A Multicenter, Randomized, Open-Label, Blinded-Endpoint Trial of Tenecteplase Versus Dual Antiplatelet Therapy in Mild Disabling Ischemic Stroke With Large Vessel Occlusion Beyond 4.5 Hours (TIME-MINOR Trial)
试验速览
- 阶段
- 3 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 864
- 试验地点
- 30
- 主要终点
- Proportion of patients with a modified Rankin Scale (mRS) score of 0-1 at 90 days.
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
盲法说明
Multicenter, randomized, open-label, blinded-endpoint (PROBE design), 1:1 allocation, 90-day follow-up.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
Tenecteplase
Tenecteplase (0.25 mg/kg, intravenous bolus, maximum dose 25 mg) + Standard Medical Management
干预措施: Tenecteplase (0.25mg/kg) (Drug)
Standard Medical Management
Immediate Standard Medical Management
干预措施: Standard Medical Management (Drug)
结局指标
主要结局
Proportion of patients with a modified Rankin Scale (mRS) score of 0-1 at 90 days.
时间窗: 3 months after randomization
Proportion of patients with a modified Rankin Scale (mRS) score of 0-1 at 90 days.
次要结局
- Proportion of patients with mRS 0-2 at 90 days.(3 months after randomization)
- Distribution of mRS score at 90 days.(3 months after randomization)
- Proportion of patients undergoing rescue mechanical thrombectomy.(cerebral infarction within 24 hours of onset)
- Rate of vessel recanalization.(3 months 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).(24 hours, 7 days, or discharge 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).(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.(3 months after randomization)
研究者
Chuansheng Zhao
Professor
First Hospital of China Medical University