Efficacy and Safety of Teriflunomide in Patients With Relapsing Multiple Sclerosis and Treated With Interferon-beta

Study Overview
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Brief Summary
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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
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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.

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 Who Are Treated With Interferon-beta

Conditions
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Multiple Sclerosis Relapse

Intervention / Treatment
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* Drug: Teriflunomide
* Drug: Placebo (for teriflunomide)
* Drug: Interferon-beta (IFN-beta)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria : Patient with relapsing forms of MS treated with IFN-beta Stable dose of IFN-beta (approved brand) for at least 6 months prior to randomization Disease activity in the 12 months prior to randomization and after first 3 months of IFN-beta treatment (defined by at least 1 relapse supported by EDSS or equivalent neurological examination, or, at least 1 brain or spinal cord MRI with at least one T1 gadolinium enhancing lesion) Exclusion criteria: McDonald criteria for MS diagnosis not met at time of screening visit EDSS score greater than (>) 5.5 at randomization visit A relapse within 30 days prior randomization Persistent significant or severe infection Patients must not have used adrenocorticotrophic hormone or systemic corticosteroids for 2 weeks prior to randomization Prior or concomitant use of cytokine therapy (except baseline interferons), glatiramer acetate or intravenous immunoglobulins in the 3 months preceding randomization Liver function impairment or persisting elevations (confirmed by retest) of alanine aminotransferase (ALT), aspartate aminotransferase (AST), or direct bilirubin greater than 2 times the upper limit of normal range (ULN) Active hepatitis or hepatobiliary disease or known history of severe hepatitis Pregnant or breast-feeding women or those who were planning to become pregnant during the study Significantly impaired bone marrow function or significant anemia, leukopenia, or thrombocytopenia Human Immunodeficiency Virus (HIV) positive Known history of active tuberculosis not adequately treated Prior use within 2 years preceding randomization or concomitant use of cladribine and mitoxantrone Prior use within 6 months preceding randomization or concomitant use of natalizumab, or any other immunosuppressive agents such as azathioprine, cyclophosphamide, cyclosporine, methotrexate, mycophenolate, or fingolimod The above information is not intended to contain all considerations relevant to a patient'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 + IFN-beta<br>Teriflunomide 7 milligram (mg) once a day concomitantly with IFN-beta therapy. | Drug: Teriflunomide<br>* Film-coated tablet Oral administration<br>* Other names: HMR1726;Drug: Interferon-beta (IFN-beta)<br>* Any of the IFN-beta which are approved for marketed use in the country where the patient is enrolled. Administration according to the package insert.<br>|
| Experimental: Teriflunomide 14 mg + IFN-beta<br>Teriflunomide 14 mg once a day concomitantly with IFN-beta therapy. | Drug: Teriflunomide<br>* Film-coated tablet Oral administration<br>* Other names: HMR1726;Drug: Interferon-beta (IFN-beta)<br>* Any of the IFN-beta which are approved for marketed use in the country where the patient is enrolled. Administration according to the package insert.<br>|
| Placebo Comparator: Placebo + IFN-beta<br>Placebo (for teriflunomide) once a day concomitantly with IFN-beta therapy. | Drug: Placebo (for teriflunomide)<br>* Film-coated tablet Oral administration<br>Drug: Interferon-beta (IFN-beta)<br>* Any of the IFN-beta which are approved for marketed use in the country where the patient is enrolled. Administration according to the package insert.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualized Relapse Rate (ARR) (Poisson Regression Estimates) | 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). | Up to a maximum of 108 weeks depending on time of enrollment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brain Magnetic Resonance Imaging (MRI) Assessment: Number of Gadolinium Enhancing (Gd-enhancing) T1-lesions Per Scan (Poisson Regression Estimates) | 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). | Up to a maximum of 108 weeks depending on time of enrollment | 
| Time to 12-Week Sustained Disability Progression | 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. | Up to a maximum of 108 weeks depending on time of enrollment | 
| Brain MRI Assessment: Volume of Gd-enhancing T1-lesions Per MRI Scan | 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. | Up to a maximum of 108 weeks depending on time of enrollment | 
| Brain MRI Assessment: Change From Baseline in Total Lesion Volume (Burden of Disease) at 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. | Baseline, Week 24 | 
| Time to Relapse: Kaplan-Meier Estimates of the Probability of no Relapse at Week 24, 48, and 72 | 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. | Up to a maximum of 108 weeks depending on time of enrollment | 
| Change From Baseline in Fatigue Impact Scale (FIS) Total Score at Week 24 | FIS is a participant-reported scale that qualifies the impact of fatigue on daily life in participants with MS. | Baseline, Week 24 | 
| Change From Baseline in Short Form Generic Health Survey - 36 Items, Version 2 (SF-36v2) Summary Scores at Week 24 | SF-36 scale is a generic, self-administered, health-related quality-of-life (QOL) instrument. | Baseline, Week 24 | 
| Resource Utilization When Relapse | 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. | Up to a maximum of 108 weeks depending on time of enrollment | 
| Overview of Adverse Events (AEs) | AEs are any unfavorable and unintended sign, symptom, syndrome, or illness observed by the investigator or reported by the participant during the study. | First study drug intake up to 28 days after last study drug intake, for up to 112 weeks |