Elsevier

The Lancet Neurology

Volume 7, Issue 10, October 2008, Pages 903-914
The Lancet Neurology

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Comparison of subcutaneous interferon beta-1a with glatiramer acetate in patients with relapsing multiple sclerosis (the REbif vs Glatiramer Acetate in Relapsing MS Disease [REGARD] study): a multicentre, randomised, parallel, open-label trial

https://doi.org/10.1016/S1474-4422(08)70200-XGet rights and content

Summary

Background

Interferon beta-1a and glatiramer acetate are commonly prescribed for relapsing-remitting multiple sclerosis (RRMS), but no published randomised trials have directly compared these two drugs. Our aim in the REGARD (REbif vs Glatiramer Acetate in Relapsing MS Disease) study was to compare interferon beta-1a with glatiramer acetate in patients with RRMS.

Methods

In this multicentre, randomised, comparative, parallel-group, open-label study, patients with RRMS diagnosed with the McDonald criteria who had had at least one relapse within the previous 12 months were randomised to receive 44 μg subcutaneous interferon beta-1a three times per week or 20 mg subcutaneous glatiramer acetate once per day for 96 weeks to assess the time to first relapse. A subpopulation of 460 patients (230 from each group) also had serial MRI scans to assess T2-weighted and gadolinium-enhancing lesion number and volume. Treatments were assigned by a computer-generated randomisation list that was stratified by centre. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00078338.

Findings

Between February and December, 2004, 764 patients were randomly assigned: 386 to interferon beta-1a and 378 to glatiramer acetate. After 96 weeks, there was no significant difference between groups in time to first relapse (hazard ratio 0·94, 95% CI 0·74 to 1·21; p=0·64). Relapse rates were lower than expected: 258 patients (126 in the interferon beta-1a group and 132 in the glatiramer acetate group) had one or more relapses (the expected number was 460). For secondary outcomes, there were no significant differences for the number and change in volume of T2 active lesions or for the change in the volume of gadolinium-enhancing lesions, although patients treated with interferon beta-1a had significantly fewer gadolinium-enhancing lesions (0·24 vs 0·41 lesions per patient per scan, 95% CI −0·4 to 0·1; p=0·0002). Safety and tolerability profiles were consistent with the known profiles for both compounds. The overall number and severity of adverse events were similar between the treatments and were not an important cause for discontinuation of the trial during the 96 weeks.

Interpretation

There was no significant difference between interferon beta-1a and glatiramer acetate in the primary outcome. The ability to predict clinical superiority on the basis of results from previous studies might be limited by a trial population with low disease activity, which is an important consideration for ongoing and future trials in patients with RRMS.

Funding

EMD Serono; Pfizer.

Introduction

Multiple sclerosis (MS) is a chronic disorder that is characterised by pathological (immune-mediated CNS demyelination and axonal injury)1, 2 and clinical (exacerbations, disability progression) dissemination in time and space.3 At present, six treatments are approved for patients with MS, including three interferon beta preparations, glatiramer acetate, mitoxantrone, and natalizumab. This study focuses on the safety, tolerability, and efficacy of 44 μg subcutaneous interferon beta-1a three times per week and 20 mg subcutaneous glatiramer acetate once per day.

The landmark trial of interferon beta-1a in patients with relapsing-remitting MS (RRMS), the Prevention of Relapses and disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis (PRISMS), showed that 44 μg subcutaneous interferon beta-1a three times per week gave significant benefit compared with placebo by reducing relapse rate, time to first relapse, disability progression, gadolinium-enhancing lesions, and T2 lesion load.4 Glatiramer acetate was superior to placebo only for reducing the relapse rate.5 Although MRI findings were not an outcome in the glatiramer acetate trial, a short-term, placebo-controlled study of an active cohort that required patients to have gadolinium-enhancing lesions at screening did show a significant, albeit less robust, treatment effect of glatiramer acetate on MRI: gadolinium-enhancing and new T2 lesions were reduced.6 The results of large, randomised, head-to-head studies have shown differences among interferon beta formulations and regimens.7, 8 Here, we present a comparative trial between interferon beta and glatiramer acetate in patients with RRMS.

Section snippets

Patients

Between February and December, 2004, 764 patients with RRMS aged between 18 and 60 years who were interferon beta and glatiramer acetate naive were recruited from 81 centres in 14 countries (Argentina, Austria, Brazil, Canada, France, Germany, Ireland, Italy, Netherlands, Russia, Spain, Switzerland, UK, and USA). RRMS was diagnosed with the McDonald criteria,9 and patients had to have an expanded disability status scale (EDSS) score of 0–5·5. Inclusion criteria were that patients had at least

Results

Of 803 patients who gave consent and were screened, 766 passed screening and were enrolled. 764 patients (the intention-to-treat population) were randomised: 386 to interferon beta-1a and 378 to glatiramer acetate. Figure 1 shows the trial profile. 758 patients received at least one injection of either treatment and 756 of these had safety follow-up data (safety population). Of the 758 patients who received one of the treatments, 625 (301 [79%] in the interferon beta-1a group and 324 [86%] in

Discussion

In this randomised, assessor-blinded study to compare glatiramer acetate and high-dose, high-frequency interferon beta-1a, no difference was seen in the primary outcome measure—time to first relapse. There was also no difference between treatment groups in the other clinical endpoints, the proportion of patients who were free from relapse, relapse rate, and disability progression.

Baseline demographics were similar between the treatment groups, with the exception that more patients in the

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