E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Intermediate high-risk acute pulmonary embolism |
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E.1.1.1 | Medical condition in easily understood language |
Intermediate high-risk acute pulmonary embolism |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To assess the efficacy of reduced dose thrombolytic therapy in patients with acute intermediate-high-risk pulmonary embolism at day 30. |
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E.2.2 | Secondary objectives of the trial |
•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 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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) 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
• Αcute 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 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 <90% (or partial arterial oxygen pressure < 60 mmHg) at rest while breathing room air, (d) history of chronic heart failure defined as previous diagnosis of heart failure (i.e. heart failure with reduced, moderately reduced or preserved ejection fraction) or treatment for heart failure at any time during the past 12 months;
• RV dysfunction indicated by RV/LV diameter ratio >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
• Abiltity to randomize patient within 6 hours after the investigator receives 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
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E.4 | Principal exclusion criteria |
• Hemodynamic instability, defined by at least one of the following criteria
- cardiac arrest;
- obstructive shock, defined as: (i) SBP <90 mmHg, or vasopressors required to achieve a SBP ≥90 mmHg despite an adequate filling status; and (ii) end-organ hypoperfusion (altered mental status; cold, clammy skin; oliguria/anuria; increased serum lactate);
- isolated persistent hypotension (SBP <90 mmHg, or a systolic pressure drop ≥40 mmHg for >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 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 < 100 x 109/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 anti-platelet 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 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 in investigator'opinions 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 |
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E.5 End points |
E.5.1 | 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. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
day 30 ; day 180; 2 years |
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E.5.2 | 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
Utilization of health care resources within 30 days and 180 days post randomization.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 90 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Serbia |
Austria |
Belgium |
Canada |
Germany |
Italy |
Netherlands |
Poland |
Portugal |
Romania |
Slovenia |
Spain |
Switzerland |
France |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 72 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 72 |