Clinical trial NCT02002325: THrombolysis for Acute Wake-up and Unclear-onset Strokes With Alteplase at 0.6 mg/kg Trial (THAWS)
Official title: THrombolysis for Acute Wake-up and Unclear-onset Strokes With Alteplase at 0.6 mg/kg Trial (THAWS)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Stroke
Lead sponsor: National Cerebral and Cardiovascular Center, Japan
Sponsor class: OTHER
Collaborators: name: Charitable Trust Mihara Cerebrovascular Disorder Research Promotion Fund
name: Japan Agency for Medical Research and Development
First posted: 2013-12-05
Enrollment: 300
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Modified Rankin Scale 0-1
timeFrame: 90 days after stroke onset
Secondary outcomes:
measure: Categorical shift in National Institutes of Health (NIHSS) score at 24 h
timeFrame: 24 hours after the initiation of treatment
measure: Categorical shift in NIHSS score at 7 days
timeFrame: 7 days after the initiation of treatment
measure: Modified Rankin Scale 0-2
timeFrame: 90 days after stroke onset
measure: Categorical shift in modified Rankin Scale score
timeFrame: 90 days after stroke onset
measure: Parenchymal hemorrhage type-2 (PH-2)
timeFrame: 24 hours after the initiation of treatment
measure: Symptomatic intracranial hemorrhage (sICH) in SITS-MOST
timeFrame: 24 hours after the initiation of treatment
measure: sICH as defined in European Cooperative Acute Stroke Study (ECASS) II
timeFrame: 24 hours after the initiation of treatment
measure: sICH as defined in National Institute of Neurological Disorders and Stroke (NINDS)
timeFrame: 24 hours after the initiation of treatment
measure: Major bleeding
timeFrame: Up to 90 days after stroke onset
measure: Modified Rankin Scale 6
timeFrame: 90 days after stroke onset
measure: Infarct volume
timeFrame: 7 days after stroke onset
measure: Infarct volume growth
timeFrame: 7 days after stroke onset
Other outcomes:
Locations:
city: Suita
country: Japan
facility: National Cerebral and Cardiovascular Center
state: Osaka
Study officials:
affiliation: National Cerebral and Cardiovascular Center, Japan
name: Kazunori Toyoda, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Koga M, Toyoda K, Kimura K, Yamamoto H, Sasaki M, Hamasaki T, Kitazono T, Aoki J, Seki K, Homma K, Sato S, Minematsu K; THAWS investigators. THrombolysis for Acute Wake-up and unclear-onset Strokes with alteplase at 0.6 mg/kg (THAWS) Trial. Int J Stroke. 2014 Dec;9(8):1117-24. doi: 10.1111/ijs.12360. Epub 2014 Aug 4.
citation: Toyoda K, Koga M, Hayakawa M, Yamagami H. Acute reperfusion therapy and stroke care in Asia after successful endovascular trials. Stroke. 2015 Jun;46(6):1474-81. doi: 10.1161/STROKEAHA.115.008781. Epub 2015 May 5.
citation: Toyoda K, Inoue M, Yoshimura S, Yamagami H, Sasaki M, Fukuda-Doi M, Kimura K, Asakura K, Miwa K, Kanzawa T, Ihara M, Kondo R, Shiozawa M, Ohtaki M, Kamiyama K, Itabashi R, Iwama T, Aoki J, Minematsu K, Yamamoto H, Koga M; THAWS trial investigators*. Magnetic Resonance Imaging-Guided Thrombolysis (0.6 mg/kg) Was Beneficial for Unknown Onset Stroke Above a Certain Core Size: THAWS RCT Substudy. Stroke. 2021 Jan;52(1):12-19. doi: 10.1161/STROKEAHA.120.030848. Epub 2020 Dec 10.
citation: Koga M, Yamamoto H, Inoue M, Asakura K, Aoki J, Hamasaki T, Kanzawa T, Kondo R, Ohtaki M, Itabashi R, Kamiyama K, Iwama T, Nakase T, Yakushiji Y, Igarashi S, Nagakane Y, Takizawa S, Okada Y, Doijiri R, Tsujino A, Ito Y, Ohnishi H, Inoue T, Takagi Y, Hasegawa Y, Shiokawa Y, Sakai N, Osaki M, Uesaka Y, Yoshimura S, Urabe T, Ueda T, Ihara M, Kitazono T, Sasaki M, Oita A, Yoshimura S, Fukuda-Doi M, Miwa K, Kimura K, Minematsu K, Toyoda K; THAWS Trial Investigators. Thrombolysis With Alteplase at 0.6 mg/kg for Stroke With Unknown Time of Onset: A Randomized Controlled Trial. Stroke. 2020 May;51(5):1530-1538. doi: 10.1161/STROKEAHA.119.028127. Epub 2020 Apr 6.