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

Phase 3

Completed

• Conditions: Multiple Sclerosis
• Interventions: Drug: Teriflunomide; Drug: Placebo (for teriflunomide)

• Registration Number: NCT00134563
• Lead Sponsor: Sanofi

Brief Summary

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

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.

Study Timeline

• Study Start: 2004-09
• Study First Submitted: 2005-08-23
• Study First Submitted QC: 2005-08-23
• Study First Posted: 2005-08-25
• Primary Completion: 2010-07
• Study Completion: 2010-07
• Disposition First Submitted: 2011-08-08
• Disposition First Submitted QC: 2011-08-08
• Disposition First Posted: 2011-08-15
• Results First Submitted: 2012-10-03
• Results First Submitted QC: 2012-10-03
• Results First Posted: 2012-11-06
• Status Verified: 2013-01
• Last Update Submitted: 2013-01-02
• Last Update Posted: 2013-01-04

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 1088

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.

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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;

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Teriflunomide 14 mg	Teriflunomide	Teriflunomide 14 mg once daily for 108 weeks
Placebo	Placebo (for teriflunomide)	Placebo (for teriflunomide) once daily for 108 weeks
Teriflunomide 7 mg	Teriflunomide	Teriflunomide 7 mg once daily for 108 weeks

Primary Outcome Measures

Name	Time	Method
Annualized Relapse Rate [ARR]: Poisson Regression Estimates	108 weeks	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).

Secondary Outcome Measures

Name	Time	Method
Time to 12-week Sustained Disability Progression: Kaplan-Meier Estimates of the Rate of Disability Progression at Timepoints	108 weeks	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)	baseline (before randomization) and 108 weeks	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	baseline (before randomization) and 108 weeks	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).

Trial Locations

Locations (12)

sanofi-aventis, Canada; 🇨🇦 Laval, Canada

Sanofi-Aventis; 🇸🇪 Bromma, Sweden

Sanofi-Aventis Deutschland GmbH; 🇩🇪 Berlin, Germany

Sanofi-Aventis Administrative Office; 🇺🇦 Kiev, Ukraine

sanofi-aventis Denmark; 🇩🇰 Horsholm, Denmark

Sanofi-Aventis Austria; 🇦🇹 Vienna, Austria

sanofi-aventis Poland; 🇵🇱 Warszawa, Poland

sanofi-aventis Turkey; 🇹🇷 Istanbul, Turkey

sanofi-aventis France; 🇫🇷 Paris, France

Sanofi-Aventis Switzerland; 🇨🇭 Geneva, Switzerland

sanofi-aventis UK; 🇬🇧 Guildford, Surrey, United Kingdom

sanofi-aventis Finland; 🇫🇮 Helsinki, Finland