Principal Investigator: Vivek Reddy
Keywords: Acute Ischemic Stroke , Thrombolysis , Intracranial Hemorrhage , Parenchymal Hemorrhage Department: Neurology
IRB Number: 00118582 Co Investigator: Adam  DeHavenon
Specialty: Neurology, Neurology
Sub Specialties: Neuro Critical Care, Stroke
Recruitment Status: Recruiting

Contact Information

Kinga Aitken
kinga.aitken@hsc.utah.edu
801-581-5523

Brief Summary

The MOST trial is a multi-arm, adaptive, blinded, randomized controlled Phase 3 clinical trial conducted at approximately 110 sites to determine whether argatroban and/or eptifibatide is superior to placebo in improving 90-day modified Rankin scores (mRS) in acute ischemic stroke (AIS) patients treated with IV rt-PA (0.9mg/kg) within three hours of symptom onset.

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 0.9mg/kg IV rt-PA within three hours of symptom onset. Patients may also receive endovascular thrombectomy (ET) per usual care.

The primary safety objective of the MOST trial is to determine the safety of argatroban and eptifibatide in combination with IV rt-PA with or without ET per usual care, where safety is measured by symptomatic intracranial hemorrhage (sICH) within 36 hours from randomization.

Detailed Description

This is a three-arm, adaptive, Phase-3, blinded, randomized controlled clinical trial at approximately 110 sites in the United States. The first 150 subjects will be randomized 1:1:1. From 150-500 patients, response adaptive randomization (RAR) will favor the treatment arm showing the greatest benefit based on accrued data. After 500 patients, one or both intervention arms may be carried forward for fixed randomization versus IV rt-PA. A maximum of 1200 patients will be enrolled.The primary efficacy outcome for MOST will be the 90-day mRS translated into utilities, which measure cost- effectiveness and benefits of a given intervention from the patient’s perspective. The primary safety outcome is sICH. Secondary outcomes include a comparison between treatment groups of: the proportion of participants with NIHSS ≤2 at 24 hours; change from baseline to 24-hour NIHSS; proportion with 90-day mRS 0 or 1 and 0- 2; 90-day ordinal analysis of the mRS; 90-day EQ-5D; the proportion of participants who have thrombectomy; the proportion of participants with parenchymal hemorrhage types 1 (PH-1) and 2 (PH-2); any ICH on brain imaging within 36 hours of randomization; major hemorrhage (defined as requiring >2 units packed red blood cells) other than intracranial hemorrhage within 7 days; 90-day all-cause mortality; evaluation of treatment effect in ET and non-ET subjects; and, evaluation of race/ethnicity and gender differences in treatment effect.

Inclusion Criteria

Inclusion Criteria
1. Acute ischemic stroke patients
2. Treated with 0.9mg/kg IV rt-PA within 3 hours of stroke onset or time last knownwell
3. Age ≥ 18
4. NIHSS score ≥ 6 prior to IV rt-PA
5. Able to receive assigned study drug within 60 minutes of initiation of IVrt-PA

Exclusion Criteria

1. Known allergy or hypersensitivity to argatroban or eptifibatide
2. Previous stroke in the past 90 days
3. Previous intracranial hemorrhage, neoplasm, subarachnoid hemorrhage, or arterial venous malformation
4. Clinical presentation suggested a subarachnoid hemorrhage, even if initial CT scan was normal
5. Surgery or biopsy of parenchymal organ in the past 30 days
6. Trauma with internal injuries or ulcerative wounds in the past 30days
7. Severe head trauma in the past 90 days
8. Systolic blood pressure >180mmHg post-IV rt-PA
9. Diastolic blood pressure >105mmHg post-IV rt-PA
10. Serious systemic hemorrhage in the past 30 days
11. Known hereditary or acquired hemorrhagic diathesis, coagulation factor deficiency, or oral anticoagulant therapy with INR >1.5
12. Positive urine pregnancy test for women of child bearing potential
13. Glucose <50 or >400 mg/dl
14. Platelets <100,000/mm3
15. Hematocrit <25 %
16. Elevated PTT above laboratory upper limit of normal
17. Creatinine > 4 mg/dl
18. Ongoing renal dialysis, regardless of creatinine
19. Received Low Molecular Weight heparins (such as Dalteparin, Enoxaparin, Tinzaparin) in full dose within the previous 24 hours
20. Abnormal PTT within 48 hours prior to randomization after receiving heparin or a direct thrombin inhibitor (such as bivalirudin, argatroban, dabigatran or lepirudin)
21. Received Factor Xa inhibitors (such as Fondaparinaux, apixaban or rivaroxaban) within the past 48 hours
22. Received glycoprotein IIb/IIIa inhibitors within the past 14days
23. Pre-existing neurological or psychiatric disease which confounded the neurological or functional evaluations e.g., baseline modified Rankin score >3
24. 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, eptifibatide or argatroban therapy wasinitiated
a. Example: known cirrhosis or clinically significant hepatic disease
25. Current participation in another research drug treatment protocol - Subjects could not start another experimental agent until after 90 days
26. Informed consent from the patient or the legally authorized representative was not or could not be obtained
27. High density lesion consistent with hemorrhage of any degree
28. 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