title: Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Genzyme (Sanofi) and Bayer Schering Pharma.
authors.affiliation: Mellen Center, Cleveland Clinic, Cleveland, OH 44195, USA. cohenj@ccf.org
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Cohen
authors.forename: Alasdair J
authors.initials: AJ
authors.lastname: Coles
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Arnold
authors.forename: Christian
authors.initials: C
authors.lastname: Confavreux
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Fox
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hartung
authors.forename: Eva
authors.initials: E
authors.lastname: Havrdova
authors.forename: Krzysztof W
authors.initials: KW
authors.lastname: Selmaj
authors.forename: Howard L
authors.initials: HL
authors.lastname: Weiner
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fisher
authors.forename: Vesna V
authors.initials: VV
authors.lastname: Brinar
authors.forename: Gavin
authors.initials: G
authors.lastname: Giovannoni
authors.forename: Miroslav
authors.initials: M
authors.lastname: Stojanovic
authors.forename: Bella I
authors.initials: BI
authors.lastname: Ertik
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Lake
authors.forename: David H
authors.initials: DH
authors.lastname: Margolin
authors.forename: Michael A
authors.initials: MA
authors.lastname: Panzara
authors.forename: D Alastair S
authors.initials: DA
authors.lastname: Compston
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000009:adverse effects; D000279:Administration, Cutaneous; D000293:Adolescent; D000328:Adult; D000074323:Alemtuzumab; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D000068556:Interferon beta-1a; D016899:Interferon-beta / Q000008:administration & dosage* / Q000009:adverse effects; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy*; D012008:Recurrence; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000276:Adjuvants, Immunologic; D061067:Antibodies, Monoclonal, Humanized; D000074323:Alemtuzumab; D016899:Interferon-beta; D000068556:Interferon beta-1a