An Efficacy Study of Teriflunomide in Participants With Relapsing Multiple Sclerosis

Study Overview
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Brief Summary
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The primary objective of the study was to assess the effect of two doses of teriflunomide, in comparison to placebo, on the frequency of multiple sclerosis (MS) relapses in participants with relapsing MS. Key secondary objective was to assess the effect of the two doses of teriflunomide, in comparison to placebo, on disability progression. Other secondary objectives were: To assess the effect of the two doses of teriflunomide in comparison to placebo on: Fatigue; Health-related quality of life, a measure of the impact of the participant's health on his or her overall well being. To evaluate the safety and tolerability of teriflunomide.

Detailed Description
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The study consists of: A core treatment period: Teriflunomide 7 mg or Teriflunomide 14 mg or placebo was administered in double-blind fashion until a fixed common end date which was approximately 48 weeks after randomization of the last participant. An extension treatment period: the highest dose of teriflunomide was administered in open-label fashion to participants who successfully complete the core treatment period and wish to continue. The overall treatment period was followed by a 4-week elimination follow-up period.

Official Title
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A Multi-center Double-blind Parallel-group Placebo-controlled Study of the Efficacy and Safety of Teriflunomide in Patients With Relapsing Multiple Sclerosis

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: Placebo
* Drug: Teriflunomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Relapsing multiple sclerosis, Two relapses in prior 2 years or one relapse in prior year. Exclusion Criteria: Clinically relevant cardiovascular, hepatic, neurological, endocrine or other major systemic disease, Significantly impaired bone marrow function or, significant anemia, leukopenia or thrombocytopenia, Pregnant or nursing woman, Alcohol or drug abuse, Prior or concomitant use of cladribine, mitoxantrone, or other immunosuppressant agents such as azathioprine, cyclophosphamide, cyclosporin, methotrexate or mycophenolate, Human immunodeficiency virus (HIV) positive, 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Teriflunomide 7 mg / 14 mg<br>Core treatment period: Teriflunomide 7 mg once daily. Extension treatment period: Teriflunomide 14 mg once daily. | Drug: Teriflunomide<br>* Film-coated tablet Oral administration<br>* Other names: HMR1726;|
| Experimental: Teriflunomide 14 mg / 14 mg<br>Core treatment period: Teriflunomide 14 mg once daily. Extension treatment period: Teriflunomide 14 mg once daily. | Drug: Teriflunomide<br>* Film-coated tablet Oral administration<br>* Other names: HMR1726;|
| Placebo Comparator: Placebo / Teriflunomide 14 mg<br>Core treatment period: Placebo (for teriflunomide) once daily. Extension treatment period: Teriflunomide 14 mg once daily. | Drug: Placebo<br>* Film-coated tablet Oral administration<br>Drug: Teriflunomide<br>* Film-coated tablet Oral administration<br>* Other names: HMR1726;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Core Treatment Period: Annualized Relapse Rate (ARR): Poisson Regression Estimate | ARR is obtained from the total number of confirmed relapses that occurred during the treatment period divided by the sum of treatment durations. 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 baseline EDSS stratum as covariates). | Core treatment period between 48 - 152 weeks depending on time of enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Core Treatment Period: Time to Disability Progression | Probability of disability progression at 24, 48, 108 and 132 weeks was estimated using Kaplan-Meier method on the time to disability progression defined as the time from randomization to first 12-week sustained disability progression [i.e. 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]. Participants free of disability progression (no disability progression observed on treatment) were censored at the date of the last on-treatment EDSS evaluation. 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 - 152 weeks depending on time of enrollment | 
| Core Treatment Period: Time Without Relapse | Probability of no relapse at 24, 48, 108 and 132 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. | Core treatment period between 48 - 152 weeks depending on time of enrollment | 
| Core Treatment Period: Change From Baseline to Week 48 in EDSS Total Score | EDSS is an ordinal scale in half-point increments that qualifies disability in participants with MS. It consists of 8 ordinal rating scales assessing 7 functional systems (visual, brainstem, pyramidal, cerebellar, sensory, bowel/bladder and cerebral) as well as ambulation. EDSS total score ranges from 0 (normal neurological examination) to 10 (death due to MS). Baseline adjusted least-squares means at Week 48 were estimated using a Mixed-effect model with repeated measures (MMRM) on EDSS score data (treatment group, region of enrollment, baseline EDSS stratum, visit, treatment-by-visit interaction, baseline value, and baseline-by-visit interaction as factors). All the timepoints from randomization up to Week 48 were included in the model. | Baseline (before randomization), Week 12, Week 24, Week 36 and Week 48 | 
| Core Treatment Period: Change From Baseline to Week 48 in Fatigue Impact Scale (FIS) Total Score | FIS is a participants-reported scale that qualifies the impact of fatigue on daily life in participants with MS. It consists of 40 statements that measure fatigue in 3 areas; physical, cognitive, and social. FIS total score ranges from 0 (no problem) to 160 (extreme problem). Baseline adjusted least-squares means at week 48 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). All the timepoints from randomization up to Week 48 were included in the model. | Baseline (before randomization), Week 12, Week 24 and Week 48 | 
| Core Treatment Period: Change From Baseline to Last Visit in Fatigue Impact Scale (FIS) Total Score | Baseline adjusted least-squares means at last visit were estimated using an analysis of covariance (ANCOVA) model on collected data for FIS total score (treatment group, region of enrollment, baseline EDSS stratum, visit number for the last visit and baseline value as factors). | Baseline (before randomization) and up to Week 152 | 
| Core Treatment Period: Change From Baseline to Week 48 in Short Form Generic Health Survey - 36 Items (SF-36) Summary Scores | SF-36 scale is a generic, self-administered, health-related quality-of-life (QOL) instrument. It is constructed such that the 36 questions represent 8 of the most important health concepts: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health. Two summary scores are obtained: the physical health component summary score, the mental health component summary score. Both scores range from 0 to 100 and a high score indicates a more favorable health state. Baseline adjusted least-squares means at week 48 were estimated using a Mixed-effect model with repeated measures [MMRM] on each summary score data (treatment group, region of enrollment, baseline EDSS stratum, visit, treatment-by-visit interaction, baseline value, and baseline-by-visit interaction as factors). All the timepoints from randomization up to Week 48 were included in the model. | Baseline (before randomization), Week 12, Week 24 and Week 48 | 
| Core Treatment Period: Change From Baseline to Last Visit in Short Form Generic Health Survey - 36 Items (SF-36) Summary Scores | Baseline adjusted least-squares means at last visit were estimated using an analysis of covariance (ANCOVA) model on collected data for each summary score (treatment group, region of enrollment, baseline EDSS stratum, visit number for the last visit and baseline value as factors). | Baseline (before randomization) and up to Week 152 | 
| Core Treatment Period: Overview of Adverse Events | Adverse Events (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 Treatment Emergent Adverse Events (TEAE) | 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: Time to Disability Progression | Probability of disability progression since the randomization of the core period was estimated using Kaplan-Meier method on the time to disability progression defined as the time from randomization to first 12 week sustained disability progression [i.e. 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]. Participants free of disability progression (no disability progression observed on treatment) were censored at the date of the last on-treatment EDSS evaluation. 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 was 1 minus the probability of being event-free for the amount of time t. | Core treatment period (maximum: 173 weeks) and Extension treatment period (maximum: 174 weeks) | 
| Extension Treatment Period: ARR: Poisson Regression Estimate | ARR was obtained from the total number of confirmed relapses that occurred during the treatment period divided by the sum of treatment durations. A relapse is defined as the appearance of a new clinical sign/symptom or clinical worsening of a previous sign/symptom (one that had been stable for at least 30 days) that persists for a minimum of 24 hours in the absence of fever. Relapse was confirmed by an increase in 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 enrolment and baseline EDSS stratum as covariates). | Extension treatment period (Maximum: 174 weeks) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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relapsing multiple sclerosis