Pulmonary Embolism International THrOmbolysis Study-3

Last updated: July 10, 2024
Sponsor: Assistance Publique - Hôpitaux de Paris
Overall Status: Active - Recruiting

Phase

3

Condition

Claudication

Chest Pain

Pulmonary Embolism

Treatment

Alteplase

Placebo

Clinical Study ID

NCT04430569
P160924
PHRCN-16-0580
P160924
2018-000816-96
  • Ages > 18
  • All Genders

Study Summary

In this study, we will assess the efficacy and safety of a reduced dose of thrombolytic therapy given in addition to low-molecular-weight heparin in patients with intermediate-high-risk acute pulmonary embolism. Half of participants will receive thrombolytic treatment, while the other half will receive a placebo.

Eligibility Criteria

Inclusion

Inclusion Criteria:

  • Age 18 years or older

  • Objectively confirmed acute PE with first symptoms occurring 2 weeks or less beforerandomization. Objective confirmation is based on at least one of the followingcriteria: (a) at least one segmental ventilation-perfusion mismatch on lungscanning; (b) a spiral computed tomography pulmonary angiography or pulmonaryangiography showing a filling defect or an abrupt obstruction of a segmental or moreproximal pulmonary artery

  • Acute PE confirmed within 24 hours prior to randomization

  • Elevated risk of early death, or of hemodynamic collapse, or PE recurrence,indicated by at least one of the following criteria: (a) systolic blood pressure ≤ 110 mm Hg over at least 15 minutes upon enrolment, (b) temporary need for fluidresuscitation and/or treatment with low-dose catecholamines, provided that thepatient could be stabilized within 2 hours of admission and maintains SBP of ≥ 90mmHg and adequate organ perfusion without catecholamine infusion; (c) respiratoryrate > 20/min or oxygen saturation on pulse oximetry SpO2 <90% o(or partial arterialoxygen pressure < 60 mm Hg) at rest while breathing room air, (d) documented historyof chronic symptomatic heart failure

  • Right ventricular dysfunction indicated by RV/LV diameter ratio >1.0 onechocardiography apical four-chamber or subcostal four-chamber view or on ComputedTomography Pulmonary Angiography (transverse plane)

  • Serum troponin I or T concentration above the upper limit of local normal using ahigh-sensitivity assay

  • Ability to randomize the patient within 6 hours after the investigator receives theresults of the second of the two criteria for RV dysfunction (RV/LV diameter ratio >1.0) and myocardial injury (serum troponin I or T concentration above the upperlimit of local normal), whichever comes latest.

  • Signed informed consent form

Exclusion

Exclusion Criteria:

  • Hemodynamic instability

  • Active bleeding

  • History of non-traumatic intracranial bleeding, any time

  • Acute ischemic stroke or transient ischemic attack (TIA) within the previous 6months

  • Known central nervous system neoplasm/metastasis

  • Neurologic, ophthalmologic, abdominal, cardiac, thoracic, vascular or orthopedicsurgery or trauma within 3 previous weeks

  • Platelet count < 100 G/L

  • INR > 1.4. If INR not available: prothrombin time ratio < 60%. If both INR andprothrombin time ratio are measured, INR is relevant for the assessment of thiscriterion.

  • Treatment with antiplatelet agents other than (a) acetylsalicylic acid (ASA) ≤ 100mg once daily or (b) clopidogrel 75 mg once daily or (c) a single loading dose ofASA or clopidogrel. Dual antiplatelet therapy (ASA + clopidogrel) is not allowed.

  • Any direct oral anticoagulant within 12 hours of inclusion

  • Uncontrolled hypertension defined by SBP > 180 mm Hg at the time of inclusion

  • Known pericarditis or endocarditis

  • Known significant bleeding risk according to the investigator's judgement

  • Administration of thrombolytic agents within the previous 4 days

  • Vena cava filter insertion or pulmonary thrombectomy within the previous 4 days

  • Current participation in another interventional clinical study

  • Previous enrolment in this study

  • Known hypersensitivity to alteplase, gentamicin (a residue of the Actilyse®manufacturing process present in trace amounts), any of the excipients of Actilyse®,or low-molecular weight heparin (LMWH)

  • Known previous immune heparin-induced thrombocytopenia

  • Known severe liver disease (grade ≥ 3) including liver failure, cirrhosis, portalhypertension (esophageal varices) and active hepatitis

  • Acute symptomatic pancreatitis

  • Gastrointestinal ulcers or esophageal varices, documented within the past 3 months

  • Known arterial aneurysm, arterial or venous malformations

  • Pregnancy or parturition within the previous 30 days or current breastfeeding.

  • Women of childbearing potential who do not have a negative pregnancy test at theinclusion visit and do not use one of the following methods of birth control:hormonal contraception or intrauterine device or bilateral tubal occlusion

  • Any other condition that the investigator feels would place the patient at increasedrisk upon start of the investigational treatment

  • Life expectancy of less than 6 months or inability to complete 6-month follow-up.

  • Patient under legal protection

Study Design

Total Participants: 650
Treatment Group(s): 2
Primary Treatment: Alteplase
Phase: 3
Study Start date:
August 04, 2021
Estimated Completion Date:
August 31, 2027

Study Description

In patients with intermediate-risk pulmonary embolism, full-dose thrombolytic treatment was associated with a reduction in the combined risk of hemodynamic instability or death but was also associated with an increased risk of major and intracranial bleeding. Previous studies suggest that reduced dose of thrombolytic treatment may be as effective as the full dosage, but with a decreased risk of life-threatening bleeding. In this study, we will assess the efficacy and safety of a reduced dosage of thrombolytic therapy in patients with intermediate-high-risk acute pulmonary embolism.

The study is a randomized, placebo-controlled, double blind, multicenter, multinational trial with long-term follow-up.

Patients fulfilling the inclusion criteria and without any of the exclusion criteria will be randomized within 6 hours after the investigator had confirmed the diagnosis.

Patients will receive:

  • Alteplase (if randomized in the experimental group) or placebo (if randomized in the reference group) given within 30 minutes of randomization as a 15 min intravenous infusion at a dosage of 0.6 mg/kg with a total dose not exceeding 50 mg.

  • Parenteral anticoagulation with low molecular weight heparin, unfractionnated heparin or fondaparinux

Primary objective is to assess the efficacy of reduced dose thrombolytic therapy in patients with acute intermediate-high-risk pulmonary embolism at day 30.

Secondary objectives are:

  1. To assess the safety of reduced dose thrombolytic therapy in patients with intermediate-high-risk acute pulmonary embolism at day 30

  2. To assess the net clinical benefit of reduced dose thrombolytic therapy in patients with intermediate-high-risk acute pulmonary embolism at day 30

  3. To assess the effect of reduced dose thrombolytic therapy on overall mortality of patients with intermediate-high-risk acute pulmonary embolism at day 30

  4. To assess the effect of reduced dose thrombolytic therapy on long-term mortality, functional impairment, residual right ventricular dysfunction and chronic thromboembolic pulmonary hypertension at 6 months and 2 years

  5. To assess the effect of reduced-dose thrombolytic therapy on utilization of health care resources at day 30 and day 180

Connect with a study center

  • Graz, Mediz Universität

    Graz, 8036
    Austria

    Site Not Available

  • Ordensklinikum Linz GmbH Elisabethinen

    Linz, 4020
    Austria

    Active - Recruiting

  • UCL Brussels

    Bruxelles,
    Belgium

    Site Not Available

  • KU Leuven

    Leuven, 3000
    Belgium

    Site Not Available

  • CHU Liège

    Liège, 4000
    Belgium

    Site Not Available

  • Foothills Medical Centre

    Calgary, Alberta
    Canada

    Site Not Available

  • Hamilton General Hospital - Hamilton Health Sciences Corporation

    Hamilton, Ontario
    Canada

    Site Not Available

  • Hamilton Health Sciences Corporation

    Hamilton, Ontario
    Canada

    Site Not Available

  • Juravinski Hospital - Hamilton Health Sciences Corporation

    Hamilton, Ontario ON L8V 1C3
    Canada

    Site Not Available

  • Kingston Health Sciences Centre

    Kingston, Ontario
    Canada

    Site Not Available

  • London Health Sciences Centre

    London, Ontario
    Canada

    Site Not Available

  • The Ottawa Hopsital, General and Civic campuses

    Ottawa, Ontario
    Canada

    Site Not Available

  • Jewish General Hospital

    Montréal, Quebec
    Canada

    Site Not Available

  • CHU d'Angers

    Angers, 49933
    France

    Active - Recruiting

  • CHU de Besançon - Hôpital Jean-Minjoz

    Besançon, 25030
    France

    Active - Recruiting

  • CHU de Brest - Hôpital de la Cavale Blanche

    Brest, 29000
    France

    Active - Recruiting

  • CHU de Tours - Hôpital Trousseau

    Chambray-lès-Tours, 37170
    France

    Active - Recruiting

  • CHU de Clermont-Ferrand - Hôpital Gabriel Montpied

    Clermont-Ferrand, 63000
    France

    Active - Recruiting

  • AP-HP - hôpital Henri-Mondor

    Créteil, 94010
    France

    Active - Recruiting

  • CHU de Grenoble - Hôpital Michallon

    La Tronche, 38700
    France

    Active - Recruiting

  • AP-HP - hôpital Bicêtre

    Le Kremlin-Bicêtre, 94270
    France

    Active - Recruiting

  • CHU de Lille - Institut Cœur Poumon

    Lille, 59000
    France

    Site Not Available

  • HCL - Hôpital Edouard Herriot

    Lyon, 69000
    France

    Site Not Available

  • AP-HM - Hôpital de la Timone

    Marseille, 13000
    France

    Active - Recruiting

  • CHU de Montpellier - Hôpital Lapeyronie

    Montpellier, 34000
    France

    Site Not Available

  • CHU de Nice - Hôpital Pasteur

    Nice, 06000
    France

    Terminated

  • AP-HP - Hôpital Bichat-Claude-Bernard

    Paris, 75018
    France

    Active - Recruiting

  • AP-HP - Hôpital Lariboisière

    Paris, 75010
    France

    Site Not Available

  • AP-HP - Hôpital Tenon

    Paris, 75020
    France

    Active - Recruiting

  • AP-HP - hôpital européen Georges-Pompidou

    Paris, 75015
    France

    Active - Recruiting

  • HCL - Centre Hospitalier Lyon-Sud

    Pierre-Bénite, 69495
    France

    Site Not Available

  • CHU de Saint-Étienne - Hôpital Nord

    Saint-Étienne, 42055
    France

    Active - Recruiting

  • CHU de Strasbourg - Hôpital Civil

    Strasbourg, 67000
    France

    Active - Recruiting

  • CHU de Toulouse - Hôpital Rangueil

    Toulouse, 31000
    France

    Active - Recruiting

  • Universitäts-Herzzentrum Freiburg - Bad Krozingen

    Bad Krozingen, 79189
    Germany

    Active - Recruiting

  • Berlin, DRK Kliniken Westend

    Berlin, 14050
    Germany

    Site Not Available

  • DRK Kliniken Berlin Köpenick

    Berlin, 10117
    Germany

    Active - Recruiting

  • Dresden, Städtisches Klinikum

    Dresden, 01067
    Germany

    Active - Recruiting

  • Düsseldorf, Augusta-Krankenhaus

    Düsseldorf, 40472
    Germany

    Site Not Available

  • Freiburg Universität

    Freiburg, 79085
    Germany

    Active - Recruiting

  • Greifswald, Univ.-Medizin

    Greifswald, 17489
    Germany

    Active - Recruiting

  • Göttingen, Univ.-Medizin

    Göttingen, 37075
    Germany

    Site Not Available

  • Hamburg, Universitäres Herzzentrum

    Hamburg, 20246
    Germany

    Site Not Available

  • Hannover, Medizinische Hochschule Hannover

    Hannover, 30625
    Germany

    Active - Recruiting

  • Augustinerinnen Hospital

    Köln, 50678
    Germany

    Active - Recruiting

  • Cologne Universität Herzzentrum

    Köln, 50937
    Germany

    Site Not Available

  • Leipzig, Univ.-Klinikum

    Leipzig, 4103
    Germany

    Active - Recruiting

  • Mainz Universitätsmedizin, CTH

    Mainz, 55131
    Germany

    Active - Recruiting

  • Mainz, Katholisches Klinikum

    Mainz, 55131
    Germany

    Active - Recruiting

  • Universitätsmedizin Mannheim UMM

    Mannheim, 68167
    Germany

    Active - Recruiting

  • Regensburg, Uniklinik

    Regensburg, 93053
    Germany

    Site Not Available

  • Tübingen, Univ.-Klinikum

    Tübingen, 72076
    Germany

    Active - Recruiting

  • Ulm, Universitätsklinikum

    Ulm, 89081
    Germany

    Site Not Available

  • University Hospital Ancona / Ospedali Riunit

    Ancona, 60020
    Italy

    Active - Recruiting

  • Poliambulanza Hospital - Brescia

    Brescia, 25124
    Italy

    Site Not Available

  • Spedali Riuniti - Cremona

    Cremona, 26100
    Italy

    Active - Recruiting

  • Ospedale San Giuseppe - Empoli

    Empoli, 50053
    Italy

    Site Not Available

  • Azienda Ospedaliera Careggi - Firenze

    Firenze, 50134
    Italy

    Active - Recruiting

  • Azienda Ospedaliera Poma - Mantova

    Mantova, 46100
    Italy

    Site Not Available

  • Humanitas Hospital - Milano

    Milano, 20089
    Italy

    Active - Recruiting

  • University of Perugia

    Perugia, 06123
    Italy

    Active - Recruiting

  • Ospedale Ca Foncello - Treviso

    Treviso, 31100
    Italy

    Active - Recruiting

  • Haaglanden hospital

    Den Haag,
    Netherlands

    Site Not Available

  • Catharina hospital

    Eindhoven,
    Netherlands

    Site Not Available

  • Medisch Spectrum Twente

    Enschede,
    Netherlands

    Site Not Available

  • Martini hospital

    Groningen,
    Netherlands

    Site Not Available

  • Maasstad hospital

    Rotterdam,
    Netherlands

    Active - Recruiting

  • Antonius hospital

    Sneek,
    Netherlands

    Site Not Available

  • Isala hospital

    Zwolle,
    Netherlands

    Site Not Available

  • Medical University of Bialystok

    Białystok,
    Poland

    Active - Recruiting

  • Department of Cardiac and Vascular Diseases

    Kraków,
    Poland

    Site Not Available

  • University of Warmia Mazury in Olsztyn - School of Medicine

    Olsztyn, 11-041
    Poland

    Active - Recruiting

  • Poznan University of Medical Sciences

    Poznań,
    Poland

    Site Not Available

  • Medical University of Warsaw

    Warsaw,
    Poland

    Active - Recruiting

  • Medical University of Lodz

    Łódź,
    Poland

    Site Not Available

  • Hospital Garcia de Orta

    Almada,
    Portugal

    Site Not Available

  • Centro Hospitalar de Lisboa Norte/ Hospitalde Santa Maria

    Lisboa,
    Portugal

    Site Not Available

  • Centro Hospitalar de Lisboa Ocidental

    Lisboa,
    Portugal

    Site Not Available

  • Hospital Pedro Hispano

    Matosinhos,
    Portugal

    Site Not Available

  • Centro Hospitalar do Porto

    Porto,
    Portugal

    Site Not Available

  • Centro Hospitalar de Setubal

    Setúbal,
    Portugal

    Site Not Available

  • Spitalul Judetean de Urgenta Baia Mare

    Baia Mare, 430031
    Romania

    Site Not Available

  • Bucuresti - Spitalul Clinic de Urgenta Sf. Pantelimon

    Bucuresti,
    Romania

    Site Not Available

  • Spitalul Judetean de Urgenta Constanta

    Constanţa, 900591
    Romania

    Site Not Available

  • Iasi - St Spiridon Emergency Conty Hospital

    Iaşi, 700111
    Romania

    Site Not Available

  • Institutul de Boli Cardio-Vasculare Timisoara

    Timişoara,
    Romania

    Site Not Available

  • Cardiology Clinic, Emergency Center, Clinical Center of Serbia

    Belgrad,
    Serbia

    Site Not Available

  • Cardiology Clinic, Clinical Center of Niš

    Niš,
    Serbia

    Site Not Available

  • Institute for Lung Diseases of Vojvodina, Sremska Kamenica

    Novi Sad,
    Serbia

    Site Not Available

  • University Medical Centre Ljubljana

    Ljubljana, 1000
    Slovenia

    Active - Recruiting

  • Hospital Germans Trias i Pujol

    Badalona, 08916
    Spain

    Active - Recruiting

  • Hospital Bellvitge

    Barcelona, 08907
    Spain

    Active - Recruiting

  • Hospital Clinic

    Barcelona, 08036
    Spain

    Active - Recruiting

  • Hospital Cartagena

    Cartagena,
    Spain

    Active - Recruiting

  • Hospital Galdakao

    Galdakao, 48960
    Spain

    Active - Recruiting

  • Clínica Universitaria Navarra

    Madrid, 28027
    Spain

    Active - Recruiting

  • Hospital Ramón y Cajal

    Madrid, 28034
    Spain

    Active - Recruiting

  • Hospital Virgen del Rocío

    Sevilla, 41013
    Spain

    Active - Recruiting

  • Hospital La Fe

    Valencia, 46026
    Spain

    Active - Recruiting

  • Hospital Araba

    Vitoria, 01009
    Spain

    Site Not Available

  • Hôpital fribourgeois

    Fribourg, 1752
    Switzerland

    Site Not Available

  • Geneva University Hospital

    Geneva, 1205
    Switzerland

    Site Not Available

  • Lausanne University Hospital

    Lausanne, 1011
    Switzerland

    Site Not Available

  • Hôpital du Valais

    Sion, 1951
    Switzerland

    Site Not Available

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