24 Hours Treatment With Alteplase in Patients With Ischemic Stroke

Study Overview
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Brief Summary
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The development of intravenous thrombolysis has greatly improved the rate of recanalization and reperfusion in patients with acute ischemic stroke, increasing the proportion of patients with good outcome and reduced mortality. The guideline recommends that patients with ischemic stroke should be treated with intravenous thrombolysis within 4.5 hours. The latest meta-analysis found that ischemic stroke with onset time of 4.5-9 hours with infarction core volume <70ml, ischemic penumbra volume >10ml, and hypoperfusion volume / infarction core volume >1.2 could be benefit from intravenous thrombolysis. The DAWN clinical trial has shown that patients with ischemic stroke with large vessel occlusion with onset time of 6-24 hours could be benefit from endovascular treatment after screening by multi-mode imaging. Therefore, we hypothesize that patients with ischemic stroke with onset time of 4.5-24 hours with a definite penumbra may also benefit from intravenous thrombolysis. The purpose of this study is to explore whether the patients with ischemic stroke with onset time of 4.5-24 hours can benefit from intravenous thrombolysis if they meet the standard of CT perfusion screening.

Detailed Description
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In recent years, the development of intravenous thrombolysis has greatly improved the rate of recanalization and reperfusion in patients with acute ischemic stroke, increasing the proportion of patients with good outcome and reduced mortality. The guideline recommends that patients with ischemic stroke should be treated with intravenous thrombolysis within 4.5 hours. The latest meta-analysis found that ischemic stroke with onset time of 4.5-9 hours with infarction core volume <70ml, ischemic penumbra volume >10ml, and hypoperfusion volume / infarction core volume >1.2 could be benefit from intravenous thrombolysis (the ratio of mRS 0-1 in 3 months, thrombolysis vs non thrombolysis: 35.4% vs 29.5%). Thus, the time window is not an absolute constant indicator. In theory, compared with time window, the physiological window based on the concept of ischemic penumbra is more reasonable. In 2015, the AHA/ASA guidelines recommended that patients with ischemic stroke with large vessel occlusion should receive endovascular treatment within 6 hours. The DAWN clinical trial has shown that patients with ischemic stroke with large vessel occlusion with onset time of 6-24 hours could be benefit from endovascular treatment after screening by multi-mode imaging (CT perfusion or MR perfusion). As a result, the 2018 AHA/ASA guidelines extended the endovascular treatment window to 24 hours for patients with large vessel occlusion stroke that meet the standard of perfusion. Therefore, we hypothesize that patients with ischemic stroke with onset time of 4.5-24 hours with a definite penumbra may also benefit from intravenous thrombolysis. Thus, the purpose of this study is to explore whether the patients with ischemic stroke with onset time of 4.5-24 hours can benefit from intravenous thrombolysis if they meet the standard of CT perfusion screening (infarction core volume <70ml, ischemic penumbra volume >10ml, and hypoperfusion volume / infarction core volume >1.2).

Official Title
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Treatment With Intravenous Alteplase in Ischemic Stroke Patients With Onset Time Between 4.5 and 24 Hours

Conditions
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Stroke

Intervention / Treatment
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* Drug: Alteplase


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients presented with clinical signs of acute ischemic stroke between 4.5 and 24 hours of stroke onset or awakening with stroke (if within 24 hours from the midpoint of sleep). Patient's age is >18 years. NIHSS 4 to 26. Imaging inclusion criteria: infarct core volume ≤ 70 mL and penumbra ≥ 10 mL with at least 20% mismatch (as evaluated by CTP). Patient, family member or legally responsible person depending on local ethics requirements has given informed consent. Exclusion Criteria: CT shows intracranial hemorrhage or lesions larger than one third of the territory of the middle cerebral artery. Pre-stroke mRS score of more than 1 (indicating previous disability); Contraindication for alteplase. Plan to receive endovascular treatment. A life expectancy of less than three months. 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 hemolytic uremic syndrome or thrombotic thrombocytopenic purpura). The judgment is left to the discretion of the investigator.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alteplase with standard therapy<br> | Drug: Alteplase<br>* Patients will receive standard dose intravenous alteplase (0.9 mg per kilogram, the first 10% administered as an initial bolus and the remainder over a 1-hour period, with a maximum dose of 90 mg)<br>|
| No Intervention: Standard therapy<br> | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| excellent recovery assessed by the ratio of modefied Rankin Scale (mRS) score of 0-1 (%) | mRS: minimum value = 0, maximum value = 6, and lower scores mean a better outcome | at 90 day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| independent recovery assessed by ratio of modefied Rankin Scale (mRS) score of 0-2 (%) | mRS: minimum value = 0, maximum value = 6, and lower scores mean a better outcome | at 90 day | 
| the frequency of parenchymal hemorrhage (PH) (%) | the presence of PH is defined according the standard from ECASS-2 study | at day 1 | 
| the change on the National Institute of Health stroke scale (NIHSS) score from baseline to 1 day | NIHSS: minimum value = 0, maximum value = 42, and higher scores mean severer symptoms | from baseline to 1 day | 
| the change on the National Institute of Health stroke scale (NIHSS) score from baseline to 7 day | NIHSS: minimum value = 0, maximum value = 42, and higher scores mean severer symptoms | from baseline to 7 day | 
| general recovery assessed by the ratio of modefied Rankin Scale (mRS) score of 0-3 (%) | mRS: minimum value = 0, maximum value = 6, and lower scores mean a better outcome | at day 90 | 
| recovery assessed by modefied Rankin Scale (mRS) score | mRS: minimum value = 0, maximum value = 6, and lower scores mean a better outcome | at day 90 |