E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Remitting-relapsing Multiple Sclerosis |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10063399 |
E.1.2 | Term | Relapsing-remitting multiple sclerosis |
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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 annual relapse rate in patients with RRMS treated up to 24 months. |
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E.2.2 | Secondary objectives of the trial |
Key secondary objectives: To evaluate: the effect of FTY720 relative to placebo on disability progression in patients treated for up to 24 months; safety and tolerability of FTY720 compared to placebo in patients with RRMS during the 24-month treatment phase. To demonstrate that FTY720 is effective in reducing the frequency of relapses compared to placebo in patients treated for up to 12 months. To evaluate: the effect of FTY720 relative to placebo on the proportion of relapse-free patients treated for up to 12 months and up to 24 months; the effect of FTY720 relative to placebo on time to the first relapse in patients treated for up to 24 months; the effect of FTY720 relative to placebo on burden of disease in patients treated for up to 24 months. To study the pharmacokinetics of FTY720 in patients with RRMS. To study the pharmacokinetic/pharmacodynamic relationship for main efficacy and safety outcomes in patients with RRMS. |
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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 04-May-05 Exploratory pharmacogenetic assessments are planned as a part of this Study with the objectives of examining whether individual genetic variation in genes relating to drug metabolism, multiple sclerosis, and the drug target pathway confer differential response to FTY720. Exploratory genomic, proteomic and metabonomic studies are planned as a part of this Study to identify gene expression patterns, proteins, and metabolites of blood and/or cerebrospinal fluid that are associated with treatment response to FTY720, or that possibly correlate with the severity or progression of multiple sclerosis. This exploratory biomarker substudy is optional. These assessments will only be performed on patients who agree to participate in this biomarker component by signing the separate exploratory biomarker informed consent form. |
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E.3 | Principal inclusion criteria |
1. Male and female patients aged 18-55 with clinically definite diagnosis of Multiple Sclerosis (McDonald criteria) see Appendix 3. 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 (signing of the study consent form). 3. Patients with Expanded Disability Status Scale (EDSS) score of 0-5.5 at Screening. 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 the Screening visit. 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 at 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 history of uncontrolled diabetes mellitus, macular edema or other retinal vascular diseases known to be associated with macular edema, e.g. retinal vein occlusion. 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 the Screening visit. 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 the Screening visit. 10. Patients who have been treated with IFN-β or glatiramer acetate in the past 3 months prior to the Screening visit. 11. Patients who have been treated with immunoglobulins and/or monoclonal antibodies (including natalizumab) in the past 6 months prior to the Screening visit. 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 (e.g. syncope); 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 at Screening or at Baseline; proven history of sino-atrial heart block; history of vagal syncope with a positive tilt test; hypertension, not controlled by prescribed medications. 14. Patients with 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; abnormal chest x-ray suggestive of active pulmonary disease; abnormal Pulmonary Function Tests values lower than 70% of predicted at Screening. 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 at Screening; alkaline phosphatase (AP) greater than 1.5 times the upper limit of the normal range at Screening; gamma-glytamyl-transferase (GGT) greater than 3 times the upper limit of the normal range at Screening; total or conjugated bilirubin greater than the upper normal limits at Screening. 16. Patients with any of the abnormal laboratory values: serum creatinine greater than 1.7 mg/dL (150 µmol/L) at Screening. white blood cell (WBC) count <3,500/mm3 or lymphocyte count <800/mm3 at Screening or Baseline. 17. Patients with any of the following neurologic/psychiatric disorders: 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. 18. Patients unable to undergo MRI scans, including 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 endpoint will be the annualized relapse rate at 24 months and will be analyzed using Poisson regression model adjusted for treatment, country, baseline relapse rate (in previous 2 years), baseline number of Gd-enhanced T1 lesions, baseline EDSS and age. Log (time on study) will be used as the offset variable in the Poisson model. Confirmed relapses only will be considered for the primary analysis. |
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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 | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
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 | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 20 |
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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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 |