METHODS IN CLINICAL TRIALS IN NEUROLOGY METHODS IN CLINICAL TRIALS IN NEUROLOGY Vascular and Degenerative Brain Disease Edited by R. CAPILDEO and J. M. ORGOGOZO M S TOCKTON P R E S S © The contributors 1988 Softcover reprint of the hardcover 1st edition 1988 978-0-333-42305-9 All rights reserved. No reproduction, copy or transmission of this publication may be made without written permission. No paragraph of this publication may be reproduced, copied or transmitted save with written permission or in accordance with the provisions of the Copyright Act 1956 (as amended), or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 7 Ridgmount Street, London WClE 7AE. Any person who does any unauthorised act in relation to this publication may be liable to criminal prosecution and civil claims for damages. First published 1988 Published by THE MACMILLAN PRESS LTD Houndmills, Basingstoke, Hampshire RG21 2XS and London Companies and representatives throughout the world British Library Cataloguing in Publication Data Methodology in clinical trials in neurology: vascular and degenerative brain disease. 1. Neurology 2. Clinical trials I. Capildeo, Rudy II. Orgogozo, J. M. 616.8'072 RC346 ISBN 978-1-349-08945-1 ISBN 978-1-349-08943-7 (eBook) DOI 10.1007/978-1-349-08943-7 Contents The Contributors vu Foreword: H. J. M. Barnett IX Preface xi SECTION 1 BACKGROUND TO CLINICAL TRIALS I Epidemiological considerations in the design of controlled clinical trials. Part I: Introduction 3 R. B. Haynes 2 Epidemiological considerations in the design of controlled clinical trials. Part II: Methodology 9 B. S. Schoenberg and S. Haberman 3 Choice and analysis of judgement criteria 29 W. Maurer and D. Commenges 4 Evaluation of diagnostic tests and the role of diagnosis in therapeutic trials 57 H. V. Fineberg SECTION 2 CLINICAL TRIALS- PAST AND FUTURE 83 5 Methodology of clinical trials in migraine 85 1. Olesen and P. Tfelt-Hansen 6 Methodology of clinical trials in neurology. Evaluation of extracranial arterial disease Ill 1. P. Kistler and M. 1. G. Harrison 7 Trials of secondary prevention after transient ischaemic attacks. Part I: Analysis of previous clinical trials 137 M. G. Bousser 8 Trials of secondary prevention after transient ischaemic attacks. Part II: Towards better clinical trials 153 C. P. War/ow 9 Methodology of clinical trials in stroke. Part I: Analysis of previous clinical trials 175 R. Capildeo and 1. M. Orgogozo 10 Methodology of clinical trials in stroke. Part II: Future trials - recommendations 207 1. M. Orgogozo and R. Capildeo VI Contents 11 Methodology of clinical trials in Parkinson's disease. Part 1: Analysis of previous clinical trials 223 X. Lataste and L. J. Findley 12 Methodology of clinical trials in Parkinson's disease. Part II: Future trials - recommendations 247 L. J. Findley and X. Lataste 13 Vascular disease and dementia: An introduction 259 M. J. G. Harrison 14 Methodology of clinical trials in dementia. Part 1: Analysis of previous tria~s 265 J. M. S. f?earce, M. G. Wallace and R. Capildeo 15 Methodology of clinical trials in dementia. Part II: Future trials - recommendations 295 J. F. Dartigues Appendix 303 Index 325 The Contributors M. G. Bousser H. V. Fineberg Clinique des Maladies du Systcme Harvard School of Public Health Nerveux du Pr. Castaigne Centre for the Analysis of Health Practice Hopital de Ia Saltpetriere Boston 47 Bd de I'Hopital Mass. Paris 17 USA France S. Haberman R. Capildeo Department of Mathematics Regional Centre for Neurology The City University Oldchurch Hospital and Neurosurgery London EC1M 7BB Rom ford UK Essex RM7 OBE UK M. J. G. Harrison Department of Neurology D. Commenges Middlesex Hospital Departement d'Informatique London WIN RAA Medicale UK Universite de Bordeaux II 146 Rue Leo-Saignat R. B. Haynes 33076 Bordeaux Faculty of Health Sciences France McMaster University Hamilton J. F. Dartigues Ontario Departement de Neurologic Canada Hopital Pellegrin J. P. Kistler and Department of Neurology Massachusetts General Departement d'Informatique Hospital Medicale Boston Universite de Bordeaux II Mass. 146 Rue Leo-Saignat USA 33076 Bordeaux France X. Lataste Neurology Department L. J. Findley Clinical Research Regional Centre for Neurology and Sandoz AG Neurosurgery CH-4002 Basel Oldchurch Hospital Switzerland Romford Essex RM7 OBE and UK Bordeaux University and France MRC Neuro-Otology Unit W. Maurer National Hospital Clinical Research Queen Square Sandoz AG London CH-4002 Basel UK Switzerland vii viii The Contributors J. Olesen P. Tfclt-Hanscn Department of Neuromcdicinc Department of Ncuromcdicinc K!llbcnhavns amts Sygehus Gcntoftc K!llbenhavns amts Sygchus Gcntoftc and Rigshospitalct and Rigshospitalct Copenhagen Copenhagen Denmark Denmark J. M. Orgogozo H6pital Pellegrin 38076 Bordeaux M.G. Wallace France Regional Centre for Neurology and Neurosurgery Oldchurch Hospital J. M. S. Pearce Rom ford Department of Neurology Essex RM7 OBE Hull Royal Infirmary UK Hull HU3 2JZ UK C. P. Warlow B. S. Schoenberg Department of Clinical Neuroepidemiology Section Neurosciences Office of the Director Northern General Hospital National Institute of Neurological Edinburgh EHS 2DQ and Communicative Disorders and UK Stroke Bethesda, Maryland USA and Georgetown University School of Medicine Washington, DC USA Discussants A. Alperovich (Paris) J. F. Dreyfus (Paris) S. Fahn (New York) R. Kniii-Jones (Glasgow) J. W. Norris (Toronto) R. Salamon (Bordeaux) Foreword The description of the clinical syndromes of disease was the gigantic contribution of physicians in the eighteenth, nineteenth and early twentieth centuries. The scientific basis which lent credibility to descriptive medicine was the correlation between the clinical syndromes and the gross and microscopic tissue changes detected by the anatomists and pathologists of that era. The burgeoning of biochemistry, pharmacology and physiology in the second half of the twentieth century introduced a scientific understand ing of disease allowing for early detection and rational treatment. Since then, revolutionary new imaging methods have added immeasurably to our diagnostic precision. The major benefit for the practice of medicine gained from the application of these scientific disciplines was first observed in dramatic cures which were effected in some acute illnesses. For example, a treatment for a disease such as tuberculous meningitis, known to kill all its victims in less than two months, was very easy to recognise and quickly accorded universal accept ance. A sample-size of two patients was needed to constitute the clinical trial to prove the benefit of streptomycin treatment. The first patient represented the pilot study but the possibility existed that the recovery was due to a diagnostic error or a miracle. A second patient going on to recovery meant that these improbable chances were eliminated, and the therapy had passed the clinical trial stage. An equally important challenge now is the development of treatment strategies to reduce the impact of chronic illness. Treatment programmes for many of the chronic disorders of the nervous system and those which manifest themselves intermittently have become confused by a variety of putative therapeutic suggestions. The benefit of treatment in chronic illness has been difficult to evaluate and hard answers are dependent on the rigid application of the newest of the advances applied to medicine: the use of methodology and biostatistics. This monograph focuses on this evolving science, and on the art of its application. It details the early steps which have been taken in coming to grips with the significance of therapeutic advances in several chronic neurological conditions: stroke, threatened stroke and Parkinson's disease, dementia and migraine. Clearly this new science of therapeutic evaluation which combines clinical expertise, epidemiology, methodology and bio statistics is to therapeutics what pathology was to the clarification of disease syndromes. ix X Foreword In the early days of therapeutics, authoritarian medicine allowed for the promulgation of directives, based on the experience, the opinion and the judgement of the gifted teacher. This reverence for tradition and acceptance of authority persists to some extent even today despite the warning from as long ago as the time of Hippocrates that 'experience is misleading'. It is increasingly apparent, however, that patients deserve better from modern scientific medicine. The next halting step beyond the acceptance of the dicta of the professor was the judgement of therapeutic advance by the comparisons of groups of patients given a new treatmen.t with some historical references to reputedly similar patients who were not given the new treatment. Modern scientific medicine denies the value of this method of 'contrived controls' for a number of reasons, including: the selection process which channels patients into any given treatment milieu; the known or unknown disparity between the treatment and comparative groups in what are now recognised as important risk factors; the changing background of baseline therapy and prognosis; and the process by which decisions to treat or not to treat led to the emergence of the particular and peculiar population which is the subject of the reports. There are many other flaws. Decision making by utilising the observations from historical controls is almost as misleading in modern medical science as is that based on 'clinical judgement'. The randomised clinical trial emerges as the only way in which convincing answers can be obtained in assaying the value of treatment in chronic disease with few endpoints. It is an expensive process, not only in terms of money, but also in energy and time. The alternative, of remaining equipped with a host of indefinite and vague answers, is infinitely less helpful to our patients. The editors of this book have been helpful to the international community of clinical neurological researchers by bringing into focus the state of the art of therapeutic evaluation in these selected neurological disorders. The essayists have focused on some of the problems which still exist in this type of disciplined search for clinical answers. The early mistakes should not be used to fuel a flame to destroy these new methods. Rather, the flame should be used to light our way to improvements in these new techniques. In the long run the sharpened tool of clinical evaluation by modern methods will be infinitely superior to previous 'commonsense decisions' and subjective evaluations. To quote from Thomas Huxley: 'The methods of science differ from those of common sense only as far as the guardsman's cut and thrust differ from the manner in which a savage wields a club'. H. J. M. Barnett, OC, MD University Hospital London, Ontario