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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04430569
Recruitment Status : Recruiting
First Posted : June 12, 2020
Last Update Posted : May 6, 2022
Sponsor:
Collaborators:
Johannes Gutenberg University Mainz
Life Sciences Research Partners (D Collen Research Foundation)
Canadian Institutes of Health Research (CIHR)
Boehringer Ingelheim
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

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.

Condition or disease Intervention/treatment Phase
Pulmonary Embolism Drug: Alteplase Drug: Placebo Phase 3

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 650 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: A Reduced Dose of Thrombolytic Treatment for Patients With Intermediate High-risk Acute Pulmonary Embolism: a Randomized Controled Trial
Actual Study Start Date : August 4, 2021
Estimated Primary Completion Date : September 2025
Estimated Study Completion Date : August 2027

Resource links provided by the National Library of Medicine

Drug Information available for: Alteplase

Arm Intervention/treatment
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.

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.




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

Secondary Outcome Measures :
  1. Fatal or GUSTO severe or life threatening bleeding [ Time Frame: 30 days ]
  2. Composite of the primary efficacy endpoint and GUSTO severe or life-threatening bleeding [ Time Frame: 30 days ]
    Assessment of net clinical benefit

  3. All-cause mortality [ Time Frame: 30 days ]
  4. PE related death [ Time Frame: 30 days ]
  5. Hemodynamic decompensation [ Time Frame: 30 days ]
  6. Recurrent PE [ Time Frame: 30 days ]
  7. Need for rescue thrombolysis, catheter-directed treatment or surgical embolectomy [ Time Frame: 30 days ]
  8. Ischemic or hemorrhagic stroke [ Time Frame: 30 days ]
  9. Serious adverse events [ Time Frame: 30 days ]
  10. Persisting dyspnea [ Time Frame: 180 days ]
  11. Persisting dyspnea [ Time Frame: 2 years ]
  12. Persistent right ventricular dysfunction [ Time Frame: 180 days ]
  13. Persistent right ventricular dysfunction [ Time Frame: 2 years ]
  14. Functional outcome [ Time Frame: 180 days ]
  15. Functional outcome [ Time Frame: 2 years ]
  16. All-cause mortality [ Time Frame: 2 years ]
  17. Confirmed chronic thromboembolic pulmonary hypertension [ Time Frame: 2 years ]
  18. Utilization of health care ressources [ Time Frame: 30 days ]
    Questionnaire assessing the impact of the treatment on utilization of health care ressources

  19. Utilization of health care ressources [ Time Frame: 180 days ]
    Questionnaire assessing the impact of the treatment on utilization of health care ressources



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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) history of chronic 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
  • 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 > 180/90 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 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04430569


Contacts
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Contact: Olivier SANCHEZ, MD PhD olivier.sanchez@aphp.fr
Contact: Yvann Frigout yvann.frigout@aphp.fr

Locations
Show Show 97 study locations
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Johannes Gutenberg University Mainz
Life Sciences Research Partners (D Collen Research Foundation)
Canadian Institutes of Health Research (CIHR)
Boehringer Ingelheim
Investigators
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Principal Investigator: Olivier SANCHEZ, MD Assistance Publique - Hôpitaux de Paris
Principal Investigator: Stavros Konstantinides, MD University Medical Center Mainz
Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT04430569    
Other Study ID Numbers: P160924
P160924 ( Other Identifier: Assistance Publique - Hôpitaux de Paris )
PHRCN-16-0580 ( Other Grant/Funding Number: French ministry of Health )
2018-000816-96 ( EudraCT Number )
First Posted: June 12, 2020    Key Record Dates
Last Update Posted: May 6, 2022
Last Verified: April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
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.
Supporting Materials: Study Protocol
Informed Consent Form (ICF)
Time Frame: One year after the last publication
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.


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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Assistance Publique - Hôpitaux de Paris:
Intermediate-high-risk acute pulmonary embolism
Thrombolysis
Additional relevant MeSH terms:
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Pulmonary Embolism
Embolism
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
Tissue Plasminogen Activator
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action