This is a double-blind parallel arm randomized trial aimed to assess efficacy and safety of intravenous Tenecteplase compared to intravenous Alteplase in eligible patients who present with symptoms of acute ischemic stroke within 3 to 4.5 hours from onset.

Patients presenting with symptoms of acute ischemic stroke (AIS) who present within 3 to 4.5 hours of symptom onset and who meet the inclusion criteria for intravenous (IV) thrombolysis will receive, in a randomized, double-blind fashion, either IV Alteplase at 0.9 mg/kg per standard protocol or IV Tenecteplase at 0.25 mg/kg with saline infusion over one hour. Patients must also have no exclusion criteria for IV thrombolysis within the 3 to 4.5 hour window. The only required imaging is non-contrasted CT of the head. Patients will be monitored according to standard post-thrombolytic care. A CT of the head will be performed at 24 hours based on standard protocol or if there is any neurological change. Neurological function at 24 hours using NIHSS and at 3 months based on modified mRS and the NIHSS.

Inclusion Criteria:

1. Age 18 to 80 years
2. Acute neurologic deficit with an NIHSS ≥ 4
3. Non-enhanced computed tomography (NECT) of the head showing no hemorrhage
4. Acute ischemic stroke symptoms with onset, or time last known well, clearly defined between 3 and 4.5 hours
5. Treatment can be initiated within 3 to 4.5 hours from symptom onset

Exclusion Criteria:

1. Evidence of intracranial hemorrhage on NECT
2. Clinical suspicion of subarachnoid hemorrhage even with normal NECT
3. NECT shows hypo-density greater than 1/3 cerebral hemisphere)
4. History of intracranial hemorrhage/stroke
5. Uncontrolled HTN: At time treatment begins SBP remains >185 mmHg or DBP remains >110 mmHg despite repeated measurements
6. Known arteriovenous malformation, neoplasm, or aneurysm
7. Witnessed seizure at stroke onset
8. Acute bleeding tendencies
9. Platelet count <100,000/mm3
10. Heparin received in prior 48 hours with elevated aPTT
11. Current use of an anticoagulant (Coumadin/Warfarin) irrespective of INR
12. Prior use (within 48 hours) of direct thrombin inhibitors (dabigatran) or direct factor Xa inhibitors (rivaroxaban, apixaban)
13. Within prior 3 months: intracranial or spinal surgery, head trauma, or previous stroke
14. Arterial puncture at non-compressible site within last 7 days
15. Woman of child bearing age who has a positive pregnancy test
16. NIH stroke scale >25 (severe deficit) or <4 and no dysphasia (mild deficit) or rapidly improving
17. Symptoms spontaneously clearing
18. 14 days post-operative or post major trauma
19. Recent gastrointestinal or urinary tract hemorrhage within the past 21 days
20. Recent acute MI within the past 3 months
21. Serum glucose <50 mg/dl or >400 mg/dL
22. Age >80 or less than 18
23. History of ischemic stroke AND diabetes mellitus
24. Unable to obtain consent from patient or power of attorney
25. Baseline mRS > 2
26. Consent not obtained by 20 minutes prior to closure of the therapeutic window.
27. The subject has been treated with a thrombolytic agent within the past 72 hours
28. The subject is a pregnant woman (positive serum βHCG pregnancy test, positive urine pregnancy test or clinically evident pregnancy)
29. The subject is, in the opinion of the investigator, unlikely to comply with the clinical study protocol or is unsuitable for any other reason