A Study Comparing the Effectiveness and Safety of Teriflunomide and Interferon Beta-1a in Patients With Relapsing Multiple Sclerosis
- Registration Number
- NCT00883337
- Lead Sponsor
- Sanofi
- Brief Summary
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.
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 324
- Relapsing form of MS meeting McDonald's criteria for MS diagnosis and Expanded Disability Status Scale [EDSS] score ≤5.5 at screening visit.
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Teriflunomide 14 mg / 14 mg Teriflunomide Teriflunomide 14 mg once daily (core treatment period) and teriflunomide 14 mg once daily (extension treatment period). IFN-β-1a / 14 mg Interferon β-1a Interferon β-1a 3 times a week (core treatment period) and teriflunomide 14 mg once daily (extended treatment period). IFN-β-1a / 14 mg Teriflunomide Interferon β-1a 3 times a week (core treatment period) and teriflunomide 14 mg once daily (extended treatment period). Teriflunomide 7 mg / 14 mg Teriflunomide Teriflunomide 7 mg once daily (core treatment period) and teriflunomide 14 mg once daily (extended treatment period).
- Primary Outcome Measures
Name Time Method Core Treatment Period: Time to Failure: Kaplan-Meier Estimates of the Rate of Failure at Timepoints Core treatment period between 48 and 118 weeks depending on when the participant was enrolled 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: Overview of Failures Core treatment period between 48 and 118 weeks depending on when the participant was enrolled 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.
- Secondary Outcome Measures
Name Time Method Core Treatment Period: Overview of Adverse Events [AE] 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 AE are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study.
Extension Treatment Period: ARR Poisson Regression Estimates Extension treatment period (Maximum: 197 weeks) 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).
Core Treatment Period: Treatment Satisfaction Questionnaire for Medication [TSQM] Scores 48 weeks 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).
Core Treatment Period: Annualized Relapse Rate [ARR] - Poisson Regression Estimates Core treatment period between 48 and 118 weeks depending on when the participant was enrolled 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: Change From Baseline in Fatigue Impact Scale (FIS) Total Score Baseline (before randomization) and 48 weeks 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).Extension Treatment Period: Overview of AEs From first intake of study drug in extension treatment period up to 28 days after the last intake in the extension treatment period AEs were any unfavourable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study.
Trial Locations
- Locations (54)
Investigational Site Number 056003
🇧🇪Bruxelles, Belgium
Investigational Site Number 056001
🇧🇪Gent, Belgium
Investigational Site Number 203004
🇨🇿Jihlava, Czech Republic
Investigational Site Number 203002
🇨🇿Praha 2, Czech Republic
Investigational Site Number 348001
🇭🇺Budapest, Hungary
Investigational Site Number 348003
🇭🇺Budapest, Hungary
Investigational Site Number 616002
🇵🇱Bialystok, Poland
Investigational Site Number 616004
🇵🇱Gdansk, Poland
Investigational Site Number 616001
🇵🇱Warszawa, Poland
Investigational Site Number 756002
🇨🇭St. Gallen, Switzerland
Investigational Site Number 276005
🇩🇪Dresden, Germany
Investigational Site Number 276007
🇩🇪Erbach, Germany
Investigational Site Number 124003
🇨🇦Lévis, Canada
Investigational Site Number 124004
🇨🇦St. John'S, Canada
Investigational Site Number 276011
🇩🇪Berlin, Germany
Investigational Site Number 276001
🇩🇪Bochum, Germany
Investigational Site Number 300002
🇬🇷Thessaloniki, Greece
Investigational Site Number 348004
🇭🇺Veszprém, Hungary
Investigational Site Number 616003
🇵🇱Lublin, Poland
Investigational Site Number 380010
🇮🇹Ancona, Italy
Investigational Site Number 380005
🇮🇹Bari, Italy
Investigational Site Number 250005
🇫🇷Clermont Ferrand Cedex 1, France
Investigational Site Number 250004
🇫🇷Lille Cedex, France
Investigational Site Number 276012
🇩🇪Berlin, Germany
Investigational Site Number 724002
🇪🇸Majadahonda, Spain
Investigational Site Number 124002
🇨🇦London, Canada
Investigational Site Number 250001
🇫🇷Montpellier Cedex 5, France
Investigational Site Number 276004
🇩🇪Halle/Saale, Germany
Investigational Site Number 380008
🇮🇹Cagliari, Italy
Investigational Site Number 380004
🇮🇹Pavia, Italy
Investigational Site Number 250002
🇫🇷Strasbourg Cedex, France
Investigational Site Number 276003
🇩🇪Bad Mergentheim, Germany
Investigational Site Number 276009
🇩🇪Mainz, Germany
Investigational Site Number 276006
🇩🇪Essen, Germany
Investigational Site Number 250003
🇫🇷Bordeaux Cedex, France
Investigational Site Number 724001
🇪🇸Bilbao, Spain
Investigational Site Number 348005
🇭🇺Budapest, Hungary
Investigational Site Number 826002
🇬🇧London, United Kingdom
Investigational Site Number 276002
🇩🇪Münster, Germany
Investigational Site Number 276010
🇩🇪Hannover, Germany
Investigational Site Number 348002
🇭🇺Esztergom, Hungary
Investigational Site Number 724007
🇪🇸Barcelona, Spain
Investigational Site Number 826003
🇬🇧Plymouth, United Kingdom
Investigational Site Number 724003
🇪🇸Murcia, Spain
Investigational Site Number 380003
🇮🇹Cefalù, Italy
Investigational Site Number 380007
🇮🇹Genova, Italy
Investigational Site Number 380001
🇮🇹Milano, Italy
Investigational Site Number 056002
🇧🇪Hasselt, Belgium
Investigational Site Number 203003
🇨🇿Praha 10, Czech Republic
Investigational Site Number 300001
🇬🇷Athens, Greece
Investigational Site Number 348007
🇭🇺Kecskemét, Hungary
Investigational Site Number 380002
🇮🇹Roma, Italy
Investigational Site Number 380006
🇮🇹Torino, Italy
Investigational Site Number 788002
🇹🇳Monastir, Tunisia