Giuseppe
Emeritus
[Source: The Lancet, full text: (LINK). Abstract, edited.]
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The Lancet, Early Online Publication, 1 November 2012
doi:10.1016/S0140-6736(12)61768-1
Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial
Original Text
Dr Alasdair J Coles FRCP a, Cary L Twyman MD e, Prof Douglas L Arnold MD b, Prof Jeffrey A Cohen MD c, Prof Christian Confavreux MD f, Edward J Fox MD g, Prof Hans-Peter Hartung FRCP h, Prof Eva Havrdova MD i, Prof Krzysztof W Selmaj MD j, Prof Howard L Weiner MD k, Tamara Miller MD l, Elizabeth Fisher PhD d, Rupert Sandbrink MD h m, Stephen L Lake ScD n, David H Margolin MD n, Pedro Oyuela MD n, Michael A Panzara MD n, Prof D Alastair S Compston FRCP a, for the CARE-MS II investigators?
Summary
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.
a Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK; b NeuroRx Research and Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada; c Mellen Center, Cleveland Clinic, Cleveland, OH, USA; d Department of Biomedical Engineering, Cleveland Clinic, Cleveland, OH, USA; e Associates in Neurology, Lexington, KY, USA; f Service de Neurologie A, Hospices Civils de Lyon, Universit? Claude Bernard Lyon 1, Lyon, France; g MS Clinic of Central Texas, Central Texas Neurology Consultants, Round Rock, TX, USA; h Heinrich-Heine University, Department of Neurology, D?sseldorf, Germany; i Department of Neurology, First School of Medicine, Charles University, Prague, Czech Republic; j Department of Neurology, Medical University of Lodz, Lodz, Poland; k Brigham and Women's Hospital Center for Neurologic Diseases, Boston, MA, USA; l Advanced Neurology of Colorado, Ft Collins, CO, USA; m Bayer HealthCare, Berlin, Germany; n Genzyme, Cambridge, MA, USA
Correspondence to: Dr Alasdair J Coles, Department of Clinical Neurosciences, University of Cambridge, Box 165, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK
? Members listed in appendix
-doi:10.1016/S0140-6736(12)61768-1
Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial
Original Text
Dr Alasdair J Coles FRCP a, Cary L Twyman MD e, Prof Douglas L Arnold MD b, Prof Jeffrey A Cohen MD c, Prof Christian Confavreux MD f, Edward J Fox MD g, Prof Hans-Peter Hartung FRCP h, Prof Eva Havrdova MD i, Prof Krzysztof W Selmaj MD j, Prof Howard L Weiner MD k, Tamara Miller MD l, Elizabeth Fisher PhD d, Rupert Sandbrink MD h m, Stephen L Lake ScD n, David H Margolin MD n, Pedro Oyuela MD n, Michael A Panzara MD n, Prof D Alastair S Compston FRCP a, for the CARE-MS II investigators?
Summary
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.
a Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK; b NeuroRx Research and Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada; c Mellen Center, Cleveland Clinic, Cleveland, OH, USA; d Department of Biomedical Engineering, Cleveland Clinic, Cleveland, OH, USA; e Associates in Neurology, Lexington, KY, USA; f Service de Neurologie A, Hospices Civils de Lyon, Universit? Claude Bernard Lyon 1, Lyon, France; g MS Clinic of Central Texas, Central Texas Neurology Consultants, Round Rock, TX, USA; h Heinrich-Heine University, Department of Neurology, D?sseldorf, Germany; i Department of Neurology, First School of Medicine, Charles University, Prague, Czech Republic; j Department of Neurology, Medical University of Lodz, Lodz, Poland; k Brigham and Women's Hospital Center for Neurologic Diseases, Boston, MA, USA; l Advanced Neurology of Colorado, Ft Collins, CO, USA; m Bayer HealthCare, Berlin, Germany; n Genzyme, Cambridge, MA, USA
Correspondence to: Dr Alasdair J Coles, Department of Clinical Neurosciences, University of Cambridge, Box 165, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK
? Members listed in appendix
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