MOST Study Update and Endovascular Discussion 8/22/2019

What happened to the double-blind? In order for MOST to be double-blinded, reconstitution and repackaging of the commercially available argatroban and eptifibatide product was required. Manufacturing was the rate-limiting step in getting the trial off the ground due to supply chain issues. We encountered 2 issues during manufacturing: During stability testing, one vial tested 136% of expected concentration Visible particulate matter in some of the 250ml vials It has taken a year from initiation of the process to unusable product.

Summary of protocol changes to single-blind In order to bypass the manufacturing process, MOST will use commercially available argatroban and eptifibatide. Single-blind: The patient and family will not know which treatment they are receiving. Study team will know, but should not disclose to individuals not involved directly in enrollment unless there is a specific need to know. aPTT and 2-12 hour infusion titration in argatroban arm only. Blinded 24-hour NIHSS.

Study Design The first 150 subjects will be randomized 1 to 1 to 1 in the 3 arms At 500 subjects 1 or both intervention arms may be carried forward for fixed randomization verus IV t-PA

Study Design Study Drug Arms: Study Arm Bolus 0-2 hour infusion Argatroban 100μg/kg 3μg/kg/ min 3μg/kg/ min Eptifibatide 135μg/kg 0.75μg/kg/min saline Placebo The first 150 subjects will be randomized 1 to 1 to 1 in the 3 arms At 500 subjects 1 or both intervention arms may be carried forward for fixed randomization verus IV t-PA

What remains the same? I&E criteria stays the same. Dosing information populated on Randomization Verification Form. Titration Table will still be populated, but only for argatroban subjects. Drug administered within 60 (+15) minutes. Concomitant antithrombotics prohibited in first 24 hours after t-PA. In-person video recording of 90-day visit.

Endovascular Therapy MOST participants are eligible to receive standard of care endovascular therapy, which should not be delayed for study procedures. Study drug administration may occur before or during the endovascular procedure; therefore, collaboration is critical. If the EVT team needs to know the study arm to make decisions, such as antiplatelet regimen after carotid stenting or groin closure devices, this can be provided by the site study investigators. Stenting for carotid stenosis or occlusion should be avoided. Angioplasty is recommended. Intracranial stenting is a protocol violation. Additional IV antithrombotics or thrombolytics during the procedure, other than heparinized saline flush, are protocol violations (heparin bolus, tPA, 2b/3a inhibitors).

Severe Carotid Stenosis or Occlusion Attempt angioplasty alone, if possible. Avoid acute placement of a stent. Recommendations if stent is deemed absolutely necessary: No oral antiplatelets until 24 hours after IV tPA and a follow up head CT or MR. ***OR*** Start 325 ASA per NG or PR at: end of the procedure (IV tPA/placebo arm); end of the eptifibatide infusion or EVT procedure (whichever is later); or at the end of the argatroban infusion at 12 hours. A second oral antiplatelet can be started at 24 hours after a CT or MR that defines size of infarction or hemorrhage. ***OR*** c) Similar ASA approach as B, but starting the second oral antiplatelet sooner (within 24 hours). In these cases, we recommend getting a CT or MR before starting the second agent to exclude hemorrhage. N.B. Hemorrhage may be difficult to exclude in some cases, owing to contrast staining.

Next Steps FDA approval and CIRB amendment in process Will start processing site CIRB amendments after FDA approval, anticipate mid-September Dedicated pharmacy call within next 6-8 weeks Study team re-training required, anticipate new modules released mid- September Will resume site readiness activities after FDA approval Study documents and database programming being updated

Please email MOST@uc.edu Questions? Please email MOST@uc.edu