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

Sponsor:	Merck KGaA
Information provided by:	Merck KGaA
ClinicalTrials.gov Identifier:	NCT01134627

Purpose

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).

Condition	Intervention	Phase
Multiple Sclerosis, Relapsing-Remitting	Drug: Minocycline Drug: Placebo	Phase II

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Investigator) Primary Purpose: Treatment
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

Resource links provided by NLM:

MedlinePlus related topics: Multiple Sclerosis

Drug Information available for: Minocycline Minocycline hydrochloride Interferon beta Interferon-beta Interferon beta 1a Interferons

U.S. FDA Resources

Further study details as provided by Merck KGaA:

Primary Outcome Measures:

Time to first relapse [ Time Frame: During the period of 2 years ] [ Designated as safety issue: No ]
The median time to first relapse was recorded in days and months

Secondary Outcome Measures:

Mean number of relapses per subject [ Time Frame: During the period of 2 years ] [ Designated as safety issue: No ]
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
Number of new or enlarging lesions on T2 weighted magnetic resonance imaging (MRI) [ Time Frame: Screening and final visit (after 96 weeks) ] [ Designated as safety issue: No ]
MRI will be performed after screening and after 96 weeks in a limited number of 120 subjects in selected centers. The appearance of new lesions, enlargement of existing lesions and the total lesion load will be measured on T2 weighted scans
Brain atrophy [ Time Frame: After 96 weeks at final visit ] [ Designated as safety issue: No ]
Brain atrophy will be measured as the brain parenchymal fraction using MRI scans measured after 96 weeks.
Time to confirmed progression in disability [ Time Frame: Baseline to 96 weeks ] [ Designated as safety issue: No ]
Time to onset of disability progression sustained over at least six months based on change from baseline in Expanded Disbaility Statsu Scale (EDSS) in subjects with relapsing-remitting multiple sclerosis who recently started treatment with IFN-beta-1a.
Number of PD/T2 active lesions over Year 1 and 2 [ Time Frame: Year 1 to Year 2 ] [ Designated as 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 ] [ Designated as safety issue: No ]
Burden of disease [ Time Frame: Baseline to Year 2 ] [ Designated as safety issue: No ]
The burden of disease (BOD) is the total area of lesions (abnormal plaques) in the brain, measured in mm2. Percentage change from baseline at Year 1 and Year 2 will be presented by treatment group.
Relapse count at Year 1 [ Time Frame: After first year of treatment ] [ Designated as safety issue: No ]
Relapse Free Subjects at Year 1 and Year 2 [ Time Frame: During the period of 2 years ] [ Designated as safety issue: No ]
Total number of documented and undocumented relapses [ Time Frame: During the period of 2 years ] [ Designated as safety issue: No ]
Severity of relapses [ Time Frame: During the period of 2 years ] [ Designated as safety issue: No ]

Enrollment:	308
Study Start Date:	March 2006
Study Completion Date:	April 2011
Primary Completion Date:	April 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Minocycline group Subjects with RRMS receiving IFN β-1a will be administered minocycline	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®)
Placebo Comparator: Placebo Group Subjects with RRMS receiving IFN β-1a will be administered placebo	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)

Detailed Description:

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

Eligibility

Ages Eligible for Study:	18 Years to 55 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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
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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01134627

Locations

Denmark
Scleroseklinikken afsnit 2082
Copenhagen, Denmark, 2100

Sponsors and Collaborators

Merck KGaA

Investigators

Principal Investigator:

Per Soelberg Sørensen, Professor

Rigshospitalet,Blegdamsvej 9, 2100 København Ø, Scleroseklinikken afsnit 2082

More Information

No publications provided

Responsible Party:	Medical Responsible, Merck Serono S.A., Geneva, an affiliate of Merck KGaA, Darmstadt, Germany
ClinicalTrials.gov Identifier:	NCT01134627 History of Changes
Obsolete Identifiers:	NCT00381459
Other Study ID Numbers:	IMP 26588, 2005-004289-18
Study First Received:	May 28, 2010
Last Updated:	July 14, 2011
Health Authority:	Denmark: Ethics Committee; France: National Consultative Ethics Committee for Health and Life Sciences; Finland: Ethics Committee; Norway: The National Committees for Research Ethics in Norway; Sweden: Regional Ethical Review Board; Switzerland: Ethikkommission

Keywords provided by Merck KGaA:

Multiple Sclerosis, Relapsing-Remitting
Interferon-β
Rebif
Minocycline

Additional relevant MeSH terms:

Multiple Sclerosis
Sclerosis
Multiple Sclerosis, Relapsing-Remitting
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Pathologic Processes
Interferon-beta
Interferons

Interferon beta 1a
Minocycline
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents
Anti-Bacterial Agents
Adjuvants, Immunologic

ClinicalTrials.gov processed this record on February 09, 2012