Background Intravenous recombinant tissue plasminogen activator is the only proven effective medication for the treatment of acute ischemic stroke. Two approaches that may augment recombinant tissue plasminogen activator thrombolysis and prevent arterial reocclusion are direct thrombin inhibition with argatroban and inhibition of the glycoprotein 2b/3a receptor with eptifibatide. Aim The multi-arm optimization of stroke thrombolysis trial aims to determine the safety and efficacy of intravenous therapy with argatroban or eptifibatide as compared with placebo in acute ischemic stroke patients treated with intravenous recombinant tissue plasminogen activator within 3 h of symptom onset. Sample size estimate A maximum of 1200 randomized subjects to test the superiority of argatroban or eptifibatide to placebo in improving 90-day modified Rankin scores. Methods and design Multiarm optimization of stroke thrombolysis is a multicenter, multiarm, adaptive, single blind, randomized controlled phase 3 clinical trial conducted within the National Institutes of Health StrokeNet clinical trial network. Patients treated with 0.9 mg/kg intravenous recombinant tissue plasminogen activator within 3 h of stroke symptom onset are randomized to receive intravenous argatroban (100 µg/kg bolus followed by 3 µg/kg/min for 12 h), intravenous eptifibatide (135 µg/kg bolus followed by 0.75 µg/kg/min infusion for 2 h) or IV placebo. Patients may receive endovascular thrombectomy per usual care. Study outcomes The primary efficacy outcome is improved modified Rankin score assessed at 90 days post-randomization. Discussion Multiarm optimization of stroke thrombolysis is an innovative and collaborative project that is the culmination of many years of dedicated efforts to improve outcomes for stroke patients.

Introduction: Recruitment into hyperacute stroke trials is challenging but ultimately depends on on-call availability of treating investigators, study coordinators, and pharmacists. These data may not be considered in initial decision-making for site selection and estimates of site recruitment are frequently based upon registry data from sites that includes all clinical cases. Hypothesis: Site recruitment on a per month basis is associated with time open for enrollment. Methods: We surveyed all Multi-arm Optimization of Stroke (MOST) trial centers open for enrollment to determine which were open for trial recruitment during business hours during Monday through Friday only, business hours 7 days a week, extended hours beyond business hours, or 24 hours/7 days a week. We also surveyed about pharmacy availability. Descriptive statistics were used to compare the average monthly enrollment by survey responses. Results: Sites open for enrollment only during business hours, Monday through Friday recruited at a rate of 0.14 participants per month compared to 0.36 per month for sites that enroll 7 days a week (see graphic). Restriction of pharmacy availability to business hours Monday through Friday was associated with decreased recruitment rate as well. Conclusions: Ability to recruit trial participants 7 days a week should be the standard for site selection, successful acute stroke trial recruitment, and estimates of needed sites. Methods to increase financial support for hours outside of week-day business hours is a potential method to enhance recruitment into acute stroke trials.

Informed consent for clinical trials in acute stroke is characterized by challenges related to urgency, cognitive impairment, and geographical separation. Context‐appropriate approaches are needed for this setting. We conducted a mixed‐methods project involving focus groups and interviews as well as collaboration with a patient advisory panel and a central institutional review board (CIRB) to design and implement a patient‐driven consent process for a multicenter trial incorporating adaptive randomization. Remote consent was recognized as challenging but acceptable. Adaptive randomization was viewed positively, but significant potential for misunderstanding was appreciated. Collaboration between the patient advisory panel and the CIRB resulted in a shortened, more patient‐centered consent form that was approved at all sites with few modifications. An information sheet was developed as a resource for patients and surrogates after enrollment. Collaboration between investigators, patient partners, and a CIRB can facilitate innovation and implementation of patient‐centered, context‐appropriate consent strategies.