Results from recent several trials provided data showing limits to the effectiveness of thrombectomy for ischemic stroke due to medium vessel occlusions.The benefit-risk profile of thrombolysis for these patients has never been investigated. We initiated a multicenter, prospective, randomized, open label, blinded-endpoint (PROBE) controlled trial to evaluate the efficacy and safety of tenecteplase (0.25mg/kg, maximum dose 25mg) compared to standard medical care for patients with acute ischemic stroke due to medium vessel occlusion (MeVO) within 4.5 to 24 hours from symptom onset.

Adult acute ischemic stroke patients due to primary medium vessel occlusions (distal M2/M3 segments of the middle cerebral artery, A1/A2/A3 segments of the anterior cerebral artery, and P1/P2/P3 segments of the posterior cerebral artery confirmed by CTA/MRA, and responsible for the signs and symptoms of acute ischemic stroke) with baseline National Institutes of Health Stroke Scale (NIHSS) ≥6 or NIHSS 3-5 with disabling symptoms will be enrolled in this trial. We use perfusion imaging to select subjects and the enrolled patients have target mismatch profile on CTP or MRI+PWI (ischemic core volume <70mL, mismatch ratio>1.2, mismatch volume >10mL). If neither MRI or CT perfusion is available at the site, an ASPECTS/PC-ASPECTS of 8 or more on NCCT /MRI-DWI will be used.We will randomly assign eligible patients to receive tenecteplase (at a dose of 0.25 mg per kilogram of body weight; maximum dose, 25 mg) or standard medical treatment 4.5 to 24 hours after the time that the patient was last known to be well (including after stroke on awakening and unwitnessed stroke). The primary outcome is the proportion of patients with an mRS score ≤ 1 at 90 days.

Inclusion Criteria:

• (1)Age≥18 years old;
• (2)Acute ischemic stroke symptom onset within 4.5 - 24 hours; including wake-up stroke and unwitnessed stroke, onset time refers to "last-seen normal time";
• (3)Primary medium vessel occlusions confirmed by CTA/MRA, including distal M2/M3 segments of the middle cerebral artery (MCA), A1/A2/A3 segments of the anterior cerebral artery (ACA), and P1/P2/P3 segments of the posterior cerebral artery (PCA) and responsible for the signs and symptoms of acute ischemic stroke;
• (4)Neuroimaging criteria: a) Perfusion criteria:Target mismatch profile on CT perfusion or MRI+MR perfusion (ischemic core volume <70mL, mismatch ratio >1.2, mismatch volume >10mL); b) If neither MRI or CT perfusion is available at the site : an Alberta Stroke Program Early CT Score [ASPECTS] of 8 or more on NCCT /MRI-DWI or PC-ASPECTS of 8 or more on NCCT/MRI-DWI.
• (5)Pre-stroke modified Rankin scale (mRS) score ≤1;
• (6)Baseline National Institutes of Health Stroke Scale (NIHSS) ≥6 or NIHSS 3-5 with disabling symptoms;
• (7)Written informed consent from patients or their legally authorized representatives.

Exclusion Criteria:

• (1)Allergy to tenecteplase;
• (2)Rapidly improving symptoms at the discretion of the investigator;
• (3)NIHSS consciousness score 1a >2, or epileptic seizure, hemiplegia after seizures (Todd's palsy) or other neurological/mental illness such that the patient is not able to cooperate or unwilling to cooperate;
• (4)Intention to undergo endovascular treatment.
• (5)Persistent blood pressure elevation (systolic ≥185 mmHg or diastolic ≥110 mmHg), despite blood pressure-lowering treatment;
• (6)Blood glucose <2.8 or >22.2 mmol/L (point of care glucose testing is acceptable);
• (7) Active internal bleeding or at high risk of bleeding, e.g., major surgery, trauma or gastrointestinal or urinary tract hemorrhage within the previous 21 days, or arterial puncture at a non-compressible site within the previous 7 days;
• (8)Any known impairment in coagulation due to comorbid disease or anticoagulant use. If on warfarin, then INR >1.7 or prothrombin time >15 seconds; use of any direct thrombin inhibitors or direct factor Xa inhibitors during the last 48 hours unless reversal of dabigatran can be achieved with idarucizumab; any full dose heparin/heparinoid during the last 24 hours or with an APTT greater than the upper limit of normal;
• (9)Known defect of platelet function or platelet count below 100,000/mm3 (NB patients taking antiplatelet medication can be included);
• (10)Ischemic stroke or myocardial infarction in previous 3 months, previous intracranial hemorrhage, severe traumatic brain injury or intracranial or intraspinal operation in previous 3 months, or known intracranial neoplasm, arteriovenous malformation, or giant aneurysm;
• (11)Any terminal illness such that the patient would not be expected to survive more than 1 year;
• (12) Unable to perform CTP or PWI;
• (13)Hypodensity in >1/3 MCA territory on non-contrast CT or hypodensity outside the current perfusion lesion suggesting distal clot migration (secondary MeVO);
• (14)Acute or past intracerebral hemorrhage (ICH) identified by CT or MRI;
• (15)Pregnant women, nursing mothers, or reluctance to use effective contraceptive measures during the period of the trial;
• (16)Unlikely to adhere to the trial protocol or follow-up;
• (17) Participation in other interventional clinical trials within the previous 3 months.