Safety and Efficacy of Teriflunomide (HMR1726) in Multiple Sclerosis With Relapses

Study Overview
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Brief Summary
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The primary objective of this study was to determine the safety and efficacy of teriflunomide in multiple sclerosis (MS) with relapses. Secondary objectives were: To determine the effect of teriflunomide on additional magnetic resonance imaging (MRI) variables as well as clinical and quality of life measures. To investigate the pharmacokinetic and pharmacodynamic relationships.

Detailed Description
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The total duration of the study period per participants was 46 weeks comprising 3 periods: a 4-week screening period, a 36-week double-blind treatment period, a 6-week post-treatment follow-up period. Participants who successfully completed the double-blind treatment phase were offered the possibility to continue study treatment in the extension study LTS6048 - NCT00228163.

Official Title
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A Phase II Study of the Safety and Efficacy of Teriflunomide (HMR1726) in Multiple Sclerosis With Relapses

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: Teriflunomide
* Drug: Placebo (placebo for teriflunomide)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinically confirmed multiple sclerosis [MS]; Expanded Disability Status Scale [EDSS] score less or equal to 6; Two documented relapses in the previous 3 years, and one clinical relapse during the preceding year; Screening magnetic resonance imaging [MRI] scan fulfilling the criteria for a diagnosis of MS. Exclusion Criteria: Clinically relevant cardiovascular, hepatic, hematologic, neurological, endocrine or other major systemic disease; Pregnant or nursing woman; Wish to parent children during the trial or following the trial (men and women were required to practice effective contraception during the trial and for 24 months after drug discontinuation); Prior treatment with interferon [IFN], gamma-globulin, glatiramer acetate, or other noncorticosteroid immunomodulatory therapies in the 4 months prior to the trial; Use of cladribine, mitoxantrone, or other immunosuppressant agents such as azathioprine, cyclophosphamide, cyclosporin, methotrexate or mycophenolate before enrollment; 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 patient's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo (for teriflunomide), two tablets once daily for 1 week then, one tablet once daily for 35 weeks. | Drug: Placebo (placebo for teriflunomide)<br>* film-coated tablet oral administration<br>|
| Experimental: Teriflunomide 7 mg<br>Teriflunomide 7 mg: two tablets once daily for 1 week then, one tablet once daily for 35 weeks. | Drug: Teriflunomide<br>* film-coated tablet oral administration<br>* Other names: HMR1726;|
| Experimental: Teriflunomide 14 mg<br>Teriflunomide 14 mg: two tablets once daily for 1 week then, one tablet once daily for 35 weeks. | 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 |
| --- | --- | --- |
| MRI assessment: number of unique active lesions per scan (T2/proton density and gadolinium-enhanced T1 scan analysis) | The number of unique active lesions per scan was calculated by dividing the sum of unique newly active lesions and unique persistently active lesions observed on treatment by the number of scans performed on treatment. Unique newly active lesions were all unique T1 and T2 lesions identified, one or more times, in a scan but not in the previous scan and, that had not been classified as unique newly active in any previous scan. Unique persistently active lesions were all unique T1 and T2 lesions identified, one or more times, in a scan and also in the previous scan. | 36 weeks | 
| Overview of Adverse Events [AE] | 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 6 weeks after last intake or entry in the extension study, whichever came first | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MRI assessment: number of T1-enhancing lesions per scan | T1-enhancing lesions included: Newly enhancing T1 lesions: lesions enhanced on the current T1 scan but not enhanced in any previous T1 scan. Persistently enhancing T1 lesions: lesions enhanced on the current T1 scan and enhanced on the previous T1 scan. | 36 weeks | 
| MRI assessment: number of T2-lesions per scan | T2-lesions included: New T2-lesions: lesions that appeared on the current T2 scan but were not visible on any previous T2 scans. Newly enlarging T2-lesions: lesions that appeared enlarged on the current T2 scan but were stable on the previous T2 scan. Persistently enlarging T2-lesions: further enlarged lesions on the current T2 scan categorized as new or enlarging on the previous T2 scan. | 36 weeks | 
| MRI assessment: Number of participants with no new lesions | New lesions included new T2 lesions, new enhanced T1 lesions and unique newly active lesions. | 36 weeks | 
| MRI assessment: Change from baseline in T2 burden of disease | T2 burden of disease was defined as the total volume of all T2 lesions. | 36 weeks | 
| Number of participants with progression on Expanded Disability Status Scale [EDSS] | EDSS is an ordinal scale in half-point increments that qualifies disability in patients with MS. It consists of 8 ordinal rating scales assessing seven 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). Progression was defined as an increase in EDSS score by at least 1-point when baseline EDSS score ≤5.5 or an increase in EDSS score by at least 0.5-point in when baseline EDSS score >5.5. | 36 weeks | 
| Number of participants with MS relapse confirmed by Scripps Neurological Rating Scale [NRS] and EDSS scores. | A relapse was defined as the appearance, reappearance or worsening of a symptom attributable to MS. The change had to persist for at least 48 hours in the absence of fever and be preceded by stability or improvement for at least 30 days. Relapses were to be confirmed by Scripps NRS and EDSS scores. NRS is a scale that qualifies the degree of impairment from a neurological exam of the following systems: mentation and mood, cranial nerves, motor nerves, deep tendon reflexes, sensory nerves, cerebellum, gait/trunk/balance, bladder/bowel/sexual dysfunction. NRS score ranges from 0 to 100 (lower degree of impairment). | 36 weeks |