E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Long-term prevention of recurrent symptomatic venous thromboembolism in patients with symptomatic deep-vein thrombosis and/or pulmonary embolism |
Prevención a largo plazo del tromboembolismo venoso (TEV) sintomático recurrente en pacientes con trombosis venosa profunda sintomática y/o embolia pulmonar |
|
E.1.1.1 | Medical condition in easily understood language |
Prevention of blood clots from reccuring in the veins of your legs or blood vessels of your lungs |
Prevención de coágulos de sangre que se repiten en las venas de sus piernas o los vasos sanguíneos de sus pulmonesge that is applicable |
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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 | 16.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10051055 |
E.1.2 | Term | Deep vein thrombosis |
E.1.2 | System Organ Class | 10047065 - Vascular disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10037439 |
E.1.2 | Term | Pulmonary thrombotic and embolic conditions |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10034572 |
E.1.2 | Term | Peripheral embolism and thrombosis |
E.1.2 | System Organ Class | 10047065 - Vascular disorders |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10037377 |
E.1.2 | Term | Pulmonary embolism |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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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 |
The primary efficacy objective is to evaluate whether rivaroxaban, in doses of 10 mg or 20 mg, is superior to acetylsalicylic acid (ASA) 100 mg in the prevention of the primary efficacy outcome (i.e. fatal or non-fatal symptomatic recurrent venous thromboembolism).
The principal safety objective is to document the incidence of the principal safety outcome (i.e. major bleeding). |
El objetivo de eficacia primario es evaluar si el rivaroxabán, a dosis de 10 mg o de 20 mg, es superior al ácido acetilsalicílico (AAS) a dosis de 100 mg en la prevención de la respuesta de eficacia primaria (es decir, el tromboembolismo venoso recurrente sintomático mortal o no mortal).
El objetivo principal de seguridad es documentar la incidencia del resultado de seguridad principal (como la hemorragia grave). |
|
E.2.2 | Secondary objectives of the trial |
The secondary efficacy objective is to evaluate whether rivaroxaban 10 mg and rivaroxaban 20 mg are superior to ASA 100 mg in the prevention of the secondary efficacy outcome (i.e. fatal or non-fatal symptomatic recurrent venous thromboembolism, myocardial infarction, ischemic stroke, systemic non-central nervous system [CNS] embolism).
The secondary safety objective is to document the incidence of the secondary safety outcome (i.e. clinically relevant non-major bleeding). |
El objetivo de eficacia secundario es evaluar si el rivaroxabán 10 mg y el rivaroxabán 20 mg son superiores al AAS 100 mg en la prevención de la respuesta de eficacia secundaria (es decir, el tromboembolismo venoso recurrente sintomático mortal o no mortal, el infarto de miocardio, el ictus isquémico y la embolia sistémica que no afecta al sistema nervioso central [SNC]).
El objetivo secundario de seguridad es documentar la incidencia del resultado de seguridad secundario (como la hemorragia leve de interés clínico). |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients with confirmed symptomatic PE and/or DVT who have been treated for 6 to 12 months and did not interrupt anticoagulation for longer than 1 week. 2. Written informed consent |
1. Pacientes con EP y/o TVP sintomática confirmada que hayan sido tratados de 6 a 12 meses sin interrupción de la anticoagulación superior a una semana. 2. Consentimiento informado escrito |
|
E.4 | Principal exclusion criteria |
1. Legal lower age limitations (country specific) 2. Indication for therapeutic-dosed anticoagulants 3. Hypersensitivity to investigational or comparator treatment 4. Any other contraindication listed in the local labeling for investigational or comparator treatment 5. Indication for antiplatelet therapy or a conventional non-steroid anti-inflammatory drug (NSAID) 6. Hepatic disease which is associated with coagulopathy leading to a clinically relevant bleeding risk 7. Calculated creatinine clearance < 30 mL/min 8. Active bleeding or high risk for bleeding contraindicating anticoagulant therapy 9. Life expectancy <6 months 10. Concomitant use of strong inhibitors of both cytochrome P450 isoenzyme 3A4 (CYP3A4) and P-glycoprotein (P-gp), i.e. all human immunodeficiency virus protease inhibitors and the following azole-antimycotics agents: ketoconazole, itraconazole, voriconazole, posaconazole, if used systemically 11. Childbearing potential without proper contraceptive measures, pregnancy or breast feeding 12. Participation in a study with an investigational drug or medical device within 30 days prior to randomization |
1. Limitaciones por no cumplir la edad legal (específicas de cada país) 2. Indicación de anticoagulantes a dosis terapéuticas 3. Hipersensibilidad al tratamiento en investigación o de comparación 4. Cualquier otra contraindicación indicada en el etiquetado local del tratamiento en investigación o de comparación 5. Indicación de tratamiento antiplaquetario o fármaco antiinflamatorio no esteroideo convencional (AINE) 6. Enfermedad hepática asociada a coagulopatía que comporta un riesgo de hemorragia clínicamente relevante. 7. Aclaramiento de creatinina calculado < 30 ml/min. 8. Hemorragia activa o riesgo elevado de hemorragia que contraindique la terapia anticoagulante 9. Esperanza de vida < 6 meses 10. Uso concomitante de inhibidores potentes de la isoenzima del citocromo P450 3A4 (CYP3A4) y la glucoproteína P (gp-P), es decir, todos los inhibidores de la proteasa del virus de la inmunodeficiencia humana y los siguientes agentes antimicóticos azoles: ketoconazol, itraconazol, voriconazol y posaconazol; si se utilizan por vía sistémica 11. Mujeres en edad fértil que no adopten las medidas anticonceptivas adecuadas, durante el embarazo o la lactancia 12. Participación en un estudio con un fármaco o producto sanitario en investigación durante los treinta días anteriores a la aleatorización |
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E.5 End points |
E.5.1 | Primary end point(s) |
Fatal or non-fatal symptomatic recurrent venous thromboembolism |
Tromboembolismo venoso recurrente sintomático mortal o no mortal |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Composite efficacy outcomes will be analyzed based on time to first event in the intended 12-month treatment period, using a stratified (for index DVT only and index PE± DVT) Cox proportional hazard model in the full analysis set (FAS). Adjudication results will be the basis for the final analyses. The primary efficacy analysis will use a hierarchical (fixed sequence) testing procedure for testing superiority of the individual rivaroxaban doses vs. ASA. |
Los resultados de eficacia combinados se analizarán en función del tiempo transcurrido desde el primer episodio en el período de tratamiento previsto de 12 meses, aplicando un modelo de riesgos proporcionales de Cox estratificado (solo para el episodio índice de TVP y el episodio índice de EP ± TVP) en el grupo completo de análisis (GCA). Los resultados de la adjudicación servirán de base para los análisis finales. El análisis de eficacia primaria utilizará un procedimiento jerárquico de pruebas (de secuencia fija) para probar la superioridad de las dosis individuales de rivaroxabán frente al AAS. |
|
E.5.2 | Secondary end point(s) |
fatal or non-fatal symptomatic recurrent venous thromboembolism, myocardial infarction, ischemic stroke, systemic non-central nervous system [CNS] embolism |
El tromboembolismo venoso recurrente sintomático mortal o no mortal, el infarto de miocardio, el ictus isquémico y la embolia sistémica que no afecta al sistema nervioso central [SNC] |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary composite outcome will be analyzed with Cox regression and with log rank test as described for the primary efficacy analysis. |
El resultado combinado secundario se analizará aplicando un ensayo de regresión de Cox y un ensayo de rango logarítmico tal como se describe para el análisis de eficacia primaria |
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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 | 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 | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
doble simulación |
double-dummy |
|
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 117 |
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 |
Belgium |
Canada |
China |
Denmark |
France |
Italy |
Austria |
Netherlands |
New Zealand |
Norway |
Sweden |
Australia |
Brazil |
Czech Republic |
Germany |
Hungary |
Korea, Republic of |
Spain |
Thailand |
Israel |
Mexico |
Philippines |
Poland |
Russian Federation |
South Africa |
Switzerland |
Taiwan |
Turkey |
United Kingdom |
United States |
Vietnam |
|
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
|
LVLS |
Última visita del último paciente |
|
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 | 5 |
E.8.9.1 | In the Member State concerned days | 30 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
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 |