E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsing-Remitting Multiple Sclerosis |
|
E.1.1.1 | Medical condition in easily understood language |
Multiple sclerosis characterized by unpredictable relapses followed by periods with no new signs of disease activity |
|
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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10063399 |
E.1.2 | Term | Relapsing-remitting multiple sclerosis |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
|
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 explore the effects of multiple regimens of natalizumab on disease activity and safety in subjects with relapsing remitting MS. |
|
E.2.2 | Secondary objectives of the trial |
• To characterize and compare PK/PD profiles across multiple dose regimens of natalizumab.
• To characterize effects on secondary brain MRI measures.
• To evaluate potential laboratory markers of immune function and trafficking across the treatment regimens.
• To assess the safety and tolerability across multiple dose regimens. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (PHI) in accordance with national and local subject privacy regulations.
2. Aged 18 to 55 years old, inclusive, at the time of informed consent.
3. Subjects of childbearing potential must practice effective contraception during the study.
4. A documented diagnosis of RRMS.
5. Free of MS relapse, as determined by the enrolling Investigator, for 12 months prior to randomization.
6. Treatment with natalizumab according to locally approved pescribing information for a minimum of the 12 months immediately prior to randomization. The subject must have received at least 11 doses of natalizumab in the 12 months prior to randomization with no missed doses in the 3 months prior to randomization.
7. In the 12 months prior to the initiation of natalizumab, subject must have experienced a minimal level of disease activity as defined by:
• 2 or more documented clinical relapses
OR
• 1 relapse and documented MRI activity, defined by the presence of at least one Gd enhancing lesion on MRI, unrelated to the relapse. |
|
E.4 | Principal exclusion criteria |
1. Known history of Human Immunodeficiency Virus (HIV).
2. Known history of hepatitis C (test for hepatitis C virus antibody [HCV Ab]) or hepatitis B virus (test for Hepatitis B Surface Antigen [HBsAg] and/or Hepatitis B Core Antibody [HBcAb]).
3. Positive for anti-natalizumab antibodies at Screening.
4. MRI positive for Gd-enhancing lesions at study entry.
5. Subjects for whom MRI is contraindicated, e.g., have a pacemaker or other contraindicated implanted metal devices, have suffered, or are at risk for, side effects from Gd, or have claustrophobia that cannot be medically managed.
6. History of any clinically significant (as determined by the Investigator) cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic (including diabetes), urologic, pulmonary, neurologic (except for RRMS), dermatologic, psychiatric, renal, or
other major disease that would preclude participation in a clinical study.
7. History of malignant disease, including solid tumors and hematologic malignancies (with the exception of basal cell and squamous cell carcinomas of the skin that have been completely excised and are considered cured).
8. History of transplantation or any anti-rejection therapy.
9. History of severe allergic or anaphylactic reactions or known hypersensitivity to any drug.
10. A clinically significant infectious illness (e.g., cellulitis, abscess, pneumonia, septicemia) within 30 days prior to Screening, or PML or other opportunistic infections at any time.
11. Signs or symptoms suggestive of any serious infection, based on medical history, physical examination, or laboratory testing, as determined by the Investigator.
MS Treatment History
12. Prior treatment with total lymphoid irradiation.
13. Prior treatment with cladribine, mitoxantrone, fingolimod, T-cell or T-cell receptor vaccination, cyclophosphamide, cyclosporine, azathioprine, methotrexate, mycophenolate mofetil, or any therapeutic monoclonal antibody other than natalizumab within 24 months
prior to randomization.
14. Prior treatment with intravenous immunoglobulin (IVIg), plasmapheresis, or cytapheresis within 12 months prior to randomization.
15. Treatment with IV or oral corticosteroids (topical corticosteroids are acceptable) or related products within 3 months prior to randomization.
Miscellaneous
16. Female subjects considering becoming pregnant while in the study.
17. Female subjects who are pregnant or currently breastfeeding.
18. History of drug or alcohol abuse within 2 years prior to entry per Investigator judgment.
19. Unwillingness or inability to comply with the requirements of this protocol including the presence of any condition (physical, mental, or social) that is likely to affect the subject's ability to comply with the study protocol.
20. Receiving any other investigational treatment within the 12 months prior to Screening or concurrent with this study.
21. Any pre-scheduled elective procedure during the study period that, in the opinion of the Investigator, would interfere with study endpoints.
22. Any other condition, clinical finding, or reason that, in the opinion of the Investigator and/or the Sponsor, makes the subject unsuitable for enrollment into this study.
23. Previous participation in this study at randomization. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Cumulative number of combined unique active lesions (sum of the number of new Gd enhancing and new or newly enlarging T2 hyperintense lesions not associated with Gd enhancement on T1 weighted scans) based on brain MRI scans. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
At weeks 12, 24, 36, 48 and 60. |
|
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 | 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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | Yes |
E.8.1.4 | Double blind | No |
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.8.2.4 | Number of treatment arms in the trial | 5 |
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 | 18 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 60 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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
|
The end of study is last subject, last visit for final collection of data. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |