Rationale: Why do we still need a large trial? IST-3 The Third International Stroke Trial:

National Coordinators’ Meeting25 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: 373-380

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 size Power

5000 50%

9000 80%

13000 90%

16000 95%

Lessons from cardiology

ISIS-2 Mortality in placebo group 13%

Trial Mortality in best treatment arm

ISIS-2 8%

ISIS-4 7%

GUSTO 6%

Message: Moderate cumulative treatment effects halved MI mortality over a 10 year period

Lessons from stroke medicine

IST Death/dependency in control group 64%

Trial Death/dependency in best treatment arm

IST 63% (aspirin)

Stroke units 58%

rt-PA 58% (i.e. current negligible impact)

Message: Moderate cumulative treatment effects have potential impact in stroke

Lessons from cardiology

ISIS-1 1986 16,000 patients

ISIS-2 1988 17,000 patients

ISIS-3 1992 40,000 patients

GUSTO 1993 41,000 patients

ISIS-4 1995 60,000 patients

Thrombolytic Time Window: Acute MI

Fibrinolytic Therapy Trialists’ Group. Lancet 1994;343:311-322

60,000 patients from “mega-trials”

Thrombolysis for acute ischaemic stroke

• Standard accepted treatment for MI

• Slow acceptance for acute stroke

NINDS Trial Published in 1995• 624 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 120-160 more independent survivors per 1,000 treatment

• Independent re-analysis 2003 confirms results

• 10 years later treatment not widely implemented

ECASS II Published in 1998• 800 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 1994 58,600

Randomised trials trials of thrombolysis vs control in acute ischaemic stroke

Total (all agents) 2005 5,675

rt-PA 2005 2,700

rt-PA < 3hrs 2005 930

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 (I2=62%) makes result unreliable

Unacceptable variation in usage in clinical practice

Only a small, variable proportion of patients get rt-PA in USA, Germany

Author no. no. % treated hospitals patients rt-PA (range)

USAJohnstone 42 1,195 4.1% (0-12%) Furlan 29 3,948 1.8% (0-10%) Reed 137 23,058 1.6% (0-5%)

GermanyHeuschmann 104 13,440 3.0% (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; 1832-44

Variation in use of rt-PA for acute ischaemic stroke ‘within licence’ in Europe

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20

30

40

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Finland

Austria

SwedenNorway

Belgium

Spain

GermanyNetherlands

Denmark

Italy

UK

GreeceFrance

Portugal

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: 768–74

0-1.5 1.5-3.0 3.0-4.5 4.5-6.0hours

Current trials

Current randomised trials of i.v. thrombolysis

Trial Thrombolytic

agent Patient selection trial size & time window

EPITHET rt-PA Clinical, CT (+ DWI/PWI MRI) 3-6 hours 100 patients

DIAS -2 Desmoteplase DWI/PWI or CT perfusion 3-9 hours 186 patients

ECASS III rt-PA Clinical and CT 3-4 hours 800 patients

Small (n< 300) trials of other interventionsIA 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%).

• 4500 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: www.ist3.com

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 hours 24 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 www.neuroimage.co.uk

• 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 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 www.ist3.com

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-2 IST-3

So we need hospital teams to be treating stroke as an emergency…

…and not lounging around drinking coffee!