Trial Outcomes & Findings for Efficacy and Safety of Teriflunomide in Patients With Relapsing Multiple Sclerosis and Treated With Interferon-beta (NCT NCT01252355)

The recruitment initiated in January 2011, was discontinued in December 2012 following the decision of the Sponsor to discontinue the study, the common treatment end date was defined as February 28th, 2013 (treatment duration between 24 and 108 weeks). A total of 846 participants were screened at 185 sites in 28 countries.

Randomization was stratified by investigational site and Interferon-beta (IFN-beta) dose level (high/low). Assignment to groups was done centrally using an Interactive Voice Response System (IVRS) in a 1:1:1 ratio after confirmation of selection criteria. A total of 534 participants were randomized.

Efficacy and Safety of Teriflunomide in Patients With Relapsing Multiple Sclerosis and Treated With Interferon-beta

ARR is the total number of confirmed relapses that occurred during the treatment period divided by the total number of patient-years treated. 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 IFN-beta dose stratum, and number of relapses in the year prior to randomization as covariates).

Number of Gd-enhancing T1-lesions per scan is the total number of Gd-enhancing T1-lesions that occurred during the treatment period divided by the total number of scans performed during the treatment period. To account for the different number of scans among participants, a Poisson regression model with robust error variance was used (total number of Gd-enhancing T1-lesions as response variable; log-transformed number of scans as offset variable; treatment group, region of enrollment, IFN-beta dose stratum and baseline number of Gd-enhancing T1-lesions as covariates).

The 12-week sustained disability progression was defined as an 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. Probability of disability progression was to be estimated using Kaplan-Meier method.

Total volume of Gd-enhancing T1-lesions per scan is the sum of the volumes of Gd-enhancing T1-lesions observed during the treatment period divided by the total number of scans performed during the treatment period.

The total lesion volume (burden of disease) is the total volumes of hyperintense on T2 plus hypointense on T1 as measured by MRI scan. Least-square means were estimated using a Mixed-effect model with repeated measures (MMRM) on cubic root transformed volume data with factors for treatment, region, IFN-beta dose stratum, visit, treatment-by-visit interaction, cubic root transformed baseline burden of disease, and baseline-by-visit interaction.

Probability of no relapse at 24, 48 and 72 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. 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.

FIS is a participant-reported scale that qualifies the impact of fatigue on daily life in participants with MS.

SF-36 scale is a generic, self-administered, health-related quality-of-life (QOL) instrument.

Resource utilization each time a participant experiences an MS relapse, specifically the number of hospitalizations, the number of over night spent in the hospital and number of intensive care admissions if hospitalized were to be reported.

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

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 or 10 Upper Limit of Normal (ULN); Aspartate Aminotransferase (AST) \>3, 5 or 10 ULN; Alkaline Phosphatase \>1.5 ULN; Total Bilirubin (TB) \>1.5 ULN; and ALT \>3 ULN and TB \>2 ULN.