Condition category
Circulatory System
Date applied
Date assigned
Last edited
Prospectively registered
Overall trial status
Recruitment status
No longer recruiting
Publication status

Plain English Summary

Background and study aims
About 85% of strokes are ischemic strokes. Ischemic strokes happen when the arteries that supply the brain with oxygen become narrowed or blocked, causing severely reduced blood flow (ischemia). As we age, a gradual build-up of a sticky substance called plaque can occur in our arteries. When there is a lot of plaque, particularly with a rough or irregular surface, blood clots can develop, depriving the brain of oxygen and leading to an acute ischemic stroke (AIS). Fast diagnosis and treatment are essential in the treatment of AIS. Thrombolysis, also known as “clot busting”, is a drug treatment that breaks down clots, helping to restore the blood supply to the brain. Recombinant tissue plasminogen activator (rt-PA) is a thrombolytic agent which, when approved for use in Europe, was restricted for use in patients under 80 years old within three hours of stroke onset. The aim of this study is to find out whether treatment with rt-PA is still effective within six hours of stroke onset, and whether it is still effective in older patients.

Who can participate?
Adults who have had an ischaemic stroke within the past six hours.

What does the study involve?
Participants are randomly allocated to one of two groups. Those in the first group receive rt-PA at a dose of 0.9 mg per kg of body weight (up to a maximum dose of 90mg) intravenously (through a drip). Those in the second group do not receive any rt-PA treatment, but are treated in the same clinical environment as participants in group one. Participants in both groups are carefully monitored for seven days and the numbers of people who die or have further strokes are recorded. Participants are also followed up for 6 months in order to record to number who are alive and independent.

What are the possible benefits and risks of participating?
Not provided at time of registration

Where is the study run from?
This study is run from 156 hospitals in 12 countries across Europe, North America and Australia

When is the study starting and how long is it expected to run for?
April 2008 to December 2012

Who is funding the study?
1. The Health Foundation (UK)
2. Medical Research Council (UK)
3. Stroke Association (UK)
4. AFA Insurances (Sweden)
5. The Norwegian Research Council (Norway)
6. The Heart Foundation (Australia)
7. The Government of Poland (Poland)

Who is the main contact?
Professor Peter A. G. Sandercock

Trial website

Contact information



Primary contact

Prof Peter A. G. Sandercock


Contact details

Department of Clinical Neurosciences
University of Edinburgh
Bramwell Dott Building
Western General Hospital
Crewe Road
United Kingdom

Additional identifiers

EudraCT number

2004-000238-36 number

Protocol/serial number

EME 08/43/52; IST399

Study information

Scientific title

The Third International Stroke Trial (IST-3) of thrombolysis for acute ischaemic stroke: an international multicentre, randomised, controlled trial to investigate the safety and efficacy of treatment with intravenous recombinant tissue plasminogen activator (rt-PA) within six hours of onset of acute ischaemic stroke



Study hypothesis

The principal research questions to be addressed are:
1. Does thrombolysis with intravenous (iv) recombinant tissue plasminogen activator (rt-PA) up to six hours increase the number of independent survivors?
2. Does early treatment with iv rt-PA benefit a wider variety of patients than that defined by the current restricted licence (especially older people, who contribute the greatest proportion of the burden of stroke)?
3. What is the effect on deaths from all causes?

Link to EME project website:
Link to protocol:

Ethics approval

Not provided at time of registration

Study design

Randomised controlled trial

Primary study design


Secondary study design

Randomised controlled trial

Trial setting


Trial type


Patient information sheet

Find out about participation section on


Acute ischaemic stroke


In each collaborating hospital, the hospital co-ordinator will implement a written protocol for the immediate assessment of patients with suspected acute stroke. Patients will be 'fast-tracked' to the computerised tomography (CT) scanner in order to exclude intracranial haemorrhage as a cause of the stroke.

Consent will be sought from those patients with definite ischaemic stroke who can be treated within six hours of onset of stroke symptoms. After appropriate consent has been granted, patients will be entered in the trial by means of a telephone call to a central computer randomisation system. At the end of the call, once the patients details have been entered on the randomisation computer, the system will allocate the treatment.

Patients allocated active treatment will receive rt-PA in a dose of 0.9 mg per kg of estimated body weight up to a maximum of 90 mg. 10% will be given as an intravenous bolus over 1 - 2 minutes and the rest of the infusion will be given over the following 60 minutes.

Patients allocated control will be managed in the same clinical environment and as carefully monitored as those allocated rt-PA.

Patients will be closely monitored to detect any adverse events. Patients will have a repeat brain scan 24 hours after randomisation. Hospital events occurring within the first week will be recorded on a seven-day form.

The main follow-up will be at six months. The six month follow-up will be performed by postal administration of a questionnaire to measure functional status and health related quality of life. If a patient, who is known to be alive, does not respond to two requests to complete a postal questionnaire, disability status will be obtained by other appropriate means, usually a telephone interview but sometimes from the patients' general practitioner.

Intervention type



Not Applicable

Drug names

Recombinant tissue plasminogen activator (rt-PA)

Primary outcome measure

Proportion of patients alive and independent at six months (Modified Rankin Scale score of 0, 1, or 2).

Secondary outcome measures

1. Events within seven days:
1.1. Deaths from any cause
1.2. Symptomatic intracranial haemorrhage (fatal or non-fatal)
1.3. Any intracranial haemorrhage (including asymptomatic bleeds on repeat computed tomography [CT])
1.4. Severe extracranial haemorrhage (i.e. fatal, severe enough to require transfusion or operation, or an absolute decrease in haemoglobin greater than 5 g/dl, or a decrease in haematocrit of greater than 15%, or bleeding associated with persistent or serious disability)
2. Status at six months:
2.1. Number of patients dead from any cause within six months
2.2. Number of patients making a complete recovery, and those who are alive but dependent (defined by the questions used in IST), Health Related Quality of Life (HRQoL), measured with the postal questionnaire version of the European quality of life (EuroQol)

Overall trial start date


Overall trial end date


Reason abandoned (if study stopped)


Participant inclusion criteria

Patients with mild, moderate or severe strokes are potentially eligible if the following criteria are met:
1. Symptoms and signs of clinically definite acute stroke
2. Time of stroke onset is known and treatment can be started within six hours of this onset
3. Computerised tomography (CT) or magnetic resonance imaging (MRI) brain scanning has reliably excluded both intracranial haemorrhage and structural brain lesions which can mimic stroke (e.g. cerebral tumour)

Participant type


Age group




Target number of participants


Participant exclusion criteria

1. The patient has previously been randomised in IST-3
2. Major surgery, trauma (e.g. major fall at time of stroke) or gastrointestinal or urinary tract haemorrhage within the previous 21 days
3. Any known defect in coagulation, e.g.:
3.1. Currently on oral anticoagulants with an International normalised ratio (INR) greater than 1.3, or
3.2. Current treatment with heparin (unless activated partial thromboplastin time [APPT] within normal laboratory limits), or
3.3. Treatment with low molecular weight heparin or heparinoid, or
3.4. Treatment with Ximelagatran
4. Known defect of clotting or plaelet function (but patients on antiplatelet agents can be randomised)
5. The patient is female and of childbearing potential (unless it is certain that pregnancy is not possible) or breastfeeding
6. Hypo- or hyperglycaemia sufficient to account for the neurological symptoms; the patient should be excluded if their blood glucose is less than 3.0 or greater than 20.0 mmol/L ('stick testing' is a sufficiently accurate test for this purpose)
7. Symptoms considered likely to resolve completely within the next few hours (i.e., a transient ischaemic attack [TIA])
8. Patient has had a stroke within the previous 14 days or has had a treatment for acute ischaemic stroke with thrombolytic therapy within the past 14 days
9. Patient was already dependent in activities of daily living before the present acute stroke
10. Patient has other life threatening illness (e.g. advanced cancer) likely to lead to death within a few months
11. Likely to be unavailable for follow-up, e.g., no fixed home address
12. Patient has blood pressure less than 90 mmHg or greater than 220 mmHg or diastolic blood pressure less than 40 mmHg or greater than 130 mmHg

Recruitment start date


Recruitment end date



Countries of recruitment

Australia, Austria, Belgium, Canada, Italy, Norway, Poland, Sweden, United Kingdom

Trial participating centre

University of Edinburgh
United Kingdom

Sponsor information


University of Edinburgh (UK)

Sponsor details

College of Medicine and Veterinary Medicine Office
Doorway 1
Medical Buildings
Teviot Place
United Kingdom

Sponsor type




Funder type


Funder name

The Health Foundation (UK) (ref: 2268/1282)

Alternative name(s)

Funding Body Type

Funding Body Subtype


Funder name

Medical Research Council (MRC)/National Institutes of Health Research (NIHR) (UK) - Efficacy and Mechanism Evaluation (EME) Programme (ref: EME 08/43/52)

Alternative name(s)

Funding Body Type

Funding Body Subtype


Funder name

Stroke Association

Alternative name(s)

Funding Body Type

private sector organisation

Funding Body Subtype

Associations and societies (private and public)


United Kingdom

Funder name

AFA Försäkring

Alternative name(s)

AFA Insurance

Funding Body Type

private sector organisation

Funding Body Subtype

For-profit companies (industry)



Funder name

Norges Forskningsråd

Alternative name(s)

Research Council of Norway, Forskningsrådet, Norwegian Research Council

Funding Body Type

government organisation

Funding Body Subtype

National government



Funder name

The Heart Foundation (Australia)

Alternative name(s)


Funding Body Type

private sector organisation

Funding Body Subtype

Trusts, charities, foundations (both publically funded and privately funded)


United States of America

Funder name

The Government of Poland (Poland)

Alternative name(s)

Funding Body Type

Funding Body Subtype


Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Basic results (scientific)

Publication list

1. 2008 validation of a prognostic model in
2. 2008 protocol in
3. 2011 update in
4. 2012 results in
5. 2013 follow-up results in
6. 2014 results in
7. 2014 results in
8. 2014 results in
9. 2014 results in
10. 2015 results in
11. 2015 results in
12. 2015 results in
13. 2015 results in
14. 2016 results in
15. 2016 results in
16. 2016 results in

Publication citations

  1. Validation of a prognostic model

    , , Lewis SC, Sandercock PA, Dennis MS, Predicting outcome in hyper-acute stroke: validation of a prognostic model in the Third International Stroke Trial (IST3)., J. Neurol. Neurosurg. Psychiatr., 2008, 79, 4, 397-400, doi: 10.1136/jnnp.2007.126045.

  2. Protocol

    Sandercock P, Lindley R, Wardlaw J, Dennis M, Lewis S, Venables G, Kobayashi A, Czlonkowska A, Berge E, Slot KB, Murray V, Peeters A, Hankey G, Matz K, Brainin M, Ricci S, Celani MG, Righetti E, Cantisani T, Gubitz G, Phillips S, Arauz A, Prasad K, Correia M, Lyrer P, , Third international stroke trial (IST-3) of thrombolysis for acute ischaemic stroke., Trials, 2008, 9, 37, doi: 10.1186/1745-6215-9-37.

  3. Update

    Sandercock P, Lindley R, Wardlaw J, Dennis M, Innes K, Cohen G, Whiteley W, Perry D, Soosay V, Buchanan D, Venables G, Czlonkowska A, Kobayashi A, Berge E, Slot KB, Murray V, Peeters A, Hankey GJ, Matz K, Brainin M, Ricci S, Cantisani TA, Gubitz G, Phillips SJ, Antonio A, Correia M, Lyrer P, Kane I, Lundstrom E, , Update on the third international stroke trial (IST-3) of thrombolysis for acute ischaemic stroke and baseline features of the 3035 patients recruited., Trials, 2011, 12, 252, doi: 10.1186/1745-6215-12-252.

  4. Results

    , Sandercock P, Wardlaw JM, Lindley RI, Dennis M, Cohen G, Murray G, Innes K, Venables G, Czlonkowska A, Kobayashi A, Ricci S, Murray V, Berge E, Slot KB, Hankey GJ, Correia M, Peeters A, Matz K, Lyrer P, Gubitz G, Phillips SJ, Arauz A, The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (the third international stroke trial [IST-3]): a randomised controlled trial., Lancet, 2012, 379, 9834, 2352-2363, doi: 10.1016/S0140-6736(12)60768-5.

  5. Results

    Whiteley WN, Thompson D, Murray G, Cohen G, Lindley RI, Wardlaw J, Sandercock P, , Targeting recombinant tissue-type plasminogen activator in acute ischemic stroke based on risk of intracranial hemorrhage or poor functional outcome: an analysis of the third international stroke trial., Stroke, 2014, 45, 4, 1000-1006, doi: 10.1161/STROKEAHA.113.004362.

  6. Results

    Mair G, von Kummer R, Adami A, White PM, Adams ME, Yan B, Demchuk AM, Farrall AJ, Sellar RJ, Ramaswamy R, Mollison D, Boyd EV, Rodrigues MA, Samji K, Baird AJ, Cohen G, Sakka E, Palmer J, Perry D, Lindley R, Sandercock PA, Wardlaw JM, , Observer reliability of CT angiography in the assessment of acute ischaemic stroke: data from the Third International Stroke Trial., Neuroradiology, 2014, doi: 10.1007/s00234-014-1441-0.

  7. Results

    Whiteley WN, Thompson D, Murray G, Cohen G, Lindley RI, Wardlaw J, Sandercock P, Effect of Alteplase Within 6 Hours of Acute Ischemic Stroke on All-Cause Mortality (Third International Stroke Trial)., Stroke, 2014, doi: 10.1161/STROKEAHA.114.006890.

  8. Effect of thrombolysis with alteplase within 6 h of acute ischaemic stroke on long-term outcomes (the third International Stroke Trial [IST-3]): 18-month follow-up of a randomised controlled trial., Lancet Neurol, 2013, 12, 8, 768-776, doi: 10.1016/S1474-4422(13)70130-3.

  9. Results

    Lindley RI, Wardlaw JM, Whiteley WN, Cohen G, Blackwell L, Murray GD, Sandercock PA; on behalf of the IST-3 Collaborative Group, Alteplase for Acute Ischemic Stroke: Outcomes by Clinically Important Subgroups in the Third International Stroke Trial, Stroke, 2015, doi: 10.1161/STROKEAHA.114.006573.

  10. Results

    Wardlaw JM, Carpenter T, Sakka E, Mair G, Cohen G, Shuler K, Palmer JM, Innes K, Sandercock PA, Imaging perfusion deficits, arterial patency and thrombolysis safety and efficacy in acute ischaemic stroke. An observational study of the effect of advanced imaging methods in The Third International Stroke Trial (IST-3), a randomised controlled trial.

  11. Results

    IST-3 collaborative group, Association between brain imaging signs, early and late outcomes, and response to intravenous alteplase after acute ischaemic stroke in the third International Stroke Trial (IST-3): secondary analysis of a randomised controlled trial, Lancet Neurol., 2015, doi: 10.1016/S1474-4422(15)00012-5.

  12. Results

    Mair G, Boyd EV, Chappell FM, von Kummer R, Lindley RI, Sandercock P, Wardlaw JM; IST-3 Collaborative Group, Sensitivity and specificity of the hyperdense artery sign for arterial obstruction in acute ischemic stroke, Stroke, 2015, 46, 1, 102-107, doi: 10.1161/STROKEAHA.114.007036.

  13. Results

    Wardlaw JM, von Kummer R, Carpenter T, Parsons M, Lindley RI, Cohen G, Murray V, Kobayashi A, Peeters A, Chappell F, Sandercock PA, Protocol for the perfusion and angiography imaging sub-study of the Third International Stroke Trial (IST-3) of alteplase treatment within six-hours of acute ischemic stroke, Int J Stroke, 2015, 10, 6, 956-968, doi: 10.1111/j.1747-4949.2012.00946.x.

  14. Results

    Berge E, Cohen G, Roaldsen MB, Lundström E, Isaksson E, Rudberg AS, Slot KB, Forbes J, Smith J, Drever J, Wardlaw JM, Lindley RI, Sandercock PA, Whiteley WN; IST-3 Collaborative Group, Effects of alteplase on survival after ischaemic stroke (IST-3): 3 year follow-up of a randomised, controlled, open-label trial, Lancet Neurol, 2016 , -S1474-4422(16)30139-9, doi: 10.1016/S1474-4422(16)30139-9.

Additional files

Editorial Notes

29/12/2016: Publication reference added. 30/11/2016: Publication reference added. 28/07/2016: Publication reference added. 05/05/2016: Publication reference added. 18/03/2016: Plain English summary added.