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.
Descripción general del estudio
Estado
Condiciones
Intervención / Tratamiento
Descripción detallada
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.
Tipo de estudio
Inscripción (Actual)
Fase
- Fase 3
Contactos y Ubicaciones
Ubicaciones de estudio
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Bad Mergentheim, Alemania, 97980
- Investigational Site Number 276003
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Berlin, Alemania, 10117
- Investigational Site Number 276011
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Berlin, Alemania, 12099
- Investigational Site Number 276012
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Bochum, Alemania, 44791
- Investigational Site Number 276001
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Dresden, Alemania, 01307
- Investigational Site Number 276005
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Erbach, Alemania, 64711
- Investigational Site Number 276007
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Essen, Alemania, 45138
- Investigational Site Number 276006
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Halle/Saale, Alemania, 06120
- Investigational Site Number 276004
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Hannover, Alemania, 30559
- Investigational Site Number 276010
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Mainz, Alemania, 55131
- Investigational Site Number 276009
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Münster, Alemania, 48149
- Investigational Site Number 276002
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Bruxelles, Bélgica, 1070
- Investigational Site Number 056003
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Gent, Bélgica, 9000
- Investigational Site Number 056001
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Hasselt, Bélgica, B-3590
- Investigational Site Number 056002
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London, Canadá, N6A 5A5
- Investigational Site Number 124002
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Lévis, Canadá, G6V 3Z1
- Investigational Site Number 124003
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St. John'S, Canadá, A1B 3V6
- Investigational Site Number 124004
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Barcelona, España, 08036
- Investigational Site Number 724007
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Bilbao, España, 48013
- Investigational Site Number 724001
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Majadahonda, España, 28222
- Investigational Site Number 724002
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Murcia, España, 30120
- Investigational Site Number 724003
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Bordeaux Cedex, Francia, 33076
- Investigational Site Number 250003
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Clermont Ferrand Cedex 1, Francia, 63003
- Investigational Site Number 250005
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Lille Cedex, Francia, 59037
- Investigational Site Number 250004
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Montpellier Cedex 5, Francia, 34000
- Investigational Site Number 250001
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Strasbourg Cedex, Francia, 67091
- Investigational Site Number 250002
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Athens, Grecia, 11527
- Investigational Site Number 300001
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Thessaloniki, Grecia
- Investigational Site Number 300002
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Budapest, Hungría, 1083
- Investigational Site Number 348001
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Budapest, Hungría, 1096
- Investigational Site Number 348005
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Budapest, Hungría, 1106
- Investigational Site Number 348003
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Esztergom, Hungría, 2500
- Investigational Site Number 348002
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Kecskemét, Hungría, 6000
- Investigational Site Number 348007
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Veszprém, Hungría, 8200
- Investigational Site Number 348004
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Ancona, Italia, 60020
- Investigational Site Number 380010
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Bari, Italia, 70124
- Investigational Site Number 380005
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Cagliari, Italia, 09126
- Investigational Site Number 380008
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Cefalù, Italia, 90015
- Investigational Site Number 380003
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Genova, Italia, 16132
- Investigational Site Number 380007
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Milano, Italia, 20132
- Investigational Site Number 380001
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Pavia, Italia, 27100
- Investigational Site Number 380004
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Roma, Italia, 00185
- Investigational Site Number 380002
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Torino, Italia, 10126
- Investigational Site Number 380006
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Bialystok, Polonia, 15-276
- Investigational Site Number 616002
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Gdansk, Polonia, 80-803
- Investigational Site Number 616004
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Lublin, Polonia, 20-718
- Investigational Site Number 616003
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Warszawa, Polonia, 02-957
- Investigational Site Number 616001
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London, Reino Unido, SW17 0QT
- Investigational Site Number 826002
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Plymouth, Reino Unido, PL6 5BX
- Investigational Site Number 826003
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Jihlava, República Checa, 58633
- Investigational Site Number 203004
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Praha 10, República Checa, 10034
- Investigational Site Number 203003
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Praha 2, República Checa, 12808
- Investigational Site Number 203002
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St. Gallen, Suiza, 9007
- Investigational Site Number 756002
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Monastir, Túnez, 5000
- Investigational Site Number 788002
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Criterios de participación
Criterio de elegibilidad
Edades elegibles para estudiar
Acepta Voluntarios Saludables
Géneros elegibles para el estudio
Descripción
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.
Plan de estudios
¿Cómo está diseñado el estudio?
Detalles de diseño
- Propósito principal: Tratamiento
- Asignación: Aleatorizado
- Modelo Intervencionista: Asignación paralela
- Enmascaramiento: Único
Armas e Intervenciones
Grupo de participantes/brazo |
Intervención / Tratamiento |
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Experimental: Teriflunomide 7 mg / 14 mg
Teriflunomide 7 mg once daily (core treatment period) and teriflunomide 14 mg once daily (extended treatment period).
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Comprimido recubierto con película Administracion oral
Otros nombres:
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Experimental: Teriflunomide 14 mg / 14 mg
Teriflunomide 14 mg once daily (core treatment period) and teriflunomide 14 mg once daily (extension treatment period).
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Comprimido recubierto con película Administracion oral
Otros nombres:
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Comparador activo: IFN-β-1a / 14 mg
Interferon β-1a 3 times a week (core treatment period) and teriflunomide 14 mg once daily (extended treatment period).
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Comprimido recubierto con película Administracion oral
Otros nombres:
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®
Otros nombres:
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¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
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Core Treatment Period: Overview of Failures
Periodo de tiempo: Core treatment period between 48 and 118 weeks depending on when the participant was enrolled
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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
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Core Treatment Period: Time to Failure: Kaplan-Meier Estimates of the Rate of Failure at Timepoints
Periodo de tiempo: Core treatment period between 48 and 118 weeks depending on when the participant was enrolled
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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
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Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
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Core Treatment Period: Annualized Relapse Rate [ARR] - Poisson Regression Estimates
Periodo de tiempo: Core treatment period between 48 and 118 weeks depending on when the participant was enrolled
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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
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Core Treatment Period: Change From Baseline in Fatigue Impact Scale (FIS) Total Score
Periodo de tiempo: Baseline (before randomization) and 48 weeks
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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
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Core Treatment Period: Treatment Satisfaction Questionnaire for Medication [TSQM] Scores
Periodo de tiempo: 48 weeks
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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).
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48 weeks
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Core Treatment Period: Overview of Adverse Events [AE]
Periodo de tiempo: 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
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AE are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study.
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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
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Extension Treatment Period: Overview of AEs
Periodo de tiempo: From first intake of study drug in extension treatment period up to 28 days after the last intake in the extension treatment period
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AEs were any unfavourable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study.
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From first intake of study drug in extension treatment period up to 28 days after the last intake in the extension treatment period
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Extension Treatment Period: ARR Poisson Regression Estimates
Periodo de tiempo: Extension treatment period (Maximum: 197 weeks)
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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).
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Extension treatment period (Maximum: 197 weeks)
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Colaboradores e Investigadores
Patrocinador
Publicaciones y enlaces útiles
Publicaciones Generales
- 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.
Fechas de registro del estudio
Fechas importantes del estudio
Inicio del estudio
Finalización primaria (Actual)
Finalización del estudio (Actual)
Fechas de registro del estudio
Enviado por primera vez
Primero enviado que cumplió con los criterios de control de calidad
Publicado por primera vez (Estimar)
Actualizaciones de registros de estudio
Última actualización publicada (Estimar)
Última actualización enviada que cumplió con los criterios de control de calidad
Última verificación
Más información
Términos relacionados con este estudio
Palabras clave
Términos MeSH relevantes adicionales
- Procesos Patológicos
- Enfermedades del Sistema Nervioso
- Enfermedades del sistema inmunológico
- Enfermedades Autoinmunes Desmielinizantes, SNC
- Enfermedades Autoinmunes del Sistema Nervioso
- Enfermedades desmielinizantes
- Enfermedades autoinmunes
- Esclerosis múltiple
- Esclerosis
- Efectos fisiológicos de las drogas
- Agentes antiinfecciosos
- Agentes del sistema nervioso periférico
- Agentes Antivirales
- Analgésicos
- Agentes del sistema sensorial
- Agentes antiinflamatorios no esteroideos
- Analgésicos no narcóticos
- Agentes antiinflamatorios
- Agentes antirreumáticos
- Agentes antineoplásicos
- Agentes inmunosupresores
- Factores inmunológicos
- Adyuvantes, Inmunológicos
- Interferones
- Interferón beta-1a
- Interferón-beta
- Teriflunomida
Otros números de identificación del estudio
- EFC10891
- 2008-006226-34 (Número EudraCT)
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