Baseline characteristics of the 3035 patients recruited in IST3 Peter Sandercock On behalf of the IST3 collaborative group UKSF Glasgow 30th November 2011 These results published today www.trialsjournal.com 1

Main features of IST - 3 Prospective, randomised, open, blinded endpoint (PROBE) study of i.v. rt-PA vs control, Target 3100 patients < 6 h of acute ischaemic stroke Primary outcome: the proportion of patients alive and independent at six months Randomisation by telephone or internet with minimisation to balance on key prognostic factors Baseline & F/U Imaging: CT or MR, Blinded central expert panel review of scans Option to collect perfusion/angio data. 2

IST-3 trial: eligibility and randomisation If patient fits main eligibility/exclusion criteria clinician/patient/family discuss. If there is a: Clear INDICATION FOR rt-PA →TREAT (i.e. meets terms of current licence and patient agrees) Clear CONTRAINDICATION TO rt-PA → DON’T TREAT rt-PA ‘PROMISING BUT UNPROVEN’ → RANDOMISE The third IST is a large double blind multicentre study. Eligibility is based on the uncertainty principle – if there are clear reasons for treating a patient, then that patient should be treated openly, and if there are clear contraindications to therapy, then the patient is not randomised. An initial CT is required to exclude h’gge – early changes of infarction are not a C/I. Patients will be randomised (via a central computerised service) to either iv alteplase 0.9mg/kg or matching placebo. Follow up is by means of blinded functional outcome assessment at 6 months – which will determine the mRS. 3

Recruitment 2000-2011 Pilot - Expansion - Main MRC phase

Recruitment by country   No. of centres No. of patients % UK 75 1447 48% Poland 9 347 11% Italy 21 326 Sweden 18 297 10% Norway 11 204 7% Australia 10 179 6% Portugal 4 82 3% Belgium 1 73 2% Austria 3 46 Switzerland 2 23 1% Canada 8 0.3% Mexico 0.1%

Age: 1617 (53%) patients > 80 6

Stroke severity: NIHSS 7

Time to randomisation 39% 33% 28%

Size of main subgroups Delay (hours) from stroke to randomisation Age 0-3  3-4.5 4.5-6  <=80 177  558 683 >80 672 620 325  All  849 1178 1008

Summary IST3 will provide data on effects of rtPA in types of patients currently outside the EU approval If positive, IST3 could justify the treatment of some patients currently excluded from treatment in EU (e.g. aged > 80) If negative or neutral, IST3 may limit ‘off-label’ use by clarifying the ‘outer limits of benefit’ for some patients The trial will provide randomised evidence on the importance (or not) of ‘clinical contraindications’ (e.g. DM + prior stroke),1 the use of advanced imaging other factors 1. Demaerschalk, 2. Mishra et al Neurology 2011

Acknowledgements: The 3035 patients, the 156 hospitals in the IST-3 group, the Data Monitoring Committee, the MRC Steering Committee, Image Reading Panel, Event adjudication panel, International Advisory Board. Funded by: 11

How many would have met the EU approval for rtPA? Would meet the 2003 approval:1 61 (2%) Would meet the 2011 approval:2 350 (13%) age <80, delay from onset to randomisation <3hours, NIHSS 6 - 25, SBP <=185, DBP <= 110, 2.7 <= glucose <=22 and no history of the combination of prior stroke and diabetes mellitus all the above + the time window was extended to 4.5 hours