Long Term Safety and Efficacy Study of Teriflunomide 7 mg or 14 mg in Patients With Relapsing-Remitting Multiple Sclerosis

Long-term Extension of the Multinational, Double-blind, Placebo Controlled Study EFC6049 (HMR1726D/3001) to Document the Safety of Two Doses of Teriflunomide (7 and 14 mg) in Patients With Multiple Sclerosis With Relapses

The primary objective of this study was to document the long-term safety and tolerability of teriflunomide in Multiple Sclerosis (MS) participants with relapse.

The secondary objective was to document the long-term efficacy on disability progression, relapse rate and Magnetic Resonance Imaging (MRI) parameters.

Study Overview

• Status: Completed
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Drug: Teriflunomide (HMR1726)

Detailed Description

Participants completing the EFC6049 (HMR1726D/3001) study were given the opportunity to continue in the extension study;

• participants receiving teriflunomide 7 mg or 14 mg were blindly maintained on the same dose of teriflunomide.
• participants receiving placebo were randomized at a 1:1 ratio to teriflunomide 7 mg or 14 mg.

The study period per participant was broken down as follows:

• Double-blind treatment: up to a maximum of 288 weeks or until teriflunomide was commercially available in the country where participant lived,
• Post-washout follow-up: 4 weeks after last treatment intake. No post-washout follow up if participant continued on teriflunomide treatment by obtaining its commercial form after end of the study.

The total duration of the extension was 292 weeks (about 6 years) from the first participant enrolled or until teriflunomide is commercially available in the country where participant lived.

• Study Type: Interventional
• Enrollment (Actual): 742
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Graz, Austria, 8036
    • Investigational Site Number 1603
  • Innsbruck, Austria, 6020
    • Investigational Site Number 1604
  • Wien, Austria, 1010
    • Investigational Site Number 1601
  • Wien, Austria, 1090
    • Investigational Site Number 1602
• Canada
  • Calgary, Canada, T2N 2T9
    • Investigational Site Number 1208
  • Gatineau, Canada, J9J 0A5
    • Investigational Site Number 1212
  • Greenfield Park, Canada, J4V 2J2
    • Investigational Site Number 1205
  • Halifax, Canada, B3H 1V7
    • Investigational Site Number 1201
  • London, Canada, N6A 5A5
    • Investigational Site Number 1206
  • Montreal, Canada, H2L 4M1
    • Investigational Site Number 1203
  • Ottawa, Canada, K1H 8L6
    • Investigational Site Number 1204
  • Quebec, Canada, G1J 1Z4
    • Investigational Site Number 1202
  • St. John'S, Canada, A1B 3V6
    • Investigational Site Number 1211
  • Toronto, Canada, M5B 1W8
    • Investigational Site Number 1209
  • Vancouver, Canada, V6T 2B5
    • Investigational Site Number 1210
  • Winnipeg, Canada, R3A 1R9
    • Investigational Site Number 1207
• Chile
  • Santiago, Chile, 750-0710
    • Investigational Site Number 3804
  • Santiago, Chile, 760-0746
    • Investigational Site Number 3802
  • Santiago, Chile, 890-0085
    • Investigational Site Number 3803
  • Santiago, Chile
    • Investigational Site Number 3801
  • Viña Del Mar, Chile
    • Investigational Site Number 3805
• Czech Republic
  • Olomouc, Czech Republic, 77520
    • Investigational Site Number 4101
• Denmark
  • Glostrup, Denmark, 2600
    • Investigational Site Number 4801
  • Sønderborg, Denmark, 6400
    • Investigational Site Number 4804
  • Vejle, Denmark, 7100
    • Investigational Site Number 4802
• Estonia
  • Tallinn, Estonia, 10617
    • Investigational Site Number 1502
  • Tartu, Estonia, 50406
    • Investigational Site Number 1501
• Finland
  • Helsinki, Finland, 00100
    • Investigational Site Number 2203
  • Pori, Finland, 28100
    • Investigational Site Number 2206
  • Tampere, Finland, 33100
    • Investigational Site Number 2201
  • Turku, Finland, 20520
    • Investigational Site Number 2202
• France
  • Besancon, France, 25030
    • Investigational Site Number 2415
  • Clermont Ferrand Cedex 1, France, 63003
    • Investigational Site Number 2403
  • Dijon, France, 21079
    • Investigational Site Number 2408
  • Lille Cedex, France, 59020
    • Investigational Site Number 2413
  • Limoges Cedex, France, 87042
    • Investigational Site Number 2404
  • Lyon Cedex 03, France, 69394
    • Investigational Site Number 2401
  • Marseille, France, 13005
    • Investigational Site Number 2409
  • Montpellier Cedex 5, France, 34000
    • Investigational Site Number 2402
  • Nancy Cedex, France, 54036
    • Investigational Site Number 2405
  • Nantes Cedex 01, France, 44093
    • Investigational Site Number 2414
  • Nice Cedex, France, 06002
    • Investigational Site Number 2407
  • Paris Cedex 12, France, 75571
    • Investigational Site Number 2410
  • Rennes Cedex, France, 35033
    • Investigational Site Number 2406
  • Toulouse, France, 31059
    • Investigational Site Number 2411
• Germany
  • Berlin, Germany, 10785
    • Investigational Site Number 2011
  • Berlin, Germany, 13347
    • Investigational Site Number 2001
  • Bochum, Germany, 44791
    • Investigational Site Number 2000
  • Erbach, Germany, 64711
    • Investigational Site Number 2012
  • Essen, Germany, 45122
    • Investigational Site Number 2004
  • Gießen, Germany, 35385
    • Investigational Site Number 2005
  • Hannover, Germany, 30625
    • Investigational Site Number 2007
  • Münster, Germany, 48149
    • Investigational Site Number 2008
  • Offenbach, Germany, 63069
    • Investigational Site Number 2010
  • Rostock, Germany, 18055
    • Investigational Site Number 2009
  • Wiesbaden, Germany, 65191
    • Investigational Site Number 2003
• Italy
  • Bari, Italy, 70124
    • Investigational Site Number 2819
  • Fidenza, Italy, 43036
    • Investigational Site Number 2827
  • Firenze, Italy, 50134
    • Investigational Site Number 2803
  • Gallarate, Italy, 21013
    • Investigational Site Number 2814
  • Milano, Italy, 20132
    • Investigational Site Number 2808
  • Padova, Italy, 35128
    • Investigational Site Number 2812
  • Pavia, Italy, 27100
    • Investigational Site Number 2809
  • Roma, Italy, 00152
    • Investigational Site Number 2813
  • Roma, Italy, 00185
    • Investigational Site Number 2824
• Netherlands
  • 'S Hertogenbosch, Netherlands, 5223 GZ
    • Investigational Site Number 4602
  • Breda, Netherlands, 4818 CK
    • Investigational Site Number 4605
  • Nijmegen, Netherlands, 6525 GC
    • Investigational Site Number 4601
  • Sittard-Geleen, Netherlands, 6162 BG
    • Investigational Site Number 4604
• Norway
  • Oslo, Norway, 0407
    • Investigational Site Number 3601
  • Tønsberg, Norway, 3116
    • Investigational Site Number 3604
• Poland
  • Bialystok, Poland, 15-276
    • Investigational Site Number 3008
  • Bialystok, Poland, 15-402
    • Investigational Site Number 3009
  • Gdansk, Poland, 80-803
    • Investigational Site Number 3007
  • Lodz, Poland, 90-153
    • Investigational Site Number 3005
  • Lublin, Poland, 20-718
    • Investigational Site Number 3006
  • Lublin, Poland, 20-954
    • Investigational Site Number 3004
  • Poznan, Poland, 60-355
    • Investigational Site Number 3001
  • Warszawa, Poland, 02-097
    • Investigational Site Number 3002
  • Warszawa, Poland, 02-957
    • Investigational Site Number 3003
• Portugal
  • Coimbra, Portugal, 3000-075
    • Investigational Site Number 4201
  • Lisboa, Portugal, 1169-050
    • Investigational Site Number 4203
• Russian Federation
  • Moscow, Russian Federation, 119049
    • Investigational Site Number 3203
  • Moscow, Russian Federation, 125015
    • Investigational Site Number 3205
  • Nizhny Novgorod, Russian Federation, 603076
    • Investigational Site Number 3207
  • Novosibirsk, Russian Federation, 630087
    • Investigational Site Number 3208
  • St-Petersburg, Russian Federation, 194044
    • Investigational Site Number 3201
  • St-Petersburg, Russian Federation, 197089
    • Investigational Site Number 3202
  • St-Petersburg, Russian Federation, 197376
    • Investigational Site Number 3206
• Sweden
  • Stockholm, Sweden, 171 76
    • Investigational Site Number 3401
• Switzerland
  • Basel, Switzerland, 4031
    • Investigational Site Number 1802
• Turkey
  • Izmir, Turkey, 35340
    • Investigational Site Number 5003
  • Izmir, Turkey, 35380
    • Investigational Site Number 5006
  • Kocaeli, Turkey, 41380
    • Investigational Site Number 5005
  • Sihhiye / Ankara, Turkey, 06100
    • Investigational Site Number 5001
• Ukraine
  • Dnipropetrovsk, Ukraine, 49027
    • Investigational Site Number 3504
  • Ivano-Frankovsk, Ukraine, 76008
    • Investigational Site Number 3505
  • Kharkiv, Ukraine, 61018
    • Investigational Site Number 3506
  • Kharkiv, Ukraine, 61178
    • Investigational Site Number 3510
  • Lviv, Ukraine, 79010
    • Investigational Site Number 3508
  • Odessa, Ukraine, 65025
    • Investigational Site Number 3502
  • Uzhgorod, Ukraine, 88018
    • Investigational Site Number 3509
  • Vinnitsa, Ukraine, 21005
    • Investigational Site Number 3507
  • Zaporizhzhya, Ukraine, 69600
    • Investigational Site Number 3501
• United Kingdom
  • Dundee, United Kingdom, DD1 9SY
    • Investigational Site Number 2604
  • London, United Kingdom, E1 1BB
    • Investigational Site Number 2607
  • London, United Kingdom, SW17 0QT
    • Investigational Site Number 2608
  • Newcastle Upon Tyne, United Kingdom, NE1 4LP
    • Investigational Site Number 2600
  • Nottingham, United Kingdom, NG7 2UH
    • Investigational Site Number 2601
  • Plymouth, United Kingdom, PL6 8BX
    • Investigational Site Number 2609
  • Sheffield, United Kingdom, S10 2JF
    • Investigational Site Number 2606
  • Stoke On Trent, United Kingdom, ST4 7LN
    • Investigational Site Number 2602
• United States
  • Florida
    • Maitland, Florida, United States, 32761
      • Investigational Site Number 1032
  • Indiana
    • Ft. Wayne, Indiana, United States, 63104
      • Investigational Site Number 1038
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Investigational Site Number 1033
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18103
      • Investigational Site Number 1037

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:

• Participant who completed the previous double-blind placebo-controlled study EFC6049 and who did not meet criteria for treatment withdrawal.
• Willingness to participate in a long-term safety/efficacy trial.

Exclusion Criteria:

• Any known condition or circumstance that would prevent in the investigator's opinion, compliance or completion of the study.

The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Placebo/Teriflunomide 7 mg; Participants who completed treatment of placebo (for teriflunomide) tablet once daily (QD) for 108 weeks in EFC6049 study, received teriflunomide tablet 7 mg QD for 288 weeks in this extension study.	Drug: Teriflunomide (HMR1726); Tablet, oral administration QD.; Other Names: Aubagio
Experimental: Teriflunomide 7 mg/7 mg; Participants who completed treatment of teriflunomide 7 mg tablet QD for 108 weeks in EFC6049 study, continued their treatment with teriflunomide 7 mg tablet QD for 288 weeks in this extension study.	Drug: Teriflunomide (HMR1726); Tablet, oral administration QD.; Other Names: Aubagio
Experimental: Placebo/Teriflunomide 14 mg; Participants who completed treatment of placebo (for teriflunomide) tablet QD for 108 weeks in EFC6049, study received teriflunomide 14 mg tablet QD for 288 weeks in this extension study.	Drug: Teriflunomide (HMR1726); Tablet, oral administration QD.; Other Names: Aubagio
Experimental: Teriflunomide 14 mg/14 mg; Participants who completed treatment of teriflunomide 14 mg tablet QD for 108 weeks in EFC6049 study, continued their treatment with teriflunomide 14 mg tablet QD for 288 weeks in this extension study.	Drug: Teriflunomide (HMR1726); Tablet, oral administration QD.; Other Names: Aubagio

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs)	Adverse event (AE) was defined as any untoward medical occurrence in a participant who received investigational medicinal product (IMP) without regard to possibility of causal relationship with this treatment. TEAEs: AEs that developed or worsened or became serious during on-treatment period which was defined as the period from the time of first dose of study drug (in LTS6050) up to 4 weeks (28 days) after last dose of study drug. Serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. Any TEAE included both serious and non-serious AEs.	Baseline (LTS6050) up to 28 days after last dose of study drug up to 450 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to 12 Week Sustained Disability Progression (DP): Kaplan-Meier Estimates of the Rate of DP	Sustained DP defined as sustained increase of at least 1 point from baseline (EFC6049) expanded disability status scale (EDSS) score (0.5 point for participants with baseline EDSS>5.5) persisting for at least 12 weeks. EDSS: an ordinal scale qualifies disability in participants with MS. EDSS total score range: 0 (normal neurological examination) to 10 (death due to Multiple Sclerosis [MS]). Probability of DP at 12 weeks was estimated using Kaplan-Meier method on time to DP defined as date of first DP minus (-) date of randomization in EFC6049 study +1 day. Participants free of DP (no DP observed on treatment) were censored at the date of last on-treatment EDSS evaluation in LTS6050. 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.	Up to 10.8 years (EFC6049: 108 weeks + LTS6050: 450 weeks)
Time to 24 Week Sustained Disability Progression (DP): Kaplan-Meier Estimates of the Rate of DP	Sustained DP was defined as sustained increase of at least 1 point from baseline (EFC6049) EDSS score (0.5 point for participants with baseline EDSS>5.5) persisting for at least 24 weeks. EDSS: an ordinal scale qualifies disability in participants with MS. EDSS total score range: 0 (normal neurological examination) to 10 (death due to MS). Probability of DP at 24 weeks was estimated using Kaplan-Meier method on time to DP defined as date of first DP minus (-) date of randomization in EFC6049 study +1 day. Participants free of DP (no DP observed on treatment) were censored at the date of last on-treatment EDSS evaluation in LTS6050. 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.	Up to 10.8 years (EFC6049: 108 weeks + LTS6050: 450 weeks)
Percentage of Participants Free of Sustained Disability Progression (DP)	Sustained DP was defined as sustained increase of at least 1 point from baseline (EFC6049) EDSS score (0.5 point for participants with baseline EDSS>5.5) persisting for at least 12 weeks and 24 weeks. EDSS is an ordinal scale in half-point increments that qualifies disability in participants with MS. It consists of 8 ordinal rating scales assessing seven functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder, cerebral) as well as ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS), where higher scores indicates worse neurological function. Percentage of participants who were considered as free of disability progression confirmed after 12 week sustained progression and 24 week sustained progression were reported. Analysis for this outcome measure was performed on combined data of EFC6049 and LTS6050 study, as pre-specified in protocol.	Up to 10.8 years since EFC6049 randomization (EFC6049: 108 weeks + LTS6050: 450 weeks)
Annualized MS Relapse Rate (ARR): Poisson Regression Estimates	ARR was obtained from total number of confirmed relapses that occurred during treatment period divided by sum of treatment durations in LTS6050 study only. 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 (FS) scores. EDSS: an ordinal scale qualifies disability. EDSS total score range: 0 (normal neurological examination) to 10 (death due to MS). FSS: to assess the neurological function. Total score range: 0 (normal) - 6(worse), higher scores = worse neurological function. To account for the different treatment duration 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 enrolment and baseline EDSS stratum as covariates).	Up to 8 years since LTS6050 randomization
Magnetic Resonance Imaging (MRI) Assessment: Change From Baseline in Total Volume of Abnormal Lesions (Burden of Disease [BOD]) at Week 192 Since LTS6050 Randomization	BOD was assessed by cerebral MRI and defined as the total volume of all abnormal brain tissue (calculated as the sum of the total volume of T2-lesion component and T1-hypointense lesion component).	Baseline, Week 192

Collaborators and Investigators

• Sponsor: Sanofi

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.
• Sprenger T, Kappos L, Radue EW, Gaetano L, Mueller-Lenke N, Wuerfel J, Poole EM, Cavalier S. Association of brain volume loss and long-term disability outcomes in patients with multiple sclerosis treated with teriflunomide. Mult Scler. 2020 Sep;26(10):1207-1216. doi: 10.1177/1352458519855722. Epub 2019 Jun 14.
• 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.

Study record dates

Study Major Dates

• Study Start: October 1, 2006
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: December 1, 2008
• First Submitted That Met QC Criteria: December 4, 2008
• First Posted (Estimate): December 5, 2008

Study Record Updates

• Last Update Posted (Estimate): January 30, 2017
• Last Update Submitted That Met QC Criteria: December 5, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Keywords: Multiple Sclerosis; Oral treatment
• 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: LTS6050; 2006-003361-14 (EudraCT Number)