| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| venous thromboembolism associated with cancer |
| Tromboembolismo venoso asociado al cáncer |
|
| E.1.1.1 | Medical condition in easily understood language |
| blood clot associated with cancer |
| coágulo de sangre asociado a cáncer |
|
| 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 | 18.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066899 |
| E.1.2 | Term | Venous thromboembolism |
| E.1.2 | System Organ Class | 100000004866 |
|
| 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 objective is to demonstrate the non-inferiority of a 12-month course of low molecular weight heparin (LMWH)/edoxaban compared with dalteparin for the prevention of the combined outcome of recurrent venous thromboembolism (VTE) or major bleeding in subjects with VTE associated with cancer. If non-inferiority is established, edoxaban will be compared with dalteparin for superiority. |
El objetivo principal es demostrar la no inferioridad de un ciclo de 12
meses de heparina de bajo peso molecular (HBPM)/edoxabán en
comparación con dalteparina para la prevención del resultado combinado
del tromboembolismo venoso (TEV) recurrente o hemorragia grave en
sujetos con TEV asociado al cáncer. Si se establece la no inferioridad,
edoxabán se comparará con dalteparina para determinar la superioridad. |
|
| E.2.2 | Secondary objectives of the trial |
To compare LMWH/edoxaban with dalteparin with regards to rates of:
1. Recurrent VTE;
2. Major bleeding;
3. Clinically relevant non-major (CRNM) bleeding;
4. Major + CRNM bleeding;
5. Event-free survival, defined as the proportion of subjects over time free of recurrent VTE, major bleeding events, and death;
6. VTE-related death;
7. Mortality from all causes;
8. Recurrent deep vein thrombosis (DVT);
9. Recurrent pulmonary embolism (PE);
10. Healthcare resource utilization for potential recurrent VTE and bleed events. |
comparar HBPM/edoxabán con dalteparina con respecto a las tasas de:
1.TEV recurrente
2.Hemorragias graves
3.Hemorragias graves y no graves clínicamente relevantes (NGCR)
4.Hemorragia grave + NGCR
5.Supervivencia libre de acontecimientos, definida como la proporción de
sujetos conforme pasa el tiempo sin TEV recurrente, episodios de
hemorragia importantes ni muerte
6.Muerte relacionada con el TEV
7.Mortalidad por todas las causas
8.Trombosis venosa profunda recurrente (TVP)
9.Embolismo pulmonar (EP) recurrente
10.Utilización de recursos sanitarios para posibles acontecimientos de
hemorragia y TEV recurrente |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Adult subjects presenting with VTE associated with cancer (other than basal-cell or squamous-cell carcinoma of the skin) for whom long-term treatment with LMWH is intended are eligible to participate in the study.
Subjects must satisfy all of the following criteria to be included in the study:
1. Male or female subjects with age ? 18 years or the otherwise legal lower age according to the country of residence;
2. Confirmed symptomatic or unsuspected lower extremity proximal DVT (ie, popliteal, femoral, iliac or inferior vena cava (IVC) vein thrombosis), or confirmed symptomatic PE, or unsuspected PE of a segmental or larger pulmonary artery;
3. Cancer (other than basal-cell or squamous-cell carcinoma of the skin), either active or diagnosed within 2 years prior to randomization. [Note: Diagnosis of cancer must be objectively documented];
4. Intention for long-term treatment (at least 6 months) with parenteral LMWH;
5. Able to provide written informed consent. |
Podrán participar en el estudio los sujetos adultos, que presenten TEV
asociado al cáncer (excepto el carcinoma cutáneo de células basales o
escamosas) para quienes esté indicado el tratamiento a largo plazo con
HBPM.
Entre los criterios de elegibilidad clave se incluyen:
Criterios de inclusión:
1.Hombres o mujeres ? 18 años de edad o la edad que se considere
legalmente adulta según el país de residencia
2.TVP sintomática o insospechada, confirmada, proximal en las
extremidades inferiores (es decir, trombosis de la vena popliteal, la vena
femoral, la vena ilíaca o la vena cava inferior) o EP sintomática
confirmada o EP insospechada de una arteria pulmonar segmental o
mayor
3.Cáncer, excepto el carcinoma cutáneo de células basales o escamosas.
El cáncer debe estar activo o se debe haber diagnosticado en un plazo de 2 años previos a la aleatorización. El diagnóstico/los antecedentes de cáncer deben estar documentados de
manera objetiva
4.Intención de recibir tratamiento a largo plazo (al menos 6 meses) con HBPM parenteral
5.Capaces de otorgar su consentimiento informado por escrito |
|
| E.4 | Principal exclusion criteria |
1. Thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent to treat the current (index) episode of DVT and/or PE;
2. More than 72 hours pre-treatment with therapeutic dosages of anticoagulant treatment (LMWH, unfractionated heparin, and fondaparinux per local labeling), oral direct anticoagulants or VKA prior to randomization to treat the current (index) episode;
3. Treatment with therapeutic doses of an anticoagulant other than that used for pretreatment of the current (index) VTE episode prior to randomization;
4. Active bleeding or any contraindication for treatment with LMWH/dalteparin or edoxaban;
5. Indication for dalteparin other than DVT and/or PE;
6. An Eastern Cooperative Oncology Group (ECOG) Performance Status of 3 or 4 at the time of randomization (Appendix 17.6);
7. Calculated CrCL < 30 mL/min;
8. History of heparin associated thrombocytopenia;
9. Acute hepatitis, chronic active hepatitis, liver cirrhosis;
10. Hepatocelullar injury with concurrent transaminase (ALT/AST > 3 x ULN) and bilirubin (> 2 x ULN) elevations in the absence of a clinical explanation;
11. Life expectancy < 3 months;
12. Platelet count < 50,000/mL;
13. Uncontrolled hypertension as judged by the Investigator (eg, systolic blood pressure (BP) > 170 mmHg or diastolic blood pressure > 100 mmHg despite antihypertensive treatment);
14. Women of childbearing potential without proper contraceptive measures, and women who are pregnant or breast feeding;
Note: Childbearing potential without proper contraceptive measures (ie, a method of contraception with a failure rate < 1 % during the course of the study including the observational period). These methods of contraception according to the note for guidance on nonclinical safety studies for the conduct of human trials for pharmaceuticals (CPMP/ICH/286/95, modification) include consistent and correct use of hormone containing implants and injectables, combined oral contraceptives, hormone containing intrauterine devices, surgical sterilization, sexual abstinence, and vasectomy for the male partner).
15. Chronic treatment with non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) including both cyclooxygenase-1 (COX-1) and cyclooxygenase-2
(COX-2) inhibitors for ? 4 days/week anticipated to continue during the study;
16. Treatment with aspirin in a dosage of more than 100 mg/per day or dual antiplatelet therapy (any 2 antiplatelet agents including aspirin plus any other oral or intravenous [IV] antiplatelet drug) anticipated to continue during the study;
17. Treatment with the P-gp inhibitors ritonavir, nelfinavir, indinavir, or saquinavir anticipated to continue during the study;
18. Systemic use of the P-gp inhibitors ketoconazole, itraconazole, erythromycin, azithromycin or clarithromycin at the time of randomization; subsequent use is permitted;
19. Subjects with any condition that as judged by the Investigator would place the subject at increased risk of harm if he/she participated in the study. |
1. Trombectomía, inserción de un filtro caval, o uso de un agente
fibrinolítico para tratar el episodio actual (de referencia) de TVP y/o EP
2. Más de 72 horas de tratamiento previo con anticoagulantes (HBPM,
heparina no fraccionada y fondaparinux según la etiqueta local),
anticoagulantes orales directos o agonistas de la vitamina K (AVK) antes
de la aleatorización para tratar el episodio actual (de referencia)
3.Tratamiento con dosis terapéuticas de un anticoagulante excepto el
que se usa para el tratamiento previo del episodio actual de TEV (de
referencia) antes de la aleatorización
4. Hemorragia activa o cualquier contraindicación para el tratamiento
con HBPM/dalteparina o edoxabán
5. Indicación para dalteparina distinta de TVP y/o EP
6. Un estado general de 3 o 4 según la Escala del Grupo Oncológico
Cooperativo del Este (ECOG) en el momento de la aleatorizaciónApéndice
17.6)
7. Aclaramiento calculado de la creatinina (ACr) < 30 ml/min
8. Antecedentes de heparina asociada a trombocitopenia
9. Hepatitis aguda, hepatitis activa crónica, cirrosis hepática
10. Lesión hepatocelular con elevaciones concurrentes de las
transaminasas (alanina transaminasa [ALT]/aspartato transaminasa
[AST] > 3 veces el límite superior de la normalidad [LSN]) y bilirrubina
(> 2 veces el LSN) a falta de una explicación clínica
11. Esperanza de vida < 3 meses
12. Recuento de plaquetas < 50.000/ml
13. Hipertensión descontrolada a criterio del investigador (p. ej., presión
arterial sistólica > 170 mmHg o presión arterial diastólica > 100 mmHg a
pesar del tratamiento antihipertensivo)
14. Mujeres en edad fértil sin medidas anticonceptivas adecuadas y
mujeres que estén embarazadas o en período de lactancia
15. El tratamiento crónico con fármacos antiinflamatorios no esteroideos
(AINE) excepto la aspirina, incluidos los inhibidores de la
ciclooxigenasa-1 (COX-1) y la ciclooxigenasa-2 (COX-2) durante ? 4
días/semana, que se prevea que continúe durante el estudio
16. Tratamiento con aspirina con dosis de más de 100 mg/al día o
tratamiento antiplaquetario doble (2 agentes antiplaquetarios
cualesquiera, entre los que se incluyen la aspirina más cualquier otro
fármaco antiplaquetario oral o intravenoso) que se prevea que continúe
durante el estudio
17. Tratamiento con los inhibidores de la gp-P ritonavir, nelfinavir,
indinavir o saquinavir. que se prevea que continúe durante el estudio
18. Uso sistémico de los inhibidores de la gp-P ketoconazol, itraconazol,
eritromicina, azitromicina o claritromicina en el momento de la
aleatorización; su uso posterior está permitido
19. Sujetos con cualquier afección que, a criterio del Investigador,
implicaría para el sujeto un aumento del riesgo de perjuicio si
participase en el estudio |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary study outcome is the composite of recurrent
VTE, and major bleeding.
Recurrent VTE is either:
-symptomatic confirmed (new) DVT or (new) PE;
-unsuspected (new) proximal DVT of the legs or unsuspected (new) PE located in segmental or more proximal arteries:
Unsuspected DVT or PE are thrombi that are detected during imaging testing performed for other reasons (eg, computed tomography (CT) for cancer staging) and not for suspicion of DVT or PE.
-fatal PE (including unexplained death for which PE cannot be ruled out). |
El resultado principal del estudio es la combinación de TEV recurrente y
hemorragia grave.
El TEV recurrente es:
- TVP (nueva) sintomática confirmada o EP (nueva)
- TVP proximal (nueva) insospechada de las piernas o EP (nueva)
insospechada localizada en las arterias segmentales o en las arterias
más proximales:
El TVP o la EP insospechados son trombos que se detectan durante las
pruebas de imagen realizadas por otras razones (p. ej., tomografía axial
computarizada [TAC] para determinar el estadio del cáncer) y no en el
caso de sospecha de TVP o EP.
- EP mortal (incluido el fallecimiento sin explicación en el que no se
pueda excluir la EP como causa) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
-Recurrent VTE;
-Major bleeding;
-CRNM bleeding;
-Major + CRNM bleeding;
-Event-free survival, defined as the proportion of subjects over time free of recurrent VTE, major bleeding events, and death;
-VTE-related death;
-Mortality from all causes;
-Recurrent DVT;
-Recurrent PE;
-Healthcare resource utilization for potential
recurrent VTE and bleed events. |
-TEV recurrente
- Hemorragias graves
- Hemorragia NGCR
- Hemorragia grave + NGCR
- Supervivencia libre de acontecimientos, definida como la proporción de
sujetos conforme pasa el tiempo sin TEV recurrente, episodios de
hemorragia importantes ni muerte
- Muerte relacionada con el TEV
- Mortalidad por todas las causas
- TVP recurrente
- EP recurrente
- Utilización de recursos sanitarios para posibles acontecimientos de
hemorragia y TEV recurrente |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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 | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Evaluador ciego (Probe) |
| Blind evaluator (probe) |
|
| 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 | 2 |
| 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 | 79 |
| 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 |
| Australia |
| Austria |
| Belgium |
| Canada |
| Czech Republic |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| New Zealand |
| Spain |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
| Once 1000 subjects are randomized, a global End-of-Treatment (EOT) date will be established that ensures a minimum of 6 months of study treatment and follow-up for the final subject(s) randomized. All subjects will permanently discontinue study treatment on or before the EOT date. |
Una vez se haya aleatorizado a 1000 sujetos en el estudio, se
establecerá una fecha de fin de tratamiento (FdT) general que
garantizará un mínimo de 6 meses de tratamiento del estudio y
seguimiento para el/los último(s) sujeto(s) aleatorizado(s). Todos los
sujetos interrumpirán de forma permanente el tratamiento del estudio
en la fecha de FdT o con anterioridad a esta. |
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
