A Multicenter, Randomized, Open-Label Study to Assess the Impact of Natalizumab versus Fingolimod on Central Nervous System Tissue Damage and Recovery in Active Relapsing-Remitting Multiple Sclerosis Subjects

INTERVENTION: Trade Name: Tysabri® Product Name: AN100226, BG00002 Pharmaceutical Form: Concentrate and solvent for solution for infusion INN or Proposed INN: NATALIZUMAB CAS Number: 189261‐10‐7 Concentration unit: mg/ml milligram(s)/millilitre Concentration type: equal Concentration number: 300‐ Trade Name: Gilenya Product Name: Fingolimod Pharmaceutical Form: Capsule, hard INN or Proposed INN: fingolimod CAS Number: 162359‐56‐0 Other descriptive name: FINGOLIMOD HYDROCHLORIDE Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 0.5‐ CONDITION: Multiple Sclerosis (MS) ; MedDRA version: 17.0 Level: PT Classification code 10063399 Term: Relapsing‐remitting multiple sclerosis System Organ Class: 10029205 ‐ Nervous system disorders Therapeutic area: Diseases [C] ‐ Nervous System Diseases [C10] PRIMARY OUTCOME: Main Objective: The primary objective of the study is to assess the effect of natalizumab compared to fingolimod on the evolution of; new on‐treatment T1‐gadolinium‐enhancing (Gd+) lesions to persistent black holes (PBH) over 52 weeks. Primary end point(s): The primary endpoint of the study is the cumulative number of =6‐month confirmed T1‐hypointense lesions (i.e., PBH) arising from new on‐treatment T1‐Gd+ lesions. Secondary Objective: The secondary objectives of this study are to assess the effect of natalizumab compared to fingolimod on:; • MRI measures of CNS tissue destruction as measured by the number of new T1‐Gd+ lesions.; • Various other MRI measures of disease activity.; • No Evidence of Disease Activity (NEDA); • Relapse on treatment over 52 weeks.; • The change in information processing speed as measured by the Symbol Digit Modalities Test (SDMT). Timepoint(s) of evaluation of this end point: Weeks 4, 8, 12, 16, 20, 24, 52 SECONDARY OUTCOME: Secondary end point(s): The secondary endpoints of this study are the follwoing: ; • MRI endpoints: ; o Cumulative number of new T1‐Gd+ lesions . ; o Change in total T1‐hypointense and total T2‐hyperintense lesion volumes. ; o Cumulative number of new or enlarging T2 lesions. ; • Proportion of subjects with NEDA according to the following definition: ; o No relapses. ; o No 12‐week confirmed disability progression based on EDSS.* ; o No new T1‐Gd+ lesions on brain MRI. ; o No new or enlarging T2‐hyperintense lesions. ; • Time to first relapse, cumulative risk of relapses and time to complete recovery from first relapse. ** ; • Change in information processing speed as measured by the SDMT from baseline to Week 24 and Week 52. ; ; * Increase of 1.0 or more on the EDSS from a baseline score of 1.0 or more, or an increase of 1.5 or more from a baseline score of 0 that was sustained for 12 weeks (progression could not be confirmed during a relapse). ; ** 12‐week confirmed complete Expanded Disability Status Scale (EDSS) recovery from first on‐treatment relapse is defined as an EDSS score that is equal to or lower than the last pre‐relapse EDSS score and sustained for at least 12 week Timepoint(s) of evaluation of this end point: Weeks 4, 8, 12, 16, 20, 24, 52 INCLUSION CRITERIA: Inclusion Criteria for MS Patients: ‐ Must have a documented diagnosis of relapsing MS (McDonald 2010 Criteria [Polman 2011]) at study screening. ‐ If the subject is on BRACE at study screening: • He/she must have been on therapy for at least 12 months, and ‐ Willing to take natalizumab or fingolimod as t • Experienced =1 relapse within the last 6 months prior to study screening with =1 new T1‐Gd+ lesion or =2 new T2 lesions on a brain MRI scan performed =6 months prior to study screening, with comparison made to a T2 MRI scan performed up to 18 months before study screening. ‐ If the subject is DMT naïve at study screening, he/she must have experienced =2 relapses in the 12 months prior to study screening. In addition, they must have had =1 new T1‐Gd+ lesion or =2 new T2 lesions on a brain MRI scan performed =6 months prior to study screening, with comparison made to a T2 MRI scan performed up to 18 months prior to study screening.