EXtending the Time Window for Thrombolysis in Posterior Circulation Stroke Without Early CT Signs

Study Overview
=================
Brief Summary
-----------------
The primary hypothesis being tested in this trial is that ischemic stroke patients in posterior circulation at 4.5 - 24 hours post onset of stroke will have improved clinical outcomes when given intravenous tissue plasminogen activator (tPA) compared to standard care.

Detailed Description
-----------------
Posterior circulation stroke accounts for 20-25% of all ischemic strokes, with an annual adjusted incidence of 18 per 100,000 person-years. Compared with anterior circulation stroke, posterior circulation stroke is less studied and has poor neurological outcomes, which requires attention. Intravenous thrombolytic therapy has greatly improved the rate of recanalization and reperfusion in patients with acute ischemic stroke, increased the proportion of patients with good prognosis, and reduced mortality. Guidelines recommend intravenous thrombolysis within 4.5 hours of onset or awakening in patients with ischemic stroke. However, the proportion of posterior circulation stroke is low or unreported in most randomized controlled trials, such as 5% of patients in the NINDS study, so it may be inappropriate to apply the results of these trials directly to patients with posterior circulation ischemic stroke. Multiple studies have also shown a lower risk of post-circulation bleeding complications compared to pre-circulation stroke. A meta-analysis of patients with posterior circulation ischemic stroke (11.9% of posterior circulation stroke) showed that posterior circulation stroke had a lower risk of intracranial hemorrhage due to intravenous thrombolysis, half the risk of anterior circulation stroke, and a higher 3-month good functional outcome. The lower risk of hemorrhagic transformation in posterior circulation stroke is due to the greater tolerance of the posterior circulation area to ischemic injury, possibly due to a greater proportion of white matter and arterial collaterals, especially in the brainstem. In addition, the smaller infarct size of posterior circulation stroke compared with anterior circulation stroke also reduced the risk of bleeding in these patients. Therefore, the purpose of this study was to investigate whether patients with posterior circulation stroke with onset or discovery time of 4.5-24 hours could benefit from intravenous thrombolysis in the Chinese population.

Official Title
-----------------
EXtending the Time Window for Thrombolysis in Posterior Circulation Stroke Without Early CT Signs

Conditions
-----------------
Stroke, Acute Ischemic

Intervention / Treatment
-----------------
* Drug: Tissue Plasminogen Activator (Alteplase)


Participation Criteria
=================
Eligibility Criteria
-----------------
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 between 4.5 and 24 hours from the midpoint of sleep). Patient's age is > 18 years (or as per local requirements). NIHSS ≥ 1. Patients with post circulation ASPECT score ≥ 7. Patients meet at least one of the below criteria: post circulation stroke considered by experienced clinicians, or infarction of posterior circulation confirmed by MRI, or the vascular examination indicates that there are symptomatic stenosis or occlusion of large posterior circulation vessels, or the perfusion image indicates that there are symptomatic hypoperfusion changes in the posterior circulation area. Pre-stroke mRS score < 2. Patients do not receive endovascular treatment at patients' and treating clinician's discretion Patient, family member or legally responsible person depending on local ethics requirements has given informed consent. Exclusion Criteria: Contraindication for alteplase. A life expectancy of less than three months. The judgment is left to the discretion of the investigator.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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>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) | Drug: Tissue Plasminogen Activator (Alteplase)<br>* 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<br>* Other names: r-tPA;|
| No Intervention: Standard therapy<br>Standard therapy | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| independent recovery assessed by ratio of modefied Rankin Scale (mRS) score of 0-2 (%) at 90 days | mRS: minimum value = 0, maximum value = 6, and lower scores mean a better outcome | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| recovery assessed by modefied Rankin Scale (mRS) score at 90 days | mRS: minimum value = 0, maximum value = 6, and lower scores mean a better outcome | 90 days | 
| excellent recovery assessed by the ratio of modefied Rankin Scale (mRS) score of 0-1 (%) at 90 days | mRS: minimum value = 0, maximum value = 6, and lower scores mean a better outcome | 90 days | 
| Change in ≥ 8 National Institutes of Health Stroke Scale (NIHSS) points or reaching ≤ 1 on this scale at 24 hours | NIHSS: minimum value = 0, maximum value = 42, and higher scores mean severer symptoms | 24 hours | 
| Change in ≥ 8 National Institutes of Health Stroke Scale (NIHSS) points or reaching ≤ 1 on this scale at 7 days | NIHSS: minimum value = 0, maximum value = 42, and higher scores mean severer symptoms | 7 days | 
| independent recovery assessed by ratio of modefied Rankin Scale (mRS) score of 0-2 (%) at 1 year | mRS: minimum value = 0, maximum value = 6, and lower scores mean a better outcome | 1 year | 
| Symptomatic Intracerebral Hemorrhage (sICH) at 24 hours | Symptomatic hemorrhage defined by SITS-MOST criteria: type 2 parenchymal hematoma associated with ≥4 point increase in NIHSS | 24 hours | 
| Symptomatic Intracerebral Hemorrhage (sICH) at 7 days | Symptomatic hemorrhage defined by SITS-MOST criteria: type 2 parenchymal hematoma associated with ≥4 point increase in NIHSS | 7 days |