A Study Comparing the Effectiveness and Safety of Teriflunomide and Interferon Beta-1a in Patients With Relapsing Multiple Sclerosis (TENERE)

A Multi-center, Randomized, Parallel-group, Rater-blinded Study Comparing the Effectiveness and Safety of Teriflunomide and Interferon Beta-1a in Patients With Relapsing Multiple Sclerosis Plus a Long Term Extension Period

Primary objective was to assess the effectiveness evaluated by the time to failure of two doses of teriflunomide in comparison to interferon beta-1a in participants with relapsing Multiple Sclerosis [MS].

Secondary objectives were:

• To assess the effect of the two doses in comparison to interferon beta-1a on:

  • Frequency of relapses,
  • Fatigue,
  • Participant's satisfaction with treatment.
• To evaluate the safety and tolerability of the two doses in comparison to interferon beta-1a.

The study consisted of a core treatment period with a common end date defined as 48 weeks after randomization of the last participant, followed by an optional long-term extension treatment period until teriflunomide is commercially available in accordance with local regulations.

Study Overview

• Status: Completed
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Drug: Teriflunomide; Drug: Interferon β-1a

Detailed Description

The core treatment period per participant was variable depending on the enrollment in the study (maximum of approximatively 118 weeks). The two doses of teriflunomide were administered in double-blind fashion, whereas interferon beta-1a (Rebif®) was open-label.

The opportunity to continue with the highest dose of teriflunomide in open-label fashion was offered to the participants who successfully completed treatment in the core study.

The overall treatment period was followed by a 4-week elimination follow-up period.

• Study Type: Interventional
• Enrollment (Actual): 324
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Bruxelles, Belgium, 1070
    • Investigational Site Number 056003
  • Gent, Belgium, 9000
    • Investigational Site Number 056001
  • Hasselt, Belgium, B-3590
    • Investigational Site Number 056002
• Canada
  • London, Canada, N6A 5A5
    • Investigational Site Number 124002
  • Lévis, Canada, G6V 3Z1
    • Investigational Site Number 124003
  • St. John'S, Canada, A1B 3V6
    • Investigational Site Number 124004
• Czech Republic
  • Jihlava, Czech Republic, 58633
    • Investigational Site Number 203004
  • Praha 10, Czech Republic, 10034
    • Investigational Site Number 203003
  • Praha 2, Czech Republic, 12808
    • Investigational Site Number 203002
• France
  • Bordeaux Cedex, France, 33076
    • Investigational Site Number 250003
  • Clermont Ferrand Cedex 1, France, 63003
    • Investigational Site Number 250005
  • Lille Cedex, France, 59037
    • Investigational Site Number 250004
  • Montpellier Cedex 5, France, 34000
    • Investigational Site Number 250001
  • Strasbourg Cedex, France, 67091
    • Investigational Site Number 250002
• Germany
  • Bad Mergentheim, Germany, 97980
    • Investigational Site Number 276003
  • Berlin, Germany, 10117
    • Investigational Site Number 276011
  • Berlin, Germany, 12099
    • Investigational Site Number 276012
  • Bochum, Germany, 44791
    • Investigational Site Number 276001
  • Dresden, Germany, 01307
    • Investigational Site Number 276005
  • Erbach, Germany, 64711
    • Investigational Site Number 276007
  • Essen, Germany, 45138
    • Investigational Site Number 276006
  • Halle/Saale, Germany, 06120
    • Investigational Site Number 276004
  • Hannover, Germany, 30559
    • Investigational Site Number 276010
  • Mainz, Germany, 55131
    • Investigational Site Number 276009
  • Münster, Germany, 48149
    • Investigational Site Number 276002
• Greece
  • Athens, Greece, 11527
    • Investigational Site Number 300001
  • Thessaloniki, Greece
    • Investigational Site Number 300002
• Hungary
  • Budapest, Hungary, 1083
    • Investigational Site Number 348001
  • Budapest, Hungary, 1096
    • Investigational Site Number 348005
  • Budapest, Hungary, 1106
    • Investigational Site Number 348003
  • Esztergom, Hungary, 2500
    • Investigational Site Number 348002
  • Kecskemét, Hungary, 6000
    • Investigational Site Number 348007
  • Veszprém, Hungary, 8200
    • Investigational Site Number 348004
• Italy
  • Ancona, Italy, 60020
    • Investigational Site Number 380010
  • Bari, Italy, 70124
    • Investigational Site Number 380005
  • Cagliari, Italy, 09126
    • Investigational Site Number 380008
  • Cefalù, Italy, 90015
    • Investigational Site Number 380003
  • Genova, Italy, 16132
    • Investigational Site Number 380007
  • Milano, Italy, 20132
    • Investigational Site Number 380001
  • Pavia, Italy, 27100
    • Investigational Site Number 380004
  • Roma, Italy, 00185
    • Investigational Site Number 380002
  • Torino, Italy, 10126
    • Investigational Site Number 380006
• Poland
  • Bialystok, Poland, 15-276
    • Investigational Site Number 616002
  • Gdansk, Poland, 80-803
    • Investigational Site Number 616004
  • Lublin, Poland, 20-718
    • Investigational Site Number 616003
  • Warszawa, Poland, 02-957
    • Investigational Site Number 616001
• Spain
  • Barcelona, Spain, 08036
    • Investigational Site Number 724007
  • Bilbao, Spain, 48013
    • Investigational Site Number 724001
  • Majadahonda, Spain, 28222
    • Investigational Site Number 724002
  • Murcia, Spain, 30120
    • Investigational Site Number 724003
• Switzerland
  • St. Gallen, Switzerland, 9007
    • Investigational Site Number 756002
• Tunisia
  • Monastir, Tunisia, 5000
    • Investigational Site Number 788002
• United Kingdom
  • London, United Kingdom, SW17 0QT
    • Investigational Site Number 826002
  • Plymouth, United Kingdom, PL6 5BX
    • Investigational Site Number 826003

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Relapsing form of MS meeting McDonald's criteria for MS diagnosis and Expanded Disability Status Scale [EDSS] score ≤5.5 at screening visit.

Exclusion Criteria:

• Significantly impaired bone marrow function or, significant anemia, leukopenia or thrombocytopenia;
• Persistent significant or severe infection.
• Liver function impairment or known history of hepatitis.
• Use of adrenocorticotrophic hormone [ACTH] or systemic corticosteroids for 2 weeks prior to randomization.
• Human immunodeficiency virus [HIV] positive.
• Prior use of Rebif®, or prior or concomitant use of other interferons in the 3 months prior to randomization.
• Prior or concomitant use of cladribine, mitoxantrone, or other immunosuppressant agents such as azathioprine, cyclophosphamide, cyclosporin, methotrexate, mycophenolate, or natalizumab.
• Pregnant or breast-feeding woman.

Extension criteria:

The participants who met all the following criteria at the end of the core study period were eligible for enrolment into the open-label extension phase:

• Participants who had not discontinued treatment in the core period and who had a minimum treatment of 48 weeks and completed the EOT visit (Visit 18).
• Participants who had not met criteria for treatment withdrawal.
• An informed consent must be obtained in writing from the participant for this open-label extension phase prior to entering and prior to completion of any extension phase procedure.
• Participants who demonstrated a willingness and ability to roll over to the extension phase with the opportunity to continue treatment on 14 mg/day of teriflunomide under open-label.

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: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Teriflunomide 7 mg / 14 mg; Teriflunomide 7 mg once daily (core treatment period) and teriflunomide 14 mg once daily (extended treatment period).	Drug: Teriflunomide; Film-coated tablet Oral administration; Other Names: HMR1726
Experimental: Teriflunomide 14 mg / 14 mg; Teriflunomide 14 mg once daily (core treatment period) and teriflunomide 14 mg once daily (extension treatment period).	Drug: Teriflunomide; Film-coated tablet Oral administration; Other Names: HMR1726
Active Comparator: IFN-β-1a / 14 mg; Interferon β-1a 3 times a week (core treatment period) and teriflunomide 14 mg once daily (extended treatment period).	Drug: Teriflunomide; Film-coated tablet Oral administration; Other Names: HMR1726; Drug: Interferon β-1a; Sterile preservative-free solution packaged in graduated pre-filled syringes Subcutaneous injection Ascending doses from 8.8 to 44 mcg according to local standard for Rebif®; Other Names: Rebif®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Core Treatment Period: Overview of Failures	Failure was defined as the first occurence of confirmed relapse or permanent treatment discontinuation (for any cause) which ever came first. If no events occurred, the participant was considered free of failure. 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 Expanded Disability Status Scale [EDSS] score or Functional System scores.	Core treatment period between 48 and 118 weeks depending on when the participant was enrolled
Core Treatment Period: Time to Failure: Kaplan-Meier Estimates of the Rate of Failure at Timepoints	Probability of disability progression at 24, 48 and 96 weeks was estimated using Kaplan-Meier method on the time to failure defined as the time from randomization to failure. Participants free of failure were censored at the date of last treatment. 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.	Core treatment period between 48 and 118 weeks depending on when the participant was enrolled

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Core Treatment Period: 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. 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).	Core treatment period between 48 and 118 weeks depending on when the participant was enrolled
Core Treatment Period: Change 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 48 weeks
Core Treatment Period: Treatment Satisfaction Questionnaire for Medication [TSQM] Scores	TSQM version 1.4 is an instrument to assess patients' satisfaction with medication. It consists of 13 questions that cover three dimensions (effectiveness, side effects and convenience) plus a global satisfaction question. Four scores ranging from 0 to 100 (extremely satisfied) are obtained. Least-square means were estimated using a Mixed-effect model with repeated measures [MMRM] on TSQM score data (treatment group, region of enrollment, baseline EDSS stratum, visit, treatment-by-visit interaction as factors).	48 weeks
Core Treatment Period: Overview of Adverse Events [AE]	AE are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study.	from first study drug intake up to 112 days after last intake in the core treatment period or up to first intake in the extension treatment period, whichever occurred first
Extension Treatment Period: Overview of AEs	AEs were any unfavourable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study.	From first intake of study drug in extension treatment period up to 28 days after the last intake in the extension treatment period
Extension Treatment Period: ARR Poisson Regression Estimates	ARR was obtained from the total number of confirmed relapses that occurred during the treatment period divided by the sum of the standardized treatment durations.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 enrolment and baseline EDSS stratum as covariates).	Extension treatment period (Maximum: 197 weeks)

Collaborators and Investigators

• Sponsor: Sanofi

Publications and helpful links

General Publications

• 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.
• Vermersch P, Czlonkowska A, Grimaldi LM, Confavreux C, Comi G, Kappos L, Olsson TP, Benamor M, Bauer D, Truffinet P, Church M, Miller AE, Wolinsky JS, Freedman MS, O'Connor P; TENERE Trial Group. Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: a randomised, controlled phase 3 trial. Mult Scler. 2014 May;20(6):705-16. doi: 10.1177/1352458513507821. Epub 2013 Oct 14.

Study record dates

Study Major Dates

• Study Start: April 1, 2009
• Primary Completion (Actual): September 1, 2011
• Study Completion (Actual): May 1, 2015

Study Registration Dates

• First Submitted: April 16, 2009
• First Submitted That Met QC Criteria: April 16, 2009
• First Posted (Estimate): April 17, 2009

Study Record Updates

• Last Update Posted (Estimate): June 13, 2016
• Last Update Submitted That Met QC Criteria: May 4, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Keywords: Relapsing-remitting multiple sclerosis
• 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; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Adjuvants, Immunologic; Interferons; Interferon beta-1a; Interferon-beta; Teriflunomide
• Other Study ID Numbers: EFC10891; 2008-006226-34 (EudraCT Number)