E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Acute low-risk pulmonary embolism (PE) |
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E.1.1.1 | Medical condition in easily understood language |
Acute low-risk pulmonary embolism |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.1 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10037379 |
E.1.2 | Term | Pulmonary embolism and thrombosis |
E.1.2 | System Organ Class | 100000004866 |
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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 determine whether early discharge and out-of-hospital treatment of patients with low-risk acute PE (as defined by the inclusion and exclusion criteria) with the new oral factor Xa inhibitor rivaroxaban is feasible, effective, and safe. |
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E.2.2 | Secondary objectives of the trial |
-To determine whether early discharge and out-of-hospital treatment of low-risk acute PE with the new oral factor Xa inhibitor rivaroxaban can result in good quality of life and patient satisfaction -To obtain valid health economic variables as a basis for description of resource utilization, including validation of a disease-specific quality of life questionnaire, and of existing Markov models. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Age ≥18 years; 2) Ability of subject to understand character and individual consequences of clinical trial; 3) Signed and dated informed consent of the subject available before the start of any specific trial procedures; 4) Women of childbearing potential have to practice a medically accepted contraception (non-hormonal intrauterine device, two independent barriers, female or male surgical sterilization, or two years postmeno-pausal) during the trial, and a negative pregnancy test (serum or urine) should be available before inclusion in the trial; 5) Objectively confirmed diagnosis of acute PE by multidetector computed tomographic (CT) pulmonary angiography, pulmonary angiography, or V/Q lung scan according to established diagnostic criteria, with or without symptomatic deep vein thrombosis; 6) Absence of right ventricular (RV) enlargement or dysfunction, and of free floating thrombi in the right atrium or right ventricle on echocardiography or computed tomography. On echocardiography, RV enlargement/dysfunction is absent when both criteria listed below are met: - Right/left ventricular end-diastolic diameter ratio < 0.9 (apical or subcostal 4-chamber view) - No paradoxical motion of the interventricular septum On CT angiography, RV enlargement/dysfunction is absent when the following criterion is met: - Right/left short-axis diameter ratio < 0.9 (transverse plane) |
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E.4 | Principal exclusion criteria |
-Hemodynamic instability at presentation, indicated by at least one of the following: (i) systolic blood pressure (SBP) < 100 mm Hg, or heart rate >100 beats per minute, or SBP drop by > 40 mm Hg, for > 15 min; (ii) need for catecholamines to maintain adequate organ perfusion and a systolic blood pressure of >100 mm Hg; (iii) need for cardiopulmonary resuscitation; -Right ventricular (RV) enlargement or dysfunction, or free floating thrombi in the right atrium or right ventricle, detected by echocardiography or computed tomography; -Treatment with low-molecular-weight heparin, fondaparinux, or unfractionated heparin for more than 48 hours, or more than a single dose of a vitamin K antagonist prior to inclusion in the study; -Treatment with rivaroxaban, dabigatran, apixaban, edoxaban or any other new generation antithrombotics on admission; -Use of a fibrinolytic agent, surgical thrombectomy, interventional (transcatheter) thrombus aspiration or lysis, or use of a cava filter to treat the index episode of PE; - Need for supplemental oxygen administration to maintain oxygen saturation >90%; -Pain requiring parenteral administration of analgesic agents; -Other medical conditions/comorbidities requiring hospitalization; - Acute PE diagnosed in a patient already hospitalized for another condition; - Pregnancy or lactation; - Active bleeding or known significant bleeding risk; -Severe renal insufficiency (estimated GFR <15 ml/min/1.73m2) or end-stage renal disease; -Severe hepatic failure; -Known allergy or intolerance to rivaroxaban; -Concomitant administration of strong inhibitors of P-gp and CYP3A4 such as azole antimycotic agents or HIV protease inhibitors; -Need for long-term treatment vitamin K antagonists, or for antiplatelet agents except acetylsalicylic acid at a dosage <100 mg/day; -Non-compliance or inability to adhere to treatment or to the follow-up visits; or lack of a family environment or support system for home treatment; -Life expectancy less than 3 months. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Symptomatic recurrent venous thromboembolism (VTE) or death related to pulmonary embolism |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
within 3 months after enrolment |
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E.5.2 | Secondary end point(s) |
- All-cause mortality within 7 days; - All-cause mortality within 3 weeks; - All-cause mortality within 3 months; - Overall duration of hospital stay (index event and repeated hospitalizations due to PE [index or recurrent event] or to a bleeding event) within 3 months; - Rehospitalization due to PE (index or recurrent event) or to a bleeding event within 3 months; - Generic and disease-specific quality of life at baseline, 1 week, 3 weeks, and 3 months; - Treatment satisfaction at 3 weeks and 3 months; - Utilization of health care resources at 3 weeks and 3 months; - All-cause mortality at one year. Safety outcomes: - Major bleeding, based on the ISTH definition, within 7 days, 3 weeks, and 3 months; - Clinically relevant bleeding, defined as a composite of major or clinically relevant non- major bleeding, within 7 days, 3 weeks, and 3 months; - Serious adverse events (SAE) within 7 days, 3 weeks, and 3 months. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
7 days, 3 weeks, and 3 months |
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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 | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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 | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |