Scleroderma is clinically heterogeneous and a variety of plausible mechanisms of disease have been hypothesized. Recent years have witnessed a significant improvement in overall survival although all of the gains in management have been therapies for specific organ involvement, e.g. renal crisis and pulmonary arterial hypertension. Future studies will rely on improved clinical science, which involves structured validation of proposed measures of outcome; development of a combined response index; and further refinement of specific subsets of disease expression. Immunoablation with stem cell reconstitution is an example of aggressive therapy chosen as appropriate for a particularly severe disease subset and in whom the pilot data are encouraging. Good science and clinical ethics force continued consideration of equipoise between risk and benefi

Furst, D. E.

Seibold, J. R.

Tyndall, A.

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Trial design: how must we move ahead?J. R. Seibold1, A. Tyndall2 and D. E. Furst3Scleroderma is clinically heterogeneous and a variety of plausible mechanisms of disease have been hypothesized. Recent years havewitnessed a significant improvement in overall survival although all of the gains in management have been therapies for specific organinvolvement, e.g. renal crisis and pulmonary arterial hypertension. Future studies will rely on improved clinical science, which involvesstructured validation of proposed measures of outcome; development of a combined response index; and further refinement of specificsubsets of disease expression. Immunoablation with stem cell reconstitution is an example of aggressive therapy chosen as appropriate for aparticularly severe disease subset and in whom the pilot data are encouraging. Good science and clinical ethics force continued considerationof equipoise between risk and benefit.KEY WORDS: Scleroderma, Systemic sclerosis, Outcome measures, Trial design, Disease modification.Systemic sclerosis (SSc, scleroderma) remains without a clearlydefined pathogenesis and thus without an effective overarchingapproach to therapy. Increasingly sophisticated scientific studieshave defined several candidate approaches of great promiseincluding specific molecular targets for anti-fibrotic therapy aswell as new approaches to modification of both vascular andimmunological features of disease. Many of these concepts areaddressed in this monograph. Recent advances suggest that SSc isin fact a family of closely related illnesses wherein clinical andserological phenotypes and specific genotype are closely inter-related. The search for a unifying mechanism for all forms of thesyndrome, while elusive, seems within reach.To the clinical student of scleroderma, the basic questionremains: if there were a truly effective drug for scleroderma,how might we recognize that it worked and what standards ofresponse would be considered meaningful and cost effective? Is itindeed possible that we have effective therapies in hand, yet ourmethods of assessing the same have led to underestimations oftheir effects?The cluster of clinical entities incorporated under the label ofSSc is of intimidating heterogeneity. There are clear differences inthe extent and severity of skin involvement between individualswith dcSSc vs lcSSc. This would apply if skin were considered asthe primary disease outcome under study, or if skin served merelyas a clinical surrogate for risk of accrual of visceral involvement.Imagine a therapy that reversed skin whilst having no effect onlung or an effective agent for interstitial lung disease that had nodiscernable effect on skin. Just what sort of therapeutic responsedo we expect?Scleroderma therapeutics is advancing. Survival from sclero-derma is improving through development of specific organ-basedstrategies such as angiotensin-converting enzyme inhibitors forscleroderma renal crisis and perhaps from modern therapies forpulmonary vascular complications [1]. Two recent prospectiverandomized controlled trials suggested that either oral or intra-venous cyclophosphamide may slow loss of pulmonary function inpatients with scleroderma interstitial lung disease [2, 3]. Thesestudies illustrate a new era of sophistication in scleroderma clinicalresearch and in many ways raise more questions than answers.The treatment effects for forced vital capacity (FVC) and for skininvolvement were within the laboratory range of intra-patientvariability for both measures, although secondary measuresalso supported the modest efficacy of the drug. A ‘minimallyimportant difference’ of change in FVC, i.e. a change thatparalleled improvement in some other outcome such as survivalor quality of life has not been defined. The beneficial effect ofcyclophosphamide was not durable beyond about 6 months afterstopping cyclophosphamide, with most differences between drugand placebo essentially absent at 24 months of follow-up [4]. Inbalancing risk vs benefit, our increasing ability to define cohortsenriched for risk of lung progression suggests that results of futurelung studies might be more easily understood. At present,cyclophosphamide must be pronounced as effective and to bejudged as true evidence-based medicine for our clinical practices.The issue remains the inability to state this as generalized for allpatients.Immunoabalation with stem cell reconstitution (‘stem celltransplant’) offers another glimpse at the future. This therapyhas a moderately high treatment-related morbidity and evenmortality, yet the magnitude of response from pilot study issingularly impressive. Major improvements in skin and disabilityand associated stabilization of visceral disease have been reportedin up to 4 yrs of follow-up [5]. Controlled follow-up trials are inprogress in both the European Union and North America.Harmonization of inclusion and exclusion criteria as well as inconsideration of the equipoise of disease severity vs treatment-related morbidity has been the hallmark of this endeavour. Is itpossible that treatment breakthrough in scleroderma will be a‘trickle down’ phenomenon wherein therapy for our sickestpatients comes first followed by extrapolation to less severelyafflicted patient groups?Much of this symposium focused on the critical science ofoutcome measures. If we know what a new therapy should looklike, should not we also have confidence in our ability to measureits effects? Collaborative exercises have led to a potentialcombined response index that is currently being validated. Whenmultiple domains of disease are studied simultaneously, sensitivityto change and our ability to interpret small levels of change will bemore robust [6].New trials are actually easy to predict. We will increasinglyemploy agents of highly specific effects and with strong scientificrationale. Studies will employ consensus definitions of homo-geneous subsets and will require multicentre collaboration forsuccessful and timely recruitment. Standardization of outcomeswill permit cross-study comparisons and will enhance the reservoirof true evidence-based medicine. Regulatory agencies will benefitfrom the breadth and depth of disease-specific information. Ourpatients deserve nothing less than the highest standards ofefficient, ethical and rational research.1University of Michigan Scleroderma Program, Ann Arbor, Michigan, MI, USA,2Department of Rheumatology, University of Basel, Basel, Switzerland and3Division of Rheumatology, UCLA Medical School, Los Angeles, CA, USA.Submitted 1 May 2008; accepted 3 July 2008.Correspondence to: J. R. Seibold, University of Michigan Scleroderma Program,24 Frank Lloyd Wright Drive, PO Box 481 Lobby M-2500, Ann Arbor, MI 48106,USA. E-mail: jseibold@umich.eduRheumatology 2008;47:v57–v58 doi:10.1093/rheumatology/ken312v57 The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.orgAcknowledgementsSupplement: This paper forms part of the supplement entitled‘Update in systemic sclerosis’. This supplement was supported byan unrestricted grant from Encysive.Disclosure statement: J.R.S. has received research support and is aconsultant to Actelion, Gilead, Pfizer, Gilead, Encysive, Pipex,Celgene, Roche, Centocor and United Therapeutics all withregard to treatments of scleroderma and its complication. J.R.S.and D.E.F. are supported by grants from the National Institutesof Health (NO1 AI05419 and UO1 AR055057). A.T. isa consultant to Actelion and Encysive. D.E.F. has receivedresearch grants/support from Abbott, Actelion, Amgen, BiogenIdec, Centocor, Celgene, Genentech, Gilead, Novartis, Roche andUCB. He has been a consultant for and received honoraria fromAbbott, Actelion, Amgen, Array, Biogen Idec, Centocor,Encysive, Genentech, Gilead, GlaxoSmithKline, Novartis,Roche, Takeda-Abbott Pharmaceuticals, UCB, Wyeth andXoma. He is on the speakers’ bureau for Abbott, Actelion andAmgen.References1 Steen VD, Medsger TA. Changes in causes of death in systemic sclerosis,1972–2002. Ann Rheum Dis 2007;66:940–4.2 Tashkin DP, Elashoff R, Clements PJ et al. Cyclophosphamide versus placebo inscleroderma lung disease. N Engl J Med 2006;354:2655–66.3 Hoyles RK, Ellis RW, Wellsbury J et al. A multicenter, prospective, randomized,double-blind, placebo-controlled trial of corticosteroids and intravenous cyclopho-sphamide followed by oral azathioprine for the treatment of pulmonary fibrosis inscleroderma. Arthritis Rheum 2006;54:3962–70.4 Tashkin DP, Elashoff R, Clements PJ et al. Effects of a one-year treatment withcyclophosphamide on outcomes at two years in scleroderma lung disease. Am JResp Crit Care Med 2007;176:1026–34.5 Nash RA, McSweeney PA, Crofford LJ et al. High-dose immunosuppressive therapyand autologous hematopoietic cell transplantation for severe systemic sclerosis: U.S.multicenter pilot study. Blood 2007;110:1388–96.6 Khanna D, Lovell DJ, Giannini E et al. For the other coauthors of theScleroderma Clinical Trial Consortium. Development of a provisional core set ofresponse measures for systemic sclerosis clinical trials. Ann Rheum Dis2008;67:703–9.Rheumatology key messages Scleroderma is pathobiologically complex and clinicallyheterogeneous. In the absence of a disease-specific overarching mechanism,plausible therapeutic targets are numerous. Development of a Combined Response Index for SystemicSclerosis (CRISS) may offer broad applicability as well asenhanced sensitivity to change. Homogeneous subsets with common problems may be studiedalthough refinement of measures of outcome is needed.v58 J. R. Seibold et al.

Trial design: how must we move ahead?

Scleroderma is clinically heterogeneous and a variety of plausible mechanisms of disease have been hypothesized. Recent years have witnessed a significant improvement in overall survival although all of the gains in management have been therapies for specific organ involvement, e.g. renal crisis and pulmonary arterial hypertension. Future studies will rely on improved clinical science, which involves structured validation of proposed measures of outcome; development of a combined response index; and further refinement of specific subsets of disease expression. Immunoablation with stem cell reconstitution is an example of aggressive therapy chosen as appropriate for a particularly severe disease subset and in whom the pilot data are encouraging. Good science and clinical ethics force continued consideration of equipoise between risk and benefit. KEY WORDS: Scleroderma, Systemic sclerosis, Outcome measures, Trial design, Disease modification. Systemic sclerosis (SSc, scleroderma) remains without a clearly defined pathogenesis and thus without an effective overarching approach to therapy. Increasingly sophisticated scientific studies have defined several candidate approaches of great promise including specific molecular targets for anti-fibrotic therapy as well as new approaches to modification of both vascular and immunological features of disease. Many of these concepts ar

Trial design: how must we move ahead?

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