E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Natalizumab is a highly efficacious therapy used in the treatment of patients with relapsing multiple sclerosis (MS). This is a prospective randomized study in subjects with relapsing forms of MS who have been receiving natalizumab treatment for at least 12 months with no MS relapses during these 12 months. |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.1 |
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 |
The primary objective of this study is to explore pharmacodynamic markers, immune function and disease activity in subjects with MS undergoing up to a 24-week interruption of natalizumab therapy as measured by: 1. Time course of restoration of immune function using surrogate markers: 2. Time course to return of radiological and/or clinical evidence of MS activity, 3. The effect of alternative immunomodulatory treatments on return of immune function and MS disease activity. 4. The relationships between natalizumab concentration and α4-integrin saturation and immunological and clinical measures within individual subjects and across the treatment groups. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are to explore: 1. The time course to return of natalizumab effects as measured by immunological function, and radiological and/or clinical measures of disease activity after reintroduction of natalizumab therapy. 2. The relationship between natalizumab concentration, α4-integrin saturation and other pharmacodynamic markers after reintroduction of natalizumab therapy. 3. Genetic analyses relevant to natalizumab therapy and JCV biology. |
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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 |
Four sub studies are included in the main protocol 101MS205 version 1 dated 14 December 2009. 1.Leukocyte Functional Assay (Adhesion and/or Transmigration) in whole blood 2.Measurement ATP secretion from CD4 T cells in whole blood 3.Presence of mononuclear cells, calculation of immunoglobulin index and assessment of oligoclonal bands in CSF 4.Exploratory genetic analyses relevant to natalizumab therapy and JCV biology of DNA from whole blood
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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 60 years old, inclusive, at the time of informed consent. 3. Subjects of childbearing potential must practice effective contraception during the study. 4. A diagnosis of a relapsing form of MS consistent with local approved prescribing information. 5. Treatment with natalizumab according to locally approved prescribing 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. 6. No MS relapses within the 12 months prior to randomization. 7. Must be considered by the Investigator to be free of signs and symptoms suggestive of any serious infection, based on medical history, physical examination, or laboratory testing. |
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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. Any evidence of Gd-enhancement at Screening. 5. Subjects for whom MRI is contraindicated, i.e., have pacemakers 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, 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. Prior treatment with total lymphoid irradiation. 12. 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. 13. Prior treatment with intravenous immunoglobulin (IVIg), plasmapheresis, or cytapheresis within 12 months prior to randomization. 14. Treatment with IV or oral corticosteroids (inhaled corticosteroids are acceptable) or related products within 3 months prior to randomization. 15. Female subjects considering becoming pregnant while in the study. 16. Female subjects who are pregnant or currently breastfeeding. 17. History of drug or alcohol abuse within 2 years prior to entry. 18. 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. 19. Receiving any other investigational treatment within the 12 months prior to Screening or concurrent with this study. 20. Any pre-scheduled elective procedure during the study period that, in the opinion of the Investigator, would interfere with study endpoints. 21. Any other condition, clinical finding, or reason that, in the opinion of the Investigator and/or the Sponsor, is determined to be unsuitable for enrollment into this study. 22. Previous participation in this study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Natalizumab concentration, immune function, pharmacodynamics, disease activity |
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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 | No |
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 | Yes |
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) | 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 | 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 | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
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.8.4.1 | Number of sites anticipated in Member State concerned | 9 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
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 | 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
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The end of study is last subject, last visit (LSLV) |
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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 | 1 |
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 | 1 |
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 |