An Efficacy Study of Teriflunomide in Participants With Relapsing Multiple Sclerosis

ARR is obtained from the total number of confirmed relapses that occurred during the treatment period divided by the sum of treatment durations. Each episode of relapse - appearance, or worsening of a clinical symptom that was stable for at least 30 days, that persisted for a minimum of 24 hours in the absence of fever - was to be confirmed by an increase in Expanded Disability Status Scale (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 enrollment and baseline EDSS stratum as covariates).

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

Population: Intent-to-treat population: all randomized and treated participants. Participants were considered in the treatment group to which they were randomized regardless of the drug they actually received.

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

Population: Intent-to-treat population

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

Population: Intent-to-treat population

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

Population: Intent-to-treat population

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

Population: Intent-to-treat population

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

Population: Intent-to-treat population

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

Population: All randomized and treated participants. Participants were considered according to the drug actually received.~The 3 participants in the placebo group who received teriflunomide were analyzed according to the teriflunomide dose.~The participant in the teriflunomide 14 mg group who received 7 mg was analyzed in the teriflunomide 7 mg group.

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

Population: Intent-to-treat population

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

Population: Intent-to-treat population

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)

Population: ITT population for extension treatment period consists of all participants with a signed informed consent form for the extension and with a date of treatment allocated or recorded in the IVRS/IWRS database, regardless of whether the treatment was actually taken.

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

Population: Safety population: all randomized participants who received at least 1 dose of investigational product.~Two participants in placebo of core study received teriflunomide and were analyzed according to teriflunomide dose.~One participant in teriflunomide 14 mg in core study group who received 7 mg was analyzed in teriflunomide 7 mg group.

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)

Population: ITT population for extension treatment period consists of all participants with a signed informed consent form for the extension and with a date of treatment allocated or recorded in the IVRS/IWRS database, regardless of whether the treatment was actually taken.

PCSA values are abnormal values considered medically important by the Sponsor according to predefined criteria based on literature review. Hepatic parameters thresholds were defined as follows: * Alanine Aminotransferase (ALT) \>3, 5, 10 or 20 upper limit of normal(ULN); * Aspartate aminotransferase (AST) \>3, 5, 10 or 20 ULN; * Alkaline Phosphatase \>1.5 ULN; * Total Bilirubin (TB) \>1.5 or 2 ULN; * ALT \>3 ULN and TB \>2 ULN.

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

Population: All randomized and treated participants. Participants were considered according to the drug actually received.~The 3 participants in the placebo group who received teriflunomide were analyzed according to the teriflunomide dose.~The participant in the teriflunomide 14 mg group who received 7 mg was analyzed in the teriflunomide 7 mg group.