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

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

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.

Study Overview

• Status: Completed
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Drug: Teriflunomide; Drug: Placebo (for 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 Type: Interventional
• Enrollment (Actual): 1088
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria
    • sanofi-aventis Austria
• Canada
  • Laval, Canada
    • sanofi-aventis, Canada
• Chile
  • Santiago de Chile, Chile
    • Sanofi-Aventis
• Czech Republic
  • Praha, Czech Republic
    • Sanofi-Aventis Administrative Office
• Denmark
  • Horsholm, Denmark
    • sanofi-aventis Denmark
• Estonia
  • Tallinn, Estonia
    • Sanofi-Aventis Administrative Office
• Finland
  • Helsinki, Finland
    • sanofi-aventis Finland
• France
  • Paris, France
    • Sanofi-Aventis France
• Germany
  • Berlin, Germany
    • Sanofi-Aventis Deutschland GmbH
• Italy
  • Milano, Italy
    • Sanofi-Aventis
• Netherlands
  • Gouda, Netherlands
    • Sanofi-Aventis
• Norway
  • Lysaker, Norway
    • Sanofi-Aventis
• Poland
  • Warszawa, Poland
    • sanofi-aventis Poland
• Portugal
  • Porto Salvo, Portugal
    • Sanofi-Aventis
• Russian Federation
  • Moscow, Russian Federation
    • Sanofi-Aventis
• Sweden
  • Bromma, Sweden
    • Sanofi-Aventis
• Switzerland
  • Geneva, Switzerland
    • sanofi-aventis Switzerland
• Turkey
  • Istanbul, Turkey
    • Sanofi-aventis Turkey
• Ukraine
  • Kiev, Ukraine
    • Sanofi-Aventis Administrative Office
• United Kingdom
  • Surrey
    • Guildford, Surrey, United Kingdom
      • Sanofi-Aventis UK
• United States
  • New Jersey
    • Bridgewater, New Jersey, United States, 08807
      • Sanofi-Aventis

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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;

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

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

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cerebral MRI Assessment: Number of Gd-enhancing T1-lesions Per Scan (Poisson Regression Estimates)	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).	108 weeks
Cerebral MRI Assessment: Volume of Gd-enhancing T1-lesions Per Scan	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.	108 weeks

Collaborators and Investigators

• Sponsor: Sanofi
• Investigators: Principal Investigator: Paul O'Connor, MD, St. Michael's Hospital (Toronto, Canada)

Publications and helpful links

General Publications

• Sprenger T, Kappos L, Sormani MP, Miller AE, Poole EM, Cavalier S, Wuerfel J. Effects of teriflunomide treatment on cognitive performance and brain volume in patients with relapsing multiple sclerosis: Post hoc analysis of the TEMSO core and extension studies. Mult Scler. 2022 Oct;28(11):1719-1728. doi: 10.1177/13524585221089534. Epub 2022 Apr 29.
• Comi G, Freedman MS, Meca-Lallana JE, Vermersch P, Kim BJ, Parajeles A, Edwards KR, Gold R, Korideck H, Chavin J, Poole EM, Coyle PK. Prior treatment status: impact on the efficacy and safety of teriflunomide in multiple sclerosis. BMC Neurol. 2020 Oct 6;20(1):364. doi: 10.1186/s12883-020-01937-4.
• Sormani MP, Truffinet P, Thangavelu K, Rufi P, Simonson C, De Stefano N. Predicting long-term disability outcomes in patients with MS treated with teriflunomide in TEMSO. Neurol Neuroimmunol Neuroinflamm. 2017 Jun 28;4(5):e379. doi: 10.1212/NXI.0000000000000379. eCollection 2017 Sep.
• 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. doi: 10.1056/NEJMoa1014656.
• Radue EW, Sprenger T, Gaetano L, Mueller-Lenke N, Cavalier S, Thangavelu K, Panzara MA, Donaldson JE, Woodward FM, Wuerfel J, Wolinsky JS, Kappos L. Teriflunomide slows BVL in relapsing MS: A reanalysis of the TEMSO MRI data set using SIENA. Neurol Neuroimmunol Neuroinflamm. 2017 Aug 9;4(5):e390. doi: 10.1212/NXI.0000000000000390. eCollection 2017 Sep.
• Freedman MS, Wolinsky JS, Comi G, Kappos L, Olsson TP, Miller AE, Thangavelu K, Benamor M, Truffinet P, O'Connor PW; TEMSO and TOWER Study Groups. The efficacy of teriflunomide in patients who received prior disease-modifying treatments: Subgroup analyses of the teriflunomide phase 3 TEMSO and TOWER studies. Mult Scler. 2018 Apr;24(4):535-539. doi: 10.1177/1352458517695468. Epub 2017 Mar 17.
• 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.

Study record dates

Study Major Dates

• Study Start: September 1, 2004
• Primary Completion (Actual): July 1, 2010
• Study Completion (Actual): July 1, 2010

Study Registration Dates

• First Submitted: August 23, 2005
• First Submitted That Met QC Criteria: August 23, 2005
• First Posted (Estimate): August 25, 2005

Study Record Updates

• Last Update Posted (Estimate): January 4, 2013
• Last Update Submitted That Met QC Criteria: January 2, 2013
• Last Verified: January 1, 2013

More Information

Terms related to this study

• Keywords: Multiple Sclerosis; Secondary Progressive; Progressive Relapsing; Relapsing Remitting
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Immunosuppressive Agents; Immunologic Factors; Teriflunomide
• Other Study ID Numbers: EFC6049; 2004-000555-42 (EudraCT Number); HMR1726D/3001 (Other Identifier: HMR)