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      Safety and efficacy of cladribine tablets in patients with relapsing-remitting multiple sclerosis: Results from the randomized extension trial of the CLARITY study.

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          Abstract

          In the 2-year CLARITY study, cladribine tablets significantly improved clinical and magnetic resonance imaging (MRI) outcomes (vs placebo) in patients with relapsing-remitting multiple sclerosis (MS).

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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.

          Jeffrey A Cohen, Alasdair J Coles, Douglas L Arnold … (2012)
          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. 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. 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. 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. Genzyme (Sanofi) and Bayer Schering Pharma. Copyright © 2012 Elsevier Ltd. All rights reserved.
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            No evidence for higher risk of cancer in patients with multiple sclerosis taking cladribine

            Julia Pakpoor, Giulio Disanto, Daniel Altmann … (2015)
            Objective: To compare the cancer risk of cladribine and other disease-modifying drugs (DMDs) in trials of people with relapsing multiple sclerosis (pwRMS). Methods: Meta-analysis of phase III trials of licensed DMDs for pwRMS and a phase III trial of cladribine (CLARITY). Cancer rates were compared using Fisher exact test. Results: Eleven trials were included. Investigated treatments included cladribine, dimethyl fumarate, fingolimod, teriflunomide, natalizumab, alemtuzumab, and glatiramer acetate. The cancer rate in the CLARITY treatment group (0.34%) was not increased compared to all other treatment groups, whether including placebo-controlled trials only (0.6%, p = 0.4631) or all trials, i.e., including those with an active comparator arm (0.67%, p = 0.3669). No cancer was reported in the CLARITY placebo group, whereas the combined cancer rate of all other placebo groups was 1.19% (p = 0.0159). The cancer rate of zero in the CLARITY placebo group was also lower than that in the phase III trial of cladribine in people with clinically isolated syndrome (ORACLE MS, 2.91%, p = 0.0012). In fact, no difference was detected between cancer rates in the treatment groups of CLARITY (0.34%) and ORACLE MS (0.49%) (p = 0.6546). Conclusions: Our study does not support an increased cancer risk from cladribine in the doses used in CLARITY and ORACLE MS, which previously contributed to refusal of market authorization of cladribine in Europe. Longer-term follow-up is required to assess the safety profile of cladribine, as well as currently licensed DMDs, to definitively assess cancer risk.
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              Safety and tolerability of cladribine tablets in multiple sclerosis: the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study.

              S. Cook, P Vermersch, G Comi … (2011)
              Cladribine is a synthetic deoxyadenosine analogue in development as an oral multiple sclerosis (MS) therapy.
              Article 0 comments Cited 49 times – based on 0 reviews     Review now
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                Author and article information

                Journal
                Journal ID (iso-abbrev): Mult. Scler.
                Title: Multiple sclerosis (Houndmills, Basingstoke, England)
                Publisher: SAGE Publications
                ISSN (Electronic): 1477-0970
                ISSN (Print): 1352-4585
                Publication date (Electronic): October 2018
                Volume: 24
                Issue: 12
                Affiliations
                [1 ] Department of Neurology, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
                [2 ] Department of Neurology, Danish Multiple Sclerosis Center, Copenhagen University Hospital, Copenhagen, Denmark.
                [3 ] Department of Neurology & Neurosciences, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, USA.
                [4 ] Department of Neurosurgery, The Ohio State University Columbus, OH, USA.
                [5 ] Department of Neurology, Neurologische Klinik, Akademisches Krankenhaus Sozialstiftung Bamberg, Bamberg, Germany.
                [6 ] Department of Neurology and Institute of Experimental Neurology, Ospedale San Raffaele, Università Vita-Salute San Raffaele, Milan, Italy.
                [7 ] Department of Neurology and Immunology, EMD Serono, Inc., Billerica, MA, USA.
                [8 ] Department of Neurosurgery, CHU Lille, Université de Lille, Lille, France.
                Article
                DOI: 10.1177/1352458517727603
                PubMed ID: 28870107
                SO-VID: 2277223c-8676-473b-a27d-ac6b94206a1c
                History

                Keywords: efficacy,randomized trial,safety,Relapsing–remitting multiple sclerosis,CLARITY Extension,cladribine tablets
                Data availability:
                Keywords: efficacy, randomized trial, safety, Relapsing–remitting multiple sclerosis, CLARITY Extension, cladribine tablets

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