Impact of Natalizumab Versus Fingolimod in Relapsing-Remitting Multiple Sclerosis (RRMS) Participants

Study Overview
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Brief Summary
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The primary objective of this 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. The secondary objectives of this study in this study population are to assess the effect of natalizumab compared to fingolimod on: magnetic resonance imaging (MRI) measures of central nervous system (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).

Detailed Description
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This study also includes a Diffusion Tensor Imaging (DTI) sub-study that includes healthy volunteers. Healthy volunteers will not receive any study medication.

Official Title
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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

Conditions
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Relapsing-Remitting Multiple Sclerosis

Intervention / Treatment
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* Drug: natalizumab
* Drug: fingolimod


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria for MS Patients: Must have a documented diagnosis of relapsing MS (McDonald 2010 Criteria) at study screening with EDSS score from 0.0 to 5.5. If the subject is on Betaseron, Rebif, Avonex, Copaxone, Extavia, Tecfidera, and Aubagio (BRACE-TA) at study screening: He/she must have been on therapy for at least 6 months (unless experiencing highly active disease), have at least 9 T2-hyperintense lesions on a brain MRI scan, and have experienced ≥1 relapse within the last 6 months prior to study screening with ≥1 new T1-Gd+ lesion on a brain MRI scan performed ≤6 months prior to study screening 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 has highly active disease, regardless of whether they are disease-modifying therapy (DMT)-naïve or had previous exposure to Betaseron, Rebif, Avonex, Copaxone, Extavia, Tecfidera, and Aubagio (BRACE-TA), they must have had ≥2 disabling relapses in the 12 months prior to study screening and either ≥1 new T1-Gd+ lesion on a brain MRI scan performed ≤6 months prior to study screening 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 Key Exclusion Criteria for MS Patients: Diagnosis of Primary Progressive Multiple Sclerosis and/or Secondary Progressive Multiple Sclerosis. History or positive test result at study screening for human immunodeficiency virus (HIV), hepatitis C virus (HCV) antibody or current hepatitis B infection (defined as positive for hepatitis B surface antigen [HBsAg] and/or hepatitis B core antibody [HBcAb]). Prior treatment with natalizumab or fingolimod. History of or known active malignant disease, including solid tumors and hematologic malignancies (subjects with cutaneous basal and squamous cell carcinoma that has been completely excised and considered cured prior to study screening remain eligible). History of opportunistic infections or any clinically significant major disease, as determined by the Investigator. A clinically significant infectious illness (e.g., pneumonia, septicemia) within the 1 month prior to study screening. History of drug or alcohol abuse (as defined by the Investigator) within 1 year prior to study screening. Prior history of immunosuppressant use (e.g., mitoxantrone, azathioprine, methotrexate, cyclophosphamide, mycophenolate, cladribine, rituximab), or exposure to intravenous immunoglobulin (IGIV), monoclonal antibodies, cytokines, growth factors, soluble receptors, other recombinant products, or fusion proteins in the last 12 months prior to study screening. History of myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure in last 6 months. Treatment with Class Ia (e.g., procainamide, quinidine, ajmaline, disopyramide) or Class III (amiodarone, bretylium, dofelitide, sotalol, ibulitide, azilimide) anti-arrhythmic drugs. Concurrent therapy with drugs that slow heart rate (e.g., beta-blockers, heart-rate lowering calcium channel blockers such as diltiazem or verapamil, or digoxin). Hypertension not controlled with prescribed medications. History of severe respiratory disease, pulmonary fibrosis or class III or IV chronic obstructive pulmonary disease. The use of live or live attenuated vaccination within 8 weeks of study screening. Key Inclusion Criteria for Healthy Volunteers: Subjects who are generally healthy as demonstrated by physical examination and by medical history, with no history or evidence of major illnesses, diseases, or disorders. Subjects of childbearing potential must practice effective contraception and be willing and able to continue contraception for duration of the study. No history of drug or alcohol abuse (as defined by the Investigator) within 1 year prior to study screening. Key Exclusion Criteria for Healthy Volunteers: Claustrophobia sufficient to interfere with generating reliable MRI scans. History of other major illness including neurological disorders as determined by the Investigator. Presence of a metal device affected by MRI (e.g., any type of electronic, mechanical or magnetic implant, cardiac pacemaker, aneurysm clips, implanted cardiac defibrillator) or potential ferromagnetic foreign body (metal slivers, metal shavings, other metal objects), which would be a contraindication for MRI. Women who are currently pregnant or breastfeeding, or who have a positive pregnancy test result at screening. NOTE: Other protocol defined Inclusion/Exclusion 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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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: natalizumab<br>Open-label natalizumab 300 mg IV every 4 weeks (Q4W) | Drug: natalizumab<br>* Administered as specified in the treatment arm<br>* Other names: Tysabri;|
| Active Comparator: fingolimod<br>Open-label fingolimod 0.5 mg once daily orally | Drug: fingolimod<br>* Administered as specified in the treatment arm<br>* Other names: Gilenya;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Number of ≥ 6-Month Confirmed T1-Hypointense Lesions Arising From New On-Treatment T1-Gadolinium-Enhancing (Gd+) Lesions |  | Up to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Number of New T1-Gd+ Lesions |  | Baseline, Week 4, Week 12, Week 24 | 
| Change From Baseline in Total T1-Hypointense and Total T2-Hyperintense Lesion Volumes at Week 24 | As assessed by magnetic resonance imaging (MRI). | Baseline, Week 24 | 
| Change From Baseline in Total T1-Hypointense and Total T2-Hyperintense Lesion Volumes at Week 52 | As assessed by MRI. | Baseline, Week 52 | 
| Cumulative Number of New or Enlarging T2 Lesions |  | Baseline, Week 24 | 
| Proportion of Participants With No Evidence of Disease Activity (NEDA) | NEDA was defined as all of the following: no relapses; no 12-week confirmed disability progression based on Expanded Disability Status Scale (EDSS; defined as an increase of 1.0 or more on the EDSS from baseline 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; no new T1-Gd+ lesions on brain MRI. No new or enlarging T2-hyperintense lesions. | Up to Week 52 | 
| Time to First Relapse | A clinical relapse was defined as new or recurrent neurological symptoms, not associated with fever, lasting for at least 24 hours, and followed by a period of 30 days of stability or improvement. | Up to Week 52 | 
| Cumulative Risk of Relapse | A clinical relapse was defined as new or recurrent neurological symptoms, not associated with fever, lasting for at least 24 hours, and followed by a period of 30 days of stability or improvement. | Up to Week 52 | 
| Time to Complete Recovery From First Relapse | 12-week confirmed complete 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 weeks. | Up to Week 52 | 
| Change From Baseline in Symbol Digit Modalities Test (SDMT) at Week 24 | The SDMT measures the time to pair abstract symbols with specific numbers. The test requires elements of attention, visuoperceptual processing, working memory, and psychomotor speed. The score is the number of correctly coded items from 0-110 in 90 seconds. The total score provides a measure of the speed and accuracy of symbol-digit substitution. | Baseline, Week 24 | 
| Change From Baseline in SDMT at Week 52 | The SDMT measures the time to pair abstract symbols with specific numbers. The test requires elements of attention, visuoperceptual processing, working memory, and psychomotor speed. The score is the number of correctly coded items from 0-110 in 90 seconds. The total score provides a measure of the speed and accuracy of symbol-digit substitution. | Baseline, Week 52 |