Elsevier

The Lancet

Volume 352, Issue 9139, 7 November 1998, Pages 1498-1504
The Lancet

Articles
Randomised double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis

https://doi.org/10.1016/S0140-6736(98)03334-0Get rights and content

Summary

Background

Previous trials of interferon β in multiple sclerosis (MS) have shown efficacy, but the degree of clinical benefit remains uncertain, and the optimum dose is not known. We undertook a double-blind, placebo-controlled study in relapsing/remitting MS to investigate the effects of subcutaneous interferon β-1a.

Methods

560 patients with Kurtzke expanded disability status scale (EDSS) scores of 0–5·0, from 22 centres in nine countries, were randomly assigned subcutaneous recombinant interferon β-1a 22 μg (n=189), or 44 μg (n=184), or placebo (n=187) three times a week for 2 years. Neurological examinations were done every 3 months. All patients had MRI twice yearly and 205 had monthly scans in the first 9 months of treatment. Analysis was by intention to treat.

Findings

Clinical data on 533 (95%) patients were available at 2 years. The relapse rate was significantly lower at 1 and 2 years with both doses of interferon β-1a than with placebo (mean number per patient 1·82 for 22 μg group, 1·73 for 44 μg group vs 2·56 for placebo group: risk reductions 27% [95% Cl 14–39] and 33 [21–44]). Time to first relapse was prolonged by 3 and 5 months in the 22 μg and 44 μg groups respectively, and the proportion of relapse-free patients was significantly increased (p < 0·05). Interferon β-1a delayed progression in disability, and decreased accumulated disability during the study. The accumulation of burden of disease and number of active lesions on MRI was lower in both treatment groups than in the placebo group.

Interpretation

Subcutaneous interferon β-1a is an effective treatment for relapsing/remitting MS in terms of relapse rate, defined disability, and all MRI outcome measures in a dose-related manner, and it is well tolerated. Longer-term benefits may become clearer with further follow-up and investigation.

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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