Stroke
Conditions
Brief summary
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
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.
Interventions
DRUGTissue-type plasminogen activator (alteplase)
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)
OTHERStandard care
Standard treatment for acute stroke without intravenous alteplase.
Sponsors
Charitable Trust Mihara Cerebrovascular Disorder Research Promotion Fund
Japan Agency for Medical Research and Development
National Cerebral and Cardiovascular Center, Japan
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Modified Rankin Scale 0-1 | 90 days after stroke onset |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | 24 hours after the initiation of treatment | MRI proven SICH |
| Symptomatic intracranial hemorrhage (sICH) in SITS-MOST | 24 hours after the initiation of treatment | MRI proven SICH |
| Categorical shift in National Institutes of Health (NIHSS) score at 24 h | 24 hours after the initiation of treatment | — |
| sICH as defined in National Institute of Neurological Disorders and Stroke (NINDS) | 24 hours after the initiation of treatment | MRI proven SICH |
| Major bleeding | Up to 90 days after stroke onset | 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 |
| Modified Rankin Scale 6 | 90 days after stroke onset | Death due to any cause |
| Infarct volume | 7 days after stroke onset | Infarct volume on FLAIR |
| Infarct volume growth | 7 days after stroke onset | Infarct volume on FLAIR at 7 days minus infarct volume on DWI at baseline |
| sICH as defined in European Cooperative Acute Stroke Study (ECASS) II | 24 hours after the initiation of treatment | MRI proven SICH |
Countries
Japan
Outcome results
None listed