Third International Stroke Trial: IST-3

Lead Research Organisation: University of Edinburgh
Department Name: Sch of Molecular. Genetics & Pop Health

Abstract

Strokes are a major cause of disability. Most strokes are due a blood clot blocking an artery in the brain. We know that the ?clot busting? drug rt-PA, given to a person with a stroke within the first 2 or 3 hours of start of the symptoms, can improve their chances of both being alive and not being disabled from the stroke.
But, we know much less about the benefits in older people and in people who only get to hospital more than 3 hours after the symptoms began.
To find out if more patients with stroke could benefit from this treatment, we are a performing a clinical trial. It will involve several thousand people from around the world. Patients who recognise that their symptoms could be a stroke and get to hospital quickly enough will be asked to help with the study.
If the study establishes that a wider variety of patients can be treated, millions of people with stroke worldwide could benefit.

Technical Summary

IST-3 is an international, multi-centre, randomised, controlled trial of iv rt-PA (0.9 mg/kg) within 6 hours of onset of acute ischaemic stroke. All potential patients must be assessed and have brain imaging without delay. CT scanning is the prime imaging modality, but CT perfusion/ CT angiography, MRI DWI/PWI/angiography and transcranial doppler can be used as additional selection criteria in centres which participate in the IST3 imaging substudy. Patients who meet clinical and brain imaging criteria are entered by means of a telephone call to a fast centralised computer system which records baseline data, balances on key prognostic factors and allocates treatment. Follow-up is conducted by postal or telephone questionnaire, independently of the clinician treating the patient. The primary measure of outcome is the proportion of patients who are dead or dependent at six months (poor functional outcome). The trial involves innovative methods to make a large scale trial feasible. The web-based CT reading tool developed in the start-up phase is already being applied in several other imaging research projects. The trial builds on our NHS HTA formal economic modelling exercise and will provide reliable evidence on the place of this controversial treatment in routine clinical practice in the NHS (and other publicly funded Health Services). The trial will also provide important - and much needed - randomised trial data on the balance of risk and benefit of this treatment in older people, who have been deliberately excluded from earlier trials of thrombolysis.

Publications

10 25 50

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Arauz A (2014) Third International Stroke Trial 3: an update. in Current opinion in neurology

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Arba F (2017) Cerebral White Matter Hypoperfusion Increases with Small-Vessel Disease Burden. Data From the Third International Stroke Trial. in Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association

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Bembenek J (2010) How many patients might receive thrombolytic therapy in the light of the ECASS-3 and IST-3 data? in International journal of stroke : official journal of the International Stroke Society

 
Guideline Title UK intercollegiate Guideline on stroke
Description Change to National Guideline for stroke
Geographic Reach Europe 
Policy Influence Type Citation in clinical guidelines
Impact Greater use of thrombolysis in the elderly
URL https://www.rcplondon.ac.uk/guidelines-policy/stroke-guidelines
 
Description MHRA expert review of alteplase for stroke
Geographic Reach Europe 
Policy Influence Type Citation in other policy documents
Impact In view of concerns expressed about the integrity of the trial data and the safety of treatment the MHRA undertook a review of the market authorisation for the use of alteplase for the treatment of acute ischaemic stroke. The review included careful review of the IST-3 data and the the MHRA requested additional analyses from the IST-3 group. As a result of this review, the MHRA saw no reason to modify the market authorisation, except that - in the light of the IST3 results showing benefit in this age category - it made a strong recommendation to the Market Authorisation Holder, Boehringer Ingelheim, to submit an application to remove the current contraindication of age > 80 years on the authorisation. This will be of benefit to elderly patients presenting with stroke worldwide.
URL https://www.gov.uk/government/publications/alteplase-for-treatment-of-acute-ischaemic-stroke-indepen...
 
Description Chest Heart and Stroke Small Grants
Amount £4,041 (GBP)
Organisation Chest Heart & Stroke Scotland 
Sector Charity/Non Profit
Country United Kingdom
Start 11/2015 
End 10/2016
 
Description Efficacy and Mechanism Evaluation Programme
Amount £264,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2009 
End 08/2012
 
Description TSA Edith Murphy Foundation Senior Clinical Lectureship for Medical Professionals: "Realising the full potential of routinely-available brain imaging to improve treatment of patients with acute stroke."
Amount £234,841 (GBP)
Funding ID SAL-SMP18/1000 
Organisation Stroke Association 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2018 
End 04/2023
 
Title IST-3 dataset 
Description The IST-3 trial is a large-scale randomised controlled trial of intravenous thrombolytic therapy with the drug Alteplase. The dataset comprises a number of files describing the IST-3 dataset, and information about how to apply to the study investigators for access to the raw patient-level data. 
Type Of Material Database/Collection of data 
Year Produced 2012 
Provided To Others? Yes  
Impact the publications of the STTC (see publication list), with impact on MHRA review of market authorisation for stroke, and on international stroke guidelines 
URL http://datashare.is.ed.ac.uk/
 
Description CT scan reading and machine learning 
Organisation Imperial College London
Department Imperial College Trust
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Enabled team from Imperial to have access to IST-3 scan files in DICOM format to permit analysis by machine learning algorithm.
Collaborator Contribution Technician to do the work and validate the algorithm. This collaboration helps build our skills in curating and sharing image repositories and in automated analysis of brain scans
Impact none yet
Start Year 2013
 
Description IST-3 UK, Norway and Sweden long-term survival study 
Organisation Karolinska University Hospital
Country Sweden 
Sector Hospitals 
PI Contribution Set up an ran the IST-3 trial, support to recruit and perform early follow-up in these 3 countries
Collaborator Contribution Continuing follow-up and collection of resource use data
Impact none
 
Description IST-3 UK, Norway and Sweden long-term survival study 
Organisation National University of Ireland, Galway
Country Ireland 
Sector Academic/University 
PI Contribution Set up an ran the IST-3 trial, support to recruit and perform early follow-up in these 3 countries
Collaborator Contribution Continuing follow-up and collection of resource use data
Impact none
 
Description IST-3 UK, Norway and Sweden long-term survival study 
Organisation Oslo University Hospital
Country Norway 
Sector Academic/University 
PI Contribution Set up an ran the IST-3 trial, support to recruit and perform early follow-up in these 3 countries
Collaborator Contribution Continuing follow-up and collection of resource use data
Impact none
 
Description IST-3 UK, Norway and Sweden long-term survival study 
Organisation University of Oxford
Department Health Economics Research Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution Set up an ran the IST-3 trial, support to recruit and perform early follow-up in these 3 countries
Collaborator Contribution Continuing follow-up and collection of resource use data
Impact none
 
Description MRC Neurogrid 
Organisation Boehringer Ingelheim
Country Germany 
Sector Private 
PI Contribution We provided stroke image data and developed the stroke ontology
Impact Publications and demonstration meetings meetings 18705995
Start Year 2006
 
Description MRC Neurogrid 
Organisation University of Oxford
Department Department of Psychiatry
Country United Kingdom 
Sector Academic/University 
PI Contribution Developed ontology for stroke CT and MR scan meta data (paper under review). Developed image viewing/searching tool for large image datasets. Gained substantial experience of differences between stroke, psychosis, dementia in terms of metadata and image analysis and image data management requirements.
Collaborator Contribution Ontology for stroke Intellectual imput to clarify stroke lesions in scans Stroke multicentre trial scan management
Impact IST-3 image data management improved. Ontology being used for multicentre/multinational image collaboration in stroke perfusion imaging (STIR) for which funding being sought. Ontology being used in SINAPSE/IST-3 collaboration image data reporting. Ontology will be used as framework for archiving IST3 trial clinical, imaging data and other relevant meta-data and facilitate open access to the trial dataset once the main analyses are published 18705995
 
Description PRISMS trial group 
Organisation University of Cincinnati
Country United States 
Sector Academic/University 
PI Contribution Data shared to allow planning of a new trial
Collaborator Contribution Publication of papers making use of the data we provided
Impact Publication to date listed under publications
Start Year 2013
 
Description Stroke Thrombolysis Trialists Collaboration 
Organisation Boehringer Ingelheim
Country Germany 
Sector Private 
PI Contribution We have contributed a subset of the IST-3 trial data
Collaborator Contribution Vacsular Overviews Group, University of Oxford provided statistical and data mangement and administrative support. Boehringer Ingelheim provided data from each of thier trials of rt-PA fro stroke
Impact publications planned for 2013
Start Year 2012
 
Description Stroke Thrombolysis Trialists Collaboration 
Organisation Medical Research Council (MRC)
Department MRC/Cancer Research UK/BHF Clinical Trial Service Unit & Epidemiological Studies Unit
Country United Kingdom 
Sector Public 
PI Contribution We have contributed a subset of the IST-3 trial data
Collaborator Contribution Vacsular Overviews Group, University of Oxford provided statistical and data mangement and administrative support. Boehringer Ingelheim provided data from each of thier trials of rt-PA fro stroke
Impact publications planned for 2013
Start Year 2012
 
Description TEMPO-2 
Organisation University of Calgary
Department Division of Neurology
Country Canada 
Sector Academic/University 
PI Contribution We shared IST-3 data to enable planning of a new trial in mild stroke
Collaborator Contribution Made a platform presentation and published an abstract of the analyses, cited the results in the the TEMPO-2 trial protocol
Impact Conference platform presentation 2014 and associated published abstract (see publications)
Start Year 2013
 
Title Alteplase for acute ischaemic stroke 
Description Alteplase now has a market authorisation for acute ischaemic stroke. The trial has established that it is safe and effective used outside the current approval. Mortality follow-up continues, funded by a small internal research fund 
Type Therapeutic Intervention - Drug
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2012
Development Status Closed
Clinical Trial? Yes
Impact Change in stroke guidelines in UK, USA, Europe, Korea and Aiustralia 
URL http://www.dcn.ed.ac.uk/ist3/
 
Title alteplase for mild ischaemic stroke 
Description PRISMS Clinical trial in USA underway, funded by Genetech 
Type Therapeutic Intervention - Drug
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2015
Development Status Under active development/distribution
Clinical Trial? Yes
Impact data sharing enabled a new clinical trial to be funded 
 
Description MHRA review of market authorisation for alteplase 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Presentation of IST-e3 results to the expert panel convened by MHRA
Year(s) Of Engagement Activity 2016
URL https://www.gov.uk/government/publications/alteplase-for-treatment-of-acute-ischaemic-stroke-indepen...
 
Description Prof Joanna Wardlaw feature in Health Matters magazine 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact A feature in Health Matters magazine, Winter 2018-2019 issue, P 24-25. Wardlaw, JM. "MRI scans of the brain".
Year(s) Of Engagement Activity 2019
 
Description Prof Joanna Wardlaw lecture "Brain Health: a small matter of the blood vessels" in Edinburgh, UK. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Edinburgh Neuroscience Public Christmas Lecture 2018
Year(s) Of Engagement Activity 2018
 
Description Prof Joanna Wardlaw lecture "Neuroimaging in acute ischaemic stroke: history, current and future" in Stockholm, Sweden. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Prof Joanna Wardlaw gave a special lecture on "Neuroimaging in acute ischaemic stroke: history, current and future" at the ESO-Karolinska Stroke Update Conference in Stockholm, Sweden on November 12, 2018.
Year(s) Of Engagement Activity 2018
 
Description Prof Joanna Wardlaw lecture "Where next for stroke research?" in Edinburgh, UK 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact 6th Edinburgh Stroke Winter School, 18th-20th February 2019.
Year(s) Of Engagement Activity 2019
 
Description Royal College of Physicians 'Women in medicine: a celebration' project 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Royal College of Physicians (RCP)'s 'Women in medicine: a celebration' project is a free exhibition of specially commissioned photographic portraits to honour contemporary and historical women in medicine. The project showcased a number of today's leading female clinicians and the women from the history of medicine who have inspired them. Prof Joanna Wardlaw is featured in the project alongside someone who inspired her, Marie Sklodowska Curie: https://www.rcplondon.ac.uk/projects/outputs/women-medicine-joanna-wardlaw-and-marie-curie
Year(s) Of Engagement Activity 2017
URL https://www.rcplondon.ac.uk/events/women-medicine-celebration
 
Description Stroke Research Network Meetings 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact As part of the Stroke Research Network Porfolio of trials IST-3 has been presented at all Stroke Research Network Meetings in the UK.

This has raised the profile of the trial in the UK and helped to raise awareness of thrombolysis as a treatment for stroke and raise awareness of the trial to a much wider audience (Chest, Heart & Stroke, Stroke Association) and members of the public. This has resulted in the UK providing the majority of recruitment into the trial to date.
Year(s) Of Engagement Activity 2008,2009,2010