A Randomized Controlled Trial of TNK-tPA Versus Standard of Care for Minor Ischemic Stroke With Proven Occlusion

Inclusion Criteria:

1. Acute ischemic stroke in an adult patient (18 years of age or older)

2. Onset (last-seen-well) time to treatment time ≤ 12 hours.

3. TIA or minor stroke defined as a baseline NIHSS ≤ 5 at the time of randomization.Patients do not have to have persistent demonstrable neurological deficit onphysical neurological examination.

4. Any acute intracranial occlusion or near occlusion (TICI 0 or 1) (MCA, ACA, PCA, VBterritories) defined by non-invasive acute imaging (CT angiography or MRangiography) that is neurologically relevant to the presenting symptoms and signs.Multiphase CTA or CT perfusion are required for this study. An acute occlusion isdefined as TICI 0 or TICI 1 flow.1 Practically this can include a small amount offorward flow in the presence of a near occlusion AND, Delayed washout of contrastwith pial vessels on multiphase CTA in a region of brain concordant with clinicalsymptoms and signs OR, Any area of focal perfusion abnormality identified using CTor MR perfusion - e.g. transit delay (TTP, MTT or T Max), in a region of brainconcordant with clinical symptoms and signs.

5. Pre-stroke independent functional status - structured mRS ≤2.

6. Informed consent from the patient or surrogate.

7. Patients can be treated within 90 minutes of the first slice of CT or MRI. Scans canbe repeated to meet this requirement; if there is no change neurologically then onlya CT head need be repeated for assessment of extent and depth of ischemia.

Exclusion Criteria:

1. Hyperdensity on NCCT consistent with intracranial hemorrhage.

2. Large acute stroke ASPECTS < 7 visible on baseline CT scan.

3. Core of established infarction. No large area (estimated > 10 cc) of grey matterhypodensity at a similar density to white matter or in the judgment of the enrollingneurologist is consistent with a subacute ischemic stroke > 12 hours of age.

4. Clinical history, past imaging or clinical judgment suggest that that intracranialocclusion is chronic.

5. Patient has a severe or fatal or disabling illness that will prevent improvement orfollow-up or such that the treatment would not likely benefit the patient.

6. Pregnancy

7. Planned thrombolysis with IV tPA or endovascular thrombolysis/thrombectomytreatment.

8. In-hospital stroke unless these patients are at their baseline prior to theirstroke. E.g. a patient who had a stroke during a diagnostic coronary angiogram.

9. Commonly accepted exclusions for medical thrombolytic treatment. These are commonlyrelative contraindications (i.e. the final decision is at the discretion of thetreating physician) but for the purposes of TEMPO-2 include the following:

• International normalized ratio > 1.7 or known full anticoagulation with use ofany standard or direct oral anticoagulant therapy with full anticoagulantdosing. [DVT prophylaxis dosing shall not prohibit enrolment]. For lowmolecular weight heparins (LMWH) more than 48 hours off drug will be consideredsufficient to allow trial enrollment. For direct oral anticoagulants; inpatients with normal renal function more than 48 hours off drug will beconsidered sufficient to allow trial enrollment. Patients on direct oralanticoagulants who have any degree of renal impairment should not be enrolledin the trial unless they have not taken a dose of the drug in the last 5 days.Dual antiplatelet therapy does not prohibit enrolment.

• Dual antiplatelet therapy does not prohibit enrolment. [For patients who areknown not to be taking anticoagulant therapy it is not necessary to wait forcoagulation lab results (e.g. PT, PTT) prior to treatment]

• Patients who have been acutely treated with GP2b3a inhibitors.

• Arterial puncture at a non-compressible site in the previous seven days

• Clinical stroke or serious head or spinal trauma in the preceding three monthsthat would normally preclude use of a thrombolytic agent.

• History of intracranial hemorrhage, subarachnoid hemorrhage or other brainhemorrhage that would normally preclude use of a thrombolytic agent.

• Major surgery within the last 3 months at a bodily site where bleeding couldresult in serious harm or death.

• Known platelet count below 100,000 per cubic millimeter. Treatment should notbe delayed to wait for platelet count unless thrombocytopenia is known orsuspected.

• Gastrointestinal or genitourinary bleeding within the past 3 months that isunresolved or associated with persisting anemia such that thrombolytictreatment of any kind would result in serious bleeding or death.