Randomized Controlled Trial of Argatroban With Tissue Plasminogen Activator (tPA) for Acute Stroke

Inclusion Criteria: * Disabling Ischemic stroke symptoms with onset \< 3 hours treated with IV rt-PA by local standards\*. \* or ≤ 4.5 hours according to local standard of care. * NIHSS ≥ 10\* or any NIHSS with an intracranial clot should be demonstrated on neurovascular imaging (TCD or CTA) in any one of the following areas: distal internal carotid artery (ICA) carotid artery (CA), middle cerebral artery (MCA - M1 or M2), posterior cerebral artery (PCA - P1 or P2), distal vertebral or basilar artery. * TCD criteria: Thrombolysis in brain ischemia (TIBI) 0, 1, 2 or 3 - CT-Angiogram: thrombolysis in myocardial ischemia (TIMI) 0 or 1 \* NIHSS ≥ 10, demonstration of clot on neuroimaging is not necessary (i.e., enrollment can proceed with non-contrast head CT alone), but if performed, a clot must be demonstrated. * For those patients who will undergo repeat CT-Angiogram at 2-3 hours, estimated glomerular filtration rate (eGFR) must be ≥ 60 mL/min/1.73m2. * Females of childbearing potential must have a negative serum pregnancy test (HCG) prior to the administration of trial medication. * Signed (written) informed consent by the patient or the patient's legal representative and/or guardian. Exclusion Criteria: * Patients whom the treating physician is planning (or could plan) to treat with intra-arterial thrombolysis or other endovascular procedures (i.e., mechanical clot retrieval) aimed at recanalization. * Evidence of intracranial hemorrhage (ICH) on baseline CT scan or diagnosis of a non-vascular cause of neurologic deficit. * National institute health stroke scale (NIHSS) Level of Consciousness score (1a) ≥ 2. * Pre-existing disability with mRS ≥ 2. * CT scan findings of hypoattenuation of the x-ray signal (hypodensity) involving ≥ 1/3 of the MCA territory. * Any evidence of clinically significant bleeding, or known coagulopathy. * INR \>1.5. * Patients with an elevated activated partial thromboplastin time (aPTT) greater than the upper limit of normal * Patients currently, or within the previous 24 hours, on an oral direct thrombin inhibitor (i.e., dabigatran). * Heparin flush required for an IV line. Line flushes with saline only. * Any history of intra-cranial hemorrhage, known arteriovenous -malformation or unsecured cerebral aneurysms. * Significant bleeding episode \[e.g. gastrointestinal (GI) or urinary tract\] within the 3 weeks before study enrollment. * Major surgery or serious trauma in last 2 weeks. * Patients who have had an arterial puncture at a non-compressible site, biopsy of parenchymal organ, or lumbar puncture within the last 2 weeks. * Previous stroke, myocardial infarction (MI), post myocardial infarction pericarditis, intracranial surgery, or significant head trauma within 3 months. * Uncontrolled hypertension \[Systolic blood pressure (SBP) \> 185 mmHg or diastolic blood pressure (DBP) \>110 mmHg\] that does not respond to intravenous anti-hypertensive agents. * Surgical intervention (any reason) anticipated within the next 48 hours. * Known history of clinically significant hepatic dysfunction or liver disease - including a current history of alcohol abuse. * Abnormal blood glucose \<50 mg/dL (2.7 mmol/L). * History of primary or metastatic brain tumor. * Current platelet count \< 100,000/mm3. * Life expectancy \< 3 months. * Patient who, in the judgment of the investigator, needs to be on concomitant (i.e., during the Argatroban infusion) anticoagulants other than Argatroban, including any form of heparin, unfractionated heparin (UFH), low molecular weight heparin (LMWH), defibrinogenating agent, dextran, other direct thrombin inhibitors or thrombolytic agents, glycoprotein llb/llla (GPIIb/IIIa) inhibitor or warfarin. * Participated in any investigational study within 30 days before the first dose of study medication. * Known hypersensitivity to Argatroban or its agents. * Additional exclusion criteria if patient presents between 3-4.5 hours: 1. Age \>80 2. Currently taking oral anticoagulants (regardless of INR) 3. A history of stroke and diabetes. 4. NIHSS \> 25.