Clinical trial NCT06310018: Augmented Ultrasound-Facilitated, Catheter-Directed Fibrinolysis for PE
Official title: A Prospective, Single-Arm, Multicenter Study of Augmented Ultrasound-Facilitated, Catheter-Directed Low-Dose Fibrinolysis for Pulmonary Embolism (SONIC-PE)
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: Pulmonary Embolism
Right Ventricular Dysfunction
Right Ventricular Failure
Keywords: pulmonary embolism
right ventricular failure
right ventricular dysfunction
catheter-directed therapy
fibrinolysis
Lead sponsor: Brigham and Women's Hospital
Sponsor class: OTHER
Collaborators: name: Boston Scientific Corporation
First posted: 2024-03-13
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: multicenter, prospective, single-arm study
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in RV-to-LV diameter ratio as measured by chest CT from baseline to 48 ± 6 hours
timeFrame: 48 ± 6 hours
measure: Frequency of ISTH major bleeding at 72 hours
timeFrame: 72 hours
Secondary outcomes:
measure: Change in chest CT-measured blood volume in the distal pulmonary vasculature from baseline to 48 ± 6 hours
timeFrame: 48 ± 6 hours
measure: 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
timeFrame: 48 ± 6 hours
Other outcomes:
Locations:
Study officials:
affiliation: BWH
name: Gregory Piazza, MD, MS
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.