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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Parallel Group Design Study to Evaluate the Efficacy and Safety of Teriflunomide in Reducing the Frequency of Relapses and Delaying the Accumulation of Physical Disability in Subjects With Multiple Sclerosis With Relapses

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: Teriflunomide
* Drug: Placebo (for teriflunomide)


Participation Criteria
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Eligibility Criteria
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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;

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Teriflunomide 7 mg<br>Teriflunomide 7 mg once daily for 108 weeks | Drug: Teriflunomide<br>* Film-coated tablet Oral administration<br>* Other names: HMR1726;|
| Experimental: Teriflunomide 14 mg<br>Teriflunomide 14 mg once daily for 108 weeks | Drug: Teriflunomide<br>* Film-coated tablet Oral administration<br>* Other names: HMR1726;|
| Placebo Comparator: Placebo<br>Placebo (for teriflunomide) once daily for 108 weeks | Drug: Placebo (for teriflunomide)<br>* Film-coated tablet Oral administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized Relapse Rate [ARR]: Poisson Regression Estimates | ARR is obtained from the total number of confirmed relapses that occured during the treatment period divided by the sum of the 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 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). | 108 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to 12-week Sustained Disability Progression: Kaplan-Meier Estimates of the Rate of Disability Progression at Timepoints | 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. | 108 weeks | 
| Cerebral Magnetic Resonance Imaging [MRI] Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) | 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. | baseline (before randomization) and 108 weeks | 
| Changes From Baseline in Fatigue Impact Scale [FIS] Total Score | 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). | baseline (before randomization) and 108 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Sclerosis, Relapsing Remitting, Secondary Progressive, Progressive Relapsing