Multi-arm Optimization of Stroke Thrombolysis (MOST)

• ClinicalTrials.gov Identifier: NCT03735979
• Recruitment Status: Active, not recruiting
• First Posted: November 8, 2018
• Last Update Posted: March 15, 2024
• Sponsor: Washington University School of Medicine
• Collaborator: National Institute of Neurological Disorders and Stroke (NINDS)
• Information provided by (Responsible Party): Opeolu Makanju Adeoye, Washington University School of Medicine

Tracking Information

• First Submitted Date: November 7, 2018
• First Posted Date: November 8, 2018
• Last Update Posted Date: March 15, 2024
• Actual Study Start Date: October 15, 2019
• Actual Primary Completion Date: December 1, 2023 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: November 7, 2018): 90-day modified Rankin scores (mRS) [ Time Frame: 90 days after randomization ]
• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: August 2, 2021)

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

Original Secondary Outcome Measures (submitted: November 7, 2018)

• proportion of participants with 90-day mRS 0-1 (or return to their historical mRS) [ Time Frame: 90 days after randomization ]
• proportion of participants with 90-day mRS 0-2 (or return to their historical mRS) [ Time Frame: 90 days after randomization ]
• 90-day ordinal analysis of the mRS [ Time Frame: 90 days after randomization ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Multi-arm Optimization of Stroke Thrombolysis
• Official Title: Multi-arm Optimization of Stroke Thrombolysis (MOST): a Single Blinded, Randomized Controlled Adaptive, Multi-arm, Adjunctive-thrombolysis Efficacy Trial in Ischemic Stroke
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Acute Ischemic Stroke

Intervention

• 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.
• 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.
• Drug: Placebo
  IV placebo solution

Study Arms

• Experimental: Argatroban
  100µg/kg bolus followed by 3µg/kg per minute for 12 hours
  Intervention: Drug: Argatroban
• Experimental: Eptifibatide
  135µg/kg bolus followed by 0.75µg/kg/min infusion for two hours
  Intervention: Drug: Eptifibatide
• Placebo Comparator: Placebo
  Intervention: Drug: Placebo

• 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.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: July 8, 2023): 514
• Original Estimated Enrollment (submitted: November 7, 2018): 1200
• Estimated Study Completion Date: April 2025
• Actual Primary Completion Date: December 1, 2023 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03735979
• Other Study ID Numbers: 2018-1464; 1U01NS100699-01A1 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Opeolu Makanju Adeoye, Washington University School of Medicine
• Original Responsible Party: Opeolu Adeoye, University of Cincinnati, Associate Professor
• Current Study Sponsor: Washington University School of Medicine
• Original Study Sponsor: University of Cincinnati
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS)

Investigators

• Principal Investigator: Opeolu Adeoye, MD; Washington University School of Medicine

• PRS Account: Washington University School of Medicine
• Verification Date: March 2024