THrombolysis for Acute Wake-up and Unclear-onset Strokes With Alteplase at 0.6 mg/kg Trial (THAWS)

Study Overview
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Brief Summary
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The purpose of this study is to clarify efficacy and safety of MRI-based intravenous thrombolysis with alteplase for patients with acute wake-up ischemic stroke and those having acute ischemic stroke with unknown time of symptom onset.

Detailed Description
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THAWS is an investigator initiated Japanese multicenter randomized controlled clinical trial of MRI based thrombolysis in patients with acute wake-up ischemic stroke and those having acute ischemic stroke with unknown time of symptom onset. Intravenous thrombolysis with alteplase of 0.6mg/kg, different from 0.9mg/kg used in other countries, is available as effective and safe treatment of acute stroke within 4.5 hours of symptom onset in Japan. However, time of symptom onset is unknown in about 25% of acute stroke patients. These patients are currently excluded from intravenous thrombolysis with alteplase. The objective of the THAWS project is to provide effective treatment options for acute stroke patients with unknown time of symptom onset. The purpose of this study is to clarify efficacy and safety of MRI-based intravenous thrombolysis with alteplase of 0.6mg/kg for patients with acute wake-up ischemic stroke and those having acute ischemic stroke with unknown time of symptom onset. Eligible patients will be selected based on MRI findings indicative of acute ischemic stroke less than 4.5 hours of age.

Official Title
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THrombolysis for Acute Wake-up and Unclear-onset Strokes With Alteplase at 0.6 mg/kg Trial (THAWS)

Conditions
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Stroke

Intervention / Treatment
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* Drug: Tissue-type plasminogen activator (alteplase)
* Other: Standard care


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Clinical diagnosis of acute ischemic stroke with unknown symptom onset (e.g. acute wake-up ischemic stroke, acute ischemic stroke with unknown time of symptom onset) Last known well without neurological symptoms >4.5 hours of treatment initiation Treatment can be started within 4.5 hours of symptom recognition (e.g. awaking) Acute stroke MRI including diffusion weighted imaging (DWI) and fluid attenuated inversion recovery (FLAIR) completed Alberta Stroke Program Early CT score (ASPECTS) on initial DWI is 5 or more No marked parenchymal hyperintensity visible on FLAIR Initial NIHSS ≥2 Written informed consent by patient or next of kin Exclusion Criteria: Pre-stroke Modified Rankin Scale (mRS) >1 (patients who have inability to carry out all daily activities and require some help or supervision) Contraindications in the Japanese guideline for the intravenous application of recombinant tissue-type plasminogen activator (alteplase) History of nontraumatic intracranial hemorrhage History of stroke within the last 1 month (excluding transient ischemic attack) History of significant head/spinal injury or surgery within the last 3 months History of gastrointestinal or urinary tract bleeding within the last 21 days History of major surgery or significant trauma other than head injury within the last 14 days Hypersensitivity to alteplase Suspected subarachnoid hemorrhage Concurrent acute aortic dissection Concurrent hemorrhage (e.g., intracranial, gastrointestinal, urinary tract, or retroperitoneal, hemoptysis) Systolic blood pressure ≥185 mmHg despite antihypertensive therapy Diastolic blood pressure ≥110 mmhg despite antihypertensive therapy Significant hepatic disorder Acute pancreatitis Blood glucose <50mg/dL or >400 mg/dL Platelet count ≤100,000/mm3 International normalized ratio of prothrombin time (PT-INR) >1.7 or Prolonged activated partial thromboplastin time (aPTT: >1.5 times the baseline value [>approximately 40 seconds only as a guide]) for patients on anticoagulation therapy or those with abnormal coagulation Any contraindication to MRI (e.g. cardiac pacemaker) Extensive early ischemic change in brain stem or cerebellum (e.g., more than half of brain stem or more than one hemisphere of cerebellum) Planned or anticipated treatment with surgery or endovascular reperfusion strategies (e.g., intra-arterial thrombolysis, mechanical recanalization techniques) Pregnant, lactating, or potentially pregnant Life expectancy 6 months or less by judgment of the investigator Inappropriate for study enrollment by judgment of the investigator

Ages Eligible for Study
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Minimum Age: 20 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Alteplase<br>Intravenous tissue-type plasminogen activator (alteplase) | Drug: Tissue-type plasminogen activator (alteplase)<br>* Intravenous tissue-type plasminogen activator (alteplase) 0.6mg/kg body-weight up to a maximum of 60 mg, 10% as bolus, 90% over 1 hour as infusion (plus other standard treatment if needed)<br>* Other names: Activase;|
| Other: Standard Care<br>Standard treatment for acute stroke | Other: Standard care<br>* Standard treatment for acute stroke without intravenous alteplase.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified Rankin Scale 0-1 |  | 90 days after stroke onset | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Categorical shift in National Institutes of Health (NIHSS) score at 24 h |  | 24 hours after the initiation of treatment | 
| Categorical shift in NIHSS score at 7 days |  | 7 days after the initiation of treatment | 
| Modified Rankin Scale 0-2 |  | 90 days after stroke onset | 
| Categorical shift in modified Rankin Scale score |  | 90 days after stroke onset | 
| Parenchymal hemorrhage type-2 (PH-2) | MRI proven SICH | 24 hours after the initiation of treatment | 
| Symptomatic intracranial hemorrhage (sICH) in SITS-MOST | MRI proven SICH | 24 hours after the initiation of treatment | 
| sICH as defined in European Cooperative Acute Stroke Study (ECASS) II | MRI proven SICH | 24 hours after the initiation of treatment | 
| sICH as defined in National Institute of Neurological Disorders and Stroke (NINDS) | MRI proven SICH | 24 hours after the initiation of treatment | 
| Major bleeding | Fatal bleeding, symptomatic bleeding in a critical area or organ, such as intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome, or bleeding causing a fall in hemoglobin level of ≥2g/dL, or leading to transfusion of ≥4.5 units of whole blood or red cells according to the definition of the International Society on Thrombosis and Haemostasis | Up to 90 days after stroke onset | 
| Modified Rankin Scale 6 | Death due to any cause | 90 days after stroke onset | 
| Infarct volume | Infarct volume on FLAIR | 7 days after stroke onset | 
| Infarct volume growth | Infarct volume on FLAIR at 7 days minus infarct volume on DWI at baseline | 7 days after stroke onset |