Trial Outcomes & Findings for Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis (MS)CombiRx (NCT NCT00211887)

Last Updated: 2014-04-03

Results Overview

Annualized relapse rate of protocol-defined exacerbations Protocol defined relapse - an relapse seen within 7 days of onset, verified by the treating physician and independently observed as a change in EDSS by the examining physician. This relapse is defined as: the appearance of a new symptom or worsening of an old symptom, attributable to MS; accompanied by a change in the neurologic examination (defined as a 0.5 or greater increase in the EDSS over the last scheduled or unscheduled visit or a 2 point change in one functional system or a 1 point change in two functional systems, except bladder and cognitive changes); lasting at least 24 hours in the absence of fever; and preceded by stability or improvement for at least 30 days.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1008 participants

Primary outcome timeframe

Baseline to Month 36

Results posted on

2014-04-03

Participant Flow

The trial enrolled participants from January 2005 through April 2009. The trial was conducted in 68 sites, both private practice and academic, in the USA and Canada.

1129 participants assessed for eligibility. 121 excluded due to recent activity (16), \<2 exacerbations (14), other medical exclusions (14), inconclusive for RRMS (12), abnormal lab value (10), cannot have Gd (5), EDSS\>5.5 (2), and other reason (46).

Participant milestones

Participant milestones
Measure	IFN + GA Interferon beta-1a 30µg intramuscularly weekly and glatiramer acetate (GA) 20mg daily	Interferon Beta 1a Interferon beta-1a 30µg intramuscularly weekly	Glatiramer Acetate glatiramer acetate 20mg daily
Overall Study STARTED	499	250	259
Overall Study COMPLETED	397	194	223
Overall Study NOT COMPLETED	102	56	36

Reasons for withdrawal

Reasons for withdrawal
Measure	IFN + GA Interferon beta-1a 30µg intramuscularly weekly and glatiramer acetate (GA) 20mg daily	Interferon Beta 1a Interferon beta-1a 30µg intramuscularly weekly	Glatiramer Acetate glatiramer acetate 20mg daily
Overall Study Adverse Event	8	4	6
Overall Study Death	1	1	1
Overall Study Lost to Follow-up	28	13	9
Overall Study Non-medical reason	31	14	8
Overall Study Other medical reason	15	11	7
Overall Study Side effects	19	13	5

Baseline Characteristics

Combination Therapy in Patients With Relapsing-Remitting Multiple Sclerosis (MS)CombiRx

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	IFN + GA n=499 Participants Interferon beta-1a intramuscularly weekly and glatiramer acetate daily	IFB-1a n=250 Participants Interferon beta-1a	Glatiramer n=259 Participants glatiramer acetate	Total n=1008 Participants Total of all reporting groups
Age, Continuous	37.1 years STANDARD_DEVIATION 9.4 • n=5 Participants	37.6 years STANDARD_DEVIATION 10.2 • n=7 Participants	39.0 years STANDARD_DEVIATION 9.5 • n=5 Participants	37.7 years STANDARD_DEVIATION 9.7 • n=4 Participants
Sex: Female, Male Female	372 Participants n=5 Participants	173 Participants n=7 Participants	185 Participants n=5 Participants	730 Participants n=4 Participants
Sex: Female, Male Male	127 Participants n=5 Participants	77 Participants n=7 Participants	74 Participants n=5 Participants	278 Participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline to Month 36

Outcome measures

Outcome measures
Measure	IFN + GA n=499 Participants Interferon beta-1a intramuscularly weekly and glatiramer acetate daily	IFB-1a n=250 Participants Interferon beta-1a	Glatiramer n=259 Participants glatiramer acetate
ARR - PDEs	0.12 relapses per year	0.16 relapses per year	0.11 relapses per year

SECONDARY outcome

Timeframe: Baseline to Month 36

% with EDSS progression Confirmed progression in a participant was defined as a 1.0 increase in the EDSS from baseline, when baseline \<=5.0; or an increase of 0.5 from baseline, when baseline \>=5.5, sustained for 6 months (2 successive quarterly visits), as assessed by the blinded EDSS examiner and confirmed centrally.

Outcome measures

Outcome measures
Measure	IFN + GA n=499 Participants Interferon beta-1a intramuscularly weekly and glatiramer acetate daily	IFB-1a n=250 Participants Interferon beta-1a	Glatiramer n=259 Participants glatiramer acetate
Confirmed Progression on the Expanded Disability Status Scale	23.9 percentage of participants 1.2	21.6 percentage of participants 1.2	24.8 percentage of participants 1.2

SECONDARY outcome

Timeframe: Baseline to month 36

Population: Due to participant dropouts, there were less participants analyzed for this particular outcome measure.

positive indicates improvement The Multiple Sclerosis Functional Composite (MSFC) is a scale measuring pyramidal functions, sensory functions, cerebellar functions, bowel \& bladder functions,brain stem functions, mental functions, and visual functions from 0 to 6. 0= normal 6= severe loss

Outcome measures

Outcome measures
Measure	IFN + GA n=472 Participants Interferon beta-1a intramuscularly weekly and glatiramer acetate daily	IFB-1a n=241 Participants Interferon beta-1a	Glatiramer n=246 Participants glatiramer acetate
Change in the Multiple Sclerosis Functional Composite	0.1 units on a scale Full Range 0.5 • Interval -3.5 to 2.3	0.1 units on a scale Full Range 0.5 • Interval -2.0 to 1.8	0.2 units on a scale Full Range 0.5 • Interval -3.0 to 2.4

SECONDARY outcome

Timeframe: Baseline to month 36

Population: Due to participant dropouts, there were less participants analyzed for this particular outcome measure.

MRI composite score (Z4 score) - the unweighted sum of the individual Z scores for enhanced tissue volume, T2 lesion burden, equivalence of the T1 hypointense lesion burden, normalized CSF (an inverse measure of atrophy with the appropriate sign so that all scores are directionally compatible - larger is worse) MRI enhancement status at baseline (0, 1-4, and 5 or more enhancing lesions)

Outcome measures

Outcome measures
Measure	IFN + GA n=381 Participants Interferon beta-1a intramuscularly weekly and glatiramer acetate daily	IFB-1a n=185 Participants Interferon beta-1a	Glatiramer n=211 Participants glatiramer acetate
Change in MRI Composite Score	-0.02 z score Standard Deviation 1.30	0.05 z score Standard Deviation 1.27	0.10 z score Standard Deviation 2.09

Adverse Events

IFN + GA

Serious events: 70 serious events

Other events: 197 other events

Deaths: 0 deaths

IFB-1a

Serious events: 38 serious events

Other events: 102 other events

Deaths: 0 deaths

Glatiramer

Serious events: 30 serious events

Other events: 98 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	IFN + GA n=499 participants at risk Interferon beta-1a intramuscularly weekly and glatiramer acetate daily	IFB-1a n=250 participants at risk Interferon beta-1a	Glatiramer n=259 participants at risk glatiramer acetate
Cardiac disorders Cardiac disorders	0.60% 3/499 • Number of events 3 Adverse events were only collected with regard to the affected organ system.	1.2% 3/250 • Number of events 3 Adverse events were only collected with regard to the affected organ system.	1.2% 3/259 • Number of events 3 Adverse events were only collected with regard to the affected organ system.
Gastrointestinal disorders Gastrointestinal disorders	1.4% 7/499 • Number of events 7 Adverse events were only collected with regard to the affected organ system.	1.2% 3/250 • Number of events 3 Adverse events were only collected with regard to the affected organ system.	0.77% 2/259 • Number of events 2 Adverse events were only collected with regard to the affected organ system.
Hepatobiliary disorders Hepato-biliary disorders	0.80% 4/499 • Number of events 4 Adverse events were only collected with regard to the affected organ system.	0.40% 1/250 • Number of events 1 Adverse events were only collected with regard to the affected organ system.	1.2% 3/259 • Number of events 3 Adverse events were only collected with regard to the affected organ system.
Infections and infestations Infections and infestations	2.2% 11/499 • Number of events 11 Adverse events were only collected with regard to the affected organ system.	1.6% 4/250 • Number of events 4 Adverse events were only collected with regard to the affected organ system.	0.39% 1/259 • Number of events 1 Adverse events were only collected with regard to the affected organ system.
Musculoskeletal and connective tissue disorders Musculoskeletal, connective tissue and bone disorders	0.80% 4/499 • Number of events 4 Adverse events were only collected with regard to the affected organ system.	0.40% 1/250 • Number of events 1 Adverse events were only collected with regard to the affected organ system.	0.77% 2/259 • Number of events 2 Adverse events were only collected with regard to the affected organ system.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasms benign and malignant	0.20% 1/499 • Number of events 1 Adverse events were only collected with regard to the affected organ system.	2.4% 6/250 • Number of events 6 Adverse events were only collected with regard to the affected organ system.	1.2% 3/259 • Number of events 3 Adverse events were only collected with regard to the affected organ system.
Nervous system disorders Nervous system disorders	3.4% 17/499 • Number of events 17 Adverse events were only collected with regard to the affected organ system.	4.4% 11/250 • Number of events 11 Adverse events were only collected with regard to the affected organ system.	1.9% 5/259 • Number of events 5 Adverse events were only collected with regard to the affected organ system.
Psychiatric disorders Psychiatric disorders	3.0% 15/499 • Number of events 15 Adverse events were only collected with regard to the affected organ system.	1.6% 4/250 • Number of events 4 Adverse events were only collected with regard to the affected organ system.	3.1% 8/259 • Number of events 8 Adverse events were only collected with regard to the affected organ system.
Renal and urinary disorders Renal and urinary disorders	0.60% 3/499 • Number of events 3 Adverse events were only collected with regard to the affected organ system.	1.2% 3/250 • Number of events 3 Adverse events were only collected with regard to the affected organ system.	0.00% 0/259 Adverse events were only collected with regard to the affected organ system.
Reproductive system and breast disorders Reproductive system and breast disorders	0.60% 3/499 • Number of events 3 Adverse events were only collected with regard to the affected organ system.	0.80% 2/250 • Number of events 2 Adverse events were only collected with regard to the affected organ system.	0.00% 0/259 Adverse events were only collected with regard to the affected organ system.
Surgical and medical procedures Surgical and medical procedures	1.8% 9/499 • Number of events 9 Adverse events were only collected with regard to the affected organ system.	2.0% 5/250 • Number of events 5 Adverse events were only collected with regard to the affected organ system.	2.3% 6/259 • Number of events 6 Adverse events were only collected with regard to the affected organ system.

Other adverse events

Additional Information

Dr. Fred D. Lublin

Icahn School of Medicine at Mount Sinai

Phone: 212-241-6854

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	IFN + GA n=499 participants at risk Interferon beta-1a intramuscularly weekly and glatiramer acetate daily	IFB-1a n=250 participants at risk Interferon beta-1a	Glatiramer n=259 participants at risk glatiramer acetate
Gastrointestinal disorders constipation	4.6% 23/499 • Number of events 29 Adverse events were only collected with regard to the affected organ system.	7.6% 19/250 • Number of events 20 Adverse events were only collected with regard to the affected organ system.	6.9% 18/259 • Number of events 19 Adverse events were only collected with regard to the affected organ system.
Gastrointestinal disorders Diarrhea	6.4% 32/499 • Number of events 36 Adverse events were only collected with regard to the affected organ system.	8.4% 21/250 • Number of events 27 Adverse events were only collected with regard to the affected organ system.	7.7% 20/259 • Number of events 20 Adverse events were only collected with regard to the affected organ system.
Gastrointestinal disorders GI Upset	8.2% 41/499 • Number of events 44 Adverse events were only collected with regard to the affected organ system.	4.4% 11/250 • Number of events 12 Adverse events were only collected with regard to the affected organ system.	5.0% 13/259 • Number of events 15 Adverse events were only collected with regard to the affected organ system.
Gastrointestinal disorders Nausea/Vomiting	4.6% 23/499 • Number of events 25 Adverse events were only collected with regard to the affected organ system.	6.8% 17/250 • Number of events 21 Adverse events were only collected with regard to the affected organ system.	3.5% 9/259 • Number of events 9 Adverse events were only collected with regard to the affected organ system.
General disorders Fatigue	16.2% 81/499 • Number of events 99 Adverse events were only collected with regard to the affected organ system.	16.0% 40/250 • Number of events 53 Adverse events were only collected with regard to the affected organ system.	16.2% 42/259 • Number of events 51 Adverse events were only collected with regard to the affected organ system.
General disorders Injection Site Reaction	12.8% 64/499 • Number of events 86 Adverse events were only collected with regard to the affected organ system.	6.0% 15/250 • Number of events 16 Adverse events were only collected with regard to the affected organ system.	10.0% 26/259 • Number of events 35 Adverse events were only collected with regard to the affected organ system.
General disorders Insomnia	5.0% 25/499 • Number of events 26 Adverse events were only collected with regard to the affected organ system.	8.8% 22/250 • Number of events 27 Adverse events were only collected with regard to the affected organ system.	8.5% 22/259 • Number of events 24 Adverse events were only collected with regard to the affected organ system.
Immune system disorders Allergies (Environmental or Seasonal)	5.8% 29/499 • Number of events 39 Adverse events were only collected with regard to the affected organ system.	7.6% 19/250 • Number of events 21 Adverse events were only collected with regard to the affected organ system.	6.9% 18/259 • Number of events 20 Adverse events were only collected with regard to the affected organ system.
Immune system disorders Bronchitis	8.8% 44/499 • Number of events 54 Adverse events were only collected with regard to the affected organ system.	5.6% 14/250 • Number of events 17 Adverse events were only collected with regard to the affected organ system.	8.5% 22/259 • Number of events 30 Adverse events were only collected with regard to the affected organ system.
Immune system disorders Cold	39.5% 197/499 • Number of events 358 Adverse events were only collected with regard to the affected organ system.	40.8% 102/250 • Number of events 172 Adverse events were only collected with regard to the affected organ system.	37.8% 98/259 • Number of events 172 Adverse events were only collected with regard to the affected organ system.
Immune system disorders Cough	4.2% 21/499 • Number of events 24 Adverse events were only collected with regard to the affected organ system.	6.8% 17/250 • Number of events 18 Adverse events were only collected with regard to the affected organ system.	4.6% 12/259 • Number of events 13 Adverse events were only collected with regard to the affected organ system.
Immune system disorders Flu/Flu Like Symptoms	19.6% 98/499 • Number of events 122 Adverse events were only collected with regard to the affected organ system.	20.4% 51/250 • Number of events 62 Adverse events were only collected with regard to the affected organ system.	17.0% 44/259 • Number of events 52 Adverse events were only collected with regard to the affected organ system.
Immune system disorders GI Virus	6.6% 33/499 • Number of events 35 Adverse events were only collected with regard to the affected organ system.	8.4% 21/250 • Number of events 24 Adverse events were only collected with regard to the affected organ system.	11.6% 30/259 • Number of events 32 Adverse events were only collected with regard to the affected organ system.
General disorders Infection	27.9% 139/499 • Number of events 213 Adverse events were only collected with regard to the affected organ system.	27.6% 69/250 • Number of events 101 Adverse events were only collected with regard to the affected organ system.	29.0% 75/259 • Number of events 122 Adverse events were only collected with regard to the affected organ system.
General disorders Sinusitis	15.8% 79/499 • Number of events 120 Adverse events were only collected with regard to the affected organ system.	12.8% 32/250 • Number of events 44 Adverse events were only collected with regard to the affected organ system.	17.8% 46/259 • Number of events 68 Adverse events were only collected with regard to the affected organ system.
General disorders Sore Throat	6.8% 34/499 • Number of events 39 Adverse events were only collected with regard to the affected organ system.	5.6% 14/250 • Number of events 14 Adverse events were only collected with regard to the affected organ system.	7.3% 19/259 • Number of events 22 Adverse events were only collected with regard to the affected organ system.
General disorders URI	19.8% 99/499 • Number of events 148 Adverse events were only collected with regard to the affected organ system.	21.2% 53/250 • Number of events 86 Adverse events were only collected with regard to the affected organ system.	19.7% 51/259 • Number of events 84 Adverse events were only collected with regard to the affected organ system.
General disorders UTI	12.8% 64/499 • Number of events 106 Adverse events were only collected with regard to the affected organ system.	14.8% 37/250 • Number of events 64 Adverse events were only collected with regard to the affected organ system.	14.3% 37/259 • Number of events 56 Adverse events were only collected with regard to the affected organ system.
Injury, poisoning and procedural complications Fall	9.2% 46/499 • Number of events 63 Adverse events were only collected with regard to the affected organ system.	8.0% 20/250 • Number of events 27 Adverse events were only collected with regard to the affected organ system.	9.7% 25/259 • Number of events 46 Adverse events were only collected with regard to the affected organ system.
Musculoskeletal and connective tissue disorders Back Pain	9.4% 47/499 • Number of events 58 Adverse events were only collected with regard to the affected organ system.	14.4% 36/250 • Number of events 37 Adverse events were only collected with regard to the affected organ system.	12.4% 32/259 • Number of events 40 Adverse events were only collected with regard to the affected organ system.
Musculoskeletal and connective tissue disorders Joint Pain/Stiffness	8.0% 40/499 • Number of events 44 Adverse events were only collected with regard to the affected organ system.	8.0% 20/250 • Number of events 25 Adverse events were only collected with regard to the affected organ system.	10.4% 27/259 • Number of events 29 Adverse events were only collected with regard to the affected organ system.
Nervous system disorders Cognitive Difficulties	5.2% 26/499 • Number of events 33 Adverse events were only collected with regard to the affected organ system.	2.0% 5/250 • Number of events 5 Adverse events were only collected with regard to the affected organ system.	6.9% 18/259 • Number of events 21 Adverse events were only collected with regard to the affected organ system.
Nervous system disorders Dizziness	7.4% 37/499 • Number of events 43 Adverse events were only collected with regard to the affected organ system.	8.0% 20/250 • Number of events 21 Adverse events were only collected with regard to the affected organ system.	6.6% 17/259 • Number of events 22 Adverse events were only collected with regard to the affected organ system.
Nervous system disorders Extremity Pain/Soreness/Stiffness	16.2% 81/499 • Number of events 105 Adverse events were only collected with regard to the affected organ system.	16.4% 41/250 • Number of events 61 Adverse events were only collected with regard to the affected organ system.	19.7% 51/259 • Number of events 68 Adverse events were only collected with regard to the affected organ system.
Nervous system disorders Extremity Weakness	5.2% 26/499 • Number of events 34 Adverse events were only collected with regard to the affected organ system.	4.0% 10/250 • Number of events 16 Adverse events were only collected with regard to the affected organ system.	6.9% 18/259 • Number of events 22 Adverse events were only collected with regard to the affected organ system.
Nervous system disorders Headaches	17.6% 88/499 • Number of events 116 Adverse events were only collected with regard to the affected organ system.	16.0% 40/250 • Number of events 50 Adverse events were only collected with regard to the affected organ system.	18.1% 47/259 • Number of events 65 Adverse events were only collected with regard to the affected organ system.
Nervous system disorders Paresthesias	7.8% 39/499 • Number of events 46 Adverse events were only collected with regard to the affected organ system.	11.2% 28/250 • Number of events 42 Adverse events were only collected with regard to the affected organ system.	6.9% 18/259 • Number of events 18 Adverse events were only collected with regard to the affected organ system.
Nervous system disorders Unspecified Neuropathic Symptoms	20.6% 103/499 • Number of events 146 Adverse events were only collected with regard to the affected organ system.	23.2% 58/250 • Number of events 92 Adverse events were only collected with regard to the affected organ system.	17.4% 45/259 • Number of events 67 Adverse events were only collected with regard to the affected organ system.
Psychiatric disorders Anxiety/Panic Attacks	8.2% 41/499 • Number of events 48 Adverse events were only collected with regard to the affected organ system.	8.0% 20/250 • Number of events 23 Adverse events were only collected with regard to the affected organ system.	8.5% 22/259 • Number of events 24 Adverse events were only collected with regard to the affected organ system.
Psychiatric disorders Depression	17.6% 88/499 • Number of events 103 Adverse events were only collected with regard to the affected organ system.	16.0% 40/250 • Number of events 50 Adverse events were only collected with regard to the affected organ system.	16.6% 43/259 • Number of events 51 Adverse events were only collected with regard to the affected organ system.
Renal and urinary disorders Urinary/Bladder Issues	8.8% 44/499 • Number of events 57 Adverse events were only collected with regard to the affected organ system.	10.8% 27/250 • Number of events 30 Adverse events were only collected with regard to the affected organ system.	8.5% 22/259 • Number of events 25 Adverse events were only collected with regard to the affected organ system.
Skin and subcutaneous tissue disorders Dental Abcess/Extraction/Procedure	8.6% 43/499 • Number of events 53 Adverse events were only collected with regard to the affected organ system.	7.2% 18/250 • Number of events 24 Adverse events were only collected with regard to the affected organ system.	12.7% 33/259 • Number of events 40 Adverse events were only collected with regard to the affected organ system.
Skin and subcutaneous tissue disorders Rash	11.4% 57/499 • Number of events 74 Adverse events were only collected with regard to the affected organ system.	8.0% 20/250 • Number of events 22 Adverse events were only collected with regard to the affected organ system.	8.5% 22/259 • Number of events 25 Adverse events were only collected with regard to the affected organ system.