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| The Third International Stroke Trial (IST-3) of thrombolysis for acute ischaemic stroke: an international multi-centre, 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 |
| ISRCTN | ISRCTN25765518 |
| ClinicalTrials.gov identifier | |
| Public title | The Third International Stroke Trial (IST-3) of thrombolysis for acute ischaemic stroke: an international multi-centre, 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 |
| Scientific title | |
| Acronym | IST-3 |
| Serial number at source | IST399 |
| 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? |
| Ethics approval | Not provided at time of registration |
| Study design | Randomised controlled trial |
| Countries of recruitment | United Kingdom, Australia, Italy, Norway, Sweden, Poland, Canada, Austria, Belgium |
| Disease/condition/study domain | Acute ischaemic stroke |
| Participants - 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) |
| Participants - 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 |
| Anticipated start date | 01/04/2005 |
| Anticipated end date | 31/03/2010 |
| Status of trial | Ongoing |
| Patient information material | |
| Target number of participants | 6000 |
| Interventions |
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. |
| Primary outcome measure(s) | Proportion of patients alive and independent at six months (Modified Rankin Scale score of 0, 1, or 2). |
| Secondary outcome measure(s) |
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) |
| Sources of funding |
1. The Health Foundation (UK) (ref: 2268/1282)
The trial is also supported by grants from the following organisations: 2. Medical Research Council (MRC) (UK) 3. The Stroke Association (UK) 4. AFA Insurances (Sweden) 5. The Norwegian Research Council (Norway) 6. The Heart Foundation (Australia) 7. The Government of Poland (Poland) |
| Trial website | http://www.dcn.ed.ac.uk/ist3/ |
| Publications | Results in http://www.ncbi.nlm.nih.gov/pubmed/17766429 |
| Contact name | Prof Peter A. G. Sandercock |
| Address |
Department of Clinical Neurosciences
University of Edinburgh Bramwell Dott Building Western General Hospital Crewe Road |
| City/town | Edinburgh |
| Zip/Postcode | EH4 2XU |
| Country | United Kingdom |
| Sponsor | University of Edinburgh (UK) |
| Address |
College of Medicine and Veterinary Medicine Office
Doorway 1 Medical Buildings Teviot Place |
| City/town | Edinburgh |
| Zip/Postcode | EH8 9AG |
| Country | United Kingdom |
| Sponsor website: | http://www.ed.ac.uk/ |
| Date applied | 29/04/2004 |
| Last edited | 18/03/2008 |
| Date ISRCTN assigned | 02/07/2004 |
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