BACKGROUND: Pulsed-wave ultrasound increases the exposure of an intracranial thrombus to alteplase (recombinant tissue plasminogen activator), potentially facilitating early reperfusion. We aimed to ascertain if a novel operator-independent transcranial ultrasound device delivering low-power high-frequency ultrasound could improve functional outcome in patients treated with alteplase after acute ischaemic stroke. METHODS: We did a multicentre, double-blind, phase 3, randomised controlled trial (CLOTBUST-ER) at 76 medical centres in 14 countries. We included patients with acute ischaemic stroke (National Institutes of Health Stroke Scale score ≥10) who received intravenous thrombolysis (alteplase bolus) within 3 h of symptom onset in North America and within 4·5 h of symptom onset in all other countries. Participants were randomly allocated (1:1) via an interactive web response system to either active ultrasound (2 MHz pulsed-wave ultrasound for 120 min [sonothrombolysis]; intervention group) or sham ultrasound (control group). Ultrasound was delivered using an operator-independent device, which had to be activated within 30 min of the alteplase bolus. Participants, investigators, and those assessing outcomes were unaware of group assignments. The primary outcome was improvement in the modified Rankin Scale score at 90 days in patients enrolled within 3 h of symptom onset, assessed in the intention-to-treat population as a common odds ratio (cOR) using ordinal logistic regression shift analysis. This trial is registered with ClinicalTrials.gov, number NCT01098981. The trial was stopped early by the funder after the second interim analysis because of futility. FINDINGS: Between August, 2013, and April, 2015, 335 patients were randomly allocated to the intervention group and 341 patients to the control group. Compared with the control group, the adjusted cOR for an improvement in modified Rankin Scale score at 90 days in the intervention group was 1·05 (95% CI 0·77-1·45; p=0·74). 51 (16%) of 317 patients in the intervention group and 44 (13%) of 329 patients in the control group died (unadjusted OR 1·24, 95% CI 0·80-1·92; p=0·37) and 83 (26%) and 79 (24%), respectively, had serious adverse events (1·12, 0·79-1·60; p=0·53). INTERPRETATION: Sonothrombolysis delivered by an operator-independent device to patients treated with alteplase after acute ischaemic stroke was feasible and most likely safe, but no clinical benefit was seen at 90 days. Sonothrombolysis could be further investigated either in randomised trials undertaken in stroke centres that are dependent on patient transfer for endovascular reperfusion therapies or in countries where these treatments cannot yet be offered as the standard of care. FUNDING: Cerevast Therapeutics.

Center for Stroke Research Berlin Charité University Medicine Berlin Berlin Germany

Cerevast Therapeutics Redmond WA USA

Clinical Innovation and Research Institute Memorial Hermann Hospital Texas Medical Center Houston TX USA

Department of Clinical Neurosciences and Radiology Hotchkiss Brain Institute University of Calgary Calgary AB Canada

Department of Hygiene and Epidemiology University of Ioannina School of Medicine Ioannina Greece; Department of Primary Education School of Education University of Ioannina Ioannina Greece

Department of Hygiene Epidemiology and Medical Statistics Medical School National and Kapodistrian University of Athens Athens Greece

Department of Medicine University of Alberta Edmonton AB Canada; Neuroscience Institute Hamad Medical Corporation Doha Qatar

Department of Neurology Helsinki University Hospital and Clinical Neurosciences Neurology University of Helsinki Helsinki Finland

Department of Neurology John Hunter Hospital University of Newcastle Newcastle NSW Australia

Department of Neurology Kepler University Clinic General Hospital Linz Linz Austria

Department of Neurology Universitätsklinikum Erlangen Erlangen Germany; Department of Neurology University Duisburg Essen Essen Germany

Department of Neurology University of Tennessee Health Science Center Memphis TN USA

Department of Neurology University of Tennessee Health Science Center Memphis TN USA; 2nd Department of Neurology Attikon University Hospital School of Medicine National and Kapodistrian University of Athens Athens Greece; International Clinical Research Center and Department of Neurology St Anne's University Hospital in Brno Brno Czech Republic

Department of Neurology University of Tennessee Health Science Center Memphis TN USA; Australian Catholic University Sydney NSW Australia

Department of Neurology University of Texas Health Science Center at Houston Houston TX USA

Departments of Neurology and Neurogeriatry John Wesling Medical Center Minden Ruhr University Bochum Minden Germany

Institute of Neuroscience and Psychology University of Glasgow Queen Elizabeth University Hospital Glasgow UK

International Clinical Research Center and Department of Neurology St Anne's University Hospital in Brno Brno Czech Republic; Medical Faculty Masaryk University Brno Czech Republic

Stroke Outcomes Laboratory Department of Neurology Baylor College of Medicine Houston TX USA; Michael E DeBakey VA Medical Center Stroke Program and Center for Translational Research on Inflammatory Diseases Houston TX USA

Stroke Unit Department of Neurology Vall d'Hebron University Hospital Vall d'Hebron Research Institute Autonomous University of Barcelona Barcelona Spain

Yong Loo Lin School of Medicine National University of Singapore and Division of Neurology Department of Medicine National University Hospital Singapore

Lancet Neurol. 2019 Apr;18(4):320-321. doi: 10.1016/S1474-4422(19)30066-3. PubMed

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Timing of Recanalization and Functional Recovery in Acute Ischemic Stroke

Endovascular equipoise shift in a phase III randomized clinical trial of sonothrombolysis for acute ischemic stroke

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ClinicalTrials.gov
NCT01098981