IST-3: progress with the trial internationally and plans for the future

1. IST-3: progress with the trial internationally and plans for the future Peter Sandercock Riunione Gruppo Italiano IST-3 Firenze 13th February 2009

2. Gruppo Italiano IST-3 Capo Riunione Gruppo 2007

3. Outline • Rationale • Progress with recruitment • Characteristics of patients in trial • Outcomes assessed in IST-3 • Long-term effects of small benefits • Data Monitoring Committee reports • Publications • Future plans

5. How many stroke patients per year might avoid being ‘dead or dependent’ with each treatment in UK? (130,000 strokes/year) *USA population average **If IST-3 overall positive?

6. Third International Stroke Trial. A large randomised trial to answer the question: can a wider variety of patients be treated? Target: up to 3100 patients from > 100 centres in 12 Countries by mid 2011

7. Even if, post- ECASS-3, the EU approval for thrombolysis extends time window to 4.5 hrs, this will still exclude patients who: • Are aged > 80 years • Have ‘very mild stroke’ or NIHSS > 25 • Had prior stroke within the last 3 months • Have a history of prior stroke + Diabetes • Arrive at 4.5 to 6.0 hours • Have other relative contraindications specified in the licence (e.g. ‘extensive infarction’, which is not defined in any way)

9. Projected recruitment At current rate of 57 per month, final n = 3157 MRC target n = 3100 12th Feb 2009, n= 1477 ECASS-3 Results published 2000 July 2011

10. Recruitment by country in IST-3

12. Characteristics of patients Age >70 =1130 >80 = 791 Time: Mean onset to randomisation = 3.95 hours NIHSS Mean =12.3

13. Trends in type of patient recruited 2000-2008: AGE No. patients recruited into trial

14. OCSP subtype POCI LACI TACI PACI

15. NIHSS at baseline

16. At the end of the trial, IST-3 will have recruited about • Older age: • 2200 patients > 70 years, of whom • 1000 patients > 80 years. • Severity of stroke: • Severe: 300 with NIHSS > 24 • Mild: 600 with NIHSS < 5 • Subtypes not much recruited in previous trials: • 800 with AF (cardioembolic infarct) • 370 with lacunar infarcts • 200 with posterior circulation infarcts

17. Long-term outcomes in stroke trials • Randomized controlled trials (RCTs) should reflect the effect of treatments on long-term outcomes.1 • BUT, the follow-up period of RCTs tends to be relatively short. • Model:2 Treatments that produce even relatively small reductions in disability after ischemic stroke are likely to be cost-effective, even if they have a high price. 1. US National panel on cost-effectiveness. 2.Samsa et al J CLIN EPIDEMIOL 1999 52;3:259–271

18. Samsa’s model predictions Samsa et al J CLIN EPIDEMIOL 52;3:259–271, 1999.

19. Model validation: Impact of functional status at six months on long term survival in 7710 patients with ischaemic stroke in 3 prospective cohort studies (OCSP). Bruins slot, Sandercock et al BMJ 2008 doi:10.1136/bmj.39456.688333.BE

20. Validation: Impact of functional status at six months on long term survival in 7710 patients with ischaemic stroke in 3 prospective cohort studies • Functional status of patients six months after onset of an ischaemic stroke has a significant and substantial effect on long term survival • A difference of one Rankin grade has a large effect • Less than half those alive with severe disability at six months will survive five years; a survival statistic comparable with that of several malignancies. • This validates Samsa’s hypothesis and model estimates with empirical data • Treatments with even modest effects could prove very cost-effective Bruins slot, Sandercock et al BMJ 2008 doi:10.1136/bmj.39456.688333.BE

21. Outcomes in IST-3 Primary: • The proportion of patients alive and independent (mRS 0-2) at 6 months Secondary: • Early (events < 7 days): Deaths, Symptomatic intracranial haemorrhage. Recurrent ischaemic stroke, Neurological deterioration attributed to swelling of the initial ischaemic stroke, Neurological deterioration not attributable to swelling of the initial ischaemic stroke or haemorrhage. • 6 months: mRS, EQ-5D (EuroQol), place of residence, • 18 months: as at 6 months • > 18 mo (UK+ Nordic): mortality follow-up via National Registers of Deaths

22. IST-3 Italy coordinator’s local support team (+visitors) hard at work…..

23. Letter from IST-3 Data Monitoring Committee 3rd November 2009 The IST-3 Data Monitoring Committee held its scheduled interim review of the unblinded data from IST-3 on 30 October 2008. Based on our review of these data, as well as the safety and efficacy data from the other trials of tPA in acute stroke (including recently reported ECASS-III among patients treated 3 and 4.5 hours after symptom onset), the DMC concluded there was no need for any change to IST-3. We would encourage the IST-3 collaborators to maintain the increase in the rate of recruitment, and in particular, to consider all eligible patients for randomisation (irrespective of the presenting time from symptom onset). Professor Rory Collins Chair, IST-3 DMC

25. IST-3 Papers in peer-reviewed journals 2007-9 1. Wardlaw JM, Bath P, Sandercock P, Perry D, Palmer J, Watson G, Lloyd S, Geddes J, Farrall A. The NeuroGrid stroke exemplar clinical trial protocol. International Journal of Stroke. 2007;2:63-9 2. Sandercock P, Lindley R, Wardlaw J, Dennis M, Lewis S, Venables G, et al. The Third International Stroke Trial (IST) of thrombolysis for acute ischaemic stroke.. Trials 2008;9(37) http://www.trialsjournal.com/content/9/1/37 3. SCOPE (Stroke Complications and Outcomes Prediction Engine) Collaborations and IST. Predicting outcome in hyper-acute stroke: validation of a prognostic model in the Third International Stroke Trial (IST3).. Journal of Neurology Neurosurgery and Psychiatry 2008;79:397-400 4. Adam Kobayashi, et al, on behalf of the IST-3 Collaborative Group. Oxfordshire Community Stroke Project clinical stroke syndrome and appearances of tissue and vascular lesions on pre-treatment CT in hyperacute ischaemic stroke among the first 510 patients in the Third International Stroke Trial (IST-3). Stroke (in Press)

26. Key Messages from Professor Colin Baigent, Chairman of IST-3 Steering Committee • There are encouraging signs that recruitment in IST-3 is continuing to accelerate, reflecting encouragement from the results of ECASS-3 • This increased rate is likely to be maintained, since new centres continue to join the trial • The revised target of 3100 by mid 2011 now appears eminently feasible • The Steering Committee was reassured and encouraged by the very positive report from the DMC

27. Plans for 2009 & beyond • 2009 Presentations • Plenary: AHA stroke conference San Diego (17th February) • 2009 Collaborators meetings • Italy (14th February) • International: ESC, Stockholm (27/28th May) • UK: UKSF (3rd-5th December) • 2010 Application for funding for • Individual patient data meta-analysis (all rt-PA trials) • Long-term survival follow-up • Image analyses • ‘Making the data publicly available’ • Mid 2011 recruitment ends • Results reported early 2012

28. Summary: IST-3 will provide evidence on the effects of rt-PA : In patients ‘outside’ the current EU approval in: • Age (>80 years) • People with other relative contraindications • In variety of clinical subgroups not studied in large numbers (cardio-embolic, lacunar, posterior circulation) • When given in a wide variety of hospitals On other outcomes: • < 7 days (inc massive oedema) • long-term: survival, QoL, cost-effectiveness

29. Summary. IST-3 Italy • Italy continues to make a significant contribution to IST-3 • New centres will be welcome join if they can start randomising before 31st Dec 2010. • The more patients we can recruit, the more reliable the estimates of effect will be • IST-3 will provide valuable randomised evidence on clinical, CT and MR factors relevant to use of thrombolysis in everyday practice