E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Primary progressive multiple sclerosis. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
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 evaluate the effect of 0.5 mg fingolimod relative to placebo on delaying the time to sustained disability progression. |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the effect of 0.5 mg fingolimod relative to placebo on delaying the time to 3-month sustained disability progression as measured by the EDSS.
• To evaluate the effect of fingolimod 0.5 mg relative to placebo on the
percent change from baseline in brain volume. |
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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-studies on pharmacogenetics, pharmacogenomics, and additional exploratory markers in blood and CSF are detailed in the enclosed protocol (section 7.6.4). These sub-studies are optional as only performed on patients who agree to participate by signing the separate exploratory biomarker/blood informed consent and the separate exploratory biomarker/CSF form.
Please see enclosed protocol, Section 7.6.4, for further details.
MRI Cortical Lesion sub-study
Primary objective:
•to evaluate the presence and evolution of cortical lesions in patients with PPMS and explore the effect of FTY720 relative to placebo in the development of such lesions with regard to the effect of FTY720 relative to placebo on the number and size of cortical lesions.
Other sub-study objectives:
•to describe the appearance and evolution of cortical lesions in patients with PPMS over up to 5 years
•to evaluate the correlation of cortical lesions with measures of disability progression
Please see protocol sections 2, 3.3, 7.4.1 for details
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E.3 | Principal inclusion criteria |
General inclusion criteria:
1. male or female
2. 25 through 65 years of age inclusive
3. females of childbearing potential must:
• have a negative pregnancy test at Baseline (prior to randomization) and
• use simultaneously two forms of effective contraception during the treatment and 3-months after discontinuation of study medication (refer to Section 7.5.9 for details)
4. sign written informed consent prior to participating in the study
Primary Progressive Multiple sclerosis / specific inclusion criteria :
1. diagnosis of primary progressive multiple sclerosis (according to the 2005 Revised McDonald criteria, Appendix 8):
• one year of disease progression plus
• two of the following:
- positive brain MRI (nine T2 lesions or four or more T2 lesions with positive visual evoked potential)
- positive spinal cord MRI (2 focal T2 lesions),
- positive CSF
• Central review of the diagnostic criteria for PPMS will be required for all patients prior to randomization (refer to Appendix 9 for details).
2. duration of disease at Baseline
• time since first reported symptoms between 2 and 10 years
3. documented evidence of clinical disability progression in the 2 years prior to Screening
• clinical disability progression should have been observed in each of the previous 2 years prior to Screening as per clinical judgment of the investigator.
• in addition, disability progression must be documented by an increase in the EDSS score of at least 0.5 points at any time point during the 2 years prior to Screening. Should documented EDSS scores not be available, a written summary of the clinical evidence of disability progression in the previous 2 years must be submitted for central review.
4. disability status at Screening (V1 or V2)
• EDSS score of 3.5-6.0 inclusive
• pyramidal functional system score of 2 or more
• 25’TWT less than 30 seconds
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E.4 | Principal exclusion criteria |
1. history of MS attack/relapse as per clinical judgement of the investigator
2. progressive disabling neurological disorder, other than PPMS
3. pure cerebellar progressive syndrome or pure visual progressive syndrome or a pure cognitive progressive syndrome
4. presence of cervical spinal cord compression on Screening MRI
5. relevant history of vitamin B12 deficit
6. history of chronic active disease of the immune system other than MS which may require systemic immunosuppressive treatment or a known immunodeficiency syndrome
7. history or presence of malignancy (except for successfully treated basal or squamous cell carcinoma of skin)
8. known or ‘new’ diagnosis of diabetes mellitus (if Screening blood glucose is suspicious for diabetes [≥126 mg/dL or ≥7 mmol/L if fasting and ≥200 mg/dL or 11.1 mmol/L if random testing] a patient should be further evaluated for diabetes mellitus)
9. 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)
10. evidence of syphilis, borreliosis, HIV, Hepatitis B, Hepatitis C infection or any other active systemic bacterial, viral or fungal infections
11. have received total lymphoid irradiation or bone marrow transplantation
12. have been treated with:
• systemic corticosteroids or adrenocorticotropic hormones (ACTH) within 3 months prior to randomization
• interferon-beta (IFN-*) or glatiramer acetate within 3 months prior to randomization
• immunosuppressive medications such as azathioprine or methotrexate within 6 months prior to randomization
• immunoglobulins and/or monoclonal antibodies within 6 months prior to randomization
• any mitoxantrone during previous 5 years prior to randomization or evidence of cardiotoxicity following mitoxantrone or mitoxantrone at a total cumulative life-time dose of more than 60 mg/m2
• cladribine, cyclophosphamide at any time
13. any medically unstable condition, as assessed by the primary treating physician
14. any of the following cardiovascular conditions (see enclosed protocol section 5.2)
15. any of the following pulmonary conditions (see enclosed protocol section 5.2)
16. any of the following hepatic conditions (see enclosed protocol section 5.2)
17. any of the following abnormal laboratory values (see enclosed protocol section 5.2)
18. 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
19. unable to undergo MRI scans, including claustrophobia or history of hypersensitivity to gadolinium-DTPA
20. participation in any clinical research study evaluating another investigational drug or therapy within 6 months prior to randomization
21. 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.
22. negative for varicella-zoster virus IgG antibodies at Screening
23. have received any live or live attenuated vaccines (including for varicella-zoster virus or measles) within 2 months prior to randomization.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the time to sustained disability progression,
which is defined based on three types of events for each subject:
• 3-month sustained increase of at least 20% from Baseline in the time
taken to complete the 25'TWT or
• 3-month sustained increase from Baseline in the EDSS score (1 point in
patients with Baseline EDSS score 3.5 to 5.0; 0.5 point in patients with
Baseline EDSS score of 5.5 or 6.0) or
• 3-month sustained increase of at least 20% from Baseline in the time
taken to complete the 9-HPT in either one of the hands (dominant or
non-dominant).
Disability progression in this study can be achieved by the occurrence of
any of three events (sustained disability progression on 25'TWT, EDSS or
9-HPT) for each subject.
In addition, primary efficacy analysis will be based on data from the 654
newly-randomized patients following implementation of FTY720D 2306
Protocol Amendment 5 and the placebo patients randomized prior to that.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
- To evaluate the effect of fingolimod 0.5 mg relative to placebo on
delaying the time to 3-month sustained disability progression as measured by the EDSS.
- To evaluate the effect of fingolimod 0.5 mg relative to placebo on the
percent change from baseline in brain volume. |
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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 | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Health-related quality of life and additional exploratory biomarkers. |
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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
| Information not present in EudraCT |
E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
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 | 96 |
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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The study will be considered completed when the last patient
randomized has 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 | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |