E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Esclerosis múltiple remitente-recurrente |
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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 |
The primary objective is to compare fingolimod 1.25 mg and 0.5 mg with interferon β-1a and to demonstrate that at least 1.25 mg fingolimod is superior to interferon β-1a in terms of annualized relapse rate for patients with RRMS treated for up to 12 months. |
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E.2.2 | Secondary objectives of the trial |
To demonstrate superiority of two doses of fingolimod (1.25 mg and 0.5 mg per day) over interferon β-1a (30 µg/week i.m.) in patients with RRMS treated for up to 12 months in the proportion of relapse-free patients.
To assess the efficacy of fingolimod 1.25 mg/day vs. fingolimod 0.5 mg/day in the annualized relapse rate and proportion of relapse free patients. To evaluate the safety and tolerability of fingolimod compared to interferon β-1a. To test for difference in efficacy of fingolimod (1.25 mg and 0.5 mg per day) vs. interferon β-1a on: other relapse-related parameters; disability progression; and burden of disease and inflammatory disease activity as measured by MRI
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
General 1. male or female; • females of childbearing potential must: have negative pregnancy tests prior to entry into the Double-Blind Treatment Phase, or be either post-menopausal for 12 months prior to Randomization or surgically sterile, or use adequate contraception during the treatment and 3 months after discontinuation of the study medication 2. 18 through 55 years of age inclusive 3. signed written informed consent prior to participating in the study.
Multiple sclerosis 4. diagnosis of multiple sclerosis as defined by 2005 revised McDonald criteria 5. a relapsing-remitting course with at least 1 documented relapse during the previous year or 2 documented relapses during the previous 2 years; prior to randomization 6. an Expanded Disability Status Scale (EDSS) score of 0-5.5 inclusive 7. neurologically stable with no evidence of relapse or corticosteroid treatment within 30 days prior to randomization
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E.4 | Principal exclusion criteria |
Patients who meet any of the following exclusion criteria during the Pre-Randomization Phase will not be eligible for enrollment in the study: 1. a manifestation of MS other than RRMS 2. a history of chronic disease of the immune system other than MS or a known immunodeficiency syndrome 3. a history of epileptic seizures within 3 months of randomization 4. a history or presence of malignancy (except for successfully treated basal or squamous cell carcinoma of skin) 5. a known or ‘new’ diagnosis of diabetes mellitus 6. a diagnosis of macular edema during Pre-randomization Phase (patients with a history of macular edema will be allowed to enter the study provided that they do not have macular edema at the ophthalmic screening visit). 7. active systemic bacterial, viral or fungal infections, or diagnosis of AIDS, Hepatitis B, Hepatitis C infection defined as a positive HIV antibody, Hepatitis B surface antigen or Hepatitis C antibody tests, respectively 8. have received total lymphoid irradiation or bone marrow transplantation 9. have been treated with: • corticosteroids or adrenocorticotropic hormones (ACTH) within 1 month prior to randomization • immunosuppressive medications such as azathioprine or methotrexate within 6 months prior to randomization • immunoglobulins and/or monoclonal antibodies (including natalizumab) within 6 months prior to randomization • cladribine, cyclophosphamide or mitoxantrone at any time 10. any medically unstable condition, as assessed by the primary treating physician 11. any of the following cardiovascular conditions: • myocardial infarction within the past 6 months prior to enrollment or current unstable ischemic heart disease • history of angina pectoris due to coronary spasm or history of Raynaud’s phenomenon • cardiac failure at time of Screening (Class III, according to NYHA Classification; or any severe cardiac disease as determined by the investigator • history of cardiac arrest • history of symptomatic bradycardia • resting pulse rate <55 bpm prior to randomization • history of sick sinus syndrome or sino-atrial heart block • history or presence of a second degree AV block or a third degree AV block or an increased QTc interval >440 ms on Screening ECG • arrhythmia requiring current treatment with Class III antiarrhythmic drugs (e.g., amiodarone, bretylium, sotalol, ibulitide, azimilide, dofelitide) • history of a positive tilt test from workup for vasovagal syncope • hypertension, uncontrolled by medication 12. any of the following pulmonary conditions: • severe respiratory disease or pulmonary fibrosis • tuberculosis, except for history of successfully treated tuberculosis or history of prophylactic treatment after positive PPD skin reaction • abnormal chest High Resolution Computer Tomography (HRCT) [or chest x-ray in case HRCT is not permitted by local regulations] suggestive of active pulmonary disease • abnormal Pulmonary Function Tests: FEV1;, FVC values lower than 70% of predicted value, DLCO values lower than 60% of predicted value • patients receiving daily therapies for asthma 13. any of the following hepatic conditions: • known history of alcohol abuse, chronic liver or biliary disease, with the exception of Gilbert’s syndrome • total or conjugated bilirubin greater than the upper limit of the normal range • alkaline phosphatase (AP) greater than 1.5 times the upper limit of the normal range • AST (SGOT), ALT (SGPT) greater than 2 times the upper limit of the normal range • gamma-glutamyl-transferase (GGT) greater than 3 times the upper limit of the normal range 14. any of the following abnormal laboratory values: • serum creatinine greater than 1.7 mg/dL (150 µmol/L) • white blood cell (WBC) count <3,500/mm3 (<3.5 X 109 / L) • lymphocyte count <800/mm3 (<0.8 X 109 / L) 15. any of the following neurologic/psychiatric disorders: • episode of severe depression within three months of randomization • relevant history of suicide attempt or who, in the opinion of the investigator, are at risk of suicide attempt • history of substance abuse (drug or alcohol) or any other factor (i.e., serious psychiatric condition) that may interfere with the subject’s ability to cooperate and comply with the study procedures; • progressive neurological disorder, other than MS, which may affect participation in the study or require the use of medications not allowed by the protocol. 16. unable to undergo MRI scans, including claustrophobia or history of hypersensitivity to gadolinium-DTPA 17. history of hypersensitivity to natural or recombinant interferon beta, human albumin, or any other component of the formulation 18. participation in any clinical research study evaluating another investigational drug or therapy within 6 months prior to randomization 19. history of fingolimod therapy. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint will be the annualized relapse rate (ARR), which is defined as the number of relapses in a year.
The key secondary endpoint will be the proportion of relapse-free patients.
Other secondary endpoints include: • time to first relapse • time to second relapse • number of hospitalizations due to relapses • frequency of corticosteroid use to treat relapses • time to confirmed disability progression • proportion of patients with confirmed disability progression • change from Baseline to the end of study on the MSFC z-score • Burden of disease as measured by MRI: • % change from baseline in volume of T2 lesions at 12 months • % change from baseline in volume of T1 hypointense lesions at 12 months • Inflammatory disease activity as measured by MRI: • proportion of scans showing Gd-enhanced T1 lesions • proportion of scans showing new/ newly enlarged T2 lesions • number of new/ newly enlarged T2 lesions • number of Gd-enhanced T1 lesions • volume of Gd-enhanced T1 lesions • proportion of scans free of new inflammatory activity (Gd-enhanced lesions or new/ newly enlarged T2 lesions) |
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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 | No |
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 | No |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
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 | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
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.8.6 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 | Information not present in EudraCT |
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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The core study will be considered complete for an individual patient, when he/she completes the Double-blind Treatment Phase. The study as a whole will be considered completed when all randomized patients remaining in the core study have completed the Double-blind Treatment Phase. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |