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

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).

Study Overview

• Status: Terminated
• Conditions: Multiple Sclerosis, Relapsing-Remitting
• Intervention / Treatment: Drug: Minocycline; Drug: Placebo

Detailed Description

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

• Study Type: Interventional
• Enrollment (Actual): 305
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Scleroseklinikken afsnit 2082

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo Group	Drug: Placebo; Participants who are self-administering Rebif® (IFN beta-1a) 44 mcg as sc injection thrice weekly will also receive placebo tablets twice daily for 96 weeks.
Experimental: Minocycline group	Drug: Minocycline; Participants who are self-administering Rebif® (IFN beta-1a) 44 microgram (mcg) as subcutaneous (sc) injection thrice weekly will also receive minocycline 100 milligram (mg) tablet twice daily as an add-on therapy in accordance with clinical practice for 96 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Experienced First Documented Relapse	Documented relapse: development of new/exacerbation of existing neurological symptoms, persisting for >48 hrs and with previous period for >30 days with stable/improving condition. Exacerbation = at least (>=)1 point increase in 2 functional systems/2 points increase in 1 system,either in pyramidal, cerebral, brain-stem, sensory, bowel and bladder, visual, cerebral or other functional system or >=0.5 point increase on expanded disability status scale (EDSS) which assesses disability in 8 functional systems with overall score ranging from 0 (normal) to 10 (death due to multiple sclerosis [MS]).	Baseline up to 96 weeks (+/- 1 week) or early termination (ET)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Documented Relapses	Documented relapse: development of new/exacerbation of existing neurological symptoms, persisting for >48 hrs and with previous period for >30 days with stable/improving condition. Exacerbation was >=1 point increase in 2 functional systems /2 points increase in 1 system, either in pyramidal, cerebral, brain-stem, sensory, bowel and bladder, visual, cerebral or other functional system or >=0.5 point increase on EDSS which assesses disability in 8 functional systems with overall score ranging from 0 (normal) to 10 (death due to MS).	Baseline up to 96 weeks (+/- 1 week) or ET
Number of New or Enlarging Lesions on Time Constant 2 (T2) Weighted Magnetic Resonance Imaging (MRI)	Inflammatory disease activity was assessed by MRI measurement of the number of new or enlarging T2 lesions.	Final visit (96 weeks [+/- 1 week]) or ET
Changes in Brain Volume Measured on Magnetic Resonance Imaging (MRI)	Changes in brain volume were measured as the brain parenchymal fraction using MRI scans.	Screening , final visit (96 weeks [+/- 1 week]) or ET

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Onset of Disability Progression	Disability progression was defined as an increase, compared to baseline evaluation of >= 1.0 points on EDSS if EDSS was >= 1.0 at baseline or >=1.5 point on EDSS if EDSS was 0.0 at baseline. EDSS assesses disability in 8 functional systems with overall score ranging from 0 (normal) to 10 (death due to MS).	Baseline up to 96 weeks (+/- 1 week) or ET
Number of Time Constant 2 (T2) Active Lesions	Inflammatory disease activity was assessed by MRI measurement of the number of T2 active lesions.	Week 48 up to Week 96 (+/- 1 week) or ET
Percentage of Time Constant 2 (T2) Active Scans Per Participant	Inflammatory disease activity was assessed by MRI measurement of the percentage of T2 active scans.	Baseline up to 96 weeks (+/- 1 week) or ET
Burden of Disease	The burden of disease (BOD) is the total area of MS lesions (abnormal plaques) in the brain measured on Time Constant 1 (T1) or T2 weighted MRI.	Baseline up to 96 weeks (+/- 1 week) or ET
Relapse Count	A relapse was 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.	Week 48 (+/- 1 week) or ET
Number of Relapse Free Participants Without Progression	Analysis based on documented relapses (relapse: development of new/exacerbation of existing neurological symptoms, persisting for >48 hrs and with previous period for >30 days with stable/improving condition; relapse documented by exacerbation >=1 point increase in 2 functional systems/2 points increase in 1 functional system, or >=0.5 point increase on EDSS which assesses disability in 8 functional systems with overall score ranging from 0 [normal] to 10 [death due to MS]) and overall relapses (documented and undocumented relapses); undocumented relapses only fulfilled condition for relapse.	Baseline up to 96 weeks (+/- 1 week) or ET
Number of Participants With Total Number of Reported Relapses (Documented and Undocumented Relapses)	Documented relapses (relapse: development of new/exacerbation of existing neurological symptoms, persisting for >48 hrs and with previous period for >30 days with stable/improving condition; relapse documented by exacerbation >=1 point increase in 2 functional systems/2 points increase in 1 functional system, or >=0.5 point increase on EDSS which assesses disability in 8 functional systems with overall score ranging from 0 [normal] to 10 [death due to MS]) and undocumented relapses only fulfilled condition for relapse.	Baseline up to 96 weeks (+/- 1 week) or ET
Relapse Severity Based on Expanded Disability Status Scale (EDSS)	EDSS assesses disability in 8 functional systems. An overall score ranging from 0 (normal) to 10 (death due to MS) was calculated. EDSS progression was defined as increase by at least 1 point if last value of EDSS was equal to 5.5 and by at least 0.5 points if last EDSS was more than 5.5.	96 weeks (+/- 1 week) or ET

Collaborators and Investigators

• Sponsor: Merck KGaA, Darmstadt, Germany
• Investigators: Principal Investigator: Per Soelberg Sørensen, Professor, Rigshospitalet,Blegdamsvej 9, 2100 København Ø, Scleroseklinikken afsnit 2082

Study record dates

Study Major Dates

• Study Start: February 1, 2006
• Primary Completion (Actual): April 1, 2011
• Study Completion (Actual): April 1, 2011

Study Registration Dates

• First Submitted: May 28, 2010
• First Submitted That Met QC Criteria: May 28, 2010
• First Posted (Estimate): June 2, 2010

Study Record Updates

• Last Update Posted (Estimate): December 27, 2013
• Last Update Submitted That Met QC Criteria: December 2, 2013
• Last Verified: December 1, 2013

More Information

Terms related to this study

• Keywords: Minocycline; Multiple Sclerosis, Relapsing-Remitting; Interferon-β; Rebif®
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Anti-Infective Agents; Anti-Bacterial Agents; Minocycline
• Other Study ID Numbers: IMP 26588; 2005-004289-18 (EudraCT Number)