Phase 2 Study for SAR443820 in Participants With Amyotrophic Lateral Sclerosis (ALS)

Study Overview
=================
Brief Summary
-----------------
This is 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, longterm extension period. Study ACT16970 consists of 2 parts (A and B) as follows: Part A is a 24week, 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 will be 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 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 United States of America [USA] and Albrioza in Canada) (yes vs no). Participants will attend in clinic study assessments at baseline (Day 1), Week 2, Week 4, Week 8, Week 16, and Week 24, and will receive a phone call at Week 12 and Week 20. All ongoing participants in Part A will rollover to part B. The Week 24 Visit is the end of Part A and the beginning of Part B. Part B is an open label, longterm extension period that starts from the end of Part A (Week 24) and continues up to Week 106. The objectives of Part B are to further determine the safety and efficacy of longterm SAR443820 treatment. The treatment assignment of participants in Part A will remain 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 , will receive BID oral tablets of SAR443820 in Part B.

Detailed Description
-----------------
Part A of the study will last for 24 weeks, and participants will receive BID oral SAR443820 or placebo in a double-blind fashion for 24 weeks. All ongoing participants in Part A will rollover to Part B. Part B begins at the end of Week 24 and continues up to Week 106. All participants except those who discontinued Investigational Medicinal Product (IMP) treatment permanently in Part A will receive BID oral tablets of 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.

Official 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

Conditions
-----------------
Amyotrophic Lateral Sclerosis

Intervention / Treatment
-----------------
* Drug: SAR443820
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Diagnosis of 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 Time since onset of first symptom of ALS ≤2 years. Slow Vital Capacity (SVC) ≥60% of the predicted value. Be able to swallow the study tablets at the screening visit. 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. Either not currently receiving edaravone or 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. Either not currently receiving the combination of sodium phenylbutyrate and taurursodiol or 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. Participants with a body weight no less than 45 kg and body mass index no less than 18 kg/m2 at the screening visit Female participants with childbearing potential are eligible to participate if they are not pregnant or breastfeeding and agree to use adequate contraceptive method during study intervention period and for at least 32 days after the last dose of study drug. Male participants must agree to use highly effective contraceptive method during the study period and for at least 92 days following their last dose of the study drug. Male participants must not donate sperms for the duration of study and 92 days after last dose of study drug. Exclusion Criteria: A history of seizure (History of febrile seizure during childhood is allowed). Having central IV lines, such as a peripherally inserted central catheter (PICC XE ' PICC ' \f Abbreviation \t 'peripherally inserted central catheter' ) or midline or portacath lines. With 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. 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. With active herpes zoster infection within 2 months prior to the screening visit. 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 (CSSRS) , or in the Investigator's judgment are at risk for a suicide attempt. 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. Participants who are pregnant or are currently breastfeeding. A known history of allergy to any ingredients of SAR443820. Currently or previously treated with any strong or moderate CYP3A4 inhibitors or strong CYP3A4 inducers listed in Appendix 10 of the protocol within the specified washout period before the screening visit. Received a live vaccine within 14 days before the screening visit. 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 halflives of the investigational agent before the screening visit, whichever is longer. Participants who have received stem cell or gene therapy for ALS at any time in the past. 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]) The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAR443820<br>twice daily (BID) oral SAR443820 | Drug: SAR443820<br>* Tablet oral<br>|
| Placebo Comparator: Placebo<br>twice daily (BID) oral placebo | Drug: Placebo<br>* Tablet<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in the ALSFRS-R total score -Part A |  | From baseline to Week 24 | 
| Combined assessment of the function and survival (CAFS) score -Part B |  | Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Combined assessment of the function and survival (CAFS) score -Part A |  | Week 24 | 
| Change from baseline in slow vital capacity (SVC) -Part A |  | From baseline to Week 24 | 
| Muscle Strength - Part A | Measured using a grip dynamometer and a handheld dynamometer (HHD) | From baseline to Week 24 | 
| Change from baseline in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ5) -Part A |  | From baseline to Week 24 | 
| Change from baseline in serum neurofilament light chain (NfL) -Part A |  | From baseline to Week 24 | 
| Number of patients with treatment emergent adverse events (TEAE) and Serious adverse event (SAE) - Part A |  | Up to Week 24 | 
| Assessment of pharmacokinetic parameter -Plasma concentration of SAR443820 -Part A |  | Day 1, Week 2, Week 8 | 
| Combined assessment of the function and survival (CAFS) score - Part B |  | Week 76, Week 104 | 
| Change from baseline in the ALSFRS R total score-Part B |  | From baseline to Week 52 and 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 - Part B |  | Up to Week 106 | 
| Time from baseline to the occurrence of death-Part B |  | Up to Week 106 | 
| Change from baseline in slow vital capacity (SVC)-Part B |  | From baseline to Week 52, Week 76 and Week 104 | 
| Change from baseline in Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-5)-Part B |  | From baseline to Week 52, Week 76 and Week 104 | 
| Change from baseline in serum neurofilament light chain (NfL)-Part B |  | Week 52 | 
| Number of patients with treatment emergent adverse events (TEAE) and Serious adverse event (SAE) -Part B |  | Up to Week 106 | 
| Assessment of pharmacokinetic parameter Plasma concentration of SAR443820 -Part B |  | Week 28 |