Augmented Ultrasound-Facilitated, Catheter-Directed Fibrinolysis for PE (SONIC-PE)

A Prospective, Single-Arm, Multicenter Study of Augmented Ultrasound-Facilitated, Catheter-Directed Low-Dose Fibrinolysis for Pulmonary Embolism (SONIC-PE)

SONIC-PE is a multicenter, prospective, single-arm study of 10 patients with bilateral PE treated with ultrasound-facilitated, catheter-directed lower-dose fibrinolysis (total dose 8 mg tPA given as 2 mg/hour/catheter over 2 hours) followed by 50 patients (total dose 6 mg tPA given as 3 mg/hour/catheter given over 1 hour) with the EKOS+™ system to determine its impact on the change in RV-to-LV diameter, refined Modified Miller Score, and distal pulmonary vascular blood volume as well as to assess International Society on Thrombosis and Haemostasis (ISTH) major bleeding.

Study Overview

• Status: Not yet recruiting
• Conditions: Pulmonary Embolism; Right Ventricular Dysfunction; Right Ventricular Failure
• Intervention / Treatment: Device: Ultrasound-facilitated, catheter-directed lower-dose fibrinolysis

Detailed Description

Patients with intermediate-high risk pulmonary embolism (PE) comprise a population at increased risk for clinical deterioration despite initially stable hemodynamics. The pathophysiology of hemodynamic deterioration in intermediate-high risk PE includes an abrupt increase in pulmonary vascular resistance, due to proximal as well as distal pulmonary artery occlusion, pulmonary hypertension, right ventricular (RV) pressure overload, and, ultimately, RV failure. While full-dose systemic fibrinolysis for PE has demonstrated efficacy for prevention of early morbidity and mortality, its net clinical benefit is attenuated by the risk of major bleeding, in particular intracranial hemorrhage. Catheter-directed therapies have been demonstrated to facilitate RV recovery while reducing the risk of major bleeding through use of lower-dose fibrinolysis or avoiding it altogether. Specifically, lower-dose regimens for ultrasound-facilitated, catheter-directed fibrinolysis result in sustained recovery of echocardiographically-determined RV function, reduction in Modified Miller Score (large-vessel pulmonary angiographic obstruction), functional status, and quality of life over the year following ultrasound-facilitated, catheter-directed fibrinolysis.

Recently, an upgrade to the output of the ultrasonic core catheter of the EKOS™ Endovascular System (EKOS+™) has demonstrated the ability to enhance fibrinolysis within a lower fibrinolytic dose range in preliminary studies (Boston Scientific Corporation, Maple Grove, MN). Compared with current EkoSonic™ system, a 50% increase in ultrasound power (measured in watts) with EKOS+™ resulted in a 130% increase in in vitro clot lysis compared with conventional catheter-directed fibrinolysis using the same dose of fibrinolytic drug.

SONIC-PE is multicenter, prospective single-arm study of 10 patients with bilateral PE treated with ultrasound-facilitated, catheter-directed lower-dose fibrinolysis (total dose 8 mg tPA given as 2 mg/hour/catheter over 2 hours) followed by 50 patients (total dose 6 mg tPA given as 3 mg/hour/catheter given over 1 hour) with the EKOS+™ system to determine its impact on the change in RV-to-LV diameter, refined Modified Miller Score, and distal pulmonary vascular blood volume as well as assess International Society on Thrombosis and Haemostasis (ISTH) major bleeding. The study will have an adaptive design component with transition to 8 mg tPA/2 hours if there is an excess of bleeding or observed lack of efficacy, as determined by an Independent Study Safety Monitor.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Gregory Piazza, MD, MS; Phone Number: 6177326984; Email: gpiazza@bwh.harvard.edu
• Study Contact Backup: Name: Darsiya Krishnathasan, MS; Phone Number: 6177326984; Email: dkrishnathasan@bwh.harvard.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. patients at least 18 years of age,
2. symptomatic PE defined as symptoms for <14 days with normal systolic blood pressure (>90 mmHg), RV-to-LV diameter ratio ≥0.9 on initial chest CT, bilateral filling defects located in at least 1 main or proximal lobar pulmonary artery, and cardiac troponin greater than the upper limit of normal (cTnI, cTnT, hsTnI, or hsTnT), AND
3. in whom ultrasound-facilitated, catheter-directed lower-dose fibrinolysis has been selected for treatment on a clinical basis.

Exclusion Criteria:

1. stroke or transient ischemic attack, head trauma, other active intracranial or intraspinal disease (including malignancy) within 1 year
2. recent active bleeding from a major organ within 1 month
3. major surgery within 7 days of screening
4. contraindication to therapeutic anticoagulation
5. systolic blood pressure <90 mm Hg, systolic blood pressure drop by at least 40 mmHg over at least 15 minutes, shock, use of vasopressors, need for CPR, or need for ECMO
6. need for mechanical ventilation, including non-invasive positive pressure ventilation
7. hematocrit <30%, platelet count <100,000/μl
8. international normalized ratio >3
9. serum creatinine > 2 mg/dL
10. liver cirrhosis
11. known hypersensitivity to tPA, heparin, or any excipients
12. perceived high risk for fatal or catastrophic bleeding
13. prescription of dual antiplatelet therapy (DAPT) at time of screening
14. Patients treated with any other advanced therapy, such as surgical embolectomy, catheter-based mechanical embolectomy, or fibrinolytic therapy, within the prior 30 days
15. pregnancy or lactation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ultrasound-facilitated, catheter-directed lower-dose fibrinolysis; 10 patients with bilateral PE will be treated with ultrasound-facilitated, catheter-directed lower-dose fibrinolysis (total dose 8 mg tPA given as 2 mg/hour/catheter over 2 hours) followed by 50 patients (total dose 6 mg tPA given as 3 mg/hour/catheter given over 1 hour) with the EKOS+™ system	Device: Ultrasound-facilitated, catheter-directed lower-dose fibrinolysis; Ultrasound-facilitated, catheter-directed lower-dose fibrinolysis (treated with a total dose 8 mg tPA given as 2 mg/hour/catheter over 2 hours for first 10 patients followed by 50 patients treated with total dose 6 mg tPA given as 3 mg/hour/catheter given over 1 hour) with the EKOS+™ system

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in RV-to-LV diameter ratio as measured by chest CT from baseline to 48 ± 6 hours	Change in RV-to-LV ratio will be determined by a dedicated core imaging laboratory, blinded to clinical data and timing of the CT studies	48 ± 6 hours
Frequency of ISTH major bleeding at 72 hours	Adjudicated independently using ISTH criteria	72 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in chest CT-measured blood volume in the distal pulmonary vasculature from baseline to 48 ± 6 hours	Baseline and 48 ± 6 hours CT scans will be analyzed offline using 3D volumetric analysis	48 ± 6 hours
Change in refined Modified Miller Score as measured by chest CT from baseline to 48 ± 6 hours as measured by chest CT from baseline to 48 ± 6 hours	Determined by a dedicated core imaging laboratory, blinded to clinical data and timing of the CT studies. Scores range from 0-40 with 0 meaning no obstruction.	48 ± 6 hours

Collaborators and Investigators

• Sponsor: Brigham and Women's Hospital
• Collaborators: Boston Scientific Corporation
• Investigators: Principal Investigator: Gregory Piazza, MD, MS, BWH

Publications and helpful links

General Publications

• Klok FA, Piazza G, Sharp ASP, Ni Ainle F, Jaff MR, Chauhan N, Patel B, Barco S, Goldhaber SZ, Kucher N, Lang IM, Schmidtmann I, Sterling KM, Becker D, Martin N, Rosenfield K, Konstantinides SV. Ultrasound-facilitated, catheter-directed thrombolysis vs anticoagulation alone for acute intermediate-high-risk pulmonary embolism: Rationale and design of the HI-PEITHO study. Am Heart J. 2022 Sep;251:43-53. doi: 10.1016/j.ahj.2022.05.011. Epub 2022 May 16.
• Konstantinides SV, Meyer G, Becattini C, Bueno H, Geersing GJ, Harjola VP, Huisman MV, Humbert M, Jennings CS, Jimenez D, Kucher N, Lang IM, Lankeit M, Lorusso R, Mazzolai L, Meneveau N, Ni Ainle F, Prandoni P, Pruszczyk P, Righini M, Torbicki A, Van Belle E, Zamorano JL; ESC Scientific Document Group. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J. 2020 Jan 21;41(4):543-603. doi: 10.1093/eurheartj/ehz405. No abstract available.
• Hassan SM, Nardelli P, Minhas JK, Ash SY, Estepar RSJ, Antkowiak MC, Badlam JB, Piazza G, Estepar RSJ, Washko GR, Rahaghi FN. CT imaging determinants of persistent hypoxemia in acute intermediate-risk pulmonary embolism. J Thromb Thrombolysis. 2023 Jul;56(1):196-201. doi: 10.1007/s11239-023-02813-x. Epub 2023 May 4.
• Piazza G. Advanced Management of Intermediate- and High-Risk Pulmonary Embolism: JACC Focus Seminar. J Am Coll Cardiol. 2020 Nov 3;76(18):2117-2127. doi: 10.1016/j.jacc.2020.05.028.
• Rahaghi FN, San Jose Estepar R, Goldhaber SZ, Minhas JK, Nardelli P, Vegas Sanchez-Ferrero G, De La Bruere I, Hassan SM, Mason S, Ash SY, Come CE, Washko GR, Piazza G. Quantification and Significance of Pulmonary Vascular Volume in Predicting Response to Ultrasound-Facilitated, Catheter-Directed Fibrinolysis in Acute Pulmonary Embolism (SEATTLE-3D). Circ Cardiovasc Imaging. 2019 Dec;12(12):e009903. doi: 10.1161/CIRCIMAGING.119.009903. Epub 2019 Dec 17. No abstract available.

Study record dates

Study Major Dates

• Study Start (Estimated): June 30, 2024
• Primary Completion (Estimated): June 30, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: March 7, 2024
• First Submitted That Met QC Criteria: March 7, 2024
• First Posted (Actual): March 13, 2024

Study Record Updates

• Last Update Posted (Actual): March 15, 2024
• Last Update Submitted That Met QC Criteria: March 13, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: pulmonary embolism; fibrinolysis; right ventricular dysfunction; catheter-directed therapy; right ventricular failure
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Embolism and Thrombosis; Embolism; Pulmonary Embolism; Ventricular Dysfunction; Ventricular Dysfunction, Right
• Other Study ID Numbers: 2023A070902

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Will consider requests of scientific merit

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No