The multiarm optimization of stroke thrombolysis phase 3 acute stroke randomized clinical trial: Rationale and methods

Abstract

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.

Endovascular thrombectomy without versus with intravenous thrombolysis in acute ischemic stroke: a non-inferiority meta-analysis of randomized clinical trials

“…Second, the current trials provide information only regarding IV alteplase as the thrombolytic strategy. Use of new IV fibrinolytic agents like tenecteplase before EVT, 25 as well as IV fibrinolytic agents combined with IV glycoprotein IIb/IIIa inhibitors or direct thrombin inhibitors, 26 continues to be an important avenue for further therapeutic study. Third, these trials were conducted in Asia and European countries and generalizability of the current results to certain population, such as African Americans, is not known.…”

Delayed Neurological Improvement

“…Particularly, as we develop new combination regimens, such as the combined approaches in the MOST trial, or start to focus on easier to administer agents like tenecteplase that facilitate quicker transport to endovascular centers, we will need to learn more about how these facilitate earlier distal reperfusion or soften the clot allowing for more prompt and effective mechanical reperfusion. 8,9 In summary, a lot of those brain cells seem to be sleeping when patients do not have dramatic improvement following reperfusion. We must learn more about how to maximize the number that wake up.…”

Recruitment in Acute Stroke Trials: Challenges and Potential Solutions

“…One of the reasons for the underestimate is that recruitment is not just based on the number of eligible patients but also the availability of study investigators. In the ongoing MOST trial, 4 sites were surveyed regarding the time when the trial was open for enrollment. Those sites that were open for enrollment every day recruited participants at twice the rate of those sites who were only open for enrollment during business hours, Monday through Friday.…”