Part 2: The primary objective of Part 2 of the study is to evaluate the safety profileof natalizumab in subjects with SPMS.
•the proportion of subjects with consistent improvement in Timed 25-foot Walk (T25FW) •the change in subject-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 subject-reported quality of life using the Multiple Sclerosis Impact Scale-29 Physical (MSIS-29 Physical)
•the change in whole brain brain volume between the end of study and Week 24 using MRI• the proportion of subjects experiencing progression of disability as measured by individual physical Expanded Disability Status Scale (EDSS) system scores
The secondary objectives of Part 2 of this study are as follows:
•to investigate long term disability (based on clinical or patient - reported assessment) in subjects with SPMS receiving natalizumab treatment for approximately 4 years.• to assess change in brain volume and T2 lesion volume
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
Part 2: To be eligible to participate in Part 2 Extension Phase of study, candidates must meet the following 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 authorisation to use PHI in accordance with national and local subject privacy regulation.
2. Subjects must have participated in and completed Part 1, have documented Wk 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 able to conticue contraception for 3 months after their last infusion.
Part1: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 PPMS as defined by the revised McDonald Committee criteria. 2.Had a recent clinical relapse (within 3 mos) prior to randomization. 3.Have a T25FW test of >30 secs 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 Inv.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(ie 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 Inv.)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 HIV. 10.Positive test result for HCV or HBV (test for hepatitis B surface antigen and/or hepatitis B core antibody). 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. 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 mos prior to randomization.17.Treatment with IV or oral corticosteroids, IvIg, or plasmapheresis for treatment of MS within the 3 mos prior to randomization. 18.Treatment with glatiramer acetate or any interferon beta preparations within 4 wks 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. 20.Female subjects considering becoming pregnant while in the study. 21.Female sub. of childbearing potential who have a positive pregnancy test at either the Screen, Visit or Wk 0. 22.Female sub. 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 prot., including the presence of any condition (physical, mental,or social) that is likely to affect the subject's ability to comply with the study prot. 25.Participation in any other investigational treatment study within the 3 mos prior to screening or concurrent with this study. 26.Any pre-scheduled elective procedure during the study period that, in the opinion of the Inv.,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 Ext. Ph. if any of following exist at time of consent into Part 2 of study
1.Subjects with any significant change in clinical status including lab tests that in opinion of Inv. would make them unsuitable to participate in extension study. Inv. must review the subject's medical fitness for participation and consider any diseases that would preclude treatment. 2.Subjects who discontinued study treatment in Part 1 OR have fewer than 20 infusions in Part 1 OR missed 2 more consecutive infusions in Part 1. 3.Considered by Inv. to be immunocompromised based on medical history, physical examination, laboratory testing or any other testing required by local guidelines. 4.Part1 exclusion criteria no 6 5.Part 1 excl. criteria no 7. 6.New onset of drug or alcohol abuse during Part 1 of study. 7.Part 1 excl. criteria no 8. 8.Signs or symptoms of PML. 9.Part 1 excl. criteria no 20. 10.Female subjscts of childbearing potential who have positive pregnancy test at either Wk 96 (serum) or Wk 108 (serum & urine). 11.Part 1 excl.criteria no 22. 12.Part 1 excl.criteria no 24. 13.Part 1 excl.criteria no 26. 14.Part1 excl.criteria no 27
confirmed at a second visit at least 6 months later and at Week 96 (or at the last available study visit for subjects who withdraw from the study early).
20% of the baseline walk, confirmed at a second visit at least 6 months later and at Week 96 (or at the last available study visit for subjects who withdraw from the study early).
of the time taken at baseline, confirmed at a second visit at least 6 months later and at Week 96 (or at the last available study visit for subjects who withdraw from the study early).
Part 2: The primary endpoints in Part 2 of the study is the incidence of AEs and SAEs
• Percentage of subjects with disability worsening at each scheduled efficacy visit in Part 2, defined as one ore more of the following:
≥ 20% worsening from Part 1 baseline in T25FW,
≥ 20% worsening from Part 1 baseline in 9HTPT, or
worsening from Part 1 baseline in EDSS ( ≥ point increase if Part 1 baseline EDSS ≤ 5.5 or ≥0.5 point increase if Part 1 baseline EDSS > 5.5)
• Absolute and percentage change in T25FW, 9HPT, and EDSS from Part 1 baseline to each scheduled efficacy visit in Part 2, in all subjects and in subjects with and without disabilityworsening and defined above.
• Absolute and percentage change in the 6MWT, MSIS-29 Physical, and SDMT, from Part 1 baseline to each scheduled efficacy visit in Part 2.
• Absolute and percentage change in the WPAI-MS Questionnaire over the Extension Phase, from Part 2 baseline to each scheduled efficacy visit in Part 2.
• Percentage change in whole brain volume from Part 1 baseline to each scheduled efficacy visit in Part 2.
• Percentage change in gray matter brain volume from Part 1 baseline to each scheduled efficacy visit in Part 2.
• Absolute and percentage change in number of new/enlarging T2 leasions from Part 1 baseline to each scheduled efficacy visit in Part 2.
• % subjects experiencing confirmed worsening in the individual EDSS Physical Functional System Scores where confirmed is defined as 2 examinations at least 6 months apart (6months intervals)
Part 2: T25FW, 9HPT, EDSS, 6MWT, MSIS-29 Physical, WPAI-MS, and brain MRI assessment will be taken annually (every 48 weeks) and SDMT will be taken every 4 weeks
Subjects who are not enrolling into Part 2 of the study are to return to the study site for a follow-up visit 12 weeks after the last dose of study treatment (Week 108). Subjects who enroll in Part 2 are to return to the study site for a follow-up visit 12 weeks after the last dose of study treatment (Week 216, or later, if commercial product not yest available).