E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsing-remitting multiple sclerosis (RRMS) |
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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 compare FTY720 1.25 mg and 0.5 mg with placebo and to demonstrate that at least the 1.25 mg FTY720 dose is superior to placebo as assessed by the annualised relapse rate in patients with RRMS treated for up to 24 months. |
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E.2.2 | Secondary objectives of the trial |
To evaluate the effect of two doses of FTY720 (1.25 mg and 0.5 mg) relative to placebo on: - time to confirmed disability progression in patients treated up to 24 months. - safety and tolerability in patients treated up to 24 months. - proportion of patients with confirmed disability progression in patients treated up to 24 months. - frequency of relapses in patients treated for up to 12 months. - proportion of relapse-free patients treated for up to 12 months and up to 24 months. - time to first relapse in patients treated for up to 24 months. - burden of disease (MRI lesion parameters) in patients treated for up to 12 and 24 months. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Exploratory Biomarker sub-study for Protocol No. CFTY720D2301. For further information, see Protocol Amendment 2. |
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E.3 | Principal inclusion criteria |
1. Male and female patients aged 18-55 with a diagnosis of Multiple Sclerosis (2005 revised McDonald criteria). 2. Patients with a relapsing-remitting course with at least 1 documented relapse during the last year or 2 documented relapses in the past 2 years, preceding their enrollment to the study. 3. Patients with Expanded Disability Status Scale (EDSS) score of 0-5.5 4. Patients who explicitly decline initiation or continuation of treatment with available disease modifying drugs for whatever reason after having been informed about their respective benefits and possible adverse events. 5. Neurologically stable patients with no evidence of relapse for at least 30 days prior to randomization. 6. Females of childbearing potential must have a negative pregnancy test at Baseline prior to entry into the Treatment period, or be either post-menopausal for 12 months prior to Screening or surgically sterile, or use adequate contraception during the treatment and 3 months after discontinuation of the study medication. 7. All patients must give written consent for participation in the study prior to the Screening.
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E.4 | Principal exclusion criteria |
1. Patients with a manifestation of MS other than RRMS. 2. Patients with a history of chronic disease of the immune system other than MS or with a known immunodeficiency syndrome. 3. Patients with a history or presence of malignancy (except of successfully treated basal or squamous cell carcinoma of skin). 4. Patients with a known diagnosis of diabetes mellitus or a screening blood glucose suspicious for diabetes, patients with macular edema at Screening visit. 5. Patients with active systemic bacterial, viral or fungal infections, or known to have AIDS, Hepatitis B, Hepatitis C infection or to have positive HIV antibody, Hepatitis B surface antigen or Hepatitis C antibody tests. 6. Patients who have received total lymphoid irradiation or bone marrow transplantation. 7. Patients who have been treated with corticosteroids or adrenocorticotropic hormones (ACTH) in the past 30 days prior to randomization. 8. Patients who have been previously treated with cladribine, cyclophosphamide or mitoxantrone. 9. Patients who have been treated with immunosuppressive medications such as azathioprine or methotrexate in the past 6 months prior to randomization. 10. Patients who have been treated with IFN-beta or glatiramer acetate in the past 3 months prior to randomization. 11. Patients who have been treated with immunoglobulins and/or monoclonal antibodies (including natalizumab) in the past 6 months prior to randomization. 12. Patients with any medically unstable condition, as assessed by the primary treating physician at each site. 13. Patients with any of the following cardiovascular conditions: • history of cardiac arrest; • myocardial infarction within the past 6 months prior to enrollment or with current unstable ischemic heart disease; • cardiac failure at time of Screening (Class III, according to New York Heart Association Classification) or any severe cardiac disease as determined by the investigator; • past or current history of recurrent symptomatic bradycardia; • 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). • resting pulse rate <55 bpm prior to randomization; • proven history of sick sinus syndrome or sino-atrial heart block; • history of a positive tilt test from workup for vasovagal syncope; • known history of angina pectoris due to coronary spasm or history of Raynaud's phenomenon; • hypertension, not controlled by prescribed medications, 14. Patients with any of the following pulmonary conditions: • severe respiratory disease or pulmonary fibrosis; • tuberculosis, except of history of successfully treated tuberculosis of history of prophylactic treatment after positive PPD skin reaction; • abnormal chest x-ray or High Resolution Computer Tomography (HRCT) [at selected sites] suggestive of active pulmonary disease; • abnormal Pulmonary Function Tests: FEV1, FVC values lower than 70% of predicted, DLCO values lower than 60% of predicted; • patients receiving daily therapies for asthma 15. Patients with any of the following hepatic conditions: • known history of alcohol abuse, chronic liver or biliary disease, with the exception of Gilbert’s syndrome; • AST (SGOT), ALT (SGPT) greater than 2 times the upper limit of the normal range; • alkaline phosphatase (AP) greater than 1.5 times the upper limit of the normal range; • gamma-glytamyl-transferase (GGT) greater than 3 times the upper limit of the normal range; • total or conjugated bilirubin greater than the upper normal limits. 16. Patients with any of the abnormal laboratory values: • serum creatinine greater than 1.7 mg/dL (150 µmol/L). • white blood cell (WBC) count <3,500/mm3 or lymphocyte count <800/mm3. 17. Patients with any of the following neurologic/psychiatric disorders: • 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. 18. Patients unable to undergo MRI scans, including claustrophobia or history of severe hypersensitivity to gadolinium-DTPA. 19. Participation in any clinical research study evaluating another investigational drug or therapy within 6 months prior to Baseline. 20. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/ml) 21. History of FTY720 therapy.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy parameter will be the annualized relapse rate at 24 months. Key secondary efficacy parameters include time to confirmed progression, proportion of patients with confirmed progression, proportion of relapse-free patients and burden of disease (MRI lesion parameters) at 2 years. |
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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 | 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.8.6 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 study will be considered completed 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 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 | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |