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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 Versus Interferon Alone in Patients With Strong Risk of Progression in the Initial Phase of Multiple Sclerosis (MITOX-REBIF)

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ClinicalTrials.gov Identifier: NCT02937285
Recruitment Status : Active, not recruiting
First Posted : October 18, 2016
Last Update Posted : October 24, 2017
Sponsor:
Information provided by (Responsible Party):
Rennes University Hospital

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.


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Study Type : Interventional  (Clinical Trial)
Estimated 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 : November 2010
Estimated Primary Completion Date : November 2020
Estimated Study Completion Date : November 2020


Arm Intervention/treatment
Active Comparator: Standard care
Interferon alone
Drug: Interferon beta 1a
Subcutaneous injection of 44µg 3 times a week
Other Name: REBIF

Experimental: Experimental group
Mitoxantrone for 6 month followed by interferon
Drug: Interferon beta 1a
Subcutaneous injection of 44µg 3 times a week
Other Name: REBIF

Drug: Mitoxantrone
10 mg / m² monthly infusion for 6 months
Other Name: ELSEP




Primary Outcome Measures :
  1. Treatment efficacy [ Time Frame: 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 :
  1. Time to first relapse [ Time Frame: From date of randomization until the date of first documented progression, assessed up to 4 years ]
  2. Frequency of relapses in 2 years [ Time Frame: Within two years following randomization ]
  3. Frequency of relapses in 4 years [ Time Frame: Within four years following randomization ]
  4. Changes in the level of disability in 2 years [ Time Frame: Two years following randomization ]
    EDSS score

  5. Changes in the level of disability in 4 years [ Time Frame: Four years following randomization ]
    EDSS score

  6. Patients in progression [ Time Frame: 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.

  7. Disease activity on MRI at 6 months [ Time Frame: 6 months following randomization ]
    To compare in the two arms, the rate of patients without radiological (MRI) sign of disease activity

  8. Patients without disease activity on MRI at 12 months [ Time Frame: 12 months following randomization ]
    To compare in the two arms, the rate of patients without radiological (MRI) sign of disease activity

  9. Patients without disease activity on MRI at 24 months [ Time Frame: 24 months following randomization ]
    To compare in the two arms, the rate of patients without radiological (MRI) sign of disease activity

  10. Patients without disease activity on MRI at 48 months [ Time Frame: 48 months following randomization ]
    To compare in the two arms, the rate of patients without radiological (MRI) sign of disease activity

  11. Number of visible lesions on MRI at 6 months [ Time Frame: 6 months following randomization ]
    To compare in the two arms, the number of lesions taking contrast

  12. Number of visible lesions on MRI at 12 months [ Time Frame: 12 months following randomization ]
    To compare in the two arms, the number of lesions taking contrast

  13. Number of visible lesions on MRI at 24 months [ Time Frame: 24 months following randomization ]
    To compare in the two arms, the number of lesions taking contrast

  14. Number of visible lesions on MRI at 48 months [ Time Frame: 48 months following randomization ]
    To compare in the two arms, the number of lesions taking contrast

  15. Lesion load on evaluated T2 weighted MRI at 12 months [ Time Frame: 12 months following randomization ]
  16. Lesion load on evaluated T2 weighted MRI at 24 months [ Time Frame: 24 months following randomization ]
  17. Lesion load on evaluated T2 weighted MRI at 48 months [ Time Frame: 48 months following randomization ]
  18. Brain atrophy [ Time Frame: 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.



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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02937285


Locations
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France
CHU Rennes
Rennes, France
Sponsors and Collaborators
Rennes University Hospital
Investigators
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Study Director: Gilles EDAN, MD, PhD CHU Rennes

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Responsible Party: Rennes University Hospital
ClinicalTrials.gov Identifier: NCT02937285     History of Changes
Other Study ID Numbers: 35RC10_8918
2004-001601-10 ( EudraCT Number )
First Posted: October 18, 2016    Key Record Dates
Last Update Posted: October 24, 2017
Last Verified: September 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Additional relevant MeSH terms:
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Sclerosis
Multiple Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Interferons
Mitoxantrone
Interferon-beta
Interferon beta-1a
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunologic Factors
Adjuvants, Immunologic