Background: Continuous exposure of intracranial arterial occlusions to pulsed wave ultrasound enhances tissue plasminogen induced recanalization. Our hypothesis is that sonothrombolysis can improve functional outcomes of stroke patients receiving tPA therapy. Methods: The primary objective is to evaluate the efficacy of a novel transcranial ultrasound device and systemic tPA (Target) compared to systemic tPA alone (Controls) in subjects with acute ischemic stroke and NIHSS scores 10 or greater. This is a randomized (1:1), placebo-controlled, multi-site, phase 3 clinical trial to evaluate the efficacy and safety of a novel ultrasound device, as an adjunctive therapy to tPA treatment in subjects with acute ischemic stroke: total projected enrollment 824 patients with interim analyses at ⅓ and ⅔ of enrollment. Current Status: CLOTBUST-ER had active enrollment at approximately 70 sites in 14 countries worldwide. DSMB recommended to stop the trial after second interim analysis. Functional outcomes are still being assessed via modified Rankin Scores at 90 days and the primary endpoint will be analyzed using ordinal shift statistical analysis. Final results will be presented at ISC 2016. Conclusions: CLOTBUST-ER is the first phase three multinational randomized blinded clinical trial of sonothrombolysis for treatment of acute ischemic stroke. ClinicalTrials.gov Trial Registry ID: NCT01098981.