Elsevier

The Lancet

Volume 370, Issue 9585, 4–10 August 2007, Pages 389-397
The Lancet

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Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study

https://doi.org/10.1016/S0140-6736(07)61194-5Get rights and content

Summary

Background

Several controlled studies provide evidence that treatment with interferon beta in patients with a first event suggestive of multiple sclerosis (MS) delays conversion to clinically definite MS (CDMS). Our aim was to determine whether early initiation of treatment with interferon beta prevents development of confirmed disability in MS.

Methods

In the initial placebo-controlled phase of the double-blinded BENEFIT study, patients with a first event suggestive of MS and a minimum of two clinically silent lesions in MRI were randomised to receive either interferon beta-1b 250 μg (n=292) or placebo (n=176) subcutaneously every other day for 2 years, or until diagnosis of CDMS. Patients were then eligible to enter the follow-up phase with open-label interferon beta-1b. In the current prospectively planned analysis 3 years after randomisation, the effects of early interferon beta-1b treatment were compared with those of delayed treatment initiated after diagnosis of CDMS or after 2 years on the study. The primary outcomes of this ITT analysis were time to diagnosis of CDMS, time to confirmed expanded disability status scale (EDSS) progression, and score on a patient-reported functional assessment scale (FAMS-TOI). This trial is registered with ClinicalTrials.gov, number NCT00185211.

Findings

Of the 468 patients originally randomised, 418 (89%) entered the follow-up phase; 392 (84%) completed 3 years' post-randomisation follow-up. After 3 years, 99 (37%) patients in the early group developed CDMS compared with 85 (51%) patients in the delayed treatment group. Early treatment reduced the risk of CDMS by 41% (hazard ratio 0·59, 95% CI 0·44–0·80; p=0·0011; absolute risk reduction 14%) compared with delayed treatment. Over 3 years, 42 (16%) patients in the early group and 40 (24%) in the delayed group had confirmed EDSS progression; early treatment reduced the risk for progression of disability by 40% compared with delayed treatment (0·60, 0·39–0·92; p=0·022; absolute risk reduction 8%). The FAMS-TOI score was high and stable in both groups over the 3-year period (p=0·31).

Interpretation

Our data suggest that early initiation of treatment with interferon beta-1b prevents the development of confirmed disability, supporting its use after the first manifestation of relapsing-remitting MS.

Introduction

Three multicentre, placebo-controlled studies have shown that treatment of patients with a first episode of neurological symptoms (also called clinically isolated syndrome) highly suggestive of multiple sclerosis (MS) with interferon beta delays conversion to clinically definite MS (CDMS).1, 2, 3, 4 Furthermore, neuropathological findings suggest the potential for immunomodulatory treatment of MS to have a greater effect early in the disease course, by early inhibition of the cascade of events that leads to irreversible axonal damage and disability.5, 6, 7 However, until now, there has been no controlled evidence showing that treatment with interferon beta initiated early after the first event has an effect on the development of confirmed disability as compared with delayed treatment. The Betaferon/Betaseron in Newly Emerging multiple sclerosis For Initial Treatment (BENEFIT) study, assessing interferon beta-1b in patients with a first event suggestive of MS, was designed to address this issue. Here, we present the results of the preplanned 3-year analysis of BENEFIT.

Section snippets

Patients and procedures

The BENEFIT study consisted of a placebo-controlled phase and a follow-up phase. The 2-year double-blinded, placebo-controlled phase, which was completed in 2005,3 assessed the safety, tolerability, and efficacy of interferon beta-1b 250 μg (8 MIU) subcutaneously every other day in patients with a first event suggestive of MS. Eligible patients had experienced a first neurological event suggestive of MS and had at least two clinically silent lesions on a T2-weighted brain magnetic resonance

Results

Figure 1 shows the trial profile. 418 (89%) of the 468 patients who had started placebo-controlled treatment chose to enter the follow-up phase; 378 of these individuals opted for follow-up treatment with interferon beta-1b 250 μg subcutaneously every other day. 392 (84%) completed 3 years' follow-up; 343 of those who had opted for further treatment were still on interferon beta-1b at this time. The median exposure time to interferon beta-1b over the 3-year period was 1080 days (IQR 854–1093)

Discussion

We found a beneficial effect of early treatment with interferon beta-1b (250 μg, every other day, subcutaneously) on 6-month confirmed EDSS progression 3 years after the first event suggestive of MS, indicating that a delay of such treatment by, essentially, just one event, even at this early stage of the disease, has an effect on later accumulation of disability. Even though most patients in both groups remained at a low level of disability 3 years after the initial event, the delay in

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    Members listed at end of report

    Contributed equally to the study

    *

    Dr Dahms died in July, 2007

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