E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Primary progressive multiple sclerosis. |
Primárně progresivní roztroušená skleróza. |
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E.1.1.1 | Medical condition in easily understood language |
a chronic autoimmune disease which attacks the central nervous system with a steady worsening of neurologic functioning, but without any distinct relapses or periods of remission |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10063401 |
E.1.2 | Term | Primary progressive multiple sclerosis |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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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 assess the long-term safety, tolerability, and efficacy (as measured by clinical and MRI parameters of disease activity) of fingolimod 0.5 mg/day in PPMS patients. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients eligible for inclusion in this study have to fulfill all of the following criteria:
Patients who have provided written informed consent
Patients initially randomized to fingolimod 1.25 mg or placebo as part of the first study cohort, who have completed at least 3 years on study drug treatment at the time of extension study initiation
Patients initially randomized to fingolimod 0.5 mg or placebo as part of the second study cohort who have continued on study drug treatment until such time as the last ongoing patient enrolled in the study has reached 3 years in study. |
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E.4 | Principal exclusion criteria |
1. active chronic disease (or stable but treated with immune therapy) of the immune system other than MS (e.g., rheumatoid arthritis, scleroderma, Sjogren’s syndrome, Crohn’s disease, ulcerative colitis) or with a known immunodeficiency syndrome (HIV-antibody
positive, AIDS, hereditary immune deficiency, drug-induced immune deficiency)
2. Patients with active systemic bacterial, viral of fungal infections, or known to have AIDS, hepatitis A, hepatitis B, hepatitis C, hepatitis E infection or to have positive HIV antibody, hepatitis B surface antigen or hepatitis C antibody tests.
3. Uncontrolled diabetes mellitus (HbA1c>7%)
4. Not applicable - this exclusion criterion was deleted in Amendment 1.
5. Macular edema at baseline
6. Treatment with Class Ia or III antiarrhythmic drugs (e.g. amiodarone, bretylium, sotalol, ibulitide, azimilide, dofelitide)
7. Any of the following cardiovascular conditions:
• myocardial infarction within the past 6 months prior to enrollment or current unstable ischemic heart disease
• cardiac failure at time of Screening (Class III, according to NYHA Classification;
Appendix 2) or any severe cardiac disease as determined by the investigator
• second degree AV block Mobitz type II or a third degree AV block on screening ECG
• an increased QTc (Fridericia and Bazett) interval >500 ms on Screening ECG
• hypertension, uncontrolled by medication
8. Any of the following pulmonary conditions:
• severe respiratory disease or pulmonary fibrosis
• active tuberculosis
• reduction of FEV1, FVC and/or DLCO below 60% of core study baseline values or if
FEV1, FVC and/or DLCO at extension study baseline is the second of two consecutive pulmonary function tests with values <80% of core study baseline
9. Any of the following hepatic conditions at Baseline:
• severe hepatic unjury (Child-Pugh class C)
• history of alcohol abuse, chronic liver or biliary disease, acute or chronic pancreatitis, with the exception of Gilbert´s syndrome.
• total or conjugated bilirubin greater than the upper limit of the normal range, unless in context of Gilbert’s syndrome
• two consecutive alkaline phosphatase (AP) values greater than 3 times the upper limit of the normal range
• two consecutive AST (SGOT), ALT (SGPT) values greater than 3 times the upper limit of the normal range
• two consecutive gamma-glutamyl-transferase (GGT) values greater than 3 times the upper limit of the normal range
10. any medically unstable condition, as assessed by the primary treating physician
11. participation in any clinical research study other than CFTY720D2306 evaluating another investigational drug or therapy within 6 months prior to extension baseline
12. 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).
13. Women of childbearing potential, defined as all women physiologically capable of becoming pregnant, UNLESS they are using highly effective contraception during dosing with study treatment. Highly effective contraception includes:
• Total abstinence (when this is in line with the preferred and usual lifestyle of the patient). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
• Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation at least 6 weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
• Male partner sterilization (at least 6 months prior to Baseline). For female patients on the study, the vasectomized male partner should be the sole partner for that patient.
• Use of oral, injected, or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example, hormone vaginal ring or transdermal hormone contraception, placement of an intrauterine device or intrauterine system.
Women are considered post-menopausal and not of child-bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to baseline. In the case of oophorectomy alone, only when the reproductive status of the
woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
Note: If a patient fails on one or more laboratory (or other) assessment criteria, the assessment(s) may be repeated at the discretion of the investigator provided the assessments
are completed within one month. |
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E.5 End points |
E.5.1 | Primary end point(s) |
long-term safety, tolerability, and efficacy |
dlouhodobá bezpečnost, snášenlivost a účinnost |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Physical examination: baseline, yearly
Vital signs: every visit
Laboratory evaluations: every visit
Electrocardiogram (ECG): baseline, day 1
Dermatological examinations: baseline,yearly
Ophthalmic examination: baseline, month 3
EDSS, 9HPT, 25TWT: baseline, every 6 months
MRI: baseline, yearly
Pregnancy test: every visit
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 65 |
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 | No |
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 |
Belgium |
Canada |
Denmark |
France |
Italy |
Netherlands |
Sweden |
Australia |
Czech Republic |
Finland |
Germany |
Hungary |
Spain |
Poland |
Switzerland |
Turkey |
United Kingdom |
United States |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |