Transcranial Ultrasound in Clinical Sonothrombolysis (TUCSON) Trial Carlos A. Molina, MD, PhD, 1 Andrew D. Barreto, MD, 2 Georgios Tsivgoulis, MD, 3,4 Paul Sierzenski, MD, 5 Marc D. Malkoff, MD, 6 Marta Rubiera, MD, 1,3 Nicole Gonzales, MD, 2 Robert Mikulik, MD, 7 Greg Pate, MA, 8 James Ostrem, PhD, 8 Walter Singleton, MD, 8 Garen Manvelian, MD, 8 Evan C. Unger, MD, 8,9 James C. Grotta, MD, 2 Peter D. Schellinger, MD, PhD, 10 and Andrei V. Alexandrov, MD 3 Objective: Microspheres (S) 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 S dose escalation with systemic throm- bolysis. Methods: Stroke patients receiving 0.9mg/kg tissue plasminogen activator (tPA) with pretreatment proximal intracranial occlu- sions on transcranial Doppler (TCD) were randomized (2:1 ratio) to S (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 S 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 S 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 Intravenous tissue plasminogen activator (tPA) can double the chance of complete recovery if given within 2 hours from symptom onset; its efficacy decreases over time. 1 Early tPA administration can benefit patients through initiation of an arterial recanalization pro- cess 2–4 ; however, the proximity of an arterial occlusion with larger thrombus burden decreases the chance of systemic tPA breaking up the clot. 5,6 Despite this, tPA From the 1 Neurovascular Unit, Department of Neurology, Hospital Vall d’Hebron, Barcelona, Spain; 2 Stroke Program, the University of Texas-Houston Medical School, Houston, TX; 3 Comprehensive Stroke Center, University of Alabama Medical School, Birmingham, AL; 4 Department of Neurology, University of Thrace Medical School, Alexandroupolis, Greece; 5 Emergency Medicine, Christiana Healthcare, Wilmington, DE; 6 Neurosonology and Stroke Program, Barrow Neurological Institute, Phoenix, AZ; 7 Department of Neu- rology, Masaryk University, St. Anne University Hospital, Brno, Czech Republic; 8 ImaRx Therapeutics, Inc., Tucson, AZ; 9 Depart- ment of Radiology, University of Arizona Health Sciences Center, Tucson, AZ; and 10 Department of Neurology, University at Erlan- gen, Erlangen, Germany. Address correspondence to Dr Alexandrov, Comprehensive Stroke Center/Neurology, the University of Alabama at Birmingham, RWUH M226, 619 19th St South, Birmingham, AL 35249-3280. E-mail: avalexandrov@att.net 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 Depart- ment, 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 Insti- tuto 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 Ther- apeutics, Inc. Dr Ostrem served as Senior Scientist at ImaRx Ther- apeutics, 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, au- thor of multiple patents in the areas of microspheres and sono- thrombolysis, 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 re- ceived grant support from the National Institute of Neurological Disorders and Stroke (CLOTBUST trial), and served as a consul- tant for ImaRx Therapeutics, Inc. Received Feb 1, 2009, and in revised form Mar 4. Accepted for publication April 3, 2009. Published online Mon 00, 2009, in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/ ana.21723 28 © 2009 American Neurological Association