CLOTBUST-Hands Free Pilot Safety Study of a Novel Operator-Independent Ultrasound Device in Patients With Acute Ischemic Stroke Andrew D. Barreto, MD; Andrei V. Alexandrov, MD; Loren Shen, BSN; April Sisson, RN; Andrew W. Bursaw, DO; Preeti Sahota, MD; Hui Peng, PhD; Manouchehr Ardjomand-Hessabi, MD, MPH; Renganayaki Pandurengan, PhD; Mohammad H. Rahbar, PhD; Kristian Barlinn, MD; Hari Indupuru, MBBS; Nicole R. Gonzales, MD; Sean I. Savitz, MD; James C. Grotta, MD 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. (Stroke. 2013;44:3376-3381.) Key Words: CLOTBUST ◼ operator-independent device ◼ reperfusion ◼ sonothrombolysis ◼ stroke ◼ thrombolytic therapy ◼ ultrasonography, doppler, transcranial
T
he benefit of tissue-type plasminogen activator (tPA) in acute stroke is linked to the speed and degree of clot lysis and artery recanalization.1–3 However, only 20% to 30% of patients have complete recanalization within 2 hours of intravenous tPA therapy, and up to one third of those with any recanalization experience reocclusion.4,5 Adjunctive strategies to augment the reperfusion benefit of intravenous (IV)-tPA include both mechanical and medical
therapies.6 Sonothrombolysis, the enhancement of clot dissolution using a low-power 2-MHz transcranial Doppler (TCD) ultrasound energy, is a safe and promising adjunct to tPA.7 Despite wide confidence intervals, meta-analyses demonstrate safety (no difference in mortality or symptomatic intracerebral hemorrhage) and efficacy (reduced odds of dependency at 3 months) of sonothrombolysis compared with IV-tPA alone.8–10
Received July 9, 2013; accepted September 3, 2013. From the Department of Neurology, Stroke Program (A.D.B., L.S., A.W.B., P.S., H.I., N.R.G., S.I.S., J.C.G.) and Center for Clinical and Translational Sciences (H.P., M.A.-H., R.P., M.H.R.), University of Texas Health Science Center at Houston, TX; Comprehensive Stroke Center, Department of Neurology, The University of Alabama at Birmingham (A.V.A., A.S.); and Department of Neurology, Dresden University Stroke Center, University of Technology Dresden, Dresden, Germany (K.B.). Guest Editor for this article was Bo Norrving, MD. Correspondence to Andrew D. Barreto, MD, 6431 Fannin St, Room MSB 7.124, Houston, TX 77030. E-mail [email protected] © 2013 American Heart Association, Inc. Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.113.002713
3376
Barreto et al CLOTBUST-HF Safety Study in Ischemic Stroke 3377 Delivery of sonothrombolysis via cranial bone windows requires training for both anatomic localization and waveform recognition. Thus, mass expansion of properly trained technicians or clinicians to provide 24/7 stroke coverage to complete a pivotal clinical trial of sonothrombolysis represents a major hurdle. To that end, the development of an operator-independent device that can target the proximal intracranial arteries without specialized neurovascular ultrasound training would make a large-scale, phase III clinical trial feasible. Through previous industry and National Institutes of Health (NIH) funding, such a device was developed and has now undergone preliminary (phase I) testing.11 This hands-free (HF) device uses 2-MHz pulsed-wave technology that never exceeds approved diagnostic ultrasound exposure levels and delivers energy through both temporal windows and the suboccipital window via 18 separate transducers.11 In that phase I study, nonstroke volunteers underwent pre– and post–gadolinium-enhanced MRI permeability imaging after 2 hours of ultrasound exposure, and no blood– brain barrier disruption or clinical adverse events occurred. The aim of this next phase of the Combined Lysis of Thrombus in Brain Ischemia With Transcranial Ultrasound and Systemic T-PA-Hands-Free (CLOTBUST-HF) study involved testing the safety of the HF device in a cohort of patients with ischemic stroke (Figure [A]). If found to be safe, a simple-to-apply HF device would facilitate a large-scale,
phase III sonothrombolysis trial in patients with acute ischemic stroke (Figure [B]).
Subjects and Methods Design This phase II trial was a prospective, 2-center (University of Texas Health Science Center at Houston and University of Alabama at Birmingham), single-arm, open-label, noncontrolled safety study of 2-hour exposure to 2-MHz pulsed-wave ultrasound, combined with standard-dose (0.9 mg/kg) IV-tPA in patients with acute ischemic stroke. Because this was the first ever exposure of patients with acute stroke to a combination of tPA and HF device, a predetermined group of 20 patients was treated to obtain a preliminary assessment of safety. Safety was defined as a rate of symptomatic intracerebral hemorrhage not exceeding 10% with ≥80% confidence.
Patient Selection Inclusion and exclusion criteria are listed in Table 1. After informed consent from the patient, family, or legal representative, and before placing the HF device, all patients had routine admission laboratory tests, TCD (computed tomographic angiography [CTA] in patients without temporal windows or lack of TCD availability), NIH Stroke Scale, and modified Rankin scale (mRS). Intravenous tPA (0.9 mg/kg) was given ≤4.5 hours from the time the patient was last seen neurologically normal. There was no delay in starting IVtPA as a result of participation in this study. Informed consent and other qualifying activities for the study took place after the IV-tPA bolus was given.
Figure. A, Hands-free (HF) device components, including demonstration of headframe on a volunteer. Note that the external output cable allows the input of the HF device to a diagnostic transcranial Doppler (TCD) system for waveform validation testing. B, Final production device (Combined Lysis of Thrombus in Brain Ischemia With Transcranial Ultrasound and Systemic T-PA [CLOTBUST]-ER; Cerevast Therapeutics; Redmond, WA) after miniaturization. Device is battery powered, portable, and currently being tested in a pivotal phase III efficacy trial (CLOTBUST-ER; www.clinicaltrials.gov NCT01098981). C, Example of computed tomographic angiogram of enrolled patient demonstrating a right middle cerebral artery branch occlusion (arrowhead) before and after tissue-type plasminogen activator (tPA) plus sonothrombolysis. D, Post hoc comparison of current study with the CLOTBUST study7: recanalization (1) and percent modified Rankin scale (mRS) 0 to 1 at 90 days (2).
3378 Stroke December 2013 Table 1. Inclusion/Exclusion Criteria for Participating in This Trial Inclusion Criteria
Exclusion Criteria
(1) Disabling focal neurological deficit
(1) Intra-arterial thrombolysis
(2) Intravenous tPA (0.9 mg/kg, 10% bolus 90% infusion for 1 h, maximum dose 90 mg) infusion initiated within 4.5 h of symptom onset
(2) Contraindications for intravenous tPA within 3–4.5 h: (a) NIHSS >25 (b) Oral anticoagulant treatment (regardless of INR level) (c) Combination previous stroke and diabetes mellitus (d) Age >80 y
(3) Diagnostic TCD (or pre-tPA CT angiogram) confirms intracranial arterial occlusion (TIBI ≤3 or TIMI 0 or 1) of the middle cerebral artery (MCA–M1 or proximal M2), anterior cerebral artery, internal carotid artery, posterior cerebral artery, vertebral or distal basilar artery (4) If patient enrolled through CTA pathway, GFR >60 (5) Baseline (prestroke) mRS 2 symptomatic hemorrhages occurred in the first or second group of 10 patients. Analyses were conducted using SAS version 9.2 (Cary, NC).
Results From October 2010 through September 2011, 20 patients (12 men) were enrolled (60% TCD and 40% CTA) at 2 stroke centers. Seventy percent of patients had middle cerebral artery (MCA) occlusions (86% M1 and 14% M2). Median baseline NIH Stroke Scale score was 15 (range, 7–35; Table 2). Median time from symptom onset to tPA bolus was 129 (interquartile range, 102–158) minutes. Table 3 details the safety results. No patients experienced symptomatic intracerebral hemorrhage. One patient was diagnosed with infective endocarditis and had resultant multifocal intracerebral bleeding that was adjudicated to be related to the underlying disease rather than the study device.
Recanalization and Clinical Outcomes The distribution of qualifying lesions on TCD and CTA is presented in Table 2. Six non-MCA cases were included (3 terminal internal carotid artery and 3 vertebral artery occlusions). Of the 14 MCA occlusions, 12 (86%) were M1 and 2 (14%) M2 segments. After 2 hours of HF ultrasound period, all patients underwent follow-up TCD or CTA recanalization assessment (Figure [C]). Recanalization occurred in half the patients: complete in 8 (40%) and partial in 2 (10%; Table 4). Compared with historical controls (tPA alone) from the original CLOTBUST study,7 the HF device–treated patients experienced higher rates of sustained complete recanalization, similar to what we observed with the handheld device (Figure [D1]). Of the patients with non-MCA occlusion, none experienced recanalization. At discharge, 13 (65%) patients went home or to acute rehabilitation, and 3 patients died (15%). At day 90, an additional patient died (mortality, 4 of 20; 20%). Two of the 4 deaths resulted from large hemispheric infarction with herniation. One patient was found to have bacterial endocarditis as the stroke etiology, which resulted in multifocal intracerebral hemorrhage, and died of septic shock. The NIH Stroke Scale only increased by 3 points, and both the local investigator and the data and safety monitoring committee adjudicated the hemorrhage to be related to the underlying disease and tPA,
Barreto et al CLOTBUST-HF Safety Study in Ischemic Stroke 3379 Table 2. Baseline Characteristics of Patients in This Study (n=20)
Table 3. Summary Measures of Safety Based on 20 Participants in This Study
Variable
Symptomatic ICH, n (%, 95% CI)
0 (0, 0–17)
Male, n (%)
12 (60)
Parenchymal hematoma type 2, n (%, 95% CI)
0 (0, 0–17)
Age, mean (SD)
63 (14)
Asymptomatic ICH, n (%, 95% CI) Parenchymal hematoma type 1 Hemorrhagic transformation type 2 Hemorrhagic transformation type 1 Total
4 (20, 6–44) 0 (0, 0–17) 2 (10, 1–32) 6 (30, 12–54)
Summary Data
Race/ethnicity, n (%) White
7 (35)
Black
9 (45)
Hispanic
3 (15)
Asian
1 (5)
NIHSS, median (range)
15 (7–35)
Medical history, n (%) Hypertension
14 (70)
Hyperlipidemia
8 (40)
Congestive heart failure
5 (25)
Diabetes mellitus
4 (20)
Atrial fibrillation
3 (15)
Occluded vessel, n (%) MCA
14 (70)
Proximal
12 (86)
Distal
2 (14)
Terminal ICA
3 (15)
Vertebral
3 (15)
Vessel imaging modality, n (%) Transcranial Doppler
12 (60)
CT angiogram
8 (40)
Time from symptom onset to tPA bolus (min), median (IQR) Time from tPA bolus to start of sonothrombolysis (min), median (IQR)
129 (102, 158) 22 (14, 29)
CT indicates computed tomography; ICA, internal carotid artery; IQR, interquartile range; MCA, middle cerebral artery; NIHSS, National Institutes of Health Stroke Scale; and tPA, tissue-type plasminogen activator.
rather than the study device. At 90 days, data were available from all patients: 5 patients (25%) reached mRS of 0 or 1; 1 (5%), mRS of 2; 5 (25%), mRS of 3; 4 (20%), mRS of 4; 1 (5%), mRS of 5; and 4 (20%) patients died. Compared with tPA-alone historical controls from the CLOTBUST study,7 the rate of excellent outcome (mRS, 0–1) did not significantly differ (Figure [D2]). Overall, a higher proportion of patients who had complete recanalization experienced an mRS of 0 or 1 at day 90 compared with nonrecanalizers (60% versus 20%; P=0.347 Fisher exact test). After excluding the 4 deaths, this comparison yielded similar results (60% versus 38%; P=0.299 Fisher exact test).
Discussion Our results add to the available literature supporting the safety of 2-MHz frequency pulsed-wave transcranial ultrasound in patients with acute ischemic stroke. No patients had dermatologic adverse events or symptomatic intracranial hemorrhage. The challenge with widespread sonothrombolysis implementation has been a lack of adequately trained sonographers who can quickly locate the intracranial thrombus and
Adverse events: total, n (average number per patient, 95% CI) Dermatologic adverse events Serious adverse events: total, n (average number per patient, 95% CI) Cerebral edema Pneumonia/respiratory failure Death (brain herniation or respiratory failure) Stroke progression/neurological worsening Intracranial hemorrhage secondary to bacterial endocarditis Sepsis Related to study device Mortality, n (%, 95% CI)
74 (3.7, 2.9–4.6) 0 (0, 0–17) 14 (0.7, 0.4–1.2) 4 (20, 6–44) 4 (20, 6–44) 3 (15, 3–38) 1 (5, 0–25) 1 (5, 0–25) 1 (5, 0–25) 0 (0, 0–17) 4 (20, 6–44)
CI indicates confidence interval; and ICH, intracerebral hemorrhage.
maintain a single, handheld transducer focused on the target.15 The HF device tested in this study represents a leap forward with regard to feasibility in executing a large phase III efficacy trial. Using easily identified anatomic landmarks (eg, the pinna, bridge of nose, and occipital protuberance), medical professionals without neurosonology training will be able to place the device quickly in an emergent setting. Because arterial recanalization is linked strongly with early clinical improvement after stroke, adjunctive tPA therapies such as sonothrombolysis would need to amplify clot dissolution greater than tPA alone. Ultrasound energy can promote motion around the thrombus, resulting in presumed enhanced delivery of tPA in areas of stagnant flow.15,16 Although lower frequency (kilohertz range) ultrasound penetrates the skull better, the ultrasound that is safe and has shown the most promise is in the megahertz range. Furthermore, 2-MHz TCD is already available in clinical practice and can provide diagnostic information, which is not possible with kilohertz frequencies. Others have combined intravenous microbubbles with tPA and TCD ultrasound energy in an effort to boost recanalization further.17–19 Gaseous microbubbles (ultrasound contrast agents) expand in size when exposed to ultrasound Table 4. Summary Measures of Recanalization and Clinical Outcome Along With 95% CI 2-h Recanalization, n (%, 95% CI) Complete Partial Total (complete or partial)
8 (40, 19–64) 2 (10, 1–32) 10 (50, 27–73)
Complete: MCA occlusions only (n=14)
8 (57, 29–82)
Favorable outcome: 90-d mRS 0 or 1, n (%, 95% CI)
5 (25, 7–49)
CI indicates confidence interval; MCA, middle cerebral artery; and mRS, modified Rankin scale.
3380 Stroke December 2013 energy and assist in clot dissolution. Although early results were promising in small studies, larger safety studies are necessary to confirm that microbubbles can augment sonothrombolysis and result in greater recanalization compared with sonothrombolysis alone. Our recanalization results parallel the original CLOTBUST study, but with important differences in patient populations. First, the current study allowed non-MCA occlusions (3 terminal internal carotid artery and 3 vertebral artery) and tPA delivery ≤4.5 hours from symptom onset. Both these factors have been associated with reduced odds of achieving a good clinical outcome.20–22 Second, as a result of the time delays inherent with obtaining consent and subsequent fitting of the HF prototype on patients’ crania, the current study only achieved ≈38 minutes of tPA-ultrasound overlap. These aspects might explain the lower rates of good clinical outcome (mRS 0–1 at 90 days). However, as a result of the small sample size, the confidence intervals are wide and overlap with those in the operator-dependent study.
Limitations As a result of the small sample size of the study, it may be difficult to draw reliable conclusions. Other limitations include possible selection bias and investigators unblinded to treatment. However, these design characteristics are typical of pilot safety analyses evaluating first human exposure to a particular treatment that may have high risks.
Conclusions In conclusion, HF delivery of transcranial sonothrombolysis, in combination with IV-tPA, seems potentially safe in patients with proximal intracranial arterial occlusions and may produce more complete recanalization compared with tPA alone. Further study of this treatment combination seems warranted and is ongoing in a phase III efficacy trial (CLOTBUST-ER; NCT01098981).
Acknowledgments We thank the members of the data safety and monitoring committee: Igor Cherches, MD, The Neurology Center, Houston, TX; Robert Hart, MD, McMaster University, Ontario, Canada; Dejian Lai, PhD, University of Texas Health Science Center, Houston, TX; and Janyce Sanford, MD, University of Alabama, Birmingham, AL.
Sources of Funding This study was supported by grant P50NS044227 from the National Institute of Neurological Disorders and Stroke (NINDS); training grant T32NS07412 from the National Institutes of Health (NIH) to the University of Texas–Houston Medical School Stroke Program; and grants 1K23NS02229-01 and 1P50NS044227 from NINDS to the Combined Lysis of Thrombus in Brain Ischemia With Transcranial Ultrasound and Systemic T-PA (CLOTBUST) trial. This work was also supported by the Center for Clinical and Translational Sciences, which is funded by the NIH Clinical and Translational Award UL1 RR024148 (TL1 RR024147 for the T32 program; KL2 RR0224149 for the K12 program) from the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or NIH. Cerevast Therapeutics (Redmond, WA) provided the study devices and was not involved in the study design, analysis, or manuscript preparation.
Disclosures Drs Barlinn and Barreto were supported by the National Institute of Neurological Disorders and Stroke (NINDS) Specialized Programs of Translational Research in Acute Stroke (SPOTRIAS) grant (PI— Dr Grotta, University of Texas Health Science Center at Houston), project CLOTBUST Hands Free, phase I/II studies of an operatorindependent device for sonothrombolysis in stroke. Dr Alexandrov serves as a consultant to Cerevast Therapeutics, Inc and holds US patent 6733450 “Therapeutic Method and Apparatus for Use of Sonication to Enhance Perfusion of Tissues,” assignee—Texas Board of Regents. Dr Alexandrov’s role in the studies sponsored by the NINDS SPOTRIAS grant has been approved by the University of Alabama Centralized Institutional Review Board, and independent Data Management and Data Safety Monitoring Boards were overseeing data analysis. Dr Barreto has been engaged as one of Cerevast Therapeutic's Scientific Advisory Board members since February 1, 2010 and is the US national principal investigator for the phase III clinical trial, CLOTBUST-ER (NCT01098981). The other authors report no conflicts.
References 1. Alexandrov AV, Burgin WS, Demchuk AM, El-Mitwalli A, Grotta JC. Speed of intracranial clot lysis with intravenous tissue plasminogen activator therapy: sonographic classification and short-term improvement. Circulation. 2001;103:2897–2902. 2. Demchuk AM, Burgin WS, Christou I, Felberg RA, Barber PA, Hill MD, et al. Thrombolysis in brain ischemia (TIBI) transcranial Doppler flow grades predict clinical severity, early recovery, and mortality in patients treated with intravenous tissue plasminogen activator. Stroke. 2001;32:89–93. 3. Labiche LA, Al-Senani F, Wojner AW, Grotta JC, Malkoff M, Alexandrov AV. Is the benefit of early recanalization sustained at 3 months? A prospective cohort study. Stroke. 2003;34:695–698. 4. Alexandrov AV, Demchuk AM, Burgin WS, Robinson DJ, Grotta JC; CLOTBUST Investigators. Ultrasound-enhanced thrombolysis for acute ischemic stroke: phase I. Findings of the CLOTBUST trial. J Neuroimaging. 2004;14:113–117. 5. Alexandrov AV, Grotta JC. Arterial reocclusion in stroke patients treated with intravenous tissue plasminogen activator. Neurology. 2002;59:862–867. 6. Barreto AD, Alexandrov AV. Adjunctive and alternative approaches to current reperfusion therapy. Stroke. 2012;43:591–598. 7. Alexandrov AV, Molina CA, Grotta JC, Garami Z, Ford SR, AlvarezSabin J, et al. Ultrasound-enhanced systemic thrombolysis for acute ischemic stroke. New Engl J Med. 2004;351:2170–2178. 8. Ricci S, Dinia L, Del Sette M, Anzola P, Mazzoli T, Cenciarelli S, et al. Sonothrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev. 2012;10:CD008348. 9. Saqqur M, Tsivgoulis G, Nicoli F, Skoloudik D, Sharma VK, Larrue V, et al. The role of sonolysis and sonothrombolysis in acute ischemic stroke: a systematic review and meta-analysis of randomized controlled trials and case-control studies. J Neuroimaging. 2013. http://onlinelibrary.wiley.com/ journal/10.1111/(ISSN)1552–6569/earlyview. Accessed August 23, 2013. 10. Tsivgoulis G, Eggers J, Ribo M, Perren F, Saqqur M, Rubiera M, et al. Safety and efficacy of ultrasound-enhanced thrombolysis: a comprehensive review and meta-analysis of randomized and nonrandomized studies. Stroke. 2010;41:280–287. 11. Barlinn K, Barreto AD, Sisson A, Liebeskind DS, Schafer ME, Alleman J, et al. Clotbust-hands free: initial safety testing of a novel operatorindependent ultrasound device in stroke-free volunteers. Stroke. 2013;44:1641–1646. 12. Alexandrov AV, Sloan MA, Tegeler CH, Newell DN, Lumsden A, Garami Z, et al. Practice standards for transcranial Doppler (TCD) ultrasound. Part II. Clinical indications and expected outcomes. J Neuroimaging. 2012;22:215–224. 13. Tsivgoulis G, Ribo M, Rubiera M, Vasdekis SN, Barlinn K, Athanasiadis D, et al. Real-time validation of transcranial Doppler criteria in assessing recanalization during intra-arterial procedures for acute ischemic stroke: an international, multicenter study. Stroke. 2013;44:394–400. 14. Tsivgoulis G, Sharma VK, Lao AY, Malkoff MD, Alexandrov AV. Validation of transcranial Doppler with computed tomography angiography in acute cerebral ischemia. Stroke. 2007;38:1245–1249.
Barreto et al CLOTBUST-HF Safety Study in Ischemic Stroke 3381 15. Tsivgoulis G, Alexandrov AV. Ultrasound-enhanced thrombolysis in acute ischemic stroke: potential, failures, and safety. Neurotherapeutics. 2007;4:420–427. 16. Meairs S, Alonso A, Hennerici MG. Progress in sonothrombolysis for the treatment of stroke. Stroke. 2012;43:1706–1710. 17. Alexandrov AV, Mikulik R, Ribo M, Sharma VK, Lao AY, Tsivgoulis G, et al. A pilot randomized clinical safety study of sonothrombolysis augmentation with ultrasound-activated perflutren-lipid microspheres for acute ischemic stroke. Stroke. 2008;39:1464–1469. 18. Molina CA, Barreto AD, Tsivgoulis G, Sierzenski P, Malkoff MD, Rubiera M, et al. Transcranial ultrasound in clinical sonothrombolysis (TUCSON) trial. Ann Neurol. 2009;66:28–38. 19. Molina CA, Ribo M, Rubiera M, Montaner J, Santamarina E, Delgado-Mederos R, et al. Microbubble administration accelerates
clot lysis during continuous 2-MHz ultrasound monitoring in stroke patients treated with intravenous tissue plasminogen activator. Stroke. 2006;37:425–429. 20. Saqqur M, Uchino K, Demchuk AM, Molina CA, Garami Z, Calleja S, et al. Site of arterial occlusion identified by transcranial Doppler predicts the response to intravenous thrombolysis for stroke. Stroke. 2007;38:948–954. 21. Saver JL, Fonarow GC, Smith EE, Reeves MJ, Grau-Sepulveda MV, Pan W, et al. Time to treatment with intravenous tissue plasminogen activator and outcome from acute ischemic stroke. J Am Med Assoc. 2013;309:2480–2488. 22. Smith WS, Lev MH, English JD, Camargo EC, Chou M, Johnston SC, et al. Significance of large vessel intracranial occlusion causing acute ischemic stroke and TIA. Stroke. 2009;40:3834–3840.
T
he benefit of tissue-type plasminogen activator (tPA) in acute stroke is linked to the speed and degree of clot lysis and artery recanalization.1–3 However, only 20% to 30% of patients have complete recanalization within 2 hours of intravenous tPA therapy, and up to one third of those with any recanalization experience reocclusion.4,5 Adjunctive strategies to augment the reperfusion benefit of intravenous (IV)-tPA include both mechanical and medical
therapies.6 Sonothrombolysis, the enhancement of clot dissolution using a low-power 2-MHz transcranial Doppler (TCD) ultrasound energy, is a safe and promising adjunct to tPA.7 Despite wide confidence intervals, meta-analyses demonstrate safety (no difference in mortality or symptomatic intracerebral hemorrhage) and efficacy (reduced odds of dependency at 3 months) of sonothrombolysis compared with IV-tPA alone.8–10
Received July 9, 2013; accepted September 3, 2013. From the Department of Neurology, Stroke Program (A.D.B., L.S., A.W.B., P.S., H.I., N.R.G., S.I.S., J.C.G.) and Center for Clinical and Translational Sciences (H.P., M.A.-H., R.P., M.H.R.), University of Texas Health Science Center at Houston, TX; Comprehensive Stroke Center, Department of Neurology, The University of Alabama at Birmingham (A.V.A., A.S.); and Department of Neurology, Dresden University Stroke Center, University of Technology Dresden, Dresden, Germany (K.B.). Guest Editor for this article was Bo Norrving, MD. Correspondence to Andrew D. Barreto, MD, 6431 Fannin St, Room MSB 7.124, Houston, TX 77030. E-mail [email protected] © 2013 American Heart Association, Inc. Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.113.002713
3376
Barreto et al CLOTBUST-HF Safety Study in Ischemic Stroke 3377 Delivery of sonothrombolysis via cranial bone windows requires training for both anatomic localization and waveform recognition. Thus, mass expansion of properly trained technicians or clinicians to provide 24/7 stroke coverage to complete a pivotal clinical trial of sonothrombolysis represents a major hurdle. To that end, the development of an operator-independent device that can target the proximal intracranial arteries without specialized neurovascular ultrasound training would make a large-scale, phase III clinical trial feasible. Through previous industry and National Institutes of Health (NIH) funding, such a device was developed and has now undergone preliminary (phase I) testing.11 This hands-free (HF) device uses 2-MHz pulsed-wave technology that never exceeds approved diagnostic ultrasound exposure levels and delivers energy through both temporal windows and the suboccipital window via 18 separate transducers.11 In that phase I study, nonstroke volunteers underwent pre– and post–gadolinium-enhanced MRI permeability imaging after 2 hours of ultrasound exposure, and no blood– brain barrier disruption or clinical adverse events occurred. The aim of this next phase of the Combined Lysis of Thrombus in Brain Ischemia With Transcranial Ultrasound and Systemic T-PA-Hands-Free (CLOTBUST-HF) study involved testing the safety of the HF device in a cohort of patients with ischemic stroke (Figure [A]). If found to be safe, a simple-to-apply HF device would facilitate a large-scale,
phase III sonothrombolysis trial in patients with acute ischemic stroke (Figure [B]).
Subjects and Methods Design This phase II trial was a prospective, 2-center (University of Texas Health Science Center at Houston and University of Alabama at Birmingham), single-arm, open-label, noncontrolled safety study of 2-hour exposure to 2-MHz pulsed-wave ultrasound, combined with standard-dose (0.9 mg/kg) IV-tPA in patients with acute ischemic stroke. Because this was the first ever exposure of patients with acute stroke to a combination of tPA and HF device, a predetermined group of 20 patients was treated to obtain a preliminary assessment of safety. Safety was defined as a rate of symptomatic intracerebral hemorrhage not exceeding 10% with ≥80% confidence.
Patient Selection Inclusion and exclusion criteria are listed in Table 1. After informed consent from the patient, family, or legal representative, and before placing the HF device, all patients had routine admission laboratory tests, TCD (computed tomographic angiography [CTA] in patients without temporal windows or lack of TCD availability), NIH Stroke Scale, and modified Rankin scale (mRS). Intravenous tPA (0.9 mg/kg) was given ≤4.5 hours from the time the patient was last seen neurologically normal. There was no delay in starting IVtPA as a result of participation in this study. Informed consent and other qualifying activities for the study took place after the IV-tPA bolus was given.
Figure. A, Hands-free (HF) device components, including demonstration of headframe on a volunteer. Note that the external output cable allows the input of the HF device to a diagnostic transcranial Doppler (TCD) system for waveform validation testing. B, Final production device (Combined Lysis of Thrombus in Brain Ischemia With Transcranial Ultrasound and Systemic T-PA [CLOTBUST]-ER; Cerevast Therapeutics; Redmond, WA) after miniaturization. Device is battery powered, portable, and currently being tested in a pivotal phase III efficacy trial (CLOTBUST-ER; www.clinicaltrials.gov NCT01098981). C, Example of computed tomographic angiogram of enrolled patient demonstrating a right middle cerebral artery branch occlusion (arrowhead) before and after tissue-type plasminogen activator (tPA) plus sonothrombolysis. D, Post hoc comparison of current study with the CLOTBUST study7: recanalization (1) and percent modified Rankin scale (mRS) 0 to 1 at 90 days (2).
3378 Stroke December 2013 Table 1. Inclusion/Exclusion Criteria for Participating in This Trial Inclusion Criteria
Exclusion Criteria
(1) Disabling focal neurological deficit
(1) Intra-arterial thrombolysis
(2) Intravenous tPA (0.9 mg/kg, 10% bolus 90% infusion for 1 h, maximum dose 90 mg) infusion initiated within 4.5 h of symptom onset
(2) Contraindications for intravenous tPA within 3–4.5 h: (a) NIHSS >25 (b) Oral anticoagulant treatment (regardless of INR level) (c) Combination previous stroke and diabetes mellitus (d) Age >80 y
(3) Diagnostic TCD (or pre-tPA CT angiogram) confirms intracranial arterial occlusion (TIBI ≤3 or TIMI 0 or 1) of the middle cerebral artery (MCA–M1 or proximal M2), anterior cerebral artery, internal carotid artery, posterior cerebral artery, vertebral or distal basilar artery (4) If patient enrolled through CTA pathway, GFR >60 (5) Baseline (prestroke) mRS 2 symptomatic hemorrhages occurred in the first or second group of 10 patients. Analyses were conducted using SAS version 9.2 (Cary, NC).
Results From October 2010 through September 2011, 20 patients (12 men) were enrolled (60% TCD and 40% CTA) at 2 stroke centers. Seventy percent of patients had middle cerebral artery (MCA) occlusions (86% M1 and 14% M2). Median baseline NIH Stroke Scale score was 15 (range, 7–35; Table 2). Median time from symptom onset to tPA bolus was 129 (interquartile range, 102–158) minutes. Table 3 details the safety results. No patients experienced symptomatic intracerebral hemorrhage. One patient was diagnosed with infective endocarditis and had resultant multifocal intracerebral bleeding that was adjudicated to be related to the underlying disease rather than the study device.
Recanalization and Clinical Outcomes The distribution of qualifying lesions on TCD and CTA is presented in Table 2. Six non-MCA cases were included (3 terminal internal carotid artery and 3 vertebral artery occlusions). Of the 14 MCA occlusions, 12 (86%) were M1 and 2 (14%) M2 segments. After 2 hours of HF ultrasound period, all patients underwent follow-up TCD or CTA recanalization assessment (Figure [C]). Recanalization occurred in half the patients: complete in 8 (40%) and partial in 2 (10%; Table 4). Compared with historical controls (tPA alone) from the original CLOTBUST study,7 the HF device–treated patients experienced higher rates of sustained complete recanalization, similar to what we observed with the handheld device (Figure [D1]). Of the patients with non-MCA occlusion, none experienced recanalization. At discharge, 13 (65%) patients went home or to acute rehabilitation, and 3 patients died (15%). At day 90, an additional patient died (mortality, 4 of 20; 20%). Two of the 4 deaths resulted from large hemispheric infarction with herniation. One patient was found to have bacterial endocarditis as the stroke etiology, which resulted in multifocal intracerebral hemorrhage, and died of septic shock. The NIH Stroke Scale only increased by 3 points, and both the local investigator and the data and safety monitoring committee adjudicated the hemorrhage to be related to the underlying disease and tPA,
Barreto et al CLOTBUST-HF Safety Study in Ischemic Stroke 3379 Table 2. Baseline Characteristics of Patients in This Study (n=20)
Table 3. Summary Measures of Safety Based on 20 Participants in This Study
Variable
Symptomatic ICH, n (%, 95% CI)
0 (0, 0–17)
Male, n (%)
12 (60)
Parenchymal hematoma type 2, n (%, 95% CI)
0 (0, 0–17)
Age, mean (SD)
63 (14)
Asymptomatic ICH, n (%, 95% CI) Parenchymal hematoma type 1 Hemorrhagic transformation type 2 Hemorrhagic transformation type 1 Total
4 (20, 6–44) 0 (0, 0–17) 2 (10, 1–32) 6 (30, 12–54)
Summary Data
Race/ethnicity, n (%) White
7 (35)
Black
9 (45)
Hispanic
3 (15)
Asian
1 (5)
NIHSS, median (range)
15 (7–35)
Medical history, n (%) Hypertension
14 (70)
Hyperlipidemia
8 (40)
Congestive heart failure
5 (25)
Diabetes mellitus
4 (20)
Atrial fibrillation
3 (15)
Occluded vessel, n (%) MCA
14 (70)
Proximal
12 (86)
Distal
2 (14)
Terminal ICA
3 (15)
Vertebral
3 (15)
Vessel imaging modality, n (%) Transcranial Doppler
12 (60)
CT angiogram
8 (40)
Time from symptom onset to tPA bolus (min), median (IQR) Time from tPA bolus to start of sonothrombolysis (min), median (IQR)
129 (102, 158) 22 (14, 29)
CT indicates computed tomography; ICA, internal carotid artery; IQR, interquartile range; MCA, middle cerebral artery; NIHSS, National Institutes of Health Stroke Scale; and tPA, tissue-type plasminogen activator.
rather than the study device. At 90 days, data were available from all patients: 5 patients (25%) reached mRS of 0 or 1; 1 (5%), mRS of 2; 5 (25%), mRS of 3; 4 (20%), mRS of 4; 1 (5%), mRS of 5; and 4 (20%) patients died. Compared with tPA-alone historical controls from the CLOTBUST study,7 the rate of excellent outcome (mRS, 0–1) did not significantly differ (Figure [D2]). Overall, a higher proportion of patients who had complete recanalization experienced an mRS of 0 or 1 at day 90 compared with nonrecanalizers (60% versus 20%; P=0.347 Fisher exact test). After excluding the 4 deaths, this comparison yielded similar results (60% versus 38%; P=0.299 Fisher exact test).
Discussion Our results add to the available literature supporting the safety of 2-MHz frequency pulsed-wave transcranial ultrasound in patients with acute ischemic stroke. No patients had dermatologic adverse events or symptomatic intracranial hemorrhage. The challenge with widespread sonothrombolysis implementation has been a lack of adequately trained sonographers who can quickly locate the intracranial thrombus and
Adverse events: total, n (average number per patient, 95% CI) Dermatologic adverse events Serious adverse events: total, n (average number per patient, 95% CI) Cerebral edema Pneumonia/respiratory failure Death (brain herniation or respiratory failure) Stroke progression/neurological worsening Intracranial hemorrhage secondary to bacterial endocarditis Sepsis Related to study device Mortality, n (%, 95% CI)
74 (3.7, 2.9–4.6) 0 (0, 0–17) 14 (0.7, 0.4–1.2) 4 (20, 6–44) 4 (20, 6–44) 3 (15, 3–38) 1 (5, 0–25) 1 (5, 0–25) 1 (5, 0–25) 0 (0, 0–17) 4 (20, 6–44)
CI indicates confidence interval; and ICH, intracerebral hemorrhage.
maintain a single, handheld transducer focused on the target.15 The HF device tested in this study represents a leap forward with regard to feasibility in executing a large phase III efficacy trial. Using easily identified anatomic landmarks (eg, the pinna, bridge of nose, and occipital protuberance), medical professionals without neurosonology training will be able to place the device quickly in an emergent setting. Because arterial recanalization is linked strongly with early clinical improvement after stroke, adjunctive tPA therapies such as sonothrombolysis would need to amplify clot dissolution greater than tPA alone. Ultrasound energy can promote motion around the thrombus, resulting in presumed enhanced delivery of tPA in areas of stagnant flow.15,16 Although lower frequency (kilohertz range) ultrasound penetrates the skull better, the ultrasound that is safe and has shown the most promise is in the megahertz range. Furthermore, 2-MHz TCD is already available in clinical practice and can provide diagnostic information, which is not possible with kilohertz frequencies. Others have combined intravenous microbubbles with tPA and TCD ultrasound energy in an effort to boost recanalization further.17–19 Gaseous microbubbles (ultrasound contrast agents) expand in size when exposed to ultrasound Table 4. Summary Measures of Recanalization and Clinical Outcome Along With 95% CI 2-h Recanalization, n (%, 95% CI) Complete Partial Total (complete or partial)
8 (40, 19–64) 2 (10, 1–32) 10 (50, 27–73)
Complete: MCA occlusions only (n=14)
8 (57, 29–82)
Favorable outcome: 90-d mRS 0 or 1, n (%, 95% CI)
5 (25, 7–49)
CI indicates confidence interval; MCA, middle cerebral artery; and mRS, modified Rankin scale.
3380 Stroke December 2013 energy and assist in clot dissolution. Although early results were promising in small studies, larger safety studies are necessary to confirm that microbubbles can augment sonothrombolysis and result in greater recanalization compared with sonothrombolysis alone. Our recanalization results parallel the original CLOTBUST study, but with important differences in patient populations. First, the current study allowed non-MCA occlusions (3 terminal internal carotid artery and 3 vertebral artery) and tPA delivery ≤4.5 hours from symptom onset. Both these factors have been associated with reduced odds of achieving a good clinical outcome.20–22 Second, as a result of the time delays inherent with obtaining consent and subsequent fitting of the HF prototype on patients’ crania, the current study only achieved ≈38 minutes of tPA-ultrasound overlap. These aspects might explain the lower rates of good clinical outcome (mRS 0–1 at 90 days). However, as a result of the small sample size, the confidence intervals are wide and overlap with those in the operator-dependent study.
Limitations As a result of the small sample size of the study, it may be difficult to draw reliable conclusions. Other limitations include possible selection bias and investigators unblinded to treatment. However, these design characteristics are typical of pilot safety analyses evaluating first human exposure to a particular treatment that may have high risks.
Conclusions In conclusion, HF delivery of transcranial sonothrombolysis, in combination with IV-tPA, seems potentially safe in patients with proximal intracranial arterial occlusions and may produce more complete recanalization compared with tPA alone. Further study of this treatment combination seems warranted and is ongoing in a phase III efficacy trial (CLOTBUST-ER; NCT01098981).
Acknowledgments We thank the members of the data safety and monitoring committee: Igor Cherches, MD, The Neurology Center, Houston, TX; Robert Hart, MD, McMaster University, Ontario, Canada; Dejian Lai, PhD, University of Texas Health Science Center, Houston, TX; and Janyce Sanford, MD, University of Alabama, Birmingham, AL.
Sources of Funding This study was supported by grant P50NS044227 from the National Institute of Neurological Disorders and Stroke (NINDS); training grant T32NS07412 from the National Institutes of Health (NIH) to the University of Texas–Houston Medical School Stroke Program; and grants 1K23NS02229-01 and 1P50NS044227 from NINDS to the Combined Lysis of Thrombus in Brain Ischemia With Transcranial Ultrasound and Systemic T-PA (CLOTBUST) trial. This work was also supported by the Center for Clinical and Translational Sciences, which is funded by the NIH Clinical and Translational Award UL1 RR024148 (TL1 RR024147 for the T32 program; KL2 RR0224149 for the K12 program) from the National Center for Research Resources. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or NIH. Cerevast Therapeutics (Redmond, WA) provided the study devices and was not involved in the study design, analysis, or manuscript preparation.
Disclosures Drs Barlinn and Barreto were supported by the National Institute of Neurological Disorders and Stroke (NINDS) Specialized Programs of Translational Research in Acute Stroke (SPOTRIAS) grant (PI— Dr Grotta, University of Texas Health Science Center at Houston), project CLOTBUST Hands Free, phase I/II studies of an operatorindependent device for sonothrombolysis in stroke. Dr Alexandrov serves as a consultant to Cerevast Therapeutics, Inc and holds US patent 6733450 “Therapeutic Method and Apparatus for Use of Sonication to Enhance Perfusion of Tissues,” assignee—Texas Board of Regents. Dr Alexandrov’s role in the studies sponsored by the NINDS SPOTRIAS grant has been approved by the University of Alabama Centralized Institutional Review Board, and independent Data Management and Data Safety Monitoring Boards were overseeing data analysis. Dr Barreto has been engaged as one of Cerevast Therapeutic's Scientific Advisory Board members since February 1, 2010 and is the US national principal investigator for the phase III clinical trial, CLOTBUST-ER (NCT01098981). The other authors report no conflicts.
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