Update on the third international stroke trial (IST-3) of thrombolysis for acute ischaemic stroke and baseline features of the 3035 patients recruited

Peter Sandercock Richard Lindley Joanna Wardlaw Martin Dennis Karen Innes Geoff Cohen Will Whiteley David Perry Vera Soosay David Buchanan Graham Venables Anna Czlonkowska Adam Kobayashi Eivind Berge Karsten Bruins Slot Veronica Murray Andre Peeters Graeme J Hankey Karl Matz Michael Brainin Stefano Ricci Teresa A Cantisani Gordon Gubitz Stephen J Phillips Arauz Antonio Manuel Correia Phillippe Lyrer Update on the third international stroke trial (IST3) of thrombolysis for acute ischaemic stroke and baseline features of the 3035 patients recruited Sandercock et al. - Open Access Ingrid Kane16, Erik Lundstrom17 and the IST-3 collaborative group Background: Intravenous recombinant tissue plasminogen activator (rtPA) is approved in Europe for use in patients with acute ischaemic stroke who meet strictly defined criteria. IST-3 sought to improve the external validity and precision of the estimates of the overall treatment effects (efficacy and safety) of rtPA in acute ischaemic stroke, and to determine whether a wider range of patients might benefit. Design: International, multi-centre, prospective, randomized, open, blinded endpoint (PROBE) trial of intravenous rtPA in acute ischaemic stroke. Suitable patients had to be assessed and able to start treatment within 6 hours of developing symptoms, and brain imaging must have excluded intracranial haemorrhage and stroke mimics. Results: The initial pilot phase was double blind and then, on 01/08/2003, changed to an open design. Recruitment began on 05/05/2000 and closed on 31/07/2011, by which time 3035 patients had been included, only 61 (2%) of whom met the criteria for the 2003 European approval for thrombolysis. 1617 patients were aged over 80 years at trial entry. The analysis plan will be finalised, without reference to the unblinded data, and published before the trial data are unblinded in early 2012. The main trial results will be presented at the European Stroke Conference in Lisbon in May 2012 with the aim to publish simultaneously in a peer-reviewed journal. The trial result will be presented in the context of an updated Cochrane systematic review. We also intend to include the trial data in an individual patient data meta-analysis of all the relevant randomised trials. Conclusion: The data from the trial will: improve the external validity and precision of the estimates of the overall treatment effects (efficacy and safety) of iv rtPA in acute ischaemic stroke; provide: new evidence on the balance of risk and benefit of intravenous rtPA among types of patients who do not clearly meet the terms of the current EU approval; and, provide the first large-scale randomised evidence on effects in patients over 80, an age group which had largely been excluded from previous acute stroke trials. Trial registration: ISRCTN25765518 * Correspondence: 1The IST-3 Co-ordinating Centre, Neurosciences Trial Unit, Bramwell Dott Building, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK Full list of author information is available at the end of the article Progress with the study and modifications to the design Planning for the third international stroke trial (IST-3) of thrombolysis for acute ischaemic stroke with intravenous recombinant tissue plasminogen activator (rtPA) began in 1998. At its outset in 2000, the trial was planned as a pragmatic trial which sought to improve the external validity and precision of the estimates of the overall treatment effects (efficacy and safety) of rtPA in acute ischaemic stroke and to determine whether a wider variety of patients than previously thought might benefit from this treatment. After the drug was approved for use in Europe in 2003, the flexible trial eligibility criteria enabled us to continue recruiting patients who did not clearly meet all the criteria set out in the provisional European licence for the drug. With these changes and the need to comply with the increasingly burdensome requirements of research regulation in Europe, some aspects of the trial protocol and its practical procedures have inevitably had to change over the 12 year course of the study. The initial pilot phase of the study, funded by the UK Stroke Association, had a double-blind design, for which Boehringer Ingelheim provided a supply of drug and matching placebo. However, Boehringer Ingelheim did not wish to provide further drug supplies for the expansion phase, funded by The UK Health Foundation, and hence the design of this phase of the study was modified. With appropriate ethical approval, the expansion phase was designed as a prospective, randomised, open blinded endpoint (PROBE) trial and the first patient was recruited in this phase on 1st August 2003. The main phase of the trial was awarded funding by the UK Medical Research Council and began on 1st April 2005. The protocol for the MRC phase of the trial was published in Trials[1].. At each stage, relevant amendments were made to the protocol, and consolidated in an updated protocol (version 1.93) which was approved by appropriate authorities and published on the trial website http://www.ist3. com (additional data file 1). When advanced imaging techniques became more widely available in the participating centres, the study group developed a nested imaging study evaluating the role of CT and MR perfusion and angiography (CTP/CTA/MRP/MRA) in patients with acute ischaemic stroke. The cost-effectiveness of thrombolysis is being investigated in a sub-study in the Scandinavian region cohort. Sample size/recruitment target In our 2004 application to the MRC for funding of the main phase of the trial we stated: Assuming the same event rate as observed in the feasibility phases, the trial could very reliably detect an absolute difference of 10% in the proportion of patients dead or dependent at 6 months after treatment. With a sample size of 6000 patients, the trial would have > 99.9% power to detect such a difference (alpha = 0.001) and sufficient power to permit reliable analyses of the pre-specified subgroups. A trial of this size could detect a smaller, but still clinically worthwhile net benefit of as little as a 3% absolute difference in the primary outcome (80% power, at alpha = 0.05). The application to the MRC for funding was successful, but by the time the grant was activated, two major changes to research regulation came into force: the European Clinical Trials Directive, the UK Clinical Trials Regulations 2004, and, shortly afterwards, the UK Research Governance Framework. These changes led to a large increase in the time taken to recruit and activate new centres and hence significantly reduced the rate of increase in patient recruitment. By 2007, it was clear that the various factors that had delayed recruitment meant that the original target of 6000 was no longer feasible, and we applied for approval to amend the recruitment target and for additional funding to extend the period of recruitment to mid 2011. These changes were su (...truncated)