The trial is a phase 3, multicenter, prospective, randomized, open-label, blinded-endpoint (PROBE) controlled design. Patients with acute ischemic stroke due to anterior circulation large vessel occlusion within 4.5-24 hours from last known well (including wake-up stroke and unwitnessed stroke) will be randomized 1:1 to 0.25mg/kg intravenous tenecteplase or standard medical treatment.

The study will be a multicenter, prospective, randomized, open-label, blinded-endpoint (PROBE), controlled phase 3 trial (2 arms with 1:1 randomization) in ischemic stroke due to anterior circulation large vessel occlusion with perfusion mismatch up to 24 hours of symptom onset. The target mismatch profiles on CTP or MRI perfusion weighted imaging include ischemic core volume <70 mL, mismatch ratio≥1.8 and mismatch volume≥15 mL demonstrated by a certified automatic software. The minimum sample size is 516 patients.

Inclusion Criteria:

1. Age ≥18 years old;
2. Acute ischemic stroke symptom onset between 4.5 to 24 hours prior to enrolment; including wake-up stroke and unwitnessed stroke, onset time refers to "last-seen normal time";
3. Internal carotid artery, middle cerebral artery M1 or M2 occlusion confirmed by CTA/MRA, internal carotid artery, middle cerebral artery M1 or M2 being responsible for signs and symptoms of acute ischemic stroke;
4. Pre-stroke modified Rankin scale (mRS) score≤1;
5. Baseline National Institutes of Health Stroke Scale (NIHSS) 6-25 (inclusive);
6. Neuroimaging: target mismatch profile on CTP or MRI+MR Perfusion (ischemic core volume <70 mL, mismatch ratio≥1.8 and mismatch volume≥15 mL;
7. Written informed consent from patients or their legally authorized representatives.

Exclusion Criteria:

1. Intended to proceed to endovascular treatment;
2. Allergy to tenecteplase;
3. Rapidly improving symptoms at the discretion of the investigator;
4. 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;
5. Persistent blood pressure elevation (systolic ≥180 mmHg or diastolic ≥100 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 effect can be achieved with a reversal agent; any full dose heparin/heparinoid during the last 24 hours or with an elevated 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;
14. Acute or past intracerebral hemorrhage (ICH) identified by CT or MRI;
15. Multiple arterial occlusion (bilateral MCA occlusion, MCA occlusion accompanied with basilar occlusion);
16. Pregnant women, nursing mothers, or reluctant to use effective contraceptive measures during the period of trial;
17. Unlikely to adhere to the trial protocol or follow-up;
18. Any condition that, in the judgment of the investigator could impose hazards to the patient if study therapy is initiated or affect the participation of the patient in the study;
19. Participation in other interventional clinical trials within the previous 3 months.