MOST Study Update and Protocol Refresher 8/26/2019

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 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

Increased pharmacy responsibilities Argatroban, eptifibatide and placebo kits will be supplied to sites. When a subject is randomized, the site pharmacy will need to reconstitute argatroban before dispensing. No preparation required for eptifibatide or placebo kits. Site labeling should cover the entirety of the commercial label on the vial and on the bag to ensure single-blind.

How will drug be administered?

Study Drug Administration Summary Dosing Information – Populated on Randomization Verification Form after entering subject weight on Randomization CRF Titration Information – Populated on aPTT CRF after entering baseline aPTT value for argatroban participants only Bolus 1. Pull from glass vial into a syringe 2. Administer over 3 minute IV push 0-2 Hour Infusion 1. Hang glass vial immediately after bolus 2. Run for 2 hours 2-12 Hour Infusion 1. Hang 250ml bag immediately after 0-2 Hour Infusion 2. Run until 12 hours after study drug bolus 3. Titrate at 2 hours and 6 hours for argatroban participants only

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.

Notable I&E Inclusion Criteria Exclusion Criteria IV rt-PA within 3 hours of LSN 2. Age ≥ 18 Pre IV rt-PA NIHSS ≥ 6 Able to receive assigned study drug within 60 minutes of initiation of IV rt-PA Exclusion Criteria 1. INR >1.5 in patients on warfarin 2. Elevated PTT (above local lab limit) 3. mRS >3 4. Large (>1/3 of MCA) clear CT hypodensity 5. Creatinine >4 or dialysis 6. Significant liver disease or known bleeding diathesis

Schedule of Events Time Baseline 2 hour (+/- 30 min) (after start of study drug)  6 hour (+/- 30 min) 24 hours (+/- 12 hrs) Day 3/Discharge* (+/- 24hrs)  Day 30 (+/- 7 days) Day 90 (+/- 14 days) Inclusion Exclusion Criteria X   Subject Enrollment Informed Consent/ Randomization History & Physical# NIH Stroke Scale Modified Rankin Score Consent experience survey EQ-5D CT/MRI scan (SOC#) CTA/MRA (if SOC) CBC with platelets# Glucose, electrolytes, BUN/creatinine, PT# aPTT# Dosing Titration$∞ Adverse events X^ End of Study #Standard of care *whichever comes first ^serious AEs only $argatroban arm only ∞as needed based on aPTT titration protocol

 

Concomitant Drugs and Procedures Concomitant use of antiplatelet or anticoagulant medications is prohibited in the first 24 hours after initiation of IV rt-PA per SOC guidelines. If clinical team has strong justification for the use of antithrombotics, a non-contrast head CT must be obtained to assess safety prior to administration. After 24 hours, antithrombotic use may proceed per standard of care.

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. Additional antithrombotics or thrombolytics during the procedure, other than heparinized saline flush, are protocol violations.

Adverse Event Reporting Non-serious Adverse Events (AEs) that are determined to be related to study drug will be reported from randomization through Day 3 or Discharge, whichever comes first, within 5 days of the site’s awareness of the event. All Serious Adverse Events (SAEs) will be reported from randomization through Day 90, within 24 hours of the site’s awareness of the event.

Imaging All standard of care head imaging should be uploaded to the Imaging Collection CRF using ASPERA software in WebDCUTM. This includes all non-contrast CT, CTA, CTP, MRI, MRA, and MRP performed within 72 hours of symptom onset.

Follow-up Assessments Day 30 (+ 7 days) mRS SAE assessment May be in-person or over the phone Day 90 (+ 14 days) mRS (must be video recorded) EQ-5D-5L Must be in-person 24 hours (+ 12 hours) NIHSS* CT/MRI (SOC) AE/SAE assessment *blinded assessor Day 3/Discharge (+ 24 hours) Consent Experience Survey

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

Questions?