Document Detail


Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial.
MedLine Citation:
PMID:  23122650     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: The anti-CD52 monoclonal antibody alemtuzumab reduces disease activity in previously untreated patients with relapsing-remitting multiple sclerosis. We aimed to assess efficacy and safety of alemtuzumab compared with interferon beta 1a in patients who have relapsed despite first-line treatment.
METHODS: In our 2 year, rater-masked, randomised controlled phase 3 trial, we enrolled adults aged 18-55 years with relapsing-remitting multiple sclerosis and at least one relapse on interferon beta or glatiramer. Eligible participants were randomly allocated in a 1:2:2 ratio by an interactive voice response system, stratified by site, to receive subcutaneous interferon beta 1a 44 μg, intravenous alemtuzumab 12 mg per day, or intravenous alemtuzumab 24 mg per day. Interferon beta 1a was given three-times per week and alemtuzumab was given once per day for 5 days at baseline and for 3 days at 12 months. The 24 mg per day group was discontinued to aid recruitment, but data are included for safety assessments. Coprimary endpoints were relapse rate and time to 6 month sustained accumulation of disability, comparing alemtuzumab 12 mg and interferon beta 1a in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00548405.
FINDINGS: 202 (87%) of 231 patients randomly allocated interferon beta 1a and 426 (98%) of 436 patients randomly allocated alemtuzumab 12 mg were included in the primary analyses. 104 (51%) patients in the interferon beta 1a group relapsed (201 events) compared with 147 (35%) patients in the alemtuzumab group (236 events; rate ratio 0·51 [95% CI 0·39-0·65]; p<0·0001), corresponding to a 49·4% improvement with alemtuzumab. 94 (47%) patients in the interferon beta 1a group were relapse-free at 2 years compared with 278 (65%) patients in the alemtuzumab group (p<0·0001). 40 (20%) patients in the interferon beta 1a group had sustained accumulation of disability compared with 54 (13%) in the alemtuzumab group (hazard ratio 0·58 [95% CI 0·38-0·87]; p=0·008), corresponding to a 42% improvement in the alemtuzumab group. For 435 patients allocated alemtuzumab 12 mg, 393 (90%) had infusion-associated reactions, 334 (77%) had infections (compared with 134 [66%] of 202 patients in the interferon beta 1a group) that were mostly mild-moderate with none fatal, 69 (16%) had thyroid disorders, and three (1%) had immune thrombocytopenia.
INTERPRETATION: For patients with first-line treatment-refractory relapsing-remitting multiple sclerosis, alemtuzumab could be used to reduce relapse rates and sustained accumulation of disability. Suitable risk management strategies allow for early identification of alemtuzumab's main adverse effect of secondary autoimmunity.
FUNDING: Genzyme (Sanofi) and Bayer Schering Pharma.
Authors:
Alasdair J Coles; Cary L Twyman; Douglas L Arnold; Jeffrey A Cohen; Christian Confavreux; Edward J Fox; Hans-Peter Hartung; Eva Havrdova; Krzysztof W Selmaj; Howard L Weiner; Tamara Miller; Elizabeth Fisher; Rupert Sandbrink; Stephen L Lake; David H Margolin; Pedro Oyuela; Michael A Panzara; D Alastair S Compston;
Publication Detail:
Type:  Clinical Trial, Phase III; 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:  1829-39     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2012 Elsevier Ltd. All rights reserved.
Affiliation:
Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK. ajc1020@medschl.cam.ac.uk
Data Bank Information
Bank Name/Acc. No.:
ClinicalTrials.gov/NCT00548405
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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
Female
Humans
Immunosuppressive Agents / administration & dosage*,  adverse effects
Infusions, Intravenous
Male
Middle Aged
Multiple Sclerosis, Relapsing-Remitting / drug therapy*
Peptides / administration & dosage*,  adverse effects
Recurrence
Treatment Outcome
Young Adult
Chemical
Reg. No./Substance:
0/Adjuvants, Immunologic; 0/Antibodies, Monoclonal, Humanized; 0/Immunosuppressive Agents; 0/Peptides; 0/copolymer 1; 3A189DH42V/alemtuzumab
Investigator
Investigator/Affiliation:
Doug Arnold / ; Jeffrey A Cohen / ; Alasdair Coles / ; Alastair Compston / ; Christian Confavareux / ; 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 / ; Volker Limmroth / ; Clyde Markowitz / ; Robert Naismith / ; David Tabby / ; Ajay S Gupta / ; Edward Fox / ; Steven A Glyman / ; Timothy K Thoits / ; Herman C Sullivan / ; Mark C Cascione / ; Kottil W Rammohan / ; Suzanne K Gazda / ; Daniel R Wynn / ; Sibyl E Wray / ; Stanton Elias / ; Corey C Ford / ; Andrew Goodman / ; Bruce L Hughes / ; Omar Azhar Khan / ; Anand G Vaishnav / ; Stephen Kirzinger / ; Sharon G Lynch / ; David H Mattson / ; Tiffany J Braley / ; Daniel D Mikol / ; Stephen Krieger / ; Aaron Miller / ; Tamara Ann Miller / ; Fort Collins / ; Peter N Riskind / ; Roberto Bomprezzi / ; Dean M Wingerchuk / ; Brian Steingo / ; Jeffrey Alan Cohen / ; Heidi J Crayton / ; Walter Royal / ; Cary L Twyman / ; Joanna A Cooper / ; Leslie P Weiner / ; Harold Moses / ; Mark A Agius / ; Ann Doan-Do Bass / ; Enrico C Lallana / ; Galen W Mitchell / ; Stanley J Krolczyk / ; Alireza Minagar / ; Burk Jubelt / ; Bradley K Evans / ; Samuel F Hunter / ; Syed A Rizvi / ; Christopher A Sheppard / ; W M David Honeycutt / ; Joseph Herbert / ; Ellen S Lathi / ; Gabriel Pardo / ; Lily Jung Ilenson / ; Ted L Rothstein / ; Ben W Thrower / ; Mary Ann Picone / ; Mariko Kita / ; Erica M Grazioli / ; Scott L Silliman / ; Thomas Giancarlo / ; Malcolm H Gottesman / ; Nuhad E Abou Zeid / ; Vernon D Rowe / ; Christine M Boutwell / ; John D Schaeffer / ; Christopher C LaGanke / ; Claire S Riley / ; Christopher Gottschalk / ; Jana Preiningerova / ; Keith R Edwards / ; Jeanette K Wendt / ; Kim Bigley / ; Barry A Singer / ; Richard A Shubin / ; Silva Markovic-Plese / ; Davis E Jones / ; Gary Clauser / ; Mark S Freedman / ; Francois Grand'Maison / ; Francois H Jacques / ; Anthony L Traboulsee / ; Donald G Brunet / ; Marcelo Kremenchutzky / ; Charles Ayotte / ; Neil S Lava / ; Stephen R Waldman / ; Todd J Janus / ; Stephen Gerard Vincent / ; Mark Gudesblatt / ; Michael Rossen / ; Lee S Stein / ; Bennett-Irving Machanic / ; Timothy Vollmer / ; Jeffrey S Gitt / ; Jeffrey Dunn / ; Donald Negroski / ; Mark H Fletcher / ; Adil Javed / ; Elliot M Frohman / ; Richard Macdonell / ; John Owen / ; Mark A Paine / ; Karyn Boundy / ; Simon Broadley / ; Steve Vucic / ; Stephen Reddel / ; Michael D Dreyer / ; Raymond Schwartz / ; Pamela Ann McCombe / ; Suzanne Hodgkinson / ; Charles Tilbery / ; Maria Lucia B Ferreira / ; Dagoberto Callegaro / ; Marcio Mena Barreto Martins / ; Jesus Arturo Violante Villanueva / ; Noemi Santos Caballero / ; Claudia Venzor Mendoza / ; Norma Haydee Deri / ; Alasdair Coles / ; Neil James Scolding / ; Gavin Giovannoni / ; Basil Sharrack / ; David J Rog / ; Giancarlo Comi / ; Angelo Ghezzi / ; Giovanni L Mancardi / ; Luca Durelli / ; Antonio Bertolotto / ; Ruggero Capra / ; Carlo Pozzilli / ; Maria Giovanna Marrosu / ; Raymond M M Hupperts / ; Erik van Munster / ; Xavier Montalbán / ; Rafael Arroyo González / ; Guillermo Izquierdo Ayuso / ; Óscar Fernández Fernández / ; Carlos Haya / ; Christian Confavreux / ; Patrick Vermersch / ; Jerome de Seze / ; Thibault Moreau / ; Pierre Clavelou / ; Catherine Lubetzki / ; Michel Clanet / ; Marc Debouverie / ; Gilles Edan / ; Hans-Peter Hartung / ; Judith Haas / ; Martin Stangel / ; Tjalf Ziemssen / ; Bernhard Hemmer / ; Karl Baum / ; U Klaus Zettl / ; U Herrlinger / ; Wolfgang Köhler / ; Gunter Ochs / ; Patrick Oschmann / ; Klaus Tiel-Wilck / ; Hayrettin Tumani / ; Peter P Urban / ; Jan Lycke / ; Anders Svenningsson / ; Ivana Kovarova / ; Marta Vachova / ; Ivan Rektor / ; Radomir Talab / ; Krzysztof Selmaj / ; Zbigniew Stelmasiak / ; Wojciech Kozubski / ; Benedicte D P Dubois / ; Dominique Dive / ; Rue Grandfossé / ; Christian Sindic / ; Karl Vass / ; Per Soelberg Sørensen / ; Thor Petersen / ; Mads Ravnborg / ; Anat Achiron / ; Adi Vaknin Dembinsky / ; Arnon Karni / ; Evgeny I Gusev / ; Igor D Stolyarov / ; Igor A Zavalishin / ; Alexander A Skoromets / ; Alexei N Boyko / ; Anna N Belova / ; Nadezhda A Malkova / ; Evgeniy R Barantsevich / ; Eduard Z Yakupov / ; Semen V Perfiliev / ; Irina E Poverennova / ; Natalia P Voloshyna / ; Tetyana I Nehrych / ; Tetyana O Kobys / ; Mario Habek / ; Vesna Brinar / ; Zlatko Trkanjec / ; Anton Vladić / ; Spomenka Kidemet Piskać / ; Ivana Meštrovića / ; Licia Antonelli / ; Jelena Drulović / ; Čongor Nadj / ; Evica Dinčić / ; Gordana Tončev /
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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