Clinical trial NCT04879615: 24 Hours Treatment with Alteplase in Patients with Ischemic Stroke
Official title: Treatment with Intravenous Alteplase in Ischemic Stroke Patients with Onset Time Between 4.5 and 24 Hours
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Stroke
Lead sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University
Sponsor class: OTHER
First posted: 2021-05-10
Enrollment: 372
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The development of intravenous thrombolysis has greatly improved the rate of recanalization and reperfusion in patients with acute ischemic stroke, increasing the proportion of patients with good outcome and reduced mortality. The guideline recommends that patients with ischemic stroke should be treated with intravenous thrombolysis within 4.5 hours. The latest meta-analysis found that ischemic stroke with onset time of 4.5-9 hours with infarction core volume \<70ml, ischemic penumbra volume \>10ml, and hypoperfusion volume / infarction core volume \>1.2 could be benefit from intravenous thrombolysis. The DAWN clinical trial has shown that patients with ischemic stroke with large vessel occlusion with onset time of 6-24 hours could be benefit from endovascular treatment after screening by multi-mode imaging. Therefore, we hypothesize that patients with ischemic stroke with onset time of 4.5-24 hours with a definite penumbra may also benefit from intravenous thrombolysis. The purpose of this study is to explore whether the patients with ischemic stroke with onset time of 4.5-24 hours can benefit from intravenous thrombolysis if they meet the standard of CT perfusion screening.

Detailed description: In recent years, the development of intravenous thrombolysis has greatly improved the rate of recanalization and reperfusion in patients with acute ischemic stroke, increasing the proportion of patients with good outcome and reduced mortality. The guideline recommends that patients with ischemic stroke should be treated with intravenous thrombolysis within 4.5 hours. The latest meta-analysis found that ischemic stroke with onset time of 4.5-9 hours with infarction core volume \<70ml, ischemic penumbra volume \>10ml, and hypoperfusion volume / infarction core volume \>1.2 could be benefit from intravenous thrombolysis (the ratio of mRS 0-1 in 3 months, thrombolysis vs non thrombolysis: 35.4% vs 29.5%). Thus, the time window is not an absolute constant indicator. In theory, compared with time window, the physiological window based on the concept of ischemic penumbra is more reasonable.

In 2015, the AHA/ASA guidelines recommended that patients with ischemic stroke with large vessel occlusion should receive endovascular treatment within 6 hours. The DAWN clinical trial has shown that patients with ischemic stroke with large vessel occlusion with onset time of 6-24 hours could be benefit from endovascular treatment after screening by multi-mode imaging (CT perfusion or MR perfusion). As a result, the 2018 AHA/ASA guidelines extended the endovascular treatment window to 24 hours for patients with large vessel occlusion stroke that meet the standard of perfusion. Therefore, we hypothesize that patients with ischemic stroke with onset time of 4.5-24 hours with a definite penumbra may also benefit from intravenous thrombolysis.

Thus, the purpose of this study is to explore whether the patients with ischemic stroke with onset time of 4.5-24 hours can benefit from intravenous thrombolysis if they meet the standard of CT perfusion screening (infarction core volume \<70ml, ischemic penumbra volume \>10ml, and hypoperfusion volume / infarction core volume \>1.2).

Eligibility criteria: Inclusion Criteria:

1. Patients presenting with clinical signs of acute ischemic stroke between 4.5 and 24 hours from stroke onset, or awakening and unwitnessed stroke (if the midpoint of the last known well time is within 4.5 to 24 hours)
2. Patients aged \> 18 years
3. NIHSS range from 4 to 26
4. Imaging inclusion criteria: ischemic core volume ≤ 70 mL, penumbra ≥ 10 mL and mismatch ≥ 20% (as evaluated by CT-perfusion)
5. Pre-stroke mRS score \< 2
6. 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 illness that prevents 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 or \>22.2 mmol/L, point-of-care glucose testing accepted)
   * 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. Large (more than one-third of the territory of middle cerebral artery) region of clear hypodensity on CT scan
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 three months
8. Life expectancy of less than three months

Primary outcomes:
measure: Excellent recovery assessed by the ratio of modefied Rankin Scale (mRS) score of 0-1 (%)
timeFrame: at 90 days
Secondary outcomes:
measure: Independent recovery assessed by ratio of modefied Rankin Scale (mRS) score of 0-2 (%)
timeFrame: at 90 days
measure: Ratio of modefied Rankin Scale (mRS) score of 0-3 (%)
timeFrame: at 90 days
measure: Ordinal distribution of mRS score
timeFrame: at 90 days
measure: Major neurologic improvement defined as an improvement of ≥8 points on the NIHSS compared with the initial deficit or a score of ≤1 achieved (%)
timeFrame: at 24 hours
measure: Major neurologic improvement defined as an improvement of ≥8 points on the NIHSS compared with the initial deficit or a score of ≤1 achieved (%)
timeFrame: at 7 days
measure: Symptomatic intracerebral hemorrhage (sICH) (%)
timeFrame: within 36 hours
measure: Parenchymal hematoma (PH) (%)
timeFrame: within 36 hours
measure: Mortality (%)
timeFrame: within 90 days
Other outcomes:
Locations:
city: Wuwei
country: China
facility: Wuwei People's Hospital
state: Gansu
city: Chongqing
country: China
facility: Chongqing University Jiangjin Hospital
city: Hangzhou
country: China
facility: Binjiang Campus of Second Affiliated Hospital of Zhejiang University, School of Medicine
city: Hangzhou
country: China
facility: Bo Ao Campus of Second Affiliated Hospital of Zhejiang University, School of Medicine
city: Hangzhou
country: China
facility: Second Affiliated Hospital of Zhejiang University, School of Medicine
city: Hangzhou
country: China
facility: Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College)
city: Huzhou
country: China
facility: Huzhou Central Hospital
city: Jiaxing
country: China
facility: First Affiliated Hospital of Jiaxing University
city: Jiaxing
country: China
facility: Second Affiliated Hospital of Jiaxing University
city: Jiaxing
country: China
facility: The First People's Hospital of Jiashan
city: Jinhua
country: China
facility: The Forth Affiliated Hospital of Zhejiang University
city: Liuan
country: China
facility: Affiliated Hospital of West Anhui Health Vocational College
city: Mianyang
country: China
facility: Mianyang Hospital of TCM
city: Mianyang
country: China
facility: The First People's Hospital of Mianyang (SiChuan Mianyang 404 Hospital)
city: Nanjing
country: China
facility: Nanjing Lishui District Hospital of Traditional Chinese Medicine
city: Ningbo
country: China
facility: Ningbo No. 2 Hospital
city: Shanghai
country: China
facility: Zhongshan Hospital
city: Shaoxing
country: China
facility: Shaoxing People's Hospital (Shaoxing Hospital of Zhejiang University)
city: Suzhou
country: China
facility: Suzhou Hospital of Anhui Medical University
city: Suzhou
country: China
facility: The First Affiliated Hospital of Soochow University
city: Taizhou
country: China
facility: Taizhou First People's Hospital
city: Taizhou
country: China
facility: The First People's Hospital of Wenling
city: Wenzhou
country: China
facility: First Affiliated Hospital of Wenzhou Medical University
city: Zhangzhou
country: China
facility: Zhangzhou Municipal Hospital of Fujian Province
city: Zhenjiang
country: China
facility: The People's Hospital of Danyang
city: Zhongshan
country: China
facility: Zhongshan City People's Hospital
Study officials:
References: