The Multi-arm Optimization of Stroke Thrombolysis (MOST) stroke trial will be a double-blinded multi-center, randomized controlled Phase 3 trial with a maximum of 1200 subjects. The trial will determine if adult (age ≥18 years) subjects with an NIH stroke scale score ≥6 at baseline treated within three hours of symptom onset with rt-PA followed by argatroban or eptifibatide are more likely to have a favorable outcome at 3 months (mRS) as compared to subjects treated with standard IV rt-PA alone. Subjects in all treatment arms may proceed to endovascular therapy (ET) as clinically warranted. The three arms of the trial include: rt-PA plus placebo, rt-PA plus argatroban, and rt-PA plus eptifibatide. Subjects are initially randomized in a 1:1:1 ratio up to 150 subjects enrolled. Response adaptive randomization would then favor the treatment arm that appears to be most favorable based on accrued data. After 500 subjects are enrolled, the treatment arm(s) that appears most favorable will be selected for fixed randomization versus standard treatment. Fixed randomization arms must be selected at 500 subjects. The trial may be stopped early for futility at 500 subjects if no intervention arm appears better than rt-PA alone (<20% predictive probability). Interim analyses will also occur at 700 and 900 subjects. At these times, the trial may be stopped for futility if no intervention arm appears better than rt-PA alone (<5% predictive probability); the trial may be stopped early for efficacy if an arm appears to be better than rt-PA (>99% predictive probability). The primary 3-month efficacy endpoint is performed by central investigators blinded to treatment assignment. Additional endpoints will include: (1) other outcome measures including NIHSS, the quality of life utility as measured via EuroQol EQ-5D at 90 days); (2) early response to treatment as determined by an NIHSSS of 0-2 at 24 hours; (3) mRS at 30 days; (4) differences in treatment effect in ET versus non-ET subjects; and, (5) racial/ethnic and gender differences in treatment effect. The trial will be supported by three NINDS cooperative agreement grants: (1) to the University of Cincinnati NINDS Stroke Trial Network (NSTN) National Clinical Coordinating Center (PI: Joseph P. Broderick, MD) to provide project and site management; (2) to the NSTN National Data Management Center (NDMC) at the Medical University of South Carolina (PI: Yuko Y. Palesch, PhD) to provide data management and statistical expertise; and (3) to the Project PI for clinical leadership, site recruitment and study conduct and operations (Multiple PIs: Opeolu Adeoye, MD; Andrew Barreto, MD; Joseph P. Broderick, MD; James Grotta, MD).

The MOST trial will test whether rt-PA combined with one or the other of two medications (argatroban and eptifibatide) is better than rt-PA alone for the treatment of acute ischemic stroke. Both of these IV medications may be combined with IV rt-PA at all hospitals capable of giving rt-PA. If shown to be better than rt-PA, these combinations have the potential to help up to 1800 additional people in the US fully recover from their stroke each year, as well as reduce the costly burden of disability in those who partially recover.