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 operatorindependent 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.
Background We designed a Phase 3 clinical trial to determine the safety and efficacy of adding transcranial ultrasound using an operator-independent headframe to recombinant tissueplasminogen-activator for the treatment of acute ischemic stroke. Methods Combined lysis of thrombus with ultrasound and systemic tissue-plasminogen-activator for emergent revascularization in acute ischemic stroke is a randomized, doubleblind, placebo-controlled clinical trial that will enroll subjects with the following main inclusion criteria: less than 4·5 hours from symptom onset (three-hours in US and Canada), age 18-80 years, baseline National Institutes of Health Stroke Scale score ≥ 10, and premorbid modified-Rankin-score of 0-1, eligibility for full dose recombinant tissue-plasminogen-activator.Subjects will receive two-hours of 2-MHz pulsed wave transcranial ultrasound (target group) or sham ultrasound (control group). The projected sample size is approximately 824 subjects. Results The primary endpoint, based on intention-to-treat criteria of patients enrolled within three-hours of symptom onset is the comparison between target and control groups of modified-Rankin-score scores at day 90 poststroke assessed using the proportional odds method. The study will have two planned interim analyses after approximately one-third and two-thirds of subjects have reached the 90-day modifiedRankin-score evaluation. Safety outcomes are symptomatic intracranial hemorrhage within 24 h and an overall analysis of adverse events. Conclusions Since intravenous recombinant tissueplasminogen-activator remains the only medical therapy to reverse ischemic stroke applicable in the emergency department, our trial will determine if the additional use of transcranial ultrasound improves functional outcomes in patients with severe acute ischemic stroke (NCT#01098981).
BLZ-100 (tozuleristide) is an intraoperative fluorescent imaging agent that selectively detects malignant tissue and can be used in real time to guide tumor resection. The purpose of this study was to assess the safety, tolerability, and pharmacokinetics of BLZ-100 and to explore the pharmacodynamics of fluorescence imaging of skin tumors. In this first-in-human study, BLZ-100 was administered intravenously to 21 adult patients 2 days before excising known or suspected skin cancers. Doses were 1, 3, 6, 12, and 18 mg, with 3–6 patients/cohort. Fluorescence imaging was conducted before and up to 48 h after dosing. BLZ-100 was well tolerated. There were no serious adverse events, deaths, or discontinuations due to adverse events, and no maximum tolerated dose (MTD) was identified. Headache (n = 2) and nausea (n = 2) were the only BLZ-100 treatment-related adverse events reported for >1 patient. Median time to maximal serum concentration was <0.5 h. Exposure based on maximal serum concentrations increased in a greater than dose-proportional manner. For intermediate dose-levels (3–12 mg), 4 of 5 basal cell carcinomas and 4 of 4 melanomas were considered positive for BLZ-100 fluorescence. BLZ-100 was well tolerated at all dose levels tested and these results support further clinical testing of this imaging agent in surgical oncology settings. Clinicaltrials.gov: NCT02097875.
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