Randomized study combining interferon and glatiramer acetate in multiple sclerosis

Abstract

Objective A double-blind, randomized, controlled study to determine if combined use of interferon beta-1a (IFN) 30ug IM weekly and glatiramer acetate (GA) 20mg daily is more efficacious than either agent alone in relapsing-remitting multiple sclerosis (RRMS). Methods 1008 participants were randomized and followed until the last participant enrolled completed 3 yrs. 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 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 EDSS 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 two most commonly prescribed therapies for MS did not produce a significant clinical benefit over three 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 if the observed differences in MRI and DAFS findings predict later clinical differences.

Comparative effectiveness of delayed-release dimethyl fumarate versus glatiramer acetate in multiple sclerosis patients: results of a matching-adjusted indirect comparison

“…For the indirect comparison, patients treated with DMF in the DEFINE and CONFIRM studies were weighted so that after weighting, the weighted mean matched to that of patients treated with GA in the US study, in the EUR/CAN study and in BEYOND Several studies of GA were not included in this post hoc analysis because the end points were not defined in the same manner as the comparators and therefore the data could not be pooled. Specifically, ARR was either not reported (in Bornstein et al [19]) or [33] and BECOME [34]). All ARR comparisons in this paper were analyzed using ARR adjusted for PBO.…”

“…All ARR comparisons in this paper were analyzed using ARR adjusted for PBO. ARR adjusted for the active-reference arm could not be used because of the different treatment comparators: REGARD compared GA with IFN β-1a [32], BECOME compared GA with IFN β-1b [34] and CombiRx compared GA with IFN β-1a or treatment with both GA and IFN β-1a [33]. These studies did not compare ARR for GA with PBO.…”

“…These studies did not compare ARR for GA with PBO. Furthermore, 12-week confirmed disability progression (CDP) was not reported in BECOME [34], REGARD [32], Bornstein et al [19] or CombiRx [33]. In REGARD [32] and CombiRx [33], 24-week CDP was reported but 12-week CDP was not.…”

The heritage of glatiramer acetate and its use in multiple sclerosis

“…Combination treatment trials Two important combination therapy trials are the CombiRx trial [84] and the GLANCE trial [85] (Table 1). In CombiRx, patients were randomised to GA 20 mg/mL once daily plus IFN-β1a 30 μg once weekly or to monotherapy with one of these medications plus placebo for 3 years.…”

Advances in and Algorithms for the Treatment of Relapsing-Remitting Multiple Sclerosis

“…In addition to ongoing developments regarding B-and T-celltargeted approaches combination therapies have been proposed in the past but remain an unresolved issue. Apart from economic considerations (the already high cost of all DMTs could be increased by combination preparations), only a few systematic approaches have been undertaken and have rather tamed enthusiasm: some were unsuccessful (e.g., CombiRx, comparing a combination of intramuscular IFN1βa plus GA with either 1 of the 2 [104]), or raised safety issues when combining 2 immunomodulatory agents (e.g., PML cases in SENTINEL comparing natalizumab plus intramuscular IFN-1βa with IFN-β alone). An interesting approach, however, may be the combination of immunomodulatory agents with neuroprotective ones like LINGO-1 [105,106].…”