Pulmonary Embolism International THrOmbolysis Study-3 (PEITHO-3)

A Reduced Dose of Thrombolytic Treatment for Patients With Intermediate High-risk Acute Pulmonary Embolism: a Randomized Controled Trial

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Pulmonary Embolism
• Intervention / Treatment: Drug: Alteplase; Drug: 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

• Study Type: Interventional
• Enrollment (Estimated): 800
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Linz, Austria, 4020
    • Ordensklinikum Linz Gmbh Elisabethinen
• Belgium
  • Brussels, Belgium
    • UCL Brussels
  • Leuven, Belgium, 3000
    • KU Leuven
  • Liège, Belgium, 4000
    • CHU Liège
• Canada
  • Alberta
    • Calgary, Alberta, Canada
      • Foothills Medical Centre
  • Ontario
    • Hamilton, Ontario, Canada, ON L8V 1C3
      • Juravinski Hospital - Hamilton Health Sciences Corporation
    • Hamilton, Ontario, Canada
      • Hamilton General Hospital - Hamilton Health Sciences Corporation
    • Kingston, Ontario, Canada
      • Kingston Health Sciences Centre
    • London, Ontario, Canada
      • London Health Sciences Centre
    • Ottawa, Ontario, Canada
      • The Ottawa Hopsital, General and Civic campuses
  • Quebec
    • Montreal, Quebec, Canada
      • Jewish General Hospital
• France
  • Angers, France, 49933
    • CHU d'Angers
  • Besançon, France, 25030
    • CHU de Besançon - Hôpital Jean-Minjoz
  • Brest, France, 29000
    • CHU de Brest - Hopital de la Cavale Blanche
  • Chambray-lès-Tours, France, 37170
    • CHU de Tours - Hôpital Trousseau
  • Clermont-Ferrand, France, 63000
    • CHU de Clermont-Ferrand - Hôpital Gabriel Montpied
  • Créteil, France, 94010
    • AP-HP - hôpital Henri-Mondor
  • La Tronche, France, 38700
    • CHU de Grenoble - Hôpital Michallon
  • Le Kremlin-Bicêtre, France, 94270
    • AP-HP - Hôpital Bicêtre
  • Lyon, France, 69000
    • HCL - Hôpital Edouard Herriot
  • Lyon, France, 69495
    • HCL - Centre Hospitalier Lyon-Sud, Pierre-Bénite
  • Marseille, France, 13000
    • AP-HM - Hopital de la Timone
  • Nice, France, 06000
    • CHU de Nice - Hopital Pasteur
  • Paris, France, 75015
    • AP-HP - hôpital européen Georges-Pompidou
  • Paris, France, 75020
    • AP-HP - Hopital Tenon
  • Paris, France, 75018
    • AP-HP - Hôpital Bichat-Claude-Bernard
  • Saint-Etienne, France, 42055
    • CHU de Saint-Etienne - Hôpital Nord
  • Strasbourg, France, 67000
    • CHU de Strasbourg - Hôpital Civil
  • Toulouse, France, 31000
    • CHU de Toulouse - Hopital Rangueil
• Germany
  • Bad Krozingen, Germany, 79189
    • Universitäts-Herzzentrum Freiburg - Bad Krozingen
  • Berlin, Germany, 10117
    • DRK Kliniken Berlin Köpenick
  • Cologne, Germany, 50678
    • Augustinerinnen Hospital
  • Cologne, Germany, 50937
    • Cologne Universität Herzzentrum
  • Dresden, Germany, 01067
    • Dresden, Städtisches Klinikum
  • Düsseldorf, Germany, 40472
    • Düsseldorf, Augusta-Krankenhaus
  • Freiburg im Breisgau, Germany, 79085
    • Freiburg Universität
  • Greifswald, Germany, 17489
    • Greifswald, Univ.-Medizin
  • Hanover, Germany, 30625
    • Hannover, Medizinische Hochschule Hannover
  • Leipzig, Germany, 4103
    • Leipzig, Univ.-Klinikum
  • Mainz, Germany, 55131
    • Mainz Universitätsmedizin, CTH
  • Mainz, Germany, 55131
    • Mainz, Katholisches Klinikum
  • Mannheim, Germany, 68167
    • Universitätsmedizin Mannheim UMM
  • Tübingen, Germany, 72076
    • Tübingen, Univ.-Klinikum
  • Ulm, Germany, 89081
    • Ulm, Universitätsklinikum
• Italy
  • Ancona, Italy, 60020
    • University Hospital Ancona / Ospedali Riunit
  • Cremona, Italy, 26100
    • Spedali Riuniti - Cremona
  • Empoli, Italy, 50053
    • Ospedale San Giuseppe - Empoli
  • Florence, Italy, 50134
    • Azienda Ospedaliera Careggi - Firenze
  • Milan, Italy, 20089
    • Humanitas Hospital - Milano
  • Perugia, Italy, 06123
    • University of Perugia
  • Treviso, Italy, 31100
    • Ospedale Ca Foncello - Treviso
• Netherlands
  • Eindhoven, Netherlands
    • Catharina Hospital
  • Enschede, Netherlands
    • Medisch Spectrum Twente
  • Groningen, Netherlands
    • Martini Hospital
  • Rotterdam, Netherlands
    • Maasstad Hospital
  • Sneek, Netherlands
    • Antonius hospital
  • The Hague, Netherlands
    • Haaglanden hospital
  • Zwolle, Netherlands
    • Isala Hospital
• Poland
  • Bialystok, Poland
    • Medical University of Bialystok
  • Olsztyn, Poland, 11-041
    • University of Warmia Mazury in Olsztyn - School of Medicine
• Portugal
  • Almada, Portugal
    • Hospital García de Orta
  • Lisbon, Portugal
    • Centro Hospitalar de Lisboa Ocidental
  • Lisbon, Portugal
    • Centro Hospitalar de Lisboa Norte/ Hospitalde Santa Maria
  • Matosinhos Municipality, Portugal
    • Hospital Pedro Hispano
  • Porto, Portugal
    • Centro Hospitalar do Porto
  • Setúbal, Portugal
    • Centro Hospitalar de Setubal
• Romania
  • Baia Mare, Romania, 430031
    • Spitalul Judetean de Urgenta Baia Mare
  • Bucharest, Romania
    • Bucuresti - Spitalul Clinic de Urgenta Sf. Pantelimon
  • Constanța, Romania, 900591
    • Spitalul Judetean de Urgenta Constanta
  • Iași, Romania, 700111
    • Iasi - St Spiridon Emergency Conty Hospital
  • Timișoara, Romania
    • Institutul de Boli Cardio-Vasculare Timisoara
• Serbia
  • Belgrade, Serbia
    • Cardiology Clinic, Emergency Center, Clinical Center of Serbia
  • Niš, Serbia
    • Cardiology Clinic, Clinical Center of Niš
  • Novi Sad, Serbia
    • Institute for Lung Diseases of Vojvodina, Sremska Kamenica
• Slovenia
  • Ljubljana, Slovenia, 1000
    • University Medical Centre Ljubljana
• Spain
  • Badalona, Spain, 08916
    • Hospital Germans Trias i Pujol
  • Barcelona, Spain, 08036
    • Hospital Clinic
  • Barcelona, Spain, 08907
    • Hospital Bellvitge
  • Cartagena, Spain
    • Hospital Cartagena
  • Galdakao, Spain, 48960
    • Hospital Galdakao
  • Madrid, Spain, 28034
    • Hospital Ramón Y Cajal
  • Seville, Spain, 41013
    • Hospital Virgen del Rocío
  • Valencia, Spain, 46026
    • Hospital La Fe
• Switzerland
  • Geneva, Switzerland, 1205
    • Geneva University Hospital
  • Sion, Switzerland, 1951
    • Hôpital du Valais

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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

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 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 Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Placebo single intravenous infusion of 0.6 mg/kg of estimated bodyweight with a maximum of 50 mg given over 15 minutes.
Experimental: Alteplase	Drug: Alteplase; Alteplase single intravenous infusion of 0.6 mg/kg of estimated bodyweight with a maximum of 50 mg given over 15 minutes.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Composite of (1) death from any cause or (2) hemodynamic decompensation or (3) objectively confirmed recurrent PE.	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
All-cause mortality		30 days
Serious adverse events		30 days
All-cause mortality		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	Assessment of net clinical benefit	30 days
PE related death		30 days
Hemodynamic decompensation		30 days
Recurrent PE		30 days
Need for rescue thrombolysis, catheter-directed treatment or surgical embolectomy		30 days
Ischemic or hemorrhagic stroke		30 days
Persisting dyspnea		180 days
Persisting dyspnea		2 years
Persistent right ventricular dysfunction		180 days
Persistent right ventricular dysfunction		2 years
Functional outcome		180 days
Functional outcome		2 years
Confirmed chronic thromboembolic pulmonary hypertension		2 years
Utilization of health care ressources	Questionnaire assessing the impact of the treatment on utilization of health care ressources	30 days
Utilization of health care ressources	Questionnaire assessing the impact of the treatment on utilization of health care ressources	180 days

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: Canadian Institutes of Health Research (CIHR); Boehringer Ingelheim; Johannes Gutenberg University Mainz; Instituto de Salud Carlos III; Life Sciences Research Partners (D Collen Research Foundation); International Network of VENous Thromboembolism Clinical Research Networks
• Investigators: Principal Investigator: Olivier SANCHEZ, MD, Assistance Publique - Hôpitaux de Paris; Principal Investigator: Stavros Konstantinides, MD, University Medical Center Mainz

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): August 4, 2021
• Primary Completion (Actual): April 13, 2026
• Study Completion (Estimated): March 1, 2028

Study Registration Dates

• First Submitted: June 10, 2020
• First Submitted That Met QC Criteria: June 10, 2020
• First Posted (Actual): June 12, 2020

Study Record Updates

• Last Update Posted (Actual): July 1, 2026
• Last Update Submitted That Met QC Criteria: June 29, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Thrombolysis; Intermediate-high-risk acute pulmonary embolism
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Respiratory Tract Diseases; Lung Diseases; Embolism and Thrombosis; Embolism; Pulmonary Embolism; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Hydrolases; Enzymes; Enzymes and Coenzymes; Blood Proteins; Endopeptidases; Peptide Hydrolases; Serine Endopeptidases; Serine Proteases; Plasminogen Activators; Blood Coagulation Factors; Tissue Plasminogen Activator
• Other Study ID Numbers: P160924 (Other Identifier: Assistance Publique - Hôpitaux de Paris); PHRCN-16-0580 (Other Grant/Funding Number: French ministry of Health); 2018-000816-96 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data (IPD) that underlie results in publication could be shared. IPD detailed in the protocol of a planned metaanalysis could be shared.
• IPD Sharing Time Frame: One year after the last publication

IPD Sharing Access Criteria

Data sharing must be accepted by the sponsor and the PI based on scientific project and scientific involvement of the PI team. The founder could be involved in the decision.

Teams wishing obtain IPD must meet the sponsor and IP team to present scientifics (and commercial) purpose, IPD needed, format of data transmission, and timeframe. Technical feasibility and financial support will be discussed before mandatory contractualization.

• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No