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Combination Therapy with Interferon Beta-1a and Glatiramer Acetate in Relapsing-Remitting Multiple Sclerosis

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Year of Publication: 2013

Authors: Lublin FD, Cofield SS, Cutter GR, ..., Wolinsky JS; CombiRx Investigators

Journal: Annals of Neurology

Citation: Lublin FD et al. Ann Neurol. 2013;73(3):327-340. DOI: 10.1002/ana.23863

Link: https://pubmed.ncbi.nlm.nih.gov/23483994/

Clinical Question

Is combination therapy with interferon beta-1a plus glatiramer acetate superior to either drug alone for reducing relapse rate in relapsing-remitting multiple sclerosis?

Bottom Line

Combination therapy with IFN beta-1a and GA was NOT superior to GA monotherapy for reducing relapse rate in RRMS (ARR 0.22 vs 0.25, p=0.27). Unexpectedly, GA alone was significantly better than IFN alone (p=0.03). The combination did show MRI benefits over IFN alone but not over GA alone, while causing more adverse events. This landmark negative trial ended the longstanding question of whether combining these two first-line therapies would produce synergistic benefit.

        Major Points
        Primary endpoint negative: combination ARR 0.22 not significantly different from GA alone ARR 0.25 (p=0.27)
GA alone was significantly superior to IFN alone for relapse rate (0.25 vs 0.33, p=0.03) -- unexpected finding favoring GA
Combination was superior to IFN alone (0.22 vs 0.33, p=0.03) but this benefit was entirely attributable to the GA component
MRI: combination reduced new/enlarging T2 lesions vs IFN alone but not vs GA alone
No significant differences in disability progression (EDSS) among the three arms
Combination had highest adverse event burden without added efficacy over GA monotherapy
Largest NIH-funded MS treatment trial; definitively answered the combination therapy question

      

Design

Study Type: Phase 3, multicenter, randomized, double-blind, double-dummy, parallel-group trial

Randomization: 1

Blinding: Double-blind, double-dummy (all patients received both IM injection and SC injection, one active and one placebo)

Enrollment Period: 2005-2009

Follow-up Duration: 3 years

Centers: 70

Countries: United States

Sample Size: 1008

Analysis: Intention-to-treat; 2:1:1 randomization (combo:IFN:GA); NCT00211887

Inclusion Criteria

Age 18-60 years
Relapsing-remitting MS by McDonald criteria
EDSS score 0-5.5
At least 2 relapses in the 3 years prior to enrollment or at least 1 relapse in the 13 months prior
MRI showing lesions consistent with MS
Able to self-inject or have caregiver administer injections

Exclusion Criteria

Primary or secondary progressive MS
Prior treatment with IFN beta or GA for more than 6 months
Treatment with mitoxantrone, cyclophosphamide, or other immunosuppressants within 12 months
Treatment with natalizumab at any time
Significant medical illness (hepatic, renal, cardiac, pulmonary)
Pregnancy or planned pregnancy during study period
History of depression with suicidal ideation

Arms

Field	Combination (IFN + GA)	Interferon beta-1a Alone	Glatiramer Acetate Alone
Intervention	Interferon beta-1a 30 mcg IM weekly + glatiramer acetate 20 mg SC daily	Interferon beta-1a 30 mcg IM weekly + SC placebo daily	IM placebo weekly + glatiramer acetate 20 mg SC daily
Duration	3 years	3 years	3 years

Outcomes

Outcome	Type	Control	Intervention	P-value
Exacerbation (relapse) rate over 3 years	Primary	GA alone: ARR 0.25; IFN alone: ARR 0.33	Combination: ARR 0.22	Combo vs GA: p=0.27 (NS); Combo vs IFN: p=0.03; GA vs IFN: p=0.03
Time to first relapse \| Result: No significant difference between combination and GA alone	Secondary
EDSS progression sustained 6 months \| Result: No significant differences among the three arms	Secondary
New/enlarging T2 lesions \| Result: Combination fewer than IFN alone; combination vs GA not significant	Secondary
T2 lesion volume change \| Result: Combination and GA similar; both superior to IFN	Secondary
Brain atrophy (BPF change) \| Result: No significant differences among arms	Secondary
Flu-like symptoms	Adverse	GA: 19%	Combo: 53%, IFN: 49%
Injection-site reactions (SC)	Adverse	IFN: 7%	Combo: 47%, GA: 50%
Liver enzyme elevation	Adverse	GA: 3%	Combo: 14%, IFN: 12%
Depression	Adverse	GA: 11%	Combo: 15%, IFN: 17%
Leukopenia	Adverse	GA: 2%	Combo: 8%, IFN: 7%
Any serious adverse event	Adverse	IFN: 16%, GA: 13%	Combo: 18%

Subgroup Analysis

Results consistent across subgroups by baseline EDSS, prior relapse frequency, and MRI activity; no subgroup showed combination benefit over GA

Criticisms

2:1:1 randomization (499 combo vs 250 IFN vs 259 GA) gives more statistical power for combo comparisons but less for head-to-head IFN vs GA
IFN beta-1a 30 mcg IM weekly (Avonex dose) is the lowest IFN dose; higher-dose IFN formulations (44 mcg SC) might have performed differently
3-year duration may be insufficient to detect differences in disability progression
Double-dummy design required patients to receive both IM and SC injections, increasing placebo-related injection-site reactions
No dose optimization period: fixed IFN dose from start may increase early dropout due to flu-like symptoms
Trial did not include high-efficacy comparators (natalizumab, fingolimod) that were available by completion

Funding

National Institute of Neurological Disorders and Stroke (NINDS), NIH -- non-industry

Based on: CombiRx (Annals of Neurology, 2013)