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

The adjusted number of new Gd-enhancing T1 hyperintense lesions per scan were derived using negative binomial model.

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.

The adjusted number of new, enlarging T2 hyperintense lesions per year were derived using negative binomial model.

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 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 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).

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).

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).

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).

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).

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).

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.

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.

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).

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.

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.

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.

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.

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.

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.

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).

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).

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.

Plasma samples were collected at specified timepoints to determine plasma concentrations of SAR443820.

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).

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).

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).