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

• Sponsor: Merck KGaA, Darmstadt, Germany (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT01134627
• Collaborator: (none)
• Enrollment: 305
• Location: 1
• Arms: 2
• Duration (Months): 61.9
• Patients Per Site Per Month: 4.9

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	Phase
Multiple Sclerosis, Relapsing-Remitting	Drug: Minocycline; Drug: Placebo	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 305 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, 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
• Study Start Date: Feb 1, 2006
• Actual Primary Completion Date: Apr 1, 2011
• Actual Study Completion Date: Apr 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
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.

Outcome Measures

Primary Outcome Measures

1. Number of Participants Who Experienced First Documented Relapse [Baseline up to 96 weeks (+/- 1 week) or early termination (ET)]

   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

1. Number of Participants With Documented Relapses [Baseline up to 96 weeks (+/- 1 week) or ET]

   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).

2. Number of New or Enlarging Lesions on Time Constant 2 (T2) Weighted Magnetic Resonance Imaging (MRI) [Final visit (96 weeks [+/- 1 week]) or ET]

   Inflammatory disease activity was assessed by MRI measurement of the number of new or enlarging T2 lesions.

3. Changes in Brain Volume Measured on Magnetic Resonance Imaging (MRI) [Screening , final visit (96 weeks [+/- 1 week]) or ET]

   Changes in brain volume were measured as the brain parenchymal fraction using MRI scans.

Other Outcome Measures

1. Number of Participants With Onset of Disability Progression [Baseline up to 96 weeks (+/- 1 week) or ET]

   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).

2. Number of Time Constant 2 (T2) Active Lesions [Week 48 up to Week 96 (+/- 1 week) or ET]

   Inflammatory disease activity was assessed by MRI measurement of the number of T2 active lesions.

3. Percentage of Time Constant 2 (T2) Active Scans Per Participant [Baseline up to 96 weeks (+/- 1 week) or ET]

   Inflammatory disease activity was assessed by MRI measurement of the percentage of T2 active scans.

4. Burden of Disease [Baseline up to 96 weeks (+/- 1 week) or ET]

   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.

5. Relapse Count [Week 48 (+/- 1 week) or ET]

   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.

6. Number of Relapse Free Participants Without Progression [Baseline up to 96 weeks (+/- 1 week) or ET]

   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.

7. Number of Participants With Total Number of Reported Relapses (Documented and Undocumented Relapses) [Baseline up to 96 weeks (+/- 1 week) or ET]

   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.

8. Relapse Severity Based on Expanded Disability Status Scale (EDSS) [96 weeks (+/- 1 week) or ET]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 55 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: 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

• 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

Locations

	Site	City	State	Country	Postal Code
1	Scleroseklinikken afsnit 2082	Copenhagen		Denmark	2100

Sponsors and Collaborators

• Merck KGaA, Darmstadt, Germany

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Merck KGaA, Darmstadt, Germany
• ClinicalTrials.gov Identifier: NCT01134627
• Other Study ID Numbers: IMP 26588; 2005-004289-18; NCT00381459
• First Posted: Jun 2, 2010
• Last Update Posted: Dec 27, 2013
• Last Verified: Dec 1, 2013

• Keywords provided by Merck KGaA, Darmstadt, Germany: Multiple Sclerosis, Relapsing-Remitting; Interferon-β; Rebif®; Minocycline
• Additional relevant MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis; Minocycline

Study Results

Participant Flow

Pre-assignment Detail	One out of 305 participants was randomized by mistake and did not receive study medication.

Arm/Group Title	Rebif®+ Minocycline	Rebif® + Placebo
Arm/Group Description	Participants who self-administered Rebif® (interferon beta-1 alpha [IFN beta-1a]) 44 microgram (mcg) as subcutaneous (sc) injection thrice weekly also received minocycline 100 milligram (mg) tablet twice daily as an add-on therapy in accordance with clinical practice for 96 weeks.	Participants who self-administered Rebif® (IFN beta-1a) 44 mcg as sc injection thrice weekly also received placebo tablets twice daily for 96 weeks.
Period Title: Overall Study
STARTED	149	155
COMPLETED	80	88
NOT COMPLETED	69	67

Baseline Characteristics

Arm/Group Title	Rebif®+ Minocycline	Rebif® + Placebo	Total
Arm/Group Description	Participants who self-administered Rebif® (interferon beta-1 alpha [IFN beta-1a]) 44 microgram (mcg) as subcutaneous (sc) injection thrice weekly also received minocycline 100 milligram (mg) tablet twice daily as an add-on therapy in accordance with clinical practice for 96 weeks.	Participants who self-administered Rebif® (IFN beta-1a) 44 mcg as sc injection thrice weekly also received placebo tablets twice daily for 96 weeks.	Total of all reporting groups
Overall Participants	149	155	304
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36.2 (8.8)	37.7 (8.6)	37.0 (8.7)
Sex: Female, Male (Count of Participants)
Female	96 64.4%	102 65.8%	198 65.1%
Male	53 35.6%	53 34.2%	106 34.9%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Who Experienced First Documented Relapse
Description	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]).
Time Frame	Baseline up to 96 weeks (+/- 1 week) or early termination (ET)

Outcome Measure Data

Analysis Population Description

The Intention to Treat (ITT) population included all the participants who were randomized and received study medication.

Arm/Group Title	Rebif®+ Minocycline	Rebif® + Placebo
Arm/Group Description	Participants who self-administered Rebif® (interferon beta-1 alpha [IFN beta-1a]) 44 microgram (mcg) as subcutaneous (sc) injection thrice weekly also received minocycline 100 milligram (mg) tablet twice daily as an add-on therapy in accordance with clinical practice for 96 weeks.	Participants who self-administered Rebif® (IFN beta-1a) 44 mcg as sc injection thrice weekly also received placebo tablets twice daily for 96 weeks.
Measure Participants	149	155
Number [participants]	32 21.5%	39 25.2%

2. Secondary Outcome

Title	Number of Participants With Documented Relapses
Description	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).
Time Frame	Baseline up to 96 weeks (+/- 1 week) or ET

Outcome Measure Data

Analysis Population Description

ITT population included all the participants who were randomized and received study medication.

Arm/Group Title	Rebif®+ Minocycline	Rebif® + Placebo
Arm/Group Description	Participants who self-administered Rebif® (interferon beta-1 alpha [IFN beta-1a]) 44 microgram (mcg) as subcutaneous (sc) injection thrice weekly also received minocycline 100 milligram (mg) tablet twice daily as an add-on therapy in accordance with clinical practice for 96 weeks.	Participants who self-administered Rebif® (IFN beta-1a) 44 mcg as sc injection thrice weekly also received placebo tablets twice daily for 96 weeks.
Measure Participants	149	155
0	117 78.5%	116 74.8%
1	27 18.1%	29 18.7%
2	2 1.3%	9 5.8%
3	2 1.3%	0 0%
4	1 0.7%	1 0.6%

3. Secondary Outcome

Title	Number of New or Enlarging Lesions on Time Constant 2 (T2) Weighted Magnetic Resonance Imaging (MRI)
Description	Inflammatory disease activity was assessed by MRI measurement of the number of new or enlarging T2 lesions.
Time Frame	Final visit (96 weeks [+/- 1 week]) or ET

Outcome Measure Data

Analysis Population Description

Sub-group of ITT population included limited number of participants at pre-selected sites selected on basis of availability of MRI scanning facilities and the willingness of the site to participate.

Arm/Group Title	Rebif®+ Minocycline	Rebif® + Placebo
Arm/Group Description	Participants who self-administered Rebif® (interferon beta-1 alpha [IFN beta-1a]) 44 microgram (mcg) as subcutaneous (sc) injection thrice weekly also received minocycline 100 milligram (mg) tablet twice daily as an add-on therapy in accordance with clinical practice for 96 weeks.	Participants who self-administered Rebif® (IFN beta-1a) 44 mcg as sc injection thrice weekly also received placebo tablets twice daily for 96 weeks.
Measure Participants	23	27
Mean (Standard Deviation) [lesions]	3.0 (3.3)	3.0 (4.6)

4. Secondary Outcome

Title	Changes in Brain Volume Measured on Magnetic Resonance Imaging (MRI)
Description	Changes in brain volume were measured as the brain parenchymal fraction using MRI scans.
Time Frame	Screening , final visit (96 weeks [+/- 1 week]) or ET

Outcome Measure Data

Analysis Population Description

Sub-group of ITT population included limited number of participants at pre-selected sites selected on basis of availability of MRI scanning facilities and the willingness of the site to participate.

Arm/Group Title	Rebif®+ Minocycline	Rebif® + Placebo
Arm/Group Description	Participants who self-administered Rebif® (interferon beta-1 alpha [IFN beta-1a]) 44 microgram (mcg) as subcutaneous (sc) injection thrice weekly also received minocycline 100 milligram (mg) tablet twice daily as an add-on therapy in accordance with clinical practice for 96 weeks.	Participants who self-administered Rebif® (IFN beta-1a) 44 mcg as sc injection thrice weekly also received placebo tablets twice daily for 96 weeks.
Measure Participants	23	26
Mean (Standard Deviation) [cubic millimeter (mm^3)]	-2997.4 (25799.3)	5834.9 (20809.4)

5. Other Pre-specified Outcome

Title	Number of Participants With Onset of Disability Progression
Description	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).
Time Frame	Baseline up to 96 weeks (+/- 1 week) or ET

Outcome Measure Data

Analysis Population Description

ITT population included all the participants who were randomized and received study medication.

Arm/Group Title	Rebif®+ Minocycline	Rebif® + Placebo
Arm/Group Description	Participants who self-administered Rebif® (interferon beta-1 alpha [IFN beta-1a]) 44 microgram (mcg) as subcutaneous (sc) injection thrice weekly also received minocycline 100 milligram (mg) tablet twice daily as an add-on therapy in accordance with clinical practice for 96 weeks.	Participants who self-administered Rebif® (IFN beta-1a) 44 mcg as sc injection thrice weekly also received placebo tablets twice daily for 96 weeks.
Measure Participants	149	155
Number [participants]	6 4%	3 1.9%

6. Other Pre-specified Outcome

Title	Number of Time Constant 2 (T2) Active Lesions
Description	Inflammatory disease activity was assessed by MRI measurement of the number of T2 active lesions.
Time Frame	Week 48 up to Week 96 (+/- 1 week) or ET

Outcome Measure Data

Analysis Population Description

Data was not analyzed due to insufficient number of participants available for the analysis of this measure and the study was prematurely terminated.

Arm/Group Title	Rebif®+ Minocycline	Rebif® + Placebo
Arm/Group Description	Participants who self-administered Rebif® (interferon beta-1 alpha [IFN beta-1a]) 44 microgram (mcg) as subcutaneous (sc) injection thrice weekly also received minocycline 100 milligram (mg) tablet twice daily as an add-on therapy in accordance with clinical practice for 96 weeks.	Participants who self-administered Rebif® (IFN beta-1a) 44 mcg as sc injection thrice weekly also received placebo tablets twice daily for 96 weeks.
Measure Participants	0	0

7. Other Pre-specified Outcome

Title	Percentage of Time Constant 2 (T2) Active Scans Per Participant
Description	Inflammatory disease activity was assessed by MRI measurement of the percentage of T2 active scans.
Time Frame	Baseline up to 96 weeks (+/- 1 week) or ET

Outcome Measure Data

Analysis Population Description

Data was not analyzed due to insufficient number of participants available for the analysis of this measure and the study was prematurely terminated.

Arm/Group Title	Rebif®+ Minocycline	Rebif® + Placebo
Arm/Group Description	Participants who self-administered Rebif® (interferon beta-1 alpha [IFN beta-1a]) 44 microgram (mcg) as subcutaneous (sc) injection thrice weekly also received minocycline 100 milligram (mg) tablet twice daily as an add-on therapy in accordance with clinical practice for 96 weeks.	Participants who self-administered Rebif® (IFN beta-1a) 44 mcg as sc injection thrice weekly also received placebo tablets twice daily for 96 weeks.
Measure Participants	0	0

8. Other Pre-specified Outcome

Title	Burden of Disease
Description	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.
Time Frame	Baseline up to 96 weeks (+/- 1 week) or ET

Outcome Measure Data

Analysis Population Description

Sub-group of ITT population included limited number of participants at pre-selected sites selected on basis of availability of MRI scanning facilities and the willingness of the site to participate.

Arm/Group Title	Rebif®+ Minocycline	Rebif® + Placebo
Arm/Group Description	Participants who self-administered Rebif® (interferon beta-1 alpha [IFN beta-1a]) 44 microgram (mcg) as subcutaneous (sc) injection thrice weekly also received minocycline 100 milligram (mg) tablet twice daily as an add-on therapy in accordance with clinical practice for 96 weeks.	Participants who self-administered Rebif® (IFN beta-1a) 44 mcg as sc injection thrice weekly also received placebo tablets twice daily for 96 weeks.
Measure Participants	23	27
Total area of lesions on T1 weighted MRI	1599.4 (3196.3)	1716.8 (2145.5)
Total area of lesions on T2 weighted MRI	4813.9 (8385.5)	5717.3 (6587.0)

9. Other Pre-specified Outcome

Title	Relapse Count
Description	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.
Time Frame	Week 48 (+/- 1 week) or ET

Outcome Measure Data

Analysis Population Description

Data was not analyzed due to insufficient number of participants available for the analysis of the measure and the study was prematurely terminated.

Arm/Group Title	Rebif®+ Minocycline	Rebif® + Placebo
Arm/Group Description	Participants who self-administered Rebif® (interferon beta-1 alpha [IFN beta-1a]) 44 microgram (mcg) as subcutaneous (sc) injection thrice weekly also received minocycline 100 milligram (mg) tablet twice daily as an add-on therapy in accordance with clinical practice for 96 weeks.	Participants who self-administered Rebif® (IFN beta-1a) 44 mcg as sc injection thrice weekly also received placebo tablets twice daily for 96 weeks.
Measure Participants	0	0

10. Other Pre-specified Outcome

Title	Number of Relapse Free Participants Without Progression
Description	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.
Time Frame	Baseline up to 96 weeks (+/- 1 week) or ET

Outcome Measure Data

Analysis Population Description

ITT population included all the participants who were randomized and received study medication. Number of participants analyzed "N" included those participants who were evaluated for this particular measure.

Arm/Group Title	Rebif®+ Minocycline	Rebif® + Placebo
Arm/Group Description	Participants who self-administered Rebif® (interferon beta-1 alpha [IFN beta-1a]) 44 microgram (mcg) as subcutaneous (sc) injection thrice weekly also received minocycline 100 milligram (mg) tablet twice daily as an add-on therapy in accordance with clinical practice for 96 weeks.	Participants who self-administered Rebif® (IFN beta-1a) 44 mcg as sc injection thrice weekly also received placebo tablets twice daily for 96 weeks.
Measure Participants	141	147
Relapse free participants (documented relapse)	105 70.5%	108 69.7%
Relapse free participants (overall relapse)	96 64.4%	89 57.4%

11. Other Pre-specified Outcome

Title	Number of Participants With Total Number of Reported Relapses (Documented and Undocumented Relapses)
Description	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.
Time Frame	Baseline up to 96 weeks (+/- 1 week) or ET

Outcome Measure Data

Analysis Population Description

ITT population included all the participants who were randomized and received study medication.

Arm/Group Title	Rebif®+ Minocycline	Rebif® + Placebo
Arm/Group Description	Participants who self-administered Rebif® (interferon beta-1 alpha [IFN beta-1a]) 44 microgram (mcg) as subcutaneous (sc) injection thrice weekly also received minocycline 100 milligram (mg) tablet twice daily as an add-on therapy in accordance with clinical practice for 96 weeks.	Participants who self-administered Rebif® (IFN beta-1a) 44 mcg as sc injection thrice weekly also received placebo tablets twice daily for 96 weeks.
Measure Participants	149	155
0	107 71.8%	96 61.9%
1	30 20.1%	38 24.5%
2	6 4%	17 11%
3	4 2.7%	3 1.9%
4	1 0.7%	0 0%
5	1 0.7%	1 0.6%

12. Other Pre-specified Outcome

Title	Relapse Severity Based on Expanded Disability Status Scale (EDSS)
Description	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.
Time Frame	96 weeks (+/- 1 week) or ET

Outcome Measure Data

Analysis Population Description

ITT population included all the participants who were randomized to study medication. Number of participants analyzed "N" included those participants who were evaluated for this particular measure.

Arm/Group Title	Rebif®+ Minocycline	Rebif® + Placebo
Arm/Group Description	Participants who self-administered Rebif® (interferon beta-1 alpha [IFN beta-1a]) 44 microgram (mcg) as subcutaneous (sc) injection thrice weekly also received minocycline 100 milligram (mg) tablet twice daily as an add-on therapy in accordance with clinical practice for 96 weeks.	Participants who self-administered Rebif® (IFN beta-1a) 44 mcg as sc injection thrice weekly also received placebo tablets twice daily for 96 weeks.
Measure Participants	125	136
Mean (Standard Deviation) [Units on a scale]	1.90 (1.38)	2.02 (1.42)

Adverse Events

Time Frame	Baseline to Week 100 (+/- 1 week) or ET.
Adverse Event Reporting Description	An adverse event (AE) was defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to baseline during a clinical study with an Investigational Medicinal Product (IMP), regardless of causal relationship and even if no IMP has been administered.
Arm/Group Title	Rebif®+ Minocycline		Rebif® + Placebo
Arm/Group Description	Participants who self-administered Rebif® (interferon beta-1 alpha [IFN beta-1a]) 44 microgram (mcg) as subcutaneous (sc) injection thrice weekly also received minocycline 100 milligram (mg) tablet twice daily as an add-on therapy in accordance with clinical practice for 96 weeks.		Participants who self-administered Rebif® (IFN beta-1a) 44 mcg as sc injection thrice weekly also received placebo tablets twice daily for 96 weeks.
All Cause Mortality
	Rebif®+ Minocycline		Rebif® + Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Rebif®+ Minocycline		Rebif® + Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/149 (7.4%)		21/155 (13.5%)
Blood and lymphatic system disorders
Lymphadenopathy	1/149 (0.7%)		0/155 (0%)
Neutropenia	1/149 (0.7%)		0/155 (0%)
Thrombocytopenia	0/149 (0%)		1/155 (0.6%)
Cardiac disorders
Arrhythmia	1/149 (0.7%)		0/155 (0%)
Ear and labyrinth disorders
Deafness unilateral	0/149 (0%)		1/155 (0.6%)
Endocrine disorders
Autoimmune thyroiditis	0/149 (0%)		1/155 (0.6%)
Eye disorders
Retinopathy	0/149 (0%)		1/155 (0.6%)
Gastrointestinal disorders
Abdominal pain	1/149 (0.7%)		1/155 (0.6%)
Constipation	0/149 (0%)		1/155 (0.6%)
General disorders
Chest pain	0/149 (0%)		1/155 (0.6%)
Hernia	1/149 (0.7%)		0/155 (0%)
Hepatobiliary disorders
Hepatic mass	1/149 (0.7%)		0/155 (0%)
Immune system disorders
Food allergy	1/149 (0.7%)		0/155 (0%)
Hypersensitivity	0/149 (0%)		1/155 (0.6%)
Infections and infestations
Erysipelas	0/149 (0%)		1/155 (0.6%)
Pneumonia	1/149 (0.7%)		0/155 (0%)
Injury, poisoning and procedural complications
Joint dislocation	0/149 (0%)		1/155 (0.6%)
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion	1/149 (0.7%)		0/155 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	1/149 (0.7%)		2/155 (1.3%)
Lymphoma	0/149 (0%)		1/155 (0.6%)
Testis cancer	1/149 (0.7%)		0/155 (0%)
Nervous system disorders
Syncope	1/149 (0.7%)		1/155 (0.6%)
Hypoesthesia	0/149 (0%)		1/155 (0.6%)
Motor dysfunction	0/149 (0%)		1/155 (0.6%)
Paresthesia	0/149 (0%)		1/155 (0.6%)
Sciatica	0/149 (0%)		1/155 (0.6%)
Subarachnoid hemorrhage	0/149 (0%)		1/155 (0.6%)
Tremor	0/149 (0%)		1/155 (0.6%)
Pregnancy, puerperium and perinatal conditions
Abortion spontaneous	1/149 (0.7%)		0/155 (0%)
Psychiatric disorders
Depressive delusion	0/149 (0%)		1/155 (0.6%)
Reproductive system and breast disorders
Fallopian tube cyst	1/149 (0.7%)		0/155 (0%)
Respiratory, thoracic and mediastinal disorders
Painful respiration	1/149 (0.7%)		0/155 (0%)
Pleurisy	1/149 (0.7%)		0/155 (0%)
Skin and subcutaneous tissue disorders
Urticaria	0/149 (0%)		1/155 (0.6%)
Surgical and medical procedures
Abscess drainage	0/149 (0%)		1/155 (0.6%)
Hysterectomy	1/149 (0.7%)		0/155 (0%)
Plastic surgery	0/149 (0%)		1/155 (0.6%)
Thyroidectomy	0/149 (0%)		1/155 (0.6%)
Transplant	0/149 (0%)		1/155 (0.6%)
Vascular disorders
Hypotension	0/149 (0%)		1/155 (0.6%)
Other (Not Including Serious) Adverse Events
	Rebif®+ Minocycline		Rebif® + Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	51/149 (34.2%)		35/155 (22.6%)
Gastrointestinal disorders
Diarrhea	13/149 (8.7%)		7/155 (4.5%)
Nausea	22/149 (14.8%)		7/155 (4.5%)
General disorders
Influenza like illness	9/149 (6%)		6/155 (3.9%)
Infections and infestations
Nasopharyngitis	7/149 (4.7%)		11/155 (7.1%)
Investigations
Hepatic enzyme increased	6/149 (4%)		8/155 (5.2%)
Nervous system disorders
Dizziness	9/149 (6%)		2/155 (1.3%)
Headache	13/149 (8.7%)		15/155 (9.7%)
Psychiatric disorders
Depression	11/149 (7.4%)		8/155 (5.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.