Minocycline as add-on to Interferon Beta-1a [IFN Beta-1a] (Rebif®) in Relapsing-Remitting Multiple Sclerosis [RRMS]

A Multi-centre, Double Blind, Randomized, Placebo Controlled, Parallel Group Trial Investigating Minocycline Versus Placebo as Add-on Therapy in Patients Who Are on Treatment With Interferon-beta-1a 44 Mcg Tiw (Rebif®) for the Treatment of Relapsing-Remitting Multiple Sclerosis

This is a multicentric, double-blind, placebo-controlled, randomized, parallel group study to estimate the effect of minocycline as add-on to interferon beta-1a (IFN beta-1a) in subjects with relapsing-remitting multiple sclerosis (RRMS).

Interferon beta-1a is the approved standard therapy in RRMS. The beneficial effects of minocycline in the experimental autoimmune encephalomyelitis (EAE) model and its possible inhibitory effect on the degradation of IFN beta-1a suggest that minocycline treatment may have beneficial effects in MS as add-on therapy in subjects who are on treatment with IFN beta-1a. Adjuvant treatment with minocycline is easy to administer, well tolerated and relatively inexpensive. This is a multicentric, double blind, placebo controlled, randomized, parallel group study. Eligible subjects already started with IFN beta-1a (Rebif®) will be randomized 1:1 for treatment with either minocycline 2*100 mg daily as add-on therapy or placebo. The subjects will be examined clinically at baseline and after 12, 24, 48, 72 and 96 weeks. Laboratory tests (hematology and clinical chemistry) will be performed at baseline and after 4, 8, 12, 24, 36, 48, 60, 72, 84 and 96 weeks (at 4, 8, 36, 60 and 84 weeks only an additional liver enzyme test will be scheduled). The MRI (T1-weighted and T2-weighted) before treatment and after 96 weeks and immunological studies before treatment and after 48 weeks will be performed in a limited number of subjects in selected centers.

OBJECTIVES

Primary Objective:

The effect of minocycline versus placebo in subjects receiving treatment with IFN beta-1a on the time to the first documented relapse

Secondary Objectives:

• To estimate the effect of minocycline versus placebo in subjects receiving treatment with IFN beta-1a on the mean number of documented relapses per subject up to year 2
• To estimate, in a limited number of 120 subjects at pre-selected sites, the effect of minocycline versus placebo in subjects receiving treatment with IFN beta-1a on the number of new or enlarging lesions on T2-weighted MRI, changes in brain volume measured on MRI

Tertiary Objectives:

• Time to onset of disability progression sustained over at least 6 months based on change from baseline in EDSS in subjects with RRMS who recently started treatment with IFN beta-1a. (Disability progression is defined as an increase of: 1.0 point on the EDSS if EDSS was >= 1.0 at baseline; and 1.5 point on the EDSS if EDSS was 0.0 at baseline)
• Time to sustained progression by 2 points in 1 Functional System or 1 point in 2 Functional Systems
• The total number of reported relapses (documented and undocumented). An undocumented relapse is defined as the appearance of new symptoms or worsening of an old symptom, in the absence of fever, over at least 24 hours that could be attributed to MS activity, preceded by stability or improvement for at least 30 days
• The requirement for treatment with glucocorticoids due to relapses
• The time to first relapse
• The number of relapse-free (documented and undocumented relapses) subjects without progression
• The disease activity measured on the integrated disability status scale (IDSS)
• The number of subjects with a permanent loss of disability of 1.0 score on the EDSS, confirmed at 2 consecutive visits with an interval of 6 months
• The total area of MS lesions on T1 and T2-weighted MRI
• Analyze the safety with respect to the combination of Rebif® and minocycline
• Rate of dose reduction of IFN beta-1a (Rebif®)
• Relapse severity based on the EDSS and IDSS
• Immunological analyses in a limited number of subjects (MRI subgroup)
• Frequency of increase of liver enzymes according to World Health Organization (WHO) II criteria

Inclusion Criteria:

• Subjects who have given written informed consent prior to any trial related activities. Trial related activities are any procedures that would not have been performed during normal management of the subject
• Subjects with stable disease without relapses in the last 30 days
• Subjects aged between 18 and 55 years (both included)
• Subjects who suffer from definite RRMS according to Poser criteria (clinical definite multiple sclerosis [CDMS] or laboratory supported definite multiple sclerosis [LSDMS]) or definite MS according to McDonald criteria
• Subjects who have started treatment with Rebif® 44 mcg 3 months ago (+/- 1 month) including the titration phase
• Subjects who have a disability equivalent to an EDSS of 5.5 or less
• Subjects who have shown clinical activity defined as at least 1 documented relapse within the last year (A documented relapse is defined as the development of new or the exacerbation of existing neurological symptoms or signs, in the absence of fever, persisting for more than 48 hours and with a previous period for more than 30 days with a stable or an improving condition. The exacerbation must be equivalent to an increase of at least 1 point in 2 functional systems or to an increase of 2 points in 1 system, either in the pyramidal, cerebellar, brain-stem, sensory, bowel and bladder, visual, cerebral or other functional system or an increase of at least half a point on the EDSS. Changes in bowel and bladder or cerebral functions should not solely be responsible for documentation of a relapse. The relapses must have been evaluated by a neurologist, retrospectively if necessary)
• Subjects must be prepared to and considered able to follow the protocol during the whole trial period and to attend the planned visits, even if the treatment has to be withdrawn
• Female subjects must either: be post-menopausal or surgically sterilized; or use a hormonal contraceptive or intra-uterine device (only following contraceptives are allowed: birth control pills, intra-uterine device, depot injection of gestagen, subdermal implant, hormonal vaginal ring and transdermal depot patches); or be sexually inactive for the duration of the study, and be neither pregnant nor breast-feeding (confirmation that the subject is not pregnant must be established by a negative serum human chorionic gonadotropin (hCG) pregnancy test within 28 days of Study Day 1 and a negative urine pregnancy test on Study Day 1. A pregnancy test is not required if the subject is post-menopausal or surgically sterilized)

Exclusion Criteria:

• Subjects with any condition that might give rise to similar symptoms as MS
• Subjects who have received any other immunomodulatory or immunosuppressive treatment 6 months prior to inclusion into the trial (the obligatory pre-study 3 months [+/- 1 month] period of Rebif® treatment not included)
• Subjects who have received mitoxantrone or total lymphoid radiation at any time
• Subjects who have received treatment with glucocorticoids or adrenocorticotropic hormone (ACTH) later than 1 month prior to inclusion into the trial
• Subjects who have experienced a relapse within 1 month prior to inclusion into the trial
• Subjects who have suffered from major depression
• Subjects with alcohol or drug dependency
• Subjects with cardiac insufficiency, cardiomyopathy, significant cardiac dysrhythmias, unstable or advanced ischemic heart disease (New York Heart Association [NYHA] grade III or IV), or significant hypertension (Blood Pressure > 180/110 millimeter of mercury [mmHg])
• Subjects with renal insufficiency defined as serum creatinine > 1.5 times the upper normal reference limit
• Subjects with alanine aminotransferase (ALAT) and asparagine aminotransferase (ASAT) (or either 1 if only 1 of the 2 is measured) levels more than 2 times the normal upper reference limit.
• Subjects with leucopoenia < 2500 per microliter (microL) or thrombopenia < 100000 per microL
• Subjects with any medical illness requiring treatment with systemic corticosteroids
• Subjects with any systemic disease that can influence the subject's safety and compliance, or the evaluation of the disability
• Female subjects who are pregnant or breastfeeding or who plan to become pregnant during the study
• Subjects with known or suspected allergy to minocycline or other tetracyclines
• Subjects who have participated in any other studies, involving other investigational products, within 30 days prior to participating in this trial