Pulmonary Embolism International THrOmbolysis Study-3
- Registration Number
- NCT04430569
- Lead Sponsor
- Assistance Publique - Hôpitaux de Paris
- Brief 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.
- Detailed 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
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 800
- Age 18 years or older
- Objectively confirmed acute PE with first symptoms occurring 2 weeks or less before randomization. Objective confirmation is based on at least one of the following criteria: (a) at least one segmental ventilation-perfusion mismatch on lung scanning; (b) a spiral computed tomography pulmonary angiography or pulmonary angiography showing a filling defect or an abrupt obstruction of a segmental or more proximal 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 fluid resuscitation and/or treatment with low-dose catecholamines, provided that the patient could be stabilized within 2 hours of admission and maintains SBP of ≥ 90 mmHg and adequate organ perfusion without catecholamine infusion; (c) respiratory rate > 20/min or oxygen saturation on pulse oximetry SpO2 <90% o(or partial arterial oxygen pressure < 60 mm Hg) at rest while breathing room air, (d) documented history of chronic symptomatic heart failure
- Right ventricular dysfunction indicated by RV/LV diameter ratio >1.0 on echocardiography apical four-chamber or subcostal four-chamber view or on Computed Tomography Pulmonary Angiography (transverse plane)
- Serum troponin I or T concentration above the upper limit of local normal using a high-sensitivity assay
- Ability to randomize the patient within 6 hours after the investigator receives the results 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 upper limit of local normal), whichever comes latest.
- Signed informed consent form
- Hemodynamic instability
- Active bleeding
- History of non-traumatic intracranial bleeding, any time
- Acute ischemic stroke or transient ischemic attack (TIA) within the previous 6 months
- Known central nervous system neoplasm/metastasis
- Neurologic, ophthalmologic, abdominal, cardiac, thoracic, vascular or orthopedic surgery 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 and prothrombin time ratio are measured, INR is relevant for the assessment of this criterion.
- Treatment with antiplatelet agents other than (a) acetylsalicylic acid (ASA) ≤ 100 mg once daily or (b) clopidogrel 75 mg once daily or (c) a single loading dose of ASA 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, portal hypertension (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 the inclusion 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 increased risk 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
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Alteplase Alteplase - Placebo Placebo -
- Primary Outcome Measures
Name Time Method Composite of (1) death from any cause or (2) hemodynamic decompensation or (3) objectively confirmed recurrent PE. 30 days
- Secondary Outcome Measures
Name Time Method PE related death 30 days Recurrent PE 30 days Need for rescue thrombolysis, catheter-directed treatment or surgical embolectomy 30 days Serious adverse events 30 days Persisting dyspnea 2 years Hemodynamic decompensation 30 days Functional outcome 2 years Fatal or GUSTO severe or life threatening bleeding 30 days Composite of the primary efficacy endpoint and GUSTO severe or life-threatening bleeding 30 days Assessment of net clinical benefit
All-cause mortality 2 years Ischemic or hemorrhagic stroke 30 days Persistent right ventricular dysfunction 2 years Utilization of health care ressources 180 days Questionnaire assessing the impact of the treatment on utilization of health care ressources
Confirmed chronic thromboembolic pulmonary hypertension 2 years
Trial Locations
- Locations (97)
Graz, Mediz Universität
🇦🇹Graz, Austria
Ordensklinikum Linz GmbH Elisabethinen
🇦🇹Linz, Austria
UCL Brussels
🇧🇪Bruxelles, Belgium
KU Leuven
🇧🇪Leuven, Belgium
CHU Liège
🇧🇪Liège, Belgium
Foothills Medical Centre
🇨🇦Calgary, Alberta, Canada
Juravinski Hospital - Hamilton Health Sciences Corporation
🇨🇦Hamilton, Ontario, Canada
Hamilton General Hospital - Hamilton Health Sciences Corporation
🇨🇦Hamilton, Ontario, Canada
Kingston Health Sciences Centre
🇨🇦Kingston, Ontario, Canada
London Health Sciences Centre
🇨🇦London, Ontario, Canada
The Ottawa Hopsital, General and Civic campuses
🇨🇦Ottawa, Ontario, Canada
Jewish General Hospital
🇨🇦Montréal, Quebec, Canada
CHU d'Angers
🇫🇷Angers, France
CHU de Besançon - Hôpital Jean-Minjoz
🇫🇷Besançon, France
CHU de Brest - Hôpital de la Cavale Blanche
🇫🇷Brest, France
CHU de Tours - Hôpital Trousseau
🇫🇷Chambray-lès-Tours, France
CHU de Clermont-Ferrand - Hôpital Gabriel Montpied
🇫🇷Clermont-Ferrand, France
AP-HP - hôpital Henri-Mondor
🇫🇷Créteil, France
CHU de Grenoble - Hôpital Michallon
🇫🇷La Tronche, France
AP-HP - hôpital Bicêtre
🇫🇷Le Kremlin-Bicêtre, France
CHU de Lille - Institut Cœur Poumon
🇫🇷Lille, France
HCL - Hôpital Edouard Herriot
🇫🇷Lyon, France
HCL - Centre Hospitalier Lyon-Sud, Pierre-Bénite
🇫🇷Lyon, France
AP-HM - Hôpital de la Timone
🇫🇷Marseille, France
CHU de Montpellier - Hôpital Lapeyronie
🇫🇷Montpellier, France
CHU de Nice - Hôpital Pasteur
🇫🇷Nice, France
AP-HP - Hôpital Lariboisière
🇫🇷Paris, France
AP-HP - hôpital européen Georges-Pompidou
🇫🇷Paris, France
AP-HP - Hôpital Bichat-Claude-Bernard
🇫🇷Paris, France
AP-HP - Hôpital Tenon
🇫🇷Paris, France
HCL - Centre Hospitalier Lyon-Sud
🇫🇷Pierre-Bénite, France
CHU de Saint-Étienne - Hôpital Nord
🇫🇷Saint-Étienne, France
CHU de Strasbourg - Hôpital Civil
🇫🇷Strasbourg, France
CHU de Toulouse - Hôpital Rangueil
🇫🇷Toulouse, France
Universitäts-Herzzentrum Freiburg - Bad Krozingen
🇩🇪Bad Krozingen, Germany
DRK Kliniken Berlin Köpenick
🇩🇪Berlin, Germany
Berlin, DRK Kliniken Westend
🇩🇪Berlin, Germany
Dresden, Städtisches Klinikum
🇩🇪Dresden, Germany
Düsseldorf, Augusta-Krankenhaus
🇩🇪Düsseldorf, Germany
Freiburg Universität
🇩🇪Freiburg, Germany
Greifswald, Univ.-Medizin
🇩🇪Greifswald, Germany
Hannover, Medizinische Hochschule Hannover
🇩🇪Hannover, Germany
Augustinerinnen Hospital
🇩🇪Köln, Germany
Cologne Universität Herzzentrum
🇩🇪Köln, Germany
Leipzig, Univ.-Klinikum
🇩🇪Leipzig, Germany
Mainz Universitätsmedizin, CTH
🇩🇪Mainz, Germany
Mainz, Katholisches Klinikum
🇩🇪Mainz, Germany
Universitätsmedizin Mannheim UMM
🇩🇪Mannheim, Germany
Regensburg, Uniklinik
🇩🇪Regensburg, Germany
Tübingen, Univ.-Klinikum
🇩🇪Tübingen, Germany
Ulm, Universitätsklinikum
🇩🇪Ulm, Germany
University Hospital Ancona / Ospedali Riunit
🇮🇹Ancona, Italy
Spedali Riuniti - Cremona
🇮🇹Cremona, Italy
Ospedale San Giuseppe - Empoli
🇮🇹Empoli, Italy
Azienda Ospedaliera Careggi - Firenze
🇮🇹Firenze, Italy
Humanitas Hospital - Milano
🇮🇹Milano, Italy
University of Perugia
🇮🇹Perugia, Italy
Ospedale Ca Foncello - Treviso
🇮🇹Treviso, Italy
Haaglanden hospital
🇳🇱Den Haag, Netherlands
Catharina hospital
🇳🇱Eindhoven, Netherlands
Medisch Spectrum Twente
🇳🇱Enschede, Netherlands
Martini hospital
🇳🇱Groningen, Netherlands
Maasstad hospital
🇳🇱Rotterdam, Netherlands
Antonius hospital
🇳🇱Sneek, Netherlands
Isala hospital
🇳🇱Zwolle, Netherlands
Medical University of Bialystok
🇵🇱Białystok, Poland
Department of Cardiac and Vascular Diseases
🇵🇱Kraków, Poland
University of Warmia Mazury in Olsztyn - School of Medicine
🇵🇱Olsztyn, Poland
Poznan University of Medical Sciences
🇵🇱Poznań, Poland
Medical University of Warsaw
🇵🇱Warsaw, Poland
Medical University of Lodz
🇵🇱Łódź, Poland
Hospital Garcia de Orta
🇵🇹Almada, Portugal
Centro Hospitalar de Lisboa Norte/ Hospitalde Santa Maria
🇵🇹Lisboa, Portugal
Centro Hospitalar de Lisboa Ocidental
🇵🇹Lisboa, Portugal
Hospital Pedro Hispano
🇵🇹Matosinhos, Portugal
Centro Hospitalar do Porto
🇵🇹Porto, Portugal
Centro Hospitalar de Setubal
🇵🇹Setúbal, Portugal
Spitalul Judetean de Urgenta Baia Mare
🇷🇴Baia Mare, Romania
Bucuresti - Spitalul Clinic de Urgenta Sf. Pantelimon
🇷🇴Bucuresti, Romania
Spitalul Judetean de Urgenta Constanta
🇷🇴Constanţa, Romania
Iasi - St Spiridon Emergency Conty Hospital
🇷🇴Iaşi, Romania
Institutul de Boli Cardio-Vasculare Timisoara
🇷🇴Timişoara, Romania
Cardiology Clinic, Emergency Center, Clinical Center of Serbia
🇷🇸Belgrad, Serbia
Cardiology Clinic, Clinical Center of Niš
🇷🇸Niš, Serbia
Institute for Lung Diseases of Vojvodina, Sremska Kamenica
🇷🇸Novi Sad, Serbia
University Medical Centre Ljubljana
🇸🇮Ljubljana, Slovenia
Hospital Germans Trias i Pujol
🇪🇸Badalona, Spain
Hospital Clinic
🇪🇸Barcelona, Spain
Hospital Bellvitge
🇪🇸Barcelona, Spain
Hospital Cartagena
🇪🇸Cartagena, Spain
Hospital Galdakao
🇪🇸Galdakao, Spain
Clínica Universitaria Navarra
🇪🇸Madrid, Spain
Hospital Ramón y Cajal
🇪🇸Madrid, Spain
Hospital Virgen del Rocío
🇪🇸Sevilla, Spain
Hospital La Fe
🇪🇸Valencia, Spain
Geneva University Hospital
🇨🇭Geneva, Switzerland
Hôpital du Valais
🇨🇭Sion, Switzerland