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

Phase 2TerminatedNCT05630547

Sanofi174 enrolled

Overview

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.

Approximately 100 weeks

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

174

Conditions

Multiple Sclerosis

Interventions

Eligibility

Sex: ALLMin age: 18 YearsMax age: 60 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Locations (35)

Investigational Site Number : 0560001

Brussels, Belgium

Investigational Site Number : 0560002

Ghent, Belgium

Investigational Site Number : 0560003

Overpelt, Belgium

Investigational Site Number : 1000001

Sofia, Bulgaria

Investigational Site Number : 1000002

Sofia, Bulgaria

Investigational Site Number : 1000003

Outcomes

Primary Outcomes

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

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

Secondary Outcomes

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

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

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

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

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

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

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

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

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

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

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)

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

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

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)

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

Part B: Volume of Slowly Expanding Lesions

Time frame: Approximately up to Week 72

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

Part B: Number of Slowly Expanding Lesions

Time frame: Approximately up to Week 72

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

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

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

Part B: Change From Baseline in the Number of Phase Rim Lesions Conducted at 3 Tesla Capable Sites

Time frame: Baseline (Day 1, pre-dose) and approximately up to Week 72

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)

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

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

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

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