Clinical trial NCT01580839: EXTEND (International): Extending the Time for Thrombolysis in Emergency Neurological Deficits (International)
Official title: Extending the Time for Thrombolysis in Emergency Neurological Deficits
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Stroke
Keywords: ischemic stroke
ischemic penumbra
magnetic resonance imaging
MRI
diffusion imaging
DWI
perfusion imaging
PWI
thrombolysis
alteplase
tPA
EPITHET
Lead sponsor: Neuroscience Trials Australia
Sponsor class: OTHER
Collaborators: name: China Medical University Hospital
First posted: 2012-04-19
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary hypothesis being tested in this trial is that ischaemic stroke patients selected with significant penumbral mismatch (according to imaging criteria) at 4.5 (or 3 hours depending on local guidelines) - 9 hours post onset of stroke or after 'wake up stroke' (WUS) will have improved clinical outcomes when given intravenous tissue plasminogen activator (tPA) compared to placebo.


Eligibility criteria: Inclusion Criteria:

* Patients presenting with hemispheric acute ischaemic stroke
* Patient, family member or legally responsible person depending on local ethics requirements has given informed consent
* Patient's age is ≥18 years (or as per local requirements)
* Treatment onset can commence within 4.5 - 9 hours after stroke onset according to registered product information, or within 3 - 9 hours according to locally accepted guidelines.
* Patients who wake with stroke may be included if neurological and other exclusion criteria are satisfied. These 'wake up' strokes are defined as having no symptoms at sleep onset, but stroke symptoms on waking. The time of stroke onset is to be taken as the mid-point between sleep onset (or last known to be normal) and time of waking. The maximum time window for randomisation is then 9 hours from the mid-point as described.
* Significant neurological deficit (eg. NIHSS score of ≥ 4 - 26) with clinical signs of hemispheric infarction.
* Penumbral mismatch - A "hypo-perfusion to core" volume ratio of greater than 1.2, and an absolute difference greater than 10ml (using a Magnetic Resonance (MR) or Computed Tomography (CT) Tmax \> 6 second delay), between perfusion lesion and MR-DWI or Computed Tomography-Cerebral Blood Flow (CT-CBF) core lesion.
* An infarct core lesion of less than or equal to 70ml using MR-DWI or CT-CBF

Exclusion Criteria:

* Intracranial haemorrhage (ICH) identified by CT or MRI
* 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
* Pre-stroke MRS score of ≥ 2 (indicating previous disability)
* Contra indication to imaging with contrast agents
* Infarct core \>1/3 Middle Cerebral Artery (MCA) territory qualitatively
* Participation in any investigational study in the previous 30 days
* Any terminal illness such that patient would not be expected to survive more than 1 year
* 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.
* Pregnant women (clinically evident)
* Previous stroke within last three months
* 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.
* Current use of oral anticoagulants or a prolonged prothrombin time (INR \> 1.7) if the patient is on warfarin
* Use of heparin, except for low dose subcutaneous heparin, in the previous 48 hours and a prolonged activated thromboplastin time exceeding the upper limit of the local laboratory normal range.
* 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.
* Clinically significant hypoglycaemia.
* 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.
* Hereditary or acquired haemorrhagic diathesis
* Gastrointestinal or urinary bleeding within the preceding 21 days
* Major surgery within the preceding 14 days which poses risk in the opinion of the investigator.
* Exposure to a thrombolytic agent within the previous 72 hours
* Clinically deemed eligible for Endovascular Clot Retrieval (ECR) treatment by the treating team

Primary outcomes:
measure: Modified Rankin Scale (mRS) 0-1
timeFrame: 3 months
Secondary outcomes:
measure: Categorical shift in modified Rankin Score (mRS)
timeFrame: 3 months
measure: Change in ≥ 8 National Institutes of Health Stroke Scale (NIHSS) points or reaching ≤ 1 on this scale
timeFrame: 3 months
measure: Death due to any cause
timeFrame: 3 months
measure: Symptomatic Intracerebral Hemorrhage (ICH)
timeFrame: 24 hours
measure: Reperfusion
timeFrame: 24 hours
measure: Recanalisation
timeFrame: 24 hours
measure: Infarct growth
timeFrame: 24 hours
measure: Recurrent stroke
timeFrame: 3 and 12 months
Other outcomes:
Locations:
city: Taichung
country: Taiwan
facility: China Medical University Hospital
Study officials:
affiliation: The Florey Institute of Neuroscience and Mental Health
name: Geoffrey Donnan, MD FRACP
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Melbourne
name: Stephen Davis, MD FRACP
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.