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Neurology Research International
Volume 2011 (2011), Article ID 195831, 6 pages
http://dx.doi.org/10.1155/2011/195831
Research Article

Short-Term Relapse Quantitation as a Fully Surrogate Endpoint for Long-Term Sustained Progression of Disability in RRMS Patients Treated with Natalizumab

1Department of Biometrics, Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142, USA
2Neurology Clinical Development, Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142, USA
3Department of Biostatistics, Boston University School of Public Health, Boston, MA 02118, USA

Received 2 May 2011; Revised 17 November 2011; Accepted 19 November 2011

Academic Editor: Mamede de Carvalho

Copyright © 2011 Y. C. Wang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Time to sustained worsening in the expanded disability status scale as the standard for evaluating the accumulation of disability has been used as a measure of clinical efficacy in many relapsing-remitting multiple sclerosis (RRMS) clinical trials. However, this measurement usually requires a large sample and long-term study to demonstrate the treatment effect. Annualized relapse rate or time to first relapse is also widely used as alternative measurements of clinical efficacy. A formal statistical validation of short-term relapse activity as a surrogate endpoint for long-term sustained progression of disability could potentially permit smaller, shorter, and less expensive clinical trials in RRMS. Four statistical validation/evaluation approaches consistently showed that relapse activity through one year of treatment serves as statistically valid surrogate endpoint for time to sustained progression of disability. The analysis demonstrates that long-term sustained progression of disability can be predicted by short-term relapse measures with 4 consistent validations of statistical approaches, including a formal statistical hypothesis test. This was demonstrated in a large phase III trial of natalizumab and showed that the beneficial clinical effect of natalizumab on sustained progression of disability at 2 years in patients with RRMS can be predicted by the total number of relapses at 1 year.