Condition category
Circulatory System
Date applied
29/04/2004
Date assigned
02/07/2004
Last edited
06/11/2014
Prospective/Retrospective
Prospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Not provided at time of registration

Trial website

http://www.dcn.ed.ac.uk/ist3/default.asp

Contact information

Type

Scientific

Primary contact

Prof Peter A. G. Sandercock

ORCID ID

Contact details

Department of Clinical Neurosciences
University of Edinburgh
Bramwell Dott Building
Western General Hospital
Crewe Road
Edinburgh
EH4 2XU
United Kingdom

Additional identifiers

EudraCT number

2004-000238-36

ClinicalTrials.gov 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

Acronym

IST-3

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: http://www.eme.ac.uk/projectfiles/084352info.pdf
Link to protocol: www.eme.ac.uk/projectfiles/084352protocol.pdf

Ethics approval

Not provided at time of registration

Study design

Randomised controlled trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Not specified

Trial type

Treatment

Patient information sheet

Find out about participation section on http://www.dcn.ed.ac.uk/ist3/

Condition

Acute ischaemic stroke

Intervention

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

Drug

Phase

Not Specified

Drug names

Recombinant tissue plasminogen activator (rt-PA)

Primary outcome measures

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

01/04/2005

Overall trial end date

31/03/2010

Reason abandoned

Eligibility

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

Patient

Age group

Adult

Gender

Not Specified

Target number of participants

6000

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

01/04/2005

Recruitment end date

31/03/2010

Locations

Countries of recruitment

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

Trial participating centre

Department of Clinical Neurosciences
Edinburgh
EH4 2XU
United Kingdom

Sponsor information

Organisation

University of Edinburgh (UK)

Sponsor details

College of Medicine and Veterinary Medicine Office
Doorway 1
Medical Buildings
Teviot Place
Edinburgh
EH8 9AG
United Kingdom

Sponsor type

University/education

Website

http://www.ed.ac.uk/

Funders

Funder type

Government

Funder name

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

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

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

Location

Funder name

The Stroke Association (UK)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

AFA Insurances (Sweden)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

The Norwegian Research Council (Norway)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

The Heart Foundation (Australia)

Alternative name(s)

THF

Funding Body Type

private sector organisation

Funding Body Subtype

foundation

Location

United States of America

Funder name

The Government of Poland (Poland)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

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

Results - basic reporting

Publication summary

1. 2008 validation of a prognostic model in http://www.ncbi.nlm.nih.gov/pubmed/17766429
2. 2008 protocol in http://www.ncbi.nlm.nih.gov/pubmed/18559104
3. 2011 update in http://www.ncbi.nlm.nih.gov/pubmed/22129158
4. 2012 results in http://www.ncbi.nlm.nih.gov/pubmed/22632908
5. 2013 follow-up results in: http://www.ncbi.nlm.nih.gov/pubmed/23791822
6. 2014 results in: http://www.ncbi.nlm.nih.gov/pubmed/24603072
7. 2014 results in: http://www.ncbi.nlm.nih.gov/pubmed/25287075
8. 2014 results in: http://www.ncbi.nlm.nih.gov/pubmed/25370587

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.

Additional files

Editorial Notes