Extending the Time for Thrombolysis in Emergency Neurological Deficits

Phase 3

Completed

• Conditions: Stroke
• Interventions: Drug: Tissue Plasminogen Activator (Alteplase); Drug: Placebo

• Registration Number: NCT00887328
• Lead Sponsor: 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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2009-04-22
• Study First Submitted QC: 2009-04-22
• Study First Posted: 2009-04-23
• Study Start: 2010-06
• Status Verified: 2018-08
• Primary Completion: 2018-08-27
• Study Completion: 2018-08-27
• Last Update Submitted: 2018-08-30
• Last Update Posted: 2018-08-31

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 180

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
IV tPA	Tissue Plasminogen Activator (Alteplase)	intravenous tissue plasminogen activator
Placebo	Placebo	-

Primary Outcome Measures

Name	Time	Method
Modified Rankin Scale (mRS) 0-1	3 months

Secondary Outcome Measures

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

Trial Locations

Locations (22)

Lyell McEwin Hospital; 🇦🇺 Elizabeth Vale, South Australia, Australia

St. Vincent's Hospital; 🇦🇺 Sydney, New South Wales, Australia

Royal Adelaide Hospital; 🇦🇺 Adelaide, South Australia, Australia

Sir Charles Gairdner Hospital; 🇦🇺 Nedlands, Western Australia, Australia

Royal Melbourne Hospital; 🇦🇺 Melbourne, Victoria, Australia

Helsinki University Central Hospital; 🇫🇮 Helsinki, Finland

Epworth Healthcare; 🇦🇺 Richmond, Victoria, Australia

Box Hill Hospital; 🇦🇺 Box Hill, Victoria, Australia

Monash Medical Centre; 🇦🇺 Clayton, Victoria, Australia

Western Hospital; 🇦🇺 Footscray, Victoria, Australia

Geelong Hospital; 🇦🇺 Geelong, Victoria, Australia

Royal North Shore Hospital; 🇦🇺 St. Leonards, New South Wales, Australia

Gosford Hospital; 🇦🇺 Kanwal, New South Wales, Australia

John Hunter Hospital; 🇦🇺 Newcastle, New South Wales, Australia

Royal Brisbane & Women's Hospital; 🇦🇺 Brisbane, Queensland, Australia

Flinders Medical Centre; 🇦🇺 Bedford Park, South Australia, Australia

Westmead Hospital; 🇦🇺 Westmead, New South Wales, Australia

Gold Coast University Hospital; 🇦🇺 Gold Coast, Queensland, Australia

Austin Hospital; 🇦🇺 Heidelberg, Victoria, Australia

Royal Perth Hospital; 🇦🇺 Perth, Western Australia, Australia

Auckland Hospital; 🇳🇿 Auckland, New Zealand

Sunshine Coast University Hospital; 🇦🇺 Nambour, Queensland, Australia