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

This study has been terminated.
Sponsor:
Information provided by (Responsible Party):
Merck KGaA
ClinicalTrials.gov Identifier:
NCT01134627
First received: May 28, 2010
Last updated: December 2, 2013
Last verified: December 2013
  Purpose

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).


Condition Intervention Phase
Multiple Sclerosis, Relapsing-Remitting
Drug: Minocycline
Drug: Placebo
Phase 2

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, 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

Resource links provided by NLM:


Further study details as provided by Merck KGaA:

Primary Outcome Measures:
  • Number of Participants Who Experienced First Documented Relapse [ Time Frame: Baseline up to 96 weeks (+/- 1 week) or early termination (ET) ] [ Designated as safety issue: No ]
    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]).


Secondary Outcome Measures:
  • Number of Participants With Documented Relapses [ Time Frame: Baseline up to 96 weeks (+/- 1 week) or ET ] [ Designated as safety issue: No ]
    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).

  • Number of New or Enlarging Lesions on Time Constant 2 (T2) Weighted Magnetic Resonance Imaging (MRI) [ Time Frame: Final visit (96 weeks [+/- 1 week]) or ET ] [ Designated as safety issue: No ]
    Inflammatory disease activity was assessed by MRI measurement of the number of new or enlarging T2 lesions.

  • Changes in Brain Volume Measured on Magnetic Resonance Imaging (MRI) [ Time Frame: Screening , final visit (96 weeks [+/- 1 week]) or ET ] [ Designated as safety issue: No ]
    Changes in brain volume were measured as the brain parenchymal fraction using MRI scans.


Other Outcome Measures:
  • Number of Participants With Onset of Disability Progression [ Time Frame: Baseline up to 96 weeks (+/- 1 week) or ET ] [ Designated as safety issue: No ]
    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).

  • Number of Time Constant 2 (T2) Active Lesions [ Time Frame: Week 48 up to Week 96 (+/- 1 week) or ET ] [ Designated as safety issue: No ]
    Inflammatory disease activity was assessed by MRI measurement of the number of T2 active lesions.

  • Percentage of Time Constant 2 (T2) Active Scans Per Participant [ Time Frame: Baseline up to 96 weeks (+/- 1 week) or ET ] [ Designated as safety issue: No ]
    Inflammatory disease activity was assessed by MRI measurement of the percentage of T2 active scans.

  • Burden of Disease [ Time Frame: Baseline up to 96 weeks (+/- 1 week) or ET ] [ Designated as safety issue: No ]
    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.

  • Relapse Count [ Time Frame: Week 48 (+/- 1 week) or ET ] [ Designated as safety issue: No ]
    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.

  • Number of Relapse Free Participants Without Progression [ Time Frame: Baseline up to 96 weeks (+/- 1 week) or ET ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With Total Number of Reported Relapses (Documented and Undocumented Relapses) [ Time Frame: Baseline up to 96 weeks (+/- 1 week) or ET ] [ Designated as safety issue: No ]
    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.

  • Relapse Severity Based on Expanded Disability Status Scale (EDSS) [ Time Frame: 96 weeks (+/- 1 week) or ET ] [ Designated as safety issue: No ]
    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.


Enrollment: 305
Study Start Date: February 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 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.
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.

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
  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
  • 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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: Merck KGaA
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
Results First Received: August 2, 2012
Last Updated: December 2, 2013
Health Authority: Denmark: Ethics Committee
France: National Consultative Ethics Committee for Health and Life Sciences
Finland: Ethics Committee
Norway:National Committee for Medical and Health Research Ethics
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, Relapsing-Remitting
Multiple Sclerosis
Sclerosis
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 July 24, 2014