Relapsing Multiple Sclerosis
Conditions
Brief summary
Primary Objective: To assess efficacy of daily SAR442168 compared to a daily dose of 14 mg teriflunomide (Aubagio) measured by annualized adjudicated relapse rate (ARR) in participants with relapsing forms of MS Secondary Objective: To assess efficacy of SAR442168 compared to teriflunomide (Aubagio) on disability progression, MRI lesions, cognitive performance and quality of life To evaluate the safety and tolerability of daily SAR442168 To evaluate population pharmacokinetics (PK) of SAR442168 and relevant metabolites and its relationship to efficacy and safety To evaluate pharmacodynamics (PD) of SAR442168
Detailed description
This was an event-driven (6-month confirmed disability worsening \[CDW\]) trial with a variable treatment duration (end-of-study \[EOS\] duration: up to approximately 48 months).
Interventions
DRUGTolebrutinib
Pharmaceutical form: Tablet Route of administration: Oral
DRUGTeriflunomide
Pharmaceutical form: Tablet Route of administration: Oral
Pharmaceutical form: Tablet Route of administration: Oral
Pharmaceutical form: Tablet Route of administration: Oral
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
: * The participant must be 18 to 55 years of age, inclusive, at the time of signing the informed consent * The participant must have been diagnosed with RMS according to the 2017 revision of the McDonald diagnostic criteria * The participant has an expanded disability status scale (EDSS) score ≤5.5 at the first Screening Visit * The participant must have at least 1 of the following prior to screening: * ≥1 documented relapse within the previous year OR * ≥2 documented relapses within the previous 2 years, OR * ≥1 documented Gd enhancing lesion on an MRI scan within the previous year * Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies * Male participants are eligible to participate if they agree to the following during the intervention period and until accelerated elimination procedure: * Refrain from donating sperm Plus either: * Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR * Must agree to use contraception/barrier as detailed below: Agree to use a male condom and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak when having sexual intercourse with a woman of childbearing potential (WOCBP) who is not currently pregnant * A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions apply: * Is not a WOCBP OR * Is a WOCBP and agrees to use a contraceptive method that is highly effective (with a failure rate of \<1% per year), preferably with low user dependency, during the intervention period and until accelerated elimination procedure is completed (or for at least 10 days after the last dose of SAR442168, if the case was unblinded) * A WOCBP must have a negative highly sensitive pregnancy test at screening and within 24hours before the first dose of study intervention. * If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. * The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy. * The participant must have given written informed consent prior to undertaking any study related procedure. This includes consent to comply with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. In countries where the legal age of maturity is greater than 18 years, a specific ICF for such legally minor participants must also be signed by the participant's legally authorized representative
Exclusion criteria
* The participant has been diagnosed with primary progressive multiple sclerosis (PPMS) according to the 2017 revision of the McDonald diagnostic criteria or with nonrelapsing secondary progressive multiple sclerosis (SPMS) * The participant has a history of infection or may be at risk for infection including but not limited to: HIV, transplantation, live attenuated vaccines, progressive multifocal leukoencephalopathy, tuberculosis, any persistent chronic or active recurring infection * Clinically significant laboratory abnormalities (including evidence of liver injury) or electrocardiogram abnormalities at Screening. * The participant has conditions or situations that would adversely affect participation in this study, including but not limited to: * A short life expectancy due to pre-existing health condition(s) as determined by their treating neurologist * Medical condition(s) or concomitant disease(s) making them nonevaluable for the primary efficacy endpoint or that would adversely affect participation in this study, as judged by the Investigator * A requirement for concomitant treatment that could bias the primary evaluation * The participant has a history of or currently has concomitant medical or clinical conditions that would adversely affect participation in this study * At screening, the participant is positive for hepatitis B surface antigen and/or hepatitis B core antibody and/or is positive for hepatitis C antibody * The participant has any of the following: * A bleeding disorder or known platelet dysfunction at any time prior to the screening visit * A platelet count \<150 000/μL at the screening visit * The participant has a lymphocyte count below the lower limit of normal (LLN) at the screening visit * The presence of psychiatric disturbance or substance abuse * Prior/concomitant therapy * The participant is receiving potent and moderate inducers of cytochrome P450 (CYP) 3A or potent inhibitors of CYP2C8 hepatic enzymes * The participant is receiving anticoagulant/antiplatelet therapies The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Relapse Rate (ARR) as Assessed by Confirmed Protocol-defined Adjudicated Relapses | Baseline (Day 1) to approximately 48 months | Multiple sclerosis (MS) relapse was defined as a monophasic, acute or subacute onset of new neurological symptoms or worsening of previous neurological symptoms with an objective change on neurological examination. Symptoms were attributable to MS, lasted for \>=24 hours with or without recovery, present at normal body temperature, and preceded by \>=30 days of clinical stability. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Onset of 6-Month Confirmed Disability Worsening as Assessed by Expanded Disability Status Scale | Baseline (Day 1) to approximately 48 months | The EDSS was a disability scale that assessed the following 7 functional domains: visual, brainstem, pyramidal \[motor\], cerebellar \[coordination\], sensory, cerebral, and bowel/bladder. The total EDSS score ranged from 0 (normal) to 10 (death due to MS), increasing in increments of 0.5 points. Higher scores indicated increased disability. Time to onset of 6-month CDW was defined as the time from randomization to the onset of a confirmed, sustained increase from baseline in EDSS score (of \>=1.5 points when the baseline score was 0, of \>=1.0 point when the baseline score was 0.5 to \<=5.5, of \>=0.5 points when the baseline EDSS score was \>5.5) over at least 6 months that was not attributable to another etiology. |
| Time to Onset of 3-Month Confirmed Disability Worsening as Assessed by Expanded Disability Status Scale | Baseline (Day 1) to approximately 48 months | The EDSS was a disability scale that assessed the following 7 functional domains: visual, brainstem, pyramidal \[motor\], cerebellar \[coordination\], sensory, cerebral, and bowel/bladder. The total EDSS score ranged from 0 (normal) to 10 (death due to MS), increasing in increments of 0.5 points. Higher scores indicated increased disability. Time to onset of 3-month CDW was defined as the time from randomization to the onset of a confirmed, sustained increase from baseline in EDSS score (of \>=1.5 points when the baseline score was 0, of \>=1.0 point when the baseline score was 0.5 to \<=5.5, of \>=0.5 points when the baseline EDSS score was \>5.5) over at least 3 months that was not attributable to another etiology. |
| Mean Number of New Gadolinium-Enhancing T1-Hyperintense Lesions Per Scan | Baseline (Day 1) to approximately 48 months | MRI of the brain was performed to identify number of new Gd-enhancing T1-hyperintense lesions defined as the sum of the individual number of new Gd- enhancing T1-hyperintense lesions starting from baseline up to and including the EOS visit. |
| Change From Baseline in Cognitive Function as Assessed by the Symbol Digit Modalities Test (SDMT) at EOS | Baseline (Day 1) to EOS (up to approximately 48 months) | The SDMT was used to assess processing speed, divided attention, visual scanning, tracking and motor speed. It involved a simple substitution task using a reference key. The number of correct substitutions and number of items completed within a 90 second interval (maximum 110 seconds) were recorded. A decrease of 4 points from baseline on the SDMT was considered meaningful worsening. The score was the number of correctly coded items from 0-110 in 90 seconds; higher scores indicating a better outcome. Baseline was defined as the last available value prior to the first dose of study intervention. |
| Change From Baseline in Cognitive Function as Assessed by the California Verbal Learning Test Second Edition (CVLT-II) at EOS | Baseline (Day 1) to EOS (up to approximately 48 months) | The CVLT-II was a verbal learning and memory test consisting of recall and recognition of a list of 16 words. For each assessment, 5 trials were completed. Total Correct Recall Trials 1-5 was scaled to a normalized T-score metric, which had a mean of 50 and standard deviation of 10, the maximum possible score was 80 and a minimum was 0. Higher values indicated improved cognitive function. Baseline was defined as the last available value prior to the first dose of study intervention. |
| Time to Onset of 6-Month Confirmed Disability Improvement (CDI) as Assessed by Expanded Disability Status Scale | Baseline (Day 1) to approximately 48 months | The EDSS was a disability scale that assessed the following 7 functional domains: visual, brainstem, pyramidal \[motor\], cerebellar \[coordination\], sensory, cerebral, and bowel/bladder. The total EDSS score ranged from 0 (normal) to 10 (death due to MS), increasing in increments of 0.5 points. Higher scores indicated increased disability. CDI was defined as a decrease of \>=1 point from baseline in the EDSS score lasting at least 6 months. |
| Percent Change in Brain Volume Loss at EOS Compared to Month 6 | Month 6 to EOS (up to approximately 48 months) | MRI of the brain was performed at the specified timepoints to detect the changes in brain volume loss. |
| Mean Number of New and/or Enlarging T2-Hyperintense Lesions Per Year | Baseline (Day 1) to approximately 48 months | Magnetic resonance imaging (MRI) of the brain was performed to identify number of new and/or enlarging T2-hyperintense lesions defined as the sum of the individual number of new and/or enlarging T2 lesions starting from baseline up to and including the EOS visit. |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), TEAEs Leading to Permanent Study Intervention Discontinuation and Treatment-emergent Adverse Events of Special Interest (AESIs) | From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months | An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. SAE was 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 disability/incapacity, was a congenital anomaly/birth defect or was an important medical event. An AESI was an AE (serious or nonserious) of scientific and medical concern specific to the Sponsor's product or program for which ongoing monitoring and immediate notification by the Investigator to the Sponsor was required. TEAEs were defined as AEs that developed, worsened or became serious during the TE period. |
| Maximum Observed Plasma Concentration (Cmax) of Tolebrutinib and M2 Metabolite | 30-90 minutes post-dose at Months 6, 9, and 12 and 2.5-5 hours post-dose at Months 6 and 12 | Blood samples were collected at specified timepoints to assess Cmax of tolebrutinib and M2 metabolite using population pharmacokinetic (PK) model. |
| Time to Maximum Observed Plasma Concentration (Tmax) of Tolebrutinib and M2 Metabolite | 30-90 minutes post-dose at Months 6, 9, and 12 and 2.5-5 hours post-dose at Months 6 and 12 | Blood samples were collected at specified timepoints to assess Tmax of tolebrutinib and M2 metabolite using population PK model. |
| Area Under the Plasma Concentration-time Curve Over the Last 24-hours Dosing Interval (AUC0-24) of Tolebrutinib and M2 Metabolite | 30-90 minutes post-dose at Months 6, 9, and 12 and 2.5-5 hours post-dose at Months 6 and 12 | Blood samples were collected at specified timepoints to assess AUC0-24 of tolebrutinib and M2 metabolite using population PK model. |
| Change From Baseline in Plasma Neurofilament Light Chain (NfL) and Serum Chitinase-3 Like Protein-1 (Chi3L1) Levels at EOS | Baseline (Day 1) to EOS (up to approximately 48 months) | Blood samples were collected at specified timepoints to assess change from baseline in NfL and Chi3L1. Baseline was defined as the last available value prior to the first dose of study intervention. |
| Change From Baseline in Cluster of Differentiation (CD)19+ B Cells at EOS | Baseline (Day 1) to EOS (up to approximately 48 months) | Blood samples were collected at specified timepoints to assess change from baseline in CD19+ B cells. Baseline was defined as the last available value prior to the first dose of study intervention. |
| Change From Baseline in Serum Immunoglobulin (Ig) Levels at EOS | Baseline (Day 1) to EOS (up to approximately 48 months) | Blood samples were collected at specified timepoints to assess change from baseline in IgG and IgM levels. Baseline was defined as the last available value prior to the first dose of study intervention. |
| Change From Baseline in Multiple Sclerosis Quality of Life 54 (MSQoL-54) Questionnaire Score at EOS | Baseline (Day 1) to EOS (up to approximately 48 months) | MSQoL-54 was standardized instrument comprising generic and MS-specific items. This 54-item instrument generated 12 subscales and 2 single-item measures (satisfaction with sexual function \[1 item\]; change in health \[1 item\]). 12 subscales were: a: physical health (10 items), b: health perceptions (5 items), c: energy (5 items), d: role limit physical (4 items), e: sexual function (4 items), f: pain (3 items), g: social function (3 items), h: health distress (4 items), i: overall quality of life (2 items), j: emotional well-being (5 items), k: role limitations emotional (3 items) and l: cognitive function (4 items). Physical and mental health composite score were calculated as weighted sum of 'a to h' and 'i to l' subscales respectively. Each composite score was transformed linearly to common 0 (worst) to 100 (best) score range; higher score indicated improved quality of life. Baseline was defined as last available value prior to first dose of study intervention. |
Countries
Austria, Belarus, Bulgaria, Canada, China, Czechia, Denmark, Estonia, Finland, Germany, Hong Kong, Italy, Japan, Lithuania, Mexico, Poland, Romania, Russia, Spain, Sweden, Taiwan, Turkey (Türkiye), Ukraine, United States
Participant flow
Recruitment details
This study was conducted at 162 sites in 24 countries. A total of 1152 participants were screened from 30-Jun-2020 to 04-Aug-2022, of which 178 were screen failures. Screen failures were mainly due to not meeting eligibility criteria.
Pre-assignment details
A total of 974 participants were randomized in this study in a 1:1 ratio to either teriflunomide 14 milligrams (mg) or tolebrutinib 60 mg group. This was an event-driven (6-month confirmed disability worsening \[CDW\]) trial with a variable treatment duration (end-of-study \[EOS\] duration: up to approximately 48 months).
Participants by arm
| Arm | Count |
|---|---|
| Teriflunomide 14 mg Participants received teriflunomide 14 mg tablet orally QD along with a placebo matched to tolebrutinib orally QD up to approximately 47 months. | 488 |
| Tolebrutinib 60 mg Participants received tolebrutinib 60 mg tablet orally QD along with a placebo matched to teriflunomide orally QD up to approximately 48 months. | 486 |
| Total | 974 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Missing study status | 1 | 0 |
| Overall Study | Other | 6 | 7 |
| Overall Study | Poor compliance to protocol | 2 | 4 |
| Overall Study | Withdrawal by Subject | 64 | 66 |
Baseline characteristics
| Characteristic | Total | Tolebrutinib 60 mg | Teriflunomide 14 mg |
|---|---|---|---|
| Age, Continuous | 36.7 years STANDARD_DEVIATION 9.2 | 36.8 years STANDARD_DEVIATION 9 | 36.6 years STANDARD_DEVIATION 9.4 |
| Race (NIH/OMB) American Indian or Alaska Native | 9 Participants | 6 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 145 Participants | 78 Participants | 67 Participants |
| Race (NIH/OMB) Black or African American | 14 Participants | 4 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 801 Participants | 395 Participants | 406 Participants |
| Sex: Female, Male Female | 659 Participants | 334 Participants | 325 Participants |
| Sex: Female, Male Male | 315 Participants | 152 Participants | 163 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 488 | 0 / 486 |
| other Total, other adverse events | 321 / 488 | 296 / 486 |
| serious Total, serious adverse events | 40 / 488 | 42 / 486 |
Outcome results
Primary
Annualized Relapse Rate (ARR) as Assessed by Confirmed Protocol-defined Adjudicated Relapses
Multiple sclerosis (MS) relapse was defined as a monophasic, acute or subacute onset of new neurological symptoms or worsening of previous neurological symptoms with an objective change on neurological examination. Symptoms were attributable to MS, lasted for \>=24 hours with or without recovery, present at normal body temperature, and preceded by \>=30 days of clinical stability.
Time frame: Baseline (Day 1) to approximately 48 months
Population: The intent-to-treat (ITT) population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Teriflunomide 14 mg | Annualized Relapse Rate (ARR) as Assessed by Confirmed Protocol-defined Adjudicated Relapses | 0.122 relapses per participant year |
| Tolebrutinib 60 mg | Annualized Relapse Rate (ARR) as Assessed by Confirmed Protocol-defined Adjudicated Relapses | 0.130 relapses per participant year |
Comparison: Analysis was performed using negative binomial model with number of adjudicated relapses onset between randomization date and EOS date as the response variable, treatment group, Gadolinium (Gd)-enhancing T1 lesions at baseline (presence, absence), expanded disability status scale (EDSS) strata (\<4, \>=4) and geographic region (United States \[US\], non-US) as covariates, and log transformed observation duration as the offset variable.p-value: 0.669195% CI: [0.808, 1.393]Chi-squared
Secondary
Area Under the Plasma Concentration-time Curve Over the Last 24-hours Dosing Interval (AUC0-24) of Tolebrutinib and M2 Metabolite
Blood samples were collected at specified timepoints to assess AUC0-24 of tolebrutinib and M2 metabolite using population PK model.
Time frame: 30-90 minutes post-dose at Months 6, 9, and 12 and 2.5-5 hours post-dose at Months 6 and 12
Population: The PK population included all participants in the safety population with at least 1 non-missing PK sample after first dose of the study intervention. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Teriflunomide 14 mg | Area Under the Plasma Concentration-time Curve Over the Last 24-hours Dosing Interval (AUC0-24) of Tolebrutinib and M2 Metabolite | Tolebrutinib | 30.5 ng*h/mL | Standard Deviation 18.2 |
| Teriflunomide 14 mg | Area Under the Plasma Concentration-time Curve Over the Last 24-hours Dosing Interval (AUC0-24) of Tolebrutinib and M2 Metabolite | M2 Metabolite | 76.7 ng*h/mL | Standard Deviation 44.1 |
Secondary
Change From Baseline in Cluster of Differentiation (CD)19+ B Cells at EOS
Blood samples were collected at specified timepoints to assess change from baseline in CD19+ B cells. Baseline was defined as the last available value prior to the first dose of study intervention.
Time frame: Baseline (Day 1) to EOS (up to approximately 48 months)
Population: The safety population included all randomized participants exposed to the study intervention, regardless of the amount of exposure, analyzed according to the intervention actually received. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Teriflunomide 14 mg | Change From Baseline in Cluster of Differentiation (CD)19+ B Cells at EOS | -45.000 cells/microliter |
| Tolebrutinib 60 mg | Change From Baseline in Cluster of Differentiation (CD)19+ B Cells at EOS | -60.500 cells/microliter |
Secondary
Change From Baseline in Cognitive Function as Assessed by the California Verbal Learning Test Second Edition (CVLT-II) at EOS
The CVLT-II was a verbal learning and memory test consisting of recall and recognition of a list of 16 words. For each assessment, 5 trials were completed. Total Correct Recall Trials 1-5 was scaled to a normalized T-score metric, which had a mean of 50 and standard deviation of 10, the maximum possible score was 80 and a minimum was 0. Higher values indicated improved cognitive function. Baseline was defined as the last available value prior to the first dose of study intervention.
Time frame: Baseline (Day 1) to EOS (up to approximately 48 months)
Population: The ITT population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Teriflunomide 14 mg | Change From Baseline in Cognitive Function as Assessed by the California Verbal Learning Test Second Edition (CVLT-II) at EOS | 15.827 T-score | Standard Error 0.7241 |
| Tolebrutinib 60 mg | Change From Baseline in Cognitive Function as Assessed by the California Verbal Learning Test Second Edition (CVLT-II) at EOS | 17.700 T-score | Standard Error 0.7236 |
Comparison: Covariates in the MMRM were treatment group, EDSS strata (\<4, \>=4), geographic region (US, non-US), visit, treatment by visit interaction, baseline value, and baseline value-by-visit interaction.p-value: 0.067595% CI: [-0.135, 3.88]MMRM
Secondary
Change From Baseline in Cognitive Function as Assessed by the Symbol Digit Modalities Test (SDMT) at EOS
The SDMT was used to assess processing speed, divided attention, visual scanning, tracking and motor speed. It involved a simple substitution task using a reference key. The number of correct substitutions and number of items completed within a 90 second interval (maximum 110 seconds) were recorded. A decrease of 4 points from baseline on the SDMT was considered meaningful worsening. The score was the number of correctly coded items from 0-110 in 90 seconds; higher scores indicating a better outcome. Baseline was defined as the last available value prior to the first dose of study intervention.
Time frame: Baseline (Day 1) to EOS (up to approximately 48 months)
Population: The ITT population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Teriflunomide 14 mg | Change From Baseline in Cognitive Function as Assessed by the Symbol Digit Modalities Test (SDMT) at EOS | 0.329 score on a scale | Standard Error 0.0318 |
| Tolebrutinib 60 mg | Change From Baseline in Cognitive Function as Assessed by the Symbol Digit Modalities Test (SDMT) at EOS | 0.364 score on a scale | Standard Error 0.0318 |
Comparison: Covariates in the mixed-effect model with repeated measures (MMRM) were treatment group, EDSS strata (\<4, \>=4), geographic region (US, non-US), visit, treatment by visit interaction, baseline value, and baseline value-by-visit interaction.p-value: 0.43295% CI: [-0.053, 0.124]MMRM
Secondary
Change From Baseline in Multiple Sclerosis Quality of Life 54 (MSQoL-54) Questionnaire Score at EOS
MSQoL-54 was standardized instrument comprising generic and MS-specific items. This 54-item instrument generated 12 subscales and 2 single-item measures (satisfaction with sexual function \[1 item\]; change in health \[1 item\]). 12 subscales were: a: physical health (10 items), b: health perceptions (5 items), c: energy (5 items), d: role limit physical (4 items), e: sexual function (4 items), f: pain (3 items), g: social function (3 items), h: health distress (4 items), i: overall quality of life (2 items), j: emotional well-being (5 items), k: role limitations emotional (3 items) and l: cognitive function (4 items). Physical and mental health composite score were calculated as weighted sum of 'a to h' and 'i to l' subscales respectively. Each composite score was transformed linearly to common 0 (worst) to 100 (best) score range; higher score indicated improved quality of life. Baseline was defined as last available value prior to first dose of study intervention.
Time frame: Baseline (Day 1) to EOS (up to approximately 48 months)
Population: The ITT population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received. Only participants with data collected at specified timepoints for the specified categories are reported.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Teriflunomide 14 mg | Change From Baseline in Multiple Sclerosis Quality of Life 54 (MSQoL-54) Questionnaire Score at EOS | Physical health composite score | -2.468 score on a scale | Standard Error 0.7014 |
| Teriflunomide 14 mg | Change From Baseline in Multiple Sclerosis Quality of Life 54 (MSQoL-54) Questionnaire Score at EOS | Mental health composite score | -2.070 score on a scale | Standard Error 0.8346 |
| Tolebrutinib 60 mg | Change From Baseline in Multiple Sclerosis Quality of Life 54 (MSQoL-54) Questionnaire Score at EOS | Physical health composite score | -0.460 score on a scale | Standard Error 0.7021 |
| Tolebrutinib 60 mg | Change From Baseline in Multiple Sclerosis Quality of Life 54 (MSQoL-54) Questionnaire Score at EOS | Mental health composite score | -0.729 score on a scale | Standard Error 0.8359 |
Secondary
Change From Baseline in Plasma Neurofilament Light Chain (NfL) and Serum Chitinase-3 Like Protein-1 (Chi3L1) Levels at EOS
Blood samples were collected at specified timepoints to assess change from baseline in NfL and Chi3L1. Baseline was defined as the last available value prior to the first dose of study intervention.
Time frame: Baseline (Day 1) to EOS (up to approximately 48 months)
Population: The safety population included all randomized participants exposed to the study intervention, regardless of the amount of exposure, analyzed according to the intervention actually received. Only participants with data collected at specified timepoints for the specified categories are reported.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Teriflunomide 14 mg | Change From Baseline in Plasma Neurofilament Light Chain (NfL) and Serum Chitinase-3 Like Protein-1 (Chi3L1) Levels at EOS | NfL | -1.665 picogram/mL |
| Teriflunomide 14 mg | Change From Baseline in Plasma Neurofilament Light Chain (NfL) and Serum Chitinase-3 Like Protein-1 (Chi3L1) Levels at EOS | Chi3L1 | 1017.100 picogram/mL |
| Tolebrutinib 60 mg | Change From Baseline in Plasma Neurofilament Light Chain (NfL) and Serum Chitinase-3 Like Protein-1 (Chi3L1) Levels at EOS | NfL | -0.325 picogram/mL |
| Tolebrutinib 60 mg | Change From Baseline in Plasma Neurofilament Light Chain (NfL) and Serum Chitinase-3 Like Protein-1 (Chi3L1) Levels at EOS | Chi3L1 | 1572.250 picogram/mL |
Secondary
Change From Baseline in Serum Immunoglobulin (Ig) Levels at EOS
Blood samples were collected at specified timepoints to assess change from baseline in IgG and IgM levels. Baseline was defined as the last available value prior to the first dose of study intervention.
Time frame: Baseline (Day 1) to EOS (up to approximately 48 months)
Population: The safety population included all randomized participants exposed to the study intervention, regardless of the amount of exposure, analyzed according to the intervention actually received. Only participants with data collected at specified timepoints for the specified categories are reported.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Teriflunomide 14 mg | Change From Baseline in Serum Immunoglobulin (Ig) Levels at EOS | IgM | -0.150 gram/liter |
| Teriflunomide 14 mg | Change From Baseline in Serum Immunoglobulin (Ig) Levels at EOS | IgG | -0.660 gram/liter |
| Tolebrutinib 60 mg | Change From Baseline in Serum Immunoglobulin (Ig) Levels at EOS | IgM | -0.340 gram/liter |
| Tolebrutinib 60 mg | Change From Baseline in Serum Immunoglobulin (Ig) Levels at EOS | IgG | 0.235 gram/liter |
Secondary
Maximum Observed Plasma Concentration (Cmax) of Tolebrutinib and M2 Metabolite
Blood samples were collected at specified timepoints to assess Cmax of tolebrutinib and M2 metabolite using population pharmacokinetic (PK) model.
Time frame: 30-90 minutes post-dose at Months 6, 9, and 12 and 2.5-5 hours post-dose at Months 6 and 12
Population: The PK population included all participants in the safety population with at least 1 non-missing PK sample after first dose of the study intervention. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Teriflunomide 14 mg | Maximum Observed Plasma Concentration (Cmax) of Tolebrutinib and M2 Metabolite | Tolebrutinib | 12.0 nanogram/milliliter (ng/mL) | Standard Deviation 7.75 |
| Teriflunomide 14 mg | Maximum Observed Plasma Concentration (Cmax) of Tolebrutinib and M2 Metabolite | M2 Metabolite | 28.3 nanogram/milliliter (ng/mL) | Standard Deviation 15.8 |
Secondary
Mean Number of New and/or Enlarging T2-Hyperintense Lesions Per Year
Magnetic resonance imaging (MRI) of the brain was performed to identify number of new and/or enlarging T2-hyperintense lesions defined as the sum of the individual number of new and/or enlarging T2 lesions starting from baseline up to and including the EOS visit.
Time frame: Baseline (Day 1) to approximately 48 months
Population: The ITT population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Teriflunomide 14 mg | Mean Number of New and/or Enlarging T2-Hyperintense Lesions Per Year | 5.175 number of new and or enlarging T2lesions |
| Tolebrutinib 60 mg | Mean Number of New and/or Enlarging T2-Hyperintense Lesions Per Year | 5.611 number of new and or enlarging T2lesions |
Comparison: Analysis was performed using negative binomial model with the number of new and/or enlarging T2-hyperintense lesions between randomization date and EOS date as the response variable, treatment group, baseline T2-hyperintense lesion count, EDSS strata (\<4, \>=4) and geographic region (US, non-US) as covariates, and log transformed observation duration as the offset variable.p-value: 0.457595% CI: [0.876, 1.342]Chi-squared
Secondary
Mean Number of New Gadolinium-Enhancing T1-Hyperintense Lesions Per Scan
MRI of the brain was performed to identify number of new Gd-enhancing T1-hyperintense lesions defined as the sum of the individual number of new Gd- enhancing T1-hyperintense lesions starting from baseline up to and including the EOS visit.
Time frame: Baseline (Day 1) to approximately 48 months
Population: The ITT population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Teriflunomide 14 mg | Mean Number of New Gadolinium-Enhancing T1-Hyperintense Lesions Per Scan | 0.285 number of new Gd-enhancing T1 lesions |
| Tolebrutinib 60 mg | Mean Number of New Gadolinium-Enhancing T1-Hyperintense Lesions Per Scan | 0.530 number of new Gd-enhancing T1 lesions |
Comparison: Analysis was performed using negative binomial model with the number of new Gd-enhancing T1-hyperintense lesions between randomization date and EOS date as the response variable, treatment group, Gd-enhancing T1 lesions at baseline (presence, absence), EDSS strata (\<4, \>=4) and geographic region (US, non-US) as covariates, and log transformed number of MRI scans as the offset variable.p-value: 0.000195% CI: [1.358, 2.548]Chi-squared
Secondary
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), TEAEs Leading to Permanent Study Intervention Discontinuation and Treatment-emergent Adverse Events of Special Interest (AESIs)
An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. SAE was 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 disability/incapacity, was a congenital anomaly/birth defect or was an important medical event. An AESI was an AE (serious or nonserious) of scientific and medical concern specific to the Sponsor's product or program for which ongoing monitoring and immediate notification by the Investigator to the Sponsor was required. TEAEs were defined as AEs that developed, worsened or became serious during the TE period.
Time frame: From first dose of study intervention (Day 1) up to the earliest of either 10 days post last dose, death or last contact; up to approximately 48 months
Population: The safety population included all randomized participants exposed to the study intervention, regardless of the amount of exposure, analyzed according to the intervention actually received.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Teriflunomide 14 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), TEAEs Leading to Permanent Study Intervention Discontinuation and Treatment-emergent Adverse Events of Special Interest (AESIs) | TEAEs | 423 Participants |
| Teriflunomide 14 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), TEAEs Leading to Permanent Study Intervention Discontinuation and Treatment-emergent Adverse Events of Special Interest (AESIs) | TESAEs | 40 Participants |
| Teriflunomide 14 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), TEAEs Leading to Permanent Study Intervention Discontinuation and Treatment-emergent Adverse Events of Special Interest (AESIs) | TEAEs leading to permanent study intervention discontinuation | 24 Participants |
| Teriflunomide 14 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), TEAEs Leading to Permanent Study Intervention Discontinuation and Treatment-emergent Adverse Events of Special Interest (AESIs) | TEAESIs | 57 Participants |
| Tolebrutinib 60 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), TEAEs Leading to Permanent Study Intervention Discontinuation and Treatment-emergent Adverse Events of Special Interest (AESIs) | TEAESIs | 53 Participants |
| Tolebrutinib 60 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), TEAEs Leading to Permanent Study Intervention Discontinuation and Treatment-emergent Adverse Events of Special Interest (AESIs) | TEAEs | 407 Participants |
| Tolebrutinib 60 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), TEAEs Leading to Permanent Study Intervention Discontinuation and Treatment-emergent Adverse Events of Special Interest (AESIs) | TEAEs leading to permanent study intervention discontinuation | 23 Participants |
| Tolebrutinib 60 mg | Number of Participants With Treatment-emergent Adverse Events (TEAEs), Treatment-emergent Serious Adverse Events (TESAEs), TEAEs Leading to Permanent Study Intervention Discontinuation and Treatment-emergent Adverse Events of Special Interest (AESIs) | TESAEs | 42 Participants |
Secondary
Percent Change in Brain Volume Loss at EOS Compared to Month 6
MRI of the brain was performed at the specified timepoints to detect the changes in brain volume loss.
Time frame: Month 6 to EOS (up to approximately 48 months)
Population: The ITT population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Teriflunomide 14 mg | Percent Change in Brain Volume Loss at EOS Compared to Month 6 | -0.884 percent change | Standard Error 0.0368 |
| Tolebrutinib 60 mg | Percent Change in Brain Volume Loss at EOS Compared to Month 6 | -0.688 percent change | Standard Error 0.0369 |
Comparison: Covariates in the MMRM were treatment group, EDSS strata (\<4, \>=4), geographic region (US, non-US), visit, treatment by visit interaction, cube root transformed Month 6 brain volume, and cube root transformed Month 6 brain volume-by-visit interaction.p-value: 0.000295% CI: [0.093, 0.298]MMRM
Secondary
Time to Maximum Observed Plasma Concentration (Tmax) of Tolebrutinib and M2 Metabolite
Blood samples were collected at specified timepoints to assess Tmax of tolebrutinib and M2 metabolite using population PK model.
Time frame: 30-90 minutes post-dose at Months 6, 9, and 12 and 2.5-5 hours post-dose at Months 6 and 12
Population: The PK population included all participants in the safety population with at least 1 non-missing PK sample after first dose of the study intervention. Only participants with data collected at specified timepoints are reported.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Teriflunomide 14 mg | Time to Maximum Observed Plasma Concentration (Tmax) of Tolebrutinib and M2 Metabolite | Tolebrutinib | 1.28 hour (h) | Standard Deviation 0.513 |
| Teriflunomide 14 mg | Time to Maximum Observed Plasma Concentration (Tmax) of Tolebrutinib and M2 Metabolite | M2 Metabolite | 1.40 hour (h) | Standard Deviation 0.508 |
Secondary
Time to Onset of 3-Month Confirmed Disability Worsening as Assessed by Expanded Disability Status Scale
The EDSS was a disability scale that assessed the following 7 functional domains: visual, brainstem, pyramidal \[motor\], cerebellar \[coordination\], sensory, cerebral, and bowel/bladder. The total EDSS score ranged from 0 (normal) to 10 (death due to MS), increasing in increments of 0.5 points. Higher scores indicated increased disability. Time to onset of 3-month CDW was defined as the time from randomization to the onset of a confirmed, sustained increase from baseline in EDSS score (of \>=1.5 points when the baseline score was 0, of \>=1.0 point when the baseline score was 0.5 to \<=5.5, of \>=0.5 points when the baseline EDSS score was \>5.5) over at least 3 months that was not attributable to another etiology.
Time frame: Baseline (Day 1) to approximately 48 months
Population: The ITT population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Teriflunomide 14 mg | Time to Onset of 3-Month Confirmed Disability Worsening as Assessed by Expanded Disability Status Scale | 17.96 months |
| Tolebrutinib 60 mg | Time to Onset of 3-Month Confirmed Disability Worsening as Assessed by Expanded Disability Status Scale | 14.93 months |
Comparison: Analysis was performed using Cox proportional-hazards model with robust variance estimation. Covariates were treatment group, Gd-enhancing T1 lesions at baseline (presence, absence), EDSS strata (\<4, \>=4), geographic region (US, non-US).p-value: 0.299195% CI: [0.582, 1.151]Log Rank
Secondary
Time to Onset of 6-Month Confirmed Disability Improvement (CDI) as Assessed by Expanded Disability Status Scale
The EDSS was a disability scale that assessed the following 7 functional domains: visual, brainstem, pyramidal \[motor\], cerebellar \[coordination\], sensory, cerebral, and bowel/bladder. The total EDSS score ranged from 0 (normal) to 10 (death due to MS), increasing in increments of 0.5 points. Higher scores indicated increased disability. CDI was defined as a decrease of \>=1 point from baseline in the EDSS score lasting at least 6 months.
Time frame: Baseline (Day 1) to approximately 48 months
Population: The ITT population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Teriflunomide 14 mg | Time to Onset of 6-Month Confirmed Disability Improvement (CDI) as Assessed by Expanded Disability Status Scale | 12.04 months |
| Tolebrutinib 60 mg | Time to Onset of 6-Month Confirmed Disability Improvement (CDI) as Assessed by Expanded Disability Status Scale | 11.82 months |
Comparison: Analysis was performed using Cox proportional-hazards model with robust variance estimation. Covariates were treatment group, Gd-enhancing T1 lesions at baseline (presence, absence), EDSS strata (\<4, \>=4), geographic region (US, non-US).p-value: 0.359495% CI: [0.554, 1.245]Log Rank
Secondary
Time to Onset of 6-Month Confirmed Disability Worsening as Assessed by Expanded Disability Status Scale
The EDSS was a disability scale that assessed the following 7 functional domains: visual, brainstem, pyramidal \[motor\], cerebellar \[coordination\], sensory, cerebral, and bowel/bladder. The total EDSS score ranged from 0 (normal) to 10 (death due to MS), increasing in increments of 0.5 points. Higher scores indicated increased disability. Time to onset of 6-month CDW was defined as the time from randomization to the onset of a confirmed, sustained increase from baseline in EDSS score (of \>=1.5 points when the baseline score was 0, of \>=1.0 point when the baseline score was 0.5 to \<=5.5, of \>=0.5 points when the baseline EDSS score was \>5.5) over at least 6 months that was not attributable to another etiology.
Time frame: Baseline (Day 1) to approximately 48 months
Population: The ITT population included all randomized participants according to the intervention group allocated by the randomization, irrespective of the study intervention received.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Teriflunomide 14 mg | Time to Onset of 6-Month Confirmed Disability Worsening as Assessed by Expanded Disability Status Scale | 17.97 months |
| Tolebrutinib 60 mg | Time to Onset of 6-Month Confirmed Disability Worsening as Assessed by Expanded Disability Status Scale | 15.38 months |
Comparison: Analysis was performed using Cox proportional-hazards model with robust variance estimation. Covariates were treatment group, Gd-enhancing T1 lesions at baseline (presence, absence), EDSS strata (\<4, \>=4), geographic region (US, non-US).p-value: 0.488895% CI: [0.565, 1.278]Log Rank