Document Detail


Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial.
MedLine Citation:
PMID:  23122652     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Jeffrey A Cohen; Alasdair J Coles; Douglas L Arnold; Christian Confavreux; Edward J Fox; Hans-Peter Hartung; Eva Havrdova; Krzysztof W Selmaj; Howard L Weiner; Elizabeth Fisher; Vesna V Brinar; Gavin Giovannoni; Miroslav Stojanovic; Bella I Ertik; Stephen L Lake; David H Margolin; Michael A Panzara; D Alastair S Compston;
Publication Detail:
Type:  Clinical Trial, Phase III; Comparative Study; Journal Article; Multicenter Study; Randomized Controlled Trial; Research Support, Non-U.S. Gov't     Date:  2012-11-01
Journal Detail:
Title:  Lancet     Volume:  380     ISSN:  1474-547X     ISO Abbreviation:  Lancet     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-11-26     Completed Date:  2012-12-10     Revised Date:  2013-05-27    
Medline Journal Info:
Nlm Unique ID:  2985213R     Medline TA:  Lancet     Country:  England    
Other Details:
Languages:  eng     Pagination:  1819-28     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2012 Elsevier Ltd. All rights reserved.
Affiliation:
Mellen Center, Cleveland Clinic, Cleveland, OH 44195, USA. cohenj@ccf.org
Data Bank Information
Bank Name/Acc. No.:
ClinicalTrials.gov/NCT00530348
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MeSH Terms
Descriptor/Qualifier:
Adjuvants, Immunologic / administration & dosage*,  adverse effects
Administration, Cutaneous
Adolescent
Adult
Antibodies, Monoclonal, Humanized / administration & dosage*,  adverse effects
Disease-Free Survival
Female
Humans
Infusions, Intravenous
Interferon-beta / administration & dosage*,  adverse effects
Kaplan-Meier Estimate
Male
Middle Aged
Multiple Sclerosis, Relapsing-Remitting / drug therapy*
Recurrence
Treatment Outcome
Young Adult
Chemical
Reg. No./Substance:
0/Adjuvants, Immunologic; 0/Antibodies, Monoclonal, Humanized; 145258-61-3/interferon beta 1a; 3A189DH42V/alemtuzumab; 77238-31-4/Interferon-beta
Investigator
Investigator/Affiliation:
Alastair Compston / ; Doug Arnold / ; Jeffrey A Cohen / ; Alasdair Coles / ; Christian Confavreux / ; Edward Fox / ; Hans-Peter Hartung / ; Eva Havrdova / ; Krzysztof Selmaj / ; Howard Weiner / ; Hillel Panitch / ; David Clifford / ; Jack Antel / ; Frederik Barkhof / ; David Snydman / ; Leslie DeGroot / ; Douglas Cines / ; Ralph D'Agostino / ; Benjamin Greenberg / ; Jörg Krauss / ; Clyde Markowitz / ; Robert Naismith / ; David Tabby / ; Ajay S Gupta / ; Edward J Fox / ; Steven A Glyman / ; Mark Cascione / ; Aaron Boster / ; Kottil Rammohan / ; Suzanne Gazda / ; Daniel R Wynn / ; Sibyl Wray / ; Corey C Ford / ; Andrew Goodman / ; George Hutton / ; Michael Kaufman / ; Omar Azhar Khan / ; Anand Vaishnav / ; Stephen Kirzinger / ; Sharon G Lynch / ; Tiffany Braley / ; Daniel Mikol / ; Tamara Miller / ; Carolina Ionete / ; Peter Riskind / ; Roberto Bomprezzi / ; Jonathan Carter / ; Brian Steingo / ; Cary Twyman / ; Ann Bass / ; Enrico Lallana / ; Lloyd Kasper / ; Alireza Minagar / ; Samuel Hunter / ; Christopher Sheppard / ; Joseph Herbert / ; Gabriel Pardo / ; Vernon D Rowe / ; Christopher C LaGanke / ; Keith Edwards / ; Jeanette K Wendt / ; David Jones / ; Gary Clauser / ; Stephen Gerard Vincent / ; Mark Gudesblatt / ; Mark Freedman / ; Michael Yeung / ; Francois Grand'Maison / ; Francois Jacques / ; Anthony Traboulsee / ; Richard Macdonell / ; John King / ; Mark Paine / ; Karyn Boundy / ; Simon Broadley / ; Steve Ostoja Vucic / ; Stephen Reddel / ; Michael Dreyer / ; Pamela McCombe / ; Maria Lucia Ferreira / ; Dagoberto Callegaro / ; Marcio Menna Barreto Martins / ; Jesus Arturo Violante Villanueva / ; Noemi Santos Caballero / ; Norma Haydee Deri / ; Alasdair Coles / ; Neil Robertson / ; Gavin Giovannoni / ; Basil Sharrack / ; Michel Clanet / ; Judith Haas / ; Martin Stangel / ; Tjalf Ziemssen / ; Karl Baum / ; Juergen Faiss / ; Ulf Ziemann / ; Jan Lycke / ; Ivana Kovarova / ; Marta Vachova / ; Krzysztof Selmaj / ; Andrzej Szczudlik / ; Zbigniew Stelmasiak / ; Wojciech Kozubski / ; Evgeniy Gusev / ; Igor Stolyarov / ; Igor Zavalishin / ; Alexander Skoromets / ; Alexei Boyko / ; Anna Belova / ; Nadezhda Malkova / ; Evgeniy Barantsevich / ; Eduard Yakupov / ; Gennadiy Mishin / ; Irina Poverennova / ; Rim Magzhanov / ; Vasyl Orzheshkovskyi / ; Volodymyr Malyy / ; Natalia Voloshyna / ; Tetyana Nehrych / ; Tetyana Kobys / ; Mario Habek / ; Vesna Brinar / ; Zlatko Trkanjec / ; Anton Vladić / ; Licija Antonelli / ; Josip Rudež / ; Spomenka Kidemet-Piskać / ; Jelena Drulović / ; Čongor Nadj / ; Evica Dinčić / ; Slobodan Vojinović / ; Miroslav Stojanović / ; Mihailo Pantović /
Comments/Corrections
Comment In:
Lancet. 2012 Nov 24;380(9856):1795-7   [PMID:  23128041 ]
J Neurol. 2013 Jan;260(1):343-5   [PMID:  23238846 ]
Dtsch Med Wochenschr. 2013 Feb;138(7):297   [PMID:  23520617 ]

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