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Extending the Time for Thrombolysis in Emergency Neurological Deficits (EXTEND)

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ClinicalTrials.gov Identifier: NCT00887328
Recruitment Status : Completed
First Posted : April 23, 2009
Last Update Posted : August 31, 2018
Commonwealth Scientific and Industrial Research Organisation, Australia
University of Melbourne
Melbourne Health
The Florey Institute of Neuroscience and Mental Health
Information provided by (Responsible Party):
Neuroscience Trials Australia

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.

Condition or disease Intervention/treatment Phase
Stroke Drug: Tissue Plasminogen Activator (Alteplase) Drug: Placebo Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 180 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Extending the Time for Thrombolysis in Emergency Neurological Deficits
Study Start Date : June 2010
Actual Primary Completion Date : August 27, 2018
Actual Study Completion Date : August 27, 2018

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: IV tPA
intravenous tissue plasminogen activator
Drug: Tissue Plasminogen Activator (Alteplase)
0.9 mg/kg up to a maximum of 90mg, intravenous, 10% as bolus and the remainder over 1 hour
Other Names:
  • Actilyse
  • Activase
  • tPA
  • r-tPA

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

Primary Outcome Measures :
  1. Modified Rankin Scale (mRS) 0-1 [ Time Frame: 3 months ]

Secondary Outcome Measures :
  1. Categorical shift in modified Rankin Score (mRS) [ Time Frame: 3 months ]
  2. Change in ≥ 8 NIHSS points or reaching ≤ 1 on this scale [ Time Frame: 3 months ]
  3. Death due to any cause [ Time Frame: 3 months ]
  4. Symptomatic ICH [ Time Frame: 24 hours ]
    Symptomatic hemorrhage defined by SITS-MOST criteria: type 2 parenchymal hematoma associated with ≥4 point increase in NIHSS

  5. Reperfusion [ Time Frame: 24 hours ]
  6. Recanalisation [ Time Frame: 24 hours ]
  7. Infarct growth [ Time Frame: 24 hours ]
    Difference in volumetric DWI volume between baseline and 24 hour MRI

  8. Recurrent stroke [ Time Frame: 3 and 12 months ]
  9. Depression (Montgomery-Asberg Depression Rating Scale [MADRS]) [ Time Frame: 3 and 12 months ]
  10. Quality of life (Stroke Impact Scale) [ Time Frame: 3 and 12 months ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00887328

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Sponsors and Collaborators
Neuroscience Trials Australia
Commonwealth Scientific and Industrial Research Organisation, Australia
University of Melbourne
Melbourne Health
The Florey Institute of Neuroscience and Mental Health
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Principal Investigator: Geoffrey Donnan, MD FRACP The Florey Institute of Neuroscence and Mental Health
Principal Investigator: Stephen Davis, MD FRACP University of Melbourne
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Neuroscience Trials Australia
ClinicalTrials.gov Identifier: NCT00887328    
Other Study ID Numbers: NTA0901
First Posted: April 23, 2009    Key Record Dates
Last Update Posted: August 31, 2018
Last Verified: August 2018
Keywords provided by Neuroscience Trials Australia:
ischemic stroke
ischemic penumbra
magnetic resonance imaging
diffusion imaging
perfusion imaging
Additional relevant MeSH terms:
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Disease Attributes
Pathologic Processes
Tissue Plasminogen Activator
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action