IST-3 Collaborators meeting Barcelona, 27 th May 2010

Outline Informed consent / GCP Update –Effect of ECASS-3 –Lancet pooled analysis –Remaining uncertainties Recruitment: ‘countdown’ to 30/6/11! Maintain high data quality

Informed Consent Oral and written information given to the patient by the investigator Before participation in trial Enough time and opportunity for questions and reflection

Informed Consent Consent signed and personally dated by patient (or a legally acceptable representative) Consent signed and dated by person who conducted the informed consent process 1 copy given to patient, 1 original kept in patient study files, 1 copy in patient medical records

Investigator Responsibilities Ensure that the rights, safety and welfare of the patients in the study are protected by ensuring that the study is conducted according to: 1.The Protocol 2.All appropriate regulations

Investigator must verify that they: Follow approved protocol and amendments Obtain written informed consent before each patient is entered into the trial Perform all trial procedures in accordance with the protocol Only delegate these functions to authorised personnel Enrol only eligible subjects

Update on the evidence and on IST-3 progress

Age and time to randomisation 2008 vs. 2009: impact of ECASS-3 ECASS-3 report Year, quarter No. patients recruited per quarter

Does this recent Lancet paper change anything?

2004 N= N=3670 Pooled analysis of rt-PA trials Time to treatment and odds of ‘good outcome’ (mRS 0-1) Lancet 2004, Lancet 2010

Time to treatment and odds of death: Does trade-off vary with time? Lancet 2010 Test for interaction p= 0.04

Time and odds of symptomatic brain haemorrhage (PH 2) Lancet 2010 Test for interaction p= 0.4

Authors conclusions: ‘We need to understand better the factors that prevent alteplase from being effective in individual patients… clinical variables e.g.: age, stroke severity, and comorbidities, factors pertaining to arterial recanalisation (e.g. clot composition, location, size, and collateral flow) ‘all must have a role in the success of thrombolysis, but are poorly understood’

Uncertainties about thrombolysis in acute ischaemic stroke: key ist-3 questions Is the upper age limit of 80 years justified? What key features identify patients most likely to benefit? –Severity (e.g. NIHSS)? –Stroke syndrome (LACI, TACI, POCI)? –Radiological (e.g. Hyperdense artery, WML) –Fancy imaging: ‘penumbra’, blocked artery? What is the latest time for net benefit? * Cochrane systematic review Wardlaw et al. BMJ ; b4584

Ongoing randomised trials iv rt-PA vs control Trial name Age (y)Time from onset (h) ImagingSample size EXTEND18+3-9Mismatch DWI/PWI 400 TESPI80+0-3CT or MR to date IST CT or MR* 3100 *CT, MR perfusion/angiography optional

IST-3 publicity response! ‘Opinion piece’ titled ‘Intravenous thrombolysis – where are we now?’ -> International Journal of Stroke. Podcast on IJS article Submit IST-3 CT/ MR perfusion & angiography protocol to IJS + podcast IST-3 newsletter editorial

Recruitment 27 th May n=2232 Need 868 more to reach target

Recruitment x country CountryNo. CentresPatients% UK % Poland930914% Italy % Sweden % Norway131738% Australia111587% Belgium3713% Portugal746 2% Austria3362% Switzerland113 1% Canada180% Mexico130%

‘Top ten’ centres with highest average recruitment / month Avg/mo. Southend University Hospital2.6 SPZZOZ w Sandomierzu2.3 Derby Royal Hospital2.3 Northwick Park Hospital2.2 Institute of Psychiatry & Neurology2.1 UAVC. Centro Hospitalar de Trás-os-Montes e Alto D1.9 St George's Healthcare NHS Trust1.7 Nuovo Ospedale Civile "S.Agostino-Estense"1.3 Uppsala University Hospital1.3 The National Hospital for Neurology & Neurosurgery1.3

Centres who randomised patients within last 30 days Derby Royal Hospital4 Nottingham City Hospital2 Aberdeen Royal Infirmary2 Leeds General Infirmary2 2nd Dept Institute of Psychiatry & Neurology, Warsaw2 Ospedale Di Branca2 Uppsala University Hospital2 Szpital Specjalistyczny w Konskich2

The end is in sight!

Recruitment target 13 months recruitment remain: need 67 patients per month to reach target Strategy = –New centres will need to work quickly to become active –Existing centres – what can we do help you increase recruitment? Other ideas to increase recruitment?

Data quality prize: the Sheila Grant Award! We aim for: 100% clinical follow up No missing scans Queries resolved Winner: Ospedale Di Branca: 100% complete data! Sheila, our data officer

We have climbed a big mountain – and we are near the top! Not far to go….

Summary Last patient to be recruited Deadlines –new centres to complete approvals to join: 31/08/10 –new centres must randomise their first patient by 31/12/10 Final follow-up Main ESC May 2012 IST-3 is very, very important! –the last large scale trial of thrombolysis versus control, –the only significant-sized trial in older people –The only controlled trial collecting baseline perfusion and angiography data in unselected patients We are moving on to trials in ICH (PATCH, TRANCHE)

IST-3 will add important new data: ~2000 outcome events -> will double total RCT weight of evidence Effects: –in all time windows up to 6h –In ~ 1000 patients aged > 80 years. –in severe and mild stroke: ~ 300 with NIHSS > 24 (severe), ~ 600 with NIHSS < 5 (mild) –On long-term survival (to 5 years+) Value of perfusion/angio data ~ 200 patients

02230 was randomised 24/05 from Helsingborgs Lasarett Sweden

Centres joined during the past 12 months pat no.av/30dy Derby Royal Hospital212.3 St George's Healthcare NHS Trust151.7 Aberdeen Royal Infirmary121.0 Szpital Powiatowy90.8 Queen Elizabeth The Queen Mother Hospital80.8 York Health Services NHS Trust80.8 Northwick Park Hospital52.2 Szpital Specjalistyczny w Konskich51.2 Royal United Hospital Bath50.8 Ospedale di Cattinara - Trieste41.2 Luton and Dunstable Hospital30.9 Doncaster Royal Infirmary30.7 Royal West Sussex NHS Trust, St Richard's Hospital30.3 Sunderland Royal Hospital30.3 Malmö Hospital21.0 Leicester General Hospital20.4 Stepping Hill Hospital20.4 Selly Oak Hospital, University Hospital Birmingham20.3 Bristol Royal Infirmary20.3 Mater Salutis Hospital, Legnago VR20.2

Ongoing RCTs intra-arterial interventional Rx vs iv therapy Trial nameTime from onset (h) ComparisonSample size MR Rescue0-8 Usual care vs usual care + MERCI 120 SYNTHESIS0-3IV vs IA+device 350 IMS-30-3IV vs IV+IA900

What is ICH GCP? International Conference on Harmonisation Guideline for Good Clinical Practice Harmonized tripartite guideline to provide a unified standard for the EU, Japan and US to facilitate the mutual acceptance of clinical data by regulatory authorities in these regions Guidance developed in consideration of current GCP practices in EU, Japan, US, Australia, Canada, Nordic countries & WHO