A Prospective, Open-label, Non-randomized, Clinical Trial to Determine if Natalizumab (Tysabri®) Improves Ambulatory Measures in Relapsing-remitting Multiple Sclerosis (RRMS) Patients

Study Overview
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Brief Summary
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The primary objective of the study is to evaluate the evolution of walking capacity as measured by the timed 100-meter walk test (T100T), timed 25-foot walk test (T25FW), maximum walking distance (MWD), and Expanded Disability Status Scale (EDSS) during the first year of therapy with natalizumab. The secondary objectives of this study are as follows: To evaluate the correlation between the MWD and EDSS and both walking tests, the T100T and the T25FW at Baseline, at Week 24 and at Week 48 of therapy. To determine how well each of the walking tests, T100T or T25FW, predicts walking limitations in all participants and in the subgroups of participants stratified by baseline EDSS.

Official Title
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A Prospective, Open-label, Non-randomized, Clinical Trial to Determine if Natalizumab (Tysabri®) Improves Ambulatory Measures in Relapsing-remitting Multiple Sclerosis (RRMS) Patients TIMER Study

Conditions
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Relapsing Remitting Multiple Sclerosis (RRMS)

Intervention / Treatment
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* Drug: BG00002 (natalizumab)


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Must give written informed consent and provide all authorizations required by local law (for example, Protected Health Information [PHI]) Men or women between 18 and 60 years of age, inclusive Must have Expanded Disability Status Scale (EDSS) less than or equal to 5.5 at baseline Must be able to walk at least 100 m without assistive devices Must be natalizumab-naïve Must have a documented diagnosis of a relapsing remitting form of multiple sclerosis (MS0 as defined by the revised McDonald Committee criteria (Polman et al., 2005) Must have had a recent (within 3 months from baseline) magnetic resonance imaging (MRI) Must have had at least 1 relapse in the previous year and must satisfy the locally approved therapeutic indications for Tysabri. If Tysabri is not yet approved in a specific country, patients must fulfill the following criteria: Patients with high disease activity despite treatment with a beta-interferon defined as patients who have failed to respond to a full and adequate course of a beta-interferon Patients must have had at least 1 relapse in the previous year while on therapy, and have at least 9 T2 hyperintense lesions in cranial MRI or at least 1 gadolinium (Gd)-enhancing lesion Patients with rapidly evolving severe relapsing remitting multiple sclerosis defined as patients who have had 2 or more disabling relapses in one year and 1 or more Gd-enhancing lesions on brain MRI or significant increase in T2 lesions as compared to a previous MRI Must be stable in disability for at least 30 days prior to enrollment to the study Must be stable in symptomatic management of the disease, specifically spasticity, depression and fatigue for at least 30 days prior to enrollment to the study Must be considered by the Investigator to be free of signs and symptoms suggestive of progressive multifocal leukoencephalopathy (PML) based on medical history, physical examination, or laboratory testing Must be willing to discontinue and remain free from concomitant immunosuppressive or immunomodulatory treatment (including interferon [IFN] and glatiramer acetate [GA]) while being treated with natalizumab during the study. Key Exclusion Criteria: Unless otherwise specified, candidates will be excluded from study entry if any of the following exclusion criteria exist at the time of the Screening Visit: Onset of a relapse within 50 days prior to first infusion Considered by the Investigator to be immunocompromised, based on medical history, physical examination, or laboratory testing or due to prior immunosuppressive treatment History of, or available abnormal laboratory results indicative of, any significant cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, gastrointestinal, dermatologic, psychiatric (including major depression), renal, and/or other major disease that would preclude the administration of a recombinant humanized antibody immunomodulating agent. The Investigator must re-review the subject's medical fitness for participation and consider any diseases that would preclude treatment History of malignancy (subjects with basal cell carcinoma that has been completely excised prior to study entry remain eligible) Known history of human immunodeficiency virus infection or hematological malignancy History of organ transplantation (including anti-rejection therapy) A clinically significant infectious illness (cellulitis, abscess, pneumonia, septicemia) within 30 days prior to the Screening Visit Treatment with immunosuppressant medications (mitoxantrone, cyclophosphamide, cyclosporine, azathioprine, methotrexate) within 6 months prior to Screening Female subjects who are not postmenopausal for at least 1 year, surgically sterile (does not include tubal ligation), or willing to practice effective contraception (as defined by the Investigator) during the study Women who are breastfeeding, pregnant, or planning to become pregnant while on study Current enrollment in any other study treatment or disease study 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 Subjects with walking impairment due to causes other than MS Other unspecified reasons that, in the opinion of the Investigator and/or Biogen Idec, make the subject unsuitable for enrollment into this study NOTE: Other eligibility criteria may apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Natalizumab<br>natalizumab 300 mg IV every 4 weeks for 48 weeks | Drug: BG00002 (natalizumab)<br> <br> * Other names: Tysabri®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Timed 100-meter Walk Test (T100T) | In the T100T, the participant is instructed to walk as fast as possible for a distance of 100 meters. | Baseline, Week 24, Week 48 | 
| Change From Baseline in the Timed 25-foot Walk Test (T25FW) | In the T25FW, the participant is instructed to walk as fast as possible for a distance of 25 feet. | Baseline, Week 24, Week 48 | 
| Change From Baseline in Maximum Walking Distance (MWD) |  | Baseline, Week 24, Week 48 | 
| Change From Baseline in Expanded Disability Status Scale (EDSS) | EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated. | Baseline, Week 24, Week 48 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlation Between the EDSS and MWD (Pearson Correlation Coefficient) | Pearson correlation coefficient is a measure of the linear correlation (dependence) between 2 variables, giving a value between +1 and -1 inclusive, where 1 is total positive correlation, 0 is no correlation, and -1 is total negative correlation. | Baseline, Week 24, Week 48 | 
| Correlation Between the EDSS and MWD (Spearman Correlation Coefficient) | Spearman correlation coefficient is a non-parametric measure of the correlation (dependence) between 2 variables, giving a value between +1 and -1 inclusive, where 1 is total positive correlation, 0 is no correlation, and -1 is total negative correlation. | Baseline, Week 24, Week 48 | 
| Correlation Between the T100T and T25FW (Pearson Correlation Coefficient) | Pearson correlation coefficient is a measure of the linear correlation (dependence) between 2 variables, giving a value between +1 and -1 inclusive, where 1 is total positive correlation, 0 is no correlation, and -1 is total negative correlation. | Baseline, Week 24, Week 48 | 
| Correlation Between the T100T and T25FW (Spearman Correlation Coefficient) | Spearman correlation coefficient is a non-parametric measure of the correlation (dependence) between 2 variables, giving a value between +1 and -1 inclusive, where 1 is total positive correlation, 0 is no correlation, and -1 is total negative correlation. | Baseline, Week 24, Week 48 | 
| Correlation Between the EDSS and T25FW (Pearson Correlation Coefficient) | Pearson correlation coefficient is a measure of the linear correlation (dependence) between 2 variables, giving a value between +1 and -1 inclusive, where 1 is total positive correlation, 0 is no correlation, and -1 is total negative correlation. | Baseline, Week 24, Week 48 | 
| Correlation Between the EDSS and T25FW (Spearman Correlation Coefficient) | Spearman correlation coefficient is a non-parametric measure of the correlation (dependence) between 2 variables, giving a value between +1 and -1 inclusive, where 1 is total positive correlation, 0 is no correlation, and -1 is total negative correlation. | Baseline, Week 24, Week 48 | 
| Correlation Between the EDSS and T100T (Pearson Correlation Coefficient) | Pearson correlation coefficient is a measure of the linear correlation (dependence) between 2 variables, giving a value between +1 and -1 inclusive, where 1 is total positive correlation, 0 is no correlation, and -1 is total negative correlation. | Baseline, Week 24, Week 48 | 
| Correlation Between the EDSS and T100T (Spearman Correlation Coefficient) | Spearman correlation coefficient is a non-parametric measure of the correlation (dependence) between 2 variables, giving a value between +1 and -1 inclusive, where 1 is total positive correlation, 0 is no correlation, and -1 is total negative correlation. | Baseline, Week 24, Week 48 | 
| Improvement in Timed 25FT Walk Speed and T100T Speed at Week 24 and 48 | To determine how well each of the walking tests, T100T or T25FW, predicts walking limitations, participants were stratified by baseline EDSS scores, and walking tests at Weeks 24 and 48 were analyzed. A 15% or 20% improvement indicates that, when compared with baseline walking speed (meters per second), there is at least 15% or 20% improvement at the corresponding timepoint, e.g. (speed at Week 24 - speed at baseline)/speed at baseline*100% ≥ 15% or 20%. Confirmed (conf) improvement at Week 48 indicates that the participant has at least 15% (or 20%) improvement in walking speed at both Week 24 and Week 48. | Baseline, Week 24, Week 48 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TYSABRI naive, Relapsing-remitting multiple sclerosis (RRMS)