EXtending the Time Window for Thrombolysis in Posterior Circulation Stroke Without Early CT Signs

The primary hypothesis being tested in this trial is that ischemic stroke patients in posterior circulation at 4.5 - 24 hours post onset of stroke will have improved clinical outcomes when given intravenous tissue plasminogen activator (tPA) compared to standard care.

Study Overview

• Status: Completed
• Conditions: Stroke, Acute Ischemic
• Intervention / Treatment: Drug: Tissue Plasminogen Activator (Alteplase)

Detailed Description

Posterior circulation stroke accounts for 20-25% of all ischemic strokes, with an annual adjusted incidence of 18 per 100,000 person-years. Compared with anterior circulation stroke, posterior circulation stroke is less studied and has poor neurological outcomes, which requires attention. Intravenous thrombolytic therapy has greatly improved the rate of recanalization and reperfusion in patients with acute ischemic stroke, increased the proportion of patients with good prognosis, and reduced mortality. Guidelines recommend intravenous thrombolysis within 4.5 hours of onset or awakening in patients with ischemic stroke. However, the proportion of posterior circulation stroke is low or unreported in most randomized controlled trials, such as 5% of patients in the NINDS study, so it may be inappropriate to apply the results of these trials directly to patients with posterior circulation ischemic stroke.

Multiple studies have also shown a lower risk of post-circulation bleeding complications compared to pre-circulation stroke. A meta-analysis of patients with posterior circulation ischemic stroke (11.9% of posterior circulation stroke) showed that posterior circulation stroke had a lower risk of intracranial hemorrhage due to intravenous thrombolysis, half the risk of anterior circulation stroke, and a higher 3-month good functional outcome. The lower risk of hemorrhagic transformation in posterior circulation stroke is due to the greater tolerance of the posterior circulation area to ischemic injury, possibly due to a greater proportion of white matter and arterial collaterals, especially in the brainstem. In addition, the smaller infarct size of posterior circulation stroke compared with anterior circulation stroke also reduced the risk of bleeding in these patients.

Therefore, the purpose of this study was to investigate whether patients with posterior circulation stroke with onset or discovery time of 4.5-24 hours could benefit from intravenous thrombolysis in the Chinese population.

• Study Type: Interventional
• Enrollment (Actual): 234
• Phase: Phase 3

Contacts and Locations

Study Locations

• China
  • Anji, China
    • People's Hospital of Anji
  • Botou, China
    • Botou City Hospital
  • Dongyang, China
    • Dongyang Affiliated Hospital of Wenzhou Medical University
  • Haiyan, China
    • Haiyan People's Hospital
  • Hangzhou, China
    • Hangzhou First People's Hospital
  • Hangzhou, China
    • Second Affiliated Hospital of Zhejiang University, School of Medicine
  • Huzhou, China
    • Huzhou Central Hospital
  • Huzhou, China
    • Huzhou First People's Hospital
  • Huzhou, China
    • Nanxun District People's Hospital
  • Huzhou, China
    • South taihu hospital affiliated to huzhou college
  • Jiashan, China
    • The First People's Hospital Jiashan
  • Jiaxing, China
    • First Affiliated Hospital of Jiaxing University
  • Jiaxing, China
    • Jiaxing Hospital of T.C.M
  • Jiaxing, China
    • Second Affiliated Hospital of Jiaxing University
  • Jinhua, China
    • Affiliated Jinhua Hospital, Zhejiang University School of Medicine
  • Longyan, China
    • Longyan First Hospital
  • Rui'an, China
    • Rui'an People's Hospital
  • Shaoxing, China
    • China Medical University Shaoxing Hospital
  • Shengzhou, China
    • Shengzhou People's Hospital
  • Taizhou, China
    • Taizhou Hospital of Zhejiang Province
  • Taizhou, China
    • Taizhou Central Hospital
  • Wenling, China
    • The First People's Hospital of Wenling
  • Yongjia, China
    • Yongjia People's Hospital
  • Yueqing, China
    • Yueqing People's Hospital
  • Zhejiang, China
    • Zhejiang Hospital
  • Zhoushan, China
    • The First People's Hospital Daishan
  • Zhuji, China
    • Zhuji Affiliated Hospital of Wenzhou Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients presenting with clinical signs of acute ischemic stroke between 4.5 and 24 hours from stroke onset, or wake-up stroke and unwitnessed stroke (if the midpoint of the last known well time is within 4.5 to 24 hours)
2. Patients aged > 18 years (or as per local requirements)
3. NIHSS ≥ 1
4. Patients with a posterior circulation ASPECT score (PC-ASPECTS) ≥ 7. If MRI is performed first and the PC-ASPECTS on diffusion-weighted imaging (DWI) is ≥ 7, a non-contrast head CT is not required. If PCASPECTS on DWI is < 7, the subsequent non-contrast CT must show a PC-ASPECTS ≥ 7 for inclusion
5. Posterior circulation stroke confirmation criteria: If MRI is performed, infarction confirmed by DWI is sufficient. If CT is performed, the non-contrast CT scan must not refute posterior circulation stroke, and clinical signs and symptoms must support the diagnosis, as confirmed by experienced clinicians. If clinical symptoms are atypical, CTA showing symptomatic stenosis or occlusion of large posterior circulation vessels, or CT perfusion showing symptomatic hypoperfusion, can provide additional evidence, though advanced imaging is not mandatory
6. Pre-stroke mRS score < 2
7. Informed consent has been obtained from the patient, a family member, or a legally responsible person, depending on local ethics requirements

Exclusion Criteria:

1. Intended to proceed to endovascular treatment

2. Contraindications for alteplase:

   • Allergy to alteplase
   • Rapidly improving symptoms at the discretion of the investigator
   • The presence of epileptic seizures, hemiplegia after seizures (Todd's palsy), or other neurological/mental illnesses that prevent cooperation or willingness to participate
   • Persistent blood pressure elevation (systolic ≥180 mmHg or diastolic ≥100 mmHg) despite treatment
   • Blood glucose levels outside the acceptable range (<2.8 mmol/L or >22.2 mmol/L), with point-of-care glucose testing considered valid
   • High risk of bleeding due to active internal bleeding, major surgery, trauma, gastrointestinal, or urinary tract hemorrhage within the previous 21 days, or arterial puncture at a non-compressible site within the previous 7 days
   • Known impairments in coagulation due to comorbid disease or anticoagulant use, including an INR >1.7 or prothrombin time >15 seconds for those on warfarin, recent use of direct thrombin inhibitors or direct factor Xa inhibitors without reversal capability, or full-dose heparin/heparinoid within the last 24 hours with an aPTT above normal limits
   • Known defect in platelet function or a platelet count below 100,000/mm³
   • History of ischemic stroke, myocardial infarction, intracranial hemorrhage, severe traumatic brain injury, or intraspinal operation within the previous 3 months, or known intracranial neoplasm, arteriovenous malformation, or giant aneurysm
   • Acute or past intracerebral hemorrhage identified by CT or MRI
3. Infarction of the anterior circulation confirmed by MRI, or vascular examination indicating occlusion of large anterior circulation vessels, or perfusion imaging showing hypoperfusion changes in the anterior circulation area
4. Pregnancy, nursing, or unwillingness to use effective contraceptive measures during the trial period
5. Likelihood of non-adherence to the trial protocol or follow-up
6. Any condition that, in the judgment of the investigator, could impose hazards if study therapy is initiated or affect patient participation in the study
7. Participation in other interventional clinical trials within the previous 3 months
8. A life expectancy of less than three months
9. The judgment is left to the discretion of the investigator

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Standard therapy
Experimental: Alteplase with standard therapy; Patients will receive standard dose intravenous alteplase (0.9 mg per kilogram, the first 10% administered as an initial bolus and the remainder over a 1-hour period, with a maximum dose of 90 mg)	Drug: Tissue Plasminogen Activator (Alteplase); Tissue Plasminogen Activator (Alteplase) 0.9 mg/kg up to a maximum of 90mg, intravenous, 10% as bolus and the remainder over 1 hour Other Names: Actilyse Activase tPA r-tPA; Other Names: tPA; r-tPA; actilyse; activase

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Independent recovery assessed by ratio of modified Rankin Scale (mRS) score of 0-2 (%) at 90 ± 7 days	mRS: minimum value = 0, maximum value = 6, and lower scores mean a better outcome	90 ± 7 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ordinal distribution of modified Rankin Scale (mRS) score at 90 ± 7 days	mRS: minimum value = 0, maximum value = 6, and lower scores mean a better outcome	90 ± 7 days
Excellent recovery assessed by the ratio of modified Rankin Scale (mRS) score of 0-1 (%) at 90 ± 7 days	mRS: minimum value = 0, maximum value = 6, and lower scores mean a better outcome	90 ± 7 days
Major neurologic improvement (%) at 24 hours defined as an improvement on National Institutes of Health Stroke Scale (NIHSS) score ≥ 8 points compared with the initial deficit or a score ≤ 1	NIHSS: minimum value = 0, maximum value = 42, and higher scores mean severer symptoms	24 hours
Major neurologic improvement (%) at 7 days defined as an improvement on National Institutes of Health Stroke Scale (NIHSS) score ≥ 8 points compared with the initial deficit or a score ≤ 1	NIHSS: minimum value = 0, maximum value = 42, and higher scores mean severer symptoms	7 days
Symptomatic intracerebral hemorrhage (sICH) within 36 hours after randomization	sICH as defined by The European Cooperative Acute Stroke Study III criteria [ECASSIII]	within 36 hours
Parenchymal hematoma (PH) (%) within 36 hours after randomization	PH as defined by the European Cooperative Acute Stroke Study [ECASS] criteria	within 36 hours
Any intracerebral hemorrhage (ICH) within 36 hours after randomization		within 36 hours
Mortality (%) within 90 days	Mortality refers to rate of death from any cause	within 90 days

Collaborators and Investigators

• Sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University

Study record dates

Study Major Dates

• Study Start (Actual): August 17, 2022
• Primary Completion (Actual): August 15, 2024
• Study Completion (Actual): August 15, 2024

Study Registration Dates

• First Submitted: June 19, 2022
• First Submitted That Met QC Criteria: June 19, 2022
• First Posted (Actual): June 23, 2022

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 15, 2024
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Ischemic Stroke; Stroke; Molecular Mechanisms of Pharmacological Action; Fibrin Modulating Agents; Fibrinolytic Agents; Tissue Plasminogen Activator; Plasminogen
• Other Study ID Numbers: EXPECTS

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No