• Acute ischemic stroke where patient is ineligible for IV thrombolytic treatment with Alteplase due to onset \>4.5 hours and is ineligible for endovascular treatment under standard of care due to absence of proximal arterial occlusion (e.g. intracranial ICA, MCA-M1 and dominant M2 segments, and vertebrobasilar arteries).

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

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

• Age ≥18 years (no upper age limit).

• Clinical or imaging mismatch evidence in distal artery territories, defined as one of 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 addition or not of motor symptoms OR any motor deficit accompanied of cortical symptoms of any severity;

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

∙ Arterial head angiotomography or arterial head angioMRI WITHOUT proximal intracranial artery occlusion that would require endovascular therapy (for example, ICA intracranial, MCA-M1 and M2 dominant segments and vertebral and 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 the vascular territory corresponding to the clinical manifestation;

∙ Arterial head angioCT or arterial head MRI WITHOUT proximal intracranial artery occlusion that would require endovascular therapy (for example, ICA intracranial, MCA-M1 and M2 dominant segments and vertebral and basilar arteries)

∙ Arterial head angioCT with distal occlusion on MIP or wedge-shaped lesion on parenchymography on the source-image of angiotomography OR CT perfusion with 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 NCCT can be used to exclude patients if the investigator believes that its volume assessment is more reliable that the CTP in any particular case.

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

⁃ Mismatch Ratio \>1.4

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

‣ Patients who have woken up with the symptoms and don't have a mismatch FLAIR-DWI according to the WAKE-UP Trial image criteria will have their window considered to be \>4.5 hours. In this case, the time last seen well must have been 12 hours at most.

• Informed consent obtained from patient or acceptable patient surrogate.