Pulmonary Embolism International THrOmbolysis Study-3

Pulmonary Embolism Clinical Trial

— PEITHO-3  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04430569
• Other study ID #: P160924
• Secondary ID: P160924PHRCN-16-
• Status: Recruiting
• Phase: Phase 3
• Start date: August 4, 2021
• Est. completion date: August 2027

Study information

• Verified date: October 2023
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: Olivier SANCHEZ, MD PhD
• Email: olivier.sanchez[@]aphp.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Recruiting
• Enrollment: 650
• Est. completion date: August 2027
• Est. primary completion date: September 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Embolism
• Pulmonary Embolism

Intervention

Drug:
• 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.

Locations

Country	Name	City	State
Austria	Graz, Mediz Universität	Graz
Austria	Ordensklinikum Linz GmbH Elisabethinen	Linz
Belgium	UCL Brussels	Bruxelles
Belgium	KU Leuven	Leuven
Belgium	CHU Liège	Liège
Canada	Foothills Medical Centre	Calgary	Alberta
Canada	Hamilton General Hospital - Hamilton Health Sciences Corporation	Hamilton	Ontario
Canada	Juravinski Hospital - Hamilton Health Sciences Corporation	Hamilton	Ontario
Canada	Kingston Health Sciences Centre	Kingston	Ontario
Canada	London Health Sciences Centre	London	Ontario
Canada	Jewish General Hospital	Montréal	Quebec
Canada	The Ottawa Hopsital, General and Civic campuses	Ottawa	Ontario
France	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	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 Bichat-Claude-Bernard	Paris
France	AP-HP - hôpital européen Georges-Pompidou	Paris
France	AP-HP - Hôpital Lariboisière	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
Germany	Universitäts-Herzzentrum Freiburg - Bad Krozingen	Bad Krozingen
Germany	Berlin, DRK Kliniken Westend	Berlin
Germany	DRK Kliniken Berlin Köpenick	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
Italy	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
Netherlands	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
Poland	Medical University of Bialystok	Bialystok
Poland	Department of Cardiac and Vascular Diseases	Kraków
Poland	Medical University of Lodz	Lódz
Poland	University of Warmia Mazury in Olsztyn - School of Medicine	Olsztyn
Poland	Poznan University of Medical Sciences	Poznan
Poland	Medical University of Warsaw	Warsaw
Portugal	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
Romania	Spitalul Judetean de Urgenta Baia Mare	Baia Mare
Romania	Bucuresti - Spitalul Clinic de Urgenta Sf. Pantelimon	Bucuresti
Romania	Spitalul Judetean de Urgenta Constanta	Constanta
Romania	Iasi - St Spiridon Emergency Conty Hospital	Iasi
Romania	Institutul de Boli Cardio-Vasculare Timisoara	Timisoara
Serbia	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
Slovenia	University Medical Centre Ljubljana	Ljubljana
Spain	Hospital Germans Trias i Pujol	Badalona
Spain	Hospital Bellvitge	Barcelona
Spain	Hospital Clinic	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
Switzerland	Geneva University Hospital	Geneva
Switzerland	Hôpital du Valais	Sion

Sponsors (7)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris	Boehringer Ingelheim, Canadian Institutes of Health Research (CIHR), Instituto de Salud Carlos III, International Network of VENous Thromboembolism Clinical Research Networks, Johannes Gutenberg University Mainz, Life Sciences Research Partners (D Collen Research Foundation)

Countries where clinical trial is conducted

Austria,  Belgium,  Canada,  France,  Germany,  Italy,  Netherlands,  Poland,  Portugal,  Romania,  Serbia,  Slovenia,  Spain,  Switzerland, 

References & Publications (5)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Composite of (1) death from any cause or (2) hemodynamic decompensation or (3) objectively confirmed recurrent PE.		30 days
Secondary	Fatal or GUSTO severe or life threatening bleeding		30 days
Secondary	Composite of the primary efficacy endpoint and GUSTO severe or life-threatening bleeding	Assessment of net clinical benefit	30 days
Secondary	All-cause mortality		30 days
Secondary	PE related death		30 days
Secondary	Hemodynamic decompensation		30 days
Secondary	Recurrent PE		30 days
Secondary	Need for rescue thrombolysis, catheter-directed treatment or surgical embolectomy		30 days
Secondary	Ischemic or hemorrhagic stroke		30 days
Secondary	Serious adverse events		30 days
Secondary	Persisting dyspnea		180 days
Secondary	Persisting dyspnea		2 years
Secondary	Persistent right ventricular dysfunction		180 days
Secondary	Persistent right ventricular dysfunction		2 years
Secondary	Functional outcome		180 days
Secondary	Functional outcome		2 years
Secondary	All-cause mortality		2 years
Secondary	Confirmed chronic thromboembolic pulmonary hypertension		2 years
Secondary	Utilization of health care ressources	Questionnaire assessing the impact of the treatment on utilization of health care ressources	30 days
Secondary	Utilization of health care ressources	Questionnaire assessing the impact of the treatment on utilization of health care ressources	180 days