Extending the Time for Thrombolysis in Emergency Neurological Deficits

Stroke Clinical Trial

— EXTEND  

Official title:

Extending the Time for Thrombolysis in Emergency Neurological Deficits

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00887328
• Other study ID #: NTA0901
• Status: Completed
• Phase: Phase 3
• Start date: June 2010
• Est. completion date: August 27, 2018

Study information

• Verified date: August 2018
• Source: Neuroscience Trials Australia
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 180
• Est. completion date: August 27, 2018
• Est. primary completion date: August 27, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Emergencies
• Stroke

Intervention

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

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	Flinders Medical Centre	Bedford Park	South Australia
Australia	Box Hill Hospital	Box Hill	Victoria
Australia	Royal Brisbane & Women's Hospital	Brisbane	Queensland
Australia	Monash Medical Centre	Clayton	Victoria
Australia	Lyell McEwin Hospital	Elizabeth Vale	South Australia
Australia	Western Hospital	Footscray	Victoria
Australia	Geelong Hospital	Geelong	Victoria
Australia	Gold Coast University Hospital	Gold Coast	Queensland
Australia	Austin Hospital	Heidelberg	Victoria
Australia	Gosford Hospital	Kanwal	New South Wales
Australia	Royal Melbourne Hospital	Melbourne	Victoria
Australia	Sunshine Coast University Hospital	Nambour	Queensland
Australia	Sir Charles Gairdner Hospital	Nedlands	Western Australia
Australia	John Hunter Hospital	Newcastle	New South Wales
Australia	Royal Perth Hospital	Perth	Western Australia
Australia	Epworth Healthcare	Richmond	Victoria
Australia	Royal North Shore Hospital	St. Leonards	New South Wales
Australia	St. Vincent's Hospital	Sydney	New South Wales
Australia	Westmead Hospital	Westmead	New South Wales
Finland	Helsinki University Central Hospital	Helsinki
New Zealand	Auckland Hospital	Auckland

Sponsors (5)

Lead Sponsor	Collaborator
Neuroscience Trials Australia	Commonwealth Scientific and Industrial Research Organisation, Australia, Melbourne Health, The Florey Institute of Neuroscience and Mental Health, University of Melbourne

Countries where clinical trial is conducted

Australia,  Finland,  New Zealand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Modified Rankin Scale (mRS) 0-1		3 months
Secondary	Categorical shift in modified Rankin Score (mRS)		3 months
Secondary	Change in = 8 NIHSS points or reaching = 1 on this scale		3 months
Secondary	Death due to any cause		3 months
Secondary	Symptomatic ICH	Symptomatic hemorrhage defined by SITS-MOST criteria: type 2 parenchymal hematoma associated with =4 point increase in NIHSS	24 hours
Secondary	Reperfusion		24 hours
Secondary	Recanalisation		24 hours
Secondary	Infarct growth	Difference in volumetric DWI volume between baseline and 24 hour MRI	24 hours
Secondary	Recurrent stroke		3 and 12 months
Secondary	Depression (Montgomery-Asberg Depression Rating Scale [MADRS])		3 and 12 months
Secondary	Quality of life (Stroke Impact Scale)		3 and 12 months

External Links

•   National Stroke Research Institute