Clinical Trials in Rheumatology

Clinical Trials in Rheumatology

Rüdiger Müller Johannes von Kempis Clinical Trials in Rheumatology

Authors Rüdiger Müller Division of Rheumatology and Rehabilitation Department of Internal Medicine Kantonsspital St. Gallen Switzerland Johannes von Kempis Division of Rheumatology and Rehabilitation Department of Internal Medicine Kantonsspital St. Gallen Switzerland ISBN 978-1-84996-383-1 e-isbn 978-1-84996-384-8 DOI 10.1007/978-1-84996-384-8 Springer London Dordrecht Heidelberg New York British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Control Number: 2010937971 Springer-Verlag London Limited 2011 Apart from any fair dealing for the purposes of research or private study, or criticism or review, as permitted under the Copyright, Designs and Patents Act 1988, this publication may only be reproduced, stored or transmitted, in any form or by any means, with the prior permission in writing of the publishers, or in the case of reprographic reproduction in accordance with the terms of licenses issued by the Copyright Licensing Agency. Enquiries concerning reproduction outside those terms should be sent to the publishers. The use of registered names, trademarks, etc., in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant laws and regulations and therefore free for general use. Product liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature. Cover design: estudiocalamar, Figueres/Berlin Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)

To our wives, and children: Sophia, and Franziska, Alexandra, Johanna, Antonius, Helena Johannes von Kempis Elke, and Ismene, Frederik and Mostafa Farmand, who was an inspiration to me during medical school Rüdiger Müller

Foreword Over the past 20 years, rheumatologists have developed and witnessed many paradigmatic changes not only in the medication of rheumatoid arthritis (RA) but also in other autoimmune rheumatic diseases. With regard to RA, less joint damage and better physical function has been demonstrated as a consequence of an early institution of disease-modifying anti-rheumatic drugs. Furthermore, the definition of core set variables and developments of composite measurements to assess RA have allowed disease activity to be assessed reliably. Finally, new biologic active agents have shown to be of major importance for fulfilling the aim of low disease activity or even remissions, specifically if treatment is commenced at a very early stage of the disease. These obvious significant advances in the treatment options for RA and other autoimmune rheumatic diseases would not have been made possible without a new culture for conducting clinical trials starting in the mid-1980s. The book Clinical Trials in Rheumatology provides a comprehensive overview of trials in different rheumatic diseases. It presents many important clinical trials conducted over the last 40 years, ranging from complex, double-blinded or open multicentric trials, e.g., the BeSt-study to case studies in situations where real trials are still missing. The different clinical trials to rheumatologic disease entities as listed in the book are not directly comparing outcome and clinical efficacy, or giving therapeutic recommendations. (For therapeutic decisions, the authors recommend to follow national and international guidelines and ongoing discussions concerning different treatment strategies in different autoimmune rheumatic diseases.) Instead, the book presents a well-founded and comprehensive selection of the most important studies. The authors present the relevant information concerning study design, medications, patient populations, clinical endpoints, and adverse events, thus offering a quick overview on the clinical trials conducted in different autoimmune rheumatic diseases. This new form of presenting the significant data of the most important studies in a comparable form renders this book a valuable help in the constantly growing multitude of clinical data in rheumatology. Prof. J. R. Kalden University of Erlangen vii

Preface The simple goal of this book is to provide a comprehensive overview of clinical trials in rheumatology in an easily readable manner. The constantly growing and increasingly confusing multitude of clinical trials in inflammatory rheumatic diseases first gave us the idea. This tremendous number of trials has been rendered possible by a steep increase in therapeutic options, such as the new therapeutic group of biologics, over roughly the last decade and by the development of more generally accepted response parameters. Many of the studies presented here were part of the clinical development program of biologics such as the TNF-inhibitors for different rheumatic diseases. They are complemented by studies with the same and older drugs, many of them investigator initiated, in different disease stages, e.g. in RA, or clinical situations, e.g. in vasculitis. The main idea of this survey in the beginning simply was to set up a list of studies named with an acronym, such as ATTAIN, ATTRACT, BeSt etc., in inflammatory joint disorders. We wanted to have such an acronym finder ready at hand at all times during the clinical day, in the laboratory and at scientific meetings. But during the selection process, more and more trials without an acronym either came to mind or appeared during online searches on public databases including ones about non-biologic DMARD in arthritis, autoimmune connective tissue diseases and vasculitis which seemed equally important. The result of all this evolutionary process is the present compilation which presents short summaries of the most relevant studies in a certain disease, without interpretation or valuation of the data. All types of studies are included, controlled prospective as well as observational ones case studies even where real studies are still missing. We did, however, exclude analyses of cohort data except for some prominent examples. We have concentrated on autoimmune inflammatory disorders and have not included studies on inflammatory metabolic diseases. Some of the studies in this book, e.g. in Sjögren s syndrome, don t fulfill the requirements of a modern drug trial, mostly due to the lack of accepted and specific response criteria. Our intention, however, was to list the relevant trials for every immunomodulatory drug in a certain disease, regardless of the trial s characteristics. For every study listed we tried to present the relevant information with regard to study design and substances used, patient population, clinical endpoints, and adverse events, and nevertheless to stay within a ix

x Preface one study-one page format wherever possible. Our focus was set on clinical, not laboratory outcomes. Changes in laboratory parameters are presented in some studies, however, but only if absolute numbers -as opposed to values presented in graphs- were available. Studies mainly represent the time span between the late 80ies and the beginning of 2010, but some historically interesting ones dating back to the seventies or even earlier are included. To hold up a simple survey principle, data are neither interpreted nor commented. Sometimes, however, details not mentioned in the original publication, such as changes in a certain parameter in percent, are added. The studies are listed by disease and compound, at the end of the book a list of acronyms and of abbreviations, respectively, used throughout the text is provided. We have made considerable efforts to reach all holders of copyright material and received permissions from all we have been able to make contact with. In only very few our repeated efforts have remained without answer. We would like to emphasize that we are not comparing studies. We are also definitely not giving therapeutic recommendations. For therapeutic decisions we recommend to follow national or international guidelines and the ongoing discussion concerning treatment strategies for the different diseases. This book presents our personal selection and we may well have missed important studies. We are planning to regularly update this book and welcome any suggestions, including for additional studies to be included, if they help improving the present format, preferably by e-mail. Rüdiger Müller Johannes von Kempis St. Gallen

How to Read This Book Trials are listed by disease according to the table of contents. In ANCA-associated vasculitis, at the beginning of a trial summary, different disease entities are listed if the trial investigated a mixture of vasculitides affecting vessels of different sizes according to the CHC-definitions. The sequence within a disease is corticosteroid trials at the beginning, followed by non biologic DMARDs in alphabetical order and trials with biologics, again alphabetically, after DMARD-trials. Several trials with one substance are presented in chronological order, beginning with the earliest. Trial Title of the publication as published Acronym: In case of an acronym, it s meaning is explained Substance Name of substances (biologic or pharmaceutic), doses used, and patient numbers in each treatment group, according to study design Only trials of registered substances or substances with far advanced registration process Concomitant medication: Additional medication permitted in the trial if mentioned in the original publication Previous medication: Medication before start of trial if mentioned in the original publication Result The main results are shortly summarized, mostly in compliance with the authors conclusions. Speculations the authors may have based on their findings are left out Patients The number of patients, the diseases treated, and, if adding to the clinical meaning of the study, details of the patient disposition at study entry, are specified The use of terms such as RA or SLE, without other details leading to the diagnosis, generally signifies that these patients fulfilled the most generally accepted international classification criteria, e.g., the ACR-criteria for RA Important inclusion and exclusion criteria are listed in some cases Authors Names according to original publication Publication Original citation xi

xii How to Read This Book Follow up Total follow up of the trial as defined or seen in the publication In many trials the follow up differed from the duration of the trial s treatment arms. In many of those trials, the duration of the trial can be seen under Substance ACR 20/50/70 In RA trials with these endpoints, the ACR response criteria are listed Note The data defined by the authors as study end points are presented as percentages or precise numbers, depending on their description in the publication, for every treatment group Changes from baseline, if available, are listed for every group Definitions of clear primary or secondary end points are restricted to more recent, controlled trials. For the sake of a standardized description scheme and to keep the trial summaries as short as possible, they are not named The same applies to informations on statistical significance, standard deviations, ranges, other methodologic details, definitions of remission, disease activity or relapse/flair and drop-out rates. For all these, please refer to the original publications Numbers either as absolute values (e.g., n = 1) or means (e.g., duration of symptoms: 40 months), if not mentioned otherwise Adverse events Adverse events are listed as described for every study drug or therapy regimen Contents

Contents Acronym-finder... xix Rheumatoid Arthritis... Corticosteroids... Atorvastatin... Azathioprine... Azathioprine vs. Methotrexate... Hydroxychloroquine vs. Sulphasalazine... Hydroxychloroquine... Chloroquine vs. Ciclosporin... Ciclosporin... Ciclosporin vs. Chloroquine... Ciclosporin vs. parenteral Gold... Ciclosporin... Ciclosporin vs. Methotrexate... Ciclosporin vs. Azathioprine... Cyclophosphamide... Gold vs. Methotrexate... Gold vs. Cyclophosphamide vs. Azathioprine... Leflunomide vs. Sulfasalazine... Methotrexate vs. Leflunomide... Sulfasalazine vs. Leflunomide... Leflunomide vs. Methotrexate... Leflunomide vs. Methotrexate... Methotrexate... Sulfasalazine... Sulfasalazine vs. Gold... Sulfasalazine... Tacrolimus... 1 1 13 14 16 17 18 24 25 26 27 29 32 33 34 37 38 39 41 43 45 46 49 51 53 55 56 69 71 72 73 xiii

xiv Contents Early DMARD therapy... Ciclosporin + Chloroquine... Methotrexate + Hydroxychloroquine... Methotrexate + Doxycycline... Methotrexate + Sulfasalazine... Methotrexate + Ciclosporin... Methotrexate + Hydroxychloroquine + Sulfasalazine... Methotrexate + Leflunomide... Methotrexate + Azathioprine... Gold + Methotrexate... Gold + Hydroxychloroquine... Abatacept... Etanercept + Abatacept... Adalimumab... Anakinra... Certolizumab pegol... Etanercept... Anakinra + Etanercept... Golimumab... Infliximab... Infliximab vs. Etanercept... Anti-TNF... Rituximab... Tocilizumab... 80 81 83 84 85 94 105 117 120 123 124 126 150 152 176 188 195 222 223 232 266 268 269 278 Ankylosing Spondylitis... Methylprednisolone... Cyclophosphamide... Methotrexate... Pamidronate... Sulfasalazine... Pred., Cyc., 5FU, MTX, MMF... Adalimumab... Etanercept... Infliximab vs. Etanercept... Golimumab... Infliximab... 297 297 299 300 302 306 307 323 325 334 343 344 346 Psoriatic Arthritis... Chloroquine... Ciclosporin vs. Methotrexate... Ciclosporine vs. Sulfasalazine... Ciclosporin ± Methotrexate... 361 361 362 363 365 366

Contents xv Leflunomide vs. Methotrexate... Methotrexate... Sulfasalazine... Adalimumab... Alefacept... Etanercept... Golimumab... Infliximab... Ustekinumab... 370 371 373 378 385 388 391 393 404 Systemic Lupus Erythematosus... Corticosteroids... Azathioprine... Azathioprine vs. Ciclosporin... Chloroquine and Hydroxychloroquine... Hydroxychloroquine + Mycophenolate Mofetil... Cyclophosphamide vs. Azathioprine... Cyclophosphamide Followed by Azathioprine... Cyclophosphamide... Cyclophosphamide Followed by Azathioprine... Cyclophosphamide... Cyclophosphamide vs. Azathioprine... Methotrexate... Mycophenolate Mofetil vs. Cyclophosphamide, Azathioprine... Mycophenolate Mofetil... Mycophenolate or Azathioprine after Cyclophosphamide... Tacrolimus... Infliximab... Rituximab... 407 407 411 413 415 422 423 426 427 429 431 434 435 437 440 442 444 445 447 449 Antiphospholipid Syndrome... Aspirin... Aspirin vs. Heparin... Aspirin + Heparin... Aspirine + Prednisone... Aspirine vs. Prednisone... Heparin... Heparin vs. Prednisone... Heparin vs. intravenous Immunoglobulin... Intravenous Immunoglobulins... Warfarin... 455 455 457 460 463 464 465 466 467 470 471 Progressive Systemic Sclerosis... 473 Corticosteroids... 473 Ambrisentan... 474

xvi Contents Azathioprine... Azathioprine + Cyclophosphamide... Bosentan... Chlorambucil... Ciclosprine... Colchicine... Cyclophosphamide... Cyclophosphamide vs. Azathioprine... Cyclophosphamide... D-Penicillamine... Methotrexate... Mycophenolate Mofetil... 5-Fluorouracil... Etanercept... Rituximab... Plasma Exchange... Stem Cell Transplantation... Autologous Stem Cell Transplantation... 479 480 481 491 492 493 494 503 504 507 510 513 515 516 517 519 521 523 Raynaud s Phenomenon... Diltiazem.... Glycerol Trinitrate... Iloprost... Nifedipine... Sildenafil... 525 525 528 529 544 548 Dermato/Polymyositis... Corticosteroids... Azathioprine... Cyclosphosphamide... Immunoglobulins... Methotrexate... Methotrexate vs. Ciclosporine... Mycophenolate Mofetil... Anti-TNF... Etanercept... Rituximab... Plasma Exchange... 549 549 550 552 553 555 558 559 560 561 562 564 Sjögren s syndrome... Hydroxychloroquine... Methotrexate... Mycophenolate... 565 565 568 570 571