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

Official Title: “A Multi-centre, Double Blind, Randomised, Placebo Controlled, Parallel Group Trial Investigating Minocycline Versus Placebo as add-on Therapy in Patients Who Are on Treatment With Interferon-beta-1a 44mcg Tiw (Rebif®) for the Treatment of Relapsing- Remitting Multiple Sclerosis”

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

Interferon β-1a is the approved standard therapy in RRMS. The beneficial effects of minocycline in the experimental autoimmune encephalomyelitis (EAE) model and its possible effect on the degradation of IFN β-1a suggest that minocycline treatment may have beneficial effects in multiple sclerosis (MS) as add-on therapy in subjects who are on treatment with IFN β-1a. Adjuvant treatment with minocycline is easy to administer, well tolerated and relatively inexpensive. This is a multicentric, double blind, placebo controlled, randomised, parallel group study. Eligible subjects already started with IFN β-1a (Rebif) will be randomised for treatment with either minocycline 200 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 will be performed at baseline, after 4, 12, 24, 48, 72, and 96 weeks (at 4 weeks only an additional liver enzyme test will be scheduled). The magnetic resonance imaging (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 β-1a on the time to first relapse

Secondary Objectives: - To estimate the effect of minocycline versus placebo in subjects receiving treatment with IFN β-1a on the mean number of relapses per subject up to year 2 - And in a limited number of 120 subjects, the effect of minocycline versus placebo in subjects receiving treatment with IFN β-1a on the number of new or enlarging lesions on T2 weighted MRI, brain atrophy measured on MRI.

Tertiary Objectives: - Time to onset of disability progression sustained over at least six months based on change from baseline in Expanded Disability Status Scale (EDSS) in subjects with relapsing-remitting multiple sclerosis who recently started treatment with IFN β-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 multiple sclerosis activity, preceded by stability or improvement for at least 30 days - The requirement for treatment with glucocorticoids due to relapses - The time to first documented relapse - The number of relapse-free (total and documented relapses) patients without progression - The disease activity measured on the Integrated Disability Status Scale (IDSS) - The percentage of subjects with a permanent loss of disability of 1.0 score on the EDSS, confirmed at two consecutive visits with an interval of six months - The total area of MS lesions on T1 and T2 weighted MRI - Analyse the safety with respect to the combination of Rebif and minocycline - Rate of dose reduction of IFN β-1a - Relapse severity based on the EDSS and IDSS - Immunological analyses in a limited number of patients (MRI subgroup) - Frequency of increase of liver enzymes according to World Health Organization (WHO) II criteria

Intervention(s) in this Clinical Trial

• Drug: Minocycline
  • Minocycline 100 mg bid will be prescribed as one tablet after the morning meal and one tablet after the evening meal as an add-on therapy to IFN β-1a (Rebif®)
• Drug: Placebo
  • Placebo bid will be prescribed as one tablet after the morning meal and one tablet after the evening meal to be taken with water as an add-on therapy to IFN β-1a (Rebif)

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: Minocycline group
  • Subjects with RRMS receiving IFN β-1a will be administered minocycline
• Placebo Comparator: Placebo Group
  • Subjects with RRMS receiving IFN β-1a will be administered placebo

Primary Measures

• Time to first relapse
  • Time Frame: During the period of 2 years
    Safety Issue?: No

Secondary Measures

• Mean number of relapses per subject
  • Time Frame: During the period of 2 years
    Safety Issue?: No
• Number of new or enlarging lesions on T2 weighted magnetic resonance imaging (MRI)
  • Time Frame: Screening and final visit (after 96 weeks)
    Safety Issue?: No
• Brain atrophy
  • Time Frame: After 96 weeks at final visit
    Safety Issue?: No
• Time to confirmed progression in disability
  • Time Frame: Baseline to 96 weeks
    Safety Issue?: No
• Number of PD/T2 active lesions over Year 1 and 2
  • Time Frame: Year 1 to Year 2
    Safety Issue?: No
• Percentage of PD/T2 Active Scans per Subject over Year 1 and Year 2
  • Time Frame: During the period of 2 years
    Safety Issue?: No
• Burden of disease
  • Time Frame: Baseline to Year 2
    Safety Issue?: No
• Relapse count at Year 1
  • Time Frame: After first year of treatment
    Safety Issue?: No
• Relapse Free Subjects at Year 1 and Year 2
  • Time Frame: During the period of 2 years
    Safety Issue?: No
• Total number of documented and undocumented relapses
  • Time Frame: During the period of 2 years
    Safety Issue?: No
• Severity of relapses
  • Time Frame: During the period of 2 years
    Safety Issue?: No

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
• Subject with stable disease without relapses in the last 30 days
• Subjects aged between 18 and 55 years (both included)
• Subject who suffers from definite RRMS according to Poser criteria (CDMS or LSDMS) or definite MS according to McDonald criteria
• Subject who has started treatment with Rebif 44 three months ago (± 1 month)
• Subject who has a disability equivalent to an EDSS of 5.5 or less
• Subject who has shown clinical activity defined as at least one 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 one point in two functional systems or to an increase of two points in one 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).
• Subject 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 sterilised; or use a hormonal contraceptive or intra-uterine device (only following contraceptives is 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 sterilised.)

Exclusion Criteria:

• Subject with any condition that might give rise to similar symptoms as MS
• Subject who has received any other immunomodulatory or immunosuppressive treatment than Rebif six months prior to inclusion into the trial
• Subject who has received mitoxantrone or total lymphoid radiation at any time
• Subject who has received treatment with glucocorticoids or adrenocorticotropic hormone (ACTH) later than one month prior to inclusion into the trial
• Subject who has experienced a relapse within one month prior to inclusion into the trial
• Subject who has suffered from major depression
• Subjects with alcohol or drug dependency
• Subjects with cardiac insufficiency, cardiomyopathy, significant cardiac dysrhythmias, unstable or advanced ischemic heart disease, or significant hypertension (Blood Pressure > 180/110 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 one if only one of the two is measured) more than 2 times the normal upper reference limit.
• Subjects with leucopoenia < 2500 per 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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 55 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: Merck KGaA Industry

Overall Clinical Trial Officials and Contacts

Per Soelberg Sørensen, Professor Principal Investigator Rigshospitalet,Blegdamsvej 9, 2100 København Ø, Scleroseklinikken afsnit 2082  

Information obtained from ClinicalTrials.gov on February 09, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT01134627

Study ID Number: IMP 26588

ClinicalTrials.gov Identifier: NCT01134627

Health Authority: Denmark: Ethics Committee