1. 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 1

2. 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

3. 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

4. Recruitment
Pilot - Expansion - Main MRC phase

5. 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%

6. Age: 1617 (53%) patients > 80 6

7. Stroke severity: NIHSS7

8. Time to randomisation
39%
33%
28%

9. 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

10. 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

11. 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

13. How many would have met the EU approval for rtPA?
Would meet the 2003 approval: (2%)
Would meet the 2011 approval: (13%)
age <80, delay from onset to randomisation <3hours, NIHSS , 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