E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Immunosuppression withdrawal in liver transplantation |
Retirada del tratamiento inmunosupresor en trasplante hepático |
|
E.1.1.1 | Medical condition in easily understood language |
Withdrawal of drugs which lower the immune system after a liver transplant |
Retirada del tratamiento inmunosuopresor tras trasplante de hígado |
|
E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Diagnosis [E01] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10024716 |
E.1.2 | Term | Liver transplantation |
E.1.2 | System Organ Class | 100000004865 |
|
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 if the use of a liver tissue transcriptional test of tolerance to stratify liver recipients prior to immunosuppression (IS) withdrawal accurately identifies operationally tolerant recipients and reduces the incidence of rejection, as compared with a control group in whom IS withdrawal is performed without stratification. |
El objetivo general del estudio es evaluar la utilidad clínica y el balance riesgo/beneficio de la utilización de una prueba transcripcional de tolerancia para estratificar los receptores de trasplante de hígado previa retirada de tratamiento inmunosupresor. |
|
E.2.2 | Secondary objectives of the trial |
1) To establish the safety of biomarker-guided IS withdrawal. 2) To determine the health-economic impact of withdrawing IS in liver transplant recipients and to assess how much this cost is influenced by the use of a diagnostic test of operational tolerance. 3) To assess the effect of IS withdrawal on the quality of life of liver transplant recipients. 4) To determine the extent to which IS withdrawal improve drug-related co-morbidities. 5) To investigate if liver transplant recipients under IS become operationally tolerant over time. 6) To determine if the presence of donor-specific anti-HLA antibodies influence the success of IS withdrawal, and whether IS withdrawal promotes the development of anti-HLA antibodies in liver transplant recipients. 7) To explore the association between operational liver transplant tolerance, iron metabolism,immunosenescence, and specific gut microbiome profiles |
1) Establecer la seguridad de la retirada de inmunosupresores (IS) basada en biomarcadores 2) Determinar el impacto económico en salud de retirar el tto IS en receptores de trasplante hepático y evaluar cómo afecta el coste del uso de una prueba diagnóstica de tolerancia operacional 3) Evaluar el efecto de retirada de tto IS en la calidad de vida de los receptores de trasplante de hígado 4) Determinar en qué medida la retirada de tto IS mejora las comorbilidades relacionadas con los fármacos 5) Investigar si los receptores de trasplante hepático en tto con IS se convierten tolerantes a lo largo del tiempo 6) Determinar si la presencia de anticuerpos anti-HLA específicos del donante influyen en el éxito de la retirada del tto IS, y si esta promueve el desarrollo de Ac anti-HLA en receptores de trasplante hepático 7) Explorar la asociación entre tolerancia operacional en trasplante hepático, metabolismo del hierro, inmunosenescencia y perfiles de microbioma intestinal específica |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. At the time of screening: more than 3 years post-transplant if participants are ?50 years old, OR ? 6 years post-transplant if participant age is 18-49 years old. 2. Recipient of either deceased or living donor liver transplant. 3. Recipient of single organ transplant only 4. Liver function tests: direct bilirubin ?17.1 umol/L and ALT ?60 IU/L at the screening visit. 5. On calcineurin inhibitor (CNI) based maintenance IS and no more than one of the following: Low dose mycophenolic acid (? 1080 mg daily), mycophenolate mofetil (MMF ? 1500 mg daily); or azathioprine ( ? 1500 mg daily); or on mycophenolate/mycopheolic acid monotherapy (effective contraception must be used before beginning mycophenolate therapy, during therapy, and for six weeks following discontinuation of therapy). 6. Ability to sign informed consent. |
1. Post-trasplantados de más de 3 años de ? 50 años de edad, o post-trasplantados de ? 6 años de 18-49 años de edad en el momento de la preselección 2. Receptores de trasplante hepático de donante fallecido o vivo. 3. Receptores de trasplante de órgano único 4. Pruebas de función hepática: bilirrubina directa ?17.1 µmolL y GPT ?60 ALT UI/L en la visita de screening. 5. En tratamiento inmunosupresor de mantenimiento con un inhibidor de calcineurina y uno de los siguientes fármacos: Ácido micofenolico a dosis bajas (? 1080 mg al día), micofenolato mofetil (MMF ? 1500 mg al día); o azatioprina (? 150mg al día), o micofenolato / ácido micofenolico en monoterapia (deberán utilizarse anticonceptivos de alta eficacia previo inicio del tratamiento con micofenolato, durante el tratamiento, y durante las siguientes 6 semanas tras la discontinuación del tratamiento). 6. Con capacidad para firmar el consentimiento informado. |
|
E.4 | Principal exclusion criteria |
1. Serum positivity for HCV-RNA. 2. Serum positivity for HIV-1 infection, HBV surface antigen or HBV-DNA. 3. Immune-mediated liver disease in which IS discontinuation is inadvisable (autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis). 4. Acute or chronic rejection within the 52 weeks prior to screening. 5. GFR <40 mL/min (to mitigate the risk of worsening renal failure should rejection occur and high level of CNI be required). 6. The need for chronic anti-coagulation that cannot be safely discontinued to safely perform for a liver biopsy. 7. Baseline (screening) liver biopsy showing any of the following: a) acute rejection according to Banff criteria; b) early or late chronic rejection according to Banff criteria; c) inflammatory activity and/or fibrosis in excess of permissive criteria (Table 1) (25) ; f) any other findings that might make participation in the trial unsafe. Elligibility will be determined by the central pathologist. 8. Patient age <18 years old at the time of transplant. 9. Pregnant females and females of childbearing age not using effective contraception. 10. Current illicit drug or alcohol abuse. 11. Inability to participate in frequent monitoring of liver function (every 3 weeks) and clinical visits during IS withdrawal. 12. Inability to comply with study directed treatment. 13. Any medical condition that in the opinion of the principal investigator would interfere with safe completion of the trial. 14. Participation in another clinical trial during the month prior to enrolment. |
1. Serología positiva para RNA-VHC. 2. Serología positiva para VIH-1, antígeno de superficie VHB o DNA-VHB. 3. Enfermedad hepática inmunomediada en la que no esté recomendada la retirada de tratamiento inmunosupresor (hepatitis autoinmune, colangitis esclerosante primaria, cirrosis biliar primaria). 4. Rechazo agudo o crónico rechazo dentro de las 52 semanas previas al screening. 5. Tasa de filtrado glomerular < 40 mL/min 6. En tratamiento con anticoagulantes crónicos que no se puedan retirar para la realización de una biopsia del hígado segura. 7. Biopsia hepática en la visita basal (screening) que muestre cualquiera de los siguientes eventos: a) rechazo agudo según los criterios de Banff; b) rechazo temprano o tardío crónico según los criterios de Banff; c) actividad inflamatoria y/o fibrosis por encima de los criterios establecidos (ver tabla 1 del protocolo); f) cualquier otro hallazgo que pueda interferir en la seguridad del estudio. La elegibilidad será determinada por el patólogo central. 8. Paciente de < 18 años de edad en el momento del trasplante. 9. Mujeres embarazadas y mujeres en edad fértil que no estén utilizando medidas de anticoncepción de alta eficacia. 10. Consumo actual de alcohol o sustancias ilícitas. 11. Pacientes con dificultad para cumplir con el seguimiento de la función hepática (cada 3 semanas) y las visitas clínicas establecidas durante la retirada del tratamiento inmunosupresor. 12. cumplir con el tratamiento según lo establecido por el protocolo. 13. Cualquier condición médica que en opinión del investigador principal pueda interferir con la seguridad y realización del estudio. 14. Participación en otro ensayo clínico durante el mes previo a la inclusión en el estudio. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is defined as the successful discontinuation of IS with maintainance of normal allograft status as assessed by liver biopsy and liver tests 12 months after IS withdrawal (operational tolerance). For the purposes of validating the clinical usefulness of the tolerance biomarker, successful IS withdrawal is considered the Gold Standard. Since this outcome is strictly restricted to the IS withdrawal process and by definition cannot be observed in Arm B-, the analysis of the primary outcome will be restricted to Arms A and B+. |
La variable principal se define como el éxito en la retirada de tratamiento inmunosupresor con mantenimiento del estado normal del aloinjerto evaluado mediante biopsia hepática y pruebas hepáticas tras los 12 meses posteriores a la retirada del tratamiento inmunosupresor (tolerancia operacional). Dado que la definición de variable principal implica un proceso de retirada de tratamiento inmunosupresor, el análisis de la variable principal se limitará a las ramas A y B+. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
12 months after IS withdrawal |
12 meses tras la retirada de tratamiento inmunosupresor |
|
E.5.2 | Secondary end point(s) |
Rejection (incidence, severity, timing, steroid resistant rejection, chronic rejection). Reasons for failure of IS withdrawal. Progression of graft fibrosis in tolerant participants and those on maintenance IS. Graft loss. All?cause mortality. Proportion of tolerant participants remaining free of rejection at 3 years post IS withdrawal. Renal function at 1, 2 and 3 years after enrollment. Change in co-morbidities associated with IS use (hypertension, cardiovascular risk profile, diabetes mellitus, hyperlipidemia, malignancy). HrQOL changes associated with IS withdrawal Pharmacoeconomic impact of IS withdrawal
The secondary mechanistic endpoints of the trial are: Intra-hepatic and systemic iron parameters. Time post-trasnplant, age, sex and type of IS. Markers of immune-exhaustion on blood and liver tissue. Gut microbiome profile. Blood and intra-hepatic lymphocite subsets (including regulatory T cells). Development of anti-HLA antibodies(before and after initiation of IS withdrawal). |
- Rechazo (incidencia, gravedad, tiempo, rechazo resistente a esteroides, rechazo crónico). - Motivos de fracaso de la retirada de tratamiento inmunosupresor - Progresión de la fibrosis del injerto en participantes tolerantes y en aquellos que mantienen el tratamiento inmunosupresor. - Pérdida del injerto - Mortalidad por cualquier causa - Proporción de participantes tolerantes libres de rechazo a los 3 años tras la retirada del tratamiento inmunosupresor. - Función renal al año, 2 ay 3 años tras la inclusión en el estudio - Cambios en la co-morbilidad asociada al uso del tratamiento inmunosupresor (hipertensión, riesgo cardiovascular, diabetes mellitus, hiperlipidemia, malignidad). - Cambios en el cuestionario de calidad de vida asociados a la retirada del tratamiento inmunosupresor. - Impacto farmacoeconómico de la retirada del tratamiento inmunosupresor.
Las variables secundarias patogénicas del estudio son: - Parámetros de hierro intra-hepático y sistémico. - Tiempo de post-trasplante, edad, sexo y tipo de tratamiento inmunosupresor. - Marcadores de desgaste inmunológico en sangre y tejido hepático. - Perfil de microbioma intestinal. - Subpoblaciones limfocitarias en sangre e intra-hepáticas (incluidas las células reguladoras T). - Desarrollo de anticuerpos anti-HLA (antes y después del inicio de la retirada del tratamiento inmunosupresor). |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Throughout the trial |
a lo largo de todo el estudio |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
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 | Yes |
E.8.2.3.1 | Comparator description |
Immunosuppression withdrawal performed without the guidance of the stratifying biomarker test |
|
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 | 11 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 4 |
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
|
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 | 6 |
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 | 6 |
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 |