IST-3 progress report: recruitment, baseline data and

future plans

Peter Sandercockon behalf of

IST-3 collaborative group.UK IST-3 National Coordinators Meeting

Bologna 25th May 2005

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

Co-ordinating centre people

Peter Sandercock and Richard Lindley

Co-principal investigators

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

IST-3 Trial Steering CommitteeIndependent chairmanProfessor D Chadwick

Independent members Dr P Tyrrell,

Professor G Lowe (haemostasis and thrombolysis advisor),

OthersProfessor M Dennis,

Professor J Wardlaw (neuroradiology advisor)Professor C Warlow

International Advisory BoardNational 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 4th july

UK thrombolysis advisor: G Ford. NINDS liaison: J Marler. ECASS-3 liaison: M Kaste.

EPITHET liaison: S Davis.

CT reading Advisory Panel

• Chair: Joanna Wardlaw

• Membership: experts in the field have been invited to become panel members

• First meeting 6th October 2005

• First run of web-based CT reading system

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!

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

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

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

New forecast

IST3: Cumulative number of patients randomised

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Recruitment by country

Country No. centres Pts. %

UK 10 153 45%

Norway 4 56 16%

Poland 1 42 12%

Italy 3 41 12%

Belgium 1 34 13%

Australia 3 7 2%

Sweden 1 4 2%

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Baseline characteristics-are we recruiting the right sort

of patients?

Analyses of baseline data, based on data available on 5th May 2005 (n=342)

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

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sIST-3. Baseline characteristics: hours

from onset to randomisation

Median = 4.0 hours

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Age at stroke onset (years)

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Population-based study of stroke incidence (OXVASC). No of first strokes by age

OXVASC Lancet 2004; 363: 1925–33

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IST-3. Baseline characteristics: age

120 patients aged over 80

Partial anterior 33%

Lacunar 9%

Total anterior 54%

Posterior circulation

4%

IST-3. Baseline characteristics: stroke syndrome

Type of consent used by stroke syndrome

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TACS PACS LACS POCS

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IST-3. Baseline BP

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Baseline Systolic Blood Pressure

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IST-3. Other baseline features

Male 55%

Antiplatelets 48 hours before rand 51%

Treatment for BP+ pre-stroke: 49%

Atrial Fibrillation 28%

History of stroke or TIA 22%

Treatment for diabetes pre-stroke 11%

IST-3. CT scan at baseline: randomising doctor’s opinion

Feature No. (%)

No signs of acute infarction 184 (54%)

Definite signs of cerebral infarction

88 (26%)

Possible cerebral infarction 50 (20%)

IST-3. CT scan at baseline: Joanna Wardlaw’s opinion

Acute ischaemic change 73%

Hyperdense artery 44%

Periventricular lucencies 40%

Old vascular lesion 39%

Normal 4%

Non-stroke lesion 0.6%

Haemorrhage 0%*categories are not mutually exclusive:

a patient may have more than one feature

CASES (1135 patients treated within licence in 60 Canadian centres) vs IST-3

CASES IST-3

Age > 70 59% 70%

Atrial Fib. 22% 28%

Diabetes 16% 11%

Pre-stroke Rankin > 2

15% 2%

Normal baseline CT

20% 27%

CASES IST-3

TACS 28% 54%

PACS 63% 23%

LACS 6% 9%

POCS 3% 4%

CASES (1135 patients treated within licence in 60 Canadian centres)

vs IST-3

• 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) and high volume (> 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

• 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

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

Data Monitoring Committee report (3.9.04)

‘The independent Data Monitoring Committee (Professors Collins, van Gijn & Bath) was provided on 20th 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.

Recruitment targetsIncrease 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.

IST3: Cumulative number of patients randomised

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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).

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