Randomized study combining interferon and glatiramer acetate in multiple sclerosis

Abstract

Objective: A double-blind, randomized, controlled study was undertaken to determine whether combined use of interferon β-1a (IFN) 30 μg intramuscularly weekly and glatiramer acetate (GA) 20 mg daily is more efficacious than either agent alone in relapsing-remitting multiple sclerosis.

Methods: A total of 1,008 participants were randomized and followed until the last participant enrolled completed 3 years. The primary endpoint was reduction in annualized relapse rate utilizing a strict definition of relapse. Secondary outcomes included time to confirmed disability, Multiple Sclerosis Functional Composite (MSFC) score, and magnetic resonance imaging (MRI) metrics.

Results: Combination IFN+GA was not superior to the better of the single agents (GA) in risk of relapse. Both the combination therapy and GA were significantly better than IFN in reducing the risk of relapse. The combination was not better than either agent alone in lessening confirmed Expanded Disability Status Scale progression or change in MSFC over 36 months. The combination was superior to either agent alone in reducing new lesion activity and accumulation of total lesion volumes. In a post hoc analysis, combination therapy resulted in a higher proportion of participants attaining disease activity-free status (DAFS) compared to either single arm, driven by the MRI results.

Interpretation: Combining the 2 most commonly prescribed therapies for multiple sclerosis did not produce a significant clinical benefit over 3 years. An effect was seen on some MRI metrics. In a test of comparative efficacy, GA was superior to IFN in reducing the risk of exacerbation. The extension phase for CombiRx will address whether the observed differences in MRI and DAFS findings predict later clinical differences.

Trial registration: ClinicalTrials.gov NCT00211887.

Figure 1

CombiRx Design & Trial Assessments

Figure 2

Relapse Definitions

Figure 3

Consort Diagram

Figure 4

Annualized Relapse Rate by Treatment Group IFN + GA – Solid Black IFN – Gray Hashed GA – Solid Gray

Figure 5. MRI Lesion Activity and Volume Measures Over Time to 36 Months^a

Figure 5A. Mean GD Lesions Figure 5B. Cumulative Combined Unique Activity (CUA) on Study Figure 5C. Total Lesion Volume Figure 5D. T1 Hypointense Lesion Volume Figure 5E. Normalized CSF ^a – Month 0 adjusted for age, Months 6 – 36 adjusted for Month 0 and age IFN + GA - Solid Black Line with Solid Black Diamond IFN – Long Dashed Line with Upright Triangle GA – Short Dashed Line with Inverse Triangle

Figure 5. MRI Lesion Activity and Volume Measures Over Time to 36 Months^a

Figure 5A. Mean GD Lesions Figure 5B. Cumulative Combined Unique Activity (CUA) on Study Figure 5C. Total Lesion Volume Figure 5D. T1 Hypointense Lesion Volume Figure 5E. Normalized CSF ^a – Month 0 adjusted for age, Months 6 – 36 adjusted for Month 0 and age IFN + GA - Solid Black Line with Solid Black Diamond IFN – Long Dashed Line with Upright Triangle GA – Short Dashed Line with Inverse Triangle

Figure 5. MRI Lesion Activity and Volume Measures Over Time to 36 Months^a

Figure 5A. Mean GD Lesions Figure 5B. Cumulative Combined Unique Activity (CUA) on Study Figure 5C. Total Lesion Volume Figure 5D. T1 Hypointense Lesion Volume Figure 5E. Normalized CSF ^a – Month 0 adjusted for age, Months 6 – 36 adjusted for Month 0 and age IFN + GA - Solid Black Line with Solid Black Diamond IFN – Long Dashed Line with Upright Triangle GA – Short Dashed Line with Inverse Triangle

Figure 5. MRI Lesion Activity and Volume Measures Over Time to 36 Months^a

Figure 5A. Mean GD Lesions Figure 5B. Cumulative Combined Unique Activity (CUA) on Study Figure 5C. Total Lesion Volume Figure 5D. T1 Hypointense Lesion Volume Figure 5E. Normalized CSF ^a – Month 0 adjusted for age, Months 6 – 36 adjusted for Month 0 and age IFN + GA - Solid Black Line with Solid Black Diamond IFN – Long Dashed Line with Upright Triangle GA – Short Dashed Line with Inverse Triangle

Figure 5. MRI Lesion Activity and Volume Measures Over Time to 36 Months^a

Figure 5A. Mean GD Lesions Figure 5B. Cumulative Combined Unique Activity (CUA) on Study Figure 5C. Total Lesion Volume Figure 5D. T1 Hypointense Lesion Volume Figure 5E. Normalized CSF ^a – Month 0 adjusted for age, Months 6 – 36 adjusted for Month 0 and age IFN + GA - Solid Black Line with Solid Black Diamond IFN – Long Dashed Line with Upright Triangle GA – Short Dashed Line with Inverse Triangle

Figure 6. Clinical and Disease Activity Free Status

Figure 6A. Clinical Activity Free Status Figure 6B. Disease Activity Free Status IFN + GA – Solid Black IFN – Gray Hashed GA – Solid Gray

Figure 6. Clinical and Disease Activity Free Status

Figure 6A. Clinical Activity Free Status Figure 6B. Disease Activity Free Status IFN + GA – Solid Black IFN – Gray Hashed GA – Solid Gray