ArticlesRandomised double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis
Introduction
Therapeutic advances in multiple sclerosis (MS) have been slow to emerge, partly because of incomplete understanding of the pathogenesis of the disorder. For empirically based treatment the major obstacles to progress include the highly variable course of MS, the long-term nature of the most important outcome measures, and the lack of objective markers of treatment effect, particularly in the short term. Although the pathogenesis of MS remains uncertain, the natural history continues to be studied.1, 2, 3, 4, 5, 6 Objective outcome measures based on magnetic resonance imaging (MRI) have been developed7, 8, 9, 10, 11 and many of the pitfalls of clinical trials are now known, which has led to improved trial methods and better interpretation of results.12
Two double-blind, placebo-controlled studies have shown interferon β to be active in relapsing/remitting MS at various doses and by different routes of administration, but evidence of efficacy has not been universally accepted.13, 14, 15, 16, 17, 18 The first of the studies used interferon β-1b, which is produced in Escherichia coli and which differs from natural interferon β by two aminoacids and by its lack of a glycosylated side-chain. At the high dose tested (8 million IU subcutaneously on alternate days), that study showed a 34% decrease in the relapse rate and a pronounced decrease in accumulation of disease burden as measured by the volume of T2-weighted lesions on MRI after 2 years. However, the effect of treatment on progression in disability was not significant8, 9, 13 There was some concern over the high immunogenicity of interferon β-1b and the possible consequences for treatment efficacy.13
The second phase 3 study14 used interferon β-1a, which is produced in mammalian cells, and which has the same aminoacid sequence and carbohydrate side-chain as the natural human cytokine. In that trial, patients with mild relapsing/remitting MS (scores on the Kurtzke expanded disability status scale [EDSS] of 1·0–3·5) were treated with weekly intramuscular injections of 30 μg for 1–2 years. The treatment had some effect on relapses (not significant at 1 year, 18% reduction at 2 years), and some effect on the MRI T2-weighted burden of disease.14, 19 There was a significant delay in 6-month confirmed progression by 1 point in the lower part of the EDSS, which measures impairment and not disability. However, the clinical significance of that result was unclear because of the small numbers of patients, the premature termination of the trial, the small and delayed effect on relapses, several analytical and methodological issues, and the disparity between the data on T2-weighted burden of disease and the data from the interferon β-1b trial.16
Our double-blind, randomised, placebo-controlled study with interferon β-1a addressed some of the questions raised by the other trials for the major outcome measures relapse rate, disability, and disease activity and burden of disease shown by MRI. The primary hypothesis was that interferon β-1a would lower the relapse rate. Earlier studies13, 20, 21 suggested a dose effect, so we chose more intensive regimens of interferon β-1a for our study (66 and 132 μg per week). Since the bioavailability of the particular formulation of interferon β-1a that we used (Rebif, Ares-Serono) is comparable after subcutaneous and intramuscular injection,22 the subcutaneous route was chosen because it is more convenient for the patient.
Section snippets
Patients
We studied 560 patients from 22 centres in nine countries, who had clinically definite or laboratory-supported definite MS23 of at least 1 year's duration. Patients were recruited between May, 1994, and February, 1995.24 Adults with relapsing/remitting MS were eligible for study if they had had at least two relapses in the preceding 2 years and had Kurtzke EDSS scores of 0–5·0.25 Exclusion criteria included any previous systemic treatment with interferons, lymphoid irradiation, or
Patients
Of the 560 patients randomised, 533 (95%) completed 1 year of treatment and 502 (90%) completed 2 years of treatment. 2 years of data were available for 533 (95%) patients, including follow-up for most patients who stopped treatment prematurely, to give a total of 1094 patient-years of observation (figure 1). 58 patients discontinued treatment prematurely; 17 had an adverse event, 26 patients decided to stop treatment, six became pregnant, four had disease progression, two died of unrelated
Discussion
Our study showed that for all major outcome measures—relapse, sustained progression in functional impairment and disability, and MRI lesion change including lesion burden and “activity” measures—there were significant benefits from subcutaneous treatment with interferon β-1a at either of two doses. The reduction in relapse rate from that with placebo (27–33%) is similar to that shown in the interferon β-1b study9 and to that shown with copolymer 1,31 and greater than that previously reported
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