Randomization to Extend Stroke Intravenous ThromboLysis In Evolving Non-Large Vessel Occlusion With TNK (RESILIENT

Inclusion Criteria:

1. Acute ischemic stroke where patient is ineligible for IV thrombolytic treatment withAlteplase due to onset >4.5 hours and is ineligible for endovascular treatment understandard of care due to absence of proximal arterial occlusion (e.g. intracranialICA, MCA-M1 and dominant M2 segments, and vertebrobasilar arteries).

• Dominant M2 segment is defined is a division supplying >50% of the MCA territoryvs co-dominant supplying 50% of the MCA territory vs non-dominant supplying <50% ofthe MCA territory.

2. No significant pre-stroke functional disability (mRS ≤2).

3. Age ≥18 years (no upper age limit).

4. Clinical or imaging mismatch evidence in distal artery territories, defined as oneof the following scenarios (A, B or C):

• Scenario A - all of the following:

• Significant cortical neurological deficit (moderate to severe afasia,moderate to severe heminegligence, severe hemianopsia) with the additionor not of motor symptoms OR any motor deficit accompanied of corticalsymptoms of any severity;

• Contrast-enhanced CT of the head or head MRI with <50% involvement of thevascular territory corresponding to the clinical manifestation;

• Arterial head angiotomography or arterial head angioMRI WITHOUT proximalintracranial artery occlusion that would require endovascular therapy (forexample, ICA intracranial, MCA-M1 and M2 dominant segments and vertebraland basilar arteries)

• Scenario B - all of the following:

• NIHSS score ≥ 4 due to any neurologic deficits;

• Non-contrast CT of the head or head MRI com <50% involvement of thevascular territory corresponding to the clinical manifestation;

• Arterial head angioCT or arterial head MRI WITHOUT proximal intracranialartery occlusion that would require endovascular therapy (for example, ICAintracranial, MCA-M1 and M2 dominant segments and vertebral and basilararteries)

• Arterial head angioCT with distal occlusion on MIP or wedge-shaped lesionon parenchymography on the source-image of angiotomography OR CT perfusionwith wedge-shaped cortical lesion.

• Scenario C - all of the following:

• NIHSS score ≥ 4 due to any neurologic deficits;

• The presence of a Target Mismatch defined as:

• Ischemic Core <50cc (defined on NCCT/CTP* or DWI MRI) *Volume NCCTcan be used to exclude patients if the investigator believes that itsvolume assessment is more reliable that the CTP in any particularcase.

• Mismatch Volume (Tmax >6sec lesion - Core volume lesion) >10cc

• Mismatch Ratio >1.4

5. Patient treatable within 4.5-12 hours of symptom onset. Symptoms onset is defined aspoint in time the patient was last seen well (at baseline). Treatment start isdefined as initiation of IV TNK or placebo infusion.

• Patients who have woken up with the symptoms and don't have a mismatchFLAIR-DWI according to the WAKE-UP Trial image criteria will have their windowconsidered to be >4.5 hours. In this case, the time last seen well must havebeen 12 hours at most.

6. Informed consent obtained from patient or acceptable patient surrogate.

Exclusion Criteria:

1. Intracranial hemorrhage (ICH) identified by CT or MRI.

2. Rapidly improving symptoms, particularly if in the judgment of the managingclinician that the improvement is likely to result in the patient withouteligibility criteria.

3. Pre-stroke mRS score of ≥ 2 (indicating previous disability)

4. Contra indication to imaging with MR or CT with contrast agents.

5. Infarct core >1/3 MCA territory qualitatively or >50 mL quantitatively (determinedby DWI lesion on MR).

6. Participation in any investigational study in the previous 30 days

7. Any terminal illness such that patient would not be expected to survive more than 1year).

8. Baseline platelet count < 100.000/µL

9. Woman of childbearing potential who is known to be pregnant or who has a positivepregnancy test on admission.

10. Previous stroke within last three months.

11. Recent past history or clinical presentation of ICH, subarachnoid hemorrhage (SAH),arterio-venous (AV) malformation, aneurysm, or cerebral neoplasm other thanmeningioma.

12. Current use of oral anticoagulants and a prolonged prothrombin time (INR > 1.6).

13. Use of heparin, except for low dose subcutaneous heparin, in the previous 48 hoursand a prolonged partial thromboplastin time exceeding the upper limit of the locallaboratory normal range

14. Use of glycoprotein IIb - IIIa inhibitors within the past 72 hours. Use of singleagent oral platelet inhibitors (clopidogrel or low-dose aspirin) prior to studyentry is permitted.

15. Clinically significant hypoglycemia.

16. Uncontrolled hypertension defined by a blood pressure > 185 mmHg systolic or >110mmHg diastolic on at least 2 separate occasions at least 10 minutes apart, orrequiring aggressive treatment to reduce the blood pressure to within these limits.The definition of "aggressive treatment" is left to the discretion of theresponsible Investigator.

17. Hereditary or acquired hemorrhagic diathesis.

18. Gastrointestinal or urinary bleeding within the preceding 21 days.

19. Major surgery within the preceding 14 days which poses risk in the opinion of theInvestigator.

20. Exposure to a thrombolytic agent within the previous 72 hours.

21. Subject participating in a study involving an investigational drug or device thatwould impact this study.