Multiple Sclerosis
Conditions
Brief summary
This was 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 was approximately 100 weeks and included the following: 4-week screening period 48-week double-blind treatment period (Part A) 48-week open-label long-term extension period (Part B) The study was terminated prior to completion (of Week 96) as primary endpoint was not met. Therefore final duration was less than 96 weeks.
Detailed description
Approximately 100 weeks
Interventions
DRUGSAR443820
Tablet by oral administration
OTHERPlacebo
Tablet by oral administration
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double-blinded treatment (Part A) and open-label long-term extension period (Part B)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
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 2 to 6 inclusive at screening. * Participants who were either untreated or in the opinion of the Investigator were 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 was 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 was 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 was 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 had significant cognitive impairment, psychiatric disease, other neurodegenerative disorders (eg, Parkinson disease or Alzheimer disease), substance abuse, or any other conditions that made the participants unsuitable for participating in the study or interfered 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 was 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 who used any medications that are moderate or strong inhibitors or strong inducers of cytochrome P450 3A4 (CYP3A4). * Participants who used 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 were not allowed within 5 half-lives before the Screening Visit and for the duration of Part A and Part B. * Participants who had prior/concurrent clinical study enrollment, ie, the participant had taken other investigational drugs within 4 weeks or 5 half-lives, whichever was 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Change From Baseline to Week 48 in Serum Neurofilament Light Chain (sNfL) Levels | Baseline (up to Day 1, pre-dose) and Week 48 | Serum blood samples were collected at indicated time points to measure changes in NfL, a marker of neuronal damage. Baseline was defined as the average value of the assessments on screening and Day 1 visits prior to the first dose of the study treatment unless the number of Gadolinium (Gd)-enhancing T1 lesion at Day 1 was greater than zero in which case baseline was the lower value of screening and Day 1 visits. |
| Part B: Change From Baseline to Week 72 in Serum Neurofilament Light Chain Levels | Baseline (up to Day 1, pre-dose) and Week 72 | Serum blood samples were collected at indicated time points to measure changes in NfL, a marker of neuronal damage. Baseline was defined as the average value of the assessments on screening and Day 1 visits prior to the first dose of the study treatment unless the number of Gd-enhancing T1 lesion at Day 1 was greater than zero in which case baseline was the lower value of screening and Day 1 visits. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Part A: Number of New, Enlarging T2 Hyperintense Lesions as Detected by MRI | Post-baseline (Baseline: Day 1, pre-dose) and up to Week 48 | The adjusted number of new, enlarging T2 hyperintense lesions per year were derived using negative binomial model. |
| Part B: Number of New, Enlarging T2 Hyperintense Lesions as Detected by MRI | From Week 48 to approximately up to Week 72 | Cumulative number of new, enlarging T2 hyperintense lesions detected by MRI, defined as the sum of the individual number of new, enlarging T2 hyperintense lesions at all scheduled visits at all scheduled visits calculated for each arm/group as a whole. |
| Part A: Time to Onset of 12 Weeks Confirmed Disability Progression (CDP) From Baseline as Assessed by the Expanded Disability Status Scale (EDSS) Score | Baseline (Day 1, pre-dose) and Week 48 | Time to onset of 12 weeks CDP was defined as time from randomization to onset of an increase in EDSS score (defined as an increase of \>=1.0 point from baseline EDSS score when baseline score was \<=5.5 or an increase of \>=0.5 points from baseline EDSS score when baseline score was \>5.5) confirmed after a 12 weeks interval. EDSS was a scale for assessing neurologic impairment in participants with MS, based on 7 functional systems (FS) in brain which was used to derive score. The standard EDSS assessments of 7 FS (visual, brain stem, pyramidal, cerebellar, sensory, bowel/bladder, and cerebral functions) scoring was performed by assessment of neurologic symptoms in each FS. Ambulation scoring was done to conclude evaluation. Individual FS scores were then used in conjugation with ambulation score to obtain EDSS score which ranged from 0 (normal) to 10 (death due to MS), with higher scores indicating greater disability. Baseline was defined as Day 1 (pre-dose). |
| Part B: Time to Onset of 24 Weeks Confirmed Disability Progression From Baseline as Assessed by the Expanded Disability Status Scale Score | Baseline (Day 1, pre-dose) and approximately up to Week 72 | Time to onset of 24 weeks CDP was defined as time from randomization to onset of an increase in EDSS score (defined as an increase of \>=1.0 point from baseline EDSS score when baseline score was \<=5.5 or an increase of \>=0.5 points from baseline EDSS score when baseline score was \>5.5) confirmed after a 12 weeks interval. EDSS was a scale for assessing neurologic impairment in participants with MS, based on 7 FS in brain which was used to derive score. The standard EDSS assessments of 7 FS (visual, brain stem, pyramidal, cerebellar, sensory, bowel/bladder, and cerebral functions) scoring was performed by assessment of neurologic symptoms in each FS. Ambulation scoring was done to conclude evaluation. Individual FS scores were then used in conjugation with ambulation score to obtain EDSS score which ranged from 0 (normal) to 10 (death due to MS), with higher scores indicating greater disability. Baseline was defined as Day 1 (pre-dose). |
| Part A: Time to Onset of Sustained 20% Increase in 9-Hole Peg Test (9-HPT) Confirmed Over at Least 12 Weeks | Baseline (Day 1, pre-dose) and Week 48 | The 9-HPT was a brief, standardized, quantitative test of upper extremity function (lower bound: 10 seconds; upper bound: 300 seconds). Two consecutive trials with the dominant hand were immediately followed by 2 consecutive trials with the non-dominant hand. The mean time to test completion served as an assessment of the participant's hand dexterity. A participant was asked to place pegs into holes and remove them with the dominant and non-dominant hand for several repetitions. A higher value of overall 9-HPT was indicative of higher disability. An increase of \>=20% from the baseline score in the 9-HPT was considered meaningful worsening. Baseline was defined as Day 1 (pre-dose). |
| Part B: Time to Onset of Sustained 20% Increase in 9-Hole Peg Test Confirmed Over at Least 24 Weeks | Baseline (Day 1, pre-dose) and approximately up to Week 72 | The 9-HPT was a brief, standardized, quantitative test of upper extremity function (lower bound: 10 seconds; upper bound: 300 seconds). Two consecutive trials with the dominant hand were immediately followed by 2 consecutive trials with the non-dominant hand. The mean time to test completion served as an assessment of the participant's hand dexterity. A participant was asked to place pegs into holes and remove them with the dominant and non-dominant hand for several repetitions. A higher value of overall 9-HPT was indicative of higher disability. An increase of \>20% from the baseline score in the 9-HPT was considered meaningful worsening. Baseline was defined as Day 1 (pre-dose). |
| Part A: Time to Onset of Sustained 20% Increase in Timed 25-Foot Walk Test (T25-FW) Confirmed Over at Least 12 Weeks | Baseline (Day 1, pre-dose) and Week 48 | The T25-FW test was used to assess a participant's walking ability, time in seconds to walk 25 feet (lower bound: 2.2 seconds; upper bound: 180 seconds). The participant was directed to 1 end of a clearly marked 25-foot course and was instructed to walk 25 feet as quickly as safely possible with several repetitions. The mean walk time was used for assessment of the participant's walking ability. An increase of \>20% from the baseline score in the T25-FW test was considered as meaningful worsening. Baseline was defined as Day 1 (pre-dose). |
| Part B: Time to Onset of Sustained 20% Increase in Timed 25-Foot Walk Test Confirmed Over at Least 24 Weeks | Baseline (Day 1, pre-dose) and approximately up to Week 72 | The T25-FW test was used to assess a participant's walking ability, time in seconds to walk 25 feet (lower bound: 2.2 seconds; upper bound: 180 seconds). The participant was directed to one end of a clearly marked 25-foot course and was instructed to walk 25 feet as quickly as safely possible with several repetitions. The mean walk time was used for assessment of the participant's walking ability. An increase of \>20% from the baseline score in the T25-FW test was considered as meaningful worsening. Baseline was defined as Day 1 (pre-dose). |
| Parts A and B: Change From Baseline in Expanded Disability Status Scale Score | Baseline (Day 1, pre-dose) and Week 48 (Part A) and approximately up to Week 72 (Part B) | EDSS was a scale for assessing neurologic impairment in participants with MS, based on 7 FS in the brain which was used to derive the EDSS (score). The standard EDSS assessments of 7 FS (visual, brain stem, pyramidal, cerebellar, sensory, bowel/bladder, and cerebral functions) scoring was performed by assessment of neurologic symptoms in each FS. Ambulation scoring was done to conclude the evaluation. Individual FS scores were then used in conjugation with ambulation score to obtain EDSS score which ranged from 0 (normal) to 10 (death due to MS), with higher scores indicating greater disability. A negative change from baseline indicates improvement. Baseline was defined as Day 1 (pre-dose). |
| Part A: Annualized Relapse Rate (ARR) of Relapsing Remitting Multiple Sclerosis (RMS) Population | Up to Week 48 | Relapse was defined as the occurrence of acute, new neurological symptoms or worsening of previous neurological symptoms with an objective change on neurological examination attributable to MS. Symptoms were as follows: attributed to MS, last for \>=24 hours, present at normal body temperature, and preceded by \>=30 days of clinical stability (no previous MS relapse). The adjusted ARR was derived using negative binomial model with the total number of relapses per participant occurring in the observation period. |
| Part B: Annualized Relapse Rate of Relapsing Remitting Multiple Sclerosis Population | Approximately up to Week 72 | Relapse was defined as the occurrence of acute, new neurological symptoms or worsening of previous neurological symptoms with an objective change on neurological examination attributable to MS. Symptoms were as follows: attributed to MS, last for \>=24 hours, present at normal body temperature, and preceded by \>=30 days of clinical stability (no previous MS relapse). The unadjusted ARR was the total number of relapses that occurred during the observation period divided by the total participant years in the study. |
| Parts A and B: Percent Change From Baseline in Brain Volume Loss (BVL) as Detected by Brain Magnetic Resonance Imaging | Baseline (Day 1, pre-dose) and Week 48 (Part A) and approximately up to Week 72 (Part B) | The basic MRI scan was performed at all sites and used to evaluate BVL. Imaging measure to detect degree of atrophy or decrease in whole brain, cortical and/or thalamic volume, which was diagnostic evidence of disease progression and played a key role in long-term disability. Baseline was defined as Day 1 (pre-dose). |
| Part A: Number of New Gadolinium-Enhancing T1 Hyperintense Lesions as Detected by Magnetic Resonance Imaging (MRI) | Post-baseline (Baseline: Day 1, pre-dose) and up to Week 48 | The adjusted number of new Gd-enhancing T1 hyperintense lesions per scan were derived using negative binomial model. |
| Part B: Volume of Slowly Expanding Lesions | Approximately up to Week 72 | The basic MRI scan was performed at all sites and used to evaluate volume of SELs. SELs represent chronic active lesions in MS where there is ongoing, smoldering inflammation primarily driven by activated microglia and macrophages at the lesion edges. This localized, radial expansion causes gradual enlargement of pre-existing T2 MRI lesions over time and leads to progressive neural tissue damage including demyelination, axonal loss, and irreversible CNS injury. |
| Part A: Number of Slowly Expanding Lesions | Week 48 | The basic MRI scan was performed at all sites and used to evaluate number of SELs. SELs represent chronic active lesions in MS where there is ongoing, smoldering inflammation primarily driven by activated microglia and macrophages at the lesion edges. This localized, radial expansion causes gradual enlargement of pre-existing T2 MRI lesions over time and leads to progressive neural tissue damage including demyelination, axonal loss, and irreversible CNS injury. |
| Part B: Number of Slowly Expanding Lesions | Approximately up to Week 72 | The basic MRI scan was performed at all sites and used to evaluate number of SELs. SELs represent chronic active lesions in MS where there is ongoing, smoldering inflammation primarily driven by activated microglia and macrophages at the lesion edges. This localized, radial expansion causes gradual enlargement of pre-existing T2 MRI lesions over time and leads to progressive neural tissue damage including demyelination, axonal loss, and irreversible CNS injury. |
| Part A: Normalized T1 Intensity of Slowly Expanding Lesions | Baseline (Day 1, pre-dose), Weeks 12, 24, 36, and 48 | The basic MRI scan was performed at all sites and used to evaluate normalization of T1 intensity of SELs. It was used to quantify tissue damage within SELs of MS, reflecting neuro-axonal loss and demyelination and correlating with clinical progression. |
| Part B: Normalized T1 Intensity of Slowly Expanding Lesions | Week 48 and Week 72 | The basic MRI scan was performed at all sites and used to evaluate normalized T1 intensity of SELs. It was used to quantify tissue damage within SELs of MS, reflecting neuro-axonal loss and demyelination and correlating with clinical progression. |
| Part A: Change From Baseline in the Number of Phase Rim Lesions (PRL) Conducted at 3 Tesla (3T) Capable Sites | Baseline (Day 1, pre-dose) and Weeks 12, 24, 36, and 48 | The basic MRI scan sequences were performed at all sites and used to evaluate number of PRL. Phase rim lesions were a subtype of MS lesion identified by a paramagnetic edge indicative chronic smoldering inflammation linked to chronic active lesions. Baseline was defined as Day 1 (pre-dose). |
| Part B: Change From Baseline in the Number of Phase Rim Lesions Conducted at 3 Tesla Capable Sites | Baseline (Day 1, pre-dose) and approximately up to Week 72 | The basic MRI scan sequences were performed at all sites and used to evaluate number of PRL. Phase rim lesions were a subtype of MS lesion identified by a paramagnetic edge indicative chronic smoldering inflammation linked to chronic active lesions. Baseline was defined as Day 1 (pre-dose). |
| Parts B and A+B: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) After SAR443820 Initiation | From first dose of SAR443820 (Day 1, post-dose) up to 14 days after last dose of SAR443820 administration in Part B, approximately 93 weeks for Parts A+B combined arm (SAR443820/SAR443820), approximately 45 weeks Part B Arm (Placebo/SAR443820) | An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. TEAEs were defined as the AEs that developed, worsened or became serious during the treatment-emergent period (defined as time from first administration of study treatment (Day 1) to last administration of study treatment + 14 days). SAE: Any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. All TEAE occurring after SAR443820 initiation are provided for both randomized treatment arms in this endpoint. |
| Part A: Plasma Concentration of SAR443820 | Day 1: 0.25-1 hour and 1-3 hours post-dose; Week 2: pre-dose, 0.5-3 hours post-dose; Weeks 6, 12, and 36: pre-dose | Plasma samples were collected at specified timepoints to determine plasma concentrations of SAR443820. |
| Part B: Time to Onset of Composite Confirmed Disability Progression Confirmed Over at Least 24 Weeks | Baseline (Day 1, pre-dose) and approximately up to Week 72 | Time to onset of 24-week CCDP, was assessed by composite endpoint EDSS-Plus (EDSS score, or T25-FW test, or 9-HPT), was confirmed over at least 24 week. The EDSS-plus event was 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: Disability progression on the EDSS was defined as an increase of \>=1.0 point from the baseline EDSS score when the baseline score was \<=5.5 or an increase of \>=0.5 points from the baseline EDSS score when the baseline score was \>5.5. Disability progression on the T25-FW test was defined as an increase (worsening) of \>=20% from the baseline score. Disability progression on the 9-HPT was defined as an increase (worsening) of \>=20% from the baseline score. Baseline was defined as Day 1 (pre-dose). |
| Part B: Change From Baseline in Multiple Sclerosis Impact Scale-29 Version 2 (MSIS-29v2) Physical and Psychological Domains Scores | Baseline (Day 1, pre-dose) and approximately up to Week 72 | The MSIS-29v2 evaluates the specific physical and psychological impact of MS from a participant's perspective. This participant reported outcome instrument has 2 subscales: a physical impact score (20 items) and a psychological impact score (9 items). The physical and psychological impact subscales of the MSIS-29v2 range from 0 to 100, with higher scores indicating greater physical or psychological impact. Each of the 2 scales are scored by summing the responses across items, then converting to score range 0-100 where 100 indicates greater impact of disease on daily function (worse health). Baseline was defined as Day 1 (pre-dose). |
| Part B: Change From Baseline in Multiple Sclerosis Walking Scale 12 Items (MSWS-12) Scores | Baseline (Day 1, pre-dose) and approximately up to Week 72 | The MSWS-12 measured the impact of walking impairment in participants with MS. This participant reported outcome instrument has 12 items with a global score ranging from 0 to 100. A higher score indicates better quality of life. The MSWS-12 score was calculated by summing the 12 components and transforming into a scale with a range of 0 to 100, with higher score indicating better quality of life. Baseline was defined as Day 1 (pre-dose). |
| Part A: Volume of Slowly Expanding Lesions (SELs) | Week 48 | The basic MRI scan was performed at all sites and used to evaluate volume of SELs. SELs represent chronic active lesions in MS where there is ongoing, smoldering inflammation primarily driven by activated microglia and macrophages at the lesion edges. This localized, radial expansion causes gradual enlargement of pre-existing T2 MRI lesions over time and leads to progressive neural tissue damage including demyelination, axonal loss, and irreversible central nervous system (CNS) injury. |
| Part B: Number of New Gadolinium-Enhancing T1 Hyperintense Lesions as Detected by MRI | From Week 48 to approximately up to Week 72 | Cumulative number of new Gd-enhancing T1 hyperintense lesions detected by MRI, defined as the sum of the individual number of new Gd-enhancing T1 hyperintense lesions at all scheduled visits calculated for each arm/group as a whole. |
Countries
Belgium, Bulgaria, Canada, Chile, China, France, Germany, Italy, Poland, Spain
Participant flow
Recruitment details
The study was conducted at 34 centers in 10 countries. A total of 190 participants were screened between 19 December 2022 and 15 September 2023, of which 16 were screen failures. Screen failures were due to not meeting the eligibility criteria.
Pre-assignment details
The study consisted of a screening period (4 weeks before randomization), treatment period (a 48-week double-blind in Part A, an 48-week open-label in Part B, with a maximum total study duration of 100 weeks. A total of 174 participants were randomized and 173 were treated in the study. The study was terminated as it did not meet its primary and key secondary endpoints, therefore Week 96 data was not collected.
Participants by arm
| Arm | Count |
|---|---|
| Part A: Placebo Participants received placebo matching SAR443820 tablet orally QD for 48 weeks in Part A. | 86 |
| Part A: SAR443820 Participants received SAR443820 20 mg tablet orally QD for 48 weeks in Part A. | 88 |
| Total | 174 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Part A (Double-blind Period: 48 Weeks) | Adverse Event | 1 | 13 | 0 | 0 |
| Part A (Double-blind Period: 48 Weeks) | Lack of Efficacy | 0 | 1 | 0 | 0 |
| Part A (Double-blind Period: 48 Weeks) | Other | 0 | 2 | 0 | 0 |
| Part A (Double-blind Period: 48 Weeks) | Randomized and not treated | 0 | 1 | 0 | 0 |
| Part A (Double-blind Period: 48 Weeks) | Withdrawal by Subject | 8 | 3 | 0 | 0 |
| Part B (Open-label Period: 48 Weeks) | Adverse Event | 0 | 0 | 3 | 1 |
| Part B (Open-label Period: 48 Weeks) | Lack of Efficacy | 0 | 0 | 1 | 1 |
| Part B (Open-label Period: 48 Weeks) | Non-compliance with study schedule | 0 | 0 | 0 | 1 |
| Part B (Open-label Period: 48 Weeks) | Study terminated by sponsor | 0 | 0 | 72 | 62 |
| Part B (Open-label Period: 48 Weeks) | Withdrawal by Subject | 0 | 0 | 1 | 3 |
Baseline characteristics
| Characteristic | Part A: SAR443820 | Total | Part A: Placebo |
|---|---|---|---|
| Age, Continuous | 48.22 years STANDARD_DEVIATION 8.21 | 47.75 years STANDARD_DEVIATION 8.88 | 47.27 years STANDARD_DEVIATION 9.54 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 10 Participants | 7 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 11 Participants | 20 Participants | 9 Participants |
| Race (NIH/OMB) White | 74 Participants | 143 Participants | 69 Participants |
| Sex: Female, Male Female | 53 Participants | 107 Participants | 54 Participants |
| Sex: Female, Male Male | 35 Participants | 67 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 86 | 0 / 87 | 0 / 77 | 0 / 68 |
| other Total, other adverse events | 37 / 86 | 43 / 87 | 15 / 77 | 8 / 68 |
| serious Total, serious adverse events | 1 / 86 | 2 / 87 | 5 / 77 | 0 / 68 |
Outcome results
Primary
Part A: Change From Baseline to Week 48 in Serum Neurofilament Light Chain (sNfL) Levels
Serum blood samples were collected at indicated time points to measure changes in NfL, a marker of neuronal damage. Baseline was defined as the average value of the assessments on screening and Day 1 visits prior to the first dose of the study treatment unless the number of Gadolinium (Gd)-enhancing T1 lesion at Day 1 was greater than zero in which case baseline was the lower value of screening and Day 1 visits.
Time frame: Baseline (up to Day 1, pre-dose) and Week 48
Population: The modified intent-to-treat (mITT) population consisted of all randomized participants who took at least 1 dose of study treatment and with an evaluable primary endpoint. Only participants with data collected at baseline and Week 48 are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | Part A: Change From Baseline to Week 48 in Serum Neurofilament Light Chain (sNfL) Levels | Baseline | 9.622 picograms per milliliter (pg/mL) | Standard Deviation 5.316 |
| Part A: Placebo | Part A: Change From Baseline to Week 48 in Serum Neurofilament Light Chain (sNfL) Levels | Week 48 | 0.958 picograms per milliliter (pg/mL) | Standard Deviation 6.983 |
| Part A: SAR443820 | Part A: Change From Baseline to Week 48 in Serum Neurofilament Light Chain (sNfL) Levels | Baseline | 10.319 picograms per milliliter (pg/mL) | Standard Deviation 7.402 |
| Part A: SAR443820 | Part A: Change From Baseline to Week 48 in Serum Neurofilament Light Chain (sNfL) Levels | Week 48 | -0.343 picograms per milliliter (pg/mL) | Standard Deviation 7.761 |
Comparison: Analysis was performed using mixed-effect model with repeated measures (MMRM) including the fixed categorical effects of the treatment group, multiple sclerosis (MS) clinical subtype (relapsing remitting multiple sclerosis \[RRMS\], secondary progressive multiple sclerosis \[SPMS\], or primary progressive multiple sclerosis \[PPMS\]), visit, treatment-by-visit interaction, log-transformed baseline sNfL levels and log-transformed baseline sNfL levels-by-visit interaction.p-value: 0.804295% CI: [0.881, 1.103]MMRM
Primary
Part B: Change From Baseline to Week 72 in Serum Neurofilament Light Chain Levels
Serum blood samples were collected at indicated time points to measure changes in NfL, a marker of neuronal damage. Baseline was defined as the average value of the assessments on screening and Day 1 visits prior to the first dose of the study treatment unless the number of Gd-enhancing T1 lesion at Day 1 was greater than zero in which case baseline was the lower value of screening and Day 1 visits.
Time frame: Baseline (up to Day 1, pre-dose) and Week 72
Population: The mITT population consisted of all randomized participants who took at least 1 dose of study treatment and with an evaluable primary endpoint. Only participants with data collected at baseline and Week 72 are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | Part B: Change From Baseline to Week 72 in Serum Neurofilament Light Chain Levels | Baseline | 9.622 pg/mL | Standard Deviation 5.316 |
| Part A: Placebo | Part B: Change From Baseline to Week 72 in Serum Neurofilament Light Chain Levels | Week 72 | -0.320 pg/mL | Standard Deviation 3.433 |
| Part A: SAR443820 | Part B: Change From Baseline to Week 72 in Serum Neurofilament Light Chain Levels | Baseline | 10.319 pg/mL | Standard Deviation 7.402 |
| Part A: SAR443820 | Part B: Change From Baseline to Week 72 in Serum Neurofilament Light Chain Levels | Week 72 | -0.270 pg/mL | Standard Deviation 5.247 |
Secondary
Part A: Annualized Relapse Rate (ARR) of Relapsing Remitting Multiple Sclerosis (RMS) Population
Relapse was defined as the occurrence of acute, new neurological symptoms or worsening of previous neurological symptoms with an objective change on neurological examination attributable to MS. Symptoms were as follows: attributed to MS, last for \>=24 hours, present at normal body temperature, and preceded by \>=30 days of clinical stability (no previous MS relapse). The adjusted ARR was derived using negative binomial model with the total number of relapses per participant occurring in the observation period.
Time frame: Up to Week 48
Population: Randomized and treated population consisted of all randomized participants who took at least 1 dose of study treatment. Only participants with RMS (RRMS plus relapsing SPMS) are reported.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Placebo | Part A: Annualized Relapse Rate (ARR) of Relapsing Remitting Multiple Sclerosis (RMS) Population | NA relapses per participant-year |
| Part A: SAR443820 | Part A: Annualized Relapse Rate (ARR) of Relapsing Remitting Multiple Sclerosis (RMS) Population | NA relapses per participant-year |
Secondary
Part A: Change From Baseline in the Number of Phase Rim Lesions (PRL) Conducted at 3 Tesla (3T) Capable Sites
The basic MRI scan sequences were performed at all sites and used to evaluate number of PRL. Phase rim lesions were a subtype of MS lesion identified by a paramagnetic edge indicative chronic smoldering inflammation linked to chronic active lesions. Baseline was defined as Day 1 (pre-dose).
Time frame: Baseline (Day 1, pre-dose) and Weeks 12, 24, 36, and 48
Population: Randomized and treated population consisted of all randomized participants who took at least 1 dose of study treatment. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | Part A: Change From Baseline in the Number of Phase Rim Lesions (PRL) Conducted at 3 Tesla (3T) Capable Sites | Week 12 | 0.05 phase rim lesions | Standard Deviation 0.22 |
| Part A: Placebo | Part A: Change From Baseline in the Number of Phase Rim Lesions (PRL) Conducted at 3 Tesla (3T) Capable Sites | Week 24 | 0.11 phase rim lesions | Standard Deviation 0.65 |
| Part A: Placebo | Part A: Change From Baseline in the Number of Phase Rim Lesions (PRL) Conducted at 3 Tesla (3T) Capable Sites | Week 36 | 0.11 phase rim lesions | Standard Deviation 0.83 |
| Part A: Placebo | Part A: Change From Baseline in the Number of Phase Rim Lesions (PRL) Conducted at 3 Tesla (3T) Capable Sites | Week 48 | 0.14 phase rim lesions | Standard Deviation 1.02 |
| Part A: SAR443820 | Part A: Change From Baseline in the Number of Phase Rim Lesions (PRL) Conducted at 3 Tesla (3T) Capable Sites | Week 48 | -0.03 phase rim lesions | Standard Deviation 0.18 |
| Part A: SAR443820 | Part A: Change From Baseline in the Number of Phase Rim Lesions (PRL) Conducted at 3 Tesla (3T) Capable Sites | Week 12 | 0.00 phase rim lesions | Standard Deviation 0 |
| Part A: SAR443820 | Part A: Change From Baseline in the Number of Phase Rim Lesions (PRL) Conducted at 3 Tesla (3T) Capable Sites | Week 36 | 0.00 phase rim lesions | Standard Deviation 0 |
| Part A: SAR443820 | Part A: Change From Baseline in the Number of Phase Rim Lesions (PRL) Conducted at 3 Tesla (3T) Capable Sites | Week 24 | 0.00 phase rim lesions | Standard Deviation 0 |
Secondary
Part A: Normalized T1 Intensity of Slowly Expanding Lesions
The basic MRI scan was performed at all sites and used to evaluate normalization of T1 intensity of SELs. It was used to quantify tissue damage within SELs of MS, reflecting neuro-axonal loss and demyelination and correlating with clinical progression.
Time frame: Baseline (Day 1, pre-dose), Weeks 12, 24, 36, and 48
Population: Randomized and treated population consisted of all randomized participants who took at least 1 dose of study treatment. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | Part A: Normalized T1 Intensity of Slowly Expanding Lesions | Week 12 | -0.066 ratio | Standard Deviation 0.369 |
| Part A: Placebo | Part A: Normalized T1 Intensity of Slowly Expanding Lesions | Week 36 | -0.107 ratio | Standard Deviation 0.355 |
| Part A: Placebo | Part A: Normalized T1 Intensity of Slowly Expanding Lesions | Week 24 | -0.096 ratio | Standard Deviation 0.352 |
| Part A: Placebo | Part A: Normalized T1 Intensity of Slowly Expanding Lesions | Week 48 | -0.123 ratio | Standard Deviation 0.357 |
| Part A: Placebo | Part A: Normalized T1 Intensity of Slowly Expanding Lesions | Baseline (Day 1, pre-dose) | -0.055 ratio | Standard Deviation 0.346 |
| Part A: SAR443820 | Part A: Normalized T1 Intensity of Slowly Expanding Lesions | Week 48 | -0.058 ratio | Standard Deviation 0.37 |
| Part A: SAR443820 | Part A: Normalized T1 Intensity of Slowly Expanding Lesions | Baseline (Day 1, pre-dose) | 0.008 ratio | Standard Deviation 0.354 |
| Part A: SAR443820 | Part A: Normalized T1 Intensity of Slowly Expanding Lesions | Week 12 | -0.026 ratio | Standard Deviation 0.325 |
| Part A: SAR443820 | Part A: Normalized T1 Intensity of Slowly Expanding Lesions | Week 24 | -0.031 ratio | Standard Deviation 0.341 |
| Part A: SAR443820 | Part A: Normalized T1 Intensity of Slowly Expanding Lesions | Week 36 | -0.053 ratio | Standard Deviation 0.35 |
Secondary
Part A: Number of New, Enlarging T2 Hyperintense Lesions as Detected by MRI
The adjusted number of new, enlarging T2 hyperintense lesions per year were derived using negative binomial model.
Time frame: Post-baseline (Baseline: Day 1, pre-dose) and up to Week 48
Population: Randomized and treated population consisted of all randomized participants who took at least 1 dose of study treatment.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Part A: Placebo | Part A: Number of New, Enlarging T2 Hyperintense Lesions as Detected by MRI | 1.285 new and enlarging T2 lesions per year |
| Part A: SAR443820 | Part A: Number of New, Enlarging T2 Hyperintense Lesions as Detected by MRI | 2.532 new and enlarging T2 lesions per year |
Secondary
Part A: Number of New Gadolinium-Enhancing T1 Hyperintense Lesions as Detected by Magnetic Resonance Imaging (MRI)
The adjusted number of new Gd-enhancing T1 hyperintense lesions per scan were derived using negative binomial model.
Time frame: Post-baseline (Baseline: Day 1, pre-dose) and up to Week 48
Population: Randomized and treated population consisted of all randomized participants who took at least 1 dose of study treatment.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Part A: Placebo | Part A: Number of New Gadolinium-Enhancing T1 Hyperintense Lesions as Detected by Magnetic Resonance Imaging (MRI) | 0.043 new Gd-enhancing T1 lesions per scan |
| Part A: SAR443820 | Part A: Number of New Gadolinium-Enhancing T1 Hyperintense Lesions as Detected by Magnetic Resonance Imaging (MRI) | 0.155 new Gd-enhancing T1 lesions per scan |
Secondary
Part A: Number of Slowly Expanding Lesions
The basic MRI scan was performed at all sites and used to evaluate number of SELs. SELs represent chronic active lesions in MS where there is ongoing, smoldering inflammation primarily driven by activated microglia and macrophages at the lesion edges. This localized, radial expansion causes gradual enlargement of pre-existing T2 MRI lesions over time and leads to progressive neural tissue damage including demyelination, axonal loss, and irreversible CNS injury.
Time frame: Week 48
Population: Randomized and treated population consisted of all randomized participants who took at least 1 dose of study treatment. Participants were analyzed according to the intervention allocated by randomization. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A: Placebo | Part A: Number of Slowly Expanding Lesions | 1.507 number of SEL |
| Part A: SAR443820 | Part A: Number of Slowly Expanding Lesions | 1.534 number of SEL |
Secondary
Part A: Plasma Concentration of SAR443820
Plasma samples were collected at specified timepoints to determine plasma concentrations of SAR443820.
Time frame: Day 1: 0.25-1 hour and 1-3 hours post-dose; Week 2: pre-dose, 0.5-3 hours post-dose; Weeks 6, 12, and 36: pre-dose
Population: Pharmacokinetic (PK) population consisted of all randomized and treated participants with at least 1 post-baseline PK result with adequate documentation of dosing and sampling dates and times. Only participants who received SAR443820 with data collected at specified timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | Part A: Plasma Concentration of SAR443820 | Day 1: 0.25-1 hours post-dose | 205.450 nanogram/mL | Standard Deviation 134.734 |
| Part A: Placebo | Part A: Plasma Concentration of SAR443820 | Day 1: 1-3 hours post-dose | 237.232 nanogram/mL | Standard Deviation 92.001 |
| Part A: Placebo | Part A: Plasma Concentration of SAR443820 | Week 2: pre-dose | 52.841 nanogram/mL | Standard Deviation 54.432 |
| Part A: Placebo | Part A: Plasma Concentration of SAR443820 | Week 2: 0.5-3 hours post-dose | 289.312 nanogram/mL | Standard Deviation 129.688 |
| Part A: Placebo | Part A: Plasma Concentration of SAR443820 | Week 6: pre-dose | 45.230 nanogram/mL | Standard Deviation 41.458 |
| Part A: Placebo | Part A: Plasma Concentration of SAR443820 | Week 12: pre-dose | 49.039 nanogram/mL | Standard Deviation 41.203 |
| Part A: Placebo | Part A: Plasma Concentration of SAR443820 | Week 36: pre-dose | 56.461 nanogram/mL | Standard Deviation 60.18 |
Secondary
Part A: Time to Onset of 12 Weeks Confirmed Disability Progression (CDP) From Baseline as Assessed by the Expanded Disability Status Scale (EDSS) Score
Time to onset of 12 weeks CDP was defined as time from randomization to onset of an increase in EDSS score (defined as an increase of \>=1.0 point from baseline EDSS score when baseline score was \<=5.5 or an increase of \>=0.5 points from baseline EDSS score when baseline score was \>5.5) confirmed after a 12 weeks interval. EDSS was a scale for assessing neurologic impairment in participants with MS, based on 7 functional systems (FS) in brain which was used to derive score. The standard EDSS assessments of 7 FS (visual, brain stem, pyramidal, cerebellar, sensory, bowel/bladder, and cerebral functions) scoring was performed by assessment of neurologic symptoms in each FS. Ambulation scoring was done to conclude evaluation. Individual FS scores were then used in conjugation with ambulation score to obtain EDSS score which ranged from 0 (normal) to 10 (death due to MS), with higher scores indicating greater disability. Baseline was defined as Day 1 (pre-dose).
Time frame: Baseline (Day 1, pre-dose) and Week 48
Population: Randomized and treated population consisted of all randomized participants who took at least 1 dose of study treatment. Only participants with data collected at baseline and Week 48 are reported.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Placebo | Part A: Time to Onset of 12 Weeks Confirmed Disability Progression (CDP) From Baseline as Assessed by the Expanded Disability Status Scale (EDSS) Score | 12.29 weeks |
| Part A: SAR443820 | Part A: Time to Onset of 12 Weeks Confirmed Disability Progression (CDP) From Baseline as Assessed by the Expanded Disability Status Scale (EDSS) Score | 24.14 weeks |
Secondary
Part A: Time to Onset of Sustained 20% Increase in 9-Hole Peg Test (9-HPT) Confirmed Over at Least 12 Weeks
The 9-HPT was a brief, standardized, quantitative test of upper extremity function (lower bound: 10 seconds; upper bound: 300 seconds). Two consecutive trials with the dominant hand were immediately followed by 2 consecutive trials with the non-dominant hand. The mean time to test completion served as an assessment of the participant's hand dexterity. A participant was asked to place pegs into holes and remove them with the dominant and non-dominant hand for several repetitions. A higher value of overall 9-HPT was indicative of higher disability. An increase of \>=20% from the baseline score in the 9-HPT was considered meaningful worsening. Baseline was defined as Day 1 (pre-dose).
Time frame: Baseline (Day 1, pre-dose) and Week 48
Population: Randomized and treated population consisted of all randomized participants who took at least 1 dose of study treatment. Only participants with data collected at baseline and Week 48 are reported.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Placebo | Part A: Time to Onset of Sustained 20% Increase in 9-Hole Peg Test (9-HPT) Confirmed Over at Least 12 Weeks | 35.86 weeks |
| Part A: SAR443820 | Part A: Time to Onset of Sustained 20% Increase in 9-Hole Peg Test (9-HPT) Confirmed Over at Least 12 Weeks | 12.14 weeks |
Secondary
Part A: Time to Onset of Sustained 20% Increase in Timed 25-Foot Walk Test (T25-FW) Confirmed Over at Least 12 Weeks
The T25-FW test was used to assess a participant's walking ability, time in seconds to walk 25 feet (lower bound: 2.2 seconds; upper bound: 180 seconds). The participant was directed to 1 end of a clearly marked 25-foot course and was instructed to walk 25 feet as quickly as safely possible with several repetitions. The mean walk time was used for assessment of the participant's walking ability. An increase of \>20% from the baseline score in the T25-FW test was considered as meaningful worsening. Baseline was defined as Day 1 (pre-dose).
Time frame: Baseline (Day 1, pre-dose) and Week 48
Population: Randomized and treated population consisted of all randomized participants who took at least 1 dose of study treatment. Only participants with data collected at baseline and Week 48 are reported.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Placebo | Part A: Time to Onset of Sustained 20% Increase in Timed 25-Foot Walk Test (T25-FW) Confirmed Over at Least 12 Weeks | 12.29 weeks |
| Part A: SAR443820 | Part A: Time to Onset of Sustained 20% Increase in Timed 25-Foot Walk Test (T25-FW) Confirmed Over at Least 12 Weeks | 18.00 weeks |
Secondary
Part A: Volume of Slowly Expanding Lesions (SELs)
The basic MRI scan was performed at all sites and used to evaluate volume of SELs. SELs represent chronic active lesions in MS where there is ongoing, smoldering inflammation primarily driven by activated microglia and macrophages at the lesion edges. This localized, radial expansion causes gradual enlargement of pre-existing T2 MRI lesions over time and leads to progressive neural tissue damage including demyelination, axonal loss, and irreversible central nervous system (CNS) injury.
Time frame: Week 48
Population: Randomized and treated population consisted of all randomized participants who took at least 1 dose of study treatment. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Part A: Placebo | Part A: Volume of Slowly Expanding Lesions (SELs) | 5.436 microliter (µL) |
| Part A: SAR443820 | Part A: Volume of Slowly Expanding Lesions (SELs) | 5.672 microliter (µL) |
Secondary
Part B: Annualized Relapse Rate of Relapsing Remitting Multiple Sclerosis Population
Relapse was defined as the occurrence of acute, new neurological symptoms or worsening of previous neurological symptoms with an objective change on neurological examination attributable to MS. Symptoms were as follows: attributed to MS, last for \>=24 hours, present at normal body temperature, and preceded by \>=30 days of clinical stability (no previous MS relapse). The unadjusted ARR was the total number of relapses that occurred during the observation period divided by the total participant years in the study.
Time frame: Approximately up to Week 72
Population: Randomized and treated population consisted of all randomized participants who took at least 1 dose of study treatment. Only participants with RMS (RRMS plus relapsing SPMS) are reported.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Placebo | Part B: Annualized Relapse Rate of Relapsing Remitting Multiple Sclerosis Population | 0.052 relapses per participant-year |
| Part A: SAR443820 | Part B: Annualized Relapse Rate of Relapsing Remitting Multiple Sclerosis Population | 0.172 relapses per participant-year |
Secondary
Part B: Change From Baseline in Multiple Sclerosis Impact Scale-29 Version 2 (MSIS-29v2) Physical and Psychological Domains Scores
The MSIS-29v2 evaluates the specific physical and psychological impact of MS from a participant's perspective. This participant reported outcome instrument has 2 subscales: a physical impact score (20 items) and a psychological impact score (9 items). The physical and psychological impact subscales of the MSIS-29v2 range from 0 to 100, with higher scores indicating greater physical or psychological impact. Each of the 2 scales are scored by summing the responses across items, then converting to score range 0-100 where 100 indicates greater impact of disease on daily function (worse health). Baseline was defined as Day 1 (pre-dose).
Time frame: Baseline (Day 1, pre-dose) and approximately up to Week 72
Population: Randomized and treated population consisted of all randomized participants who took at least 1 dose of study treatment. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | Part B: Change From Baseline in Multiple Sclerosis Impact Scale-29 Version 2 (MSIS-29v2) Physical and Psychological Domains Scores | Physical domains score | 11.667 score on a scale | Standard Deviation 28.447 |
| Part A: Placebo | Part B: Change From Baseline in Multiple Sclerosis Impact Scale-29 Version 2 (MSIS-29v2) Physical and Psychological Domains Scores | Psychological domains score | 13.889 score on a scale | Standard Deviation 52.498 |
| Part A: SAR443820 | Part B: Change From Baseline in Multiple Sclerosis Impact Scale-29 Version 2 (MSIS-29v2) Physical and Psychological Domains Scores | Physical domains score | 2.222 score on a scale | Standard Deviation 1.925 |
| Part A: SAR443820 | Part B: Change From Baseline in Multiple Sclerosis Impact Scale-29 Version 2 (MSIS-29v2) Physical and Psychological Domains Scores | Psychological domains score | 4.938 score on a scale | Standard Deviation 5.658 |
Secondary
Part B: Change From Baseline in Multiple Sclerosis Walking Scale 12 Items (MSWS-12) Scores
The MSWS-12 measured the impact of walking impairment in participants with MS. This participant reported outcome instrument has 12 items with a global score ranging from 0 to 100. A higher score indicates better quality of life. The MSWS-12 score was calculated by summing the 12 components and transforming into a scale with a range of 0 to 100, with higher score indicating better quality of life. Baseline was defined as Day 1 (pre-dose).
Time frame: Baseline (Day 1, pre-dose) and approximately up to Week 72
Population: Randomized and treated population consisted of all randomized participants who took at least 1 dose of study treatment. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Part B: Change From Baseline in Multiple Sclerosis Walking Scale 12 Items (MSWS-12) Scores | 4.861 score on a scale | Standard Deviation 17.472 |
| Part A: SAR443820 | Part B: Change From Baseline in Multiple Sclerosis Walking Scale 12 Items (MSWS-12) Scores | -1.389 score on a scale | Standard Deviation 6.365 |
Secondary
Part B: Change From Baseline in the Number of Phase Rim Lesions Conducted at 3 Tesla Capable Sites
The basic MRI scan sequences were performed at all sites and used to evaluate number of PRL. Phase rim lesions were a subtype of MS lesion identified by a paramagnetic edge indicative chronic smoldering inflammation linked to chronic active lesions. Baseline was defined as Day 1 (pre-dose).
Time frame: Baseline (Day 1, pre-dose) and approximately up to Week 72
Population: Randomized and treated population consisted of all randomized participants who took at least 1 dose of study treatment. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Part B: Change From Baseline in the Number of Phase Rim Lesions Conducted at 3 Tesla Capable Sites | 2.33 phase rim lesions | Standard Deviation 4.93 |
| Part A: SAR443820 | Part B: Change From Baseline in the Number of Phase Rim Lesions Conducted at 3 Tesla Capable Sites | -0.25 phase rim lesions | Standard Deviation 0.5 |
Secondary
Part B: Normalized T1 Intensity of Slowly Expanding Lesions
The basic MRI scan was performed at all sites and used to evaluate normalized T1 intensity of SELs. It was used to quantify tissue damage within SELs of MS, reflecting neuro-axonal loss and demyelination and correlating with clinical progression.
Time frame: Week 48 and Week 72
Population: Randomized and treated population consisted of all randomized participants who took at least 1 dose of study treatment. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Part A: Placebo | Part B: Normalized T1 Intensity of Slowly Expanding Lesions | Week 48 | -0.342 ratio | Standard Deviation 0.118 |
| Part A: Placebo | Part B: Normalized T1 Intensity of Slowly Expanding Lesions | Week 72 | -0.507 ratio | Standard Deviation 0.236 |
| Part A: SAR443820 | Part B: Normalized T1 Intensity of Slowly Expanding Lesions | Week 48 | -0.083 ratio | Standard Deviation 0.241 |
| Part A: SAR443820 | Part B: Normalized T1 Intensity of Slowly Expanding Lesions | Week 72 | -0.183 ratio | Standard Deviation 0.201 |
Secondary
Part B: Number of New, Enlarging T2 Hyperintense Lesions as Detected by MRI
Cumulative number of new, enlarging T2 hyperintense lesions detected by MRI, defined as the sum of the individual number of new, enlarging T2 hyperintense lesions at all scheduled visits at all scheduled visits calculated for each arm/group as a whole.
Time frame: From Week 48 to approximately up to Week 72
Population: Randomized and treated population consisted of all randomized participants who took at least 1 dose of study treatment. Here, number of participants analyzed = participants with \>=1 new and/or enlarging T2-hyperintense lesions.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Placebo | Part B: Number of New, Enlarging T2 Hyperintense Lesions as Detected by MRI | 42 new and enlarging T2 lesions |
| Part A: SAR443820 | Part B: Number of New, Enlarging T2 Hyperintense Lesions as Detected by MRI | 57 new and enlarging T2 lesions |
Secondary
Part B: Number of New Gadolinium-Enhancing T1 Hyperintense Lesions as Detected by MRI
Cumulative number of new Gd-enhancing T1 hyperintense lesions detected by MRI, defined as the sum of the individual number of new Gd-enhancing T1 hyperintense lesions at all scheduled visits calculated for each arm/group as a whole.
Time frame: From Week 48 to approximately up to Week 72
Population: Randomized and treated population consisted of all randomized participants who took at least 1 dose of study treatment. Here, number of participants analyzed = participants with \>=1 new enlarging T1-hyperintense lesions.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A: Placebo | Part B: Number of New Gadolinium-Enhancing T1 Hyperintense Lesions as Detected by MRI | 14 new Gd-enhancing T1 lesions |
| Part A: SAR443820 | Part B: Number of New Gadolinium-Enhancing T1 Hyperintense Lesions as Detected by MRI | 13 new Gd-enhancing T1 lesions |
Secondary
Part B: Number of Slowly Expanding Lesions
The basic MRI scan was performed at all sites and used to evaluate number of SELs. SELs represent chronic active lesions in MS where there is ongoing, smoldering inflammation primarily driven by activated microglia and macrophages at the lesion edges. This localized, radial expansion causes gradual enlargement of pre-existing T2 MRI lesions over time and leads to progressive neural tissue damage including demyelination, axonal loss, and irreversible CNS injury.
Time frame: Approximately up to Week 72
Population: Randomized and treated population consisted of all randomized participants who took at least 1 dose of study treatment. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Part B: Number of Slowly Expanding Lesions | 6.60 number of SEL | Standard Deviation 9.84 |
| Part A: SAR443820 | Part B: Number of Slowly Expanding Lesions | 6.25 number of SEL | Standard Deviation 5.32 |
Secondary
Part B: Time to Onset of 24 Weeks Confirmed Disability Progression From Baseline as Assessed by the Expanded Disability Status Scale Score
Time to onset of 24 weeks CDP was defined as time from randomization to onset of an increase in EDSS score (defined as an increase of \>=1.0 point from baseline EDSS score when baseline score was \<=5.5 or an increase of \>=0.5 points from baseline EDSS score when baseline score was \>5.5) confirmed after a 12 weeks interval. EDSS was a scale for assessing neurologic impairment in participants with MS, based on 7 FS in brain which was used to derive score. The standard EDSS assessments of 7 FS (visual, brain stem, pyramidal, cerebellar, sensory, bowel/bladder, and cerebral functions) scoring was performed by assessment of neurologic symptoms in each FS. Ambulation scoring was done to conclude evaluation. Individual FS scores were then used in conjugation with ambulation score to obtain EDSS score which ranged from 0 (normal) to 10 (death due to MS), with higher scores indicating greater disability. Baseline was defined as Day 1 (pre-dose).
Time frame: Baseline (Day 1, pre-dose) and approximately up to Week 72
Population: Randomized and treated population consisted of all randomized participants who took at least 1 dose of study treatment. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Placebo | Part B: Time to Onset of 24 Weeks Confirmed Disability Progression From Baseline as Assessed by the Expanded Disability Status Scale Score | 12.43 weeks |
| Part A: SAR443820 | Part B: Time to Onset of 24 Weeks Confirmed Disability Progression From Baseline as Assessed by the Expanded Disability Status Scale Score | 24.14 weeks |
Secondary
Part B: Time to Onset of Composite Confirmed Disability Progression Confirmed Over at Least 24 Weeks
Time to onset of 24-week CCDP, was assessed by composite endpoint EDSS-Plus (EDSS score, or T25-FW test, or 9-HPT), was confirmed over at least 24 week. The EDSS-plus event was 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: Disability progression on the EDSS was defined as an increase of \>=1.0 point from the baseline EDSS score when the baseline score was \<=5.5 or an increase of \>=0.5 points from the baseline EDSS score when the baseline score was \>5.5. Disability progression on the T25-FW test was defined as an increase (worsening) of \>=20% from the baseline score. Disability progression on the 9-HPT was defined as an increase (worsening) of \>=20% from the baseline score. Baseline was defined as Day 1 (pre-dose).
Time frame: Baseline (Day 1, pre-dose) and approximately up to Week 72
Population: Randomized and treated population consisted of all randomized participants who took at least 1 dose of study treatment. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Placebo | Part B: Time to Onset of Composite Confirmed Disability Progression Confirmed Over at Least 24 Weeks | 12.29 weeks |
| Part A: SAR443820 | Part B: Time to Onset of Composite Confirmed Disability Progression Confirmed Over at Least 24 Weeks | 24.00 weeks |
Secondary
Part B: Time to Onset of Sustained 20% Increase in 9-Hole Peg Test Confirmed Over at Least 24 Weeks
The 9-HPT was a brief, standardized, quantitative test of upper extremity function (lower bound: 10 seconds; upper bound: 300 seconds). Two consecutive trials with the dominant hand were immediately followed by 2 consecutive trials with the non-dominant hand. The mean time to test completion served as an assessment of the participant's hand dexterity. A participant was asked to place pegs into holes and remove them with the dominant and non-dominant hand for several repetitions. A higher value of overall 9-HPT was indicative of higher disability. An increase of \>20% from the baseline score in the 9-HPT was considered meaningful worsening. Baseline was defined as Day 1 (pre-dose).
Time frame: Baseline (Day 1, pre-dose) and approximately up to Week 72
Population: Randomized and treated population consisted of all randomized participants who took at least 1 dose of study treatment. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Placebo | Part B: Time to Onset of Sustained 20% Increase in 9-Hole Peg Test Confirmed Over at Least 24 Weeks | 36.1 weeks |
Secondary
Part B: Time to Onset of Sustained 20% Increase in Timed 25-Foot Walk Test Confirmed Over at Least 24 Weeks
The T25-FW test was used to assess a participant's walking ability, time in seconds to walk 25 feet (lower bound: 2.2 seconds; upper bound: 180 seconds). The participant was directed to one end of a clearly marked 25-foot course and was instructed to walk 25 feet as quickly as safely possible with several repetitions. The mean walk time was used for assessment of the participant's walking ability. An increase of \>20% from the baseline score in the T25-FW test was considered as meaningful worsening. Baseline was defined as Day 1 (pre-dose).
Time frame: Baseline (Day 1, pre-dose) and approximately up to Week 72
Population: Randomized and treated population consisted of all randomized participants who took at least 1 dose of study treatment. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A: Placebo | Part B: Time to Onset of Sustained 20% Increase in Timed 25-Foot Walk Test Confirmed Over at Least 24 Weeks | 12.14 weeks |
| Part A: SAR443820 | Part B: Time to Onset of Sustained 20% Increase in Timed 25-Foot Walk Test Confirmed Over at Least 24 Weeks | 18.00 weeks |
Secondary
Part B: Volume of Slowly Expanding Lesions
The basic MRI scan was performed at all sites and used to evaluate volume of SELs. SELs represent chronic active lesions in MS where there is ongoing, smoldering inflammation primarily driven by activated microglia and macrophages at the lesion edges. This localized, radial expansion causes gradual enlargement of pre-existing T2 MRI lesions over time and leads to progressive neural tissue damage including demyelination, axonal loss, and irreversible CNS injury.
Time frame: Approximately up to Week 72
Population: Randomized and treated population consisted of all randomized participants who took at least 1 dose of study treatment. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Part B: Volume of Slowly Expanding Lesions | 1485.00 µL | Standard Deviation 2657.22 |
| Part A: SAR443820 | Part B: Volume of Slowly Expanding Lesions | 1152.00 µL | Standard Deviation 998.67 |
Secondary
Parts A and B: Change From Baseline in Expanded Disability Status Scale Score
EDSS was a scale for assessing neurologic impairment in participants with MS, based on 7 FS in the brain which was used to derive the EDSS (score). The standard EDSS assessments of 7 FS (visual, brain stem, pyramidal, cerebellar, sensory, bowel/bladder, and cerebral functions) scoring was performed by assessment of neurologic symptoms in each FS. Ambulation scoring was done to conclude the evaluation. Individual FS scores were then used in conjugation with ambulation score to obtain EDSS score which ranged from 0 (normal) to 10 (death due to MS), with higher scores indicating greater disability. A negative change from baseline indicates improvement. Baseline was defined as Day 1 (pre-dose).
Time frame: Baseline (Day 1, pre-dose) and Week 48 (Part A) and approximately up to Week 72 (Part B)
Population: Randomized and treated population consisted of all randomized participants who took at least 1 dose of study treatment. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Parts A and B: Change From Baseline in Expanded Disability Status Scale Score | -0.013 score on a scale | Standard Deviation 0.611 |
| Part A: SAR443820 | Parts A and B: Change From Baseline in Expanded Disability Status Scale Score | -0.023 score on a scale | Standard Deviation 0.676 |
| Part B: Placebo/SAR443820 | Parts A and B: Change From Baseline in Expanded Disability Status Scale Score | -0.167 score on a scale | Standard Deviation 0.722 |
| Part B: SAR443820/SAR443820 | Parts A and B: Change From Baseline in Expanded Disability Status Scale Score | -1.000 score on a scale | — |
Secondary
Parts A and B: Percent Change From Baseline in Brain Volume Loss (BVL) as Detected by Brain Magnetic Resonance Imaging
The basic MRI scan was performed at all sites and used to evaluate BVL. Imaging measure to detect degree of atrophy or decrease in whole brain, cortical and/or thalamic volume, which was diagnostic evidence of disease progression and played a key role in long-term disability. Baseline was defined as Day 1 (pre-dose).
Time frame: Baseline (Day 1, pre-dose) and Week 48 (Part A) and approximately up to Week 72 (Part B)
Population: Randomized and treated population consisted of all randomized participants who took at least 1 dose of study treatment. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A: Placebo | Parts A and B: Percent Change From Baseline in Brain Volume Loss (BVL) as Detected by Brain Magnetic Resonance Imaging | -0.177 percent change | Standard Deviation 0.426 |
| Part A: SAR443820 | Parts A and B: Percent Change From Baseline in Brain Volume Loss (BVL) as Detected by Brain Magnetic Resonance Imaging | -0.397 percent change | Standard Deviation 0.462 |
| Part B: Placebo/SAR443820 | Parts A and B: Percent Change From Baseline in Brain Volume Loss (BVL) as Detected by Brain Magnetic Resonance Imaging | -0.502 percent change | Standard Deviation 0.526 |
| Part B: SAR443820/SAR443820 | Parts A and B: Percent Change From Baseline in Brain Volume Loss (BVL) as Detected by Brain Magnetic Resonance Imaging | -0.462 percent change | Standard Deviation 0.869 |
Secondary
Parts B and A+B: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) After SAR443820 Initiation
An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. TEAEs were defined as the AEs that developed, worsened or became serious during the treatment-emergent period (defined as time from first administration of study treatment (Day 1) to last administration of study treatment + 14 days). SAE: Any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. All TEAE occurring after SAR443820 initiation are provided for both randomized treatment arms in this endpoint.
Time frame: From first dose of SAR443820 (Day 1, post-dose) up to 14 days after last dose of SAR443820 administration in Part B, approximately 93 weeks for Parts A+B combined arm (SAR443820/SAR443820), approximately 45 weeks Part B Arm (Placebo/SAR443820)
Population: Safety population consisted of all randomized participants who took at least 1 dose of SAR443820. All participants from safety population and treated with SAR443820 are included in Part B arm and participants from safety population are included in Parts A+B arm. The combined safety analysis for TEAE provided the accurate summary of all TEAE in both treatment groups after the initiation of SAR443820.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A: Placebo | Parts B and A+B: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) After SAR443820 Initiation | TEAEs | 39 Participants |
| Part A: Placebo | Parts B and A+B: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) After SAR443820 Initiation | TESAEs | 5 Participants |
| Part A: SAR443820 | Parts B and A+B: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) After SAR443820 Initiation | TEAEs | 108 Participants |
| Part A: SAR443820 | Parts B and A+B: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) After SAR443820 Initiation | TESAEs | 7 Participants |