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From the Unit of Clinical Epidemiology and Trials (Drs. Sormani and Bruzzi), National Institute for Cancer Research, Genoa; Neuroimaging Research Unit (Drs. Sormani and Filippi), Department of Neuroscience, Scientific Institute and University Ospedale San Raffaele, Milan, Italy; Schering AG (K. Beckmann and Dr. Wagner), Berlin, Germany; NMR Research Unit (Dr. Miller), Institute of Neurology, London, UK; and Neurologische Poliklinik (Dr. Kappos), Universitätsspital, Basel, Switzerland.
Address correspondence and reprint requests to Dr. Massimo Filippi, Neuroimaging Research Unit, Department of Neuroscience, Scientific Institute and University Ospedale San Raffaele, Via Olgettina, 60, 20132 Milan, Italy; e-mail: massimo.filippi{at}hsr.it
Background: Although metrics derived from conventional MRI (cMRI) are widely used as outcome measures in clinical trials of MS, no formal study has been performed to validate cMRI metrics as surrogate endpoints for disability progression in MS.
Methods: A validation procedure was applied to the clinical and MRI data collected in the context of the European randomized, double-blind, placebo-controlled trial of interferon ß-1b (IFNß-1b) in patients with secondary progressive MS. The Prentice operational criteria were used to assess surrogacy for the number of active lesions seen on the first year T2-weighted MRI scans and the percentage T2 lesion volume change between the baseline and the first year MRI scans. The primary clinical outcome was disability at study exit (3 years), adjusted for the baseline disability.
Results: The number of active T2 lesions and the T2 lesion volume percentage change over the first year of the study accounted for 57% of the treatment effect on disability progression over the entire study duration. On the contrary, the same cMRI metrics accounted for 79% of the treatment effect on the relapse rate.
Conclusions: This study shows that the beneficial effect of IFNß-1b on disability accumulation in patients with secondary progressive MS is, to a large extent, independent of the changes detected using cMRI. As a consequence, cMRI metrics should not be used as a stand-alone measure of outcome in phase III trials of IFNß in secondary progressive MS.
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