A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Efficacy of Natalizumab on Reducing Disability Progression in Subjects With Secondary Progressive Multiple Sclerosis, With optional Open-label Extension

Part 1: To be eligible to participate in this study, candidates must meet the following eligibility criteria at the time of randomization (Day 0), or at the timepoint specified in the individual eligibility criterion listed:;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. Be between the ages of 18 and 58, inclusive, at the time of informed consent.;3. Onset of SPMS at least 2 years prior to enrollment. SPMS is defined as relapsing-remitting disease followed by progression of disability independent of or not explained by MS relapses (Lublin, Reingold, 1996) ) for at least 2 years. ;4. Have EDSS score of 3.0 to 6.5, inclusive.;5. Have an MS Severity Score (MSSS) of 4 or higher.;6. Have documented confirmed evidence of disease progression independent of clinical relapses over the 1 year prior to enrollment as defined in the Study Reference Guide.;7. Subjects must have completed those baseline assessments associated with components of the primary endpoint (EDSS, T25FW, 9HPT) prior to randomization (Day 0).;8. Subjects of childbearing potential must practice effective contraception during the study and be willing and able to continue contraception for 3 months after their last infusion.;Part 2: To be eligible to participate in the Part 2 Extension Phase of this study, candidates must meet the folowing eligibility criteria at the time of consent into Part 2, or at the timepoint specified in the individual eligibility criterion listed:;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. Subjects must have participated in Part 1, have documented Week 108 assessment attempts for EDSS, T25FW, and 9HPT prior to first open-label dosing at Week 108 and not have missed 2 or more consecutive infusions in Part 1 of the study.;3. Subjects of childbearing potential must practice effective contraception during the study and be willing and able to continue contraception for 3 months after their last infusion.

Part 1: Candidates will be excluded from study entry if any of the following exclusion criteria exist at the time of randomization (Day 0), or at the timepoint specified in the individual criterion listed:;1.Have a diagnosis of RRMS or primary progressive MS as defined by the revised McDonald Committee criteria (Polman et al 2005).;2. Had a recent clinical relapse (within 3 months) prior to randomization. ;3. Have a T25FW test of >30 seconds during the screening period.;4. Any value below the lower limit of normal for blood levels of leukocytes, lymphocytes, or neutrophils.;5. Considered by the Investigator to be immunocompromised based on medical history, physical examination, laboratory testing, or any other testing required by local guidelines, or due to prior immunosuppressive or immunomodulating treatment.;6. Subjects for whom MRI is contraindicated (i.e., have pacemakers or other contraindicated implanted metal devices or have claustrophobia that cannot be medically managed).;7. History of any clinically significant (as determined by the Investigator) cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic (other than MS), dermatologic, psychiatric, and renal, or other major disease that would preclude participation in a clinical study.;8. 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).;9. Known history of or positive test result for Human Immunodeficiency Virus (HIV).;10. Positive test result for hepatitis C virus (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]).;11. History of transplantation or any anti-rejection therapy.;12. Presence of any infectious disease (e.g., cellulitis, abscess, pneumonia, septicemia) within 30 days prior to screening.;13. History of PML or other opportunistic infections including active tuberculosis.;Treatment History;14. Any prior treatment with cell-depleting therapies, including total lymphoid irradiation, cladribine, rituximab, alemtuzumab, or bone marrow ablation.;15. Any prior treatment with natalizumab. ;16. Treatment with mitoxantrone, cyclophosphamide, cyclosporine, azathioprine, methotrexate, mycophenolate mofetil, T cell or T cell receptor vaccination, fingolimod, daclizumab, or cytapheresis within 6 months prior to randomization.;17. Treatment with IV or oral corticosteroids, intravenous immunoglobulin (IVIg), or plasmapheresis for treatment of MS within the 3 months prior to randomization.;18. Treatment with glatiramer acetate or any interferon beta preparations within 4 weeks prior to randomization.;19. Treatment with 4-aminopyridine within 30 days prior to randomization, unless a stable dose has been maintained for at least 30 days prior to randomization and will be continued for the course of this study.;Miscellaneous;20. Female subjects considering becoming pregnant while in the study. ;21. Female subjects of childbearing potential who have a positive pregnancy test at either the Screening Visit or Week 0.;22. Female subjects who are pregnant or currently breastfeeding. ;23. History of drug or alcohol abuse, in the opinion of the Investigator, within 2 years prior to entry.;24. 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.;25. Participation in any other investigational treatment study within the 3 months prior to screening or concurrent with this study.;26. Any pre-scheduled elective procedure during the study period that, in the opinion of the Investigator, would interfere with study parameters.;27. Any other condition, clinical finding, or reason that, in the opinion of the Investigator, is determined to be unsuitable for enrollment into this study.;28. Previous participation in this study.;Part 2: Candidates will be excluded from Part 2 Extension Phase if any of following exist at time of consent into Part 2 of study:;1. Subjects with any significant change in clinical status including laboratory tests that in opinion of Investigator would make them unsuitable to participate in extension study. Investigator must rereview the subjects's medical fitness for participation and consider any diseases that would preclude treatment.;2. Subjects sho discontinued study treatment in Part 1 OR had fewer than 20 infusions in Part 1 OR missed 2 or more consecutive infucions in Part 1;3. Considered by Investigator to be immunocompromised based on medical hsitory, physical examination, laboratory testing or any other testing required by local guidelines.;4. Part 1 exclusion ciretia no.6
5. Part 1 exclusion critearia no. 7
6. New onset of drug or alcohol abuse during Part 1 of study.
7. Part exclusion creteria no. 8
8. Signs or symptomps of PML
9. Part exclusion criteria no. 20
10. Female subjects of childbearing potential who have positive pregnancy test at either Wk 96 (serum) or Wk 108 (serum and urine)
11. Part 1 exclusion criteria no. 22
12. Part 1 exclusion criteria no. 24
13. Part 1 exclusion criteria no. 26
24. Part 1 exclusion criteria no. 27