An Efficacy Study of Teriflunomide in Participants With Relapsing Multiple Sclerosis

Core Treatment Period: Time to Disability Progression

Probability of disability progression at 24, 48, 108 and 132 weeks was estimated using Kaplan-Meier method on the time to disability progression defined as the time from randomization to first 12-week sustained disability progression \[i.e. increase from baseline of at least 1 point in EDSS score (at least 0.5 point for participants with baseline EDSS score \>5.5) that persisted for at least 12 weeks\]. Participants free of disability progression (no disability progression observed on treatment) were censored at the date of the last on-treatment EDSS evaluation. Kaplan-Meier method consists in computing probabilities of non occurrence of event at any observed time of event and multiplying successive probabilities for time ≤t by any earlier computed probabilities to estimate the probability of being event-free for the amount of time t. Probability of event at time t is 1 minus the probability of being event-free for the amount of time t.

Time frame: Core treatment period between 48 - 152 weeks depending on time of enrollment

Core Treatment Period: Time Without Relapse

Probability of no relapse at 24, 48, 108 and 132 weeks was estimated using Kaplan-Meier method on the time to relapse defined as the time from randomization to first EDSS confirmed relapse. Participants free of confirmed relapse (no EDSS confirmed relapse observed on treatment) were censored at the date of the last study drug intake.

Time frame: Core treatment period between 48 - 152 weeks depending on time of enrollment

Core Treatment Period: Change From Baseline to Week 48 in EDSS Total Score

EDSS is an ordinal scale in half-point increments that qualifies disability in participants with MS. It consists of 8 ordinal rating scales assessing 7 functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS). Baseline adjusted least-squares means at Week 48 were estimated using a Mixed-effect model with repeated measures (MMRM) on EDSS score data (treatment group, region of enrollment, baseline EDSS stratum, visit, treatment-by-visit interaction, baseline value, and baseline-by-visit interaction as factors). All the timepoints from randomization up to Week 48 were included in the model.

Time frame: Baseline (before randomization), Week 12, Week 24, Week 36 and Week 48

Core Treatment Period: Change From Baseline to Week 48 in Fatigue Impact Scale (FIS) Total Score

FIS is a participants-reported scale that qualifies the impact of fatigue on daily life in participants with MS. It consists of 40 statements that measure fatigue in 3 areas; physical, cognitive, and social. FIS total score ranges from 0 (no problem) to 160 (extreme problem). Baseline adjusted least-squares means at week 48 were estimated using a Mixed-effect model with repeated measures (MMRM) on FIS total score data (treatment group, region of enrollment, baseline EDSS stratum, visit, treatment-by-visit interaction, baseline value, and baseline-by-visit interaction as factors). All the timepoints from randomization up to Week 48 were included in the model.

Time frame: Baseline (before randomization), Week 12, Week 24 and Week 48

Core Treatment Period: Change From Baseline to Last Visit in Fatigue Impact Scale (FIS) Total Score

Baseline adjusted least-squares means at last visit were estimated using an analysis of covariance (ANCOVA) model on collected data for FIS total score (treatment group, region of enrollment, baseline EDSS stratum, visit number for the last visit and baseline value as factors).

Time frame: Baseline (before randomization) and up to Week 152

Core Treatment Period: Change From Baseline to Week 48 in Short Form Generic Health Survey - 36 Items (SF-36) Summary Scores

SF-36 scale is a generic, self-administered, health-related quality-of-life (QOL) instrument. It is constructed such that the 36 questions represent 8 of the most important health concepts: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health. Two summary scores are obtained: * the physical health component summary score, * the mental health component summary score. Both scores range from 0 to 100 and a high score indicates a more favorable health state. Baseline adjusted least-squares means at week 48 were estimated using a Mixed-effect model with repeated measures \[MMRM\] on each summary score data (treatment group, region of enrollment, baseline EDSS stratum, visit, treatment-by-visit interaction, baseline value, and baseline-by-visit interaction as factors). All the timepoints from randomization up to Week 48 were included in the model.

Time frame: Baseline (before randomization), Week 12, Week 24 and Week 48

Core Treatment Period: Change From Baseline to Last Visit in Short Form Generic Health Survey - 36 Items (SF-36) Summary Scores

Baseline adjusted least-squares means at last visit were estimated using an analysis of covariance (ANCOVA) model on collected data for each summary score (treatment group, region of enrollment, baseline EDSS stratum, visit number for the last visit and baseline value as factors).

Time frame: Baseline (before randomization) and up to Week 152

Core Treatment Period: Overview of Adverse Events

Adverse Events (AE) are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study.

Time frame: From first study drug intake up to 112 days after last intake in the core treatment period or up to first intake in the extension treatment period, whichever occurred first

Extension Treatment Period: Overview of Treatment Emergent Adverse Events (TEAE)

AEs were any unfavourable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study.

Time frame: From first intake of study drug in extension treatment period up to 28 days after the last intake in the extension treatment period

Extension Treatment Period: Time to Disability Progression

Probability of disability progression since the randomization of the core period was estimated using Kaplan-Meier method on the time to disability progression defined as the time from randomization to first 12 week sustained disability progression \[i.e. increase from baseline of at least 1 point in EDSS score (at least 0.5 point for participants with baseline EDSS score \>5.5) that persisted for at least 12 weeks\]. Participants free of disability progression (no disability progression observed on treatment) were censored at the date of the last on-treatment EDSS evaluation. Kaplan-Meier method consists in computing probabilities of non occurrence of event at any observed time of event and multiplying successive probabilities for time ≤t by any earlier computed probabilities to estimate the probability of being event free for the amount of time t. Probability of event at time t was 1 minus the probability of being event-free for the amount of time t.

Time frame: Core treatment period (maximum: 173 weeks) and Extension treatment period (maximum: 174 weeks)

Extension Treatment Period: ARR: Poisson Regression Estimate

ARR was obtained from the total number of confirmed relapses that occurred during the treatment period divided by the sum of treatment durations. A relapse is defined as the appearance of a new clinical sign/symptom or clinical worsening of a previous sign/symptom (one that had been stable for at least 30 days) that persists for a minimum of 24 hours in the absence of fever. Relapse was confirmed by an increase in EDSS score or Functional System scores. To account for the different treatment durations among participants, a Poisson regression model with robust error variance was used (total number of confirmed relapses as response variable; log-transformed treatment duration as "offset" variable; treatment group, region of enrolment and baseline EDSS stratum as covariates).

Time frame: Extension treatment period (Maximum: 174 weeks)