A Randomized Controlled Trial of TNK-tPA Versus Standard of Care for Minor Ischemic Stroke With Proven Occlusion
A Randomized Controlled Trial of TNK-tPA Versus Standard of Care for Minor Ischemic Stroke With Proven Occlusion
This trial will enroll patients that have been diagnosed with a transient ischemic attack
 (TIA) or minor stroke that has occurred within the past 12 hours. Anyone diagnosed with a
 minor stroke faces the possibility of long-term disability and even death, regardless of
 treatment. Stroke symptoms such as weakness, difficulty speaking and paralysis may improve or
 worsen over the hours or days immediately following a stroke. TEMPO-2 is a minor stroke trial
 for patients presenting within 12 hours of their symptom onset. Patients will be randomized
 to TNK-tPA or standard of care. In the intervention group TNK-tPA is given as a single,
 intravenous bolus (0.25mg/Kg) immediately upon randomization. Maximum dose 50mg. The control
 group will receive antiplatelet agent(s) as decided by the treating physician. Antiplatelet
 agent(s) choice will be at the treating physician's discretion.

 TEMPO-2 Coordinating Centre is located in Calgary, AB, Canada. There will be approximately 50
 sites participating worldwide.

 Dr. Shelagh Coutts is the Principal Investigator.
TEMPO2 is an multicentre, prospective randomized open label, blinded-endpoint (PROBE)
 controlled trial of thrombolysis with low dose Tenecteplase (TNK-tPA) versus standard of
 care. A total of 1274 patients will be enrolled, at approximately 50 sites worldwide.

 TEMPO-2 will enroll patients within a 12 hour time window with a NIHSS score of <6 and an
 ASPECTS >7. All patients will be evaluated clinically and then undergo brain imaging using CT
 followed immediately by a CT angiogram. Patients must have an intracranial occlusion on CTA
 or CTP.

 Randomization will be 1:1 to TNK-tPA (experimental) or standard of care antiplatelet agents
 (control).

 Experimental: TNK-tPA (0.25mg/kg) given as a single, intravenous bolus immediately upon
 randomization. Experimental treatment will be administered as a single intravenous bolus over
 1-2 minutes.

 Control: Patients will be treated with standard of care based antiplatelet treatment - choice
 at the discretion of the investigator. Low dose aspirin (single agent) will be the choice of
 most physicians, some will chose to use the combination of aspirin and clopidogrel. The local
 investigator to chose which antithrombotic regime should be used

 All patients will be treated within 90 minutes of the first slice of the baseline CT.
 Patients will undergo a study CT angiogram of the intracranial circulation between 4-8 hours
 after treatment to determine whether the occluded artery has recanalized or not. In sites
 where MRI/MRA is routinely used this can be substituted for CT/CTA. Any patient who has
 neurological worsening should have standard of care brain imaging completed to rule out
 intracranial hemorrhage.

 All patients will have standard of care medical management on an acute stroke unit and
 undergo follow-up imaging at 24 hours with CT or MR. Use of MR will be encouraged.

 Patients will be assessed at 24 hours and at Days 5 and 90. The Day 90 Outcomes will be
 performed by a blinded assessor.
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 on physical
 neurological examination.

 4. Any acute intracranial occlusion or near occlusion (TICI 0 or 1) (MCA, ACA, PCA, VB
 territories) defined by non-invasive acute imaging (CT angiography or MR angiography)
 that is neurologically relevant to the presenting symptoms and signs. Multiphase CTA
 or CT perfusion are required for this study. An acute occlusion is defined as TICI 0
 or TICI 1 flow.1 Practically this can include a small amount of forward flow in the
 presence of a near occlusion AND, Delayed washout of contrast with pial vessels on
 multiphase CTA in a region of brain concordant with clinical symptoms and signs OR,
 Any area of focal perfusion abnormality identified using CT or MR perfusion - e.g.
 transit delay (TTP, MTT or T Max), in a region of brain concordant 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 can
 be repeated to meet this requirement; if there is no change neurologically then only a
 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 matter
 hypodensity at a similar density to white matter or in the judgment of the enrolling
 neurologist is consistent with a subacute ischemic stroke > 12 hours of age.

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

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

 6. Pregnancy

 7. Planned thrombolysis with IV tPA or endovascular thrombolysis/thrombectomy treatment.

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

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

 -  International normalized ratio > 1.7 or known full anticoagulation with use of
 any standard or direct oral anticoagulant therapy with full anticoagulant dosing.
 [DVT prophylaxis dosing shall not prohibit enrolment]. For low molecular weight
 heparins (LMWH) more than 48 hours off drug will be considered sufficient to
 allow trial enrollment. For direct oral anticoagulants; in patients with normal
 renal function more than 48 hours off drug will be considered sufficient to allow
 trial enrollment. Patients on direct oral anticoagulants who have any degree of
 renal impairment should not be enrolled in 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 are
 known not to be taking anticoagulant therapy it is not necessary to wait for
 coagulation 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 months
 that would normally preclude use of a thrombolytic agent.

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

 -  Major surgery within the last 3 months at a bodily site where bleeding could
 result in serious harm or death.

 -  Known platelet count below 100,000 per cubic millimeter. Treatment should not be
 delayed to wait for platelet count unless thrombocytopenia is known or suspected.

 -  Gastrointestinal or genitourinary bleeding within the past 3 months that is
 unresolved or associated with persisting anemia such that thrombolytic treatment
 of any kind would result in serious bleeding or death.