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Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial.
Lancet. 2012 Nov 24; 380(9856):1819-28.Lct

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.

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+Show Affiliations

Mellen Center, Cleveland Clinic, Cleveland, OH 44195, USA. cohenj@ccf.orgNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Clinical Trial, Phase III
Comparative Study
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23122652

Citation

Cohen, Jeffrey A., et al. "Alemtuzumab Versus Interferon Beta 1a as First-line Treatment for Patients With Relapsing-remitting Multiple Sclerosis: a Randomised Controlled Phase 3 Trial." Lancet (London, England), vol. 380, no. 9856, 2012, pp. 1819-28.
Cohen JA, Coles AJ, Arnold DL, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet. 2012;380(9856):1819-28.
Cohen, J. A., Coles, A. J., Arnold, D. L., Confavreux, C., Fox, E. J., Hartung, H. P., Havrdova, E., Selmaj, K. W., Weiner, H. L., Fisher, E., Brinar, V. V., Giovannoni, G., Stojanovic, M., Ertik, B. I., Lake, S. L., Margolin, D. H., Panzara, M. A., & Compston, D. A. (2012). Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet (London, England), 380(9856), 1819-28. https://doi.org/10.1016/S0140-6736(12)61769-3
Cohen JA, et al. Alemtuzumab Versus Interferon Beta 1a as First-line Treatment for Patients With Relapsing-remitting Multiple Sclerosis: a Randomised Controlled Phase 3 Trial. Lancet. 2012 Nov 24;380(9856):1819-28. PubMed PMID: 23122652.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. AU - Cohen,Jeffrey A, AU - Coles,Alasdair J, AU - Arnold,Douglas L, AU - Confavreux,Christian, AU - Fox,Edward J, AU - Hartung,Hans-Peter, AU - Havrdova,Eva, AU - Selmaj,Krzysztof W, AU - Weiner,Howard L, AU - Fisher,Elizabeth, AU - Brinar,Vesna V, AU - Giovannoni,Gavin, AU - Stojanovic,Miroslav, AU - Ertik,Bella I, AU - Lake,Stephen L, AU - Margolin,David H, AU - Panzara,Michael A, AU - Compston,D Alastair S, AU - ,, Y1 - 2012/11/01/ PY - 2012/11/6/entrez PY - 2012/11/6/pubmed PY - 2012/12/12/medline SP - 1819 EP - 28 JF - Lancet (London, England) JO - Lancet VL - 380 IS - 9856 N2 - 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. SN - 1474-547X UR - https://www.unboundmedicine.com/medline/citation/23122652/Alemtuzumab_versus_interferon_beta_1a_as_first_line_treatment_for_patients_with_relapsing_remitting_multiple_sclerosis:_a_randomised_controlled_phase_3_trial_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0140-6736(12)61769-3 DB - PRIME DP - Unbound Medicine ER -