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February 24, 2009; 72 (8) Articles

MRI as an outcome in multiple sclerosis clinical trials

M. Daumer, A. Neuhaus, S. Morrissey, R. Hintzen, G. C. Ebers
First published December 10, 2008, DOI: https://doi.org/10.1212/01.wnl.0000336916.38629.43
M. Daumer
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A. Neuhaus
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S. Morrissey
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R. Hintzen
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Citation
MRI as an outcome in multiple sclerosis clinical trials
M. Daumer, A. Neuhaus, S. Morrissey, R. Hintzen, G. C. Ebers
Neurology Feb 2009, 72 (8) 705-711; DOI: 10.1212/01.wnl.0000336916.38629.43

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Abstract

Introduction: T2-weighted and gadolinium enhanced T1-weighted MRI scans measure plaque burden and breakdown of the blood-brain barrier, respectively, in multiple sclerosis (MS) lesions. These have become widely used outcome measures for monitoring disease activity in clinical trials and clinical practice. However, their use as surrogates or biomarkers for disability and relapses, key clinical outcome measures, has remained incompletely validated.

Methods: In a clinical trial database comprised of 31 relapsing-remitting and secondary progressive MS trial placebo groups, we assessed relationships between 1) T2 lesion load (TLL) change and disability change and 2) gadolinium enhancement of MS lesions and on-study relapses with univariate and multivariate analyses.

Results: In relapsing-remitting MS, TLL change (n = 223) made no independent contribution to predicting change in disability from baseline to trials’ end. Similarly, inclusion of gadolinium enhancing lesions (n = 170) into multivariate models did not independently contribute to the predictive value for on-trial relapses. In secondary progressive MS, a small effect of TLL was found for disability change (n = 355) but in multivariate analysis this accounted for less than 5% of the variance in end-of-trial disability. Results were replicated in independent datasets, more than doubling effective sample sizes.

Conclusions: MRI measures widely used in trials of relapsing-remitting and progressive multiple sclerosis add little if anything independently to the clinically relevant relapse and disability outcomes. These results reemphasize the importance of validating potential surrogate markers against clinical measures and highlight the need for better MRI markers of disease activity and progression.

AIC = Akaike’s information criterion; EDSS = Expanded Disability Status Scale; LME = linear mixed effects; MS = multiple sclerosis; RCT = randomized clinical trial; RRMS = relapsing-remitting MS; SLC = Sylvia Lawry Centre; SPMS = secondary progressive MS; TLL = T2 lesion load.

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Disputes & Debates: Rapid online correspondence

  • MRI as an outcome in multiple sclerosis clinical trials
    • Richard B. Tenser, Penn State University College of Medicine, 30 Hope Dr. Hershey, PA 17033rtenser@psu.edu
    Submitted June 22, 2009
  • Reply from the authors
    • Prof. George C. Ebers, University of Oxford, John Radcliffe Hospital Oxford OX39DU, United Kingdomgeorge.ebers@clneuro.ox.ac.uk
    • Martin Daumer
    Submitted June 22, 2009
  • MRI as an outcome in multiple sclerosis clinical trials
    • Maria Pia Sormani, Biostatistics Unit, Department of Health Sciences, University of Genoa, Genoa, Italym.filippi@hsr.it
    • Massimo Filippi (Neuroimaging Research Unit, Department of Neurology, San Raffaele Scientific Institute, Milan, Italy) and Nicola De Stefano (Quantitative Neuroimaging Lab, Dept. of Neurological & Behavioral Sciences, University of Siena, Siena, Italy)
    Submitted May 26, 2009
  • Reply from the author
    • George Ebers, University of Oxford, Oxford, United KingdomGeorge.Ebers@clneuro.ox.ac.uk
    • Martin Daumer,Technical University of Munich, Ludwig Maximilian University and the Sylvia Lawry Centre, Munich, Germany
    Submitted May 26, 2009
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