Trial Outcomes & Findings for Minocycline as add-on to Interferon Beta-1a [IFN Beta-1a] (Rebif®) in Relapsing-Remitting Multiple Sclerosis [RRMS] (NCT NCT01134627)

Last Updated: 2013-12-27

Results Overview

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 \[MS\]).

Recruitment status

TERMINATED

Study phase

PHASE2

Target enrollment

305 participants

Primary outcome timeframe

Baseline up to 96 weeks (+/- 1 week) or early termination (ET)

Results posted on

2013-12-27

Participant Flow

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

Participant milestones

Participant milestones
Measure	Rebif®+ Minocycline 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.	Rebif® + Placebo Participants who self-administered Rebif® (IFN beta-1a) 44 mcg as sc injection thrice weekly also received placebo tablets twice daily for 96 weeks.
Overall Study STARTED	149	155
Overall Study COMPLETED	80	88
Overall Study NOT COMPLETED	69	67

Reasons for withdrawal

Reasons for withdrawal
Measure	Rebif®+ Minocycline 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.	Rebif® + Placebo Participants who self-administered Rebif® (IFN beta-1a) 44 mcg as sc injection thrice weekly also received placebo tablets twice daily for 96 weeks.
Overall Study Adverse Event	47	31
Overall Study Lost to Follow-up	1	2
Overall Study Protocol Violation	3	5
Overall Study Lack of Efficacy	2	12
Overall Study Withdrawal by Subject	4	3
Overall Study Planning to become pregnant/pregnancy	1	0
Overall Study Other	11	14

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Rebif®+ Minocycline n=149 Participants 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.	Rebif® + Placebo n=155 Participants 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 n=304 Participants Total of all reporting groups
Age, Continuous	36.2 years STANDARD_DEVIATION 8.8 • n=5 Participants	37.7 years STANDARD_DEVIATION 8.6 • n=7 Participants	37.0 years STANDARD_DEVIATION 8.7 • n=5 Participants
Sex: Female, Male Female	96 Participants n=5 Participants	102 Participants n=7 Participants	198 Participants n=5 Participants
Sex: Female, Male Male	53 Participants n=5 Participants	53 Participants n=7 Participants	106 Participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline up to 96 weeks (+/- 1 week) or early termination (ET)

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

Outcome measures

Outcome measures
Measure	Rebif®+ Minocycline n=149 Participants 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.	Rebif® + Placebo n=155 Participants Participants who self-administered Rebif® (IFN beta-1a) 44 mcg as sc injection thrice weekly also received placebo tablets twice daily for 96 weeks.
Number of Participants Who Experienced First Documented Relapse	32 participants	39 participants

SECONDARY outcome

Timeframe: Baseline up to 96 weeks (+/- 1 week) or ET

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

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).

Outcome measures

Outcome measures
Measure	Rebif®+ Minocycline n=149 Participants 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.	Rebif® + Placebo n=155 Participants Participants who self-administered Rebif® (IFN beta-1a) 44 mcg as sc injection thrice weekly also received placebo tablets twice daily for 96 weeks.
Number of Participants With Documented Relapses 0	117 participants	116 participants
Number of Participants With Documented Relapses 1	27 participants	29 participants
Number of Participants With Documented Relapses 2	2 participants	9 participants
Number of Participants With Documented Relapses 3	2 participants	0 participants
Number of Participants With Documented Relapses 4	1 participants	1 participants

SECONDARY outcome

Timeframe: Final visit (96 weeks [+/- 1 week]) or ET

Population: 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.

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

Outcome measures

Outcome measures
Measure	Rebif®+ Minocycline n=23 Participants 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.	Rebif® + Placebo n=27 Participants Participants who self-administered Rebif® (IFN beta-1a) 44 mcg as sc injection thrice weekly also received placebo tablets twice daily for 96 weeks.
Number of New or Enlarging Lesions on Time Constant 2 (T2) Weighted Magnetic Resonance Imaging (MRI)	3.0 lesions Standard Deviation 3.3	3.0 lesions Standard Deviation 4.6

SECONDARY outcome

Timeframe: Screening , final visit (96 weeks [+/- 1 week]) or ET

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

Outcome measures

Outcome measures
Measure	Rebif®+ Minocycline n=23 Participants 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.	Rebif® + Placebo n=26 Participants Participants who self-administered Rebif® (IFN beta-1a) 44 mcg as sc injection thrice weekly also received placebo tablets twice daily for 96 weeks.
Changes in Brain Volume Measured on Magnetic Resonance Imaging (MRI)	-2997.4 cubic millimeter (mm^3) Standard Deviation 25799.3	5834.9 cubic millimeter (mm^3) Standard Deviation 20809.4

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline up to 96 weeks (+/- 1 week) or ET

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

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).

Outcome measures

Outcome measures
Measure	Rebif®+ Minocycline n=149 Participants 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.	Rebif® + Placebo n=155 Participants Participants who self-administered Rebif® (IFN beta-1a) 44 mcg as sc injection thrice weekly also received placebo tablets twice daily for 96 weeks.
Number of Participants With Onset of Disability Progression	6 participants	3 participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 48 up to Week 96 (+/- 1 week) or ET

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

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

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline up to 96 weeks (+/- 1 week) or ET

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

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

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Rebif®+ Minocycline n=23 Participants 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.	Rebif® + Placebo n=27 Participants Participants who self-administered Rebif® (IFN beta-1a) 44 mcg as sc injection thrice weekly also received placebo tablets twice daily for 96 weeks.
Burden of Disease Total area of lesions on T1 weighted MRI	1599.4 square millimeter (mm^2) Standard Deviation 3196.3	1716.8 square millimeter (mm^2) Standard Deviation 2145.5
Burden of Disease Total area of lesions on T2 weighted MRI	4813.9 square millimeter (mm^2) Standard Deviation 8385.5	5717.3 square millimeter (mm^2) Standard Deviation 6587.0

OTHER_PRE_SPECIFIED outcome

Timeframe: Week 48 (+/- 1 week) or ET

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

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.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline up to 96 weeks (+/- 1 week) or ET

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Rebif®+ Minocycline n=141 Participants 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.	Rebif® + Placebo n=147 Participants Participants who self-administered Rebif® (IFN beta-1a) 44 mcg as sc injection thrice weekly also received placebo tablets twice daily for 96 weeks.
Number of Relapse Free Participants Without Progression Relapse free participants (documented relapse)	105 participants	108 participants
Number of Relapse Free Participants Without Progression Relapse free participants (overall relapse)	96 participants	89 participants

OTHER_PRE_SPECIFIED outcome

Timeframe: Baseline up to 96 weeks (+/- 1 week) or ET

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

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.

Outcome measures

Outcome measures
Measure	Rebif®+ Minocycline n=149 Participants 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.	Rebif® + Placebo n=155 Participants Participants who self-administered Rebif® (IFN beta-1a) 44 mcg as sc injection thrice weekly also received placebo tablets twice daily for 96 weeks.
Number of Participants With Total Number of Reported Relapses (Documented and Undocumented Relapses) 0	107 participants	96 participants
Number of Participants With Total Number of Reported Relapses (Documented and Undocumented Relapses) 1	30 participants	38 participants
Number of Participants With Total Number of Reported Relapses (Documented and Undocumented Relapses) 4	1 participants	0 participants
Number of Participants With Total Number of Reported Relapses (Documented and Undocumented Relapses) 2	6 participants	17 participants
Number of Participants With Total Number of Reported Relapses (Documented and Undocumented Relapses) 3	4 participants	3 participants
Number of Participants With Total Number of Reported Relapses (Documented and Undocumented Relapses) 5	1 participants	1 participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 96 weeks (+/- 1 week) or ET

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Rebif®+ Minocycline n=125 Participants 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.	Rebif® + Placebo n=136 Participants Participants who self-administered Rebif® (IFN beta-1a) 44 mcg as sc injection thrice weekly also received placebo tablets twice daily for 96 weeks.
Relapse Severity Based on Expanded Disability Status Scale (EDSS)	1.90 Units on a scale Standard Deviation 1.38	2.02 Units on a scale Standard Deviation 1.42

Adverse Events

Rebif®+ Minocycline

Serious events: 11 serious events

Other events: 51 other events

Deaths: 0 deaths

Rebif® + Placebo

Serious events: 21 serious events

Other events: 35 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Rebif®+ Minocycline n=149 participants at risk 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.	Rebif® + Placebo n=155 participants at risk Participants who self-administered Rebif® (IFN beta-1a) 44 mcg as sc injection thrice weekly also received placebo tablets twice daily for 96 weeks.
Gastrointestinal disorders Diarrhea	8.7% 13/149 • Baseline to Week 100 (+/- 1 week) or ET. 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.	4.5% 7/155 • Baseline to Week 100 (+/- 1 week) or ET. 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.
Gastrointestinal disorders Nausea	14.8% 22/149 • Baseline to Week 100 (+/- 1 week) or ET. 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.	4.5% 7/155 • Baseline to Week 100 (+/- 1 week) or ET. 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.
General disorders Influenza like illness	6.0% 9/149 • Baseline to Week 100 (+/- 1 week) or ET. 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.	3.9% 6/155 • Baseline to Week 100 (+/- 1 week) or ET. 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.
Infections and infestations Nasopharyngitis	4.7% 7/149 • Baseline to Week 100 (+/- 1 week) or ET. 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.	7.1% 11/155 • Baseline to Week 100 (+/- 1 week) or ET. 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.
Investigations Hepatic enzyme increased	4.0% 6/149 • Baseline to Week 100 (+/- 1 week) or ET. 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.	5.2% 8/155 • Baseline to Week 100 (+/- 1 week) or ET. 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.
Nervous system disorders Dizziness	6.0% 9/149 • Baseline to Week 100 (+/- 1 week) or ET. 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.	1.3% 2/155 • Baseline to Week 100 (+/- 1 week) or ET. 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.
Nervous system disorders Headache	8.7% 13/149 • Baseline to Week 100 (+/- 1 week) or ET. 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.	9.7% 15/155 • Baseline to Week 100 (+/- 1 week) or ET. 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.
Psychiatric disorders Depression	7.4% 11/149 • Baseline to Week 100 (+/- 1 week) or ET. 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.	5.2% 8/155 • Baseline to Week 100 (+/- 1 week) or ET. 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.

Additional Information

Merck KGaA Communication Center

Merck Serono, a division of Merck KGaA

Phone: +49-6151-72-5200

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: OTHER