Elsevier

The Lancet

Volume 352, Issue 9139, 7 November 1998, Pages 1491-1497
The Lancet

Articles
Placebo-controlled multicentre randomised trial of interferon β-1b in treatment of secondary progressive multiple sclerosis

https://doi.org/10.1016/S0140-6736(98)10039-9Get rights and content

Summary

Background

The beneficial effects of interferon β have only been shown for patients in the relapsing-remitting phase of multiple sclerosis (MS). The role of interferon β in the treatment of patients who are in the secondary progressive phase of the disease (SP-MS), and for whom no effective drug treatment is available, has not been assessed.

Methods

In this multicentre, double-masked, randomised, placebo-controlled trial, outpatients with SP-MS having scores of 3·0–6·5 on the Expanded Disability Status Scale (EDSS) received either 8 million IU interferon β-1b every other day subcutaneously, or placebo, for up to 3 years. The primary outcome was the time to confirmed progression in disability as measured by a 1·0 point increase on the EDSS, sustained for at least 3 months, or a 0·5 point increase if the baseline EDSS was 6·0 or 6·5. A prospectively planned interim analysis of safety and efficacy of the intention-to-treat population was done after all patients had been in the study for at least 2 years.

Findings

358 patients with SP-MS were allocated placebo and 360 were allocated interferon β-1b; 57 patients (31 placebo, 26 interferon β-1b) were lost to follow-up. There was a highly significant difference in time to confirmed progression of disability in favour of interferon β-1b (p=0·0008). Interferon β-1b delayed progression for 9–12 months in a study period of 2–3 years. The odds ratio for confirmed progression was 0·65 (95% Cl 0·52–0·83). This beneficial effect was seen in patients with superimposed relapses and in patients who had only progressive deterioration without relapses. Positive results were also obtained regarding time to becoming wheelchair-bound, relapse rate and severity, number of steroid treatments and hospital admissions, as well as on magnetic resonance imaging variables. The drug was safe and side effects were in line with previous experience with interferon β-1b. The study was stopped after the interim results gave clear evidence of efficacy.

Interpretation

Treatment with interferon β-1b delays sustained neurological deterioration in patients with SP-MS. Interferon β-1b is the first treatment to show a therapeutic effect in patients with SP-MS.

Introduction

In 1993, interferon β-1b emerged as a therapeutic option in multiple sclerosis (MS) and has been hailed as a major advance in the management of this disorder.1 Three products containing interferon β are available, and phase III trials for each product have shown a reduction in relapse rate by 18–34% in patients with relapsing-remitting MS.1, 2, 3 This reduction in disease activity was associated with a striking effect on abnormalities detected by magnetic resonance imaging (MRI), particularly on the development of new and contrast enhancing lesions.

A major concern of patients with MS and their physicians, is accrual of disability when the disease has reached the secondary-progressive (SP-MS) phase. In SP-MS, disability becomes the dominant factor and determines the level of support required and costs incurred.4 Three studies1, 2, 3 have given some indication of an effect of interferon β on the accrual of disability but such an effect was difficult to address persuasively: the patient groups studied were in the early stage of the disease with little if any disability, reflected by low Expanded Disability Status Scale (EDSS) scores, and at a time when disability was unlikely to develop over a 2–3 year period. The EDSS measured impairment rather than disability in the group of patients who had scores in the lower part (0–3·0) of the scale.5, 6 The one study2 in which time to sustained change on the EDSS was used as the primary outcome measure, recruited patients with the lowest EDSS scores and was of the shortest duration.

Disability in MS can result from two distinct, though in many cases, overlapping mechanisms: failure to recover from relapse (incomplete remission) and slow insidious progression. These mechanisms may have different underlying pathologies.7 In patients with relapsing-remitting disease, the failure to recover from relapse is the sole cause of disability, while patients with secondary progressive MS accrue disability from both relapses and insidious progression.

To address the effects of interferon β-1b on disease progression in patients with SP-MS, we started a large placebo-controlled multicentre European study in 1994.8 The main clinical findings of a prospectively planned interim analysis are presented here.

Section snippets

Design

This is a European, multicentre, double-blind, placebo-controlled study of two parallel-treatment groups of outpatients with SP-MS. The study was planned to have a 36-month period of treatment, followed by a drug-free follow-up of 3 months. Regular visits were scheduled for days 1, 3, 5, and 15, months 1–3, and thereafter every 3 months until month 36 (end of treatment) and month 39 (end of drug-free follow-up). Unscheduled visits for assessment and treatment of relapses and other non-MS

Study population

As shown in figure 1, 718 of 768 patients screened in 32 European centres were randomly assigned interferon β-1b (n=360) or placebo (n=358). The mean follow-up time at inerim cut-off was 892 study days in the placebo group and 901 days in the interferon β-1b group, comprising about 85% of EDSS information anticipated over the planned study duration of 3 years. Treatment groups were comparable for all baseline variables (table 2). Of these, 57 patients (31 [8·7%] placebo, 26 [7·2%] interferon

Discussion

This phase III study shows a therapeutic benefit of interferon β-1b in SP-MS. SP-MS is reported to be the most common phase of the disease and the one during which major irreversible disabilities most often appear.17, 18

The cohort studied was representative for this disease group, including patients who progressed with or without superimposed relapses following an initial relapsing-remitting phase.10 Patients were in the early stage of progression beginning about 10 years after initial

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