Extending the Time for Thrombolysis in Emergency Neurological Deficits

NCT ID: NCT00887328

Last Updated: 2018-08-31

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE3

Total Enrollment

180 participants

Study Classification

INTERVENTIONAL

Study Start Date

2010-06-30

Study Completion Date

2018-08-27

Brief Summary

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The primary hypothesis being tested in this trial is that ischaemic stroke patients selected with significant penumbral mismatch (measured by MRI criteria) at 3 - 9 hours post onset of stroke will have improved clinical outcomes when given intravenous tissue plasminogen activator (tPA) compared to placebo.

Detailed Description

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Conditions

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Stroke

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

TRIPLE

Participants Caregivers Investigators

Study Groups

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IV tPA

intravenous tissue plasminogen activator

Group Type EXPERIMENTAL

Tissue Plasminogen Activator (Alteplase)

Intervention Type DRUG

0.9 mg/kg up to a maximum of 90mg, intravenous, 10% as bolus and the remainder over 1 hour

Placebo

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

placebo provided as 50mg lyophilised powder to be reconstituted with sterile water in glass vials indistinguishable from active drug

Interventions

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Tissue Plasminogen Activator (Alteplase)

0.9 mg/kg up to a maximum of 90mg, intravenous, 10% as bolus and the remainder over 1 hour

Intervention Type DRUG

Placebo

placebo provided as 50mg lyophilised powder to be reconstituted with sterile water in glass vials indistinguishable from active drug

Intervention Type DRUG

Other Intervention Names

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Actilyse Activase tPA r-tPA

Eligibility Criteria

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Inclusion Criteria

1. Patients presenting with hemispheric acute ischaemic stroke
2. Patient, family member or legally responsible person depending on local ethics requirements has given informed consent
3. Patient's age is ≥18 years
4. Treatment onset can commence within ≥ 3 - 9 hours after stroke onset according to registered product information, or within 4.5 - 9 hours according to locally accepted guidelines\*.

(\*Guidelines are currently under international review - advisory statement issued by the Stroke Council, American Heart Association and American Stroke Association)

Exclusion Criteria

6. NIHSS score of ≥ 4 - 26 with clinical signs of hemispheric infarction.
7. Penumbral mismatch - A "hypo-perfusion to core" volume ratio of greater than 1.2 and an absolute difference greater than 10mL (using a MR or CT Tmax \> 6 second delay) between perfusion lesion and MR-DWI or CT-CBF core lesion.
8. An ischaemic core lesion volume of less than or equal to 70 ml using MR-DWI or CT-CBF \*\* Patients may be consented before or after penumbral screening depending upon local practice. The entire cohort of patients consented onto the study will be followed up with clinical assessments and biomarker studies regardless of eligibility for randomisation to treatment based on penumbral mismatch criteria


1. Intracranial haemorrhage (ICH) identified by CT or MRI
2. Rapidly improving symptoms, particularly if in the judgment of the managing clinician that the improvement is likely to result in the patient having an NIHSS score of \< 4 at randomization
3. Pre-stroke MRS score of ≥ 2 (indicating previous disability)
4. Contra indication to imaging with MR with contrast agents
5. Infarct core \>1/3 MCA territory qualitatively
6. Participation in any investigational study in the previous 30 days
7. Any terminal illness such that patient would not be expected to survive more than 1 year
8. Any condition that could impose hazards to the patient if study therapy is initiated or affect the participation of the patient in the study (this applies to patients with severe microangiopathy such as haemolytic uremic syndrome or thrombotic thrombocytopenic purpura). The judgment is left to the discretion of the Investigator.
9. Pregnant women (clinically evident)
10. Previous stroke within last three months
11. Recent past history or clinical presentation of ICH, subarachnoid haemorrhage (SAH), arterio-venous (AV) malformation, aneurysm, or cerebral neoplasm. At the discretion of each Investigator.
12. Current use of oral anticoagulants or a prolonged prothrombin time (INR \> 1.7) if the patient is on warfarin
13. Use of heparin, except for low dose subcutaneous heparin, in the previous 48 hours and an activated prolonged partial thromboplastin time exceeding the upper limit of the local laboratory normal range.
14. Use of glycoprotein IIb - IIIa inhibitors within the past 72 hours. Use of single or dual agent oral platelet inhibitors (clopidogrel and/or low-dose aspirin) prior to study entry is permitted.
15. Clinically significant hypoglycaemia.
16. Uncontrolled hypertension defined by a blood pressure \> 185 mmHg systolic or \>110 mmHg diastolic on at least 2 separate occasions at least 10 minutes apart, or requiring aggressive treatment to reduce the blood pressure to within these limits. The definition of "aggressive treatment" is left to the discretion of the responsible Investigator.
17. Hereditary or acquired haemorrhagic diathesis
18. Gastrointestinal or urinary bleeding within the preceding 21 days
19. Major surgery within the preceding 14 days which poses risk in the opinion of the investigator.
20. Exposure to a thrombolytic agent within the previous 72 hours
21. Clinically deemed eligible for Endovascular Clot Retrieval (ECR) treatment by the treating team
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Commonwealth Scientific and Industrial Research Organisation, Australia

OTHER_GOV

Sponsor Role collaborator

University of Melbourne

OTHER

Sponsor Role collaborator

Melbourne Health

OTHER

Sponsor Role collaborator

The Florey Institute of Neuroscience and Mental Health

OTHER

Sponsor Role collaborator

Neuroscience Trials Australia

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Geoffrey Donnan, MD FRACP

Role: PRINCIPAL_INVESTIGATOR

The Florey Institute of Neuroscence and Mental Health

Stephen Davis, MD FRACP

Role: PRINCIPAL_INVESTIGATOR

University of Melbourne

Locations

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Gosford Hospital

Kanwal, New South Wales, Australia

Site Status

John Hunter Hospital

Newcastle, New South Wales, Australia

Site Status

Royal North Shore Hospital

St Leonards, New South Wales, Australia

Site Status

St. Vincent's Hospital

Sydney, New South Wales, Australia

Site Status

Westmead Hospital

Westmead, New South Wales, Australia

Site Status

Royal Brisbane & Women's Hospital

Brisbane, Queensland, Australia

Site Status

Gold Coast University Hospital

Gold Coast, Queensland, Australia

Site Status

Sunshine Coast University Hospital

Nambour, Queensland, Australia

Site Status

Royal Adelaide Hospital

Adelaide, South Australia, Australia

Site Status

Flinders Medical Centre

Bedford Park, South Australia, Australia

Site Status

Lyell McEwin Hospital

Elizabeth Vale, South Australia, Australia

Site Status

Box Hill Hospital

Box Hill, Victoria, Australia

Site Status

Monash Medical Centre

Clayton, Victoria, Australia

Site Status

Western Hospital

Footscray, Victoria, Australia

Site Status

Geelong Hospital

Geelong, Victoria, Australia

Site Status

Austin Hospital

Heidelberg, Victoria, Australia

Site Status

Royal Melbourne Hospital

Melbourne, Victoria, Australia

Site Status

Epworth Healthcare

Richmond, Victoria, Australia

Site Status

Sir Charles Gairdner Hospital

Nedlands, Western Australia, Australia

Site Status

Royal Perth Hospital

Perth, Western Australia, Australia

Site Status

Helsinki University Central Hospital

Helsinki, , Finland

Site Status

Auckland Hospital

Auckland, , New Zealand

Site Status

Countries

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Australia Finland New Zealand

References

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Bivard A, Churilov L, Ma H, Levi C, Campbell B, Yassi N, Meretoja A, Zhao H, Sharma G, Chen C, Davis S, Donnan G, Yan B, Parsons M; EXTEND investigators. Does variability in automated perfusion software outputs for acute ischemic stroke matter? Reanalysis of EXTEND perfusion imaging. CNS Neurosci Ther. 2022 Jan;28(1):139-144. doi: 10.1111/cns.13756. Epub 2021 Nov 16.

Reference Type DERIVED
PMID: 34786868 (View on PubMed)

Goodin P, Lamp G, Vidyasagar R, Connelly A, Rose S, Campbell BCV, Tse T, Ma H, Howells D, Hankey GJ, Davis S, Donnan G, Carey LM. Correlated Resting-State Functional MRI Activity of Frontostriatal, Thalamic, Temporal, and Cerebellar Brain Regions Differentiates Stroke Survivors with High Compared to Low Depressive Symptom Scores. Neural Plast. 2019 Jul 28;2019:2357107. doi: 10.1155/2019/2357107. eCollection 2019.

Reference Type DERIVED
PMID: 31467520 (View on PubMed)

Ma H, Campbell BCV, Parsons MW, Churilov L, Levi CR, Hsu C, Kleinig TJ, Wijeratne T, Curtze S, Dewey HM, Miteff F, Tsai CH, Lee JT, Phan TG, Mahant N, Sun MC, Krause M, Sturm J, Grimley R, Chen CH, Hu CJ, Wong AA, Field D, Sun Y, Barber PA, Sabet A, Jannes J, Jeng JS, Clissold B, Markus R, Lin CH, Lien LM, Bladin CF, Christensen S, Yassi N, Sharma G, Bivard A, Desmond PM, Yan B, Mitchell PJ, Thijs V, Carey L, Meretoja A, Davis SM, Donnan GA; EXTEND Investigators. Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke. N Engl J Med. 2019 May 9;380(19):1795-1803. doi: 10.1056/NEJMoa1813046.

Reference Type DERIVED
PMID: 31067369 (View on PubMed)

Churilov L, Ma H, Campbell BC, Davis SM, Donnan GA. Statistical Analysis Plan for EXtending the time for Thrombolysis in Emergency Neurological Deficits (EXTEND) trial. Int J Stroke. 2020 Feb;15(2):231-238. doi: 10.1177/1747493018816101. Epub 2018 Dec 7.

Reference Type DERIVED
PMID: 30523735 (View on PubMed)

Tse T, Binte Yusoff SZ, Churilov L, Ma H, Davis S, Donnan GA, Carey LM; START research team. Increased work and social engagement is associated with increased stroke specific quality of life in stroke survivors at 3 months and 12 months post-stroke: a longitudinal study of an Australian stroke cohort. Top Stroke Rehabil. 2017 Sep;24(6):405-414. doi: 10.1080/10749357.2017.1318339. Epub 2017 Apr 24.

Reference Type DERIVED
PMID: 28438076 (View on PubMed)

Other Identifiers

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NTA0901

Identifier Type: -

Identifier Source: org_study_id

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