ArticlesAlemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial
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
References (38)
- et al.
Preliminary evidence from magnetic resonance imaging for reduction in disease activity after lymphocyte depletion in multiple sclerosis
Lancet
(1994) - et al.
Neutralization of the biological activity of cytokines and other protein effectors by antibody: theoretical formulation of antibody titration curves in relation to antibody affinity
J Immunol Methods
(2003) - et al.
Comparison of subcutaneous 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
Lancet Neurol
(2008) - et al.
Statistical methods for the analysis of relapse data in MS clinical trials
J Neurol Sci
(2009) - et al.
250 mg or 500 mg interferon beta-1b versus 20 mg glatiramer acetate in relapsing-remitting multiple sclerosis: a prospective, randomised, multicentre study
Lancet Neurol
(2009) - et al.
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
Lancet
(2007) - et al.
Lymphocyte homeostasis following therapeutic lymphocyte depletion in multiple sclerosis
Eur J Immunol
(2005) - et al.
IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H)
J Clin Invest
(2009) - et al.
B-cell reconstitution and BAFF after alemtuzumab (Campath-1H) treatment of multiple sclerosis
J Clin Immunol
(2010) - et al.
Monoclonal antibody treatment exposes three mechanisms underlying the clinical course of multiple sclerosis
Ann Neurol
(1999)