ArticlesComparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomised controlled trial
Introduction
The first clinical manifestation of multiple sclerosis (MS) is often a single neurological event consistent with one or more white matter lesions in the CNS, such as optic neuritis.1 This event is usually followed by the recurrent attacks that characterise relapsing MS.2, 3 The recurrence of attacks consistent with CNS demyelination has traditionally been used to make a definitive diagnosis of MS (clinically definite MS [CDMS]).4, 5 The criteria introduced by Poser and colleagues5 in 1983 required two clinical attacks for a diagnosis of CDMS, although clinical, paraclinical, and laboratory evidence could be taken into account for a diagnosis of probable MS. More recently, advances in MRI techniques have led to the development of the McDonald criteria6, 7, 8 for an earlier diagnosis of MS (McDonald MS) if the first clinical event is accompanied by specific subclinical MRI features. For a diagnosis of McDonald MS, the MRI evidence of disease must show that CNS lesions are disseminated in time and space. These criteria, first introduced in 2001,6 were revised in 20057 and 20108 to improve their sensitivity for early MS diagnosis without compromising specificity.
Many patients are now treated as early as possible after a first clinical event, without the need to wait for a diagnosis of definite MS.9 In several studies, treatment with interferon beta or glatiramer acetate at the time of the first clinical event delayed the occurrence of further attacks and the onset of MS.10, 11, 12, 13, 14 Furthermore, early treatment with interferon beta can also affect long-term disease progression.11, 15 In the Early Treatment of MS (ETOMS) study,16 subcutaneous interferon beta-1a at 22 μg once a week was effective in delaying MS. However, until now the effect of subcutaneous interferon beta-1a at 44 μg three times a week—the licensed dosing regimen for MS—has not been assessed in people with a clinically isolated event. In our 2-year, double-blind phase 3 study (REbif FLEXible dosing in early MS [REFLEX]), we compared the effects of two dosing frequencies of a serum-free formulation of subcutaneous interferon beta-1a 44 μg with placebo on time to development of MS, as defined in the 2005 version of the McDonald criteria.7
Section snippets
Patients
Patients from 80 centres in 28 countries were recruited into the phase 3 REFLEX study. They were eligible for inclusion if they were aged 18–50 years and had the following: an expanded disability status scale (EDSS)17 score of 0–5·0; a single event suggestive of MS within 60 days before study entry; and at least two clinically silent lesions of 3 mm or more on T2-weighted brain MRI scan, at least one of which was ovoid, periventricular, or infratentorial. Exclusion criteria included diagnosis
Results
The first patient's first visit was on Nov 16, 2006; the last patient's last visit was on Aug 13, 2010. 701 patients were screened and of these 517 were randomly assigned and included in the intention-to-treat population (subcutaneous interferon beta-1a three times a week, n=171; subcutaneous interferon beta-1a once a week, n=175; and placebo, n=171; figure 1). One patient in each group withdrew consent before treatment, resulting in a total of 514 patients from the intention-to-treat
Discussion
The serum-free formulation of subcutaneous interferon beta-1a significantly delayed time to McDonald MS and CDMS compared with placebo in patients with a first demyelinating event that was suggestive of MS, thereby further supporting the early treatment model of MS. The effect was consistent across subgroups defined according to baseline characteristics. In this subgroup analysis, the risk reductions in the interferon beta-1a group were around 50%, which can be regarded as clinically relevant.
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