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

Overview

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.