1. Update on IST-3 and other trials. Or, ‘how the ECASS-3 results have helped re-launch IST-3!’ Professor Peter Sandercock, Co-chief investigator IST-3 collaborator’s webcast 10 th November 2008 (recruitment data updated post webcast) Note: please feel free to use these slides in presentations and for discussions with colleagues, but please do not cite these data in publications without prior permission of the Trial management Group

2. IST-3 funding agencies

3. Outline What do we know now? Updated Cochrane Review of all trials Current usage in clinical practice Remaining questions IST-3 Progress with recruitment Data Monitoring Committee reports Key messages from Steering Committee Publications

4. Cochrane Systematic Review of Thrombolysis Trials All randomised controlled trials of any thrombolytic drug versus control 2003 version included 18 trials (no. patients =5675) Drugs: rt-PA, streptokinase, uro-kinase, rPro-urokinase, Time windows: 0-3, 0-6 hrs Brain Imaging : CT Age over 80 :42 patients JM Wardlaw, V Murray (in preparation)

5. New trials included in 2008 update 8 new trials (n=+1477, total: n=7152) Drugs: 3 rt-PA; 2 UK; 3 desmoteplase Route: 2 intra-arterial, 6 intravenous Time windows: 0-6, 3-4.5, 3-9, 0-24 hrs Imaging pre randomisation: –CT: 5 –MR: 3 (+1) DWI/PWI mismatch Age over 80: ≈42 JM Wardlaw, V Murray (in preparation)

6. ECASS 3 Inclusion: 3-4.5 hours Age 18-80 yrs Excluded : NIHSS>25 or CT infarct signs >1/3MCA diabetes and prior stroke stroke in previous 3 months,etc,etc Outcomes: Good functional outcome: mRS 0-1 vs 2-6 Baseline Imbalance in age, NIHSS, prior stroke, DM (all in favour of rt-PA)

7. IV urokinase IV streptokinase IV rt-PA IV streptokinase + aspirin IA pro-urokinase IA urokinase IV desmoteplase Death or dependency at the end of follow-up Total 0.91 (0.64, 1.42) 0.94 (0.72, 1.24) 0.77 (0.47, 0.89) 1.09 (0.49, 1.72) 0.55 (0.31, 1.00) 0.57 (0.28, 1.14) 0.85 (0.53, 1.38) 0.82 (0.73, 0.91)

8. Effect of rt-PA on death or dependency

9. rt-PA trials: 2003 versus 2008 Odds Ratios and 95% CI SICH Late Death or (incl fatal) Death Dependency 2003 3.1 1.2 * 0.8 * n=2955 2.3 - 4.2 0.9 - 1.5 0.7 - 0.9 p<0.00001 p=0.14 p=0.003 2008 3.1 1.1 0.8 * n=3977 2.3 - 4.0 1.0 - 1.4 0.7 - 0.9 p<0.00001 p=0.16 p<0.0001 * significant heterogeneity confounds interpretation

10. rt-PA trials: 2008. Absolute effects (no. Events avoided /caused per 1000 treated, 95% CI) all 0-3 hrs 3-6 hrs SICH 60 70 60 50, 80 40, 100 50, 80 Death 10 0 20 10, 40 50, 50 0, 50 Death or 60 110 40 Depend. 100, 30 170, 50 80, 10 X = events avoided (benefit) X = events caused (harm)

11. Update 2008 conclusions, Heterogeneity still confounds interpretation Potential for benefit to at least six hours Limited new knowledge on latest time windows. Almost complete lack of randomised evidence on effects in –older patients; –concomitant antithrombotic use; –stroke severity/subtype, –diabetes Outcome following selection on MR mismatch not apparently different to CT. No material change in main outcomes since 2003.

12. Estimated % of all ischaemic strokes treated with thrombolysis USA: 1-7% 1 Canada 3% 2 Germany 3% 3 Sweden 5.5% 4 1.Cocho et al.,Qureshi et al., 2.Kapral et al,3. Heuschmann et al, 4. (http://www.riks-stroke.org).

13. How many stroke patients per year in UK* might avoid being ‘dead or dependent’ with each treatment? % treated with this intervention Number treated per year Benefit per 1000 treated Number who avoid death or dependency Aspirin80%104000131350 Stroke Unit60%78000564370 Thrombolysis2%208063163 Thrombolysis30%31200471470 *130,000 strokes per year

14. Even if the EU approval for thrombolysis is extended to 4.5 hrs, this will still exclude patients who Are aged > 80 years Either ‘very mild stroke’ or NIHSS > 25 Prior stroke within the last 3 months Have a history of prior stroke + Diabetes Arrive at 4.5 to 6.0 hours Other relative contraindications specified in the licence (e.g. ‘extensive infarction’, which is not defined in any way)

15. Stroke patients > 80 years Patients over 80 have been excluded from randomised trials and the licence In the UK 30% of all strokes are aged > 80 = 31,000 ischaemic stroke patients each year automatically excluded from thrombolysis

16. Severe stroke (NIHSS > 25) This man had a large MCA infarct NIHSS > 25, rt-PA not approved for him He spent many months in hospital He was very disabled He was no longer able to care for his wife

17. Mild, or rapidly improving strokes (NIHSS < 4) 2 hours ago, this man developed right hemiparesis, now rapidly improving. NIHSS < 4, so rt-PA not approved Many such patients recover without rt-PA, BUT 15-30% later deteriorate suddenly -> disabling stroke Should we treat them to prevent deterioration?

18. Vertebro-basilar territory ischaemic strokes Acute cerebellar infarct Excluded from previous trials of iv rt-PA Time window for treatment unclear Is there benefit from iv thrombolysis for such patients?

19. ‘Extensive infarction’ Does this patient have ‘extensive infarction?’ Not defined in EU approval Much debate about definition Should this patient be excluded from thrombolysis?

20. 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

21. IST 3 Sample size with 1000 patients we could detect a 7% absolute difference in the primary outcome, which is consistent with the effect size among patients randomised within 3 hours of stroke in the Cochrane review. If 3100 patients were recruited, the trial could detect a 4.7% absolute difference in the primary outcome. (remarkably close to the 4% difference seen in the updated Cochrane review) With 6000 patients, mostly treated between 3 & 6 hours of onset, the trial could detect a 3% absolute difference in the primary outcome Protocol version 1.92 September 2005

22. Recruitment by 10.11.2008 = 1343 patients

24. 46 patients in past month = increased recruitment rate after ECASS-3 results released! ECASS-3 results

25. Projected numbers of patients by mid 2011 MRC target = 3100 At 46 per month = 2806 If we can recruit an extra 9 patients per month, we’ll reach our target!

26. Recruitment by country in IST-3 CountryNo. centresPts.% UK4453440% Poland519715% Norway1315112% Sweden1413710% Italy201249% Australia101078% Belgium3615% Austria2171% Canada181% Mexico130% Portugal33 0% Total1191343

27. Analyses of data on the 1281 patients recruited by 24.9.2008

28. Type of patient recruited Age: IST-3 largest randomised controlled trial in ‘older’ hyper-acute stroke –893 patients > 70 years, –564 patients > 80 years. Severity & subtype: –Wide range of severity –Subtypes not much recruited in previous trials: 153 Lacunar infarcts 77 Posterior circulation infarcts

29. Age and time to randomisation stroke onset to randomisation (hrs) < 80 years>80 Years 0-389 (12%)186 (33%) 3-4.5323 (45%)249 (44%) >4.5305 (43%)129 (23%) Age

30. No. patients recruited into trial Trends in type of patient recruited since trial began: Infarct subtype

31. Trends in type of patient recruited since trial began: Time to randomisation No. patients recruited into trial

32. Type of patient recruited in main phase

33. Perfusion imaging in IST3 The trial imaging system can store and analyse CT and MR perfusion data from patients recruited in IST-3 We have been collecting these perfusion data If you have CT or MR perfusion and angiography data on your IST-3 patients, please send the data with the routine plain (non-contrast) images to the trial office. IST-3 will be able to add greatly to the evidence base on perfusion/diffusion mismatch and response to rt-PA.

34. Impact of ECASS-3 on IST-3 No evidence of a decline in IST-3 recruitment since results released, in fact recruitment has increased from ~30/month to 44 in the past month! Recruitment of patients < 80 yrs, 3-4.5 hrs with NIHSS < 25 is only 15% of those recruited since ECASS-3 published Many centres will be assessing more patients for thrombolysis up to 4.5 now, and so more may be considered for entry in IST-3

35. Data Monitoring Committee and MRC Steering Committee Data Monitoring Committee (DMC) meeting 23 rd September, rapid review of ECASS3 data, updated Cochrane review, and IST3 data to inform discussions at collaborators meeting 26 th Sept, Vienna Full DMC meeting 30 th October to consider above data in detail MRC trial Steering Committee: review of progress of trial and plans for future

36. Letter from IST-3 Data Monitoring Committee 23 rd September Dear Peter In preparation for the release of the ECASS-III results (and blind to those results), the IST-3 Data Monitoring Committee had arranged a teleconference for today (23 September 2008). Our review of the available data from IST-3 and the other trials, including safety information from ECASS-III, does not lead us to consider there to be any need for a change to IST-3. We would encourage the IST-3 collaborators to maintain the increase in the rate of recruitment. The DMC will continue to monitor interim results from IST-3 as planned. Yours sincerely Professor Rory Collins Chair, IST-3 DMC

37. Letter from IST-3 Data Monitoring Committee 3 rd November 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

38. Summary Current EU approval is very strict and permits treatment of only small numbers of patients; public health impact is small ECASS3 results help widen the time window a bit, but will not increase randomised evidence of effects in older people, or the many other categories excluded from treatment by EU approval If IST-3 results confirm benefits in a wider range, more could be treated and public health impact greatly increased

39. 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

41. IST-3 Papers in peer-reviewed journals 2007/8 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 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)