Clinical trial NCT05237284
Conditions: Amyotrophic Lateral Sclerosis
Sponsor: Sanofi
Start date: 2022-04-13; Completion date: 2024-03-07
Enrollment: 305 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a parallel treatment, Phase 2, randomized, double-blind study to assess the efficacy, safety, tolerability, PK, and PD of twice daily (BID) oral SAR443820 compared with placebo in male and female participants, 18 to 80 years of age with ALS followed by an open-label, long-term extension period.

Study ACT16970 consisted of 2 parts (A and B) as follows:

Part A was a 24-week, double blind, placebo-controlled part, preceded by a screening period of up to 4 weeks before Day 1.

On Day 1 of Part A, participants were randomized in a 2:1 ratio to the SAR443820 treatment arm or matching placebo arm as listed below:

* Treatment arm: SAR443820, BID
* Placebo arm: Placebo, BID

Randomization was stratified by the geographic region of the study site, region of ALS onset (bulbar vs other areas), use of riluzole (yes vs no), use of edaravone (yes vs no) and use of the combination of sodium phenylbutyrate and taurursodiol (named Relyvrio in the United States of America \[USA\] and Albrioza in Canada) (yes vs no). Participants attended in-clinic study assessments at baseline (Day 1), Week 2, Week 4, Week 6, Week 8, Week 10, Week 12, Week 16, Week 20, Week 21, Week 22, Week 23, and Week 24. All ongoing participants at Week 24 rolled to open-label extension Part B. The Week 24 Visit was the end of Part A and the beginning of Part B.

Part B was an open-label, long-term extension period that starts from Week 24 and continues up to Week 106. The objectives of Part B were to provide extended access to SAR443820 participants in Part A and to further evaluate the safety and efficacy of long-term SAR443820 treatment. The treatment assignment of participants at randomization in Part A remained blinded to Investigators, participants, and site personnel until the end of Part B. Every participant, except those who discontinued Investigational Medicinal Product (IMP) treatment permanently in Part A, received BID oral tablets of SAR443820 in Part B.

Detailed description:
The study duration included an up to 4-week screening period, 24-week double-blind treatment period in Part A, 80-week open-label treatment period in Part B and 2-week post-treatment follow-up period, with a maximum total study duration of 110 weeks.

Arms: arm 1: twice daily (BID) oral SAR443820 arm 2: twice daily (BID) oral placebo
Interventions: intervention 1: SAR443820 intervention 2: Placebo
Intervention descriptions: intervention 1: Tablet oral intervention 2: Tablet

Protocol documents:
Prot_000.pdf: 
 
 
 
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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: Sanofi OneDocument Version 5.1, dated 11-FEB-2021 
Page 1 
AMENDED CLINICAL TRIAL PROTOCOL 05 
Protocol title: 
A Phase 2, multicenter, randomized, double-blind, 
placebo-controlled study to evaluate the efficacy and safety 
of SAR443820 in adult participants with amyotrophic lateral 
sclerosis, followed by an open-label extension. 
Protocol number: 
ACT16970 
Amendment number: 
05 
Compound number 
(INN/Trademark): 
SAR443820 
Not applicable 
Brief title: 
Phase 2 study for SAR443820 in participants with amyotrophic lateral 
sclerosis (ALS)  
Study phase: 
2 
Sponsor name: 
Sanofi-Aventis Recherche & Développement 
Legal registered address:  
1 avenue Pierre Brossolette  
91380 Chilly-Mazarin, France 
Manufacturer: Same as Sponsor 
Monitoring team’s 
representative name and 
contact information 
  
Regulatory agency identifier number(s): 
IND: 
151444 
EudraCT: 
2021-004156-42 
NCT: 
NCT05237284 
WHO: 
U1111-1263-5766 
EUDAMED: 
Not applicable 
Other: 
Not applicable 
 
 
 
 
 
Date: 
13-Dec-2023 
Total number of pages: 117 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY 
 
Document 
Country/countries 
impacted by amendment 
Date, version 
Amended Clinical Trial Protocol 05 
All 
13 December 2023, version 1 (electronic 11.0) 
Amended Clinical Trial Protocol 04 
All 
12 May 2023, version 1 (electronic 6.0) 
Amended Clinical Trial Protocol 03 
All 
06 Mar 2023, version 1 (electronic 5.0) 
Amended Clinical Trial Protocol 02 
All 
02 December 2022, version 1 (electronic 4.0) 
Amended Clinical Trial Protocol 01 
All 
07 April 2022, version 1 (electronic 1.0) 
Original Protocol 
 
10 November 2021, version 1 (electronic 3.0) 
Amended protocol 05 (13 December 2023) 
This amended protocol (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 
An idenfied risk of ALT increase/drug induced liver injury (DILI) for SAR443820 is added based 
on interal data review. 
The main purpose of the protocol amendment 05 is to increase liver chemistry monitoring 
frequency in Part A to detect ALT increase early if occurs and pause IMP administration 
immediately in Part B (open-label extension) to minimize the risk of further exposure to 
SAR443820. Also, clarification on alcohol restriction during the study and a few additional 
diagnostic tests as mandatory tests in case of events of ALT increase are added.  
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis, 
1.2 Schema, 
1.3.1 Part A 
4.1 Overall Design 
Replaced the phone visit with a site visit and include 
a liver chemistry test at Week 20 (Part A). Added 3 
visits which include a liver chemistry test at Week 21, 
Week 22 and Week 23. 
To allow early detection of ALT increases 
through weekly liver chemistry testing for 
participants who are still in Part A and 
collect data to optimize the characterization 
of the safety profile of SAR443820. As of 
05 December 2023, all participants have 
passed the Week 19 time point, therefore 
no additional weekly visits to be added prior 
to the Week 20 visit.   
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Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
1.2 Schema, 
1.3.2 Part B 
4.1 Overall Design 
Paused all SAR443820 administration in Part B  
To minimize the risk for participants who 
are on SAR443820 until DMC 
recommendation to resume dosing based 
on benefit-risk considerations when Part A 
data is available.   
1.3.1 Part A 
“Only liver chemistry monitoring will be conducted, 
which includes testing of alanine transaminase (ALT), 
aspartate aminotransferase (AST), bilirubin direct, 
bilirubin total and alkaline phosphatase” were added 
in the footnote p in Part A and j in Part B. 
To clarify the extend of liver chemistry 
monitoring tests to be performed. 
1.3.1 Part A 
1.3.2 Part B 
Edited footnote b in Part A and footnote e in Part B to 
provide instructions on what assessment should be 
performed in the scheduled visits if participants 
continue in the study after early IMP discontinuation 
visit.  
To simplify the follow-up visits for 
participants continuing in the study without 
IMP administration 
2.3.1 Risk assessment 
2.3.3 Overall benefit/risk 
conclusion 
Added an identified risk of ALT increase/DILI for 
SAR443820. 
Added clinical data and mitigation strategy supporting 
the potential risk of ALT increase.  
To update the risk of SAR443820 based on 
current data from the ongoing clinical trial 
and minimize the risk for participants.  
5.3.2 Caffeine, alcohol, and 
tobacco 
Added the instruction for participants to limit the 
consumption of alcohol during the study 
To minimize exposure to alcohol during the 
study, to not exacerbate potential liver 
injury risks of SAR443820 
7.1.2 Temporary 
discontinuation 
7.1.2.1 Study intervention 
restart or rechallenge after 
temporary discontinuation of 
study intervention 
Added guidance on temporary discontinuation with 
regard to pause of IMP administration during Part B 
Added information on temporary discontinuation 
criteria in case a participant can not follow the 
scheduled liver chemistry monitoring. 
Modified the statement on the conditions to 
restart/rechallenge IMP 
Clarification 
To clarify the criteria for IMP rechallenge 
and refer to 10.6 Appendix 6 to avoid 
repetitive information 
10.6 Appendix 6: liver and 
other safety: actions and 
follow-up assessments 
Added a Hepatitis B surface antigen test and 
modified a liver ultrasound from optional to a 
mandatory test. 
Replaced “When ALT< 2 ULN (if baseline 
ALT ≤2 ULN) or baseline (if baseline ALT> 2 ULN)” 
to “When the rechallenge criteria are met as 
described in the box below" in ALT increase 
algorithm. 
Modified the IMP rechallenging criteria from 
“ALT/AST decreases below 2 x ULN” to “ALT and 
AST both decrease < 2 x ULN) 
To enhance the possibility of finding 
potential causes of ALT increase.   
To clarity the criteria of IMP 
rechallenge after ALT increase 
and avoid repetitive information 
10.11 Appendix 11 Blood 
volume details  
Blood volume updated due to additional liver 
chemistry monitoring at Week 20, Week 21, Week 22 
and Week 23.  
Update  
10.13 Appendix 13: Protocol 
amendment history  
Summary of changes pertaining amendment 04 were 
moved to appendices 
Administrative change  
 
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TABLE OF CONTENTS  
AMENDED CLINICAL TRIAL PROTOCOL 05 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 4 
LIST OF TABLES ........................................................................................................................................... 9 
LIST OF FIGURES .......................................................................................................................................... 9 
1 
PROTOCOL SUMMARY ............................................................................................................... 10 
1.1 
SYNOPSIS ..................................................................................................................................... 10 
1.2 
SCHEMA ........................................................................................................................................ 18 
1.3 
SCHEDULE OF ACTIVITIES ......................................................................................................... 19 
1.3.1 
Part A ............................................................................................................................................. 19 
1.3.2 
Part B ............................................................................................................................................. 25 
2 
INTRODUCTION ............................................................................................................................ 28 
2.1 
STUDY RATIONALE...................................................................................................................... 28 
2.2 
BACKGROUND ............................................................................................................................. 29 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 29 
2.3.1 
Risk assessment ............................................................................................................................ 29 
2.3.2 
Benefit assessment ........................................................................................................................ 31 
2.3.3 
Overall benefit/risk conclusion ....................................................................................................... 31 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 32 
3.1 
APPROPRIATENESS OF MEASUREMENTS  ............................................................................. 34 
3.1.1 
Measurements for efficacy assessment......................................................................................... 34 
3.1.2 
Pharmacokinetic assessments ...................................................................................................... 34 
3.1.3 
Pharmacodynamic assessments ................................................................................................... 35 
3.1.4 
Safety and tolerability assessment ................................................................................................ 35 
4 
STUDY DESIGN ............................................................................................................................ 36 
4.1 
OVERALL DESIGN ........................................................................................................................ 36 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 37 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 37 
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4.4 
END OF STUDY DEFINITION ....................................................................................................... 38 
5 
STUDY POPULATION .................................................................................................................. 39 
5.1 
INCLUSION CRITERIA  ................................................................................................................. 39 
5.2 
EXCLUSION CRITERIA  ............................................................................................................... 41 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 43 
5.3.1 
Meals and dietary restrictions ........................................................................................................ 43 
5.3.2 
Caffeine, alcohol, and tobacco ....................................................................................................... 43 
5.3.3 
Activity ............................................................................................................................................ 43 
5.4 
SCREEN FAILURES...................................................................................................................... 43 
5.5 
CRITERIA FOR TEMPORARILY DELAYING 
ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY INTERVENTION 
ADMINISTRATION ........................................................................................................................ 44 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................................... 45 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 45 
6.1.1 
Devices .......................................................................................................................................... 46 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 46 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 46 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 47 
6.5 
DOSE MODIFICATION .................................................................................................................. 48 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY....................... 48 
6.7 
TREATMENT OF OVERDOSE ...................................................................................................... 48 
6.8 
CONCOMITANT THERAPY .......................................................................................................... 49 
6.8.1 
Rescue medicine ............................................................................................................................ 50 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 51 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  ..................................................................... 51 
7.1.1 
Permanent discontinuation ............................................................................................................ 51 
7.1.2 
Temporary discontinuation ............................................................................................................. 52 
7.1.2.1 
Study intervention restart or rechallenge after temporary discontinuation of study 
intervention ..................................................................................................................................... 52 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 53 
7.3 
STUDY LEVEL STOPPING CRITERIA ......................................................................................... 53 
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7.4 
LOST TO FOLLOW UP ................................................................................................................. 54 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 55 
8.1 
EFFICACY ASSESSMENTS  ........................................................................................................ 55 
8.1.1 
ALSFRS-R ..................................................................................................................................... 55 
8.1.2 
Slow vital capacity (SVC) ............................................................................................................... 55 
8.1.3 
Muscle strength measurement ....................................................................................................... 56 
8.1.4 
ALSAQ-5 ........................................................................................................................................ 56 
 ....................................................................................................................................... 56 
8.1.6 
Survival .......................................................................................................................................... 56 
 ..................................................................................... 56 
 
.......................................................................................... 57 
 .................................................................................... 57 
8.2 
SAFETY ASSESSMENTS  ............................................................................................................ 57 
8.2.1 
Physical examinations ................................................................................................................... 57 
8.2.2 
Neurological examinations ............................................................................................................. 58 
8.2.3 
Vital signs ....................................................................................................................................... 58 
8.2.4 
Electrocardiograms ........................................................................................................................ 58 
8.2.5 
Clinical safety laboratory assessments .......................................................................................... 59 
8.2.6 
Pregnancy testing .......................................................................................................................... 59 
8.2.7 
Suicidal ideation and behavior (SIB) risk monitoring ..................................................................... 59 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING ................................................................................................................... 60 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 60 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 61 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 61 
8.3.4 
Regulatory reporting requirements for SAEs ................................................................................. 61 
8.3.5 
Pregnancy ...................................................................................................................................... 61 
8.3.6 
Cardiovascular and death events .................................................................................................. 62 
8.3.7 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 62 
8.3.8 
Adverse event of special interest ................................................................................................... 63 
8.3.9 
Guidelines for reporting product complaints .................................................................................. 63 
8.4 
PHARMACOKINETICS .................................................................................................................. 64 
8.5 
GENETICS AND/OR PHARMACOGENOMICS ............................................................................ 64 
8.6 
BIOMARKERS ............................................................................................................................... 65 
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8.7 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 65 
8.8 
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS ........................................... 65 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 65 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 67 
9.1 
STATISTICAL HYPOTHESIS ........................................................................................................ 67 
9.2 
SAMPLE SIZE DETERMINATION ................................................................................................. 67 
9.3 
POPULATIONS FOR ANALYSES ................................................................................................. 67 
9.4 
STATISTICAL ANALYSES ............................................................................................................ 68 
9.4.1 
General considerations .................................................................................................................. 68 
9.4.2 
Primary endpoint(s) in Part A ......................................................................................................... 68 
9.4.3 
Secondary endpoint(s) in Part A .................................................................................................... 69 
9.4.4 
Primary endpoint in Part B ............................................................................................................. 69 
9.4.5 
Tertiary endpoints .......................................................................................................................... 70 
9.4.6 
Safety analysis ............................................................................................................................... 70 
9.4.6.1 
Adverse events .............................................................................................................................. 70 
9.4.6.2 
Laboratory variables, vital signs and electrocardiograms (ECGs) ................................................. 71 
9.4.6.3 
Product complaints......................................................................................................................... 71 
9.4.7 
Other analysis ................................................................................................................................ 71 
9.5 
INTERIM ANALYSES .................................................................................................................... 72 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ........................ 73 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ....... 73 
10.1.1 
Regulatory and ethical considerations ........................................................................................... 73 
10.1.2 
Financial disclosure........................................................................................................................ 74 
10.1.3 
Informed consent process .............................................................................................................. 74 
10.1.4 
Data protection ............................................................................................................................... 75 
10.1.5 
Committee structure ....................................................................................................................... 77 
10.1.5.1 Study Steering Committee ............................................................................................................. 77 
10.1.5.2 Independent Data Monitoring Committee (DMC) .......................................................................... 77 
10.1.6 
Dissemination of clinical study data ............................................................................................... 77 
10.1.7 
Data quality assurance .................................................................................................................. 78 
10.1.8 
Source documents ......................................................................................................................... 79 
10.1.9 
Study and site start and closure ..................................................................................................... 79 
10.1.10 Publication policy ........................................................................................................................... 80 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ......................................................................... 80 
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10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING ......................................................................... 82 
10.3.1 
Definition of AE .............................................................................................................................. 82 
10.3.2 
Definition of SAE ............................................................................................................................ 84 
10.3.3 
Recording and follow-up of AE and/or SAE ................................................................................... 85 
10.3.4 
Reporting of SAEs.......................................................................................................................... 86 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE ................................................... 87 
10.4.1 
Definitions ...................................................................................................................................... 87 
10.4.2 
Contraception guidance ................................................................................................................. 88 
10.5 
APPENDIX 5: GENETICS ............................................................................................................. 89 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: ACTIONS AND FOLLOW-UP 
ASSESSMENTS  ........................................................................................................................... 90 
10.7 
APPENDIX 7: AES, ADES, SAES, SADES, USADES AND DEVICE DEFICIENCIES: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, FOLLOW-UP, 
AND REPORTING IN MEDICAL DEVICE STUDIES .................................................................... 96 
10.8 
APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS .............................................................. 96 
10.8.1 
China .............................................................................................................................................. 97 
10.8.1.1 Study objectives and endpoints ..................................................................................................... 97 
10.8.1.2 Sample storage and disposition of samples after study completion .............................................. 99 
10.8.2 
Germany ........................................................................................................................................ 99 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................... 99 
10.10 
APPENDIX 10: STRONG AND MODERATE CYP3A4 INHIBITORS AND STRONG 
CYP3A4 INDUCERS.................................................................................................................... 100 
10.11 
APPENDIX 11: BLOOD VOLUME DETAILS ............................................................................... 102 
10.12 
APPENDIX 12: ABBREVIATIONS ............................................................................................... 104 
10.13 
APPENDIX 13: PROTOCOL AMENDMENT HISTORY .............................................................. 106 
10.13.1 Amended protocol 04 (12 May 2023)........................................................................................... 106 
10.13.2 Amended protocol 03 (06 March 2023) ....................................................................................... 107 
10.13.3 Amended protocol 02 (02 December 2022) ................................................................................. 108 
10.13.4 Amended protocol 01 (07 April 2022) .......................................................................................... 111 
11 
REFERENCES ............................................................................................................................. 115 
 
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LIST OF TABLES  
Table 1 - Risk assessment (identified risk of clinical significance) ................................................................ 29 
Table 2 - Risk assessment (potential risk of clinical significance) ................................................................ 30 
Table 3 - Objectives and endpoints ............................................................................................................... 32 
Table 4 - Overview of study interventions administered ............................................................................... 45 
Table 5 - Schedule of PK sampling ............................................................................................................... 64 
Table 6 - Populations for analyses ................................................................................................................ 67 
Table 7 - Protocol-required laboratory tests .................................................................................................. 81 
Table 8 - Strong and moderate CYP3A4 inhibitors and strong CYP3A4 inducers ..................................... 100 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 18 
 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title:  
A Phase 2, multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and 
safety of SAR443820 in adult participants with amyotrophic lateral sclerosis, followed by an open-label 
extension. 
Brief title: 
 
Phase 2 study for SAR443820 in participants with amyotrophic lateral sclerosis (ALS) 
 
IND: 
151444 
EudraCT: 
2021-004156-42 
NCT: 
NCT05237284 
WHO: 
U1111-1263-5766 
EUDAMED 
Not applicable 
Other 
Not applicable 
Rationale: 
SAR443820 is a selective, orally bioavailable, central nervous system (CNS)-penetrant, 
receptor-interacting serine/threonine-protein kinase 1 (RIPK1) inhibitor. The aim of this Phase 2 
study is to determine the efficacy, safety, tolerability, pharmacokinetics (PK), and 
pharmacodynamics (PD) of SAR443820 in treating adult participants with amyotrophic lateral 
sclerosis (ALS). 
Multiple pathways have been suggested to be involved in ALS pathogenesis, including pathways 
involved in oxidative stress, mitochondrial dysfunction, axonal damage, excitotoxicity, 
neuroinflammation, and protein aggregation (1). Treatment targeting the common mediator of 
these mechanisms can provide more robust disease intervention than targeting any individual 
pathway. More specifically, inhibition of microglial activation and inflammatory-driven neuronal 
death, the common consequence of multiple pathways in the pathophysiology of ALS, has the 
potential to provide an effective treatment for this relentless disease. 
RIPK1 is an intracellular protein involved in the regulation of inflammation, cytokine release, and 
cell death. RIPK1 is activated in response to several inflammatory stimuli, most notably tumor 
necrosis factor alpha (TNF-) signaling through its receptor 1 (TNF1), with subsequent RIPK1 
initiation of a complex signaling cascade that triggers intracellular responses, including cytokine 
release, microglial activation, and necroptosis, a regulated form of cell death (2, 3). Inhibition of 
RIPK1 activity has been shown to protect against necroptotic cell death in vitro across a range of 
cell death models (4, 5, 6). Similarly, in various animal models of diseases ranging from 
Alzheimer’s disease (AD) to multiple sclerosis (MS), inhibition of RIPK1 protects against their 
respective pathologies and attributed cell death (7, 8, 9, 10). These nonclinical findings, coupled 
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with observations of increased RIPK1 activity in human diseases (6, 7, 11), suggest that inhibition 
of RIPK1 could ameliorate ALS. 
The RIPK1 pathway is activated in spinal cords from patients with ALS. These postmortem samples 
show elevated levels of RIPK1 and its downstream signaling partners, receptor-interacting 
serine/threonine-protein kinase 3 (RIPK3) and mixed lineage kinase domain–like pseudokinase 
(MLKL) (8). Similar increases have been observed in the spinal cord of the SOD1 (G93A) transgenic 
mouse with ALS. Furthermore, both genetic inhibition of the RIPK1 pathway (RIPK3 -/-) and 
treatment with a RIPK1 inhibitor reduced axonal pathology and delayed the onset of motor 
dysfunction in this model (8). Several ALS-inducing mutations, including TANK-binding kinase 1 
(TBK1) and optineurin (OPTN), have been shown to sensitize cells to RIPK1-dependent cell death 
and inflammation (8, 12, 13). Notably, another RIPK1 activity inhibitor, transforming growth factor 
-activated kinase 1 (TAK1), declines with age, which may predispose the CNS to neuroinflammation 
and neurodegeneration in the setting of genetic or environmental stresses (13). 
In summary, both preclinical and patient-derived data have suggested RIPK1 may be a key 
mediator of necroptosis and inflammatory pathways in ALS. SAR443820, a CNS-penetrant 
inhibitor of RIPK1, has the potential to modify the course of neurodegenerative processes and 
slow disease progression in patients with ALS. Therefore, the aim of this Phase 2 study is to 
determine the efficacy, safety, and tolerability of SAR443820 in participants with ALS. 
Objectives and endpoints  
Part A 
 
  
Objectives 
Endpoints 
Primary 
 
• 
To assess the effect of SAR443820 compared to 
placebo in reducing ALS progression as measured 
by the Amyotrophic Lateral Sclerosis Functional 
Rating Scale Revised (ALSFRS-R) 
• 
Change from baseline in the ALSFRS-R total score to 
Week 24 
Secondary 
 
• 
To assess the effect of SAR443820 compared to 
placebo on a combined assessment of function and 
survival, respiratory function, muscle strength, and 
quality of life (QoL) 
• 
Combined assessment of the function and survival 
(CAFS) score at Week 24 
• 
Change from baseline in slow vital capacity (SVC) to 
Week 24 
• 
Change from baseline in muscle strength to Week 24 
• 
Change from baseline in Amyotrophic Lateral 
Sclerosis Assessment Questionnaire (ALSAQ-5) to 
Week 24 
• 
To assess the pharmacodynamic (PD) effect of 
SAR443820 compared to placebo on a key disease 
biomarker 
• 
Change from baseline in serum neurofilament light 
chain (NfL) to Week 24 
• 
To assess the safety and tolerability of SAR443820 
compared to placebo 
• 
Incidence of adverse events (AE), serious adverse 
events (SAE), treatment-emergent adverse events 
(TEAE), potentially clinically significant abnormalities 
(PCSA) in laboratory tests, electrocardiogram (ECG), 
and vital signs over 24 weeks 
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Objectives 
Endpoints 
• 
To assess the pharmacokinetics (PK) of 
SAR443820 
• 
Plasma concentration of SAR443820 
 
Tertiary 
 
SAR443820 
 
• 
To assess the effects of SAR443820 compared to 
placebo on neurodegeneration and inflammation 
disease biomarkers 
• 
Change from baseline in soluble triggering receptor 
expressed on myeloid cells-2 (sTREM2) in plasma, 
chitinase-3-like protein-1 (CHI3L1), a selected panel of 
cytokines and chemokines in serum, and extracellular 
domain of p75 (p75ECD) in urine to Week 24 
 
 
 
Part B 
 
Objectives 
Endpoints 
Primary 
 
• 
To assess the long-term effects of SAR443820 on 
function and survival 
• 
Combined assessment of the function and survival 
(CAFS) score at Week 52 
Secondary 
• 
To assess the long-term effects of SAR443820 on 
disease progression, survival, respiratory function, 
and quality of life (QoL) 
• 
Combined assessment of the function and survival 
(CAFS) score at Week 76 and Week 104 
• 
Change from baseline in the ALSFRS-R total score to 
Week 52, Week 76, and Week 104 
• 
Time from baseline to the occurrence of either death or 
permanent assisted ventilation (>22 hours daily for 
>7 consecutive days), whichever comes first 
• 
Time from baseline to the occurrence of death 
• 
Change from baseline in slow vital capacity (SVC) to 
Week 52, Week 76, and Week 104 
• 
Change from baseline in Amyotrophic Lateral Sclerosis 
Assessment Questionnaire (ALSAQ-5) to Week 52, 
Week 76, and Week 104 
• 
To assess the long-term effect of SAR443820 on 
a key disease biomarker 
• 
Change from baseline in serum neurofilament light 
chain (NfL) to Week 52 
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Objectives 
Endpoints 
• 
To assess the long-term safety and tolerability of 
SAR443820 
• 
Incidence of adverse events (AE), serious adverse 
events (SAE), treatment-emergent adverse events 
(TEAE), potentially clinically significant abnormalities 
(PCSA) in laboratory tests, electrocardiogram (ECG), 
and vital signs during Part B 
• 
To assess the pharmacokinetics (PK) of 
SAR443820 
• 
Plasma concentration of SAR443820 
Tertiary 
 SAR443820 
SAR443820 
 
For China, please see Appendix 8 (Section 10.8) for details. 
Overall design: 
Study ACT16970 is a Phase 2, randomized, double-blind, placebo-controlled study followed by 
an open-label extension period. 
Brief summary: 
This is a parallel-treatment, phase 2, randomized, double-blind study to assess the efficacy, safety, 
tolerability, PK, and PD of 20 mg twice daily (BID) oral SAR443820 compared with placebo in 
male and female participants aged 18 to 80 years with ALS followed by an open-label, long-term 
extension period. 
Study ACT16970 consists of 2 parts (A and B) as follows: 
Part A is a 24-week, double-blind, placebo-controlled part, preceded by a screening period of up 
to 4 weeks before Day 1. 
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On Day 1 of Part A, participants will be randomized in a 2:1 ratio to the SAR443820 treatment 
arm or matching placebo arm as listed below: 
• Treatment arm: SAR443820, 20 mg, BID 
• Placebo arm: Placebo, BID 
Randomization will be stratified by the geographic region of the study site, region of ALS onset 
(bulbar vs other areas), use of riluzole (yes vs no), use of edaravone (yes vs no) and use of the 
combination of sodium phenylbutyrate and taurursodiol (named Relyvrio® in the USA and 
Albrioza® in Canada) (yes vs no). Participants will attend in-clinic study assessments at baseline 
(Day 1), Week 2, Week 4, Week 6, Week 8, Week 10, Week 12, Week 16, Week 20, Week 21, 
Week 22, Week 23 and Week 24. All ongoing participants at Week 24 will rollover to open-label 
extension (Part B). The Week 24 Visit is the end of Part A and the beginning of Part B.  
Part B is an open-label, long-term extension period that starts from Week 24 and continues up to 
Week 106. The objectives of Part B are to provide extended access to SAR443820 participants in 
Part A and to further evaluate the safety and efficacy of long-term SAR443820 treatment. The 
treatment assignment of participants at randomization in Part A will remain blinded to 
Investigators, participants, and site personnel until the end of Part B. Every participant, except 
those who discontinue IMP treatment permanently in Part A, will receive BID oral tablets of 
20 mg SAR443820 in Part B. 
The study duration includes an up to 4-week screening period, 24-week double-blind treatment 
period in Part A, 80-week open-label treatment period in Part B, and 2-week post-treatment 
follow-up period, with a maximum total study duration of 110 weeks. 
Number of participants: 
Approximately 326 participants will be screened to achieve 261 participants randomly assigned to 
the study intervention (based on a 20% screening failure rate). 
Intervention groups and duration: 
Part A of the study will last for 24 weeks, and participants will receive 20 mg BID oral 
SAR443820 or placebo in a double-blind fashion for 24 weeks. All ongoing participants at 
Week 24 will rollover to open-label extension (Part B). 
Part B begins at the end of Week 24 and continues up to Week 106. All participants, except those 
who discontinue IMP treatment permanently in Part A, will receive BID oral tablets of 20 mg 
SAR443820 in Part B. 
Study intervention(s) 
SAR443820 or placebo matched to SAR443820. 
Investigational medicinal product(s) (IMP) 
• Formulation: Both SAR443820 and matched placebo will be formulated in tablets. 
• Route(s) of administration: Tablets will be taken orally. The suggested method for 
investigational medicinal product (IMP) administration in detail is listed in Section 6. 
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• Dose regimen: 
- 
Part A: 
- 
Treatment arm: SAR443820, 20 mg, BID 
- 
Placebo arm: Placebo, BID 
- 
Part B: 
- 
All participants: SAR443820, 20 mg, BID. 
Based on a data review, in accordance with Data Monitoring Committee (DMC) 
recommendations leading to an urgent safety measure submitted on 05 December 2023, the sites 
have been instructed to pause the administration of SAR443820 in Part B (open-label extension) 
immediately. All participants in Part B will be encouraged to continue follow-up visits, but no 
doses of SAR443820 should be administered. Rollover to Part B for follow-up visits after 
completing Part A is also encouraged, but without taking SAR443820 in Part B. The decision of 
whether resuming SAR443820 administration in Part B will be made based on DMC 
recommendation when Part A data is available and benefit risk ratio will be evaluated. 
Noninvestigational medicinal products(s) 
No noninvestigational medicinal products (NIMP) will be provided by the Sponsor. 
As of November 2022, riluzole and edaravone constitute the standard of care and are the currently 
approved treatment options for patients with ALS in the United States, Canada, China, and Japan. 
Riluzole has also been approved in the European Union (EU) for ALS treatment. The combination 
of sodium phenylbutyrate and taurursodiol has been approved in the USA and Canada for ALS 
treatment. Since riluzole, edaravone and the combination of sodium phenylbutyrate and 
taurursodiol are the standard of care for ALS, they are considered to be NIMP in our study. The 
dosing of riluzole, edaravone and the combination of sodium phenylbutyrate and taurursodiol 
should be consistent with local labeling requirements. 
Riluzole: 
• Route of administration: oral 
• Dose regimen: as per the label 
Edaravone: 
• Route of administration: intravenous (IV) or oral 
• Dose regimen: as per the label 
Combination of sodium phenylbutyrate and taurursodiol: 
• Route of administration: oral 
• Dose regimen: as per the label 
Devices 
Not applicable. 
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Poststudy access to the study medication 
In addition to the 104 weeks of treatment with the IMP in Part A and Part B of this trial, 
a separate, open-label, long-term safety follow-up study may be proposed for the participants in 
this study if a positive benefit/risk ratio is confirmed in this trial. The details of the long-term 
study will be provided in a separate protocol. 
Statistical considerations: 
Sample size determination: 
A sample size of 261 participants in total is needed to achieve an 80% power to detect 
a 30% reduction in SAR443820 compared with placebo in change of the Amyotrophic Lateral 
Sclerosis Functional Rating Scale Revised (ALSFRS-R) from baseline to Week 24, assuming 
a change of 
 points from baseline in ALSFRS-R in the placebo arm with a standard deviation 
of 
 points at Week 24, and a 20% drop-out rate. Sample size is estimated via simulation with 
a 2-sided 5% significance level. 
Primary endpoint in Part A: The primary efficacy endpoint in Part A is the change from 
baseline in the ALSFRS-R total score to Week 24. 
The primary estimand will be the difference (SAR443820 vs placebo) in the mean change from 
baseline in the ALSFRS-R score estimated in the intent-to-treat (ITT) population regardless of 
whether participants completed the treatment period. This estimand corresponds to a “treatment 
policy strategy” and will be using all available data and missing data will not be imputed. 
The primary analysis will be based on the primary estimand, which includes data collected for the 
primary endpoint for all participants included in the ITT population. 
A mixed-effect model with repeated measure (MMRM) model will be fitted to change from 
baseline in the ALSFRS-R score, which will include the fix effects of treatment (SAR443820 or 
placebo), visit (as a categorical variable), baseline ALSFRS-R score, baseline serum 
neurofilament light chain (NfL), randomization strata of the geographic region of the study site, 
ALS onset region (bulbar or other areas), use of riluzole (yes or no), use of edaravone (yes or no), 
use of the combination of sodium phenylbutyrate and taurursodiol (yes vs no), treatment-by-visit 
interaction, baseline NfL-by-visit interaction and baseline ALSFRS-R score-by-visit interaction. 
The least squares mean difference in the ALSFRS-R change from baseline at Week 24 between 
SAR443820 and placebo, together with the p-value and the 95% confidence interval (CI) for the 
difference, will be estimated from the MMRM model. 
Subgroup analysis will be specified in the SAP. 
Main secondary endpoints in Part A: The key secondary efficacy endpoints include the 
combined assessment of function and survival (CAFS) score at Week 24, and change from 
baseline in slow vital capacity (SVC), muscle strength, Amyotrophic Lateral Sclerosis 
Assessment Scales - 5 items (ALSAQ-5), and serum NfL to Week 24. All the secondary efficacy 
endpoints will be analyzed based on the ITT population. 
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For continuous variables, an MMRM approach under the missing at random (MAR) assumption 
will be used. This model will include the fixed effect of treatment (SAR443820 or placebo), visit 
as a categorical variable, baseline value of the endpoint, baseline NfL (if different from the 
baseline value of the endpoint), randomization strata of the geographic region of the study site, 
ALS onset region (bulbar or other areas), use of riluzole (yes or no), use of edaravone (yes or no), 
use of the combination of sodium phenylbutyrate and taurursodiol (yes vs no), treatment-by-visit 
interaction, baseline value of endpoint-by-visit interaction and baseline NfL-by-visit interaction 
(if different from the baseline value of the endpoint-by-visit interaction). The primary comparison 
of interest will be the difference between SAR443820 and placebo at Week 24, carried out using 
contrast within the treatment-by-time interaction term. 
Primary endpoint in Part B: The primary endpoint in Part B is the CAFS at Week 52. 
Comparison will be conducted between participants who receive SAR443820 and those who 
receive placebo in Part A. 
Data Monitoring Committee: Yes 
 
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1.2 
SCHEMA  
Figure 1 - Graphical study design  
 
AE = adverse event; BID = twice daily; D = day; N = number of participants; PK = pharmacokinetic(s); R = randomization; SAE = serious adverse event; W = week; FU = follow up. 
As of 5 December 2023, the administration of SAR443820 will be paused immediately until DMC recommendation to resume dosing based on benefit-risk considerations when Part A data is available. 
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1.3 
SCHEDULE OF ACTIVITIES  
1.3.1 Part A  
 
Procedure 
Screening  
(up to 
4 weeks 
before 
Day 1) 
Intervention period (Part A) 
Early IMP 
discon-
tinuation 
visitb 
Day 1 
Week 
2 
(Day 
15±3) 
Week 
4 
(Day 
29±3) 
Week 
6 
 (Day 
43±3)  
Week 
8 
(Day 
57±3) 
Week 
10 
 (Day 
71±3) 
Week 
12 
(Day 
85±3) 
Week 
16 
(Day 
113±3) 
Week  
20 
(Day 
141±3) 
Week  
21 
 (Day 
148±3) 
Week  
22 
 (Day 
155±3) 
Week  
23 
 (Day 
162±3) 
Week 
24 
(Day 
169±3)a 
Predose 
(baseline) 
Postdose 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit 
1c 
2 
3 
4 
4.5 
5 
5.5 
6 
7 
8 
8.25 
8.5 
8.75 
9 
 
Visit 
location or 
medium 
Site 
Site 
Site 
Site 
Sited 
Site 
Sited 
Sited 
Site 
Sited 
Sited 
Sited 
Sited 
Site 
Site 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility check 
(inclusion and 
exclusion 
criteria) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study 
intervention 
dispensing and 
reconciliationf 
 
X 
 
Xg  
X 
 
X 
 
 
X 
 
 
 
 
Xh 
Xg 
Physical 
examinationi 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
 
 
 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
 
 
 
X 
X 
12-lead ECG 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
 
 
X 
X 
Vital signsj 
X 
X 
Xk 
X 
X 
 
X 
 
 
X 
 
 
 
 
X 
X 
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Procedure 
Screening  
(up to 
4 weeks 
before 
Day 1) 
Intervention period (Part A) 
Early IMP 
discon-
tinuation 
visitb 
Day 1 
Week 
2 
(Day 
15±3) 
Week 
4 
(Day 
29±3) 
Week 
6 
 (Day 
43±3)  
Week 
8 
(Day 
57±3) 
Week 
10 
 (Day 
71±3) 
Week 
12 
(Day 
85±3) 
Week 
16 
(Day 
113±3) 
Week  
20 
(Day 
141±3) 
Week  
21 
 (Day 
148±3) 
Week  
22 
 (Day 
155±3) 
Week  
23 
 (Day 
162±3) 
Week 
24 
(Day 
169±3)a 
Predose 
(baseline) 
Postdose 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit 
1c 
2 
3 
4 
4.5 
5 
5.5 
6 
7 
8 
8.25 
8.5 
8.75 
9 
 
Visit 
location or 
medium 
Site 
Site 
Site 
Site 
Sited 
Site 
Sited 
Sited 
Site 
Sited 
Sited 
Sited 
Sited 
Site 
Site 
C-SSRS 
questionnaire 
X 
Xl 
 
Xl 
Xl 
 
Xl 
 
 
Xl 
 
 
 
 
Xl 
Xl 
Neurological 
examinationm 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
 
 
 
X 
X 
Past and current 
medical 
conditions 
(includes 
substance 
usage)n 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum β-HCG 
test (WOCBP 
only) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum FSH and 
estradiolo 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy 
test (WOCBP 
only)  
 
X 
 
X 
X 
 
X 
 
X 
X 
X 
 
 
 
X 
 
HIV and 
hepatitis B and 
C screening 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory tests 
for hematology 
and chemistry 
X 
X 
 
X 
X 
Xp 
X 
Xp 
Xp 
X 
Xp 
Xp 
Xp 
Xp 
X 
X 
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Procedure 
Screening  
(up to 
4 weeks 
before 
Day 1) 
Intervention period (Part A) 
Early IMP 
discon-
tinuation 
visitb 
Day 1 
Week 
2 
(Day 
15±3) 
Week 
4 
(Day 
29±3) 
Week 
6 
 (Day 
43±3)  
Week 
8 
(Day 
57±3) 
Week 
10 
 (Day 
71±3) 
Week 
12 
(Day 
85±3) 
Week 
16 
(Day 
113±3) 
Week  
20 
(Day 
141±3) 
Week  
21 
 (Day 
148±3) 
Week  
22 
 (Day 
155±3) 
Week  
23 
 (Day 
162±3) 
Week 
24 
(Day 
169±3)a 
Predose 
(baseline) 
Postdose 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit 
1c 
2 
3 
4 
4.5 
5 
5.5 
6 
7 
8 
8.25 
8.5 
8.75 
9 
 
Visit 
location or 
medium 
Site 
Site 
Site 
Site 
Sited 
Site 
Sited 
Sited 
Site 
Sited 
Sited 
Sited 
Sited 
Site 
Site 
Blood draw for 
optional DNA 
collection 
 
 
 
Xq 
Xq 
 
 
 
 
 
 
 
 
 
 
 
SVC 
X 
X 
 
 
 
X 
 
 
X 
 
 
 
X 
X 
ALSFRS-R 
X 
X 
 
 
X 
 
X 
 
X 
X 
X 
 
 
 
X 
X 
ALSAQ-5  
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
Muscle strengthr 
 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
 
Blood sample 
for plasma PKt  
 
 
Xu 
Xv 
 
 
Xv, w 
 
 
 
 
 
 
 
 
 
Blood samples 
for plasma 
sTREM2 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
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Procedure 
Screening  
(up to 
4 weeks 
before 
Day 1) 
Intervention period (Part A) 
Early IMP 
discon-
tinuation 
visitb 
Day 1 
Week 
2 
(Day 
15±3) 
Week 
4 
(Day 
29±3) 
Week 
6 
 (Day 
43±3)  
Week 
8 
(Day 
57±3) 
Week 
10 
 (Day 
71±3) 
Week 
12 
(Day 
85±3) 
Week 
16 
(Day 
113±3) 
Week  
20 
(Day 
141±3) 
Week  
21 
 (Day 
148±3) 
Week  
22 
 (Day 
155±3) 
Week  
23 
 (Day 
162±3) 
Week 
24 
(Day 
169±3)a 
Predose 
(baseline) 
Postdose 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit 
1c 
2 
3 
4 
4.5 
5 
5.5 
6 
7 
8 
8.25 
8.5 
8.75 
9 
 
Visit 
location or 
medium 
Site 
Site 
Site 
Site 
Sited 
Site 
Sited 
Sited 
Site 
Sited 
Sited 
Sited 
Sited 
Site 
Site 
Blood samples 
for serum 
biomarkers, 
including NfL, 
CHI3L1, 
cytokine and 
chemokine 
panelx 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
Urine sample for 
biomarker 
analysis 
(p75ECD)y 
X 
X 
 
 
 
 
X 
 
 
X 
 
 
 
 
X 
X 
Urine sample for 
urinalysis 
X 
X 
 
X 
X 
 
X 
 
 
X 
 
 
 
 
X 
X 
Blood sample 
for archiving 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AE review  
 
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------→ 
X 
SAE review 
 
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------→ 
X 
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Procedure 
Screening  
(up to 
4 weeks 
before 
Day 1) 
Intervention period (Part A) 
Early IMP 
discon-
tinuation 
visitb 
Day 1 
Week 
2 
(Day 
15±3) 
Week 
4 
(Day 
29±3) 
Week 
6 
 (Day 
43±3)  
Week 
8 
(Day 
57±3) 
Week 
10 
 (Day 
71±3) 
Week 
12 
(Day 
85±3) 
Week 
16 
(Day 
113±3) 
Week  
20 
(Day 
141±3) 
Week  
21 
 (Day 
148±3) 
Week  
22 
 (Day 
155±3) 
Week  
23 
 (Day 
162±3) 
Week 
24 
(Day 
169±3)a 
Predose 
(baseline) 
Postdose 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visit 
1c 
2 
3 
4 
4.5 
5 
5.5 
6 
7 
8 
8.25 
8.5 
8.75 
9 
 
Visit 
location or 
medium 
Site 
Site 
Site 
Site 
Sited 
Site 
Sited 
Sited 
Site 
Sited 
Sited 
Sited 
Sited 
Site 
Site 
Concomitant 
therapy and 
procedures 
recording 
 
------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------→ 
X 
Abbreviations: AE = adverse event; ALS = amyotrophic lateral sclerosis; ALSAQ-5 = Amyotrophic Lateral Sclerosis Assessment Questionnaire – 5; ALSFRS-R = Amyotrophic Lateral Sclerosis Functional Rating Scale 
– Revised; β-HCG = beta human chorionic gonadotropin; CHI3L1 = chitinase-3-like protein 1; C-SSRS = Columbia Suicide Severity Rating Scale; DTP = direct-to-patient; ECG = electrocardiogram; 
; FSH = follicle stimulating hormone; 
 HIV = human immunodeficiency virus; IFNγ = interferon γ; IL = interleukin; IMP = investigational medicinal product; 
IP-10 = interferon gamma-induced protein 10; MCP = monocyte chemoattractant protein; MIP1 = macrophage inflammatory protein-1; NfL = neurofilament light chain; p75ECD = extracellular domain of p75; 
PK = pharmacokinetic(s); SAE = serious adverse event; sTREM2 = soluble triggering receptor expressed on myeloid cells 2; SVC = slow vital capacity; TARC = thymus- and activation-regulated chemokine; 
TNF = tumor necrosis factor; WOCBP = woman of childbearing potential 
a The Week 24 visit is considered as both the last visit for Part A and the first visit for Part B. For all participants, last dose of double-blind IMP should be taken on the day prior to the Week 24 visit. Week 24 visit will 
consist of first open-label (Part B) IMP. All assessments for end of Part A should be completed prior to first dose of open-label IMP. 
b For participants who prematurely discontinue IMP, the early discontinuation visit will happen 2 weeks (±3 days) after the last dose of the IMP. If, after the early IMP discontinuation visit, participants decide to 
continue the study, they will follow the same schedule for visits, but only ALSFRS-R, SVC, blood samples for plasma sTREM2, blood samples for serum biomarkers, including NfL, CHI3L1, cytokine and 
chemokine panel and urine sample for biomarker analysis (p75ECD), vital signs, physical examination, neurological examination, AE review, SAE review and concomitant therapy and procedures recordings will be 
performed in the visits, as applicable according to the schedule of activities. 
c The screening visit can be performed over up to 2 days if needed (they do not need to be consecutive days) to minimize the burden on participants. 
d Alternatively, the Week 6, Week 10, Week 12, Week 20, Week 21, Week 22, and Week 23 visit can be conducted by phone. If the study visit is conducted by phone, the blood sample must be collected at a local 
clinic or at home by a nurse, and the sample must be tested at a local lab or the central lab. In case of testing at a local lab, the study site staff must contact participants, within 2 working days after the results are 
expected to be available, to collect results of blood test.; For Week 12, and Week 20 visit, if conducted by phone, 1) the urine pregnancy test will be provided directly to participants and self-conducted at home. 
The study site staff will call the participants to remind them to conduct the pregnancy test and collect the result. If pregnancy test result is positive, participant should discontinue IMP immediately; 2) ALSFRS-R will 
be measured through the phone call.   
e Participants will be randomized in a 2:1 ratio to the SAR443820 treatment arm or placebo arm. The randomization will be stratified by the geographic region of the study site, region of ALS onset (bulbar vs other 
areas), use of riluzole (yes vs no), and use of edaravone (yes vs no) and use of the combination of sodium phenylbutyrate and taurursodiol (yes vs no). 
f 
In addition to the IMP being dispensed in the clinic, the IMP may be dispensed for home administration via DTP services, except if prohibited by local regulatory authorities. 
g Only IMP reconciliation will be done at this visit. 
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h Reconciliation of the IMP dispensed in Part A and dispensation of the open-label IMP in Part B at this visit (Week 24). 
i 
A full physical examination will be performed at the screening visit, and a brief physical examination will be performed at all other visits. The skin and lymph nodes need to be checked at each site visit. 
j 
Vital signs include blood pressure, heart rate, respiratory rate, and temperature. 
k  Postdose vital signs should be measured at least 10 minutes after the second PK sample collection (recommended to be measured within 10 to 30 minutes after the second PK sample collection). 
l 
The “Since Last Visit” version of the C-SSRS will be used. 
m A full neurological examination will be performed at the screening visit, and a brief neurological examination pertaining to cranial nerves, coordination/cerebellar function, reflexes, and motor function will be 
performed at other visits. 
n Substances include drugs of abuse, alcohol, tobacco, and caffeine. 
o Only in female participants, if needed to establish menopausal status. 
p Only liver chemistry monitoring will be conducted, which includes testing of alanine transaminase (ALT), aspartate aminotransferase (AST), bilirubin direct, bilirubin total and alkaline phosphatase.  
q Optional one-time blood draw for DNA analysis can be completed at either Week 2 or Week 4 visit.  
r 
The muscles measured include both upper-limb and lower-limb muscle groups. Bilateral hand grip will be measured using a Jamar grip dynamometer and all other muscles included in this study will be measured 
using a handheld dynamometer. 
. 
t 
The IMP can be taken under either fasting or non-fasting condition. 
u Two samples for PK will be collected at this visit, 1 within 15 minutes to 1 hour and another within 1 to 3 hours after the morning dose of IMP. There will be at least 45 minutes between the 2 samplings. 
v One sample for PK will be collected within 1 hour before the morning dose of IMP. 
w One sample for PK will be collected within 15 minutes to 3 hours after the morning dose of IMP. 
x The cytokines measured in this study include IFN-, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL12p70, IL-13, and TNF-α. The chemokines measured in this study include eotaxin-1, eotaxin-3, TARC, IP-10, MIP1α, 
MIP1β, MCP1, and MCP4. 
y This assessment will not be conducted in China (see Appendix 8 [Section 10.8]). 
 
 
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1.3.2 Part B  
 
 
Intervention period (Part B)a 
 
 
Procedureb 
Week 
28 
(Day 
197±3) 
Week 
30 
(Day 
211±3) 
Week 
32 
(Day 
225±3)  
Week 
34 
(Day 
239±3) 
Week 
36  
(Day 
253±3) 
Week 
40 
(Day 
281±3)  
Week 
44  
(Day 
309±3) 
Week 
52  
(Day 
365±3) 
Week  
64  
(Day 
449±3) 
Week  
76 
(Day  
533 ±3) 
Week 
88 
(Day 
617 ±7) 
Week 
104 
(Day 
729 ±7) 
Last 
follow-
up 
visitc 
Early 
IMP 
disconti-
nuation 
visite 
Visit 
10 
10.25 
10.5 
10.75 
11 
11.5 
12 
13 
14 
15 
16 
17 
18 
Visit location 
or medium 
Site 
Sited 
Sited 
Sited 
Site 
Sited 
Site 
Site 
Site 
Site 
Site 
Site 
Site 
Site 
Study intervention 
dispensing and 
reconciliationf 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
Xg 
 
Xg 
Physical 
examinationh 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Neurological 
examinationi 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory tests 
for hematology 
and chemistry  
X 
Xj 
Xj 
Xj 
X 
Xj 
X 
X 
X 
X 
X 
X 
 
X 
X 
12-lead ECG 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
C-SSRS 
questionnairek 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signsl 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Weight 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
SVC 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
ALSFRS-R 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
ALSAQ-5  
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
Blood sample for 
plasma PK 
Xm 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Intervention period (Part B)a 
 
 
Procedureb 
Week 
28 
(Day 
197±3) 
Week 
30 
(Day 
211±3) 
Week 
32 
(Day 
225±3)  
Week 
34 
(Day 
239±3) 
Week 
36  
(Day 
253±3) 
Week 
40 
(Day 
281±3)  
Week 
44  
(Day 
309±3) 
Week 
52  
(Day 
365±3) 
Week  
64  
(Day 
449±3) 
Week  
76 
(Day  
533 ±3) 
Week 
88 
(Day 
617 ±7) 
Week 
104 
(Day 
729 ±7) 
Last 
follow-
up 
visitc 
Early 
IMP 
disconti-
nuation 
visite 
Visit 
10 
10.25 
10.5 
10.75 
11 
11.5 
12 
13 
14 
15 
16 
17 
18 
Visit location 
or medium 
Site 
Sited 
Sited 
Sited 
Site 
Sited 
Site 
Site 
Site 
Site 
Site 
Site 
Site 
Site 
Blood samples for 
serum NfL 
X 
 
 
 
X 
 
X 
X 
 
 
 
 
 
Xn 
Urine sample for 
urinalysis 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Urine pregnancy 
test (WOCBP 
only)o 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Serum β-HCG 
test (WOCBP 
only) 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
 
AE review 
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------→ 
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------→ 
 
 
----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------→ 
X 
SAE review 
X 
Concomitant 
therapy and 
procedures 
recording 
X 
Abbreviations: AE = adverse event; ALSAQ-5 = Amyotrophic Lateral Sclerosis Assessment Questionnaire–5; ALSFRS-R = Amyotrophic Lateral Sclerosis Functional Rating Scale – Revised; β-HCG = beta human 
chorionic gonadotropin; C-SSRS = Columbia Suicide Severity Rating Scale; DTP = direct-to-patient; ECG = electrocardiogram; 
;  
IMP = investigational medicinal product; NfL=neurofilament light; PK = pharmacokinetic(s); SAE = serious adverse event; SVC = slow vital capacity; WOCBP = woman of childbearing potential 
a An urgent safety measure was submitted on 05 December 2023 to request pause of SAR443820 administration in Part B (open-label extension) immediately. All participants in Part B will be encouraged to 
continue follow-up visits, but no doses of SAR443820 should be administered until DMC recommendation to resume dosing based on benefit-risk considerations when Part A data is available. 
b The first visit for Part B is the Week 24 Visit in Part A. 
c The last follow-up visit will happen 2 weeks (±3 days) after Week 104 visit (Visit 17). 
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d Alternatively, the Week 30, Week 32, Week 34 and Week 40 visit can be conducted by phone. The blood sample at these visits must be collected either at study site, at a local clinic or at home by a nurse. In case 
of testing at a local lab, the study site staff must contact the participant, within 2 working days after the results are expected to be available, to collect results of blood test and update them in the eCRF. When 
Week 32 and Week 40 visits are conducted by phone, the urine pregnancy test will be provided directly to participants and self-conducted at home. The study site staff will call the participants to remind them to 
conduct the pregnancy test and collect the result. If pregnancy test result is positive, participant should discontinue IMP immediately. 
e For participants who prematurely discontinue IMP, the early IMP discontinuation visit will happen 2 weeks (±3 days) after the last dose of the IMP. If, after the IMP discontinuation visit, participants decide to 
continue the study, they will follow the same schedule for visits, but only ALSFRS-R, blood sample for NfL, vital signs, physical examination, neurological examination, AE review, SAE review and concomitant 
therapy and procedures recordings will be performed in the visits, as applicable according to the schedule of activities.   
f 
In addition to the IMP being dispensed in the clinic, the IMP may be dispensed for home administration via DTP services, except if prohibited by local regulatory authorities. 
g Only IMP reconciliation will be done at this visit. 
h A brief physical examination will be performed at each visit. The skin and lymph nodes need to be checked at each visit. 
i 
A brief neurological examination pertaining to cranial nerves, coordination/cerebellar function, reflexes, and motor function will be performed at each visit. 
j 
Only liver chemistry monitoring will be conducted, which includes testing of alanine transaminase (ALT), aspartate aminotransferase (AST), bilirubin direct, bilirubin total and alkaline phosphatase. 
k The “Since Last Visit” version of the C-SSRS will be used. 
l 
Vital signs include blood pressure, heart rate, respiratory rate, weight, and temperature. 
m One sample for PK will be collected within 1 hour before the morning dose of IMP. This PK sample can be taken under either fasting or non-fasting condition. 
n The blood sample for serum NfL will be collected only when the participant terminates IMP before Week 52.  
o Monthly urine pregnancy tests will be provided directly to participants and self-conducted by them at home when not coinciding with a clinic visit. The study site staff will call the participants to remind them to 
conduct the monthly pregnancy tests and collect the results. If pregnancy test result is positive, participant should discontinue IMP immediately. 
 
 
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2 
INTRODUCTION  
SAR443820 is a novel, potent, selective, CNS-penetrant RIPK1 inhibitor that is being developed 
for neurodegenerative diseases, including ALS. 
2.1 
STUDY RATIONALE  
SAR443820 is a selective, orally bioavailable, CNS-penetrant, RIPK1 inhibitor. The aim of this 
placebo-controlled Phase 2 study is to determine the efficacy, safety, tolerability, PK, and PD of 
SAR443820 in treating adult participants with ALS. 
Multiple pathways have been suggested to be involved in ALS pathogenesis, including pathways 
involved in oxidative stress, mitochondrial dysfunction, axonal damage, excitotoxicity, 
neuroinflammation, and protein aggregation (1). Treatment targeting the common mediator of 
these mechanisms can provide a more robust disease intervention than targeting any individual 
pathway. More specifically, inhibition of microglial activation and inflammatory-driven neuronal 
death, the common consequence of multiple pathways in the pathophysiology of ALS, has the 
potential to provide an effective treatment for this relentless disease. 
RIPK1 is an intracellular protein involved in the regulation of inflammation, cytokine release, and 
cell death. RIPK1 is activated in response to several inflammatory stimuli, most notably TNF- 
signaling through its receptor 1 (TNF1), with subsequent RIPK1 initiation of a complex signaling 
cascade that triggers intracellular responses, including cytokine release, microglial activation, and 
necroptosis, a regulated form of cell death (2, 3). Inhibition of RIPK1 activity has been shown to 
protect against necroptotic cell death in vitro across a range of cell death models (4, 5, 6). 
Similarly, in various animal models of diseases ranging from AD to MS, inhibition of RIPK1 
protects against their respective pathologies and attributed cell death (7, 8, 9, 10). These 
nonclinical findings, coupled with observations of increased RIPK1 activity in human diseases 
(6, 7, 11), suggest that inhibition of RIPK1 could ameliorate ALS. 
The RIPK1 pathway is activated in spinal cords from patients with ALS. These postmortem 
samples show elevated levels of RIPK1 and its downstream signaling partners, RIPK3 and MLKL 
(8). Similar increases have been observed in the spinal cord of the SOD1 (G93A) transgenic 
mouse with ALS. Furthermore, both genetic inhibition of the RIPK1 pathway (RIPK3 -/-) and 
treatment with a RIPK1 inhibitor reduced axonal pathology and delayed the onset of motor 
dysfunction in this model (8). Several ALS-inducing mutations, including TBK1 and OPTN, have 
been shown to sensitize cells to RIPK1-dependent cell death and inflammation (8, 12, 13). 
Notably, another RIPK1 activity inhibitor, transforming growth factor -activated kinase-1 
(TAK1), declines with age, which might predispose the CNS to neuroinflammation and 
neurodegeneration in the setting of genetic or environmental stresses (13). 
In summary, both preclinical and patient-derived data have suggested RIPK1 may be a key 
mediator of necroptosis and inflammatory pathways in ALS. SAR443820, a CNS-penetrant 
inhibitor of RIPK1, has the potential to modify the course of neurodegenerative processes and 
slow disease progression in patients with ALS. Therefore, the aim of this Phase 2 study is to 
assess the efficacy, safety, and tolerability of SAR443820 in treating participants with ALS. 
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2.2 
BACKGROUND  
ALS is a fatal neurodegenerative disorder characterized by progressive loss of motor neurons in 
the cortex, brain stem, and spinal cord. Relentless and progressive muscle atrophy and weakness 
are hallmarks of ALS. Most patients with ALS die from respiratory failure within 3 to 5 years 
after disease onset. Among the 3 Food and Drug Administration (FDA)-approved ALS treatments, 
riluzole and edaravone demonstrate only a moderate effect either on survival or functional 
decline, respectively, and more data is needed to further support the treatment effect of the 
recently approved treatment, the combination of sodium phenylbutyrate and taurursodiol. 
Therefore, there is still a significant unmet medical need for treating individuals with ALS. 
SAR443820 has demonstrated strong RIPK1 inhibition with high potency in vitro in various cell 
types. Refer to the SAR443820 Investigator’s Brochure (IB) for a detailed description of the 
chemistry, pharmacology, efficacy, and safety of SAR443820. 
2.3 
BENEFIT/RISK ASSESSMENT  
2.3.1 Risk assessment  
Table 1 - Risk assessment (identified risk of clinical significance)   
Identified risk of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
Study intervention(s) 
 
 
ALT increase/Drug induced liver 
injury (DILI) 
During clinical trials with SAR443820, mild-
severe ALT increases have been reported, 
including 2 SUSARs with total bilirubin 
increase > 2 ULN reported in the ALS 
patients. These events often involved 
patients who were also taking concomitant 
medications that are known to induce liver 
function abnormalities, or who had 
concomitant diseases that could also affect 
ALT level. 
Implemented through an USM dated on 
5th December 2023, all participants in 
Part A are requested to conduct weekly 
liver chemistry monitoring and all 
participants in Part B are requested to 
pause SAR443820 immediately until DMC 
recommendation to resume dosing based 
on benefit-risk considerations when Part A 
data is available. Additionally, all 
participants are requested to limit their 
alcohol consumption during the whole 
study period. 
Detailed instructions to be followed in case 
of the occurrence of an AESI of ALT 
increase >3ULN are described in Appendix 
6 in this protocol, and cover ALT 
monitoring, IMP administration, etiology 
assessment and IMP rechallenge. 
Abbreviations: ALT=alanine transaminase; DILI=drug induced liver injury; IMP=investigational medicinal product, SUSAR=suspected 
unexpectedserious adverse event, ULN=upper limit normal, USM=urgent safety measure, AESI=adverse event of special interest 
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Table 2 - Risk assessment (potential risk of clinical significance)  
Potential risk of 
clinical significance 
Summary of data/rationale for risk 
Mitigation strategy 
Study intervention(s) 
Convulsion 
Convulsions are considered to be a potential 
risk based on nonclinical findings in 
single-dose, 9-day and 28-day nonhuman 
primate toxicity studies and in a 6-month rat 
study. 
In nonhuman primate studies, the following 
were observed: Convulsions/tremors at a dose 
of 75 mg/kg in the single-dose study, at a dose 
of 100 mg/kg/day in the 9-day study, and at a 
dose of 60 mg/kg/day in the 28-day study. 
No convulsions have been observed up to the 
dose level of
 mg/kg/day in both the 3-month 
and 9-month studies. 
In the 6-month study in rats, convulsions were 
noted at a dose of 400 mg/kg/day (males) and 
200 mg/kg/day (females). Convulsions and 
other findings that necessitated euthanasia 
were also observed in a single female rat 
receiving 50 mg/kg/day. 
Based on the uncertainty in the interspecies 
translatability of convulsive risk, a conservative 
safety approach to limit human exposure 
(ie, Cmax and AUC) was taken regarding the 
selected dose of 20 mg BID, which maintained 
a 
 to the NOAEL exposure 
(Cmax and AUC) in the 3-month toxicology study 
in nonhuman primates. 
Moreover, to mitigate the risk, participants with 
a history of seizure will not be eligible to 
participate in this study. 
Additionally, concomitant medications that may 
increase significantly exposure
(including strong and moderate 
CYP3A4 inhibitors) are not allowed in this 
study. Patients in whom exposure may be 
 (participants 
weighing <45 kg or patients with a moderate or 
severe hepatic impairment) will also be 
excluded from this study. 
Immunomodulatory Effects 
Findings consistent with immune system 
modulation were observed with SAR443820 in 
the 3-month and 9-month nonhuman primate 
studies. These findings included mononuclear 
cell infiltrates in various tissues and changes in 
lymphoid tissues (increased/decreased 
cellularity and/or increased germinal centers). 
None of these microscopic findings for 
SAR443820 were considered adverse based 
on their incidence, severity, and/or 
recoverability or the lack of clinical pathology 
correlates or relevant clinical observations. 
Frequent monitoring of the results of 
a hematology test, physical examinations 
(eg, skin, lymph nodes), and occurrence of 
infections TEAEs are planned. 
Pregnancy maintenance 
and embryo-fetal toxicity 
Adverse, test article-related effects on litter 
viability/pregnancy maintenance were noted at 
200 mg/kg/day in a rat embryo-fetal 
development study. Two rats given 
200 mg/kg/day were pregnant but had total 
litter loss. In addition, test article-related 
increases in early resorptions, late resorptions, 
total resorptions, post implantation loss, post-
implantation loss percentage, and reduced fetal 
weight were observed for groups administered 
20, 60, or 200 mg/kg/day. 
Pregnant females are not allowed to participate 
in this study and monthly pregnancy testing is 
requested for all female participants of 
childbearing potential. Pregnancy of a female 
participant will lead to permanent IMP 
discontinuation in the participant. Additionally, 
contraceptive use by female participants of 
childbearing potential is requested during study 
period. 
Study procedures 
Blood drawing 
Pain or other discomfort from collection of 
blood samples. 
Minimize the frequency and amount of blood 
drawing. 
Abbreviations: AESI = adverse event of special interest; ALT = alanine transaminase; AUC = area under the curve; BID = twice daily; Cmax = 
maximum plasma concentration; CYP = cytochrome P450; IMP = investigational medicinal product; NOAEL = no-observed-adverse-effect level; 
TEAEs = treatment-emergent adverse events. ULN = upper limit of normal.  
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2.3.2 Benefit assessment  
SAR443820 is expected to slow disease progression, improve quality of life (QoL), and prolong 
survival for participants with ALS based on scientific rationale and preclinical data. 
2.3.3 Overall benefit/risk conclusion  
In the completed first-in-human studies, SAR443820 was found to be safe and well-tolerated up 
to the highest doses administered, ie, a single dose of
 mg and multiple 14-day dose of 20 mg 
BID, in 100 healthy subjects who received SAR443820 as of April 2022. In addition, 
a preliminary physiological based pharmacokinetic modeling and simulation (PBPK) model 
indicates that at a dose of 20 mg SAR443820 BID,
 
 
 value determined in vivo using the 
pS166-RIPK1 inhibitor assay in peripheral blood mononuclear cells (PBMC), which supports the 
potential for clinical efficacy. Convulsions believed to be SAR443820-related have been observed 
in 
 The risk of convulsions will be mitigated through 
1) limiting the dose chosen in this study with maximum plasma concentration (Cmax) and area 
under the curve (AUC) 
 at the 
no-observed–adverse-effect-level (NOAEL) in the 3-month monkey study; 2) excluding 
participants with a history of seizures; 3) excluding concomitant medications that may increase 
exposure 
 (potent and moderate cytochrome P450 (CYP)3A4 inhibitors); 
and 4) excluding participants with moderate or severe hepatic impairment. Since 
immunomodulatory effects of SAR443820 were observed in the 3-month nonhuman primate 
study but not in the first-in-human study in healthy volunteers, frequent monitoring of safety 
through hematology tests, physical examinations (eg, skin, lymph nodes), and the occurrence of 
infection, will be implemented in both Parts A and B. Considering the measures taken to 
minimize risk to participants in this study, the potential risks identified in association with 
SAR443820 are justified by the anticipated benefits that may be afforded to participants with 
ALS. 
In the ongoing study ACT16970, a limited number of cases meeting criteria for severe DILI have 
been reported. ALT and bilirubin levels fully recovered in these cases after stopping the IMP and 
riluzole. These blinded data suggest that DILI is an identified risk of SAR443820, in particular 
when used in combination with hepatotoxic concomitant medications. The exact mechanism is not 
known. In nonclinical studies in rats and monkeys, non-adverse microscopic changes were noted 
in the liver without ALT increases. In Phase 1 studies, there were three mild (<3 ULN) 
asymptomatic cases of ALT increase (all recovered). Risk minimization measures during the 
study include limitation of alcohol consumption, although a relationship with alcohol use has not 
been established. In addition, frequent monitoring of liver chemistry is implemented to allow for 
early detection and mitigation. The Benefit Risk ratio remains acceptable for the use of 
SAR443820 in participants with ALS. 
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3 
OBJECTIVES AND ENDPOINTS  
Table 3 - Objectives and endpoints  
Part A 
 
Objectives 
Endpoints 
Primary 
 
• 
To assess the effect of SAR443820 
compared to placebo in reducing ALS 
progression as measured by the 
Amyotrophic Lateral Sclerosis Functional 
Rating Scale Revised (ALSFRS-R) 
• 
Change from baseline in the ALSFRS-R total score to Week 24 
Secondary 
 
• 
To assess the effect of SAR443820 
compared to placebo on a combined 
assessment of function and survival, 
respiratory function, muscle strength, and 
quality of life (QoL) 
• 
Combined assessment of the function and survival (CAFS) 
score at Week 24 
• 
Change from baseline in slow vital capacity (SVC) to Week 24 
• 
Change from baseline in muscle strength to Week 24 
• 
Change from baseline in Amyotrophic Lateral Sclerosis 
Assessment Questionnaire (ALSAQ-5) to Week 24 
• 
To assess the pharmacodynamic (PD) 
effect of SAR443820 compared to placebo 
on a key disease biomarker 
• 
Change from baseline in serum neurofilament light chain (NfL) 
to Week 24 
• 
To assess the safety and tolerability of 
SAR443820 compared to placebo 
• 
Incidence of adverse events (AE), serious adverse events 
(SAE), treatment-emergent adverse events (TEAE), potentially 
clinically significant abnormalities (PCSA) in laboratory tests, 
electrocardiogram (ECG), and vital signs over 24 weeks 
• 
To assess the pharmacokinetics (PK) of 
SAR443820 
• 
Plasma concentration of SAR443820 
Tertiary 
 
 SAR443820 
 
• 
To assess the effects of SAR443820 
compared to placebo on neurodegeneration 
and inflammation disease biomarkers 
• 
Change from baseline in soluble triggering receptor expressed 
on myeloid cells-2 (sTREM2) in plasma chitinase-3-like 
protein-1 (CHI3L1), a selected panel of cytokines and 
chemokines in serum, and extracellular domain of p75 
(p75ECD) in urine to Week 24 
 
 
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Part B 
 
Objectives 
Endpoints 
Primary 
 
• 
To assess the long-term effects of 
SAR443820 on function and survival 
• 
Combined assessment of the function and survival (CAFS) 
score at Week 52 
Secondary 
• 
To assess the long-term effects of 
SAR443820 on disease progression, 
survival, respiratory function, and quality of 
life (QoL) 
• 
Combined assessment of the function and survival (CAFS) 
score at Week 76 and Week 104 
• 
Change from baseline in the ALSFRS-R total score to 
Week 52, Week 76, and Week 104 
• 
Time from baseline to the occurrence of either death or 
permanent assisted ventilation (>22 hours daily for 
>7 consecutive days), whichever comes first 
• 
Time from baseline to the occurrence of death 
• 
Change from baseline in slow vital capacity (SVC) to Week 52, 
Week 76, and Week 104 
• 
Change from baseline in Amyotrophic Lateral Sclerosis 
Assessment Questionnaire (ALSAQ-5) to Week 52, Week 76, 
and Week 104 
• 
To assess the long-term effect of 
SAR443820 on a key disease biomarker 
• 
Change from baseline in serum neurofilament light chain (NfL) 
to Week 52 
• 
To assess the long-term safety and 
tolerability of SAR443820 
• 
Incidence of adverse events (AE), serious adverse events 
(SAE), treatment-emergent adverse events (TEAE), potentially 
clinically significant abnormalities (PCSA) in laboratory tests, 
electrocardiogram (ECG), and vital signs during Part B 
• 
To assess the pharmacokinetics (PK) of 
SAR443820 
• 
Plasma concentration of SAR443820 
Tertiary 
 
SAR443820 
 
SAR443820 
For China, please see Appendix 8 (Section 10.8) for details. 
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3.1 
APPROPRIATENESS OF MEASUREMENTS   
3.1.1 Measurements for efficacy assessment  
The primary endpoint of this study is the change of ALS disease progression as measured by the 
ALSFRS-R, which is a validated and established outcome measurement of therapeutic efficacy 
for ALS. The ALSFRS-R is a widely accepted measure of ALS progression used by clinical 
trialists and regulatory bodies (14). 
The CAFS is a measurement ranking the clinical outcomes of patients with ALS based on survival 
time and change in the ALSFRS-R score (15). The combined endpoint can decrease the 
confounding effect of mortality on the results of an analysis of functional outcomes as it 
appropriately accounts for and weights mortality in the analysis of function. 
For the survival assessment, in addition to mortality, a composite time-to-event endpoint 
recording the time to death or permanent continuous ventilator dependence, whichever occurs 
first, will be assessed as 1 of the efficacy endpoints since survival data may be confounded by the 
use of ventilation strategies. This approach is consistent with guidance from the FDA and 
European Medicines Agency (EMA) (14, 16). 
The SVC percentage of predicted normal provides a quantitative means to assess reductions in the 
strength of the diaphragm and other respiratory muscles. The SVC change over time has been 
demonstrated to be associated with meaningful clinical events, including the time to respiratory 
insufficiency or death (17). 
Muscle weakness is a typical feature of ALS and an important determinant of participants’ daily 
function and QoL. Handheld dynamometry provides a quantitative means to assess limb muscle 
strength. 
The ALSAQ-5 has been demonstrated to be a sensitive and reliable instrument for estimating QoL 
in patients with ALS (18) and provides similar results to the ALSAQ-40 but with a considerable 
reduction in patient burden (19). 
. 
3.1.2 Pharmacokinetic assessments  
Whole blood samples will be collected for measurement of the plasma concentration of 
SAR443820 as specified in the schedule of assessments (SoA). 
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3.1.3 Pharmacodynamic assessments  
Serum blood samples will be used to measure changes in NfL, a marker of neuronal injury. Levels 
of NfL in both CSF and plasma have been reported to be increased and stable over time in 
participant with ALS compared to healthy controls. Patients with ALS with a fast progression rate 
have demonstrated higher levels of NfL in CSF and plasma than those with a slow progression 
rate (21). Only serum NfL will be measured in this study to reduce the collection burden on 
participants. 
Blood samples will also be collected to measure changes in markers of neuroinflammation, 
including soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in plasma, 
Chitinase-3-like protein 1 (CHI3L1), and several cytokines in serum (interferon gamma [IFN, 
interleukin [IL]-1, IL-2, IL-4, IL-6, IL-8, IL-10, IL12p70, IL-13, and TNF-) and chemokines 
(eotaxin 1, eotaxin 3, thymus- and activation-regulated chemokine [TARC], interferon 
gamma-induced protein-10 [IP-10], macrophage inflammatory protein (MIP) (MIP1α and 
MIP1), monocyte chemoattractant proteins (MCP) 1 and 4 (MCP1 and MCP4). 
Urine samples will be collected to measure changes in the level of neurotrophin receptor 
extracellular domain p75 (p75ECD). 
3.1.4 Safety and tolerability assessment  
Adverse events (AE), serious adverse events (SAE), treatment-emergent adverse events (TEAE), 
adverse events of special interest (AESI), electrocardiogram (ECG), vital signs, and laboratory 
test analyses will be reported. 
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
Study ACT16970 is a Phase 2, randomized, double-blind, placebo-controlled, 2 parallel-group 
study followed by an open-label, long-term extension period. 
The study consists of 2 parts (A and B) as follows: 
Part A is a 24-week, double-blind, placebo-controlled part, preceded by a screening period of up 
to 4 weeks before Day 1. 
• A screening period of up to 4 weeks, designed to evaluate the suitability of participants to 
participate in the study in terms of ALS diagnosis, ALS duration, and ALS progression 
rate; respiratory function (SVC); and safety screening evaluations. No IMP will be 
administered in this period. 
• A double-blind treatment period with a total duration of 24 weeks for each participant: 
- 
Participants will be randomized in a ratio of 2:1 to receive 20 mg BID SAR443820 
(n=174) or placebo BID (n=87). 
- 
Randomization will be stratified by the geographic region of the study site, region of 
ALS onset (bulbar vs other areas), use of riluzole (yes vs no), and use of edaravone 
(yes vs no) and use of the combination of sodium phenylbutyrate and taurursodiol (yes 
vs no). Participants will attend in-clinic study assessments at baseline (Day 1), Week 2, 
Week 4, Week 6, Week 8, Week 10, Week 12, Week 16, Week 20, Week 21, Week 
22, Week 23, and Week 24. All ongoing participants at Week 24 will rollover to open-
label extension (Part B). 
• Participants who discontinue the treatment or choose not to enter Part B will have their 
follow-up visit 2 weeks after the last dose of the study intervention. 
Part B is an open-label, long-term extension of Part A. Part B starts from Week 24 and continues 
up to Week 106. 
• The study intervention assignment of participants in Part A will remain double-blinded 
during Part B unless there is medical need to unblind the study intervention assignment. 
• All participants will receive 20 mg BID SAR443820 in Part B starting from Week 24, 
except those who discontinue IMP treatment permanently in Part A. 
Based on a data review, and in accordance with Data Monitoring Committee (DMC) 
recommendations, sites have been instructed on 5th December 2023 to pause the 
administration of SAR443820 in Part B (open-label extension) immediately. All 
participants in Part B will be encouraged to continue follow-up visits, but no doses of 
SAR443820 should be administered. Rollover to Part B for follow-up visits after 
completing Part A is also encouraged, but without taking SAR443820 in Part B. The 
decision of whether resuming SAR443820 administration in Part B will be made based on 
DMC recommendation when Part A data is available and benefit risk ratio will be 
evaluated. 
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4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
The participants enrolled in this study will be at an early stage of ALS to capture the effect of 
treatment on the disease course, especially because the mechanism of action of SR443820 
modifies the disease pathology, rather than providing symptomatic alleviation. Participants who 
have a very slow ALS progression rate (<0.5 points/month in ALSFRS-R) prior to the screening 
visit will be excluded from the study to ensure that the study efficacy results will be interpretable. 
Part A of this study uses a randomized, double-blind, placebo-controlled design as it is the gold 
standard to demonstrate the efficacy and safety of SAR443820. Meanwhile, Part B of this study is 
an open-label extension during which both safety and efficacy data are collected to characterize 
the long-term treatment effects of SAR443820. 
4.3 
JUSTIFICATION FOR DOSE  
The choice of the dose of 20 mg BID SAR443820 is based on all available nonclinical and 
clinical data at the time of protocol development. 
The NOAEL was 
 mg/kg/day in nonhuman primates (cynomolgus monkeys). A 
 this NOAEL was implemented as the human exposure cap in Phase 1 single ascending 
dose (SAD) and multiple ascending dose (MAD) studies. 
Overall, in the first-in-human study, SAR443820 up to a highest single dose of 
 mg and multiple 
14-day dose of 20 mg BID, was found to be safe and well tolerated. In the Phase 1a SAD study, there 
were no SAEs. All the TEAEs were of mild to moderate intensity except 1 severe TEAE (blood 
creatine phosphokinase [CPK] increase of Grade 3) reported in the placebo group. Since convulsions 
 mg and 
. In the MAD study, no SAEs, other than dose limiting AEs or laboratory findings, 
were reported. All the AEs reported in the MAD study were of mild to moderate intensity. At 20 mg 
BID, the highest dose administered, the mean observed Cmax was 1.22 µM and the AUC0-24h 
(corresponding to AUC0-12h *2) was 15.0 µM*hour. These values are estimated to be 
, respectively. 
The dose of 20 mg BID SAR443820 is estimated to provide a high level of target engagement 
required for obtaining a clinical effect. Internal preclinical data in animal models suggest CNS 
is a predictor of a clinical therapeutic effect. Preliminary data 
indicate a good penetration of SAR443820 in CSF with mean values of the CSF/unbound plasma 
ratio of at least 0.81 and 1.27 before and after plasma tmax, respectively. A preliminary PBPK 
model indicates that at a dose of 20 mg BID, 
, which has been determined in vivo using the pS166-RIPK1 inhibitor 
assay in PBMC. 
Therefore, 20 mg BID, which has been demonstrated to be well tolerated in healthy subjects, is 
selected for this Phase 2 study to achieve the best potential treatment effectiveness in participants 
with ALS while maintaining 
 to the NOAEL exposure in the 
nonhuman primate study. 
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4.4 
END OF STUDY DEFINITION  
The end of the study is defined as the date of the last visit of the last participant in the study or 
last scheduled assessment and/or procedure shown in the SoA for the last participant in the study 
globally. 
A participant is considered to have completed the study if he/she has completed all phases of the 
study, including the last visit or the last scheduled procedure as shown in the SoA (Section 1.3).  
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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. Participants must be 18 to 80 years of age inclusive, at the time of signing the informed 
consent form. 
Type of participant and disease characteristics 
I 02. Participants must have been diagnosed with possible, clinically probable ALS, clinically 
probable laboratory-supported ALS, or clinically definite ALS according to the revised 
version of the El Escorial World Federation of Neurology criteria (22). 
I 03. Participants must have an ALS disease duration (from first symptom onset to the screening 
visit) ≤2 years. 
I 04. Participants must have an ALSFRS-R prestudy slope ≥0.5 points/month prior to the 
screening visit (ALSFRS-R = (48 - ALSFRS-R score at the screening visit)/duration in 
months between the screening visit and disease onset). 
I 05. Participants must have an upright (sitting position) SVC ≥60% of the predicted value as 
adjusted for sex, age, and height at the screening visit. 
I 06. Participants must be able to swallow the study tablets at the screening visit. 
I 07. Participants must either not currently receiving riluzole or on a stable dose of riluzole for at 
least 4 weeks before the screening visit. Participants receiving riluzole are expected to 
remain on the same dose throughout the duration of the study. 
I 08. Participants must either not currently receiving edaravone or are on the approved standard 
schedule of edaravone treatment. Participants receiving edaravone must have completed at 
least 1 cycle of treatment before the screening visit and are expected to continue edaravone 
treatment throughout the duration of the study. 
Weight 
I 09. Participants with a body weight no less than 45 kg and body mass index (BMI) no less 
than 18.0 kg/m2 at the screening visit. 
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Sex, contraceptive/barrier method and pregnancy testing requirements 
I 10. All 
Contraceptive use by men and women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies. 
a) Male participants 
Male participants are eligible to participate if they agree to the following during the 
study period and for at least 92 days following their last dose of the IMP: 
• Refrain from donating or cryopreserving sperm 
PLUS, either: 
• Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent 
OR 
• Must agree to use contraception/barrier method as detailed below: 
- 
A male condom and an additional highly effective contraceptive method as 
described in Appendix 4 (Section 10.4) when having sexual intercourse with a 
woman of childbearing potential (WOCBP) who is not currently pregnant. 
b) Female participants 
Female participants are eligible to participate if they are not pregnant or breastfeeding 
and 1 of the following conditions applies: 
• Are woman of nonchildbearing potential (WONCBP) as defined in Appendix 4 
(Section 10.4) 
OR 
• Are WOCBP and agree to use a contraceptive method that is highly effective (with 
a failure rate of <1% per year), preferably with low user dependency, as described 
in Appendix 4 (Section 10.4) during the study intervention period (to be effective 
before starting the study intervention) and for at least 32 days after the last 
administration of the IMP and agree not to donate or cryopreserve eggs (ova, 
oocytes) for the purpose of reproduction during this period. 
• WOCBP must have a negative highly sensitive pregnancy test within 24 hours 
before the first administration of the study intervention, see Section 8.2.6. 
• If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum 
pregnancy test is required. In such cases, the participant must be excluded from 
participation if the serum pregnancy result is positive. 
Informed consent 
I 11. Participants must be capable of giving signed informed consent as described in Appendix 1 
(Section 10.1), which includes compliance with the requirements and restrictions listed in 
the informed consent form (ICF) and in this protocol. 
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Criteria added in amended protocol 
I 12. Participants must either not currently be receiving the combination of sodium 
phenylbutyrate and taurursodiol or are on the approved standard schedule of the 
combination of sodium phenylbutyrate and taurursodiol treatment for at least 4 weeks 
before the screening visit. Participants receiving the combination of sodium phenylbutyrate 
and taurursodiol are expected to remain on the approved standard schedule throughout the 
duration of the study 
5.2 
EXCLUSION CRITERIA   
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. Participants with a history of seizure or epilepsy (History of febrile seizure during 
childhood is allowed). 
E 02. Participants with central IV lines, such as a peripherally inserted central catheter (PICC) or 
midline or port-a-cath lines. 
E 03. Participants with a significant cognitive impairment, psychiatric disease, other 
neurodegenerative disorder (eg, Parkinson disease or AD), substance abuse, other causes 
of neuromuscular weakness, or any other condition that would make the participants 
unsuitable for participating in the study or could interfere with assessment or completing 
the study in the opinion of the Investigator. 
E 04. Participants with a history of recent serious infection (eg, pneumonia, septicemia) within 
4 weeks of the screening visit; infection requiring hospitalization or treatment with IV 
antibiotics, antivirals, or antifungals within 4 weeks of screening; or chronic bacterial 
infection (such as tuberculosis) deemed unacceptable as per the Investigator’s judgment. 
E 05. Participants with an active herpes zoster infection within 2 months prior to the screening 
visit. 
E 06. Participants with a documented history of attempted suicide within 6 months prior to the 
screening visit, present with suicidal ideation of category 4 or 5 on the Columbia Suicide 
Severity Rating Scale (C-SSRS), or in the Investigator’s judgment are at risk for a suicide 
attempt. 
E 07. Participants with a history of unstable or severe cardiac, pulmonary, oncological, hepatic, 
or renal disease or another medically significant illness other than ALS precluding their 
safe participation in this study. 
E 08. Participants who are pregnant or are currently breastfeeding. 
E 09. Participants with a known history of allergy to any ingredients of SAR443820 (mannitol, 
lactose monohydrate, sodium starch glycolate, colloidal silicon dioxide, magnesium 
stearate, hypromellose, titanium dioxide, polyethylene glycol, and microcrystalline 
cellulose). 
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Prior/concomitant therapy 
E 10. Participants who have received any strong or moderate CYP3A4 inhibitors or strong 
CYP3A4 inducers listed in Appendix 10, Section 10.10, Table 8 within the specified 
washout period before the screening visit. 
E 11. Participants who have received a live vaccine within 14 days before the screening visit. 
Prior/concurrent clinical study experience 
E 12. Participants with concurrent participation in any other interventional clinical study or who 
have received treatment with another investigational drug (eg, sodium phenylbutyrate or 
taurursodiol) within 4 weeks or 5 half-lives of the investigational agent before the 
screening visit, whichever is longer. 
E 13. Participants who have received stem cell or gene therapy for ALS at any time in the past. 
Diagnostic assessments 
E 14. Participants with a positive human immunodeficiency virus (HIV) antibody test. 
E 15. Participants with abnormal laboratory test(s) at the screening visit including the following: 
- 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3.0 × upper 
limit of normal (ULN) 
- 
Bilirubin >1.5 × ULN unless the participant has documented Gilbert syndrome 
(isolated bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and direct 
bilirubin is <35%) 
- 
Serum albumin <3.5 g/dL 
- 
Estimated glomerular filtration rate <60 mL/min/1.73 m2 (Modification of Diet in 
Renal Disease [MDRD]) 
- 
Other abnormal laboratory values or ECG changes that are deemed clinically 
significant as per the Investigator’s judgment 
E 16. Participants with hepatitis B surface antigen (HBsAg) or antihepatitis B core antibodies 
(anti-HBcAb) at the screening visit or within 3 months prior to the first dose of the study 
intervention. Serologies consistent with a resolved infection or vaccination, such as the 
presence of HBsAb, may not exclude potential participants from the trial. 
E 17. Participants with a positive hepatitis C antibody test result at the screening visit or within 
3 months prior to starting the study intervention. NOTE: Participants with a positive 
hepatitis C antibody test due to prior resolved disease can be enrolled only if 
a confirmatory negative hepatitis C RNA test is obtained. 
Other exclusions 
E 18. Participants who are accommodated in an institution because of a regulatory or legal order; 
prisoners or participants who are legally institutionalized. 
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E 19. Participants who are employees of the clinical study site, other individuals directly 
involved in the conduct of the study, or immediate family members of such individuals (in 
conjunction with Section 1.61 of the International Council for Harmonisation (ICH)-Good 
Clinical Practice (GCP) Ordinance E6). 
5.3 
LIFESTYLE CONSIDERATIONS  
5.3.1 Meals and dietary restrictions  
Participants should be prohibited from consuming grapefruit or grapefruit juice (including 
pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices) from 5 days before the start of the 
study intervention until 2 days after the final dose. 
PK samples can be collected at either fasting or non-fasting condition. 
5.3.2 Caffeine, alcohol, and tobacco  
The information of participant’s regular use of alcohol and tobacco should be recorded in the 
electronic case report form (eCRF). During the entire study, participants should be warned not to 
consume substantial quantities of alcohol, defined as >14 grams (1 standard drink) per day in 
female participants or >28 grams (2 standard drinks) per day in male participants on a regular 
basis. 
5.3.3 Activity  
No special restrictions. 
5.4 
SCREEN FAILURES  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized. 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. 
When a participant does not meet the eligibility criteria but is likely to be eligible within the 
4-week screening window after the initial screening visit, selected assessment(s), such as 
laboratory tests, can be repeated within the 4-week screening window as per the Investigator’s 
medical judgment. The same initial consent form and study identification number will be 
applicable for the repeated assessments within the screening window. 
Rescreening is allowed for participants who fail the initial screening at the Investigator’s medical 
judgment for any manageable reasons that caused the initial screening failure. Participants who 
fail the initial screening may be rescreened up to 2 times during the study recruitment period. 
A new consent form will need to be signed and a new identification number will be issued for 
participants who undergo rescreening. 
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5.5 
CRITERIA FOR TEMPORARILY DELAYING 
ENROLLMENT/RANDOMIZATION/ADMINISTRATION OF STUDY INTERVENTION 
ADMINISTRATION  
During a regional or national emergency declared by a governmental agency, if the site is unable 
to adequately follow protocol-mandated procedures, contingency measures are proposed in 
Appendix 9 (Section 10.9). 
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6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY  
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, 
or medical device(s) intended to be administered to a study participant according to the study 
protocol. In this study, the study intervention includes SAR443820 and placebo. 
6.1 
STUDY INTERVENTION(S) ADMINISTERED  
Table 4 - Overview of study interventions administered  
Intervention label 
SAR443820 
Placebo 
Intervention name 
SAR443820 
Placebo 
Type 
Drug 
Drug 
Dose formulation 
Tablet 
Tablet 
Unit dose strength(s) 
20 mg 
0 mg 
Dosage level(s) 
Twice daily 
Twice daily 
Route of administration 
Oral 
Oral 
Use 
Experimental 
Experimental 
IMP or NIMP 
IMP 
IMP 
Packaging and labeling 
Study Intervention will be provided in 
wallet blister packaging. Each wallet 
blister packaging will be labeled as 
required per country requirement. 
Study Intervention will be provided in 
wallet blister packaging. Each wallet 
blister packaging will be labeled as 
required per country requirement. 
Current/Former name(s) or alias(es) 
SAR443820 
Not Applicable 
SAR443820 or matching placebo tablets are to be taken twice daily, 1 in the morning and 1 in the 
evening approximately 12 hours apart. The IMP tablet will be taken orally with approximately 
100 mL of water for participants who can swallow tablets or with thickening agents to assist in 
swallowing for participants who develop swallowing difficulties during the study (tablets should 
be added to the thickening agents in their entirety and need to be taken immediately after mixing). 
For participants who have a gastrostomy tube (G-tube), the entire IMP tablet needs to be put in 
a glass with approximate 40 mL of water at ambient temperature, crushed roughly after 
approximately 10 minutes, and mixed manually for a few minutes before administration. The 
suspension will then be withdrawn with a syringe and administered through the G-tube, which 
will then be rinsed twice with approximately 40 mL of water and then 20 mL of water. The 
administration should take place within 15 minutes of suspension preparation. The IMP should be 
taken around the same time each day under the same condition (with or without food) throughout 
the study unless adjustment is specifically requested due to PK sampling at Day 1 and Week 2, 
Week 8, and Week 28 site visits. 
SAR443820 or placebo may be supplied at the site or from the Investigator/site/Sponsor to the 
participant via a Sponsor-approved courier company if allowed by local regulations and agreed 
upon by the participant. 
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For a regional or national emergency declared by a governmental agency that results in travel 
restrictions, confinement, or restricted site access, contingency measures are included in 
Appendix 9 (Section 10.9). 
6.1.1 Devices  
Not applicable. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention.  
3. 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. 
4. 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). 
SAR443820 and placebo tablets require no preparation and will be supplied to the study 
participants in labeled child-resistant wallets. 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) must be promptly notified to the Sponsor. 
Some deficiencies may be recorded through a complaint procedure (see Section 8.3.9). 
A potential defect in the quality of IMP may be subject to initiation of a recall procedure by the 
Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply IMP to a third party (except for 
direct-to-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 study will be performed in a double-blind fashion for Part A. The placebo tablet will 
be identical to the SAR443820 tablet in appearance, quantity, taste, odor, and packaging. 
• All participants will be centrally assigned to a randomized study intervention using an 
interactive response technology (IRT). Before the study is initiated, the login information 
and directions for the interactive web response system (IWRS) will be provided to each 
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site. The study intervention will be dispensed at the study visits summarized in the SoA. 
Returned IMP should not be redispensed to participants. 
• A randomized participant is defined as a participant from the screened population who has 
been allocated to a randomized intervention regardless of whether the intervention was 
received or not. A participant cannot be randomized more than once in the study. 
• The randomization in Part A is stratified by the geographic region of the study site, region 
of ALS onset (bulbar vs other areas), use of riluzole (yes vs no), use of edaravone (yes vs 
no) and use of the combination of sodium phenylbutyrate and taurursodiol (yes vs no). 
• The Investigator, site staff, Sponsor monitoring team, and participants will remain blinded 
to the treatment assignment in Part A until the end of Part B. The sponsor study team, 
except Sponsor monitors, will be unblinded after database lock of Part A. 
• The bioanalyst and the pharmacokineticist responsible for sample analysis and PK 
evaluation will be unblinded. However, they will agree not to disclose the randomization 
schedule or the individual unblinded analytical results before the official opening of the 
randomization schedule. Preliminary PK data, if needed and available during the study, 
will refer to means with descriptive statistics, and individual data will not be associated 
with any individual randomization numbers or participant numbers. 
• This is a double-blind study in which participants/care providers/Investigators/outcomes 
assessors, etc. are blinded to the study intervention. The IRT will be programmed with 
blind-breaking instructions. In case of an emergency, the Investigator has the sole 
responsibility for determining if the unblinding of a participant’s intervention assignment 
is warranted. Participant safety must always be the first consideration in making such 
a determination. If the Investigator decides that unblinding is warranted, he/she may, at 
his/her discretion, contact the Sponsor to discuss the situation prior to unblinding 
a participant’s intervention assignment unless this could delay emergency treatment for the 
participant. If a participant’s intervention assignment is unblinded, the Sponsor must be 
notified within 24 hours of this occurrence. The date and reason for the unblinding must be 
recorded. 
• For regulatory reporting purposes, and if required by local health authorities, the Sponsor 
or designee will break the treatment code for all suspected unexpected serious adverse 
reactions (SUSARs) that are considered by the Investigator or Sponsor to be related to the 
study intervention. 
6.4 
STUDY INTERVENTION COMPLIANCE  
• IMP accountability: 
- 
Intervention units 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 counts the number of tablets remaining in the returned packs, and fills 
in the Intervention Log Form 
- 
The Investigator records the dosing information on the appropriate page(s) of the 
eCRF 
- 
The monitor in charge of the study then checks the eCRF data by comparing them with 
the IMP which he/she has retrieved and intervention log forms 
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When participants are dosed at the site, they will receive the study intervention directly from the 
Investigator or designee, under medical supervision. The date and time of each dose administered 
in the site will be recorded in the source documents. The dose of the study intervention and study 
participant identification will be confirmed at the time of dosing by a member of the study site 
staff other than the person administering the study intervention. 
When participants self-administer the study intervention(s) at home, compliance with the study 
intervention will be assessed at each visit. Compliance will be assessed by direct questioning and 
counting the returned tablets during the site visits and documented in the source documents and 
relevant form. Deviation(s) from the prescribed dosage regimen should be recorded. 
A record of the quantity of SAR443820 and matching placebo dispensed to and administered by 
each participant must be maintained and reconciled with the study intervention and compliance 
records. The intervention start and stop dates, including dates for intervention delays and/or dose 
reductions, will also be recorded. 
6.5 
DOSE MODIFICATION  
Dose modification is not foreseen in this study. The IMP treatment may need to be interrupted or 
permanently discontinued if deemed necessary due to an AE. 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY  
In addition to the 104 weeks of SAR443820 treatment in Part A and Part B of this trial, a separate, 
open-label, long-term safety follow-up study may be proposed for participants who complete this 
study if a positive benefit/risk ratio is confirmed in this trial. The details of the long-term study 
will be provided in a separate protocol. 
6.7 
TREATMENT OF OVERDOSE  
For this study, overdose is defined as at least 
 mg IMP within 12 hours. Taking 
 mg IMP at 
the same time is considering a dosing error, but not an overdose as long as the participant skips 
the next dose.  
The Sponsor does not recommend a specific treatment for an overdose. 
In the event of an overdose, the Investigator should: 
1. Closely monitor the participant for any AE/SAE and laboratory abnormalities until the 
IMP can no longer be detected systemically (at least 2 days). Provide supportive and 
symptomatic treatment as needed. 
2. Evaluate the participant to determine whether study intervention should be interrupted or 
whether the dose should be reduced. 
3. Obtain a plasma sample for PK analysis as soon as possible from the date of the last dose 
of the study intervention. 
4. Document appropriately in the eCRF. 
5. Contact the Sponsor as soon as possible. 
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6.8 
CONCOMITANT THERAPY  
Any medications or vaccines (including over-the-counter or prescription medicines, recreational 
drugs, 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 
The Sponsor should be contacted if there are any questions regarding concomitant or prior 
therapy. 
Any concomitant therapy should be reported to the Investigator and recorded in the Concomitant 
Medications eCRF. The reported medications will be reviewed and evaluated by the Investigator 
or designee to determine whether they affect a participant’s eligibility to participate or continue to 
participate in the study. 
As of November 2022, riluzole and edaravone are currently approved treatment options for 
patients with ALS in the United States, Canada, China, and Japan, and edaravone is not currently 
approved in the EU. The combination of sodium phenylbutyrate and taurursodiol has been 
approved for ALS treatment in the USA and Canada. Although these agents have only moderate 
effects, they constitute the standard of care, along with various supportive care treatments. 
Participants are allowed to enter the study if they are either not receiving riluzole or receiving 
stable doses of riluzole for at least 4 weeks prior to the screening visit and are expected to 
continue riluzole treatment throughout the duration of the study, provided liver function tests meet 
the entry criteria. Participants are allowed to enter the study if they are either not receiving 
edaravone or receiving the standard schedule of edaravone treatment. Participants who are 
receiving edaravone must have completed at least 1 cycle of edaravone treatment before the 
screening visit and are expected to continue edaravone treatment throughout the duration of the 
study. Participants are allowed to enter the study if they either not receiving the combination of 
sodium phenylbutyrate and taurursodiol or receiving the standard schedule of the combination of 
sodium phenylbutyrate and taurursodiol treatment for at least 4 weeks prior to the screening visit 
and are expected to continue the combination of sodium phenylbutyrate and taurursodiol 
treatment throughout the duration of the study. Dosage changes or discontinuations of riluzole 
and/or edaravone and/or the combination of sodium phenylbutyrate and taurursodiol during the 
study period are only allowed if continued treatment of riluzole and/or edaravone and/or the 
combination of sodium phenylbutyrate and taurursodiol would risk the safety of participants as 
assessed by the Investigator. Initiation of riluzole and/or edaravone and/or the combination of 
sodium phenylbutyrate and taurursodiol treatment during Part A is not allowed. Initiation of 
riluzole and/or edaravone and/or the combination of sodium phenylbutyrate and taurursodiol 
treatment during Part B is allowed if considered absolutely necessary in the medical judgment of 
the Investigator. Participants with central IV lines, such as PICC, midline, or port-a-cath lines, 
will be excluded due to the concern of an increased risk of infection. Initiation of central 
intravenous lines is not allowed during Part A but is allowed during Part B if considered 
absolutely necessary in the medical judgment of the Investigator. Switching between IV and oral 
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formulation of edaravone in the countries where both formulations have been approved is allowed 
at any time during the study. 
Based on in vitro results, SAR443820 is mainly metabolized by CYP3A4. A PK interaction with 
strong and moderate CYP3A4 inhibitors is
SAR443820 
. A PK interaction with strong CYP3A4 inducers is predicted to 
decrease the SAR443820 AUC. Therefore, concomitant medications or substances that are strong 
or moderate inhibitors or strong inducers of CYP3A4 (Appendix 10, Section 10.10, Table 8) are 
not allowed within the specified wash out period before the screening visit and for the duration of 
Part A and Part B. 
The use of any live vaccine is prohibited within 14 days before the screening visit and during the 
study duration. 
6.8.1 Rescue medicine  
Not applicable. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
7.1 
DISCONTINUATION OF STUDY INTERVENTION   
7.1.1 Permanent discontinuation  
The study intervention should be continued whenever possible. 
In rare instances, it may be necessary for a participant to permanently discontinue the study 
intervention. 
In case of the following events, permanent discontinuation of the IMP is mandatory. This list is 
not intended to be exclusive. 
• The Investigator or Sponsor determines it is in the best interest of the participant 
• Occurrence of AEs or any other medical condition that, in the opinion of the Investigator 
or Sponsor, may jeopardize the participant’s safety or data integrity. These include, but are 
not limited to, abnormal livers tests and meeting the stopping criteria (see Appendix 6 
[Section 10.6]) 
• Noncompliance with the protocol, including the dosing regimen and visits 
• Pregnancy of a female participant 
• Any IMP discontinuation lasting longer than 2 weeks accumulative in Part A or 8 weeks 
accumulative in Part B  
• Occurrence of convulsions 
• Initiation of riluzole and/or edaravone and/or the combination of sodium phenylbutyrate 
and taurursodiol treatment during Part A 
Any abnormal laboratory value or ECG parameter will be immediately rechecked for 
confirmation after 24 hours before making a decision regarding permanent discontinuation of the 
IMP for the concerned participant. 
Handling of participants after permanent intervention discontinuation 
If a participant is withdrawn from study intervention permanently, the Sponsor will be notified 
within 2 business days and the date and reason(s) for the withdrawal will be documented by the 
Investigator in the appropriate pages of the eCRF when considered as confirmed. 
Participants who prematurely discontinue the IMP will be encouraged to complete the rest of 
study visits for safety and efficacy assessments up to and including the last scheduled visit 
(Week 106). A separate PK sample may be taken if appropriate. At a minimum, participants 
should complete an early discontinuation visit 2 weeks after the last IMP dosing. All withdrawn 
participants will be followed until resolution of all their AEs or until the unresolved AEs are 
judged by the Investigator or Sponsor to have stabilized (see Section 10.3.3). 
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7.1.2 Temporary discontinuation  
Temporary intervention discontinuation may be considered by the Investigator because of 
suspected AEs or disruption of the clinical trial due to a regional or national emergency declared 
by a governmental agency (Appendix 9 [Section 10.9]). For all temporary intervention 
discontinuations, duration should be recorded by the Investigator in the appropriate pages of 
eCRF. Temporary discontinuation of study intervention is defined as stopping study intervention 
for a minimum of 1 day and a maximum of 2 weeks accumulative in Part A or 8 weeks 
accumulative in Part B. 
Based on a data review and in accordance with DMC recommendations, the sites were instructed 
on 5th December 2023 to pause administration of SAR443820 in Part B (open-label extension) 
immediately. An early IMP discontinuation visit should happen 2 weeks after the last dose of 
IMP. All participants in Part B will be encouraged to continue follow-up visits, but no doses of 
SAR443820 should be administered. Participants who are in Part A, rollover to Part B for follow-
up visits after completing Part A is encouraged, but without taking SAR443820 in Part B. An 
early IMP discontinuation visit should also happen 2 weeks after the last dose of IMP. The 
decision of whether resuming SAR443820 administration in Part B will be made based on DMC 
recommendation when Part A data is available and benefit risk ratio will be evaluated.  
If a scheduled liver chemistry monitoring is missed during weekly assessments, an unscheduled 
assessment for liver chemistry monitoring should be completed within 3 days. If a participant is 
receiving IMP and is unable to comply with the monitoring schedule, but does not meet the 
permanent discontinuation criteria, the participant must stop IMP administration until liver 
chemistry monitoring can be completed. 
7.1.2.1 Study intervention restart or rechallenge after temporary discontinuation of study 
intervention  
Reinitiation of the study intervention will be done under close and appropriate clinical and/or 
laboratory monitoring once the Investigator has considered, according to his/her best medical 
judgment that the responsibility of the IMP in the occurrence of the concerned AE was unlikely to 
reoccur. 
If the participant meets liver chemistry stopping criteria, do not restart/rechallenge the participant 
with study intervention unless: 
• There is a clear, documented etiology for increase in ALT with no relationship to study 
drug.  
• When the rechallenge criteria are met as described in Section 10.6.  
• Ethics Committee and/or Institutional Review Board (IRB) approval is obtained, if 
required based on local practice 
NOTE: If study intervention was interrupted for suspected intervention-induced liver injury, the 
participant should be informed of the risk of death, liver transplantation, hospitalization, and 
jaundice and reconsented before resumption of dosing. In case of confirmed drug-induced liver 
injury caused by the IMP, the rechallenge with the IMP is not permitted, and the participants must 
be permanently discontinued from IMP treatment.  
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For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 9 (Section 10.9). 
Refer to Appendix 6 (Section 10.6) for details on the restart/rechallenge process. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
• A participant may withdraw from the study at any time at his/her own request,or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, or 
compliance reasons. This is expected to be uncommon. 
• At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the SoA. See SoA (Section 1.3) for data to be collected 
at the time of study discontinuation and follow-up and for any further evaluations that 
need to be completed. 
• If the participant withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the site study records. 
The Investigators should discuss with study participants 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 pages of the eCRF 
and in the participant’s medical records. In the medical record, at least the date of the withdrawal 
and the reason should be documented. 
In addition, a participant may withdraw his/her consent to stop participating in the study. 
Withdrawal of consent for study 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 rerandomized (treated) in the study. 
Their inclusion and intervention numbers must not be reused. 
7.3 
STUDY LEVEL STOPPING CRITERIA  
The study may be stopped if any of the following criteria are met: 
• Cancellation of or change in the drug development program per the discretion of the 
Sponsor. 
• Emergence of AEs unknown to date or increased frequency and/or severity and/or 
a duration of known AEs that makes the benefit-risk for study continuation negative. 
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• The results of the interim data review meet no-go criteria as detailed in the Statistical 
Analysis Plan (SAP). 
• Participant enrollment (evaluated after a reasonable amount of time) is unsatisfactory. 
7.4 
LOST TO FOLLOW UP  
A participant will be considered lost to follow-up if he/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 site for a required study 
visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• Before a participant is deemed lost to follow up, the Investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
• Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomized, including 
those who did not get study intervention. Public sources may be searched for vital status 
information. If vital status is determined as deceased, this will be documented and the 
participant will not be considered lost to follow-up. Sponsor personnel will not be 
involved in any attempts to collect vital status information. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix 1 
(Section 10.1). 
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8 
STUDY ASSESSMENTS AND PROCEDURES  
• Study procedures and their timing are summarized in the SoA (Section 1.3). 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, urine tests) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and were 
performed within the time frame defined in the SoA. 
- 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. 
- 
If onsite visits are not feasible (due to ALS progression, increased monitoring for AE 
follow-up), remote visits (eg, with home nurses, a home health vendor, a local clinic 
etc.) may be planned for the collection of safety and/or efficacy data. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 9 (Section 10.9). 
8.1 
EFFICACY ASSESSMENTS   
Planned time points for all efficacy assessments are provided in the SoA (Section 1.3). 
Key efficacy assessments will be measured by trained Investigator or rater. Same Investigator or 
rater is preferred to conduct the same assessment for individual participant at each visit, if 
possible. 
8.1.1 ALSFRS-R  
The ALSFRS-R is composed of 12 items across 4 subdomains of bodily function (bulbar, fine 
motor, gross motor, and breathing), with each item scored on an ordinal scale from 0 (total loss of 
function) to 4 (no loss of function). The total score of the ALSFRS-R ranges from 0 to 48, with 
a higher score indicating better function (23). Good reliability between face-to-face and telephone 
administration of the ALSFRS-R has been demonstrated (24). 
8.1.2 Slow vital capacity (SVC)  
SVC is measured in participants while they are in an upright position at least 3 trials per 
assessment or up to 5 trials when the highest and second highest of the first 3 measurements differ 
by 10% or more. SVC volumes are standardized to the percentage of the predicted normal value 
based on age, sex, and height (25). The highest SVC score among all attempts will be used for 
analysis. 
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8.1.3 Muscle strength measurement   
The muscles measured in the study include upper-limb and lower-limb muscle groups.Bilateral 
hand grip will be measured using a grip dynamometer and all other muscles included in this study 
will be measured using a handheld dynamometer. For each muscle to be tested, 2 trials will be 
performed. If the variability of the 2 trials is 15% or less, values from both trials will be recorded 
and the higher score will be used for analysis. If the variability is greater than 15%, a 3 trial will 
be performed, all the values will be recorded and the maximum value of the 3 trials will be 
accepted. The order of muscle testing is standardized (26). 
8.1.4 ALSAQ-5  
The ALSAQ-5 is a PRO that consists of 5 items derived from the ALSAQ-40. The 5 items closely 
resemble those of the 5-dimension scores of the ALSAQ-40: eating and drinking; communication; 
activities of daily living/independence; physical mobility; and emotional functioning. The 
ALSAQ-5 has a recall period of the past 2 weeks and takes approximately 5 minutes to complete. 
Each item is scored on a 5-point Likert scale ranging from 0 (never) to 4 (always or cannot do at 
all) according to the frequency of a particular problem. Total scores range from 0 to 20, with 
higher scores indicative of greater physical and emotional limitations. 
 
8.1.6 Survival  
The survival endpoint will be defined as the time to death or permanent assisted ventilation 
(>22 hours a day for >7 consecutive days), whichever comes first. The CAFS is a combined 
endpoint that evaluates function and survival together to provide a more accurate indication of 
a treatment effect than independent analyses. Results from the ALSFRS-R and survival data will 
be used together to generate the CAFS scale.  
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. 
 
 
 
8.2 
SAFETY ASSESSMENTS   
This section presents safety assessments other than AEs, which are presented in Section 8.3. 
Planned time points for all safety assessments are provided in the SoA. 
8.2.1 Physical examinations  
• A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, neurological systems, skin and lymph node 
area systems. Height and weight will also be measured and recorded. 
• A brief physical examination will include, at a minimum, assessments of the skin, lymph 
node areas, lungs, cardiovascular system, and abdomen (liver and spleen). 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
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8.2.2 Neurological examinations  
• A neurological examination will be performed and the results recorded. A complete 
neurological examination will include, at a minimum, assessments of mental status, cranial 
nerves, motor and sensory function, reflexes, coordination, and stance/gait. 
• A brief neurological examination will include, at a minimum, assessments of assessments 
of cranial nerves, coordination/cerebellar function, reflexes, and motor function. 
• Investigators should pay special attention to clinical signs related to previous neurological 
illnesses, including ALS. 
8.2.3 Vital signs  
• Oral, tympanic, axillary, or skin temperature, heart rate, respiratory rate, and blood 
pressure will be assessed. 
• 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 (usually should be taken before blood collection for laboratory tests) will 
consist of 1 pulse and 3 blood pressure measurements (3 consecutive sitting blood pressure 
readings will be recorded at intervals of at least 1 minute). The average of the 3 blood 
pressure readings will be recorded. At Day 1 visit, postdose vital signs should be measured 
at least 10 minutes after the second PK sample collection (recommended to be measured 
within 10 to 30 minutes after the second PK sample collection). 
8.2.4 Electrocardiograms  
• Single 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using 
an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, 
and QTc intervals. 
• In case the ECG machine does not automatically calculate QTcF, manual calculation using 
following formula (QTcF=QT/RR1/3) or automatic website calculator 
(eg, https://reference.medscape.com/calculator/48/ecg-corrected-qt) is acceptable. 
• ECGs and (longer) rhythm strips will be obtained locally. 
• If a clinically significant finding is identified in the ECG (including, but not limited to 
changes from baseline in QTcF after enrollment), the Investigator or delegate will 
determine if the participant can continue in the study and if any change in participant 
management is needed including but not limited to referral to cardiology, and/or Holter 
monitor. The Investigator or delegate should perform the following tasks: 
- 
Review the ECG in a timely manner 
- 
Document the interpretation, sign and date it on ECG printout 
- 
Record your (or appropriate qualified physician) medical opinion (“normal” or 
“abnormal”) on the study participant´s records and in the eCRF 
- 
Assess for any symptoms of cardiac issues 
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- 
Each time when it is medically needed for clinical management of the study participant 
or/and in case of any safety concerns, additional ECG should be performed, and 
findings reported in the eCRF dedicated unscheduled visits ECG forms 
- 
Clinically significant findings are to be checked with pre-existing medical history 
or/and, if appropriate, consider AE. 
Please refer to (27) and (28) for definitions of heart failures classification. 
8.2.5 Clinical safety laboratory assessments  
• See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and 
to the SoA (Section 1.3) for the timing and frequency. 
• The Investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE. The laboratory reports 
must be filed with the source documents. Abnormal laboratory findings associated with 
the underlying disease are not considered clinically significant, unless judged by the 
Investigator to be more severe than expected for the participant’s condition. 
• All abnormal laboratory values that are considered by the Investigator as clinically 
significant during participation in the study or within 2 weeks after the last dose of study 
intervention should be repeated until the values return to normal or baseline or are no 
longer considered clinically significant by the Investigator. 
- 
If clinically significant values do not return to normal/baseline within a period of time 
judged reasonable by the Investigator, the etiology should be identified and the 
Sponsor notified. 
- 
All protocol-required laboratory tests, as defined in Appendix 2 (Section 10.2), must 
be conducted in accordance with the laboratory manual and the SoA (Section 1.3). 
- 
If laboratory values from nonprotocol-specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (eg, SAE or AE or dose 
modification), then the results must be recorded. 
8.2.6 Pregnancy testing  
For female participants of childbearing potential, a pregnancy test will be performed at each 
onsite visit during the whole study period. Additionally, monthly urine pregnancy tests will be 
provided directly to participants and self-conducted by them at home when not coinciding with 
a clinic visit. The study site staff will call the participants to remind them to conduct the monthly 
pregnancy tests and collect the results. A serum pregnancy test will be conducted at the screening 
visit, the last follow-up visit at Week 106, and the early discontinuation visit, and a urine 
pregnancy test will be performed for all other visits.  
8.2.7 Suicidal ideation and behavior (SIB) risk monitoring  
SAR443820 crosses the blood-brain barrier. Assessment of suicidal ideation and 
behavior/treatment-emergent suicidal ideation and behavior will be monitored during ACT16970 
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using the C-SSRS. For safety reasons, the C-SSRS will be administered throughout the study by 
the Investigator or delegated to an individual who is certified to administer the scale. 
Study intervention administration must be interrupted if a participant scores “yes” on items 4 or 
5 of the Suicidal Ideation Section of the C-SSRS or “yes” on any item of the Suicidal Behavior 
Section. A mental health professional will be consulted and will decide whether the study 
intervention can be restarted and if any additional risk mitigation strategies are required 
(eg, increased monitoring, antidepressant administration). 
Participants being treated with the study intervention should be monitored appropriately and 
observed closely for suicidal ideation and behavior or any other unusual changes in behavior. 
Especially at the beginning and end of the course of treatment, consideration should be given to 
discontinuing the study medication in participants who experience signs of suicidal ideation or 
behavior following a risk assessment. 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING  
The definitions of AEs and SAEs can be found in Appendix 3 (Section 10.3). The definition of 
AESI is provided in Section 8.3.8. 
AEs 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 (see Section 7). 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
8.3.1 Time period and frequency for collecting AE and SAE information  
All AEs (serious or nonserious) will be collected from the signing of the ICF until the 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 information on AEs or SAEs after conclusion of 
the study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the Investigator must promptly 
notify the Sponsor. 
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8.3.2 Method of detecting AEs and SAEs  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences. 
8.3.3 Follow-up of AEs and SAEs  
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. At the prespecified study end-date, all SAEs will be 
followed until resolution, stabilization, the event is otherwise explained, or the participant is lost 
to follow-up (as defined in Section 7.4). Further information on follow-up procedures is provided 
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, IRB/Independent Ethics Committee 
(IEC), and Investigators. 
• Serious adverse events that are considered expected will be specified in IB. 
• Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to Investigators as necessary. 
• An Investigator who receives an Investigator safety report describing an SAE, SUSAR or 
any other specific safety information (eg, summary or listing of SAEs) from the Sponsor 
will review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. It is the responsibility of the Sponsor to assess whether 
an event meets the criteria for a SUSAR, and therefore, is expedited to regulatory 
authorities. 
8.3.5 Pregnancy  
• Details of all pregnancies in female participants and female partners of male participants 
will be collected after the start of study intervention and until the time period for 
postintervention contraception determined in Section 5.1. 
• If a pregnancy is reported, the Investigator will record pregnancy information on the 
appropriate form and submit it to the Sponsor within 24 hours of learning of the pregnancy 
of a female participant or female partner of male participant after obtaining the necessary 
signed informed consent from the female partner. 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 
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• The participant or female partner of a male participant will be followed to determine the 
outcome of the pregnancy. The Investigator will collect follow-up information on the 
participant or female partner of a male participant and the neonate, and the information 
will be forwarded to the Sponsor. 
• Any poststudy pregnancy-related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in  
Section 8.3.4. While the Investigator is not obligated to actively seek this information in 
former study participants, 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. 
8.3.6 Cardiovascular and death events  
Since the risk of cardiovascular events is low based on preclinical and Phase 1 study results, 
cardiovascular events are not AESIs and will be reported per standard safety reporting and safety 
oversight practices (including a data review by the data monitoring committee [DMC]). 
Death events will be reported per standard SAE reporting rules. Every effort will be made to 
clarify the cause of death and to report the diagnosis of a fatal event, except ALS, as an SAE. 
8.3.7 Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs  
Respiratory function decline is a type of disease-related event (DRE). DREs are common in 
participants with ALS and can be serious/life threatening. 
Because a decline in respiratory function, including respiratory failure, is typically associated with 
ALS, it will not be reported according to the standard process for expedited reporting of SAEs 
even though the event may meet the definition of an SAE. These events will be recorded within 
the eCRF. These DREs will be monitored by an independent DMC on a routine basis (See  
Section 10.1). Disease progression-related measures will not be recorded as AEs/SAsE, including 
ALSFRS-R, vital capacity results, and muscle strength results. Additionally, the scheduled events, 
eg, hospitalization for an elective procedure, including G-tube placement, are not considered 
SAEs since an elective or scheduled “procedure” or a “treatment” are not an untoward medical 
occurrence. 
NOTE: However, if either of the following conditions applies, then the events must be recorded 
and reported as an AE/SAE (instead of a DRE): 
• The event is, in the Investigator’s opinion, of greater intensity, frequency, or duration than 
expected for the individual participant. 
OR 
• The Investigator considers that there is a reasonable possibility that the event was related 
to study intervention. 
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8.3.8 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. 
For AESIs, the Sponsor is to be informed immediately (ie, within 24 hours), as per the SAE 
notification guidelines described in Appendix 3 (Section 10.3), even if a seriousness criterion is 
not met, using the corresponding pages of the case report form or screens in the eCRF: 
• Pregnancy of a female participant who has taken the IMP at least once as well as 
pregnancy occurring in a female partner of a male participant who has taken the IMP at 
least once during this study 
- 
Pregnancy will be qualified as an SAE only if it fulfills 1 of the seriousness criteria 
(see Appendix 3 [Section 10.3]). 
- 
In the event of pregnancy in a female participant, the 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 a systematic pill 
count) and defined as at least 3 tablets of the IMP taken within 12 hours. 
- 
Note: An asymptomatic overdose has to be reported as a standard AE. 
• Other project-specific AESIs 
- 
Convulsions. 
- 
Serious infections meeting SAE definitions criteria (please see Section 10.3.2 for SAE 
definitions). 
- 
Increase in ALT >3.0 × ULN (confirmed at retest): see the “Increase in ALT 
algorithm” flow chart in Appendix 6 (Section 10.6). 
8.3.9 Guidelines for reporting product complaints  
Any defect in the IMP must be reported as soon as possible by the Investigator to the monitoring 
team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
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8.4 
PHARMACOKINETICS  
Whole blood samples will be collected for measurement of the plasma concentration of 
SAR443820 as specified in the SoA (Section 1.3), which is summarized in Table 5 below. 
PK samples can be collected at either fasting or non-fasting condition. 
Table 5 - Schedule of PK sampling  
 
Day 1* 
Week 2 
Week 8 
Week 28 
Before dose (within 1 hour predose) 
 
X 
X 
X 
After dose (15 minutes to 1 hour) 
X 
 
 
 
After dose (1 hour to 3 hours) 
X 
 
 
 
After dose (15 minutes to 3 hours) 
 
 
X 
 
* At least 45 minutes between the 2 PK samples at Day 1. 
The timing of sampling may be altered during the course of the study based on newly available 
data to ensure appropriate monitoring. 
Instructions for the collection and handling of biological samples will be provided by the Sponsor 
or Sponsor’s designee in a separate document. The actual date and time of each sample will be 
recorded. 
Samples collected for analysis of the SAR443820 plasma concentration may also be used to 
evaluate safety or efficacy aspects related to concerns raised during or after the study. 
Pharmacokinetic samples will be tested by the Sponsor or Sponsor’s designee. 
Pharmacokinetic samples could be used for testing analytical method performance such as 
comparability and incurred sample reproducibility and for possible exploratory analysis of drug 
metabolites and biomarkers. The exploratory data will not be included in the study report but will 
be kept on file. 
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded. 
8.5 
GENETICS AND/OR PHARMACOGENOMICS  
An optional single blood collection for the isolation of DNA will be conducted in participants of 
Part A only if they provide informed consent for this collection. Analysis of DNA may include the 
identification of determinants of disease (mutations and genetic variation) or response to 
treatment. 
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8.6 
BIOMARKERS  
• Collection of biological samples for biomarker research is also part of this study. The 
following samples for biomarker research are required and will be collected from all 
participants in this study as specified in the SoA: 
- 
Blood, which will be used to isolate either serum or plasma components 
- 
Urine 
• Samples will be tested for protocol-specific objectives to evaluate their association with 
the observed clinical responses to the IMP. 
• Blood derivatives and urine collected during the study may be used for exploratory 
research, including development of PD assays and/or exploration of target- and 
disease-related exploratory biomarkers related to RIPK1 kinase inhibition, such as 
cytokines, lipids, metabolites, cellular markers, immune cell phenotypes, and other 
inflammatory and neurodegenerative biomarkers. Samples collected for biomarker 
analyses and their derivatives will be stored for a period of up to 5 years after the 
last participant last visit for potential reanalyses (see details in Section 8.9). 
For China, please see Appendix 8 (Section 10.8) for details. 
8.7 
IMMUNOGENICITY ASSESSMENTS  
Not applicable. 
8.8 
MEDICAL RESOURCE UTILIZATION AND HEALTH ECONOMICS  
Medical resource utilization and health economics data, associated with medical encounters, will 
be collected by the Investigator and study-site personnel for all participants throughout the study. 
Protocol-mandated procedures, tests, and encounters are excluded. As there have been ample 
publications on
among participants with ALS, this study will focus on
 data 
collection for the data elements that most significantly impact participants that may be used to 
further supplement health economic analyses, specifically walking aids and
, 
during the study. 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH  
Future research may help further the understanding of disease subtypes, disease biology, related 
conditions, drug response and toxicity, and can help identify new drug targets or biomarkers that 
predict participant response to treatment. For example, additional biomarkers analyses related to 
RIPK1 and/or ALS biology, such as serum glial fibrillary acidic protein (GFAP), may be 
performed. 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 and/or extra 
clinical samples, data and samples may be used after the study ends for future research related 
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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 other proteins, lipids, or 
metabolites. 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. Additional consent will be 
collected if the participant opts in for the additional blood sample for DNA analysis.  
Data and samples will be used in compliance with the information provided to participants in the 
ICF Part 2 (future research). 
All study participant data and samples will be coded such that no participant direct identifiers will be 
linked to them. Coded data and samples may be transferred to a Sponsor site (or a subcontractor site), 
which may be located outside of the country where the study is conducted. The Sponsor adopts 
safeguards for protecting participant confidentiality and personal data (see Section 10.1.4). 
Samples consented for future research use will be stored for a maximum of 15 years after the end 
of the study. Any samples remaining at the end of retention period will be destroyed. If 
a participant requests destruction of his/her samples before the end of the retention period, the 
Investigator must notify the Sponsor (or its contract organization) in writing. In such case, 
samples will be destroyed, and related coded data will be anonymized unless otherwise required 
by applicable laws. Samples from study participants who do not give consent for future research 
use will be held for up to 5 years until all testing and reporting related to the clinical study have 
been completed (Section 8.6). 
Study participant coded data will be stored for future research for up to 25 years after the end of 
the study. If data are still considered of important scientific value after this period, coded data 
already available will be anonymized unless otherwise required by applicable laws (the same will 
apply to the data of a study participant who has requested the destruction of his/her samples). 
Participant’s coded data sets provided to researchers for a specific research project will be 
available to the researchers for a maximum of 2 years after the end of their specific project (end of 
project is defined by publication of the results or finalization of the future research project report). 
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9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESIS  
The null hypothesis for the primary efficacy endpoint of change from baseline in the ALSFRS-R 
total score to Week 24 is that there is no treatment difference between SAR443820 and placebo, 
and the alternative hypothesis is that there is a between-treatment difference. 
To strongly control the Type 1 error rate for the study, a hierarchical testing procedure will be applied 
at a 2-sided 5% significance level, ie, each hypothesis will be formally tested only if the preceding 
one is significant at the 5% level. If SAR443820 is significant for the primary endpoint, a selective 
set of secondary endpoints will be tested following the hierarchical testing procedure. The complete 
list of the secondary endpoints that will be adjusted for multiplicity with their testing order will be 
detailed in the SAP prior to database lock or any interim analysis, if applicable.  
The study will be declared positive if the null hypothesis for primary endpoint in Part A, change 
from baseline in the ALSFRS-R total score to Week 24 (end of Part A) for SAR443820 versus 
placebo is rejected in the primary analysis. 
9.2 
SAMPLE SIZE DETERMINATION  
The proposed sample size (n = 261) provides an approximately 80% power to detect a 
30% reduction in SAR443820 compared with placebo in the change of ALSFRS-R from baseline 
at Week 24, assuming a change of
 points from baseline in ALSFRS-R in the placebo arm with 
a standard deviation of
 points, and a 20% drop-out rate. Sample size is estimated via 
simulation with a 2-sided 5% significance level. 
9.3 
POPULATIONS FOR ANALYSES  
The following populations for analyses are defined: 
Table 6 - Populations for analyses  
Population 
Description 
Screened 
All participants who signed the ICF. 
Randomized 
All participants from the screened population who have been allocated to a randomized intervention by 
IRT regardless of whether the intervention was received. 
Exposed 
All screened participants who  take at least 1 dose of the study intervention. 
Intent-to-treat (ITT) 
All randomized participants. Participants will be analyzed according to the intervention allocated by 
randomization. 
Safety 
All randomized participants who receive at least 1 dose (including partial dose) of the study 
intervention. 
Pharmacokinetic (PK) 
All randomized participants who receive at least 1 dose of the study intervention and have at least 
1 PK assessment with adequate documentation of dosing and sampling dates and times. Participants 
will be analyzed according to the intervention they actually received. 
ICF = informed consent form; IRT = interactive response technology; ITT = intent-to-treat; PK = pharmacokinetic 
 
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9.4 
STATISTICAL ANALYSES  
The SAP will include a more technical and detailed description of the statistical analyses 
described in this section. This section is a summary of the planned statistical analyses of the most 
important endpoints including primary and key secondary endpoints in Part A and primary 
endpoint in Part B. 
9.4.1 General considerations  
The baseline values of NfL, CHI3L1, the cytokine and chemokine panel in serum, sTREM2 in 
plasma and p75ECD in urine, are defined as the average value from samples collected at the 
screening visit and at Day 1 prior to the first dose of the study intervention. For the other 
assessments, the baseline value is defined as the last nonmissing value before the first dose of 
study intervention. 
Typically, continuous variables will be summarized by the mean, median, standard deviation 
(SD), first and third quartiles, minimum, and maximum; categorical variables will be summarized 
by the number and percentage of participants in each category. For estimates from statistical 
models for the primary and key secondary endpoints, estimates with the standard error (SE), 
95% CI, and p-value will be determined. 
9.4.2 Primary endpoint(s) in Part A  
The primary efficacy endpoint is change from baseline in the ALSFRS-R total score to Week 24. 
Estimands 
The primary estimand will be the difference (SAR443820 vs placebo) in the mean change from 
baseline in the ALSFRS-R score estimated from baseline to Week 24 in the ITT population 
regardless of whether participants completed the treatment period. This estimand corresponds to 
a “treatment policy strategy” and will be using all available data and missing data will be not 
imputed. 
The secondary estimand will be the difference (SAR443820 vs placebo) in the mean change 
from baseline in the ALSFRS-R score estimated in the ITT population during the 
treatment-emergent period. This estimand corresponds to a “while on treatment strategy.” This 
estimand will be considered for describing the effect of treatment as long as participants adhere to 
their randomized treatment. 
Primary analysis 
The primary analysis will be based on the primary estimand, which includes data collected for the 
primary endpoint for all participants included in the ITT population. 
An MMRM will be fitted to change from baseline in the ALSFRS-R, which will include the fix 
effects of treatment (SAR443820 or placebo), visit (as a categorical variable), baseline 
ALSFRS-R score, baseline NfL, randomization strata of the geographic region of the study site, 
ALS onset region (bulbar or other areas), use of riluzole (yes or no), use of edaravone (yes or no), 
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use of the combination of sodium phenylbutyrate and taurursodiol (yes vs no), treatment-by-visit 
interaction, baseline NfL-by-visit interaction, and baseline ALSFRS-R score-by-visit interaction.  
The least squares mean difference in the ALSFRS-R change from baseline at Week 24 between 
SAR443820 vs placebo, together with the p-value and the 95% CI for the difference, will be 
estimated from the MMRM model using weights for each stratum equal to the overall proportion 
of participants in each stratum (ie, “population weight”). 
This model will be implemented using the SAS MIXED procedure with an unstructured 
correlation matrix to model the within-participant errors. Parameters will be estimated using the 
restricted maximum likelihood method. The denominator degrees of freedom will be estimated 
using the Kenward-Roger approximation. This model will provide baseline adjusted least-squares 
means estimates at Week 24 for SAR443820 and placebo, together with their corresponding 
standard errors and CIs. 
Subgroup analysis will be specified in the SAP. 
9.4.3 Secondary endpoint(s) in Part A  
The key secondary efficacy endpoints include the CAFS at Week 24, and change from baseline in 
SVC, change from baseline in muscle strength, ALSAQ-5, and serum NfL to Week 24. All 
secondary efficacy endpoints will be analyzed based on the ITT population. 
For continuous variables, an MMRM approach under the MAR assumption will be used. This 
model will include the fixed effect of treatment (SAR443820 or placebo), visit as a categorical 
variable, baseline value of the endpoint, baseline NfL (if different from the baseline value of the 
enpoint), randomization strata of the geographic region of the study site, ALS onset region (bulbar 
or other areas), use of riluzole (yes or no), use of edaravone (yes or no), use of the combination of 
sodium phenylbutyrate and taurursodiol (yes vs no), treatment-by-visit interaction, and baseline 
value of the endpoint-by-visit interaction and baseline NfL-by-visit interaction (if different from 
the baseline value of the endpoint-by-visit interaction). The primary comparison of interest will be 
the difference between SAR443820 and placebo at Week 24, carried out using contrast within the 
treatment-by-time interaction term. Available data will be used for all secondary analyses. 
To have strong control of the Type I error rate, a closed sequential testing approach will be used. 
The order of the secondary efficacy endpoints and all the details of sequential testing will be 
specified in the full SAP. The details of the analysis for other secondary endpoints will be 
outlined in the full SAP. 
9.4.4 Primary endpoint in Part B  
The primary endpoint in Part B is the CAFS at Week 52. The CAFS for each participant is the 
sum of all pairwise rankings based on survival data and change from baseline in ALSFRS-R score 
at Week 52 (15). The comparison of the CAFS will be conducted between the participants who 
are treated with SAR443820 and placebo in Part A. A Wilcoxon rank sum test will be used to 
compare these 2 groups. Different approaches handling missing data will be used in the sensitivity 
analysis and details will be described in the SAP. 
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9.4.5 Tertiary endpoints  
Methods for analysis of tertiary endpoints will be included in the SAP. A matched analysis using 
data from the Phase 3 clinical trial for Ceftriaxone (NCT00349622) as a historical control might 
be conducted to demonstrate the superiority of SAR443820 on slowing down disease progression 
and prolonging survival over 104 weeks of treatment period. 
9.4.6 Safety analysis  
All safety analyses will be performed with the safety population. Safety summaries will be based 
on descriptive statistics, presented by treatment group. No statistical testing will be performed for 
safety analyses. 
Safety analyses will be based on the reported AEs and other safety data, including clinical 
laboratory data, vital signs, and ECG. All AEs reported in the trial will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) with a version in effect at the time of the 
database lock. 
9.4.6.1 Adverse events  
General common rules for adverse events 
The AEs that developed, worsened or became serious during the study observation period will be 
used for safety analysis. The safety observation period will be divided into 3 phases: 
• Pretreatment AEs: AEs that developed, worsened or became serious during the 
pretreatment period. 
• TEAEs: AEs that developed, worsened or became serious during the treatment-emergent 
period. 
• Post-treatment AEs: AEs that developed, worsened or became serious during the 
post-treatment period. 
Similarly, the deaths will be analyzed in the pretreatment, treatment-emergent, and post-treatment 
periods. 
Summaries will be provided for all grades combined and for Grades ≥3 (including Grade 5). 
Missing grades, if any, will be included in the “all grades” category. 
Analysis of all adverse events 
Adverse event incidence table with the number and the percentage of participants with at least 
1 event will be provided by treatment group for: all TEAEs, all treatment-emergent AESI (defined 
with a preferred term (PT) or a prespecified grouping), all treatment-emergent SAEs, all TEAEs 
leading to permanent treatment discontinuation and death. Multiple occurrences of the same event 
in the sample participant will be counted once in the summary. 
Deaths will also be analyzed. 
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9.4.6.2 Laboratory variables, vital signs and electrocardiograms (ECGs)  
Quantitative analyses 
For laboratory variables, vital signs and ECG variables, descriptive statistics by treatment group 
for results and changes from baseline will be provided for each scheduled visit during the 
treatment period. 
Analyses according to potential clinically significant abnormality (PCSA) 
Potentially clinically significant abnormality (PCSA) analyses will be performed based on the 
PCSA list currently in effect at Sanofi at the time of the database lock. 
Analyses according to PCSA will be performed based on the worst value during the 
treatment-emergent period, using all measurements (either local or central, either scheduled, 
nonscheduled or repeated). 
For laboratory variables, vital signs and ECG variables, the incidence of participants with at least 
1 PCSA during the treatment-emergent period will be summarized regardless of the baseline level 
and according to the following baseline status categories: 
• Normal/missing 
• Abnormal according to PCSA criterion or criteria 
For ECG, the incidence of participants with at least 1 abnormal ECG during the 
treatment-emergent period will be summarized regardless of the baseline level and according to 
the following baseline status categories: 
• Normal/missing 
• Abnormal 
9.4.6.3 Product complaints  
Product complaints will be summarized in the safety population. 
9.4.7 Other analysis  
The population PK analyses will be presented separately from the main clinical study report 
(CSR). 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Appendix 9 (Section 10.9). 
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9.5 
INTERIM ANALYSES  
A nonbinding interim analysis for futility may be conducted when approximately 40% of the 
participants complete Part A, the double-blind placebo-controlled period. If both stopping criteria 
for change from baseline in the ALSFRS-R total score to Week 24 and change from baseline in 
NfL to Week 24 are met, the futility may be declared. An independent statistical group, external 
to the Sponsor, will conduct the IA and support the DMC activities. At the time of the IA, if the 
DMC recommends the study to continue, the Sponsor will be informed of the decision without 
receiving any unblinded results. Only if the DMC considers recommending the study to stop for 
futility, will a prespecified limited number of the Sponsor’s senior management team be informed 
of the unblinded results. This limited Sponsor’s senior management team will decide to stop or 
continue the study. No one involved in the conduct of the study will have access to the unblinded 
data. Interim analysis details, including the futility criteria and dissemination plan, will be 
provided in the SAP. 
A second interim analysis will be performed when all patients complete the double-blind 
randomization period (from baseline to Week 24). An interim CSR containing all efficacy and 
safety results for Part A will be prepared.  
An additional interim analysis during Part B may be performed at Sponsor’s discretion. 
 
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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  
A) 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 (eg, data protection laws such as the General Data 
Protection Regulation - GDPR) 
B) The protocol, protocol amendments, ICF, IB, IDFU, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the Investigator and reviewed 
and approved by the IRB/IEC before the study is initiated. 
C) 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. 
D) Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard 
to study participants. 
E) The Investigator will be responsible for the following: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
- 
Determining whether an incidental finding (as per Sanofi policy) should be returned to 
a participant and, if it meets the appropriate criteria, to ensure the finding is returned 
(an incidental finding is a previously undiagnosed medical condition that is discovered 
unintentionally and is unrelated to the aims of the study for which the tests are being 
performed). The following should be considered when determining the return of 
an incidental finding: 
- 
The return of such information to the study participant (and/or his/her designated 
healthcare professional, if so designated by the participant) is consistent with all 
applicable national, state, or regional laws and regulations in the country where the 
study is being conducted, and 
- 
The finding reveals a substantial risk of a serious health condition or has 
reproductive importance, AND has analytical validity, AND has clinical validity. 
- 
The participant in a clinical study has the right to opt out of being notified by the 
Investigator of such incidental findings. In the event that the participant has opted 
out of being notified and the finding has consequences for other individuals, eg, the 
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finding relates to a communicable disease, Investigators should seek independent 
ethical advice before determining next steps. 
- 
In case the participant has decided to opt out, the Investigator must record in the 
site medical files that she/he does not want to know about such findings. 
- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), European Medical Device Regulation 2017/745 for 
clinical device research (if applicable), and all other applicable local regulations 
As applicable, according to Directive 2001/20/EC, the Sponsor will be responsible for obtaining 
approval from the Competent Authorities of the EU Member States and/or Ethics Committees, as 
appropriate, for any amendments to the clinical trial that are deemed as “substantial” (ie, changes 
which are likely to have a significant impact on the safety or physical or mental integrity of the 
clinical trial participants or on the scientific value of the trial) prior to their implementation. 
10.1.2 Financial disclosure  
Investigators and subinvestigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3 Informed consent process  
• The Investigator or his/her representative will explain the nature of the study to the 
participants, and answer all questions regarding the study, including what happens to the 
participant when his/her participation ends (post-trial access strategy for the study). 
• Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 Code of Federal Regulation (CFR) 50, local regulations, 
ICH guidelines, Privacy and Data Protection requirements including those of the Global 
Data Protection Regulation (GDPR) and of the French law, Health Insurance Portability 
and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or 
study center. 
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• In case of ICF amendment while the participants are still included in the study, they must 
be reconsented to the most current version of the ICF(s). Where participants are not in the 
study anymore, teams in charge of the amendment must define if those participants must 
or not reconsent or be informed of the amendment (eg, if the processing of personal data is 
modified, if the Sponsor changes, etc.). 
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• A copy of the ICF(s) must be provided to the participant or their legally authorized 
representative, where applicable. 
• Please refer to Section 10.8.2 for participants from Germany. 
Participants who are rescreened are required to sign a new ICF. 
The ICF contains 2 separate sections that address the use for research of participants’ data and/or 
samples (remaining mandatory ones or new extra samples collected for optional research). 
Optional exploratory research must be detailed in the section “Optional tests/procedures” and 
future research is to be defined in Core Study Informed Consent Form (CSICF) Part 2. Each 
option is subject to an independent consent and must be confirmed by ticking a checkbox in 
CSICF Part 3. The Investigator or authorized designee will explain to each participant the 
objectives of the exploratory research and why data and samples are important for future research. 
Participants will be told that they are free to refuse to participate and may withdraw their consent 
at any time and for any reason during the storage period. 
10.1.4 Data protection  
All personal data collected and/or processed in relation to this study will be handled in 
compliance with all applicable Privacy & Data Protection laws and regulations, including the 
General Data Protection Regulation (GDPR). The study Sponsor is the Sanofi company 
responsible for ensuring compliance with this matter, when processing data from any individual 
who may be included in the Sanofi databases, including Investigators, nurses, experts, service 
providers, Ethics Committee members, etc. 
When archiving or processing personal data pertaining to the Investigator and/or to the 
participants, the Sponsor takes all appropriate measures to safeguard and prevent access to this 
data by any unauthorized third party. 
Protection of participant data 
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
Participant race and ethnicity will be collected in this study because they are required by 
regulatory agencies (eg, on Japanese population for the Pharmaceuticals and Medical Devices 
Agency in Japan). They will not be collected in the countries where this is prohibited by local 
regulation. 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor or its service providers will be identifiable only 
by the unique identifier; participant names or any information which would make the 
participant identifiable will not be transferred to the Sponsor. 
• The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with applicable data protection laws. The level of disclosure 
must also be explained to the participant as described in the informed consent. 
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• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• Participants must be informed that their study-related data will be used for the whole “drug 
development program”, ie, for this trial as well as for the following steps necessary for the 
development of the investigational product, including to support negotiations with payers 
and publication of results. 
Protection of data related to professionals involved in the study 
• Personal data (eg, contact details, affiliation(s) details, job title and related professional 
information, role in the study, professional resume, training records) are necessary to 
allow Sanofi to manage involvement in the study and/or the related contractual or 
precontractual relationship. They may be communicated to any company of the Sanofi 
group (“Sanofi”) or to Sanofi service providers, where needed. 
• Personal data can be processed for other studies and projects. At any time, objection to 
processing can be made by contacting the Sanofi Data Protection Officer (link available at 
Sanofi.com). 
• In case of refusal to the processing of personal data by or on behalf of Sanofi, it will be 
impossible to involve the professionals in any Sanofi study. In case the professionals have 
already been involved in a Sanofi study, they will not be able to object to the processing of 
their personal data as long as they are required to be processed by applicable regulations. 
The same rule applies in case the professionals are listed on a regulatory agencies 
disqualification list. 
• Personal data can be communicated to the following recipients: 
- 
Personnel within Sanofi or partners or service providers involved in the study 
- 
Judicial, administrative and regulatory authorities, in order to comply with legal or 
regulatory requirements and/or to respond to specific requests or orders in the 
framework of judicial or administrative procedures. Contact details and identity may 
also be published on public websites in the interest of scientific research transparency 
• Personal data may be transferred towards entities located outside the Economic European 
Area, in countries where the legislation does not necessarily offer the same level of data 
protection or in countries not recognized by the European Commission as offering 
an adequate level of protection. Those transfers are safeguarded by Sanofi in accordance 
with the requirement of European law including, notably: 
- 
The standard contractual clauses of the European Commission for transfers towards 
our partners and service providers 
- 
Sanofi’s Binding Corporate Rules for intra-group transfers 
• Professionals have the possibility to lodge a complaint with Sanofi leading Supervisory 
Authority, the “Commission Nationale de l’Informatique et des Libertés” (CNIL) or with 
any competent local regulatory authority. 
• Personal data of professionals will be retained by Sanofi for up to thirty (30) years, unless 
further retention is required by applicable regulations. 
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• In order to facilitate the maintenance of Investigators personal data, especially if they 
contribute to studies sponsored by several pharmaceuticals companies, Sanofi participates 
in the Shared Investigator Platform (SIP) and in the TransCelerate Investigator Registry 
(IR) project (https://transceleratebiopharmainc.com/initiatives/investigator-registry/). 
Therefore, personal data will be securely shared by Sanofi with other pharmaceutical 
company members of the TransCelerate project. This sharing allows Investigators to keep 
their data up-to-date once for all across pharmaceutical companies participating in the 
project, with the right to object to the transfer of the data to the TransCelerate project. 
• Professionals have the right to request the access to and the rectification of their personal 
data, as well as their erasure (where applicable) by contacting the Sanofi Data Protection 
Officer: Sanofi DPO - 54 rue La Boétie - 75008 PARIS - France (to contact Sanofi by 
email, visit https://www.sanofi.com/en/our-responsibility/sanofi-global-privacy-
policy/contact). 
10.1.5 Committee structure  
10.1.5.1 Study Steering Committee  
A study Steering Committee, composed of 5 experts in the field of ALS, will advise the Sponsor 
on the study design and conduct. In collaboration with the Sponsor, the committee will provide 
scientific leadership to the study to ensure that the highest standards are maintained. Details 
describing the committee processes and procedures are outlined in the Steering Committee 
charter. 
10.1.5.2 Independent Data Monitoring Committee (DMC)  
A DMC, operating independently of the Sponsor and clinical Investigators, will be responsible for 
overseeing the safety of participants throughout the study. This committee is composed of 
externally based individuals with expertise in the disease under study, biostatistics, or clinical 
research. The primary responsibilities of the DMC are to review and evaluate the safety data and 
assess futility through an interim analysis during the trial and to make appropriate 
recommendations to the Sponsor regarding the conduct of the clinical trial. 
Details describing the DMC processes and procedures are outlined in the DMC charter. To 
maintain continuous blinding and study integrity, the analysis will be conducted by 
an independent statistician who will directly transfer data to DMC members. 
10.1.6 Dissemination of clinical study data  
Study participants 
Sanofi shares information about clinical trials and results on publicly accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations. These 
websites include clinicaltrials.gov, euclinicaltrials.eu, and sanofi.com, as well as some national 
registries. 
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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 vivli.org. 
Individual participant data and supporting clinical documents are available for request at vivli.org. 
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: vivli.org. 
Professionals involved in the study or in the drug development program 
Sanofi undertakes the legal obligation to disclose the full name of the Investigator and his/her 
affiliated institute/ hospital’s name and location on the China Trial Disclosure website as required by 
the National Medical Products Administration (NMPA) in its guidance “Drug Clinical Trial 
Registration and Information Disclosure Management Practice (Trial Implementation), requesting 
name disclosure of Chinese and foreign investigational sites and Investigators in any eligible clinical 
trial. 
Sanofi may publicly disclose, and communicate to relevant authorities/institutions, the funding, 
including payments and transfers of value, direct or indirect, made to healthcare organizations and 
professionals and/or any direct or indirect advantages and/or any related information or document 
if required by applicable law, by regulation or by a code of conduct such as the “European 
Federation of Pharmaceutical Industries and Associations (EFPIA) Code on Disclosure of 
Transfers of Value from Pharmaceutical Companies to Healthcare Professionals and Healthcare 
Organisations”. 
10.1.7 Data quality assurance  
• All participant data relating to the study will be recorded on printed or eCRF unless 
transmitted to the Sponsor or designee electronically (eg, laboratory data). The 
Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the eCRF. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. The Investigator must permit study-related monitoring, 
audits, IRB/IEC review, and regulatory agency inspections and provide direct access to 
source data documents. 
• Quality tolerance limits (QTLs) will be predefined to identify systematic issues that can 
impact participant safety and/or reliability of study results. These pre-defined parameters 
will be monitored during the study, and important deviations from the QTLs and remedial 
actions taken will be summarized in the CSR.  
• 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 onsite monitoring) 
are provided in separate study documents. 
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• The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations). 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 25 years after the signature of the final study 
report unless local regulations or institutional policies require a longer retention period. 
No records may be destroyed during the retention period without the written approval of 
the Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor. 
10.1.8 Source documents  
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data reported on the case report form (CRF) or entered in the eCRF that are transcribed 
from source documents must be consistent with the source documents or the discrepancies 
must be explained. The Investigator may need to request previous medical records or 
transfer records, depending on the study. Also, current medical records must be available. 
• Definition of what constitutes source data can be found in the study manual. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH-GCP, and all applicable regulatory requirements. 
10.1.9 Study and site start and closure  
First act of recruitment 
The study start date is the date on which the clinical study will be open for recruitment of 
participants. 
The first act of recruitment is the first site open and will be the study start date. 
Study/Site termination 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
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Reasons for study termination by the Sponsor, as well as reasons for the early closure of a study 
site by the Sponsor or Investigator may include but are not limited to: 
• For study termination: 
- 
Information on the product leads to doubt as to the benefit/risk ratio 
- 
Discontinuation of further study intervention development 
• For site termination: 
- 
Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor’s procedures, or GCP guidelines 
- 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator 
- 
Total number of participants included earlier than expected 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.10 Publication policy  
• The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor 
before submission. This allows the Sponsor to protect proprietary information and to 
provide comments. 
• The Sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the Sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating Investigator will be designated by mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.2 APPENDIX 2: CLINICAL LABORATORY TESTS  
• The tests detailed in Table 7 will be performed by the central laboratory. 
• Local laboratory results are only required in the event that the central laboratory results are 
not available in time for either study intervention administration and/or response 
evaluation. If a local sample is required, it is important that the sample for central analysis 
is obtained at the same time. Additionally, if the local laboratory results are used to make 
either a study intervention decision or response evaluation, the results must be recorded. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 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. 
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Table 7 - Protocol-required laboratory tests  
Laboratory tests 
Parameters 
Hematology 
 
 
Platelet count 
 
Red blood cell (RBC) count 
 
Hemoglobin 
 
Hematocrit 
 
RBC indices: 
 
Mean corpuscle volume (MCV) 
 
Mean corpuscle hemoglobin (MCH) 
 
%Reticulocytes 
 
White blood cell (WBC) count with differential: 
 
Neutrophils 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
Clinical chemistrya 
 
 
Blood urea nitrogen (BUN) 
 
Creatinine 
 
Glucoseb 
 
Potassium 
 
Sodium 
 
Calcium 
 
Aspartate aminotransferase (AST)/ Serum glutamic-oxaloacetic transaminase (SGOT) 
 
Alanine aminotransferase (ALT)/ Serum glutamic-pyruvic transaminase (SGPT) 
 
Alkaline phosphatasec 
 
Albumin 
 
Creatine phosphokinase (at screening visit only) 
 
Total and direct bilirubin 
 
Total protein 
Routine urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase by dipstick 
• 
Microscopic examination (if blood or protein is abnormal) 
Pregnancy testing 
• 
Serum or highly sensitive urine human chorionic gonadotropin (hCG) pregnancy 
test (as needed for women of childbearing potential)d 
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Laboratory tests 
Parameters 
Other screening tests 
• 
Follicle-stimulating hormone (FSH) and estradiol (as needed in women of 
non-childbearing potential only) 
• 
Serology (human immunodeficiency virus [HIV] antibody, hepatitis B surface 
antigen [HBsAg], and hepatitis C virus antibody or specify other tests) 
• 
All study-required laboratory tests will be performed by a central laboratory. 
NOTES : 
a Details of liver chemistry stopping criteria and required actions and follow-up are given in Appendix 6 (Section 10.6) [Liver and other 
safety. Suggested actions and follow-up assessments [and study intervention rechallenge guidelines]. All events of ALT >3 × ULN, which 
may indicate liver injury, must be reported to Sponsor in an expedited manner (refer to the section on AESIs [Section 8.3.8]). Clinical 
laboratory findings of ALT >3 ULN and bilirubin >2 × ULN (>35% direct bilirubin), which may suggest severe liver injury (possible Hy’s 
Law), must be reported to Sponsor in an expedited manner. 
b Fasting glucose is preferred. Fasting/nonfasting status will be recorded at the time of blood collection for glucose assessment. 
c If alkaline phosphatase is elevated, consider fractionating.  
d Local urine testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC. 
Investigators must document their review of each laboratory safety report. 
10.3 APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING  
10.3.1 Definition of AE  
AE definition 
• An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
• NOTE: An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
Definition of unsolicited and solicited AE 
• An unsolicited AE is an AE that was not solicited using a participant diary and that is 
communicated by a participant who has signed the informed consent. Unsolicited AEs 
include serious and non-serious AEs. 
• Potential unsolicited AEs may be medically attended (ie, symptoms or illnesses requiring 
a hospitalization, or emergency room visit, or visit to/by a health care provider). The 
participants will be instructed to contact the site as soon as possible to report medically 
attended event(s), as well as any events that, though not medically attended, are of 
participant concern. Detailed information about reported unsolicited AEs will be collected 
by qualified site personnel and documented in the participant’s records. 
• Unsolicited AEs that are not medically attended nor perceived as a concern by participant 
will be collected during interview with the participants and by review of available medical 
records at the next visit. 
• Solicited AEs are predefined systemic events for which the participant is specifically 
questioned. 
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Events meeting the AE definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, and vital signs measurements), 
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 fulfill the definition of an AE or SAE. 
• The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. 
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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10.3.2 Definition of SAE  
An SAE is defined as any adverse event that, at any dose: 
A) Results in death 
B) Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, which 
hypothetically might have caused death, if it were more severe. 
C) Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If 
a complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
D) Results in persistent or significant disability/incapacity 
- 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
- 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
E) Is a congenital anomaly/birth defect 
F) Is a suspected transmission of any infectious agent via an authorized medicinal 
product 
G) Other situations: 
• Medical or scientific judgment should be exercised by the Investigator in deciding 
whether SAE reporting is appropriate in other situations such as significant medical 
events that may jeopardize the participant or may require medical or surgical 
intervention to prevent 1 of the other outcomes listed in the above definition. These 
events should usually be considered serious. 
- 
Note: The following list of medically important events is intended to serve as a 
guideline for determining which condition has to be considered as a medically 
important event. The list is not intended to be exhaustive: 
• Intensive treatment in an emergency room or at home for: 
- 
Allergic bronchospasm 
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow aplasia, 
myelodysplasia, pancytopenia, etc) 
- 
Convulsions 
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• Development of drug dependence or drug abuse 
• ALT >3 × ULN + total bilirubin >2 × ULN or asymptomatic ALT increase >10 × ULN 
• Suicide attempt or any event suggestive of suicidality 
• Syncope, loss of consciousness (except if documented as a consequence of blood 
sampling)  
• Bullous cutaneous eruptions 
10.3.3 Recording and follow-up of AE and/or SAE  
AE and SAE recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The Investigator will then record all relevant AE/SAE information. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor’s representative in lieu of completion of the required form. 
• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor’s representative. In this case, all participant identifiers, with the exception of 
the participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor’s representative. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during the 
study and assign it to 1 of the following categories: 
• Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities. 
• Moderate: An event that causes sufficient discomfort to interfere with normal everyday 
activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. “Severe” is a category used for rating the 
intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe. 
Assessment of causality 
• The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than that a relationship cannot be ruled 
out. 
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• The Investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The Investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor’s representative. However, it is 
very important that the Investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to the Sponsor’s 
representative. 
• The Investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
• The causality assessment is 1 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’s 
representative to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
• If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor’s representative with a copy of any 
postmortem findings including histopathology. 
• New or updated information will be recorded in the originally submitted documents. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
10.3.4 Reporting of SAEs  
SAE reporting to the Sponsor via an electronic data collection tool 
• The primary mechanism for reporting an SAE to the Sponsor’s representative will be the 
electronic data collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes available. 
• After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
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• 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’s representative by telephone. 
• Contacts for SAE reporting can be found in the Investigator Study File. 
SAE reporting to the Sponsor via paper data collection tool 
• Facsimile transmission of the SAE paper data collection tool is the preferred method to 
transmit this information to the Sponsor’s representative. 
• In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
• Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE data collection tool within the designated reporting time frames. 
• Contacts for SAE reporting can be found in the contact list in the Investigator Study File. 
10.4 APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE  
10.4.1 Definitions  
A woman is considered a WOCBP (fertile) from the time of menarche until becoming 
postmenopausal (see below) unless permanently sterile (see below). 
• A postmenopausal state is defined as the period of time after a woman has experienced no 
menses for 12 consecutive months without an alternative medical cause. 
• A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be used 
to confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT). 
• Females on HRT and whose menopausal status is in doubt will be required to use 1 of the 
nonestrogen hormonal highly effective contraception methods if they want to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation 
of postmenopausal status before study enrollment. 
Permanent sterilization methods include: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
• For individuals with permanent infertility due to an alternate medical cause other than the 
above, (eg, Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), Investigator 
discretion should be applied to determining study entry eligibility 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
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If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first administration of the study intervention, additional evaluations should be 
considered. 
10.4.2 Contraception guidance  
If locally required, acceptable contraceptive methods are limited to those that inhibit ovulation as 
the primary mode of action. 
 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly effective methodsb that have low user dependency Failure rate of <1% per year when used consistently and 
correctly. 
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS)c 
• 
Bilateral tubal occlusion 
• 
Documented azoospermic partner (vasectomized or due to a medical cause) 
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual partner of the 
woman of childbearing potential and the absence of sperm has been confirmed. If not, an additional highly effective 
method of contraception should be used. 
Note: Documentation of azoospermia for a male participant can come from the site personnel’s review of the 
participant’s medical records, medical examination, or medical history interview. 
Highly effective methodsb that are user dependent Failure rate of <1% per year when used consistently and correctly. 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulationc 
- 
oral 
- 
intravaginal 
- 
transdermal 
- 
injectable 
• 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
- 
oral 
- 
injectable 
• 
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 Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for those 
participating in clinical studies. 
b Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when used consistently and 
correctly. 
c Male condoms must be used in addition to hormonal contraception. 
Note: Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method (LAM) are not acceptable methods of contraception for this study. A male condom and female condom should 
not be used together (due to risk of failure from friction). 
For male study participants whose partner is a WOCBP, a barrier method, ie, a male condom or 
a female barrier contraceptive (eg, a cervical cap, diaphragm or sponge), in combination with 
a spermicide, is acceptable in this study. Male participants should be advised of the benefit for 
a female partner who is a WOCBP to use a highly effective method of contraception. 
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COLLECTION OF PREGNANCY INFORMATION: 
Male participants with partners who could 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 the IMP. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the Investigator will record pregnancy information on the appropriate form and 
submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the Sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
Female participants who could become pregnant 
• The Investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the Sponsor within 24 hours of learning 
of a participant's pregnancy. 
• The participant will be followed to determine the outcome of the pregnancy. The 
Investigator will collect follow-up information on the participant and the neonate and the 
information will be forwarded to the Sponsor. Generally, follow-up will not be required 
for longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of 
pregnancy will be reported, regardless of fetal status (presence or absence of anomalies) or 
indication for the procedure. 
• Any pregnancy complication or elective termination of a pregnancy for medical reasons 
will be reported as an AE or SAE. 
• A spontaneous abortion (occurring at 22 weeks gestational age) 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 the study intervention or be withdrawn from the study. 
10.5 APPENDIX 5: GENETICS  
Please refer to Section 8.5 for related information on an optional single blood collection for the 
isolation of DNA. 
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10.6 APPENDIX 6: LIVER AND OTHER SAFETY: ACTIONS AND FOLLOW-UP 
ASSESSMENTS   
These actions are required for ALT increase events ONLY. For all other safety events described, 
these are suggested per the Investigator’s medical judgement. 
 
Neutropenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting adverse events in Section 10.3 is met. 
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Thrombocytopenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting adverse events in Section 10.3 is met. 
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*If unable to retest in 72 hours, use original lab results to decide on further reporting/monitoring/discontinuation.  
** Unless a protocol-defined criterion for permanent discontinuation is met.  
*** See box below 
Note: 
• “Baseline” refers to ALT sampled at baseline visit; or if baseline value unavailable, to the latest ALT sampled before the baseline visit. The 
algorithm does not apply to the instances of increase in ALT during screening. 
• See Section 10.3 for guidance on safety reporting. 
 
 
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In ANY CONFIRMED CASE of ALT >5 × ULN, the following steps are REQUIRED 
(recommended for ALT between 3 - 5 × ULN, as clinically indicated): 
 
- 
INFORM the Site Monitor who will forward the information to the Study 
Manager 
- 
INVESTIGATE specifically for malaise with or without loss of consciousness, 
dizziness, and/or hypotension and/or episode of arrhythmia in the previous 
72 hours; rule out muscular injury 
- 
INVESTIGATE if any recent alcohol use or travel 
- 
INVESTIGATE if any use of non-prescription medications including herbal or 
dietary supplements 
- 
PERFORM the following tests:  
- 
Liver function test (LFT): AST, ALT, alkaline phosphatase, total and conjugated 
bilirubin, gamma-glutamyl transferase, and prothrombin time (PT)/international 
normalized ratio (INR) 
- 
CPK, serum creatinine, complete blood count 
- 
Anti-Hepatitis A virus IgM, Hepatitis B surface antigen, anti-Hepatitis B core 
IgM, (Hepatitis B virus-DNA if clinically indicated), anti-Hepatitis C virus 
(HCV) and HCV RNA, and anti-Hepatitis E virus IgM antibodies 
- 
Auto-antibodies: antinuclear, antineutrophil cytoplasmic antibodies, anti-double 
stranded DNA, anti-smooth muscle, anti-liver kidney microsome, anti-
mitochondrial 
- 
Evaluate recent infection with Epstein-Barr virus, cytomegalovirus, herpes 
viruses. Depending on the clinical context, consider testing for toxoplasma 
- 
Iron, ferritin, transferrin saturation 
- 
Collect and freeze serum sample (5 mL × 2) 
- 
Collect and store one PK sample following the instructions in the central 
laboratory manual 
- 
Hepatobiliary ultrasonography is mandatory (and other imaging investigations, as 
indicated). 
- 
CONSIDER DNA test for Gilbert’s disease if clinically indicated 
- 
CONSIDER consulting with a hepatologist (mandatory if ALT >8 x ULN or is 
associated with elevated bilirubin)  
- 
CONSIDER patient hospitalization if INR >2 (or PT <50%) and/or CNS 
disturbances suggesting hepatic encephalopathy  
- 
MONITOR LFTs after permanent discontinuation of IMP: 
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- 
Monitor as closely as possible (every 2-3 days) every week until ALT is down-
trending, then every week until ALT is < 2 × ULN, and then every scheduled 
visit. 
- 
This frequent LFT monitoring may be done through central or local lab, or via 
home visit (depending on the Investigator’s assessment and/or local regulatory 
requirements). 
• Rechallenge: Reinitiation of the study drug can only be considered when the 
ALT and AST both decrease below 2 × ULN (if baseline ALT ≤2 x ULN) or 
below baseline levels (if baseline ALT > 2 × ULN) and there is no clinical 
contraindication. In case the Investigator decides to restart the study drug, it is 
recommended that ALT/AST be assessed weekly for the first month and then 
monthly for the second and third months. The occurrence of new elevation 
above 3 × ULN for the ALT or AST values will lead to permanent 
discontinuation of the study drug. If liver injury is confirmed and determined 
to be related to the IMP, the rechallenge with the IMP is not permitted, and 
the participants must be permanently discontinued from IMP treatment.  
  
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Increase in serum creatinine is to be recorded as an AE only if at least 1 of the criteria listed in the 
general guidelines for reporting adverse events in Section 10.3 is met. 
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Increase in CPK is to be recorded as an AE only if at least 1 of the criteria in the general 
guidelines for reporting adverse events in Section 10.3 is met. 
10.7 APPENDIX 7: AES, ADES, SAES, SADES, USADES AND DEVICE DEFICIENCIES: 
DEFINITIONS AND PROCEDURES FOR RECORDING, EVALUATING, FOLLOW-UP, 
AND REPORTING IN MEDICAL DEVICE STUDIES  
Not applicable. 
10.8 APPENDIX 8: COUNTRY-SPECIFIC REQUIREMENTS  
The primary objectives and endpoints for both study parts will be unchanged for participants in 
China. The 
 and urine p75ECD will not be measured in China. 
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10.8.1 China  
10.8.1.1 Study objectives and endpoints  
Part A 
 
Objectives 
Endpoints 
Primary 
 
• 
To assess the effect of SAR443820 
compared to placebo in reducing ALS 
progression as measured by Amyotrophic 
Lateral Sclerosis Functional Rating 
Scale-Revised (ALSFRS-R)  
• 
Change from baseline in the ALSFRS-R total score to 
Week 24 
Secondary 
• 
To assess the effect of SAR443820 
compared to placebo on a combined 
assessment of function and survival, 
respiratory function, muscle strength, and 
quality of life (QoL) 
• 
Combined assessment of the function and survival (CAFS) 
score at Week 24 
• 
Change from baseline in slow vital capacity (SVC) to Week 24 
• 
Change from baseline in muscle strength to Week 24 
• 
Change from baseline in Amyotrophic Lateral Sclerosis 
Assessment Questionnaire (ALSAQ-5) to Week 24 
• 
To assess the pharmacodynamic (PD) 
effect of SAR443820 compared to 
placebo on a key disease biomarker 
• 
Change from baseline in serum neurofilament light chain (NfL) 
to Week 24 
• 
To assess the safety and tolerability of 
SAR443820 compared to placebo 
• 
Incidence of adverse events (AE), serious adverse events 
(SAE), treatment-emergent adverse events (TEAE), potentially 
clinically significant abnormalities (PCSA) in laboratory tests, 
electrocardiogram (ECG), and vital signs over 24 weeks 
• 
To assess the pharmacokinetics (PK) of 
SAR443820 
• 
Plasma concentration of SAR443820 
Tertiary 
 
 
• 
To assess the effects of SAR443820 
compared to placebo on other 
neurodegeneration and inflammation 
biomarkers 
• 
Change from baseline in soluble triggering receptor expressed 
on myeloid cells-2 (sTREM2) in plasma, chitinase-3-like 
protein-1 (CHI3L1), and a selected panel of cytokines and 
chemokines in serum to Week 24 
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Part B 
 
Objectives 
Endpoints 
Primary 
 
• 
To assess the long-term effects of 
SAR443820 on function and survival 
• 
Combined assessment of the function and survival (CAFS) 
score at Week 52 
Secondary 
• 
To assess the long-term effects of 
SAR443820 on disease progression, 
survival, respiratory function, and quality 
of life (QoL) 
• 
Combined assessment of the function and survival (CAFS) 
score at Week 76 and Week 104 
• 
Change from baseline in the ALSFRS-R total score to 
Week 52, Week 76, and Week 104 
• 
Time from baseline to the occurrence of either death or 
permanent assisted ventilation (>22 hours daily for 
>7 consecutive days), whichever comes first 
• 
Time from baseline to the occurrence of death  
• 
Change from baseline in slow vital capacity (SVC) to Week 52, 
Week 76, and Week 104 
• 
Change from baseline in Amyotrophic Lateral Sclerosis 
Assessment Questionnaire (ALSAQ-5) to Week 52, Week 76, 
and Week 104 
• 
To assess the long-term effect of 
SAR443820 on a key disease biomarker 
• 
Change from baseline in serum neurofilament light chain (NfL) 
to Week 52 
• 
To assess the long-term safety and 
tolerability of SAR443820 
• 
Incidence of adverse events (AE), serious adverse events 
(SAE), treatment-emergent adverse events (TEAE), potentially 
clinically significant abnormalities (PCSA) in laboratory tests, 
electrocardiogram (ECG), and vital signs during Part B 
• 
To assess the pharmacokinetics (PK) of 
SAR443820 
• 
Plasma concentration of SAR443820 
Tertiary 
SAR443820 
 
SAR443820 
 
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10.8.1.2 Sample storage and disposition of samples after study completion  
Blood samples for storage to support additional tertiary objectives beyond those in the study 
protocol will not be collected for participants in China. 
All samples from participants in China will be disposed of following completion of the CSR. 
10.8.2 Germany  
Informed consent process: All references to "legally authorized representative" are not applicable 
in Germany; only participants who can give written consent themselves are included in the study. 
References to "legally authorized representative" are found in Section 8.3 and Section 10.1.3. 
10.9 
APPENDIX 9: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY  
For European countries, contingency measures are currently only applicable for the COVID-19 
pandemic. 
The following contingencies may be implemented for the duration of the emergency (after 
Sponsor agreement is obtained). 
Study intervention 
The following contingencies may be implemented to make clinical supplies available to the 
participant for the duration of the emergency: 
• DTP supply of the IMP from the PI/site/Sponsor where allowed by local regulations and 
agreed upon by the participant. 
If a participant has to stop the IMP due to a regional or national emergency (eg, coronavirus 
disease-2019 [COVID-19]), reinitiation of the study intervention will be done under close and 
appropriate clinical/and or laboratory monitoring and following the instructions provided in 
Section 7.1.2. 
Study assessments and procedures 
During the emergency, if the site will be unable to adequately follow protocol-mandated 
procedures, alternative treatment outside the clinical trial should be proposed, and 
screening/enrollment/administration of the study intervention may be temporarily delayed. 
Attempts should be made to perform all assessments in accordance with the approved protocol to 
the fullest 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. 
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The following procedures are 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, a home health vendor, 
etc.) may be planned for the collection of possible safety and/or efficacy data, including 
1) collection of samples for screening and clinical safety analyses, 2) ECG and vital signs 
assessments, 3) AEs, and 4) phone-based ALSFRS-R. 
• If onsite visits are not possible, visit windows may be extended for assessments of safety 
and/or efficacy data that cannot be obtained remotely. 
• Use of local site or laboratory locations may be allowed when central laboratory 
assessments cannot be performed due to a government declared national emergency. 
Statistical analyses 
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 of the emergency on efficacy (eg, missing data due to the emergency) and safety will be 
detailed in the SAP. 
Informed consent 
For a regional or national emergency declared by a governmental agency, contingency procedures 
may be implemented for the duration of the emergency. The participant should be verbally 
informed prior to initiating any changes that are to be implemented for the duration of the 
emergency (eg, study visit delays/treatment extension, use of local laboratories). 
10.10 APPENDIX 10: STRONG AND MODERATE CYP3A4 INHIBITORS AND STRONG 
CYP3A4 INDUCERS  
Table 8 - Strong and moderate CYP3A4 inhibitors and strong CYP3A4 inducers  
Reason for exclusion 
Compound (INN) 
Therapeutic class 
Wash out period (day) 
Strong CYP3A4 inducer 
Apalutamide 
Antiandrogens 
21 
Avasimibe 
Other antilipemics 
5 
Phenobarbital 
Anticonvulsant 
20 
Phenytoin 
Anticonvulsant 
14 
Rifampin 
Antibiotics 
14 
Rifapentine 
Antibiotics 
14 
St John’s wort 
Herbal medicine 
14 
Carbamazepine 
Anticonvulsant 
14 
Enzalutamide 
Antiandrogens 
14 
Ivosidenib 
Cancer treatment 
19 
Lumacaftor 
Cystic fibrosis treatment 
14 
Mitotane 
Other antineoplastics 
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Reason for exclusion 
Compound (INN) 
Therapeutic class 
Wash out period (day) 
Strong or moderate CYP3A4 
inhibitor 
ACT-539313 
Hypnotic 
2 
ACT17882 
Renin inhibitor 
5 
Amprenavir 
Protease inhibitor 
10 
Aprepitant 
Antiemetics 
3 
Atazanavir, atazanavir/ritonavir 
Protease inhibitor 
9 
Berotralstat 
Cardiovascular drug 
20 
Boceprevir 
Antiviral 
8 
Casopitant 
Antiemetics 
11 
Cenotavir/ritonavir 
Antiviral 
9 
Ceritinib 
Kinase inhibitor 
10 
Cimetidine 
H-2 receptor antagonist 
8 
Ciprofloxacin 
Antibiotics 
1 
Clarithromycin 
Antibiotics 
8 
Cobicistat 
None 
8 
Conivaptan 
Diuretics 
9 
Crizotinib 
Kinase inhibitor 
16 
Danoprevir/ritonavir 
Antiviral 
9 
Darunavir, darunavir/ritonavir 
Protease inhibitor 
11 
Diltiazem 
Calcium channel blocker 
8 
Dronedarone 
Antiarrhythmic 
14 
Duvelisib 
Kinase Inhibitor 
9 
Elvitegravir/ritonavir 
AIDS treatment 
10 
Erythromycin 
Antibiotic 
8 
Faldaprevir 
Antiviral 
15 
Fedratinib 
Kinase inhibitor 
31 
FK1706 
Central nervous system agent 
15 
Fluconazole 
Antifungal 
7 
Grapefruit juice 
N/A 
9 
Idelalisib 
Kinase inhibitor 
2 
Imatinib 
Antineoplastic agent 
12 
Indinavir, indinavir/ritonavir 
Protease inhibitor 
9 
Isavuconazole 
Antifungal 
27 
Istradefylline 
Antiparkinsonian 
25 
Itraconazole 
Antifungal 
12 
Josamycin 
Antibiotic 
1 
Ketoconazole 
Antifungal 
8 
LCL161 
Cancer treatment 
2 
Lefamulin 
Antibiotic 
2 
Letermovir 
Antiviral 
10 
Lonafarnib 
Other 
9 
Lopinavir, lopinavir/ritonavir 
Protease inhibitor 
9 
Mibefradil 
Calcium channel blocker 
12 
Mifepristone 
Antiprogestins 
25 
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Reason for exclusion 
Compound (INN) 
Therapeutic class 
Wash out period (day) 
Nefazodone 
Antidepressant 
8 
Nelfinavir 
Protease inhibitor 
9 
Netupitant 
Antiemetic 
20 
Nilotinib 
Kinase inhibitor 
11 
Nirmatrelvir/ritonavir 
Antiviral 
9 
Posaconazole 
Antifungal 
14 
Ravuconazole 
Antifungal 
40 
Ribociclib 
Kinase inhibitor 
14 
Ritonavir 
Protease inhibitor 
9 
Saquinavir, saquinavir/ritonavir 
Protease inhibitor 
10 
Schisandra sphenanthera 
Herbal medicine 
21 
Telaprevir 
Antiviral 
10 
Telithromycin 
Antibiotic 
10 
Tipranavir/ritonavir 
Protease inhibitor 
9 
Tofisopam 
Benzodiazepine 
8 
Troleandomycin 
Antibiotic 
8 
Tucatinib 
Kinase Inhibitor 
9 
Verapamil 
Calcium channel blocker 
8 
Voriconazole 
Antifungal 
8 
Voxelotor 
Hemoglobin inhibitor 
8 
Please note that the lists provided are not exhaustive and that the product information of drugs intended for concomitant use should be 
consulted. 
10.11 APPENDIX 11: BLOOD VOLUME DETAILS  
 
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Part A 
 
 
Screening 
(mL) 
Day  
1  
(mL) 
Week 
2 
(mL) 
Week 
4 
(mL) 
Week 
6 
(mL) 
DNA 
Sampling#* 
(mL) 
Week 
8 
(mL) 
Week 
10 
(mL) 
Week 
12 
(mL) 
Week 
16 
(mL) 
Week 
20 
(mL) 
Week 
21 
(mL) 
Week 
22 
(mL) 
Week 
23 
(mL) 
Week 
24 
(mL) 
E/D* visit 
(unscheduled) 
(mL) 
China  
24.5 
26.5 
7.5 
5.5 
2.5 
NA 
16.5 
2.5 
2.5 
12.5 
2.5 
2.5 
2.5 
2.5 
12.5 
12.5 
Other 
countries  
26 
26.5 
7.5 
5.5 
2.5 
2 
16.5 
2.5 
2.5 
12.5 
2.5 
2.5 
2.5 
2.5 
12.5 
12.5 
Part B 
 
 
Week 
28  
(mL) 
Week 
30  
(mL)  
Week 
32 ( 
mL) 
Week 
34  
(mL) 
Week 
36  
(mL) 
Week 
40  
(mL)  
Week 
44  
(mL) 
Week 
52  
(mL) 
Week 
64  
(mL) 
Week 
76  
(mL) 
Week 
88  
(mL) 
Week 
104 
(mL) 
Last 
follow-up 
visit (mL) 
E/D* visit  
(unscheduled) 
(mL) 
All regions 
11 
2.5 
2.5 
2.5 
9 
2.5 
9 
9 
5.5 
5.5 
5.5 
5.5 
5.5 
9 
Abbreviations: DNA: deoxyribonucleic acid; E/D: early discontinuation; NA: not applicable. 
#Optional visit; can be performed at Week 2 or Week 4. 
*Optional or unscheduled visit; not counted in the total blood volume. 
Total blood volume including all required visits is approximately 202 mL in China and 198.5 mL in all other countries. Please note that there 
might be some additional blood withdrawal due to additional visit(s), retesting, or safety-related testing. 
 
 
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10.12 APPENDIX 12: ABBREVIATIONS  
 
AD: 
Alzheimer's disease 
AE: 
adverse event 
AESI: 
adverse event of special interest 
ALS: 
amyotrophic lateral sclerosis 
ALSAQ-5: 
Amyotrophic Lateral Sclerosis Assessment Scales - 5 items 
ALSFRS-R: 
Amyotrophic Lateral Sclerosis Functional Rating Scale Revised 
ALT: 
alanine aminotransferase 
AST: 
aspartate aminotransferase 
AUC: 
area under the curve 
BID: 
twice daily 
BMI: 
body mass index 
CAFS: 
combined assessment of function and survival 
CHI3L1: 
Chitinase-3-like protein 1 
CI: 
confidence interval 
Cmax: 
maximum plasma concentration 
CNS: 
central nervous system 
CPK: 
creatine phosphokinase 
CSF: 
cerebrospinal fluid 
CSICF: 
Core Study Informed Consent Form 
CSR: 
clinical study report 
C-SSRS: 
Columbia Suicide Severity Rating Scale 
CYP: 
cytochrome P450 
DMC: 
data monitoring committee 
DRE: 
disease-related event 
DTP: 
direct-to-patient 
ECG: 
electrocardiogram 
eCRF: 
electronic case report form 
 
FDA: 
Food and Drug Administration 
FSH: 
follicle-stimulating hormone 
GCP: 
Good Clinical Practice 
GFAP: 
glial fibrillary acidic protein 
G-tube: 
gastrostomy tube 
HBcAb: 
hepatitis B core antibodies 
HBsAg: 
Hepatitis B surface antigen 
 
HCV: 
Hepatitis C virus 
HIV: 
human immunodeficiency virus 
HRT: 
hormonal replacement therapy 
IB: 
Investigator’s Brochure 
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ICF: 
informed consent form 
ICH: 
International Council for Harmonisation 
IEC: 
Independent Ethics Committee 
IMP: 
investigational medicinal product 
INR: 
International normalized ratio 
IP-10: 
interferon gamma-induced protein-10 
IRB: 
Institutional Review Board 
IRT: 
interactive response technology 
ITT: 
intent-to-treat 
IV: 
intravenous 
LFT: 
Liver function test 
MAD: 
multiple ascending dose 
MAR: 
missing at random 
MCP: 
monocyte chemoattractant protein 
MIP: 
macrophage inflammatory protein 
MLKL: 
mixed lineage kinase domain-like pseudokinase 
MMRM: 
mixed-effect model with repeated measures 
MS: 
multiple sclerosis 
NfL: 
neurofilament light chain 
NIMP: 
noninvestigational medicinal product 
NOAEL: 
no-observed-adverse-effect-level 
OPTN: 
optineurin 
p75ECD: 
extracellular domain p75 
PBMC: 
peripheral blood mononuclear cell 
PBPK: 
physiological-based pharmacokinetic modeling and simulation 
PCSA: 
potentially clinically significant abnormality 
PD: 
pharmacodynamic 
PICC: 
peripherally inserted central catheter 
PK: 
pharmacokinetic 
PRO: 
patient-reported outcome 
PT: 
preferred term 
PT: 
Prothrombin Time 
QoL: 
quality of life 
QTLs: 
Quality tolerance limits 
RIPK1: 
receptor-interacting serine/threonine-protein kinase 1 
RIPK3: 
receptor-interacting serine/threonine-protein kinase 3 
SAD: 
single ascending dose 
SAE: 
serious adverse event 
SAP: 
Statistical Analysis Plan 
SD: 
standard deviation 
SE: 
standard error 
SoA: 
schedule of assessments 
sTREM2: 
soluble triggering receptor expressed on myeloid cells 2 
SUSAR: 
suspected unexpected serious adverse reaction 
SVC: 
slow vital capacity 
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TARC: 
thymus- and activation-regulated chemokine 
TBK1: 
TANK-binding kinase 1 
TEAE: 
treatment-emergent adverse event 
TNF-: 
tumor necrosis factor alpha 
ULN: 
upper limit of normal 
USA: 
United States of America 
VAS: 
visual analog scale 
WOCBP: 
woman of childbearing potential 
 
10.13 APPENDIX 13: PROTOCOL AMENDMENT HISTORY  
10.13.1 Amended protocol 04 (12 May 2023)  
This amended protocol (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 purpose of the protocol amendment 04 is to increase liver enzyme monitoring frequency 
to allow earlier detection of liver enzyme abnormality, if it occurs, and optimize our 
understanding on the safety profile of SAR443820. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis, 
1.2 Schema, 
1.3.1 Part A, 
1.3.2 Part B, 
4.1 Overall Design 
 
Added 5 visits which include a liver chemistry test at each 
visit following visit (Week 6, Week 10 in Part A and at 
Week 30, Week 34 and Week 40 in Part B). Blood 
samples can also be collected at home and can be tested 
at the central or local lab.  
To detect ALT increase early if it 
occurs and optimize our 
understanding on the safety 
profile of SAR443820 
1.3.1 Part A,  
1.3.2 Part B 
New footnotes were added  
To further describe parameters of 
assessment in the added visits 
10.11 Appendix 11 Blood 
volume details  
Part A  
Part B 
Blood volume updated due to increased visits in Part A 
(Week 6 and Week 10) and Part B (Week 30, Week 34 
and Week 40) 
To detect ALT increase early if it 
occurs and optimize our 
understanding on the safety 
profile of SAR443820 
10.13 Appendix 13: Protocol 
amendment history 
Order of appearance of amended protocols has been 
rearranged from newest to oldest  
Internal compliance rules  
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Section # and Name 
Description of Change 
Brief Rationale 
Protocol amendment 
Summary of Changes  
Summary of changes pertaining amendment 03 were 
moved to appendices 
Internal compliance rules  
10.13.2 Amended protocol 03 (06 March 2023)  
This amended protocol (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 purpose of the protocol amendment 03 is to include an additional liver laboratory 
monitoring at Week 12 in Part A and at Week 32 in Part B. Blood samples can also be collected at 
home and can be tested at the central or local lab. Also, an additional blood sample will be 
collected at baseline, which will be stored and may be used for future analysis, if needed, in case 
of an AE/SAE during the study. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis, 
1.2 Schema, 
1.3.1 Part A, 
1.3.2 Part B, 
4.1 Overall Design 
 
Updated Week 12 from phone call to site visit and added 
a liver chemistry test at Week 12 visit. Added a site visit 
at Week 32 which includes a liver chemistry test. Added 
instructions on sample collecting, testing and results 
reporting at Week 12 and Week 32 visits and updated the 
respective footnotes. Updated the study schema to 
modify Week 12 visit and added Week 32 visit.  
To increase liver monitoring as 
related to a Suspected 
Unexpected Serious Adverse 
Reaction (SUSAR) case of ALT 
and bilirubin increase 
1.3.1 Part A, 
10.11 Appendix 11: Blood 
Volume Details 
Added blood sample for archiving at baseline visit and 
updated the total blood volume details to include 
changes/addition for baseline, Week 12, and Week 32 
visits. 
Save the sample before IMP 
initiation for future analysis if 
needed in case of an AE/SAE 
during the study. 
6.8 Concomitant Therapy 
Updated the text to reflect that concomitant medications 
or substances that are strong or moderate inhibitors or 
strong inducers of CYP3A4 are not allowed within the 
specified wash out period, in stead of “5 half lives” as 
mentioned previously 
Correction 
8 Study Assessments and 
Procedures 
Added below text: 
• If onsite visits are not feasible (due to ALS progression, 
increased monitoring for AE follow-up, etc.), remote visits 
(eg, with home nurses, a home health vendor, a local 
clinic) may be planned for the collection of safety and/or 
efficacy data. 
To provide flexibility of 
assessment when it is not 
feasible for participants to 
conduct site visits 
8.9 Use of Biological Samples 
and Data for Future Research 
Added an example of future research 
Clarification 
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Section # and Name 
Description of Change 
Brief Rationale 
10.1.6 Dissemination of 
Clinical Study Data 
Replaced clinicaltrialregister (eu.ctr) by euclinicaltrials.eu, 
and clinicalstudydatarequest.com by vivli.org. 
Administrative change 
10.6 Appendix 6: Liver and 
Other Safety: Actions and 
Follow-Up Assessments 
Updated the appendix heading from: 
Appendix 6: Liver and other Safety: Suggested Actions 
and Follow-Up Assessments and Study Intervention 
Rechallenge Guidelines 
To: 
Appendix 6: Liver and Other Safety: Actions and 
Follow-Up Assessments 
To clarify that it is required to 
follow the procedure described in 
this appendix. 
Updated the algorithm graphical chart with increased 
frequency of ALT monitoring after ALT increase and 
updated the guidance text 
To ensure all listed tests for 
etiology analysis of ALT increase 
will be conducted and to increase 
the frequency of liver function 
monitoring after ALT increase.  
10.8.2 Germany 
Added new sub-section and text to reflect that adult 
patients would be eligible for study only if they are able to 
give written consent themselves 
And added cross reference to this sub-section in 
Section 10.1.3 
Update of local process 
10.9 Appendix 9: Contingency 
Measures for A Regional or 
National Emergency that is 
Declared by A Governmental 
Agency 
Added below text: 
For European countries contingency measures are 
currently only applicable for the COVID-19 pandemic. 
Update of local process 
10.10 Appendix 10: Strong 
and moderate CYP3A4 
inhibitors and strong CYP3A4 
inducers 
Added cenotavir/ritonavir and nirmatrelvir/ritonavir in the 
list of CYP3A4 inhibitors.  
Modified the washout period of medications which are 
mechanism based CYP3A4 inhibitors  
To update the list and correct the 
washout period of the 
medications  
Throughout 
Minor grammatical, stylistic, and minor typographical 
error corrections 
Editorial changes 
 
10.13.3 Amended protocol 02 (02 December 2022)  
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. 
OVERALL RATIONALE FOR THE AMENDMENT 
The main purpose of the protocol amendment 02 is to include the combination of sodium 
phenylbutyrate and taurursodiol (named Relyvrio® in the United States of America [USA] and 
Albrioza® in Canada) and oral edaravone as standard of care for ALS in countries where they 
have been approved. Some editorial and operational modifications are made. 
Protocol amendment summary of changes table 
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Section # and Name 
Description of Change 
Brief Rationale 
Synopsis 
Route of administration for edaravone is changed from 
“intravenous” to:” intravenous (IV) or oral” 
Adding the oral formulation as it 
has been approved in the United 
States of America and China 
Synopsis, Section 3 
Objectives and Endpoints, 
Section 10.8.1.1 Study 
objectives and endpoints 
In part B, deleting the text “before Week 52, Week 76, 
and Week 104” for the endpoints: time from baseline to 
the occurrence of either death or permanent assisted 
ventilation (>22 hours daily for >7 consecutive days), 
whichever comes first, time from baseline to the 
occurrence of death, time from baseline to the installation 
of a gastrostomy tube (G-tube) 
To use all available data up to the 
time of cutoff 
Synopsis, Section 1.3.1 
Schedule of Activities. Part A, 
Section 2.2 Background, 
Section 4.1 Overall design, 
Section 5.1 Inclusion criteria, 
Section 6.3 Measures to 
minimize bias: randomization 
and blinding, Section 6.8 
Concomitant therapy, Section 
7.1.1 Permanent 
discontinuation, Section 9.4.2 
Primary endpoint(s) in Part A, 
Section 9.4.3 Secondary 
endpoint(s) in Part A 
The texts for noninvestigational medicinal products are 
changed to include the combination of sodium 
phenylbutyrate and taurursodiol (taurursodiol is also 
known as ursodoxicoltaurine). 
 
The combination of sodium 
phenylbutyrate and taurursodiol is 
included as a standard of care for 
ALS in countries where it has 
been approved 
Synopsis, Section 9.4.2 
Primary endpoint(s) in Part A 
The sentence “The model will also include a random 
intercept and slope” is deleted 
Clarification of terms in the 
MMRM model 
Synopsis, Section 9.4.3 
Secondary endpoint(s) in 
Part A 
For the main secondary endpoints in Part A, the text for 
continuous variables is changed to include baseline NfL 
(if different from the baseline value of the endpoint), use 
of the combination of sodium phenylbutyrate and 
taurursodiol, baseline value of endpoint-by-visit 
interaction, and baseline NfL-by-visit interaction (if 
different from the baseline value of the endpoint-by-visit 
interaction). 
Clarification of terms in the 
MMRM model 
Synopsis, Section 9.4.2 
Primary endpoint(s) in Part A, 
Section 9.4.3 Secondary 
endpoint(s) in Part A 
For the primary analysis, the text for the mixed effect 
model with repeated measure is changed to include 
baseline neurofilament light chain (NfL), use of the 
combination of sodium phenylbutyrate and taurursodiol, 
baseline NfL-by-visit interaction and ALSFRS-R score-
by-visit interaction 
Clarification of terms in the 
MMRM model  
Section 1.3. Schedule of 
Activities. 
Dates of visits are corrected in the way how it is 
calculated during intervention period, Part A and Part B 
Align with actual calculation of the 
dates for visits during intervention 
period (Part A and Part B) 
 
IMP is added to the text “Early IMP discontinuation visit” 
Editorial clarification 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 2.3.1 Risk 
assessment 
Added potential risk of effects on pregnancy maintenance 
and embryo-fetal toxicity 
To align the wording of the 
protocol with the IB edition 6 
dated 15 June 2022, where this 
risk was already included. 
Section 5.1 Inclusion criteria 
Inclusion criterion I 09 is changed. The text: “at the 
screening visit” is added to the sentence: “Participants 
with a body weight no less than 45 kg and body mass 
index (BMI) no less than 18.0 kg/m2 at the screening 
visit.” 
Clarification of body weight and 
BMI assessments at the 
screening visit for inclusion into 
the study 
Section 5.2 Exclusion criteria 
Exclusion criterion E12 is changed. The text “and/or” is 
changed to “or” in the sentence: “sodium phenylbutyrate 
or taurursodiol” 
The combination of sodium 
phenylbutyrate and taurursodiol is 
now allowed 
 
In Exclusion criterion E16, HgBsAb is corrected to HBsAb 
Typo 
Section 6.8 Concomitant 
therapy 
The text “prior to the screening visit” is added to the 
sentence: “Participants are allowed to enter the study if 
they are either not receiving riluzole or receiving stable 
doses of riluzole for at least 4 weeks prior to the 
screening visit” 
Clarification of participants 
treated with riluzole who may 
enter the study 
 
The text “Switching between IV and oral formulation of 
edaravone in the countries where both formulations have 
been approved is allowed at any time during the study.” 
is added 
Clarification on the route of 
administration for edaravone 
Appendix 13 Section 10.13 
Updated to include the amendment history of amended 
protocol 01 
To refer to previous amended 
protocol 
Throughout the document 
Other minor editorial changes (eg, grammatical, stylistic, 
and minor typographical corrections). 
To increase the clarity or 
consistency of the protocol. 
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10.13.4 Amended protocol 01 (07 April 2022)  
This amended protocol (amendment 01) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union. 
OVERALL RATIONALE FOR THE AMENDMENT 
The main purpose of the protocol amendment 01 is to provide monthly pregnancy test for female 
participants of childbearing potential, to modify the criterion for IMP reinitiation, and to address 
health authority requests. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Title Page  
Updated IND number from: 15444 
To: 151444. 
Error correction 
Title Page  
Updated NCT number as NCT05237284. 
Update 
1.1 Synopsis  
(Main Secondary; endpoints in Part A);  
3 Objectives and Endpoints (Part A);  
9.4.3 Secondary endpoint(s) in Part A; 
10.8.1.1 Study objectives and endpoints 
(Part A)  
Clarify the secondary endpoint, muscle strength 
will be analyzed as the change from baseline to 
Week 24. 
Clarification 
1.1 Synopsis (Brief summary and 
Intervention groups and duration);  
4.1 Overall design; Part A 
Reworded to clarify that All ongoing participants in 
Part A will rollover to Part B. 
To clarify the request for 
participants to rollover from 
Part A to Part B 
1.1 Synopsis (Brief summary);  
4.1 Overall design; Part B 
Reworded to clarify that participants who 
permanently discontinue IMP in Part A will not 
receive SAR443820 in Part B. 
Clarification 
1.1 Synopsis (Rationale);  
2.1 Study Rationale 
The text “In summary, both preclinical and clinical 
studies have affirmed RIPK1 is a key mediator of 
necroptosis and inflammatory pathways in ALS.” 
has been modified to “In summary, both preclinical 
and patient-derived data have suggested RIPK1 
may be a key mediator of necroptosis and 
inflammatory pathways in ALS.” 
To be specific on the 
evidence supporting the 
study rationale  
1 .1 Synopsis (Intervention groups and 
duration);  
2.3.3 Overall benefit/risk conclusion; 
6.8 Concomitant therapy 
Updated from “November 2021” to “April 2022” on 
the available standard of care. 
Update 
1.3 Schedule of Activities, Part A 
Instruction on IMP dosing at Week 24 has been 
added in footnote a (Part A). 
Clarification 
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Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of Activities Part A;  
8.2.3 Vital signs 
Footnote ‘j’ added and details in Section 8.2.3 was 
reworded to provide instruction on when vital 
signs will be measured after first dose of IMP on 
Day 1. 
Clarification 
1.3 Schedule of Activities, Part A and 
Part B 
In footnote b (Part A) and footnote c (Part B), 
‘discontinue from the study early’ has been 
replaced by ‘prematurely discontinue IMP’. 
To clarify the participants 
who are required to take 
early discontinuation visit 
1.3 Schedule of Activities, Part A and 
Part B; 
8.2.6 Pregnancy testing 
New footnote ‘o’ (Part A) and footnote ‘l’ (Part B) 
have been added to include instructions on 
pregnancy test.  
To increase pregnancy test 
frequency to monthly since 
complete definite embryo-
fetal study results are not 
available yet 
1.3 Schedule of Activities, Part A 
Procedure ‘HHD’was replaced with ‘Muscle 
strength’ and a new footnote ‘q’ (Part A) have 
been added to include instructions on measuring 
muscle strength. 
Adding hand grip in the 
muscle strength 
measurement 
2 .3.1 Table 1 Risk assessment  
Summary of data/rationale for risk related to 
convulsion was updated to include following text: 
No convulsions have been observed up to the 
dose level of 
mg/kg/day in both the 3-month 
and 9-month studies. 
Preclinical data update 
 
Mitigation strategy for convulsion was updated to 
include The following text: participants weighing 
<45 kg. 
Clarification 
 
Summary of data/rationale for risk related to 
Immunomodulatory Effects was updated to 
include “9-month” for the nonhuman primate 
studies. 
Preclinical data update 
2.3.3 Overall benefit/risk conclusion 
 
Updated with reference to 
completed first-in-human 
Phase 1 study result 
3 Objectives and Endpoints, Part B 
‘Week 102’ has been corrected to ‘Week 104’. 
Correction of typographical 
error 
5.2 Exclusion Criteria 
The following text has been added to E 03: 
“other causes of neuromuscular weakness” 
Clarification 
 
The following text has been added to E 12: 
“(eg, sodium phenylbutyrate and/or taurursodiol)”. 
Clarification 
5.3.1 Meals and dietary restrictions 
Information was updated to clarify that participants 
should be prohibited from consuming grapefruit 
and grapefruit juices from 5 days before the start 
of the study intervention until 2 days after the final 
dose. 
To avoid effect of grapefruit 
on SAR443820 metabolism 
as SAR443820 is mainly 
metabolized by CYP3A4 
and grapefruit is a strong 
inhibitor of CYP3A4  
6.1 Study Intervention(s) Administered 
The instruction on drug administration has been 
modified to add details on the volume of water to 
use and how to mix the tablet with water. 
To keep the instruction on 
drug administration 
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Section # and Name 
Description of Change 
Brief Rationale 
consistent between protocol 
and pharmacy manual 
7.1.1 Permanent Discontinuation 
Initiation of riluzole and/or edaravone during Part 
A was added as one of the criteria for study 
discontinuation. 
To emphasize the criteria of 
study discontinuation 
 
The text in “Handling of participants after 
permanent intervention discontinuation” was 
updated to clarify that participants who 
prematurely discontinue the IMP will be 
encouraged to continue the rest of study visits for 
safety and efficacy assessments up to the last 
scheduled visit. 
To be aligned with the 
intent-to-treat (ITT) analysis 
strategy 
7.1.2.1 Study intervention restart or 
rechallenge after temporary 
discontinuation of study intervention 
Any content related to the request of Sponsor 
approval to restart/rechallenge IMP has been 
deleted 
To be aligned with ICH GCP 
guidance that investigator is 
responsible for all 
trial-related medical 
decisions 
 
If required “based on local practice” has been 
added after “Ethics Committee and/or Institutional 
Review Board (IRB) approval is obtained” 
To provide flexibility on the 
request of IRB approval 
 
“In case of confirmed liver injury caused by the 
IMP, the rechallenge with the IMP is not permitted 
and the participants must be permanently 
discontinued from IMP treatment.” has been 
added. 
To emphasize confirmed 
IMP-induced liver injury will 
lead to permanent 
discontinuation of IMP 
8.1.3 Muscle strength measurement 
Heading title for Section 8.1.3 updated from 
“Handheld dynamometry (HHD)”  to  “Muscle 
strength measurement and the following text of 
“Bilateral hand grip will be measured using a grip 
dynamometer and all other muscles included in 
this study will be measured using a handheld 
dynamometer.” was added  
Adding hand grip in the 
muscle strength 
measurement 
8.3.7 Disease-related events and/or 
disease-related outcomes not qualifying 
as AEs or SAEs 
Disease-related events and disease-related 
outcomes have been defined and examples 
provided. 
Clarification 
8.3.8 Adverse event of special interest 
The criterion of overdose has been updated. 
Correction of error 
 
Reworded to clarify two AESI: serious infection 
and ALT increase. 
Clarification 
8.5 Genetics and/or pharmacogenomics 
Added following text for an optional blood 
collection for isolation of DNA: “single”. 
Clarification 
8.6 Biomarkers 
Sample storage period was updated from ‘15 
years’ to ‘5 years’ when the samples will be used 
only for clinical study related testing. 
To clarify how long the 
sample will be stored for the 
clinical study related testing 
8.9 Use Of Biological Samples And Data 
For Future Research 
Reworded to clarify the purpose of future 
research. 
Clarification 
9.1 Statistical Hypothesis 
Added new section to explain the statistical 
hypothesis.  
To provide clarity on 
statistical hypothesis based 
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Section # and Name 
Description of Change 
Brief Rationale 
on request from 
Pharmaceuticals and 
Medical Devices Agency in 
Japan 
 
“The study will be declared positive if the null 
hypothesis for the primary endpoint in Part A 
change from baseline in the ALSFRS-R total 
score to Week 24 (end of Part A) for SAR443820 
versus placebo is rejected in the primary 
analysis.” has been added. 
To add declaration of 
success 
9.5 Interim Analyses 
Added text to clarify when interim analysis will be 
conducted. 
To provide clarity on interim 
analysis 
10.1.7 Data quality assurance 
Added description on how quality tolerance limits 
(QTLs) will be managed in the study. 
Clarification 
10.6 Appendix 6 
Instructions on ALT increase have been added 
following the “Increase in ALT algorithm”. 
To provide detailed 
instruction on ALT increase 
10.11 Appendix 11 
Added a new appendix for blood volume details. 
Clarification 
Throughout the document 
Editorial changes. 
Grammatical corrections 
 
 
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11 
REFERENCES  
  
1. Geevasinga N, Menon P, Özdinler PH, Kiernan MC, Vucic S. Pathophysiological and 
diagnostic implications of cortical dysfunction in ALS. Nat Rev Neurol. 2016;12(11):651‑61. 
2. Kelliher MA, Seldin DC, Leder P. Tal-1 induces T cell acute lymphoblastic leukemia 
accelerated by casein kinase IIalpha. EMBO J. 1996;15(19):5160‑6. 
3. Ting AT, Pimentel-Muiños FX, Seed B. RIP mediates tumor necrosis factor receptor 1 
activation of NF‑kappaB but not Fas/APO‑1‑initiated apoptosis. EMBO J. 
1996;15(22):6189‑96. 
4. Degterev A, Hitomi J, Germscheid M, Ch'en IL, Korkina O, Teng X, et al. Identification of 
RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol. 2008;4(5):313‑21. 
5. Re DB, Le Verche V, Yu C, Amoroso MW, Politi KA, Phana S, et al. Necroptosis drives 
motor neuron death in models of both sporadic and familial ALS. Neuron. 2014;81(5):1001‑8. 
6. Cougnoux A, Cluzeau C, Mitra S, Li R, Williams I, Burkert K, et al. Necroptosis in Niemann-
Pick disease, type C1: a potential therapeutic target. Cell Death Dis. 2016;7(3):e2147. 
7. Ofengeim D, Ito Y, Najafov A, Zhang Y, Shan B, Park DeWitt J, et al. Activation of 
necroptosis in multiple sclerosis. Cell Rep. 2015;10(11):1836‑49. 
8. Ito Y, Ofengeim D, Najafov A, Das S, Saberi S, Li Y, et al. RIPK1 mediates axonal 
degeneration by promoting inflammation and necrosis in ALS. Science. 
2016;353(6299):603‑8. 
9. Su X, Wang H, Kang D, Zhu J, Sun Q, Ki T, et al. Necrostatin-1 ameliorates intracerebral 
hemorrhage‑induced brain injury in mice through inhibiting RIP1/RIP3 pathway. Neurochem 
Res. 2015;40(4):643‑50. 
10. Liu M, Wu W, Li H, Li S, Huang L, Yang Y, et al. Necroptosis, a novel type of programmed 
cell death, contributes to early neural cells damage after spinal cord injury in adult mice. J 
Spinal Cord Med. 2015;38(6):745‑53. 
11. Ofengeim D, Mazzitelli S, Ito Y, Park DeWitt J, Mifflin L, Zou C, et al. RIPK1 mediates a 
disease-associated microglial response in Alzheimer’s disease. Proc Natl Acad Sci U S A. 
2017;114(41):E8788‑97. 
12. Freischmidt A, Wieland T, Richter B, Ruf W, Schaeffer V, Müller K, et al. Haploinsufficiency 
of TBK1 causes familial ALS and fronto‑temporal dementia. Nat Neurosci. 2015;18(5):631‑6. 
13. Xu D, Jin T, Zhu H, Chen H, Ofengeim D, Zou C, et al. TBK1 suppresses RIPK1‑driven 
apoptosis and inflammation during development and in aging. Cell. 2018;174(6):1477‑91. 
14. FDA 2019 Guidance Amyotrophic Lateral Sclerosis: Developing Drugs for Treatment. 
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15. Berry JD, Miller R, Moore DH, Cudkowicz ME, van den Berg LH, Kerr DA, et al. The 
Combined Assessment of Function and Survival (CAFS): a new endpoint for ALS clinical 
trials. Amyotroph Lateral Scler Frontotemporal Degener. 2013;14(3):162‑8. 
16. EMA 2015 Guideline on clinical investigation of medicinal products for the treatment of 
amyotrophic lateral sclerosis (ALS). 
17. Andrews JA, Meng L, Kulke SF, Rudnicki SA, Wolff AA, Bozik ME, et al. Association 
between decline in slow vital capacity and respiratory insufficiency, use of assisted 
ventilation, tracheostomy, or death in patients with amyotrophic lateral sclerosis. JAMA 
Neurol. 2018;75(1):58‑64. 
18. Gołąb‑Janowska M, Honczarenko K, Stankiewicz J. Usefulness of the ALSAQ‑5 scale in 
evaluation of quality of life in amyotrophic lateral sclerosis. Neurol Neurochir Pol. 
2010;44(6):560‑6. 
19. Jenkinson C, Fitzpatrick R. Reduced item set for the amyotrophic lateral sclerosis assessment 
questionnaire: development and validation of the ALSAQ‑5. J Neurol Neurosurg Psychiatry. 
2001;70(1):70‑3. 
20. Herdman M, Gudex C, Lloyd A, Janssen M, Kind P, Parkin D, et al. Development and 
preliminary testing of the new five‑level version of EQ‑5D (EQ‑5D‑5L). Qual Life Res. 
2011;20(10):1727‑36. 
21. Huang F, Zhu Y, Hsiao-Nakamoto J, Tang X, Dugas JC, Moscovitch-Lopatin M, et al. 
Longitudinal biomarkers in amyotrophic lateral sclerosis. Ann Clin Transl Neurol. 
2020;7(7):1103‑16. 
22. Brooks BR, Miller RG, Swash M, Munsat TL; World Federation of Neurology Research 
Group on Motor Neuron Diseases. El Escorial revisited: revised criteria for the diagnosis of 
amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 
2000;1(5):293‑9. 
23. Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B, et al; BDNF ALS Study 
Group (Phase III). The ALSFRS‑R: a revised ALS functional rating scale that incorporates 
assessments of respiratory function. J Neurol Sci. 1999;169(1-2):13‑21. 
24. Kaufmann P, Levy G, Montes J, Buchsbaum R, Barsdorf AI, Battista V, et al. Excellent 
inter‑rater, intra‑rater, and telephone‑administered reliability of the ALSFRS‑R in a 
multicenter clinical trial. Amyotroph Lateral Scler. 2007;8(1):42‑6. 
25. Knudson RJ, Lebowitz MD, Holberg CJ, Burrows B. Changes in the normal maximal 
expiratory flow-volume curve with growth and aging. Am Rev Respir Dis. 
1983;127(6):725‑34. 
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26. Shefner JM, Liu D, Leitner ML, Schoenfeld D, Johns DR, Ferguson T, et al. Quantitative 
strength testing in ALS clinical trials. Neurology. 2016;87(6):617‑24. 
27. The Criteria Committee of the New York Heart Association Nomenclature and Criteria for 
Diagnosis of Diseases of the Heart and Great Vessels. 9th Edition, Little, Brown & Co, 
Boston, Mass. 1994;253-6. 
28. Criteria Committee, New York Heart Association, Inc. Disease of the Heart and Blood 
Vessels. Nomenclature and Criteria for diagnosis, 6th edition, Boston, Little, Brown & Co. 
1964;114.  
 
 
 
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SAP_001.pdf: 
 
 
 
Any and all information presented in this document shall be treated as confidential and shall remain the exclusive 
property of Sanofi (or any of its 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: Sanofi eSAP Version 2.0, dated 20-OCT-2021 
 Page 1 
 
 
 
STATISTICAL ANALYSIS PLAN  
Protocol title: 
A Phase 2, multicenter, randomized, double-blind, placebo-
controlled study to evaluate the efficacy and safety of 
SAR443820 in adult participants with amyotrophic lateral 
sclerosis, followed by an open-label extension 
Protocol number: 
ACT16970 
Compound number 
(INN/Trademark): 
SAR443820 
Not applicable 
Study phase: 
Phase 2 
Short Title: 
Phase 2 study for SAR443820 in participants with 
amyotrophic lateral sclerosis (ALS) 
HIMALAYA 
Statistician: 
 
Statistical project leader: 
 
Date of issue: 
08-Jan-2024 
Regulatory agency identifier number(s): 
IND: 
151444 
EudraCT: 
2021-004156-42 
NCT: 
NCT05237284 
WHO: 
U1111-1263-5766 
EUDAMED: 
N/A 
Other: 
N/A 
 
: 
08-Jan-2024 
Total number of pages: 47 
 
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Statistical Analysis Plan  
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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN .........................................................................................................1 
TABLE OF CONTENTS ........................................................................................................................2 
LIST OF TABLES .................................................................................................................................4 
VERSION HISTORY .............................................................................................................................5 
1 
INTRODUCTION....................................................................................................................6 
1.1 
STUDY DESIGN ....................................................................................................................6 
1.2 
OBJECTIVES AND ENDPOINTS ..........................................................................................7 
1.2.1 
Estimands ..............................................................................................................................9 
2 
ANALYSIS POPULATIONS ............................................................................................... 12 
3 
STATISTICAL ANALYSES ................................................................................................ 13 
3.1 
GENERAL CONSIDERATIONS ......................................................................................... 13 
3.2 
PRIMARY ENDPOINT(S) ANALYSIS................................................................................. 14 
3.2.1 
Definition of endpoint(s) ...................................................................................................... 14 
3.2.2 
Main analytical approach .................................................................................................... 15 
3.2.3 
Sensitivity analyses ............................................................................................................. 16 
3.2.4 
Supplementary analyses for primary endpoint in Part A..................................................... 17 
3.2.5 
Subgroup analyses for primary endpoint in Part A ............................................................. 17 
3.3 
SECONDARY ENDPOINT(S) ANALYSIS .......................................................................... 18 
3.3.1 
Secondary endpoint(s) ........................................................................................................ 19 
3.3.1.1 
Definition of endpoint(s) ...................................................................................................... 19 
3.3.1.2 
Main analytical approach .................................................................................................... 21 
3.3.1.3 
Sensitivity analyses ............................................................................................................. 22 
3.4 
TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS ................................................... 23 
3.4.1 
Definition of endpoint(s) ...................................................................................................... 24 
3.4.2 
Main analytical approach .................................................................................................... 24 
3.4.3 
Comparison with external control ........................................................................................ 25 
3.5 
MULTIPLICITY ISSUES ..................................................................................................... 26 
3.6 
SAFETY ANALYSES .......................................................................................................... 27 
3.6.1 
Extent of exposure .............................................................................................................. 28 
3.6.2 
Adverse events ................................................................................................................... 29 
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3.6.3 
Additional safety assessments ............................................................................................ 32 
3.6.3.1 
Laboratory variables, vital signs and electrocardiograms (ECGs) ...................................... 32 
3.6.3.2 
Analysis of suicidality assessment ...................................................................................... 34 
3.7 
OTHER ANALYSES ........................................................................................................... 34 
3.7.1 
Other variables and/or parameters ..................................................................................... 34 
3.7.1.1 
Pharmacokinetic (PK) analyses .......................................................................................... 34 
3.7.1.2 
Pharmacodynamic (PD) analyses ....................................................................................... 34 
3.7.1.3 
PK/PD analysis ................................................................................................................... 35 
3.8 
INTERIM ANALYSES ......................................................................................................... 35 
3.9 
CHANGES TO PROTOCOL-PLANNED ANALYSES......................................................... 35 
4 
SAMPLE SIZE DETERMINATION ..................................................................................... 37 
5 
SUPPORTING DOCUMENTATION ................................................................................... 38 
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS .......................................................................... 38 
5.2 
APPENDIX 2 PARTICIPANT DISPOSITIONS ................................................................... 38 
5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS ....................................................................................... 40 
5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS ............................................................. 42 
6 
REFERENCES.................................................................................................................... 47 
 
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LIST OF TABLES  
Table 1 - Objectives and endpoints ................................................................................................................. 7 
Table 2 - Summary of primary estimand for main endpoints ........................................................................ 10 
Table 3 - Populations for analyses ................................................................................................................ 12 
Table 4 - Sorting of AE tables ....................................................................................................................... 30 
Table 5 - Analyses of adverse events ........................................................................................................... 31 
Table 6 - Selections for AESIs ...................................................................................................................... 32 
Table 7 - Analyses window definition of efficacy variables ........................................................................... 42 
Table 8 - Analyses window definition of safety variables .............................................................................. 43 
Table 9 - Analyses window definition of PD variables ................................................................................... 45 
 
 
 
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Statistical Analysis Plan  
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Page 5 
VERSION HISTORY  
This amended statistical analysis plan (SAP) for study ACT16970 is based on the Amended 
Clinical Trial Protocol 05 dated 13-Dec-2023. The first participant was randomized on 
28-Apr-2022. The initial SAP V1 was approved before the interim analysis for futility was 
conducted.  This amended SAP is approved before the first database lock.  
Major changes in statistical analysis plan 
SAP Version 
Approval Date 
Changes from Protocol Amendment  
Rationale 
1 
28-Apr-2023 
Disease duration (from first symptom onset to the 
screening visit) and the corresponding by-visit interaction 
are added as covariates in the Part A primary analysis 
model.  
Based on clinical input 
 
 
. Instead, 
each of the 5 dimensions will be included in the analysis.   
Index score is not really 
used for 
regulatory/clinical 
development purposes 
2 
08-Jan-2024 
MMRM will be applied to the complete datasets after 
multiple imputation instead of ANCOVA in the sensitivity 
analysis of the primary endpoint in Part A. 
Based on FDA feedback 
 
 
Based on FDA feedback 
 
 
Update megascore derivation if there are missing 
measurements  
Clarification 
 
 
Add the analysis of grip strength and its derivation  
Clarification 
Additional changes have been made to improve clarity and consistency. 
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1 
INTRODUCTION  
1.1 
STUDY DESIGN  
This is a Phase 2, multicenter, randomized, double-blind, placebo-controlled, 2 parallel-group 
study to evaluate the efficacy and safety of SAR443820 in adult participants with amyotrophic 
lateral sclerosis, followed by an open-label extension.  
Part A is a 24-week, double-blind, placebo-controlled part, preceded by a screening period of up 
to 4 weeks before Day 1. After a screening phase of up to 4 weeks, participants will be 
randomized in a ratio of 2:1 to receive 20 mg BID SAR443820 (n=174) or placebo BID (n=87). 
Randomization will be stratified by the geographic region of the study site (Asia, Europe or North 
America), region of ALS onset (bulbar or other areas), use of riluzole (yes or no), use of 
edaravone (yes or no), and use of the combination of sodium phenylbutyrate and taurursodiol 
(named Relyvrio in the USA and Albrioza in Canada) (yes or no). Participants will attend in-clinic 
study assessments at baseline (Day 1), Week 2, Week 4, Week 6, Week 8, Week 10, Week 12, 
Week 16, Week 20 and Week 24. All ongoing participants at Week 24 will rollover to open-label 
extension Part B. Participants who discontinue the treatment or choose not to enter Part B will 
have their follow up visit 2 weeks after the last dose of the study intervention. 
Part B is an open-label, long-term extension of Part A, which starts from Week 24 and continues 
up to Week 106. The study intervention assignment of participants at randomization in Part A will 
remain blinded to Investigators, participants, and site personnel until the end of Part B unless 
there is medical need to unblind the study intervention assignment. All participants will receive 
20 mg BID SAR443820 in Part B starting from Week 24, except those who discontinue IMP 
treatment permanently in Part A. Based on a data review, and in accordance with Data Monitoring 
Committee (DMC) recommendations, sites have been instructed on 5th December 2023 to pause 
the administration of SAR443820 in Part B (open-label extension) immediately. All participants 
in Part B will be encouraged to continue follow-up visits, but no doses of SAR443820 should be 
administered. Rollover to Part B for follow-up visits after completing Part A is also encouraged, 
but without taking SAR443820 in Part B. The decision of whether resuming SAR443820 
administration in Part B will be made based on DMC recommendation when Part A data is 
available and benefit risk evaluation is made. 
The study duration includes an up to 4-week screening period, 24-week double-blind treatment 
period in Part A, 80-week open-label treatment period (Part B) and 2-week post-treatment 
follow-up period, with a maximum total study duration of 110 weeks. 
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1.2 
OBJECTIVES AND ENDPOINTS  
Table 1 - Objectives and endpoints  
Part A 
Objectives 
Endpoints 
Primary 
• 
To assess the effect of SAR443820 compared to 
placebo in reducing ALS progression as measured 
by the Amyotrophic Lateral Sclerosis Functional 
Rating Scale Revised (ALSFRS-R) 
• 
Change from baseline in the ALSFRS-R total score 
to Week 24 
Secondary 
• 
To assess the effect of SAR443820 compared to 
placebo on a combined assessment of function and 
survival, respiratory function, muscle strength, and 
quality of life (QoL) 
• 
Combined assessment of the function and survival 
(CAFS) score at Week 24 
• 
Change from baseline in slow vital capacity (SVC) 
to Week 24 
• 
Change from baseline in muscle strength to 
Week 24 
• 
Change from baseline in Amyotrophic Lateral 
Sclerosis Assessment Questionnaire (ALSAQ-5) to 
Week 24 
• 
To assess the pharmacodynamic (PD) effect of 
SAR443820 compared to placebo on a key disease 
biomarker 
• 
Change from baseline in serum neurofilament light 
chain (NfL) to Week 24 
• 
To assess the safety and tolerability of SAR443820 
compared to placebo 
• 
Incidence of adverse events (AE), serious adverse 
events (SAE), treatment-emergent adverse events 
(TEAE), potentially clinically significant 
abnormalities (PCSA) in laboratory tests, 
electrocardiogram (ECG), and vital signs over 
24 weeks 
• 
To assess the pharmacokinetics (PK) of 
SAR443820 
• 
Plasma concentration of SAR443820 
 
SAR443820 
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Objectives 
Endpoints 
 
• 
To assess the effects of SAR443820 compared to 
placebo on neurodegeneration and inflammation 
disease biomarkers 
• 
Change from baseline in soluble triggering receptor 
expressed on myeloid cells-2 (sTREM2) in plasma 
chitinase-3-like protein-1 (CHI3L1), a selected panel 
of cytokines and chemokines in serum, and 
extracellular domain of p75 (p75ECD) in urine to 
Week 24 
 
Part B 
Objectives 
Endpoints 
Primary 
 
• 
To assess the long-term effects of SAR443820 on 
function and survival 
• 
Combined assessment of the function and survival 
(CAFS) score at Week 52 
Secondary 
• 
To assess the long-term effects of SAR443820 on 
disease progression, survival, respiratory function, 
and quality of life (QoL) 
• 
Combined assessment of the function and survival 
(CAFS) score at Week 76 and Week 104 
• 
Change from baseline in the ALSFRS-R total score 
to Week 52, Week 76, and Week 104 
• 
Time from baseline to the occurrence of either 
death or permanent assisted ventilation (>22 hours 
daily for >7 consecutive days), whichever comes 
first 
• 
Time from baseline to the occurrence of death  
• 
Change from baseline in slow vital capacity (SVC) 
to Week 52, Week 76, and Week 104 
• 
Change from baseline in Amyotrophic Lateral 
Sclerosis Assessment Questionnaire (ALSAQ-5) to 
Week 52, Week 76, and Week 104 
• 
To assess the long-term effect of SAR443820 on a 
key disease biomarker 
• 
Change from baseline in serum neurofilament light 
chain (NfL) to Week 52 
• 
To assess the long-term safety and tolerability of 
SAR443820 
• 
Incidence of adverse events (AE), serious adverse 
events (SAE), treatment-emergent adverse events 
(TEAE), potentially clinically significant 
abnormalities (PCSA) in laboratory tests, 
electrocardiogram (ECG), and vital signs during 
Part B 
• 
To assess the pharmacokinetics (PK) of 
SAR443820 
• 
Plasma concentration of SAR443820 
Tertiary 
 SAR443820 
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Objectives 
Endpoints 
SAR443820 
  
1.2.1 Estimands  
Primary estimands defined for main endpoints in Part A are summarized in below Table 2. More 
details are provided in Section 3. 
For all these estimands, the comparison of interest will be the comparison of  SAR443820 vs. 
placebo. 
 
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Table 2 - Summary of primary estimand for main endpoints  
Endpoint 
Category 
(estimand) 
Estimands 
Endpoint 
Population 
Intercurrent event(s) handling strategy 
Population-level summary  
(Analysis and missing data handling) 
Primary objective: To assess the effect of SAR443820 compared to placebo in reducing ALS progression as measured by the Amyotrophic Lateral Sclerosis 
Functional Rating Scale Revised (ALSFRS-R) 
Primary endpoint 
(treatment policy) 
Change from baseline in 
the ALSFRS-R total score 
to Week 24 
ITT 
Permanent study intervention discontinuation 
before Week 24 – regardless of treatment 
discontinuation (treatment policy)  
The primary endpoint will be analyzed using MMRM with change 
from baseline in ALSFRS-R total score up to Week 24 as 
response variable, and treatment, visit, randomization strata of 
the geographic region of the study site, ALS onset region (bulbar 
or other areas), use of riluzole (yes or no), use of edaravone 
(yes or no), use of the combination of sodium phenylbutyrate 
and taurursodiol (yes or no), treatment-by-visit interaction, 
disease duration (from first symptom onset to the screening 
visit), baseline ALSFRS-R score, baseline NfL, disease duration-
by-visit interaction, baseline NfL-by-visit interaction and baseline 
ALSFRS-R score-by-visit interaction as covariates. 
All available data will be used, and missing data will be handled 
by MMRM based on missing at random assumption. 
Secondary 
endpoints 
(treatment policy) 
Combined assessment of 
the function and survival 
(CAFS) score at Week 24 
mITT 
Permanent study intervention discontinuation 
before Week 24 – regardless of treatment 
discontinuation (treatment policy) 
CAFS at Week 24 will be analyzed using the Wilcoxon-Mann-
Whitney test to compare mean scores between the treatment 
groups at Week 24. 
 
Change from baseline in 
slow vital capacity (SVC) 
(muscle strength, 
Amyotrophic Lateral 
Sclerosis Assessment 
Questionnaire (ALSAQ-5), 
serum neurofilament light 
chain (NfL)) to Week 24 
ITT 
Permanent study intervention discontinuation 
before Week 24 – regardless of treatment 
discontinuation (treatment policy) 
These secondary endpoints will be analyzed using MMRM with 
change from baseline value up to Week 24 as response variable, 
and treatment, visit, randomization strata of the geographic 
region of the study site, ALS onset region (bulbar or other 
areas), use of riluzole (yes or no), use of edaravone (yes or no), 
use of the combination of sodium phenylbutyrate and 
taurursodiol (yes or no), treatment-by-visit interaction, disease 
duration (from first symptom onset to the screening visit), 
baseline value of the endpoint, baseline NfL (if different from the 
baseline value of the endpoint), disease duration-by-visit 
interaction, baseline value of the endpoint-by-visit interaction and 
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Endpoint 
Category 
(estimand) 
Estimands 
Endpoint 
Population 
Intercurrent event(s) handling strategy 
Population-level summary  
(Analysis and missing data handling) 
baseline NfL-by-visit interaction (if different from the baseline 
value of the endpoint-by-visit interaction) as covariates. 
All available data will be used, and missing data will be handled 
by MMRM based on missing at random assumption. 
For muscle strength data, if there is a missing value for one 
muscle measurement which continues to have the missing value 
through the final assessment (eg, at least 2 consecutive missing 
values up to the final assessment), then these missing values for 
this muscle measurement will be imputed as zero; all the other 
missing values will not be imputed. 
 
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2 
ANALYSIS POPULATIONS  
The following populations for analyses are defined.  
Table 3 - Populations for analyses  
Population 
Description 
Screened 
All participants who signed the ICF. 
Randomized 
All participants from the screened population who have been allocated to a randomized 
intervention by IRT regardless of whether the intervention was received. 
Exposed 
All screened participants who have taken at least 1 dose of study intervention. 
Intent-to-treat (ITT) 
All randomized participants. Participants will be analyzed according to the intervention 
allocated by randomization. 
Modified Intent-to-treat (mITT) 
All randomized participants who either died or have available baseline and at least one post-
baseline ALSFRS-R assessment 
Safety 
All randomized participants who receive at least 1 dose (including partial dose) of the study 
intervention. 
Pharmacokinetic (PK) 
All randomized participants who receive at least 1 dose of the study intervention and have at 
least 1 PK assessment with adequate documentation of dosing and sampling dates and 
times. Participants will be analysed according to the intervention they actually received. 
ICF = informed consent form; IRT = interactive response technology; ITT = intent-to-treat; PK = pharmacokinetic 
Participants exposed to study intervention before or without being randomized will not be 
considered randomized and will not be included in any analysis population. The safety experience 
of these participants will be reported separately. 
Randomized participants for whom it is unclear whether they took the study intervention will be 
considered as exposed and will be included in the safety population as randomized. 
For any participant randomized more than once, only the data associated with the first 
randomization (except if the first randomization is done by error) will be used in any analysis 
population. The safety experience associated with any later randomization will be reported 
separately. 
For participants receiving more than one study intervention during the study, the intervention 
group for as-treated analyses will be SAR443820 20 mg BID. 
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3 
STATISTICAL ANALYSES  
3.1 
GENERAL CONSIDERATIONS  
In general, continuous data will be summarized using the number of observations available, mean, 
standard deviation (SD), median, interquartile range (Q1, Q3), minimum, and maximum. 
Categorical and ordinal data will be summarized using the count and percentage of participants. 
Efficacy data will be analyzed in the ITT population, except CAFS endpoints in Part A and Part B 
will be analyzed in the mITT population. Safety data will be analyzed in the safety population, 
unless specified otherwise. 
In Part A, baseline values are defined as follows. The baseline values of NfL, CHI3L1, the 
cytokine and chemokine panel in serum, sTREM2 in plasma and 𝑝75𝐸𝐶𝐷 in urine, are defined as 
the average value from samples collected at the screening visit and at Day 1 prior to the first dose 
of the study intervention. For the C-SSRS, the baseline value will be the worst assessment 
between the past 6 months evaluation at screening and the since last visit evaluation on Day 1. For 
the other efficacy and safety assessments, the baseline values are defined as the last available 
value prior to the first dose of study intervention. For participants randomized but not treated, the 
baseline value is defined as the last available value before randomization. Unless otherwise 
indicated, 2-sided p-values and 95% confidence intervals [CI(s)] will be provided for efficacy 
assessment of treatment differences. Unless otherwise specified, analyses will be performed by 
treatment group (and overall for baseline and demographics characteristics).  
Efficacy analyses in Part B will be conducted accumulatively according to the treatment group 
allocated by randomization in Part A (ie, Placebo/SAR443820 versus SAR443820/SAR443820). 
Baseline values defined above for Part A will be used as the baseline in the efficacy analyses for 
Part B, unless otherwise noted. Safety analyses in Part B are stated in Section 3.6. 
Observation period  
The observation period for safety will be divided into 4 segments:  
• The pre-treatment period is defined as the period up to first investigational medicinal 
product (IMP) administration. 
• The on-treatment period (ie, treatment-emergent (TE) period) for the Part A is 
defined as the period from the first IMP administration to the earliest of 1) last IMP 
administration + 14 days, 2) first IMP in Part B, 3) death date, or 4) last contact date.  
• The on-treatment period (ie, treatment-emergent (TE) period) for the Part B is 
defined as the period from the first IMP administration in Part B to the earliest of 1) 
last IMP administration + 14 days, 2) death date, or 3) last contact date. 
• The post-treatment period, if applicable, is defined as the period from the end of the 
on-treatment period to the last contact date. 
The on-study period is defined as the time from randomization until the end of the study defined 
as the last scheduled visit for those who completed the study and the end-of-study date collected 
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on electronic case report form (e-CRF) page “Completion of End of Study” for those who did not 
complete the study. If death is the end-of-study reason, date of death will be used. 
3.2 
PRIMARY ENDPOINT(S) ANALYSIS  
The primary endpoint in Part A detailed in this section is change from baseline in the ALSFRS-R 
total score to Week 24.  
The primary endpoint in Part B detailed in this section is CAFS score at Week 52.  
3.2.1 Definition of endpoint(s)  
Part A 
The ALSFRS-R is composed of 12 items across 4 subdomains of bodily function (bulbar, fine 
motor, gross motor, and breathing), with each item scored on an ordinal scale from 0 (total loss of 
function) to 4 (no loss of function). The total score of the ALSFRS-R ranges from 0 to 48, with a 
higher score indicating better function (1). Good reliability between face-to-face and telephone 
administration of the ALSFRS-R has been demonstrated (2). 
Part B 
The survival endpoint will be defined as the time to death or permanent assisted ventilation 
(>22 hours a day for >7 consecutive days), whichever comes first. CAFS is used to compare each 
study participant’s outcome to others in the trial in a series of pairwise comparisons, based on 
function and survival (3). For each pairwise comparison, a study participant is assigned a score 
and then the summed scores are ranked for all participants. To calculate a participant’s CAFS, 
each participant is compared individually to all other participants in the trial. The summary score 
for each participant is the sum of the comparisons (+1, 0, −1) against all other participants. For 
each pairwise comparison of patients, the participant who fares better earns a point, and the one 
who fares worse loses a point. In the case of a tie, no points are added or subtracted. If both 
participants die, the one surviving longer fared better; if only one survives then that participant 
fared better; and if both participants survive, the one with the smaller decline in ALSFRS-R from 
baseline fared better. If a participant discontinues early, comparison to each other participant uses 
time to death if the comparator died; otherwise, the comparison is based on the last ALSFRS-R 
time-point available for both participants. Once these scores have been calculated for all subjects, 
they are ranked, from lowest (died first) to highest (best ALSFRS-R outcome among those who 
survived), yielding the final CAFS score used as the endpoint. The average rank score is then 
calculated for each treatment group. A higher mean rank score indicates that participants in that 
treatment group, on average, fared better.  
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3.2.2 Main analytical approach  
Part A 
The primary endpoint in Part A will be analyzed with the estimand defined according to the 
following attributes: 
• Endpoint: Change from baseline in the ALSFRS-R total score to Week 24 
• Treatment condition:  SAR443820 will be compared to placebo 
• Analysis population: ITT population 
• Intercurrent events (IE): 
- 
The IMP discontinuation IE will be handled with the treatment policy strategy; The 
primary endpoint will be assessed based on all assessments irrespective of the IMP 
discontinuation 
• Population-level summary: The primary endpoint will be analyzed using MMRM with 
change from baseline in ALSFRS-R total score up to Week 24 as response variable, 
and treatment, visit, randomization strata of the geographic region of the study site, 
ALS onset region (bulbar or other areas), use of riluzole (yes or no), use of edaravone 
(yes or no), use of the combination of sodium phenylbutyrate and taurursodiol (yes or 
no), treatment-by-visit interaction, disease duration (from first symptom onset to the 
screening visit), baseline ALSFRS-R score, baseline NfL, disease duration-by-visit 
interaction, baseline NfL-by-visit interaction and baseline ALSFRS-R score-by-visit 
interaction as covariates. If less than 10 participants in a randomization strata level, 
then the corresponding factor will not be included as a covariate in the MMRM model.  
The least squares mean difference in the ALSFRS-R change from baseline at Week 24 between 
SAR443820 vs placebo, together with the p-value and the 95% CI for the difference, will be 
estimated from the MMRM model using weights for each stratum equal to the overall proportion 
of participants in each stratum (ie, “population weight”) by inclusion of the OBSMARGINS 
option in the LSMEANS statement. Plots of least squares means (± standard error) over time will 
be provided.  
This model will be implemented using the SAS MIXED procedure with an unstructured 
covariance matrix to model the within-participant errors. Parameters will be estimated using the 
restricted maximum likelihood method. The denominator degrees of freedom will be estimated 
using the Kenward-Roger approximation. This model will provide baseline adjusted least-squares 
means estimates at Week 24 for SAR443820 and placebo, together with their corresponding 
standard errors and CIs. If this model fails to converge, the following variance-covariance 
structures will be tested in this order: 
• Heterogeneous Toeplitz 
• Heterogeneous AR(1) 
• Heterogeneous CS 
• Toeplitz 
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• AR(1) 
• CS.  
The first (co)variance structure yielding convergence will be used as the primary analysis. When a 
variance-covariance structure other than unstructured is used, the denominator degree of freedom 
will be estimated using the between within method (DDFM=BW in SAS PROC MIXED) (4). 
We assume a priori that change from baseline in the ALSFRS-R total score to Week 24 are 
normally distributed. Given the large sample size, the impact of violation of normality should not 
be great. In order to assess the impact of deviation from the normality assumption, a sensitivity 
analysis using rank analysis of covariance (ANCOVA) with the same covariates as for the 
MMRM analysis except visit and related interaction terms, will be performed to test the 
significance of the treatment effect.  
Part B 
CAFS score at Week 52 will be analyzed in the mITT population using the Wilcoxon-Mann-
Whitney test to compare mean scores between the treatment groups at Week 52.  
3.2.3 Sensitivity analyses  
.  
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 SAR443820 
  
. 
3.2.4 Supplementary analyses for primary endpoint in Part A  
To assess the treatment effect when the participants adhere to the study treatment as directed, the 
difference (SAR443820 vs placebo) in the mean change from baseline in the ALSFRS-R total 
score to Week 24 will be analyzed in the ITT population based on data collected during the 
treatment-emergent period for the Part A using the same model as primary analysis. ALSFRS-R 
total scores obtained after the IMP discontinuation will be considered as missing. 
3.2.5 Subgroup analyses for primary endpoint in Part A  
To assess the homogeneity of the treatment effect across various subgroups, analyses will be 
performed on the primary endpoint across the following subgroups (categories with fewer than 
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10% participants will be combined with other categories; for factors with only two categories, no 
subgroup analysis will be performed if fewer than 10% participants in one category): 
• Geographic region (US, non-US) 
• Region (Europe, North America, Asia) 
• Age at screening (≤ 40, > 40 years) 
• Sex (Male or Female) 
• Race (White, Black or African American, Asian, Other) 
• ALS onset region (bulbar or other areas) 
• Use of riluzole (yes or no)  
• Use of edaravone (yes or no) 
• Use of the combination of sodium phenylbutyrate and taurursodiol (yes or no) 
The estimated treatment effect (SAR443820 versus placebo) for the primary endpoint will be 
provided, as well as the corresponding 95% CI, for each subgroup separately, using the same 
method as applied in the primary analysis. Forest plots of differences in treatment group means 
and corresponding 95% CIs comparing SAR443820 to placebo within each subgroup will be 
provided. 
Treatment by subgroup interaction and its p-value will be derived from a MMRM with terms for 
treatment, visit, randomization strata of the geographic region of the study site, ALS onset region 
(bulbar or other areas), use of riluzole (yes or no), use of edaravone (yes or no), use of the 
combination of sodium phenylbutyrate and taurursodiol (yes or no), treatment-by-visit interaction, 
disease duration (from first symptom onset to the screening visit), baseline ALSFRS-R score, 
baseline NfL, disease duration-by-visit interaction, baseline ALSFRS-R score-by-visit interaction, 
baseline NfL-by-visit interaction, subgroup (if different than the aforementioned covariates), 
subgroup-by-treatment interaction as covariates. If a quantitative treatment by subgroup 
interaction is detected with nominal p-value <0.1 for any subgroup factor, a further investigation 
will be performed to evaluate possible qualitative interaction. 
3.3 
SECONDARY ENDPOINT(S) ANALYSIS  
The secondary endpoints detailed in this section are as follows: 
Part A 
• CAFS at Week 24  
• change from baseline in SVC to Week 24  
• change from baseline in muscle strength to Week 24  
- 
change from baseline in megascore to Week 24 
- 
change from baseline in grip strength to Week 24 
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• change from baseline in ALSAQ-5 to Week 24   
• change from baseline in serum NfL to Week 24  
Part B 
• CAFS at Week 76 and Week 104 
• change from baseline in the ALSFRS-R total score to Week 52, Week 76, and 
Week 104 
• time from baseline to occurrence of either death or permanent assisted ventilation 
(>22 hours daily for >7 consecutive days), whichever comes first 
• time from baseline to the occurrence of death 
• change from baseline in SVC to Week 52, Week 76, and Week 104 
• change from baseline in ALSAQ-5 to Week 52, Week 76, and Week 104  
• change from baseline in serum NfL to Week 52 
Other secondary endpoints analyses are defined in Section 3.6.2 (AE, SAE), Section 3.6.3.1 
(laboratory abnormalities), Section 3.7.1.1 (PK) and Section 3.7.1.2 (PD).  
3.3.1 Secondary endpoint(s)  
3.3.1.1 Definition of endpoint(s)  
SVC 
SVC is measured in participants while they are in an upright position at least 3 trials per 
assessment or up to 5 trials when the highest and second highest of the first 3 measurements differ 
by 10% or more. SVC volumes are standardized to the percentage of the predicted normal value 
based on age, sex, and height (7). The highest SVC score among all attempts will be used for 
analysis. 
Muscle Strength 
The muscles measured in the study include upper-limb and lower-limb muscle groups. Bilateral 
hand grip will be measured using a grip dynamometer and all other muscles included in this study 
will be measured using a handheld dynamometer (HHD). For each muscle to be tested, 2 trials 
will be performed. If the variability of the 2 trials is 15% or less, values from both trials will be 
recorded and the higher score will be used for analysis. If the variability is greater than 15%, a 3rd 
trial will be performed, all the values will be recorded and the maximum value of the 3 trials will 
be accepted. The order of testing is standardized and should be the same for each session. Grip 
strength will be tested first, followed by the arms and then the legs. 
HHD data will be analyzed by combined muscle groups named (megascores). To create a 
megascore, individual muscles will be standardized using table e-1 in (8), from which individual 
muscle means and SDs were calculated from 228 healthy people. Note that in (8), each muscle 
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strength was measured in lbs, so the corresponding mean and SD in table e-1 are transformed to 
kg by multiplying a constant 0.453592. Two decimal places are kept as in (8). The transformed 
table is provided below. Z scores for each muscle measurement will be calculated from these 
means and SDs by subtracting the corresponding mean and dividing by the corresponding SD. 
Individual Z scores will then be averaged to produce a total megascore including all available 
muscle groups. To handle the missing data, the derivation rule for primary analysis is determined 
as follows: If a participant has a missing value for one muscle measurement and continues to have 
the missing value through the final assessment (eg, at least 2 consecutive missing values up to the 
final assessment), then these missing values for this muscle measurement will be imputed as zero; 
all the other missing values will not be imputed.  
Mean strength, standard deviation for all muscles in 228 normal volunteers (table e-1 in (8)) 
HHD 
Mean (kg)  SD 
HHD 
Mean (kg) 
SD 
L shoulder flexion 
13.48 
4.20 
R shoulder flexion 
14.01 
4.11 
L elbow flexion 
15.78 
5.22 
R elbow flexion 
15.87 
5.34 
L elbow extension 
12.80 
3.96 
R elbow extension 
12.79 
3.78 
L wrist extension 
11.35 
3.96 
R wrist extension 
12.02 
3.97 
L hip flexion 
19.90 
7.19 
R hip flexion 
20.15 
7.08 
L knee flexion 
16.65 
5.96 
R knee flexion 
16.77 
5.71 
L knee extension 
16.00 
6.03 
R knee extension 
16.24 
6.42 
L ankle dorsiflexion 
17.25 
6.91 
R ankle dorsiflexion 
17.45 
7.03 
L first dorsal interosseous 
5.07 
1.74 
R first dorsal interosseous 
5.35 
1.97 
Each mean and SD are derived from the table e-1 in (8) by multiplying a constant 0.453592 to change the unit from lbs to kg. 
Grip strength data will be analyzed by the scores collected from left hand and right hand 
respectively. To handle the missing data, the derivation rule for primary analysis is determined as 
follows: If a participant has a missing value at one visit and continues to have the missing value 
through the final assessment (eg, at least 2 consecutive missing values up to the final assessment), 
then these missing values will be imputed as zero; all the other missing values will not be 
imputed. 
ALSAQ-5 
The ALSAQ-5 consists of 5 items derived from the ALSAQ-40. The 5 items closely resemble 
those of the 5-dimension scores of the ALSAQ-40: eating and drinking; communication; activities 
of daily living/independence; physical mobility; and emotional functioning. The ALSAQ-5 has a 
recall period of the past 2 weeks and takes approximately 5 minutes to complete. Each item is 
scored on a 5-point Likert scale ranging from 0 (never) to 4 (always or cannot do at all) according 
to the frequency of a particular problem. Total scores range from 0 to 20, with higher scores 
indicative of greater physical and emotional limitations.  
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Serum NfL 
Serum blood samples will be used to measure changes in NfL, a marker of neuronal injury. Levels 
of NfL in both cerebrospinal fluid and plasma have been reported to be increased and stable over 
time in participant with ALS compared to healthy controls. Patients with ALS with a fast 
progression rate have demonstrated higher levels of NfL in CSF and plasma than those with a 
slow progression rate. Only serum NfL will be measured in this study to reduce the collection 
burden on participants. 
3.3.1.2 Main analytical approach  
Treatment policy will be used for the analyses of all secondary endpoints in Part A and Part B as 
stated in Table 2. 
CAFS 
CAFS at Week 24, Week 76 and Week 104 will be analyzed in the same manner as that used to 
analyze the primary endpoint in Part B in Section 3.2.2. 
Continuous Endpoints 
Continuous endpoints include: 
Part A 
• change from baseline in SVC to Week 24 
• change from baseline in muscle strength to Week 24 
- 
change from baseline in megascore to Week 24 
- 
change from baseline in grip strength to Week 24 
• change from baseline in ALSAQ-5 to Week 24  
• change from baseline in serum NfL to Week 24  
Part B 
• change from baseline in the ALSFRS-R total score to Week 52, Week 76, and Week 
104 
• change from baseline in SVC to Week 52, Week 76, and Week 104 
• change from baseline in ALSAQ-5 to Week 52, Week 76, and Week 104  
• change from baseline in serum NfL to Week 52 
These continuous endpoints will be analyzed using the same manner as that used to analyze the 
primary endpoint in Part A in Section 3.2.2, except that baseline ALSFRS-R score will be 
replaced by the baseline value of the corresponding endpoint. Plots of least squares means 
(± standard error) over time will be provided. Plots of mean (±SD) and/or mean change (±SD) 
and/or median over time will also be provided. For NfL data, log transformation will be applied in 
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the MMRM model. The treatment difference will then be back-transformed to the original scale. 
The back-transformed LS means stand for geometric mean ratios compared to baseline, and the 
back-transformed LS means difference stands for ratio of the geometric mean ratios compared to 
baseline between SAR443820 and placebo. In order to assess the impact of deviation from the 
normality assumption, a sensitivity analysis using rank analysis of covariance (ANCOVA) with 
the same covariates as for the MMRM analysis except visit and related interaction terms, will be 
performed to provide the p-value for the comparison between the treatment groups. 
Time-to-event endpoints  
Time-to-event endpoints in Part B include: 
• time from baseline to occurrence of either death or permanent assisted ventilation 
(>22 hours daily for >7 consecutive days), whichever comes first 
• time from baseline to the occurrence of death 
For the time-to-event endpoints, baseline is defined as randomization. The time to event will be 
modeled by a Cox proportional hazards model. The covariates included in the model are treatment 
group, randomization strata of the geographic region of the study site, ALS onset region (bulbar 
or other areas), use of riluzole (yes or no), use of edaravone (yes or no), use of the combination of 
sodium phenylbutyrate and taurursodiol (yes or no), disease duration (from first symptom onset to 
the screening visit), baseline ALSFRS-R score and baseline NfL. The hazard ratio between 
SAR443820 and placebo, its 95% confidence interval and the p-value for comparing SAR443820 
and placebo will be estimated from this model with robust variance estimation (9). Comparison 
between SAR443820 and placebo will also be assessed by a log-rank test stratified by 
randomization strata of the geographic region of the study site, ALS onset region (bulbar or other 
areas), use of riluzole (yes or no), use of edaravone (yes or no), use of the combination of sodium 
phenylbutyrate and taurursodiol (yes or no) and baseline NfL (< median baseline NfL or 
>= median baseline NfL). Kaplan-Meier (KM) plots of the cumulative incidence rate will be 
provided by treatment group to depict the course of occurrence of event over time. The proportion 
of participants with events at given time points (eg, Week 4, 8, 12, 16, 20, 24, etc.) and median 
time to event (if feasible) will be calculated using the KM estimates. 
3.3.1.3 Sensitivity analyses  
CAFS endpoints in Part A and Part B 
To assess the impact of baseline characteristics in the comparison of CAFS scores between 
treatment groups, a sensitivity analysis using a similar rank ANCOVA model to adjust for 
baseline prognostic factors in the mITT population as mentioned in Section 3.2.3 will be 
performed at Week 24, Week 76 and Week 104, respectively. 
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3.4 
TERTIARY/EXPLORATORY ENDPOINT(S) ANALYSIS  
Tertiary/exploratory endpoints in Part A and Part B are listed in Table 1.  
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3.4.1 Definition of endpoint(s)  
3.4.2 Main analytical approach  
Missing data will not be imputed in the analysis of tertiary endpoints, nor will sensitivity or 
subgroup analyses be conducted.  
For continuous endpoints, summary statistics including mean, standard deviation, median, 
interquartile range (Q1, Q3), minimum, and maximum will be provided for these continuous 
endpoints at scheduled visits in Part A and Part B. Only participants with baseline and post-
baseline data will be summarized. Plots of mean (±SD) and/or mean change (±SD) and/or median 
over time will also be provided for better visualization. These continuous endpoints will also be 
analyzed using a similar MMRM approach as described for the primary endpoint in Part A in 
Section 3.2.2, except that the baseline ALSFRS-R score will be replaced by the baseline values of 
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the corresponding endpoint. In addition, for the change from baseline in maximum phonation time 
on 
, age, height, and gender will also be included in the MMRM model as 
covariates. Plots of least squares means (± standard error) over time will be provided.  
 
Time-to-event endpoints will be analyzed using the same manner as that used to analyze the 
secondary time-to-event endpoints in Part B in Section 3.3.1.2. 
3.4.3 Comparison with external control  
A matched analysis using data from historical clinical trial database (for example, PROACT) as a 
control will be conducted to demonstrate the superiority of SAR443820 on slowing down disease 
progression and prolonging survival over 104 weeks of treatment period. 
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Matching procedure  
1. Pre-matching filtering: The participants in the historical clinical trial database will be 
filtered by the following factors that match our trial eligibility criteria and duration:  
• Age 18 – 80 years, inclusive 
• First ALS symptom onset <= 2 years 
• Baseline SVC (%) >= 60% 
• Baseline ALSFRS-R decline rate >= 0.5/month 
 
2. Propensity score matching: Propensity score matching seeks to balance the distributions of 
known prognostic covariates in treatment and control group to resemble what would occur 
had the treatment been randomly assigned.  A logistic regression for the treatment group 
as the dependent variable is performed to obtain the propensity score with the 
abovementioned matching variables, using all the participants (planned for 174) 
randomized to the SAR443820 arm and the participants from the historical clinical trial 
database after filtering as described above. Each participant in the SAR443820 treated 
group will be matched 1:1 using the Mahalanobis distance to a participant in the historical 
clinical trial database. Matching will be performed with replacement.   
To assess the success of the matching procedure, summary statistics of baseline matching 
variables will be presented and compared between the two treatment groups before and 
after matching to assess post-match balance. 
Post-matching statistical analysis 
Once the matching is performed, the comparison between participants who were randomized to 
SAR443820 and placebo arm generated from the historical trial database will be provided for the 
following endpoints using the similar analyses models as described for the primary and secondary 
endpoints in Section 3.2.2 and Section 3.3.1.2. 
• Combined assessment of function and survival (CAFS) score at Week 52, Week 76, 
and Week 104 
• Change from baseline in ALSFRS-R total score to Week 52, Week 76, and Week 104 
• Time from baseline to the occurrence of either death or permanent assisted ventilation 
(>22 hour daily for >7 consecutive days) whichever comes first 
• Time from baseline to the occurrence of death 
3.5 
MULTIPLICITY ISSUES  
To control the Type 1 error rate for the study, a hierarchical testing procedure will be applied at a 
2-sided 5% significance level for primary and selected secondary endpoints in Part A, ie, each 
hypothesis will be formally tested only if the preceding one is significant at the 5% level. If 
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SAR443820 is significant for the primary endpoint in part A, a selective set of secondary 
endpoints in Part A will be tested following the hierarchical testing procedure shown below: 
• CAFS score at Week 24 
• Change from baseline in ALSAQ-5 to Week 24  
• Change from baseline in serum NfL to Week 24 
• Change from baseline in SVC to Week 24 
• Change from baseline in megascore to Week 24 
3.6 
SAFETY ANALYSES  
All safety analyses will be performed on the safety population as defined in Section 2, unless 
otherwise specified, using the following common rules: 
• The analysis of the safety variables will be essentially descriptive, and no testing is 
planned.  
• Safety data in participants who do not belong to the safety population (eg, exposed but 
not randomized) will be provided separately. 
In Part A safety analysis, the safety analyses will be carried out with patients by the actual 
treatment received, irrespective of the treatment the patient has been randomized to.  
Part A + Part B Safety Analyses 
For categorical safety measures, such as AE, PCSA, shift summaries, data throughout both Part A 
and Part B will be summarized in three groups:  
• Placebo/SAR443820 group includes participants who actually received placebo in Part 
A and SAR443820 in Part B. For participants in this group, only the data during 
SAR443820 exposure in Part B will be summarized. The baseline will be defined as 
the last available value prior to the first dose of SAR443820 in Part B. 
• SAR443820/SAR443820 group includes participants who actually received 
SAR443820 in Part A, regardless of whether they entered Part B. For participants in 
this group, all data during SAR443820 exposure will be summarized. The baseline will 
be defined as the last available value prior to the first dose of the study intervention 
(same baseline defined for Part A in Section 3.1). 
• Overall SAR443820 group includes participants from Placebo/SAR443820 group and 
SAR443820/SAR443820 group. 
For continuous safety measures collected at longitudinal time point, such as labs and vital signs, 
data throughout both Part A and Part B will be summarized in two groups: 
• Placebo/SAR443820 group includes participants who actually received placebo in Part 
A, regardless of whether they entered Part B. For participants in this group, all data 
during the on-treatment period of Part A and Part B will be summarized at each 
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protocol scheduled visit. The baseline will be defined as the last available value prior 
to the first dose of study intervention (same baseline defined for Part A in Section 3.1). 
• SAR443820/SAR443820 group includes participants who actually received 
SAR443820 in Part A, regardless of whether they entered Part B. For participants in 
this group, all data during the on-treatment period of Part A and Part B will be 
summarized at each protocol scheduled visit. The baseline will be defined as the last 
available value prior to the first dose of study intervention (same baseline defined for 
Part A in Section 3.1). 
 
3.6.1 Extent of exposure  
The extent of IMP exposure will be assessed by the duration of IMP exposure and summarized 
within the safety population.  
Duration of IMP exposure 
Duration of IMP exposure in Part A is defined as last IMP administration date in Part A – first 
IMP administration date + 1 day, regardless of unplanned intermittent discontinuations. If the date 
of the last dose of IMP in Part A is missing, the duration of IMP exposure in Part A will be left as 
missing. 
Duration of cumulative SAR443820 exposure in Part A + Part B is defined as last dose date of 
SAR443820 – first dose date of SAR443820 + 1 day, regardless of unplanned intermittent 
discontinuations. If the last dose date of SAR443820 is missing, this duration will be left as 
missing. 
Duration of IMP exposure in Part A will be summarized quantitatively and categorically by the 
treatment group participants actually received in Part A (Placebo versus SAR443820):  
• > 0 and ≤ 4 weeks 
• > 4 and ≤ 8 weeks 
• > 8 and ≤ 12 weeks 
• > 12 and ≤ 16 weeks 
• > 16 and ≤ 20 weeks 
• > 20 and ≤ 24 weeks 
• > 24 weeks 
Duration of cumulative SAR443820 exposure in Part A + Part B will also be summarized 
quantitatively and categorically by actual treatment group (Placebo/SAR443820, 
SAR443820/SAR443820 and overall) within the safety population: 
• > 0 and ≤ 4 weeks 
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• > 4 and ≤ 8 weeks 
• > 8 and ≤ 12 weeks 
• > 12 and ≤ 16 weeks 
• > 16 and ≤ 20 weeks 
• > 20 and ≤ 24 weeks 
• > 24 and ≤ 52 weeks 
• > 52 and ≤ 76 weeks 
• > 76 and ≤ 104 weeks 
• > 104 weeks 
Additionally, the cumulative duration of treatment exposure (expressed in participant-years) will 
be provided for Part A and Part A + Part B separately. 
Treatment compliance 
A given administration will be considered noncompliant if the participant did not take the number 
of administrations as required by the protocol. No imputation will be made for participants with 
missing or incomplete data. 
Percentage of treatment compliance for a participant will be defined as the number of 
administrations that the participant was compliant divided by the total number of administrations 
that the participant was planned to take from the first administration of IMP up to the actual last 
administration of IMP. 
Treatment compliance will be summarized quantitatively and categorically (<80%, ≥80%) for Part 
A and Part A + Part B using the similar format as stated above for exposure. 
3.6.2 Adverse events  
General common rules for adverse events 
All adverse events (AEs) will be coded to a lower-level term (LLT), preferred term (PT), high-
level term (HLT), high-level group term (HLGT), and associated primary system organ class 
(SOC) using the Medical Dictionary for Regulatory Activities (MedDRA) version currently in 
effect at Sanofi at the time of database lock.  
The AEs will be analyzed in the following 4 categories: 
• Pre-treatment AEs: AEs that developed, worsened or became serious during the pre-
treatment period. 
• Treatment-emergent adverse events (TEAE)s for Part A: AEs that developed, 
worsened or became serious during the on-treatment period for Part A 
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• Treatment-emergent adverse events (TEAE)s for Part B: AEs that developed, 
worsened or became serious during the on-treatment period for Part B 
• Post-treatment AEs: AEs that developed, worsened or became serious during the post-
treatment period  
Similarly, if occurring, deaths will be analyzed in the pre-treatment, treatment-emergent, and post-
treatment periods.  
The primary AE analyses will be on TEAEs. Pre-treatment and post-treatment AEs will be 
described separately.  
An AE with incomplete or missing date/time of onset (occurrence, worsening, or becoming 
serious) will be classified as a TEAE unless there is definitive information to determine it is a 
pre-treatment or a post-treatment AE.  
If the assessment of the relationship to IMP is missing for an AE, this AE will be assumed as 
related to IMP. Missing severity will be left as missing. 
Multiple occurrences of the same event in the same participant will be counted only once in the 
tables within a treatment period, using the maximum (worst) severity by treatment phase.  
The AE tables will be sorted as indicated in Table 4.  
Table 4 - Sorting of AE tables  
AE presentation 
Sorting rules 
SOC and PT 
By the internationally agreed SOC order and decreasing frequency of PTsa  
AESI category and PT 
By AESI category (protocol order) and decreasing frequency of PTsa 
PT 
By decreasing frequency of PTsa 
a Sorting will be based on the SAR443820 treatment group incidence, alphabetic order in case of equal frequency. 
Analysis of all adverse events in Part A and Part A + Part B 
The overview of TEAE will be generated presenting the number (%) of participants with: 
• Any TEAE  
• Any severe TEAE 
• Any treatment-emergent SAE 
• TEAE leading to death 
• Any TEAE leading to permanent intervention discontinuation of IMP 
• Any treatment-emergent AESI 
• Any TEAE considered by the investigator as related to IMP 
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An additional overview summary including the number and rate of events will be provided. 
The AE summaries of Table 5 will be generated with number (%) of participants experiencing at 
least one event.  
Listings of SAEs from randomized participants, AEs from participants who are treated but not 
randomized, AEs leading to treatment/study discontinuation and severe AEs will be provided. 
Table 5 - Analyses of adverse events  
Type of AE 
MedDRA levels 
All TEAEs 
Primary SOC and PT 
Common TEAE (≥2% in any group) 
PT 
TEAEs related to IMP as per Investigator’s judgment 
Primary SOC and PT 
 
PT 
TEAE by maximal intensity 
Primary SOC and PT 
Treatment emergent SAEs 
Primary SOC and PT 
 
PT 
Treatment emergent SAEs related to IMP as per Investigator’s 
judgment 
Primary SOC and PT 
Treatment emergent AESIs 
AESI category and PT 
TEAEs leading to permanent intervention discontinuation 
Primary SOC and PT 
 
PT 
TEAEs leading to deathb 
Primary SOC and PT 
Pretreatment AEs 
Overviewa 
 
Primary SOC and PT 
Post-treatment AEs 
Overviewa 
 
Primary SOC and PT 
a Will include the following AE categories: any AEs, any serious AEs, any AEs leading to death, any AEs leading to permanent intervention 
discontinuation 
b Death as an outcome of the AE as reported by the Investigator in the AE page 
Analysis of deaths in Part A and Part A + Part B 
In addition to the analyses of deaths included in Table 5, the number (%) of participants in the 
following categories will be provided: 
• Deaths during the treatment-emergent period and post-treatment period  
• Deaths in non-randomized participants or randomized but not treated participants 
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Analysis of adverse events of special interest (AESIs) in Part A and Part A + Part B 
Adverse events of special interest (AESIs) will be selected for analyses as indicated in Table 6. 
Number (%) of participants experiencing at least one event will be provided for each event of 
interest. Tables will be sorted as indicated in Table 4. A listing of AESIs will also be provided. 
Table 6 - Selections for AESIs  
AESIs  
Selection 
Pregnancy of a female participant or female partner of a 
male participant 
Dedicated CRF page (AECAT=”PREGNANCY DATA”) 
Symptomatic overdose (serious or non-serious) with IMP 
Dedicated CRF page (AECAT=”OVERDOSE DATA”; must be 
symptomatic and AESI marked “Y” 
Convulsions 
CMQsn00079 for selection and AESI marked “Y” 
Serious infections meeting SAE definitions criteria 
SOC of Infections and Infestations, both AESER and AESI marked 
“Y” 
Increase in ALT > 3 x ULN  
Dedicated CRF page (AECAT=”ALT INCREASE DATA”) and 
AESI marked “Y” 
 
 
3.6.3 Additional safety assessments  
3.6.3.1 Laboratory variables, vital signs and electrocardiograms (ECGs)  
The following laboratory variables, vital signs and electrocardiogram (ECG) variables will be 
analyzed. They will be converted into standard international units and conventional unit, if 
applicable. 
• Hematology:  
- 
Red blood cells and platelets and coagulation: hemoglobin, hematocrit, mean 
corpuscular volume, mean corpuscular hemoglobin, red blood cell count, platelet 
count 
- 
White blood cells: white blood cell count, neutrophils, lymphocytes, monocytes, 
basophils, eosinophils 
• Clinical chemistry: 
- 
Metabolism: glucose, total protein, albumin, creatine phosphokinase 
- 
Electrolytes: sodium, potassium, calcium 
- 
Renal function: creatinine, blood urea nitrogen 
- 
Liver function: alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase, total and direct bilirubin 
- 
Pregnancy test: Serum β-human chorionic gonadotropin (all female participants)  
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- 
Hepatitis screen: human immunodeficiency virus antibody, hepatitis B surface 
antigen, hepatitis C virus antibody  
• Urinalysis: 
- 
Urinalysis for quantitative analysis: pH, specific gravity, proteins, glucose, blood, 
ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase (by dipstick) 
• Vital signs: heart rate, systolic and diastolic blood pressure, weight, respiratory rate, 
temperature 
• ECG variables: heart rate, PR, QRS, QT, and corrected QTc (according to Bazett and 
Fridericia)  
Data below the lower limit of quantitation/detection limit (LLOQ) will be replaced by half of the 
LLOQ, data above the upper limit of quantification (ULOQ)will be replaced by ULOQ value for 
quantitative analysis. 
Quantitative analyses 
When relevant, for laboratory variables, vital signs and ECG variables above, descriptive statistics 
for results and changes from baseline will be provided for each analysis visit window during the 
on-treatment period for Part A and Part A + Part B. These analyses will be performed using 
central measurements only (when available) for laboratory variables.  
For each laboratory parameter, vital sign parameter and ECG parameter, mean changes from 
baseline with the corresponding standard error will be plotted over time.  
Analyses according to PCSA 
Potentially clinically significant abnormality (PCSA) analyses will be performed based on the 
PCSA list currently in effect at Sanofi at the time of the database lock. For parameters for which 
no PCSA criteria are defined, similar analyses will be done using the normal range, if applicable. 
Analyses according to PCSA (normal range) will be performed based on the worst value during 
the treatment-emergent period, using all measurements (either local or central, either scheduled, 
nonscheduled or repeated). 
For laboratory variables, vital signs and ECG variables above, the incidence of participants with at 
least one PCSA during the on-treatment period for Part A and Part A + Part B will be summarized 
regardless of the baseline level and according to the following baseline status categories: 
• Normal/missing 
• Abnormal according to PCSA (normal range) criterion or criteria 
Additional analyses for drug-induced liver injury 
The following additional analyses will be performed for drug-induced liver injury in Part A and 
Part A + Part B:  
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• Time to onset of the initial alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) elevation (>3 x ULN) and total bilirubin elevation (>2 x ULN) 
during the treatment-emergent period will be analyzed using Kaplan-Meier method.  
• A graph of the distribution of peak values of ALT versus peak values of total bilirubin 
during the treatment-emergent period will be provided.  
• For each liver function test (eg, ALT), participants having experienced a PCSA (eg, 
ALT >5 ULN) will be summarized using the following categories: Returned to 
baseline PCSA status (or returned to value ≤ ULN in case of missing baseline) before 
last IMP dose, Returned to baseline PCSA status after last IMP dose, Never returned to 
baseline PCSA status, No assessment after elevation. This summary will be performed 
by categories of elevation (ALT >3, >5, >10, >20 ULN). 
3.6.3.2 Analysis of suicidality assessment  
The number (%) of participants with suicidal ideation, suicidal behavior, and self-injurious 
behavior without suicidal intent based on the C-SSRS during treatment will be summarized. A 
shift table for baseline versus during treatment responses in Part A and Part A + Part B will be 
provided according to the categories of no suicidal ideation or behavior, suicidal ideation and 
suicidal behavior. 
3.7 
OTHER ANALYSES  
3.7.1 Other variables and/or parameters  
3.7.1.1 Pharmacokinetic (PK) analyses  
Plasma concentration of SAR443820 will be summarized in the PK population using arithmetic 
and geometric means, standard deviation, standard error of the mean, coefficient of variation, 
minimum, median and maximum per sampling time. For drug-treated participants, where 
concentration values are below the lower limit of quantification (LLOQ), one-half of the LLOQ 
will be used. Values will be expressed in the tables with no more than three decimal places. These 
analyses will be performed for all participants received SAR443820 and by baseline body weight 
(by quartiles).  
The population PK analyses will be presented separately from the main clinical study report. 
3.7.1.2 Pharmacodynamic (PD) analyses  
PD parameters include NfL, chitinase-3-like protein-1, a selected panel of cytokines and 
chemokines in serum, soluble triggering receptor expressed on myeloid cells-2 in plasma and 
extracellular domain of p75 in urine. NfL data will be analyzed under secondary endpoints as 
described in Section 3.3.1.2. The rest of PD parameters will be summarized in Part A by actual 
treatment group in the safety population using the following descriptive statistics: mean, 
geometric mean, median, standard deviation, coefficient of variation, minimum, and maximum. 
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The corresponding change from baseline values will also be provided. Plots of mean (±SD) and/or 
mean change (±SD) over time will also be provided for better visualization. 
3.7.1.3 PK/PD analysis  
Exploratory exposure response analysis will be provided in a standalone report. The 
documentation of the methods of analysis will be described in a standalone plan. 
3.8 
INTERIM ANALYSES  
A nonbinding interim analysis (IA) for futility may be conducted when approximately 40% of the 
participants complete Part A, the double-blind placebo-controlled period, or discontinue the study 
before Week 24. If both stopping criteria for change from baseline in the ALSFRS-R total score to 
Week 24 and change from baseline in NfL to Week 24 are met, the futility may be declared. An 
independent statistical group, external to the Sponsor (not involved with the conduct of the study), 
will conduct this IA and support the DMC activities. At the time of the IA, if the DMC 
recommends the study to continue, the Sponsor will be informed of the decision without receiving 
any unblinded results. Only if the DMC considers recommending the study to stop for futility, a 
prespecified limited number of the Sponsor’s senior management team will be informed of the 
unblinded results. This limited Sponsor’s senior management team will decide to stop or continue 
the study. No one involved in the conduct of the study will have access to the unblinded data. 
Interim analysis details will be provided in the DMC SAP. 
When all participants complete Part A, which is the 24 weeks of double-blind treatment period, or 
discontinue from the study before Week 24 (ie, last participant last visit for Part A), the final 
confirmatory analyses for Part A will be performed from the database lock for Part A, and the 
results will be provided in a study report.   
For Part (open label, long-term extension period), interim analyses/reports may be prepared to 
support regulatory submission or other purpose.  
When all participants complete Part B or discontinue from the study before the end of Part B (ie, 
last participant last visit for Part B), the final analyses for the entire study period will be 
conducted and the final clinical study report will be generated.   
3.9 
CHANGES TO PROTOCOL-PLANNED ANALYSES  
This section summarizes major statistical changes in the protocol amendment(s). 
Major statistical changes in protocol amendment(s) 
Amendment 
Number 
Approval 
Date 
Changes 
Rationale 
2 
02-Dec-2022 
In MMRM model for change from baseline in 
continuous endpoints, baseline NfL (if different from the 
baseline value of the endpoint), use of the combination 
Clarification of the terms in 
MMRM model 
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Amendment 
Number 
Approval 
Date 
Changes 
Rationale 
of sodium phenylbutyrate and taurursodiol (yes vs no), 
baseline NfL-by-visit interaction (if different from the 
baseline value of the endpoint-by-visit interaction), 
baseline value of the endpoint-by-visit interaction are 
also included, while randomization strata-by-visit 
interaction is removed.  
5 
13-Dec-2023 
In MMRM for change from baseline in continuous 
endpoints, disease duration (first symptom onset to 
screening visit) and disease duration by visit interaction 
are also included 
Clarification of the terms in 
MMRM model 
 
 
 
 
 
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4 
SAMPLE SIZE DETERMINATION  
The proposed sample size (n = 261) provides an approximately 80% power to detect a 30% 
reduction in SAR443820 compared with placebo in the change of ALSFRS-R from baseline at 
Week 24, assuming a change of 
 points from baseline in ALSFRS-R in the placebo arm with a 
standard deviation of 
 points, and a 20% drop-out rate. Sample size is estimated via simulation 
with a 2-sided 5% significance level. 
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5 
SUPPORTING DOCUMENTATION  
5.1 
APPENDIX 1 LIST OF ABBREVIATIONS  
 
AE: 
adverse event 
AESIs: 
adverse events of special interest 
ALSAQ-5: 
Amyotrophic Lateral Sclerosis Assessment Questionnaire 
ALT: 
alanine aminotransferase 
ANCOVA: 
analysis of covariance 
ATC: 
anatomic therapeutic category 
ECG: 
electrocardiogram 
EU: 
Europe 
HDD: 
handheld dynamometer 
HLT: 
high level term 
IMP: 
investigational medicinal product 
ITT: 
intent-to-treat 
LLOQ: 
lower limit of quantification 
LLT: 
lower-level term 
MedDRA: 
medical dictionary for regulatory activities 
mITT: 
modified intent-to-treat 
NfL: 
serum neurofilament light chain 
PCSA: 
potentially clinically significant abnormality 
PK: 
pharmacokinetic 
PT: 
preferred term 
ROW: 
rest of the world 
SAP: 
statistical analysis plan 
SD: 
standard deviation 
SOC: 
system organ class 
TE: 
treatment-emergent 
TEAE: 
treatment-emergent adverse event 
WHO-DD: 
World Health Organization-drug dictionary 
 
5.2 
APPENDIX 2 PARTICIPANT DISPOSITIONS  
The number (%) of participants included in each of the analysis populations listed in Table 3 will 
be summarized. 
Screened participants are those with a signed informed consent. Screen failures are defined as 
participants who consent to participate in the study but are not subsequently randomized. The 
number of screened participants will be summarized along with the number (%) of screen failures 
overall and by reasons. 
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The number (%) of participants in the following categories will be provided: 
• Exposed but not randomized, if applicable 
• Randomized 
• Randomized but not exposed, if applicable 
• Randomized and exposed 
- 
Completed the treatment period  
- 
Did not complete the treatment period including main reason for permanent 
intervention discontinuation and reason for intervention withdrawal by participant 
• Completed the Part A study period 
• Did not complete the Part A study period including main reason for study 
discontinuation 
• Completed the Part B study period 
• Did not complete the Part B study period including main reason for study 
discontinuation 
• Status at last contact (alive, dead) 
Reasons for permanent study intervention and study discontinuation, “adverse event” and “other 
reasons” will be split as related versus not related to COVID-19, if applicable. 
For all categories of participants (except for screened and nonrandomized), percentages will be 
calculated using the number of randomized participants as the denominator.  
In addition, the number (%) of participants screened, screened-failed, randomized, with 
permanent intervention discontinuation and with early study discontinuation for Part A/Part B 
study period will be provided by country and site. Listings of other reasons for treatment 
discontinuation, and participants who are exposed but not randomized will be provided. 
Protocol deviations 
Critical and major protocol deviations (automatic or manual) will be summarized in the 
randomized population as well as displayed separately as related versus not related to COVID-19 
if applicable in Part A and Part A + Part B respectively. A listing of critical and major protocol 
deviations will be provided. 
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5.3 
APPENDIX 3 DEMOGRAPHICS AND BASELINE CHARACTERISTICS, PRIOR OR 
CONCOMITANT MEDICATIONS  
Demographics, baseline characteristics, medical surgical history 
The following demographics and baseline characteristics, smoking and alcohol history, medical 
and surgical history and disease characteristics at baseline will be summarized using descriptive 
statistics in the randomized population. 
Demographic and baseline characteristics include:  
• age in years as quantitative variable and in categories (< 65, ≥ 65)  
• gender (Male, Female) 
• race (White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Multiple, Unknown, Not reported) 
• ethnicity (Hispanic or Latino, not Hispanic or Latino, Unknown, Not reported) 
• region (US, non-US; North America, Europe, Asia) 
• weight in kg as a quantitative variable 
• BMI in kg/m2 as a quantitative variable and in categories (< 25, ≥ 25 to < 30, ≥ 30)  
Smoking and alcohol habits: 
• smoking history (Never, Current, Former) 
• cessation prior to screening for Former smokers in months 
• cigarettes per day for smokers 
• frequency of alcohol drinking in the past 12 months (Never, Occasional, At least 
monthly, At least weekly, At least daily) 
• Number of standard alcohol drinks on typical day when drinking (1 or 2, >2) 
Disease characteristics at baseline include: 
• ALS diagnosis type (possible, clinically probable ALS, clinically probable laboratory-
supported, or clinically definite) 
• initial disease onset location (bulbar, other) 
• ALS disease duration (years) from first symptom onset to the screening visit 
• time since diagnosis (years) 
• ALSFRS-R total score 
• ALSFRS-R pre-study slope defined as (48-ALSFRS-R score at the screening 
visit)/duration in months between the screening visit and disease onset) 
• SVC 
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• use of Riluzole collected from IRT 
• use of Edarovone collected from IRT 
• use of the combination of sodium phenylbutyrate and taurursodiol collected from IRT 
• use of Riluzole and Edarovone collected from IRT 
• use of Riluzole and the combination of sodium phenylbutyrate and taurursodiol 
collected from IRT 
• use of Edaravone and the combination of sodium phenylbutyrate and taurursodiol 
collected from IRT 
• use of Edaravone and the combination of sodium phenylbutyrate and taurursodiol 
collected from IRT 
Baseline safety and efficacy parameters (apart from those listed above) will be presented along 
with the safety and efficacy summaries.  
Relevant medical and surgical history collected in the eCRF will be coded to a LLT, PT, HLT, 
HLGT, and associated primary SOC using the MedDRA version currently in effect at Sanofi at 
the time of database lock and will be summarized by primary SOC and HLT (internationally 
agreed SOC order and decreasing frequency of HLTs in the Overall group). 
Prior or concomitant medications 
All medications will be coded using the World Health Organization-Drug Dictionary (WHO-DD) 
using the version currently in effect at Sanofi at the time of database lock. 
• Prior medications are those the participant received prior to first IMP intake. Prior 
medications can be discontinued before first administration or can be ongoing during 
treatment period. 
• Concomitant medications are any medications received by the participant 
concomitantly to the IMP during the on-treatment period. 
• Post-treatment medications are those the participant received in the period running 
from the end of the concomitant medications period up to the end of the study, if 
applicable.  
• A given medication can be classified as a prior medication and/or as a concomitant 
medication and/or as post-treatment medication. If it cannot be determined whether a 
given medication was taken prior or concomitantly or post, it will be considered as 
prior, concomitant, and post-treatment medication. 
The prior, concomitant and post-treatment (if applicable) medications will be summarized for the 
randomized and exposed population, by anatomic and therapeutic level. Concomitant medications 
will be summarized the summary in Part A and Part A + Part B respectively. The summaries will 
be sorted by decreasing frequency of anatomic category (ATC) based on incidence in the 
SAR443820 group. In case of equal frequency, alphabetical order will be used. Participants will 
be counted once in each ATC category (anatomic or therapeutic) linked to the medication.  
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Any use of noninvestigational medicinal products (riluzole, edaravone, and the combination of 
sodium phenylbutyrate and taurursodiol, or any combinations of these medicinal products) will be 
summarized for the randomized and exposed population in Part A and Part A + Part B 
respectively.  
5.4 
APPENDIX 4 DATA HANDLING CONVENTIONS  
Analysis windows for time points 
The following analysis windows will decide how the scheduled and/or unscheduled visits will be 
used in the by-visit analyses of efficacy, safety, and PD variables. 
A measurement (scheduled or unscheduled) will be used if it is available and measurement date is 
within the analysis window.  
After applying these time windows, if multiple assessments are associated to the same time point, 
the closest from the targeted study day will be used. If the difference is a tie, the value after the 
targeted study day will be used. If multiple valid values exist within a same day, then the first 
value of the day will be selected.  
If there is no measurement for a given parameter in an analysis window, data will be considered 
missing for the corresponding visit.  
Table 7 - Analyses window definition of efficacy variables  
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Table 8 - Analyses window definition of safety variables  
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Table 9 - Analyses window definition of PD variables  
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Unscheduled visits 
Unscheduled visit measurements of laboratory data, vital signs, and ECG will be used for 
computation of baseline, the last on-treatment value, analysis according to PCSAs, and the shift 
summaries for safety. They will also be included in the by-visit summaries (central lab only for 
laboratory) if they are re-allocated to scheduled visits based on the analysis windows defined 
above. 
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6 
REFERENCES  
 
1. Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B, et al; BDNF ALS Study 
Group (Phase III). The ALSFRS‑R: a revised ALS functional rating scale that incorporates 
assessments of respiratory function. J Neurol Sci. 1999;169(1-2):13‑21. 
2. Kaufmann P, Levy G, Montes J, Buchsbaum R, Barsdorf AI, Battista V, et al. Excellent 
inter‑rater, intra‑rater, and telephone‑administered reliability of the ALSFRS‑R in a 
multicenter clinical trial. Amyotroph Lateral Scler. 2007;8(1):42‑6. 
3. Berry JD, Miller R, Moore DH, Cudkowicz ME, van den Berg LH, Kerr DA, et al. The 
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