AbstractChapter 1 provides an introduction to stroke including its current prevalence bothnationally and globally, aetiology, global importance and social & financial burden. Wealso describe here current acute stroke management practices, the role of clinical trialsin the development of therapies, the richness of data within clinical trials and changesin regulatory thinking regarding data access. We provide recommendations for the useof trial data for novel exploratory investigations of clinical trial design andepidemiological studies.In Chapter 2 we describe the establishment of the Virtual International Stroke TrialsArchive (VISTA) to address the need for reliable data on which to plan future clinicaltrials. This chapter details the methodology and logistics of establishing the resource,including details of regulatory policy for data collection and use, establishment of aSteering Committee and development of a constitution to safeguard data access anduse.As of June 2008, VISTA contains 28 acute stroke clinical trials and one acute strokeregistry. We collated data on over 27,500 patients with either ischaemic orhaemorrhagic stroke. Patient age ranges from 18 to 103 years and outcome measuresinclude Barthel Index, Scandinavian Stroke Scale, National Institutes of Health StrokeScale, Orgogozo Scale, and modified Rankin Scale. Medical history and onset totreatment times are readily available and computed tomography (CT) lesion data areavailable for selected trials. We discuss the establishment and potential uses of thisresource in the context of existing stroke resources.Chapter 3 demonstrates how we utilised VISTA to investigate natural history patterns inacute stroke. There are prominent differences in stroke incidence and outcome acrossdifferent geographical locations; these are not confined to the Eastern- Western axis.We aimed to examine whether there were any differences in index stroke severity,stroke risk factors, and stroke outcome between geographical locations, after adjustingfor case-mix.We found that patients who were enrolled in the USA and Canada had the worst indexstrokes, whilst patients enrolled in Austria and Switzerland had the mildest indexstroke, and better functional (p=0.023) and neurological outcome (p=0.034) at 90 days.90 –day survival was greater in patients who were enrolled in Spain and Portugal(p<0.0001).Chapter 4 demonstrates the use of VISTA to inform stroke clinical trial design byexamining the impact of early follow up on adverse event and functional outcomeprofiles. We aimed to assess the contribution of adverse complications unrelated tostroke, to 30 and 90- day functional outcome. If fewer ‘stroke-unrelated’ adverseevents were seen at later time points, and if the absence of these events appeared toinfluence functional outcome, then further investigation into shortening the follow upperiod of clinical trials with a view to minimizing complications may be warranted.We identified idiopathic post-stroke complications (deemed to be ‘stroke- unrelated’)but their absence did not beneficially alter outcome at either 30 days (p<0.0001,adjusted OR for good outcome =0.47, 95% CI [0.26, 0.67]), or 90 days (p=0.002, adjustedOR for good outcome =0.38, 95% CI [0.14, 0.61]). We concluded that shortening thefollow up period with the aim of minimizing ‘stroke-unrelated’ complications did notbenefit functional outcome, however further investigation is required.Chapter 5 illustrates the use of VISTA to investigate the natural history of complicationsafter intracerebral haemorrhage (ICH). Treatments available for ICH remain limited.The use of haemostatic agents to promote local coagulation has had no significantbenefit on outcome. However promising results from a subgroup analysis of patientsfrom the FAST trial has raised the possibility of treatment with recombinant factor VIIa(rFVIIa) in patients with ICH. We sought to document the natural history ofcomplications after ICH in order to inform safety in future trials of haemostatic agentsfor ICH.We found that the risk of thromboembolic complications after ICH was low (4 eventsaffecting 2% of patients). The absence of these thromboembolic complications did notsignificantly affect the attainment of good functional outcome (p>0.05). The occurrenceof haemorrhagic expansion was common, affecting 14% of patients, and significantlyinfluenced attainment of good functional outcome at 90 days (p= p<0.0001, adjustedodds ratio for good functional outcome=21.9, 95% confidence interval [5.5, 88.3]).Although infection occurred in 11% of patients, this did not significantly influenceattainment of good functional outcome at 90 days (p=0.8). The complicationsencountered in this investigation and their time to onset will serve to informprophylaxis in future ICH clinical trials.Chapter 6 describes the processes involved in drug development from phase I, first- in –man studies to phase III efficacy trials and identifies a key area in the drug developmentprocess where use of VISTA as a historical comparator resource could be of benefit:phase II studies. We detail here the types of conventional comparator groups availablefor use in a phase II investigation, advantages and disadvantages of using each of thesecomparator groups, the potential for use of historical comparators in some scenarioswhere use of conventional comparator groups is infeasible, and possible solutions toaddress the limitations associated with use of historical comparators.Chapter 7 illustrates the use of VISTA as a resource for historical comparators in thecontext of an acute stroke device trial conducted by a small company with limitedresources. BrainsGate, the manufacturers of the NeuroPath™ Device for treatment ofischaemic stroke, sought to collaborate with the VISTA group to examine initial efficacyof their device against outcomes derived from VISTA historical comparators. We discussthe example of this device in early phase testing, where VISTA was primed for use as aresource for historical comparators. We also describe the limitations associated with theuse of historical comparators, how these limitations could be overcome in practicethrough use of matched patients, implementation of strict eligibility criteria and use ofsimilar follow up periods and stroke scales, as well as the measures taken to ensure thevalidity of results.Chapter 8 describes a collaboration with the DESTINY trial group to investigate strokeoutcomes after malignant middle cerebral artery occlusion (mMCAO). The DESTINY trialexamined the impact of decompressive hemicraniectomy on outcome after mMCAO,compared with randomised controls. We compared the outcomes of operated patientsfrom the DESTINY trial with historical comparators from VISTA to determine whetherthe findings could be replicated and if historical comparators could be used as analternative in a situation where a randomised controlled trial (RCT) is infeasible orunethical.We found that fewer patients in the VISTA comparator group achieved a good functionaloutcome by mRS at final follow up (19%), when compared with the DESTINY surgicalgroup (47%, Chi- Square test p=0.04). This difference persisted after adjusting forbaseline NIHSS (logistic regression p=0.04). Analysis of Barthel Index at final follow uprevealed no significant difference between the two groups and we also found nodifference in 6 month survival rates between the surgical and VISTA comparator groups(Cox Proportional Hazards model p>0.05). We concluded that for effective replication ofresults, the database from which historical comparators are to be drawn should cover asimilar or broader spectrum of patient prognostic factors.Chapter 9 discusses the implications of the investigations described in this thesis,outlines the scope for expanding the resource and proposes areas for future research.
【 预 览 】
附件列表
Files
Size
Format
View
The Virtual International Stroke Trials Archive (VISTA): promulgation of a clinial trial resource
PDF
download
878987797
028-85220240
