IST-3 Collaborators meeting

Barcelona, 27th 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

0

20

40

60

80

100

120

140

160

180

20

07

, 4

20

08

, 1

20

08

, 2

20

08

, 3

20

08

, 4

20

09

, 1

20

09

, 2

20

09

, 3

20

09

, 4

>80 - TOTAL - >4.5-6

>80 - TOTAL - >3-4.5

>80 - TOTAL - 0-3

<=80 - TOTAL - >4.5-6

<=80 - TOTAL - >3-4.5

<=80 - TOTAL - 0-3

ECASS-3report

Year, quarter

No

. pat

ien

ts r

ecru

ited

per

qu

arte

r

Does this recent Lancet paper change anything?

2004N=2775

2010N=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 2009 339; b4584

Ongoing randomised trials iv rt-PA vs control

Trial name

Age (y) Time from

onset (h)

Imaging Sample size

EXTEND 18+ 3-9 Mismatch

DWI/PWI

400

TESPI 80+ 0-3 CT or MR 60070 to date

IST3 18+ 0-6 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

27th Mayn=2232

Need 868 more to reach target

Recruitment x country Country No. Centres Patients %

UK 64 963 43%

Poland 9 309 14%

Italy 21 228 10%

Sweden 15 213 10%

Norway 13 173 8%

Australia 11 158 7%

Belgium 3 71 3%

Portugal 7 46 2%

Austria 3 36 2%

Switzerland 1 13 1%

Canada 1 8 0%

Mexico 1 3 0%

‘Top ten’ centres with highest average recruitment / month

Avg/mo.

Southend University Hospital 2.6

SPZZOZ w Sandomierzu 2.3

Derby Royal Hospital 2.3

Northwick Park Hospital 2.2

Institute of Psychiatry & Neurology 2.1

UAVC. Centro Hospitalar de Trás-os-Montes e Alto D 1.9

St George's Healthcare NHS Trust 1.7

Nuovo Ospedale Civile "S.Agostino-Estense" 1.3

Uppsala University Hospital 1.3

The National Hospital for Neurology & Neurosurgery 1.3

Centres who randomised patients within last 30 days

Derby Royal Hospital 4

Nottingham City Hospital 2

Aberdeen Royal Infirmary 2

Leeds General Infirmary 2

2nd Dept Institute of Psychiatry & Neurology, Warsaw 2

Ospedale Di Branca 2

Uppsala University Hospital 2

Szpital Specjalistyczny w Konskich 2

The end is in sight!

Recruitment target• 13 months recruitment remain: need

67 patients per month to reach target 3100.

• 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 30.06.2011• 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 31.12.2011• Main results @ 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 Hospital 21 2.3

St George's Healthcare NHS Trust 15 1.7

Aberdeen Royal Infirmary 12 1.0

Szpital Powiatowy 9 0.8

Queen Elizabeth The Queen Mother Hospital 8 0.8

York Health Services NHS Trust 8 0.8

Northwick Park Hospital 5 2.2

Szpital Specjalistyczny w Konskich 5 1.2

Royal United Hospital Bath 5 0.8

Ospedale di Cattinara - Trieste 4 1.2

Luton and Dunstable Hospital 3 0.9

Doncaster Royal Infirmary 3 0.7

Royal West Sussex NHS Trust, St Richard's Hospital 3 0.3

Sunderland Royal Hospital 3 0.3

Malmö Hospital 2 1.0

Leicester General Hospital 2 0.4

Stepping Hill Hospital 2 0.4

Selly Oak Hospital, University Hospital Birmingham 2 0.3

Bristol Royal Infirmary 2 0.3

Mater Salutis Hospital, Legnago VR 2 0.2

www.stroketraining.org

Ongoing RCTs intra-arterial interventional Rx vs iv therapyTrial name Time from

onset (h)Comparison Sample

size

MR Rescue 0-8 Usual care vs usual care +

MERCI

120

SYNTHESIS 0-3 IV vs IA+device

350

IMS-3 0-3 IV vs IV+IA 900

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