A Phase IV Study of Rebif ® 44mcg Administered Three Times Per Week by Subcutaneous Injection Compared With no Treatment in the Therapy of Relapsing Multiple Sclerosis After Mitoxantrone

In the course of therapy escalation, the multiple sclerosis (MS) subjects with high activity of disease receive mainly mitoxantrone. The duration of therapy is limited because of a cumulative dose for life (140 mg/m\^2 body surface area). In practice lower doses of mitoxantrone (60-120 mg/m\^2 body surface area) are being used. The specific reason for this limited total dose are potential cardiotoxic side effects of mitoxantrone. Once this cumulative dose of mitoxantrone is reached and the subject becomes stable, there is the question for subsequent therapy. A possibility at this time, is the so-called "de-escalation", therefore reducing the subject back to immunomodulating basic treatment.

The target of this open-label, randomised, multicentric, comparative, parallel-group study was to inquire systematically into the use and course of basic therapy with Rebif 44 mcg thrice weekly (tiw) for a larger number of subjects.

Multiple sclerosis is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) and is one of the most common causes of neurological disability in young adults. It is characterised by multi-focal recurrent attacks of neurological symptoms and signs with variable recovery. Eventually, the majority of subjects develop a progressive clinical course. The exact cause of MS is unknown, although an autoimmune process has been implicated. Genetic susceptibility plays a role in disease initiation but unidentified environmental factors may also be involved. Three clinical forms of MS are recognized: primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS) and relapsing remitting multiple sclerosis (RRMS). Primary progressive subjects are characterised by slow and steady accumulation of neurological deficits from onset without superimposed attacks. Subjects with RRMS have exacerbations or relapses with subsequent variable recovery (remission). Secondary progressive multiple sclerosis is characterised by the steady accumulation of significant and persistent neurological deficit with or without superimposed relapses.

Rebif \[recombinant interferon (IFN) beta-1a\] has been tested in a series of studies in MS subjects at doses ranging from 22 mcg to 132 mcg weekly with a dose frequency ranging from weekly (qw) to tiw. Rebif has been found to be well tolerated in all clinical pharmacology studies, even at high doses (up to 66 mcg/m\^2). In later phase trials, Rebif has been tested across a broad range of doses, for varying duration, and in different stages of MS disease. Dose testing has ranged from 22 mcg to 132 mcg weekly with frequency of administration being qw to tiw.

OBJECTIVES

Primary objective:

* To asses if treatment with Rebif 44 mcg tiw compared with subjects not treated during 96 weeks can maintain or prolong clinical or magnetic resonance imaging (MRI) stability after previous treatment with mitoxantrone

Secondary objectives:

* To compare the mean number of T2 active lesions, defined as new or enlarging T2 lesions, per subject per scan during 96 weeks of treatment with Rebif 44 mcg three times per week with subjects not treated
* To assess the safety and efficacy of Rebif 44 mcg

This was an open-label, randomised, multicentric, comparative, parallel-group study with a neurologist blinded to treatment for performing neurologic exams and a neuro-radiologist blinded to treatment for assessing central MRI scans. The study was divided into a screening phase (up to 28 days before the start of IFN-beta-1a treatment), a treatment phase of 96 weeks as well as a follow-up period of 4 weeks for subjects with ongoing serious adverse events (SAEs) at week 96. The study consisted of 2 groups to compare the therapeutic effect of high dose, high frequency IFN beta-1a therapy (Rebif 44 mcg) to subjects who will not be treated with Rebif 44 mcg. Subjects of both groups were previously treated with mitoxantrone in the \< 3 months prior to study inclusion. Subjects assigned to no treatment were switched to Rebif 44 mcg x 3 after reaching the primary endpoint or defined stopping criteria. The treatment period of this study begun with the completion of all baseline evaluations and the initiation of study drug treatment on Study Day 1 (baseline visit) and continues through until completion of the treatment period at the Week 96 visit.

Eligibility Criteria:
Inclusion Criteria:

* Subject who had given written informed consent.
* Subjects with definite RRMS or SPMS with relapses
* Subjects with EDSS 1-6
* Subjects aged between 18-60 years
* Subjects who were escalated to mitoxantrone due to high relapse activity or MRI activity (not due to EDSS progression exclusively)
* Subjects who may not have a confirmed 1 point EDSS progression (0.5 points for EDSS \>5.5) within the last 9 months
* Subjects free of relapses over the last 6 months
* Subjects with last mitoxantrone treatment between 1 and 6 months prior to screening
* Subjects treated with mitoxantrone for minimum 9 months and maximum 36 months, total cumulative dose being 40-120 mg/m\^2
* Female subjects who must be neither pregnant nor breast-feeding and must lack childbearing potential, as defined by either:

  1. Being post-menopausal or surgically sterile,or
  2. Using a hormonal contraceptive, intra-uterine device, diaphragm with spermicide or condom with spermicide for the duration of the study. Confirmation that the subject is not pregnant must be established by a negative serum or urinary human chorionic gonadotropin (hCG) test within 7 days prior to start of study treatment. A pregnancy test is not required if the subject is post menopausal or surgically sterile.

Exclusion Criteria:

* Subject who has received any cytokine or anti-cytokine therapy within the 3 months prior to study Day 1
* Subject who has been escalated to mitoxantrone due to EDSS progression
* Subject with an ongoing MS relapse
* Subject with PPMS
* Subject with SPMS without superimposed relapses
* Subject who has received immunomodulatory treatment other than IFN-beta or glatiramer acetate before mitoxantrone
* Subject who has previously received total lymphoid irradiation
* Subject who has received oral or systemic corticosteroids or adrenocorticotrophic hormone ACTH within 30 days of study Day 1
* Subject who has received intravenous immunoglobulins or underwent plasmapheresis within the 6 months prior to study day 1
* Subject who has received immunomodulatory or immunosuppressive therapy (including but not limited to cyclophosphamide, cyclosporin, methotrexate, azathioprine, linomide, teriflunomide, natalizumab, laquinimod, Campath) within the 12 months prior to study Day 1
* Subject who requires chronic or monthly pulse corticosteroids during the study
* Subject who has received any investigational drug or experimental procedure within 12 month of study Day 1
* Subject who has inadequate liver function, defined by a total bilirubin, aspartate aminotransferase (AST) or alanine aminotransferase (ALT) or alkaline phosphatase greater than 2.5 times the upper limit of the normal values.
* Subject who has inadequate bone marrow reserve, defined as a white blood cell count less than 0.5 times the lower limit of normal
* Subject who suffers from current autoimmune disease
* Subject with known allergy to IFN or the excipient(s)
* Subject who suffers from major medical or psychiatric illness that in the opinion of the investigator creates undue risk to the subject or could affect compliance with the study protocol
* Subject treated with drugs other than IFN-beta or glatiramer acetate within 2 years before mitoxantrone
* Subject with known cardiac or other systemic diseases
* Subjects who are pregnant.