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

October 18, 2023 updated by: Assistance Publique - Hôpitaux de Paris

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

Recruiting

Conditions

Intervention / Treatment

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)

650

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • Austria
  • Belgium
      • Bruxelles, Belgium
        • Not yet recruiting
        • UCL Brussels
        • Contact:
          • Franck Verschuren, MD
      • Leuven, Belgium, 3000
        • Not yet recruiting
        • KU Leuven
        • Contact:
          • Thomas Vanassche, MD
      • Liège, Belgium, 4000
        • Not yet recruiting
        • Chu Liege
        • Contact:
          • Alexandre Ghuysen, MD
  • Canada
    • Alberta
      • Calgary, Alberta, Canada
        • Not yet recruiting
        • Foothills Medical Centre
        • Contact:
          • Kevin Solverson, MD
    • Ontario
      • Hamilton, Ontario, Canada, ON L8V 1C3
        • Not yet recruiting
        • Juravinski Hospital - Hamilton Health Sciences Corporation
        • Contact:
      • Hamilton, Ontario, Canada
        • Not yet recruiting
        • Hamilton General Hospital - Hamilton Health Sciences Corporation
        • Contact:
          • Sam Schulman, MD
      • Kingston, Ontario, Canada
        • Not yet recruiting
        • Kingston Health Sciences Centre
        • Contact:
          • Kerstin de Wit, MD
      • London, Ontario, Canada
        • Not yet recruiting
        • London Health Sciences Centre
        • Contact:
          • Justin Yan, MD
      • Ottawa, Ontario, Canada
        • Not yet recruiting
        • The Ottawa Hopsital, General and Civic campuses
        • Contact:
          • Lana Castellucci, MD
    • Quebec
      • Montréal, Quebec, Canada
        • Not yet recruiting
        • Jewish General Hospital
        • Contact:
          • Andrew Hirsch, MD
  • France
      • Angers, France, 49933
      • Besançon, France, 25030
      • Brest, France, 29000
      • Chambray-lès-Tours, France, 37170
      • Clermont-Ferrand, France, 63000
      • Créteil, France, 94010
        • Recruiting
        • AP-HP - hôpital Henri-Mondor
        • Contact:
      • La Tronche, France, 38700
      • Le Kremlin-Bicêtre, France, 94270
        • Recruiting
        • AP-HP - hôpital Bicêtre
        • Contact:
          • Laurent Savale, MD
      • Lille, France, 59000
        • Withdrawn
        • CHU de Lille - Institut coeur poumon
      • Lyon, France, 69000
      • Lyon, France, 69000
        • Withdrawn
        • HCL - Hôpital Edouard Herriot
      • Marseille, France, 13000
      • Montpellier, France, 34000
      • Nice, France, 06000
        • Terminated
        • CHU de Nice - Hopital Pasteur
      • Paris, France, 75010
        • Withdrawn
        • AP-HP - hôpital Lariboisière
      • Paris, France, 75015
      • Paris, France, 75018
      • Paris, France, 75020
      • Pierre-Bénite, France, 69495
      • Saint-Étienne, France, 42055
      • Strasbourg, France, 67000
      • Toulouse, France, 31000
  • Germany
      • Bad Krozingen, Germany, 79189
      • Berlin, Germany, 10117
        • Recruiting
        • DRK Kliniken Berlin Köpenick
        • Contact:
          • Dirk Habedank, MD
      • Berlin, Germany, 14050
        • Withdrawn
        • Berlin, DRK Kliniken Westend
      • Dresden, Germany, 01067
        • Recruiting
        • Dresden, Städtisches Klinikum
        • Contact:
          • Sebastian Schellong, MD
      • Düsseldorf, Germany, 40472
        • Not yet recruiting
        • Düsseldorf, Augusta-Krankenhaus
        • Contact:
          • Anamaria Wolf-Pütz, MD
      • Freiburg, Germany, 79085
        • Recruiting
        • Freiburg Universität
        • Contact:
          • Daniel Dürschmied, MD
      • Greifswald, Germany, 17489
        • Recruiting
        • Greifswald, Univ.-Medizin
        • Contact:
          • Ralf Eswert, MD
      • Hannover, Germany, 30625
        • Recruiting
        • Hannover, Medizinische Hochschule Hannover
        • Contact:
          • Andreas Schäfer, MD
      • Köln, Germany, 50678
        • Recruiting
        • Augustinerinnen Hospital
        • Contact:
          • Ingo Ahrens, MD
      • Köln, Germany, 50937
        • Not yet recruiting
        • Cologne Universität Herzzentrum
        • Contact:
          • Stephan Rosenkranz, MD
      • Leipzig, Germany, 4103
        • Recruiting
        • Leipzig, Univ.-Klinikum
        • Contact:
          • Holger Thiele, MD
      • Mainz, Germany, 55131
      • Mainz, Germany, 55131
        • Recruiting
        • Mainz, Katholisches Klinikum
        • Contact:
          • Sabine Genth-Zotz, MD
      • Mannheim, Germany, 68167
        • Recruiting
        • Universitätsmedizin Mannheim UMM
        • Contact:
          • Ibrahim Akin, MD
      • Regensburg, Germany, 93053
        • Withdrawn
        • Regensburg, Uniklinik
      • Tübingen, Germany, 72076
        • Recruiting
        • Tübingen, Univ.-Klinikum
        • Contact:
          • Tobias Geisler, MD
      • Ulm, Germany, 89081
        • Not yet recruiting
        • Ulm, Universitätsklinikum
        • Contact:
          • Armin Imhof, MD
  • Italy
      • Ancona, Italy, 60020
        • Recruiting
        • University Hospital Ancona / Ospedali Riunit
        • Contact:
          • Aldo Salvi, MD
      • Cremona, Italy, 26100
        • Not yet recruiting
        • Spedali Riuniti - Cremona
        • Contact:
          • Enrico Passamonti, MD
      • Empoli, Italy, 50053
        • Not yet recruiting
        • Ospedale San Giuseppe - Empoli
        • Contact:
          • Simone Vanni, MD
      • Firenze, Italy, 50134
        • Recruiting
        • Azienda Ospedaliera Careggi - Firenze
        • Contact:
          • Maddalena Ottaviani, MD
      • Milano, Italy, 20089
        • Recruiting
        • Humanitas Hospital - Milano
        • Contact:
          • Corrado Lodigiani, MD
      • Perugia, Italy, 06123
        • Recruiting
        • University Of Perugia
        • Contact:
          • Cecilia Becattini, MD
      • Treviso, Italy, 31100
        • Recruiting
        • Ospedale Ca Foncello - Treviso
        • Contact:
          • Michele Diamanti, MD
  • Netherlands
      • Den Haag, Netherlands
        • Not yet recruiting
        • Haaglanden hospital
      • Eindhoven, Netherlands
        • Not yet recruiting
        • Catharina hospital
      • Enschede, Netherlands
        • Not yet recruiting
        • Medisch Spectrum Twente
      • Groningen, Netherlands
        • Not yet recruiting
        • Martini Hospital
      • Rotterdam, Netherlands
        • Not yet recruiting
        • Maasstad Hospital
      • Sneek, Netherlands
        • Not yet recruiting
        • Antonius hospital
      • Zwolle, Netherlands
        • Not yet recruiting
        • Isala hospital
  • Poland
      • Białystok, Poland
        • Recruiting
        • Medical University of Bialystok
        • Contact:
          • Bożena Sobkowicz, MD
      • Kraków, Poland
        • Not yet recruiting
        • Department of Cardiac and Vascular Diseases
        • Contact:
          • Piotr Podolec, MD
      • Olsztyn, Poland, 11-041
        • Recruiting
        • University of Warmia Mazury in Olsztyn - School of Medicine
        • Contact:
      • Poznań, Poland
        • Not yet recruiting
        • Poznan University of Medical Sciences
        • Contact:
          • Tatiana Mularek, MD
      • Warsaw, Poland
        • Not yet recruiting
        • Medical University of Warsaw
        • Contact:
          • Zbigniew Gaciong, MD
      • Łódź, Poland
        • Not yet recruiting
        • Medical University of Lodz
        • Contact:
          • Jarosław Kasprzak, MD
  • Portugal
      • Almada, Portugal
        • Not yet recruiting
        • Hospital Garcia de Orta
        • Contact:
          • Melanie Ferreira, MD
      • Lisboa, Portugal
        • Not yet recruiting
        • Centro Hospitalar de Lisboa Norte/ Hospitalde Santa Maria
        • Contact:
          • Rui Placido, MD
      • Lisboa, Portugal
        • Not yet recruiting
        • Centro Hospitalar de Lisboa Ocidental
        • Contact:
          • Hugo Moreira, MD
      • Matosinhos, Portugal
        • Not yet recruiting
        • Hospital Pedro Hispano
        • Contact:
          • Carolina Guedes, MD
      • Porto, Portugal
        • Not yet recruiting
        • Centro Hospitalar do Porto
        • Contact:
          • Fabienne Gonçalves, MD
      • Setúbal, Portugal
        • Not yet recruiting
        • Centro Hospitalar de Setubal
        • Contact:
          • Sonia Serra, MD
  • Romania
      • Baia Mare, Romania, 430031
        • Not yet recruiting
        • Spitalul Judetean de Urgenta Baia Mare
        • Contact:
          • Calin Pop, MD
      • Bucuresti, Romania
        • Not yet recruiting
        • Bucuresti - Spitalul Clinic de Urgenta Sf. Pantelimon
        • Contact:
          • Alexandru Nechita, MD
      • Constanţa, Romania, 900591
        • Not yet recruiting
        • Spitalul Judetean de Urgenta Constanta
        • Contact:
          • Anca Mihaela Radulescu, MD
      • Iaşi, Romania, 700111
        • Not yet recruiting
        • Iasi - St Spiridon Emergency Conty Hospital
        • Contact:
          • Antoniu Petris, MD
      • Timişoara, Romania
        • Not yet recruiting
        • Institutul de Boli Cardio-Vasculare Timisoara
        • Contact:
          • Lucian Petrescu, MD
  • Serbia
      • Belgrad, Serbia
        • Not yet recruiting
        • Cardiology Clinic, Emergency Center, Clinical Center of Serbia
        • Contact:
          • Branislav Stefanovic, MD
      • Niš, Serbia
        • Not yet recruiting
        • Cardiology Clinic, Clinical Center of Niš
      • Novi Sad, Serbia
        • Not yet recruiting
        • Institute for Lung Diseases of Vojvodina, Sremska Kamenica
  • Slovenia
      • Ljubljana, Slovenia, 1000
        • Recruiting
        • University Medical Centre Ljubljana
        • Contact:
          • Matija Kozak, MD
  • Spain
      • Badalona, Spain, 08916
        • Recruiting
        • Hospital Germans Trias i Pujol
        • Contact:
          • Manuel Monreal, MD
      • Barcelona, Spain, 08036
        • Recruiting
        • Hospital Clínic
        • Contact:
          • Jorge Moises, MD
      • Barcelona, Spain, 08907
        • Recruiting
        • Hospital Bellvitge
        • Contact:
          • Antoni Riera-Mestre, MD
      • Cartagena, Spain
        • Recruiting
        • Hospital Cartagena
        • Contact:
          • Javier Trujillo-Santos, MD
      • Galdakao, Spain, 48960
        • Recruiting
        • Hospital Galdakao
        • Contact:
          • Aitor Ballaz, MD
      • Madrid, Spain, 28034
        • Recruiting
        • Hospital Ramon Y Cajal
        • Contact:
          • David Jimenez, MD
      • Madrid, Spain, 28027
        • Recruiting
        • Clínica Universitaria Navarra
        • Contact:
          • Pedro Ruiz-Artacho, MD
      • Sevilla, Spain, 41013
        • Recruiting
        • Hospital Virgen del Rocío
        • Contact:
          • Remedios Otero, MD
      • Valencia, Spain, 46026
        • Not yet recruiting
        • Hospital la Fe
        • Contact:
          • Raquel Lopez, MD
  • Switzerland
      • Geneva, Switzerland, 1205
        • Not yet recruiting
        • Geneva University Hospital
        • Contact:
          • Marc Righini, MD
      • Sion, Switzerland, 1951

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

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.
Time Frame: 30 days
30 days

Secondary Outcome Measures

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

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

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 4, 2021

Primary Completion (Estimated)

September 1, 2025

Study Completion (Estimated)

August 1, 2027

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)

October 19, 2023

Last Update Submitted That Met QC Criteria

October 18, 2023

Last Verified

October 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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