1. IST-3 progress report: recruitment, baseline data and future plans Peter Sandercock on behalf of IST-3 collaborative group. UK IST-3 National Coordinators Meeting Bologna 25 th May 2005

2. Outline IST-3 teams –At trial co-ordinating centre, Edinburgh –International Advisory Board –CT reading advisory panel Update on recruitment, centres and countries Baseline characteristics: are we recruiting the right sort of patients? Future targets: importance of National Co- ordinators

3. Co-ordinating centre people Peter Sandercock and Richard Lindley Co-principal investigators

4. Co-ordinating centre people Trial manager: Karen Innes Trial Centre Manager: Alison Clark Statistician: Steff Lewis Data entry/management: Sheila Grant Programming/website: Vera Soosay Clinical Research fellow: Ingrid Kane ACCESS study/CT reading: Joanna Wardlaw, Andrew Farrall, Eleni Sakka, David Perry

5. IST-3 Trial Steering Committee Independent chairman Professor D Chadwick Independent members Dr P Tyrrell, Professor G Lowe (haemostasis and thrombolysis advisor), Others Professor M Dennis, Professor J Wardlaw (neuroradiology advisor) Professor C Warlow

6. International Advisory Board National Coordinators: Australia (G Hankey & R Lindley), Austria (K Matz, M Brainin), Belgium (A Peeters), Brazil (J Fernandes), Canada (S Phillips, G Gubitz), Chile (P Lavados), China (ZM Chen M Liu), Germany (M von Reutern), Greece (K Vemmos), Hungary (D Bereczki), India (K Prasad), Italy (S Ricci), Norway (E Berge, KS Bruins), Poland (A Czlonkowska), Sweden (V Murray), Singapore (HM Chang), Slovak Republic (M Brozman), Switzerland (P Lyrer), S Africa (M Connor), Taiwan (KC Chang), UK (G Venables). National co-ordinators telconference 4 th july UK thrombolysis advisor: G Ford. NINDS liaison: J Marler. ECASS-3 liaison: M Kaste. EPITHET liaison: S Davis.

7. CT reading Advisory Panel Chair: Joanna Wardlaw Membership: experts in the field have been invited to become panel members First meeting 6 th October 2005 First run of web-based CT reading system

8. Funding 1999- 1999-2004 2002-6 2005-9 UK Norway: Norwegian Research Council Sweden: AFA Insurances, Swedish Heart & Lung Foundation Australia: Australian Heart Foundation Poland: Government of Poland Canada: funds in reserve for when approval finally granted!

9. Resources for National Coordinators Reimbursement of costs of postage, telephone calls, site visits for training, quality control and performing centralised follow-up. Support from International Recruitment & Quality Control Co-ordinator, who will help provide: –support and training to new centres; –support to all centre staff working on project –help identify and recruit new centres –visit centres to monitor compliance with the protocol and procedures in random sample of patients; –attend local and regional meetings; –visit ‘problem’ centres

10. Funding for each participating hospital First patient recruited: We will reimburse new centres the costs of setting up the trial and getting local ethics approval by a single payment of £100 when they have successfully randomised their first patient, and the co-ordinating centre confirm that the patient fulfilled trial eligibility and have received all the initial trial data. For each subsequent patient randomised, centres will be reimbursed £25 to cover cost of copying scans, courier postage, telephone calls and other minor expenses

11. A note about the data The data are provisional, and changing all the time. Collaborators: please free to present/discuss these data at meetings, but please do not cite them in publications! Note: these slides will be posted on the IST-3 website after the conference for you to download

12. New forecast

13. Recruitment by country CountryNo. centresPts.% UK10 15345% Norway45616% Poland14212% Italy34112% Belgium13413% Australia372% Sweden142%

15. Baseline characteristics -are we recruiting the right sort of patients? Analyses of baseline data, based on data available on 5 th May 2005 (n=342)

16. What sort of patients do we need data on? Patients outside licence Arriving at hospital 2-5hrs after onset Older patients (over 80) TACS,PACS,POCS and LACS Severe stroke Mild stroke Diabetics Prior aspirin? Blood pressure range? With and without ‘early ischaemia’ on pre- treatment CT scan

17. IST-3. Baseline characteristics: hours from onset to randomisation Median = 4.0 hours

18. Population-based study of stroke incidence (OXVASC). No of first strokes by age OXVASC Lancet 2004; 363: 1925–33

19. IST-3. Baseline characteristics: age 120 patients aged over 80

20. IST-3. Baseline characteristics: stroke syndrome

21. Type of consent used by stroke syndrome

22. IST-3. Baseline BP

23. IST-3. Other baseline features Male55% Antiplatelets  48 hours before rand 51% Treatment for BP+ pre-stroke:49% Atrial Fibrillation28% History of stroke or TIA22% Treatment for diabetes pre-stroke11%

24. IST-3. CT scan at baseline: randomising doctor’s opinion FeatureNo.(%) No signs of acute infarction 184(54%) Definite signs of cerebral infarction 88(26%) Possible cerebral infarction50(20%)

25. IST-3. CT scan at baseline: Joanna Wardlaw’s opinion Acute ischaemic change73% Hyperdense artery44% Periventricular lucencies40% Old vascular lesion39% Normal4% Non-stroke lesion0.6% Haemorrhage0% *categories are not mutually exclusive: a patient may have more than one feature

26. CASES (1135 patients treated within licence in 60 Canadian centres) vs IST-3 CASESIST-3 Age > 7059%70% Atrial Fib.22%28% Diabetes16%11% Pre-stroke Rankin > 2 15%2% Normal baseline CT 20%27%

27. CASESIST-3 TACS28%54% PACS63%23% LACS6%9% POCS3%4% CASES (1135 patients treated within licence in 60 Canadian centres) vs IST-3

28. Baseline ASPECTS score –Strong predictor of poor outcome –But NOT a predictor of symptomatic ICH (SICH) Age > 80 –Less likely to have good outcome –But age NOT a risk factor for ICH Protocol violations –Predictor of SICH –But NOT a predictor of poor outcome Low ( 1 per month) centres similar outcomes Active lowering of BP before thrombolysis –associated with WORSE outcome –No apparent reduction in risk of SICH CASES: Effect of baseline features on risk and benefit of rt-PA

29. Orolingual angioedema = 1.3% (related to frequent use of ACE inhibitors?) –All managed conservatively, except: –1 intubated, 1 cricothyroidotomy Acute hypotension during rt-PA infusion = 0.4% –Managed with crystalloid infusion rt-PA in routine use: CASES. Other outcomes

30. Are we recruiting the right sort of patients? Arriving at hospital 2-5hrs after onset YES Older patients (over 80) YES TACS:YES, PACS,POCS & LACS: NEED MORE! Severe stroke: YES Mild stroke: NEED MORE! Diabetics: YES Prior aspirin: YES Blood pressure range: YES Some ‘early ischaemia’ on pre-treatment CT:YES

31. Data Monitoring Committee report (3.9.04) ‘The independent Data Monitoring Committee (Professors Collins, van Gijn & Bath) was provided on 20 th August 2004 with the unblinded interim analysis for 253 randomised patients in the IST-3 trial. These analyses included information about the primary outcomes of death and disability, as well as about specific fatal and non-fatal events (including intracranial haemorrhage). Following review of these analyses, the DMC considers that it remains important for IST-3 to continue as planned. Consequently, we encourage you strongly in your efforts to increase the rate of recruitment to the trial, which appears to be progressing well.

32. Recruitment targets Increase recruitment 10x Increase active centres from 23 to 200 Increase recruitment from 35 patients per 3 months to 350 per 3 months Final target = 6000 patients Continue to recruit similar patients within 3 hours: the type of patients who do not exactly fit the conditions of the licence, but who might benefit from rt-PA 3-6 hours: in patients where you consider thrombolysis is promising but unproven.

35. Targets for number of new centres To achieve our target of 200 active centres, we will need to start about 250 centres. The National co-ordinator in each country will be responsible for recruiting new centres. At the start of the MRC phase, we expect to have 50 centres, and we aim to activate an average of 55 centres per year over 2004-8 (more than this in years 1 & 2).

36. Summary to date Recruitment of patients is going well –But need to increase it 10-fold –Recruiting correct type of patients –Results will be clinically very important Other active countries: –Keep up the good work/excellent data quality! –Seek to recruit less severe strokes –Keep up the work of recruiting new centres New countries: –Try and recruit your first patient! –Tell everyone in your country about the trial Publicise the trial Encourage well organised centres to join