A Clinical Study of the Efficacy of Natalizumab on Reducing Disability Progression in Participants With Secondary Progressive Multiple Sclerosis

Key Inclusion Criteria (Part 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.

- Secondary progressive multiple sclerosis (SPMS) defined as relapsing-remitting
disease followed by progression of disability independent of or not explained by
multiple sclerosis (MS) relapses for at least 2 years.

- Expanded Disability Status Scale (EDSS) score of 3.0 to 6.5, inclusive.

- Multiple Sclerosis Severity Score (MSSS) of 4 or higher.

- Documented confirmed evidence of disease progression independent of clinical relapses
over the 1 year prior to enrollment as defined in the Study Reference Guide.

Key Exclusion Criteria (Part 1):

- Relapsing remitting multiple sclerosis (RRMS) or primary progressive multiple
sclerosis (MS) as defined by the revised McDonald Committee criteria.

- Clinical relapse (within 3 months) prior to randomization.

- Timed 25-Foot Walk (T25FW) test of >30 seconds during the screening period.

- Any value below the lower limit of normal for blood levels of leukocytes,
lymphocytes, or neutrophils.

- 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.

- Subjects for whom magnetic resonance imaging (MRI) is contraindicated (i.e., have
pacemakers or other contraindicated implanted metal devices, are allergic to
gadolinium, or have claustrophobia that cannot be medically managed).

- 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.

- 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).

- Known history of or positive test result for Human Immunodeficiency Virus (HIV).

- 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]).

- History of transplantation or any anti-rejection therapy.

- Presence of any infectious disease (e.g., cellulitis, abscess, pneumonia, septicemia)
within 30 days prior to screening.

- History of progressive multifocal leukoencephalopathy (PML) or other opportunistic
infections.

Treatment History (Part 1)

- Any prior treatment with cell-depleting therapies, including total lymphoid
irradiation, cladribine, rituximab, alemtuzumab, or bone marrow ablation.

- Any prior treatment with natalizumab.

- 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.

- Treatment with intravenous or oral corticosteroids, intravenous immunoglobulin
(IVIg), or plasmapheresis for treatment of multiple sclerosis within the 3 months
prior to randomization.

- Treatment with glatiramer acetate or any interferon beta preparations within 4 weeks
prior to randomization.

- 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.

Key Inclusion Criteria (Part 2):

- Subjects must have participated in and completed Part 1 per protocol, and have
documented assessment attempts for Expanded Disability Status Scale (EDSS), Timed
25-Foot Walk (T25FW), and 9-Hole Peg Test (9HPT) prior to first open-label dosing.

Key Exclusion Criteria (Part 2):

- Subjects with any significant change in clinical status, including laboratory tests
that, in the opinion of the Investigator, would make them unsuitable to participate
in this extension study. The Investigator must re-review the subject's medical
fitness for participation and consider any diseases that would preclude treatment.

- Subjects who discontinued study treatment in Part 1 OR had fewer than 20 infusions in
Part 1 OR missed 2 or more consecutive infusions in Part 1.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.