E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine the effect of teriflunomide in reducing the frequency of relapses in subjects with relapsing multiple sclerosis. |
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E.2.2 | Secondary objectives of the trial |
To Evaluate - the effect of teriflunomide on delaying the accumulation of disability AT 2 YEARS as assessed by the Kurtzke EDSS - the effects of teriflunomide on MRI variables, burden of disease (volume of abnormal brain tissue on MRI) and other MRI variables including number and volume of gadolinium-enhanced T1 lesions, volume of T2 lesion, volume of T1 hypointense lesions, atrophy and a composite. - the effect of teriflunomide on subject-reported fatigue as assessed by the Fatigue Impact Scale (FIS) - the safety and tolerability of teriflunomide by means of adverse event reports, physical examinations, vital signs, and laboratory evaluations |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects meeting all of the following criteria will be considered for enrollment into the study: - MS subjects, aged 18 to 55, who are ambulatory (EDSS less or equal than 5.5) - Exhibiting a relapsing clinical course, with or without progression (Relapsing Remitting, Secondary Progressive or Progressive Relapsing) - Meeting McDonald’s criteria for MS diagnosis - Experienced at least 1 relapse over the 1 year preceding the trial or at least 2 relapses over the 2 years preceding the trial - No relapse onset in the preceding 60 days prior to randomization - During the 4 weeks prior to randomization, subjects must have been clinically stable, without adrenocorticotrophic hormone (ACTH) or systemic steroid treatment - Signed main informed consent form and the informed consent for HIV testing |
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E.4 | Principal exclusion criteria |
- Subjects with significantly impaired bone marrow function or significant anemia, leukopenia, or thrombocytopenia - Subjects with a congenital or acquired severe immunodeficiency, a history of cancer (except for basal or squamous cell skin lesions which have been surgically excised, with no evidence of metastasis), lymphoproliferative disease, or any subject who has received lymphoid irradiation - Known human immunodeficiency virus (HIV) positive status; known history of active tuberculosis not adequately treated; persistent significant or severe infection - Pregnancy, breastfeeding, subjects wishing to parent children during the course of the trial - Therapies that are disallowed (minimum of 4 weeks prior to randomization): phenytoin, warfarin, tolbutamide, St. John's Wort or cholestyramine - Subjects must not have used ACTH or systemic corticosteroids for 4 weeks prior to randomization - Prior or concomitant use of cladribine, mitoxantrone, or other immunosuppressant agents such as azathioprine, cyclophosphamide, cyclosporin, methotrexate or MYCOPHENOLATE; - Prior use of natalizumab (Tysabri) - Prior use of interferons or cytokine therapy in the preceding 4 months; prior use of glatiramer acetate therapy in the preceding 6 months; prior use of intravenous immunoglobulins in the preceding 6 months; prior use of any investigational drug in the preceding 6 months; previous treatment with teriflunomide or leflunomide (ARAVA®) - Contraindication for MRI, i.e., presence of pacemaker, metallic implants in high-risk areas (i.e., artificial heart valves, aneurysm/vessel clips), presence of metallic material (i.e., shrapnel) in high risk areas, known history of allergy to any contrast medium, or history of claustrophobia that would prevent completion of all protocol-scheduled MRI. Hip implants are not contraindicated. - Liver function impairment or persisting elevations of SGPT/ALT, serum glutamic oxaloacetic transaminase (SGOT/AST), or direct bilirubin greater than 1.5-fold the upper limit of normal (ULN); - Persisting elevations of serum amylase or lipase greater than 2-fold the upper limit of normal - Known history of active hepatitis - Hypoproteinemia (e.g., in case of severe liver disease or nephrotic syndrome) with serum albumin <3.0 g/dL - Known history of chronic pancreatic disease or pancreatitis - Moderate to severe impairment of renal function, as shown by serum creatinine >133 µmol/L (or >1.5 mg/dL) - Likelihood of requiring treatment during the study period with drugs not permitted by the clinical study protocol - Clinically relevant cardiovascular, hepatic, neurological, endocrine, or other major systemic disease making implementation of the protocol or interpretation of the study results difficult or that would put the subject at risk by participating in the study - History of drug or alcohol abuse - Mental condition rendering the subject unable to understand the nature, scope, and possible consequences of the study - Subject is the investigator or any sub-investigator, research assistant, pharmacist, study coordinator, other staff or relative thereof directly involved in the conduct of the protocol |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy variable will be the annual relapse rate, defined as the number of relapses per subject-year. A gross estimate of annual relapse rate for a treatment group would be the total number of relapses incurred by the subjects in that group divided by the sum of study durations (in year) of all subjects in the group. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Subject Reported Outcomes |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 88 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Last subject, last visit. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 60 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 60 |