Clinical trial NCT04430569: Pulmonary Embolism International THrOmbolysis Study-3
Official title: A Reduced Dose of Thrombolytic Treatment for Patients With Intermediate High-risk Acute Pulmonary Embolism: a Randomized Controled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Pulmonary Embolism
Keywords: Intermediate-high-risk acute pulmonary embolism
Thrombolysis
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Johannes Gutenberg University Mainz
name: Life Sciences Research Partners (D Collen Research Foundation)
name: Canadian Institutes of Health Research (CIHR)
name: Instituto de Salud Carlos III
name: International Network of VENous Thromboembolism Clinical Research Networks
name: Boehringer Ingelheim
First posted: 2020-06-12
Enrollment: 800
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Eligibility criteria: 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

Primary outcomes:
measure: Composite of (1) death from any cause or (2) hemodynamic decompensation or (3) objectively confirmed recurrent PE.
timeFrame: 30 days
Secondary outcomes:
measure: Fatal or GUSTO severe or life threatening bleeding
timeFrame: 30 days
measure: Composite of the primary efficacy endpoint and GUSTO severe or life-threatening bleeding
timeFrame: 30 days
measure: All-cause mortality
timeFrame: 30 days
measure: PE related death
timeFrame: 30 days
measure: Hemodynamic decompensation
timeFrame: 30 days
measure: Recurrent PE
timeFrame: 30 days
measure: Need for rescue thrombolysis, catheter-directed treatment or surgical embolectomy
timeFrame: 30 days
measure: Ischemic or hemorrhagic stroke
timeFrame: 30 days
measure: Serious adverse events
timeFrame: 30 days
measure: Persisting dyspnea
timeFrame: 180 days
measure: Persisting dyspnea
timeFrame: 2 years
measure: Persistent right ventricular dysfunction
timeFrame: 180 days
measure: Persistent right ventricular dysfunction
timeFrame: 2 years
measure: Functional outcome
timeFrame: 180 days
measure: Functional outcome
timeFrame: 2 years
measure: All-cause mortality
timeFrame: 2 years
measure: Confirmed chronic thromboembolic pulmonary hypertension
timeFrame: 2 years
measure: Utilization of health care ressources
timeFrame: 30 days
measure: Utilization of health care ressources
timeFrame: 180 days
Other outcomes:
Locations:
city: Graz
country: Austria
facility: Graz, Mediz Universität
city: Linz
country: Austria
facility: Ordensklinikum Linz GmbH Elisabethinen
city: Bruxelles
country: Belgium
facility: UCL Brussels
city: Leuven
country: Belgium
facility: KU Leuven
city: Liège
country: Belgium
facility: CHU Liège
city: Calgary
country: Canada
facility: Foothills Medical Centre
state: Alberta
city: Hamilton
country: Canada
facility: Juravinski Hospital - Hamilton Health Sciences Corporation
state: Ontario
city: Hamilton
country: Canada
facility: Hamilton General Hospital - Hamilton Health Sciences Corporation
state: Ontario
city: Kingston
country: Canada
facility: Kingston Health Sciences Centre
state: Ontario
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hopsital, General and Civic campuses
state: Ontario
city: Montréal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Angers
country: France
facility: CHU d'Angers
city: Besançon
country: France
facility: CHU de Besançon - Hôpital Jean-Minjoz
city: Brest
country: France
facility: CHU de Brest - Hôpital de la Cavale Blanche
city: Chambray-lès-Tours
country: France
facility: CHU de Tours - Hôpital Trousseau
city: Clermont-Ferrand
country: France
facility: CHU de Clermont-Ferrand - Hôpital Gabriel Montpied
city: Créteil
country: France
facility: AP-HP - hôpital Henri-Mondor
city: La Tronche
country: France
facility: CHU de Grenoble - Hôpital Michallon
city: Le Kremlin-Bicêtre
country: France
facility: AP-HP - hôpital Bicêtre
city: Lille
country: France
facility: CHU de Lille - Institut Cœur Poumon
city: Lyon
country: France
facility: HCL - Hôpital Edouard Herriot
city: Lyon
country: France
facility: HCL - Hôpital Edouard Herriot
city: Lyon
country: France
facility: HCL - Centre Hospitalier Lyon-Sud, Pierre-Bénite
city: Marseille
country: France
facility: AP-HM - Hôpital de la Timone
city: Montpellier
country: France
facility: CHU de Montpellier - Hôpital Lapeyronie
city: Nice
country: France
facility: CHU de Nice - Hôpital Pasteur
city: Paris
country: France
facility: AP-HP - Hôpital Lariboisière
city: Paris
country: France
facility: AP-HP - hôpital européen Georges-Pompidou
city: Paris
country: France
facility: AP-HP - Hôpital Bichat-Claude-Bernard
city: Paris
country: France
facility: AP-HP - Hôpital Tenon
city: Pierre-Bénite
country: France
facility: HCL - Centre Hospitalier Lyon-Sud
city: Saint-Étienne
country: France
facility: CHU de Saint-Étienne - Hôpital Nord
city: Strasbourg
country: France
facility: CHU de Strasbourg - Hôpital Civil
city: Toulouse
country: France
facility: CHU de Toulouse - Hôpital Rangueil
city: Bad Krozingen
country: Germany
facility: Universitäts-Herzzentrum Freiburg - Bad Krozingen
city: Berlin
country: Germany
facility: DRK Kliniken Berlin Köpenick
city: Berlin
country: Germany
facility: Berlin, DRK Kliniken Westend
city: Dresden
country: Germany
facility: Dresden, Städtisches Klinikum
city: Düsseldorf
country: Germany
facility: Düsseldorf, Augusta-Krankenhaus
city: Freiburg
country: Germany
facility: Freiburg Universität
city: Greifswald
country: Germany
facility: Greifswald, Univ.-Medizin
city: Hannover
country: Germany
facility: Hannover, Medizinische Hochschule Hannover
city: Köln
country: Germany
facility: Augustinerinnen Hospital
city: Köln
country: Germany
facility: Cologne Universität Herzzentrum
city: Leipzig
country: Germany
facility: Leipzig, Univ.-Klinikum
city: Mainz
country: Germany
facility: Mainz Universitätsmedizin, CTH
city: Mainz
country: Germany
facility: Mainz, Katholisches Klinikum
city: Mannheim
country: Germany
facility: Universitätsmedizin Mannheim UMM
city: Regensburg
country: Germany
facility: Regensburg, Uniklinik
city: Tübingen
country: Germany
facility: Tübingen, Univ.-Klinikum
city: Ulm
country: Germany
facility: Ulm, Universitätsklinikum
city: Ancona
country: Italy
facility: University Hospital Ancona / Ospedali Riunit
city: Cremona
country: Italy
facility: Spedali Riuniti - Cremona
city: Empoli
country: Italy
facility: Ospedale San Giuseppe - Empoli
city: Firenze
country: Italy
facility: Azienda Ospedaliera Careggi - Firenze
city: Milano
country: Italy
facility: Humanitas Hospital - Milano
city: Perugia
country: Italy
facility: University of Perugia
city: Treviso
country: Italy
facility: Ospedale Ca Foncello - Treviso
city: Den Haag
country: Netherlands
facility: Haaglanden hospital
city: Eindhoven
country: Netherlands
facility: Catharina hospital
city: Enschede
country: Netherlands
facility: Medisch Spectrum Twente
city: Groningen
country: Netherlands
facility: Martini hospital
city: Rotterdam
country: Netherlands
facility: Maasstad hospital
city: Sneek
country: Netherlands
facility: Antonius hospital
city: Zwolle
country: Netherlands
facility: Isala hospital
city: Białystok
country: Poland
facility: Medical University of Bialystok
city: Kraków
country: Poland
facility: Department of Cardiac and Vascular Diseases
city: Olsztyn
country: Poland
facility: University of Warmia Mazury in Olsztyn - School of Medicine
city: Poznań
country: Poland
facility: Poznan University of Medical Sciences
city: Warsaw
country: Poland
facility: Medical University of Warsaw
city: Łódź
country: Poland
facility: Medical University of Lodz
city: Almada
country: Portugal
facility: Hospital Garcia de Orta
city: Lisboa
country: Portugal
facility: Centro Hospitalar de Lisboa Norte/ Hospitalde Santa Maria
city: Lisboa
country: Portugal
facility: Centro Hospitalar de Lisboa Ocidental
city: Matosinhos
country: Portugal
facility: Hospital Pedro Hispano
city: Porto
country: Portugal
facility: Centro Hospitalar do Porto
city: Setúbal
country: Portugal
facility: Centro Hospitalar de Setubal
city: Baia Mare
country: Romania
facility: Spitalul Judetean de Urgenta Baia Mare
city: Bucuresti
country: Romania
facility: Bucuresti - Spitalul Clinic de Urgenta Sf. Pantelimon
city: Constanţa
country: Romania
facility: Spitalul Judetean de Urgenta Constanta
city: Iaşi
country: Romania
facility: Iasi - St Spiridon Emergency Conty Hospital
city: Timişoara
country: Romania
facility: Institutul de Boli Cardio-Vasculare Timisoara
city: Belgrad
country: Serbia
facility: Cardiology Clinic, Emergency Center, Clinical Center of Serbia
city: Niš
country: Serbia
facility: Cardiology Clinic, Clinical Center of Niš
city: Novi Sad
country: Serbia
facility: Institute for Lung Diseases of Vojvodina, Sremska Kamenica
city: Ljubljana
country: Slovenia
facility: University Medical Centre Ljubljana
city: Badalona
country: Spain
facility: Hospital Germans Trias i Pujol
city: Barcelona
country: Spain
facility: Hospital Clinic
city: Barcelona
country: Spain
facility: Hospital Bellvitge
city: Cartagena
country: Spain
facility: Hospital Cartagena
city: Galdakao
country: Spain
facility: Hospital Galdakao
city: Madrid
country: Spain
facility: Clínica Universitaria Navarra
city: Madrid
country: Spain
facility: Hospital Ramón y Cajal
city: Sevilla
country: Spain
facility: Hospital Virgen del Rocío
city: Valencia
country: Spain
facility: Hospital La Fe
city: Geneva
country: Switzerland
facility: Geneva University Hospital
city: Sion
country: Switzerland
facility: Hôpital du Valais
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Olivier SANCHEZ, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University Medical Center Mainz
name: Stavros Konstantinides, MD
role: PRINCIPAL_INVESTIGATOR
References:
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.
citation: 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.
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.
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.
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.