E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Paediatric liver transplant recipients with age equal/greater to 1 month and younger than 18 years. |
Receptores pediátricos de trasplante de hígado , y de edad igual o mayor de 1 mes y menor de 18 años. |
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E.1.1.1 | Medical condition in easily understood language |
Paediatric patients with age equal/greater to 1 month and younger than 18 years, who have received a liver from a another person and need medication to avoid the loss of the organ. |
Pacientes pediátricos de edad igual o mayor de 1 mes y menor de 18 años, que han recibido un hígado de otra persona y necesitan medicación para evitar la pérdida del órgano. |
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E.1.1.2 | Therapeutic area | Body processes [G] - Immune system processes [G12] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10024716 |
E.1.2 | Term | Liver transplantation |
E.1.2 | System Organ Class | 10042613 - Surgical and medical procedures |
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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 |
Evaluate the evolution of renal function assessed by Glomerular Filtration Rate estimated by the Chronic Kidney Disease in Children (Schwartz) formula from start to Month 12 of an everolimus based regimen. |
Evaluar la evolución de la función renal, según la tasa de filtración glomerular (TFGe) estimada mediante la fórmula de Schwartz para enfermedad renal crónica en niños (ERCeN) (Schwartz 2009), desde el inicio hasta el mes 12 con un tratamiento basado en everolimus hasta el mes 12. |
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E.2.2 | Secondary objectives of the trial |
As per protocol:
--> Further efficacy objectives --> Renal function related objectives --> Development objectives --> Safety objectives --> Other objective |
Por protocolo:
--> Otros objetivos de eficacia --> Objetivos sobre la función renal --> Objetivos de desarrollo --> Objectives de seguridad --> Otros objetivos |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
This sub-study will characterize the pharmacokinetics (PK) of everolimus in combination with reduced CNI in a total of at least 16 male or female paediatric recipients of a full-size or technically modified liver allograft. |
En este subestudio se caracterizará la farmacocinética (PK) de everolimus en combinación con el ICN reducido en un total de al menos 16 receptores pediátricos de ambos sexos de aloinjerto hepático de tamaño completo o técnicamente modificado. |
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E.3 | Principal inclusion criteria |
1. A signed informed consent/assent must have been obtained from both parents or legal guardian(s) prior to patient participation in the study.
2. Paediatric liver transplant recipients aged greater than or equal to 1 month and younger than 18 years of age.
3. Paediatric liver transplant recipients at the earliest 1 month and latest 6 month after liver transplantation. |
1. Se debe obtener un consentimiento informado/asentimiento firmado de los padres y de los tutores legales antes de que el paciente participe en el estudio y antes de realizar cualquier evaluación. 2. Receptores pediátricos de trasplante hepático de edad mayor o igual a 1 mes y menores de 18 años de edad con un peso corporal superior a 5 kg y tratados con un régimen inmunosupresor basado en ICN con/sin ácido micofenólico y corticosteroides. 3. Los receptores pediátricos de trasplante hepático de tamaño completo o técnicamente modificado serán elegibles como mínimo 1 mes y como máximo 6 meses después del trasplante hepático. |
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E.4 | Principal exclusion criteria |
1. Patients who experienced more than two episodes of tBPAR or who received T-cell depleting induction agents or acute rejection therapy.
2. Patients with hepato-biliary malignancies.
3. Patients transplanted due to fulminant hepatitis/acute liver failure.
4. Presence of thrombosis of any major hepatic arteries, major/reconstructed hepatic veins, portal vein or inferior vena cava at any time prior to the start of everolimus treatment (graft vessel patency by Doppler ultrasound confirmed and documented).
5. Patients with serum creatinine value >2 times age-related ULN at baseline or who received renal replacement therapy within one week prior to the start of everolimus treatment.
6. Patients with a confirmed spot urine protein/creatinine ratio indicating a urinary protein excretion >500 mg/m2/24 hrs, at baseline.
7. Patients who are recipients of multiple solid organ transplants, (e.g., multivisceral or combined liver-kidney transplants), or have previously received an organ or tissue transplanted, or who received an ABO incompatible transplant.
8. Patients who have severe hypercholesterolemia (>215 mg/dL; >5.5 mmol/L) or hypertriglyceridemia (>265 mg/dL; >3.0 mmol/L) at Baseline.
9. Patients with platelet count <35,000 mm3 and/or an absolute neutrophil count <1,000/mm3 or white blood cell count of <2,000/mm3 at Baseline.
10. Patients who have any surgical or medical condition, which in the opinion of the investigator, might significantly alter the absorption, distribution, metabolism and excretion of study drug.
11. Patients with a known hypersensitivity to the drugs used on study or their class, or to any of the excipients.
12. Patients with clinically significant systemic infection and/or in a critical care setting requiring life support measures such as mechanical ventilation, dialysis, or vasopressor agents.
13. Pregnant or nursing (lactating) female patients, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive ?HCG laboratory test (>9 mIU/mL) at Baseline.
14. Female patients of child-bearing potential, defined as all women physiologically capable of becoming pregnant, UNLESS they agree for abstinence from sexual activity. |
1.Los pacientes que experimenten más de dos episodios de rechazo agudo que haya sido tratado y confirmado por biopsia o que reciban agentes inductores de depleción de células T o tratamiento para rechazo agudo. 2.Pacientes con cáncer hepatobiliar. 3.Pacientes trasplantados debido a hepatitis fulminante/insuficiencia hepática aguda. 4.Presencia de trombosis de cualquier arteria hepática principal, venas hepáticas, vena porta y vena cava principales/reconstruidas en cualquier momento antes del inicio del tratamiento con everolimus (confirmado y documentado según la permeabilidad del vaso de injerto mediante ecografía Doppler). 5.Pacientes con un valor de creatinina sérica >2 veces el LSN ajustado por edad en la visita basal o que hayan recibido un tratamiento renal sustitutivo durante la semana anterior al inicio del tratamiento con everolimus. 6.Pacientes con una tasa confirmada de proteína/creatinina en orina que indique una secreción de proteína en orina >500 mg/m2/24 h en la visita basal. 7.Pacientes que sean receptores de trasplantes múltiples de órganos sólidos (p. ej., trasplante multivisceral o trasplante combinado de hígado-riñón), o que hayan recibido previamente un órgano o tejido trasplantado o que hayan recibido un trasplante ABO incompatible. 8.Pacientes con hipercolesterolemia grave (>215 mg/dl; >5,5 mmol/l) o hipertrigliceridemia (>265 mg/dl; >3,0 mmol/l) en la visita basal. 9.Pacientes con recuento de plaquetas <35 000/mm3 y/o recuento absoluto de neutrófilos <1000/mm3 o recuento de glóbulos blancos <2000/mm3 en la visita basal. 10.Pacientes con una condición médica o quirúrgica que según el criterio del investigador puede alterar de forma significativa la absorción, distribución, metabolismo y excreción del fármaco del estudio. 11.Pacientes con hipersensibilidad conocida a los fármacos utilizados en el estudio o a los fármacos de la misma clase terapéutica o a cualquiera de los excipientes. 12.Pacientes con una infección sistémica clínicamente significativa y/o en caso crítico que requieran medidas de soporte vital como ventilación mecánica, diálisis o vasopresores. 13.Mujeres embarazadas o en periodo de lactancia, donde embarazo se define como el estado de una mujer después de la concepción y hasta que finalice la gestación, confirmado por un resultado positivo de ?HCG en la analítica (>9 mUI/ml) en la visita basal. 14.Pacientes potencialmente fértiles, definida como toda mujer fisiológicamente capaz de quedarse embarazada, SALVO que acepten abstenerse de la actividad sexual. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Title: Renal function
To evaluate the evolution of renal function assessed by Glomerular Filtration Rate. |
Función Renal Evaluar la evolución de la función renal a partir de la tasa de filtración glomerular. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At 12-month after start of study drug. |
A los 12 meses después del comienzo del fármaco del estudio. |
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E.5.2 | Secondary end point(s) |
Rate of composite efficacy failure of tBPAR, GL or D.
Renal function over time.
AE/SAEs as per preferred term and SOC.
Evaluate incidence of treatment-related side effects.
Incidence and reason (e.g. AE) for premature discontinuation of study medication, and premature withdrawal from the study.
Incidence and reason (e.g. AE) for dose interruption and dose adjustment of study medication. |
?La tasa de de la variable combinada de fracaso de eficacia compuesta por rechazo agudo que ha sido tratado y confirmado por biopsia (BPAR), pérdida de injerto (PI) o muerte (M). ?La función renal a lo largo del tiempo ?Todos los AA/SAE según el término preferente y la clasificación de órganos del sistema (SOC) ?Incidencia de efectos secundarios relacionados con el tratamiento ?Incidencia y motivo (p. ej., AA) de la suspensión prematura de la medicación del estudio y de la retirada prematura del estudio. ?Incidencia y motivo (p. ej., AA) de la suspensión de la dosis y de los ajustes de dosis de la medicación del estudio. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
At 12-month and 24-month after start of everolimus based regimen |
A los 12 y 24 meses después del inicio del tratamiento con everolimus. |
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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 | Yes |
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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
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.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 17 |
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 |
Denmark |
Germany |
Hungary |
Italy |
Netherlands |
Norway |
Spain |
Sweden |
United Kingdom |
United States |
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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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The study will be completed when LPLV occurs. The study will be ended after: - all patients have completed the month 24 visit, - all data have been cleaned and teh database has been locked, - statistical outputs have been received. |
El estudio será completado tras la última visita del último paciente. El estudio finalizará después de que: -Todos los pacientes hayan realizado la visita del mes 24 -Todos los datos hayan sido revisados y la base de datos cerrada -Los resultados estadísticos hayan sido recibidos. |
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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 | 4 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |