Multi-arm Optimization of Stroke Thrombolysis (MOST) Stroke Trial

Objectives The primary efficacy objective of the MOST trial is to determine if argatroban (100ƒÊg/kg bolus followed by 3ƒÊg/kg per minute for 12 hours) plus 0.9mg/kg of IV rt-PA, or eptifibatide (135ƒÊg/kg bolus followed by 0.75ƒÊg/kg/min infusion for two hours) plus 0.9mg/kg of IV rt-PA, results in improved 90-day modified Rankin scores (mRS) as compared with 0.9mg/kg of IV rt-PA alone in acute ischemic stroke (AIS) patients treated with IV rt-PA within three hours of symptom onset. Time of onset is defined as the last time the patient was witnessed to be at baseline. The primary safety objective of the MOST trial is to determine the safety of combining rt-PA with argatroban or eptifibatide as compared to IV rt-PA alone, as measured by symptomatic intracranial hemorrhage (sICH) within 36 hours from onset. Design and Outcomes This is a three-arm, adaptive, Phase-3, double-blinded, randomized controlled clinical trial at 110 sites in the United States. The first 150 subjects will be randomized 1:1:1. From 150-500 patients, response adaptive randomization (RAR) will favor the treatment arm(s) showing the greatest benefit based on accrued data. After 500 patients, one or both intervention arms may be carried forward for fixed randomization versus IV rt-PA. A maximum of 1200 patients will be enrolled. Eligible patients will be aged 18 or older, receive IV rt-PA within three hours of symptom onset, and receive study drug (placebo, argatroban or eptifibatide) within an hour of rt-PA. Endovascular therapy will be per standard of care as needed. The primary efficacy outcome for MOST will be the 90-day mRS translated into utilities, which measure cost-effectiveness and benefits of a given intervention from the patientfs perspective. The primary safety outcome is sICH. Secondary outcomes include a comparison between treatment groups of: the proportion of patients with NIHSS .2 at 24 hours; change from baseline to 24-hour NIHSS; proportion with 90-day mRS 0 or 1 and 0-2; 90-day ordinal analysis of the mRS; 90-day EQ-5D; the proportion of patients who have thrombectomy; the proportion of patients with parenchymal hemorrhage types 1 (PH-1) and 2 (PH-2); any ICH on brain imaging within 36 hours; major systemic bleeding (defined as requiring >2 units packed red blood cells) within 7 days; 90-day all-cause mortality; evaluation of treatment effect in endovascular therapy (ET) and non-ET subjects; and, evaluation of race/ethnicity and gender differences in treatment effect.