Primary Outcome Measures:
Percentage of participants with confirmed progression of disability in one or more of the Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk (T25FW), or 9-Hole Peg Test (9HPT) [Time Frame: Up to 96 weeks ]
Confirmed disability progression is defined as one or more of the following criteria, confirmed at a second visit at least 6 months later and at Week 96:
Confirmed progression in EDSS: EDSS score increased from baseline by at least 1 point if baseline EDSS ≤5.5 or by at least 0.5 points if baseline EDSS ≥6.
Or
Confirmed progression in T25FW: T25FW increased by at least 20% of the baseline walk.
Or
Confirmed progression in 9HPT: 9HPT increased by at least 20% of the time taken at baseline. The progression in 9HPT can occur on either hand, but will have to be confirmed on the same hand.
Eligibility
- Ages Eligible for Study: 18 Years to 58 Years
- Genders Eligible for Study: Both
- Accepts Healthy Volunteers: No
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
- 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.
CoI: multiple