CLOTBUST-hands free: initial safety testing of a novel operator-independent ultrasound device in stroke-free volunteers.

BACKGROUND AND PURPOSE: We aimed to evaluate safety and tolerability of a novel operator-independent ultrasound device among stroke-free volunteers. METHODS: A headframe containing 18 ultrasound transducers (each operating at 2 MHz, pulsed-wave) was used to expose both temporal windows and the suboccipital window. The transmission characteristics were set to emulate the acoustic characteristics of the exposure levels in the Combined Lysis of Thrombus in Brain Ischemia using Transcranial Ultrasound and Systemic tPA (CLOTBUST) trial and to never exceed Food and Drug Administration mandated diagnostic ultrasound exposure limits. Volunteers underwent 2 hours of insonation with transducer activation one at a time. Safety was captured using serial neurological examinations and pre- and postinsonation MRI for detection of the blood brain barrier permeability. RESULTS: A total of 15 volunteers (40% men; 49 ± 16 years; 27% black; all pre-exposure National Institutes of Health Stroke Scale scores 0) were enrolled. Five volunteers received pulsed-wave ultrasound via the best pair temporal transducers, 5 via sequential activation of the suboccipital transducers, and 5 via sequential activation of all bilateral temporal and suboccipital transducers. All subjects were safely insonated with no adverse effects as indicated by the neurological examinations during, immediately after the exposure, and at 24 hours, and no abnormality of the blood brain barrier was found on any of the MRIs. CONCLUSIONS: Our novel device was well tolerated by stroke-free volunteers and did not cause any neurological dysfunction nor did it affect blood brain barrier integrity. The safety and efficacy of the device are now being tested in stroke patients receiving intravenous tissue-type plasminogen activator in phase II-III clinical trials.

CLOTBUST-Hands Free: pilot safety study of a novel operator-independent ultrasound device in patients with acute ischemic stroke.

BACKGROUND AND PURPOSE: The Combined Lysis of Thrombus in Brain Ischemia With Transcranial Ultrasound and Systemic T-PA-Hands-Free (CLOTBUST-HF) study is a first-in-human, National Institutes of Health-sponsored, multicenter, open-label, pilot safety trial of tissue-type plasminogen activator (tPA) plus a novel operator-independent ultrasound device in patients with ischemic stroke caused by proximal intracranial occlusion. METHODS: All patients received standard-dose intravenous tPA, and shortly after tPA bolus, the CLOTBUST-HF device delivered 2-hour therapeutic exposure to 2-MHz pulsed-wave ultrasound. Primary outcome was occurrence of symptomatic intracerebral hemorrhage. All patients underwent pretreatment and post-treatment transcranial Doppler ultrasound or CT angiography. National Institutes of Health Stroke Scale scores were collected at 2 hours and modified Rankin scale at 90 days. RESULTS: Summary characteristics of all 20 enrolled patients were 60% men, mean age of 63 (SD=14) years, and median National Institutes of Health Stroke Scale of 15. Sites of pretreatment occlusion were as follows: 14 of 20 (70%) middle cerebral artery, 3 of 20 (15%) terminal internal carotid artery, and 3 of 20 (15%) vertebral artery. The median (interquartile range) time to tPA at the beginning of sonothrombolysis was 22 (13.5-29.0) minutes. All patients tolerated the entire 2 hours of insonation, and none developed symptomatic intracerebral hemorrhage. No serious adverse events were related to the study device. Rates of 2-hour recanalization were as follows: 8 of 20 (40%; 95% confidence interval, 19%-64%) complete and 2 of 20 (10%; 95% confidence interval, 1%-32%) partial. Middle cerebral artery occlusions demonstrated the greatest complete recanalization rate: 8 of 14 (57%; 95% confidence interval, 29%-82%). At 90 days, 5 of 20 (25%, 95% confidence interval, 7%-49) patients had a modified Rankin scale of 0 to 1. CONCLUSIONS: Sonothrombolysis using a novel, operator-independent device, in combination with systemic tPA, seems safe, and recanalization rates warrant evaluation in a phase III efficacy trial. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: CLOTBUST-HF NCT01240356.