National Multicenter, Controlled, Single-blind Study With Two Parallel Groups Evaluating the Safety and Efficacy of Sequential Treatment With Mitoxantrone and Interferon Versus Interferon Alone in Patients With Strong Risk of Progression in the Initial Phase of Multiple Sclerosis

Study Overview
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Brief Summary
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The relative effectiveness of current treatments and their different mechanisms of action yield to consider more and more that the multiple sclerosis (MS) therapeutic approach must use multiple molecules, both combined and sequential. In this sense, one can assume that the combination of two molecules with different but complementary mechanisms of action, can delay progression of the disease. Mitoxantrone has a powerful action, immediate and total, whereas interferon a selective action, immunomodulatory and delayed.

Detailed Description
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This study is based on the hypothesis that there is a synergistic effect of both increasing the dose of interferon and also the use of mitoxantrone, allowing to further reduce the conversion rate MS. Because mitoxantrone decreases the rate of relapses 2 times more than interferon beta, a (at least) 2 times higher benefit on the disease activity is expected with interferon mitoxantrone combination than with interferon alone.

Official Title
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National Multicenter, Controlled, Single-blind Study With Two Parallel Groups Evaluating the Safety and Efficacy of Sequential Treatment With Mitoxantrone and Interferon Beta-1a (REBIF 44mg 3 Times / Week) Versus Interferon Alone in Patients With Strong Risk of Progression in the Initial Phase of Multiple Sclerosis

Conditions
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Multiple Sclerosis

Intervention / Treatment
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* Drug: Interferon beta 1a
* Drug: Mitoxantrone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients should have a MS according to the McDonald criteria: One relapse with time dissemination shown by an MRI performed less than 2 months before inclusion, with at least one of these criteria: multifocal presentation relapse determining a severe disability (EDSS greater than 3.5) at least 2 lesions taking contrast on MRI at least 9 T2 lesions with contrast enhancement. Patients must be 18 to 50 years. The duration of disease progression should be less than one year. Women of childbearing age must have an effective contraception. Patients have to be able to give their own informed consent before inclusion in the study. Exclusion Criteria: presence of another disease that could explain the symptoms / signs of the patient. Any other condition / disability that may interfere with the clinical state. Prior treatment with immunosuppressive (mitoxantrone, azathioprine, cyclophosphamide) or immunomodulator. Treatment with corticosteroids in the previous 2 weeks, regardless of the dose. Corticosteroids for over a month. Pregnancy and lactation. Patient whose antecedents may contra-indicate the use of immunosuppressive therapy. Hypersensitivity to mitoxantrone or one of the excipients. Clinical cardiac disease with reduced ejection fraction of the left ventricle. Patient suffering from myelodysplasia. Abnormalities of Complete Blood Count. History of hematologic malignancy. Hepatic impairment. Vaccination against yellow fever. Vaccination with an attenuated vaccine assets. Treatment with phenytoin or fosphenytoin. Hypersensitivity to interferon beta-1a natural or recombinant or any of the excipients. Current severe depression and / or suicidal thoughts. Uncontrolled epilepsy. History of addiction. A history of hypersensitivity to gadolinium, history of severe renal impairment Inability to undergo MRI (claustrophobia, tics, involuntary movements, tremor, etc.). Participation in another trial in the preceding 6 months or during the study. Minors, protected adults and persons deprived of their liberty.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard care<br>Interferon alone | Drug: Interferon beta 1a<br>* Subcutaneous injection of 44µg 3 times a week<br>* Other names: REBIF;|
| Experimental: Experimental group<br>Mitoxantrone for 6 month followed by interferon | Drug: Interferon beta 1a<br>* Subcutaneous injection of 44µg 3 times a week<br>* Other names: REBIF;Drug: Mitoxantrone<br>* 10 mg / m² monthly infusion for 6 months<br>* Other names: ELSEP;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment efficacy | Efficacy is judged based on the absence of relapse within the 2 first years; AND a disease progression as determined by an increase in the Expanded Disability Status Scale (EDSS) not greater than 1 during the 4 years treatment. | Four years after inclusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to first relapse |  | From date of randomization until the date of first documented progression, assessed up to 4 years | 
| Frequency of relapses in 2 years |  | Within two years following randomization | 
| Frequency of relapses in 4 years |  | Within four years following randomization | 
| Changes in the level of disability in 2 years | EDSS score | Two years following randomization | 
| Changes in the level of disability in 4 years | EDSS score | Four years following randomization | 
| Patients in progression | Rate of patients who progressed to a clinically definite MS (according to the criteria of Mc Donald) in the subgroup of patients who had only one clinical event. | Four years following randomization | 
| Disease activity on MRI at 6 months | To compare in the two arms, the rate of patients without radiological (MRI) sign of disease activity | 6 months following randomization | 
| Patients without disease activity on MRI at 12 months | To compare in the two arms, the rate of patients without radiological (MRI) sign of disease activity | 12 months following randomization | 
| Patients without disease activity on MRI at 24 months | To compare in the two arms, the rate of patients without radiological (MRI) sign of disease activity | 24 months following randomization | 
| Patients without disease activity on MRI at 48 months | To compare in the two arms, the rate of patients without radiological (MRI) sign of disease activity | 48 months following randomization | 
| Number of visible lesions on MRI at 6 months | To compare in the two arms, the number of lesions taking contrast | 6 months following randomization | 
| Number of visible lesions on MRI at 12 months | To compare in the two arms, the number of lesions taking contrast | 12 months following randomization | 
| Number of visible lesions on MRI at 24 months | To compare in the two arms, the number of lesions taking contrast | 24 months following randomization | 
| Number of visible lesions on MRI at 48 months | To compare in the two arms, the number of lesions taking contrast | 48 months following randomization | 
| Lesion load on evaluated T2 weighted MRI at 12 months |  | 12 months following randomization | 
| Lesion load on evaluated T2 weighted MRI at 24 months |  | 24 months following randomization | 
| Lesion load on evaluated T2 weighted MRI at 48 months |  | 48 months following randomization | 
| Brain atrophy | To assess the presence and progression of brain atrophy, changes in the total brain volume after 24 and 48 months will be automatically measured from MR images with dedicated software and expressed as percent change, from a standardized estimation of cerebral volume. | 24 and 48 months following randomization |