Multi-arm Optimization of Stroke Thrombolysis

Study Overview
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Brief Summary
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The primary efficacy objective of the MOST trial is to determine if argatroban (100µg/kg bolus followed by 3µg/kg per minute for 12 hours) or eptifibatide (135µg/kg bolus followed by 0.75µg/kg/min infusion for two hours) results in improved 90-day modified Rankin scores (mRS) as compared with placebo in acute ischemic stroke (AIS) patients treated with standard of care thrombolysis (0.9mg/kg IV rt-PA or 0.25mg/kg IV tenecteplase or TNK) within three hours of symptom onset. Patients may also receive endovascular thrombectomy (ET) per usual care. Time of onset is defined as the last time the patient was last known to be well.

Official Title
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Multi-arm Optimization of Stroke Thrombolysis (MOST): a Single Blinded, Randomized Controlled Adaptive, Multi-arm, Adjunctive-thrombolysis Efficacy Trial in Ischemic Stroke

Conditions
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Acute Ischemic Stroke

Intervention / Treatment
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* Drug: Argatroban
* Drug: Eptifibatide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Acute ischemic stroke patients Treated with 0.9mg/kg IV rt-PA or 0.25mg/kg IV TNK within 3 hours of stroke onset or time last known well Age ≥ 18 NIHSS score ≥ 6 prior to IV thrombolysis Able to receive assigned study drug within 60 minutes but no later than 75 minutes of initiation of IV thrombolysis Exclusion Criteria: Known allergy or hypersensitivity to argatroban or eptifibatide Previous stroke in the past 90 days Previous intracranial hemorrhage, neoplasm, subarachnoid hemorrhage, or arterial venous malformation Clinical presentation suggested a subarachnoid hemorrhage, even if initial CT scan was normal Any surgery, or biopsy of parenchymal organ in the past 30 days Trauma with internal injuries or ulcerative wounds in the past 30 days Severe head trauma in the past 90 days Systolic blood pressure persistently >180mmHg post-IV thrombolysis despite antihypertensive intervention Diastolic blood pressure persistently >105mmHg post-IV thrombolysis despite antihypertensive intervention Serious systemic hemorrhage in the past 30 days Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency, or oral anticoagulant therapy with INR >1.5 Positive urine or serum pregnancy test for women of child bearing potential Glucose <50 or >400 mg/dl Platelets <100,000/mm3 Hematocrit <25 % Elevated pre-thrombolysis PTT above laboratory upper limit of normal Creatinine > 4 mg/dl Ongoing renal dialysis, regardless of creatinine Received Low Molecular Weight heparins (such as Dalteparin, Enoxaparin, Tinzaparin) in full dose within the previous 24 hours Abnormal PTT within 48 hours prior to randomization after receiving heparin or a direct thrombin inhibitor (such as bivalirudin, argatroban, dabigatran or lepirudin) Received Factor Xa inhibitors (such as Fondaparinaux, apixaban or rivaroxaban) within the past 48 hours Received glycoprotein IIb/IIIa inhibitors within the past 14 days Pre-existing neurological or psychiatric disease which confounded the neurological or functional evaluations e.g., baseline modified Rankin score >3 Other serious, advanced, or terminal illness or any other condition that the investigator felt would pose a significant hazard to the patient if rt-PA, TNK, eptifibatide or argatroban therapy was initiated a. Example: known cirrhosis or clinically significant hepatic disease Current participation in another research drug treatment or interventional device trial - Subjects could not start another experimental agent until after 90 days Informed consent from the patient or the legally authorized representative was not or could not be obtained High density lesion consistent with hemorrhage of any degree Large (more than 1/3 of the middle cerebral artery) regions of clear hypodensity on the baseline CT Scan. Sulcal effacement and/or loss of grey-white differentiation alone are not contraindications for treatment

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Argatroban<br>100µg/kg bolus followed by 3µg/kg per minute for 12 hours | Drug: Argatroban<br>* Direct Thrombin Inhibitor - Argatroban is a derivative of arginine that competitively binds to the active site of thrombin thereby preventing fibrin deposition. With a half-life of 30 minutes, argatroban has an immediate anticoagulant effect after IV administration which is rapidly reversed with discontinuation of the drug.<br>|
| Experimental: Eptifibatide<br>135µg/kg bolus followed by 0.75µg/kg/min infusion for two hours | Drug: Eptifibatide<br>* GP 2b/3a Receptor Inhibitor - The final step of platelet aggregation is mediated via the GP2b/3a receptor. Eptifibatide was specifically developed to ensure rapid inhibition of platelet aggregation (within 15 minutes), a short half-life ( 2 hours) and rapid dissociation from platelets with 50% restoration of platelet function within 2-4 hours of discontinuation.<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* IV placebo solution<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 90-day modified Rankin scores (mRS) |  | 90 days after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| proportion of participants with NIHSS less than or equal to 2 at 24 hours |  | 2 at 24 hours after randomization | 
| change from baseline to 24-hour NIHSS |  | 24 hours after randomization | 
| proportion of participants with 90-day mRS 0-1 (or return to their historical mRS) |  | 90 days after randomization | 
| proportion of participants with 90-day mRS 0-2 (or return to their historical mRS) |  | 90 days after randomization | 
| 90-day ordinal analysis of the mRS |  | 90 days after randomization | 
| 90-day EQ-5D |  | 90 days after randomization | 
| proportion of participants who have thrombectomy |  | baseline |