 
adverse events (SAEs), laboratory parameters, vital 
signs, electrocardiogram and findings from physical 
examination will be assessed through the study and 
will be reported in the electronic case report form 
(eCRF). 
• 
To evaluate the effect of venglustat on the lens by 
ophthalmological examination. 
• 
Change from EFC15392 study baseline in the lens 
clarity by ophthalmological examination during the 
open-label extension treatment-emergent period. 
• 
To evaluate the effect of venglustat on mood using 
Beck Depression Inventory-II (BDI-II). 
• 
Change from EFC15392 study baseline in BDI-II 
score during the open-label extension 
treatment-emergent period. 
Tertiary 
• 
To explore the impact of venglustat on total liver 
volume (TLV) (in participants with height-adjusted 
TLV [htTLV] >2 L/m). 
• 
Change in TLV based on MRI (in participants with 
htTLV >2 L/m) from EFC15392 study baseline to 
24 months of the open-label extension study. 
• 
To explore the effect of venglustat on systolic blood 
pressure (SBP) and diastolic blood pressure (DBP). 
• 
Change from EFC15392 study baseline during the 
open-label extension treatment-emergent period in: 
- 
SBP, 
- 
DBP. 
• 
To explore the effect of venglustat on type, 
frequency and dosage of analgesic/over the counter 
(OTC) pain medication administration. 
• 
Change from EFC15392 study baseline in type, 
frequency, and dosage of analgesic/OTC pain 
medication administration during the open-label 
extension study. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 31 
Objectives 
Endpoints 
• 
To explore the effect of venglustat on time to 
confirmed 30% and 40% reduction in eGFR. 
• 
Time to confirmed 30% reduction in eGFR since 
randomization in the EFC15392 study, in 
early-treated compared to late-treated participants 
during the combined EFC15392 and LTS15823 
period. 
• 
Time to confirmed 40% reduction in eGFR since 
randomization in the EFC15392 study, in 
early-treated compared to late-treated participants 
during the combined EFC15392 and LTS15823 
period. 
• 
To explore the effect of venglustat on biomarkers 
associated with ADPKD (eg, Fibroblast Growth 
Factor 23 [FGF23], asymmetric dimethylarginine 
[ADMA]) (not applicable for Chinese participants). 
• 
Change in the levels of biomarkers associated with 
ADPKD (eg, FGF23, ADMA) from EFC15392 study 
baseline to 24 months of open-label extension 
study (not applicable for Chinese participants). 
• 
To explore the pharmacodynamic (PD) effects of 
venglustat by measuring downstream metabolites 
of glucosylceramide synthase (GCS) in plasma (not 
applicable for Chinese participants). 
• 
Change in the levels of downstream metabolites of 
GCS in plasma from EFC15392 study baseline to 
24 months of open-label extension study (not 
applicable for Chinese participants). 
• 
To explore the effect of venglustat on pain (brief 
pain inventory short form [BPI-SF]), fatigue (Brief 
Fatigue Inventory [BFI]), and the EuroQoL 
5 dimension 5 level (EQ-5D-5L) score. 
• 
Change from EFC15392 study baseline to 
24 months of open-label extension study in: 
- 
BPI-SF, 
- 
BFI, 
- 
EQ-5D-5L. 
 
 
3.1 
APPROPRIATENESS OF MEASUREMENTS  
For details please refer to Section 2.1, Section 2.2, and Section 4. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 32 
4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This will be an international, multicenter, open-label extension study rolling over adult 
participants at risk of rapidly progressive ADPKD who have previously completed Stage 1 or 
Stage 2 of Study EFC15392. All participants will be treated with venglustat 15 mg once daily for 
24 months or until venglustat is commercially available for patients, whichever comes first. See 
Appendix 8 (Section 10.8) for definition applicable for patients participating in Belgium, Czech 
Republic, Denmark, Germany, Italy, Poland, Portugal, Romania, and Spain (Section 10.8.2). 
Duration of study: 25.5 months at the maximum. Screening period (when applicable): up to 
2 weeks. Core treatment period: 24 months. Follow-up: 30 days after final dose of the IMP 
(venglustat). 
Enrollment in the LTS15823 study must coincide with Visit 12 (Month 24; end-of-treatment visit) 
of the EFC15392 study. Patients who cannot be included in the extension study at the time of 
Visit 12 for administrative or logistical reasons, and provided they agree to participate in the 
LTS15823 study, will have a separate Screening visit (Visit 0) performed and must be enrolled in 
the LTS15823 study within 2 months of the last dose of IMP (Visit 12 [Month 24]) administered 
in the EFC15392 study. This 2-month window can be further extended up to 6 months following 
review and approval by the Sponsor. 
Dose regimen: 15 mg orally once daily of venglustat. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
This is an international, multicenter, open-label extension study rolling over adult participants at 
risk of rapidly progressive ADPKD who have previously completed Stage 1 or Stage 2 of 
Study EFC15392. The purpose of the study is to obtain long-term efficacy and safety data, up to 
4 years, with venglustat administration. Long-term efficacy will focus on patients treated early 
with venglustat (patients having received venglustat in Stage 1 or Stage 2 of the EFC15392 study) 
versus patients with delayed treatment (patients having received placebo in Stage 1 or Stage 2 of 
the EFC15392 study). The objective of the study is to demonstrate that patients treated early have 
a better long-term efficacy than patients treated with delay by evaluating the effect of early versus 
delayed treatment with venglustat on the TKV (primary objective) and on the rate of eGFR 
decline (secondary objective). In addition, patients previously treated with placebo will get the 
opportunity to benefit from venglustat treatment in this open label extension study. 
4.2.1 Participant input into design  
Not applicable. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 33 
4.3 
JUSTIFICATION FOR DOSE  
The 8 mg and 15 mg QD doses of venglustat resulted in about 70% and 75% reduction in plasma 
GL-1 from baseline, respectively, in the healthy volunteers (repeated dose study, TDR12768). 
This is in the similar range of plasma GL-1 reduction where efficacy was demonstrated in the 
nonclinical disease animal model of ADPKD by oral treatment of GCS inhibitors (Section 2.2.3). 
Therefore, 8 mg and 15 mg QD doses of venglustat in ADPKD patients anticipated to translate 
into ADPKD efficacy were selected for Stage 1 of the EFC15392 study. 
All participants in the LTS15823 study will be treated with venglustat 15 mg once daily. The 
15 mg dose was the highest dose determined to be safe and well-tolerated following review by the 
Data Monitoring Committee (DMC) of unblinded aggregate safety data from 150 participants who 
had completed at least 1 month of treatment (8 mg or 15 mg) in Stage 1 of the EFC15392 study. 
The 15 mg dose was the dose selected for Stage 2 of Study EFC15392. This dose selection 
process was specified in the EFC15392 protocol. 
4.4 
END OF STUDY DEFINITION  
The end of the study is defined as the date of last scheduled procedure shown in the SoA for the 
last participant in the trial globally. 
A participant is considered to have completed the study if he/she has completed 24 months of the 
treatment in the study including the Month 25 visit. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 34 
5 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
INCLUSION CRITERIA  
Participants are eligible to be included in the study only if all of the following criteria apply:  
Type of participant and disease characteristics 
I 01. Male or female adult with ADPKD who has completed the treatment period in Stage 1 or 
Stage 2 of Study EFC15392*. 
* Eligible patients who agreed to participate in the long-term extension study must be 
enrolled in the LTS15823 study at the time of Visit 12 (Month 24; end-of treatment visit) 
of the EFC15392 study. Patients who cannot be included in the extension study at the time 
of the end-of-treatment visit of the EFC15392 study for administrative or logistical reasons 
will have a separate Screening visit (Visit 0) of LTS15823 study performed and must be 
enrolled in the LTS15823 study within 2 months of the last dose of IMP (Visit 12 
[Month 24]) in the EFC15392 study. This 2-month window can be further extended up to 
6 months following review and approval by the Sponsor. 
I 02. The patient has an eGFR >30 mL/min/1.73 m2: 
- 
That was measured at Visit 11 of the EFC15392 study for participant enrolled in the 
LTS15823 study at the time of Visit 12 (Month 24; end-of treatment visit) of the 
EFC15392 study. 
- 
At Screening visit ** for participant enrolled in the LTS15823 study not concomitantly 
to the Visit 12 (Month 24; end-of treatment visit) of the EFC15392 study. 
**If necessary, a second pretreatment eGFR value can be obtained for confirmation of 
eligibility to account for potential eGFR variability. 
 Sex, contraceptive/barrier method and pregnancy testing requirements 
I 03. All 
Contraceptive use by men and women should be consistent with local regulations 
regarding the methods of contraception for those participating in clinical studies. 
a) Male participants 
- 
Male participants must agree to practice true abstinence in line with their preferred and 
usual lifestyle or to use double-contraceptive methods (see contraceptive guidance in 
Appendix 4 [Section 10.4.2]) for the entire duration of the study and for at least 
90 days following their last dose of IMP. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 35 
b) Female participants 
- 
The participant, if female of childbearing potential, must have a negative urine 
pregnancy test at the Baseline visit. 
- 
Female participants of childbearing potential must agree to practice true abstinence in 
line with their preferred and usual lifestyle or to use double-contraceptive methods 
(including a highly effective method of contraception) for the entire duration of the 
study and for at least 6 weeks following their last dose of IMP (see contraceptive 
guidance in Appendix 4 [Section 10.4.2]). 
Informed Consent 
I 04. Capable of giving signed informed consent as described in Appendix 1 (Section 10.1) of 
the protocol before performance of any study related procedures not part of standard 
medical care which includes compliance with the requirements and restrictions listed in the 
informed consent form (ICF) and in this protocol. 
Other inclusions 
I 05. Able to read, comprehend, and respond to the study questionnaires. 
5.2 
EXCLUSION CRITERIA   
Participants are excluded from the study if any of the following criteria apply: 
For participants who have lag phase between the end of the EFC15392 study and Screening 
visit (Visit 0) in the LTS15823 study: 
Medical conditions 
E 01. The patient has a new clinically significant, uncontrolled medical condition that, in the 
opinion of the Investigator, would put the safety of the patient at risk through participation, 
or which would affect the efficacy or safety analysis if the condition exacerbated during 
the study, or that may significantly interfere with study compliance, including all 
prescribed evaluations and follow-up activities. The list of medical conditions that should 
be taken into account includes, but is not limited to the following: 
 
Congestive heart failure New York Heart Association (NYHA) Grade III/IV 
Clinically significant cardiac arrhythmia 
Severe unstable angina pectoris within 6 months of Visit 0 
Hypertensive emergencya within 6 months 
of Visit 0 
Stroke or transient ischemic attack within 3 months of Visit 0 
Current malignancyb 
Myocardial infarction within 3 months of Visit 0 
Current tuberculosis  
Cushing's disease 
Uncontrolled diabetes mellitus 
Addison's disease 
Uncontrolled thyroid disorder 
a Systolic blood pressure (SBP) >180 mm Hg or diastolic blood pressure (DBP) >120 mm Hg, and acute target organ damage (11). 
b Localized basal cell or squamous cell carcinoma of the skin that has been resected is not exclusionary.  
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 36 
E 02.  A history of drug abuse and/or alcohol abuse or alcohol dependence during the lag phase 
between the end of the EFC15392 study and Screening visit (Visit 0) in the 
LTS15823 study when applicable. 
Prior/concomitant therapy 
E 03. Administration of tolvaptan or other polycystic kidney disease-modifying agents 
(somatostatin analogues) within 3 months prior to the Screening visit (Visit 0) in the 
LTS15823 study when applicable.  
E 04. The patient is currently receiving potentially cataractogenic medications, including a 
chronic regimen (more frequently than every 2 weeks) of any route of corticosteroids 
(including medium and high potency topical steroids), or any medication that may cause 
cataract, according to the Prescribing Information. 
E 05. The patient has received strong or moderate inducers or inhibitors of CYP3A4 within 
14 days or 5 half-lives, whichever is longer, prior to the Baseline visit. This also includes 
the consumption of grapefruit, grapefruit juice, or grapefruit-containing products within 
72 hours of starting venglustat administration. 
Prior/concurrent clinical study experience 
E 06. Participation in another investigational interventional study or use of IMP, within 3 months 
or 5 half-lives, whichever is longer, before the Baseline visit (Visit 1) except participation 
in the EFC15392 study when applicable. 
Diagnostic assessments 
E 07. Liver enzymes (alanine aminotransferase /aspartate aminotransferase) or total bilirubin 
>2 times the upper limit of normal (ULN) unless the patient has the diagnosis of Gilbert 
syndrome. Patients with the Gilbert syndrome should have no additional symptoms or 
signs which suggest hepatobiliary disease and serum total bilirubin level no more than 
3 mg/dL (51 μmol/L) with conjugated bilirubin less than 20% of the total bilirubin 
fraction. 
Other exclusions 
E 08. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized. See Appendix 8 (Section 10.8) for any 
country-related specific regulation that would prevent the patient from entering the study. 
E 09. Participant not suitable for participation, whatever the reason, as judged by the 
Investigator, including medical or clinical conditions, or participants potentially at risk of 
noncompliance to study procedures. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 37 
For participants with or without lag phase between the end of EFC15392 study and entry 
into LTS15823 study: 
Medical conditions 
E 10. The patient is pregnant or lactating. 
E 11. Presence of severe depression as measured by Beck Depression Inventory II (BDI-II) >28 
at Visit 1 (for participants enrolled in the LTS15823 study at the time of the 
end-of-treatment visit of the EFC15392 study) or at Visit 0 (for participants enrolled in the 
LTS15823 study after the end-of-treatment visit of the EFC15392 study). 
Other exclusions 
E 12. Participants are employees of the clinical study site or other individuals directly involved 
in the conduct of the study, or immediate family members of such individuals (in 
conjunction with Section 1.61 of the International Council for Harmonisation Good 
Clinical Practice (ICH-GCP) Ordinance E6). 
E 13. Any specific situation during study implementation/course that may raise ethics 
considerations. 
E 14. Sensitivity to any of the study interventions, or components thereof, or drug or other 
allergy that, in the opinion of the Investigator, contraindicates participation in the study. 
 
5.3 
LIFESTYLE CONSIDERATIONS  
5.3.1 Meals and dietary restrictions  
1. Refrain from consumption of grapefruit, grapefruit juice or grapefruit-containing products 
from 3 days before the start of study intervention until after the final dose. 
2. Blood samples (biochemistry, blood glucose, biomarkers, etc) will be collected at the 
beginning of the visit in fasted conditions (fast overnight [eat nothing and drink only 
water] for at least 8 hours before blood samples are taken). 
3. Over-the-counter dietary supplements (eg, herbal remedies) or prescriptions, are permitted 
during the study period. The Investigator should consider substituting medications that 
have cataractogenic potential according to their Prescribing Information for 
noncataractogenic treatments, as appropriate. 
5.3.2 Caffeine, alcohol, and tobacco  
No specific restrictions are required. 
5.3.3 Activity  
No specific restrictions are required. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 38 
5.4 
SCREEN FAILURES  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently enrolled. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure reasons, eligibility criteria, 
and any SAE. 
Participant number will remain the same for rescreened participants for every 
screening/rescreening event. 
Rescreening is possible for participants who have lag phase between the end of the 
EFC15392 study and the Screening visit (Visit 0) in the LTS15823 study, in cases where the 
original screening failure was due to reasons expected to change at rescreening and based upon 
the Investigator’s clinical judgment. The patient may be rescreened once, after consultation with 
the Sponsor, while the screening period is still open if a participant failed for reasons of a 
nonpermanent medical condition, such as an acute disease or an event that could be corrected or 
resolved in an acceptable timeframe. 
If a patient had screen-failed during a regional or national emergency for reasons not related to 
eligibility, rescreening shall be permitted when the situation normalizes (provided the rescreening 
will be still within 6 months of the last dose of IMP (Visit 12 [Month 24]) administered in the 
EFC15392 study and after consultation with the Sponsor). 
5.5 
CRITERIA FOR TEMPORARILY DELAYING ENROLLMENT OR ADMINISTRATION OF 
STUDY INTERVENTION ADMINISTRATION  
During a regional or national emergency declared by a governmental agency that results in travel 
restrictions, confinement, or restricted site access, if the site is unable to adequately follow 
protocol mandated procedures, contingency measures should be considered for enrollment or 
administration of study treatment. Contingency measures proposed in Appendix 9 (Section 10.9) 
should be considered for enrollment or administration of study intervention. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 39 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
Study intervention(s) 
Investigational medicinal product(s) 
• Formulation: venglustat is provided in capsule formulation containing 15 mg of venglustat 
(active moiety). Venglustat is not approved in any territory. 
• Route(s) of administration: oral. 
• Dose regimen: 15 mg once daily. 
Table 3 - Overview of study interventions administered  
Intervention label 
GZ402671 or SAR402671 
Intervention name 
Venglustat 
Type 
Drug 
Dose formulation 
Capsule 
Unit dose strength(s) 
15 mg 
Dosage level(s) 
15 mg once daily 
Route of administration 
Oral 
Use 
Experimental 
IMP or NIMP 
IMP 
Packaging and labeling 
Venglustat will be packaged in blister packs. Packaging is in 
accordance with the administration schedule. The content of 
the labeling is in accordance with Good Manufacturing 
Practices (GMP) requirements and the local regulatory 
specifications and requirements. 
Current/Former name(s) or alias(es) 
Not applicable 
Table 4 - Arms and associated interventions  
Arm name 
Venglustat 
Associated interventions (intervention label) 
Venglustat 
Venglustat may be supplied at the site or from the Principal Investigator (PI)/site to the participant 
via a Sponsor-approved courier company where allowed by local regulations and agreed upon by 
the participant. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 40 
For a regional or national emergency declared by a governmental agency that results in travel 
restrictions, confinement, or restricted site access, contingency measures are included in 
Appendix 9 (Section 10.9). 
6.1.1 Devices  
Not applicable. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention. All study intervention must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area 
in accordance with the labeled storage conditions with access limited to the Investigator 
and authorized site staff. 
3. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) must be promptly notified to the Sponsor. 
Some deficiencies may be recorded through a complaint procedure (see Section 8.3.9). 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party (except for direct-to 
participant (DTP) shipment, for which a courier company has been approved by the Sponsor), 
allow the IMP to be used other than as directed by this clinical trial protocol, or dispose of IMP in 
any other manner. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
This is a single-arm open-label study; therefore this section is not applicable.  
6.4 
STUDY INTERVENTION COMPLIANCE  
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed at each visit. Compliance will be assessed by direct questioning, 
counting returned capsules, etc during the site visits and documented in the source documents and 
relevant form. Deviation(s) from the prescribed dosage regimen should be recorded. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 41 
A record of the quantity of venglustat capsules dispensed to and administered by each participant 
must be maintained and reconciled with study intervention and compliance records. Intervention 
start and stop dates, including dates for intervention delays and/or dose reductions will also be 
recorded. 
6.5 
DOSE MODIFICATION  
Not applicable. 
6.5.1 Retreatment criteria  
Temporary treatment discontinuation because of suspected AEs may be considered by the 
Investigator. After close and appropriate clinical and/or laboratory monitoring, once the 
Investigator considers, according to his/her best medical judgment that the occurrence of the 
concerned event was unlikely due to the IMP, the safety of the participant is not affected, and if 
the selection criteria for the study are still met (refer to Section 5), treatment with the IMP may be 
re-initiated. For all temporary treatment discontinuations, duration should be recorded by the 
Investigator in the appropriate pages of the electronic case report form (eCRF). 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY  
Continued access to the study intervention after the end of the study will be handled according to 
the local regulations. 
6.7 
TREATMENT OF OVERDOSE  
For this study, any dose of venglustat greater than 15 mg within a 24-hour time period will be 
considered an overdose. 
Sponsor does not recommend specific treatment for an overdose. 
In the event of an overdose, the Investigator should do the following: 
1. Contact the Sponsor immediately. 
2. Evaluate the participant to determine, in consultation with the Sponsor, whether study 
intervention should be interrupted or whether the dose should be reduced. 
3. Closely monitor the participant for any AE/SAE and laboratory abnormalities until 
venglustat can no longer be detected systemically (at least 6 days). 
4. Document appropriately in the eCRF. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 42 
6.8 
CONCOMITANT THERAPY  
A concomitant medication is any treatment received by the participant concomitantly to the IMP. 
Concomitant medications should be kept to a minimum during the study. Furthermore, changes in 
concomitant medications should be kept to a minimum and only occur if considered to be 
absolutely necessary in the medical judgment of the Investigator. However, if these are considered 
necessary for the participant's welfare and are unlikely to interfere with the IMP, they may be 
given at the discretion of the Investigator and must be recorded in the eCRF. 
Concomitant medications, including over-the-counter dietary supplements (eg, herbal remedies) 
or prescriptions, are permitted during the study period, except for tolvaptan use which is forbidden 
throughout the study and the medications listed in the following section. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.8.1 List of forbidden concomitant medication  
During the study treatment periods, the following medications are prohibited: 
• Use of investigational medication in any other clinical study. 
• Chronic use of strong or moderate CYP3A inducers or inhibitors.  
• Tolvaptan. 
• Polycystic Kidney Disease-modifying agents (eg, somatostatin analogues). 
• Alpha-adrenergic receptor agonist glaucoma medications because they can worsen the 
vision of participants with cataracts. 
Venglustat interruptions are permitted for those participants who require temporary use 
(≤2 weeks) of strong or moderate inhibitors or inducers of CYP3A (per the United States Food 
and Drug Administration [FDA] classification) 
(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling) for the treatment of acute illness. Such medications must not be used on more than a 
total of 2 occasions (ie, up to 2 weeks per occasion for a maximum of 30 days of 
venglustat interruptions) during the study treatment periods. 
Given nonclinical lens findings (see IB), a chronic regimen (ie, more frequent than once every 
2 weeks) of the following medications is forbidden during the clinical trial: 
• Corticosteroids: 
- 
May be used on a restricted basis in participants who require temporary use (≤1 week) 
for the treatment of any acute condition for which no appropriate substitute is found. 
Such medications must not be used on more than a total of 4 occasions (ie, up to 
1 week per occasion) during the study treatment periods. 
- 
Participants with chronic skin diseases can use low and least potent (Class VI to VII) 
topical steroids. Application to eyelids and periorbital region should be avoided. 
• Psoralens used in dermatology with ultraviolet light therapy. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 43 
• Typical antipsychotics. 
• Amiodarone. 
• Allopurinol. 
The Investigator should consider substituting medications listed in the previous paragraphs and 
medications that have cataractogenic potential according to their Prescribing Information for 
noncataractogenic treatments, as appropriate.  
Atypical antipsychotics are allowed. 
Other medications which are unlikely to interfere with the PK or PD of the IMP or confound 
interpretation of the study endpoints are allowed as needed and discussed with the Investigator. 
However, doses of chronically administered medicines should be kept fixed during the trial if at 
all possible. 
6.8.2 Rescue medicine  
Not applicable. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 44 
7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL   
7.1 
DISCONTINUATION OF STUDY INTERVENTION   
7.1.1 Permanent discontinuation  
In rare instances, it may be necessary for a participant to permanently discontinue study 
intervention. 
Definitive (permanent) intervention discontinuation is any treatment discontinuation associated 
with the definitive decision from the Investigator not to re-expose the participant to the IMP at 
any time during the study, or from the participant not to be re-exposed to the IMP, whatever the 
reason. 
The participants who develop loss of 3 or more lines of BCVA in either eye due to posterior 
subcapsular cataract could be discontinued from study treatment if recommended by the DMC (if 
DMC will decide that benefit/risk ratio is not favorable for this participant). 
If a participant experiences a 50% reduction in eGFR compared to the screening value on at least 
2 occasions separated by a period of at least 30 days during the course of this trial, the participant 
will stop the treatment and alternative therapy will have to be discussed by the Investigator.  
If a participant experiences a reduction in eGFR below 30 mL/min/1.73 m2 at on 2 occasions 
separated by a period of 3 months during the course of this study, the participant will be 
discontinued from the study. 
If a participant experiences a reduction in eGFR below 25 mL/min/1.73 m2, a repeated test must 
be performed in 30 days. If eGFR result repeated in 30 days is below 30 mL/min/1.73 m2, the 
participant will be discontinued from the study. 
The following may be justifiable reasons for the Investigator or Sponsor to discontinue a 
participant from treatment. 
Participant specific: 
• The participant experiences 2 similar SAEs or 1 life-threatening SAE (assessed as related 
by the Investigator and/or the Sponsor). 
• The participant meets criteria for Hy's law (confirmed alanine aminotransferase  
ALT >5 × ULN range or confirmed ALT >3 × ULN and bilirubin >2 × ULN). 
• The participant becomes pregnant (see Appendix 4 [Section 10.4] and Section 8.3.5). 
Trial specific: 
• Any AEs, per Investigator judgment, that may jeopardize the participant's safety. 
• Any use of prohibited concomitant treatment (see Section 6.8.1). 
• At participant’s request, ie, withdrawal of the consent for intervention. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 45 
Any abnormal laboratory value or ECG parameter will be immediately rechecked for 
confirmation (after 24 hours) before making a decision of permanent discontinuation of the IMP 
for the concerned participant. 
See the SoA for data to be collected at the time of discontinuation of study intervention and 
follow-up and for any further evaluations that need to be completed. 
Handling of participants after permanent intervention discontinuation 
Participants will be followed-up according to the study procedures 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 as specified in this protocol, whichever comes last. 
If possible, and after the permanent discontinuation of intervention, the participants will be 
assessed using the procedure normally planned for the last dosing day with the IMP. 
All cases of permanent intervention discontinuation must be recorded by the Investigator in the 
appropriate pages of the eCRF when considered as confirmed. 
Participants who prematurely and permanently discontinue IMP should complete rapidly (within 
7 days) an end-of-treatment (EOT) assessment visit without MRI. 
Investigator should ask participant who prematurely and permanently discontinued IMP to 
continue study visits for safety and efficacy assessments up to and including the last scheduled 
visit, if possible. 
If the participant refuses to attend all scheduled visits, the Investigator should ask the participant 
to return to the site at 24 months (to have at least an MRI and blood sample for eGFR evaluation, 
as well as safety assessments performed).  
Participants who withdraw from the study due to pregnancy should be followed-up throughout the 
pregnancy up to approximately 6 to 8 weeks beyond the estimated delivery date so that the 
outcome of the pregnancy is determined. Additional follow-up information may be requested 
about the baby until at least 1 year after the birth of the baby, due to potential risk of abnormalities 
not present at birth. See Appendix 4 for guidance. 
7.1.2 Liver chemistry stopping criteria  
Discontinuation of study intervention for abnormal liver tests is required by the Investigator when 
a participant meets one of the conditions outlined in the algorithm in Appendix 6 (Section 10.6) or 
in the presence of abnormal liver chemistries not meeting protocol-specified stopping rules if the 
Investigator believes that it is in best interest of the participant. 
7.1.3 QTc stopping criteria  
If a clinically significant finding is identified (including, but not limited to changes from baseline 
in QT interval corrected using Fridericia’s formula [QTcF]) after enrollment, the Investigator or 
qualified designee will determine if the participant can continue in the study and if any change in 
participant management is needed. This review of the ECG printed at the time of collection must 
be documented. Any new clinically relevant finding should be reported as an AE. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 46 
7.1.4 Temporary discontinuation  
Temporary intervention discontinuation may be considered by the Investigator because of 
suspected AEs or disruption of the clinical trial due to a regional or national emergency declared 
by a governmental agency (Appendix 9 [Section 10.9]). For all temporary intervention 
discontinuations, duration should be recorded by the Investigator in the appropriate pages of the 
eCRF.  
Temporary intervention discontinuation decided by the Investigator corresponds to more than 
1 dose not administered to the participant. 
7.1.5 Rechallenge  
Reinitiation of intervention 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 AE was unlikely 
and if the selection criteria for the study are still met (refer to Section 5). 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 9 (Section 10.9). 
7.1.5.1 Study intervention restart or rechallenge after liver stopping criteria met  
Study intervention restart or rechallenge after liver chemistry stopping criteria are met by any 
participant in this study is not allowed. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
• A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral or 
compliance reasons. This is expected to be uncommon. 
• At the time of discontinuing from the study, if possible, an early discontinuation visit (with 
procedures identical to EOT visit without MRI) should be conducted, as shown in the 
SoA. See SoA for data to be collected at the time of study discontinuation and follow-up 
and for any further evaluations that need to be completed. 
• If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
If participants no longer wish to take the IMP, they will be encouraged to remain in the study. 
The Investigators should discuss with them key visits to attend. The value of all their study data 
collected during their continued involvement will be emphasized as important to the public health 
value of the study. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 47 
Participants who withdraw from the study intervention should be explicitly asked about the 
contribution of possible AEs to their decision, and any AE information elicited must be 
documented. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of the 
eCRF and in the participant’s medical records. In the medical record, at least the date of the 
withdrawal and the reason should be documented. 
In addition, a participant may withdraw his/her consent to stop participating in the study. 
Withdrawal of consent for intervention should be distinguished from withdrawal of consent for 
follow-up visits and from withdrawal of consent for non-participant contact follow-up, eg, 
medical record checks. The site should document any case of withdrawal of consent. 
Participants who have withdrawn from the study cannot be reallocated (treated) in the study. Their 
inclusion and intervention numbers must not be reused. 
7.3 
LOST TO FOLLOW UP  
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• Before a participant is deemed lost-to-follow-up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
• Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomized, including 
those who did not get study intervention. Public sources may be searched for vital status 
information. If vital status is determined as deceased, this will be documented and the 
participant will not be considered lost-to-follow-up. Sponsor personnel will not be 
involved in any attempts to collect vital status information. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1). 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 48 
8 
STUDY ASSESSMENTS AND PROCEDURES  
• Study procedures and their timing are summarized in the SoA. Protocol waivers or 
exemptions are not allowed. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All eligibility evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count, urine tests) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and were 
performed within the time frame defined in the SoA. 
• For participants enrolled in the LTS15823 study at Visit 12 (Month 24; end-of-treatment 
visit) of the EFC15392 study, the maximum amount of blood collected from each 
participant at scheduled visits over the duration of the study will not exceed 76 mL 
(samples collected at Baseline visit/Visit 1 of the LTS15823 study will be collected as part 
of the Visit 12 [Month 24] of the EFC15392 study as described in Section 1.3.1. 
• For participants with the lag phase between end-of-treatment in the EFC15392 study and 
the start of the LTS15823 study (when patient will have a separate Screening visit (Visit 0) 
as described in Section 1.3.2), the maximum amount of blood collected from each 
participant at scheduled visits over the duration of the study will not exceed 109 mL. 
• Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 9 (Section 10.9). 
8.1 
EFFICACY ASSESSMENTS   
Planned time points for all efficacy assessments are provided in the SoA. 
8.1.1 Magnetic resonance imaging  
Magnetic resonance imaging will be performed at certified facilities and liver and kidney volumes 
calculated according to a separate protocol. Images will be reviewed/assessed by a central reader. 
8.1.2 Estimated glomerular filtration rate  
Estimated glomerular filtration rate will be calculated from the creatinine result from the general 
chemistry laboratory assessments according to the SoA (Section 1.3). The Chronic Kidney 
Disease Epidemiology Collaboration (CKD-EPI) equation will be used: 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 49 
eGFR = 141 × min (SCr/κ, 1)α x max (SCr /κ, 1)-1.209 x 0.993Age x 1.018 (if female) x 1.159 
(if Black) 
Where: 
• SCr is serum creatinine in mg/dL. 
• κ is 0.7 for females and 0.9 for males. 
• α is -0.329 for females and -0.411 for males. 
• Min indicates the minimum of SCr/κ or 1, and 
• Max indicates the maximum of SCr/κ or 1. 
• For calculation of eGFR in Asian population of participants (except Japanese participants), 
the Asian-modified CKD-EPI (aCKD-EPI) equation will be used (12): 
Female and SCr ≤0.7: 151 × (SCr / 0.7)−0.328 × (0.993)age 
Female and SCr >0.7: 151 × (SCr / 0.7)−1.210 × (0.993)age 
 Male and SCr ≤0.9: 149 × (SCr / 0.9)−0.412 × (0.993)age 
 Male and SCr >0.9: 149 × (SCr / 0.9)−1.210 × (0.993)age 
• For calculation of eGFR in Japanese participants, CKD-EPI Study equation multiplied by 
a Japanese coefficient of 0.813 will be used (13). 
8.2 
SAFETY ASSESSMENTS   
This section presents safety assessments other than adverse events which are presented 
in Section 8.3. 
Planned time points for all safety assessments are provided in the SoA. 
8.2.1 Physical examinations  
Whenever possible, the same physician or appropriately trained member of the site study team (in 
countries/states which permit nurse practitioners or physician assistants to perform physical 
examinations under the supervision of a physician) should perform the physical examination at all 
study visits. The findings of each examination will be recorded.  
• A complete physical examination will include, at a minimum, assessments of the skin, 
cardiovascular, respiratory, gastrointestinal, musculo/skeletal, and neurological systems. 
Height and weight will also be measured and recorded. 
• A full standard basic neurological examination will be performed as part of the complete 
physical examination. Results will be documented in the eCRF pages dedicated to 
neurological examination. For details, please refer to the Study Reference Manual.  
• A mental status evaluation will be performed as part of the complete physical examination 
and should include a Mini Mental State Examination (MMSE) or an equivalent local 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 50 
standard method for assessment of the cognitive state of a participant, provided the method 
covers all the areas assessed by MMSE. 
• Height measured in the EFC15392 study will be recorded only at first visit 
(Visit 1/Visit 0). Weight will be measured and recorded at time points provided in the 
SoA. 
• Abbreviated physical examinations will focus on areas important for assessment of AEs if 
necessary. 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.2.2 Vital signs  
• Oral or tympanic temperature [°C], pulse rate, respiratory rate, and blood pressure will be 
assessed. 
• Heart rate, SBP and DBP will be recorded after 10 minutes in the sitting position. The arm 
with the higher pressure at the initial Screening visit should be used for all subsequent BP 
measurements (14). Blood pressure will be measured under standardized conditions using 
the same method for a given participant. It will be determined at each study visit using a 
well calibrated apparatus. 
• For all seated BP measurements, 3 separate measurements should be taken with at least 
1 minute between readings, following at least 10-minute rest period and prior to 
phlebotomy. 
• If there is a difference of more than 10 mm Hg (systolic) between the second and third 
readings in one sitting, a fourth and fifth reading will be recorded for that sitting. 
8.2.3 Electrocardiograms  
• Single 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using an 
ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and 
QTc intervals. Refer to Section 7.1.3 for QTc withdrawal criteria and any additional QTc 
readings that may be necessary. 
• ECG recordings should be performed before blood samplings. The ECG will be evaluated 
as “normal” or “abnormal”. 
• All ECG recordings will be centrally read by independent experts. Refer to central ECG 
reading manual for more details. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 51 
8.2.4 Clinical safety laboratory assessments  
• See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and 
to the SoA (Section 1.3) for the timing and frequency. 
• The Investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports 
must be filed with the source documents. Abnormal laboratory findings associated with 
the underlying disease are not considered clinically significant, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 5 half-lives after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the Investigator. 
- 
If clinically significant values do not return to normal/baseline within a period of time 
judged reasonable by the Investigator, the etiology should be identified and the 
Sponsor notified. 
- 
All protocol-required laboratory tests, as defined in Appendix 2 (Section 10.2), must 
be conducted in accordance with the laboratory manual and the SoA (Section 1.3). 
- 
If laboratory values from non-protocol specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the eCRF. 
8.2.5 Pregnancy testing  
• Refer to Section 5.1 for pregnancy testing entry criteria; the Investigator is responsible for 
review of medical history, menstrual history, and recent sexual activity to decrease the risk 
for inclusion of a woman with an early undetected pregnancy. 
• Pregnancy testing (urine or serum as required by local regulations) should be conducted at 
the intervals specified in the SoA. 
• Additional serum or urine pregnancy tests may be performed, as determined necessary by 
the Investigator or required by local regulation, to establish the absence of pregnancy at 
any time during the participant’s participation in the study. 
8.2.6 Suicidal ideation and behavior risk monitoring  
Venglustat is considered to be CNS-active. In addition, there has been an isolated report of 
suicidal ideation/behavior as reported in the IB in participant with FD with depressed mood 
receiving venglustat. The Sponsor considers important to monitor for such events before and 
during this clinical study. 
Participants being treated with venglustat should be monitored appropriately and observed closely 
for suicidal ideation and behavior or any other unusual changes in behavior. Consideration should 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 52 
be given to discontinuing venglustat in participants who experience signs of suicidal ideation or 
behavior. 
Families and caregivers of participants being treated with venglustat should be instructed to 
monitor participants for the emergence of unusual changes in behavior, as well as the emergence 
of suicidal ideation and behavior, and to report such symptoms immediately to the study 
Investigator. 
Participants will be screened during planned interactive visits utilizing the Beck Depression 
Inventory-II (BDI-II) to assess for evidence of evolved depression.  
8.2.6.1 Beck Depression Inventory, second edition  
Depression will be monitored during the study by using the BDI-II according to the SoA (see 
Section 1.3). Beck Depression Inventory-II (Appendix 10 [Section 10.10]) is a 21-question, 
multiple choice, self-report inventory. It is composed of items relating to symptoms of depression 
such as hopelessness and irritability, cognitions such as guilt or feelings of being punished, as 
well as physical symptoms such as fatigue, weight loss, and disinterest in sex. 
The wording of the BDI-II is clear and concise. The test contains 21 items, most of which assess 
depressive symptoms on a Likert scale of 0 to 3. The 2 exceptions to this are Questions 16 and 18. 
Question 16 addresses changes in sleeping pattern, while Question 18 addresses changes in 
appetite. Participants will be asked to report their own feelings over the past 2 weeks instead of 
1 week, as in the BDI and BDI-IA. The reason for this is to be consistent with the Diagnostic and 
Statistical Manual of Mental Disorders, 4th Edition criteria for depression. There were also 2 items 
added to indicate any directional changes in eating and sleeping patterns. Finally, all forms of the 
inventory are written at the 5th grade reading level. 
Clinical interpretation of scores is accomplished through criterion-referenced procedures utilizing 
the following interpretive ranges: total BDI-II scores of 0 to 13 indicate minimal depression, 
scores of 14 to 19 indicate mild depression, scores of 20 to 28 indicate moderate depression, and 
scores of 29 to 63 indicate severe depression.  
Whenever possible, the BDI-II should be done prior to clinical interaction with the Investigator. 
At Visit 1 (Section 1.3.1) or Visit 0 (Section 1.3.2), participants with BDI-II of 20 to 28, inclusive, 
should be evaluated by a mental health specialist before the Investigator can determine if the 
participant would be able to fully participate in the trial. Participants with a BDI-II of >28 (severe 
depression) at Visit 1 (Section 1.3.1) or Visit 0 (Section 1.3.2) will be excluded. 
If a participant has a score of ≥20 during the study, the participant must be referred to his or her 
health care professional for psychiatric evaluation. If the participant has any score but picks out 
Statement 2 or 3 for Question 9, the local suicide assessment and management protocol must be 
followed, and participant must be supervised until appropriate mental health personnel is 
available. This will be captured as an AE. The participant may continue on the study, but this is 
dependent on the outcome of psychiatric evaluation and judgment of the PI. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 53 
8.2.7 Ophthalmological examination  
The effect of venglustat on the lens will be closely monitored throughout the study. The full 
ophthalmological examination will include BCVA using Snellen chart, and examination of the 
cornea, lens, and retina with slit-lamp. The examination should include pupil dilation and 
evaluation of the lens according to the WHO simplified cataract grading system. If a new or 
worsening lens abnormality is found, documentation of finding with lens photography using 
standard local photographic methods is recommended. For opacities present at baseline/previous 
visit, changes in WHO Grade ≥1.0 for nuclear, cortical, or posterior subcapsular opacification 
compared with baseline or previous assessment will be considered as a worsening. 
In countries where the Latin alphabet is not used, the Snellen chart could be substituted with the 
Tumbling E distance chart based on the Snellen fraction. 
For participants enrolled in LTS15823 study at Visit 12 (Month 24) of the EFC15392 study, a full 
ophthalmological examination will be performed prior to start of treatment (at Month 24 Visit of 
the EFC15392 study), at Month 12 (Visit 6), and at Month 24 (Visit 10) (or upon withdrawal or 
discontinuation) with pupil dilation and WHO simplified cataract grading system evaluation of 
lens opacities.  
For participants enrolled in the LTS15823 study after the end-of-treatment visit of the EFC15392 
study, a full ophthalmological examination will be performed prior to start of treatment (at Visit 0 
or at Visit 1), at Month 12 (Visit 6), and at Month 24 (Visit 10) (or upon withdrawal or 
discontinuation) with pupil dilation and WHO simplified cataract grading system evaluation of 
lens opacities.  
For all participants, at the visits at Month 6 (Visit 4) and Month 18 (Visit 8), only BCVA 
examination will be required.  
If at any time during study participation the participant experiences a decrease ≥2 lines in BCVA 
compared to baseline or previous assessment, full ophthalmological examination with pupil 
dilation and WHO simplified cataract grading system evaluation should be performed. If a new or 
worsening lens abnormality is found, documentation of the finding with lens photography is 
recommended. 
If participant had change in WHO Grade ≥1.0 in any of the 3 features (nuclear, cortical and 
posterior subcapsular opacification) of the lens, all subsequent scheduled (every 3 month) 
ophthalmic assessments in this participant should include pupil dilation with WHO simplified 
cataract grading system evaluation. 
Pupil dilation and full eye examination can be performed at any time if deemed medically 
necessary; WHO simplified cataract grading system evaluation should be performed if a change 
from baseline is observed during slit-lamp examination. 
The examination should be performed by the same ophthalmologist (optometrist if allowed 
according to local regulations) throughout the study, if possible. Abnormal findings reported by 
the clinical sites will be reviewed by the DMC and/or the clinical site to adjudicate these findings 
as AE of special interest (AESI) and assess their seriousness/severity. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 54 
8.2.8 Participant reported outcomes  
Table 5 shows the concepts of measurement and their related PRO questionnaires to be used in the 
trial. Participant reported outcomes performed on site will be completed prior to any procedures 
or discussions about the treatment and disease. 
Table 5 - Participant reported outcome (PRO) concepts and questionnaires  
Concept 
PRO questionnaire 
Overall pain 
BPI-SF (Appendix 11 [Section 10.11]) 
Overall fatigue 
BFI (Appendix 12 [Section 10.12]) 
Health status 
EQ-5D-5L (Appendix 13 [Section 10.13]) 
BFI = Brief Fatigue Inventory: BPI-SF = Brief Pain Inventory short-form; EQ-5D-5L = EuroQoL 5-dimension 5-level; PRO = Participant 
reported outcome.  
Overall pain 
Overall pain will be measured using the Brief Pain Inventory Short Form (BPI-SF) (15); one of 
the most widely used instruments for measuring pain in clinical trials (Appendix 11 
[Section 10.11]). The BPI-SF comprises 15 questions related to pain severity, location, treatment 
and pain interference in the previous 24 hours; and 1 item asks about pain “right now”. Most 
items provide an 11-point numeric rating scale (NRS) to indicate severity of pain (n=4), pain 
interference (n=7) and treatment relief (n=1). A binary categorical response is given to a single 
item about pain incidence, and a body diagram is completed to indicate pain location. Scores are 
by items and by dimensions; the global score ranges from 0 to 10. Lower scores indicate lower 
pain. The BPI-SF will be administered at the Baseline and Months 1, 6, 12, 18, and 24 visits. 
Overall fatigue 
The Brief Fatigue Inventory (BFI) (16) has been used widely in clinical research in both drug 
development and observational studies (Appendix 12 [Section 10.12]). It will be used in the 
current study to measure overall fatigue. The BFI comprises 10 questions related to fatigue 
incidence in the past week (1 item; yes/no), fatigue severity (3 items; 2 recalling the past 24 hours, 
1 “right now”, all on an 11-point NRS) and fatigue impact in the past 24 hours (6 items on 
11-point NRS). Scores are by dimension, 1-item and the global score ranging from 0 to 10. 
Lower scores indicate lower fatigue. The BFI will be administered at the Baseline and Months 1, 
6, 12, 18, and 24 visits. 
Quality of life/health status 
The EuroQoL 5-dimension 5-level (EQ-5D-5L) is used widely in clinical trials to assess 
5 dimensions of health outcome (mobility, self-care, usual activities, pain/discomfort, 
anxiety/depression) from a wide variety of interventions on a common scale, for purposes of 
evaluation, allocation, and monitoring. The EQ-5D-5L will be measured at Baseline and 
Months 1, 3, 6, 12, 18, and 24 visits (Appendix 13 [Section 10.13]). 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 55 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING  
The definitions of AEs and SAEs) can be found in Appendix 3 (Section 10.3). The definition of 
AESI is provided in Section 8.3.8. 
The definitions of unsolicited and solicited AEs can be found in Appendix 3 (Section 10.3). 
The device-related safety events and device deficiencies are not applicable for this study. 
AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative).  
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up all AEs (see Section 7). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
8.3.1 Time period and frequency for collecting AE and SAE information  
All AEs (serious or nonserious) will be collected from the end–of-study visit in the EFC15392 
study (including AEs prior to signing the ICF) until end of the study at the time points specified in 
the SoA (Section 1.3). 
All SAEs and AESIs (collected from the signing the ICF) will be recorded and reported to the 
Sponsor or designee immediately and under no circumstance should this exceed 24 hours, as 
indicated in Appendix 3 (Section 10.3). The Investigator will submit any updated SAE data to the 
Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the Investigator must promptly 
notify the Sponsor. 
8.3.2 Method of detecting AEs and SAEs  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
8.3.3 Follow-up of AEs and SAEs  
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. At the prespecified study end-date, all SAEs, and AESIs 
(as defined in Section 8.3.8), will be followed until resolution, stabilization, the event is otherwise 
explained, or the participant is lost to follow-up (as defined in Section 7.3). Further information 
on follow-up procedures is provided in Appendix 3 (Section 10.3). 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 56 
8.3.4 Regulatory reporting requirements for SAEs  
• Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
• Serious adverse events that are considered expected will be specified in the reference 
safety information in the IB.  
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
• An Investigator who receives an Investigator safety report describing an SAE, SUSAR or 
any other specific safety information (eg, summary or listing of SAEs) from the Sponsor 
will review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. It is the responsibility of the Sponsor to assess whether an 
event meets the criteria for a SUSAR, and therefore, is expedited to regulatory authorities. 
8.3.5 Pregnancy  
• Details of all pregnancies in female participants and female partners of male participants 
will be collected after the start of study intervention and until the follow-up visit (30 days 
after the last dose of IMP). 
• If a pregnancy is reported, the Investigator will record pregnancy information on the 
appropriate form and submit it to the Sponsor within 24 hours of learning of the 
pregnancy. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication 
or elective termination of a pregnancy for medical reasons will be reported as an AE or 
SAE.  
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 
• The participant/pregnant female partner will be followed-up to determine the outcome of 
the pregnancy. The Investigator will collect follow-up information on the 
participant/pregnant female partner and the neonate and the information will be forwarded 
to the Sponsor. 
• Any poststudy pregnancy-related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described 
in Section 8.3.4. While the Investigator is not obligated to actively seek this information in 
former study participants/pregnant female partner, he or she may learn of an SAE through 
spontaneous reporting. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 57 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention and will be withdrawn from the study. 
8.3.6 Cardiovascular and death events  
Not applicable. 
8.3.7 Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs  
Not applicable. 
8.3.8 Adverse event of special interest  
Adverse event of special interest 
An AESI is an AE (serious or nonserious) of scientific and medical concern specific to the 
Sponsor’s product or program, for which ongoing monitoring and immediate notification by the 
Investigator to the Sponsor is required. Such events may require further investigation in order to 
characterize and understand them. An AESI may be added, modified or removed during a study 
by protocol amendment. 
• Pregnancy of a female participant entered in a study as well as pregnancy occurring in a 
female partner of a male participant entered in a study with IMP:  
- 
Pregnancy occurring in a female participant entered in the clinical trial or in a female 
partner of a male participant entered in the clinical trial. It will be qualified as an SAE 
only if it fulfills one of the seriousness criteria (see Appendix 3 [Section 10.3]). 
- 
In the event of pregnancy in a female participant, IMP should be discontinued.  
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined (See Appendix 4 
[Section 10.4]). 
• Symptomatic overdose (serious or nonserious) with IMP. 
- 
An overdose (accidental or intentional) with the IMP is an event suspected by the 
Investigator or spontaneously notified by the participant (not based on systematic pills 
count) and defined as at least twice the intended dose within the intended therapeutic 
interval, adjusted according to the tested drug.  
• Increase in ALT >3 ULN (see Appendix 6 [Section 10.6]). 
• Other project specific AESI(s): 
- 
New or worsening lenticular opacities and cataracts. 
For opacities present at baseline/previous visit, increase in WHO Grade ≥1.0 for nuclear, cortical, 
or posterior subcapsular opacification compared with baseline or previous assessment will be 
considered as a worsening.  
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 58 
8.3.9 Guidelines for reporting product complaints  
Any defect in the IMP must be reported as soon as possible by the Investigator to the monitoring 
team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
8.3.9.1 Medical device deficiencies  
Not applicable. 
8.4 
PHARMACOKINETICS  
• PK parameters are not evaluated in this study. 
8.5 
GENETICS AND/OR PHARMACOGENOMICS  
Genetics are not evaluated in this study. 
8.6 
BIOMARKERS  
• Collection of biological samples for other biomarker research is also part of this study. 
The following samples for biomarker research are required and will be collected from all 
participants in this study as specified in the SoA: 
- 
Serum (fibroblast growth factor 23 [FGF23]), 
- 
Plasma (GL-1, GM3, asymmetric dimethylarginine [ADMA]), 
- 
Urine (monocyte chemoattractant protein 1 [MCP1] detection). 
Samples will be tested for PD biomarkers associated with ADPKD such as FGF23 and ADMA in 
plasma to evaluate their association with the observed clinical responses. Urine samples (24-hour 
urine collections) will be analyzed for markers of kidney injury such as MCP1.  
The final list of biomarkers that will be analyzed in samples collected in the LTS15823 study may 
change based on the results of the analysis of biomarkers performed in the EFC15392 study. 
Special procedures for collection, storage, and shipment of serum, plasma, and urine samples will 
be described in a separate laboratory manual provided by the central laboratory. Approximately 
6 mL of whole blood will be collected at each time point. 
Additional exploratory biomarkers may be evaluated from remnant samples if available data 
during the sample retention period suggests a relationship to disease course and/or treatment 
response. These assessments may include analysis of protein and/or sphingolipid biomarkers 
using targeted or proteomic/metabolomic approaches.  
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 59 
In addition, remnant samples may be used for research to develop methods, assays, prognostics 
and/or companion diagnostics related to the disease process, pathways associated with the disease 
state, and/or mechanism of action of venglustat. 
Samples may be stored for a maximum of 5 years (or according to local regulations) following the 
last participant’s last visit for the study at a facility selected by the Sponsor to enable further 
analysis of biomarker responses to venglustat. Participation is optional and participants will have 
to provide consent to participate in this future use of nongenomic samples analysis. 
Collection of samples for biomarker research is not applicable for Chinese participants. 
8.7 
IMMUNOGENICITY ASSESSMENTS  
Not applicable. 
8.8 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS  
Health economics or medical resource utilization and health economics parameters are not 
evaluated in this study. 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH  
Future research may help further the understanding of disease subtypes, disease biology, related 
conditions, drug response and toxicity, and can help identify new drug targets or biomarkers that 
predict participant response to treatment. Therefore, data and biological samples will be stored 
and used for future research when consented to by participants (biobanking) (see Section 10.1.3) 
unless prohibited by local laws or IRBs/IECs (in such case, consent for future use of sample will 
not be included in the local ICF).  
For participants who consent to the storage and use of their data and remaining and/or extra 
clinical samples, data and samples may be used after the study ends for future research related 
either to the drug, the mechanism of action, and the disease or its associated conditions. Such 
research may include, but is not limited to, performing assessments on DNA, RNA, proteins or 
metabolites.  If future research on genetic material is performed, this will also be limited to the 
purpose of addressing research questions related to the drug, the mechanism of action, the disease 
or its associated conditions. 
In the event future research is conducted for other purposes, the study participants will be 
informed of those purposes and will be given means to object to those research projects. 
Data and samples will be used in compliance with the information provided to participants in the 
ICF Part 2 (future research). 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 60 
All study participant data and samples will be coded such that no participant direct identifiers will 
be linked to them. Coded data and samples may be transferred to a Sponsor site (or a 
subcontractor site), which may be located outside of the country where the study is conducted. 
The Sponsor adopts safeguards for protecting participant confidentiality and personal data (see 
Section 10.1.4). 
The samples will be stored for a maximum of 15 years after the end of the study. Any samples 
remaining at the end of retention period will be destroyed. If a participant requests destruction of 
his/her samples before the end of the retention period, the Investigator must notify the Sponsor (or 
its contract organization) in writing. In such case, samples will be destroyed and related coded 
data will be anonymized unless otherwise required by applicable laws. 
Study participant coded data will be stored for future research for up to 25 years after the end of 
the study. If data are still considered of important scientific value after this period, coded data 
already available will be anonymized unless otherwise required by applicable laws (the same will 
apply to the data of a study participant who has requested the destruction of his/her samples). 
Participant’s coded data sets provided to researchers for a specific research project will be 
available to the researchers for a maximum of 2 years after the end of their specific project (end of 
project is defined by publication of the results or finalization of the future research project report). 
All samples from Chinese participants will be disposed following completion of the clinical study 
report. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 61 
9 
STATISTICAL CONSIDERATIONS  
The study is designed to test the following hypotheses for the primary efficacy endpoint: percent 
change in TKV based on MRI from the EFC15392 study baseline to 24 months of open-label 
extension study, in early treated and delayed-treated participants: 
• Null hypothesis: No difference between early-treated participants and delayed-treated 
participants with regards to the mean percent change in TKV from the EFC15392 study 
baseline to 24 months of open-label extension study. 
• Alternative hypothesis: Early-treated participants have lower mean percent change in TKV 
from the EFC15392 study baseline to 24 months of open-label extension study, compared 
to delayed-treated participants. 
9.1 
SAMPLE SIZE DETERMINATION  
Since this study is the extension of the EFC15392 study, no formal sample size calculation was 
performed. A maximum of 640 participants who completed the EFC15392 study will be enrolled, 
including: 
• Early venglustat: A maximum of 280 participants who were randomized to venglustat 
15 mg in the EFC15392 study. 
• Early venglustat: A maximum of 80 participants who were randomized to venglustat 8 mg 
in the EFC15392 study. 
• Delayed venglustat: A maximum of 280 participants who were randomized to placebo in 
the EFC15392 study. 
9.2 
POPULATIONS FOR ANALYSES  
The following populations for analyses are defined: 
Table 6 - Populations for analyses  
Population 
Description 
Screened 
All participants who sign the LTS15823 study ICF. 
Enrolled 
All participants from screened population who have been allocated to an LTS15823 
intervention kit by interactive response technology (IRT) regardless of whether the 
intervention was received or not. 
Primary Efficacy 
All participants who completed Stage 1 or Stage 2 treatment in the EFC15392 study 
within 3 months prior to inclusion in the LTS15823 study. Participants will be 
analyzed according to the intervention assigned by randomization in the EFC15392 
study (early venglustat or delayed venglustat). 
Participants randomized to venglustat 8 mg in Stage 1 of the EFC15392 study will 
be included in the primary efficacy population (in the early venglustat group), only if 
venglustat 8 mg shows similar effect compared to venglustat 15 mg in Stage 1 of 
the EFC15392 study, with regards to TKV slope (see Section 9.3.1 for details). 
Safety 
All participants who take at least 1 dose of study intervention in the LTS15823 
study. Participants will be analyzed according to the intervention they actually 
received (early venglustat or delayed venglustat). 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 62 
Enrolled participants for whom it is unclear whether they took the study intervention will be 
considered as exposed and will be included in the safety population as randomized. 
For any participant enrolled more than once, only the data associated with the first enrollment will 
be used in any analysis population. The safety experience associated with any later enrollment 
will be reported separately. 
9.3 
STATISTICAL ANALYSES  
The statistical analysis plan (SAP) will include a more technical and detailed description of the 
statistical analyses described in this section. This section is a summary of the planned statistical 
analyses of the most important endpoints including primary and key secondary endpoints. 
9.3.1 General considerations  
Statistical tests and confidence intervals will be based on 2-sided tests with nominal significance 
level of 0.05. 
For efficacy analyses, the 2 following groups will be compared: 
• Delayed venglustat: participants who were randomized to placebo in Stage 1 or Stage 2 of 
the EFC15392 study. 
• Early venglustat: participants who were randomized to venglustat (8 mg or 15 mg) in 
Stage 1 or Stage 2 of the EFC15392 study. 
Participants randomized to venglustat 8 mg in Stage 1 of the EFC15392 study will be included in 
the primary efficacy population (in the “Early venglustat” group) only if venglustat 8 mg and 
15 mg show similar effect with regards to the primary efficacy endpoint in the EFC15392 Stage 1 
study. RR8 and RR15 denote the relative reduction versus placebo with regards to the annualized 
rate of change in TKV, for the venglustat 8 mg and venglustat 15 mg, respectively. The following 
rule will apply: 
• If RR8 ≥2/3 RR15 then participants randomized to venglustat 8 mg in Stage 1 of the 
EFC15392 study will be included in the primary efficacy population and part of the “Early 
venglustat” group. 
• If RR8 <2/3 RR15 then participants randomized to venglustat 8 mg in Stage 1 of the 
EFC15392 study will be not be included in the primary efficacy population. 
In addition, participants included in the LTS15823 study more than 3 months (91 days) after 
having completed the EFC15392 study treatment will be excluded from the primary efficacy 
population. 
While the primary comparison of interest is at 24 months of the LTS15823 study, efficacy 
analyses will present each scheduled assessment from the EFC15392 and LTS15823 studies. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 63 
For safety analyses, the 2 following groups will be presented: 
• Delayed venglustat: participants having received placebo in Stage 1 or Stage 2 of the 
EFC15392 study. 
• Early venglustat: participants having received venglustat (8 mg or 15 mg) in Stage 1 or 
Stage 2 of the EFC15392 study. 
All participants having received venglustat in the LTS15823 study (whether included less or more 
than 3 months after having completed the EFC15392 study treatment) will be included in the 
safety population. 
Baseline value is generally defined as the last available value before first IMP administration in 
the EFC15392 study. For eGFR, baseline is defined as the average of eGFR values assessed prior 
to first IMP administration in the EFC15392 study. 
In addition, the baseline value in the LTS15823 study is defined as the last available value before 
first IMP administration in the LTS15823 study. For TKV and total liver volume (TLV), due to 
the possibility to perform the LTS15823 first visit remotely and then to have potential late MRI 
examination, baseline in the LTS15823 study is defined as the first available value up to first IMP 
administration in the LTS15823 study + 30 days. For eGFR, baseline in the LTS15823 study is 
defined as the average of eGFR values assessed prior to first IMP administration in the 
LTS15823 study. 
Observation period  
The observation period will be divided into 4 segments:  
• The pretreatment period is defined as the period up to first IMP administration in the 
LTS15823 study. 
• The treatment-emergent (TE) period is defined as the period from the first IMP 
administration in the LTS15823 study to the last IMP administration in the 
LTS15823 study + 30 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 period from the end of the 
on-treatment period to the end of the treatment-emergent period.  
• The post-treatment period is defined as the period from the end of the 
treatment-emergent period. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 64 
9.3.2 Primary endpoint  
The primary endpoint is percent change in TKV based on MRI from the EFC15392 study baseline 
to 24 months of open-label extension study, in early treated and delayed-treated participants. 
The primary estimand will be the difference (early venglustat versus delayed venglustat) in mean 
percent change in TKV from the EFC15392 study baseline to 24 months in the LTS15823 study, 
in all participants from the primary efficacy population, regardless of whether or not participants 
completed the LTS15823 treatment period (treatment policy strategy). 
Percent change from the EFC15392 study baseline in TKV will be analyzed using a mixed effect 
model with repeated measures (MMRM). The MMRM will include percent change in TKV at the 
following time points:  
• Month 18 in the EFC15392 study. 
• Baseline in the LTS15823 study. 
• Month 24 in the LTS15823 study. 
Percent change in TKV at Month 1 and Month 9 in the EFC15392 study will not be included in 
the MMRM since TKV at these time points was only assessed in participants from Stage 1. 
The MMRM will include fix effect of treatment group (early venglustat versus delayed 
venglustat), Mayo Imaging Classification (as per randomization stratification factor in the 
EFC15392 study: Class 1C versus 1D versus 1E), time point (as a categorical variable), 
treatment*time point interaction, Mayo Imaging Classification*time point interaction as well as 
the continuous fixed covariates of baseline TKV and the baseline-by-time point interaction. 
This model will include an unstructured covariance matrix to model the within-participant errors. 
Parameters will be estimated using restricted maximum likelihood method. Denominator degrees 
of freedom will be estimated using Kenward-Roger approximation.  
Within group mean percent change in TKV will be obtained from MMRM, using weights for each 
stratum (Mayo Class 1C, 1D, and 1E) equal to the observed proportion of participants in each 
stratum in the primary efficacy population (ie, “population weight”). The difference in baseline 
adjusted least-squares means will be used to compare the early venglustat group to the delayed 
venglustat group, at the 2-sided 0.05 level. 
The primary analysis will include all observed TKV data in participants from the primary efficacy 
population, regardless of whether or not participants completed the treatment period. Participants 
who prematurely and permanently discontinue IMP in the LTS15823 study will be requested to 
obtain an MRI scan at 24-month visit and their data collected after treatment discontinuation will 
be included in the primary analysis. All efforts will be made to minimize the amount of missing 
data. 
In order to evaluate the robustness of the primary analysis, sensibility analyses will be performed 
and described in the SAP. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 65 
Secondary analysis 
A secondary analysis will estimate the difference in mean percent change in TKV from baseline 
during the on-treatment period (while on treatment strategy). In this secondary analysis, TKV 
assessed more than 30 days after the last LTS15823 study IMP administration will be excluded 
from the analysis. The TKV assessed in enrolled but not treated participants will also be excluded 
from the analysis. Any missing data during the on-treatment period will be considered “at 
random” in this secondary analysis; therefore, no imputation will be required since the MMRM 
provides valid inference under missing at random assumption. 
9.3.3 Secondary endpoints  
Change in eGFR from the EFC15392 study baseline to 24 months of open-label extension study 
will be analyzed using a MMRM similar to those used to analyze percent change in TKV. The 
MMRM will include change in eGFR at all time points in the EFC15392 and LTS15823 studies 
(change at Months 1, 3, 6, 9, 12, 15, 18, 21, and 24 in the EFC15392 study and at Baseline, 
Months 1, 6, 12, 18, and 24 in the LTS15823 study). 
If the model does not converge with an unstructured covariance matrix (due to the high number of 
time points), the following covariance matrix structures will be used in the order:  
• Heterogeneous Toeplitz (TOEPH). 
• First-order heterogeneous autoregressive (ARH[1]). 
• Heterogeneous Compound Symmetry (CSH). 
• Toeplitz (TOEP). 
• First-order autoregressive (AR[1]). 
• Compound Symmetry (CS). 
The first covariance structure yielding convergence will be used as the primary analysis. 
Missing data will be handled using a multiple imputation method similar to those of the primary 
endpoint. 
Secondary analysis 
The difference in mean percent change in eGFR from baseline during the on-treatment period 
(while on treatment strategy) will be estimated using method similar to the primary endpoint. 
Supplemental analysis 
In addition, a supplemental analysis will be performed using the same method as the primary 
analysis but excluding all participants with an eGFR at screening in the EFC15392 study of 30 to 
44.9 mL/min/1.73 m2.  
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 66 
Multiplicity considerations 
A fixed-sequence testing procedure will be used in order to control the Type I error rate for 
primary and secondary endpoints. The primary endpoint will be tested at the 0.05 level, then only 
if significant (p-value <0.05), then the secondary endpoint will be tested at the same 0.05 level. 
9.3.4 Tertiary/exploratory endpoint(s)  
Tertiary and exploratory endpoints analysis will be described in the SAP. 
9.3.5 Safety analysis  
Safety data will be presented separately for the 2 following periods: 
• Safety analysis of the open-label extension study. This analysis will present safety data 
during the open-label extension treatment-emergent period, on the LTS15823 safety 
population (see Section 9.3.1). Safety analyses will present safety data from the following 
groups: 
- 
Delayed venglustat, 
- 
Early venglustat. 
• Safety analysis of the overall venglustat treatment period. This analysis will present all 
safety data collected from the first intake of venglustat (either during the EFC15392 study 
or during the long-term extension LTS15823 study) to the last intake of venglustat 
+30 days. All participants having received venglustat will be included in this analysis. 
Safety analyses will present safety data from the following group: 
- 
Overall venglustat: participants having received venglustat during the EFC15392 study 
and/or during the long-term extension LTS15823 study. 
9.3.5.1 Adverse events  
General common rules for adverse events 
The AEs will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA) 
and analyzed in the following 3 categories: 
• Pretreatment AEs: AEs that developed, worsened, or became serious during the 
pretreatment period. 
• Treatment-emergent adverse events (TEAEs): AEs that developed, worsened, or became 
serious during the treatment-emergent period. 
• Post-treatment AEs: AEs that developed, worsened, or became serious during the 
post-treatment period.  
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 67 
Similarly, deaths will be analyzed in the pretreatment, treatment-emergent, and post-treatment 
periods. 
Analysis of all adverse events 
Adverse event incidence table will be provided by treatment group for all types of TEAEs: all 
TEAEs, all treatment-emergent AESIs (defined with a preferred term or a prespecified grouping), 
all treatment-emergent SAEs, and all TEAEs leading to permanent treatment discontinuation. 
The AE summaries will be generated with number (%) of participants experiencing at least one 
event.  
Deaths will also be analyzed. 
9.3.5.2 Laboratory variables, vital signs, and electrocardiograms (ECGs)  
Quantitative analyses 
For laboratory variables, vital signs, and ECG variables, descriptive statistics for results and 
changes from baseline will be provided for each analysis window, the last value and the worst 
value (minimum and/or maximum value depending on the parameter) during the on-treatment 
period. These analyses will be performed using central measurements (when available) for 
laboratory variables and ECG variables.  
Analyses according to PCSA  
Potentially clinically significant abnormality (PCSA) analyses will be performed based on the 
PCSA list currently in effect at Sanofi at the time of the database lock. 
Analyses according to PCSA will be performed based on the worst value during the 
treatment-emergent period, using all measurements (either local or central, either scheduled, 
nonscheduled, or repeated). 
For laboratory variables, vital signs, the incidence of participants with at least one PCSA during 
the treatment-emergent period will be summarized regardless of the baseline level and according 
to the following baseline status categories: 
• Normal/missing. 
• Abnormal according to PCSA criterion or criteria. 
For ECG, the incidence of participants with at least one abnormal ECG during the 
treatment-emergent period will be summarized regardless of the baseline level and according to 
the following baseline status categories:  
• Normal/missing. 
• Abnormal. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 68 
9.3.6 Other analysis  
Not applicable 
9.4 
INTERIM ANALYSES   
No interim analysis is planned. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 69 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS  
10.1.1 Regulatory and ethical considerations  
• This study will be conducted in accordance with the protocol and with the following: 
- 
Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and the applicable amendments and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines, 
- 
Applicable ICH Good Clinical Practice (GCP) Guidelines, 
- 
Applicable laws and regulations (eg, data protection law as General Data Protection 
Regulation - GDPR). 
• The protocol, protocol amendments, ICF, IB, IDFU and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
• Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard 
to study participants. 
• The Investigator will be responsible for the following: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC.  
- 
Determining whether an incidental finding (as per Sanofi policy) should be returned to 
a participant and, if it meets the appropriate criteria, to ensure the finding is returned 
(an incidental finding is a previously undiagnosed medical condition that is discovered 
unintentionally and is unrelated to the aims of the study for which the tests are being 
performed). The following should be considered when determining the return of an 
incidental finding: 
- 
The return of such information to the study participant (and/or his/her 
designated healthcare professional, if so designated by the participant) is 
consistent with all applicable national, state, or regional laws and regulations in 
the country where the study is being conducted. And 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 70 
- 
The finding reveals a substantial risk of a serious health condition or has 
reproductive importance, AND has analytical validity, AND has clinical 
validity.  
- 
The participant in a clinical study has the right to opt out of being notified by 
the Investigator of such incidental findings. In the event that the participant has 
opted out of being notified and the finding has consequences for other 
individuals, eg, the finding relates to a communicable disease, Investigators 
should seek independent ethical advice before determining next steps. 
- 
In case the participant has decided to opt out, the Investigator must record in 
the site medical files that she/he does not want to know about such findings. 
- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), European Medical Device Regulation 2017/745 for 
clinical device research (if applicable), and all other applicable local regulations. 
As applicable, according to Directive 2001/20/EC, the Sponsor will be responsible for obtaining 
approval from the Competent Authorities of the EU Member States and/or Ethics Committees, as 
appropriate, for any amendments to the clinical trial that are deemed as “substantial” (ie, changes 
which are likely to have a significant impact on the safety or physical or mental integrity of the 
clinical trial participants or on the scientific value of the trial) prior to their implementation. 
10.1.2 Financial disclosure  
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3 Informed consent process  
• The Investigator or his/her representative will explain the nature of the study to the 
participants, and answer all questions regarding the study, including what happens to the 
participant when his/her participation ends (post-trial access strategy for the study).  
• Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 
50, local regulations, ICH guidelines, Privacy and Data Protection requirements including 
those of the Global Data Protection Regulation (GDPR) and of the French law, Health 
Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, 
and the IRB/IEC or study center.  
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 71 
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• In case of ICF amendment while the participants are still included in the study, they must 
be re-consented to the most current version of the ICF(s).Where participants are not in the 
study anymore, teams in charge of the amendment must define if those participants must 
or not re-consent or be informed of the amendment (eg, if the processing of personal data 
is modified, if the Sponsor changes, etc). 
• A copy of the ICF(s) must be provided to the participant.  
Participants who are rescreened are required to sign a new ICF. 
The ICF contains 2 separate sections that address the use for research of participants’ data and/or 
samples (remaining mandatory ones or new extra samples collected for optional research). 
Optional exploratory research must be detailed in the section “Optional tests/procedures” and 
future research is to be defined in Core Study Informed Consent Form (CSICF) Part 2. Each 
option is subject to an independent consent and must be confirmed by ticking a checkbox in 
CSICF Part 3. The Investigator or authorized designee will explain to each participant the 
objectives of the exploratory research and why data and samples are important for future research. 
Participants will be told that they are free to refuse to participate and may withdraw their consent 
at any time and for any reason during the storage period. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 9 (Section 10.9). 
10.1.4 Data protection  
All personal data collected and/or processed in relation to this study will be handled in 
compliance with all applicable Privacy and Data Protection laws and regulations, including the 
GDPR (General Data Protection Regulation). The study Sponsor is the Sanofi company 
responsible for ensuring compliance with this matter, when processing data from any individual 
who may be included in the Sanofi databases, including Investigators, nurses, experts, service 
providers, Ethics Committee members, etc.  
When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor takes all appropriate measures to safeguard and prevent access to this 
data by any unauthorized third party. 
Protection of participant data 
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
“Participant race and ethnicity will be collected in this study because they are expected to modify 
the drug response/because they are required by regulatory agencies (eg, on African American 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 72 
population for the FDA or on Japanese population for the Pharmaceuticals and Medical Devices 
Agency in Japan)”. They will not be collected in the countries where this is prohibited by local 
regulation. 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor or its service providers will be identifiable only 
by the unique identifier; participant names or any information which would make the 
participant identifiable will not be transferred to the Sponsor.  
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with applicable data protection laws. The level of disclosure 
must also be explained to the participant as described in the informed consent.  
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• Participants must be informed that their study-related data will be used for the whole “drug 
development program”, ie, for this trial as well as for the following steps necessary for the 
development of the investigational product, including to support negotiations with payers 
and publication of results. 
Protection of data related to professionals involved in the study  
• Personal data (eg, contact details, affiliation(s) details, job title and related professional 
information, role in the study, professional resume, training records) are necessary to 
allow Sanofi to manage involvement in the study and/or the related contractual or 
precontractual relationship. They may be communicated to any company of the Sanofi 
group (“Sanofi”) or to Sanofi service providers, where needed. 
• Personal data can be processed for other studies and projects. At any time, objection to 
processing can be made by contacting the Sanofi Data Protection Officer (link available at 
Sanofi.com).  
• In case of refusal to the processing of personal data by or on behalf of Sanofi, it will be 
impossible to involve the professionals in any Sanofi study. In case the professionals have 
already been involved in a Sanofi study, they will not be able to object to the processing of 
their personal data as long as they are required to be processed by applicable regulations. 
The same rule applies in case the professionals are listed on a regulatory agencies 
disqualification list. 
• Personal data can be communicated to the following recipients:  
- 
Personnel within Sanofi or partners or service providers involved in the study, 
- 
Judicial, administrative and regulatory authorities, in order to comply with legal or 
regulatory requirements and/or to respond to specific requests or orders in the 
framework of judicial or administrative procedures. Contact details and identity may 
also be published on public websites in the interest of scientific research transparency. 
• Personal data may be transferred towards entities located outside the Economic European 
Area, in countries where the legislation does not necessarily offer the same level of data 
protection or in countries not recognized by the European Commission as offering an 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 73 
adequate level of protection. Those transfers are safeguarded by Sanofi in accordance with 
the requirement of European law including, notably:  
- 
The standard contractual clauses of the European Commission for transfers towards 
our partners and service providers, 
- 
Sanofi’s Binding Corporate Rules for intra-group transfers.  
• Professionals have the possibility to lodge a complaint with Sanofi leading Supervisory 
Authority, the “Commission Nationale de l’Informatique et des Libertés” (CNIL) or with 
any competent local regulatory authority. 
• Personal data of professionals will be retained by Sanofi for up to 30 years, unless further 
retention is required by applicable regulations. 
• In order to facilitate the maintenance of Investigators personal data, especially if they 
contribute to studies sponsored by several pharmaceuticals companies, Sanofi participates 
in the Shared Investigator Platform (SIP) and in the TransCelerate Investigator Registry 
(IR) project (https://transceleratebiopharmainc.com/initiatives/investigator-registry/). 
Therefore, personal data will be securely shared by Sanofi with other pharmaceutical 
company members of the TransCelerate project. This sharing allows Investigators to keep 
their data up-to-date once for all across pharmaceutical companies participating in the 
project, with the right to object to the transfer of the data to the TransCelerate project.  
• Professionals have the right to request the access to and the rectification of their personal 
data, as well as their erasure (where applicable) by contacting the Sanofi Data Protection 
Officer: 
 (to contact Sanofi by 
email, visit https://www.sanofi.com/en/our-responsibility/sanofi-global-privacy-
policy/contact). 
10.1.5 Committees structure  
10.1.5.1 Data Monitoring Committee  
• Participant safety will be continuously monitored by the DMC, operating independently 
from the Sponsor and Clinical Investigators, which includes safety signal detection at any 
time during the study. The DMC will be reviewing safety data in an unblinded fashion, 
aggregated by treatment group (ie, groups labelled delayed venglustat or early venglustat). 
• The specific responsibilities of the DMC and the frequency of data review will be 
described in the DMC charter. 
10.1.5.2 Steering committee  
• The Steering Committee (SC) is composed of field experts and Sponsor-based scientists 
with clinical and methodological expertise. This Committee, led by a Chairperson, 
selected by the Sponsor, will provide advice to the Sponsor regarding scientific issues and 
operational conduct of the study. The SC will also review any amendments, and provide 
input regarding interpretation of study results. The members will remain blinded to   
treatment group (ie, groups labelled delayed venglustat or early venglustat) until 
completion and unblinding of the EFC15392 study. Detailed activities and responsibilities 
of the SC will be provided in the SC charter. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 74 
10.1.6 Dissemination of clinical study data  
Study participants 
Sanofi shares information about clinical trials and results on publicly accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations.  These 
websites include clinicaltrials.gov, EU clinicaltrialregister (eu.ctr), and sanofi.com, as well as 
some national registries. 
In addition, results from clinical trials in participants are required to be submitted to 
peer-reviewed journals following internal company review for accuracy, fair balance and 
intellectual property. For those journals that request sharing of the analyzable data sets that are 
reported in the publication, interested researchers are directed to submit their request to 
clinicalstudydatarequest.com. 
Individual participant data and supporting clinical documents are available for request at 
clinicalstudydatarequest.com. While making information available we continue to protect the 
privacy of participants in our clinical trials. Details on data sharing criteria and process for 
requesting access can be found at this web address: clinicalstudydatarequest.com. 
Professionals involved in the study or in the drug development program 
Sanofi undertakes the legal obligation to disclose the full name of the Investigator and his/her 
affiliated institute/ hospital’s name and location on the China Trial Disclosure website as required 
by the National Medical Products Administration (NMPA) in its guidance “Implementation of 
Drug Clinical Trial Information Registration and Disclosure” (“Notification No. 28”), requesting 
name disclosure of Chinese and foreign investigational sites and Investigators in any eligible 
clinical trial.  
Sanofi may publicly disclose, and communicate to relevant authorities/institutions, the funding, 
including payments and transfers of value, direct or indirect, made to healthcare organizations and 
professionals and/or any direct or indirect advantages and/or any related information or document 
if required by applicable law, by regulation or by a code of conduct such as the “European 
Federation of Pharmaceutical Industries and Associations (EFPIA) Code on Disclosure of 
Transfers of Value from Pharmaceutical Companies to Healthcare Professionals and Healthcare 
Organisations”. 
10.1.7 Data quality assurance  
• All participant data relating to the study will be recorded on printed eCRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the eCRF. 
• Guidance on completion of eCRFs will be provided in eCRF Completion Instructions. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 75 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in separate study documents. 
• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations). 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 25 years after the signature of the final study 
report unless local regulations or institutional policies require a longer retention period. No 
records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor. 
10.1.8 Source documents  
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The Investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available. 
• Definition of what constitutes source data can be found in the Monitoring Plan. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.9 Study and site start and closure  
First act of recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open and will be the study start date. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 76 
Study/Site termination 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for study termination by the Sponsor, as well as reasons for the early closure of a study 
site by the Sponsor or Investigator may include but are not limited to: 
• For study termination: 
- 
Information on the product leads to doubt as to the benefit/risk ratio, 
- 
Discontinuation of further study intervention development. 
• For site termination: 
- 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines, 
- 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator, 
- 
Total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.10 Publication policy  
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments. 
• The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating Investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 77 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS  
• The tests detailed in Table 7 will be performed by the central laboratory. 
• Local laboratory results are only required in the event that the central laboratory results are 
not available in time for either study intervention administration and/or response 
evaluation, or as a part of contingency measures included in Appendix 9 (Section 10.9). 
Additionally, if the local laboratory results are used to make either a study intervention 
decision or response evaluation, the results must be recorded. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed 
in Section 5. 
• Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations. 
Table 7 - Protocol-required laboratory tests  
 
Laboratory tests 
Parameters 
Hematology 
 
 
Platelet count 
 
Red blood cell (RBC) count 
 
Hemoglobin 
 
Hematocrit 
 
RBC indices: 
 
MCV 
 
MCH 
 
%Reticulocytes 
 
White blood cell (WBC) count with differential: 
 
Neutrophils 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
 
Prothrombin time (PT) 
Partial thromboplastin time (PTT) 
International normalized ratio (INR) 
Clinical chemistrya 
 
 
Blood urea nitrogen (BUN) 
 
Serum cystatin C 
 
Urea 
 
Creatinine  
 
Glucose [fasting] 
 
Potassium 
 
Sodium 
 
Calcium 
 
Aspartate aminotransferase (AST)/ Serum glutamic-oxaloacetic transaminase (SGOT) 
 
ALT/ Serum glutamic-pyruvic transaminase (SGPT) 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 78 
Laboratory tests 
Parameters 
 
Alkaline phosphataseb 
 
Total and direct bilirubin 
 
Total protein 
Routine urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase by dipstick 
• 
Microscopic examination (if blood or protein is abnormal) 
Pregnancy testing 
• 
Serum or highly sensitive urine human chorionic gonadotropin (hCG) pregnancy 
test (as needed for women of childbearing potential)c 
Other screening tests 
• 
Follicle-stimulating hormone and estradiol (as needed in women of 
non-childbearing potential only) (if applicable)d 
• 
Serology (HIV antibody, hepatitis B surface antigen [HBsAg], and hepatitis C virus 
antibody) (if applicable)d 
• 
All study-required laboratory tests will be performed by a central laboratory, with 
the exception of urine dipstick 
NOTES : 
a Details of liver chemistry stopping criteria and required actions and follow-up are given in Section 7.1.2 and Appendix 6 (Section 10.6). All 
events which may indicate severe liver injury (possible Hy’s Law) must be reported to Sponsor in an expedited manner. 
b If alkaline phosphatase is elevated, consider fractionating.  
c Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC. 
d According to SoA. 
Investigators must document their review of each laboratory safety report. All samples from 
Chinese participants will be analyzed in a qualified bioanalytical laboratory in China. 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING  
10.3.1 Definition of AE  
AE definition 
• An AE is any untoward medical occurrence in a participant or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Definition of unsolicited and solicited AE 
• An unsolicited AE is an AE that was not solicited using a participant diary and that is 
communicated by a participant who has signed the informed consent. Unsolicited AEs 
include serious and non-serious AEs. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 79 
• Potential unsolicited AEs may be medically attended (ie, symptoms or illnesses requiring a 
hospitalisation, or emergency room visit, or visit to/by a health care provider). The 
participants will be instructed to contact the site as soon as possible to report medically 
attended event(s), as well as any events that, though not medically attended, are of 
participant’s concern. Detailed information about reported unsolicited AEs will be 
collected by qualified site personnel and documented in the participant’s records. 
• Unsolicited AEs that are not medically attended nor perceived as a concern by participant 
will be collected during interview with the participants and by review of available medical 
records at the next visit. 
• Solicited AEs are predefined systemic events for which the participant is specifically 
questioned, and which are noted by the participants in their diary. 
Events meeting the AE definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements, 
ophthalmic examination abnormalities), including those that worsen from baseline, 
considered clinically significant in the medical and scientific judgment of the Investigator 
(ie, not related to progression of underlying disease), eg: 
- 
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, 
- 
Leading to unscheduled full ophthalmological examination with or without WHO 
simplified cataract grading system evaluation. 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
• “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE. 
• The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, “lack of 
efficacy” or “failure of expected pharmacological action” also constitutes an AE or SAE. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 80 
Events NOT meeting the AE definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.3.2 Definition of SAE  
An SAE is defined as any adverse event that, at any dose: 
A) Results in death 
B) Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant 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. 
C) Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
D) Results in persistent or significant disability/incapacity 
- 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
- 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 81 
E) Is a congenital anomaly/birth defect 
F) Is a suspected transmission of any infectious agent via an authorized medicinal 
product 
G) Other situations: 
- 
Medical or scientific judgment should be exercised by the Investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant medical 
events that may jeopardize the participant or may require medical or surgical 
intervention to prevent one of the other outcomes listed in the above definition. These 
events should usually be considered serious. 
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:  
- 
Intensive treatment in an emergency room or at home for:  
- 
Allergic bronchospasm, 
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow 
aplasia, myelodysplasia, pancytopenia, etc), 
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc).  
- 
Development of drug dependence or drug abuse, 
- 
ALT >3 × ULN + total bilirubin >2 × ULN or asymptomatic ALT increase  
>10 × ULN, 
- 
Suicide attempt or any event suggestive of suicidality,  
- 
Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling),  
- 
Bullous cutaneous eruptions. 
10.3.3 Recording and follow-up of AE and/or SAE  
AE and SAE recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The Investigator will then record all relevant AE/SAE information. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor’s representative in lieu of completion of the required form. 
• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor’s representative. In this case, all participant identifiers, with the exception of 
the participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor’s representative. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 82 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories: 
• Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort to interfere with normal everyday 
activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. “Severe” is a category used for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe. 
Assessment of causality 
• The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than that a relationship cannot be ruled 
out. 
• The Investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The Investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor representative. However, it is 
very important that the Investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the Sponsor 
representative. 
• The Investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 83 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor’s 
representative to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor representative with a copy of any 
postmortem findings including histopathology. 
• New or updated information will be recorded in the originally submitted documents. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
10.3.4 Reporting of SAEs  
SAE reporting to the Sponsor via an electronic data collection tool 
• The primary mechanism for reporting an SAE to the Sponsor’s representative will be the 
electronic data collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes available. 
• After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
offline, then the site can report this information on a paper SAE form (see next section) or 
to the Sponsor’s representative by telephone. 
• Contacts for SAE reporting can be found in the Investigator Study File. 
SAE reporting to the Sponsor via paper data collection tool 
• Facsimile transmission of the SAE paper data collection tool is the preferred method to 
transmit this information to the Sponsor’s representative. 
• In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
• Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE data collection tool within the designated reporting time frames. 
• Contacts for SAE reporting can be found in the Investigator Study File. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 84 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE  
10.4.1 Definitions  
A woman is considered WOCBP (fertile) from the time of menarche until becoming 
postmenopausal (see below) unless permanently sterile (see below). 
• A postmenopausal state is defined as the period of time after a woman has experienced no 
menses for 12 consecutive months without an alternative medical cause. 
• A high follicle-stimulating hormone (FSH) level in the postmenopausal range should be 
used to confirm a postmenopausal state in women not using hormonal contraception or 
hormone replacement therapy (HRT).  
• Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-estrogen 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. 
Permanent sterilization methods include the following: 
• Documented hysterectomy. 
• Documented bilateral salpingectomy. 
• Documented bilateral oophorectomy. 
• For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), Investigator 
discretion should be applied to determining study entry eligibility. 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first administration of study intervention, additional evaluation should be 
considered. 
10.4.2 Contraception guidance  
DEFINITIONS 
Nonreproductive potential 
1. Premenopausal female with 1 of the following: 
NOTE: Documentation can come from the review of participant’s medical records, 
medical examination, or medical history interview. 
- 
Documented hysterectomy, 
- 
Documented bilateral salpingectomy, 
- 
Documented bilateral oophorectomy. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 85 
2. Postmenopausal 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high FSH/estradiol level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, a single FSH/estradiol 
measurement is insufficient.  
- 
Females on HRT and whose menopausal status is in doubt will be required to use 1 of 
the 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. 
Reproductive potential (WOCBP) 
A woman is considered of reproductive potential (WOCBP), ie, fertile, following menarche and 
until becoming postmenopausal unless permanently sterile. Permanent sterilization methods 
include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. 
CONTRACEPTIVE GUIDANCE 
Male participants 
• Male participants with heterosexual partners of reproductive potential (WOCBP) are 
eligible to participate if they agree to use the following for the duration of the study and 
for 90 days following their last dose of IMP: 
- 
Refrain from donating sperm, 
and 
- 
At least 1 of the following conditions applies: 
- 
Are and agree to remain abstinent from penile-vaginal intercourse on a long-term 
and persistent basis, when this is their preferred and usual lifestyle, 
or 
- 
Agree to use a male condom plus an additional contraceptive method with a failure 
rate of 1% per year (see Table 8 for female participants). 
• Men with a pregnant or breastfeeding partner must agree to remain abstinent from 
penile-vaginal intercourse or use a male condom for the time defined in the protocol. 
Female participants: 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly for the duration of the study 
and for at least 6 weeks following their last dose of IMP as described in Table 8. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 86 
Table 8 - Highly effective contraceptive methods  
Highly Effective Contraceptive Methods That Are User Dependenta 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: 
- 
Oral, 
- 
Intravaginal, 
- 
Transdermal. 
• 
Progestogen-only hormone contraception associated with inhibition of ovulation: 
- 
Oral, 
- 
Injectable. 
Highly Effective Methods That Are User Independent 
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationb 
- 
Intrauterine device, 
- 
Intrauterine hormone-releasing system. 
• 
Bilateral tubal occlusion. 
Vasectomized partner. 
A vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual partner of the 
WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception 
should be used. 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during 
the entire period of risk associated with the study treatment. The reliability of sexual abstinence needs to be evaluated in 
relation to the duration of the study and the preferred and usual lifestyle of the participant. 
Note:  
a Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations 
regarding the use of contraceptive methods for participants participating in clinical studies. 
b Hormonal contraception may be susceptible to interaction with the study treatment, which may reduce the efficacy of the contraceptive 
method. In this case 2 highly effective methods of contraception should be utilized during the treatment period and for at least 6 weeks for 
females and 90 days for males following their last dose of IMP. 
Male participants with partners of reproductive potential who become pregnant:  
• The Investigator will attempt to collect pregnancy information on any female partner of a 
male study participant who becomes pregnant while participating in this study. This 
applies only to 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.  
• 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, 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.  
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 87 
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.  
• Participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on participant and neonate, which 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.  
• Additional follow-up information may be requested about the baby until at least 1 year 
after the birth of the baby, due to potential risk of abnormalities not present at birth. 
• Any termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for procedure.  
• While pregnancy itself is not considered to be an AE or SAE, 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. 
• Any poststudy pregnancy-related SAE considered reasonably related to the study 
treatment by the Investigator will be reported to the Sponsor as described 
in Section 10.3.4. 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 will 
discontinue study treatment and will be withdrawn from the study. 
10.5 
APPENDIX 5: GENETICS  
Not applicable. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 88 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND 
FOLLOW-UP ASSESSMENTS  
 
*If unable to retest in 72 hours, use original laboratory results to decide on further reporting/monitoring/discontinuation. 
Note: 
“Baseline” refers to ALT sampled at Baseline visit; or if baseline value unavailable, to the latest ALT sampled before the Baseline 
visit. The algorithm does not apply to the instances of increase in ALT during screening. 
See Section 10.3 for guidance on safety reporting. 
Normalization is defined as ≤ULN or baseline value, if baseline value is >ULN. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 89 
10.7 
APPENDIX 7: AES, ADES, SAES, SADES, USADES AND DEVICE DEFICIENCIES: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, FOLLOW-UP, 
AND REPORTING IN MEDICAL DEVICE STUDIES  
Not applicable. 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS  
10.8.1 Germany  
• Exclusion criterion E08 
The participant will not be eligible to participate in the trial if the participant has been committed 
to an institution by virtue of an order issued either by the judicial or the administrative authorities, 
or if the participant is an employee of the Sponsor or Investigator or otherwise dependent on 
them. 
10.8.2 Belgium, Czech Republic, Denmark, Germany, Italy, Poland, Portugal, Romania, 
Spain  
In order to comply with the request received during the European VHP review phase, patients 
participating in the countries listed above will be treated with venglustat 15 mg once daily (QD) 
for 24 months. 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY  
A regional or national emergency declared by a governmental agency (eg, public health 
emergency, natural disaster, pandemic, terrorist attack) may prevent access to the clinical trial 
site. 
Contingency procedures are suggested below and in sections (Section 5.2, Section 5.5, Section 1, 
Section 7.1.4, Section 7.1.5, Section 8, and Section 10.1.3) for an emergency that prevents access 
to the study site, to ensure the safety of the participants, to consider continuity of the clinical study 
conduct, protect trial integrity, and assist in maintaining compliance with Good Clinical Practice 
in Conduct of Clinical Trials Guidance. Sponsor agreement MUST be obtained prior to the 
implementation of these procedures for the duration of the emergency. 
During the emergency, if the site will be unable to adequately follow protocol mandated 
procedures, alternative treatment outside the clinical trial should be proposed, and screening, 
enrollment, and/or administration of study treatment may be temporarily delayed/halted. 
The participant or their legally authorized representative should be verbally informed prior to 
initiating any changes that are to be implemented for the duration of the emergency (eg, study 
visit delays/treatment extension, use of local laboratories). 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 90 
Attempts should be made to perform all assessments in accordance with the approved protocol to 
the extent possible.  In case this is not possible due to a temporary disruption caused by an 
emergency, focus should be given to assessments necessary to ensure the safety of participants 
and those important to preserving the main scientific value of the study. 
The following contingencies may be implemented for the duration of the emergency (after 
Sponsor agreement is obtained) to make clinical supplies available to the participant for the 
duration of the emergency: the DTP supply of venglustat from the site where allowed by local 
regulations and agreed upon by the participant. The DTP supply of IMP is not contingent on 
availability of contemporaneous laboratory results or other study specific assessments. 
Procedures to be considered in the event of a regional or national emergency declared by a 
governmental agency (where allowed by local regulations) if onsite visits are not possible: 
• Telephone contacts are to be performed in place of an onsite study visits and per study 
protocol schedule. Essential data (that can be checked via interview to evaluate participant 
safety) to be captured via telephone contact and documented in the source records include, 
but is not limited to, AEs, SAEs, change in or new concomitant medications, urine 
pregnancy test results, IMP compliance, potential signs of depressed mood, complaints 
about changes in vision, vital signs (if participants can measure temperature and BP at 
home). 
• Visit ePROs (questionnaires) should be completed by the participant in the eDiary as 
usual. eDiary data can still be checked online by the Investigator/site team prior to calling 
the participant to ensure any follow‐up questions or findings can be discussed. 
• If it is feasible and there is no additional risk for a participant from the hazard the led to 
declaration of national emergency, consider performing blood tests in local laboratories: 
- 
Blood chemistry: at the minimum blood creatinine, AST, ALT, eGFR calculated with 
CKD-EPI equation, 
- 
Complete blood count. 
• Participants with a recent eGFR >45 mL/min/1.73 m2, may continue IMP up to 
6 months, without having an onsite visit. 
• Participants with a recent eGFR ≤45 and >30 mL/min/1.73 m2, may continue IMP up to 
3 months, without having an onsite visit. Participant who are not be able to repeat eGFR in 
3 months will have to interrupt the treatment. Temporary IMP discontinuation will need 
to be registered in IRT. 
• Participants with a recent eGFR ≤30 and >25 mL/min/1.73 m2, who are not be able to 
repeat creatinine in 30 days will have to interrupt the treatment. If eGFR result repeated in 
30 days is below 30 mL/min/1.73 m2, the participant will have to stop the treatment 
permanently. 
• When telephone contact is performed in place of an onsite study visits, assessments of 
efficacy and safety data that cannot be obtained remotely (eg, MRI, ECG, 
ophthalmological and neurological examination) will be performed when participants are 
able to resume normal site visits. Safety assessment that cannot be obtained remotely 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 91 
may be performed prior to next regular onsite visit if Investigator considers that this is 
clinically indicated and feasible, and that this will not involve an additional risk for a 
participant from the hazard that led to declaration of national emergency. 
If eligible participants who agreed to enter in the long-term extension study at Visit 12 (end-of 
treatment) of the EFC15392 study cannot attend site to perform this visit because of a regional or 
national emergency declared by a governmental agency, a remote LTS15823 Visit 1 can be 
performed where allowed by local regulations if the following conditions are fulfilled: 
• Site must receive from the participant signed and dated written informed consent for 
participation in the LTS15823 study. This consent must be signed and dated prior to the 
visit of home health vendor to collect assessments for a remote LTS15823 Visit 1. 
• A home health vendor must visit the participant on the day of the remote Visit 1 to collect 
laboratory samples planned for Visit 12 (end-of treatment) of the EFC15392 study and to 
perform urine pregnancy test (for WOCBP).  
• The DTP supply of venglustat from the site is allowed by local regulations and agreed 
upon by the participant. 
• A home health vendor service is in place to visit participant in 1 month (for Visit 2 of the 
LTS15823 study) to collect laboratory samples and assess AEs after 1 month on venglustat 
treatment in the LTS15823 study. 
On the day of the remote Visit 1, the Investigator will have a call with the patient and inquire 
about BP measurements, AEs, concomitant medications and results of performed urine pregnancy 
test (if applicable), will evaluate BDI-II score completed by the patient, and will enroll patient if 
eligibility is confirmed. If patient is enrolled, IMP will be sent to participant via DTP process. Site 
will need to follow up via telephone with the participant once IMP is delivered. 
Missing assessments of Visit 12 of the EFC15392 and LTS15823 Visit 1(including body weight 
measurement and MRI examination) will be performed as soon as onsite visit is possible. 
For participants who had lag phase between the end of the EFC15392 study and Screening visit in 
the LTS15823 study: 
• Screening in the LTS15823 study during a regional or national emergency declared by a 
governmental agency can be performed only if allowed by local competent authorities 
and after Sponsor`s agreement is obtained. 
• If a participant who completed the treatment period in Stage 1 or Stage 2 of the 
EFC15392 study was screen-failed during a regional or national emergency for reasons 
not related to eligibility, rescreening shall be permitted when the situation normalizes and 
after Sponsor`s agreement is obtained. 
• If eligibility assessment cannot be performed due to department/service shutdowns (MRI, 
ophthalmology, etc) during the screening period, the participant cannot be randomized, 
and screening period can be extended with randomization after site will be able to reopen. 
In such scenario, certain screening assessment will have to be repeated before Visit 1: 
- 
Blood chemistry (if >2 weeks after Visit 0), 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 92 
- 
Complete blood count (if >4 weeks after Visit 0), 
- 
BCVA and lens assessment according to WHO simplified cataract grading system (if 
>3 months from initial assessment in the LTS15823 study), 
- 
ECG (if >3 months from Visit 0 ECG test), 
- 
BDI-II (if >2 weeks after Visit 0), 
- 
MRI (decision on case by case basis: if >1 to 3 months before Visit 1). 
Contingencies implemented due to emergency will be documented. 
 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 93 
10.10 APPENDIX 10: BECK DEPRESSION INVENTORY II  
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 94 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 95 
10.11 APPENDIX 11: BRIEF PAIN INVENTORY (SHORT FORM) (BPI-SF)  
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
Property of the Sanofi group - strictly confidential 
Page 96 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 97 
10.12  APPENDIX 12: BRIEF FATIGUE INVENTORY (BFI)  
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 98 
10.13 APPENDIX 13: EUROQOL (EQ-5D-5L)  
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 99 
10.14 APPENDIX 14: ABBREVIATIONS  
 
ADMA: 
asymmetric dimethylarginine 
ADPKD: 
autosomal dominant polycystic kidney disease 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase 
BCVA: 
best corrected visual acuity 
BDI-II: 
Beck depression inventory II 
BFI: 
brief fatigue inventory 
BP: 
blood pressure 
BPI-SF: 
brief pain inventory short form 
CKD: 
chronic kidney disease 
CKD-EPI: 
Chronic Kidney Disease Epidemiology Collaboration 
CNS: 
central nervous system 
CSF: 
cerebral spinal fluid 
CYP3A4: 
cytochrome P450 3A4 
DBP: 
diastolic blood pressure 
DMC: 
data monitoring committee 
DTP: 
direct-to participant 
eCRF: 
electronic case report form 
eGFR: 
estimated glomerular filtration rate 
EOT: 
end-of-treatment 
EQ-5D-5L: 
EuroQol 5 dimension 5 level 
EU: 
European Union 
FD: 
Fabry disease 
FDA: 
United States Food and Drug Administration 
FGF23: 
fibroblast growth factor 23 
FSH: 
follicle-stimulating hormone 
GBA: 
glucocerebrosidase 
GBA-PD: 
Parkinson's disease with a confirmed acid-β-glucosidase gene mutation 
GCS: 
glucosylceramide synthase 
GD: 
Gaucher disease 
GD3: 
Gaucher disease Type 3 
GL-1: 
glucosylceramide 
GM3: 
monosialodihexosylganglioside 
GSL: 
glycosphingolipid 
HRT: 
hormone replacement therapy 
IB: 
investigator's brochure 
ICF: 
informed consent form 
IMP: 
investigational medicinal product 
IRT: 
interactive response technology 
MCP1: 
monocyte chemoattractant protein 1 
MedDRA: 
Medical Dictionary for Regulatory Activities 
MMRM: 
mixed effect model with repeated measures 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 100 
MMSE: 
mini mental state examination 
MRI: 
magnetic resonance imaging 
NMPA: 
National Medical Products Administration 
NRS: 
numeric rating scale 
PCSA: 
potentially clinically significant abnormality 
PD: 
pharmacodynamics(s) 
PI: 
principal investigator 
PK: 
pharmacokinetic(s) 
QD: 
once daily 
SAE: 
serious adverse event 
SBP: 
systolic blood pressure 
SRT: 
substrate reduction therapy 
SUSAR: 
suspected unexpected serious adverse reaction 
TE: 
treatment emergent 
TEAE: 
treatment-emergent adverse event 
TKV: 
total kidney volume 
TLV: 
total liver volume 
ULN: 
upper limit of normal 
VHP: 
Voluntary Harmonization Procedure 
WHO: 
World Health Organization 
WOCBP: 
women of childbearing potential 
 
10.15 APPENDIX 15: PROTOCOL AMENDMENT HISTORY  
The summary of changes for the current protocol amendment (amended protocol 01) is included 
after the title page. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 101 
11 
REFERENCES  
 
1. Willey CJ, Blais JD, Hall AK, Krasa HB, Makin AJ, Czerwiec FS. Prevalence of autosomal 
dominant polycystic kidney disease in the European Union. Nephrol Dial Transplant. 
2017;32(8):1356-63. 
2. Irazabal MV, Abebe KZ, Bae KT, Perrone RD, Chapman AB, Schrier RW, et al. Prognostic 
enrichment design in clinical trials for autosomal dominant polycystic kidney disease: the 
HALT-PKD clinical trial. Nephrol Dial Transplant. 2017;32(11):1857-65. 
3. Irazabal MV, Rangel LJ, Bergstralh EJ, Osborn SL, Harmon AJ, Sundsbak JL, et al. Imaging 
classification of autosomal dominant polycystic kidney disease: a simple model for selecting 
patients for clinical trials. J Am Soc Nephrol. 2015;26(1):160-72. 
4. Torres VE, Chapman AB, Devuyst O, Gansevoort RT, Grantham JJ, Higashihara E, et al. 
Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 
2012;367(25):2407-18. 
5. Schrier RW, Abebe KZ, Perrone RD, Torres VE, Braun WE, Steinman TI, et al. Blood 
pressure in early autosomal dominant polycystic kidney disease. N Engl J Med. 
2014;371(24):2255-66. 
6. Sommerer C, Zeier M. Clinical manifestation and management of ADPKD in western 
countries. Kidney Dis (Basel). 2016;2(3):120-7. 
7. Campbell KL, Rangan GK, Lopez-Vargas P, Tong A. KHA-CARI Autosomal Dominant 
Polycystic Kidney Disease Guideline: Diet and Lifestyle Management. Semin Nephrol. 
2015;35(6):572-81. 
8. Deshmukh GD, Radin NS, Gattone VH 2nd, Shayman JA. Abnormalities of 
glycosphingolipid, sulfatide, and ceramide in the polycystic (cpk/cpk) mouse. J Lipid Res. 
1994;35(9):1611-8. 
9. Chatterjee S, Shi WY, Wilson P, Mazumdar A. Role of lactosylceramide and MAP kinase in 
the proliferation of proximal tubular cells in human polycystic kidney disease. J Lipid Res. 
1996;37(6):1334-44. 
10. Natoli TA, Smith LA, Rogers KA, Wang B, Komarnitsky S, Budman Y, et al. Inhibition of 
glucosylceramide accumulation results in effective blockade of polycystic kidney disease in 
mouse models. Nat Med. 2010;16(7):788-92. 
11. Aronow WS. Treatment of hypertensive emergencies. Ann Transl Med. 2017;5 (Suppl 1):S5. 
12. Ji H, Zhang H, Xiong J, Yu S, Chi C, Bai B, et al. eGFRs from Asian-modified CKD-EPI and 
Chinese-modified CKD-EPI equations were associated better with hypertensive target organ 
damage in the community-dwelling elderly Chinese: the Northern Shanghai Study. Clin Interv 
Aging. 2017;12:1297-308. 
VV-CLIN-0607739 1.0


Amended Clinical Trial Protocol 01 
GZ/SAR402671-LTS15823 - venglustat 
16-Mar-2021 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
Page 102 
13. Horio M, Imai E, Yasuda Y, Watanabe T, Matsuo S. Modification of the CKD epidemiology 
collaboration (CKD-EPI) equation for Japanese: accuracy and use for population estimates. 
Am J Kidney Dis. 2010;56(1):32-8. 
14. Pickering TG, Hall JE, Appel LJ, Falkner BE, Graves J, Hill MN, et al. Recommendations for 
blood pressure measurement in humans and experimental animals: part 1: blood pressure 
measurements in humans: a statement for professionals from the Subcommittee of 
Professional and Public Education of the American Heart Association Council on High Blood 
Pressure Research. Circulation. 2005;111(5):697-716. 
15. Cleeland CS. The brief pain inventory: User guide. 2009. 
16. Mendoza TR, Wang XS, Cleeland CS, Morrissey M, Johnson BA, Wendt JK, et al. The rapid 
assessment of fatigue severity in cancer patients: use of the Brief Fatigue Inventory. Cancer. 
1999;85(5):1186-96. 
 
VV-CLIN-0607739 1.0


Signature Page for VV-CLIN-0607739 v1.0
lts15823-16-1-1-amended-protocol01
Approve & eSign
Approve & eSign
VV-CLIN-0607739 1.0

SAP_001.pdf: 


Statistical Analysis Plan  
22-Jun-2021 
GZ402671-LTS15823 - venglustat 
Version number: 1 
Property of the Sanofi group - strictly confidential 
Page 2 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................................... 1 
TABLE OF CONTENTS .................................................................................................................................. 2 
LIST OF TABLES ........................................................................................................................................... 4 
VERSION HISTORY ....................................................................................................................................... 5 
1 
INTRODUCTION .............................................................................................................................. 6 
1.1 
STUDY DESIGN .............................................................................................................................. 6 
1.2 
OBJECTIVE AND ENDPOINTS ...................................................................................................... 6 
1.2.1 
Estimands ........................................................................................................................................ 8 
2 
SAMPLE SIZE DETERMINATION .................................................................................................. 8 
3 
ANALYSIS POPULATIONS ............................................................................................................ 9 
4 
STATISTICAL ANALYSES ........................................................................................................... 10 
4.1 
GENERAL CONSIDERATIONS .................................................................................................... 10 
4.2 
PARTICIPANT DISPOSITIONS ..................................................................................................... 10 
4.3 
PRIMARY ENDPOINT(S) ANALYSIS ............................................................................................ 11 
4.3.1 
Definition of endpoint(s) ................................................................................................................. 11 
4.3.2 
Main analytical approach ............................................................................................................... 11 
4.3.3 
Sensitivity analysis ......................................................................................................................... 11 
4.3.4 
Supplementary analyses ................................................................................................................ 11 
4.3.5 
Subgroup analyses ........................................................................................................................ 11 
4.4 
SECONDARY ENDPOINT(S) ANALYSIS ..................................................................................... 12 
4.4.1 
Key/Confirmatory secondary endpoint(s) ...................................................................................... 12 
4.4.1.1 
Definition of endpoint(s) ................................................................................................................. 12 
4.4.1.2 
Main analytical approach ............................................................................................................... 12 
4.4.2 
Supportive secondary endpoint(s) ................................................................................................. 12 
4.5 
TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS .............................................................. 12 
4.5.1 
Definition of endpoint(s) ................................................................................................................. 12 
4.5.2 
Main analytical approach ............................................................................................................... 12 
4.6 
MULTIPLICITY ISSUES ................................................................................................................ 12 
VV-CLIN-0614287 1.0


Statistical Analysis Plan  
22-Jun-2021 
GZ402671-LTS15823 - venglustat 
Version number: 1 
Property of the Sanofi group - strictly confidential 
Page 3 
4.7 
SAFETY ANALYSES ..................................................................................................................... 12 
4.7.1 
Extent of exposure ......................................................................................................................... 12 
4.7.2 
Adverse events .............................................................................................................................. 13 
4.7.3 
Additional safety assessments ....................................................................................................... 15 
4.7.3.1 
Laboratory variables, vital signs and electrocardiograms (ECGs) ................................................. 15 
4.7.3.2 
Neurological examination ............................................................................................................... 15 
4.7.3.3 
Ophtalomological examination ....................................................................................................... 15 
4.7.3.4 
Depression (BDI_II) examination ................................................................................................... 16 
4.8 
OTHER ANALYSES....................................................................................................................... 16 
4.8.1 
Pharmacodynamic analyses .......................................................................................................... 16 
4.8.2 
Patient reported outcomes analyses.............................................................................................. 16 
4.8.3 
Biomarker analyses........................................................................................................................ 16 
4.9 
INTERIM ANALYSES .................................................................................................................... 16 
5 
SUPPORTING DOCUMENTATION .............................................................................................. 17 
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS ..................................................................................... 17 
5.2 
APPENDIX 2 CHANGES TO PROTOCOL-PLANNED ANALYSES ............................................. 17 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS .................................................................................................. 17 
5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS ........................................................................ 18 
6 
REFERENCES ............................................................................................................................... 20 
 
VV-CLIN-0614287 1.0


Statistical Analysis Plan  
22-Jun-2021 
GZ402671-LTS15823 - venglustat 
Version number: 1 
Property of the Sanofi group - strictly confidential 
Page 4 
LIST OF TABLES  
Table 1 - Major changes in statistical analysis plan ........................................................................................ 5 
Table 2 - Objectives and endpoints ................................................................................................................. 6 
Table 3 - Populations for analyses .................................................................................................................. 9 
Table 4 - Sorting of AE tables ....................................................................................................................... 14 
Table 5 - Analyses of adverse events ........................................................................................................... 14 
Table 6 - Selections for AESIs and other AEs of interest .............................................................................. 15 
Table 7 - Major statistical changes in protocol amendment(s) ...................................................................... 17 
Table 8 - eGFR values example .................................................................................................................... 18 
 
 
VV-CLIN-0614287 1.0


Statistical Analysis Plan  
22-Jun-2021 
GZ402671-LTS15823 - venglustat 
Version number: 1 
Property of the Sanofi group - strictly confidential 
Page 5 
VERSION HISTORY  
This statistical analysis plan (SAP) for study LTS15823 is based on the protocol amendment 1 
dated 16-Mar-2021. This section summarizes the major changes to the statistical analysis features 
in the SAP. 
This SAP is approved before the Stage 1 database lock of the parent study EFC15392 and before 
LTS15823 database lock.  
The first participant was enrolled on 09-Feb-2021. 
Table 1 - Major changes in statistical analysis plan  
SAP 
Version 
Approval Date 
Changes 
Rationale 
1 
22-Jun-2021 
All analyses of primary, secondary and tertiary efficacy 
endpoints are removed (Section 1.2, Section 4.3, 
Section 4.4, Section 4.5). 
Safety analyses is restricted to the summaries of treatment 
emergent adverse events in the long-term safety population 
only. Any other analyses are not done (Section 4.7.2, 
Section 4.7.3, Section 4.8) 
Analysis populations are limited to screened, enrolled and 
safety population (see Section 3). All analyses will be 
presented on a single overall all participants group (see 
Section 4.1) 
Following decision to 
discontinue 
EFC15392 and 
LTS15823 studies 
based on EFC15392 
futility analysis 
VV-CLIN-0614287 1.0


Statistical Analysis Plan  
22-Jun-2021 
GZ402671-LTS15823 - venglustat 
Version number: 1 
Property of the Sanofi group - strictly confidential 
Page 6 
1 
INTRODUCTION  
1.1 
STUDY DESIGN  
This is international, multicenter, open-label extension study to characterize the long-term 
efficacy and safety of early versus delayed treatment with venglustat (GZ/SAR402671) in patients 
at risk of rapidly progressive autosomal dominant polycystic kidney disease (ADPKD). All 
participants will be treated with venglustat 15 mg once daily for up to 24 months. 
After completion of 24 month of treatment in the parent study EFC15392, participants may be 
enrolled immediately in the LTS15823. Participants who cannot be included in the extension 
study at the time of Visit 12 of the EFC15392 study will have a separate Screening visit (Visit 0) 
performed and must be enrolled in the LTS15823 study within 2 months of the last dose of IMP 
(Visit 12 [Month 24]) administered in the EFC15392 study. This 2-month window can be further 
extended up to 6 months following review and approval by the Sponsor. 
After a screening phase, when applicable, of up to 2 weeks, participants will be centrally enrolled 
via Interactive Response Technology (IRT) and treated with open label venglustat 15 mg for 
2 years. A maximum of 640 participants who completed the EFC15392 study will be enrolled in 
LTS15823. 
Based on the EFC15392 futility analysis and the sponsor decision to discontinue the EFC15392 
and LTS15823 studies, the LTS15823 study analysis will be conducted after the early study 
termination. 
1.2 
OBJECTIVE AND ENDPOINTS  
The Table 2 provides the objectives and endpoints as planned in protocol. Considering the 
decision to discontinue the study after enrollment of only 24 patients, statistical analyses of the 
study are revised and only demographic, baseline characteristics and adverse events will be 
summarized overall. 
Table 2 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
• 
To determine the effect of early versus delayed 
treatment with venglustat on the total kidney 
volume (TKV) in participants at risk of rapidly 
progressive ADPKD. 
• 
Percent change in TKV based on magnetic resonance 
imaging (MRI) from the EFC15392 study baseline to 
24 months of open-label extension study, in 
early-treated and delayed-treated participants. 
Secondary 
• 
To determine the effect of early versus delayed 
treatment with venglustat on the renal function 
(estimated glomerular filtration rate [eGFR]). 
• 
Change in eGFR (Chronic Kidney Disease 
Epidemiology Collaboration [CKD-EPI] equation) from 
the EFC15392 study baseline to 24 months of 
open-label extension study, in early-treated and 
delayed-treated participants. 
VV-CLIN-0614287 1.0


Statistical Analysis Plan  
22-Jun-2021 
GZ402671-LTS15823 - venglustat 
Version number: 1 
Property of the Sanofi group - strictly confidential 
Page 7 
Objectives 
Endpoints 
• 
To characterize the safety profile of venglustat. 
• 
Safety in terms of treatment-emergent adverse events 
(TEAEs), adverse events (AEs), serious adverse 
events (SAEs), laboratory parameters, vital signs, 
electrocardiogram and findings from physical 
examination will be assessed through the study and 
will be reported in the electronic case report form 
(eCRF). 
• 
To evaluate the effect of venglustat on the lens 
by ophthalmological examination. 
• 
Change from EFC15392 study baseline in the lens 
clarity by ophthalmological examination during the 
open-label extension treatment-emergent period. 
• 
To evaluate the effect of venglustat on mood 
using Beck Depression Inventory-II (BDI-II). 
• 
Change from EFC15392 study baseline in BDI-II score 
during the open-label extension treatment-emergent 
period. 
Tertiary 
• 
To explore the impact of venglustat on total liver 
volume (TLV) (in participants with height 
adjusted TLV [htTLV] >2 L/m). 
• 
Change in TLV based on MRI (in participants with 
htTLV >2 L/m) from EFC15392 study baseline to 
24 months of the open-label extension study. 
• 
To explore the effect of venglustat on systolic 
blood pressure (SBP) and diastolic blood 
pressure (DBP). 
• 
Change from EFC15392 study baseline during the 
open-label extension treatment-emergent period in: 
- 
SBP, 
- 
DBP. 
• 
To explore the effect of venglustat on type, 
frequency and dosage of analgesic/over the 
counter (OTC) pain medication administration. 
• 
Change from EFC15392 study baseline in type, 
frequency, and dosage of analgesic/OTC pain 
medication administration during the open-label 
extension study. 
• 
To explore the effect of venglustat on time to 
confirmed 30% and 40% reduction in eGFR. 
• 
Time to confirmed 30% reduction in eGFR since 
randomization in the EFC15392 study, in early-treated 
compared to late-treated participants during the 
combined EFC15392 and LTS15823 period. 
• 
Time to confirmed 40% reduction in eGFR since 
randomization in the EFC15392 study, in early-treated 
compared to late-treated participants during the 
combined EFC15392 and LTS15823 period. 
• 
To explore the effect of venglustat on biomarkers 
associated with ADPKD (eg, Fibroblast Growth 
Factor 23 [FGF23], asymmetric dimethylarginine 
[ADMA]) (not applicable for Chinese 
participants). 
• 
Change in the levels of biomarkers associated with 
ADPKD (eg, FGF23, ADMA) from EFC15392 study 
baseline to 24 months of open-label extension study 
(not applicable for Chinese participants). 
• 
To explore the pharmacodynamic (PD) effects of 
venglustat by measuring downstream 
metabolites of glucosylceramide synthase (GCS) 
in plasma (not applicable for Chinese 
participants). 
• 
Change in the levels of downstream metabolites of 
GCS in plasma from EFC15392 study baseline to 
24 months of open-label extension study (not 
applicable for Chinese participants). 
• 
To explore the effect of venglustat on pain (brief 
pain inventory short form [BPI-SF]), fatigue (Brief 
Fatigue Inventory [BFI]), and the EuroQoL 5-
dimension 5 level (EQ-5D-5L) score. 
• 
Change from EFC15392 study baseline to 24 months 
of open-label extension study in: 
- 
BPI-SF, 
- 
BFI, 
- 
EQ-5D-5L. 
VV-CLIN-0614287 1.0


Statistical Analysis Plan  
22-Jun-2021 
GZ402671-LTS15823 - venglustat 
Version number: 1 
Property of the Sanofi group - strictly confidential 
Page 8 
1.2.1 Estimands  
Not applicable. 
2 
SAMPLE SIZE DETERMINATION  
Since this study is the extension of the EFC15392 study, no formal sample size calculation was 
performed. A maximum of 640 participants who completed the EFC15392 study will be enrolled, 
including: 
• Early venglustat: A maximum of 280 participants who were randomized to venglustat 
15 mg in the EFC15392 study. 
• Early venglustat: A maximum of 80 participants who were randomized to venglustat 8 mg 
in the EFC15392 study. 
• Delayed venglustat: A maximum of 280 participants who were randomized to placebo in 
the EFC15392 study. 
Nevertheless, based on the following protocol assumptions: 
• TKV growth rate in EFC15392: 
- 
in placebo group of 0.02764 on log10 scale (6.6%/year) 
- 
in venglustat group, expecting a 50% reduction of the TKV growth rate, 
ie, 0.01404/year on log10 scale (3.3%/year) 
• TKV growth rate in LTS15823: 
- 
in Early venglustat group, of 0.01404 on log10 scale (3.3%/year) 
- 
in Delayed venglustat group: 0.01404 on log10 scale (3.3%/year) 
• a standard deviation for the residual error of TKV (on the log10 scale) of 0.02566 and 
• a standard deviation for the random effect of slope of 0.01477 
And assuming 10% of dropout rate in EFC15392, 20% of participants having completed 
EFC15392 will not participate to LTS15823 (or will be enrolled with more than 3 months delay), 
then 25% additional will dropout during LTS15823 (due to venglustat becoming commercially 
available in some countries), the power to detect a difference in TKV at Month 24 between “Early 
venglustat” and “Delayed venglustat” is approximately 95%.  
In the case the venglustat 8 mg will not show similar effect compared to venglustat 15 mg in 
Stage 1 of the EFC15392 study (RR8 <2/3 RR15), then participants from venglustat 8mg will be 
excluded from the efficacy analyses, in that case the LTS15823 has 92% power to detect a 
difference in TKV at Month 24 between “Early venglustat” and “Delayed venglustat”. 
VV-CLIN-0614287 1.0


Statistical Analysis Plan  
22-Jun-2021 
GZ402671-LTS15823 - venglustat 
Version number: 1 
Property of the Sanofi group - strictly confidential 
Page 9 
3 
ANALYSIS POPULATIONS  
The following populations for analyses are defined:  
Table 3 - Populations for analyses  
Population 
Description 
Screened 
All participants who sign the LTS15823 study ICF. 
Enrolled 
All participants from screened population who have been allocated to an LTS15823 
intervention kit by interactive response technology (IRT) regardless of whether the 
intervention was received or not. 
Long-term extension safety 
All participants who take at least 1 dose of study intervention in the LTS15823 
study. 
Enrolled participants for whom it is unclear whether they took the study intervention will be 
considered as exposed and will be included in the safety population. 
VV-CLIN-0614287 1.0


Statistical Analysis Plan  
22-Jun-2021 
GZ402671-LTS15823 - venglustat 
Version number: 1 
Property of the Sanofi group - strictly confidential 
Page 10 
4 
STATISTICAL ANALYSES  
4.1 
GENERAL CONSIDERATIONS  
Continuous data will be summarized using the number of observations available, mean, standard 
deviation (SD), median, [Q1, Q3] minimum, and maximum. Categorical and ordinal data will be 
summarized using the count and percentage of participants. 
All analyses will be presented on a single all participants group.  
Observation period of the open-label extension study 
The observation period will be divided into 4 segments:  
• The pre-treatment period is defined as the period up to first investigational medicinal 
product (IMP) administration in the LTS15823 study. 
• The treatment-emergent (TE) period is defined as the period from the first IMP 
administration in the LTS15823 study to the last IMP administration in the LTS15823 
study +30 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 period from the end of the on-
treatment period to the end of the treatment-emergent period.  
• The post-treatment period is defined as the period from the end of the treatment-
emergent period. 
The on-study period is defined as the time from enrollment until the end of the study defined as 
the last scheduled visit for those who completed the study and the end-of-study date collected on 
electronic case report form (e-CRF) page “Completion of End of Study” for those who did not 
complete the study. If death is the end-of-study reason, date of death will be used. 
4.2 
PARTICIPANT DISPOSITIONS  
The number (%) of participants included in each of the analysis populations listed in Table 3 will 
be summarized. 
Screen failures are defined as participants who consent to participate in the LTS15823 study but 
are not subsequently enrolled. The number (%) of screen failures and reasons for screen failures 
will be provided in the screened population. 
The number (%) of participants in the following categories will be provided:  
• Enrolled participants. 
• Enrolled but not exposed participants.  
VV-CLIN-0614287 1.0


Statistical Analysis Plan  
22-Jun-2021 
GZ402671-LTS15823 - venglustat 
Version number: 1 
Property of the Sanofi group - strictly confidential 
Page 11 
• Enrolled and exposed participants. 
• Participants who did not complete the study treatment period as per protocol and main 
reason for permanent intervention discontinuation.  
• Participants who did not complete the study period as per protocol and main reason for 
study discontinuation. 
Reasons for permanent study intervention and study discontinuation “adverse event” and “other 
reasons” will be split as related versus not related to Covid-19, if applicable. 
The number (%) of exposed and not enrolled participants will also be summarized.  
In addition, the number (%) of participants screened, screened-failed, enrolled, with permanent 
intervention discontinuation and with early study discontinuation will be provided by country and 
site. 
Protocol deviations 
Critical and major protocol deviations (automatic or manual) during the long-term extension 
open-label period will be summarized in the enrolled population, as well as displayed separately 
as related versus not related to Covid-19 if applicable. 
4.3 
PRIMARY ENDPOINT(S) ANALYSIS  
Not done. 
4.3.1 Definition of endpoint(s)  
The primary endpoint of percent change in TKV based on MRI from the EFC15392 study 
baseline to 24 months of open-label extension study will not be analyzed. 
4.3.2 Main analytical approach  
Not applicable. 
4.3.3 Sensitivity analysis  
Not applicable. 
4.3.4 Supplementary analyses  
Not applicable. 
4.3.5 Subgroup analyses  
Not applicable. 
VV-CLIN-0614287 1.0


Statistical Analysis Plan  
22-Jun-2021 
GZ402671-LTS15823 - venglustat 
Version number: 1 
Property of the Sanofi group - strictly confidential 
Page 12 
4.4 
SECONDARY ENDPOINT(S) ANALYSIS  
4.4.1 Key/Confirmatory secondary endpoint(s)  
The secondary endpoint of change in eGFR from the EFC15392 study baseline to 24 months of 
open-label extension study will not be analyzed.  
Other secondary endpoints analyses are defined in Section 4.7.2 (AE, SAE).  
4.4.1.1 Definition of endpoint(s)  
4.4.1.2 Main analytical approach  
Not applicable. 
4.4.2 Supportive secondary endpoint(s)  
Not applicable. 
4.5 
TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS  
4.5.1 Definition of endpoint(s)  
Not applicable. 
4.5.2 Main analytical approach  
Not applicable. 
4.6 
MULTIPLICITY ISSUES  
Not applicable. 
4.7 
SAFETY ANALYSES  
All safety analyses will be essentially descriptive, and no testing is planned. 
4.7.1 Extent of exposure  
The extent of IMP exposure will be assessed by the duration of IMP exposure and summarized 
within the long-term safety population.  
VV-CLIN-0614287 1.0


Statistical Analysis Plan  
22-Jun-2021 
GZ402671-LTS15823 - venglustat 
Version number: 1 
Property of the Sanofi group - strictly confidential 
Page 13 
Duration of IMP exposure 
Duration of LTS15823 IMP exposure is defined as last LTS15823 IMP administration date – first 
LTS15823 IMP administration date +1 day, regardless of unplanned intermittent discontinuations.  
If the date of the last dose of IMP is missing, the duration of IMP will be left as missing. 
Duration of IMP exposure will be summarized quantitatively and categorically:  
• ≥1 day 
• ≥1 Month 
• ≥3 months 
• ≥6 months 
Additionally, the cumulative duration of treatment exposure (expressed in participant-years) will 
be provided. 
4.7.2 Adverse events  
General common rules for adverse events 
All adverse events (AEs) 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 Medical Dictionary for Regulatory Activities (MedDRA) version currently in 
effect at Sanofi at the time of database lock. 
The AEs will be analyzed in the following 3 categories: 
• Pre-treatment AEs: AEs that developed, worsened or became serious during the pre-
treatment period. 
• Treatment-emergent adverse events (TEAE)s: AEs that developed, worsened or became 
serious during the treatment-emergent period. 
• Post-treatment AEs: AEs that developed, worsened or became serious during the post-
treatment period.  
Similarly, the deaths will be analyzed in the pre-treatment, treatment-emergent and post-treatment 
periods.  
The AE reporting will be on TEAEs.  
An AE with incomplete or missing date/time of onset (occurrence, worsening, or becoming 
serious) will be classified as a TEAE unless there is definitive information to determine it is a pre-
treatment or a post-treatment AE. 
If the assessment of the relationship to IMP is missing for an AE, this AE will be assumed as 
related to IMP. If the severity is missing for 1 of the treatment-emergent occurrences of an AE, 
the severity will be imputed with the maximal severity of the other occurrences. If the severity is 
missing for all the occurrences, the severity will be left as missing. 
VV-CLIN-0614287 1.0


Statistical Analysis Plan  
22-Jun-2021 
GZ402671-LTS15823 - venglustat 
Version number: 1 
Property of the Sanofi group - strictly confidential 
Page 14 
Multiple occurrences of the same event in the same participant will be counted only once in the 
tables within a treatment phase.  
The AE tables will be sorted as indicated in Table 4.  
Table 4 - Sorting of AE tables  
AE presentation 
Sorting rules 
SOC, HLGT, HLT and PT 
By the internationally agreed SOC order and by alphabetic order of HLGTs, HLTs and PTs.  
SOC and PT 
By the internationally agreed SOC order and decreasing frequency of PTsa, b 
[SMQ/CMQ] and PT 
By decreasing frequency of [SMQs/CMQs] and PTsa 
a Sorting will be based on the overall incidence 
b The table of all TEAEs presented by SOC and PT will define the presentation order for all other tables (eg, treatment-emergent SAE) 
presented by SOC and PT, unless otherwise specified.  
Analysis of all adverse events 
The overview of TEAE with the details below will be generated: 
• Any TEAE  
• Any treatment emergent SAE 
• TEAE leading to death  
• Any TEAE leading to permanent intervention discontinuation 
• Any treatment emergent AESI  
The AE summaries of Table 5 will be generated with number (%) of participants experiencing at 
least one event.  
Table 5 - Analyses of adverse events  
Type of AE 
MedDRA levels 
All TEAE 
Primary SOC, HGLT, HLT and PT 
 
Primary SOC and PT 
TEAE related to IMP as per Investigator’s judgment 
Primary SOC and PT 
TEAE by maximal intensity 
Primary SOC and PT  
Treatment emergent SAE 
Primary SOC and PT 
TEAE leading to permanent intervention discontinuation 
Primary SOC and PT 
TEAE leading to death (death as an outcome of the AE as reported 
by the Investigator in the AE page) 
Primary SOC and PT 
Treatment emergent AESI 
Primary SOC and PT 
Treatment emergent COVID-19 related AE 
Primary SOC and PT 
 
VV-CLIN-0614287 1.0


Statistical Analysis Plan  
22-Jun-2021 
GZ402671-LTS15823 - venglustat 
Version number: 1 
Property of the Sanofi group - strictly confidential 
Page 15 
Analysis of deaths 
In addition to the analyses of deaths included in Table 4 the number (%) of participants in the 
following categories will be provided: 
• Deaths during the treatment-emergent and post-treatment periods by reason for death  
• Deaths in non-enrolled participants or enrolled but not treated participants 
Analysis of adverse events of special interest (AESIs) and other AEs of interest 
Adverse events of special interest (AESIs) and other AEs of interest will be selected for analyses 
as indicated in Table 6. Number (%) of participants experiencing at least one event will be 
provided for each event of interest. Tables will be sorted as indicated in Table 4.  
Table 6 - Selections for AESIs and other AEs of interest  
AESIsand other AEs of interest] 
Selection 
Pregnancy of a female subject or female 
partner of a male subject 
e-CRF specific pregnancy page 
Symptomatic overdose (serious or non-
serious) with IMP 
e-CRF specific symptomatic overdose page 
Increase in alanine transaminase (ALT) 
e-CRF specific AESI tick box on the AE page 
New or worsening lenticular opacities and 
cataracts 
e-CRF specific AESI tick box on the AE page 
AE related to COVID-19 illness 
SMQ COVID19 
 
4.7.3 Additional safety assessments  
The analyses of additional safety assessments will not be done. 
4.7.3.1 Laboratory variables, vital signs and electrocardiograms (ECGs)  
Not applicable. 
4.7.3.2 Neurological examination  
Not applicable. 
4.7.3.3 Ophtalomological examination  
Not applicable. 
VV-CLIN-0614287 1.0


Statistical Analysis Plan  
22-Jun-2021 
GZ402671-LTS15823 - venglustat 
Version number: 1 
Property of the Sanofi group - strictly confidential 
Page 16 
4.7.3.4 Depression (BDI_II) examination  
Not applicable. 
4.8 
OTHER ANALYSES  
The analysis of the other parameters will not be done. 
4.8.1 Pharmacodynamic analyses  
Not applicable. 
4.8.2 Patient reported outcomes analyses  
Not applicable. 
4.8.3 Biomarker analyses  
Not applicable. 
4.9 
INTERIM ANALYSES  
No interim analysis is planned. 
VV-CLIN-0614287 1.0


Statistical Analysis Plan  
22-Jun-2021 
GZ402671-LTS15823 - venglustat 
Version number: 1 
Property of the Sanofi group - strictly confidential 
Page 17 
5 
SUPPORTING DOCUMENTATION  
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS  
 
AESIs: 
adverse events of special interest 
ALT: 
Alanine transaminase 
HGLT: 
high level group term 
IMP: 
Investigational medicinal product 
MedDRA: 
medicinal dictionary for regulatory activities 
PT: 
preferred term 
SAP: 
statistical analysis plan 
SD: 
standard deviation 
SOC: 
system organ class 
TEAE: 
treatment-emergent adverse event 
 
5.2 
APPENDIX 2 CHANGES TO PROTOCOL-PLANNED ANALYSES  
This section summarizes major statistical changes in the protocol amendment(s). 
Table 7 - Major statistical changes in protocol amendment(s)  
Amendment 
Number 
Approval 
Date 
Changes 
Rationale 
1 
16 Mar 2021 
All participants will be treated for the 
duration of 24 months. The protocol 
instruction “or until venglustat is 
commercially available for patients, 
whichever comes first” is not applicable 
to the countries listed 
To comply with the request raised during the 
EU VHP review phase, study participants in 
Belgium, Czech Republic, Denmark, 
Germany, Italy, Poland, Portugal, Romania, 
and Spain will receive venglustat (15 mg 
once daily) for the duration of 24 months 
 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS  
Demographics, baseline characteristics 
The following demographics and baseline characteristics and disease characteristics at baseline 
will be summarized using descriptive statistics in the enrolled population. 
Demographic and baseline characteristics  
• Gender (Male, Female) 
• Age in years (quantitative and categorical variable: <40, and ≥40 years) at the EFC15392 
baseline as well as the LTS15823 baseline 
VV-CLIN-0614287 1.0


Statistical Analysis Plan  
22-Jun-2021 
GZ402671-LTS15823 - venglustat 
Version number: 1 
Property of the Sanofi group - strictly confidential 
Page 18 
• Race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or other Pacific Island, other) 
• Ethnicity (Hispanic, non-Hispanic) 
• Weight in kilograms (quantitative and categorical variable: <50, 50 to <100, ≥100) at the 
EFC15392 as well as the LTS15823 baseline  
Disease characteristics 
eGFR at EFC15392 screening, EFC15392 baseline and LTS15823 baseline (quantitative variable 
and qualitative variable: <30,30 to <45, 45 to <60, 60 to <75, 75 to <90, >=90) (see Section 5.4). 
5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS  
General conventions 
The following formulas will be used for computation of parameters. 
Demographic formulas 
• BMI = 
height(m)
weight(kg)
2  
eGFR at EFC15392 screening 
The screening eGFR is defined as the eGFR value that was selected to enroll the participant in the 
study: 
• If eGFR at EFC15392 Visit 1 was between 45 and 89.9 mL/min/1.73 m² (or between 
30 and 89.9 mL/min/1.73 m² for Stage 2), then the value at Visit 1 is considered as the 
screening value 
• Else, if an additional eGFR measurement was done between EFC15392 Visit 1 and 
EFC15392 Visit 2, then this additional value is considered as the screening value 
• Else, the eGFR at EFC15392 Visit 2 is considered as the screening value 
Table 8 - eGFR values example  
Subject 
EFC15392 V1 
EFC15392 Additional 
(between V1 and V2) 
EFC15392 V2 
1 
87 
ND 
91 
2 
92 
ND 
85 
3 
95 
86 
93 
4 
92 
95 
88 
VV-CLIN-0614287 1.0


Statistical Analysis Plan  
22-Jun-2021 
GZ402671-LTS15823 - venglustat 
Version number: 1 
Property of the Sanofi group - strictly confidential 
Page 19 
eGFR at EFC15392 baseline 
EFC15392 Baseline eGFR is defined for each participant as the average of eGFR values assessed 
prior or equal to 1st IMP in the EFC15392 study or prior or equal to randomization for randomized 
and not exposed participants. 
eGFR at LTS15823 baseline 
LTS15823 Baseline eGFR is defined: 
• as the eGFR assessment performed at the time of EFC15392 V12 for each participant 
enrolled at the time of the EFC15392 V12. 
• else, as the average of eGFR values assessed between LTS15823 screening visit up to 1st 
IMP in the LTS15823 (including) or prior or equal to enrollment for enrolled and not 
exposed participants. 
VV-CLIN-0614287 1.0


Statistical Analysis Plan  
22-Jun-2021 
GZ402671-LTS15823 - venglustat 
Version number: 1 
Property of the Sanofi group - strictly confidential 
Page 20 
6 
REFERENCES  
Not applicable. 
VV-CLIN-0614287 1.0


Signature Page for VV-CLIN-0614287 v1.0
lts15823-16-1-9-sap
Approve & eSign
Approve & eSign
VV-CLIN-0614287 1.0