Stroke
Conditions
Keywords
Ischemic Stroke with Large Vessel Occlusion, Tenecteplase, beyond 4.5 hours
Brief summary
To verify the efficacy and safety of intravenous tenecteplase (TNK) in patients with disabling minor stroke and large vessel occlusion (LVO) within a 4.5-24 hour time window.
Detailed description
Stroke is a leading cause of death and disability. Minor stroke (NIHSS ≤5) accounts for 48% of ischemic strokes, with its "mild symptom" presentation masking the potential risk of disability. About 30% of patients have poor 90-day outcomes (mRS ≥2) due to disabling deficits (e.g., unilateral limb weakness ≥2, aphasia, or hemianopia), resulting not only in loss of personal independence but also a surge in family and social medical expenses. Notably, up to 55% of patients present beyond the standard time window (4.5-24 hours). Having missed the golden window for thrombolysis, they are often relegated to conservative treatment. When complicated by large vessel occlusion (LVO), the recanalization rate with dual antiplatelet therapy (DAPT) alone is less than 5%, creating a "silent epidemic" of accumulating disability risk. The PRISMS trial showed no benefit of thrombolysis within 4.5 hours in non-disabling stroke, but due to the exclusion of the LVO subgroup and early termination (actual enrollment only 313), the potential benefit for disabling patients remains an open question. The TEMPO-2 trial found increased mortality (5% vs 1%) in patients receiving tenecteplase (TNK) without selecting for ischemic penumbra, potentially masking recanalization benefits in certain subgroups (e.g., those with mismatch ratio ≥1.8). A subgroup analysis of TEMPO-2 for onset 4.5-12h, minor disabling stroke (median NIHSS 4), showed a 3-month mRS 0-1 rate of 61.7% in the tenecteplase group vs. 47.2% in the standard care group, but this was not statistically significant due to the small subgroup size. While CHANCE series studies confirmed that DAPT reduces the risk of stroke recurrence by 33%, it is ineffective for LVO recanalization, leaving disability rates high. The 2023 "Chinese Guidelines for Clinical Management of Cerebrovascular Diseases" and the European Stroke Organisation (ESO) guidelines explicitly state that treatment for disabling minor stroke with LVO beyond the time window (4.5-24 hours) lacks a Class I recommendation (Evidence Level C), leaving clinical decision-making in a dilemma without evidence-based guidance. DAWN/DEFUSE-3/TRACE Ⅲ studies validated the value of imaging selection in thrombectomy, but they excluded patients with NIHSS ≤5, leaving a gap in penumbra assessment criteria for minor stroke. Therefore, the investigators designed the TIME-MINOR trial to evaluate whether intravenous tenecteplase, guided by multimodal imaging, can improve outcomes in patients with NIHSS ≤5 and LVO presenting 4.5-24 hours after onset.
Interventions
Tenecteplase (0.25 mg/kg, intravenous bolus, maximum dose 25 mg) + Delayed dual antiplatelet therapy (initiated 24 hours after thrombolysis: Aspirin 100 mg orally once daily + Clopidogrel 75 mg orally once daily, or Aspirin 100 mg + Ticagrelor 90 mg orally twice daily, continued for 21 days)
Immediate dual antiplatelet therapy (Aspirin 100 mg orally once daily + Clopidogrel 75 mg orally once daily, or Aspirin 100 mg + Ticagrelor 90 mg orally twice daily, continued for 21 days)
Sponsors
First Hospital of China Medical University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Multicenter, randomized, open-label, blinded-endpoint (PROBE design), 1:1 allocation, 90-day follow-up.
Intervention model description
Multicenter, randomized, open-label, blinded-endpoint (PROBE design), 1:1 allocation, 90-day follow-up.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female subjects (age ≥ 18 years). * Diagnosis of acute ischemic stroke, with intracranial hemorrhage ruled out by CT or MRI. * Time from stroke onset or last known well to randomization is 4.5 to 24 hours. * NIHSS score 2-5 and meeting the definition of disabling deficit: complete hemianopia (NIHSS question 3 score ≥ 2); severe aphasia (NIHSS question 9 score ≥ 2); neglect (NIHSS question 11 score ≥ 1); any persistent limb weakness against gravity (NIHSS question 6 or 7 score ≥ 2); any functional deficit considered potentially disabling by the physician and patient, such as inability to perform basic activities of daily living (bathing, independent walking, toileting, personal hygiene, and eating) or return to work. * LVO (internal carotid artery, middle cerebral artery M1/M2 segments) confirmed by CTA or MRA, including tandem lesions. * Core infarct volume \< 70 ml, ischemic penumbra volume ≥ 15 ml, and mismatch ratio ≥ 1.8, as shown by CTP or MRI+MRP. * Written informed consent.
Exclusion criteria
* Significant pre-stroke neurological deficit (pre-stroke mRS ≥ 2). * History of stroke within the last 3 months. * History of intracranial hemorrhage. * Suspected subarachnoid hemorrhage. * Intracranial tumor, vascular malformation, or aneurysm. * Major surgery within the last 1 month. * Systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 110 mmHg. * Platelet count \< 10⁵/mm³. * Heparin or oral anticoagulant therapy within 48 hours. * Abnormal APTT. * Thrombin or factor Xa inhibitors. * Severe illness with life expectancy \< 3 months. * Blood glucose \< 50 mg/dL (2.7 mmol/L). * Participation in any other investigational drug or device study within the last 3 months. * Pregnancy. * Patients deemed unsuitable for the registry study by the investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of patients with a modified Rankin Scale (mRS) score of 0-1 at 90 days. | 3 months after randomization | Proportion of patients with a modified Rankin Scale (mRS) score of 0-1 at 90 days. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of patients with mRS 0-2 at 90 days. | 3 months after randomization | Proportion of patients with mRS 0-2 at 90 days. |
| Distribution of mRS score at 90 days. | 3 months after randomization | Distribution of mRS score at 90 days. |
| Rate of vessel recanalization. | 3 months after randomization | Rate of vessel recanalization. |
| Proportion of patients undergoing rescue mechanical thrombectomy. | cerebral infarction within 24 hours of onset | Proportion of patients undergoing rescue mechanical thrombectomy. |
| Proportion of patients with NIHSS score 0-1 or an improvement of ≥4 points from baseline at 24 hours, 7 days, or discharge (whichever occurs first). | 24 hours, 7 days, or discharge after randomization | Proportion of patients with NIHSS score 0-1 or an improvement of ≥4 points from baseline at 24 hours, 7 days, or discharge (whichever occurs first). |
| Proportion of patients with neurological deterioration at 90 days (increase in NIHSS score ≥4 points from baseline at the 90-day follow-up). | 3 months after randomization | Proportion of patients with neurological deterioration at 90 days (increase in NIHSS score ≥4 points from baseline at the 90-day follow-up). |
| New vascular events within 90 days (including ischemic stroke, hemorrhagic stroke, myocardial infarction, and vascular death), with independent evaluation of each event. | 3 months after randomization | New vascular events within 90 days (including ischemic stroke, hemorrhagic stroke, myocardial infarction, and vascular death), with independent evaluation of each event. |
Countries
China
Contacts
CONTACTChuansheng Zhao, M.D
CONTACTJinwei Li, M.D
Outcome results
None listed