Long-term Extension to Study AC-058B301 to Investigate Safety, Tolerability and Disease Control of Ponesimod 20 mg in Patients With Relapsing Multiple Sclerosis

Multicenter, Non-comparative Extension of Study AC-058B301, to Investigate the Long-term Safety, Tolerability, and Control of Disease of Ponesimod 20 mg in Subjects With Relapsing Multiple Sclerosis

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT03232073

Acronym

OPTIMUM-LT

Enrollment

877

Registered

2017-07-27

Start date

2017-07-05

Completion date

2024-01-16

Last updated

2025-06-22

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Multiple Sclerosis

Brief summary

The study AC-058B301 (OPTIMUM; NCT02425644) has been designed to investigate the efficacy, safety and tolerability of ponesimod in subjects with relapsing multiple sclerosis (RMS). The AC-058B303 study is the long-term extension for the core study AC-058B301. The purpose of this long term extension of the core study AC-058B301 is to characterize the long-term safety, tolerability, and control of disease of ponesimod 20 mg in subjects with RMS.

Detailed description

The AC-058B303 study (extension study) is the long-term extension for the AC-058B301 study (core study). The core study has been designed to investigate the efficacy, safety and tolerability of ponesimod in subjects with RMS. The subjects are treated with either ponesimod or the active comparator, teriflunomide in the core study. The purpose of this long term extension of the core study is to characterize the long-term safety and control of disease of ponesimod in subjects with RMS. In particular, the study will allow to observe potential adverse events which may only occur after long term treatment with ponesimod. The study will also investigate the effect of re-initiation of ponesimod after a brief interruption in a relatively large population (all subjects treated with ponesimod in the core study and eligible for the extension study) on disease activity in terms of relapses and MS-related MRI lesions. There is currently limited guidance on when a new MS treatment should be started after discontinuation of teriflunomide and the study will contribute with data on safety and efficacy of switching from teriflunomide to ponesimod after an interruption as mandated by the protocol. The study will also allow confirmation of sustained efficacy of ponesimod in terms of relapses, MRI lesions and reduction of disability accumulation during long-term treatment. In addition, combined data from the core study together with the results of the current extension study will allow comparison of MS activity in subjects who were switched from teriflunomide to ponesimod versus those who were treated with ponesimod in both studies.

Interventions

DRUGPonesimod

Ponesimod; Film-coated tablet; Oral use. From Day 1 to Day 14, ponesimod is gradually up-titrated until a maintenance dose of 20 mg is reached from Day 15

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Intervention model description

This is a single-group open-label extension study to investigate long-term safety, tolerability and control of disease of ponesimod 20 mg in subjects with RMS. Statistical analyses will be descriptive and therefore all endpoints are exploratory in nature. All exploratory endpoints are listed under primary outcomes.

Eligibility

Sex/Gender

ALL

Age

18 Years to 65 Years

Healthy volunteers

Inclusion criteria

1. Signed informed consent 2. Subjects with MS having completed the double-blind treatment in the core study as scheduled 3. Compliance with teriflunomide elimination procedure 4. Women of childbearing potential (WOCBP) must have a negative pre-treatment urine pregnancy test, must agree to undertake 4-weekly urine pregnancy tests, and must have been using reliable methods of contraception. Fertile male subjects participating in the study must agree to use a condom.

Exclusion criteria

1. Any of the following cardiovascular conditions on Day 1 pre-dose: 1. Resting heart rate (HR) \< 50 bpm; 2. Presence of second degree atrioventricular (AV) block or third degree AV block or a QTcF interval \> 470 ms (females), \> 450 ms (males); 2. Any of the following alerts from central laboratory at Visit 14 of the core study (EOT) which was confirmed as an alert at repeated testing or not repeated prior to FU1 of the core study: 1. Lymphocyte count: \< 0.2 x 109/L; 2. Neutrophil count \<1.0 × 109/L; 3. Platelet count \< 50 × 109/L; 4. Creatinine clearance \< 30 mL/min 3. At Visit 14 of the core study (EOT) \>30% decrease from core study baseline FEV1 and/or FVC; 4. Clinically significant, persistent respiratory AEs (e.g., dyspnea) not resolved prior to first dosing in the extension study. 5. Macular edema at any time between Visit 1 (Screening) in the core study and Day 1 of the extension study. 6. Presence of the following at core study Visit 14 (EOT, Week 108), FU1, or abbreviated visit FU2, or on Day 1 of the extension study pre-dose: 1. Suspected opportunistic infection of the CNS or any other infection which, in the opinion of the investigator, contraindicates re-start of the study drug; 2. Stevens-Johnson syndrome or toxic epidermal necrolysis or drug reaction with eosinophilia and systemic symptoms. 7. Need for and intention to administer forbidden study treatment-concomitant therapy 8. Women who are pregnant or lactating. 9. Male subjects wishing to parent a child; 10. Treatment with any MS Disease Modifying Therapies; 11. Any other clinically relevant medical or surgical condition, which, in the opinion of the investigator, would put the subject at risk by participating in the study; 12. Subjects unlikely to comply with the extension study protocol based on investigator best judgment

Design outcomes

Primary

Measure	Time frame	Description
Change in DL[CO] (% Predicted) From Baseline to EOS	From extension study baseline up to the end of study in the extension study. The actual time varied for each participant and could be up to 73.2 months	Change in DL\[CO\] (% predicted) from baseline to EOS were predicted. Extension baseline for safety is the last valid non-missing assessment that is taken on or after EOT visit in the core study, and prior to first study drug intake in the extension study.
Absolute Change in Lung Diffusion Capacity as Assessed by Diffusing Capacity for the Lungs Measured Using Carbon Monoxide (DL[CO]) From Baseline	From extension study baseline up to the end of study in the extension study. The actual time varied for each participant and could be up to 73.2 months	Absolute change in lung diffusion capacity as assessed by DL\[CO\] from baseline were reported. Extension baseline for safety is the last valid non-missing assessment that is taken on or after EOT visit in the core study, and prior to first study drug intake in the extension study.
Change in DL[CO] (% Predicted) From Baseline to EOT	From extension study baseline up to the end of study treatment in the extension study. The actual time varied for each participant and could be up to 71.8 months	Change in DL\[CO\] (% predicted) from baseline to EOT were predicted. Extension baseline for safety is the last valid non-missing assessment that is taken on or after EOT visit in the core study, and prior to first study drug intake in the extension study.
Annualized Confirmed Relapse Rate (ARR)	From randomization in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months	ARR: number of confirmed relapses per patient-year. Relapse: new, worsening, or recurrent neurological symptoms that occurred at least 30 days after the onset of a preceding relapse, and that lasted at least 24 hours, in the absence of fever or infection. A confirmed relapse is identified when a patient's symptoms worsen as indicated by an increase in their Expanded Disability Status Scale (EDSS) or Functional Systems (FS) scores, consistent with previous clinically stable assessments. Specific criteria for a confirmed relapse include: An increase of 0.5 points on EDSS; (unless EDSS=0, then requires an increase of 1.0-point); An increase of at least 1.0 point in at least two FS scores; or a 2.0-point increase in one FS score (excluding bladder/bowel and cerebral). Rating individual FS scores is used to rate EDSS along with observations and information concerning gait and use of assistance. EDSS is ordinal clinical rating scale ranging:0 (normal)-10 (death due to MS).
Time From Core Study Randomization to First Confirmed Relapse	From randomization in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months	Time to first confirmed relapse: date of first confirmed relapse (in either core or extension study) minus date of randomization in core study+1 day. Relapse: new, worsening, or recurrent neurological symptoms that occurred at least 30 days after the onset of a preceding relapse, and that lasted at least 24 hours in absence of fever or infection. A confirmed relapse: when patient's symptoms worsen as indicated by an increase in their EDSS/FS scores, consistent with previous clinically stable assessments. Specific criteria for confirmed relapse are: An increase of 0.5 points on EDSS; (unless EDSS=0, then requires an increase of 1.0-point); An increase of at least 1.0 point in at least two FS scores; or a 2.0-point increase in one FS score (excluding bladder/bowel and cerebral). Rating individual FS scores is used to rate EDSS along with observations and information concerning gait and use of assistance. EDSS is ordinal clinical rating scale ranging:0(normal)-10(death due to MS).
Time to First 12-week Confirmed Disability Accumulation (CDA)	From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months	Time to first 12-week CDA is defined as start date of the first 12-week CDA minus date of randomization in the core study + 1 day. A 12-week CDA is defined as a 12-week sustained increase from the core baseline EDSS score, which is confirmed at a scheduled visit after 12-weeks. CDA is defined as: (a) Sustained increase of at least 1.5 in EDSS for participants with a core baseline EDSS score of 0; (b) Sustained increase of at least 1.0 in EDSS for participants with a core baseline EDSS score of 1.0 to 5.0; (c) Sustained increase of at least 0.5 in EDSS for participants with a core baseline EDSS score \>=5.5, confirmed after 12 weeks. EDSS is an ordinal clinical rating scale ranging from 0 (normal neurological examination) to 10 (death due to MS). Core baseline for efficacy: last non-missing value recorded before or on randomization in the core study for each outcome measure and participant individually.
Time to First 24-week Confirmed Disability Accumulation (CDA)	From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months	Time to first 24-week CDA was defined as start date of the first 24-week CDA minus date of randomization in the core study + 1 day. A 24-week CDA was defined as a 24-week sustained increase from the core baseline EDSS score, which is confirmed at a scheduled visit after 24-weeks. CDA was defined as: (a) Sustained increase of at least 1.5 in EDSS for participants with a core baseline EDSS score of 0; (b) Sustained increase of at least 1.0 in EDSS for participants with a core baseline EDSS score of 1.0 to 5.0; (c) Sustained increase of at least 0.5 in EDSS for participants with a core baseline EDSS score \>=5.5, confirmed after 24 weeks. EDSS was an ordinal clinical rating scale ranging from 0 (normal neurological examination) to 10 (death due to MS). Core baseline for efficacy: last non-missing value recorded before or on randomization in the core study for each outcome measure and participant individually.
Percentage of Participants With Absence of Relapses	From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months	Relapse: new, worsening, or recurrent neurological symptoms that occurred at least 30 days after the onset of a preceding relapse, and that lasted at least 24 hours in absence of fever or infection. A confirmed relapse: when patient's symptoms worsen as indicated by an increase in their EDSS/FS scores, consistent with previous clinically stable assessments. Specific criteria for confirmed relapse: An increase of 0.5 points on EDSS; (unless EDSS=0, then requires an increase of 1.0-point); An increase of at least 1.0 point in at least two FS scores; or a 2.0-point increase in one FS score (excluding bladder/bowel and cerebral). Rating individual FS scores is used to rate EDSS along with observations and information concerning gait and use of assistance. EDSS is ordinal clinical rating scale ranging:0(normal)-10(death due to MS). Core baseline for efficacy: last non-missing value recorded before or on randomization in the core study for each outcome measure and participant individually.
Change From Baseline in Expanded Disability Status Scale (EDSS)	From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months	EDSS is ordinal clinical rating scale based on standard neurological examination for assessing neurological disability and impairment in MS. Seven FS scores were rated on a scale ranged from 0 to 5 or 6 to assess visual, brain, stem, pyramidal, cerebellar, sensory, bowel and bladder, and cerebral functions while ambulation was scored on scale ranged from 0 to 12 to assess walking distance and assistance. 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) in 0.5 unit increments that represented higher levels of disability. Core baseline for efficacy is defined as the last non-missing value recorded before or on randomization in the core study for each outcome measure and each participant individually.
Percentage of Participants With No Evidence of Disease Activity (NEDA) Status According to NEDA With Three Components (NEDA-3) at Extension End of Study	From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months	NEDA-3 up to extension EOS is defined by the absence of confirmed relapse, gadolinium-enhancing (Gd+ T1) lesions, new or enlarging T2 lesions, and 12-week CDA. If at least one of the criteria was not fulfilled or the participant discontinued treatment prematurely, the participant was not considered to have achieved NEDA-3. Confirmed relapse: when patient's symptoms worsen as indicated by an increase in their EDSS/FS scores, consistent with previous clinically stable assessments. Rating individual FS scores is used to rate EDSS along with observations and information concerning gait and use of assistance. EDSS is ordinal clinical rating scale ranging: 0 (normal)-10 (death due to MS). Core baseline for efficacy is defined as the last non-missing value recorded before or on randomization in the core study for each outcome measure and each participant individually.
Percentage of Participants With No Evidence of Disease Activity (NEDA) Status According to NEDA With Four Components (NEDA-4) at Extension End of Study	From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months	NEDA-4 up to EOS is defined by the absence of confirmed relapse, Gd+ T1 lesions, new or enlarging T2 lesions, 12-week CDA until EOS, and absence of annual brain volume decrease \>=0.4% from core baseline up to extension EOS. If at least one of the criteria was not fulfilled or the participant discontinued treatment prematurely, the participant was not considered to have achieved NEDA-4. Confirmed relapse: when patient's symptoms worsen by an increase in their EDSS/FS scores, consistent with previous clinically stable assessments. Rating individual FS scores is used to rate EDSS along with observations and information concerning gait and use of assistance. EDSS is ordinal clinical rating scale ranging: 0 (normal)-10 (death due to MS). Core baseline for efficacy is defined as the last non-missing value recorded before or on randomization in core study for each outcome measure and each participant individually.
Percent Change From Baseline in Brain Volume (PCBV) Measured by Magnetic Resonance Imaging (MRI)	From baseline in the core study up to the end of treatment (EOT) in the extension study. The actual time varied for each participant and could be up to 94.8 months	Percent change from baseline in brain volume (PCBV) measured by MRI were reported. Normalized Brain Volume at core baseline was measured in cubic centimeter (cm\^3). Core baseline for efficacy is defined as the last non-missing value recorded before or on randomization in the core study for each outcome measure and each participant individually. In this outcome measure, results were presented for extension end of treatment visit.
Cumulative Number of Combined Unique Active Lesions (CUAL) Measured by MRI	From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months	CUALs was calculated as sum of new T1 Gadolinium-enhanced (Gd+) lesions and new or enlarging T2 lesions (without double-counting of lesions) from baseline up to extension EOS based on the Magnetic resonance imaging (MRI). Average number of lesions per patient-year were reported. Results are based on a negative-binomial regression model. Core baseline for efficacy is defined as the last non-missing value recorded before or on randomization in the core study for each outcome measure and each participant individually.
Number of Gadolinium-enhancing (Gd+) T1 Lesions Measured by MRI	From baseline in the core study up to the end of treatment (EOT) in the extension study. The actual time varied for each participant and could be up to 94.8 months	Number of Gd+ T1 lesions measured by MRI were reported. Results are based on a negative-binomial regression model. Core baseline for efficacy is defined as the last non-missing value recorded before or on randomization in the core study for each outcome measure and each participant individually. For this outcome measure, results presented here are for the Extension end-of-treatment visit.
Cumulative Number of New or Enlarging T2 Lesions Measured by MRI	From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months	Cumulative number of new or enlarging T2 lesions measured by MRI were reported. Average number of lesions per year were reported. Results are based on a negative-binomial regression model. Core baseline for efficacy is defined as the last non-missing value recorded before or on randomization in the core study for each outcome measure and each participant individually.
Change From Baseline in Volume of MRI Lesions (T2 Lesions and T1 Hypointense Lesions)	From baseline in the core study up to the end of treatment (EOT) in the extension study. The actual time varied for each participant and could be up to 94.8 months	Change from baseline in volume of MRI lesions (T2 lesions, T1 hypointense lesions) were reported. Core baseline for efficacy is defined as the last non-missing value recorded before or on randomization in the core study for each outcome measure and each participant individually. In this outcome measure, results were presented for extension end of treatment visit.
Number of Participants With Absence of MRI Lesions (Gd+ T1 Lesions, New or Enlarging T2 Lesions)	From baseline in the core study up to the end of treatment (EOT) in the extension study. The actual time varied for each participant and could be up to 94.8 months	Number of participants with absence of MRI lesions (Gd+ T1 lesions, new or enlarging T2 lesions) were reported. Core baseline for efficacy is defined as the last non-missing value recorded before or on randomization in the core study for each outcome measure and each participant individually. In this outcome measure, results were presented for extension end of treatment visit.
Percentage of Gd+ Lesions at Baseline Evolving to Persistent Black Holes (PBHs)	From baseline in the core study up to the end of treatment (EOT) in the extension study. The actual time varied for each participant and could be up to 94.8 months	Percentage of Gd+ lesions at baseline evolving to PBHs were reported. Core baseline for efficacy is defined as the last non-missing value recorded before or on randomization in the core study for each outcome measure and each participant individually. In this outcome measure, results were presented for extension end of treatment visit.
Number of Participants With Treatment-emergent Adverse Events (TEAEs)	From the start of study treatment in the extension study up to the end of study treatment + 15 days in the extension study. The actual time varied for each participant and could be up to 71.8 months + 15 days	Number of participants with TEAEs were reported. An AE is any untoward medical event that occurs in a participants being administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. TEAEs are defined as AEs occurring from start of treatment up to treatment end date + 15 days.
Number of Participants With Treatment-emergent New Morphological Electrocardiogram (ECG) Abnormalities	From the start of study treatment in the extension study up to the end of study treatment + 15 days in the extension study. The actual time varied for each participant and could be up to 71.8 months + 15 days	Number of participants with treatment-emergent new morphological ECG abnormalities were reported. Treatment-emergent new morphological ECG abnormalities are defined as those ECG abnormalities occurring from start of treatment up to treatment end date + 15 days.
Actual Values of 12-lead ECG Measurements up to End of Study Treatment: Heart Rate	From the start of study treatment in the extension study up to the end of study treatment in the extension study. The actual time varied for each participant and could be up to 71.8 months	Actual values of 12-lead ECG measurements up to end of study treatment: heart rate were reported. In this outcome measure, results were presented for extension end of treatment visit.
Actual Values of 12-lead ECG Measurements up to End of Study Treatment: PR, QRS, QT, QTcB, QTcF	From the start of study treatment in the extension study up to the end of study treatment in the extension study. The actual time varied for each participant and could be up to 71.8 months	Actual values of 12-lead ECG measurements up to end of study treatment: PR, QRS, QT, QTcB, QTcF were reported. In this outcome measure, results were presented for extension end of treatment visit.
Change in Heart Rate (HR) From Baseline up to End of Study Treatment	From the start of study treatment in the extension study up to the end of study treatment in the extension study. The actual time varied for each participant and could be up to 71.8 months	Change in heart rate (HR) from baseline up to end of study treatment were reported.
Change in PR, QRS, QT, QTcB, QTcF From Baseline up to End of Study Treatment	From the start of study treatment in the extension study up to the end of study treatment in the extension study. The actual time varied for each participant and could be up to 71.8 months	Change in PR, QRS, QT, QTcB, QTcF from baseline up to end of study treatment were reported.
Absolute Values in Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) Values	From extension study baseline up to the end of study treatment in the extension study. The actual time varied for each participant and could be up to 71.8 months	Absolute values in FEV1 and FVC values were reported. FEV1: the maximal volume of air exhaled from the lungs in 1 second of a forced expiration from a position of full inspiration as measured by spirometer. FVC: the volume of air (in liters) that can be forcibly blown out after full inspiration in the upright position. Extension baseline for safety is the last valid non-missing assessment that is taken on or after EOT visit in the core study, and prior to first study drug intake in the extension study. Results are presented for extension end of treatment visit.
Percent Change in (FEV1) and Forced Vital Capacity (FVC) From Baseline (%)	From extension study baseline up to the end of study treatment in the extension study. The actual time varied for each participant and could be up to 71.8 months	Percent change in FEV1 and FVC from baseline (%) were reported. FEV1: the maximal volume of air exhaled from the lungs in 1 second of a forced expiration from a position of full inspiration as measured by spirometer. FVC: the volume of air (in liters) that can be forcibly blown out after full inspiration in the upright position. Extension baseline for safety is the last valid non-missing assessment that is taken on or after EOT visit in the core study, and prior to first study drug intake in the extension study. In this outcome measure, results were presented for extension end of treatment visit.
Number of Participants With Treatment-emergent Serious Adverse Events (SAEs)	From the start of study treatment in the extension study up to the end of study treatment + 15 days in the extension study. The actual time varied for each participant and could be up to 71.8 months + 15 days	Number of participants with treatment-emergent SAEs were reported. A SAE was defined as any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, leads to a congenital anomaly/birth defect in the offspring of a participant, or was an important medical event. Treatment-emergent SAEs are defined as SAEs occurring from start of treatment up to treatment end date + 15 days.
Number of Participants With Treatment-emergent Adverse Events of Special Interest (AESIs)	From the start of study treatment in the extension study up to the end of study treatment + 15 days in the extension study. The actual time varied for each participant and could be up to 71.8 months + 15 days	Number of participants with treatment-emergent AESIs were reported. AESIs included bradyarrhythmia occurred post-first dose, macular edema, bronchoconstriction, severe liver injury, serious opportunistic infections including progressive multifocal leukoencephalopathy (PML), skin cancer, non-skin malignancy, convulsions, unexpected neurological or psychiatric symptoms/signs (posterior reversible encephalopathy syndrome \[PRES\], acute disseminated encephalomyelitis \[ADEM\], and atypical MS relapses). Treatment-emergent AESIs are defined as AESIs occurring from start of treatment up to treatment end date + 15 days.
Number of Participants With AE Leading to Premature Discontinuation of Study Treatment	From the start of study treatment in the extension study up to the end of study treatment + 15 days in the extension study. The actual time varied for each participant and could be up to 71.8 months + 15 days	Number of participants with AE leading to premature discontinuation of study treatment were reported. An AE is any untoward medical event that occurs in a participant being administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. TEAEs are defined as AEs occurring from start of treatment up to treatment end date + 15 days.
Number of Participants With Treatment-emergent Decrease From Baseline >20% and >30% in FEV1 or FVC	From the start of study treatment in the extension study up to the end of study treatment + 15 days in the extension study. The actual time varied for each participant and could be up to 71.8 months + 15 days	Number of participants with treatment-emergent decrease from baseline \>20% and \>30% in FEV1 or FVC were reported. Treatment-emergent is defined as events occurring from start of treatment up to treatment end date + 15 days (that is, findings not present at any assessment prior to first treatment in the extension study).
Number of Participants With Treatment-emergent Decrease of >20% Points in Percent Predicted FEV1 and FVC From Baseline	From the start of study treatment in the extension study up to the end of study treatment + 15 days in the extension study. The actual time varied for each participant and could be up to 71.8 months + 15 days	Number of participants with treatment-emergent decrease of \>20% points in percent predicted FEV1 and FVC from baseline were reported. Treatment-emergent is defined as events occurring from start of treatment up to treatment end date + 15 days (that is, findings not present at any assessment prior to first treatment in the extension study).
Number of Participants With a Decrease of >=200 mL or >=12% in FEV1 or FVC From Baseline to EOT	From extension study baseline up to the end of study treatment in the extension study. The actual time varied for each participant and could be up to 71.8 months	Number of participants with a decrease of \>=200 mL or \>=12% in FEV1 or FVC from baseline to EOT were planned to be reported. Extension baseline for safety is the last valid non-missing assessment that is taken on or after EOT visit in the core study, and prior to first study drug intake in the extension study. This endpoint is not relevant as a substantial proportion of patients continued onto post-treatment disease-modifying therapy (DMT), hence it cannot provide an assessment of reversibility.
Change in FEV1 and FVC (% Predicted) From Baseline to End of Treatment (EOT)	From extension study baseline up to the end of study treatment in the extension study. The actual time varied for each participant and could be up to 71.8 months	Change in FEV1 and FVC (% predicted) from baseline to EOT were predicted. Extension baseline for safety is the last valid non-missing assessment that is taken on or after EOT visit in the core study, and prior to first study drug intake in the extension study.
Change in FEV1 and FVC (% Predicted) From Baseline to End of Study (EOS)	From extension study baseline up to the end of study in the extension study. The actual time varied for each participant and could be up to 73.2 months	Change in FEV1 and FVC (% predicted) from baseline to EOS were predicted. Extension baseline for safety is the last valid non-missing assessment that is taken on or after EOT visit in the core study, and prior to first study drug intake in the extension study.

Other

Measure	Time frame	Description
Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	Extension analysis period: Predose, 1, 2, 3, 4 hours post dose on Day 1 of re-initiation (re-initiation could occur on any day during the treatment period when drug was interrupted for at least 3 consecutive days [up to 71.8 months])	Actual values of 12-lead ECG measurements on day of first Re-initiation (Day 1) of study drug: PR, QRS, QT, QTcB, QTcF were reported.
Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: Heart Rate	Extension analysis period: Predose, 1, 2, 3, 4 hours post dose on Day 1 of re-initiation (re-initiation could occur on any day during the treatment period when drug was interrupted for at least 3 consecutive days [up to 71.8 months])	Actual values of 12-lead ECG measurements on day of first Re-initiation (Day 1) of study drug: heart rate were reported.

Countries

Belarus, Bosnia and Herzegovina, Bulgaria, Canada, Croatia, Czechia, Finland, France, Georgia, Germany, Greece, Hungary, Israel, Italy, Latvia, Lithuania, Mexico, Poland, Portugal, Romania, Russia, Serbia, Spain, Sweden, Turkey (Türkiye), Ukraine, United Kingdom, United States

Participant flow

Recruitment details

Total of 877 participants entered this extension study from the core study (NCT02425644) and all received at least one dose of ponesimod 20 milligrams (mg) treatment.

Pre-assignment details

Efficacy data: presented for extension set (ES; who consented and had 1 dose of ponesimod in extension study) in combined analysis period (included all available data from randomization in core study up to extension end of study \[EOS\] for those who entered ES). Safety data: presented for ES in extension analysis period (included all available data collected on or after date of 1st intake of ponesimod in extension study, through last treatment date in extension study+15 days).

Participants by arm

Arm	Count
Ponesimod 20 mg (Core and Extension Study) Participants with multiple sclerosis (MS) who were treated with ponesimod 20 milligrams (mg) in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	439
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension) Participants with multiple sclerosis (MS) who were treated with teriflunomide 14 mg in the core study (NCT02425644), and entered into this extension study, received a 14-day gradual up-titrated treatment (from 2 mg to 10 mg) of ponesimod tablet orally once daily from Days 1 to 14. Participants received a daily maintenance dose of ponesimod 20 mg tablet orally once daily from Day 15 up to Week 240 or till ponesimod became commercially available in a participant's country. Participants located in Ukraine had an extended treatment duration up to 288 weeks in the extension study due to the regional crisis.	438
Total	877

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	7	12
Overall Study	Death	1	0
Overall Study	Lack of Efficacy	10	8
Overall Study	Lost to Follow-up	6	6
Overall Study	Physician Decision	9	2
Overall Study	Withdrawal by Subject	54	39

Baseline characteristics

Characteristic	Ponesimod 20 mg (Core and Extension Study)	Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	439 Participants	438 Participants	877 Participants
Age, Continuous	36.5 years STANDARD_DEVIATION 8.75	37.2 years STANDARD_DEVIATION 8.75	36.8 years STANDARD_DEVIATION 8.75
Ethnicity (NIH/OMB) Hispanic or Latino	22 Participants	17 Participants	39 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	409 Participants	411 Participants	820 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	8 Participants	10 Participants	18 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	2 Participants	2 Participants	4 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	8 Participants	6 Participants	14 Participants
Race (NIH/OMB) White	429 Participants	430 Participants	859 Participants
Sex: Female, Male Female	286 Participants	290 Participants	576 Participants
Sex: Female, Male Male	153 Participants	148 Participants	301 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	1 / 439	0 / 438
other Total, other adverse events	339 / 439	328 / 438
serious Total, serious adverse events	56 / 439	57 / 438

Outcome results

Primary

Absolute Change in Lung Diffusion Capacity as Assessed by Diffusing Capacity for the Lungs Measured Using Carbon Monoxide (DL[CO]) From Baseline

Absolute change in lung diffusion capacity as assessed by DL\[CO\] from baseline were reported. Extension baseline for safety is the last valid non-missing assessment that is taken on or after EOT visit in the core study, and prior to first study drug intake in the extension study.

Time frame: From extension study baseline up to the end of study in the extension study. The actual time varied for each participant and could be up to 73.2 months

Population: The DL\[CO\] sub-study extension set included all participants in the extension set who have consented to participate in the DL\[CO\] sub-study during the extension study. Here, 'N' (number of participants analyzed) signifies number of participants evaluable for this outcome measure.

Arm	Measure	Value (MEAN)	Dispersion
Ponesimod 20 mg (Core and Extension Study)	Absolute Change in Lung Diffusion Capacity as Assessed by Diffusing Capacity for the Lungs Measured Using Carbon Monoxide (DL[CO]) From Baseline	0.7 Millimoles/minute/kilopascal	Standard Deviation 3.44
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Absolute Change in Lung Diffusion Capacity as Assessed by Diffusing Capacity for the Lungs Measured Using Carbon Monoxide (DL[CO]) From Baseline	0.1 Millimoles/minute/kilopascal	Standard Deviation 4.17

Primary

Absolute Values in Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) Values

Absolute values in FEV1 and FVC values were reported. FEV1: the maximal volume of air exhaled from the lungs in 1 second of a forced expiration from a position of full inspiration as measured by spirometer. FVC: the volume of air (in liters) that can be forcibly blown out after full inspiration in the upright position. Extension baseline for safety is the last valid non-missing assessment that is taken on or after EOT visit in the core study, and prior to first study drug intake in the extension study. Results are presented for extension end of treatment visit.

Time frame: From extension study baseline up to the end of study treatment in the extension study. The actual time varied for each participant and could be up to 71.8 months

Population: The extension set included all participants who signed an informed consent to enter the extension study and who received at least one dose of ponesimod study medication in the extension study. Here, 'N' (number of participants analyzed) signifies number of participants evaluable for this outcome measure.

Arm	Measure	Group	Value (MEAN)	Dispersion
Ponesimod 20 mg (Core and Extension Study)	Absolute Values in Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) Values	FEV1	3.01 Liters (L)	Standard Deviation 0.768
Ponesimod 20 mg (Core and Extension Study)	Absolute Values in Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) Values	FVC	-3.96 Liters (L)	Standard Deviation 0.965
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Absolute Values in Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) Values	FEV1	3.08 Liters (L)	Standard Deviation 0.797
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Absolute Values in Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) Values	FVC	4.04 Liters (L)	Standard Deviation 1.031

Primary

Actual Values of 12-lead ECG Measurements up to End of Study Treatment: Heart Rate

Actual values of 12-lead ECG measurements up to end of study treatment: heart rate were reported. In this outcome measure, results were presented for extension end of treatment visit.

Time frame: From the start of study treatment in the extension study up to the end of study treatment in the extension study. The actual time varied for each participant and could be up to 71.8 months

Arm	Measure	Value (MEAN)	Dispersion
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements up to End of Study Treatment: Heart Rate	67.4 Beats per minute (bpm)	Standard Deviation 9.64
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements up to End of Study Treatment: Heart Rate	67.6 Beats per minute (bpm)	Standard Deviation 9.33

Primary

Actual Values of 12-lead ECG Measurements up to End of Study Treatment: PR, QRS, QT, QTcB, QTcF

Actual values of 12-lead ECG measurements up to end of study treatment: PR, QRS, QT, QTcB, QTcF were reported. In this outcome measure, results were presented for extension end of treatment visit.

Arm	Measure	Group	Value (MEAN)	Dispersion
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements up to End of Study Treatment: PR, QRS, QT, QTcB, QTcF	QRS Duration	92.1 millisecond (ms)	Standard Deviation 9.22
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements up to End of Study Treatment: PR, QRS, QT, QTcB, QTcF	QTcB Interval	414.8 millisecond (ms)	Standard Deviation 19.2
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements up to End of Study Treatment: PR, QRS, QT, QTcB, QTcF	QT Interval	392.5 millisecond (ms)	Standard Deviation 27.26
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements up to End of Study Treatment: PR, QRS, QT, QTcB, QTcF	QTcF Interval	406.9 millisecond (ms)	Standard Deviation 17.78
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements up to End of Study Treatment: PR, QRS, QT, QTcB, QTcF	PR Interval	150.0 millisecond (ms)	Standard Deviation 20.41
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements up to End of Study Treatment: PR, QRS, QT, QTcB, QTcF	QTcF Interval	405.7 millisecond (ms)	Standard Deviation 17.78
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements up to End of Study Treatment: PR, QRS, QT, QTcB, QTcF	PR Interval	153.3 millisecond (ms)	Standard Deviation 20.27
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements up to End of Study Treatment: PR, QRS, QT, QTcB, QTcF	QRS Duration	93.3 millisecond (ms)	Standard Deviation 10.63
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements up to End of Study Treatment: PR, QRS, QT, QTcB, QTcF	QT Interval	391.0 millisecond (ms)	Standard Deviation 25.67
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements up to End of Study Treatment: PR, QRS, QT, QTcB, QTcF	QTcB Interval	413.8 millisecond (ms)	Standard Deviation 19.66

Primary

Annualized Confirmed Relapse Rate (ARR)

ARR: number of confirmed relapses per patient-year. Relapse: new, worsening, or recurrent neurological symptoms that occurred at least 30 days after the onset of a preceding relapse, and that lasted at least 24 hours, in the absence of fever or infection. A confirmed relapse is identified when a patient's symptoms worsen as indicated by an increase in their Expanded Disability Status Scale (EDSS) or Functional Systems (FS) scores, consistent with previous clinically stable assessments. Specific criteria for a confirmed relapse include: An increase of 0.5 points on EDSS; (unless EDSS=0, then requires an increase of 1.0-point); An increase of at least 1.0 point in at least two FS scores; or a 2.0-point increase in one FS score (excluding bladder/bowel and cerebral). Rating individual FS scores is used to rate EDSS along with observations and information concerning gait and use of assistance. EDSS is ordinal clinical rating scale ranging:0 (normal)-10 (death due to MS).

Time frame: From randomization in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months

Arm	Measure	Value (MEAN)
Ponesimod 20 mg (Core and Extension Study)	Annualized Confirmed Relapse Rate (ARR)	0.143 relapses per patient-year
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Annualized Confirmed Relapse Rate (ARR)	0.184 relapses per patient-year

95% CI: [0.629, 0.965]

Primary

Change From Baseline in Expanded Disability Status Scale (EDSS)

EDSS is ordinal clinical rating scale based on standard neurological examination for assessing neurological disability and impairment in MS. Seven FS scores were rated on a scale ranged from 0 to 5 or 6 to assess visual, brain, stem, pyramidal, cerebellar, sensory, bowel and bladder, and cerebral functions while ambulation was scored on scale ranged from 0 to 12 to assess walking distance and assistance. 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) in 0.5 unit increments that represented higher levels of disability. Core baseline for efficacy is defined as the last non-missing value recorded before or on randomization in the core study for each outcome measure and each participant individually.

Time frame: From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months

Arm	Measure	Value (MEAN)	Dispersion
Ponesimod 20 mg (Core and Extension Study)	Change From Baseline in Expanded Disability Status Scale (EDSS)	0.16 Score on a scale	Standard Deviation 1.008
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Change From Baseline in Expanded Disability Status Scale (EDSS)	0.34 Score on a scale	Standard Deviation 1.105

Primary

Change From Baseline in Volume of MRI Lesions (T2 Lesions and T1 Hypointense Lesions)

Change from baseline in volume of MRI lesions (T2 lesions, T1 hypointense lesions) were reported. Core baseline for efficacy is defined as the last non-missing value recorded before or on randomization in the core study for each outcome measure and each participant individually. In this outcome measure, results were presented for extension end of treatment visit.

Time frame: From baseline in the core study up to the end of treatment (EOT) in the extension study. The actual time varied for each participant and could be up to 94.8 months

Arm	Measure	Group	Value (MEAN)	Dispersion
Ponesimod 20 mg (Core and Extension Study)	Change From Baseline in Volume of MRI Lesions (T2 Lesions and T1 Hypointense Lesions)	T2 Lesions	-435.7 cubic millimeters (mm^3)	Standard Deviation 2822.71
Ponesimod 20 mg (Core and Extension Study)	Change From Baseline in Volume of MRI Lesions (T2 Lesions and T1 Hypointense Lesions)	T1 Hypointense Lesions	165.6 cubic millimeters (mm^3)	Standard Deviation 1427.3
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Change From Baseline in Volume of MRI Lesions (T2 Lesions and T1 Hypointense Lesions)	T2 Lesions	91.5 cubic millimeters (mm^3)	Standard Deviation 3647.08
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Change From Baseline in Volume of MRI Lesions (T2 Lesions and T1 Hypointense Lesions)	T1 Hypointense Lesions	309.4 cubic millimeters (mm^3)	Standard Deviation 1712.36

Primary

Change in DL[CO] (% Predicted) From Baseline to EOS

Change in DL\[CO\] (% predicted) from baseline to EOS were predicted. Extension baseline for safety is the last valid non-missing assessment that is taken on or after EOT visit in the core study, and prior to first study drug intake in the extension study.

Time frame: From extension study baseline up to the end of study in the extension study. The actual time varied for each participant and could be up to 73.2 months

Population: The DL\[CO\] sub-study extension set includes all participants in the extension set who have consented to participate in the DL\[CO\] sub-study during the extension study. Here, 'N' (number of participants analyzed) signifies number of participants evaluable for this outcome measure.

Arm	Measure	Value (MEAN)	Dispersion
Ponesimod 20 mg (Core and Extension Study)	Change in DL[CO] (% Predicted) From Baseline to EOS	9.3 Percentage predicted DL[CO]	Standard Deviation 39.38
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Change in DL[CO] (% Predicted) From Baseline to EOS	2.2 Percentage predicted DL[CO]	Standard Deviation 49.5

Primary

Change in DL[CO] (% Predicted) From Baseline to EOT

Change in DL\[CO\] (% predicted) from baseline to EOT were predicted. Extension baseline for safety is the last valid non-missing assessment that is taken on or after EOT visit in the core study, and prior to first study drug intake in the extension study.

Time frame: From extension study baseline up to the end of study treatment in the extension study. The actual time varied for each participant and could be up to 71.8 months

Arm	Measure	Value (MEAN)	Dispersion
Ponesimod 20 mg (Core and Extension Study)	Change in DL[CO] (% Predicted) From Baseline to EOT	5.7 Percentage predicted DL[CO]	Standard Deviation 32.2
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Change in DL[CO] (% Predicted) From Baseline to EOT	-9.4 Percentage predicted DL[CO]	Standard Deviation 7.82

Primary

Change in FEV1 and FVC (% Predicted) From Baseline to End of Study (EOS)

Change in FEV1 and FVC (% predicted) from baseline to EOS were predicted. Extension baseline for safety is the last valid non-missing assessment that is taken on or after EOT visit in the core study, and prior to first study drug intake in the extension study.

Time frame: From extension study baseline up to the end of study in the extension study. The actual time varied for each participant and could be up to 73.2 months

Arm	Measure	Group	Value (MEAN)	Dispersion
Ponesimod 20 mg (Core and Extension Study)	Change in FEV1 and FVC (% Predicted) From Baseline to End of Study (EOS)	FEV1	-5.95 Percentage predicted change	Standard Deviation 12.854
Ponesimod 20 mg (Core and Extension Study)	Change in FEV1 and FVC (% Predicted) From Baseline to End of Study (EOS)	FVC	-4.48 Percentage predicted change	Standard Deviation 13.727
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Change in FEV1 and FVC (% Predicted) From Baseline to End of Study (EOS)	FEV1	-4.08 Percentage predicted change	Standard Deviation 14.365
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Change in FEV1 and FVC (% Predicted) From Baseline to End of Study (EOS)	FVC	-1.98 Percentage predicted change	Standard Deviation 15.747

Primary

Change in FEV1 and FVC (% Predicted) From Baseline to End of Treatment (EOT)

Change in FEV1 and FVC (% predicted) from baseline to EOT were predicted. Extension baseline for safety is the last valid non-missing assessment that is taken on or after EOT visit in the core study, and prior to first study drug intake in the extension study.

Time frame: From extension study baseline up to the end of study treatment in the extension study. The actual time varied for each participant and could be up to 71.8 months

Arm	Measure	Group	Value (MEAN)	Dispersion
Ponesimod 20 mg (Core and Extension Study)	Change in FEV1 and FVC (% Predicted) From Baseline to End of Treatment (EOT)	FEV1	-7.14 Percentage predicted change	Standard Deviation 13.315
Ponesimod 20 mg (Core and Extension Study)	Change in FEV1 and FVC (% Predicted) From Baseline to End of Treatment (EOT)	FVC	-4.70 Percentage predicted change	Standard Deviation 13.129
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Change in FEV1 and FVC (% Predicted) From Baseline to End of Treatment (EOT)	FEV1	-5.43 Percentage predicted change	Standard Deviation 11.839
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Change in FEV1 and FVC (% Predicted) From Baseline to End of Treatment (EOT)	FVC	-3.19 Percentage predicted change	Standard Deviation 13.081

Primary

Change in Heart Rate (HR) From Baseline up to End of Study Treatment

Change in heart rate (HR) from baseline up to end of study treatment were reported.

Arm	Measure	Value (MEAN)	Dispersion
Ponesimod 20 mg (Core and Extension Study)	Change in Heart Rate (HR) From Baseline up to End of Study Treatment	-1.7 beats per minute (bpm)	Standard Deviation 10
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Change in Heart Rate (HR) From Baseline up to End of Study Treatment	-1.5 beats per minute (bpm)	Standard Deviation 9.17

Primary

Change in PR, QRS, QT, QTcB, QTcF From Baseline up to End of Study Treatment

Change in PR, QRS, QT, QTcB, QTcF from baseline up to end of study treatment were reported.

Arm	Measure	Group	Value (MEAN)	Dispersion
Ponesimod 20 mg (Core and Extension Study)	Change in PR, QRS, QT, QTcB, QTcF From Baseline up to End of Study Treatment	QRS Duration	-0.4 millisecond (ms)	Standard Deviation 6.79
Ponesimod 20 mg (Core and Extension Study)	Change in PR, QRS, QT, QTcB, QTcF From Baseline up to End of Study Treatment	QTcB Interval	2.9 millisecond (ms)	Standard Deviation 16.75
Ponesimod 20 mg (Core and Extension Study)	Change in PR, QRS, QT, QTcB, QTcF From Baseline up to End of Study Treatment	QT Interval	7.8 millisecond (ms)	Standard Deviation 25.68
Ponesimod 20 mg (Core and Extension Study)	Change in PR, QRS, QT, QTcB, QTcF From Baseline up to End of Study Treatment	QTcF Interval	4.6 millisecond (ms)	Standard Deviation 15.28
Ponesimod 20 mg (Core and Extension Study)	Change in PR, QRS, QT, QTcB, QTcF From Baseline up to End of Study Treatment	PR Interval	0.5 millisecond (ms)	Standard Deviation 14.09
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Change in PR, QRS, QT, QTcB, QTcF From Baseline up to End of Study Treatment	QTcF Interval	6.5 millisecond (ms)	Standard Deviation 14.18
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Change in PR, QRS, QT, QTcB, QTcF From Baseline up to End of Study Treatment	PR Interval	2.0 millisecond (ms)	Standard Deviation 14.37
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Change in PR, QRS, QT, QTcB, QTcF From Baseline up to End of Study Treatment	QRS Duration	2.9 millisecond (ms)	Standard Deviation 6.88
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Change in PR, QRS, QT, QTcB, QTcF From Baseline up to End of Study Treatment	QT Interval	8.9 millisecond (ms)	Standard Deviation 21.66
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Change in PR, QRS, QT, QTcB, QTcF From Baseline up to End of Study Treatment	QTcB Interval	5.2 millisecond (ms)	Standard Deviation 17.07

Primary

Cumulative Number of Combined Unique Active Lesions (CUAL) Measured by MRI

CUALs was calculated as sum of new T1 Gadolinium-enhanced (Gd+) lesions and new or enlarging T2 lesions (without double-counting of lesions) from baseline up to extension EOS based on the Magnetic resonance imaging (MRI). Average number of lesions per patient-year were reported. Results are based on a negative-binomial regression model. Core baseline for efficacy is defined as the last non-missing value recorded before or on randomization in the core study for each outcome measure and each participant individually.

Time frame: From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months

Arm	Measure	Value (MEAN)
Ponesimod 20 mg (Core and Extension Study)	Cumulative Number of Combined Unique Active Lesions (CUAL) Measured by MRI	1.352 CUAL per patient-year
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Cumulative Number of Combined Unique Active Lesions (CUAL) Measured by MRI	1.954 CUAL per patient-year

Primary

Cumulative Number of New or Enlarging T2 Lesions Measured by MRI

Cumulative number of new or enlarging T2 lesions measured by MRI were reported. Average number of lesions per year were reported. Results are based on a negative-binomial regression model. Core baseline for efficacy is defined as the last non-missing value recorded before or on randomization in the core study for each outcome measure and each participant individually.

Time frame: From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months

Arm	Measure	Value (MEAN)
Ponesimod 20 mg (Core and Extension Study)	Cumulative Number of New or Enlarging T2 Lesions Measured by MRI	1.352 Lesions per year
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Cumulative Number of New or Enlarging T2 Lesions Measured by MRI	1.951 Lesions per year

Primary

Number of Gadolinium-enhancing (Gd+) T1 Lesions Measured by MRI

Number of Gd+ T1 lesions measured by MRI were reported. Results are based on a negative-binomial regression model. Core baseline for efficacy is defined as the last non-missing value recorded before or on randomization in the core study for each outcome measure and each participant individually. For this outcome measure, results presented here are for the Extension end-of-treatment visit.

Time frame: From baseline in the core study up to the end of treatment (EOT) in the extension study. The actual time varied for each participant and could be up to 94.8 months

Arm	Measure	Value (MEAN)
Ponesimod 20 mg (Core and Extension Study)	Number of Gadolinium-enhancing (Gd+) T1 Lesions Measured by MRI	0.211 Gd+ T1 lesions
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Number of Gadolinium-enhancing (Gd+) T1 Lesions Measured by MRI	0.395 Gd+ T1 lesions

Primary

Number of Participants With Absence of MRI Lesions (Gd+ T1 Lesions, New or Enlarging T2 Lesions)

Number of participants with absence of MRI lesions (Gd+ T1 lesions, new or enlarging T2 lesions) were reported. Core baseline for efficacy is defined as the last non-missing value recorded before or on randomization in the core study for each outcome measure and each participant individually. In this outcome measure, results were presented for extension end of treatment visit.

Time frame: From baseline in the core study up to the end of treatment (EOT) in the extension study. The actual time varied for each participant and could be up to 94.8 months

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Ponesimod 20 mg (Core and Extension Study)	Number of Participants With Absence of MRI Lesions (Gd+ T1 Lesions, New or Enlarging T2 Lesions)	Gd+ T1 lesions	293 Participants
Ponesimod 20 mg (Core and Extension Study)	Number of Participants With Absence of MRI Lesions (Gd+ T1 Lesions, New or Enlarging T2 Lesions)	T2 lesions	152 Participants
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Number of Participants With Absence of MRI Lesions (Gd+ T1 Lesions, New or Enlarging T2 Lesions)	Gd+ T1 lesions	236 Participants
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Number of Participants With Absence of MRI Lesions (Gd+ T1 Lesions, New or Enlarging T2 Lesions)	T2 lesions	101 Participants

Primary

Number of Participants With a Decrease of >=200 mL or >=12% in FEV1 or FVC From Baseline to EOT

Number of participants with a decrease of \>=200 mL or \>=12% in FEV1 or FVC from baseline to EOT were planned to be reported. Extension baseline for safety is the last valid non-missing assessment that is taken on or after EOT visit in the core study, and prior to first study drug intake in the extension study. This endpoint is not relevant as a substantial proportion of patients continued onto post-treatment disease-modifying therapy (DMT), hence it cannot provide an assessment of reversibility.

Time frame: From extension study baseline up to the end of study treatment in the extension study. The actual time varied for each participant and could be up to 71.8 months

Primary

Number of Participants With AE Leading to Premature Discontinuation of Study Treatment

Number of participants with AE leading to premature discontinuation of study treatment were reported. An AE is any untoward medical event that occurs in a participant being administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. TEAEs are defined as AEs occurring from start of treatment up to treatment end date + 15 days.

Time frame: From the start of study treatment in the extension study up to the end of study treatment + 15 days in the extension study. The actual time varied for each participant and could be up to 71.8 months + 15 days

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Ponesimod 20 mg (Core and Extension Study)	Number of Participants With AE Leading to Premature Discontinuation of Study Treatment	34 Participants
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Number of Participants With AE Leading to Premature Discontinuation of Study Treatment	41 Participants

Primary

Number of Participants With Treatment-emergent Adverse Events of Special Interest (AESIs)

Number of participants with treatment-emergent AESIs were reported. AESIs included bradyarrhythmia occurred post-first dose, macular edema, bronchoconstriction, severe liver injury, serious opportunistic infections including progressive multifocal leukoencephalopathy (PML), skin cancer, non-skin malignancy, convulsions, unexpected neurological or psychiatric symptoms/signs (posterior reversible encephalopathy syndrome \[PRES\], acute disseminated encephalomyelitis \[ADEM\], and atypical MS relapses). Treatment-emergent AESIs are defined as AESIs occurring from start of treatment up to treatment end date + 15 days.

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Ponesimod 20 mg (Core and Extension Study)	Number of Participants With Treatment-emergent Adverse Events of Special Interest (AESIs)	Severe liver injury	5 Participants
Ponesimod 20 mg (Core and Extension Study)	Number of Participants With Treatment-emergent Adverse Events of Special Interest (AESIs)	Skin cancer	4 Participants
Ponesimod 20 mg (Core and Extension Study)	Number of Participants With Treatment-emergent Adverse Events of Special Interest (AESIs)	Macular edema	4 Participants
Ponesimod 20 mg (Core and Extension Study)	Number of Participants With Treatment-emergent Adverse Events of Special Interest (AESIs)	Non-skin malignancy	4 Participants
Ponesimod 20 mg (Core and Extension Study)	Number of Participants With Treatment-emergent Adverse Events of Special Interest (AESIs)	Bronchoconstriction	31 Participants
Ponesimod 20 mg (Core and Extension Study)	Number of Participants With Treatment-emergent Adverse Events of Special Interest (AESIs)	Unexpected neurological or psychiatric symptoms / signs (PRES, ADEM, atypical MS relapses)	1 Participants
Ponesimod 20 mg (Core and Extension Study)	Number of Participants With Treatment-emergent Adverse Events of Special Interest (AESIs)	Serious opportunistic infections including PML	2 Participants
Ponesimod 20 mg (Core and Extension Study)	Number of Participants With Treatment-emergent Adverse Events of Special Interest (AESIs)	Convulsions	2 Participants
Ponesimod 20 mg (Core and Extension Study)	Number of Participants With Treatment-emergent Adverse Events of Special Interest (AESIs)	Bradyarrhythmia occurring post-first dose	11 Participants
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Number of Participants With Treatment-emergent Adverse Events of Special Interest (AESIs)	Convulsions	3 Participants
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Number of Participants With Treatment-emergent Adverse Events of Special Interest (AESIs)	Bradyarrhythmia occurring post-first dose	13 Participants
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Number of Participants With Treatment-emergent Adverse Events of Special Interest (AESIs)	Severe liver injury	5 Participants
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Number of Participants With Treatment-emergent Adverse Events of Special Interest (AESIs)	Bronchoconstriction	25 Participants
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Number of Participants With Treatment-emergent Adverse Events of Special Interest (AESIs)	Macular edema	6 Participants
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Number of Participants With Treatment-emergent Adverse Events of Special Interest (AESIs)	Serious opportunistic infections including PML	1 Participants
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Number of Participants With Treatment-emergent Adverse Events of Special Interest (AESIs)	Skin cancer	3 Participants
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Number of Participants With Treatment-emergent Adverse Events of Special Interest (AESIs)	Non-skin malignancy	3 Participants
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Number of Participants With Treatment-emergent Adverse Events of Special Interest (AESIs)	Unexpected neurological or psychiatric symptoms / signs (PRES, ADEM, atypical MS relapses)	2 Participants

Primary

Number of Participants With Treatment-emergent Adverse Events (TEAEs)

Number of participants with TEAEs were reported. An AE is any untoward medical event that occurs in a participants being administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. TEAEs are defined as AEs occurring from start of treatment up to treatment end date + 15 days.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Ponesimod 20 mg (Core and Extension Study)	Number of Participants With Treatment-emergent Adverse Events (TEAEs)	411 Participants
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Number of Participants With Treatment-emergent Adverse Events (TEAEs)	410 Participants

Primary

Number of Participants With Treatment-emergent Decrease From Baseline >20% and >30% in FEV1 or FVC

Number of participants with treatment-emergent decrease from baseline \>20% and \>30% in FEV1 or FVC were reported. Treatment-emergent is defined as events occurring from start of treatment up to treatment end date + 15 days (that is, findings not present at any assessment prior to first treatment in the extension study).

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Ponesimod 20 mg (Core and Extension Study)	Number of Participants With Treatment-emergent Decrease From Baseline >20% and >30% in FEV1 or FVC	FVC: >20 %	54 Participants
Ponesimod 20 mg (Core and Extension Study)	Number of Participants With Treatment-emergent Decrease From Baseline >20% and >30% in FEV1 or FVC	FEV1: >20 %	80 Participants
Ponesimod 20 mg (Core and Extension Study)	Number of Participants With Treatment-emergent Decrease From Baseline >20% and >30% in FEV1 or FVC	FEV1: >30 %	18 Participants
Ponesimod 20 mg (Core and Extension Study)	Number of Participants With Treatment-emergent Decrease From Baseline >20% and >30% in FEV1 or FVC	FVC: >30 %	19 Participants
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Number of Participants With Treatment-emergent Decrease From Baseline >20% and >30% in FEV1 or FVC	FVC: >30 %	15 Participants
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Number of Participants With Treatment-emergent Decrease From Baseline >20% and >30% in FEV1 or FVC	FVC: >20 %	60 Participants
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Number of Participants With Treatment-emergent Decrease From Baseline >20% and >30% in FEV1 or FVC	FEV1: >30 %	21 Participants
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Number of Participants With Treatment-emergent Decrease From Baseline >20% and >30% in FEV1 or FVC	FEV1: >20 %	82 Participants

Primary

Number of Participants With Treatment-emergent Decrease of >20% Points in Percent Predicted FEV1 and FVC From Baseline

Number of participants with treatment-emergent decrease of \>20% points in percent predicted FEV1 and FVC from baseline were reported. Treatment-emergent is defined as events occurring from start of treatment up to treatment end date + 15 days (that is, findings not present at any assessment prior to first treatment in the extension study).

Arm	Measure	Group	Value (COUNT_OF_PARTICIPANTS)
Ponesimod 20 mg (Core and Extension Study)	Number of Participants With Treatment-emergent Decrease of >20% Points in Percent Predicted FEV1 and FVC From Baseline	FEV1: >20 %	70 Participants
Ponesimod 20 mg (Core and Extension Study)	Number of Participants With Treatment-emergent Decrease of >20% Points in Percent Predicted FEV1 and FVC From Baseline	FVC: >20 %	59 Participants
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Number of Participants With Treatment-emergent Decrease of >20% Points in Percent Predicted FEV1 and FVC From Baseline	FEV1: >20 %	68 Participants
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Number of Participants With Treatment-emergent Decrease of >20% Points in Percent Predicted FEV1 and FVC From Baseline	FVC: >20 %	57 Participants

Primary

Number of Participants With Treatment-emergent New Morphological Electrocardiogram (ECG) Abnormalities

Number of participants with treatment-emergent new morphological ECG abnormalities were reported. Treatment-emergent new morphological ECG abnormalities are defined as those ECG abnormalities occurring from start of treatment up to treatment end date + 15 days.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Ponesimod 20 mg (Core and Extension Study)	Number of Participants With Treatment-emergent New Morphological Electrocardiogram (ECG) Abnormalities	153 Participants
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Number of Participants With Treatment-emergent New Morphological Electrocardiogram (ECG) Abnormalities	140 Participants

Primary

Number of Participants With Treatment-emergent Serious Adverse Events (SAEs)

Number of participants with treatment-emergent SAEs were reported. A SAE was defined as any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, leads to a congenital anomaly/birth defect in the offspring of a participant, or was an important medical event. Treatment-emergent SAEs are defined as SAEs occurring from start of treatment up to treatment end date + 15 days.

Arm	Measure	Value (COUNT_OF_PARTICIPANTS)
Ponesimod 20 mg (Core and Extension Study)	Number of Participants With Treatment-emergent Serious Adverse Events (SAEs)	56 Participants
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Number of Participants With Treatment-emergent Serious Adverse Events (SAEs)	57 Participants

Primary

Percentage of Gd+ Lesions at Baseline Evolving to Persistent Black Holes (PBHs)

Percentage of Gd+ lesions at baseline evolving to PBHs were reported. Core baseline for efficacy is defined as the last non-missing value recorded before or on randomization in the core study for each outcome measure and each participant individually. In this outcome measure, results were presented for extension end of treatment visit.

Time frame: From baseline in the core study up to the end of treatment (EOT) in the extension study. The actual time varied for each participant and could be up to 94.8 months

Arm	Measure	Value (NUMBER)
Ponesimod 20 mg (Core and Extension Study)	Percentage of Gd+ Lesions at Baseline Evolving to Persistent Black Holes (PBHs)	22.3 Percentage of lesions
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Percentage of Gd+ Lesions at Baseline Evolving to Persistent Black Holes (PBHs)	25.1 Percentage of lesions

Primary

Percentage of Participants With Absence of Relapses

Relapse: new, worsening, or recurrent neurological symptoms that occurred at least 30 days after the onset of a preceding relapse, and that lasted at least 24 hours in absence of fever or infection. A confirmed relapse: when patient's symptoms worsen as indicated by an increase in their EDSS/FS scores, consistent with previous clinically stable assessments. Specific criteria for confirmed relapse: An increase of 0.5 points on EDSS; (unless EDSS=0, then requires an increase of 1.0-point); An increase of at least 1.0 point in at least two FS scores; or a 2.0-point increase in one FS score (excluding bladder/bowel and cerebral). Rating individual FS scores is used to rate EDSS along with observations and information concerning gait and use of assistance. EDSS is ordinal clinical rating scale ranging:0(normal)-10(death due to MS). Core baseline for efficacy: last non-missing value recorded before or on randomization in the core study for each outcome measure and participant individually.

Time frame: From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months

Arm	Measure	Value (NUMBER)
Ponesimod 20 mg (Core and Extension Study)	Percentage of Participants With Absence of Relapses	56.7 Percentage of Participants
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Percentage of Participants With Absence of Relapses	51.6 Percentage of Participants

Primary

Percentage of Participants With No Evidence of Disease Activity (NEDA) Status According to NEDA With Four Components (NEDA-4) at Extension End of Study

NEDA-4 up to EOS is defined by the absence of confirmed relapse, Gd+ T1 lesions, new or enlarging T2 lesions, 12-week CDA until EOS, and absence of annual brain volume decrease \>=0.4% from core baseline up to extension EOS. If at least one of the criteria was not fulfilled or the participant discontinued treatment prematurely, the participant was not considered to have achieved NEDA-4. Confirmed relapse: when patient's symptoms worsen by an increase in their EDSS/FS scores, consistent with previous clinically stable assessments. Rating individual FS scores is used to rate EDSS along with observations and information concerning gait and use of assistance. EDSS is ordinal clinical rating scale ranging: 0 (normal)-10 (death due to MS). Core baseline for efficacy is defined as the last non-missing value recorded before or on randomization in core study for each outcome measure and each participant individually.

Time frame: From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months

Arm	Measure	Value (NUMBER)
Ponesimod 20 mg (Core and Extension Study)	Percentage of Participants With No Evidence of Disease Activity (NEDA) Status According to NEDA With Four Components (NEDA-4) at Extension End of Study	5.2 Percentage of Participants
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Percentage of Participants With No Evidence of Disease Activity (NEDA) Status According to NEDA With Four Components (NEDA-4) at Extension End of Study	2.3 Percentage of Participants

Primary

Percentage of Participants With No Evidence of Disease Activity (NEDA) Status According to NEDA With Three Components (NEDA-3) at Extension End of Study

NEDA-3 up to extension EOS is defined by the absence of confirmed relapse, gadolinium-enhancing (Gd+ T1) lesions, new or enlarging T2 lesions, and 12-week CDA. If at least one of the criteria was not fulfilled or the participant discontinued treatment prematurely, the participant was not considered to have achieved NEDA-3. Confirmed relapse: when patient's symptoms worsen as indicated by an increase in their EDSS/FS scores, consistent with previous clinically stable assessments. Rating individual FS scores is used to rate EDSS along with observations and information concerning gait and use of assistance. EDSS is ordinal clinical rating scale ranging: 0 (normal)-10 (death due to MS). Core baseline for efficacy is defined as the last non-missing value recorded before or on randomization in the core study for each outcome measure and each participant individually.

Time frame: From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months

Arm	Measure	Value (NUMBER)
Ponesimod 20 mg (Core and Extension Study)	Percentage of Participants With No Evidence of Disease Activity (NEDA) Status According to NEDA With Three Components (NEDA-3) at Extension End of Study	17.5 Percentage of Participants
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Percentage of Participants With No Evidence of Disease Activity (NEDA) Status According to NEDA With Three Components (NEDA-3) at Extension End of Study	7.5 Percentage of Participants

Primary

Percent Change From Baseline in Brain Volume (PCBV) Measured by Magnetic Resonance Imaging (MRI)

Percent change from baseline in brain volume (PCBV) measured by MRI were reported. Normalized Brain Volume at core baseline was measured in cubic centimeter (cm\^3). Core baseline for efficacy is defined as the last non-missing value recorded before or on randomization in the core study for each outcome measure and each participant individually. In this outcome measure, results were presented for extension end of treatment visit.

Time frame: From baseline in the core study up to the end of treatment (EOT) in the extension study. The actual time varied for each participant and could be up to 94.8 months

Arm	Measure	Value (MEAN)	Dispersion
Ponesimod 20 mg (Core and Extension Study)	Percent Change From Baseline in Brain Volume (PCBV) Measured by Magnetic Resonance Imaging (MRI)	-2.52 Percent Change	Standard Deviation 2.179
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Percent Change From Baseline in Brain Volume (PCBV) Measured by Magnetic Resonance Imaging (MRI)	-2.72 Percent Change	Standard Deviation 2.024

Primary

Percent Change in (FEV1) and Forced Vital Capacity (FVC) From Baseline (%)

Percent change in FEV1 and FVC from baseline (%) were reported. FEV1: the maximal volume of air exhaled from the lungs in 1 second of a forced expiration from a position of full inspiration as measured by spirometer. FVC: the volume of air (in liters) that can be forcibly blown out after full inspiration in the upright position. Extension baseline for safety is the last valid non-missing assessment that is taken on or after EOT visit in the core study, and prior to first study drug intake in the extension study. In this outcome measure, results were presented for extension end of treatment visit.

Time frame: From extension study baseline up to the end of study treatment in the extension study. The actual time varied for each participant and could be up to 71.8 months

Arm	Measure	Group	Value (MEAN)	Dispersion
Ponesimod 20 mg (Core and Extension Study)	Percent Change in (FEV1) and Forced Vital Capacity (FVC) From Baseline (%)	FEV1	-7.96 Percent change	Standard Deviation 13.356
Ponesimod 20 mg (Core and Extension Study)	Percent Change in (FEV1) and Forced Vital Capacity (FVC) From Baseline (%)	FVC	-5.09 Percent change	Standard Deviation 11.793
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Percent Change in (FEV1) and Forced Vital Capacity (FVC) From Baseline (%)	FEV1	-6.75 Percent change	Standard Deviation 12.323
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Percent Change in (FEV1) and Forced Vital Capacity (FVC) From Baseline (%)	FVC	-3.93 Percent change	Standard Deviation 12.141

Primary

Time From Core Study Randomization to First Confirmed Relapse

Time to first confirmed relapse: date of first confirmed relapse (in either core or extension study) minus date of randomization in core study+1 day. Relapse: new, worsening, or recurrent neurological symptoms that occurred at least 30 days after the onset of a preceding relapse, and that lasted at least 24 hours in absence of fever or infection. A confirmed relapse: when patient's symptoms worsen as indicated by an increase in their EDSS/FS scores, consistent with previous clinically stable assessments. Specific criteria for confirmed relapse are: An increase of 0.5 points on EDSS; (unless EDSS=0, then requires an increase of 1.0-point); An increase of at least 1.0 point in at least two FS scores; or a 2.0-point increase in one FS score (excluding bladder/bowel and cerebral). Rating individual FS scores is used to rate EDSS along with observations and information concerning gait and use of assistance. EDSS is ordinal clinical rating scale ranging:0(normal)-10(death due to MS).

Time frame: From randomization in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months

Arm	Measure	Value (MEDIAN)
Ponesimod 20 mg (Core and Extension Study)	Time From Core Study Randomization to First Confirmed Relapse	402.71 Weeks
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Time From Core Study Randomization to First Confirmed Relapse	NA Weeks

Primary

Time to First 12-week Confirmed Disability Accumulation (CDA)

Time to first 12-week CDA is defined as start date of the first 12-week CDA minus date of randomization in the core study + 1 day. A 12-week CDA is defined as a 12-week sustained increase from the core baseline EDSS score, which is confirmed at a scheduled visit after 12-weeks. CDA is defined as: (a) Sustained increase of at least 1.5 in EDSS for participants with a core baseline EDSS score of 0; (b) Sustained increase of at least 1.0 in EDSS for participants with a core baseline EDSS score of 1.0 to 5.0; (c) Sustained increase of at least 0.5 in EDSS for participants with a core baseline EDSS score \>=5.5, confirmed after 12 weeks. EDSS is an ordinal clinical rating scale ranging from 0 (normal neurological examination) to 10 (death due to MS). Core baseline for efficacy: last non-missing value recorded before or on randomization in the core study for each outcome measure and participant individually.

Time frame: From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months

Arm	Measure	Value (MEDIAN)
Ponesimod 20 mg (Core and Extension Study)	Time to First 12-week Confirmed Disability Accumulation (CDA)	NA Weeks
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Time to First 12-week Confirmed Disability Accumulation (CDA)	NA Weeks

Primary

Time to First 24-week Confirmed Disability Accumulation (CDA)

Time to first 24-week CDA was defined as start date of the first 24-week CDA minus date of randomization in the core study + 1 day. A 24-week CDA was defined as a 24-week sustained increase from the core baseline EDSS score, which is confirmed at a scheduled visit after 24-weeks. CDA was defined as: (a) Sustained increase of at least 1.5 in EDSS for participants with a core baseline EDSS score of 0; (b) Sustained increase of at least 1.0 in EDSS for participants with a core baseline EDSS score of 1.0 to 5.0; (c) Sustained increase of at least 0.5 in EDSS for participants with a core baseline EDSS score \>=5.5, confirmed after 24 weeks. EDSS was an ordinal clinical rating scale ranging from 0 (normal neurological examination) to 10 (death due to MS). Core baseline for efficacy: last non-missing value recorded before or on randomization in the core study for each outcome measure and participant individually.

Time frame: From baseline in the core study up to the end of study (EOS) in the extension study. The actual time varied for each participant and could be up to 98.5 months

Arm	Measure	Value (MEDIAN)
Ponesimod 20 mg (Core and Extension Study)	Time to First 24-week Confirmed Disability Accumulation (CDA)	NA Weeks
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Time to First 24-week Confirmed Disability Accumulation (CDA)	NA Weeks

Other Pre-specified

Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: Heart Rate

Actual values of 12-lead ECG measurements on day of first Re-initiation (Day 1) of study drug: heart rate were reported.

Time frame: Extension analysis period: Predose, 1, 2, 3, 4 hours post dose on Day 1 of re-initiation (re-initiation could occur on any day during the treatment period when drug was interrupted for at least 3 consecutive days [up to 71.8 months])

Population: Population analysis included numbers of participants based on sub-set of extension set who had a re-initiation. Here, 'n' (number analyzed) is defined as participants analyzed at specified timepoints.

Arm	Measure	Group	Value (MEAN)	Dispersion
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: Heart Rate	1 hour Post-dose	66.5 beats per minute (bpm)	Standard Deviation 10.53
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: Heart Rate	3 hours Post-dose	64.6 beats per minute (bpm)	Standard Deviation 9.33
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: Heart Rate	2 hours Post-dose	64.3 beats per minute (bpm)	Standard Deviation 9.91
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: Heart Rate	4 hours Post-dose	66.0 beats per minute (bpm)	Standard Deviation 9.73
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: Heart Rate	Predose	68.1 beats per minute (bpm)	Standard Deviation 8.73
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: Heart Rate	4 hours Post-dose	67.6 beats per minute (bpm)	Standard Deviation 10.01
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: Heart Rate	Predose	71.0 beats per minute (bpm)	Standard Deviation 9.21
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: Heart Rate	1 hour Post-dose	69.0 beats per minute (bpm)	Standard Deviation 10.13
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: Heart Rate	2 hours Post-dose	65.1 beats per minute (bpm)	Standard Deviation 8.68
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: Heart Rate	3 hours Post-dose	67.8 beats per minute (bpm)	Standard Deviation 10.71

Other Pre-specified

Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF

Actual values of 12-lead ECG measurements on day of first Re-initiation (Day 1) of study drug: PR, QRS, QT, QTcB, QTcF were reported.

Arm	Measure	Group	Value (MEAN)	Dispersion
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QTcF Interval: 4 hours Post-dose	411.5 millisecond (ms)	Standard Deviation 18.36
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QRS Duration: 3 hours Post-dose	94.5 millisecond (ms)	Standard Deviation 11.6
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	PR Interval: Predose	152.8 millisecond (ms)	Standard Deviation 17.66
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	PR Interval: 1 hour Post-dose	150.5 millisecond (ms)	Standard Deviation 17.25
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	PR Interval: 2 hours Post-dose	150.1 millisecond (ms)	Standard Deviation 16.6
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	PR Interval: 3 hours Post-dose	152.3 millisecond (ms)	Standard Deviation 17.73
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	PR Interval: 4 hours Post-dose	150.7 millisecond (ms)	Standard Deviation 17.82
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QRS Duration: Predose	94.6 millisecond (ms)	Standard Deviation 11.06
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QRS Duration: 1 hour Post-dose	95.2 millisecond (ms)	Standard Deviation 11.42
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QRS Duration: 2 hours Post-dose	93.9 millisecond (ms)	Standard Deviation 11.71
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QRS Duration: 4 hours Post-dose	94.7 millisecond (ms)	Standard Deviation 10.48
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QT Interval: Predose	391.5 millisecond (ms)	Standard Deviation 24.8
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QT Interval: 1 hour Post-dose	396.7 millisecond (ms)	Standard Deviation 28.76
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QT Interval: 2 hours Post-dose	402.0 millisecond (ms)	Standard Deviation 29
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QT Interval: 3 hours Post-dose	400.2 millisecond (ms)	Standard Deviation 27.78
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QT Interval: 4 hours Post-dose	400.0 millisecond (ms)	Standard Deviation 27.49
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QTcB Interval: Predose	416.2 millisecond (ms)	Standard Deviation 19.05
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QTcB Interval: 1 hour Post-dose	416.0 millisecond (ms)	Standard Deviation 24.11
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QTcB Interval: 2 hours Post-dose	414.8 millisecond (ms)	Standard Deviation 22.83
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QTcB Interval: 3 hours Post-dose	414.2 millisecond (ms)	Standard Deviation 23.3
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QTcB Interval: 4 hours Post-dose	418.0 millisecond (ms)	Standard Deviation 20.3
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QTcF Interval: Predose	407.4 millisecond (ms)	Standard Deviation 17.09
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QTcF Interval: 1 hour Post-dose	409.2 millisecond (ms)	Standard Deviation 20.58
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QTcF Interval: 2 hours Post-dose	410.1 millisecond (ms)	Standard Deviation 20.41
Ponesimod 20 mg (Core and Extension Study)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QTcF Interval: 3 hours Post-dose	409.0 millisecond (ms)	Standard Deviation 20.97
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QTcB Interval: 3 hours Post-dose	410.1 millisecond (ms)	Standard Deviation 22.33
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QT Interval: 2 hours Post-dose	386.0 millisecond (ms)	Standard Deviation 19.62
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QRS Duration: 3 hours Post-dose	94.5 millisecond (ms)	Standard Deviation 7.8
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QTcF Interval: 4 hours Post-dose	398.5 millisecond (ms)	Standard Deviation 18.27
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QTcF Interval: 3 hours Post-dose	402.0 millisecond (ms)	Standard Deviation 16.82
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	PR Interval: Predose	149.8 millisecond (ms)	Standard Deviation 19.13
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QT Interval: 3 hours Post-dose	386.9 millisecond (ms)	Standard Deviation 21.38
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	PR Interval: 1 hour Post-dose	152.6 millisecond (ms)	Standard Deviation 22.66
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QTcB Interval: 4 hours Post-dose	406.6 millisecond (ms)	Standard Deviation 22.33
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	PR Interval: 2 hours Post-dose	153.6 millisecond (ms)	Standard Deviation 23.51
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QT Interval: 4 hours Post-dose	383.9 millisecond (ms)	Standard Deviation 23.14
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	PR Interval: 3 hours Post-dose	154.5 millisecond (ms)	Standard Deviation 21.91
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QTcF Interval: 2 hours Post-dose	396.2 millisecond (ms)	Standard Deviation 16.61
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	PR Interval: 4 hours Post-dose	151.8 millisecond (ms)	Standard Deviation 19.68
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QTcB Interval: Predose	411.4 millisecond (ms)	Standard Deviation 20.85
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QRS Duration: Predose	91.5 millisecond (ms)	Standard Deviation 7.03
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QTcF Interval: Predose	400.0 millisecond (ms)	Standard Deviation 18.69
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QRS Duration: 1 hour Post-dose	93.2 millisecond (ms)	Standard Deviation 8.72
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QTcB Interval: 1 hour Post-dose	407.6 millisecond (ms)	Standard Deviation 22.96
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QRS Duration: 2 hours Post-dose	92.7 millisecond (ms)	Standard Deviation 7.57
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QRS Duration: 4 hours Post-dose	92.5 millisecond (ms)	Standard Deviation 7.35
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QTcB Interval: 2 hours Post-dose	401.7 millisecond (ms)	Standard Deviation 20.88
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QT Interval: Predose	378.8 millisecond (ms)	Standard Deviation 23.61
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QTcF Interval: 1 hour Post-dose	398.1 millisecond (ms)	Standard Deviation 18.22
Teriflunomide 14 mg (Core) Then Ponesimod 20 mg (Extension)	Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF	QT Interval: 1 hour Post-dose	380.9 millisecond (ms)	Standard Deviation 21.78

Source: ClinicalTrials.gov · Data processed: Feb 4, 2026

Long-term Extension to Study AC-058B301 to Investigate Safety, Tolerability and Disease Control of Ponesimod 20 mg in Patients With Relapsing Multiple Sclerosis

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Detailed description

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Interventions

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Study design

Intervention model description

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Other

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Participant flow

Recruitment details

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Participants by arm

Withdrawals & dropouts

Baseline characteristics

Adverse events

Outcome results

Absolute Change in Lung Diffusion Capacity as Assessed by Diffusing Capacity for the Lungs Measured Using Carbon Monoxide (DL[CO]) From Baseline

Absolute Values in Forced Expiratory Volume in 1 Second (FEV1) and Forced Vital Capacity (FVC) Values

Actual Values of 12-lead ECG Measurements up to End of Study Treatment: Heart Rate

Actual Values of 12-lead ECG Measurements up to End of Study Treatment: PR, QRS, QT, QTcB, QTcF

Annualized Confirmed Relapse Rate (ARR)

Change From Baseline in Expanded Disability Status Scale (EDSS)

Change From Baseline in Volume of MRI Lesions (T2 Lesions and T1 Hypointense Lesions)

Change in DL[CO] (% Predicted) From Baseline to EOS

Change in DL[CO] (% Predicted) From Baseline to EOT

Change in FEV1 and FVC (% Predicted) From Baseline to End of Study (EOS)

Change in FEV1 and FVC (% Predicted) From Baseline to End of Treatment (EOT)

Change in Heart Rate (HR) From Baseline up to End of Study Treatment

Change in PR, QRS, QT, QTcB, QTcF From Baseline up to End of Study Treatment

Cumulative Number of Combined Unique Active Lesions (CUAL) Measured by MRI

Cumulative Number of New or Enlarging T2 Lesions Measured by MRI

Number of Gadolinium-enhancing (Gd+) T1 Lesions Measured by MRI

Number of Participants With Absence of MRI Lesions (Gd+ T1 Lesions, New or Enlarging T2 Lesions)

Number of Participants With a Decrease of >=200 mL or >=12% in FEV1 or FVC From Baseline to EOT

Number of Participants With AE Leading to Premature Discontinuation of Study Treatment

Number of Participants With Treatment-emergent Adverse Events of Special Interest (AESIs)

Number of Participants With Treatment-emergent Adverse Events (TEAEs)

Number of Participants With Treatment-emergent Decrease From Baseline >20% and >30% in FEV1 or FVC

Number of Participants With Treatment-emergent Decrease of >20% Points in Percent Predicted FEV1 and FVC From Baseline

Number of Participants With Treatment-emergent New Morphological Electrocardiogram (ECG) Abnormalities

Number of Participants With Treatment-emergent Serious Adverse Events (SAEs)

Percentage of Gd+ Lesions at Baseline Evolving to Persistent Black Holes (PBHs)

Percentage of Participants With Absence of Relapses

Percentage of Participants With No Evidence of Disease Activity (NEDA) Status According to NEDA With Four Components (NEDA-4) at Extension End of Study

Percentage of Participants With No Evidence of Disease Activity (NEDA) Status According to NEDA With Three Components (NEDA-3) at Extension End of Study

Percent Change From Baseline in Brain Volume (PCBV) Measured by Magnetic Resonance Imaging (MRI)

Percent Change in (FEV1) and Forced Vital Capacity (FVC) From Baseline (%)

Time From Core Study Randomization to First Confirmed Relapse

Time to First 12-week Confirmed Disability Accumulation (CDA)

Time to First 24-week Confirmed Disability Accumulation (CDA)

Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: Heart Rate

Actual Values of 12-lead ECG Measurements on Day of First Re-initiation (Day 1) of Study Drug: PR, QRS, QT, QTcB, QTcF