ULTrasound Accelerated ThrombolysIs of PulMonAry Embolism (ULTIMA)

Randomized, Controlled Study Comparing EKOS EkoSonic Ultrasound Accelerated Thrombolysis to Anticoagulation in the Treatment of Sub-massive Pulmonary Embolism

The ULTIMA study is intended to prove that in patients with pulmonary embolism and a right ventricular end diastolic diameter to left ventricular end diastolic diameter ratio ≥1 (RV/LV ratio) will benefit from treatment with ultrasound accelerated thrombolysis (rt-PA) as compared to unfractionated heparin anticoagulation. Specifically, at 24 hours the RV/LV ratio will be significantly reduced in the treatment arm compared to the control arm.

Study Overview

• Status: Completed
• Conditions: Submassive Pulmonary Embolism
• Intervention / Treatment: Device: EkoSonic Endovascular System; Drug: Unfractionated heparin

• Study Type: Interventional
• Enrollment (Actual): 59
• Phase: Phase 3

Contacts and Locations

Study Locations

• Germany
  • Detmold, Germany, 32756
    • Klinikum Lippe-Detmold
  • Dortmund, Germany, 44137
    • Klinikum Dortmund gGmbH
  • Dresden, Germany, 01307
    • Universitätsklinikum Carl Gustav Carus an der TU Dresden
  • Greifswald, Germany, 17475
    • Universitätsklinikum der Ernst-Moritz-Arndt-Universität,
  • Heidelberg, Germany, 69120
    • Universitätsklinikum Heidelberg
  • München, Germany, 81377
    • Klinikum der Ludwig-Maximilians-Universität (LMU)
  • Quakenbrueck, Germany, 49610
    • Christliches Krankenhaus Quakenbrueck
  • Siegburg, Germany, 53721
    • Helios Klinikum Siegburg
  • Suhl, Germany, 98527
    • SRH Zentralklinikum Suhl
• Switzerland
  • Bern, Switzerland, 3010
    • Inselspital Bern, Kliniken fur Kardiologie and Angiologie

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 76 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with acute PE symptoms < 14 days.
• Filling defect by contrast-enhanced chest CT in at least one main or proximal lower lobe pulmonary artery
• Right ventricular dysfunction confirmed by echocardiography where the RV/LV end diastolic diameter ratio is ≥ 1.0.

Exclusion Criteria:

• Age less than 18 years or greater than 80 years
• Index PE symptom duration > 14 days
• Insufficient echocardiographic image quality in the apical or subcostal four-chamber view that prohibits the measurement of the right and left ventricular end-diastolic dimensions
• Known significant bleeding risk
• Administration of thrombolytic agents, e.g., tissue plasminogen activator, streptokinase, or urokinase, within the previous 4 days
• Active bleeding
• Known bleeding diathesis
• Known coagulation disorder, platelet count < 100 000/mm3, or previous use of vitamin K antagonists with INR > 2.5
• History of any intracranial or intraspinal surgery or trauma or intracranial/intraspinal bleed
• Intracranial neoplasm, arteriovenous malformation, or aneurysm
• Recent (< 3 months) GI bleeding.
• Recent (< 3 months) internal eye surgery or hemorrhagic retinopathy; recent (< 10 days) major surgery, cataract surgery, trauma, CPR, obstetrical delivery, or other invasive procedure.
• Allergy, hypersensitivity, or thrombocytopenia from heparin, rt-PA, or iodinated contrast, except for mild-moderate contrast allergies for which steroid pre-medication can be used.
• Estimated glomerular filtration rate (eGFR) < 50 ml/min as calculated by the Cockroft formula.
• Hemodynamic collapse at presentation defined as: need for cardiopulmonary resuscitation; or systolic blood pressure < 90 mm Hg for at least 15 min, or drop of systolic blood pressure by at least 40 mm Hg for at least 15 min with signs of end organ hypoperfusion (cold extremities or low urinary output < 30 mL/h or mental confusion); or need for catecholamine administration to maintain adequate organ perfusion and a systolic blood pressure of > 90 mm Hg.
• Severe hypertension on repeated readings (systolic > 180 mmHg or diastolic > 105 mmHg).
• Pregnant, lactation or parturition within the previous 30 days (positive pregnancy test, women of childbearing age must be tested).
• Participating in any other investigational drug or device study.
• Life expectancy < 90 days.
• Inability to comply with study assessments (e.g. due to geographic distance).
• Previous enrollment in this study
• Any other condition that the investigator feels would place the patient at increased risk if the investigational therapy is initiated.
• Known right-to-left shunt, for example from large patent foramen ovale or atrial septal defect
• Large (>10 mm) right atrial or right ventricular thrombus

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ultrasound accelerated thrombolysis; Patients in this arm will receive anti-coagulation (intravenous unfractionated heparin) plus the EkoSonic Endovascular System will be used to deliver a low dose <20mg rt-PA (Actilyse) directly into the occlusive pulmonary thrombus.	Device: EkoSonic Endovascular System; The EkoSonic Endovascular System will be used to deliver < 20 mg of rt-PA ( Actilyse) directly into the occlusive pulmonary thrombus.
Active Comparator: Intravenous unfractionated heparin; Patients in this arm will receive the standard of care: intravenous unfractionated heparin used as anti-coagulation treatment.	Drug: Unfractionated heparin; Intravenous unfractionated heparin used for anticoagulation treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction of RV/LV Ratio	Change in the end-diastolic RV/LV ratio from baseline to 24 hours by echocardiography.	24 hours
Major Bleeding and Intracranial Bleeding at 30 Days.	Bleeding will be classified as major if it is associated with a fall in the hemoglobin level of at least 2.0 g/dl, transfusion of ≥ 2 units of red blood cells, or involvement of a critical site (e.g., intracranial, intraspinal). To aid in evaluating the relationship of bleeding events to rt-PA administration, they will also be categorized by whether they occurred within 3 days after the initiation of thrombolytic therapy.	30 days

Collaborators and Investigators

• Sponsor: Boston Scientific Corporation
• Collaborators: EKOS Corporation
• Investigators: Principal Investigator: Nils Kucher, Prof Dr med, Inselspital Bern, Kliniken für Angiologie und Kardiologie

Publications and helpful links

General Publications

• Kucher N, Boekstegers P, Muller OJ, Kupatt C, Beyer-Westendorf J, Heitzer T, Tebbe U, Horstkotte J, Muller R, Blessing E, Greif M, Lange P, Hoffmann RT, Werth S, Barmeyer A, Hartel D, Grunwald H, Empen K, Baumgartner I. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation. 2014 Jan 28;129(4):479-86. doi: 10.1161/CIRCULATIONAHA.113.005544. Epub 2013 Nov 13.

Study record dates

Study Major Dates

• Study Start: July 1, 2010
• Primary Completion (Actual): April 1, 2013
• Study Completion (Actual): May 1, 2013

Study Registration Dates

• First Submitted: July 15, 2010
• First Submitted That Met QC Criteria: July 20, 2010
• First Posted (Estimate): July 21, 2010

Study Record Updates

• Last Update Posted (Actual): July 19, 2021
• Last Update Submitted That Met QC Criteria: July 15, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Keywords: thrombolysis; Pulmonary embolism; anticoagulation; Pulmonary thromboembolism; ultrasound accelerated thrombolysis
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Embolism and Thrombosis; Embolism; Pulmonary Embolism; Molecular Mechanisms of Pharmacological Action; Fibrinolytic Agents; Fibrin Modulating Agents; Anticoagulants; Heparin; Calcium heparin
• Other Study ID Numbers: EKOS Protocol Number 08