Extending the Time for Thrombolysis in Emergency Neurological Deficits

NCT00887328 | Completed Phase 3 DMC

• 1 other identifier: NTA0901
• Study Type: interventional
• Target: 180
• Locations: 3 countries
• Sites: 22

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.

Conditions

Stroke

Keywords

ischemic stroke; ischemic penumbra; magnetic resonance imaging; MRI; diffusion imaging; DWI; perfusion imaging; PWI; thrombolysis; alteplase; tPA; EPITHET

Outcome Measures

Primary Outcomes (1)

• Modified Rankin Scale (mRS) 0-1

  3 months

Secondary Outcomes (10)

• Categorical shift in modified Rankin Score (mRS)

  3 months

• Change in ≥ 8 NIHSS points or reaching ≤ 1 on this scale

  3 months

• Death due to any cause

  3 months

• Symptomatic ICH

  24 hours

• Reperfusion

  24 hours

Study Arms (2)

IV tPA

EXPERIMENTAL

intravenous tissue plasminogen activator

Drug: Tissue Plasminogen Activator (Alteplase)

Placebo

PLACEBO COMPARATOR

Drug: Placebo

Interventions

Tissue Plasminogen Activator (Alteplase) DRUG

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

Also known as: Actilyse, Activase, tPA, r-tPA

IV tPA

Placebo DRUG

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

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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)

You may not qualify if:

• 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 MR or CT Tmax \> 6 second delay) between perfusion lesion and MR-DWI or CT-CBF core lesion.
• 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
• 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 MR with contrast agents
• Infarct core \>1/3 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

Sponsors & Collaborators

• Neuroscience Trials Australia: lead
• Commonwealth Scientific and Industrial Research Organisation, Australia: collaborator
• University of Melbourne: collaborator
• Melbourne Health: collaborator
• The Florey Institute of Neuroscience and Mental Health: collaborator

Study Sites (22)

Gosford Hospital

Kanwal, New South Wales, 2259, Australia

Location

John Hunter Hospital

Newcastle, New South Wales, Australia

Location

Royal North Shore Hospital

St Leonards, New South Wales, 2065, Australia

Location

St. Vincent's Hospital

Sydney, New South Wales, 6009, Australia

Location

Westmead Hospital

Westmead, New South Wales, 2145, Australia

Location

Royal Brisbane & Women's Hospital

Brisbane, Queensland, 4029, Australia

Location

Gold Coast University Hospital

Gold Coast, Queensland, Australia

Location

Sunshine Coast University Hospital

Nambour, Queensland, 4560, Australia

Location

Royal Adelaide Hospital

Adelaide, South Australia, 5000, Australia

Location

Flinders Medical Centre

Bedford Park, South Australia, 5042, Australia

Location

Lyell McEwin Hospital

Elizabeth Vale, South Australia, 5112, Australia

Location

Box Hill Hospital

Box Hill, Victoria, 3128, Australia

Location

Monash Medical Centre

Clayton, Victoria, 3168, Australia

Location

Western Hospital

Footscray, Victoria, 3011, Australia

Location

Geelong Hospital

Geelong, Victoria, 3220, Australia

Location

Austin Hospital

Heidelberg, Victoria, Australia

Location

Royal Melbourne Hospital

Melbourne, Victoria, 3050, Australia

Location

Epworth Healthcare

Richmond, Victoria, 3121, Australia

Location

Sir Charles Gairdner Hospital

Nedlands, Western Australia, 6009, Australia

Location

Royal Perth Hospital

Perth, Western Australia, 6000, Australia

Location

Helsinki University Central Hospital

Helsinki, Finland

Location

Auckland Hospital

Auckland, 1001, New Zealand

Location

Related Publications (5)

• 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.

  PMID: 34786868 DERIVED

• 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.

  PMID: 31467520 DERIVED

• 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.

  PMID: 31067369 DERIVED

• 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.

  PMID: 30523735 DERIVED

• 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.

  PMID: 28438076 DERIVED

MeSH Terms

Conditions

Stroke; Ischemic Stroke

Interventions

Tissue Plasminogen Activator

Condition Hierarchy (Ancestors)

Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Serine Endopeptidases; Endopeptidases; Peptide Hydrolases; Hydrolases; Enzymes; Enzymes and Coenzymes; Serine Proteases; Plasminogen Activators; Blood Coagulation Factors; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Biological Factors

Study Officials

• Geoffrey Donnan, MD FRACP

  The Florey Institute of Neuroscence and Mental Health

  PRINCIPAL INVESTIGATOR

• Stephen Davis, MD FRACP

  University of Melbourne

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 22, 2009
• First Posted: April 23, 2009
• Study Start: June 1, 2010
• Primary Completion: August 27, 2018
• Study Completion: August 27, 2018
• Last Updated: August 31, 2018

Record last verified: 2018-08

Locations

AU (20); NZ (1); FI (1)