MITOX-REBIF: 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

Sponsor

Rennes University Hospital (Other)

Overall Status

Unknown status

CT.gov ID

NCT02937285

Collaborator

(none)

266

Enrollment

Location

Arms

120

Duration (Months)

2.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Multiple Sclerosis	Drug: Interferon beta 1a Drug: Mitoxantrone	Phase 3

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

266 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

Nov 1, 2010

Anticipated Primary Completion Date :

Nov 1, 2020

Anticipated Study Completion Date :

Nov 1, 2020

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Standard care Interferon alone	Drug: Interferon beta 1a Subcutaneous injection of 44µg 3 times a week Other Names: REBIF
Experimental: Experimental group Mitoxantrone for 6 month followed by interferon	Drug: Interferon beta 1a Subcutaneous injection of 44µg 3 times a week Other Names: REBIF Drug: Mitoxantrone 10 mg / m² monthly infusion for 6 months Other Names: ELSEP

Arm

Intervention/Treatment

Active Comparator: Standard care

Interferon alone

Drug: Interferon beta 1a

Subcutaneous injection of 44µg 3 times a week

Other Names:

REBIF

Experimental: Experimental group

Mitoxantrone for 6 month followed by interferon

Drug: Interferon beta 1a

Subcutaneous injection of 44µg 3 times a week

Other Names:

REBIF

Drug: Mitoxantrone

10 mg / m² monthly infusion for 6 months

Other Names:

ELSEP

Outcome Measures

Primary Outcome Measures

Treatment efficacy [Four years after inclusion]
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.

Secondary Outcome Measures

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 [Two years following randomization]
EDSS score
Changes in the level of disability in 4 years [Four years following randomization]
EDSS score
Patients in progression [Four years following randomization]
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.
Disease activity on MRI at 6 months [6 months following randomization]
To compare in the two arms, the rate of patients without radiological (MRI) sign of disease activity
Patients without disease activity on MRI at 12 months [12 months following randomization]
To compare in the two arms, the rate of patients without radiological (MRI) sign of disease activity
Patients without disease activity on MRI at 24 months [24 months following randomization]
To compare in the two arms, the rate of patients without radiological (MRI) sign of disease activity
Patients without disease activity on MRI at 48 months [48 months following randomization]
To compare in the two arms, the rate of patients without radiological (MRI) sign of disease activity
Number of visible lesions on MRI at 6 months [6 months following randomization]
To compare in the two arms, the number of lesions taking contrast
Number of visible lesions on MRI at 12 months [12 months following randomization]
To compare in the two arms, the number of lesions taking contrast
Number of visible lesions on MRI at 24 months [24 months following randomization]
To compare in the two arms, the number of lesions taking contrast
Number of visible lesions on MRI at 48 months [48 months following randomization]
To compare in the two arms, the number of lesions taking contrast
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 [24 and 48 months following randomization]
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.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 50 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.