Clinical trial NCT05429476: EXtending the Time Window for Thrombolysis in Posterior Circulation Stroke Without Early CT Signs
Official title: EXtending the Time Window for Thrombolysis in Posterior Circulation Stroke Without Early CT Signs
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Stroke, Acute Ischemic
Lead sponsor: Second Affiliated Hospital, School of Medicine, Zhejiang University
Sponsor class: OTHER
First posted: 2022-06-23
Enrollment: 234
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 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Independent recovery assessed by ratio of modified Rankin Scale (mRS) score of 0-2 (%) at 90 ± 7 days
timeFrame: 90 ± 7 days
Secondary outcomes:
measure: Ordinal distribution of modified Rankin Scale (mRS) score at 90 ± 7 days
timeFrame: 90 ± 7 days
measure: Excellent recovery assessed by the ratio of modified Rankin Scale (mRS) score of 0-1 (%) at 90 ± 7 days
timeFrame: 90 ± 7 days
measure: 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
timeFrame: 24 hours
measure: 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
timeFrame: 7 days
measure: Symptomatic intracerebral hemorrhage (sICH) within 36 hours after randomization
timeFrame: within 36 hours
measure: Parenchymal hematoma (PH) (%) within 36 hours after randomization
timeFrame: within 36 hours
measure: Any intracerebral hemorrhage (ICH) within 36 hours after randomization
timeFrame: within 36 hours
measure: Mortality (%) within 90 days
timeFrame: within 90 days
Other outcomes:
Locations:
city: Anji
country: China
facility: People's Hospital of Anji
city: Botou
country: China
facility: Botou City Hospital
city: Dongyang
country: China
facility: Dongyang Affiliated Hospital of Wenzhou Medical University
city: Haiyan
country: China
facility: Haiyan People's Hospital
city: Hangzhou
country: China
facility: Hangzhou First People's Hospital
city: Hangzhou
country: China
facility: Second Affiliated Hospital of Zhejiang University, School of Medicine
city: Huzhou
country: China
facility: Huzhou Central Hospital
city: Huzhou
country: China
facility: Huzhou First People's Hospital
city: Huzhou
country: China
facility: Nanxun District People's Hospital
city: Huzhou
country: China
facility: South Taihu Hospital Affiliated to Huzhou College
city: Jiashan
country: China
facility: The First People's Hospital Jiashan
city: Jiaxing
country: China
facility: First Affiliated Hospital of Jiaxing University
city: Jiaxing
country: China
facility: Jiaxing Hospital of T.C.M
city: Jiaxing
country: China
facility: Second Affiliated Hospital of Jiaxing University
city: Jinhua
country: China
facility: Affiliated Jinhua Hospital, Zhejiang University School of Medicine
city: Longyan
country: China
facility: Longyan First Hospital
city: Rui'an
country: China
facility: Rui'an People's Hospital
city: Shaoxing
country: China
facility: China Medical University Shaoxing Hospital
city: Shengzhou
country: China
facility: Shengzhou People's Hospital
city: Taizhou
country: China
facility: Taizhou Central Hospital
city: Taizhou
country: China
facility: Taizhou Hospital of Zhejiang Province
city: Wenling
country: China
facility: The First People's Hospital of Wenling
city: Yongjia
country: China
facility: Yongjia People's Hospital
city: Yueqing
country: China
facility: Yueqing People's Hospital
city: Zhejiang
country: China
facility: Zhejiang Hospital
city: Zhoushan
country: China
facility: The First People's Hospital Daishan
city: Zhuji
country: China
facility: Zhuji Affiliated Hospital of Wenzhou Medical University
Study officials:
References: