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

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.

Study Overview

• Status: Unknown
• Conditions: Stroke
• Intervention / Treatment: Drug: Tissue-type plasminogen activator (alteplase); Other: Standard care

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.

• Study Type: Interventional
• Enrollment (Anticipated): 300
• Phase: Phase 3

Contacts and Locations

Study Locations

• Japan
  • Osaka
    • Suita, Osaka, Japan, 565-8565
      • National Cerebral and Cardiovascular Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Alteplase; Intravenous tissue-type plasminogen activator (alteplase)	Drug: Tissue-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); Other Names: Activase; Actilyse; rt-PA; Activacin; Grtpa
Other: Standard Care; Standard treatment for acute stroke	Other: Standard care; Standard treatment for acute stroke without intravenous alteplase.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: National Cerebral and Cardiovascular Center
• Collaborators: Japan Agency for Medical Research and Development; Charitable Trust Mihara Cerebrovascular Disorder Research Promotion Fund
• Investigators: Principal Investigator: Kazunori Toyoda, MD, National Cerebral and Cardiovascular Center

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Helpful Links

• THrombolysis for Acute Wake-up and unclear-onset Strokes with alteplase at 0·6 mg/kg (THAWS) Trial

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2014
• Primary Completion (Anticipated): December 1, 2019
• Study Completion (Anticipated): March 1, 2020

Study Registration Dates

• First Submitted: November 28, 2013
• First Submitted That Met QC Criteria: November 28, 2013
• First Posted (Estimate): December 5, 2013

Study Record Updates

• Last Update Posted (Actual): December 20, 2018
• Last Update Submitted That Met QC Criteria: December 18, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Tissue Plasminogen Activator; Plasminogen
• Other Study ID Numbers: NCVC-STROKE-001; UMIN000011630 (Registry Identifier: UMIN)