A Multicenter, Multinational, Randomized, Double-blind, Placebo-controlled Study to Assess the Efficacy, Pharmacodynamics, Pharmacokinetics, Safety, and Tolerability 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
Phase: PHASE3
Conditions: Tay-Sachs Disease, Sandhoff Disease
Sponsor: Genzyme, a Sanofi Company

 
 
 
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affiliated companies). The use of such confidential information must be restricted to the recipient for the agreed purpose and must not be 
disclosed, published or otherwise communicated to any unauthorized persons, for any reason, in any form whatsoever without the prior written 
consent of Sanofi (or the concerned affiliated company); ‘affiliated company’ means any corporation, partnership or other entity which at the date 
of communication or afterwards (i) controls directly or indirectly Sanofi, (ii) is directly or indirectly controlled by Sanofi, with ‘control’ meaning 
direct or indirect ownership of more than 50% of the capital stock or the voting rights in such corporation, partnership or other entity 
According to template: RDSD-002540 VERSION N° 2.0 (11-OCT-2018) based on TransCelerate CPT version 5 
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AMENDED CLINICAL TRIAL PROTOCOL 06  
Protocol title: 
A multicenter, multinational, randomized, double-blind, placebo-
controlled study to assess the efficacy, pharmacodynamics, 
pharmacokinetics, safety, and tolerability 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 
Protocol number: 
EFC15299 
Amendment number: 
06 
Compound number 
(INN/Trademark): 
GZ402671 
Venglustat 
Study phase: 
Phase 3 
Short title: 
A multinational, randomized, double-blind, placebo-controlled 
study to assess the efficacy, pharmacodynamics, 
pharmacokinetics, and safety of venglustat in late-onset GM2 
(AMETHIST) 
Sponsor name: 
Genzyme Corporation 
450 Water Street 
Cambridge 
MA 02141  
USA 
Legal registered 
address: 
  
Monitoring Team’s 
Representative Name 
and Contact Information 
  
Regulatory agency identifier number(s): 
IND: 
136347 
EudraCT: 
2019-002375-34 
NCT: 
NCT04221451 
WHO: 
U1111-1197-7905 
Other: 
Not applicable 
 
Approval Date: 
16-Aug-2023 
Total number of pages: 135 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY  
 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 06 
Amended Clinical Trial Protocol 05 
All 
All 
16 August 2023, version 1 (electronic 8.0) 
11 November 2022, version 1 (electronic 6.0) 
Amended Clinical Trial Protocol 04 
All 
20 April 2022, version 1 (electronic 5.0) 
Amended Clinical Trial Protocol 03 
All 
08 March 2021, version 2 (electronic 4.0) 
Amended Clinical Trial Protocol 02 
All 
09 March 2020, version 1 (electronic 2.0) 
Amended Clinical Trial Protocol 01 
All 
05 November 2019, version 1 (electronic 1.0) 
Original Protocol 
 
06 August 2019, version 2 (electronic 2.0) 
Amended protocol 06 (16 August 2023) 
This amended protocol 06 (Amendment 06) 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 main reason for this amendment is to update the statistical considerations section, mainly to 
account for potential outliers in the primary and secondary analyses, and add a secondary 
endpoint per FDA recommendation. 
Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis, 
Objectives and 
endpoints 
 
Section 3, Table 3 
Objectives and 
endpoints 
For the primary population, add a secondary 
endpoint of absolute change in CSF GM2 
biomarker from baseline to Week 104 
For the secondary population, add a secondary 
endpoint to assess the acceptability and palatability 
of the venglustat tablet 
As per FDA recommendation related to the 
addition of this secondary endpoint in the 
primary population  
The addition of this secondary endpoint for 
the secondary population is to align with the 
PIP commitment to document as 
an endpoint. The assessments have been 
included in this study.  
Section 1.1 Synopsis, 
Statistical 
considerations 
Primary analysis of 9-HPT with Bayesian analysis 
using noninformative prior is replaced by a 
Frequentist analysis 
 
Bayesian analysis using non-informative 
prior is equivalent to a Frequentist analysis. 
Bayesian analysis with informative prior 
remains a secondary analysis of the 9-HPT. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
 
For primary and secondary endpoints, use of robust 
ANCOVA in case of outliers. 
 
 
Include in the analysis of secondary endpoints the 
new secondary endpoint of absolute change in CSF 
GM2 biomarker 
 
Simulations showed that the power of the 
linear mixed effect model would be severely 
impacted if a small proportion of participants 
have extreme slope 
 
Inclusion of new secondary endpoint as per 
FDA recommendation 
Section 1.3 Schedule of 
Activities, Visit at 
clinical site 
Clarify that, for United States participants, Visits 3, 
8, 10, and 12 can be provided remotely under a 
decentralized clinical trial (DCT) model 
 
Removed the specification that the IMP can be 
dispensed and sent to participants at the visits 
provided under DCT model via DTP shipment 
except if the local regulatory authority requires the 
IMP dispensed at site. 
Clarification of remote visits option for United 
States participants 
 
 
Editorial correction 
Section 1.3 Schedule of 
Activities, Venglustat or 
placebo 
Added note to clarify the first dose in the open-label 
extension phase 
Clarification 
Section 1.3 Schedule of 
Activities, Dispense IMP 
Replaced: "In addition to the IMP dispensing at 
these site visits, the IMP will be dispensed and sent 
to participants at W39 and W65 via DTP shipment.”  
 
With: “In addition to the IMP dispensing at these 
clinical site visits, IMP will be dispensed at remote 
site visits where appplicable via DTP shipment. At 
Visit 4.1 (W39) and Visit 5.1(W65), IMP will be 
dispensed and sent to participants via DTP 
shipment.” 
 
Clarification of IMP dispensation via DTP 
Section 1.3 Schedule of 
Activities, 
Dispense/check 
Participant Diary 
Changed title to: “Dispense/Check/Retrieve Patient 
Diary” 
Clarification to check diary at each visit 
Section 1.3 Schedule of 
Activities, 12-lead ECG 
Add in column Notes: “Please note that ECG is 
required in triplicate only at Visit 2” 
Clarification of EGC at Visit 2 
Section 1.3 Schedule of 
Activities, Urine 
biochemistry (including 
UPCR and UACR) 
Reduced the number of urine samples  
collected for protein:creatinine and  
albumin:creatinine ratios from 3 samples  
collected on successive days (2 days  
preceding a visit, plus the day of the visit) to  
single samples collected on the day of a  
visit. 
Venglustat study participants found the  
collection of second-void morning samples  
on 3 successive days to be burdensome.  
One first-void morning sample will  
therefore be collected which should also  
aid compliance. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Section 1.3 Schedule of 
Activities, 
ophthalmological 
examination  
 
A full ophthalmological examination will also be 
performed at Week 130, Week 156, and Week 182 
for participants aged ≥2 and <18 years 
Revised to include participants aged ≥2 and 
<18 years 
Section 1.3 Schedule of 
Activities, PK Plasma 
samples 
Clarify the PK sample ID for early withdrawal visit 
Clarification 
Section 2.3.1.1 
Potential risks specific 
for pediatric population 
 
Update potential risk for venglustat-mediated 
lenticular degeneration in pediatric population 
Clarification 
Section 2.3.1.1 
Potential risks specific 
for pediatric population 
 
 
Risk title updated: Potential male infertility due to 
exposure in childhood (<12 years of age) 
 
Deleted the wording audited draft results for 
JUV0046 study 
For alignment and clarification 
 
 
JUV0046 study results final report available  
Table 2 Risk mitigation 
strategy 
Potential risk of new or worsening lens opacity is 
updated to include children two to less than 18 
years old 
 
Risk title updated: Potential male infertility due to 
exposure in childhood (<12 years of age) 
 
Per FDA feedback 
 
 
 
For alignment and clarification 
 
Section 3, Table 3 
Objectives and 
endpoints 
Added in exploratory endpoints for primary 
population “Additional plasma and CSF 
biomarkers may include but are not limited to: 
lipidomics, glycoprotein nonmetastatic protein 
B (gpNMB), neurofilament” 
 
To clarify the exploratory biomarkers 
endpoints of primary population and align 
with Section 8.6 
Section 6.5.1.3, 
Medications with risk to 
cause cataract 
Revised text to specify that listed medications 
are prohibited for participants age <18 (rather 
than for participants age <12). 
Updated for consistency with safety 
information regarding cataract risks. 
Section 8.2.5 
Ophthalmological 
examination 
A full ophthalmological examination will be 
performed at Week 26, Week 52, and Week 78 for 
all participants and also at Week 130, Week 156, 
and Week 182 for participants aged ≥2 and <18 12 
years 
Revised to include participants aged ≥2 and 
<18 years 
Section 8.7 
acceptability and 
palatability  
Add this section that clarifies the acceptability and 
palatability assessments 
To align with the PIP commitment, which 
missed documenting acceptability and 
palatability of venglustat tablet as endpoints. 
The assessments have been included in this 
study 
Section 9.4.1 Efficacy 
analyses 
For primary and secondary endpoints in the primary 
population: primary analyses are updated to use a 
robust ANCOVA in case of outliers, with pre-
specified criteria. 
 
Simulations showed that the power of the 
linear mixed effect model would be severely 
impacted if a small proportion of participants 
have extreme slope. 
 
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Section # and 
Name 
Description of Change 
Brief Rationale 
Primary analysis of 9-HPT with Bayesian analysis 
using noninformative prior is replaced by a 
Frequentist analysis                                                     
 
 
Update of prior distribution of placebo slope, used 
as secondary analysis of the 9-HPT 
 
 
 
 
 
Addition of the analysis planned for the new 
secondary endpoint of absolute change in CSF 
GM2 biomarker from baseline to Week 104, similar 
to the analysis of the percent change in CSF GM2 
biomarker   
 
The procedure for handling multiplicity of tests for 
secondary endpoints using a hierarchical approach 
was replaced by the Hochberg procedure  
Bayesian analysis using non-informative 
prior is equivalent to a Frequentist analysis. 
Bayesian analysis with informative prior 
remains a secondary analysis of the 9-HPT. 
 
Prior distribution in the initial protocol was 
based on data collected from 2015 to 2018 
during the National Tay-Sachs and Allied 
Disease annual conference. Additional data 
were collected in 2019 and integrated in 
updated analysis. 
 
For consistency between analyses of 
the co-primary efficacy endpoint of percent 
change in CSF GM2 and secondary efficacy 
endpoint of absolute change in CSF GM2, 
similar methodology will be used 
 
To account for the new secondary efficacy 
endpoint that was added 
 
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TABLE OF CONTENTS  
AMENDED CLINICAL TRIAL PROTOCOL 06 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 6 
LIST OF TABLES ......................................................................................................................................... 11 
LIST OF FIGURES ........................................................................................................................................ 11 
1 
PROTOCOL SUMMARY ............................................................................................................... 12 
1.1 
SYNOPSIS ..................................................................................................................................... 12 
1.2 
SCHEMA ........................................................................................................................................ 19 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 20 
2 
INTRODUCTION ............................................................................................................................ 32 
2.1 
STUDY RATIONALE...................................................................................................................... 32 
2.2 
BACKGROUND ............................................................................................................................. 33 
2.2.1 
GM2 gangliosidosis (Tay-Sachs disease and Sandhoff disease) ................................................. 33 
2.2.2 
Venglustat ...................................................................................................................................... 33 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 35 
2.3.1 
Risk assessment ............................................................................................................................ 35 
2.3.1.1 
Potential risks specific for pediatric population .............................................................................. 35 
2.3.1.2 
Depression ..................................................................................................................................... 37 
2.3.1.3 
Syncope ......................................................................................................................................... 37 
2.3.1.4 
............................................................................................................................... 38 
2.3.1.5 
Transient increase in blood pressure ............................................................................................. 38 
2.3.1.6 
Embryo-fetal toxicity ....................................................................................................................... 39 
2.3.2 
Benefit assessment ........................................................................................................................ 41 
2.3.3 
Overall benefit: risk conclusion ...................................................................................................... 41 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 42 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 46 
4 
STUDY DESIGN ............................................................................................................................ 48 
4.1 
OVERALL DESIGN ........................................................................................................................ 48 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 49 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 49 
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4.4 
END OF STUDY DEFINITION ....................................................................................................... 50 
5 
STUDY POPULATION .................................................................................................................. 51 
5.1 
INCLUSION CRITERIA .................................................................................................................. 51 
5.2 
EXCLUSION CRITERIA  ............................................................................................................... 52 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 54 
5.3.1 
 Meals and dietary restrictions ....................................................................................................... 54 
5.4 
SCREEN FAILURES...................................................................................................................... 55 
6 
STUDY INTERVENTION ............................................................................................................... 56 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 56 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 57 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 57 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 59 
6.5 
CONCOMITANT THERAPY .......................................................................................................... 60 
6.5.1 
Prohibited concomitant medicine ................................................................................................... 60 
6.5.1.1 
.................................................................................................... 60 
6.5.1.2 
.......................................... 61 
6.5.1.3 
Medications with risk to cause cataract ......................................................................................... 61 
6.5.1.4 
Other medications .......................................................................................................................... 62 
6.5.2 
COVID-19 vaccination.................................................................................................................... 62 
6.6 
DOSE MODIFICATION .................................................................................................................. 62 
6.7 
INTERVENTION AFTER THE END OF THE STUDY ................................................................... 62 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 63 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  ..................................................................... 63 
7.1.1 
Definitive discontinuation ............................................................................................................... 63 
7.1.2 
Discontinuation criteria ................................................................................................................... 64 
7.1.2.1 
Rechallenge ................................................................................................................................... 65 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 65 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 66 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 67 
8.1 
EFFICACY ASSESSMENTS  ........................................................................................................ 67 
8.1.1 
9-hole peg test ............................................................................................................................... 67 
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8.1.2 
25-Foot walk test ............................................................................................................................ 68 
8.1.3 
Friedreich’s Ataxia Rating Scale (excluding the 9-HPT portion and the 25FWT) .......................... 68 
8.1.4 
........................................................................... 68 
8.1.5 
................................................................................. 68 
8.1.6 
......................................................... 69 
8.1.7 
................................................................................... 69 
8.1.8 
.............................................................................................. 69 
8.1.8.1 
 .................................................................................................................................. 69 
8.1.8.2 
 .............................................................................................. 70 
8.1.8.3 
 ........................................................ 71 
8.1.8.4 
 .................................................................................... 71 
8.1.9 
 ........................................................................................................... 72 
8.1.10 
................................................................................................................................ 72 
8.1.11 
Muscle weakness of triceps and quadriceps ................................................................................. 72 
8.1.12 
Regional or national emergency .................................................................................................... 73 
8.2 
SAFETY ASSESSMENTS  ............................................................................................................ 73 
8.2.1 
Physical examinations ................................................................................................................... 73 
8.2.2 
Neurological examination ............................................................................................................... 74 
8.2.3 
Vital signs ....................................................................................................................................... 74 
8.2.4 
Electrocardiograms ........................................................................................................................ 74 
8.2.5 
Ophthalmological examination ....................................................................................................... 74 
8.2.6 
Clinical safety laboratory assessments .......................................................................................... 75 
8.2.7 
.............................................................................. 76 
8.2.7.1
.................................................................... 76 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ........................................................... 77 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 77 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 78 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 78 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 78 
8.3.5 
Pregnancy ...................................................................................................................................... 79 
8.3.6 
Guidelines for reporting product complaints .................................................................................. 79 
8.4 
TREATMENT OF OVERDOSE ...................................................................................................... 79 
8.5 
PHARMACOKINETICS .................................................................................................................. 79 
8.6 
PHARMACODYNAMICS ............................................................................................................... 80 
8.6.1 
Lumbar puncture ............................................................................................................................ 81 
8.7 
ACCEPTABILITY AND PALATABILITY......................................................................................... 81 
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8.8 
..................................................................................................................................... 81 
8.9 
 ............................................................................................................................... 82 
8.10 
................................................................................................................................. 82 
8.11 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 83 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 84 
9.1 
STATISTICAL HYPOTHESES ....................................................................................................... 84 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 84 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 85 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 86 
9.4.1 
Efficacy analyses ........................................................................................................................... 86 
9.4.2 
Safety analyses .............................................................................................................................. 88 
9.4.3 
Pharmacokinetic analyses ............................................................................................................. 88 
9.4.4 
Other analyses ............................................................................................................................... 89 
9.5 
INTERIM ANALYSES  ................................................................................................................... 89 
9.5.1 
Data Monitoring Committee (DMC) ................................................................................................ 89 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 90 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 90 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 90 
10.1.2 
Financial disclosure........................................................................................................................ 90 
10.1.3 
Informed consent process .............................................................................................................. 91 
10.1.4 
Data protection ............................................................................................................................... 91 
10.1.5 
Committees structure ..................................................................................................................... 92 
10.1.6 
Dissemination of clinical study data ............................................................................................... 92 
10.1.7 
Data quality assurance .................................................................................................................. 93 
10.1.8 
Source documents ......................................................................................................................... 93 
10.1.9 
Study and site closure .................................................................................................................... 94 
10.1.10 Publication policy ........................................................................................................................... 94 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 94 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ................................................ 96 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION ............................................................................................................................ 101 
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10.5 
APPENDIX 5: 
 ........................................................................................................... 104 
10.6 
APPENDIX 6: LIVER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS .......................................................................................................................... 106 
10.7 
APPENDIX 7: MEDICAL DEVICE INCIDENTS: DEFINITION AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING .............................................. 107 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS ............................................................ 107 
10.9 
APPENDIX 9: ABBREVIATIONS ................................................................................................. 110 
10.10 
APPENDIX 10: PROTOCOL AMENDMENT HISTORY .............................................................. 112 
10.10.1 Amended protocol 01 (05 November 2019) ................................................................................. 112 
10.10.2 Amended protocol 02 (09 March 2020) ....................................................................................... 117 
10.10.3 Amended protocol 03 (08 March 2021) ....................................................................................... 121 
10.10.4 Amended protocol 04 (20 April 2022) .......................................................................................... 124 
10.10.5 Amended protocol 05 (11 November 2022) ................................................................................. 127 
10.11 
APPENDIX 11: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY AS DECLARED BY A GOVERNMENTAL AGENCY .......................................... 130 
11 
REFERENCES ............................................................................................................................. 133 
 
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LIST OF TABLES  
Table 1 - Schedule of assessments .............................................................................................................. 20 
Table 2 - Risk mitigation strategy .................................................................................................................. 39 
Table 3 - Objectives and endpoints ............................................................................................................... 42 
Table 4 - Overview of study interventions administered ............................................................................... 56 
Table 5 - Populations for analyses ................................................................................................................ 85 
Table 6 - Efficacy analyses ........................................................................................................................... 86 
Table 7 - Protocol-required laboratory assessments .................................................................................... 95 
Table 8 - Highly effective contraceptive methods ....................................................................................... 102 
Table 9 - Schedule of Activities (SoA) addition for Canadian participants .................................................. 108 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 19 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title:  
A multicenter, multinational, randomized, double-blind, placebo-controlled study to assess the 
efficacy, pharmacodynamics, pharmacokinetics, safety, and tolerability 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 
Short title: 
 
A multinational, randomized, double-blind, placebo-controlled study to assess the efficacy, 
pharmacodynamics, pharmacokinetics, and safety of venglustat in late-onset GM2 (AMETHIST) 
Rationale: 
 
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Objectives and endpoints 
 
Objectives 
Endpoints 
Primary 
Primary population: 
• 
To assess the efficacy and pharmacodynamics (PD) 
of daily oral dosing of venglustat when administered 
over a 104-week period.   
Co-primary endpoints: 
• 
Percent change in cerebrospinal fluid (CSF) GM2 
biomarker from baseline to Week 104. 
• 
Annualized rate of change in the 9-hole peg test  
(9-HPT) from baseline to Week 104.   
Secondary population: 
• 
To assess PD response (plasma and CSF GL-1 
biomarker and disease specific biomarkers) of 
venglustat when administered once daily over 
a 104-week period.   
 
• 
Plasma and CSF GL-1 biomarker and a pathway 
specific biomarker will be assessed as follows: 
Disease 
Biomarker 
GM2 gangliosidosis 
GL-1, GM2 
GM1 gangliosidosis 
GL-1, GM1 
Sialidosis 
GL-1, GM2, GM3 
Galactosialidosis 
GL-1, GM1, GM3 
Saposin C Deficiency 
GL-1 only 
• 
Additional plasma and CSF biomarkers may include 
but are not limited to: lipidomics, glycoprotein 
nonmetastatic protein B (gpNMB), neurofilament.   
 Secondary 
Primary population: 
• 
To assess the PD of daily oral dosing of venglustat 
and the effect of venglustat on selected 
performance test and scale over a 104-week period. 
 
• 
Absolute change in CSF GM2 biomarker from 
baseline to Week 104. 
• 
Change in 25-foot walk test (25FWT) from baseline 
to Week 104 (in participants able to walk at 
baseline).   
• 
Change in the neurological examination of the 
Friedreich’s Ataxia Rating Scale (FARS) from 
baseline to Week 104. 
Primary population: 
• 
To determine the safety and tolerability of 
venglustat when administered orally once daily over 
a 104-week period.    
 
• 
Changes from baseline to Week 104 in the 
following: 
- 
Assessment of adverse events (AEs) and 
concomitant medication 
- 
Neurological examination 
- 
Ophthalmological examination 
- 
Vital signs 
- 
Clinical laboratory evaluations including 
hematology, biochemistry, urinalysis, and 
serology 
- 
Electrocardiogram (ECG)   
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Objectives 
Endpoints 
Primary population: 
• 
To assess the pharmacokinetics (PK) of venglustat 
in plasma and CSF.   
 
• 
Plasma and CSF venglustat concentrations at 
prespecified visits over the study duration and 
plasma PK parameters (when applicable) including 
maximum plasma concentration observed (Cmax), 
tmax, and area under the plasma concentration 
versus time curve calculated using the trapezoidal 
method over a predefined time period (from time 
t=0 to 24 hours; AUC0-24).   
Secondary population: 
• 
To assess the effect of venglustat on selected 
performance tests and scale over a 104-week 
period.   
 
 
• 
Annualized rate of change in the 9-HPT from 
baseline to Week 104.   
• 
Change in 25FWT from baseline to Week 104 (in 
participants able to walk at baseline).   
• 
Change in the neurological examination of the 
FARS from baseline to Week 104.  
• 
   
Secondary population: 
• 
To determine the safety and tolerability of 
venglustat when administered once daily over 
a 104-week period.   
 
• 
Changes from baseline to Week 104 in the 
following: 
- 
Assessment of AEs and concomitant 
medication 
- 
Neurological examination 
- 
Ophthalmological examination 
- 
Vital signs 
- 
Clinical laboratory evaluations including 
hematology, biochemistry, urinalysis, and 
serology 
- 
ECG   
Secondary population: 
• 
To assess the PK of venglustat in plasma and CSF. 
 
 
 
Secondary population:  
• 
To assess the acceptability and palatability of the 
venglustat tablet 
 
 
• 
Plasma and CSF venglustat concentrations over 
the study duration and plasma PK parameters 
(when applicable) including Cmax, tmax, and AUC0-24 
calculated using the trapezoidal method. 
 
 
• 
Acceptability and palatability assessments  
Overall design: 
This is a multicenter, multinational, randomized, double-blind, placebo-controlled, 2-arm, 
104-week study (primary population only) to assess the efficacy and safety of venglustat as 
compared with placebo in adult participants with a diagnosis of late-onset GM2 gangliosidosis 
(referred to as primary population) and venglustat received in an open-label design in participants 
with a clinical diagnosis of juvenile/adolescent late-onset GM2 gangliosidosis, 
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GM1 gangliosidosis, Saposin C deficiency, Sialidosis Type 1, or juvenile/adult galactosialidosis, 
if any of the sites have such participants meeting the inclusion and none of the exclusion criteria 
(referred to as secondary population). The secondary population is composed of participants with 
juvenile/adolescent late-onset GM2 gangliosidosis and ultra-rare conditions within the same 
biochemical pathway as the primary population. The 104-week treatment period (primary analysis 
period) will be followed by an open-label extension period with venglustat treatment for all 
patients. The study will be conducted at multiple multinational sites (approximately 30 sites). 
The study will include 4 main periods:  
1. Period 1 (screening period from Day -60 to Day -1): Participant and/or participant’s 
parent(s)/legal guardian(s) will sign and date informed consent and the participant will 
undergo screening assessments to determine participant eligibility. If all eligibility criteria 
are met, the participant will start study treatment. 
2. Period 2 (primary analysis period, 104-week treatment period): Participants in the primary 
population will be randomly assigned in a 2:1 ratio to receive venglustat or placebo once 
daily for 104 weeks in a double-blind design. Randomization will be stratified on the 
participant’s ability to walk at the baseline visit (yes/no). Participants in the secondary 
population will receive venglustat for 104 weeks in an open-label design. Safety, 
tolerability, PK, PD, and efficacy of venglustat once daily administration will be 
determined during the 104-week treatment period. 
3. Period 3 (104-week OLE period): Participants in both the primary and secondary 
populations will be automatically entered into the OLE period following completion of the 
primary analysis period (period 2). All participants will receive venglustat for 104 weeks 
in an open-label design. Long-term safety, tolerability, PD, and efficacy of venglustat once 
daily administration will be assessed during the 104-week OLE period. Participants who 
complete the primary analysis period but would not continue to the OLE period, and safety 
follow-up/end-of-study (EOS) visit will be conducted 6 weeks after the W104 visit.  
Participants who complete the primary analysis period within 3 months prior to the OLE 
(amended protocol 4) approval by local regulations, will have the option to enroll into the 
OLE when the OLE (amended protocol 4) is approved. Participants who prematurely 
discontinue the study treatment from the primary analysis period will not have the option 
to enroll into the OLE. 
4. Period 4 (post-treatment safety observation period, 6-week follow-up period). The 
post-treatment safety observation period will be for 6 weeks after Period 3, and safety and 
tolerability will continue to be assessed. 
Post-trial access to venglustat will be in compliance with all applicable national and local laws 
and regulations, including safety reporting obligations. 
Disclosure Statement: This is a Parallel, Treatment study with 2 arms that are blinded/masked 
for Investigator and participants in the primary population for the primary analysis at 104 weeks. 
For the secondary population, this is an open-label, single-arm treatment study. 
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Number of participants: 
Approximately 57 participants with late-onset adult GM2 gangliosidosis will be treated in the 
study (primary population). After safety data from Week 1/Day 1 to Week 12 visits for the 
first 5 participants of the primary population are reviewed and considered satisfactory, enrollment 
of the secondary population will begin. In addition to the primary population, up to 20 participants 
in total are planned for the secondary population. An attempt will be made and first prioritized to 
enroll at least 1 participant (age 2 years or older) in each of the following disorders: 
juvenile/adolescent late-onset GM2 gangliosidosis, GM1 gangliosidosis, Saposin C deficiency, 
Sialidosis Type 1, and juvenile/adult galactosialidosis. 
Intervention groups and duration: 
During the 104-week primary analysis treatment period, participants in the primary population 
will be randomly assigned in a 2:1 ratio to receive venglustat or placebo once daily in a double-
blind manner. Randomization will be stratified on the participant’s ability to walk at the baseline 
visit (yes/no). Participants in the secondary population will receive venglustat for 104 weeks in 
an open-label manner. 
During the 104-week OLE treatment period, all participants in both primary and secondary 
populations will receive venglustat in an open-label manner. 
Study intervention(s) 
Investigational medicinal products: Venglustat or placebo 
• 
Formulation: venglustat 
 and 15 mg and placebo (identical to venglustat 15 mg 
tablets in appearance) tablets. The placebo is only for 15 mg venglustat tablets. Strength 
refers to the free base corresponding to the active moiety. 
• 
Route of administration: oral. 
• 
Dose regimen:  
- 
The investigational medicinal product (IMP) can be swallowed whole or chewed and 
then swallowed. Administration of IMP by chewing and swallowing or swallowing 
whole should be as consistent as possible throughout study treatment, and the method 
should be documented in the electronic case report form. 
- 
Adult onset GM2 gangliosidosis participants will receive a venglustat 15 mg tablet or 
placebo once daily in the primary analysis period and will receive a venglustat 15 mg 
tablet once daily in the OLE treatment period.  
- 
Adult participants in the secondary population will receive a venglustat 15 mg tablet 
once daily in the primary analysis period and OLE treatment period.  
- 
Adolescents and juvenile participants in the secondary population (≥2 years of age) 
will receive venglustat 
As adolescent and juvenile participants grow, venglustat doses 
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Statistical considerations: 
• 
Sample size calculations: In the primary population, approximately 57 participants will 
be randomly assigned with a 2:1 randomization ratio to venglustat (n=38) or placebo 
(n=19). This sample size will provide approximately 80% power to detect a difference 
between venglustat and placebo with regards to the primary efficacy endpoint of 
annualized rate of change in 9-HPT. It will also provide >99% power to detect a difference 
between venglustat and placebo with regards to the co-primary endpoint of percent change 
in CSF GM2 biomarker from baseline to Week 104. The sample size for the secondary 
population up to 20 is not based on statistical power calculation, but on empirical 
considerations. The Sponsor will attempt to enroll at least 1 participant, aged 2 years or 
older (or ages 2 to <18 years for juvenile/adolescent late-onset GM2 gangliosidosis), in 
each disorder. This is in addition to the 57 participants from the primary population. 
• 
Primary analysis: Percent change in cerebrospinal fluid (CSF) GM2 biomarker from 
baseline to Week 104 will be analyzed using an analysis of covariance (ANCOVA) 
including the fixed effect of treatment (venglustat versus placebo) and the continuous 
fixed covariate of baseline value.  If the results from the ANCOVA approach are severely 
impacted by the presence of outliers, a robust ANCOVA, using Huber’s M estimation, will 
be used. Annualized rate of change in 9-HPT from baseline to Week 104 will be compared 
between venglustat and placebo using a linear mixed-effect model with random intercept 
and slopes, estimated in a frequentist framework. Actual time relative to randomization of 
all planned assessments at Week 12, Week 26, Week 52, Week 78, and Week 104 will be 
taken into account in the model.  If the results from the linear mixed-effect model are 
severely impacted by the presence of outliers, a robust ANCOVA on individual slopes, 
using Huber’s M estimation, will be used. A secondary analysis will use a Bayesian 
approach with an informative prior distribution for the slope in the placebo arm, based on 
natural history data.  
• 
Analysis of secondary endpoints: Absolute change in CSF GM2 biomarker will be 
analyzed using an ANCOVA or a robust ANCOVA; similar to the model use for the 
percent change in CSF GM2.  
Change in 25FWT and neurological examination of the FARS will be compared between 
venglustat and placebo using a linear mixed-effect model with random intercept and slopes 
or using a robust ANCOVA on individual slopes, similar to the model used for 9-HPT. 
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• 
Plasma and CSF GL-1 biomarker and pathway specific biomarkers in the secondary 
population will be summarized descriptively. Percent change from baseline in plasma and 
CSF GL-1 biomarker will be described for the entire secondary population. The pathway 
specific biomarker will be described separately for each disease in the secondary 
population. When at least 5 participants have available data in the entire secondary 
population or within a specific disease, a 95% confidence interval for the percent change 
from baseline will be provided. In addition, biomarker data will be summarized 
descriptively with individual plots and listings. No formal comparison will be performed 
in the secondary population. 
Data Monitoring Committee: Yes 
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1.2 
SCHEMA  
Figure 1 - Graphical study design  
 
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1.3 
SCHEDULE OF ACTIVITIES (SOA)  
Table 1 - Schedule of assessments  
Study Period/ 
Procedure 
Screening 
Primary analysis treatment period 
Open-label extension treatment 
period 
FU 
Period 
Notes 
Day or Week 
Up to 60 d 
before D1 W1/D1 W12 
(±7d) 
W26 
(±7d) 
W39 
(±7d) 
W52 
(±7d) 
W65 
(±7d) 
W78 
(±7d) 
W104 
(±7d)/ 
EWa 
W130 
(±14d) 
W156 
(±14d) 
W182 
(±14d) 
W208 
(±14d)/ 
EOT/EW
b 
W214 
(±7d) 
SFU 
after 
EOT 
W1/D1 visit will be Baseline visit.  
For further details, see footnotes 
“a” and “b” at end of the table. 
Visit number 
1 
2 
3 
4 
4.1c 
5 
5.1c 
6 
7 
8 
9 
10 
11 
12 
For further details, see footnote 
“c” at the end of the table. 
Visit at clinical site 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
For participants in United States, 
Visit 3, 8, 10 and 12 can be 
provided remotely under 
a decentralized clinical trial (DCT) 
model (Optional).  
For Visits 8 (W130), 10 (W182) 
and 12 (W214), may be provided 
remotely under a DCT model 
(optional) where applicable, 
allowed by local regulations, and 
approved by the participant.  
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and 
baseline 
characteristics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical/treat
ment history/alcohol 
use history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Experience of 
participating in the 
Natural History Study 
(NIH/NTSAD) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
For participants in the United 
States only. 
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Study Period/ 
Procedure 
Screening 
Primary analysis treatment period 
Open-label extension treatment 
period 
FU 
Period 
Notes 
Day or Week 
Up to 60 d 
before D1 W1/D1 W12 
(±7d) 
W26 
(±7d) 
W39 
(±7d) 
W52 
(±7d) 
W65 
(±7d) 
W78 
(±7d) 
W104 
(±7d)/ 
EWa 
W130 
(±14d) 
W156 
(±14d) 
W182 
(±14d) 
W208 
(±14d)/ 
EOT/EW
b 
W214 
(±7d) 
SFU 
after 
EOT 
W1/D1 visit will be Baseline visit.  
For further details, see footnotes 
“a” and “b” at end of the table. 
Visit number 
1 
2 
3 
4 
4.1c 
5 
5.1c 
6 
7 
8 
9 
10 
11 
12 
For further details, see footnote 
“c” at the end of the table. 
Hexosaminidase 
enzyme activity  
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Only for primary population.  
Samples will be collected for all 
participants during screening or 
at D1 (predose). Only 1 sample 
will be collected, during screening 
or at D1 after 4 hr fasting. For 
those with historical results, they 
may begin the study without 
Lumbar puncture 
Xd 
 
 
 
 
 
 
 
Xe 
 
 
 
 
 
d LP will be performed once 
participant demonstrates 
eligibility based on screening 
criteria. The LP may be done 
during the screening period 
within 14 days prior to 
treatment initiation (D -14 to 
D -1). The LP should be done 
successfully before first dose 
and/or randomization.  
e The LP should be done after 
all other assessments if 
possible.  
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Study Period/ 
Procedure 
Screening 
Primary analysis treatment period 
Open-label extension treatment 
period 
FU 
Period 
Notes 
Day or Week 
Up to 60 d 
before D1 W1/D1 W12 
(±7d) 
W26 
(±7d) 
W39 
(±7d) 
W52 
(±7d) 
W65 
(±7d) 
W78 
(±7d) 
W104 
(±7d)/ 
EWa 
W130 
(±14d) 
W156 
(±14d) 
W182 
(±14d) 
W208 
(±14d)/ 
EOT/EW
b 
W214 
(±7d) 
SFU 
after 
EOT 
W1/D1 visit will be Baseline visit.  
For further details, see footnotes 
“a” and “b” at end of the table. 
Visit number 
1 
2 
3 
4 
4.1c 
5 
5.1c 
6 
7 
8 
9 
10 
11 
12 
For further details, see footnote 
“c” at the end of the table. 
Study IMP 
administration 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
For the primary population only. 
IRT contact 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
For Canadian participants 
enrolled in the US, see 
Section 10.8. 
Dispense IMP 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
In addition to the IMP dispensing 
at these clinical site visits, IMP 
will be dispensed at remote site 
visits where applicable via DTP 
shipment. At Visit 4.1 (W39) and 
Visit 5.1(W65), IMP will be 
dispensed and sent to 
participants via DTP shipment. 
For Canadian participants 
enrolled in the US, see 
Section 10.8. 
. 
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Study Period/ 
Procedure 
Screening 
Primary analysis treatment period 
Open-label extension treatment 
period 
FU 
Period 
Notes 
Day or Week 
Up to 60 d 
before D1 W1/D1 W12 
(±7d) 
W26 
(±7d) 
W39 
(±7d) 
W52 
(±7d) 
W65 
(±7d) 
W78 
(±7d) 
W104 
(±7d)/ 
EWa 
W130 
(±14d) 
W156 
(±14d) 
W182 
(±14d) 
W208 
(±14d)/ 
EOT/EW
b 
W214 
(±7d) 
SFU 
after 
EOT 
W1/D1 visit will be Baseline visit.  
For further details, see footnotes 
“a” and “b” at end of the table. 
Visit number 
1 
2 
3 
4 
4.1c 
5 
5.1c 
6 
7 
8 
9 
10 
11 
12 
For further details, see footnote 
“c” at the end of the table. 
Venglustat or placebo 
 
<---------------------------------------------------------------- Once daily --------------------------------------------------------> 
 
Participants in the primary 
population will receive venglustat 
or placebo once daily for 
104 weeks in a double-blind 
manner in the primary analysis 
period and receive venglustat once 
daily for 104 weeks in an open-
label manner in the open-label 
extension period. Participants in 
the secondary population will 
receive venglustat for 208 weeks in 
an open-label manner. Participants 
will take the first IMP dose of open-
label extension period dispensed at 
Visit 7 on the day after completion 
all Visit 7assessments.  
Dispense 
/Check/Retrieve 
Patient Diary 
Xf 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
Xg 
f 
dispense only 
g retrieve only 
Telephone call to 
participants 
 
<--------------------------------------------------------------------------------------------------------------------------------------------------------> 
Telephone call follow-ups to occur 
every 60 ±3 days after D 1, except 
for scheduled follow up phone calls 
which would fall within a few days 
(up to 10 days) from a site visit. 
Assessments include participant 
status, AEs, participant diary, IMP 
compliance, and concomitant 
medications. For participants who 
withdraw early from the treatment, 
follow-up telephone call should 
occur up to 6 weeks after last dose 
of study IMP. An unscheduled 
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Study Period/ 
Procedure 
Screening 
Primary analysis treatment period 
Open-label extension treatment 
period 
FU 
Period 
Notes 
Day or Week 
Up to 60 d 
before D1 W1/D1 W12 
(±7d) 
W26 
(±7d) 
W39 
(±7d) 
W52 
(±7d) 
W65 
(±7d) 
W78 
(±7d) 
W104 
(±7d)/ 
EWa 
W130 
(±14d) 
W156 
(±14d) 
W182 
(±14d) 
W208 
(±14d)/ 
EOT/EW
b 
W214 
(±7d) 
SFU 
after 
EOT 
W1/D1 visit will be Baseline visit.  
For further details, see footnotes 
“a” and “b” at end of the table. 
Visit number 
1 
2 
3 
4 
4.1c 
5 
5.1c 
6 
7 
8 
9 
10 
11 
12 
For further details, see footnote 
“c” at the end of the table. 
phone visit or a remote monitoring 
may be required due to regional or 
national emergency as declared by 
a governmental agency. 
Physical examination  
Xh 
Xh 
Xh 
Xh 
 
Xh 
 
Xh 
Xh 
Xh 
Xh 
Xh 
Xh 
Xi 
h complete/full physical 
examination including visual 
acuity. 
i 
abbreviated/brief physical 
examination. 
Neurological 
examination 
X 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
When neurological and 
ophthalmological examinations 
are performed on the same day, 
the neurological examination 
should be performed before the 
ophthalmological examination. 
Body weight 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Height 
X 
Xj 
Xj 
Xj 
 
Xj 
 
Xj 
Xj 
Xj 
Xj 
Xj 
Xj 
 
j 
For juvenile and adolescent 
participants only. 
Archival blood sample 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
This sample will be collected and 
stored for use if any unexpected 
safety issue occurs to ensure that 
a predose baseline value is 
available for previously 
nonassessed parameters. 
 
Vital signs 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Includes heart rate, systolic and 
diastolic blood pressure, 
respiratory rate, and body 
temperature. 
 
Serum β-hCG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Study Period/ 
Procedure 
Screening 
Primary analysis treatment period 
Open-label extension treatment 
period 
FU 
Period 
Notes 
Day or Week 
Up to 60 d 
before D1 W1/D1 W12 
(±7d) 
W26 
(±7d) 
W39 
(±7d) 
W52 
(±7d) 
W65 
(±7d) 
W78 
(±7d) 
W104 
(±7d)/ 
EWa 
W130 
(±14d) 
W156 
(±14d) 
W182 
(±14d) 
W208 
(±14d)/ 
EOT/EW
b 
W214 
(±7d) 
SFU 
after 
EOT 
W1/D1 visit will be Baseline visit.  
For further details, see footnotes 
“a” and “b” at end of the table. 
Visit number 
1 
2 
3 
4 
4.1c 
5 
5.1c 
6 
7 
8 
9 
10 
11 
12 
For further details, see footnote 
“c” at the end of the table. 
pregnancy test (for 
WOCBP) 
Urine pregnancy test 
(for WOCBP)  
 
<--------------------------------------------------------------Every 4 weeks----------------------------------------------------------------> 
Female patients of childbearing 
potential only. Results will be 
captured in patient diary when 
test is not taken at the clinic. At 
V2, it must be negative before the 
first IMP administration. 
 
Serology tests for 
hepatitis B, C, and 
other infectious 
disease, if locally 
required 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology, 
biochemistry, 
urinalysis  
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Urinalysis by dipstick will be 
performed at the site. If 
abnormal, a complete urinalysis 
will be performed by the central 
laboratory 
 
Urine biochemistry 
(including UPCR and 
UACR) k 
 
 X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
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Study Period/ 
Procedure 
Screening 
Primary analysis treatment period 
Open-label extension treatment 
period 
FU 
Period 
Notes 
Day or Week 
Up to 60 d 
before D1 W1/D1 W12 
(±7d) 
W26 
(±7d) 
W39 
(±7d) 
W52 
(±7d) 
W65 
(±7d) 
W78 
(±7d) 
W104 
(±7d)/ 
EWa 
W130 
(±14d) 
W156 
(±14d) 
W182 
(±14d) 
W208 
(±14d)/ 
EOT/EW
b 
W214 
(±7d) 
SFU 
after 
EOT 
W1/D1 visit will be Baseline visit.  
For further details, see footnotes 
“a” and “b” at end of the table. 
Visit number 
1 
2 
3 
4 
4.1c 
5 
5.1c 
6 
7 
8 
9 
10 
11 
12 
For further details, see footnote 
“c” at the end of the table. 
k First morning void urine 
sample to be collected on the 
day of the site visit or home 
visit (where allowed per local 
regulations). Second morning 
void urine sample can be 
collected if first morning void 
urine sample was not 
collected. Courier 
transportation can be 
arranged as required and if 
allowed per local regulations. 
Urine sample should be sent 
to the central laboratory for 
quantitative measurement of 
creatinine, total protein and 
albumin which will be used to 
calculate the urine 
albumin/creatinine ratio and 
urine protein/creatinine ratio. 
12-lead ECG 
X 
Xl 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
l 
ECG in triplicate will be 
performed prior to IMP 
administration. 
Please note that ECG is 
required in triplicate only at 
Visit 2. 
Ophthalmological 
examination 
Xm 
 
 
Xn 
 
Xn 
 
Xn 
Xm 
Xo 
Xo 
Xo 
Xm 
 
m Full ophthalmological 
examination (including slit 
lamp fundoscopy with 
dilation), photography, and 
ARLNS for all participants. 
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Study Period/ 
Procedure 
Screening 
Primary analysis treatment period 
Open-label extension treatment 
period 
FU 
Period 
Notes 
Day or Week 
Up to 60 d 
before D1 W1/D1 W12 
(±7d) 
W26 
(±7d) 
W39 
(±7d) 
W52 
(±7d) 
W65 
(±7d) 
W78 
(±7d) 
W104 
(±7d)/ 
EWa 
W130 
(±14d) 
W156 
(±14d) 
W182 
(±14d) 
W208 
(±14d)/ 
EOT/EW
b 
W214 
(±7d) 
SFU 
after 
EOT 
W1/D1 visit will be Baseline visit.  
For further details, see footnotes 
“a” and “b” at end of the table. 
Visit number 
1 
2 
3 
4 
4.1c 
5 
5.1c 
6 
7 
8 
9 
10 
11 
12 
For further details, see footnote 
“c” at the end of the table. 
n Full ophthalmological 
examination (including slit 
lamp fundoscopy with 
dilation) for all participants. 
o Full ophthalmological 
examination (including slit 
lamp fundoscopy with 
dilation), for participants 
≥2 and <18 years of age only.  
  
Full ophthalmological 
examination, photography, and 
ARLNS can be performed at any 
time if deemed medically 
necessary. When neurological 
and ophthalmological 
examinations are performed on 
the same day, the neurological 
examination should be performed 
before the ophthalmological 
examination. 
AE collection 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
AEs will be captured from the 
time the participant provides 
signed informed consent through 
the safety follow-up period up to 
6 weeks after the W208 EOT 
visit. 
Prior and concomitant 
medications 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
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Study Period/ 
Procedure 
Screening 
Primary analysis treatment period 
Open-label extension treatment 
period 
FU 
Period 
Notes 
Day or Week 
Up to 60 d 
before D1 W1/D1 W12 
(±7d) 
W26 
(±7d) 
W39 
(±7d) 
W52 
(±7d) 
W65 
(±7d) 
W78 
(±7d) 
W104 
(±7d)/ 
EWa 
W130 
(±14d) 
W156 
(±14d) 
W182 
(±14d) 
W208 
(±14d)/ 
EOT/EW
b 
W214 
(±7d) 
SFU 
after 
EOT 
W1/D1 visit will be Baseline visit.  
For further details, see footnotes 
“a” and “b” at end of the table. 
Visit number 
1 
2 
3 
4 
4.1c 
5 
5.1c 
6 
7 
8 
9 
10 
11 
12 
For further details, see footnote 
Pharmacokinetics 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma samples 
 
Xr 
Xs 
Xt 
 
Xt 
 
 
Xu 
 
 
 
 
 
r 
For primary population, 
sampling will be performed 
predose and 0.5, 3, 8, 12, and 
24 hours postdose in 
15 participants (Plasma 
sample ID P00, P01, P02, P03, 
P04, P05, respectively). This 
PK profile sub study will stop 
when required numbers of 
samplings are collected. For all 
other participants, sampling will 
be performed only at 3 hours 
postdose (P02). Participants 
will receive IMP at clinical site 
on this day. 
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Study Period/ 
Procedure 
Screening 
Primary analysis treatment period 
Open-label extension treatment 
period 
FU 
Period 
Notes 
Day or Week 
Up to 60 d 
before D1 W1/D1 W12 
(±7d) 
W26 
(±7d) 
W39 
(±7d) 
W52 
(±7d) 
W65 
(±7d) 
W78 
(±7d) 
W104 
(±7d)/ 
EWa 
W130 
(±14d) 
W156 
(±14d) 
W182 
(±14d) 
W208 
(±14d)/ 
EOT/EW
b 
W214 
(±7d) 
SFU 
after 
EOT 
W1/D1 visit will be Baseline visit.  
For further details, see footnotes 
“a” and “b” at end of the table. 
Visit number 
1 
2 
3 
4 
4.1c 
5 
5.1c 
6 
7 
8 
9 
10 
11 
12 
For further details, see footnote 
“c” at the end of the table. 
s Sampling will be performed 
predose and 0.5, 3, 8, 12, and 
24 hours postdose (Plasma 
sample ID P06, P07, P08, P09, 
P10, P11 respectively). 
t 
Sampling will be performed 
predose and 3 hours postdose. 
(Plasma sample ID P12, P13 
at Visit 4/Week 26 and P14 
and P15 at Visit 5/Week 52, 
respectively). Participants will 
receive IMP at the clinical site 
on these days. 
u Sampling will be performed 
predose (plasma sample ID 
P16 for participants who 
complete the V7/W104 visit; 
plasma sample ID P18 for 
participants who complete the 
EW visit.) 
CSF samples  
 
 
 
 
 
 
 
 
Xv 
 
 
 
 
 
v Sampling will be performed 
predose (CSF sample ID 
C00). 
Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9-HPT 
X 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
 
Timed 25-FWT 
X 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
 
FARS Part I, 
functional staging of 
ataxia  
X 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
 
FARS Part II, 
Activities of Daily 
X 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
 
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Study Period/ 
Procedure 
Screening 
Primary analysis treatment period 
Open-label extension treatment 
period 
FU 
Period 
Notes 
Day or Week 
Up to 60 d 
before D1 W1/D1 W12 
(±7d) 
W26 
(±7d) 
W39 
(±7d) 
W52 
(±7d) 
W65 
(±7d) 
W78 
(±7d) 
W104 
(±7d)/ 
EWa 
W130 
(±14d) 
W156 
(±14d) 
W182 
(±14d) 
W208 
(±14d)/ 
EOT/EW
b 
W214 
(±7d) 
SFU 
after 
EOT 
W1/D1 visit will be Baseline visit.  
For further details, see footnotes 
“a” and “b” at end of the table. 
Visit number 
1 
2 
3 
4 
4.1c 
5 
5.1c 
6 
7 
8 
9 
10 
11 
12 
For further details, see footnote 
“c” at the end of the table. 
Living 
FARS Part III, 
neurological 
examination 
X 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
 
Muscle weakness of 
triceps and quadriceps 
 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
 
FARS functional test, 
PATA 
X 
X 
X 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
 
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Study Period/ 
Procedure 
Screening 
Primary analysis treatment period 
Open-label extension treatment 
period 
FU 
Period 
Notes 
Day or Week 
Up to 60 d 
before D1 W1/D1 W12 
(±7d) 
W26 
(±7d) 
W39 
(±7d) 
W52 
(±7d) 
W65 
(±7d) 
W78 
(±7d) 
W104 
(±7d)/ 
EWa 
W130 
(±14d) 
W156 
(±14d) 
W182 
(±14d) 
W208 
(±14d)/ 
EOT/EW
b 
W214 
(±7d) 
SFU 
after 
EOT 
W1/D1 visit will be Baseline visit.  
For further details, see footnotes 
“a” and “b” at end of the table. 
Visit number 
1 
2 
3 
4 
4.1c 
5 
5.1c 
6 
7 
8 
9 
10 
11 
12 
For further details, see footnote 
“c” at the end of the table. 
Abbreviations: 9-HPT, 9-hole peg test; ADL, activities of daily living, a PRO from the FARS; ADME, absorption, distribution, metabolism, excretion; 
; AE, adverse 
event; ARLNS, Age-Related Eye Disease Study (AREDS) Clinical Lens Grading System; β-hCG, beta human chorionic gonadotropin; 
; CSF, cerebrospinal fluid;  d, days; D, day; DTP, direct to patient; ECG, electrocardiogram; EOT, end of treatment; EW, early withdrawal; FARS, Friedreich’s Ataxia Rating Scale; FU, follow-up; 
HBV, hepatitis B; HCV, hepatitis C; HIV, human immunodeficiency virus; IMP, investigational medicinal product; IRT, interactive response technology; LP, lumbar puncture; 
 NIH, National Institutes of Health; NTSAD, National Tay-Sachs & Allied Diseases Associations; 
PATA, a speech test using 
the phrase “pata”; 
 PK, pharmacokinetic; 
; W, week; WOCBP, woman of childbearing potential. 
Note: All screening assessments are not required to be repeated for participant rescreening. Cognitive, behavioral, and ataxia assessments are not required to be repeated if performed within 3 months. 
Note: 
 questionnaires should be completed by the participants before the consultation and/or clinical tests. 
a In case of early treatment withdrawal before W104, and if participant does not wish to stay in the study, assessments mentioned in the W104 visit will be performed, followed by safety follow-up visit 6 weeks after 
the W104/EW visit. 
b In case of early treatment withdrawal after W104, and if participant does not wish to stay in the study after W104, assessments mentioned in the W208 will be performed, followed by safety follow-up visit 6 weeks 
after the W208/EOT/EW visit. 
c The IMP can be dispensed and sent to participants at Visits 4.1 (W39) and 5.1 (W65) via DTP shipment except if the local regulatory authority requires the IMP dispensed at site. No other study assessments are 
planned during these 2 visits. 
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2 
INTRODUCTION  
Sanofi Genzyme is investigating venglustat (GZ/SAR402671) as a possible oral SRT for the 
treatment of lysosomal storage disorders characterized by deficits in the GL-1 catabolism 
pathway. In this trial, venglustat will be investigated in adult late-onset GM2 gangliosidosis 
(late-onset 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 GL-1-based sphingolipid pathway. 
2.1 
STUDY RATIONALE  
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. 
2.2 
BACKGROUND  
2.2.1 GM2 gangliosidosis (Tay-Sachs disease and Sandhoff disease)  
Tay-Sachs disease and Sandhoff disease are known as GM2 gangliosidosis due to excessive 
accumulation of GM2 and related glycolipids in the lysosomes and neurons. Degradation of GM2 
requires it to be complexed with a substrate-specific cofactor known as GM2 activator and 
presented to the catabolic enzyme beta-hexosaminidase comprised of alpha and beta subunits 
encoded by the HEXA and HEXB genes, respectively. Beta-hexosaminidase exists as 2 distinct 
isozymes; beta-hexosaminidase A (an alpha/beta heterodimer that associates with the GM2 
activator protein) and beta-hexosaminidase B (a beta/beta homodimer). Patients with Tay-Sachs 
disease have mutations in the HEXA gene, lack of beta-hexosaminidase A activity, and 
accumulation of GM2 in the brain and spinal cord leading to progressive neurodegeneration. 
Defects in the HEXB gene result in the loss of both beta-hexosaminidase A and B and cause the 
more severe Sandhoff disease associated with the accumulation of GM2, GM2’s asialo derivative 
(GA2), and a number of oligosaccharides and glycoproteins that contain hexosaminidase 
substrates. The clinical phenotypes associated with Tay-Sachs disease and Sandhoff disease vary 
depending upon the age at which symptoms first appear. Infantile-onset disease is a rapidly 
progressive neurodegenerative disease culminating in death before age of 4 years (classical 
Tay-Sachs disease and Sandhoff disease, as well as GM2 activator deficiency). Late-onset, 
subacute or chronic, and progressive neurologic conditions are compatible with survival into 
childhood or teens (subacute form) or long survival (chronic form). Chronic forms include several 
different clinical phenotypes in which symptoms referable to one or another part of the CNS 
dominate, including progressive dystonia, spinocerebellar degeneration, motor neuron disease, or 
psychosis. Specific therapy for GM2 gangliosidosis is not available to date (4, 5, 6, 7, 8, 9, 10, 11, 
12, 13, 14, 15). 
2.2.2 Venglustat  
Venglustat is a novel GCS inhibitor that partially inhibits the synthesis of GL-1. Venglustat has 
been shown to have CNS activity and/or exposure in nonclinical studies performed in rats and 
dogs respectively and in ongoing clinical studies in patients with GD3 and GBA-PD. 
As GL-1 serves as the central building block for more complex glycosphingolipids such as 
globotriaosylceramide, GM3, and GM2 ganglioside, SRT with GCS inhibitors is expected to have 
broad therapeutic applicability across a number of lysosomal storage diseases. 
In vitro studies demonstrate that venglustat is a potent and selective inhibitor of murine and 
human GCS in biochemical and cell-based assays. In vivo pharmacology studies utilized plasma 
GL-1 lowering as a PD marker of GCS inhibition. In vivo activity was established in rodents and 
dogs with reductions in plasma (rodent and dog) and tissue (rodents only) GL-1 following oral 
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administration of venglustat. In both species, the effects of venglustat on plasma GL-1 were 
dose-dependent and correlated with plasma exposure of the compound. In rodents, venglustat has 
been shown to cross the BBB and reduce the synthesis of the major isoform of GL-1 in the CNS 
(ie, C18 GL-1). The CNS exposure has also been confirmed in dogs where the CSF 
concentrations of venglustat following repeat oral dosing were approximately 2-fold greater than 
the unbound plasma concentration of drug. 
In Phase 1 healthy volunteer studies, once daily oral administration of venglustat at free base 
doses ranging from 3.72 mg to 14.9 mg was shown to be safe and reduce plasma levels of GL-1 in 
a time and dose-dependent manner. In these studies, venglustat was absorbed with a median tmax 
of 2 to 3 hours and eliminated with a pooled geometric mean terminal elimination half-life of 
31.3 hours on Day 14. 
The therapeutic effect of SRT for the treatment of systemic disease in GD1 has been established 
clinically with eliglustat (Cerdelga®), a specific, but structurally unrelated GCS inhibitor and 
negligible exposure in the brain, in both previously untreated, and ERT-controlled patients (1, 2). 
By reducing substrate influx, eliglustat significantly improved disease manifestations in untreated 
GD1 patients with existing visceral and hematologic involvement. In this cohort with GD1 and 
substantial disease manifestations, the slight decrease in clinical status of patients in the placebo 
group over 9 months underscored the progressive nature of GD. The magnitude of the 
improvements observed suggests that SRT alone has the potential to effectively restore balance in 
the production and degradation of GL-1 without prior reconstitution of the macrophage system 
with exogenous acid β-glucosidase. In GD1 patients already receiving ERT, and having reached 
therapeutic goals, oral eliglustat as monotherapy maintained hematological and organ volume 
stability (2).  
Given the positive impact on visceral disease with SRT, it is anticipated that GCS inhibitors with 
appropriate CNS exposure and activity could address other lysosomal storage diseases where 
gangliosides and globosides accumulate. This hypothesis has been tested in HEXb-/- mice, 
a model of Sandhoff disease where the lipids that accumulate, GM2 and GA2, are downstream of 
GL1. Substrate accumulation in the Sandhoff mice is apparent throughout the CNS as well as in 
visceral tissues with CNS manifestations of disease apparent by approximately 90 days resulting 
in a median lifespan of approximately 130 days. In this aggressive model (complete deficiency), 
treatment with GZ466161, a GCS inhibitor from the same chemical series as venglustat, starting 
at 4 weeks of age was shown to delay the onset of clinical symptoms, reduce lipid accumulation in 
the CNS/liver and significantly increase the median survival of the mice (3). Analysis of lipids in 
the feline Sandhoff model via a gene therapy study further support the GCS inhibition hypothesis 
(16). Central nervous system, CSF, and serum samples from control and Sandhoff cats with or 
without AAV hexosaminidase gene therapy were analyzed for GM2 and lyso-GM2 levels. 
Preliminary data demonstrated a marked increase in GM2/lyso-GM2 in CNS tissue and CSF of 
Sandhoff cats relative to controls, and a reduction of lipids in both compartments following 
enzyme replacement (internal data, not published). Treatment of Sandhoff cats with the AAV 
same therapy results in improved clinical conditions scores and prolonged survival (16, 17). 
More information on the safety of venglustat and on the clinical program can be found in the 
Investigator’s Brochure. 
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2.3 
BENEFIT/RISK ASSESSMENT  
Venglustat has not been studied in patients with GM2 gangliosidosis. The information provided 
below mainly concern venglustat. More detailed information about the known and expected 
benefits and risks and reasonably expected Adverse Events (AEs) of venglustat may be found in 
the Investigator’s Brochure (IB). 
In the completed Phase 1 clinical trials in healthy volunteers, oral administration of venglustat 
was safe and well tolerated. 
Ongoing studies are being conducted in patients with GD3 and Fabry disease (FD). One study in 
patients with GBA-PD and 2 studies in patients with autosomal dominant polycystic kidney 
disease were terminated due to lack of efficacy. The studies’ termination was not due to safety 
reasons. The majority of reported AEs were assessed as mild to moderate; most of which resolved 
spontaneously. Serious adverse events (SAEs) and discontinuations due to AEs have been limited 
in Phase 2 studies. Based on an evaluation of the cumulative safety data from the clinical 
program, venglustat is generally safe and well tolerated. 
2.3.1 Risk assessment  
There is no important identified risk in humans at this time. Potential risks identified based on 
available non-clinical and clinical data are described below: 
2.3.1.1 Potential risks specific for pediatric population  
New or worsening lens opacity in children two to less than 18 years old 
An important potential risk of new or worsening lens opacity was initially identified from juvenile 
toxicity study, where reversible lens degeneration was observed in both male and female rats 
administered 45 and ≥ 15 mg/kg/day venglustat, respectively. It was also reported from a 26-week 
study in adult female rats given a high dose of 20 mg/kg/day; incidence and severity decreased 
after the treatment-free period. 
The potential risk of new or worsening lens opacities/cataracts in humans was evaluated in 
two large, placebo-controlled studies of venglustat. Studies EFC15392 and ACT14820 were 
randomized, double-blind, placebo-controlled trials in adult participants with autosomal dominant 
polycystic kidney disease (ADPKD) and adult participants with Parkinson’s disease associated 
with GBA mutations (GBA-PD), respectively. Further details of these studies are provided in 
Section 6.2 of the Investigator’s Brochure.  
Both studies included comprehensive ophthalmological examinations, and the incidence of new or 
worsening cataracts was evaluated as an adverse event of special interest. Pooled data from both 
trials comparing placebo to venglustat 15 mg (placebo n=321, venglustat n=322) showed that the 
overall incidence of any treatment-emergent cataract was balanced between the treatment arms 
(7.5% in venglustat 15 mg vs 8.1% in placebo, respectively). The incidence of cataract subtypes 
(nuclear, cortical, subcapsular) was also balanced between placebo and venglustat 15 mg. 
Furthermore, Kaplan-Meier analyses did not demonstrate differences in the time to onset of new 
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cataracts or worsening of pre-existing cataracts. In EFC15392, decrease in distance best corrected 
visual acuity (BCVA) by one or more lines was comparable in placebo vs venglustat 15 mg 
(placebo 13.0%, venglustat 11.6%).  
Based on these data, new or worsening lens opacity is no longer considered an important potential 
risk of venglustat in adults, and therefore the frequency of ophthalmological examinations is 
reduced in OLE phase in this study for adult participants. 
During the time of the review of this risk on 15th August 2022, there were 13 participants aged 
2 to <18 years enrolled in the AMETHIST study, 8 of whom were aged 2 to <12, and no lens 
opacity or cataracts have been observed in these participants. However, there is the potential for 
venglustat-related lenticular degeneration based on results from the juvenile rat toxicity study. 
Due to limited pediatric data in children from 2 to <18 years old, there still is a potential for 
venglustat-mediated lenticular degeneration and therefore children are potentially at greater risk 
than adults (EM = 3.7), given that juvenile female rat NOAEL exposure is less than therapeutic 
(ie, EM = 0.6). Importantly, a cataract that develops during childhood before the age of 8 to 
10 year can lead to irreversible severe sequelae including blindness. The outcome of cataract 
surgery for younger participants is not as successful as for adults. Therefore, the potential risk of 
new or worsening lens opacity cannot be excluded in children 2 to less than 18 years old. Close 
ophthalmology monitoring of this population, if included in venglustat studies, will therefore be 
maintained. Children <2 years of age are excluded in the venglustat development program. 
If a participant develops signs or symptoms concerning for cataract development or other visual 
problems at any time during the study, the Investigator may refer the participant to a specialist for 
a comprehensive ophthalmological examination as a part of participant’s medical care. 
Potential male infertility due to exposure in childhood (<12 years of age) 
Potential effects on male fertility is an important potential risk derived from preclinical findings. 
In the 10-week oral juvenile toxicity study in the rat, degeneration of the germinal epithelium of 
the testes was observed at 45 mg/kg/day given from postnatal days 22 to 92 (age of the animals at 
the beginning of the dosing corresponds to 2-year-old humans). This finding was generally 
reversible at the end of the 12-week recovery period.  In a male juvenile toxicity study with an 
18-week recovery period (JUV0046), non-reversing microscopic changes in the testes 
(degeneration/atrophy) and epididymides (cellular debris, decreased sperm) were observed in rats 
administered 45 mg/kg/day during PND 22-90 and PND 22-50. In addition, non-reversing 
microscopic changes in the coagulating glands (mixed cell inflammation) were noted for males 
administered 45 mg/kg/day during PND 22-90 and PND 35-63. No venglustat-related effect on 
reproductive performance (male mating, fertility, and pregnancy indices) was observed. Slightly 
lower mean epididymal sperm concentrations that were not statistically significant were noted in 
the 45 mg/kg/day PND 22-90 and PND 22-50 groups compared to the control group. There were 
no other venglustat-related effects on sperm parameters (concentration, motility, and morphology) 
across all test article-treated groups during the dosing and recovery periods. No venglustat-related 
effects were noted for any parameter tested at 15 mg/kg/day. There were no similar findings in the 
13-week-repeat-dose toxicity study in the adult rat in which there was a comparable level and 
duration of drug exposure. Also, no similar findings were observed in the 4-week and 26-week 
studies in the rat (age of the rats in the 26-week-repeat-dose study corresponds to 12-year-old 
humans), and in the 4-, 13-, and 39-week-repeat-dose studies in the adult dog. 
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The finding of degeneration of testicular germinal epithelium, which was restricted to juvenile 
rats, could be related to the development stage of the animals, and is currently considered to be 
a potential risk only for male participants exposed to venglustat below the age of 12 years. 
Exposure under 12 years of age has a potential to negatively impact male fertility, an effect which 
would manifest at the time of sexual maturity. Monitoring the effects of venglustat on germinal 
testicular epithelium in pediatric patients would be invasive, requiring the use of tissue biopsies. 
Given that there are currently no available therapies indicated or used in these pediatric patients 
and the burden of disease includes significant neurological deficits and reduced life expectancy, 
the expected benefit of venglustat in preventing or slowing disease progression appears to 
outweigh the potential risk of future male fertility issues. Although the secondary population will 
include patients aged ≤12 years, the Sponsor does not consider clinical monitoring of effects on 
germinal testicular epithelium in this study. 
2.3.1.2 Depression  
Adverse neurological and psychiatric events are being monitored in all venglustat studies given 
the compound’s access to the central nervous system.  
This is based on the fact that venglustat crosses the blood brain barrier and venglustat-related 
central nervous system (CNS) AEs were observed at 100 mg/kg/day in a non-Good Laboratory 
Practice (GLP) 7-day functional observational battery (FOB) study in rats. In this study, 
venglustat-related CNS AEs were reported, such as abnormal gait, abnormal breathing, hunched 
posture, ptyalism, piloerection, hypoactivity, and abnormal responses to auditory and tactile to 
stimuli and to a sudden noise. Given the poor clinical condition of the animals at this high 
dose/exposure, a direct effect on the CNS is unclear. In the 28-day-repeat-dose study, slight 
piloerection, hypoactivity, abnormal gait, or posture along with marked lower motor activity was 
noted for 45 mg/kg/day females, the highest dose evaluated. No venglustat-related CNS 
microscopic findings were observed at the highest dose of 45 mg/kg/day. A study to assess seizure 
threshold did not reveal any effect of venglustat in rats. Venglustat was detected in dog 
cerebrospinal fluid following a single and repeated oral administration at 10 mg/kg/day. Exposure 
of venglustat in cerebrospinal fluid was approximately 2-fold greater than the unbound plasma 
exposure in dogs. 
An analysis of the clinical data from all venglustat study participants (FD, ADPKD, GBA-PD, 
GD3, GM2) concluded that depression is a potential risk in GBA-PD. Available data in the other 
populations receiving venglustat (ie, FD, GD3, GM2) was not sufficient to draw any conclusion. 
Periodic assessment of depression symptoms will continue as a monitored event in all ongoing 
and upcoming venglustat clinical programs.   
2.3.1.3 Syncope  
In the completed placebo-controlled phase 2 study ACT14820 for GBA-PD indication, the events 
of syncope were more frequently observed in venglustat arm compared to placebo arm. 
An analysis of this information concluded that syncope is a potential risk specific for GBA-PD 
participants.  Data were not sufficient to draw any conclusions in the other populations receiving 
venglustat (ie, FD, GD3, GM2). 
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2.3.1.4 
2.3.1.5 Transient increase in blood pressure  
In the completed or unblinded phase 2/3 studies in ADPKD, and GBA-PD indications, a transient 
increase in systolic (SBP) and diastolic blood pressure (DBP) was observed in the venglustat arm 
compared to the placebo arm. This difference peaked at Month 1 by approximately 5 mm Hg from 
the mean value of placebo-treated participants, and no notable difference compared to placebo 
was observed after 6 months. In the Phase 2 FD (Study ACT13739/LTS14116) and GD3 
(PDY13949/LEAP), the SBP and DBP returned to baseline by Month 6. It should be noted that 
although the renal and cardiovascular systems are affected during the course of Fabry disease, 
based on the 3 year follow up data from the completed ACT13739/LTS14116 study, there is no 
evidence of disease progression and consequently no impact of the transient increase in BP on the 
course of disease. 
In non-clinical studies, the cardiovascular system was not considered to be a target based on 
macroscopic and microscopic evaluation of the heart, electrocardiographic evaluations, and 
measurement of BP in repeat-dose studies up to 39 weeks in duration in dogs or in an in vivo 
cardiovascular safety pharmacology study in dogs. 
Based on the above information, it was concluded that transient increase of blood pressure is 
a potential risk in all indications.   
Blood pressure monitoring is part of the safety monitoring plan in all venglustat trials and is 
detailed in the SoA for this study. The management of hypertension should be in accordance with 
the protocol and at the discretion of the Investigator.  
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2.3.1.6  Embryo-fetal toxicity   
The important potential risk of embryo-fetal toxicity is based on the non-clinical findings in rats 
and rabbits such as increased implantation loss (in rats) and reduced fetal weight (in both rats and 
rabbits). In the pre-/postnatal development toxicity study in rats, increased unaccounted-for sites 
(implantation sites without a corresponding pup), decreased mean numbers of pups born and 
decreased mean pup weight were observed. There have been no studies of venglustat in pregnant 
women.  
Pregnant women should not receive venglustat, thus contraception measures are part of the 
protocol (Section 5.1 and Section 10.4). 
Table 2 - Risk mitigation strategy  
Description 
Summary of data/rationale 
Mitigation strategy 
Potential risks (venglustat) 
New or 
worsening lens 
opacity in children two to less than 
18 years old (important potential risk) 
Based on the review of the 
available clinical data, and 
the development of human 
eye, this is no longer 
considered as potential risk in adult 
populations. In the absence of clinical 
pediatric data in children 
two-years to <18 years of age, children 
are 
potentially at risk for 
venglustat. Importantly, 
cataract that develops during 
childhood before the age of 
eight to 10 year can lead to 
irreversible severe sequelae 
including blindness. 
For pediatric population: 
comprehensive 
ophthalmological examination 
and periodic monitoring. 
If a participant develops signs 
or symptoms concerning for 
cataract development or other 
visual problems at any time 
during the study,  
comprehensive ophthalmological 
examination will be performed. 
 
 Potential male infertility due to 
exposure in childhood (<12 years of 
age) (important potential risk) 
Preclinical findings (rat). See IB 
Section 7.1. 
Individual benefit-risk assessment by the 
Investigator and 
patients/parents/guardians. 
 
Depression  
 
Adverse neurological and psychiatric 
events are being monitored in all 
venglustat studies given the 
compound’s access to the central 
nervous system.  
 
Based on the available clinical data the 
risk of depression was assessed as 
a potential risk for GBA-PD population. 
The limited available data doesn’t allow 
Ability of venglustat to cross the blood-
brain barrier. See IB Section 7.1. 
 
Neurological examinations 
 
Depression is considered as a treatment 
monitored event in all ongoing and 
upcoming venglustat clinical programs.  
 
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Description 
Summary of data/rationale 
Mitigation strategy 
to confirm this risk for other venglustat 
indications. 
Syncope 
Based on the available clinical data the 
risk of syncope was assessed as 
a potential risk for GBA-PD population. 
The limited available data doesn’t allow 
to confirm this risk for other venglustat 
indications 
Clinical findings specific for GBA-PD 
population suggesting more frequent 
events of syncope in venglustat arm 
compared to placebo arm. 
Neurological examinations and adverse 
events monitoring. 
Transient increase in BP at the 
beginning of venglustat treatment 
Transient BP increase in venglustat-
treated participants of approximately 5 
mmHg, within the first 6 months of 
treatment.  See IB Section 7.1. 
BP monitoring at site visits and at home. 
See SOA (Section 1.3) and Section 8.3 
of the protocol. 
Embryo-fetal toxicity (important 
potential risk) 
In the embryo-fetal toxicology studies in 
rats and rabbits, increased implantation 
loss (in rats) and reduced fetal weight 
(in both rats and rabbits) were 
observed. See IB, Section 7.2.1.3. 
Men and women of childbearing 
potential (premenopausal and not 
surgically sterile) are required to either 
practice true abstinence consistent with 
their preferred and usual lifestyle, or use 
double contraceptive methods, including 
a highly effective method (see 
Section 5.1 and Section 10.4 for details) 
for the entire duration of the study and 
for at least 6 weeks for females and at 
least 90 days for males following their 
last dose of IMP. 
Drug interactions  
i
j
i
Abbreviations: 
 IB=Investigator’s Brochure; IMP=Investigational 
Medicinal Product. 
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2.3.2 Benefit assessment  
2.3.3 Overall benefit: risk conclusion  
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3 
OBJECTIVES AND ENDPOINTS  
Table 3 - Objectives and endpoints  
Objectives 
Endpoints 
Primary 
Primary population: 
• 
To assess the efficacy and pharmacodynamics 
(PD) of daily oral dosing of venglustat when 
administered over a 104-week period.   
Co-primary endpoints: 
• 
Percent change in cerebrospinal fluid (CSF) GM2 
biomarker from baseline to Week 104. 
• 
Annualized rate of change in the 9-hole peg test  
(9-HPT) from baseline to Week 104.   
 
Secondary population: 
• 
To assess PD response (plasma and CSF GL-1 
biomarker and disease specific biomarkers) of 
venglustat when administered once daily over 
a 104-week period.   
 
• 
Plasma and CSF GL-1 biomarker and a pathway 
specific biomarker will be assessed as follows: 
Disease 
Biomarker 
GM2 gangliosidosis 
GL-1, GM2 
GM1 gangliosidosis 
GL-1, GM1 
Sialidosis 
GL-1, GM2, GM3 
Galactosialidosis 
GL-1, GM1, GM3 
Saposin C Deficiency 
GL-1 only 
• 
Additional plasma and CSF biomarkers may include 
but are not limited to: lipidomics, glycoprotein 
nonmetastatic protein B (gpNMB), neurofilament.   
 
Secondary 
Primary population: 
• 
To assess the PD of daily oral dosing of venglustat 
and the effect of venglustat on selected 
performance test and scale over a 104-week 
period. 
 
• 
Absolute change in CSF GM2 biomarker from 
baseline to Week 104. 
• 
Change in 25-foot walk test (25FWT) from baseline 
to Week 104 (in participants able to walk at 
baseline).   
• 
Change in the neurological examination of the 
Friedreich’s Ataxia Rating Scale (FARS) from 
baseline to Week 104. 
Primary population: 
• 
To determine the safety and tolerability of 
venglustat when administered orally once daily 
over a 104-week period.    
 
• 
Changes from baseline to Week 104 in the following: 
- 
Assessment of adverse events (AEs) and 
concomitant medication 
- 
Neurological examination 
- 
Ophthalmological examination 
- 
Vital signs 
- 
Clinical laboratory evaluations including 
hematology, biochemistry, urinalysis, and 
serology 
- 
Electrocardiogram (ECG)   
 
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Objectives 
Endpoints 
Primary population: 
• 
To assess the pharmacokinetics (PK) of venglustat 
in plasma and CSF.   
 
• 
Plasma and CSF venglustat concentrations at 
prespecified visits over the study duration and 
plasma PK parameters (when applicable) including 
maximum plasma concentration observed (Cmax), 
tmax, and area under the plasma concentration 
versus time curve calculated using the trapezoidal 
method over a predefined time period (from time t=0 
to 24 hours; AUC0-24).   
 
Secondary population: 
• 
To assess the effect of venglustat on selected 
performance tests and scale over a 104-week 
period.   
 
• 
Annualized rate of change in the 9-HPT from 
baseline to Week 104.   
• 
Change in 25FWT from baseline to Week 104 (in 
participants able to walk at baseline).   
• 
Change in the neurological examination of the FARS 
from baseline to Week 104.  
  
Secondary population: 
• 
To determine the safety and tolerability of 
venglustat when administered once daily over a 
104-week period.   
 
• 
Changes from baseline to Week 104 in the following: 
- 
Assessment of AEs and concomitant 
medication 
- 
Neurological examination 
- 
Ophthalmological examination 
- 
Vital signs 
- 
Clinical laboratory evaluations including 
hematology, biochemistry, urinalysis, and 
serology 
- 
ECG   
 
Secondary population: 
• 
To assess the PK of venglustat in plasma and 
CSF. 
 
 
 
Secondary population:  
• 
To assess the acceptability and palatability of the 
venglustat tablet 
 
• 
Plasma and CSF venglustat concentrations over the 
study duration and plasma PK parameters (when 
applicable) including Cmax, tmax, and AUC0-24 
calculated using the trapezoidal method. 
 
 
• 
Acceptability and palatability assessments  
Tertiary/exploratory 
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Objectives 
Endpoints 
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Objectives 
Endpoints 
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Objectives 
Endpoints 
3.1 
APPROPRIATENESS OF MEASUREMENTS  
One of the co-primary endpoints is the percent change from baseline in CSF GM2 biomarker 
levels. The pathology of GM2 gangliosidosis and the related secondary indications result from 
an accumulation of GM2 or other glycosphingolipids in the CNS. Demonstration of a reduction of 
these accumulation products with venglustat would demonstrate CNS exposure and is expected to 
predict clinical efficacy. 
The 9-HPT is to be used as another co-primary efficacy endpoint for this group of participants. This 
assessment was chosen based on natural history data collected from the National Tay-Sachs & Allied 
Diseases Associations (NTSAD) which showed 9-HPT progression over time. It assesses the 
function of upper extremity mobility, one of the most bothersome aspects of the disease for the 
patients. This can be assessed in all patients including many of whom may be nonambulatory during 
the study. This clinical endpoint selection makes it a consistent and homogeneous measure for 
consideration in the full trial population. This assessment has demonstrated a decline in the natural 
history data. Therefore, without active treatment this assessment would be expected to decline in this 
target population. This assessment would also support the use of the GM2 biomarker as 
a mechanistic and confirmatory endpoint supporting the assumption that venglustat crosses the BBB 
and results in an expected lowering of the GM2 biomarker with resultant improvement or 
stabilization of the 9-HPT result over time versus a placebo population.  
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The 25FWT is a quantitative mobility and leg function performance test based on a timed 25-foot 
walk. The patient is directed to one end of a clearly marked 25-foot course and is instructed to 
walk 25 feet as quickly as possible, but safely. The time is calculated from the initiation of the 
instruction to start and ends when the patient has reached the 25-foot mark. The task is 
immediately administered again by having the patient walk back the same distance. Patients may 
use assistive devices when doing this task. Administration time will vary depending upon the 
ability of the patient. Total administration time should be approximately 1 to 5 minutes. The score 
for the 25FWT is the average of the 2 completed trials. The 25FWT will be administered in 
patients able to walk at baseline. Patients who cannot walk even with assistance will not be 
assessed. Since approximately 21% of patients who participated in the NTSAD study were 
wheelchair bound, it is expected that 25FWT will not be ascertained in a substantial fraction of 
the study population. For this reason, the 25FWT will not be considered as the primary endpoint 
in this study but will be included as a supportive secondary endpoint. 
The FARS includes a neurological examination that specifically reflects neural substrates affected 
in Friedreich ataxia. The FARS-neuro is a performance outcome (PerfO), composed of 4 sections 
that assess different neurological faculties: bulbar activity (4 items), upper limb coordination 
(5 items), lower limb coordination (2 items), peripheral nervous system (5 items) and upright 
stability (7 items). The total score ranges from 0 to 117. The neurological examination domain of 
FARS is conducted by the clinician and has shown sensitivity to change overtime in a Sanofi 
natural history study. Based on the study findings, FARS neuro could be used to assess the 
different neurological signs in patients with GM2 gangliosidosis. To avoid dilution of this small 
effect in this slowly progressive disease, the Sponsor proposes studying the change in the 
neurological component of the FARS as an individual secondary endpoint. 
Further, a functional staging of ataxia and activities of daily living (ADL) assessment are 
incorporated. Depending on the progression of the GM2 disease, these patients have varying 
abilities to utilize their upper and lower limbs. This limited mobility impairs the ability to conduct 
ADL. This clinical study allows the inclusion of patients provided that they have the use of their 
upper limbs. Therefore, the FARS will allow for monitoring and comparison of additional aspects 
of upper body function over the treatment period.  
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
This is a multicenter, multinational, randomized, double-blind, placebo-controlled, 2-arm, 
104-week study (primary population only) to assess the efficacy and safety of venglustat as 
compared with placebo in adult participants with a diagnosis of late-onset GM2 gangliosidosis 
(referred to as the primary population) and venglustat received in an open-label design in 
participants with a clinical diagnosis of juvenile/adolescent late-onset GM2 gangliosidosis, GM1 
gangliosidosis, Saposin C deficiency, Sialidosis Type 1, or juvenile/adult galactosialidosis if any 
of the sites have such participants meeting the inclusion and none of the exclusion criteria 
(referred to as secondary population). The secondary population is composed of participants with 
juvenile/adolescent late-onset GM2 gangliosidosis and ultra-rare conditions within the same 
biochemical pathway as the primary population. The 104-week treatment period (primary analysis 
period) will be followed by an OLE period with venglustat treatment for all patients. The study 
will be conducted at multiple, multinational sites (approximately 30 sites).  
The study will include 4 main periods:  
1. Period 1 (screening period from Day -60 to Day -1): Participant and/or participant’s 
parent(s)/legal guardian(s) will sign and date the informed consent and the participant will 
undergo screening assessments to determine participant eligibility. If all eligibility criteria 
are met, the participant will start study treatment. 
2. Period 2 (primary analysis period, 104-week treatment period): Participants in the primary 
population will be randomly assigned in a 2:1 ratio to receive venglustat or placebo once 
daily for 104 weeks in a double-blind manner. Randomization will be stratified on the 
participant’s ability to walk at the baseline visit (yes/no). Participants in the secondary 
population will receive venglustat for 104 weeks in an open-label manner. Safety, 
tolerability, PK, PD, and efficacy of venglustat once-daily administration will be 
determined during the 104-week treatment period. 
3. Period 3 (104-week OLE period): Participants in both the primary and secondary 
population will be automatically entered into the OLE period following completion of 
primary analysis period (period 2). All participants will receive venglustat for 104 weeks 
in an open-label design. Long-term safety, tolerability, PD, and efficacy of venglustat once 
daily administration will be assessed during the 104-week treatment period. Participants 
who complete the primary analysis period but would not continue to OLE period, and 
safety follow up /end of study (EOS) visit will be conducted 6 weeks after the W104 visit. 
Participants who complete the primary analysis period within 3 months prior to the OLE 
(amended protocol 4) approval by local regulations, will have the option to enroll into the 
OLE when the OLE (amended protocol 4) is approved. Participants who prematurely 
discontinue the study treatment from the primary analysis period will not have the option 
to enroll into the OLE. 
4. Period 4 (post-treatment safety observation period, 6-week follow-up period). The 
post-treatment safety observation period will be for 6 weeks after Period 3, and safety and 
tolerability will continue to be assessed. 
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Post-trial access to venglustat will be in compliance with all applicable national and local laws 
and regulations, including safety reporting obligations. 
After safety data from Week 1/Day 1 to Week 12 visits of the first 5 participants of the primary 
population are reviewed and considered satisfactory by the DMC, enrollment of the secondary 
population will begin. In addition to the primary population, up to 20 participants in total are 
planned for the secondary population. An attempt will be made and first prioritized to enroll at 
least 1 participant (aged 2 years or older) in each of the following disorders: juvenile/adolescent 
late-onset GM2 gangliosidosis, GM1 gangliosidosis, Saposin C deficiency, Sialidosis Type 1, and 
juvenile/adult galactosialidosis (secondary population). 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
This is a multicenter, multinational, randomized, double-blind, placebo-controlled study in the 
primary population (adult participants with late-onset GM2 gangliosidosis). Safety/tolerability, 
PK, PD, and efficacy assessment will be conducted. The primary objective is evaluation of CSF 
GM2 biomarker changes and clinical efficacy of venglustat using the 9-HPT. After safety data 
from Week 1/Day 1 to Week 12 visits of the first 5 participants of the primary population are 
reviewed and considered satisfactory by the DMC, enrollment of the secondary population will 
begin. The trial will include 104 weeks of IMP dosing, during which venglustat or placebo will be 
administered orally once daily in a double-blind manner. Of note, to date, no large-scale studies 
have been successful in specifically addressing the relative benefits and risks of a treatment for 
participants with late-onset GM2 gangliosidosis. Thus, there is a high medical need to address 
motor, coordination and speech, and neuropsychiatric manifestations in in these patients. 
The study may also enroll a secondary population of participants (≥2 years of age) with a clinical 
diagnosis of juvenile/adolescent late-onset GM2 gangliosidosis and an ultra-rare bundle consisting 
of GM1 gangliosidosis, Saposin C deficiency, Sialidosis Type 1, and juvenile/adult 
galactosialidosis, if any of the sites have such participants meeting the inclusion criteria and none 
of the exclusion criteria. Such participants will be enrolled only after a 12-week safety data review 
of the first 5 treated adult late-onset GM2 gangliosidosis participants has been considered 
satisfactory. The secondary population will have the same assessments and evaluations as the 
primary population. 
4.3 
JUSTIFICATION FOR DOSE  
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4.4 
END OF STUDY DEFINITION  
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the last visit. 
The end of the study is defined as the date of the last visit of the last participant in the study. 
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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: 
Age 
I 01. Participant must be at least 18 years of age at the time of signing the informed consent for 
the primary population and adult secondary population. Participant must be ≥2 to <18 years 
of age at the time of signing the informed consents [by parent(s)/guardian(s)] for the 
juvenile and adolescent secondary population. 
Type of participant and disease characteristics 
I 02. The participant has a clinical diagnosis of late-onset GM2 gangliosidosis (Tay-Sachs 
disease and Sandhoff disease) and documented respective enzyme deficiency (for the 
primary population only). The documented enzyme deficiency should support a genetically 
confirmed diagnosis of GM2-gangliosidosis caused by β-hexosaminidase deficiency 
resulting from mutations in the 
Note: The study may also enroll participants with a clinical diagnosis of 
juvenile/adolescent late-onset GM2 gangliosidosis, GM1 gangliosidosis, Saposin C 
deficiency, Sialidosis Type 1, or juvenile/adult galactosialidosis if any of the sites have 
such participants meeting the other inclusion and none of the exclusion criteria (secondary 
population). The secondary population is composed of participants with ultra-rare 
conditions within the same biochemical pathway as the primary population. 
I 03. For primary population, the participant has the ability to perform the 9-HPT at the 
screening visit in ≤240 seconds for the 2 consecutive trials of the dominant hands and the 
2 consecutive trials of the nondominant hand.  
I 04. If the participant has a history of seizures, they are well controlled under appropriate 
medication not identified as a 
. 
I 05. The participant is cooperative, able to ingest oral medication, willing to travel to a study 
site (if applicable), and able to comply with all aspects of the study, including all 
assessments, according to the Investigator’s judgment. 
Weight 
I 06. For the juvenile and adolescent secondary population, participant must have body weight 
≥10 kg at the time of signing the informed consent. 
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Sex 
I 07. Male or Female 
Female patients of childbearing potential and sexually active male patients must be willing 
to practice true abstinence in line with their preferred and usual lifestyle, or use 
2 acceptable effective methods of contraception for the duration of the study and for at 
least 6 weeks for females and 90 days for males following their last dose of IMP. In 
addition, male participants must refrain from donating sperm for the duration of the study 
and for 90 days after the last dose of IMP.  
a) Sexually active male participants 
A male participant must agree to use contraception as detailed in Appendix 4 
(Section 10.4) of this protocol for the duration of the study and 90 days following their 
last dose of IMP. 
b) Female participants 
A female participant is eligible to participate if she is not pregnant (see Appendix 4 
[Section 10.4]), not breastfeeding, and at least one of the following conditions applies: 
- 
Not a woman of childbearing potential (WOCBP) as defined in Appendix 4 
(Section 10.4) 
OR 
- 
A WOCBP who agrees to follow the contraceptive guidance in Appendix 4 
(Section 10.4) for the duration of the study and for at least 6 weeks after the last 
dose of IMP. 
Informed Consent 
I 08. The participant or, if appropriate, parent(s) or legal guardian(s) must provide written 
informed assent/consent prior to any study-related procedures being performed as 
described in Appendix 1 (Section 10.1). Note: For criteria specific to participants enrolled 
in Japan and France, see Appendix 8 (Section 10.8). 
5.2 
EXCLUSION CRITERIA   
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. Participant has clinical features of Tay-Sachs or Sandhoff disease, but a completely 
negative result on a genetic test for GM2 gangliosidosis caused by β-hexosaminidase 
deficiency resulting from mutations in the 
 and/or is without 
clinical features. 
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E 02. For primary population and participants with juvenile/adolescent late onset GM2 
gangliosidosis and GM1 gangliosidosis, the participant cannot understand and perform all 
age-appropriate study assessments, with the exception of 25FWT and PROs. 
E 03. Any clinically relevant medical disorders other than late-onset GM2 gangliosidosis 
(primary population) or the diseases specified for the secondary population, clinically 
relevant findings in the physical examination, medical history, or laboratory assessments 
which would compromise the safety of the participant. This includes condition(s) that 
precludes the safe performance of routine lumbar puncture (eg, prohibitive lumbar spinal 
disease), as well as cardiovascular, renal, hepatic, gastrointestinal, pulmonary, neurologic, 
endocrine, metabolic (eg, hypokalemia, hypomagnesemia), or psychiatric disease, other 
medical conditions, or serious intercurrent illnesses. 
E 04. The participant has a documented diagnosis of any of the following infections: hepatitis B, 
hepatitis C, human immunodeficiency virus 1 or 2. 
E 05. A history of drug and/or alcohol abuse within the past year prior to the first screening visit. 
E 06. The participant is scheduled for in-patient hospitalization including elective surgery during 
the study. 
E 07. The participant has, according to World Health Organization (WHO) grading, a cortical 
cataract ≥ one-quarter of the lens circumference (Grade cortical cataract-2) or a posterior 
subcapsular cataract ≥2 mm (Grade posterior subcapsular cataract-2). Participants with 
nuclear cataracts will not be excluded.  
Prior/concomitant therapy 
E 08. The participant requires use of invasive ventilatory support. 
E 09. The participant is receiving current treatment with anticoagulants (eg, coumadin, heparin) 
that might preclude safe completion of the LP. 
E 10. The participant has received SRT within 3 months prior to study enrollment. 
E 12. The participant is currently receiving potentially cataractogenic medications as listed in 
Section 6.5.1.3 or any medication that may worsen the vision of participant with cataract 
(eg, alpha-adrenergic glaucoma medications) according to the prescribing information. 
Prior/concurrent clinical study experience 
E 13. Currently participating in another investigational interventional study. 
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E 14. Use of IMP, within 3 months or 5 half-lives, whichever is longer, before study enrollment. 
Note: For participants using N-acetyl-leucine as IMP, within 5 half-lives before study 
enrollment. 
Diagnostic assessments 
E 15. Liver enzymes (alanine aminotransferase [ALT]/aspartate aminotransferase [AST]) or total 
bilirubin >2 × the upper limit of normal (ULN) at the time of screening unless the 
participant has the diagnosis of Gilbert syndrome and maintains a level of total bilirubin 
<5 mg/dL and direct bilirubin <1 mg/dL (20%) of total bilirubin level. 
Other exclusions 
E 17. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized. 
E 18. Any country-related specific regulation that would prevent the participant from entering 
the study - see Appendix 8 (Section 10.8) (country-specific requirements). 
E 19. Participant not suitable for participation, whatever the reason, including medical or clinical 
conditions, or participants potentially at risk of noncompliance to study procedures. 
E 20. Participants are dependent on the Sponsor or Investigator (in conjunction with Section 1.61 
of the International Council for Harmonisation (ICH)-Good Clinical Practice (GCP) 
Ordinance E6) 
E 21. 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. 
E 22. Any specific situation during study implementation/course that may raise ethics 
considerations. 
E 23. Sensitivity to any of the study interventions, or components thereof, or drug or other 
allergy, that contraindicates participation in the study 
Note: For exclusion criteria specific to participants enrolled in France, see Appendix 8 
(Section 10.8).  
5.3 
LIFESTYLE CONSIDERATIONS  
5.3.1  Meals and dietary restrictions  
 
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5.4 
SCREEN FAILURES  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study. 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. 
A participant cannot be randomized more than once in the study. Participants who fail screening 
may be rescreened once during the recruitment period in cases where the original screening failure 
was due to reasons expected to change at rescreening and based upon the Investigator’s clinical 
judgment. Different participant identification will be issued for such participants. 
There is no requirement for a waiting period between the screen-failure date and the rescreening 
date. The interactive response technology (IRT) report will flag rescreened participants. 
Participants that are rescreened must sign a new consent form. Not all screening assessments are 
required to be repeated for participants rescreening. Coordination and speech, behavioral, and 
ataxia assessments are not required to be repeated if performed within the past 3 months. For 
participants rescreened within 2 weeks of the initial screening visit, the Investigator may use the 
initial screening visit results for biomarkers, chemistry, hematology, and urinalysis. 
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6 
STUDY INTERVENTION  
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  
Table 4 - Overview of study interventions administered  
ARM namea 
Venglustat 
Placebo 
 
Intervention name 
Venglustat 
Placebo 
 
Type 
Drug 
Drug 
 
Dose formulation 
Tablet 
Tablet 
 
Unit dose 
strength(s)b 
 and 15 mg 
NA 
 
Dosage level(s) 
Adult onset GM2 gangliosidosis participants will receive venglustat a 15 mg tablet or 
placebo once daily. Adult participants in the secondary population will receive a venglustat 
15 mg tablet once daily. Adolescents and juvenile participants in the secondary population 
(≥2 years) will receive venglustat 
  
Route of administration        Oral: The IMP can be swallowed whole or chewed and then swallowed. Administration of IMP      
by chewing and swallowing or swallowing whole should be as consistent as possible throughout study treatment, and the 
method should be documented in the electronic case report form. 
IMP and NIMP 
IMP 
IMP 
 
Packaging and 
labeling 
During the primary analysis period, study 
Intervention will be provided in a double-blind wallet 
for the primary population and in an open-label 
wallet for the secondary population. Each wallet will 
be labeled as required per country requirements. 
During the OLE, study intervention will be provided 
in an open-label wallet for both primary and 
secondary populations. 
During the primary analysis period, 
study Intervention will be provided in 
a double-blind wallet for the primary 
population. Each wallet will be 
labeled as required per country 
requirements. 
Not applicable during the OLE. 
  
Current/Former 
name(s) or alias(es) 
GZ/SAR402671 
 
 
Abbreviations: eCRF, electronic case report form; IMP, investigational medicinal product; NIMP, noninvestigational medicinal product. 
a The placebo is only for the 15 mg venglustat tablets. 
b Strength refers to the free base corresponding to the active moiety. 
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Between the protocol-scheduled on-site visits, interim visits may be required for IMP dispensing. 
As an alternative to these visits, venglustat or placebo may be supplied from the site to the 
participant via a Sponsor-approved courier company where allowed by local regulations and 
approved by the participant. 
Venglustat or matching placebo is to be taken daily, around the same time each day throughout 
the study. 
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  
Section 10.11 (Appendix 11). 
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 (Refer to Pharmacy manual for additional details). 
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 8.3.6). 
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-patient (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  
The randomized intervention kit number list will be generated centrally by the Sponsor. The IMPs 
will be packaged in accordance with this list. Participants in the primary population will be 
centrally assigned to randomized study IMP using IRT as summarized in the SOA (Section 1.3). 
The IRT will allocate the intervention kit numbers corresponding to the visit and the arm at each 
dispensation for each participant in the primary and secondary population. Before the study is 
initiated, instructions on how to access IRT will be provided to each site.  
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A randomized participant is a participant who has been randomly allocated to a study IMP, 
regardless whether the IMP kit was used or not. A participant cannot be randomly assigned more 
than once in the study. 
Returned study IMP should not be redispensed to the participants. 
Methods of blinding 
For the primary population, Investigators and participants will be blinded to the allocation of 
active or placebo treatment arms. Venglustat and matching placebo for venglustat tablets will be 
indistinguishable from one another and be provided in identically matched packaging which 
includes labeling to protect the blind. 
In accordance with the double-blind study design, Investigators will remain blinded to IMP and 
will not have access to the randomization (treatment) codes except under exceptional medical 
circumstances. 
Randomization code breaking  
The code may be broken only in the case of a serious, unexpected, related AE. If possible, contact 
should be initiated with the Monitoring Team before breaking the code. In case of an emergency, 
the Interactive Web Response System (IWRS) in the first instance/Interactive Voice Response 
System (IVRS) can be contacted by the Investigator or Sub-Investigator to reveal the IMP 
assignment of a particular patient. In case of a Suspected Unexpected Serious Adverse Reaction 
(SUSAR), the Global Pharmacovigilance department of the Sponsor will contact IWRS/IVRS to 
reveal IMP assignment for regulatory reporting requirements for the particular case. The 
IWRS/IVRS unblinding procedures should be followed as outlined in the IVRS manual.  
Participant safety must always be the first consideration in making such a determination. If the 
Investigator decides that unblinding is warranted, the investigator should make every effort to 
contact the Sponsor to discuss the situation prior to unblinding a participant’s intervention 
assignment unless this could delay emergency treatment of the participant. 
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If the blind is broken by the Investigator he/she will document the date, time of day and reason for 
code breaking. The IWRS/IVRS will send a confirmation of unblinding report. The patient must 
discontinue study medication, but should be encouraged to continue in the study, completing all 
assessments at the scheduled time points. At a minimum, the patient may withdraw from the 
clinical trial and complete an end of treatment assessment visit (similar to Visit 7) followed by 
a safety follow-up visit (similar to Visit 12) 6 weeks after their last scheduled received dose or 
until resolution of the related SAE. 
Patient withdrawal will only occur when the code break call is made at the site level and/or at the 
study level. This means that if the Emergency Unblinding transaction is performed by the 
Investigator (ie, at the site level), then the patient will be withdrawn from treatment. However, if 
the Emergency Unblinding transaction is performed by the Sponsor (ie, at the study level), then 
the patient may or may not be withdrawn from treatment. 
Participants hold an ESMS (24 hours- Emergency Scientific and Medical Services) card, with 
ESMS phone number and back-up number to be called if the investigator (first contact person) 
cannot be reached. The 24-hour emergency system number is to be used in medical urgency 
situation by competent medical personnel after first study treatment administration. 
6.4 
STUDY INTERVENTION COMPLIANCE  
Participant compliance with study intervention will be assessed at each visit. Compliance will be 
assessed by reviewing participant diary and counting returned tablets. Deviation(s) from the 
prescribed dosage regimen should be recorded in the eCRF. 
The Investigator or designee will keep an accurate record of all IMP that is received, dispensed, 
and returned on a per participant basis using an IMP accountability log. Measures taken to ensure 
and document treatment compliance and IMP accountability include: 
• 
Accurate recording of treatment kit number as required on appropriate eCRF page for 
accounting purposes. 
• 
All medication treatment kits (whether empty or unused) are returned by the participant at 
each visit. In case of DTP process, the intervention units can be returned by the carrier 
(if defined in the contract). 
• 
The Investigator or designee tracks treatment accountability/compliance, either by diary, 
or by counting the number of used treatment kits and fills in the appropriate page of the 
participant treatment log. 
• 
The monitor in charge of the study then checks the data entered on the IMP administration 
page by comparing them with the IMP that has been retrieved and the participant treatment 
log form. 
A participant diary will be issued to the participant at the screening visit with instructions to 
record any safety issue. For eligible participants, the same diary will be used to record missing 
doses after randomization. A brief explanation should be provided if a dose is missed. The 
participant should bring the diary and any remaining IMP to each clinic visit. 
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The site staff will review the participant diary during each clinic visit and record excursions from 
treatment into the eCRF. The participant diary will be retrieved when the participant finishes their 
participation in the study. 
At the completion of the study, all IMPs will be accounted for and retained or destroyed according 
to regulatory requirements regarding drug accountability. Investigational medicinal products will 
not be destroyed unless the Sponsor provides written authorization. Authorization for destruction 
will be given by the Sponsor once reconciliation has been completed. Whenever possible, this 
destruction will occur on-site, depending on local regulations and site-specific capabilities; 
alternatively, IMP may be returned to the Sponsor or designee for destruction. Additional details 
will be provided in the pharmacy manual. 
6.5 
CONCOMITANT THERAPY  
A concomitant medication is any treatment received by the participant during the study aside from 
the IMP. Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins, and/or herbal supplements) that the participant is receiving at the time of enrollment or 
receives during the study must be recorded along with: 
• 
Reason for use 
• 
Dates of administration including start and end dates 
• 
Dosage information including dose and frequency 
Concomitant medications should be kept to a minimum during the study. Furthermore, changes in 
concomitant medications should be kept to a minimum and only be administered if considered 
absolutely necessary in the medical judgement of the Investigator. If excluded prescription or 
nonprescription medicines are considered necessary for the patient’s welfare and no alternative 
treatment is available, such treatment may be provided as long as it is unlikely to significantly 
interfere with the IMP. Participants may be given such therapy as rescue medication at the 
discretion of the Investigator and this must be recorded in the eCRF. The participants must abstain 
from taking pyrimethamine and/or acetyl-leucine throughout this clinical study. 
6.5.1 Prohibited concomitant medicine  
6.5.1.1 
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6.5.1.2 
6.5.1.3 Medications with risk to cause cataract  
Given nonclinical lens findings (see the latest Investigator’s Brochure), a chronic regimen 
(ie, more frequent than once every 2 weeks) of the following medications is forbidden during the 
clinical trial for participants age <18: 
• 
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) each 52 weeks, for an overall maximum of 8 occasions during 
the 104 weeks of treatment in Period 2.  
- 
A special provision is made to allow enrollment of GM2 gangliosidosis participants 
who require inhaled corticosteroids for the management of a stable medical condition 
(eg, allergies, asthma etc), in which corticosteroid withdrawal would be detrimental. In 
this case the Investigator would administer the lowest efficacious dose. The potential 
benefits expected by the administration of venglustat outweigh the potential drawbacks 
that can be observed by the initiation/worsening of cataracts. 
• 
Psoralens used in dermatology with ultraviolet light therapy. 
• 
Typical antipsychotics. 
The Investigator should consider substituting medications listed in the previous paragraphs for 
noncataractogenic treatments, as appropriate.  
In addition, alpha-adrenergic glaucoma medications are excluded from the current trial since they 
can worsen the vision of participants with cataracts. 
Atypical antipsychotics are allowed. 
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6.5.1.4 Other medications  
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. 
6.5.2 COVID-19 vaccination  
Immunotoxicology-related parameters (eg, immunophenotyping, total immunoglobulin levels) 
were not evaluated in the repeat-dose toxicology studies.  Based on the available preclinical data 
(venglustat-related hematological and histopathological changes to immune system 
tissues/organs) and data from clinical studies, it is unlikely that venglustat has immunomodulatory 
properties and would have an impact on the immune system. 
The coronavirus disease-2019 (COVID-19) vaccines that have been authorized for use are 
considered as a concomitant medication with no interaction that requires advice on timing or other 
aspects of the vaccination. 
If the COVID-19 vaccine is authorized, available, and recommended by the local regulatory 
authority and/or health authority for patients like those in this study, the vaccine can be 
administered during the study and should be administered according to the label or 
recommendations of the local regulatory authority and/or health authority. 
COVID-19 vaccination during study period should be reported in the ‘concomitant medications’ 
eCRF page.  
Each injection will be reported into different loglines.  
The vaccine name (brand or generic), dose and date of injection will be captured.  
Adverse events related to COVID-19 vaccination will be collected and reported similarly to any 
other AEs in study. 
6.6 
DOSE MODIFICATION  
and criteria for study intervention discontinuation described in Section 7.1, study 
intervention dose reduction or modification is not allowed during the study. 
6.7 
INTERVENTION AFTER THE END OF THE STUDY  
Not applicable. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
7.1 
DISCONTINUATION OF STUDY INTERVENTION   
7.1.1 Definitive discontinuation  
The IMP should be continued whenever possible.  
In case the IMP is stopped, it should be determined whether the stop can be made temporarily. In 
rare instances, it may be necessary for a participant to permanently discontinue study intervention 
before the end of treatment visit. If study intervention is permanently discontinued, the participant 
will remain in the study to be evaluated for safety and efficacy. See the SoA (Section 1.3) for data 
to be collected at the time of discontinuation of study intervention. 
Definitive intervention discontinuation is any intervention 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 due to whatever the 
reason. 
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 ALT >5 × ULN range or confirmed 
ALT >3 × ULN and bilirubin >2 × ULN). 
• 
The participant is no longer deriving a therapeutic/clinical benefit in the opinion of the 
Investigator. 
• 
The participant develops grade 3 cataract or higher. 
• 
The participant becomes pregnant. 
Study specific: 
• 
Any AEs, per Investigator judgment, that may jeopardize the participant’s safety. 
• 
Any use of prohibited concomitant treatment (see Section 6.5.1). 
• 
At participant’s request, ie, withdrawal of the consent for treatment. 
Discontinuation of study intervention for abnormal liver function should be considered by the 
Investigator when a participant meets one of the conditions outlined in Appendix 6 (Section 10.6) 
or if the Investigator believes that it is in best interest of the participant.    
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See the SoA for data to be collected at the time of intervention discontinuation and follow-up and 
for any further evaluations that need to be completed. 
Any clinically significant abnormal laboratory value or ECG parameter will be immediately 
rechecked for confirmation before making a decision of definitive discontinuation of the IMP for 
the concerned participant. 
The DMC will also review data if applicable to assist in determining if AEs should preclude 
continued treatment with study intervention and if stopping rules apply. 
Handling of participants after definitive 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 definitive discontinuation of intervention, the participants will be 
assessed using the procedure normally planned for the last dosing day with the IMP including 
a PK sample, if appropriate. 
All cases of definitive intervention discontinuation must be recorded by the Investigator in the 
appropriate pages of the eCRF when considered as confirmed. 
7.1.2 Discontinuation criteria  
Temporary intervention discontinuation may be considered by the Investigator because of 
suspected AEs. In case of an SAE or ≥ Grade 3 AE (NCI, CTCAE v5) that is considered by the 
Investigator to be related to IMP and not to underlying disease or concomitant medication, the 
dose may be temporarily discontinued. For all temporary intervention discontinuations, duration 
should be recorded by the Investigator in the appropriate pages of the eCRF.  
In the event that an SAE or ≥ Grade 3 AE (NCI CTCAE Version 5) is observed that is considered 
by the Investigator to be related to IMP and not to underlying disease or concomitant medication, 
the case will be communicated to the DMC and a decision reached regarding continued dosing. If 
≥2 patients receiving IMP develop the same SAE or AE (≥ Grade 3) that is considered related to 
IMP dosing, the study may be halted. The DMC will review the data and provide recommendations 
on how to proceed. Additionally, the DMC can recommend stopping or modifying the study based 
on a single event or on aggregate analysis of multiple events. Should any major safety issues arise, 
final decisions regarding the study will be made by the Sponsor’s Medical Lead and Global Safety 
Officer, taking into consideration the DMC opinion (as applicable). 
Temporary intervention discontinuation may be considered by the Investigator because of 
suspected AEs, life emergencies for the patient, or disruption of the clinical trial due to a regional 
or national emergency declared by a governmental agency (Section 10.11 (Appendix 11): 
Contingency Measures for a regional or national emergency that is declared by a governmental 
agency). For all temporary intervention discontinuations, duration of the discontinuation should 
be recorded by the Investigator in the appropriate pages of the CRF or eCRF. 
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7.1.2.1 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 event was 
unlikely and if the selection criteria for the study are still met (refer Section 5.1 and Section 5.2). 
During a regional or national emergency declared by a governmental agency, reinitiation of IMP 
can only occur once the Investigator has determined, according to his/her best judgement, that the 
contribution of the IMP(s) to the occurrence of the epidemic event (eg, COVID-19) was unlikely.  
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 10.11 (Appendix 11).  
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, 
compliance, or administrative reasons. This is expected to be uncommon. 
• 
At the time of discontinuing from the study, if possible, an early discontinuation visit 
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. Lumbar puncture will not be repeated if it has been performed recently and 
will be decided on case by case basis. 
• 
The participant will be permanently discontinued both from the study intervention and 
from the study at that time. 
• 
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. 
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. 
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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 nonparticipant 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 re-enrolled 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. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1.9). 
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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 screening 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) and obtained before signing of the informed consent form (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. 
• 
The maximum amount of blood collected from each adult participant over the duration of 
the study, will be approximately 208 mL for participants of the main study and 216 mL for 
participants of the W1/D1 PK profile evaluation substudy. Additional repeat or 
unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 
For pediatric participants blood samples will be obtained as blood volume permits and will 
not exceed the blood volume collection limit of 5-7 mL/kg over an 8 week period. 
Sampling is prioritized for biomarker, PK hematology and biochemistry labs and then 
archival, ADME and pharmacogenetics tests.  
8.1 
EFFICACY ASSESSMENTS   
8.1.1 9-hole peg test  
The 9-HPT was originally introduced in 1971 as a measure of dexterity, in an official publication 
of the American Society for Occupational Therapy (19). The report provided approximate 
dimensions of the material and general procedures of administration. A detailed test instructions 
and adult normative values according to hand, sex, and age were available in 1985 (20).  
Manual dexterity (including hand function) is an individual’s ability to coordinate the fingers and 
manipulate objects in a timely manner. Such ability greatly impacts a person’s performance in 
daily activities (bathing, grooming, eating), completing work-related tasks, and engaging in 
leisure activities. It also serves as an indicator of academic performance (eg, handwriting), work 
performance (eg, machine workers, dentists, surgeons), and independent living.  
Further details will be provided in the study reference manual. 
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8.1.2 25-Foot walk test  
The 25FWT is a quantitative mobility and leg function performance test based on a timed 25-foot 
walk. The 25FWT has high inter-rater and test-retest reliability and shows evidence of good 
concurrent validity. The participant is directed to one end of a clearly marked 25-foot course and 
is instructed to walk 25 feet as quickly as possible, but safely. The time is calculated from the 
initiation of the instruction to start and ends when the participant has reached the 25-foot mark. 
The task is immediately administered again by having the participant walk back the same 
distance. Participants may use assistive devices when doing this task. Further details will be 
provided in the study reference manual. 
8.1.3 Friedreich’s Ataxia Rating Scale (excluding the 9-HPT portion and the 25FWT)  
The FARS scale is a composite clinician-reported outcome (ClinRO)/patient-reported outcome 
(PRO)/observer-reported outcome (ObsRO)/PerfO, which measures the severity of neurologic 
dysfunction in patients with inherited ataxias. It includes 4 domains: functional staging for ataxia 
(1 item; ClinRO); ADL (9 items; PRO/ClinRO/ObsRO); FARS-Neuro (23 items; PerfO); and 
a battery of related tests including 25FWT, 9-HPT, and PATA rate (PerfO). It assesses not only 
functional staging of ataxia, but also evaluates bulbar manifestations, coordination, muscle 
weakness, gait, speech, and swallowing, as well as the impact of the neurological deficits on 
activities of daily living, all areas affected by GM2 gangliosidosis. The results are gathered with 
a paper questionnaire with sections for each subdomain. Further details will be provided in the 
study reference manual. 
8.1.4 
8.1.5 
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8.1.6 
 
8.1.7 
8.1.8 
8.1.8.1 
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8.1.8.2 
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8.1.8.3 
8.1.8.4 
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8.1.9 
8.1.10 
8.1.11 Muscle weakness of triceps and quadriceps  
Muscle weakness is one of the typical clinical presentations of late onset GM2-gangliosidosis. 
Natural history data shows that psoas was the first and most affected muscle in the lower limbs, 
the quadriceps was also commonly involved. The triceps and interosseous were predominantly 
involved in the upper limbs (28). Psoas and interosseous weakness will be evaluated in 
FARS-Neuro. The muscle weakness of triceps and quadriceps will be assessed and considered 
a sensitivity analysis of the FARS-Neuro. 
8.1.12 Regional or national emergency  
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 
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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.  
Procedures to be considered in the event of a regional or national emergency declared by 
a governmental agency: 
• 
If onsite visits are not possible, remote visits (eg, with home nurses, home health vendor, 
etc) may be planned for the collection of possible safety and/or efficacy data.  
• 
If onsite visits are not possible visit windows may be extended for assessment of safety 
and/or efficacy data that cannot be obtained remotely.  
• 
Use of local clinic or laboratory locations may be allowed. 
Contingencies implemented due to emergency will be documented in eCRF.  
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  
Section 10.11 (Appendix 11). 
8.2 
SAFETY ASSESSMENTS   
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1 Physical examinations  
• 
A complete/full physical examination will include, at a minimum, assessments of the 
general appearance, examination of the skin; head, eyes (including visual acuity), ears, 
nose, and throat; lymph nodes; heart, lungs, and abdomen; extremities and joints; and 
neurological and mental status. Height and weight will also be measured and recorded. 
• 
An abbreviated/brief physical examination will include, at a minimum, general 
assessments. 
• 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
• 
Any new finding or worsening of previous finding should be reported as a new AE. 
8.2.2 Neurological examination  
• 
Each neurological examination will include, but not be limited to, assessments of the 
patient’s mental status, cranial nerves, motor system (including muscle atrophy, tone and 
power), deep tendon reflex, sensory, and cerebellar function. The examination should be 
performed by the same neurologist throughout the study, if possible. When neurological 
and ophthalmological examinations are performed on the same day, the neurological 
examination should be performed before the ophthalmological examination. 
8.2.3 Vital signs  
• 
Body temperature, heart rate, respiratory rate, and blood pressure will be assessed. 
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• 
Blood pressure and pulse measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available. 
• 
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions (eg, television, cell phones). 
• 
Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse 
and 3 blood pressure measurements (3 consecutive blood pressure readings will be 
recorded at intervals of at least 1 minute). The average of the 3 blood pressure readings 
will be recorded on the eCRF.  
• 
Ideally, pulse and blood pressure should be obtained and recorded while the participant is 
in the supine position as well as in the standing position. If the participant is unable to 
stand, blood pressure may be taken while the participant is sitting with feet dangling. If the 
participant is unable to stand or sit, pulse and blood pressure may be taken in supine 
position only. 
8.2.4 Electrocardiograms  
• 
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 
corrected QT (QTc) intervals.  
• 
For Day 1/Week 1, triplicate ECG (3 ECGs) will be recorded within 5 minutes with at 
least 1 minute between 2 replicates prior to IMP administration. 
• 
The ECG will be read centrally.  
8.2.5 Ophthalmological examination  
The effect of venglustat on the lens will be closely monitored throughout the whole study for all 
participants. The full ophthalmological examination will include slit-lamp examination, 
fundoscopy with pupil dilation and examination of the cornea, lens, and retina.  
The evaluation of the lens by photography according to the Age-Related Eye Disease Study 
(AREDS) Clinical Lens Grading System (ARLNS) will be performed during screening, 
Week 104, Week 208, early withdrawal or treatment discontinuation, or any time deemed 
medically necessary. 
A conventional confrontation visual field examination such as the Donders’ test can be performed 
by the local ophthalmologist as needed as a part of the eye examination. Systematic visual field 
test by perimetry is not required for this trial.  
A full ophthalmological examination, photography, and ARLNS will be performed during 
screening (this will serve as a baseline assessment), at Week 104 and at Week 208, or at early 
withdrawal or treatment discontinuation for all participants.  
A full ophthalmological examination will be performed at Week 26, Week 52, and Week 78 for all 
participants and also at Week 130, Week 156, and Week 182 for participants aged ≥2 and <18 years. 
Full ophthalmological examination can be performed at any time if deemed medically necessary. 
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If a lens abnormality is found, the ophthalmologist at the site should perform pupil dilation, 
photography, and ARLNS evaluation. 
The full ophthalmological examination should be performed by the same ophthalmologist 
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 an adverse event of special 
interest (AESI) and assess their seriousness/severity. 
When neurological and ophthalmological examinations are performed on the same day, the 
neurological examination should be performed before the ophthalmological examination. 
8.2.6 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 relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant 
abnormal laboratory findings are those which are not associated with the underlying 
disease, 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 or Medical Monitor. 
- 
If such 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 assessments, as defined in Appendix 2 (Section 10.2), 
must be conducted in accordance with the laboratory manual and the SoA.  
- 
If laboratory values from nonprotocol-specified laboratory assessments 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.  
8.2.7 
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8.2.7.1 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
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. Adverse events of special interest 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; 
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- 
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 (see the “Increase in ALT” flow diagram in Appendix 6 [Section 10.6]). 
• 
Other project specific AESI(s) 
- 
New or worsening lens opacities and cataracts.  
The definitions of an AE or SAE can be found in Appendix 3 (Section 10.3). 
Adverse events 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 AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention and/or study (see Section 7). 
8.3.1 Time period and frequency for collecting AE and SAE information  
All AEs, AESIs, and SAEs will be collected from the signing of the ICF until the 6-week 
follow-up visit at the time points specified in the SoA (Section 1.3). 
All SAEs and AESI 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 AE or SAE 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. 
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8.3.2 Method of detecting AEs and SAEs  
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading 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 
nonserious AESI (as defined in Section 8.3) 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 given in Appendix 3 (Section 10.3). 
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. 
• 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
• 
Adverse events that are considered expected will be specified in the reference safety 
information. 
• 
An Investigator who receives an Investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the Sponsor will review 
and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, if 
appropriate according to local requirements. 
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 6-week follow-up visit. 
• 
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4 
(Section 10.4). 
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• 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
8.3.6 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. 
8.4 
TREATMENT OF OVERDOSE  
Overdose is defined as at least twice the intended dose within the intended therapeutic interval, 
adjusted according to the tested drug. Sponsor does not recommend specific treatment for 
an overdose. 
In the event of an overdose, the Investigator should: 
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 case report form (CRF). 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
8.5 
PHARMACOKINETICS  
• 
Sampling time: Blood and CSF samples for plasma and CSF venglustat concentration 
assessment will be collected from all participants throughout the study according to the 
time points shown in the SoA (Section 1.3). Exact date and time of IMP administration 
and PK sampling are to be recorded in eCRF. For PK sample collected at end-of-treatment 
visit in case of premature treatment discontinuation, time of last dose and time of PK 
sample collected should be accurately recorded in eCRF. 
• 
Pharmacokinetics sample handling procedure: Special procedures for collection, storage, 
and shipment of plasma and CSF samples will be described in a separate laboratory 
manual provided by the central laboratory. Approximately 2 mL of blood sample and 
0.5 mL of CSF sample will be collected at each time point. 
• 
Bioanalytical method: Venglustat plasma concentrations will be determined using 
a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) method 
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(DMPK15-R012) with a lower limit of quantification (LLOQ) of 0.5 ng/mL under the 
responsibility of QPS, Newark, Delaware, USA. Venglustat CSF concentrations will be 
determined using a validated LC-MS/MS method (DMPK15-R016) with a LLOQ of 
0.1 ng/mL under the responsibility of QPS, Newark, Delaware, USA. 
• 
Pharmacokinetic parameters: Plasma PK parameters including, Cmax, tmax, and AUC0-24 
will be determined using noncompartmental methods (when data permits). In addition, PK 
variables will include plasma and CSF venglustat concentrations determined at each time 
point described in the SoA (Section 1.3). Depending on the timing of the PK sample 
collection versus the previous dose, venglustat PK parameters will be defined as follows:  
- 
Cmax: Venglustat concentration sample taken 2 to 4 hours after IMP administration 
- 
Ctrough: Venglustat concentration sample taken just prior to IMP administration 
• 
Exploratory venglustat metabolite profiling and/or metabolite exposure analysis may be 
conducted in the collected plasma samples. 
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded.  
8.6 
PHARMACODYNAMICS  
Cerebrospinal fluid and plasma will be collected at the times specified in the SoA (Section 1.3) 
for the assessment of PD markers. Special procedures for collection, storage, and shipment of 
plasma and CSF samples will be described in a separate laboratory manual provided by the central 
laboratory. Approximately 7-8 mL of whole blood and 3-4 mL of CSF will be collected at each 
time point. 
GM2 and GL-1 biomarkers will be assessed from plasma and CSF from all participants in the 
primary population using validated methods performed at the Sponsor’s laboratory or at 
a subcontracted laboratory.  
For the secondary population participants only, GL-1 biomarker and a pathway specific biomarker 
will be assessed from CSF and plasma as follows: 
Disease 
Biomarker 
GM2 gangliosidosis 
GL-1, GM2 
GM1 gangliosidosis 
GL-1, GM1 
Sialidosis 
GL-1, GM2, GM3 
Galactosialidosis 
GL-1, GM1, GM3 
Saposin C Deficiency 
GL-1 only 
Additional plasma and CSF biomarkers may include but are not limited to the following: 
lipidomics, gpNMB, and neurofilament. 
Biomarker results may unblind the study; they will not be reported to investigative sites or blinded 
personnel until the study has been unblinded. 
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8.6.1 Lumbar puncture  
The lumbar puncture (LP) will be performed by the site Investigator or another qualified clinician 
appointed by the Investigator.  
An LP for the collection of approximately 7 to 8 mL of CSF at each collection will be conducted 
for participants per the visit schedule, unless there is evidence of clinically significant 
coagulopathy or thrombocytopenia or other relevant reason that would interfere with the safe 
conduct of the procedure. It is expected that all participants will undergo an LP at baseline and 
W104. The baseline LP can be done within 14 days prior to the day of randomization (pre-dose).  
The first 1 to 2 mL of CSF may be discarded; the subsequent 2 mL will be processed at the site’s 
local laboratory facility (unless the laboratory is not able to process the CSF within 4 hours) to 
conduct standard analyses on cell count, including red blood cell counts, protein and glucose. The 
remaining CSF will be processed and shipped to a central laboratory for biomarker (approximate 
3 mL) and PK assessments (approximate 0.5 mL). For pediatric participants, the CSF sampling is 
prioritized for biomarker and PK. Please refer to the laboratory manual provided by the central 
laboratory. 
Participants will be closely monitored during the procedure and lying flat in bed rest for at least 
1 hour following the procedure. 
8.7 
ACCEPTABILITY AND PALATABILITY  
For the secondary pediatric population, the acceptability and palatability of venglustat tablets will 
be assessed through the route of venglustat administration collected in the eCRF and study 
intervention compliance (see Section 6.4) throughout the whole study.   
8.8 
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8.9 
Refer to Section 8.11 for further details regarding use of biological samples and data for future 
use. 
8.10 
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8.11 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH  
Future research may help further the understanding of disease subtypes, disease biology, related 
conditions, mechanism of action, or possible 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 (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 (leftover) and/or 
extra (additional) clinical samples, data and samples may be used 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. 
Remaining leftover samples will be used only after the study ends, ie, end of study as defined in 
the study protocol. Additional/extra samples can be collected and used during the study conduct at 
a given timepoint (eg, at randomization visit) as defined in the study protocol. 
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 alignment with the information provided to participants in the ICF Part 2 
(future research). For future research projects, all biological samples and relating data to be used 
will be coded such that no participant direct identifiers will be linked to them. These 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). 
Relating data and biological samples for future research will be stored for up to 25 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. 
Participant’s coded datasets 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). 
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9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES  
The study is designed to test the following hypotheses for the 2 co-primary endpoints in the 
primary population: 
• 
Percent change in CSF GM2 biomarker: 
- 
Null hypothesis: No difference between venglustat and placebo with regards to mean 
percent change in CSF GM2 biomarker from baseline to Week 104 
- 
Alternative hypothesis: Venglustat has higher reduction in CSF GM2 biomarker from 
baseline to Week 104 compared to placebo 
• 
Annualized rate of change in 9-HPT: 
- 
Null hypothesis: No difference between venglustat and placebo with regards to mean 
annualized rate of change in 9-HPT 
- 
Alternative hypothesis: Venglustat has lower mean annualized rate of change in 9-HPT 
compared to placebo 
9.2 
SAMPLE SIZE DETERMINATION  
In the primary population, approximately 57 participants will be randomly assigned with 
a 2:1 randomization ratio to venglustat (n=38) or placebo (n=19). This sample size will provide 
approximately 80% power to detect a difference between venglustat and placebo with regards to 
the primary efficacy endpoint of annualized rate of change in 9-HPT. 
 
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The sample size for the secondary population (up to 20) is not based on statistical power calculation, 
but on empirical considerations. The Sponsor will attempt to enroll at least 1 participant, aged 2 years 
or older (or aged 2 to <18 years for juvenile/adolescent late-onset GM2 gangliosidosis), in each 
disorder. This is in addition to the 57 participants from the primary population. 
9.3 
POPULATIONS FOR ANALYSES  
For purposes of analysis, the following populations are defined (Table 5): 
Table 5 - Populations for analyses  
Population 
Description 
Screened 
All participants who sign the ICF 
Randomized population 
All participants who have been allocated a treatment kit based on the randomization 
process and recorded in the IRT database, regardless of whether the treatment kit was 
used or not 
Primary efficacy population 
All randomized participants with diagnosis of late-onset GM2 gangliosidosis aged 
≥18 years. Participants will be analyzed according to the intervention assigned by 
randomization. 
Primary PD population 
All randomized participants with diagnosis of late-onset GM2 gangliosidosis aged 
≥18 years who received at least 1 dose of study medication and who have baseline and 
postbaseline assessments of PD. Participants will be analyzed according to the 
intervention they actually received. 
Primary PK population 
All randomized participants with diagnosis of late-onset GM2 gangliosidosis aged 
≥18 years who received at least 1 dose of study medication and who have at least 1 PK 
assessment 
Primary safety population 
All randomized participants with diagnosis of late-onset GM2 gangliosidosis aged 
≥18 years who received at least 1 dose of study medication. Participants will be 
analyzed according to the intervention they actually received. 
Secondary efficacy population 
All enrolled participants with a clinical diagnosis of juvenile/adolescent late-onset GM2 
gangliosidosis, GM1 gangliosidosis, Saposin C deficiency, Sialidosis Type 1, or 
juvenile/adult galactosialidosis. 
Secondary PD population 
All enrolled participants with a clinical diagnosis of juvenile/adolescent late-onset GM2 
gangliosidosis, GM1 gangliosidosis, Saposin C deficiency, Sialidosis Type 1, or 
juvenile/adult galactosialidosis, who received at least 1 dose of study medication and 
who have baseline and postbaseline assessments of PD.  
Secondary PK population 
All enrolled participants with a clinical diagnosis of juvenile/adolescent late-onset GM2 
gangliosidosis, GM1 gangliosidosis, Saposin C deficiency, Sialidosis Type 1, or 
juvenile/adult galactosialidosis, who received at least 1 dose of study medication and 
who have who have at least one PK assessment 
Secondary safety population 
All enrolled participants with a clinical diagnosis of juvenile/adolescent late-onset GM2 
gangliosidosis, GM1 gangliosidosis, Saposin C deficiency, Sialidosis Type 1, or 
juvenile/adult galactosialidosis, who received at least 1 dose of study medication. 
Abbreviations: ICF, informed consent form; IRT, interactive response technology; PD, pharmacodynamics; PK, pharmacokinetics. 
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9.4 
STATISTICAL ANALYSES  
The statistical analysis plan will be developed and finalized before the analysis of the primary 
analysis treatment period and will describe the participant populations to be included in the 
analyses, and procedures for accounting for missing, unused, and spurious data. This section is 
a summary of the planned statistical analyses of the primary and secondary endpoints. 
9.4.1 Efficacy analyses  
Table 6 - Efficacy analyses  
ndpoint 
Statistical Analysis Methods 
Primary 
Coprimary endpoint in the primary population: 
Percent change in CSF GM2 biomarker from baseline to Week 104 
Percent change in CSF GM2 biomarker from baseline to Week 104 will be analyzed using an ANCOVA 
including the fixed effect of treatment (venglustat versus placebo) and the continuous fixed covariate of 
baseline value. 
In case the results from the ANCOVA may be severely impacted by the presence of outliers (participants 
with extremely low or high percent change in CSF GM2), the ANCOVA will be replaced by a robust 
ANCOVA, using Huber’s M estimation. The robust ANCOVA will also include the fixed effect of treatment 
(venglustat vs. placebo) and the continuous fixed covariate of baseline value. 
The exact criterion to determine whether the robust ANCOVA should be used will be described in the 
Statistical Analysis Plan (SAP). 
 
Annualized rate of change in 9-HPT from baseline to Week 104 
Annualized rate of change in 9-HPT will be compared between venglustat and placebo using a linear 
mixed-effect model. 
The model will assume linear change over time in 9-HPT (after log transformation). The logarithm 
transformation was selected due to anticipated non-normal distribution of the 9-HPT. Analysis of natural 
history data showed that logarithm transformation improved the normality of the distribution and reduced 
the impact of outliers. A logarithm transformation will allow interpretation in terms of relative increase in 
time to complete the 9-HPT (annual % increase per year).  
The model will include separate slopes for the venglustat and placebo arms. Actual time relative to 
randomization of all planned assessments at Week 12, Week 26, Week 52, Week 78, and Week 104 will 
be taken into account in the model. In addition, the model will include a random intercept and slope in 
order to account for the between participants variability. A residual variance will account for the within-
participant variability. 
The linear mixed-effect model will be estimated in a Frequentist framework. 
If the results from the linear mixed-effect model are severely impacted by the presence of data outliers 
(participants with extremely low or extremely high slope of log-transformed 9-HPT), the linear mixed-effect 
model will be replaced by the robust ANCOVA on individual slopes.  
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ndpoint 
Statistical Analysis Methods 
The exact criterion to determine whether the robust ANCOVA should be used will be described in the SAP. 
A secondary analysis will be estimated in a Bayesian framework with an informative prior distribution for 
the slope in the placebo arm. This informative prior distribution was determined based on the annualized 
rate of change in 9-HPT observed in a natural history study. The prior distribution will assume a normal 
distribution for the annual slope of 9-HPT (on a logarithm scale) in the placebo arm, with mean of 0.0264 
and standard deviation of 0.0118. 
A sensitivity analysis will assess the impact of the assumption of joint multivariate normal distribution for 
the random intercept and slope. In this sensitivity analysis, individual slopes of each participant will be 
estimated from a linear model fitted separately in each participant, with log-transformed 9-HPT as 
dependent variable and time (in years) as explanatory variable. A comparison of mean slopes between the 
venglustat and the placebo arm will then be conducted using a robust ANCOVA of individual slopes using 
Huber’s M estimation, including the fixed effect of treatment (venglustat versus placebo) and the 
continuous fixed covariate of baseline value. In order to take into account potential differences between 
participants with regards to the number of assessments and duration of follow-up, the ANCOVA will be 
weighted by the sum of squares of centered time of assessment of each participant. This sensitivity 
analysis will be conducted in a Frequentist framework and correspond to the analysis planned in case of 
outliers. 
A sensitivity analysis will assess the impact of the logarithm transformation. In this sensitivity analysis, the 
linear mixed-effect model will be fitted to the 9-HPT without logarithm transformation. In case of presence 
of outlier, the linear mixed-effect model will be replaced by the robust ANCOVA on individual slopes as for 
the primary analysis. Another sensitivity analysis will use the reciprocal of the 9-HPT.These sensitivity 
analyses will be conducted in a Frequentist framework. 
A sensitivity analysis will assess the impact of the assumption of linearity of change. A mixed effect model 
with repeated measures (MMRM) with the categorical fixed factor of time (representing scheduled visits) 
will be used. Change from baseline in log-transformed 9-HPT at the different time-points will be included in 
this model, with the fixed effects of treatment group (venglustat versus placebo), time point (Week 12, 
Week 26, Week 52, Week 78, and Week 104) treatment-by-time point interaction as well as the continuous 
fixed covariates of baseline log-transformed 9-HPT. This sensitivity analysis will be conducted in 
a Frequentist framework. 
Handling of missing data 
The primary analysis will include all data collected in participants from the primary population, regardless of 
whether or not participants completed the treatment period. Participants who prematurely and permanently 
discontinue study medication will be requested to continue to be assessed after treatment discontinuation, 
up to the Week 104 visit. Data collected after treatment discontinuation will be included in the primary 
analysis. All efforts will be made to minimize the amount of missing data. 
The linear mixed effect model described for the primary analysis will be run on all observed data, including 
data collected after treatment discontinuation. Missing data will be handled by the model assuming 
a Missing At Random mechanism. 
Due to the small sample size in this study, it is expected that a model based imputation of missing data will 
not be feasible. In particular, imputation of missing data based on a model estimated from participants from 
the same treatment arm who discontinued the study treatment but continued to have their data collected 
will likely be unfeasible, due to the small number of participants in this category. 
Multiplicity of primary endpoints: No adjustment for multiplicity will be considered for the co-primary 
endpoints (percent change in CSF GM2 biomarker from baseline to Week 104 and annualized rate of 
change in 9-HPT) since it will be necessary to demonstrate an effect on both co-primary endpoint to 
conclude to efficacy. 
Primary endpoints in the secondary population: 
Plasma and CSF GL 1 biomarker and pathway specific biomarkers in the secondary population will be 
summarized descriptively. Percent change from baseline in plasma and CSF GL-1 biomarker will be 
described for the entire secondary population. The pathway specific biomarker will be described separately 
for each disease in the secondary population. When at least 5 participants have available data in the entire 
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ndpoint 
Statistical Analysis Methods 
secondary population or within a specific disease, a 95% confidence interval for the percent change from 
baseline will be provided. In addition, biomarker data will be summarized descriptively with individual plots 
and listings. No formal comparison will be performed in the secondary population. 
Secondary 
Secondary endpoints in the primary population: 
Absolute change in CSF GM2 biomarker from baseline to Week 104 
Absolute change in CSF GM2 biomarker will be analyzed with the similar approach used for the percent 
change in CSF GM2 biomarker.  
Change in 25FWT from baseline to Week 104 (in participants able to walk at baseline) 
Change in 25FWT will be analyzed only in participants able to walk at baseline. Participants who did not 
complete the 25FWT at baseline will be excluded from this analysis. 
Change in 25FWT will be compared between venglustat and placebo using a linear mixed-effect model 
with random intercept and slopes or using a robust ANCOVA on individual slopes, similar to the model 
used for the primary analysis of 9-HPT.  
Change in the neurological examination of the FARS from baseline to Week 104 
Change in the neurological examination of the FARS will be compared between venglustat and placebo 
using the same statistical model described for the primary analysis of 9-HPT.  
Multiplicity of secondary endpoints: In order to handle multiple secondary endpoints, the overall type-I error 
will be controlled by the Hochberg procedure. Statistical significance of the two co-primary endpoints is 
required before drawing inferential conclusions about secondary endpoints. 
Secondary endpoints in the secondary population: 
Secondary endpoints in the secondary population will be summarized descriptively with individual plots and 
listings. When at least 5 participants have available data at baseline and Week 104, mean change from 
baseline to Week 104 will be provided with 95% confidence interval. No formal comparison will be 
performed in the secondary population. 
Exploratory 
Will be described in the statistical analysis plan finalized before database lock. 
Abbreviations: 25FWT, 25-foot walk test; 9-HPT, 9-hole peg test; ANCOVA, analysis of covariance; CSF, cerebrospinal fluid; FARS, Friedreich’s 
Ataxia Rating Scale. 
9.4.2 Safety analyses  
Primary safety analyses will be performed on the primary safety population. 
Safety data will be described separately for the participants in the secondary safety population. 
9.4.3 Pharmacokinetic analyses  
Plasma PK parameters will be determined using noncompartmental methods (when data permits) 
and summarized using descriptive statistics. Plasma and CSF venglustat concentrations will be 
summarized separately using descriptive stats, by visit and will be described in the statistical 
analysis plan. PK data will be described separately in the secondary population. 
Plasma and CSF venglustat concentration data might be used for population PK modeling if 
considered necessary and the results for population PK modeling will be reported separately from 
the clinical study report (CSR). The population PK analyses will characterize the inter- and intra-
participant variability in pharmacokinetic parameters and evaluate the effect of covariates such as, 
renal function status (creatinine clearance) on the venglustat PK. 
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An evaluation of the correlation between exposure and efficacy and safety may be performed to 
evaluate exposure-response relationships. Plasma PK parameters may be estimated for 
metabolites using noncompartmental methods and reported for individual participants and 
summarized using descriptive statistics. 
9.4.4 Other analyses  
Pharmacodynamic and biomarker exploratory analyses will be described in the statistical analysis 
plan finalized before database lock. 
The impact of the regional or national emergency declared by a governmental agency on study 
conduct will be summarized (eg, study discontinuation or discontinuation/delay/omission of the 
intervention due to the emergency). Any additional analyses and methods required to evaluate the 
impact on efficacy (eg, missing data due to the emergency) and safety will be detailed in the SAP. 
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  
Section 10.11 (Appendix 11). 
9.5 
INTERIM ANALYSES   
No interim analyses are planned.  
The analysis will be conducted in two steps: 
• 
First step: Primary analysis treatment period: 
The final analysis of the primary analysis period of the study will be conducted when all 
participants have completed the primary analysis period of the study. It will consist in the 
final analysis of the primary, secondary, and exploratory endpoints at 104 weeks. The 
analysis of the primary analysis period will be conducted when all participants have 
completed the Week 104 visit or have prematurely discontinued the study. 
• 
Second step: analysis of the OLE treatment period: 
The final analysis of the OLE treatment period of the study will be conducted when all 
participants have completed the Week 208 visit and safety follow up visit or have 
prematurely discontinued the study. 
9.5.1 Data Monitoring Committee (DMC)  
An independent DMC will be used to monitor safety of the study. Unblinded DMC reports will be 
prepared by an independent unblinded statistician. Timing of such reviews as well as the specific 
responsibilities and mode of operation of the DMC will be described in the DMC charter.  
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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 GCP Guidelines 
- 
Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, Investigator Brochure, 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. 
• 
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 
- 
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 Code of Federal Regulation (CFR), ICH guidelines, the IRB/IEC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations 
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. 
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10.1.3 Informed consent process  
• 
The Investigator or his/her representative will explain the nature of the study to the 
participant and/or participant’s parent(s)/legal guardian(s) and answer all questions 
regarding the study.  
• 
Participant and/or participant’s parent(s)/legal guardian(s) must be informed that their 
participation is voluntary. Participant and/or participant’s parent(s)/legal guardian(s) will 
be required to sign a statement of informed consent that meets the requirements of 21 CFR 
50, local regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study center.  
• 
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. 
• 
Participant and/or participant’s parent(s)/legal guardian(s) must be re-consented to the 
most current version of the ICF(s) during their participation in the study.  
• 
A copy of the ICF(s) must be provided to the participant and/or participant’s 
parent(s)/legal guardian(s).  
Participants who are rescreened are required to sign a new ICF. 
The ICF will contain a separate section that addresses the use of remaining mandatory samples for 
optional exploratory research. The Investigator or authorized designee will explain to each 
participant the objectives of the exploratory 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. A separate signature will be required to document a participant's agreement to 
allow any remaining specimens to be used for exploratory research. Participants who decline to 
participate in this optional research will not provide this separate signature. 
10.1.4 Data protection  
All personal data collected related to participants, Investigators, or any person involved in the 
study, which may be included in the Sponsor’s databases, shall be treated in compliance with all 
applicable laws and regulations including the Global Data Protection Regulation (GDPR). 
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 these data are required by 
regulatory agencies (eg, on afro American population for the FDA or on Japanese population for 
the Pharmaceuticals and Medical Devices Agency in Japan)”. 
• 
Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
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• 
The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must also 
be explained to the participant. 
• 
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. 
• 
When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor shall take all appropriate measures to safeguard and prevent 
access to this data by any unauthorized third party. 
10.1.5 Committees structure  
Study committees 
A DMC, operating independently from the Sponsor and Clinical Investigators, will be responsible 
for overseeing the safety of participants and the risk/benefit ratio throughout the study. This 
committee is composed of externally based individuals with expertise in the disease under study, 
biostatistics, and/or clinical research. The primary responsibilities of the DMC are to ensure the 
participant’s welfare as well as to evaluate and review the safety and other applicable data 
throughout the course of the study and make appropriate recommendations to the Sponsor 
regarding the conduct of the clinical trial. The specific responsibilities of the DMC will be 
described in the DMC Charter. 
10.1.6 Dissemination of clinical study data  
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, European Union 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. 
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10.1.7 Data quality assurance  
• 
All participant data relating to the study will be recorded on printed or electronic CRF 
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 CRF. 
• 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• 
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). 
• 
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF 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. 
• 
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 study reference manual. 
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10.1.9 Study and site closure  
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 the early closure of a study site by the Sponsor or Investigator may include but are 
not limited to: 
• 
The information on the product leads to doubt as to the benefit/risk ratio. 
• 
Participant enrollment is unsatisfactory. 
• 
Noncompliance of the Investigator or Sub-Investigator, delegated staff with any provision 
of the clinical trial protocol, and breach of the applicable laws and regulations or breach of 
the ICH GCP. 
• 
The Investigator has received from the Sponsor all IMP, means, and information necessary 
to perform the clinical trial and has not included any participant after a reasonable period 
of time mutually agreed upon. 
• 
The total number of participants are included earlier than expected. 
• 
If the study no longer meets the development needs of the compound or business needs of 
the company. 
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. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS  
• 
The tests detailed in Table 7 will be performed by the central laboratory, except urinalysis 
by dipstick and “other tests” as listed in Table 7. 
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• 
, which will be performed at the study site. If local laboratory results are used to make a 
study treatment decision, response evaluation, or to diagnose/follow-up an AE, the results 
must be entered into the eCRF. 
• 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
• 
Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations. 
• 
The first 1 to 2 mL of CSF may be discarded; the subsequent 2 to 4 mL will be processed 
at the site’s local laboratory facility (unless the laboratory is not able to process the CSF 
within 4 hours) to conduct standard analyses on cell count (including red blood cell 
counts), protein and glucose levels. The remaining CSF will be processed and shipped to 
a central laboratory for biomarker and PK assessments. Further details will be in the 
laboratory manual provided by the central laboratory.  
  
Table 7 - Protocol-required laboratory assessments  
Laboratory assessments 
Parameters 
Hematology 
Platelet count 
 
Red blood cell (RBC) count 
 
Hemoglobin 
 
Hematocrit 
 
RBC indices: 
 
Mean corpuscular volume (MCV) 
 
Mean corpuscular hemoglobin (MCH) 
 
% Reticulocytes 
 
White blood cell (WBC) count with differential: 
 
Neutrophils 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
Clinical chemistrya 
Blood urea nitrogen (BUN) 
 
Creatinine, estimated glomerular filtration rate  
 
Glucose 
 
Potassium 
 
Sodium 
 
Calcium 
 
Aspartate aminotransferase (AST)/Serum glutamic-oxaloacetic transaminase (SGOT) 
 
Alanine aminotransferase (ALT)/Serum glutamic-pyruvic transaminase (SGPT) 
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Laboratory assessments 
Parameters 
 
Alkaline phosphatase 
 
Total and direct bilirubin 
 
Total protein 
Routine urinalysisb 
Specific gravity 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase by 
dipstick 
Microscopic examination (if blood or protein is abnormal) 
Urine biochemistry 
Creatinine 
Total protein 
Albumin 
UPCR 
UACR 
Other screening tests 
Human chorionic gonadotropin (hCG) pregnancy test (as needed for women of childbearing 
potential)c 
The results of each test must be entered into the eCRF. 
 
Serology (HIV antibody, hepatitis B surface antigen (HBsAg), and hepatitis C virus 
antibody, other infectious disease or other tests) if locally required. 
Abbreviations: eCRF, electronic case report form; IRB/IEC, Institutional Review Board/Independent Ethics Committee; SAE, serious adverse 
event. 
NOTES : 
a Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or monitoring event are 
given in Section 10.6 (Appendix 6). All events which may indicate severe liver injury (possible Hy’s Law) must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis).  
b Urinalysis by dipstick will be performed at the site. If abnormal, a complete urinalysis will be performed by the central laboratory. 
c Urinalysis by dipstick will be performed at the site and home. Local urine testing will be standard for the protocol unless serum testing is 
required by local regulation or the IRB/IEC. 
Investigators must document their review of each laboratory safety report. 
10.3 
APPENDIX 3: ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING  
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. 
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), 
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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 
• 
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 fulfil 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 fulfil the definition of an AE or SAE. Also, “lack of 
efficacy” or “failure of expected pharmacological action” also constitutes an AE or SAE. 
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. 
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DEFINITION OF SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence 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 detained (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 
outpatients 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 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. 
E) Is a congenital anomaly/birth defect 
F) Other situations: 
- 
Medical or scientific judgment should be exercised in deciding whether SAE reporting 
is appropriate in other situations such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the 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. 
- 
Examples of such events include invasive or malignant cancers, intensive treatment in 
an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
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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 in the eCRF. 
• 
It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor or its designee in lieu of completion of the AE/SAE eCRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by 
the Sponsor or its designee. 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 or its designee. 
• 
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 and interferes with normal everyday 
activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with a SAE. Severe is a category utilized 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 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. 
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• 
The Investigator will also consult the Investigator’s Brochure (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 or its designee. 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 or its 
designee. 
• 
The Investigator may change his/her opinion of causality in light of follow-up information 
and send a SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
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 or 
its designee 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 or its designee with a copy of any 
postmortem findings including histopathology.  
• 
New or updated information will be recorded in the originally completed eCRF. 
• 
The Investigator will submit any updated SAE data to the Sponsor or its designee within 
24 hours of receipt of the information. 
REPORTING OF SAES 
SAE reporting to the Sponsor or its designee via an electronic data collection tool 
• 
The primary mechanism for reporting an SAE to the Sponsor or its designee 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) in order 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 
off-line, then the site can report this information on a paper SAE form (see next section) or 
to the Sponsor or its designee by telephone. 
• 
Contacts for SAE reporting can be found in study reference manual. 
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SAE reporting to the Sponsor or its designee via paper CRF 
• 
Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information to the Sponsor or its designee. 
• 
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 CRF pages within the designated reporting time frames. 
• 
Contacts for SAE reporting can be found in study reference manual. 
10.4 
APPENDIX 4: CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION  
DEFINITIONS: 
Woman of childbearing potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
- 
Documented hysterectomy 
- 
Documented bilateral salpingectomy 
- 
Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), Investigator discretion 
should be applied to determining study entry. 
Note: Documentation can come from the site personnel’s: review of the participant’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female 
- 
A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
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- 
A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception or 
hormone replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with more than one FSH measurement is required. 
- 
Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonestrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
CONTRACEPTION GUIDANCE: 
Male participants 
• 
Male participants with female partners of childbearing potential are eligible to participate 
if they agree to ONE of the following (during the protocol-defined time frame in 
Section 5.1):  
- 
Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
- 
Agree to use a male condom plus partner use of a contraceptive method with a failure 
rate of <1% per year as described in Table 8 when having penile-vaginal intercourse 
with a WOCBP who is not currently pregnant 
• 
In addition, male participants must refrain from donating sperm for the duration of the 
study and for 90 days after the last dose of study intervention. 
• 
Male participants with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile-vaginal intercourse or use a male condom during each episode of penile 
penetration during the protocol-defined time frame. 
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 study drug as described in Table 8. 
Table 8 - Highly effective contraceptive methods  
Highly effective contraceptive methods that are user dependenta 
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulationb  
• 
Oral  
• 
Intravaginal  
• 
Transdermal 
Progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Oral 
• 
Injectable 
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Highly effective methods that are user independent 
Implantable progestogen only hormonal contraception associated with inhibition of ovulation 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS) 
• 
Bilateral tubal occlusion 
Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual partner of 
the woman of childbearing potential (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 intervention. 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. 
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 intervention, which may reduce the efficacy of the contraceptive 
method. In this case, 2 highly effective methods of contraception should be utilized during the intervention period and for at least 6 weeks 
after the last dose of study intervention. 
PREGNANCY TESTING: 
• 
WOCBP should only be included after a negative serum pregnancy test. 
• 
Additional pregnancy testing should be performed at monthly intervals during the 
intervention period and as required locally. 
• 
Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected. 
COLLECTION OF PREGNANCY INFORMATION: 
Male participants with partners who become pregnant 
• 
The Investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study intervention. 
• 
After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the neonate (Note: follow-up to 1 year 
after birth) and the information will be forwarded to the Sponsor. Information on the status 
of the mother and child will be forwarded to the Sponsor. Generally, the follow-up will be 
no longer than 6 to 8 weeks following the estimated delivery date. Any termination of the 
pregnancy will be reported regardless of fetal status (presence or absence of anomalies) or 
indication for the procedure. 
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Female participants who become pregnant 
• 
The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. Information will be recorded on the 
appropriate form and submitted to the Sponsor within 24 hours of learning of 
a participant’s pregnancy. The participant will be followed to determine the outcome of 
the pregnancy. The Investigator will collect follow-up information on the participant and 
the neonate (Note: follow-up to 1 year after birth) and the information will be forwarded to 
the Sponsor. Generally, follow-up will not be required for longer than 6 to 8 weeks beyond 
the estimated delivery date. Any termination of pregnancy will be reported, regardless of 
fetal status (presence or absence of anomalies) or indication for the procedure. 
• 
Any pregnancy complication or elective termination of a pregnancy will be reported as 
an AE or SAE. A spontaneous abortion is always considered to be an SAE and will be 
reported as such. 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, 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 intervention or be withdrawn from the study. 
10.5 
APPENDIX 5: 
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10.6 
APPENDIX 6: LIVER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS  
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10.7 
APPENDIX 7: MEDICAL DEVICE INCIDENTS: DEFINITION AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING  
Not applicable. 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS  
For Canadian participants enrolled in US: 
The IMP will be dispensed every 13 weeks at site or through DTP. 
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Table 9 - Schedule of Activities (SoA) addition for Canadian participants  
Study 
Period/ 
Procedure 
Screening 
Primary analysis treatment period 
Open-label extension treatment period 
FU 
Period 
Day or Week 
Up to 60 d 
before D1 
W1
/D1 
W12 
(±7d) 
W26 
(±7d) 
W39 
(±7d) 
W52 
(±7d) 
W65 
(±7d) 
W78 
(±7d) 
W91 
(±7d) 
W104 
(±7d)/ 
EWa 
W117 
(±7d)/ 
EW 
W130 
(±14d) 
W143 
(±14d) 
W156 
(±14d) 
W169 
(±14d) 
W182 
(±14d) 
W195 
(±14d) 
W208 
(±14d)/ 
EOT/EWb 
W214 
(±7d) 
SFU 
after 
EOT 
Visit number 
1 
2 
3 
4 
4.1c 
5 
5.1c 
6 
6.1 c*  
7 
7.1  c*  
8 
8.1c*  
9 
9.1 c*  
10 
10.1c*  
11 
12 
IRT contact 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense IMP  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
a In case of early treatment withdrawal before W104, and if participant does not wish to stay in the study, assessments mentioned in the W104 visit will be performed, followed by safety follow-up visit 6 weeks after 
the W104/EW visit. 
b In case of early treatment withdrawal after W104, and if participant does not wish to stay in the study after W104, assessments mentioned in the W208 will be performed, followed by safety follow-up visit 6 weeks 
after the W208/EOT/EW visit. 
c The IMP can be dispensed and sent to participants at Visits 4.1 (W39) and 5.1 (W65) via DTP shipment except if the local regulatory authority requires the IMP dispensed at site. No other study assessments are 
planned during these 2 visits. 
c* For Canadian participants, the IMP will be dispensed and sent to participants at Visits 6.1 (W91), 7.1 (W117), 8.1 (W143), 9.1 (W169), and 10.1 (W195) via DTP shipment or the IMP will be dispensed at site per 
local regulatory authority requirements. No other study assessments are planned during these visits. 
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For participants enrolled in Japan:  
Inclusion Criterion 08: The participant or if appropriate parent(s) or legal guardian(s) must 
provide written informed assent/consent prior to any study-related procedures being performed as 
described in Appendix 1 (Section 10.1). For Japanese participants 18 and 19 years old, the 
informed consent is required from both parent/guardian and the participant. 
For participants enrolled in France:  
I 08: For patients ≥18 years of age: the patient must provide written informed consent prior to any 
study-related procedures being performed, as described in Appendix 1 (Section 10.1).  
OR  
French Public Health Code 
For patients ≥18 years of age who are the subject of a legal protection measure or who are unable 
to express their consent, as per Article L1121-8 of French Public Health Code, the patient can 
only be requested for research mentioned in 1° or 2° of Article L1121-1 if research of comparable 
effectiveness cannot be carried out on another category of the population and under one of the two 
following conditions: 
• 
Either the importance of the expected benefit for these persons is such as to justify the 
foreseeable risk incurred. 
• 
Or this research is justified in terms of the expected benefit for other people in the same 
situation. In this case, the foreseeable risks and constraints involved in the research must 
be minimal. 
In view of the research concerned and the regulations cited above, the inclusion criteria I08(a), 
I08(b) and exclusion criteria E24(a), E24(b) have been added for France. 
Inclusion criteria 
• 
I08(a): For patient under tutorship, the legal representative must provide written informed 
consent prior to any study-related procedures being performed.  
• 
I08(b): For patient under curatorship, the patient and the curator must provide written 
informed consent prior to any study-related procedures being performed. 
Exclusion criteria 
• 
E24(a): the participant is under safeguard of justice or deprived of his/her liberty by 
a court decision. 
• 
E24(b): the participant is unable to express his/her consent. 
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10.9 
APPENDIX 9: ABBREVIATIONS  
 
25FWT: 
25-foot walk test 
9-HPT: 
9-hole peg test 
ADL: 
activities of daily living 
ADME: 
absorption, distribution, metabolism, excretion 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase 
ANCOVA: 
analysis of covariance 
AREDS: 
Age-Related Eye Disease Study 
ARLNS: 
Age-Related Eye Disease Study (AREDS) Clinical Lens Grading System 
AST: 
aspartate aminotransferase 
AUC0-24: 
area under the plasma concentration versus time curve calculated using the 
trapezoidal method over a predefined time period (0 to 24 hours) 
BBB: 
blood brain barrier 
CFR: 
Code of Federal Regulation 
ClinRO: 
clinician-reported outcome 
Cmax: 
maximum plasma concentration observed 
CNS: 
central nervous system 
CNS: 
central nervous system 
CSF: 
cerebrospinal fluid 
CSR: 
clinical study report 
CYP: 
cytochrome P450 
ECG: 
electrocardiogram 
ERT: 
enzyme-replacement therapy 
FARS: 
Friedreich’s Ataxia Rating Scale 
FD: 
Fabry disease 
FDA: 
Food and Drug Administration 
FES: 
falls efficacy scale 
FSH: 
follicle-stimulating hormone 
GBA-PD: 
Parkinson’s disease and a glucocerebrosidase mutation 
GCP: 
Good Clinical Practice 
GCS: 
glucosylceramide synthase 
GD1: 
Gaucher disease type 1 
GD3: 
Gaucher disease type 3 
GL-1: 
glucosylceramide 
GM3: 
monosialodihexosylganglioside 
gpNMB: 
glycoprotein nonmetastatic protein B 
HRT: 
hormone replacement therapy 
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ICF: 
informed consent form 
ICH: 
International Council for Harmonisation 
IEC: 
Independent Ethics Committee 
IMP: 
investigational medicinal product 
IRB: 
Institutional Review Board 
IRT: 
interactive response technology 
LC-MS/MS: 
liquid chromatography tandem mass spectrometry 
LLOQ: 
lower limit of quantification 
LP: 
lumbar puncture 
NTSAD: 
National Tay-Sachs & Allied Diseases Associations 
ObsRO: 
observer-reported outcome 
OLE: 
open-label extension 
PD: 
pharmacodynamic 
PerfO: 
performance outcome 
PK: 
pharmacokinetic 
PRO: 
patient-reported outcome 
SAE: 
serious adverse event 
SAP: 
Statistical Analysis Plan 
SoA: 
schedule of activities 
SRT: 
substrate reduction therapy 
SUSAR: 
suspected unexpected serious adverse reaction 
tmax: 
time to reach maximum plasma concentration 
UACR: 
urine albumin creatinine ratio 
ULN: 
upper limit of normal 
UPCR: 
urine protein creatinine ratio 
WOCBP: 
woman of childbearing potential 
β-hCG: 
beta human chorionic gonadotropin 
 
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10.10 APPENDIX 10: PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
10.10.1 
Amended protocol 01 (05 November 2019)  
This amended protocol (Amendment 01) is considered to be not 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 because it does not significantly impact the safety or physical/mental 
integrity of participants, nor the scientific value of the study. 
OVERALL RATIONALE FOR THE AMENDMENT  
The main reason for this amendment is to include clarifications requested by the U.S. Food and 
Drug Administration (FDA). Other modifications or editorial changes are included to correct 
inconsistencies and improve operational feasibility. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis and 
Section 4.1 Overall Design 
Added “Randomization will be stratified on 
the participant’s ability to walk at the 
baseline visit (yes/no).” 
To ensure balanced randomization of subjects 
able to walk at baseline. 
Section1.1 Synopsis and 
Section 6.1 Study 
intervention(s) administered  
The sentences “The investigational 
medicinal product (IMP) can be chewed or 
swallowed whole. Whether the IMP is 
swallowed or chewed should be as 
consistent as possible throughout the whole 
study treatment duration, and the method 
should be documented in the electronic 
case report form (eCRF)” were modified to 
“investigational medicinal product (IMP) 
should be swallowed whole.”  
Waiting bioavailability (BA) study results to 
support the administration of the tablets by 
chewing.  
Section 1.1 Synopsis/ 
Section 3 Objective and 
endpoints/Section 8.6 
Pharmacodynamics 
Deleted “LDH” from “Additional plasma and 
CSF biomarkers may include but are not 
limited to: lactate dehydrogenase (LDH), 
lipidomics, glycoprotein nonmetastatic 
protein B (gpNMB), neurofilament.”   
Remove LDH. 
Section 1.1 Synopsis 
(Statistical considerations) 
Added “It will also provide >99% power to 
detect a difference between venglustat and 
placebo with regards to the co-primary 
endpoint of percent change in CSF GM2 
biomarker from baseline to Week 104.” 
Clarify the power on the co-primary endpoint. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3 Schedule of 
Activities (SoA) 
The sentence “The IMP will be dispensed 
and sent to participants at Visits 4.1 (W39) 
and 5.1 (W65) via DTP shipment,” was 
modified to “The IMP can be dispensed and 
sent to participants at Visits 4.1 (W39) and 
5.1 (W65) via DTP shipment, except if the 
local regulatory authority requires the IMP 
dispensed at site.” 
To meet the local regulatory requirement.  
Section 1.3 Schedule of 
Activities (SoA) 
Added 12-lead ECG at W26, W52 and W78 
visits.   
To evaluate the ECG more frequently considering 
that this represents the first clinical exposure in 
this patient population. 
Section 1.3 Schedule of 
Activities (SoA) 
For PK plasma sample notes: 
Added “(Plasma sample ID P00, P01, P02, 
P03, P04, P05 respectively).” to “For primary 
population, sampling will be performed 
predose and 0.5, 3, 8, 12, and 24 hours 
postdose in 15 participants”. 
Added “(P02)” to “For all other participants, 
sampling will be performed only at 3 hours 
postdose”. 
Added (Plasma sample ID P06, P07, P08, 
P09, P10, P11 respectively)” to “Sampling 
will be performed predose and 0.5, 3, 8, 12, 
and 24 hours postdose”. 
Added “(Plasma sample ID P12, P13 at 
Visit 4/Week 26 and P14 and P15 at 
Visit 5/week 52 respectively)” to “Sampling 
will be performed predose and 3 hours 
postdose”. 
Added “(plasma sample ID P16)” to 
“Sampling will be performed predose”. 
Added “(Plasma sample ID P17)” to” Sample 
may be collected at any time and the time of 
sample collection should be recorded”. 
For PK CSF sample notes:  
Added “(CSF sample ID C00)” to” Sampling 
will be performed predose”. 
Sample ID is a required field for doing PK 
analysis within PKDMS (PK data management 
system). Adding sample IDs in protocol will help 
to provide a single source of information for PK 
samples analyzed at BA lab and PK sampling 
data to be collected in clinical database and 
avoids any errors. 
 
Section 1.3 Schedule of 
Activities 
(SoA)/Section 10.8  
Deleted “Optional for participants in Japan”. 
TMT A/B is now available in Japanese. 
 
Section 1.3 Schedule of 
Activities (SoA) and 
Section 8.1.11 
Added text to footnote and in 8.1.11 
“Qualitative structured interviews will be 
conducted between Week 104 and 
Week 106 or within the 2 weeks following 
the participant’s end of treatment or early 
withdrawal last visit.” 
Replaced “For English-speaking 
participants only” by “For participants from 
primarily English-Speaking countries”. 
To clarify when the exit interview is conducted.   
To clarify participants who will be interviewed. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 5.1 Inclusion 
Criteria  
Deleted “or chew and swallow” from I 05. 
Waiting bioavailability (BA) study results to 
support the administration of the tablets by 
chewing.  
Section 5.1 Inclusion 
Criteria 
Deleted “Note: the participant must have 
bilateral antigravity ability in upper 
extremities.” In I 03.  
The note is not necessary.  
Section 5.2 Exclusion 
Criteria E 01 
“completely asymptomatic” was modified to 
“without clinical features”. 
Correction. 
Section 5.2 Exclusion 
Criteria E 15 
 
Added “and maintains a level of total 
bilirubin <5 mg/dl and direct bilirubin 
<1 mg/dl (20%) of total bilirubin level” to 
“Gilbert syndrome”.  
To clarify the limits of total and direct bilirubin that 
are allowed for patients with Gilbert’s syndrome. 
Section 6.3 
Added a paragraph regarding 
“Randomization code breaking”. 
To clarify the procedure of code unbinding.    
Section 6.5 Concomitant 
therapy  
Added “The participants must abstain from 
taking pyrimethamine and/or acetyl-leucine 
throughout this clinical study” Replaced “the 
follow up visit” by “the final safety follow-up 
visit (Week 110 or 6 weeks after EOT)”. 
To clarify the prohibition of using pyrimethamine 
and acetyl-leucine in this study.  
 
To clarify “the follow up visit”.  
Section 7.1.2 Temporary 
discontinuation  
Added “If an SAE or ≥ Grade 3 AE (NCI, 
CTCAE v4.03) that is considered by the 
Investigator to be related to 
GZ/SAR402671 and not to underlying 
disease or concomitant medication, the 
dose may be temporarily discontinued”.  
To clarify the temporary discontinuation criteria.  
Section 8 Study 
assessments and 
procedures  
Added a paragraph regarding the 
procedure of “lumbar puncture”. 
To clarify the procedure of lumbar puncture. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 8 Study 
assessments and 
procedures 
Replaced “120 mL” by “130 mL”, replaced 
“135 mL” by “145 mL” regarding the 
maximum amount of blood collected.  
To correct the blood volume collected in this 
study.  
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Section 8.2.4 
Added “The ECG will be read centrally.”  
To clarify the central reading of ECG.  
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Section # and Name 
Description of Change 
Brief Rationale 
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Section 8.6  
Replaced “Approximately 4 mL of whole 
blood” by “Approximately 6 mL of whole 
blood”. 
To correct the blood volume collected for the 
assessment of PD markers.  
Section 9.2 Sample size 
determination 
Added a paragraph regarding power for the 
co-primary endpoint of percent change in 
CSF GM2 from baseline to Week 104. 
Clarify the power on the co-primary endpoint. 
Section 9.3 Populations for 
analyses 
Deleted “who received at least 1 dose of 
study medication” in the definition of 
Primary efficacy population and Secondary 
efficacy population. 
Clarify that primary and secondary efficacy 
populations will include all randomized patients, 
not only those who received at least one dose of 
study medication. 
Section 9.4.1 Efficacy 
analyses 
Added a paragraph regarding handling of 
missing data. 
Clarify the strategy for handling of missing data. 
Section 10.2 Appendix 2: 
Clinical laboratory tests 
Deleted “(fasted)” for glucose test. 
“Fasted” is not necessary for glucose test in this 
study population.  
Section 10.2 
Deleted “If abnormal, a complete urinalysis 
will be performed by the central laboratory” 
in footnote “b” of Table 6. 
Replaced “will” with “may” in the sentence 
“The first 1 to 2 mL of CSF will be 
discarded” 
Correction. 
Section 10. 4  
Deleted “a” from “Highly effective methods 
that are user independenta” in Table 7. 
Deleted “b” from “Implantable progestogen 
only hormonal contraception associated 
with inhibition of ovulationb” in Table 7. 
Correction. 
 
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10.10.2 
Amended protocol 02 (09 March 2020)  
This amended protocol (Amendment 02) 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. 
The main reason for this amendment is to update safety monitoring per regulatory guidance. 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
(Number of Participants) 
and Section 4.1, Overall 
Design (last paragraph) 
Added the following text (in bold) to the 
paragraph as follows: “In addition to the primary 
population, approximately 5 participants in 
total are planned for the secondary 
population. An attempt will be made and 
first prioritized to enroll at least 1 participant 
(age 2 years or older) in each of the following 
disorders: juvenile/adolescent late-onset GM2 
gangliosidosis, GM1 gangliosidosis, Saposin C 
deficiency, Sialidosis Type 1, and juvenile/adult 
galactosialidosis.” 
To clarify the recruitment of the secondary 
population. 
Section 1.1 Synopsis 
(Intervention groups and 
duration, Study 
interventions, 
investigational medicinal 
products: Venglustat or 
placebo, first bullet), and 
Added 2 sentences to this bullet as follows: “The 
placebo is only for 15 mg venglustat tablets. 
Strength refers to the free base corresponding to 
the active moiety.” 
Clarification regarding venglustat placebo 
tablets and venglustat strength. 
Section 6.1, Study 
intervention(s) 
administered (Table 3) 
Added text regarding venglustat placebo and 
venglustat strength to a new footnotes “a” and “b” 
under table. 
Section 1.1 Synopsis 
(Intervention groups and 
duration), Study 
Interventions, 
Investigational medicinal 
products: Venglustat or 
placebo, third bullet, first 
sub-bullet, and Section 
6.1, Study intervention(s) 
administered (Table 3) 
Added explanation regarding swallowing the 
investigational medicinal product (IMP) whole or 
chewing and then swallowing as follows: 
“Assessment of relative bioavailability following 
chewing and then swallowing of the tablet is 
ongoing in a Phase 1 study. Based on the results 
from this study, this mode of tablet administration 
may be allowed. Once the administration by 
chewing is available, administration of IMP by 
chewing and swallowing or swallowing whole 
should be as consistent as possible throughout 
study treatment, and the method should be 
documented in the electronic case report form.” 
Some patients are not able to swallow pills 
whole (such as younger children); responds to 
Food and drug administration (FDA) request. 
The tablet is designed to be able to be chewed; 
however, per FDA requirement, administration 
by chewing and then swallowing the tablet will 
not begin until the bioavailability results are 
available. 
Section 1.1 Synopsis 
(Intervention groups and 
duration, Study 
Interventions, 
Investigational medicinal 
products: Venglustat or 
placebo, third bullet, 
table), and Section 6.1, 
Study intervention(s) 
administered, Table 3, 
Dosage levels, table 
The table was updated to include revised weight 
groups as follows: 
Additional pharmacokinetic (PK) simulations run 
to predict venglustat exposure in pediatrics 
showed that the revised weight bins based 
dosing (table of 4 weight bins compared to 
5 weight bins in earlier pediatric dosing table) 
still provides exposures in each pediatric weight 
bin matching the adult exposure following 
15 mg QD dose. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3, Schedules of 
Activities 
Row “Visit at clinical site”, Notes column: the first 
sentence was revised to state “For participants in 
United States only; up to 2 visits (Visits 3 and 8) 
can be provided remotely under a decentralized 
clinical trial (DCT) model (optional).” 
Patients previously were able to have remote 
assessments at Visits 3, 4, 5, 6, and 8 under 
a DCT model; however because of the addition 
of a full ophthalmological examination at Visits 
4, 5, and 6, a clinic visit will now be required at 
those visits. 
 
Row “Medical/surgical/treatment history”: added 
“alcohol use history.” 
To clarify the collection of alcohol use history. 
 
Row “Hexosaminidase enzyme activity”: Revised 
notes column text as follows: For primary 
population, samples will be collected for all 
participants during screening or at D1 (predose). 
Only 1 sample will be collected, during screening 
or at D1. For those with historical results, they 
may begin the study without waiting for results. 
Also added an “X” to this row on D1. 
Per FDA comments, this is in order to test the 
samples using the same methodology to ensure 
consistency in study results that will be used to 
assess the relationship between residual 
enzyme activity and PK, pharmacodynamic 
(PD), and efficacy. The sample will be collected 
for the primary population. The sample may be 
collected during screening or at D1 for 
convenience. 
 
. 
 
Row “Lumbar puncture” and row “CSF sample”: 
Added statement in notes column that “The LP 
(lumbar puncture) should be done successfully 
before the first dose and/or randomization.” Also, 
removed the requirement for lumbar puncture on 
Day 1. 
Clarification of timing of lumbar puncture. 
 
Row “12-lead ECG”: Revised footnote “a” to read 
as follows: “ECG in triplicate will be performed 
prior to IMP administration.” 
Clarification. 
 
Row “Ophthalmological examination”: Added 
2 footnotes to the notes section as follows: 
a Full ophthalmological examination (including 
slit lamp fundoscopy with dilation), 
photography, and ARLNS. 
b Full ophthalmological examination (including 
slit lamp fundoscopy with dilation). 
“X”s were added to columns for Visits 4, 5, and 
6 and footnoted (with “a” or “b”) appropriately. 
Solution to FDA feedback.  
 
New row added for the following: “Muscle 
weakness of triceps and quadriceps.” “Xs were 
added for Visits 2, 3, 4, 5, 6, and 7. 
Muscle weakness is one of the typical clinical 
presentations of late onset GM2 gangliosidosis. 
The muscle weakness of triceps and quadriceps 
will be assessed and considered a sensitivity 
analysis of the FARS-Neuro. 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 5.1, Inclusion 
Criteria 
E 01: Removed the following sentence from this 
criterion as it is not applicable here: “Note: For 
criteria specific to participants enrolled in Japan, 
see Appendix 8 (Section 10.8).” 
Correction. 
E 03: Added the phrase “For primary population” 
to the beginning of the criterion as follows: “For 
primary population, the participant has the ability 
to .  .  .  “ 
Clarification that this inclusion criterion applies 
to participants in the primary population. 
E08: Added the following sentence to this 
criterion as it is applicable here: “Note: For 
criteria specific to participants enrolled in 
Japan, see Appendix 8 (Section 10.8).” 
Correction. 
Section 5.2, Exclusion 
Criteria 
E 02: Added “For primary population and 
participants with juvenile/adolescent late onset 
GM2 gangliosidosis and GM1 gangliosidosis” to 
the beginning of the criterion. 
Clarify the study population for this criterion. 
Added “age-appropriate” in front the “study 
assessments.” 
Clarification. 
E 02: 
 and added “25FWT” 
(25-foot walk test) as an exception to age-
appropriate assessments. 
Clarify exceptions to the age-appropriate 
assessments. 
E 14: Added note as follows: “Note: For 
participants using N-acetyl-leucine as IMP, within 
5 half-lives before study enrollment.” 
Due to the very short half-life, patients taking 
N-acetyl-leucine will not have to wait 3 months 
to start this study. 
Section 6.3, Measures to 
minimize bias: 
randomization and blinding 
In the section “Randomization code breaking,” 
next to last paragraph: changed “will not be” to 
“may or may not be.” 
To clarify the treatment with code breaking. 
Section 6.5, Concomitant 
therapy 
The previous text regarding prescription or 
nonprescription drugs was removed from the last 
paragraph and replaced with text to specify that 
concomitant medications and changes in 
concomitant medications should be kept to 
a minimum. Excluded prescription or 
nonprescription medication that are considered 
necessary for the patient’s welfare may be 
provided as long as it is unlikely to significantly 
interfere with the IMP. Patients may be given 
such therapy as rescue mediation at the 
discretion of the Investigator. 
Response to agency request.  
Section 7.1.2, Temporary 
discontinuation (now 
Discontinuation criteria) 
The previous heading “Temporary 
Discontinuation” was changed to “Discontinuation 
Criteria.” A paragraph was added to this section 
to provide rules for continued dosing in the event 
of a serious adverse event or ≥Grade 3 adverse 
event is observed that is considered by the 
Investigator to be related to venglustat, which will 
be applied with recommendations from the data 
monitoring committee. 
Response to agency request. Stopping criteria 
added as response to FDA. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.1.12, Muscle 
weakness of triceps and 
quadriceps 
The new efficacy assessment of muscle 
weakness was added, and the relevant 
information was inserted in a new Section 8.1.12. 
A new reference cited in this section was inserted 
into Section 11 (Marion, 2020) as new reference 
#31. 
The most involved muscle groups in GM2 
patients are triceps and quadriceps. These 
muscle groups are not tested in FARS-Neuro. 
Thus, this efficacy assessment was added and 
will be considered a sensitivity analysis of the 
FARS-Neuro. 
Section 8.2.5, 
ophthalmological 
examination 
Updated ophthalmological examination 
information for adult and pediatric patients in 
paragraphs 1, 2, 4, 5, and 6, as follows:  
Paragraph 1: The effect of venglustat on the lens 
will be closely monitored throughout the study. 
The full ophthalmological examination will include 
slit-lamp examination, fundoscopy with pupil 
dilation, and examination of the cornea, lens, and 
retina. 
Paragraph 2: The evaluation of the lens by 
photography according to Age-Related Eye 
Disease Study (AREDS) Clinical Lens Grading 
System (ARLNS) will be performed during 
screening, Week 104, early withdrawal or 
treatment discontinuation, or any timed deemed 
medically necessary. 
Paragraph 4: A full ophthalmological examination, 
photography, and ARLNS will be performed 
during screening (this will serve as a baseline 
assessment) and at Week 104 or at early 
withdrawal or treatment discontinuation.  
Paragraph 5: A full ophthalmological examination 
will be performed at Week 26, Week 52, and 
Week 78. 
Paragraph 6: If a lens abnormality is found, the 
ophthalmologist at the site should perform pupil 
dilation, photography, and ARLNS evaluation. 
Solution to FDA feedback.  
Section 8.8, Biomarkers. 
Last paragraph: remove “separate” in the phrase 
“separate consent.” 
A separate consent form is not mandatory. 
Section 8.9, Lumbar 
Puncture 
Paragraph 2: The last sentence was revised to 
state the following: The baseline LP can be done 
within 14 days prior to or on the day of 
randomization (predose). Specifically, the phrase 
“or on” was removed. 
Clarification of timing of the lumbar puncture. 
Section 10.2 Appendix 2: 
Clinical Laboratory Tests 
Other screening tests: Removed follicle 
stimulating hormone.  
Other screening tests: Added serology tests. 
Follicle stimulating hormone is not required in 
this protocol. 
For consistency with Section 1.3, Schedule of 
Activities. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 10.8 Appendix 8: 
Country-specific 
requirements 
Revised appendix to state the following:  
“For participants enrolled in Japan:  
Inclusion Criterion 08: The participant or if 
appropriate parent(s) or legal guardian(s) must 
provide written informed assent/consent prior to 
any study-related procedures being performed as 
described in Appendix 1 (Section 10.1). For 
Japanese participants 18 and 19 years old, the 
informed consent is required from both 
parent/guardian and the participant.” 
Correction. 
Section 10.10 Appendix 
10: Protocol Amendment 
History 
New appendix added and protocol amendment 1 
rationale and summary of changes table moved 
to this appendix. 
Per Sanofi template. 
10.10.3 
Amended protocol 03 (08 March 2021)  
This amended protocol 03 (Amendment 03) 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 main reason for this amendment is to update contingency measures for a regional or national 
emergency as declared by a governmental agency, to update sample size for secondary 
population, to update inclusion/exclusion criteria, and to improve operational efficiency. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Section 1.1 Synopsis 
Based on the results of a bioavailability study, 
chewable tablet option may be allowed 
Clarification. In a Phase 1 relative 
bioavailability study that was recently 
completed (PKM16157), the bioavailability of 
the 15 mg venglustat tablet (planned 
commercial dosage form) chewed and then 
swallowed without water was similar to that for 
the tablet swallowed whole with water. 
Therefore, this protocol amendment includes 
information to allow for the use of either modes 
of administration. 
Section 1.2 Schema 
Schema update to show up to 20 participants 
in the secondary population  
Update. 
Section 1.3 Schedules of 
Activities (SoA) 
Following text added (bold font) for 
hexosaminidase enzymatic activity 
measurement: 
For primary population, samples will be 
collected for all participants during screening or 
at D1 (predose). Only 1 sample will be 
collected, during screening or at D1 after 4 hr 
Clarification. 
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Section # and Name 
Description of Change 
Brief Rationale 
fasting. For those with historical results, they 
may begin the study without waiting for results. 
Following telephone call clarification added: 
except for scheduled follow up phone calls 
which would fall within a few days (up to 
10 days) from a site visit. 
Monthly pregnancy test will be performed 
between Week 1 and Week 104. 
 
Annotation ‘b’ is newly inserted for W26 and 
W78 Ophthalmological examination. 
Section 1.1 Synopsis: 
Number of participants, 
Statistical considerations, 
Section 4.1 Overall Study 
Design, Section 9.2 
Sample size 
determination, Section 
9.4.1 Efficacy analyses 
Table 5 
Approximately 20 participants are planned for 
secondary population. 
Primary analysis time point added. 
Update. 
Section 5.1 Inclusion 
Criteria 
I01: for juvenile secondary population the ICF 
must be signed by parent(s)/guardian(s). 
I07: Contraception related text added. 
I08: France specific criterion added. 
Update. 
Section 5.2, Exclusion 
Criteria 
E02: Criterion updated to add the following 
text: and GM1 gangliosidosis, the participant 
cannot understand and perform all age-
appropriate study assessments, with the 
exception of 25FWT and PROs. 
Exclusion criteria update, country specific 
criteria provided. 
 
Section 6 Study 
intervention 
Venglustat tablets can be chewed or 
swallowed. 
Clarification and update. 
Section 6.1 Study 
intervention(s) 
administered 
Added a sentence “Venglustat or matching 
placebo is to be taken daily, around the same 
time each day throughout the study.”  
To clarify the time of intake of IMP.  
 
Section 6.2 Preparation/ 
Handling/ 
Storage/Accountability 
Reference to a pharmacy manual added. 
Update. 
Section 6.1 Study 
Intervention(s) 
administered, Section 
7.1.2 Discontinuation 
criteria, Section 7.1.2.1 
Rechallenge, 8.1.12 
Regional or national 
emergency, Section 9.4.4 
Other analyses,  
Contingency measures during a national 
emergency added. 
The management of the clinical trial during 
a national emergency. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.1 Efficacy 
assessments 
Subsections in Section 8.1 were resequenced 
from subsection 8.1.5 
Update. 
l
i
i
i
. 
Section 8.2.2 Neurological 
examination, Section 
8.2.5 Ophthalmological 
examination 
Added the following text: When neurological and 
ophthalmological examinations are performed 
on the same day (Visit 1 and Visit 7) the 
neurological examination should be performed 
before the ophthalmological examination. 
Operational clarification. 
Section 8.3 Adverse 
events and serious 
adverse events 
The sentence “Of note, asymptomatic 
overdose has to be reported as a standard AE” 
deleted.  
Update. 
Section 8.6.1 Lumbar 
puncture 
The original Section 8.9 has been renumbered 
Section 8.6.1. 
Renumbered a section. 
Section 10.2 Appendix 2 
Table 6 
A footnote added “Urinalysis by dipstick will be 
performed at the site. If abnormal, a complete 
urinalysis will be performed by the central 
laboratory.” 
Clarification. 
Section 10.4 Appendix 4 
Contraceptive Guidance 
and Collection of 
Pregnancy Information 
Clarified that babies born to the participants or 
partners of participants will be followed up to 
1 year after birth. 
Update. 
Section 10.8 Appendix 8 
Country-Specific 
Requirements 
France specific criteria added. 
Updated country specific criteria based on the 
ethics committee recommendations. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 10.10.2 Protocol 
Amendment 02 (09 March 
2020) 
New section for protocol amendment 02 history 
added. 
Template required section added. 
Section 10.11 Appendix 
11 Contingency measures 
for a regional or national 
emergency as declared by 
a governmental agency 
A new Appendix 10.11 added to specify 
contingency measures for a regional or 
national emergency as declared by 
a governmental agency. 
Contingency measures added to cover 
COVID-19 and other potential emergencies. 
Section 1.2 Schema, 
Section 1.3 Footnote, 
Section 4.2 Scientific 
rationale for study design, 
Section 5.3.1 Meals and 
dietary restrictions, 
Section 5.4 Screen 
failures, Section 6.1 Study 
interventions 
administered, Section 6.2 
Preparation/ 
handling/storage/ 
accountability, Section 
i
i
Minor edits for clarification and or updates 
made. 
Minor editorial changes and or updates for 
clarity. 
10.10.4 
Amended protocol 04 (20 April 2022)  
This amended protocol 04 (Amendment 04) 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 main reason for this amendment is to add an open-label extension (OLE) treatment phase to 
the study. The OLE period is an extended treatment phase to obtain the long-term efficacy and 
safety of additional 24-month treatment with venglustat in patients with late-onset GM2 
gangliosidosis and patients with juvenile/adolescent late-onset GM2 gangliosidosis or ultra-rare 
diseases within the same and similar glucosylceramide-based sphingolipid pathway who 
completed the 104-week primary analysis period of the study. 
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Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Document history table 
Revised to include amended protocol 4 information and date. 
Per Sanofi template. 
Section 1.1, Synopsis, 
Objectives and endpoints; 
Section 3, Objectives and 
endpoints 
Removed “physical examination” from secondary endpoints, 
primary population and secondary population at 104 weeks. 
Physical examination is 
overlapping with visual 
acuity assessments that 
are collected separately 
with ophthalmological 
data as a separate item, 
and any abnormal finding 
will be collected as 
an adverse event. 
Section 1.1, Synopsis, Overall 
design; Section 4.1, Overall 
design 
Added text to specify that the study is a 2-arm, 104-week study 
(primary population only) of venglustat compared with placebo, and 
venglustat received in an open-label design in the secondary 
population. Added “text to specify that the 104-week treatment 
period (primary analysis period) will be followed by an OLE period 
with venglustat treatment for all patients. Updated “3 main periods” 
to “4 main periods”; clarified that Period 2 is the primary analysis 
period; added description of Period 3 (104-week OLE period); and 
updated previous Period “3” to Period “4.” Updated text regarding 
post-trial access to venglustat. 
Addition of OLE to study. 
With addition of the OLE 
to the study, the long-
term study (LTS) is no 
longer applicable; thus, 
updated text for 
clarification. 
Section 1.1, Synopsis, 
Disclosure statement, 
Intervention groups and 
duration 
Clarified that the primary analysis will occur at 104 weeks. 
Addition of OLE to study. 
Section 1.1, Synopsis, 
Intervention groups and 
duration 
Added text to specify that during the 104-week OLE, all 
participants in the primary and secondary populations will 
receive venglustat in an open-label manner, specifically 15 mg 
tablet once daily for adult participants; clarified that for 
adolescents and juvenile participants in the secondary 
population ≥2 years of age, venglustat dosing will be adjusted in 
the primary analysis period and the OLE treatment period. 
Section 1.1, Synopsis, 
Statistical considerations; 
Section 9.4.1, Efficacy 
analysis 
Added details about descriptive analyses conduction in the 
secondary population.  
Added text regarding analysis of plasma and CSF GL-1 
biomarker data. 
Clarification. 
Section 1.2, Schema  
Inserted updated graphical study design. 
Addition of OLE to study. 
Section 1.3, Schedule of 
activities (SOA) 
Added columns for the OLE (W130, W156, W182, W208) (also 
Visits 9, 10, 11, and 12); modified EOT from W104 to W208; 
modified “treatment period” to “primary analysis treatment period”; 
revised FU period visit from W110 to W214; added/revised 
assessments as needed; revised/added to notes column as 
applicable; added note “b” to provide instructions regarding early 
treatment withdrawal after W104. Updated notes regarding the 
decentralized clinical trial (DTC) model as appropriate. Added note 
to clarify that full ophthalmological examination (including slit lamp 
fundoscopy with dilation) in the OLE will be performed for 
participants ≥2 and <12 years of age only. 
Addition of OLE to study. 
Moved notes in repeated header rows (“a,” “b”, and “c”) to end of 
table to reduce length of table. 
Clarification, and editorial 
for readability. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 2.3, Benefit/risk 
assessment 
Updated text regarding ongoing studies. Added new text 
regarding potential risk of new or worsening lens 
opacities/cataracts in human with rationale for discontinuing 
ophthalmological examinations for participants ≥12 years of age 
who continue in the OLE. Added new text regarding the potential 
risk of
 in ADPKD indication. Added new text 
regarding the potential risk of transient increase in blood 
pressure at the beginning of venglustat treatment. 
New safety information 
for venglustat per 
updated Investigator’s 
Brochure (v17.0, 
08-Mar-2022). 
Section 3, Objectives and 
endpoints 
Added tertiary/exploratory endpoints for the primary population 
and for the secondary population at Week 208. 
Addition of OLE to the 
study. 
Section 6.1, Study 
intervention(s) administered; 
Section 1.3, Schedule of 
activities 
Added text to clarify packing and labeling of IMP during the 
primary analysis period and the OLE. 
Section 6.3, Measures to 
minimize bias: randomization 
and blinding 
Randomization and code breaking: Added the following text as 
a new second paragraph: “Participant safety must always be 
the first consideration in making such a determination. If 
the Investigator decides that unblinding is warranted, the 
investigator must make every effort to contact the Sponsor 
to discuss the situation prior to unblinding a participant’s 
intervention assignment unless this could delay emergency 
treatment of the participant.” 
Sanofi template update. 
Section 6.5.1.3, Medications 
with risk to cause cataract 
Revised text to specify that listed medications are prohibited for 
participants age <12 (rather than for all participants). 
Updated for consistency 
with other safety 
information regarding 
cataract risks. 
Section 6.5.2, COVID-19 
vaccination 
Added new section for COVID-19 vaccination. 
Sanofi template update. 
Section 8, Study assessments 
and procedures, Section 8.6, 
Pharmacodynamics, 
Section 8.7, Genetics 
Updated blood volumes as applicable. 
Addition of OLE to the 
study. 
i
i
 
Section 8.2.5, 
Ophthalmological examination 
Revised text to clarify timing of ophthalmological examinations 
for all participants and for participants <12 years of age. 
No ophthalmological 
examinations required in 
OLE for participants age 
≥12 years. 
Section 8.8, Biomarkers; 
Section 8.10, Use of biological 
samples and data for future 
research 
Replaced last paragraph of Section 8.8 with the following: 
“Refer to Section 8.10 for further details regarding use of 
biological samples and data for future use.” 
Added new Section 8.10 with details use of biological samples 
and data for future research. 
Sanofi template update. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 9.4, Statistical 
analyses 
Revised text to specify that the statistical analysis plan will be 
developed and finalized before the analysis of the primary 
analysis treatment period. 
Clarification. 
Section 9.5, Interim analyses 
Added a 2-step analysis for the study, first step for the final 
analysis of the primary analysis period and second step for the 
final analysis of the OLE treatment period. 
Addition of OLE to the 
study. 
Section 10.11, Appendix 11, 
Contingency Measures for 
a regional or national 
emergency as declared by 
a government agency 
Updated text regarding visit windows to include V3 to V12 
(rather than V3 to V8). 
Section 11, References 
Updated reference #14 as a newer version is available. 
Editorial change. 
Throughout the document 
Minor editorial and formatting changes were made for clarity and 
consistency 
Consistency with 
document edits. 
 
10.10.5 
Amended protocol 05 (11 November 2022)  
This amended protocol 05 (Amendment 05) 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 main reason for this amendment is to add urine albumin creatinine ratio (UACR) and urine 
protein creatinine ratio (UPCR) assessments in the renal monitoring per FDA requirement. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Document history table 
Revised to include amended protocol 5 information and date. 
Per Sanofi template. 
Sponsor name 
Revised Sponsor address from “50 Binney Street Cambridge 
MA 02142 USA” to “450 Water Street Cambridge MA 02141  
USA.” 
Updated Sanofi address. 
Table of Contents 
Updated entries for the following new sections and subsections 
“2.3.1 Risk assessment," “2.3.1.1 Potential risks specific for 
pediatric population,” “2.3.1.2 Depression,” “2.3.1.3 Syncope,” 
“
” “2.3.1.5 Transient increase in blood 
pressure, “2.3.1.6 Embryo-fetal toxicity,” and “10.10.4 Amended 
protocol 04 (20 April 2022).” 
Consistency with document 
edits. 
List of Figures 
Added new entry for “Table 2 - Risk mitigation strategy.” 
Consistency with new table 
added in Section 2.3.1, Risk 
Assessment. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3, Schedule of 
Activities (SOA) 
Added the note “For Canadian participants enrolled in the US, 
see Section 10.8.” for the “IRT contact” and “Dispense IMP” 
study procedures. 
Updated for new country-
specific requirement in 
Appendix 8. 
New annotation ‘k’ was added for urine biochemistry test for 
measurement of UACR and UPCR for Visits 2-10 with 
subsequent footnotes renamed, and the footnote was updated 
with the following text:  "Three second-voided morning urine 
samples to be collected on successive days (2 days preceding 
a visit, plus the day of the visit. Urine sample should be sent to 
the central laboratory for quantitative measurement of creatinine, 
total protein and albumin which will be used to calculate the urine 
albumin/creatinine ratio and urine protein/creatinine ratio. 
Per FDA requirement. 
“Dipstick only” removed from from procedure "Hematology, 
biochemistry, urinalysis" and corresponding note "Urinalysis by 
dipstick will be performed at the site. If abnormal, a complete 
urinalysis will be performed by the central laboratory." has been 
newly added. 
Revised to align with updated 
laboratory procedures. 
Included full ophthalmology examinations for all participants, and 
not only for participants ≥2 and <12 years of age, at Week 208 
(end of the open-label extension treatment period). 
To align with all venglustat 
studies following FDA 
feedback on lens monitoring 
to be done at the end of the 
treatment period. This will be 
conducted as a conservative 
approach. There was no new 
safety information on this 
potential risk since protocol 
amendment 4. 
Added “The LP should be done after all other assessments if 
possible.” to footnote ‘e’ and ‘q”. 
To clarify the order of 
assessments to avoid any 
impact of LP on other clinical 
assessments. 
Section 2.3, Benefit/Risk 
Assessment 
Updated this section per template to update the risk assessment 
and include the following subsections: “2.3.1 Risk assessment," 
“2.3.1.1 Potential risks specific for pediatric population,” 
“2.3.1.2 Depression,” “2.3.1.3 Syncope,” “2.3.1.4 
,” 
“2.3.1.5 Transient increase in blood pressure,” and 
“2.3.1.6 Embryo-fetal toxicity.”  
Updated the potential risks 
for venglustat in Section 2.3 
Benefit/Risk Assessment to 
align with IB 18.  
Section 3.1, 
Appropriateness of 
Measurements 
Changed “30% of patients who participated in the NTSAD study” 
to “21% of patients who participated in the NTSAD study.”  
Updated the percentage of 
wheelchair bound patients 
who participated in the 
National Tay-Sachs & Allied 
Diseases Associations 
(NTSAD) Study based on the 
natural history data collected 
from the study. 
Section 8, Study 
Assessments and 
Procedures 
Changed maximum amount of blood volume collected from each 
adult participant over the duration of the study from “175 mL” to 
“208 mL” for participants of the main study and “185 mL” to 
“216 mL for participants of the W1/D1 PK profile evaluation 
substudy. 
Updated volumes to reflect 
changes in the new 
pharmacy manual. 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 8.2.5, 
Ophthalmological 
examination 
Text was revised to update the timing of ophthalmological 
examination and clarify that the effect of venglustat on the lens 
will be closely monitored throughout the study including Week 
208 for all participants and not only for participants <12 years of 
age. 
To align with all venglustat 
studies following FDA 
feedback on lens monitoring 
to be done at the end of the 
treatment period. This will be 
conducted as a conservative 
approach. There was no new 
safety information of this risk 
since protocol amendment 4. 
Section 8.6, 
Pharmacodynamics 
Revised “8 mL of whole blood” to “7-8 mL of whole blood” and 
“3 mL of CSF” to “3-4 mL of CSF.” 
Correction of blood volume 
collected in this study based 
on the new pharmacy manual 
Section 10.2, Appendix 2: 
Clinical Laboratory Tests 
In Table 7 - Protocol-required laboratory assessments, the 
laboratory assessment “Urine biochemistry” and its parameters 
“Creatinine,” “Total protein,” “Albumin,” “UPCR,” and “UACR” are 
added. 
Consistency with addition of 
urine biochemistry as 
a laboratory procedure. 
Section 10.8, Appendix 8: 
Country-Specific 
Requirements 
Added country-specific criteria for Canadian participants enrolled 
in the US and expanded on Schedule of Activities for these 
participants to include additional IRT contact and Dispense IMP 
procedure to be conducted at Visits 6.1, 7.1, 8.1, 9.1, and 10.1. 
 
Introduced additional 
dispensation in protocol for 
Canadian participants 
enrolled in US to meet 
customs restrictions limiting 
IMP dispensation to a 90-day 
supply. After Visit 6 of study, 
the number of weeks 
between IMP dispensation 
increases from 13 weeks to 
26 weeks. Thus, additional 
IRT contact and IMP 
dispensation dates were 
included to ensure Canadian 
participants have adequate 
IMP supply between visits.  
Section 10.9, Appendix 9: 
Abbreviations 
Added abbreviations for urine albumin-to-creatinine ratio (UACR) 
and urine protein-to-creatinine ratio (UPCR).  
Consistency with document 
edits. 
Section 10.10, Appendix 
10: Protocol Amendment 
History 
Appendix 10 is updated to reflect the document history of 
previous amendment ie, amendment 04 in newly added as 
Subsection 10.10.4. 
Consistency with document 
edits. 
Section 11, References 
Reference number 18, 19 and 20 from amended protocol 4 were 
deleted in current amendment and subsequent references were 
re-numbered in body-text and in Section 11. 
Consistency with document 
edits. 
Throughout the document 
Minor editorial and formatting changes were made for clarity and 
consistency. 
Consistency with document 
edits. 
 
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10.11 APPENDIX 11: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY AS 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. 
Investigators may be unable to adequately follow protocol-mandated procedures, eg, for 
performance of on-site visits, screening, enrollment, randomization, administration of study IMP, 
imaging procedures or other study assessments. 
Contingency procedures are suggested in the respective sections (Section 6.1, Section 7.1.2, 
Section 7.1.2.1, Section 8.1.12, Section 10.10.3) for such an emergency, 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's agreement MUST be obtained prior to the implementation of these 
procedures for the duration of the emergency. 
The following contingency may be applied for the duration of the emergency (after Sponsor's 
agreement is obtained) to make clinical supplies available to the study participants for the duration 
of the emergency: 
The IMP may be supplied at the site or from the PI/site/Sponsor to the participant via a Sponsor-
approved courier company (direct-to-patient [DTP]) supply of IMP) where allowed by local 
regulations. 
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. 
• 
Postponement of visits is preferred to cancellation of visits, if possible. Visit window 
(V3 toV12) can be extended up to 3 months. In this case, IMP can be dispensed to the 
patient at the planned visit dates (via direct-to-patient) for a maximum duration of 
6 months until V4, and thereafter for a maximum duration of 9 months without on-site 
visit, but with a follow-up by phone every 2 weeks. In general, no patient should continue 
IMP for >9 months without an on-site visit for safety assessments or without laboratory 
safety assessments being performed (eg, at the local practitioner). The safety laboratory 
parameters at least include hematology, biochemistry, urinalysis according to protocol.  
• 
If Week 104 visit is delayed, the blinded treatment will be continued until Week 104 visit 
is performed. 
• 
To reduce the time spent on-site during a study visit, the focus should be on the following 
safety assessments and if scheduled for the concerned visit (applicable to V3 to V12): 
- 
laboratory assessments (biochemistry, hematology and urinalysis) 
- 
urine pregnancy test 
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- 
ECG  
- 
Physical (including vital signs), neurological and ophthalmological examinations (if 
required). For patients with existing cataracts at baseline, full eye exams with pupil 
dilation, photography and ARLNS evaluation at pre-specified visits should be carried 
out, to detect any worsening.  
For efficacy assessments, should be prioritized to perform primary endpoints: CSF 
biomarker test (baseline and W104 only) and 9-HPT. 
.  
For D1/W1 visit (V2), if it is within 2 weeks of V1, no need to redo the exams already 
performed at V1 except 9-HPT, 25-FWT and FARS Part III neurological examination and 
weight (for participants age <18). If D1/W1 visit (V2) is 2 to 4 weeks from the screening 
visit, assessments with the same request at screening and V2 may use the results at 
screening as baseline, except 9-HPT, 25-FWT, FARS Part III neurological examination, 
, chemistry, hematology, urinalysis and weight (for participants age 
<18). 
During the emergency, if the site is unable to adequately follow protocol-mandated procedures, 
alternative treatment outside the clinical trial should be proposed, and 
screening/enrollment/randomization/administration of study intervention etc may be (temporarily) 
delayed/halted.  
The participant and/or their legally authorized representative should be verbally informed prior to 
initiating any emergency-related changes that are to be implemented (eg, study visit 
delays/treatment extension, use of local labs). 
Treatment extension after temporary treatment discontinuation may be considered, depending on 
Sponsor agreement. 
Procedures to be considered in the event of a regional or national emergency declared by 
a governmental agency: 
If on-site visits are not possible, remote visits (eg, with Telemedicine, etc if locally agreed) may 
be planned for safety and efficacy assessments; home nurses/home health vendor, etc may be 
planned for the collection of blood samples for safety assessments and efficacy data. 
If onsite visits are not possible, visit windows may be extended up to 3 months for assessment of 
safety and/or efficacy data that cannot be obtained remotely. 
Phone contacts can be performed in place of an onsite study visits and per study protocol 
schedule. Essential data (that can be checked via interview to evaluate patient safety) to be 
captured via phone 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 patients can measure temperature and BP at home).  
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When phone contact is performed in place of an onsite study visits, assessments of efficacy and 
safety data that cannot be obtained remotely (eg, ECG, ophthalmological and neurological 
examination) will be performed when patients are able to resume normal site visits. Safety 
assessment that cannot be obtained remotely 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 patient from the hazard that led to declaration of national emergency.  
Remote collection of ObsROs and PROs by sites will be attempted via telephone using a secure 
line (eg, teleconference line), including videoconference if possible to aid in the accuracy of data 
collection and increase the quality of data, with the prioritization of ObsROs that contribute to 
secondary endpoints. If none of the options above can be achieved, the PROs and ObsROs should 
not be collected for the visit. 
Use of local clinic or laboratory locations may be allowed. 
New screenings 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 rescreened patient was screen-failed during a regional or national emergency for reasons not 
related to eligibility, rescreening shall be permitted when the situation normalizes.  
Contingencies implemented due to emergency will be documented, eg, in the eCRF. 
The impact of the regional or national emergency declared by a governmental agency on study 
conduct (eg, study discontinuation or discontinuation/delay/omission of the intervention due to the 
emergency, missing data) needs to be closely monitored and summarized by each study site in 
a dedicated document. Monitoring will ensure comprehensive and correct documentation of the 
site-specific impact of the emergency on the study conduct. 
It will be important to capture specific information in the case report form (eCRF) that explains 
rationale for why protocol-specified data is missing, including whether it is attributable to the 
emergency precautions/measures taken by governmental agencies, or due to the patient directly 
being affected (such as by COVID-19). 
If a patient is infected or displays symptoms that could be attributed to COVID-19, the 
investigator should determine whether to maintain the patient on treatment, to temporarily 
discontinue treatment, to pause the study visits/assessments (to be pushed out until recuperation 
allows it), or to withdraw the patient from the study. 
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11 
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