Elsevier

The Lancet

Volume 380, Issue 9856, 24–30 November 2012, Pages 1819-1828
The Lancet

Articles
Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial

https://doi.org/10.1016/S0140-6736(12)61769-3Get rights and content

Summary

Background

The anti-CD52 monoclonal antibody alemtuzumab reduced disease activity in a phase 2 trial of previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of first-line alemtuzumab compared with interferon beta 1a in a phase 3 trial.

Methods

In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18–50 years with previously untreated relapsing-remitting multiple sclerosis. Eligible participants were randomly allocated in a 2:1 ratio by an interactive voice response system, stratified by site, to receive intravenous alemtuzumab 12 mg per day or subcutaneous interferon beta 1a 44 μg. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and once per day for 3 days at 12 months. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00530348.

Findings

187 (96%) of 195 patients randomly allocated interferon beta 1a and 376 (97%) of 386 patients randomly allocated alemtuzumab were included in the primary analyses. 75 (40%) patients in the interferon beta 1a group relapsed (122 events) compared with 82 (22%) patients in the alemtuzumab group (119 events; rate ratio 0·45 [95% CI 0·32–0·63]; p<0.0001), corresponding to a 54·9% improvement with alemtuzumab. Based on Kaplan-Meier estimates, 59% of patients in the interferon beta 1a group were relapse-free at 2 years compared with 78% of patients in the alemtuzumab group (p<0·0001). 20 (11%) of patients in the interferon beta 1a group had sustained accumulation of disability compared with 30 (8%) in the alemtuzumab group (hazard ratio 0·70 [95% CI 0·40–1·23]; p=0·22). 338 (90%) of patients in the alemtuzumab group had infusion-associated reactions; 12 (3%) of which were regarded as serious. Infections, predominantly of mild or moderate severity, occurred in 253 (67%) patients treated with alemtuzumab versus 85 (45%) patients treated with interferon beta 1a. 62 (16%) patients treated with alemtuzumab had herpes infections (predominantly cutaneous) compared with three (2%) patients treated with interferon beta 1a. By 24 months, 68 (18%) patients in the alemtuzumab group had thyroid-associated adverse events compared with 12 (6%) in the interferon beta 1a group, and three (1%) had immune thrombocytopenia compared with none in the interferon beta 1a group. Two patients in the alemtuzumab group developed thyroid papillary carcinoma.

Interpretation

Alemtuzumab's consistent safety profile and benefit in terms of reductions of relapse support its use for patients with previously untreated relapsing-remitting multiple sclerosis; however, benefit in terms of disability endpoints noted in previous trials was not observed here.

Funding

Genzyme (Sanofi) and Bayer Schering Pharma.

Introduction

Alemtuzumab, a humanised anti-CD52 monoclonal antibody used for treatment of multiple sclerosis, works via depletion and subsequent repopulation of circulating T lymphocytes and B lymphocytes. This action leads to changes in the number, proportions, and functions of some lymphocyte subsets.1, 2, 3 Alemtuzumab has been shown to decrease the rate of relapses, disability accumulation, and MRI lesion activity.4, 5, 6, 7 Superiority for alemtuzumab compared with interferon beta 1a, which was noted in a phase 2 trial,7 was maintained in an open-label follow-up study through 5 years.8 In the Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS I) trial, we aimed to assess the effect of alemtuzumab compared with interferon beta 1a in a phase 3 trial of previously untreated patients with early, active relapsing-remitting multiple sclerosis.

Section snippets

Study design and patients

In this randomised, rater-masked, phase 3 trial, we enrolled patients from 101 academic medical centres and clinical practices in 16 countries between Sept 7, 2007, and April 17, 2009. Eligible patients were aged 18–50 years and had relapsing-remitting multiple sclerosis fulfilling the 2005 McDonald criteria,9 a disease duration of up to 5 years, at least two relapses in the previous 2 years and at least one in the previous year, expanded disability status scale (EDSS)10 scores of 3·0 or lower,

Results

563 (97%) of 581 patients who were randomly assigned received at least one dose of study drug and 526 (93%) of these patients completed the study on assigned treatment (figure 1). Baseline characteristics were typical for an early, active relapsing-remitting multiple sclerosis population (table 1). 17 (5%) of 376 patients received aciclovir with the first course of alemtuzumab and 243 (66%) of 370 patients received aciclovir with the second course of alemtuzumab.

Alemtuzumab reduced the rate of

Discussion

Our phase 3 study supports and extends previous findings7 that alemtuzumab is more effective than high-dose subcutaneous interferon beta 1a for reduction of rates of relapse in previously untreated patients with early, active relapsing-remitting multiple sclerosis (panel). The mode of action of alemtuzumab, involving depletion and repopulation of the immune repertoire, might explain its durable effects despite infrequent administration. However, we did not note differences between the effects

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