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

Primary Purpose

Stroke

Status

Unknown status

Phase

Phase 3

Locations

Japan

Study Type

Interventional

Intervention

Tissue-type plasminogen activator (alteplase)

Standard care

About this trial

This is an interventional treatment trial for Stroke

Eligibility Criteria

20 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

National Cerebral and Cardiovascular Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Other

Arm Label

Alteplase

Standard Care

Arm Description

Intravenous tissue-type plasminogen activator (alteplase)

Standard treatment for acute stroke

Outcomes

Primary Outcome Measures

Modified Rankin Scale 0-1

Secondary Outcome Measures

Categorical shift in National Institutes of Health (NIHSS) score at 24 h

Categorical shift in NIHSS score at 7 days

Modified Rankin Scale 0-2

Categorical shift in modified Rankin Scale score

Parenchymal hemorrhage type-2 (PH-2)

MRI proven SICH

Symptomatic intracranial hemorrhage (sICH) in SITS-MOST

MRI proven SICH

sICH as defined in European Cooperative Acute Stroke Study (ECASS) II

MRI proven SICH

sICH as defined in National Institute of Neurological Disorders and Stroke (NINDS)

MRI proven SICH

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

Modified Rankin Scale 6

Death due to any cause

Infarct volume

Infarct volume on FLAIR

Infarct volume growth

Infarct volume on FLAIR at 7 days minus infarct volume on DWI at baseline

Full Information

NCT ID

NCT02002325

First Posted

November 28, 2013

Last Updated

December 18, 2018

Sponsor

National Cerebral and Cardiovascular Center, Japan

Collaborators

Charitable Trust Mihara Cerebrovascular Disorder Research Promotion Fund, Japan Agency for Medical Research and Development

1. Study Identification

Unique Protocol Identification Number

NCT02002325

Brief Title

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

Acronym

THAWS

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

August 2018

Overall Recruitment Status

Unknown status

Study Start Date

May 2014 (Actual)

Primary Completion Date

December 2019 (Anticipated)

Study Completion Date

March 2020 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

National Cerebral and Cardiovascular Center, Japan

Collaborators

Charitable Trust Mihara Cerebrovascular Disorder Research Promotion Fund, Japan Agency for Medical Research and Development

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Stroke

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

Outcomes Assessor

Allocation

Randomized

Enrollment

300 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Alteplase

Arm Type

Experimental

Arm Description

Intravenous tissue-type plasminogen activator (alteplase)

Arm Title

Standard Care

Arm Type

Other

Arm Description

Standard treatment for acute stroke

Intervention Type

Drug

Intervention Name(s)

Tissue-type plasminogen activator (alteplase)

Other Intervention Name(s)

rt-PA, Activacin, Grtpa, Actilyse, Activase

Intervention Description

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)

Intervention Type

Other

Intervention Name(s)

Standard care

Intervention Description

Standard treatment for acute stroke without intravenous alteplase.

Primary Outcome Measure Information:

Title

Modified Rankin Scale 0-1

Time Frame

90 days after stroke onset

Secondary Outcome Measure Information:

Title

Categorical shift in National Institutes of Health (NIHSS) score at 24 h

Time Frame

24 hours after the initiation of treatment

Title

Categorical shift in NIHSS score at 7 days

Time Frame

7 days after the initiation of treatment

Title

Modified Rankin Scale 0-2

Time Frame

90 days after stroke onset

Title

Categorical shift in modified Rankin Scale score

Time Frame

90 days after stroke onset

Title

Parenchymal hemorrhage type-2 (PH-2)

Description

MRI proven SICH

Time Frame

24 hours after the initiation of treatment

Title

Symptomatic intracranial hemorrhage (sICH) in SITS-MOST

Description

MRI proven SICH

Time Frame

24 hours after the initiation of treatment

Title

sICH as defined in European Cooperative Acute Stroke Study (ECASS) II

Description

MRI proven SICH

Time Frame

24 hours after the initiation of treatment

Title

sICH as defined in National Institute of Neurological Disorders and Stroke (NINDS)

Description

MRI proven SICH

Time Frame

24 hours after the initiation of treatment

Title

Major bleeding

Description

Time Frame

Up to 90 days after stroke onset

Title

Modified Rankin Scale 6

Description

Death due to any cause

Time Frame

90 days after stroke onset

Title

Infarct volume

Description

Infarct volume on FLAIR

Time Frame

7 days after stroke onset

Title

Infarct volume growth

Description

Infarct volume on FLAIR at 7 days minus infarct volume on DWI at baseline

Time Frame

7 days after stroke onset

10. Eligibility

Sex

All

Minimum Age & Unit of Time

20 Years

Accepts Healthy Volunteers

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Kazunori Toyoda, MD

Organizational Affiliation

National Cerebral and Cardiovascular Center, Japan

Official's Role

Principal Investigator

Facility Information:

Facility Name

National Cerebral and Cardiovascular Center

City

Suita

State/Province

Osaka

ZIP/Postal Code

565-8565

Country

Japan

12. IPD Sharing Statement

Citations:

PubMed Identifier

25088843

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.

Results Reference

background

PubMed Identifier

25944322

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.

Results Reference

background

PubMed Identifier

33297866

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.

Results Reference

derived

PubMed Identifier

32248771

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.

Results Reference

derived

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

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