Rationale: Why do we still need a large trial? IST-3 The Third International Stroke Trial: National Coordinators’ Meeting 25 May 2005, Bologna Professor Richard Lindley, Co-Principal Investigator

Outline Why large trials? Why do we need more randomised evidence? –Small evidence base –Variation in clinical practice Areas of uncertainty Current trials IST3 design

Rationale for large trials Acute ischaemic stroke treatment currently unsatisfactory Aspirin effective but has only modest benefit (approximately 1% absolute benefit) BUT currently has a greater public health impact than thrombolysis (large number of patients treated with a modestly effective treatment) Thrombolysis proven to be effective for only highly selected patients (10-15% absolute benefit) BUT few treated and minimal public health benefit (small number of patients treated with a powerful treatment)

History of acute stroke trials Modern era dependent on wide-spread availability of CT (and MRI) scanners, therefore a short history Only two “mega-trials” IST and CAST Industry dominated acute stroke trials all seriously underpowered (in comparison to secondary prevention stroke trials)

Lubeluzole N = 3510 patients, confidence interval for death or dependency at the end of follow-up 0.91 to 1.19 Trials only powered to detect a 10-15% absolute benefit

Gavestinel (GAIN trials) GAIN Americas, 90% power to detect a 10% absolute benefit (n = 1646), 2% absolute benefit observed for independent survival BUT 4% more dead GAIN International, 90% power to detect a 6- 10% absolute benefit (n=1800), - 0.8% absolute benefit observed for independent survival and 1.6% more dead (95% CI for odds ratio for worse outcome 0.81 to 1.26)

Trials in acute stroke are far too small “It is still not sufficiently widely appreciated just how large clinical trials need to be to detect reliably the sort of moderate, but important, differences in major outcomes that might exist (especially if effects in different subgroups are to be assessed reliably).” Collins and MacMahon Lancet 2001; 357:

Neuroprotectors unlikely to have a major treatment benefit You need to OPEN occluded arteries

With trials of about 20,000 subjects, the pharmaceutical industry can be reassured that they have not missed an important new treatment for acute stroke

Worthwhile reductions in stroke death and disability 60% dead or disabled at six months in control group 58% dead or disabled at six months in treatment group Sample sizePower % % % %

Lessons from cardiology ISIS-2Mortality in placebo group13% TrialMortality in best treatment arm ISIS-28% ISIS-47% GUSTO6% Message: Moderate cumulative treatment effects halved MI mortality over a 10 year period

Lessons from stroke medicine ISTDeath/dependency in control group 64% TrialDeath/dependency in best treatment arm IST63% (aspirin) Stroke units58% rt-PA58% (i.e. current negligible impact) Message: Moderate cumulative treatment effects have potential impact in stroke

Lessons from cardiology ISIS ,000 patients ISIS ,000 patients ISIS ,000 patients GUSTO199341,000 patients ISIS ,000 patients

Thrombolytic Time Window: Acute MI Fibrinolytic Therapy Trialists’ Group. Lancet 1994;343: ,000 patients from “mega-trials”

Thrombolysis for acute ischaemic stroke Standard accepted treatment for MI Slow acceptance for acute stroke

NINDS Trial Published in patients Clinical inclusion criteria CT scan to exclude a bleed or mimic (no other exclusions) Treatment to begin within 3 hours of stroke i.v. rt-PA 0.9mg/kg over 1 hour Major treatment effect more independent survivors per 1,000 treatment Independent re- analysis 2003 confirms results 10 years later treatment not widely implemented

ECASS II Published in patients 18 to 80 years Clinical inclusion criteria CT scan to exclude a bleed, mimic and > 1/3 MCA ischaemia) Treatment to begin within 6 hours of stroke i.v. rt-PA 0.9mg/kg over 1 hour Non-significant modest benefit 37 more independent survivors per 1,000 treatment 7 years later treatment not implemented for 3-6 hour time window

ECASS II Published in 1998 Powered to detect a 10% absolute difference with 80% power Detected a 3.7% absolute difference

ECASS III Currently recruiting Aged 18 to 80 years 800 patients recruited 3-4 hours post stroke Still powered to detect a 10% absolute difference, this time with 90% power

Evidence

Randomised trials of thrombolysis vs control in acute myocardial infarction Total no. patients ,600 Randomised trials trials of thrombolysis vs control in acute ischaemic stroke Total (all agents) ,675 rt-PA ,700 rt-PA < 3hrs rt-PA aged > 80 years 42

i.v. rt-PA benefit <6 hours: reduction in ‘death or dependency’ 20% reduction with rt-PA (95% CI 7-23%) BUT the significant between- trial heterogeneity (I 2 =62%) makes result unreliable

Unacceptable variation in usage in clinical practice

Only a small, variable proportion of patients get rt-PA in USA, Germany Authorno.no. % treated hospitals patients rt-PA (range) USA Johnstone 42 1, % (0-12%) Furlan 29 3, % (0-10%) Reed , % (0-5%) Germany Heuschmann , % (0-18%)

Effect of hospital, age and presence of neurologist on likelihood of receiving thrombolysis for acute ischaemic stroke among 23,058 acute stroke patients from 137 community hospitals in USA In 35% of hospitals, no patients at all given rt-PA. Strong trends to less rt-PA use: –with increasing age, –if no neurologist available Reed et al. Stroke 2001: 32;

Variation in use of rt-PA for acute ischaemic stroke ‘within licence’ in Europe SITS register (2003-5) March 2005

‘Grey areas’ of uncertainty: i.v. rt-PA promising but unproven for patients who: Present < 3hrs & do not exactly meet NINDS criteria All patients 3-6hours Older patients (>75 years) Severe stroke, mild stroke…... Have subtle, early ischaemic change on CT Etc etc …

Sample size required to answer these questions about iv rt-PA reliably rt-PA study group. Lancet 2004; 363: 768– hours

Current trials

Current randomised trials of i.v. thrombolysis

Small (n< 300) trials of other interventions IA thrombolysis MELT SYNTHESIS GP IIb/IIIA AbESTT2 (n=1800) CLEAR ROSIE SETIS SATIS Mechanical MR-RESCUE Ultrasound +/- rt-PA CLOTBUST-2? MUST

None of these trials will reliably answer the main questions

IST - 3 Protocol Main features of IST - 3 International, multi-centre, Prospective, Randomised, Open, Blinded Endpoints study of i.v. rt-PA vs control. Target 6000 patients Primary outcome: the proportion of patients alive and independent at six months (Modified Rankin 0,1 or 2) Central telephone randomisation with on-line minimisation to balance key prognostic factors. Web-based blinded detailed central review of all scans (ASPECTS, 1/3 MCA rule, dense MCA etc) Conducted to EU GCP standards.

IST - 3 Protocol IST-3 Sample size: 6,000 patients 1500 patients randomised within 3 hours will give >95% power (alpha 0.05) to detect a 10% increase in the proportion of patients alive and independent at 6 months (40% to 50%) patients randomised from 3 to 6 hours will give >90% power (alpha 0.05) to detect a 5% increase in the proportion of patients alive and independent at 6 months (40% to 45%).

IST-3 main eligibility criteria Symptoms and signs of clinically definite acute stroke Time of onset of stroke is known and treatment can be started within 6 hours of this onset CT or MRI has reliably excluded both intracranial haemorrhage and structural brain lesions which can mimic stroke Fuller details at:

IST-3 main exclusion criteria Major surgery, trauma,GI or urinary tract haemorrhage within previous 21 days Arterial puncture at a non-compressible site within the previous 7 days Any known coagulation defect Hypo- or hyperglycaemia sufficient to account for neurological symptoms

Early infarct signs on CT 4 hours24 hours Hypodensity : loss of grey/white differentiation, loss of the lentiform nucleus Swelling : effacement of sulci, squashing the ventricle

web-based CT reading and feedback system: Log on to Register Do first 20 scans (2 batches) - get 1 CPD credit -get feedback Do all six batches - get 5 CPD credits IST-3: Training to read CT scans what you, the reference standard, five experts and all other specialties said about that scan, and a follow-up scan to see where the infarct appeared

IST-3 Imaging: Training materials to read scans

IST-3 trial: randomisation If patient fits main eligibility/exclusion criteria, Clinician/patient/family discuss. If: 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

Conclusion. Need to Implement existing knowledge: redesign services to increase equity of access to thrombolysis within licence Increase the evidence base; worldwide effort to randomise sufficient patients to in IST-3 (and other trials) to provide reliable evidence on current questions Be aware of benefits of participating in IST-3: –It helps address a ‘real world’ intervention –You will get education on acute stroke care/CT scanning –If the trial result is positive, active trial centres more likely to be able to adopt new treatment quickly

New UK centres needed: please encourage other centres to join the trial register at

Can we get 10-20% of ischaemic stroke treated with rt-PA? 999 Nurse led Stroke Management process - Evaluation and Triage Within 6 Hrs

To achieve this we need seriously reliable data on: Treatment effect to 6 hours (and maybe beyond) Treatment effects by age, stroke subtype, severity, presence of aspirin and early ischaemic change on CT etc

Such change requires a convincing trial! Impact of megatrials in cardiology on thrombolysis for MI

IST-3: The window of opportunity In 1998 acute stroke services were too under-developed for a thrombolysis “mega-trial” Stroke services world-wide are being developed and maturing rt-PA has a track record in an “effective but not useful” time window It is now the most promising treatment to evaluate

IST-3: Streamlined design Methodology of large simple stroke trial developed over 15 years IST-3 designed with consumers and collaborative group Central organisation and delegated responsibilities share as much of the work as possible Evidence based trial monitoring!

IST-3 is simple & streamlined! Compare the paperwork needed for AbESTT-2 trial vs IST-3 AbESTT-2IST-3

So we need hospital teams to be treating stroke as an emergency… …and not lounging around drinking coffee!