Natalizumab Temporary Discontinuation Study

Study Overview
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Brief Summary
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This study evaluates the discontinuation of natalizumab either immediately or tapered off in the treatment of multiple sclerosis. Half of the fifty (50) participants will discontinue natalizumab immediately and the other half will taper off the drug, having two additional infusions, one at six weeks- and one at eight weeks-post discontinuation.

Detailed Description
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Natalizumab is a pharmaceutical intervention used in the management of multiple sclerosis. The decision to discontinue natalizumab therapy is often raised in patients defined as high-risk for PML despite good clinical efficacy. During the therapy cessation period following large phase III trials, a return to the prestudy disease activity was reached by four months post-discontinuation. Shorter therapy was associated with a trend for a more severe disease activity pointing to a possible 'rebound' effect after natalizumab discontinuation. This study focuses on two different approaches: an immediate versus a step-wise/tapered down natalizumab discontinuation protocol, both with reinstitution of a different disease modifying therapy (DMT) within 1-6 months from the last natalizumab infusion.

Official Title
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Natalizumab Temporary Discontinuation Study

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Other: Natalizumab discontinuation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient with relapsing-remitting or relapsing-progressive (relapsing-remitting with incomplete recovery and secondary progressive with superimposed relapses) MS according to the McDonald criteria who have been on natalizumab therapy for at least 12 months Age 18-65 Have EDSS scores less than or equal to 7.0 Positive John Cunningham (JC) virus antibody results at screening Signed informed consent None of the exclusion criteria Exclusion Criteria: Patients not willing or able to personally provide informed consent (subjects with cognitive impairment that effects the ability to provide informed consent for participation) Patients with active disease per clinical and MRI evaluation at baseline Patients with renal disease that precludes having an MRI with gadolinium contrast

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Immediate Discontinuation Group<br>Patients will discontinue the natalizumab therapy at once and initiate another disease modifying therapy at 1 month following the last natalizumab infusion. The disease modifying therapy at 1 month following natalizumab discontinuation will be at the discretion of the neurologist and may differ among patients. | Other: Natalizumab discontinuation<br>* Patients will be randomized to one of two groups: The Immediate Discontinuation Group (stop natalizumab immediately and continue with new DMT 1 month afterward) and the Taper-off Group (two additional infusions of natalizumab, one at 6 weeks and the next at 8 weeks following discontinuation. A new DMT will be initiated within 2 months of final natalizumab infusion).<br>|
| Experimental: Taper-off Group<br>Patients will be administered two more natalizumab infusion, one at six weeks and the second at eight weeks (14 weeks from study entry), followed by six months natalizumab discontinuation. Another DMT will be initiated within two months after the last natalizumab infusion. | Other: Natalizumab discontinuation<br>* Patients will be randomized to one of two groups: The Immediate Discontinuation Group (stop natalizumab immediately and continue with new DMT 1 month afterward) and the Taper-off Group (two additional infusions of natalizumab, one at 6 weeks and the next at 8 weeks following discontinuation. A new DMT will be initiated within 2 months of final natalizumab infusion).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of recorded infections including viral opportunistic infection | Number of recorded infections including viral opportunistic infections (i.e., shingles) will be recorded up to 1-year follow-up; continuous close vigilance will be maintained for possible cases of progressive multifocal leukoencephalopathy (PML) | Up to 1 year follow-up | 
| Saturation percentage of α4β1integrin receptors on the surface of lymphocytes |  | 12 months | 
| Number gadolinium-enhancing lesions | Number of gadolinium-enhancing lesions | Change between baseline-6 months, 6 months-12 months, and baseline-12 months | 
| Absolute changes in gadolinium-enhancing and T2-weighted lesion volume between timepoints | Absolute changes in gadolinium-enhancing and T2-weighted lesion volume | Change between baseline-6 months, 6 months-12 months, and baseline-12 months | 
| Sum of new and enlarging T2-weighted lesions | Sum of new and enlarging lesions as seen on T2-weighted images | Change between baseline-6 months, 6 months-12 months, and baseline-12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of clinical relapses | Number of clinical relapses will be assessed at the time of natalizumab therapy discontinuation which will be different between the two groups | Either baseline (immediate discontinuation group) or 6 months (taper-off group) | 
| Expanded Disability Status Scale (EDSS) score | Expanded disability status scale score | Either baseline (immediate discontinuation group) or 6 months (taper-off group) |