Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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RECRUITING
PHASE3
800 participants
INTERVENTIONAL
2021-08-04
2028-08-31
Brief Summary
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Detailed Description
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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
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
TRIPLE
Study Groups
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Alteplase
Alteplase
Alteplase single intravenous infusion of 0.6 mg/kg of estimated bodyweight with a maximum of 50 mg given over 15 minutes.
Placebo
Placebo
Placebo single intravenous infusion of 0.6 mg/kg of estimated bodyweight with a maximum of 50 mg given over 15 minutes.
Interventions
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Alteplase
Alteplase single intravenous infusion of 0.6 mg/kg of estimated bodyweight with a maximum of 50 mg given over 15 minutes.
Placebo
Placebo single intravenous infusion of 0.6 mg/kg of estimated bodyweight with a maximum of 50 mg given over 15 minutes.
Eligibility Criteria
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Inclusion Criteria
* 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
Exclusion Criteria
* 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
18 Years
ALL
No
Sponsors
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Johannes Gutenberg University Mainz
OTHER
Life Sciences Research Partners (D Collen Research Foundation)
UNKNOWN
Canadian Institutes of Health Research (CIHR)
OTHER_GOV
Instituto de Salud Carlos III
OTHER_GOV
International Network of VENous Thromboembolism Clinical Research Networks
UNKNOWN
Boehringer Ingelheim
INDUSTRY
Assistance Publique - Hôpitaux de Paris
OTHER
Responsible Party
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Principal Investigators
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Olivier SANCHEZ, MD
Role: PRINCIPAL_INVESTIGATOR
Assistance Publique - Hôpitaux de Paris
Stavros Konstantinides, MD
Role: PRINCIPAL_INVESTIGATOR
University Medical Center Mainz
Locations
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Graz, Mediz Universität
Graz, , Austria
Ordensklinikum Linz GmbH Elisabethinen
Linz, , Austria
UCL Brussels
Brussels, , 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
Montreal, 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 - 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-Etienne, , 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
Augustinerinnen Hospital
Cologne, , Germany
Cologne Universität Herzzentrum
Cologne, , Germany
Dresden, Städtisches Klinikum
Dresden, , Germany
Düsseldorf, Augusta-Krankenhaus
Düsseldorf, , Germany
Freiburg Universität
Freiburg im Breisgau, , Germany
Greifswald, Univ.-Medizin
Greifswald, , Germany
Hannover, Medizinische Hochschule Hannover
Hanover, , 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
Florence, , Italy
Humanitas Hospital - Milano
Milan, , Italy
University of Perugia
Perugia, , Italy
Ospedale Ca Foncello - Treviso
Treviso, , Italy
Catharina hospital
Eindhoven, , Netherlands
Medisch Spectrum Twente
Enschede, , Netherlands
Martini hospital
Groningen, , Netherlands
Maasstad hospital
Rotterdam, , Netherlands
Antonius hospital
Sneek, , Netherlands
Haaglanden hospital
The Hague, , Netherlands
Isala hospital
Zwolle, , Netherlands
Medical University of Bialystok
Bialystok, , Poland
Department of Cardiac and Vascular Diseases
Krakow, , Poland
Medical University of Lodz
Lodz, , Poland
University of Warmia Mazury in Olsztyn - School of Medicine
Olsztyn, , Poland
Poznan University of Medical Sciences
Poznan, , Poland
Medical University of Warsaw
Warsaw, , Poland
Hospital Garcia de Orta
Almada, , Portugal
Centro Hospitalar de Lisboa Norte/ Hospitalde Santa Maria
Lisbon, , Portugal
Centro Hospitalar de Lisboa Ocidental
Lisbon, , Portugal
Hospital Pedro Hispano
Matosinhos Municipality, , 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
Bucharest, , Romania
Spitalul Judetean de Urgenta Constanta
Constanța, , Romania
Iasi - St Spiridon Emergency Conty Hospital
Iași, , Romania
Institutul de Boli Cardio-Vasculare Timisoara
Timișoara, , Romania
Cardiology Clinic, Emergency Center, Clinical Center of Serbia
Belgrade, , 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
Seville, , Spain
Hospital La Fe
Valencia, , Spain
Geneva University Hospital
Geneva, , Switzerland
Hôpital du Valais
Sion, , Switzerland
Countries
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Central Contacts
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Facility Contacts
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Franck Verschuren, MD
Role: primary
Thomas Vanassche, MD
Role: primary
Alexandre Ghuysen, MD
Role: primary
Kevin Solverson, MD
Role: primary
Sam Schulman, MD
Role: primary
Kerstin de Wit, MD
Role: primary
Justin Yan, MD
Role: primary
Lana Castellucci, MD
Role: primary
Andrew Hirsch, MD
Role: primary
Laurent Savale, MD
Role: primary
Dirk Habedank, MD
Role: primary
Ingo Ahrens, MD
Role: primary
Stephan Rosenkranz, MD
Role: primary
Sebastian Schellong, MD
Role: primary
Anamaria Wolf-Pütz, MD
Role: primary
Daniel Dürschmied, MD
Role: primary
Ralf Eswert, MD
Role: primary
Andreas Schäfer, MD
Role: primary
Holger Thiele, MD
Role: primary
Sabine Genth-Zotz, MD
Role: primary
Ibrahim Akin, MD
Role: primary
Tobias Geisler, MD
Role: primary
Armin Imhof, MD
Role: primary
Aldo Salvi, MD
Role: primary
Enrico Passamonti, MD
Role: primary
Simone Vanni, MD
Role: primary
Maddalena Ottaviani, MD
Role: primary
Corrado Lodigiani, MD
Role: primary
Cecilia Becattini, MD
Role: primary
Michele Diamanti, MD
Role: primary
Bożena Sobkowicz, MD
Role: primary
Melanie Ferreira, MD
Role: primary
Rui Placido, MD
Role: primary
Hugo Moreira, MD
Role: primary
Carolina Guedes, MD
Role: primary
Fabienne Gonçalves, MD
Role: primary
Sonia Serra, MD
Role: primary
Calin Pop, MD
Role: primary
Alexandru Nechita, MD
Role: primary
Anca Mihaela Radulescu, MD
Role: primary
Antoniu Petris, MD
Role: primary
Lucian Petrescu, MD
Role: primary
Branislav Stefanovic, MD
Role: primary
Matija Kozak, MD
Role: primary
Manuel Monreal, MD
Role: primary
Jorge Moises, MD
Role: primary
Antoni Riera-Mestre, MD
Role: primary
Javier Trujillo-Santos, MD
Role: primary
Aitor Ballaz, MD
Role: primary
David Jimenez, MD
Role: primary
Remedios Otero, MD
Role: primary
Raquel Lopez, MD
Role: primary
Marc Righini, MD
Role: primary
References
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Meyer G, Vicaut E, Danays T, Agnelli G, Becattini C, Beyer-Westendorf J, Bluhmki E, Bouvaist H, Brenner B, Couturaud F, Dellas C, Empen K, Franca A, Galie N, Geibel A, Goldhaber SZ, Jimenez D, Kozak M, Kupatt C, Kucher N, Lang IM, Lankeit M, Meneveau N, Pacouret G, Palazzini M, Petris A, Pruszczyk P, Rugolotto M, Salvi A, Schellong S, Sebbane M, Sobkowicz B, Stefanovic BS, Thiele H, Torbicki A, Verschuren F, Konstantinides SV; PEITHO Investigators. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J Med. 2014 Apr 10;370(15):1402-11. doi: 10.1056/NEJMoa1302097.
Barco S, Vicaut E, Klok FA, Lankeit M, Meyer G, Konstantinides SV; PEITHO Investigators. Improved identification of thrombolysis candidates amongst intermediate-risk pulmonary embolism patients: implications for future trials. Eur Respir J. 2018 Jan 18;51(1):1701775. doi: 10.1183/13993003.01775-2017. Print 2018 Jan. No abstract available.
Konstantinides SV, Vicaut E, Danays T, Becattini C, Bertoletti L, Beyer-Westendorf J, Bouvaist H, Couturaud F, Dellas C, Duerschmied D, Empen K, Ferrari E, Galie N, Jimenez D, Kostrubiec M, Kozak M, Kupatt C, Lang IM, Lankeit M, Meneveau N, Palazzini M, Pruszczyk P, Rugolotto M, Salvi A, Sanchez O, Schellong S, Sobkowicz B, Meyer G. Impact of Thrombolytic Therapy on the Long-Term Outcome of Intermediate-Risk Pulmonary Embolism. J Am Coll Cardiol. 2017 Mar 28;69(12):1536-1544. doi: 10.1016/j.jacc.2016.12.039.
Marti C, John G, Konstantinides S, Combescure C, Sanchez O, Lankeit M, Meyer G, Perrier A. Systemic thrombolytic therapy for acute pulmonary embolism: a systematic review and meta-analysis. Eur Heart J. 2015 Mar 7;36(10):605-14. doi: 10.1093/eurheartj/ehu218. Epub 2014 Jun 10.
Sanchez O, Charles-Nelson A, Ageno W, Barco S, Binder H, Chatellier G, Duerschmied D, Empen K, Ferreira M, Girard P, Huisman MV, Jimenez D, Katsahian S, Kozak M, Lankeit M, Meneveau N, Pruszczyk P, Petris A, Righini M, Rosenkranz S, Schellong S, Stefanovic B, Verhamme P, de Wit K, Vicaut E, Zirlik A, Konstantinides SV, Meyer G; PEITHO-3 Investigators. Reduced-Dose Intravenous Thrombolysis for Acute Intermediate-High-risk Pulmonary Embolism: Rationale and Design of the Pulmonary Embolism International THrOmbolysis (PEITHO)-3 trial. Thromb Haemost. 2022 May;122(5):857-866. doi: 10.1055/a-1653-4699. Epub 2021 Oct 31.
Other Identifiers
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P160924
Identifier Type: OTHER
Identifier Source: secondary_id
PHRCN-16-0580
Identifier Type: OTHER_GRANT
Identifier Source: secondary_id
2018-000816-96
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
P160924
Identifier Type: -
Identifier Source: org_study_id
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