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
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.
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.