Methylprednisolone During the Switch Between Natalizumab and Fingolimod

Study Overview
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Brief Summary
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Progressive multifocal leukoencephalopathy (PML) is the most feared complication when natalizumab (NTZ) is used in the treatment of relapsing multiple sclerosis (MS). The risk of PML increases after 18 months of treatment. When switching from NTZ to another disease modifying treatment (DMT) in these MS patients with an active disease, there is a high risk of inflammatory reactivation. Nonetheless, a washout period of several weeks is necessary before initiating a new DMT. The primary purpose of this protocol is to investigate the impact of high dose of oral methylprednisolone, given once a month during the washout period between NTZ and Fingolimod (FTY).

Detailed Description
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Patients with MS receiving NTZ for at least 18 months and without any disease activity during the previous year will be eligible. Included patients will receive either methylprednisolone (1 gramme, 1 day every 4 weeks for a total of 3 grammes) or undistinguishable capsules of placebo. Every patient will initiate a treatment with FTY 7 weeks after the last NTZ perfusion. Methylprednisolone or placebo will be taken 4, 8 and 12 weeks (W4, W8 and W12) after NTZ discontinuation. A spinal and brain MRI will be performed at baseline (last NTZ perfusion, noted W0) and 16 to 18 weeks after. The last clinical follow-up will be made after 24 weeks.

Official Title
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Once a Month High-dose Methylprednisolone During Wash-out Period Between Natalizumab and Fingolimod Treatments in Patients With Multiple Sclerosis: a Randomised, Controlled, Double-blind Trial (NTZ2FTY)

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: Methylprednisolone
* Drug: Placebo
* Drug: natalizumab (NTZ)
* Drug: fingolimob (FTY)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Relapsing-Remitting Multiple Sclerosis (Mc Donald's 2010 criteria) EDSS<6.0 At least18 natalizumab infusions Planned switch from natalizumab to fingolimod Aged between 18 and 65 Patients must have received high dose IV methylprednisolone during the 5 previous years Exclusion Criteria: Progressive MS Uncontrolled MS with natalizumab (existence of a relapse during the previous 12 months or existence of a gadolinium enhancing lesion on a MRI performed during the last 12 months) SEP de forme progressive Contra-indication to the use of high dose oral methylprednisolone Marked cognitive impairment altering protocole understanding Switch from natalizumab to a disease modifying treatment different from fingolimod Contra-indication to fingolimod use Existence of a disease or condition that could alter study completion Chronic treatment with steroids Acute treatment with steroids (more than 300mg during the month prior to inclusion) Contra-indication to gadolinium containing products injection Pregnancy

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Methylprednisolone<br>The primary purpose of this protocol is to investigate the impact of high dose of oral methylprednisolone, given once a month during the washout period between NTZ and Fingolimod (FTY). | Drug: Methylprednisolone<br>* Included patients will receive either methylprednisolone (1 gramme, 1 day every 4 weeks for a total of 3 grammes) or undistinguishable capsules of placebo<br>Drug: natalizumab (NTZ)<br>* Patients with MS receiving NTZ for at least 18 months and without any disease activity during the previous year will be eligible. Included patients will receive either methylprednisolone (1 gramme, 1 day every 4 weeks for a total of 3 grammes) or undistinguishable capsules of placebo<br>Drug: fingolimob (FTY)<br>* Every patient will initiate a treatment with FTY 7 weeks after the last NTZ perfusion. Methylprednisolone or placebo will be taken 4, 8 and 12 weeks (W4, W8 and W12) after NTZ discontinuation.<br>|
| Placebo Comparator: Placebo<br>Included patients will receive either methylprednisolone (1 gramme, 1 day every 4 weeks for a total of 3 grammes) or undistinguishable capsules of placebo | Drug: Placebo<br>* Included patients will receive either methylprednisolone (1 gramme, 1 day every 4 weeks for a total of 3 grammes) or undistinguishable capsules of placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| efficacy of high dose methylprednisolone compared to that of a placebo | To evaluate the efficacy of high dose methylprednisolone given once a month during the washout period for the switch between natalizumab and fingolimod, compared to that of a placebo, on multiple sclerosis inflammatory rebound evaluated using MRI, 16 to 18 weeks after natalizumab discontinuation and clinically at 6 months | at 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| comparison of the number of new T2 or gadolinium enhanced lesions on MRI in the 2 treatment groups |  | at 4 months | 
| comparison of the number of MS relapses during the 6 months after natalizumab discontinuation, in the 2 treatment groups |  | at 6 months | 
| potential correlations between previous MS activity and the risk of relapse or inflammatory rebound on MRI after natalizumab discontinuation | To study the potential correlations between previous MS activity (annualised relapse rate during the year before natalizumab initiation) and the risk of relapse or inflammatory rebound on MRI after natalizumab discontinuation, in the whole group | at 6 months | 
| adverse effects of high dose oral prednisolone |  | at 6 months | 
| use of methylprednisolone once every 4 weeks during the switch between natalizumab and fingolimod in patients with MS | To perform a cost utility analysis in order to evaluate the use of methylprednisolone once every 4 weeks during the switch between natalizumab and fingolimod in patients with MS | at 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple sclerosis, Natalizumab, Fingolimod, Methylprednisolone