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

Study Overview
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Brief Summary
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Randomized controlled clinical trial to estimate overall treatment benefit (improvement in disability) among stroke patients treated with rt-PA who are randomized to also receive either low-dose Argatroban, high-dose Argatroban or neither.

Detailed Description
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Recombinant tissue plasminogen activator (rt-PA), the only proven treatment for acute ischemic stroke, fails to reperfuse brain in most patients with large thrombi. In our Phase 2a low-dose safety study (n=65), the two drugs appeared safe when delivered concomitantly and recanalization rates were greater than historical controls. This study will provide evidence-based hypotheses and data needed to design a larger definitive trial. The purpose of this trial is to estimate overall treatment benefit (improvement in disability) among stroke patients treated with rt-PA who are randomized to also receive either low-dose Argatroban, high-dose Argatroban or neither.

Official Title
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ARTSS-2: A Pilot, Phase 2b, Randomized, Multi-center Trial of Argatroban in Combination With Recombinant Tissue Plasminogen Activator for Acute Stroke

Conditions
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Ischemic Stroke

Intervention / Treatment
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* Drug: Low Dose Argatroban
* Drug: High Dose Argatroban
* Drug: rt-PA (alteplase)


Participation Criteria
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Eligibility Criteria
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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: Age >80 Currently taking oral anticoagulants (regardless of INR) A history of stroke and diabetes. NIHSS > 25.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low dose Argatroban + rt-PA (alteplase)<br>100 micrograms/kilogram bolus, followed by 1 microgram/kilogram/minute IV infusion for 48 hours and rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour | Drug: Low Dose Argatroban<br>* 100 micrograms/kilogram bolus, followed by 1 microgram/kilogram/minute IV infusion for 48 hours and rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour<br>* Other names: Argatroban;Drug: rt-PA (alteplase)<br>* rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour<br>|
| Experimental: High dose Argatroban + rt-PA (alteplase)<br>100 micrograms/kilogram bolus, followed by 3 micrograms/kilogram/minute IV infusion for 48 hours and rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour | Drug: High Dose Argatroban<br>* 100 micrograms/kilogram bolus, followed by 3 micrograms/kilogram/minute IV infusion for 48 hours and rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour<br>* Other names: Argatroban;Drug: rt-PA (alteplase)<br>* rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour<br>|
| Active Comparator: rt-PA (alteplase)<br>rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour | Drug: rt-PA (alteplase)<br>* rt-PA (alteplase) 0.9mg/kg (max dose 90mg) - 10% bolus, then 90% over 1-hour<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With 0 or 1 on Modified Rankin Scale | Excellent functional outcome as measured by the number of patients with a 0 or 1 on the modified Rankin Scale (mRS) at day 90 as assessed by study personnel blinded to treatment. | 90 days | 
| Number of Participants With Symptomatic Intracranial Hemorrhage Within 48 Hours of tPA Administration | Symptomatic intracranial hemorrhage (sICH) is defined as any evidence of bleeding on CT scan that in the opinion of the treating physician and/or an independent safety monitor is associated with a clinically significant neurological worsening. A four or more point increase in the NIHSS score from baseline (or last score obtained prior to blood found on CT scan) to subsequent CT scan at the time of potential worsening can be used as a guide by the clinical investigator or safety monitor for what represents a significant worsening in neurologic status but sICH can include any worsening deemed significant by the clinical investigator or independent safety monitor. | 48-hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stroke, Argatroban, thrombin-inhibition, thrombolysis, anticoagulation