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MRI outcomes with cladribine tablets for multiple sclerosis in the CLARITY study

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Abstract

We herein provide a comprehensive assessment of magnetic resonance imaging (MRI) outcomes from CLARITY, a 96-week, double-blind study demonstrating significant clinical and MRI improvements in patients with relapsing–remitting multiple sclerosis (RRMS) treated with cladribine tablets. Patients with RRMS were randomized 1:1:1 to annual short-course therapy with cladribine tablets cumulative dose 3.5 or 5.25 mg/kg or placebo. MRI endpoints included mean number of T1 gadolinium-enhancing (Gd+), active T2 and combined unique (CU) lesions/patient/scan. MRI-measured disease activity was significantly reduced in both cladribine tablets groups versus placebo. The proportion of patients with no active lesions at study end was: T1 Gd+ lesions: 86.8 and 91.0 versus 48.3 % (p < 0.001); active T2 lesions: 61.7 and 62.5 versus 28.4 % (p < 0.001); CU lesions: 59.6 and 60.7 versus 26.1 % (p < 0.001). Clinically meaningful and significant reductions in active lesion counts and increases in proportions of active lesion-free patients were achieved consistently in cladribine tablet groups when data were stratified by baseline disease characteristics. For example, the percentage of patients who remained lesion-free over the study was significantly greater in cladribine tablet groups than in the placebo group for all lesion types regardless of relapse category at baseline (p < 0.001 for all analyses of patients with ≤1 or 2 relapses; p ≤ 0.022 for analyses of patients with ≥3 relapses). MRI-measured disease activity was greatly reduced by both doses of cladribine tablets, with consistent effect across clinically relevant patient populations. These findings add to our scientific understanding of the neurological impact of this therapeutic modality in patients with RRMS.

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Acknowledgments

This study was sponsored by Merck Serono S.A., Geneva, Switzerland, a branch of Merck Serono S.A. Coinsins, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany. The authors thank Peter Chang (formerly of Merck Serono S.A., Geneva, Switzerland) for his input into the statistical analysis of data for this manuscript, and Mary Goodsell of ACUMED®, Tytherington, UK (supported by Merck Serono, S.A., Geneva, Switzerland) for her assistance in the preparation of this manuscript.

Conflicts of interest

Professor Comi has received consulting fees for participating on advisory boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from Novartis, Teva Pharmaceutical Ind. Ltd., Sanofi-Aventis, Merck Serono, and Bayer Schering; lecture fees from Novartis, Teva Pharmaceutical Ind. Ltd., Sanofi-Aventis, Merck Serono, Biogen Dompè, Bayer Schering and Serono Symposia International Foundation; and clinical trial grant support from Novartis, Teva Pharmaceutical Ind. Ltd., Sanofi-Aventis, Merck Serono, Biogen Dompè, and Bayer Schering. Professor Cook has received honoraria for lectures from Merck Serono and Bayer; and consultation fees from Sanofi-Aventis, Bayer, Biogen Idec, Merck Serono, Actinobac Scientific, Inc., and Teva. He has served on scientific advisory boards for Bayer, Biogen Idec, Merck Serono and Actinobac Scientific, Inc. He has received research grants for the BEYOND and BECOME studies from Bayer and the CLARITY and CLARITY EXTENSION studies from Merck Serono. Professor Giovannoni has received consulting fees for participating on advisory boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from Bayer-Schering, Biogen Idec, Five Prime Therapeutics, Genzyme, Ironwood Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi-Aventis, Teva-Aventis, UCB Pharma, and Vertex Pharmaceuticals; lecture fees from Bayer-Schering, Biogen Idec, Genzyme, Merck Serono, and Vertex Pharmaceuticals; and grant support from Bayer-Schering, Biogen Idec, GW Pharmaceuticals, Ironwood Pharmaceuticals, Merck Serono, Merz, Novartis, and Teva-Aventis. Professor Rammohan has received consulting fees for speaker and consultancy activities from Bayer, EMD Serono/Pfizer, Teva, Genentech, Biogen, Genzyme, Acorda, UCB Pharma, and Novartis; lecture fees from Bayer, EMD Serono/Pfizer, Teva, Biogen, Genzyme, Acorda, and UCB Pharma; and clinical trial and investigator initiated research grant support from Bayer, EMD Serono/Pfizer, Teva, Acorda, Biogen, Genzyme, UCB Pharma, and Novartis. Professor Rieckmann has received consulting fees for speaker and consultancy activities from Merck Serono, Biogen Idec, Teva, Bayer, and Novartis; lecture fees from Merck Serono, Biogen Idec, and Teva; and grant support from Merck Serono, Bayer, Teva, the MS Society of Canada, and the Ilich Foundation. Professor Soelberg Sørensen has served on scientific advisory boards for Biogen Idec, Merck Serono, Novartis, Genmab, Teva, Elan, GSK, steering committees or independent data monitoring boards in clinical trials sponsored by Merck Serono, Genmab, Teva, GSK, Bayer-Schering, and received funding of travel for these activities. He has served as Editor-in-Chief of the European Journal of Neurology, and is editorial board member for Therapeutic Advances in Neurological Disorders and Multiple Sclerosis; has received speaker honoraria from Biogen Idec, Merck Serono, Teva, Bayer Schering, Sanofi-Aventis, and Novartis; and has received research support from Biogen Idec, Bayer-Schering, Merck Serono, Teva, Baxter, Sanofi-Aventis, BioMS, Novartis, Bayer, RoFAR, Roche, Genzyme, from the Danish Multiple Sclerosis Society, the Danish Medical Research Council, and the European Union Sixth Framework Programme: Life sciences, Genomics and Biotechnology for Health. Professor Vermersch has received consulting fees for speaker and advisory board activities from Merck Serono, Bayer-Schering, Teva-Aventis, Biogen Idec, Novartis, and Roche; lecture fees from Merck Serono, Biogen Idec, Bayer-Schering, and Novartis; and grant support from Biogen Idec, Bayer-Schering Pharma, Merck Serono, and Teva-Aventis. Dr. Hamlett, Dr. Greenberg and Dr. Viglietta are current or former employees of the study sponsor (Merck Serono S.A., Geneva, Switzerland, a branch of Merck Serono S.A. Coinsins, Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany). Dr. Greenberg is currently an employee of Abbott Biotherapeutics Corp, and Dr. Viglietta is currently an employee of Biogen Idec.

Ethical standards

The protocol was reviewed and approved by the local review board or ethics committee at each study center. An independent data and safety monitoring board reviewed the study conduct and all safety data.

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Authors and Affiliations

  1. Department of Neurology and Institute of Experimental Neurology, Scientific Institute H.S. Raffaele, Università Vita-Salute San Raffaele, via Olgettina 60, 20132, Milan, Italy

    Giancarlo Comi

  2. New Jersey Medical School, University of Medicine and Dentistry, Newark, NJ, USA

    Stuart D. Cook

  3. Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, London, UK

    Gavin Giovannoni

  4. Department of Neurology, University of Miami, Miami, FL, USA

    Kottil Rammohan

  5. Bamberg Hospital, University of Erlangen, Bamberg, Germany

    Peter Rieckmann

  6. Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

    Per Soelberg Sørensen

  7. University of Lille, Nord de France, Lille, France

    Patrick Vermersch

  8. Merck Serono S.A., Geneva, Switzerland

    Anthony C. Hamlett, Vissia Viglietta & Steven J. Greenberg

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  1. Giancarlo Comi
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  2. Stuart D. Cook
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  3. Gavin Giovannoni
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  4. Kottil Rammohan
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  6. Per Soelberg Sørensen
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  7. Patrick Vermersch
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  8. Anthony C. Hamlett
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  9. Vissia Viglietta
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  10. Steven J. Greenberg
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Corresponding author

Correspondence to Giancarlo Comi.

Additional information

On behalf of the CLARITY study group.

V. Viglietta and S. J. Greenberg were in Merck Serono S.A., Geneva, Switzerland at the time of manuscript preparation.

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Comi, G., Cook, S.D., Giovannoni, G. et al. MRI outcomes with cladribine tablets for multiple sclerosis in the CLARITY study. J Neurol 260, 1136–1146 (2013). https://doi.org/10.1007/s00415-012-6775-0

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  • DOI: https://doi.org/10.1007/s00415-012-6775-0

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