HI-PEITHO: Ultrasound-facilitated, Catheter-directed, Thrombolysis in Intermediate-high Risk Pulmonary Embolism

• Sponsor: Boston Scientific Corporation (Industry)
• Overall Status: Recruiting
• CT.gov ID: NCT04790370
• Collaborator: National PERT Consortium, Inc. (Other), University Medical Center Mainz (Other)
• Enrollment: 406
• Locations: 65
• Arms: 2
• Anticipated Duration (Months): 46.9
• Patients Per Site: 6.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

There are many available treatments for pulmonary embolism (PE), but the best treatment for this condition is not known. The HI-PEITHO study will compare two treatment options that are both available on the market for the treatment of PE.

Patients will be randomized 1:1 to receive either blood thinners (anticoagulation) or blood thinners (anticoagulation) in combination with a device called the EkoSonicTM Endovascular device to dissolve blood clots. Patients will be followed for 12 months after randomization and have assessments while in the hospital as well as at 7 days, 30 days, 6 months and 12 months after randomization. The study will try to find out if one of these treatments is better than the other at reducing the risk of death and other serious problems.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Embolism	Drug: Anticoagulation with heparin; Device: EkoSonicTM Endovascular System	Phase 4

Detailed Description

This study will assess whether ultrasound-facilitated, catheter-directed thrombolysis and standard anticoagulation are associated with a significant reduction in the composite outcome of pulmonary embolism (PE)-related mortality, cardiorespiratory decompensation or collapse, or nonfatal symptomatic and objectively confirmed recurrence of PE compared to anticoagulation alone within seven days of randomization

The HI-PEITHO study has been designed to address the important gaps in clinical evidence by comparing the clinical benefit of the ultrasound-facilitated local delivery of a low dose thrombolytic agent and anticoagulation with those of anticoagulation alone in patients with intermediate-high risk PE at a higher estimated risk of early decompensation based on clinical parameters at presentation.

This study has a focus on improving the safety of thrombolysis and advancing the concept of intermediate-high risk and the PE severity criteria, to better identify patients who may clinically benefit from thrombolysis.

The results of this study will contribute further evidence to the existing data on the treatment and outcomes of acute, intermediate-high risk PE and provide controlled data related to catheter-based interventions.

Data will be entered by the site into an electronic database. The database will include data checks to compare data entered into the database against predefined rules for ranges and consistency with other data fields in the database.

Site monitoring will take place with source data verification to assess the accuracy and completeness of registry data by comparing the data to medical records and study assessments.

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 406 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: 1:1 randomization1:1 randomization
• Masking: Single (Outcomes Assessor)
• Masking Description: Blinded adjudication of primary composite outcome
• Primary Purpose: Treatment
• Official Title: A Randomized Trial of Ultrasound-facilitated, Catheter-directed, Thrombolysis Versus Anticoagulation for Acute Intermediate-high Risk Pulmonary Embolism: The Higher-risk Pulmonary Embolism Thrombolysis Study
• Actual Study Start Date: Aug 2, 2021
• Anticipated Primary Completion Date: Jul 1, 2024
• Anticipated Study Completion Date: Jul 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Anticoagulation Low-molecular weight heparin (LMWH) or unfractionated heparin (UFH)	Drug: Anticoagulation with heparin; Low-molecular weight heparin (LMWH) or unfractionated heparin (UFH); Other Names: heparin, LMWH, UFH, anticoag, antiplatelet, anticoax
Active Comparator: Anticoagulation and EkoSonicTM Endovascular System Low-molecular weight heparin (LMWH) or unfractionated heparin (UFH) and EkoSonicTM Endovascular System [ultrasound-facilitated catheter-directed delivery of thrombolytic: 2 mg bolus/catheter + 1 mg/hour/catheter for 7 hours (total of 9 or 18 mg]	Drug: Anticoagulation with heparin; Low-molecular weight heparin (LMWH) or unfractionated heparin (UFH); Other Names: heparin, LMWH, UFH, anticoag, antiplatelet, anticoax ; Device: EkoSonicTM Endovascular System; EkoSonicTM Endovascular System [ultrasound-facilitated catheter-directed delivery of thrombolytic: 2 mg bolus/catheter + 1 mg/hour/catheter for 7 hours (total of 9 or 18 mg]; Other Names: EKOS, USCDT, CDT, thrombolysis, fibrinolysis

Outcome Measures

Primary Outcome Measures

1. PE-related mortality [Within seven days of randomization]

   death resulting from PE

2. PE recurrence [Within seven days of randomization]

   nonfatal symptomatic and objectively confirmed recurrence of PE

3. Cardiorespiratory decompensation or collapse [Within seven days of randomization]

   Cardiorespiratory collapse or decompensation is defined as at least one of the following criteria: cardiac arrest or need for CPR at any time between randomization and day 7; signs of shock: new-onset persistent arterial hypotension (systolic blood pressure (SBP) below 90 mmHg or SBP drop by at least 40 mm Hg, over at least 15 minutes and despite an adequate volume status; or need for vasopressors to maintain SBP of at least 90 mmHg), accompanied by end-organ hypoperfusion (altered mental status; oliguria/anuria; or increased serum lactate) at any time between randomization and day 7; placement on extracorporeal membrane oxygenation (ECMO) at any time between randomization and day 7; intubation, or initiation of noninvasive mechanical ventilation at any time between randomization and day 7; National Early Warning Score (NEWS) of 9 or higher, between 24 hours and 7 days after randomization, confirmed on consecutive measurements taken twice, 15 minutes apart.

Other Outcome Measures

1. Change in the RV-to-LV diameter ratio as measured by echocardiography [Between baseline and 48±6 hours]

2. PE-related death [Within 7 days]

   Death cause by pulmonary embolism (PE)

3. Cardiorespiratory decompensation [Within 7 days]

4. Placement on ECMO or mechanical ventilation [Within 7 days]

5. GUSTO major (moderate and severe) bleeding [Within 7 days]

   Major bleeding will be adjudicated according to the GUSTO criteria: GUSTO severe or life-threatening bleeding: A bleeding episode that leads to hemodynamic compromise requiring emergency intervention (such as replacement of fluid and/or blood products, inotropic support, or surgical treatment), or is life-threatening or fatal. GUSTO moderate bleeding (a bleeding episode requiring blood transfusion(s), but which is not deemed life-threatening and does not lead to hemodynamic compromise requiring emergency fluid replacement, inotropic support, or interventional treatment) .

6. International Society on Thrombosis and Hemostasis (ISTH) major bleeding [Within 7 days, 30 days, and 6 months]

   Major bleeding will also be adjudicated according to the ISTH criteria: Fatal bleeding and/or Symptomatic bleeding in a critical area or organ (intracranial, intraspinal, intraocular, retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome) and/or Bleeding causing a fall in hemoglobin level of 20 g/L (2 g/dL) or more, or leading to transfusion of two or more units of whole blood or red blood cells.

7. Ischemic or hemorrhagic stroke [Within 7 days and 30 days]

8. All-cause mortality [Within 7 days, 30 days, 6 months, and 12 months]

   Death due to any cause

9. Serious adverse events [Within 30 days]

10. All-cause mortality, cardiorespiratory collapse or recurrence of PE [Within 30 days]

    Death due to any cause, Cardiorespiratory collapse or decompensation should fulfill at least one of the following criteria: cardiac arrest or need for CPR at any time between randomization and day 7; signs of shock: new-onset persistent arterial hypotension (SBP below 90 mmHg or SBP drop by at least 40 mmHg over at least 15 minutes, and despite an adequate filling status; or need for vasopressors to maintain SBP of at least 90 mmHg), accompanied by end-organ hypoperfusion (altered mental status; oliguria/anuria; or increased serum lactate) at any time between randomization and day 7; placement on ECMO at any time between randomization and day 7; intubation, or initiation of non-invasive mechanical ventilation at any time between randomization and day 7; National Early Warning Score (NEWS) of 9 or higher, between 24 hours and 7 days after randomization, confirmed on consecutive measurements, taken twice.

11. Symptomatic PE recurrence [Within 30 days and 6 months]

12. Change from baseline in RV dysfunction on echocardiography [6 months]

    Right ventricle to left ventricle end diastolic diameter ratio (RV/LV)

13. Duration of hospitalization for the index PE event [Within 30 days]

    Time from admission to discharge from hospital

14. Duration of stay at the intensive, intermediate or coronary care unit during hospitalization for the index PE event [Within 30 days]

    Time from admission to discharge from ICU, intermediate, or ICC

15. Functional status as measured by World Health Organization (WHO) functional class [Up to 7 days, 30 days, 6 and 12 months]

    The World Health Organization (WHO) Functional Class assessment is a system for assessing the severity of dyspnea in patients with pulmonary hypertension. Subjects will be classified as Class 1-4 at time points throughout their participation in the study.

16. Functional status as measured by 6-Minute Walk Test (6MWT) [30 days, 6 and 12 months]

    The 6MWT measures the distance a patient can walk on a flat surface in a period of 6 minutes. A 100 meter distance is measured in a hallway and the patient is asked to walk quickly as many laps as they can over the course of the timed test. The total distance is measured. The patient's baseline vitals and symptoms are compared to their condition at the completion of the test.

17. Functional status as measured by Post-Venous Thromboembolism Functional Status (PVFS) scale [30 days, 6 and 12 months]

    The Post-Venous Thromboembolism (VTE) Functional Status (PVFS) scale focuses on relevant aspects of daily life during follow-up after a venous thromboembolic event. The scale is neither intended to solely focus on VTE-associated functional limitations nor to diagnose post-VTE syndrome. In contrast, the scale has been developed to help users become aware of current functional limitations in patients who have suffered a VTE, whether or not as a result of the specific VTE, and to objectively determine the degree of disability,

18. Quality of life using PEmb-QOL [6 and 12 months]

    PEmb-QOL is a questionnaire that assesses post-pulmonary embolism quality of life in the context of pulmonary-specific symptoms. The PEmb-QOL questionnaire contains six dimensions based on the contents of the items: frequency of complaints, limitations in activities of daily living, work-related problems, social limitations, intensity of complaints and emotional complaints. Higher scores indicate worse outcome.

19. Quality of life using SF-36 [6 and 12 months]

    The SF-36 questionnaire is a generic quality of life measure containing eight health domains (physical functioning, physical role, pain, general health, vitality, social function, emotional role functioning, and mental health). The scoring is on a 0-100 scale, with a higher score indicating better health. Scores are combined into two overall summary scores: physical health summary score and mental health summary score.

20. Quality of life using EQ-5D scale [6 and 12 months]

    The EQ-5D is a patient reported outcome that provides a simple descriptive profile and single index value for health status. The questionnaire consists of 5 questions pertaining to specific health dimensions, including mobility, self-care, usual activities, pain/discomfort, anxiety/depression, and overall health status rating scale.

21. Diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH) [Within 12 months]

    CTEPH will be diagnosed by the investigational site according to presence of all of the following criteria: At least one mismatched segmental perfusion defect demonstrated by ventilation/perfusion scanning after 3 months of adequate therapeutic anticoagulation Resting mean pulmonary arterial pressure (mPAP) ≥25 mmHg measured by invasive right heart catheterization Pulmonary capillary wedge pressure ≤15 mmHg.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age 18-80 years, inclusive

• Objectively confirmed acute PE, based on computed tomography pulmonary angiography (CTPA) showing a filling defect in at least one main or proximal lobar pulmonary artery

• Elevated risk of early death/hemodynamic collapse, indicated by at least two of the following new-onset clinical criteria:

1. ECG-documented tachycardia with heart rate ≥100 beats per minute, not due to hypovolemia, arrhythmia, or sepsis;

2. SBP ≤ 110 mm Hg for at least 15 minutes;

3. respiratory rate > 20 x min-1 or oxygen saturation on pulse oximetry (SpO2) < 90% (or partial arterial oxygen pressure < 60 mmHg) at rest while breathing room air;

• Right-to-left ventricular (RV/LV) diameter ratio ≥ 1.0 on CTPA

• Serum troponin I or T levels above the upper limit of normal

• Signed informed consent

Exclusion Criteria:

• Hemodynamic instability*, i.e. at least one of the following present:

1. cardiac arrest or need for cardiopulmonary resuscitation;

2. need for ECMO, or ECMO initiated before randomization

3. PE-related shock, defined as: (i) SBP < 90 mmHg, or vasopressors required to achieve SBP ≥ 90 mmHg, despite an adequate volume status; and (ii) end-organ hypoperfusion (altered mental status; oliguria/anuria; increased serum lactate);

4. isolated persistent hypotension (SBP < 90 mmHg, or a systolic pressure drop by at least 40 mmHg for at least 15 minutes), not caused by new-onset arrhythmia, hypovolemia, or sepsis * Patients who presented with temporary need for fluid resuscitation and/or low-dose catecholamines may be included, provided that they could be stabilized within 2 hours of admission and maintain SBP of ≥ 90 mmHg and adequate organ perfusion without catecholamine infusion.

• Need for admission to an intensive care unit for a reason other than the index PE episode. NB: Patients who test positive for SARS-CoV-2 can be enrolled where the investigator believes that the pulmonary embolism is the dominant pathology in the patient's clinical presentation and qualifying cardiorespiratory parameters.

• Temperature above 39 degrees C / 102.2 degrees F

• Logistical reasons limiting the rapid availability of interventional procedures to treat acute PE (e.g., during the outbreak of an epidemic)

• Index PE symptom duration > 14 days

• Active bleeding

• History of intracranial or intraocular bleeding at any time

• Stroke or transient ischemic attack within the past 6 months, or previous stroke at any time if associated with permanent disability

• Central nervous system neoplasm, or metastatic cancer

• Major neurologic, ophthalmologic, abdominal, cardiac, thoracic, vascular or orthopedic surgery or trauma (including syncope-associated with head strike or skeletal fracture) within the past 3 weeks

• Platelet count < 100 x 109 x L-1

• Patients who have received a once-daily therapeutic dose of LMWH or a therapeutic dose of fondaparinux within 24 hours prior to randomization

• Patients who have received one of the direct oral anticoagulants apixaban or rivaroxaban within 12 hours prior to randomization

• Patients who have received one of the direct oral anticoagulants dabigatran or edoxaban for the index PE episode, as these drugs are not approved for patients who have not received heparin for at least 5 days

• Administration of a thrombolytic agent or a glycoprotein IIb/IIIa receptor antagonist during the current hospital stay and/or within 30 days, for any reason

• Chronic treatment with antiplatelet agents other than low-dose acetylsalicylic acid or clopidogrel 75 mg once daily (but not both). Dual antiplatelet therapy is excluded.

• Chronic treatment with a direct oral anticoagulant (apixaban, dabigatran, edoxaban or rivaroxaban)

• Chronic treatment with a vitamin K antagonist, or known coagulopathy including severe hepatic dysfunction, with an International Normalized Ratio (INR) > 1.5

• Pregnancy or lactation

• Previous inclusion in the study

• Known hypersensitivity to alteplase, LMWH or UFH, or to any of the excipients

• Life expectancy less than 6 months

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
2	Cedars - Sinai Medical Center	Los Angeles	California	United States	90048
3	University of California Davis	Sacramento	California	United States	95817
4	Christiana Hospital	Newark	Delaware	United States	19718
5	Washington Hospital Center	Washington	District of Columbia	United States	20010
6	Piedmont Hospital	Atlanta	Georgia	United States	30309
7	Emory University Hospital	Atlanta	Georgia	United States	30322
8	Augusta University	Augusta	Georgia	United States	30904
9	St. Vincent Heart Center of Indiana	Indianapolis	Indiana	United States	46260
10	Baptist Health East Louisville	Louisville	Kentucky	United States	40207
11	University of Maryland School of Medicine	Baltimore	Maryland	United States	21201
12	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
13	University of Michigan Hospitals	Ann Arbor	Michigan	United States	48109
14	Henry Ford Hospital	Detroit	Michigan	United States	48202
15	St. John Hospital & Medical Center	Detroit	Michigan	United States	48236
16	North Mississippi Medical Center	Tupelo	Mississippi	United States	38801
17	Nebraska Methodist Hospital	Omaha	Nebraska	United States	68114
18	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756
19	Newark Beth Israel Medical Center	Newark	New Jersey	United States	07112
20	Mount Sinai Medical Center	New York	New York	United States	10029
21	Columbia University Medical Center	New York	New York	United States	10032
22	Lenox Hill Hospital	New York	New York	United States	10075
23	St. Francis Hospital	Roslyn	New York	United States	11576
24	University Hospitals of Cleveland	Cleveland	Ohio	United States	44106
25	Kettering Health	Kettering	Ohio	United States	45429
26	University of Oklahoma Health Science Center	Oklahoma City	Oklahoma	United States	73104
27	Wellmont Holston Valley Medical Center	Kingsport	Tennessee	United States	37660
28	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37232
29	Seton Medical Center	Austin	Texas	United States	78705
30	Houston Methodist Sugarland Hospital	Houston	Texas	United States	77479
31	The Heart Hospital Baylor Plano	Plano	Texas	United States	75093
32	University of Virginia Medical Center	Charlottesville	Virginia	United States	22908
33	University of Wisconsin Hospitals	Madison	Wisconsin	United States	53792
34	Medizinische Univ.-Kliniken Graz	Graz		Austria
35	A.o. LKH Univ.-Kliniken Innsbruck	Innsbruck		Austria
36	Universitätsklinikum St. Pölten	St. Pölten		Austria
37	Austria Klinik Ottakring Vienna	Vienna		Austria
38	Allgemeines Krankenhaus AKH	Wien		Austria
39	CHU de Besancon	Besançon		France
40	Hopital Nord de Marseille	Marseille		France
41	Uniklinik Aachen	Aachen		Germany
42	Klinikum Bielefeld	Bielefeld		Germany
43	GFO Kliniken Bonn	Bonn		Germany
44	Klinikum Chemnitz	Chemnitz		Germany
45	Klinikum Coburg GmbH	Coburg		Germany
46	Universitaetsklinikum Freiburg	Freiburg		Germany
47	Klinik Immenstadt	Immenstädt		Germany
48	Johannes Gutenberg Universitaet Mainz	Mainz		Germany
49	Klinikum Rechts der Isar	Munich		Germany
50	Universitaetsklinikum Tuebingen	Tuebingen		Germany
51	Universitaetsklinikum Wuerzburg	Würzburg		Germany
52	Mater Misericordiae University Hospital	Dublin		Ireland
53	University Hospital Galway	Galway		Ireland
54	Leiden University Medical Center	Leiden		Netherlands
55	St. Antonius Ziekenhuis	Nieuwegein		Netherlands
56	Universitair Medisch Centrum	Utrecht		Netherlands
57	John Paul II Hospital	Kraków		Poland
58	Medical University of Warsaw	Warsaw		Poland
59	University Hospital Basel	Basel		Switzerland
60	Centre Hospitalier Universitaire Vaudois	Lausanne		Switzerland
61	University Hospital Zurich	Zürich		Switzerland
62	University Hospital of Wales	Cardiff		United Kingdom
63	Guys and St. Thomas NHS Foundation Trust	London		United Kingdom
64	The Royal Free Hospital	London		United Kingdom
65	Northwick Park Hospital	Middlesex		United Kingdom

Sponsors and Collaborators

• Boston Scientific Corporation
• National PERT Consortium, Inc.
• University Medical Center Mainz

Investigators

• Principal Investigator: Stavros Konstantinides, MD, University Medical Center Mainz, Mainz, Germany
• Principal Investigator: Kenneth Rosenfield, MD, Massachusetts General Hospital, Boston, Massachusetts, USA

Study Documents (Full-Text)

None provided.

More Information

Publications

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• Responsible Party: Boston Scientific Corporation
• ClinicalTrials.gov Identifier: NCT04790370
• Other Study ID Numbers: S2479
• First Posted: Mar 10, 2021
• Last Update Posted: Aug 18, 2022
• Last Verified: Aug 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Product Manufactured in and Exported from the U.S.: Yes
• Keywords provided by Boston Scientific Corporation: Acute intermediate-high risk pulmonary embolism; Ultrasound-facilitated, catheter-directed thrombolysis; Thrombolysis
• Additional relevant MeSH terms: Pulmonary Embolism; Embolism; Heparin; Calcium heparin

Study Results

No Results Posted as of Aug 18, 2022