cohen - multiple sclerosis therapeutics

Multiple Sclerosis TherapeuticsSecond edition

Multiple Sclerosis TherapeuticsSecond edition Edited by

Jeffrey A Cohen MD Mellen Center for Multiple Sclerosis Treatment and Research The Cleveland Clinic Foundation Cleveland Ohio USARichard A Rudick MD Mellen Center for Multiple Sclerosis Treatment and Research The Cleveland Clinic Foundation Cleveland Ohio USAPrefaces written by

Henry McFarland MD Chief, Immunology Branch National Institute of Neurological Disorders and Stroke National Institute of Health Bethesda MD USA

LONDON AND NEW YORK

1999, 2003, Martin Dunitz Ltd, a member of the Taylor & Francis Group First edition published in the United Kingdom in 1999 by Martin Dunitz Ltd, The Livery House, 79 Pratt Street, London NW1 0AE Tel: +44 (0) 20 74822202 Fax: +44 (0) 20 72670159 E-mail: [email protected] Website: http://www.dunitz.co.uk/ This edition published in the Taylor & Francis e-Library, 2005. To purchase your own copy of this or any of Taylor & Francis or Routledges collection of thousands of eBooks please go to http://www.ebookstore.tandf.co.uk/. Second edition 2003 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of the publisher or in accordance with the provisions of the Copyright, Designs and Patents Act 1988 or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London W1P 0LP. Although every effort has been made to ensure that drug doses and other information are presented accurately in this publication, the ultimate responsibility rests with the prescribing physician. Neither the publishers nor the authors can be held responsible for errors or for any consequences arising from the use of information contained herein. For detailed prescribing information or instructions on the use of any product or procedure discussed herein, please consult the prescribing information or instructional material issued by the manufacturer. A CIP record for this book is available from the British Library. ISBN 0-203-63911-1 Master e-book ISBN

ISBN 0-203-63937-5 (Adobe e-Reader Format) ISBN-1-84184-226-5 (Print Edition) Distributed in the USA by Fulfilment Center Taylor & Francis 10650 Tobben Drive Independence, KY 41051, USA Toll Free Tel: +1 800 634 7064 E-mail: [email protected] Distributed in Canada by Taylor & Francis 74 Rolark Drive Scarborough, Ontario M1R 4G2, Canada Toll Free Tel: +1 877 226 2237 E-mail: [email protected] Distributed in the rest of the world by Thomson Publishing Services Cheriton House North Way Andover, Hampshire SP10 5BE, UK Tel: +44 (0) 1264 332424 E-mail: [email protected] Composition by Wearset Ltd, Boldon, Tyne & Wear

ContentsContributors Preface to first edition Preface to second edition Acknowledgements x xxii xxv xxvii

I Introduction 1 Aspects of multiple sclerosis that relate to clinical trial design and treatment Jeffrey A Cohen and Richard A Rudick II Clinical trial methodology 2 Measures of neurologic impairment and disability in multiple sclerosis Gary R Cutter 3 Assessment of neuropsychological function in multiple sclerosis Jill S Fischer 4 Health-related quality of life assessment in multiple sclerosis Deborah M Miller 5 Magnetic resonance imaging in multiple sclerosis: an overview David H Miller 6 Measures of gadolinium enhancement in multiple sclerosis Jack H Simon 7 Measures of magnetization transfer in multiple sclerosis Massimo Filippi, Marco Rovaris, Joseph C McGowan and Carla Tortorella 8 Measures of T1 and T2 relaxation in multiple sclerosis Marianne AA van Walderveen and Frederick Barkhof 9 Measurement of central nervous system atrophy in multiple sclerosis Elizabeth Fisher and Richard A Rudick 10 Measures to quantify axonal damage in vivo based on magnetic resonance spectroscopy in multiple sclerosis Douglas L Arnold and Paul M Matthews 23 38 66 86 103 136 176 197 220 3

11 Functional imaging in multiple sclerosis Nancy L Sicotte 12 Use of cost analyses to improve our understanding of the therapeutic tradeoffs for multiple sclerosis Elizabeth D Kulas and Kathryn Whetten-Goldstein 13 Ethical considerations in multiple sclerosis clinical trials William Pryse-Phillips 14 The process of drug development and approval in the USA, the European Union and Canada Nadine Cohen, Ann Dodds-Frerichs, Tammy Phinney and John Watson 15 Sponsors, monitoring committees and investigators: the investigators perspective Fred D Lublin and Stephen C Reingold 16 Guidelines for clinical trials of new therapeutic agents in multiple sclerosis: reporting extended results from phase III clinical trials Donald E Goodkin, Stephen C Reingold, William A Sibley, Jerry S Wolinsky, Henry F McFarland, Diane L Cookfair and Fred D Lublin 17 The failed clinical trial in multiple sclerosis Lael A Stone, Richard A Rudick and Nancy D Richert 18 The challenge of long-term studies in multiple sclerosis: use of pooled data, historical controls, and observational studies to determine efficacy John H Noseworthy 19 Emerging concepts of pathogenesis: relationship to MS therapies Jorge R Oksenberg, Sergio E Baranzini and Stephen L Hauser

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III Clinical trials of disease-modifying therapy 20 Interferons in relapsing-remitting multiple sclerosis Ludwig Kappos 21 Interferons in secondary progressive multiple sclerosis Ruth Ann Marrie and Jeffrey A Cohen 22 Biological responses to type I interferons: relationship to therapeutic effects in multiple sclerosis Richard M Ransohoff 23 Glatiramer acetate as therapy for multiple sclerosis Corey C Ford 24 Use of mitoxantrone to treat multiple sclerosis Gilles Edan, Sean Patrick Morrissey and Hans-Peter Hartung 25 Intravenous immunoglobulin to treat multiple sclerosis Franz Fazekas, Siegrid Strasser-Fuchs, Ralf Gold and Otto R Hommes 26 Therapeutic plasma exchange for multiple sclerosis Brian G Weinshenker and Mark Keegan 360 386 402

418 450 478 495

27 Treatment of multiple sclerosis with methylprednisolone Robert J Fox and R Philip Kinkel 28 Cyclophosphamide treatment of multiple sclerosis Derek R Smith and Howard L Weiner 29 Treatment of multiple sclerosis by hematopoietic stem cell transplantation Richard K Burt, Bruce Cohen, Lorri Lobeck, William H Burns and Christopher Bredeson 30 Emerging disease-modifying therapies for multiple sclerosis Karim Makhlouf and Samia J Khoury 31 Combination therapies in multiple sclerosis Christian Confavreux 32 Sex hormones and other pregnancy-related factors with therapeutic potential in multiple sclerosis Rhonda R Voskuhl 33 Complementary and alternative treatments in multiple sclerosis Vijayshree Yadav and Dennis N Bourdette IV Disease-modifying drug therapy in clinical practice 34 Disease-modifying drug therapy for multiple sclerosis in clinical practice Lawrence M Samkoff and Andrew D Goodman 35 Treatment for patients with primary progressive multiple sclerosis Siobhan M Leary and Alan J Thompson 36 Fatigue in multiple sclerosis Lauren B Krupp 37 Management of spasticity in multiple sclerosis Franois A Bethoux 38 Management of bladder and sexual dysfunction in multiple sclerosis Scott E Litwiller 39 Treatment of disorders of mood and affect in multiple sclerosis Sarah L Minden, Melissa Frumin and Jane L Erb 40 Treatment of pain, paresthesias, and paroxysmal disorders in multiple sclerosis Marco A Rizzo 41 Treatment of tremor caused by multiple sclerosis Anwar Ahmed, Jorge A Gonzalez-Martinez and Erwin B Montgomery 42 Management of cognitive impairment in multiple sclerosis Steven R Schwid 43 Rehabilitation in multiple sclerosis patients Franois A Bethoux

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ContributorsAnwar Ahmed MD Movement Disorders Section Department of Neurology Cleveland Clinic Foundation Cleveland OH USA Douglas L Arnold MD MR Spectroscopy Unit Montral Neurological Institute and Hospital Montral PQ Canada Sergio E Baranzini PhD Department of Neurology University of California at San Francisco, School of Medicine San Francisco CA USA Frederick Barkhof MD MR Center for MS Research Vrije Universiteit Medical Center Amsterdam The Netherlands Franois A Bethoux MD Staff Physician Mellen Center for Multiple Sclerosis Treatment and Research Cleveland Clinic Foundation Cleveland OH USA Dennis N Bourdette MD Interim Chair and Roy & Eulalia Eulalia Swank Family Research Professor Department of Neurology Oregon Health & Sciences University Portland OR USA

Christopher Bredeson MD Bone Marrow Transplant Program Department of Medicine Medical College of Wisconsin Milwaukee WI USA William H Burns MD Professor of Medicine and Microbiology Director, Bone Marrow Transplant Program Medical College of Wisconsin Milwaukee WI USA Richard K Burt MD Assistant Professor of Medicine Division of Immune Therapy and Autoimmune Disease Northwestern University Medical School Chicago IL USA Bruce Cohen MD Department of Neurology Northwestern University Medical School Chicago IL USA Nadine Cohen PhD Senior Vice President, Regulatory Affairs Biogen, Inc. Cambridge MA USA Christian Confavreux MD Professor of Neurology Head of Department, INSERM U 433 Service de Neurologie and EDMUS Co-ordinating Center Hpital Neurologique Lyon France Diane L Cookfair PhD Department of Neurology University at Buffalo, SUNY

Buffalo NY USA Gary R Cutter PhD Professor of Medicine Director, Center for Research, Design & Statistical Methods Department of Internal Medicine UNR School of Medicine University of Nevada Reno NV USA Ann Dodds-Frerichs MBA Director, Regulatory Affairs Biogen, Inc. Cambridge MA USA Gilles Edan Department of Neurology CHU Pontchaillou Rennes France Jane L Erb MD Department of Psychiatry Brigham and Womens Hospital Boston MA USA Franz Fazekas MD Professor of Neurology Department of Neurology and MRI Centre Karl-Franzens-Universitt Graz Graz Austria Massimo Filippi MD Head, Neuroimaging Research Unit Department of Neuroscience San Raffaele Institute Milan Italy Jill S Fischer PhD Consultant, Neuropsychological &

Health Outcomes Research Chicago IL USA Elizabeth Fisher PhD Department of Biomedical Engineering Whitaker Biomedical Imaging Laboratory Lerner Research Institute Cleveland Clinic Foundation Cleveland OH USA Corey C Ford MD PhD Medical Director Clinical and MR Research Center and Multiple Sclerosis Specialty Clinic Albuquerque NM USA Robert J Fox MD Associate Staff Mellen Center for Multiple Sclerosis Treatment and Research Cleveland Clinic Foundation Cleveland OH USA Melissa Frumin MD Instructor in Psychiatry Harvard Medical School and Neuropsychiatrist Brigham Behavioral Neurology Group Brigham and Womens Hospital Boston MA USA Ralf Gold MD Department of Neurology Julius-Maximilians-Universitt Wrzburg Germany Jorge A Gonzalez-Martinez MD Section of Stereotactic and Functional Neurosurgery Department of Neurosurgery Cleveland Clinic Foundation Cleveland OH USA

Donald E Goodkin MD Director, Medical Affairs Amgen Corporation Seattle WA USA Andrew D Goodman MD Department of Neurology University of Rochester School of Medicine and Dentistry Rochester NY USA Hans-Peter Hartung MD Professor and Chairman Department of Neurology Karl-Franzens-Universitt Graz Graz Austria Stephen L Hauser MD Professor and Chairman Department of Neurology University of California at San Francisco, School of Medicine San Francisco USA Otto R Hommes MD Chairman European Charcot Foundation for MS Research Nijmegen The Netherlands Ludwig Kappos Outpatient Clinic Neurology-Neurosurgery University Clinics/Kantonsspital Basel Switzerland Mark Keegan MD FRCP(C) Department of Neurology Mayo Clinic and Foundation Rochester MN USA Samia J Khoury MD Associate Professor of Neurology

Co-Director, Partners MS Center Director, Clinical Immunology Laboratory Center for Neurologic Diseases Brigham and Womens Hospital Boston MA USA R Philip Kinkel MD Director, Multiple Sclerosis Center Beth Israel Deaconess Medical Center Boston MA USA Lauren B Krupp MD Professor of Neurology Director, Neuropsychology Research Co-Director, MS Comprehensive Care Center Department of Neurology State University of New York at Stony Brook Stony Brook NY USA Elizabeth D Kulas Center for Health Economics Research Waltham MA USA Siobhan M Leary MD MRCP Institute of Neurology University of London National Hospital for Neurology and Neurosurgery London UK Scott E Litwiller MD FACS Urologic Specialists of Oklahoma Tulsa OK USA Lorri Lobeck MD Department of Neurology Medical College of Wisconsin Milwaukee WI USA

Fred D Lublin MD Corinne Goldsmith Dickinson Center for Multiple Sclerosis Mount Sinai Medical Center New York NY USA Karim Makhlouf MD Department of Neurology Odense University Hospital Odense Denmark Ruth Ann Marrie MD Department of Neurology Mellen Center for Multiple Sclerosis Treatment and Research Cleveland Clinic Foundation Cleveland OH USA Paul M Matthews MD Centre for Functional Magnetic Research Imaging of the Brain Department of Clinical Neurology University of Oxford John Radcliffe Hospital Oxford UK Henry F McFarland MD Chief, Neuroimmunology Branch National Institute of Neurological Disorders and Stroke Bethesda MD USA Joseph C McGowan PhD Department of Electrical Engineering United States Naval Academy Annapolis MD USA David H Miller MD FRCP NMR Unit The National Institute for Neurology London UK

Deborah M Miller PhD LISW Director, Comprehensive Care Mellen Center for Multiple Sclerosis Treatment and Research Cleveland Clinic Foundation Cleveland OH USA Sarah L Minden MD Assistant Professor of Psychiatry Harvard School of Medicine Brigham and Womens Hospital Boston MA USA Erwin B Montgomery, Jr MD Center for Functional and Restorative Neuroscience Departments of Neurology and Neuroscience Lerner Research Institute Cleveland Clinic Foundation Cleveland OH USA Sean Patrick Morrissey MD Abteilung fr Psychiatrie Universittsklinikum Regensburg Regensburg Germany John H Noseworthy MD FRCP(C) Department of Neurology Mayo Clinic and Foundation Rochester MN USA Jorge R Oksenberg PhD Assistant Professor Department of Neurology University of California at San Francisco San Francisco CA USA Tammy Phinney MSc Manager, Regulatory Affairs Biogen, Inc.

Cambridge MA USA William Pryse-Phillips MD FRCP FRCP(C) Professor of Medicine (Neurology) Memorial University of Newfoundland Health Sciences Centre St Johns Newfoundland Canada Richard M Ransohoff MD Department of Neurosciences Lerner Research Institute Cleveland Clinic Foundation Cleveland OH USA Stephen C Reingold PhD Research Programs National Multiple Sclerosis Society New York NY USA Nancy D Richert MD PhD Staff Clinician, Neuroimmunology Branch National Institutes of Neurological Disorders and Stroke (NINDS) NIH, Bethesda MD USA Marco A Rizzo MD PhD Associate Director Yale Center for Multiple Sclerosis Treatment and Research Yale University School of Medicine New Haven CT USA Marco Rovaris MD Neuroimaging Research Unit Department of Neuroscience San Raffaele Institute Milan Italy Lawrence M Samkoff MD Department of Neurology

University of Rochester School of Medicine and Dentistry Rochester NY USA Steven R Schwid MD Assistant Professor of Neurology University of Rochester School of Medicine Department of Neurology Rochester NY USA William A Sibley MD Professor of Neurology Arizona Health Sciences Center Tucson AZ USA Nancy L Sicotte MD Assistant Professor of Neurology Division of Brain Mapping Department of Neurology UCLA School of Medicine Los Angeles CA USA Jack H Simon MD PhD Professor of Radiology, Neurology and Neurosurgery Director of Neuroradiology and MRI University of Colorado Health Sciences Center Denver CO USA Derek R Smith MD MS Center, Brigham and Womens Hospital Boston MA USA Lael A Stone MD Staff Neurologist Mellen Center for Multiple Sclerosis Treatment and Research Cleveland Clinic Foundation Cleveland OH USA Siegrid Strasser-Fuchs MD Department of Neurology

Karl-Franzens-University Graz Graz Austria Alan J Thompson MD FRCP FRCPI Garfield Weston Professor of Clinical Neurology and Neurorehabilitation Institute of Neurology University of London National Hospital for Neurology and Neurosurgery London UK Carla Tortorella MD Neuroimaging Research Unit Department of Neuroscience San Raffaele Scientific Institute Milan Italy Rhonda R Voskuhl MD Associate Professor Department of Neurology University of California, Los Angeles Los Angeles CA USA Marianne AA van Walderveen MD MR Center for MS Research Vrije Universiteit Medical Center Amsterdam The Netherlands John Watson BSc Director, Regulatory Affairs Biogen, Ltd. Maidenhead, Berks UK Howard L Weiner MD MS Center, Brigham and Womens Hospital Boston MA USA Brian G Weinshenker MD FRCP(C) Professor of Neurology Mayo Clinic and Foundation

Rochester MN USA Kathryn Whetten-Goldstein MPH PhD Duke University Center for Health Policy, Law and Management and the Terry Sanford Institute of Public Policy Duke University Durham NC USA Jerry S Wolinsky MD Department of Neurology The University of Texas at Houston Medical School Houston TX USA Vijayshree Yadav MD Fellow, Neuroimmunology Oregon Health & Sciences University Portland VA Medical Center Portland OR USA

Preface to first editionA little over 20 years ago it was thought by many that research into experimental therapies in multiple sclerosis (MS) was, at best, unlikely to provide valid or reproducible information relating to the treatment of the disease. This pessimistic opinion was reflected at the First International Conference on Therapeutics in Multiple Sclerosis, held in 1982. The concerns were based on many unsubstantial claims for efficacy for treatments that could not be confirmed and on the failure to identify a significant treatment effect in the many trials that had been done prior to the meeting. While the failures were due in part to a highly variable and unpredictable clinical course, which is the clinical hallmark of the disease, there was also concern that a higher level of scientific quality was needed in experimental therapeutic research in MS. Today, research on new therapies in MS has become increasingly efficient and effective in identifying the effect of these therapies on the course of the disease. In fact, research into the treatment of MS can be considered an example of excellence in experimental therapeutics in neurological disease. The change is evidenced by the approval in the USA of three therapies for the relapsing-remitting phase of the disease. The change can be related to several factors. Certainly, demonstration that magnetic resonance imaging (MRI) can provide an objective means for monitoring MS, at least in some phases of the disease course, has provided a very powerful tool in experimental therapeutics in MS. Most important, however, has been the growth of expertise in clinical research in MS. Impressive advances in the attention given to the design of clinical trials in MS ranging from early phase 1 or 2 studies to pivotal phase 3 studies are now evident. Examples of clinical trials with severe or fatal flaws in trials design, common in the past, are now unusual. These advances reflect the growing importance given to clinical research in MS. Despite these advances, many unresolved questions relating to the study of new therapies in MS persist. Beginning with an important meeting focusing on clinical outcomes in MS research sponsored by the National Multiple Sclerosis Society and held in 1994, use of both clinical and MRI outcomes has been carefully studied. New approaches to the assessment of clinical disease progression have been described and are now beginning to be used in clinical trials. Further, use of MRI as an outcome measure has been and continues to be carefully evaluated. Thus, summary of the advances in MS experimental therapeutics, including detailed assessment of clinical and MRI outcomes, is especially timely. Early in the use of MRI as an outcome measure, many investigators were convinced that measure of disease activity on MRI could replace clinical outcome measures completely. It was hoped that MRI was a direct measure of the disease activity occurring in MS and that monitoring changes in disease activity as seen on MRI during the use of a new treatment could establish the effectiveness of that treatment. It is now clear that, although MRI is a very powerful tool, the ability to translate changes in disease activity

seen using conventional MR imaging directly to clinical outcomes is not perfect. It is becoming increasingly evident that the evolution of the MS lesion is complex and probably variable among patients. Further, the evolution of the pathological processes involved in the disease probably does not represent a continuum of a single process, but, instead, various components each contributing in different ways to damage of the myelin sheath and the axon. Thus, it is likely that the correlation between various MRI modalities differs during various stages of the disease process. For example, the level of disease activity as measured on T2-weighted images or on post-contrast T1-weighted images early in the course of the disease may be helpful in predicting the severity of future disease. These same measures of disease activity, when examined later in the course of the disease, may have little relationship to the level of disability existing at the time of study or to the future progression of the disease. It is likely that progression is closely related to irreversible damage to the myelin sheath and to axonal damage, neither of which are specifically reflected on T2-weighted images. Further, the level of new activity seen in contrast-enhanced T1-weighted images may only have a small impact on the overall level of disease once a large degree of diseased brain exists. Thus, it is hoped that imaging sequences, which have greater pathological specificity for the events contributing most directly to progression, will provide a more useful tool for monitoring new therapies in clinical trials. The chapters incorporated in the first section of this book, written by individuals with particular expertise in their respective areas, will provide an up-to-date review of the assessment of clinical and MRI outcomes measures that are and that will be used in clinical trials in MS. Overall, the reader will develop an understanding of the problems in experimental therapeutics that are unique to MS, knowledge about clinical outcomes that form the heart of clinical trials, and a solid foundation regarding the strengths and weaknesses of imaging as an outcome measure in clinical trials in MS. The interest is experimental therapeutics in MS is growing rapidly as advances in immunology and genetics point to therapies that may have potential for modifying the disease process. The issues discussed will provide the reader with the information necessary to assess and to participate in this exciting area of clinical research. Following this basic foundation, subsequent chapters examine the results of the most important symptomatic and disease-modifying therapies in MS. As one reviews current understanding of many of these therapies, one can understand the importance of welldesigned clinical studies. Unfortunately, in many cases, the effectiveness of these therapies is incompletely resolved. More importantly, the ability of many of the therapies to have a truly modifying effect on the course of the disease is uncertain. As implied above, it is likely that the effect of some of these therapies will differ among patients and with respect to the stage of the disease process when they are administered. As the reader evaluates the results obtained with therapies that have been tested in MS, the need for continued improvement in trial design will become apparent. The decision as to whether and when to treat is dependent upon both the physician and the patient having a complete understanding of the effect of the therapy in relation to the stage of the disease and in relation to side effects. In many cases, considerable uncertainty still exists and assessment by both physician and patient of the risks in relation to the benefit is difficult.

It is hoped that careful attention to future trial design and the use of new imaging modalities to define better the effect of the therapies will lead not only to new, effective treatments but also to improved understanding of the disease process. Henry McFarland MD National Institutes of Health, Bethesda, USA

Preface to second editionProgress in our understanding of multiple sclerosis or in our ability to treat the disease was remarkably small until the beginning of the 1990s. In contrast, during the 1990s progress both in the identification of therapies and in the understanding of the pathophysiology of the illness progressed rapidly. The first edition of Multiple Sclerosis Therapeutics presented an excellent state-of-the-art review of the results of advances in the understanding of the mechanisms and treatment of the disease. Fortunately, progress in MS research seen during the early 1990s has continued and over the past 3 years important new findings have emerged and observations made in previous years have been refined and focused. With respect to our understanding of the biology of the disease, the past 3 years have seen a continued focus on the events occurring in the MS lesion and important new information on the heterogeneity of the pathological processes leading to myelin destruction has been described. The importance of damage to the axon, even early in the disease process, has been further defined and new information on repair processes or, more accurately, the failure of repair processes has been studied. The implications of heterogeneity in the pathological processes producing myelin damage are great with respect to the probable impact of therapies; therapies that target an inflammatory component to the disease may have limited value in patients in whom myelin damage occurs in the absence of an important inflammatory component. Although the ability to determine which patient will or will not benefit from a particular therapy is not yet known, progress has been made over the past 3 years in understanding some of the mechanisms of the approved therapies and, slowly, the longer term value of these treatments is becoming better understood. Probably most important the results of recent clinical trials have made the value of treatment early in the disease course clearer. Imaging continues to be an important tool for helping to establish the benefit of new therapies and for understanding the disease process. Formal guidelines for the use of MRI as a diagnostic tool have been developed and the value of MRI in selecting patients for early therapy is now generally accepted. The application of functional imaging to MS has increased, as has the focus on the cognitive changes caused by the disease. Finally, a new emphasis is being placed on the management of the disease using approaches that can be an adjunct to disease modifying therapies. The role of rehabilitative strategies is being actively studied, as are other symptomatic therapies designed to improve the quality of life for individuals with the illness. This new edition of Multiple Sclerosis Therapeutics has both updated prior chapters and added new chapters to reflect advances over the past few years. Because of the importance of new information which has appeared over the past three years on both approved and emerging therapies, chapters dealing with approved therapies such as beta interferon, glatiramer acetate and mitoxantrone, non-approved therapies used clinically such as IVIg and plasma exchange and new or evolving strategies such as stem cell

transplantation and the combination of multiple therapies have been extensively revised. Further, new chapters have been added to review topics that have received attention since the publication of the first edition. These include chapters on sex hormones and pregnancy-related factors as well as a discussion of complementary and alternative therapies. Finally, a discussion on cost-benefit analyses has been included. It is fortunate that a second edition is needed as it reflects the continued progress in helping to alleviate disease activity and the resulting symptoms of MS. Hopefully a third edition will be needed within a few years. Henry McFarland MD National Institutes of Health, Bethesda, USA

AcknowledgementsOur thanks are due to the many authors who contributed towards this book. The publishers have been a pleasure to work with: our thanks to Martin Dunitz for providing early advice, and to Alan Burgess and Charlotte Mossop for all their efforts in coordinating the project and ensuring the expeditious publication of this book. Dr Bruce Trapp generously provided the beautiful micrograph on the cover. Finally, this book is dedicated to Sally, Jennifer, Joshua, Marilyn, Brian and Jamie.

I Introduction

1 Aspects of multiple sclerosis that relate to clinical trial design and treatmentJeffrey A Cohen and Richard A Rudick

INTRODUCTION The past decade has witnessed substantial progress in our understanding of the pathogenesis of multiple sclerosis (MS), improvement in our ability to diagnose the disease and monitor its course, and the emergence of MS as a treatable neurologic disease. Nevertheless, the development of effective treatments for MS has been impeded by several characteristics of the disease. The purpose of this chapter is to discuss the aspects of MS that have an impact on the design of clinical trials, the development of new disease therapies, and patient care. These aspects include heterogeneity in disease course, in severity, and in manifestations; the presence of subclinical disease activity early in the disease; and the complexity of pathogenic mechanisms.

HETEROGENEITY IN MS Disease course The clinical course of MS presents challenges because the disease has strikingly heterogeneous clinical manifestations that evolve over decades in most patients. A classification of disease course has been developed by consensus (Table 1.1).[1] During the relapsing-remitting stage, periodic relapses occur at irregular and unpredictable intervals, averaging approximately one per year. The episodic attacks of neurologic dysfunction are followed by partial or complete recovery, and individual relapses are separated by a clinically stable phase. Relapses tend to become less conspicuous over the years, and the majority of patients (approximately 75%) ultimately evolve into a pattern of gradual neurologic deterioration, termed secondary progression. During this stage, physical, cognitive, emotional, social, and economic decline is the rule, and the illness seems more refractory to treatment. This stage of the disease is also difficult to study, because deterioration typically occurs slowly over the course of years, and the significant individual variability persists. The transition from relapsing-remitting MS to secondary progressive MS does not occur at a precise point in time. Rather, clinical relapses become less distinct episodes, recovery becomes less robust, and the relapsing-remitting stage blends into the secondary progressive stage, typically 1020 years after the onset of symptoms. The transition to the secondary progressive stage can be dated only in retrospect, once it is clear that the patient has continuously worsened for months or years.

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Eighty-five percent of patients have relapsing

Table 1.1 Clinical categories of multiple sclerosisDisease categoryRelapsingremitting MS

Description

Episodic relapses with recovery and a stable phase between relapses. MS begins as relapsing-remitting MS in approximately 85% of cases. Clinical relapses imply that the disease is active, but clinical remission does not mean the disease is quiescent. MRI studies have shown that the disease may be active when the disease is clinically inactive. Secondary Gradual neurologic deterioration with or without progressive superimposed acute relapses in a patient who previously had MS relapsing-remitting MS. Over 75% of patients with relapsing-remitting MS will develop secondary progressive MS. A major goal of disease therapy in relapsing-remitting MS patients is to prevent evolution to secondary progressive MS. Gradual, nearly continuous neurologic deterioration from the Primary progressive onset of symptoms. Some patients with primary progressive MS MS have onset in middle age and MRI and CSF findings identical to patients with secondary progressive MS. These patients probably have secondary progressive MS, but without evident clinical relapses during the early stage of disease. Other primary progressive MS patients appear to have a degenerative process with minimal evidence of inflammation. These patients present with a gradually worsening gait disorder and often have minimal cranial disease by MRI scans. Progressive Gradual neurologic deterioration from onset but with subsequent superimposed relapses. This is an unusual relapsing MS clinical pattern that may also be analogous to secondary progressive MS without an initial relapsing-remitting course. Adapted from Lublin and Reingold.[1]

forms of MS, either relapsing-remitting MS or secondary progressive MS. Approximately 1015% of patients have so-called primary progressive MS, in which continuous clinical deterioration occurs from the onset of disease (see chapter 34). Patients with primary progressive MS tend to have symptom onset at a later age (typically between the ages of 40 and 60 years), and the female preponderance seen with relapsing forms of MS is not evident. Patients with primary progressive MS present clinically with insidiously progressive spastic weakness, imbalance, and sphincter dysfunction; diffuse and less nodular T2 lesions on magnetic resonance imaging (MRI); fewer or no gadoliniumenhancing lesions; and little inflammatory change in the cerebrospinal fluid (CSF).[2] These cases may represent a type of MS that is less dependent on inflammation and that may be primarily degenerative. A consensus has emerged that primary progressive MS should be considered separately from the other groups for the purpose of controlled clinical trials, in part because of uncertainty about the etiologic relationship between this

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form and the other categories. Some patients with primary progressive MS exhibit clinical features, MRI findings, and a CSF profile similar to those of patients with secondary progressive MS and probably have the same disease as secondary progressive MS, but without clinically distinct relapses during the early stage. This is probably also true of progressive relapsing MS. Thus, studies in primary progressive MS are problematic because these cases are relatively uncommon, and because the primary progressive MS category probably comprises a combination of secondary progressive MS patients who did not have a symptomatic relapsing-remitting stage and patients with a less inflammatory central nervous system (CNS) disease that is less responsive to immunomodulatory treatment approaches. Common practice has been to attempt to select relatively homogeneous patient groups for inclusion in clinical trials, typically by defining disability limits using the Kurtzke Expanded Disability Status Scale (EDSS)[3] and by entering patients within specified disease categories. This strategy aims at reducing between-patient variability and increasing the power to show therapeutic effects with a given sample size. This explains why separate trials have been conducted for patients with relapsing-remitting MS, secondary progressive MS, and primary progressive MS. There are several caveats to restricting trials to certain types of patients. First, excessively narrow entry criteria may impede recruitment. Second, it may not be clear whether the results of a trial enrolling a selected cohort of patients can be extrapolated to other groups of MS patients. Third, the distinction between clinical disease categories is not precise, and the reliability of classifying patients into these categories has never been tested. In all likelihood, there is an admixture of patients in MS trials. This point is well illustrated by the European and North American trials of interferon beta-1b in secondary progressive MS, in which two trials with very similar entry criteria enrolled different patient populations and yielded different results with the same therapeutic agent. The problems of classifying patients are most intense at the interface between relapsingremitting MS and secondary progressive MS. As disease duration and EDSS increase, the patient is more likely to be categorized as having secondary progressive MS, and the cutoff point appears to be around EDSS 4.0. At this level and above, the large majority of patients would be classified as secondary progressive MS. Finally, it must be recognized that clinical disease categories are defined empiricallybiologic markers for the categories are not available. Table 1.2 lists characteristics of patients entered into several large MS clinical trials. Despite overlap, disease duration and disability level are clearly different in trials in relapsing-remitting MS from trials in secondary progressive MS. Because the reliability and utility of restricting entry by disease category is unclear, some trials allowed entry of patients based only on disability criteria (e.g. the studies of sulfasalazine[4] and linomide[5]). Patients in these trials were intermediate between the populations in trials restricted to relapsing-remitting MS or secondary progressive MS in terms of disability score and disease duration.


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Clinical manifestations The potential clinical manifestations of MS are myriad and can include, among others, cognitive impairments of a variety of types, loss of vision or abnormalities of eye movements, weakness, spasticity, cerebellar dysfunction, sensory loss or positive sensory phenomena, bowel and bladder

Table 1.2 Patient characteristics in selected controlled clinical trialsAgent tested by clinical n Age trial (years) Duration of disease (years) EDSS

Trials with entry restricted to relapsing-remitting MS Interferon beta-1b[8] 372 35 4.4 Interferon beta-1a[10] 301 37 6.5 Interferon beta-1a[11] 560 35* 5.3* Glatiramer acetate[9] 251 34 6.9 35.2 5.6 Mean Trials with entry restricted to secondary progressive MS Interferon beta-1b 718 41 13.1 (European)[83] 939 47 14.7 Interferon beta-1b (North American)[84] 618 43 13.3 Interferon beta-1a (SPECTRIMS)[85] 436 47 14.2 lnterferon beta-1a (IMPACT)[27] 44.5 14.3 Mean Trials with entry not restricted by disease category Sulfasalazine[4] 199 28 5.5 Linomide[5] 715 46 15.3 42.1 13.2 Mean *Median; all other values are mean.

2.9 2.4 2.5 2.6 2.6 5.1 5.1 5.4 5.2 5.2 2.5 5.2 4.6

dysfunction, fatigue, and paroxysmal phenomena.[6] Patients within a disease category exhibit a wide range of clinical manifestations in varying combinations, and manifestations typically change in individual patients over time. Even within multiply affected families, there is striking clinical heterogeneity between affected family members. Management of the wide variety of MS symptoms is a challenge to the clinician. However, with the increased emphasis on disease-modifying therapies, one needs to remember that identification and effective treatment of troublesome symptoms of MS can have a major beneficial effect on the patients ability to function and quality of life (see chapters 3542). The heterogeneity in potential clinical manifestations also presents significant challenges for the design of clinical trials. Separate trials and treatment arms within a given trial contain variable admixtures of clinical manifestations that are not necessarily


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evenly matched between studies. Outcome measures must be multidimensional to capture the ways in which MS affects patients. Traditional clinical outcome measures are heavily weighted towards motor impairment, particularly gait dysfunction. Common symptoms such as sphincter disturbances, pain, and fatigue may have significant effects on quality of life without affecting measures of physical impairment and disability. Finally, symptomatic and disease-modifying therapies may have differing effects on different disease manifestations (i.e. benefit for some with no effect on others, or even worsening). Disease severity and prognostic factors Because of pronounced variability, there is a need for accurate prognostic markers that could be used both for treatment decisions concerning individual patients and for selecting appropriate patients for clinical trials. Overall, 50% of patients are unable to carry out household and employment responsibilities 10 years after disease onset, 50% require an assistive device to walk after 15 years, and 50% are unable to walk after 25 years.[7] However, about 10% of patients have unusually bad disease and deteriorate to severe irreversible disability in only a few years. Another 10% have benign disease, with intermittent neurologic symptoms but little disease progression and minimal disability decades after the initial symptoms. Although the ultimate prognosis for MS is poor, it is a chronic disease that usually changes slowly. During the time frame of a clinical trial, typically 23 years, clinical evidence of disease activity is modest. For example, most patients in large-scale trials in relapsing-remitting MS experienced no relapses or only one relapse.[811] Also, in these studies, one-third or fewer of the placebo patients demonstrated worsening on traditional measures of impairment or disability, such as the EDSS, over 23 years. Clinical stability in the majority of placebo-treated patients results in the need for large sample sizes. One approach to this problem has been to develop more sensitive outcome measures (see below). Another approach has been to attempt to enroll patients at risk of disease activity and exclude patients who are not likely to change during the trial. In groups of patients, benign disease has been associated with sensory symptoms or optic neuritis at onset, good recovery from relapses, and infrequent relapses early in the disease course.[1214] Conversely, symptom onset at an older age, progressive disease from onset, or poor recovery from relapses mark a relatively worse prognosis. However, clinical features are only weak predictors of overall prognosis, and their value for assigning prognosis for the purpose of informative enrollment in clinical trials has not been successful.[15] The presence of multicentric white matter lesions at the time of first MS symptoms has been associated with a higher risk of MRI and clinical disease progression in the subsequent 5 years.[16] The presence of gadolinium-enhancing lesions at baseline in a clinical trial predicts the frequency of clinical relapses, increase in T2 lesion volume, and the risk of brain atrophy progression over the subsequent 2 years.[17,18] Thus, most trials employ some entry criteria, either clinical (e.g. relapses or progression over a specified time period before the trial) or imaging (e.g. gadolinium-enhancing lesions on screening MRI scans), to identify patients with increased likelihood of exhibiting disease activity during the trial (so that they will be informative) and to exclude patients who are not likely to change during the trial period. However, these criteria are only partially effective. Also,


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as discussed above, it must be remembered that overly restrictive entry criteria aimed at identifying active patients can make it difficult to find eligible patients and so impede recruitment.

CLINICAL OUTCOME MEASURES FOR MS TRIALS Traditional clinical outcome measures Traditional clinical outcome measures for MS trials include enumerating relapses and rating neurologic impairment or disability (see chapter 2). Relapses are defined as neurologic symptoms lasting at least 48 hours accompanied by a change in the neurologic examination that cannot be explained by infection or other intercurrent illness. Although seemingly straightforward, relapses can be difficult to identify precisely in clinical trials. Patients often report changes in their symptoms without clear-cut changes on neurologic examination, or have changes recorded on their neurologic examination that are not associated with a change in symptoms. Furthermore, different neurologists almost certainly define relapses differently despite using the same broad definition above. To address this inconsistency, investigators have attempted to create operational definitions for relapses, including predefined changes on the examination or rating scales required to confirm a relapse, but this creates different types of problems. Other investigators have graded the severity of clinical relapses on the basis of the magnitude of change on clinical rating scales or the extent of interference with functioning. These definitions of severity are somewhat arbitrary, however, and have not been validated. The relapse rate remains useful as an outcome measure in controlled trials, but it is critical to mask the treatment from patients and evaluator effectively, because a relapse is in large part patient-defined. It is also absolutely mandatory that the relapse data be analysed in terms of impairment and disability data derived from the neurologic examination or quantitative tests of neurologic function. This is particularly important because patients typically experience fewer relapses while converting to steadily progressive neurologic deterioration. A sizeable number of MS clinical rating scales of impairment and disability have been developed. Traditionally, the EDSS[3] has been the most frequently used scale in MS trials. The EDSS is an ordinal scale that comprises 19 steps between 0 and 10 in 0.5-point increments; increasing score represents increasing disability. Between 0 and 3.5, the composite score is based on the scores assigned to eight functional system scales. Between 4.0 and 5.5, the composite score represents the distance that the patient can ambulate; 6.0 represents the use of unilateral assistance such as a cane to walk; 6.5 represents the need for bilateral assistance, such as a walker. Scores from 7.0 to 9.5 represent increasing degrees of immobility and dependence. Groups of patients progress up the EDSS in a reasonably ordered and consistent way, and the EDSS has become well accepted as the standard method for categorizing patients by disease severity. The EDSS has been criticized because of several shortcomings related to its use as an outcome measure for controlled clinical trials.[19] The main problems with the EDSS can be summarized as follows:


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1 The standard neurologic examination is inherently subjective. In the lower range of the EDSS, the definitions for scoring the functional system scales based on the examination are vague and subjective. As a result, intra-rater and inter-rater reliability of the EDSS are poor even with formal training of evaluators. 2 In the middle range of the scale, the EDSS is almost entirely an ambulation instrument. Changes in other neurologic manifestations (e.g. arm function and vision) have no impact on the score. Furthermore, the information about ambulation is truncated into a small number of discrete categories, and so important information about change in walking ability is discarded. For example, an individual patient may remain at the 6.5 level for several years, during which walking becomes increasingly limited. The change may be apparent to both the patient and the evaluator, but the EDSS does not reflect it. 3 Because it is based on the standard neurologic examination, the EDSS is insensitive to cognitive impairment, a common and clinically important aspect of MS (see chapters 3 and 41). 4 In the upper range, the EDSS steps are so vague and stable as to be almost useless as a rating scale for clinical trials. 5 The EDSS steps are non-linear, and so the rate at which patients progress through the scale varies at different points. These attributes make the EDSS relatively insensitive to change in neurologic function and impair its ability to demonstrate treatment effects in clinical trials. The Multiple Sclerosis Functional Composite In response to these concerns, a workshop was held in Charleston, South Carolina, USA, in 1994. The consensus from the workshop indicated that the majority of participants felt that an improved clinical outcome measure was required for future clinical trials.[19] The new clinical outcome measure was to retain the best elements of the EDSS but include measure(s) of cognitive impairment and be quantitative, reproducible, and more useful in monitoring treatment effects in controlled clinical trials. The National Multiple Sclerosis Societys Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis appointed the Clinical Outcomes Assessment Task Force and charged them with making specific recommendations for improved clinical outcome measures. The Task Force articulated desirable attributes of a clinical outcome measure for MS trials:[20] 1 The measure should be quantitative, continuous, and linear to the extent possible. 2 The measure should have high intra-rater and inter-rater reliability or, for self-report measures, should have high test-retest reproducibility. 3 The measure should be sensitive to clinical change over a relatively short time interval, so that it could be reasonably expected to show therapeutic effects during a clinical trial. 4 The measure should be valid. 5 The measure should be easy to administer, well tolerated by subjects, economical, and time-efficient. The need for increasingly sensitive clinical measures was considered of extreme importance to allow progress in the field. Table 1.3 shows sample size calculations for


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two clinical trials using EDSS worsening as the primary outcome. The first clinical trial is placebo-controlled. The sample size calculation assumes that 40% of placebo recipients will reach the clinical endpoint in 3 years. It is assumed that the active therapy will be 40% effective (i.e. only 24% of patients in the active treatment group will reach the clinical endpoint). Such a trial would require 132 subjects per arm, or a total of 264 subjects. Assuming a 20% drop-out rate, the study would require 317 patients to achieve a power of 80% to show the therapeutic effect at the required significance level of p

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