Multi-arm Optimization of Stroke Thrombolysis (MOST)

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Acute Ischemic Stroke
• Intervention / Treatment: Drug: Argatroban; Drug: Eptifibatide; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 514
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Opeolu Adeoye, MD; Phone Number: 314-747-4156; Email: adeoye@wustl.edu
• Study Contact Backup: Name: Andrew Barreto, MD; Phone Number: 713-500-7002; Email: Andrew.d.barreto@uth.tmc.edu

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • University of Alabama Hospital
  • California
    • Fullerton, California, United States, 92835
      • St. Jude Medical Center
    • La Jolla, California, United States, 92037
      • UCSD Health La Jolla
    • Los Angeles, California, United States, 90048
      • Cedars-Sinai Medical Center
    • Los Angeles, California, United States, 90027
      • Kaiser Permanente Los Angeles Medical Center
    • Orange, California, United States, 92868
      • UC Irvine Medical Center
    • San Diego, California, United States, 92103
      • UCSD Medical Center - Hillcrest Hospital
    • San Francisco, California, United States, 94110
      • San Francisco General Hospital
    • San Francisco, California, United States, 94143
      • UCSF Medical Center
    • Santa Barbara, California, United States, 93105
      • Santa Barbara Cottage Hospital
  • Connecticut
    • New Haven, Connecticut, United States, 06510
      • Yale New Haven Hospital
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Hospital
    • Jacksonville, Florida, United States, 32207
      • Baptist Medical Center Jacksonville
    • Miami, Florida, United States, 33136
      • Jackson Memorial Hospital
    • Sarasota, Florida, United States, 34239
      • Sarasota Memorial Hospital
    • Tampa, Florida, United States, 33606
      • Tampa General Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30303
      • Grady Memorial Hospital
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medical Center
    • Maywood, Illinois, United States, 60153
      • Loyola University Medical Center
    • Rockford, Illinois, United States, 61114
      • Javon Bea Hospital - Riverside
    • Winfield, Illinois, United States, 60190
      • Central DuPage Hospital
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University Of Kansas Hospital
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky Hospital
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Worcester, Massachusetts, United States, 01655
      • Umass Memorial Medical Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan University Hospital
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
    • Flint, Michigan, United States, 48532
      • McLaren Flint
    • Grand Rapids, Michigan, United States, 49503
      • Trinity Health Saint Mary's
  • Minnesota
    • Edina, Minnesota, United States, 55425
      • Fairview Southdale Hospital
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota Medical Center Hospital
    • Saint Paul, Minnesota, United States, 55101
      • Regions Hospital
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Saint Luke's Hospital
    • Saint Louis, Missouri, United States, 63110
      • Barnes Jewish Hospital
    • Saint Louis, Missouri, United States, 63108
      • St. Louis University Hospital
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • University of New Mexico Hospital
  • New York
    • Manhasset, New York, United States, 11030
      • North Shore University Hospital
    • New York, New York, United States, 10003
      • Mount Sinai Beth Israel
    • Syracuse, New York, United States, 13210
      • SUNY Upstate University Hospital
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27103
      • Wake Forest Baptist Medical Center
    • Winston-Salem, North Carolina, United States, 27103
      • Forsyth Medical Center
  • Ohio
    • Akron, Ohio, United States, 44307
      • Cleveland Clinic Akron General
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati Medical Center
    • Cincinnati, Ohio, United States, 45236
      • The Jewish Hospital
    • Cincinnati, Ohio, United States, 45211
      • Mercy Health West Hospital
    • Columbus, Ohio, United States, 43210
      • OSU Wexner Medical Center
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74104
      • St. John Medical Center
  • Pennsylvania
    • Abington, Pennsylvania, United States, 19001
      • Abington Memorial Hospital
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Hospital
    • Pittsburgh, Pennsylvania, United States, 15213
      • UPMC Presbyterian Hospital
    • Pittsburgh, Pennsylvania, United States, 15219
      • UPMC Mercy Hospital
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
    • Greenville, South Carolina, United States, 29605
      • Prisma Health Greenville Memorial Hospital
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Hospital
  • Texas
    • Houston, Texas, United States, 77030
      • Houston Methodist Hospital
    • Houston, Texas, United States, 77030
      • Memorial Hermann-Texas Medical Center
    • McAllen, Texas, United States, 78503
      • South Texas Health System McAllen
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah Healthcare
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • UVA Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Acute ischemic stroke patients
2. 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
3. Age ≥ 18
4. NIHSS score ≥ 6 prior to IV thrombolysis
5. Able to receive assigned study drug within 60 minutes but no later than 75 minutes of initiation of IV thrombolysis

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. Any surgery, or biopsy of parenchymal organ in the past 30 days
6. Trauma with internal injuries or ulcerative wounds in the past 30 days
7. Severe head trauma in the past 90 days
8. Systolic blood pressure persistently >180mmHg post-IV thrombolysis despite antihypertensive intervention
9. Diastolic blood pressure persistently >105mmHg post-IV thrombolysis despite antihypertensive intervention
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 or serum 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 pre-thrombolysis 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 14 days
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, TNK, eptifibatide or argatroban therapy was initiated

    a. Example: known cirrhosis or clinically significant hepatic disease

25. Current participation in another research drug treatment or interventional device trial - 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; IV placebo solution
Experimental: Argatroban; 100µg/kg bolus followed by 3µg/kg per minute for 12 hours	Drug: Argatroban; 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.
Experimental: Eptifibatide; 135µg/kg bolus followed by 0.75µg/kg/min infusion for two hours	Drug: Eptifibatide; 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.

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS)
• Investigators: Principal Investigator: Opeolu Adeoye, MD, Washington University School of Medicine

Publications and helpful links

General Publications

• Deeds SI, Barreto A, Elm J, Derdeyn CP, Berry S, Khatri P, Moy C, Janis S, Broderick J, Grotta J, Adeoye O. The multiarm optimization of stroke thrombolysis phase 3 acute stroke randomized clinical trial: Rationale and methods. Int J Stroke. 2021 Oct;16(7):873-880. doi: 10.1177/1747493020978345. Epub 2020 Dec 9.

Study record dates

Study Major Dates

• Study Start (Actual): October 15, 2019
• Primary Completion (Actual): December 1, 2023
• Study Completion (Estimated): April 1, 2025

Study Registration Dates

• First Submitted: November 7, 2018
• First Submitted That Met QC Criteria: November 7, 2018
• First Posted (Actual): November 8, 2018

Study Record Updates

• Last Update Posted (Actual): March 15, 2024
• Last Update Submitted That Met QC Criteria: March 13, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke; Ischemic Stroke; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Protease Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Argatroban; Eptifibatide
• Other Study ID Numbers: 2018-1464; 1U01NS100699-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No