Clinical trial NCT00887328: Extending the Time for Thrombolysis in Emergency Neurological Deficits
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: Commonwealth Scientific and Industrial Research Organisation, Australia
name: University of Melbourne
name: Melbourne Health
name: The Florey Institute of Neuroscience and Mental Health
First posted: 2009-04-23
Enrollment: 180
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 (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.


Eligibility criteria: 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)
5. 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.
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

Exclusion 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

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 NIHSS points or reaching ≤ 1 on this scale
timeFrame: 3 months
measure: Death due to any cause
timeFrame: 3 months
measure: Symptomatic 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
measure: Depression (Montgomery-Asberg Depression Rating Scale [MADRS])
timeFrame: 3 and 12 months
measure: Quality of life (Stroke Impact Scale)
timeFrame: 3 and 12 months
Other outcomes:
Locations:
city: Kanwal
country: Australia
facility: Gosford Hospital
state: New South Wales
city: Newcastle
country: Australia
facility: John Hunter Hospital
state: New South Wales
city: St. Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Sydney
country: Australia
facility: St. Vincent's Hospital
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: Brisbane
country: Australia
facility: Royal Brisbane & Women's Hospital
state: Queensland
city: Gold Coast
country: Australia
facility: Gold Coast University Hospital
state: Queensland
city: Nambour
country: Australia
facility: Sunshine Coast University Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Bedford Park
country: Australia
facility: Flinders Medical Centre
state: South Australia
city: Elizabeth Vale
country: Australia
facility: Lyell McEwin Hospital
state: South Australia
city: Box Hill
country: Australia
facility: Box Hill Hospital
state: Victoria
city: Clayton
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Footscray
country: Australia
facility: Western Hospital
state: Victoria
city: Geelong
country: Australia
facility: Geelong Hospital
state: Victoria
city: Heidelberg
country: Australia
facility: Austin Hospital
state: Victoria
city: Melbourne
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Richmond
country: Australia
facility: Epworth Healthcare
state: Victoria
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital
state: Western Australia
city: Perth
country: Australia
facility: Royal Perth Hospital
state: Western Australia
city: Helsinki
country: Finland
facility: Helsinki University Central Hospital
city: Auckland
country: New Zealand
facility: Auckland Hospital
Study officials:
affiliation: The Florey Institute of Neuroscence 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: 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.
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.
citation: 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.