Elsevier

The Lancet Neurology

Volume 8, Issue 11, November 2009, Pages 987-997
The Lancet Neurology

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Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial

https://doi.org/10.1016/S1474-4422(09)70237-6Get rights and content

Summary

Background

The Betaferon/Betaseron in newly emerging multiple sclerosis for initial treatment (BENEFIT) trial investigated the effect of treatment with interferon beta-1b after a clinically isolated syndrome. The 5-year active treatment extension compares the effects of early and delayed treatment with interferon beta-1b on time to clinically definite multiple sclerosis (CDMS) and other disease outcomes, including disability progression.

Methods

Patients with a first event suggestive of multiple sclerosis and a minimum of two clinically silent lesions in MRI were randomly assigned to receive interferon beta-1b 250 μg (n=292; early treatment) or placebo (n=176; delayed treatment) subcutaneously every other day for 2 years, or until diagnosis of CDMS. All patients were then eligible to enter a prospectively planned follow-up phase with open-label interferon beta-1b up to a maximum of 5 years after randomisation. Patients and study personnel remained unaware of initial treatment allocation throughout the study. Primary endpoints were time to CDMS, time to confirmed disability progression measured with the expanded disability status scale, and the functional assessment of multiple sclerosis trial outcomes index (FAMS-TOI) at 5 years. Analysis of the primary endpoints was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00185211.

Findings

235 (80%) patients from the early treatment and 123 (70%) from the delayed treatment group completed the 5-year study. Early treatment reduced the risk of CDMS by 37% (hazard ratio [HR] 0·63, 95% CI 0·48–0·83; p=0·003) compared with delayed treatment. The risk for confirmed disability progression was not significantly lower in the early treatment group (0·76, 0·52–1·11; p=0·177). At 5 years, median FAMS-TOI scores were 125 in both groups. No significant differences in other disability related outcomes were recorded. Frequency and severity of adverse events remained within the established safety and tolerability profile of interferon beta-1b.

Interpretation

Effects on the rate of conversion to CDMS and the favourable long-term safety and tolerability profile support early initiation of treatment with interferon beta-1b, although a delay in treatment by up to 2 years did not affect long-term disability outcomes.

Funding

Bayer Schering Pharma.

Introduction

Multiple sclerosis typically presents with a first episode of neurological dysfunction from which most patients eventually recover fully. This episode is known as a clinically isolated syndrome. Over time, most patients with a clinically isolated syndrome in whom additional clinically silent brain lesions on MRI suggest disseminated inflammatory CNS disease develop relapsing-remitting multiple sclerosis and have a substantial risk for later progression of disability.1, 2, 3 Previous studies in patients with clinically isolated syndromes have shown a beneficial effect of early treatment with interferon beta and glatiramer acetate on the risk of conversion to clinically definite multiple sclerosis (CDMS), but they were too short and not prospectively designed to capture any effect on disability.4, 5, 6, 7 Moreover, these trials did not address whether a delay in starting treatment has a long-term effect on disease course.

In the Betaferon/Betaseron in newly emerging multiple sclerosis for initial treatment (BENEFIT) trial, patients who had a clinically isolated syndrome and a minimum of two clinically silent lesions on brain MRI were randomly assigned to receive either interferon beta-1b 250 μg or placebo subcutaneously every other day for 2 years, or until diagnosis of CDMS. Patients were then eligible to enter a prospectively planned follow-up phase with open-label interferon beta-1b for up to 5 years. The effects of early interferon beta-1b treatment were compared with those of delayed treatment initiated after diagnosis of CDMS or after 2 years of study.

At the preplanned 3-year analysis of the BENEFIT study, disability progression was delayed in patients treated early with interferon beta-1b, with a 40% lower relative risk of confirmed progression on the expanded disability status scale (EDSS; p=0·022) and a 41% lower relative risk of conversion to CDMS (p=0·0011).8 Here we report the 5-year analysis of this trial.

Section snippets

Patients

Eligible patients had experienced a first neurological event suggestive of multiple sclerosis and had at least two clinically silent lesions on a T2-weighted brain MRI. Patients were aged 18–45 years with a baseline EDSS score9 of 0–5. Patients in whom any disease other than multiple sclerosis could explain their signs and symptoms were excluded, as were those with any previous episode that could possibly be attributed to an acute demyelinating event, those with complete transverse myelitis or

Results

418 (89%) of the 468 patients who had started placebo-controlled treatment between February, 2002, and June, 2003, entered the follow-up phase (261 in the early treatment group, 157 in the delayed treatment group; of these, 235 and 147 patients received active treatment in the follow-up phase; figure 1).8 235 (80%) of 292 patients from the interferon beta-1b group and 123 (70%) of 176 from the placebo group completed the full 5 years of the study (of these, 191 and 90 respectively were

Discussion

The 5-year analysis of the BENEFIT study substantiates some findings in favour of early intervention that had already been observed at the 3-year timepoint.8 An earlier initiation of interferon beta-1b reduced the risk for a diagnosis of multiple sclerosis with clinical or McDonald criteria at 5 years, even though both treatment groups had received active intervention for at least 3 years. Likewise, the annualised relapse rate over 5 years was significantly lower in the early treatment group;

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