Transcranial ultrasound in clinical sonothrombolysis (TUCSON) trial

Authors


  • Potential conflict of interest: Dr Molina received consultant fees from ImaRx Therapeutics, Inc. Dr Barreto has no disclosures. Dr Tsivgoulis received a fellowship grant from the Neurology Department, Eginition Hospital, University of Athens School of Medicine, Athens, Greece. Dr Sierzenski has no disclosures. Dr Malkoff has no disclosures. Dr Rubiera received a fellowship grant from the Instituto de Salud Carlos III and Instititut de Recerca Hospital Vall d'Hebron, Barcelona, Spain. Dr Gonzales has no disclosures. Dr Mikulik received consultant fees from ImaRx Therapeutics, Inc. Mr Pate was responsible for TUCSON trial operations at ImaRx Therapeutics, Inc. Dr Ostrem served as Senior Scientist at ImaRx Therapeutics, Inc. Dr Singleton served as Chief Medical Officer of ImaRx Therapeutics, Inc. Dr Manvelian served as Chief Medical Officer at ImaRx Therapeutics, Inc. Dr Unger is an inventor, author of multiple patents in the areas of microspheres and sonothrombolysis, and served as CEO of ImaRx Therapeutics, Inc. Dr Grotta has no disclosures. Dr Schellinger received speaker honoraria from Boehringer Ingelheim, the manufacturer of rt-PA, and served as a consultant for ImaRx Therapeutics, Inc. Dr Alexandrov received grant support from the National Institute of Neurological Disorders and Stroke (CLOTBUST trial), and served as a consultant for ImaRx Therapeutics, Inc.

Abstract

Objective

Microspheres (μS) reach intracranial occlusions and transmit energy momentum from an ultrasound wave to residual flow to promote recanalization. We report a randomized multicenter phase II trial of μS dose escalation with systemic thrombolysis.

Methods

Stroke patients receiving 0.9mg/kg tissue plasminogen activator (tPA) with pretreatment proximal intracranial occlusions on transcranial Doppler (TCD) were randomized (2:1 ratio) to μS (MRX-801) infusion over 90 minutes (Cohort 1, 1.4ml; Cohort 2, 2.8ml) with continuous TCD insonation, whereas controls received tPA and brief TCD assessments. The primary endpoint was symptomatic intracerebral hemorrhage (sICH) within 36 hours after tPA.

Results

Among 35 patients (Cohort 1 = 12, Cohort 2 = 11, controls = 12) no sICH occurred in Cohort 1 and controls, whereas 3 (27%, 2 fatal) sICHs occurred in Cohort 2 (p = 0.028). Sustained complete recanalization/clinical recovery rates (end of TCD monitoring/3 month) were 67%/75% for Cohort 1, 46%/50% for Cohort 2, and 33%/36% for controls (p = 0.255/0.167). The median time to any recanalization tended to be shorter in Cohort 1 (30 min; interquartile range [IQR], 6) and Cohort 2 (30 min; IQR, 69) compared to controls (60 min; IQR, 5; p = 0.054). Although patients with sICH had similar screening and pretreatment systolic blood pressure (SBP) levels in comparison to the rest, higher SBP levels were documented in sICH+ patients at 30 minutes, 60 minutes, 90 minutes, and 24–36 hours following tPA bolus.

Interpretation

Perflutren lipid μS can be safely combined with systemic tPA and ultrasound at a dose of 1.4ml. Safety concerns in the second dose tier may necessitate extended enrollment and further experiments to determine the mechanisms by which microspheres interact with tissues. In both dose tiers, sonothrombolysis with μS and tPA shows a trend toward higher early recanalization and clinical recovery rates compared to standard intravenous tPA therapy. Ann Neurol 2009;66:28–38

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