Intermediate-high-risk acute pulmonary embolism
Conditions
Interventions
Trade Name: ACTILYSE 50 mg
Pharmaceutical Form: Powder and solvent for solution for injection/infusion
INN or Proposed INN: Alteplase
Other descriptive name: ALTEPLASE FOR INJECTION
Concentration unit
Sponsors
Assistance Publique – Hôpitaux de Paris, Clinical Research and Innovation Delegation (DRCI)
Eligibility
Sex/Gender
All
Inclusion 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 (CTPA) or selective 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 (SBP) = 110 mm Hg over at least 15 minutes upon enrolment, (b) temporary need for fluid resuscitation and/or treatment with low dose catecholamines because of arterial hypotension at presentation, 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 SpO2 1.0 on echocardiography apical four- chamber or subcostal four-chamber view or on CTPA (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 had received the result 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 the latest. • Signed informed consent form • [France]: Patient insured under a social security system Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 586 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 64
Exclusion criteria
Exclusion criteria: • Hemodynamic instability, defined by at least one of the following criteria - cardiac arrest; - obstructive shock, defined as: (i) SBP 15 min), if not caused by new-onset arrhythmia, hypovolemia, or sepsis • 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 the previous 3 weeks • Platelet count 1.4 (If INR not available: prothrombin time ratio 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 • [Italy and the Netherlands] Participation in another interventional clinical study within 30 days from the inclusion • [All countries except Italy and the Netherlands] • 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 • Known previous immune heparin-induced thrombo-cytepenia • 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 in the investigator's opinion 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the efficacy of reduced-dose thrombolytic therapy in patients with acute intermediate-high-risk pulmonary embolism at day 30.;Secondary Objective: •To assess the safety of reduced-dose thrombolytic therapy in patients with intermediate-high-risk acute pulmonary embolism •To assess the net clinical benefit of reduced-dose thrombolytic therapy in patients with intermediate-high-risk acute pulmonary embolism •To assess the effect of reduced-dose thrombolytic therapy on overall mortality of patients with intermediate-high-risk acute pulmonary embolism •To assess the effect of reduced-dose thrombolytic therapy on long-term mortality, functional impairment, residual right ventricular (RV) dysfunction and chronic thromboembolic pulmonary hypertension •To assess the effect of reduced-dose thrombolytic therapy on utilization of health care resources. ;Primary end point(s): The primary outcome is the composite of (1) death from any cause or (2) hemodynamic decompensation or (3) objectively confirmed recurrent PE at day 30.;Timepoint(s) of evaluation of this end point: day 30 ; day 180; 2 years | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The following key secondary outcomes will be included in a hierarchical analysis: 1) Fatal or GUSTO severe or life-threatening bleeding within 30 days 2) Net clinical benefit defined as the composite of the primary efficacy outcome and GUSTO severe or life-threatening bleeding within 30 days 3) All-cause mortality within 30 days The following secondary outcomes are not entered in the hierarchical analysis: 4) PE related death within 30 days 5) Hemodynamic decompensation within 30 days 6) Need for rescue thrombolysis, catheter-directed treatment or surgical embolectomy within 30 days 7) Recurrent PE within 30 days 8) Ischemic or hemorrhagic stroke within 30 days 9) Serious adverse events within 30 days 10) All-cause mortality at two years 11) Dyspnea assessed by the Medical Research Council scale at day 180 and at two years 12) Functional outcome using the post-VTE functional scale at day 180 and at 2 years 13) Persistent RV dysfunction at day 180 and at 2 years 14) Confirmed chronic thromboembolic pulmonary hypertension at 2 years 15) Utilization of health care resources within 30 days and 180 days post randomization. ;Timepoint(s) of evaluation of this end point: 2 years | — |
Countries
Austria, France, Germany, Italy, Netherlands, Slovenia, Spain
Contacts
Public ContactProf. Dr. med. S. Konstantinides
Universitätsmedizin der Johannes Gutenberg Universität, CTH
Outcome results
None listed