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 (MITOX-REBIF)

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

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.

Study Overview

• Status: Completed
• Conditions: Multiple Sclerosis
• Intervention / Treatment: Drug: Interferon beta 1a; Drug: Mitoxantrone

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 Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Rennes, France
    • CHU Rennes

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Rennes University Hospital
• Investigators: Study Director: Gilles EDAN, MD, PhD, CHU Rennes

Study record dates

Study Major Dates

• Study Start (Actual): December 6, 2010
• Primary Completion (Actual): May 28, 2020
• Study Completion (Actual): May 28, 2020

Study Registration Dates

• First Submitted: September 9, 2016
• First Submitted That Met QC Criteria: October 14, 2016
• First Posted (Estimate): October 18, 2016

Study Record Updates

• Last Update Posted (Actual): March 29, 2023
• Last Update Submitted That Met QC Criteria: March 28, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Antiviral Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Antineoplastic Agents; Immunologic Factors; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Adjuvants, Immunologic; Interferons; Interferon beta-1a; Mitoxantrone; Interferon-beta
• Other Study ID Numbers: 35RC10_8918; 2004-001601-10 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO