Study of Teriflunomide in Reducing the Frequency of Relapses and Accumulation of Disability in Patients With Multiple Sclerosis (TEMSO)

• Time to 12-week Sustained Disability Progression: Kaplan-Meier Estimates of the Rate of Disability Progression at Timepoints [ Time Frame: 108 weeks ] [ Designated as safety issue: No ]

  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 at 24, 48 and 108 weeks was estimated using Kaplan-Meier method on the time to disability progression defined as the time from randomization to first EDSS increase. 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.

• Cerebral Magnetic Resonance Imaging [MRI] Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) [ Time Frame: baseline (before randomization) and 108 weeks ] [ Designated as safety issue: No ]
  Total lesion volume is the sum of the total volume of all T2-lesions and the total volume all T1-hypointense post-gadolinium lesions measured through T2/proton density scan analysis and gadolinium-enhanced T1 scan analysis.
• Changes From Baseline in Fatigue Impact Scale [FIS] Total Score [ Time Frame: baseline (before randomization) and 108 weeks ] [ Designated as safety issue: No ]

  FIS is a subject-reported scale that qualifies the impact of fatigue on daily life in patients with MS. It consists of 40 statements that measure fatigue in three areas; physical, cognitive, and social.

  FIS total score ranges from 0 (no problem) to 160 (extreme problem).

  Least-square means 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).

• Cerebral MRI Assessment: Number of Gd-enhancing T1-lesions Per Scan (Poisson Regression Estimates) [ Time Frame: 108 weeks ] [ Designated as safety issue: No ]

  Number of Gd-enhancing T1-lesions per scan is obtained from the total number of Gd-enhancing T1-lesions observed during the study divided by the total number of scans performed during the study.

  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, baseline EDSS stratum and baseline number of Gd-enhancing T1-lesions as covariates).

• Cerebral MRI Assessment: Volume of Gd-enhancing T1-lesions Per Scan [ Time Frame: 108 weeks ] [ Designated as safety issue: No ]
  Total volume of Gd-enhancing T1-lesions per scan is obtained from the sum of the volumes of Gd-enhancing T1-lesions observed during the study divided by the total number of scans performed during the study.

The primary objective was to determine the effect of teriflunomide on the frequency of relapses in patients with relapsing multiple sclerosis (MS).

Secondary objectives were:

• to evaluate the effect of teriflunomide on the accumulation of disability as measured by Expanded Disability Status Scale [EDSS], the burden of disease as measured by Magnetic Resonance Imaging [MRI] and patient-reported fatigue;
• to evaluate the safety and tolerability of teriflunomide.

The study period per participant was approximatively 128 weeks broken down as follows:

• Screening period up to 4 weeks,
• 108-week double-blind treatment period (approximatively 2 years)*,
• 16-week post-treatment elimination follow-up period.

'*' Participants successfully completing the week 108 visit were offered the opportunity to enter the optional long-term extension study LTS6050 - NCT00803049.

• Drug: Teriflunomide

  Film-coated tablet

  Oral administration

  Other Name: HMR1726
• Drug: Placebo (for teriflunomide)

  Film-coated tablet

  Oral administration

• Experimental: Teriflunomide 7 mg
  Teriflunomide 7 mg once daily for 108 weeks
  Intervention: Drug: Teriflunomide
• Experimental: Teriflunomide 14 mg
  Teriflunomide 14 mg once daily for 108 weeks
  Intervention: Drug: Teriflunomide
• Placebo Comparator: Placebo
  Placebo (for teriflunomide) once daily for 108 weeks
  Intervention: Drug: Placebo (for teriflunomide)

• O'Connor P, Wolinsky JS, Confavreux C, Comi G, Kappos L, Olsson TP, Benzerdjeb H, Truffinet P, Wang L, Miller A, Freedman MS; TEMSO Trial Group. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011 Oct 6;365(14):1293-303.
• Miller AE, O'Connor P, Wolinsky JS, Confavreux C, Kappos L, Olsson TP, Truffinet P, Wang L, D'Castro L, Comi G, Freedman MS; Teriflunomide Multiple Sclerosis Trial Group. Pre-specified subgroup analyses of a placebo-controlled phase III trial (TEMSO) of oral teriflunomide in relapsing multiple sclerosis. Mult Scler. 2012 Nov;18(11):1625-32. doi: 10.1177/1352458512450354. Epub 2012 Jun 21.

Inclusion Criteria:

• Multiple sclerosis [MS] subject who was ambulatory (EDSS of ≤ 5.5)
• Exhibiting a relapsing clinical course, with or without progression (relapsing remitting, secondary progressive or progressive relapsing);
• Meeting McDonald's criteria for MS diagnosis;
• Experienced at least 1 relapse over the 1 year preceding the trial or at least 2 relapses over the 2 years preceding the trial;
• No relapse onset in the preceding 60 days prior to randomization;
• Clinically stable during the 30 days prior to randomization, without adrenocorticotrophic hormone [ACTH] or systemic steroid treatment.

Exclusion Criteria:

• Clinically relevant cardiovascular, hepatic, neurological, endocrine or other major systemic disease;
• Significantly impaired bone marrow function;
• Pregnant or nursing woman;
• Alcohol or drug abuse;
• Use of cladribine, mitoxantrone, or other immunosuppressant agents such as azathioprine, cyclophosphamide, cyclosporin, methotrexate or mycophenolate before enrollment;
• Any known condition or circumstance that would prevent in the investigator's opinion compliance or completion of the study;