Magnetic Resonance Techniques in Clinical Trials in Multiple Sclerosis

200 Pages·1999·3.91 MB·English

by  M. Filippi, R. I. Grossman, G. Comi (auth.), Massimo Filippi, Robert I. Grossman, Giancarlo Comi (eds.)

Topics in Neuroscience
Managing Editor:
GIANCARLO COMI
Co-Editor:
JACOPO MELDOLESI
Associate Editors:
UGO ECARI
MASSIMO FILIPPI
GIANVITO MARTINO
Springer-Verlag Italia Srl.
M. Filippi. R.I. Grossman. G. Comi (Eds)
Magnetic Resonance
Techniques in Clinical
Trials in Multiple Sclerosis
, Springer
MASSIMO FILIPPI
Neuroimaging Research Unit, Department of Neuroscience
Scientific Institute Ospedale San Raffaele
University of Milan, Italy
ROBERT 1. GROSSMAN
Department of Radiology
University of Pennsylvania, Philadelphia, USA
GIANCARLO COMI
Clinical Trials Unit, Department of Neuroscience
Scientific Institute Ospedale San Raffaele
University of Milan, Italy
The Editors and Authors wish to thank FARMADES-SCHERING GROUP (Italy)
for the support and help in the realization and promotion of this volume
© Springer-Verlag Italia 1999
Originally published by Springer-Verlag Italia, Milano in 1999
ISBN 978-88-470-2180-8 ISBN 978-88-470-2153-2 (eBook)
DOI 10.1007/978-88-470-2153-2
Library of Congress Cataloging-in-Publication Data: Magnetic Resonance Techniques in
Clinical Trials in Multiple Sclerosis I editors, M. Filippi, R.1. Grossman, C. Comi - p. cm.
Includes bibliographical references and index. ISBN 8847000416 1. Multiple Sclerosis-
Magnetic resonance imaging. 2. Clinical trials.1. Filippi, M. (Massimo), 1961 - II. Grossman.
Robert 1. III. Comi,G. (Giancarlo), 1947-RC377.M2451998 616 8'3407548--dc2198-51407 CIP
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To my parents who taught me to speak Italian,
to Alessandra who taught me to enjoy speaking
and writing in English and to Bobo
wno is teaching me to bark
(M. Filippi)
To Elizabeth
you are my sunshine
(R.!. Grossman)
To Professor Nicola Canal
(G. Comi)
Preface
We have entered an exciting period in the study of multiple sclerosis and its
treatment. Central to this progress has been the introduction of magnetic reso
nance techniques. When Young and his colleagues published the first images of
the brain in multiple sclerosis at the end of 1981, it was at once obvious that
magnetic resonance imaging would playa major role in diagnosis. Intuitively
one felt that it would also have a role in increasing our understanding of the
pathogenesis of the disease and in monitoring treatment. And so it has proved.
Important problems however remain, perhaps the most important of which
at present is the weak predictive power of standard magnetic resonance ima
ging methods in determining the possibility of progression of impairment and
disability. Recently, there have been advances which promise to overcome some
of these problems, but decisions about what approach to adopt in selecting
patients for clinical trials and which techniques to use in monitoring treatment
during their course are still difficult.
In this book, Dr. Filippi and his colleagues have assembled an outstanding
group of contributors whose work is central to the progress that is being made.
The coverage of the issues involved in the use of magnetic resonance techniques
in assessing therapeutic effect is comprehensive and, though the field is chan
ging rapidly, the principles and much of the detail in the book are likely to have
lasting value.
Ian W. McDonald
Table of Contents
Introduction
M. FILIPPI, R.I. GROSSMAN, G. COMI. . • • . . . . • • • . . . . . • . • • . . . . • • . . . . . . 1
Clinical and Paraclinical Outcomes for Treatment Trials in Multiple Sclerosis
G. COMI, M. ROVARIS . . . . . . • . . . . . . . . . . . . . . . . . . . . . . . . . • . . . . . . . . . 3
The Use of Magnetic Resonance Imaging to Select Patients
for Multiple Sclerosis Clinical Trials
J.H. SIMON . . . • . . • • • . . • • . . . . . . . . . . . . . . . • . . . . . . . . . • . . . . • . . • .. 21
The Application of Magnetic Resonance Imaging to Phase II Trials in Multiple Sclerosis
H.E McFARLAND, J.A. FRANK. . • • • • . . . . • . . . . . . . . . . . . . . . • . . . . . . . •• 37
Magnetic Resonance Imaging Techniques to Monitor Phase III Treatment Trials
P.D. MOLYNEUX, D.H. MILLER. . . . • . . • . . . . . • . . . . . . • . . . . . . . . . • . . . .. 49
New Strategies to Increase Magnetic Resonance Imaging Sensitivity in Detecting
Individual Multiple Sclerosis Lesions and Short-term Disease Activity:
Perspectives for Future Clinical Trials
M. FILIPPI • . . . . • . . . . . . . . . . . . . . . • . . . . . . . . . . . . . . . . . • . . . . • • . . .. 74
Problems with Conventional Magnetic Resonance Imaging and New Strategies
to Improve the Utility of MRI in Future Clinical Trials
R.I. GROSSMAN . . . . . . • . . . . . . . . . . . . . . . . . . . • . . . . . . . . . . • . . . . . . •• 85
Review of the Results of Previous Phase II, Magnetic Resonance Imaging-monitored
Clinical Trials
P.S. SOELBERG S0RENSEN ........................................ 106
x Table of Contents
Magnetic Resonance Imaging Techniques in Phase III Clinical Trials
in Multiple Sclerosis
D.W. PATY, D.K.B. LI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 134
Standardisation, Optimisation and Organisation of Magnetic Resonance Imaging
for Monitoring Clinical Trials
M.A. HORSFIELD . . . . . . . . . . • • . . . . . . . . . . . . • . . . . . . • . . . . . . . . • . . •• 145
Statistical Approaches to the Use of Magnetic Resonance Imaging Data
for Clinical Trials
P. BRUZZI, M.P. SORMANI ....................................... 168
Subject Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 187
List of Contributors
Paolo Bruzzi Henry F. McFarland,
Unit of Clinical Epidemiology and Trials, Neuroimmunology Branch,
National Institute for Cancer Research, National Institute of Neurological
and BETA, Biomedical Technology Disorders and Stroke,
Assessment, Advanced Biotechnology National Institutes of Health,
Center, Genoa, Italy Bethesda, Maryland, USA
Giancarlo Comi David H. Miller
Clinical Trials Unit, NMR Research Unit, Institute of Neurology,
Department of Neuroscience, National Hospital, London, UK
Scientific Institute Ospedale San Raffaele,
University of Milan, Italy Paul D. Molyneux
NMR Research Unit, Institute of Neurology,
Joseph A. Frank National Hospital, London, UK
Laboratory of Diagnostic Radiology,
Clinical Radiology, Donald W. Paty
Division of Neurology,
National Institutes of Health, Bethesda,
Department of Medicine,
Maryland, USA
The University of British Columbia,
Vancouver, BC, Canada
Massimo Filippi
Neuroimaging Research Unit,
Marco Rovaris
Department of Neuroscience,
Neuroimaging Research Unit,
Scientific Institute Ospedale San Raffaele,
Department of Neuroscience,
University of Milan, Italy
Scientific Institute Ospedale San Raffaele,
University of Milan, Italy
Robert 1. Grossman
Department of Radiology,
Jack H. Simon
University of Pennsylvania
Department of Radiology,
Medical Center, Philadelphia,
University of Colorado, Health Sciences
Pennsylvania, USA
Center, Denver, Colorado, USA
Mark A. Horsfield
Per Soelberg S(Jrensen
Division of Medical Physics,
MS Research Unit, the Neuroscience
University of Leicester,
Center, Copenhagen University Hospital,
Leicester Royal Infirmary,
Rigshospitalet, Copenhagen, Denmark
Leicester, UK
Maria Pia Sormani
David K.B. Li
Neuroimaging Research Unit,
Department of Radiology, Department of Neuroscience,
Vancouver Hospital & Health Science, Scientific Institute Ospedale San Raffaele,
Center, Vancouver, BC, Canada
University of Milan, Italy
Introduction
M. FILIPPI!, R.I. GROSSMAN2, G. COMI3
Magnetic resonance imaging (MRI) has had a dramatic impact on multiple scle
rosis (MS) in both clinical practice and basic science. It has increased the level of
certainty with which the diagnosis of MS can be made, improved our under
standing of the pathogenesis and the natural history of the disease and, most
importantly, provided objective and reliable measures to monitor the effects of
experimental treatments.
There is, indeed, a general perception that the therapeutic era for MS has
begun and many new, potentially effective treatments are now available. This
means that neuroscientists must be able to define accurately, objectively and effi
ciently whether a treatment behaves better than a placebo in modifying the nat
ural evolution of the disease and, in the near future, which of the many effective
treatments is the most beneficial for particular cohorts of patients. At present,
MRI is the best tool to fulfIll these requirements. MRI offers a range of techniques
which are more sensitive and reliable than any other presently available approach
in detecting brain and spinal cord abnormalities, monitoring their evolution, and
providing in vivo information about the heterogeneous pathological substrates of
the MS lesions. This requires clinical neurologists and radiologists to have current
and comprehensive knowledge regarding the role of MRI in monitoring treat
ment effects as well as a robust understanding of the principles of MRI to inter
pret the results of clinical trials.
The first chapter of this book outlines the limitations of clinical endpoint mea
sures. MS is characterized by highly variable clinical manifestations and its evo
lution is almost unpredictable on clinical grounds alone. This, coupled with the
intrinsic drawbacks of the presently available clinical scales, implies that hun
dreds of patients have to be evaluated for many years to show any significant
treatment effect. Similar limitations affect other possible measures of disease evo
lution which can be derived from immunological or neurophysiological tests. In
the next three chapters, the MRI approaches which have been traditionally used
to select patients (Chapter 2) and to monitor treatment effects in phase II
Neuroimaging Research Unit, Department of Neuroscience, Scientific Institute Ospedale
1
San Raffaele, University of Milan, Italy
Department of Radiology, University of Pennsylvania Medical Center, Philadelphia,
2
Pennsylvania, USA
Clinical Trials Unit, Department of Neuroscience, Scientific Institute Ospedale San
3
Raffaele, University of Milan, Italy