A Study to Evaluate the Effect of SAR443820 on Serum Neurofilament Levels in Male and Female Adult Participants With Multiple Sclerosis

Study Overview
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Brief Summary
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This is a Phase 2, randomized, double-blind, placebo-controlled 2 parallel-arm study to assess the effect on serum neurofilament light chain (sNfL), safety and tolerability of oral SAR443820 compared to placebo in male and female participants aged 18 to 60 years with relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS) (relapsing or non-relapsing), or primary progressive multiple sclerosis (PPMS) followed by an open-label long-term extension period. The total study duration is approximately 100 weeks and includes the following: 4-week screening period 48-week double-blind treatment period (Part A) 48-week open-label long-term extension period (Part B)

Detailed Description
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Approximately 100 weeks

Official Title
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A Phase 2 Double-blind, Randomized, Placebo-controlled Study Evaluating the Effect of SAR443820 on Serum Neurofilament Levels in Participants With Multiple Sclerosis, Followed by an Open-label Long-term Extension Period

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: SAR443820
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, 18 to 60 years (inclusive) of age, at the time of signing the informed consent. Participants with diagnosis of RRMS, SPMS (relapsing or non-relapsing) or primary progressive subtype according to the 2017 revision of the McDonald diagnostic criteria (SPMS diagnostic criteria according to initial relapsing remitting disease course followed by progression with or without occasional relapses, minor remissions, and plateaus; progression denotes the continuous worsening of neurological impairment over at least 6 months). Participants with Expanded Disability Status Scale (EDSS) score of 26 inclusive at screening. Participants who are either untreated or in the opinion of the Investigator are stable on an allowed disease-modifying therapy (DMT) (interferons, glatiramer acetate, fumarates, or teriflunomide) for at least the past 3 months, AND not anticipated to require a change in multiple sclerosis (MS) treatment for the duration of Part A and Part B (through Week 96); in Part B changes in dose of allowed DMTs or transition to other allowed DMTs is permitted). Participants with body weight at least 45 kg and body mass index (BMI) at least 18.0 kg/m^2. Contraceptive use by men and women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Exclusion Criteria: Participants with immunodeficiency syndromes or other autoimmune diseases requiring immunosuppressive therapy Participants with a history of seizures or epilepsy (history of febrile seizure during childhood is allowed). Participants with known clinical relapse (acute or subacute episodes of new or increasing neurological dysfunction followed by full or partial recovery, in absence of fever or infection) within 8 weeks of screening. Participants with neurological disease history other than MS, eg, head trauma within 3 months, cerebrovascular disease, and vascular dementia. Participants with a history of recent serious infection (eg, pneumonia, septicemia) within 4 weeks of screening; an infection requiring hospitalization or intravenous antibiotics, antivirals, or antifungals within 4 weeks of screening; or chronic bacterial infections (such as tuberculosis) deemed unacceptable, as per Investigator's judgment. Participants who have significant cognitive impairment, psychiatric disease, other neurodegenerative disorders (eg, Parkinson disease or Alzheimer disease), substance abuse, or any other conditions 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. Participants with a documented history of attempted suicide over the 24 weeks prior to the Screening Visit, presents with suicidal ideation of category 4 or 5 on the Columbia Suicide Severity Rating Scale (CSSRS), or if in the Investigator's judgment, the participant is at risk for a suicide attempt. Participants with a history of unstable or severe cardiac, pulmonary, oncological, hepatic, or renal disease or another medically significant illness other than MS precluding their safe participation in this study. Participants who received a live vaccine within 14 days before the Screening Visit. 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). - Participants with a current use of any medications that are moderate or strong inhibitors or strong inducers of cytochrome P450 3A4 (CYP3A4). Participants with a current use of any of the following medications/treatments: fampridine/dalfampridine, ofatumumab, fingolimod, cladribine, siponimod, ponesimod, ozanimod, alemtuzumab, mitoxantrone, ocrelizumab, natalizumab, or similar approved compounds but with different trade names and any unapproved treatments or therapies for MS; any DMTs newly approved after January 2023 that are marketed at any time during the course of the double-blind study period. These medications are not allowed within 5 half-lives before the Screening Visit and for the duration of Part A and Part B. Participants who have prior/concurrent clinical study enrollment, ie, the participant has taken other investigational drugs within 4 weeks or 5 half-lives, whichever is longer, before the first Screening Visit; concurrent or recent participation in non-interventional studies may be permitted. Participants with abnormal laboratory test(s) at the Screening Visit: Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) more than 3.0 x upper limit of normal (ULN) Bilirubin more than 1.5 x ULN; unless the participant has documented Gilbert syndrome (isolated bilirubin more than 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin less than 35%) Serum albumin less than 3.5 g/dL Estimated Glomerular filtration rate less than 60 mL/min/1.73 m^2 (Modification of Diet in Renal Disease [MDRD]) Other abnormal laboratory values or electrocardiogram (ECG) changes that are deemed clinically significant as per Investigator's judgment The above information is not intended to contain all considerations relevant to a potential participation in a clinical trial

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SAR443820<br>Oral SAR443820 | Drug: SAR443820<br>* Tablet by oral administration<br>|
| Placebo Comparator: Placebo<br>Oral placebo | Other: Placebo<br>* Tablet by oral administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Week 48 sNfL levels relative to baseline |  | From baseline (Week 0) to Week 48 | 
| Part B: Week 96 sNfL levels relative to baseline |  | From baseline (Week 0) to Week 96 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part A: Cumulative number of new gadolinium (Gd)-enhancing T1 hyperintense lesions as detected by magnetic resonance imaging (MRI) | The sum of the individual number of new Gd enhancing T1 hyperintense lesions at all scheduled visits starting after baseline up to and including the Week 48 visit. | Baseline (Week 0) to Week 48 | 
| Part A: Cumulative number of new and/or enlarging T2 hyperintense lesions as detected by MRI | The sum of the individual number of new and/or enlarging T2 lesions at all scheduled visits starting after baseline up to and including the Week 48 visit. | Baseline (Week 0) to Week 48 | 
| Part A: Time to onset of 12 weeks confirmed disability progression (CDP) from baseline as assessed by the Expanded Disability Status Scale (EDSS) score | Standard EDSS assessments of 7 functional domains (visual, brainstem, pyramidal [motor], cerebellar [coordination], sensory, cerebral, and bowel/bladder) scoring will be performed by assessing neurological symptoms in each of these domains. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS), where higher scores indicats worst outcomes. Confirmed disease progressions (CDPs) are defined as an increase in EDSS score (defined as an increase of ≥1.0 point from the baseline EDSS score when the baseline score is ≤5.5 or an increase of ≥0.5 points from the baseline EDSS score when the baseline score is >5.5). | Up to Week 48 | 
| Part A: Time to onset of sustained 20% increase in 9-Hole Peg Test (9-HPT) confirmed over at least 12 weeks |  | Up to Week 48 | 
| Part A: Time to onset of sustained 20% increase in timed 25-foot walk test (T25-FW) confirmed over at least 12 weeks |  | Up to Week 48 | 
| Part A: Change from baseline in EDSS Plus | The EDSS-plus event is defined as disability progression on at least 1 of 3 components, EDSS score, or T25-FW test, or 9-HPT. Disability criteria for the individual components are defined as follows: 1) Disability progression on the EDSS is defined as an increase of ≥1.0 point from the baseline EDSS score when the baseline score is ≤5.5 or an increase of ≥0.5 points from the baseline EDSS score when the baseline score is >5.5. 2) Disability progression on the T25-FW test is defined as an increase (worsening) of ≥20% from the baseline score. 3) Disability progression on the 9-HPT is defined as an increase (worsening) of ≥20% from the baseline score. | From baseline (Week 0) to Week 48 | 
| Part A: Annualized relapse rate (ARR) of RMS population (relapsing SPMS and RRMS) |  | Up to Week 48 | 
| Part A: Percent change from baseline in brain volume loss (BVL) as detected by brain MRI |  | From baseline (Week 0) to Weeks 48 | 
| Part A: Change from baseline in the volume of slowly expanding lesions (SELs) |  | From baseline (Week 0) to Weeks 12, 24, 36 and 48 | 
| Part A: Change from baseline in the number of SELs |  | From baseline (Week 0) to Weeks 12, 24, 36 and 48 | 
| Part A: Change from baseline in the intensity (T1) of SELs |  | From baseline (Week 0) to Weeks 12, 24, 36 and 48 | 
| Part A: Change from baseline in the normalized T1 intensity in lesions |  | From baseline (Week 0) to Weeks 12, 24, 36 and 48 | 
| Part A: Change from baseline in the total number of non-enhancing lesions |  | From baseline (Week 0) to Weeks 12, 24, 36 and 48 | 
| Part A: Change from baseline in the volume of non-enhancing lesions |  | From baseline (Week 0) to Weeks 12, 24, 36 and 48 | 
| Part A: Change from baseline in the number of phase rim lesions (PRL) will be conducted at 3 Tesla (3T) capable sites |  | From baseline (Week 0) to Weeks 12, 24, 36 and 48 | 
| Part A: Incidence of adverse event (AE) |  | Week 0 to Week 48 | 
| Part A: Incidence of serious adverse event (SAE) |  | Week 0 to Week 48 | 
| Part A: Incidence of treatment emergent adverse event (TEAE) |  | Week 0 to Week 48 | 
| Part A: Incidence of potentially clinically significant abnormality (PCSA) in laboratory tests |  | Week 0 to Week 48 | 
| Part A: Plasma concentration of SAR443820 | Pre-dose concentration at steady state (Ctrough,ss) | Up to Week 36 | 
| Part B: Percent change from baseline in BVL as detected by brain MRI |  | From baseline (Week 0) to Week 96 | 
| Part B: Change from baseline in the volume of slowly expanding lesions (SELs) |  | From baseline (Week 0) to Weeks 96 | 
| Part B: Change from baseline in the number of SELs |  | From baseline (Week 0) to Weeks 96 | 
| Part B: Change from baseline in the intensity (T1) of SELs |  | From baseline (Week 0) to Weeks 96 | 
| Part B: Change from baseline in the normalized T1 intensity in lesions |  | From baseline (Week 0) to Weeks 96 | 
| Part B: Change from baseline in the total number of non-enhancing lesions |  | From baseline (Week 0) to Weeks 96 | 
| Part B: Change from baseline in the volume of non-enhancing lesions |  | From baseline (Week 0) to Weeks 96 | 
| Part B: Change from baseline in the number of PRLs (same participants/centers from Part A with 3T capability) |  | From baseline (Week 0) to Weeks 96 | 
| Part B: Incidence of AE |  | Week 48 to Week 96 | 
| Part B: Incidence of SAE |  | Week 48 to Week 96 | 
| Part B: Incidence of TEAE |  | Week 48 to Week 96 | 
| Part B: Incidence of potentially clinically significant abnormality (PCSA) in laboratory tests |  | Week 48 to Week 96 | 
| Part B: Incidence of PCSA in ECG |  | Week 48 to Week 96 | 
| Part B: Incidence of PCSA in vital signs |  | Week 48 to Week 96 | 
| Part B: Cumulative number of new Gd-enhancing lesions as detected by T1-weighted MRI |  | Week 48 to Week 96 | 
| Part B: number of new or enlarging T2-hyperintense lesions on MRI |  | Week 48 to Week 96 | 
| Part B: ARR of RMS population (relapsing SPMS and RRMS) |  | Up to Week 96 | 
| Part B: Time to onset of composite CDP (CCDP), confirmed over at least 12 weeks (3-month CCDP), by the EDSS Plus composite (EDSS score increase, OR 20% increase in the T25-FW test, OR 20% increase in the 9-HPT) | The EDSS-plus event is defined as disability progression on at least 1 of 3 components, EDSS score, or T25-FW test, or 9-HPT. Disability criteria for the individual components are defined as follows: 1) Disability progression on the EDSS is defined as an increase of ≥1.0 point from the baseline EDSS score when the baseline score is ≤5.5 or an increase of ≥0.5 points from the baseline EDSS score when the baseline score is >5.5. 2) Disability progression on the T25-FW test is defined as an increase (worsening) of ≥20% from the baseline score. 3) Disability progression on the 9-HPT is defined as an increase (worsening) of ≥20% from the baseline score. | Up to Week 96 | 
| Part B: Time to onset of 12 weeks CDP as assessed by the EDSS score |  | Up to Week 96 | 
| Part B: Time to onset of sustained 20% increase in 9-HPT confirmed over at least 12 weeks |  | Up to Week 96 | 
| Part B: Time to onset of sustained 20% increase T25-FW test confirmed over at least 12 weeks |  | Up to Week 96 | 
| Part B: Change from baseline in EDSS Plus | The EDSS-plus event is defined as disability progression on at least 1 of 3 components, EDSS score, or T25-FW test, or 9-HPT. Disability criteria for the individual components are defined as follows: 1) Disability progression on the EDSS is defined as an increase of ≥1.0 point from the baseline EDSS score when the baseline score is ≤5.5 or an increase of ≥0.5 points from the baseline EDSS score when the baseline score is >5.5. 2) Disability progression on the T25-FW test is defined as an increase (worsening) of ≥20% from the baseline score. 3) Disability progression on the 9-HPT is defined as an increase (worsening) of ≥20% from the baseline score. | From baseline (Week 0) to Week 96 | 
| Part B: Change in Multiple Sclerosis Impact Scale -29 version 2 (MSIS-29v2) physical and psychological domains scoring | The Multiple Sclerosis Impact Scale with 29 items (MSIS-29m) evaluates the specific physical and psychological impact of MS from a patient's perspective. This patient reported outcome (PRO) instrument has 2 subscales: 1) a physical impact score (20 items) and 2) a psychological impact score (9 items). The physical and psychological impact subscales of the MSIS-29v2m range from 0 to 100, with higher scores indicating greater physical or psychological impact. | From baseline (Week 0) to Week 96 | 
| Part B: Change in Multiple Sclerosis Walking Scale 12 items (MSWS-12 | The Multiple Sclerosis Walking Scale (MSWS-12m) measures the impact of walking impairment in patients with MS. This PRO instrument has 12 items with a global score ranging from 0 to 100. A higher score indicates better quality of life. | From baseline (Week 0) to Week 96 |