Efficacy and Safety of Teriflunomide in Patients With Relapsing Multiple Sclerosis and Treated With Interferon-beta
- Conditions
- Multiple Sclerosis Relapse
- Interventions
- Registration Number
- NCT01252355
- Lead Sponsor
- Sanofi
- Brief Summary
The primary objective was to demonstrate the effect of teriflunomide, in comparison to placebo, on frequency of Multiple Sclerosis (MS) relapses in patients with relapsing forms of MS who are treated with Interferon-beta (IFN-beta).
The secondary objectives were:
* Assess the effect of teriflunomide, in comparison to placebo, when added to IFN-beta on:
* Disease activity as measured by brain Magnetic Resonance Imaging (MRI)
* Disability progression
* Burden of disease and disease progression as measured by brain MRI
* Evaluate the safety and tolerability of teriflunomide when added to IFN-beta therapy
* Assess the pharmacokinetics of teriflunomide in use in addition to baseline IFN-beta therapy
* Assess associations between variations in genes and clinical outcomes (safety and efficacy)
* Assess other measures of efficacy of teriflunomide such as fatigue and health-related quality of life
* Assess measures of health economics (hospitalization due to relapse, including the length of stay and any admission to intensive care unit)
- Detailed Description
The study period per patient was expected to be between 56 and 160 weeks depending on when the patient was randomized and this included the following:
* a screening period up to 4 weeks,
* a treatment period expected to be between 48 and 152 weeks,
* 4-week post rapid elimination follow-up period.
Patients were to continue on treatment until a fixed common end date which was approximately 48 weeks after randomization of the last patient.
For those patients who completed the treatment period, a long term extension study of approximately 1 year (including teriflunomide alone) was initially planned to be proposed.
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 534
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Teriflunomide 7 mg + IFN-beta Teriflunomide Teriflunomide 7 milligram (mg) once a day concomitantly with IFN-beta therapy. Teriflunomide 14 mg + IFN-beta Teriflunomide Teriflunomide 14 mg once a day concomitantly with IFN-beta therapy. Placebo + IFN-beta Placebo (for teriflunomide) Placebo (for teriflunomide) once a day concomitantly with IFN-beta therapy. Teriflunomide 7 mg + IFN-beta Interferon-beta (IFN-beta) Teriflunomide 7 milligram (mg) once a day concomitantly with IFN-beta therapy. Placebo + IFN-beta Interferon-beta (IFN-beta) Placebo (for teriflunomide) once a day concomitantly with IFN-beta therapy. Teriflunomide 14 mg + IFN-beta Interferon-beta (IFN-beta) Teriflunomide 14 mg once a day concomitantly with IFN-beta therapy.
- Primary Outcome Measures
Name Time Method Annualized Relapse Rate (ARR) (Poisson Regression Estimates) Up to a maximum of 108 weeks depending on time of enrollment ARR is the total number of confirmed relapses that occurred during the treatment period divided by the total number of patient-years treated. 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. 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 IFN-beta dose stratum, and number of relapses in the year prior to randomization as covariates).
- Secondary Outcome Measures
Name Time Method Brain Magnetic Resonance Imaging (MRI) Assessment: Number of Gadolinium Enhancing (Gd-enhancing) T1-lesions Per Scan (Poisson Regression Estimates) Up to a maximum of 108 weeks depending on time of enrollment Number of Gd-enhancing T1-lesions per scan is the total number of Gd-enhancing T1-lesions that occurred during the treatment period divided by the total number of scans performed during the treatment period. 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, IFN-beta dose stratum and baseline number of Gd-enhancing T1-lesions as covariates).
Time to 12-Week Sustained Disability Progression Up to a maximum of 108 weeks depending on time of enrollment The 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 was to be estimated using Kaplan-Meier method.
Brain MRI Assessment: Volume of Gd-enhancing T1-lesions Per MRI Scan Up to a maximum of 108 weeks depending on time of enrollment Total volume of Gd-enhancing T1-lesions per scan is the sum of the volumes of Gd-enhancing T1-lesions observed during the treatment period divided by the total number of scans performed during the treatment period.
Brain MRI Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) at Week 24 Baseline, Week 24 The total lesion volume (burden of disease) is the total volumes of hyperintense on T2 plus hypointense on T1 as measured by MRI scan. Least-square means were estimated using a Mixed-effect model with repeated measures (MMRM) on cubic root transformed volume data with factors for treatment, region, IFN-beta dose stratum, visit, treatment-by-visit interaction, cubic root transformed baseline burden of disease, and baseline-by-visit interaction.
Time to Relapse: Kaplan-Meier Estimates of the Probability of no Relapse at Week 24, 48, and 72 Up to a maximum of 108 weeks depending on time of enrollment Probability of no relapse at 24, 48 and 72 weeks was estimated using Kaplan-Meier method on the time to relapse defined as the time from randomization to first EDSS confirmed relapse. Participants free of confirmed relapse (no EDSS confirmed relapse observed on treatment) were censored at the date of the last study drug intake. 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.
Change From Baseline in Fatigue Impact Scale (FIS) Total Score at Week 24 Baseline, Week 24 FIS is a participant-reported scale that qualifies the impact of fatigue on daily life in participants with MS.
Change From Baseline in Short Form Generic Health Survey - 36 Items, Version 2 (SF-36v2) Summary Scores at Week 24 Baseline, Week 24 SF-36 scale is a generic, self-administered, health-related quality-of-life (QOL) instrument.
Resource Utilization When Relapse Up to a maximum of 108 weeks depending on time of enrollment Resource utilization each time a participant experiences an MS relapse, specifically the number of hospitalizations, the number of over night spent in the hospital and number of intensive care admissions if hospitalized were to be reported.
Overview of Adverse Events (AEs) First study drug intake up to 28 days after last study drug intake, for up to 112 weeks AEs are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study.
Trial Locations
- Locations (185)
Investigational Site Number 170001
🇨🇴Barranquilla, Colombia
Investigational Site Number 170007
🇨🇴Bogota, Colombia
Investigational Site Number 233002
🇪🇪Tallinn, Estonia
Investigational Site Number 170009
🇨🇴Medellin, Colombia
Investigational Site Number 233001
🇪🇪Tartu, Estonia
Investigational Site Number 246006
🇫🇮Hyvinkää, Finland
Investigational Site Number 246002
🇫🇮Pori, Finland
Investigational Site Number 840021
🇺🇸St. Petersburg, Florida, United States
Investigational Site Number 840047
🇺🇸Tampa, Florida, United States
Investigational Site Number 840037
🇺🇸Elk Grove Village, Illinois, United States
Investigational Site Number 840005
🇺🇸Cordova, Alaska, United States
Investigational Site Number 840011
🇺🇸Oceanside, California, United States
Investigational Site Number 840004
🇺🇸Tampa, Florida, United States
Investigational Site Number 840007
🇺🇸Fargo, North Dakota, United States
Investigational Site Number 840009
🇺🇸Missoula, Montana, United States
Investigational Site Number 840040
🇺🇸Round Rock, Texas, United States
Investigational Site Number 840002
🇺🇸Nashville, Tennessee, United States
Investigational Site Number 840030
🇺🇸St Louis, Missouri, United States
Investigational Site Number 840015
🇺🇸New York, New York, United States
Investigational Site Number 036005
🇦🇺Chatswood, Australia
Investigational Site Number 840049
🇺🇸Cullman, Alabama, United States
Investigational Site Number 840013
🇺🇸Ormond Beach, Florida, United States
Investigational Site Number 840020
🇺🇸San Antonio, Texas, United States
Investigational Site Number 840032
🇺🇸Vienna, Virginia, United States
Investigational Site Number 840003
🇺🇸Phoenix, Arizona, United States
Investigational Site Number 124003
🇨🇦Gatineau, Canada
Investigational Site Number 840043
🇺🇸Tulsa, Oklahoma, United States
Investigational Site Number 246001
🇫🇮Turku, Finland
Investigational Site Number 276015
🇩🇪Berlin, Germany
Investigational Site Number 348006
🇭🇺Budapest, Hungary
Investigational Site Number 276010
🇩🇪Hamburg, Germany
Investigational Site Number 032002
🇦🇷Argentina, Argentina
Investigational Site Number 250004
🇫🇷Montpellier Cedex 5, France
Investigational Site Number 246003
🇫🇮Helsinki, Finland
Investigational Site Number 276012
🇩🇪Bonn, Germany
Investigational Site Number 276020
🇩🇪Bamberg, Germany
Investigational Site Number 250001
🇫🇷Nancy Cedex, France
Investigational Site Number 276003
🇩🇪Bayreuth, Germany
Investigational Site Number 276005
🇩🇪Dresden, Germany
Investigational Site Number 276032
🇩🇪Düsseldorf, Germany
Investigational Site Number 250010
🇫🇷Clermont Ferrand Cedex 1, France
Investigational Site Number 056005
🇧🇪Charleroi, Belgium
Investigational Site Number 208002
🇩🇰Aarhus C, Denmark
Investigational Site Number 250002
🇫🇷Lyon Cedex 03, France
Investigational Site Number 276018
🇩🇪Erbach, Germany
Investigational Site Number 276024
🇩🇪Kassel, Germany
Investigational Site Number 276013
🇩🇪Mainz, Germany
Investigational Site Number 276026
🇩🇪Wuppertal, Germany
Investigational Site Number 170005
🇨🇴Bogota, Colombia
Investigational Site Number 300001
🇬🇷Athens, Greece
Investigational Site Number 380009
🇮🇹Catania, Italy
Investigational Site Number 380011
🇮🇹Napoli, Italy
Investigational Site Number 250003
🇫🇷Besancon, France
Investigational Site Number 276004
🇩🇪Erlangen, Germany
Investigational Site Number 250006
🇫🇷Nantes Cedex 01, France
Investigational Site Number 276031
🇩🇪Rostock, Germany
Investigational Site Number 440004
🇱🇹Klaipeda, Lithuania
Investigational Site Number 620004
🇵🇹Coimbra, Portugal
Investigational Site Number 620003
🇵🇹Setubal, Portugal
Investigational Site Number 300006
🇬🇷Thessaloniki, Greece
Investigational Site Number 276023
🇩🇪Minden, Germany
Investigational Site Number 276008
🇩🇪Wiesbaden, Germany
Investigational Site Number 348005
🇭🇺Szekesfehervar, Hungary
Investigational Site Number 410002
🇰🇷Goyang-Si, Korea, Republic of
Investigational Site Number 440003
🇱🇹Siauliai, Lithuania
Investigational Site Number 578002
🇳🇴Tønsberg, Norway
Investigational Site Number 703002
🇸🇰Martin, Slovakia
Investigational Site Number 380002
🇮🇹Cefalù, Italy
Investigational Site Number 380006
🇮🇹Padova, Italy
Investigational Site Number 348002
🇭🇺Budapest, Hungary
Investigational Site Number 643011
🇷🇺St-Petersburg, Russian Federation
Investigational Site Number 724005
🇪🇸Madrid, Spain
Investigational Site Number 643003
🇷🇺St-Petersburg, Russian Federation
Investigational Site Number 380005
🇮🇹Roma, Italy
Investigational Site Number 620001
🇵🇹Amadora, Portugal
Investigational Site Number 643001
🇷🇺Kemerovo, Russian Federation
Investigational Site Number 380003
🇮🇹Fidenza, Italy
Investigational Site Number 380004
🇮🇹Gallarate, Italy
Investigational Site Number 643015
🇷🇺Novosibirsk, Russian Federation
Investigational Site Number 348007
🇭🇺Zalaegerszeg, Hungary
Investigational Site Number 643006
🇷🇺Nizhny Novgorod, Russian Federation
Investigational Site Number 380008
🇮🇹Roma, Italy
Investigational Site Number 643009
🇷🇺Rostov-On-Don, Russian Federation
Investigational Site Number 643017
🇷🇺St-Petersburg, Russian Federation
Investigational Site Number 724003
🇪🇸Girona, Spain
Investigational Site Number 440002
🇱🇹Kaunas, Lithuania
Investigational Site Number 620002
🇵🇹Coimbra, Portugal
Investigational Site Number 788002
🇹🇳Manouba, Tunisia
Investigational Site Number 752003
🇸🇪Stockholm, Sweden
Investigational Site Number 380010
🇮🇹Napoli, Italy
Investigational Site Number 380014
🇮🇹Verona, Italy
Investigational Site Number 703001
🇸🇰Trnava, Slovakia
Investigational Site Number 643014
🇷🇺Yaroslavl, Russian Federation
Investigational Site Number 643004
🇷🇺Nizhny Novgorod, Russian Federation
Investigational Site Number 724009
🇪🇸Córdoba, Spain
Investigational Site Number 826004
🇬🇧Plymouth, United Kingdom
Investigational Site Number 643005
🇷🇺Smolensk, Russian Federation
Investigational Site Number 788004
🇹🇳Sfax, Tunisia
Investigational Site Number 752001
🇸🇪Stockholm, Sweden
Investigational Site Number 724002
🇪🇸Barcelona, Spain
Investigational Site Number 826001
🇬🇧Salford, United Kingdom
Investigational Site Number 752004
🇸🇪Göteborg, Sweden
Investigational Site Number 826008
🇬🇧Birmingham, United Kingdom
Investigational Site Number 826005
🇬🇧Leeds, United Kingdom
Investigational Site Number 724004
🇪🇸Madrid, Spain
Investigational Site Number 788006
🇹🇳Tunis, Tunisia
Investigational Site Number 840034
🇺🇸Chicago, Illinois, United States
Investigational Site Number 840028
🇺🇸Baltimore, Maryland, United States
Investigational Site Number 840041
🇺🇸Baltimore, Maryland, United States
Investigational Site Number 300003
🇬🇷Heraklion, Greece
Investigational Site Number 300002
🇬🇷Athens, Greece
Investigational Site Number 528005
🇳🇱Nieuwegein, Netherlands
Investigational Site Number 528002
🇳🇱Sittard-Geleen, Netherlands
Investigational Site Number 276022
🇩🇪Hennigsdorf, Germany
Investigational Site Number 276001
🇩🇪Leipzig, Germany
Investigational Site Number 840023
🇺🇸Albuquerque, New Mexico, United States
Investigational Site Number 276016
🇩🇪Berlin, Germany
Investigational Site Number 276021
🇩🇪Berlin, Germany
Investigational Site Number 840016
🇺🇸Clinton Township, Michigan, United States
Investigational Site Number 840031
🇺🇸St Louis, Missouri, United States
Investigational Site Number 840027
🇺🇸Charlotte, North Carolina, United States
Investigational Site Number 032004
🇦🇷Caba, Argentina
Investigational Site Number 032003
🇦🇷Buenos Aires, Argentina
Investigational Site Number 036010
🇦🇺New Lambton, Australia
Investigational Site Number 036004
🇦🇺Kogarah, Australia
Investigational Site Number 036008
🇦🇺Bedford Park, Australia
Investigational Site Number 040001
🇦🇹Graz, Austria
Investigational Site Number 036001
🇦🇺Heidelberg West, Australia
Investigational Site Number 056002
🇧🇪Leuven, Belgium
Investigational Site Number 040004
🇦🇹Linz, Austria
Investigational Site Number 056003
🇧🇪Hasselt, Belgium
Investigational Site Number 056004
🇧🇪Gent, Belgium
Investigational Site Number 056006
🇧🇪La Louvière, Belgium
Investigational Site Number 056001
🇧🇪Sijsele-Damme, Belgium
Investigational Site Number 056007
🇧🇪Wilrijk, Belgium
Investigational Site Number 076009
🇧🇷Joinville, Brazil
Investigational Site Number 076012
🇧🇷Passo Fundo, Brazil
Investigational Site Number 076003
🇧🇷Porto Alegre, Brazil
Investigational Site Number 076007
🇧🇷Sao Paulo, Brazil
Investigational Site Number 076013
🇧🇷Sao Paulo, Brazil
Investigational Site Number 124005
🇨🇦Calgary, Canada
Investigational Site Number 124004
🇨🇦Edmonton, Canada
Investigational Site Number 124006
🇨🇦Kingston, Canada
Investigational Site Number 124007
🇨🇦Montreal, Canada
Investigational Site Number 124008
🇨🇦Ottawa, Canada
Investigational Site Number 124002
🇨🇦Regina, Canada
Investigational Site Number 124009
🇨🇦Winnipeg, Canada
Investigational Site Number 124001
🇨🇦Sherbrooke, Canada
Investigational Site Number 152004
🇨🇱Santiago, Chile
Investigational Site Number 152005
🇨🇱Viña Del Mar, Chile
Investigational Site Number 152003
🇨🇱Santiago, Chile
Investigational Site Number 246004
🇫🇮Oulu, Finland
Investigational Site Number 276009
🇩🇪Bad Mergentheim, Germany
Investigational Site Number 276002
🇩🇪Münster, Germany
Investigational Site Number 276028
🇩🇪Freiburg, Germany
Investigational Site Number 276006
🇩🇪Gießen, Germany
Investigational Site Number 348009
🇭🇺Eger, Hungary
Investigational Site Number 348010
🇭🇺Budapest, Hungary
Investigational Site Number 348003
🇭🇺Esztergom, Hungary
Investigational Site Number 348001
🇭🇺Szeged, Hungary
Investigational Site Number 380012
🇮🇹Montichiari, Italy
Investigational Site Number 410004
🇰🇷Seoul, Korea, Republic of
Investigational Site Number 410001
🇰🇷Seoul, Korea, Republic of
Investigational Site Number 528001
🇳🇱Breda, Netherlands
Investigational Site Number 528006
🇳🇱Venray, Netherlands
Investigational Site Number 643012
🇷🇺Kaluga, Russian Federation
Investigational Site Number 643007
🇷🇺Kazan, Russian Federation
Investigational Site Number 643013
🇷🇺Moscow, Russian Federation
Investigational Site Number 643010
🇷🇺Rostov-On-Don, Russian Federation
Investigational Site Number 643016
🇷🇺Samara, Russian Federation
Investigational Site Number 643018
🇷🇺St-Petersburg, Russian Federation
Investigational Site Number 643002
🇷🇺St-Petersburg, Russian Federation
Investigational Site Number 724001
🇪🇸Barcelona, Spain
Investigational Site Number 724007
🇪🇸Murcia, Spain
Investigational Site Number 788005
🇹🇳Monastir, Tunisia
Investigational Site Number 724008
🇪🇸Sevilla, Spain
Investigational Site Number 826006
🇬🇧Liverpool, United Kingdom
Investigational Site Number 826003
🇬🇧London, United Kingdom
Investigational Site Number 840036
🇺🇸Fort Collins, Colorado, United States
Investigational Site Number 840012
🇺🇸Maitland, Florida, United States
Investigational Site Number 840055
🇺🇸Pompano Beach, Florida, United States
Investigational Site Number 840033
🇺🇸Louisville, Kentucky, United States
Investigational Site Number 840006
🇺🇸Bismark, North Dakota, United States
Investigational Site Number 840046
🇺🇸Dayton, Ohio, United States
Investigational Site Number 840017
🇺🇸Toledo, Ohio, United States