A Clinical Study of the Efficacy of Natalizumab on Reducing Disability Progression in Participants With Secondary Progressive Multiple Sclerosis
Condition: Secondary Progressive Multiple Sclerosis
MeSH terms: Neoplasm Metastasis; Multiple Sclerosis; Multiple Sclerosis, Chronic Progressive; Sclerosis
Intervention: natalizumab; Placebo
Intervention description: Administered as specified in the treatment arm; Matched placebo in part 1
Intervention MeSH terms: Natalizumab
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 889.0
Sex: All
Minimum age: 18 Years
Maximum age: 58 Years
Healthy volunteers: No
Keywords: Natalizumab; secondary; multiple sclerosis; MS; SPMS; Tysabri

Summary:

      This is a Phase 3b, multicenter, international study conducted in 2 parts. Upon completion of
      the placebo-controlled period (Part 1), participants will have the option of enrolling in a
      2-year open-label extension (Part 2).

      Part 1: The primary objective of the study is to investigate whether treatment with
      natalizumab slows the accumulation of disability not related to relapses in participants with
      secondary progressive multiple sclerosis (SPMS).

      The secondary objectives of Part 1 of this study are to determine the proportion of
      participants with consistent improvement in Timed 25-Foot Walk (T25FW), the change in
      participant-reported ambulatory status as measured by the 12-item MS Walking Scale (MSWS-12),
      the change in manual ability based on the ABILHAND Questionnaire, the impact of natalizumab
      on participant-reported quality of life using the Multiple Sclerosis Impact Scale-29 Physical
      (MSIS-29 Physical), the change in whole brain volume between the end of study and Week 24
      using magnetic resonance imaging (MRI) and the proportion of participants experiencing
      progression of disability as measured by individual physical Expanded Disability Status Scale
      (EDSS) system scores.

      Part 2: The primary objective of Part 2 of the study is to evaluate the safety profile of
      natalizumab in participants with SPMS.

      The secondary objectives of Part 2 of the study are to investigate long-term disability
      (based on clinical or participant-reported assessments) in participants with SPMS receiving
      natalizumab treatment for approximately 4 years and to assess change in brain volume and T2
      lesion volume.
    

Eligibility criteria:

        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 in accordance
             with national and local subject privacy regulations.

          -  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.

          -  EDSS score of 3.0 to 6.5, inclusive.

          -  Multiple Sclerosis Severity Score 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 MS as defined by
             the revised McDonald Committee criteria.

          -  Clinical relapse (within 3 months) prior to randomization.

          -  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 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.

          -  Positive test result for hepatitis C virus (test for hepatitis C virus antibody or
             hepatitis B virus (test for hepatitis B surface antigen and/or hepatitis B core
             antibody).

          -  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 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, or
             plasmapheresis for treatment of MS 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 EDSS, T25FW, and 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.