Abstract
Over the past 15 years, MRI lesion activity has become the accepted surrogate primary outcome measure in proof-of-concept placebo-controlled clinical trials of new immunomodulating therapies in relapse-onset multiple sclerosis (MS). In parallel, the number of patients that are available for the placebo arm of trials has declined, and more-aggressive drugs are being developed. A critical review is warranted to ensure efficient MRI—and patient—resource utilization. Recently, an international panel reviewed the methodology for efficient use of MRI-monitored trials in relapse-onset MS. In this article, we provide up-to-date recommendations for scan acquisition, image analysis, outcome-measure definition and standards of reporting. Factors to consider for optimizing trial design, such as outcome measure selection and the unique requirements of phase II and phase III trials, including active-comparator studies, are outlined. Finally, we address safety considerations in the use of MRI in MS trials, and the safety-related responsibilities of the various parties involved in conducting such trials.
Key Points
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Active lesions on MRI scans are accepted as a surrogate for disease activity in relapsing–remitting multiple sclerosis and as the primary outcome in proof-of-concept phase II studies of immunomodulation
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New post-processing techniques will increase the sensitivity and accuracy of MRI to detect active lesions, and will reduce the amount of contrast material needed
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In definitive phase III trials, clinical end points remain primary, but MRI scans provide important information about subgroup performance
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In clinical trials evaluating new therapies with unknown or more-aggressive mechanisms of action, MRI conveys important safety information
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Acknowledgements
This work is based on a workshop of the Magnetic Resonance Imaging Network in Multiple Sclerosis (MAGNIMS) working group, co-sponsored by MAGNIMS, the US National Multiple Sclerosis Society and the Multiple Sclerosis Society of Canada, and supported by an unrestricted educational grant by Bayer-Schering Pharma. We thank A. Thompson and J. Palace for their helpful input.
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All authors contributed to researching data for the article. F. Barkhof, J. H. Simon, F. Fazekas, M. Rovaris, L. Kappos, N. de Stefano, C. H. Polman, M. P. Sormani, D. K. Li, D. H. Miller and M. Filippi made substantial contributions to discussion of the article content. F. Barkhof, J. H. Simon, F. Fazekas, M. Rovaris, N. de Stefano, J. Petkau, M. P. Sormani, D. H. Miller and M. Filippi wrote the article. F. Barkhof, J. H. Simon, F. Fazekas, M. Rovaris, N. de Stefano, J. Petkau, M. P. Sormani, D. K. Li, P. O'Connor, D. H. Miller and M. Filippi contributed to review and/or editing of the manuscript before submission.
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F. Barkhof serves on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, GE Healthcare, Lundbeck, Merck Serono, Novartis, Sanofi-Aventis and Synthon . He has received speaker honoraria from Novartis, Serono Symposia, and BioClinica. He serves as a consultant for Sanofi-Aventis, Roche, Novartis, Biogen Idec, Jansen Alzheimer Immunotherapy, and GE Healthcare.
J. H. Simon declares no competing interests.
F. Fazekas has served on scientific advisory boards for Biogen Idec, Merck Serono, Novartis, Teva Pharmaceutical Industries, and Sanofi-Aventis. He has received travel support from Bayer Schering Pharma and Merck Serono, and research support from Biogen Idec, Merck Serono, Sanofi-Aventis and Teva Pharmaceutical Industries.
M. Rovaris has received funding for travel from Biogen-Dompé and Teva Pharmaceutical Industries. He has received speaker honoraria from Bayer Schering Pharma, Biogen-Dompé, Sanofi-Aventis and Teva Pharmaceutical Industries.
L. Kappos has received research support through the University Hospital Basel from Acorda Therapeutics, Actelion Pharmaceuticals, Advancell, Allozyne, Barofold, Bayer HealthCare Pharmaceuticals, Bayer Schering Pharma, Bayhill, Biogen Idec, BioMarin, Boehringer Ingelheim, CSL Behring, Geneuro, Genmab, GlaxoSmithKline, Glenmark, Merck Serono, MediciNova, Novartis, Sanofi-Aventis, Santhera Pharmaceuticals, Shire, Roche, Teva Pharmaceutical Industries, UCB and Wyeth, and also from the Swiss MS Society, the Swiss National Research Foundation, European Union,as well as Gianni Rubato, and Roche and Novartis Foundations.
N. De Stefano serves on a scientific advisory board for Merck Serono. He has received funding for travel from Merck Serono and Teva Pharmaceutical Industries. He has received speaker honoraria from Bayer Schering Pharma, Biogen-Dompé, BioMS Medical, Merck Serono and Teva Pharmaceutical Industries.
C. H. Polman serves on scientific advisory boards for and has received funding for travel and speaker honoraria from Actelion Pharmaceuticals, Bayer Schering Pharma, Biogen Idec, GlaxoSmithKline, Merck Serono, Novartis, Roche, Teva Pharmaceutical Industries and UCB. He receives research support from Biogen Idec, Merck Serono, Novartis and UCB.
J. Petkau has served on scientific advisory boards for Bayer Schering Pharma, Bayhill Therapeutics, Eisai, Merck Serono, Opexa Therapeutics, Schering-Plough and Solstice Neurosciences. He has received funding for travel and speaker honoraria from Bayer Schering Pharma, Biogen Idec, Merck Serono/Pfizer and Solstice Neurosciences. He serves as a consultant for Bayer Schering Pharma, Bayhill Therapeutics, BTG International, Opexa Therapeutics, PRA International and Solstice Neurosciences. He receives research support from Bayer Schering Pharma and Opexa Therapeutics.
E. W. Radue has received payments through his institution for membership of advisory boards of Biogen Idec and Novartis, honoraria for consultancy from Biogen Idec, Bayer Schering Pharma, Merck, and Novartis, and for lecturing from Bayer Schering Pharma, Biogen Idec, and Novartis.
M. P. Sormani has received speaker honoraria from Biogen-Dompé, Biogen Idec, Merck Serono and Teva Pharmaceutical Industries. She serves as a consultant for Actelion Pharmaceuticals, Biogen Idec, Eidetica and Merck Serono.
D. K. Li has served on scientific advisory boards for Nuron Biotech and Roche. He serves on the speakers' bureaus for the Consortium of MS Centers, Merck Serono and Teva Pharmaceutical Industries. He serves as a consultant for Genzyme Corporation; performs MRI (50% clinical effort). He is the Director of the University of British Columbia MS/MRI Research Group, which has been contracted to perform central analysis of MRI scans for therapeutic trials with Angiotech, Bayer Schering Pharma, Berlex-Schering, BioMS Medical, Centocor (Janssen), Daiichi Sankyo, Genzyme Corporation, Roche, Merck Serono, Novartis, Sanofi-Aventis, Schering-Plough, Teva Pharmaceutical Industries and Transition Therapeutics, and receives research support from the MS Society of Canada and the Canadian Institute of Health Research.
P. O'Connor has received consulting fees and/or research support for MS trials from Actelion, Bayer, Biogen Idec, BioMS, Cognosci, Daiichi Sankyo, EMD Serono, Genentech and Genmab.
X. Montalban serves on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis and Teva Pharmaceutical Industries. He has received funding for travel and speaker honoraria from Bayer Schering Pharma, Biogen Idec, Merck Serono, Novartis, Sanofi-Aventis and Teva Pharmaceutical Industries. He serves as a consultant to Almirall, Bayer Schering Pharma, Biogen Idec, Eli Lilly and Company, Merck Serono, Novartis, Sanofi-Aventis and Teva Pharmaceutical Industries. He has received research support for clinical trials from Genentech, Genzyme and Wyeth.
D. H. Miller serves on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, GlaxoSmithKline and Novartis. He has received funding for travel or speaker honoraria from Bayer Schering Pharma, Biogen Idec, the Cleveland Clinic, GlaxoSmithKline, Novartis, the National MS Society. He receives publishing royalties for McAlpine's Multiple Sclerosis, fourth edition (Churchill Livingstone, 2005). He serves as a consultant for Biogen Idec and GlaxoSmithKline, and receives research support through his institution from Biogen Idec, GlaxoSmithKline, Novartis and Schering-Plough.
M. Filippi serves on scientific advisory boards for Genmab and Teva Pharmaceutical Industries, and has received funding for travel from Bayer Schering Pharma, Biogen-Dompé, Genmab, Merck Serono, and Teva Pharmaceutical Industries. He serves as a consultant to Bayer Schering Pharma, Biogen-Dompé, Genmab, Merck Serono, Pepgen Corporation and Teva Pharmaceutical Industries. He serves on speakers' bureaus for Bayer Schering Pharma, Biogen-Dompé, Genmab, Merck Serono and Teva Pharmaceutical Industries. He receives research support from Bayer Schering Pharma, Biogen-Dompé, Genmab, Merck Serono and Teva Pharmaceutical Industries.
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Barkhof, F., Simon, J., Fazekas, F. et al. MRI monitoring of immunomodulation in relapse-onset multiple sclerosis trials. Nat Rev Neurol 8, 13–21 (2012). https://doi.org/10.1038/nrneurol.2011.190
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DOI: https://doi.org/10.1038/nrneurol.2011.190
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