Multi-arm Optimization of Stroke Thrombolysis

NCT ID: NCT03735979

Last Updated: 2025-02-07

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 514 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-10-15
• Study Completion Date: 2024-10-31

Brief Summary

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.

Conditions

Acute Ischemic Stroke

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Argatroban

100µg/kg bolus followed by 3µg/kg per minute for 12 hours

Group Type: EXPERIMENTAL

Argatroban

Intervention Type: DRUG

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.

Eptifibatide

135µg/kg bolus followed by 0.75µg/kg/min infusion for two hours

Group Type: EXPERIMENTAL

Eptifibatide

Intervention Type: DRUG

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.

Placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

IV placebo solution

Interventions

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.

Intervention Type: 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.

Intervention Type: DRUG

Placebo

IV placebo solution

Intervention Type: DRUG

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Neurological Disorders and Stroke (NINDS)

NIH

Sponsor Role: collaborator

Washington University School of Medicine

OTHER

Sponsor Role: lead

Responsible Party

Opeolu Makanju Adeoye

Professor and Chair, Department of Emergency Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Opeolu Adeoye, MD

Role: PRINCIPAL_INVESTIGATOR

Washington University School of Medicine

Locations

University of Alabama Hospital

Birmingham, Alabama, United States

St. Jude Medical Center

Fullerton, California, United States

UCSD Health La Jolla

La Jolla, California, United States

Kaiser Permanente Los Angeles Medical Center

Los Angeles, California, United States

Cedars-Sinai Medical Center

Los Angeles, California, United States

UC Irvine Medical Center

Orange, California, United States

UCSD Medical Center - Hillcrest Hospital

San Diego, California, United States

San Francisco General Hospital

San Francisco, California, United States

UCSF Medical Center

San Francisco, California, United States

Santa Barbara Cottage Hospital

Santa Barbara, California, United States

Yale New Haven Hospital

New Haven, Connecticut, United States

Baptist Medical Center Jacksonville

Jacksonville, Florida, United States

Mayo Clinic Hospital

Jacksonville, Florida, United States

Jackson Memorial Hospital

Miami, Florida, United States

Sarasota Memorial Hospital

Sarasota, Florida, United States

Tampa General Hospital

Tampa, Florida, United States

Grady Memorial Hospital

Atlanta, Georgia, United States

University of Chicago Medical Center

Chicago, Illinois, United States

Loyola University Medical Center

Maywood, Illinois, United States

Javon Bea Hospital - Riverside

Rockford, Illinois, United States

Central DuPage Hospital

Winfield, Illinois, United States

University of Kansas Hospital

Kansas City, Kansas, United States

University of Kentucky Hospital

Lexington, Kentucky, United States

Massachusetts General Hospital

Boston, Massachusetts, United States

Beth Israel Deaconess Medical Center

Boston, Massachusetts, United States

UMASS Memorial Medical Center

Worcester, Massachusetts, United States

University of Michigan University Hospital

Ann Arbor, Michigan, United States

Henry Ford Hospital

Detroit, Michigan, United States

McLaren Flint

Flint, Michigan, United States

Trinity Health Saint Mary's

Grand Rapids, Michigan, United States

Fairview Southdale Hospital

Edina, Minnesota, United States

University of Minnesota Medical Center Hospital

Minneapolis, Minnesota, United States

Regions Hospital

Saint Paul, Minnesota, United States

Saint Luke's Hospital

Kansas City, Missouri, United States

St. Louis University Hospital

St Louis, Missouri, United States

Barnes Jewish Hospital

St Louis, Missouri, United States

University of New Mexico Hospital

Albuquerque, New Mexico, United States

North Shore University Hospital

Manhasset, New York, United States

Mount Sinai Beth Israel

New York, New York, United States

SUNY Upstate University Hospital

Syracuse, New York, United States

Forsyth Medical Center

Winston-Salem, North Carolina, United States

Wake Forest Baptist Medical Center

Winston-Salem, North Carolina, United States

Cleveland Clinic Akron General

Akron, Ohio, United States

Mercy Health West Hospital

Cincinnati, Ohio, United States

University of Cincinnati Medical Center

Cincinnati, Ohio, United States

The Jewish Hospital

Cincinnati, Ohio, United States

OSU Wexner Medical Center

Columbus, Ohio, United States

St. John Medical Center

Tulsa, Oklahoma, United States

Abington Memorial Hospital

Abington, Pennsylvania, United States

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, United States

Temple University Hospital

Philadelphia, Pennsylvania, United States

UPMC Presbyterian Hospital

Pittsburgh, Pennsylvania, United States

UPMC Mercy Hospital

Pittsburgh, Pennsylvania, United States

Medical University of South Carolina

Charleston, South Carolina, United States

Prisma Health Greenville Memorial Hospital

Greenville, South Carolina, United States

Vanderbilt University Hospital

Nashville, Tennessee, United States

Houston Methodist Hospital

Houston, Texas, United States

Memorial Hermann-Texas Medical Center

Houston, Texas, United States

South Texas Health System McAllen

McAllen, Texas, United States

University of Utah Healthcare

Salt Lake City, Utah, United States

UVA Medical Center

Charlottesville, Virginia, United States

Countries

United States

References

Roy A, Elm J, Ingles JR, Sabagha N, Huang JF, Bentho O, Ranasinghe T, Streib C, Concha M, Khatri P, Vagal A, Wintermark M, Derdeyn CP, Broderick JP, Barreto AD, Adeoye O, Grotta JC. Thrombolysis Alone vs With Argatroban or Eptifibatide: A Prespecified Subgroup Analysis of the MOST Trial. Neurology. 2025 Nov 11;105(9):e214228. doi: 10.1212/WNL.0000000000214228. Epub 2025 Oct 10.

Reference Type: DERIVED

PMID: 41071964 (View on PubMed)

Rines I, Adeoye O, Barreto AD, Broderick J, Carrozzella J, Chen H, Concha M, Elm J, Grotta JC, Jasne AS, Khatri P, Roy A, Vagal A, Wintermark M, Yoo AJ, Derdeyn CP; MOST Investigators. Intravenous Argatroban or Eptifibatide in Patients Undergoing Mechanical Thrombectomy: A Subgroup Analysis of the MOST Randomized Clinical Trial. JAMA Neurol. 2025 Aug 18;82(10):1004-12. doi: 10.1001/jamaneurol.2025.2794. Online ahead of print.

Reference Type: DERIVED

PMID: 40824660 (View on PubMed)

Shawkat A, Barreto AD, Broderick JP, Derdeyn CP, Grotta JC, Khatri P, Pizzella S, Rines I, Roy A, Wilson A, Wintermark M, Adeoye OM. Comparison of Local and Centrally Adjudicated Modified Rankin Scale Scores in the MOST Trial. Stroke. 2025 May;56(5):1280-1284. doi: 10.1161/STROKEAHA.124.049825. Epub 2025 Mar 24.

Reference Type: DERIVED

PMID: 40123511 (View on PubMed)

Adeoye O, Broderick J, Derdeyn CP, Grotta JC, Barsan W, Bentho O, Berry S, Concha M, Davis I, Demel S, Elm J, Gentile N, Graves T, Hoffman M, Huang J, Ingles J, Janis S, Jasne AS, Khatri P, Levine SR, Majjhoo A, Panagos P, Pancioli A, Pizzella S, Ranasinghe T, Sabagha N, Sivakumar S, Streib C, Vagal A, Wilson A, Wintermark M, Yoo AJ, Barreto AD. Adjunctive Intravenous Argatroban or Eptifibatide for Ischemic Stroke. N Engl J Med. 2024 Sep 5;391(9):810-820. doi: 10.1056/NEJMoa2314779.

Reference Type: DERIVED

PMID: 39231343 (View on PubMed)

Romano JG, Rundek T. Expanding Treatment for Acute Ischemic Stroke beyond Revascularization. N Engl J Med. 2023 Jun 1;388(22):2095-2096. doi: 10.1056/NEJMe2303184. No abstract available.

Reference Type: DERIVED

PMID: 37256980 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33297893 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

1U01NS100699-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

2018-1464

Identifier Type: -

Identifier Source: org_study_id